2023 Pediatric Pulmonology 2ed - AAP

Am Po
er licy
of ican of t
Pediatric
Pediatric Pulmonology, 2nd Edition Pe A he
di cad
at
ric em
Pediatric Pulmonology
Author: American Academy of Pediatrics Section on Pediatric Pulmonology and Sleep Medicine s y
Editors in Chief: Michael J. Light, MD, FAAP, and Kristin Van Hook, MD, MPH, FAAP
Pulmonology
Associate Editors: Lee J. Brooks, MD, FAAP; Mary Bono Cataletto, MD, FAAP; Allen J. Dozor, MD, FAAP;
Thomas G. Keens, MD, FAAP; Richard M. Kravitz, MD, FAAP; Shruti M. Paranjape, MD, FAAP;
Michael S. Schechter, MD, MPH, FAAP; Girish D. Sharma, MD, FAAP, FCCP; and Dennis C. Stokes, MD, MPH, FAAP
Completely revised and updated, the second edition of this authoritative American Academy of Pediatrics (AAP) guide
provides the latest information on the diagnosis, treatment, and ongoing management of the full range of pulmonary
conditions seen in the pediatric office.
Explore the latest AAP findings and recommendations on pediatric pulmonology: assessment and testing; proven therapeu- 2ND EDITION
tic strategies, procedures, and techniques; home care and monitoring considerations; indications for referral and admission;
and much more.
New Second Edition Features
• A full section dedicated to sleep medicine More than 300
• Cystic fibrosis newborn screening and CFTR-related metabolic syndrome
• Expanded coverage of pneumonia, including when caused by COVID-19 finely detailed
• Expanded coverage of genetic lung diseases images complement
• Up-to-date information on vaping and other forms of nicotine exposure
the text.
Highlights Include
• Allergic Conditions—bronchopulmonary aspergillosis; eosinophilic pneumonia; asthma
• Anatomical Disorders—congenital abnormalities of the upper airway; congenital lung anomalies
2ND EDITION
• Upper Airway Infections—croup, epiglottitis, and bacterial tracheitis
• Lower Airway Infections—bronchiectasis; bronchiolitis; complications of pneumonia; tuberculosis
• Noninfectious Pulmonary Disorders—atelectasis; interstitial lung disease; pneumothorax and pneumo-
mediastinum; pulmonary hemorrhage
• Pediatric Sleep Medicine—obstructive sleep apnea; sleep testing; insomnia; sudden infant death syndrome
• Other Pulmonary Issues—acute aspiration and aspiration-related lung disease; lung transplantation; functional
respiratory disorders
• Genetic Disorders—cystic fibrosis; CFTR-related metabolic syndrome; primary ciliary dyskinesia
• Lung Disease Associated With Systemic Disorders—respiratory considerations in children with cardiac disease;
lung disease associated with endocrine disorders; pulmonary complications related to various diseases and disorders
• Treating and Managing Pulmonary Disease—airway clearance techniques; bronchodilators; oxygen therapy
For other pediatric resources, visit the American Academy of Pediatrics at aap.org/shopaap.
AAP
Pediatric
Pulmonology
2ND EDITION
Author
American Academy of Pediatrics
Section on Pediatric Pulmonology and Sleep Medicine
Editors in Chief
Michael J. Light, MD, FAAP
Kristin Van Hook, MD, MPH, FAAP
Associate Editors
Lee J. Brooks, MD, FAAP
Mary Bono Cataletto, MD, FAAP
Allen J. Dozor, MD, FAAP
Thomas G. Keens, MD, FAAP
Richard M. Kravitz, MD, FAAP
Shruti M. Paranjape, MD, FAAP
Michael S. Schechter, MD, MPH, FAAP
Girish D. Sharma, MD, FAAP, FCCP
Dennis C. Stokes, MD, MPH, FAAP
00 FM PP 2ND ED.indd 1 11/7/23 8:03 AM

American Academy of Pediatrics Publishing Staff
Mary Lou White, Chief Product and Services Officer/SVP, Membership, Marketing, and Publishing
Mark Grimes, Vice President, Publishing
Chris Wiberg, Senior Editor, Professional/Clinical Publishing
Grace Klooster, Editorial Assistant
Jason Crase, Senior Manager, Production and Editorial Services
Theresa Wiener, Production Manager, Clinical and Professional Publications
Soraya Alem, Digital Production Specialist
Mary Louise Carr, MBA, Marketing Manager, Clinical Publications
Published by the American Academy of Pediatrics
345 Park Blvd
Itasca, IL 60143
Telephone: 630/626-6000
Facsimile: 847/434-8000
www.aap.org
The American Academy of Pediatrics is an organization of 67,000 primary care pediatricians, pediatric medical
subspecialists, and pediatric surgical specialists dedicated to the health, safety, and well-being of all infants, children,
adolescents, and young adults.
The recommendations in this publication do not indicate an exclusive course of treatment or serve as a standard of medical
care. Variations, taking into account individual circumstances, may be appropriate.
Any websites, brand names, products, or manufacturers are mentioned for informational and identification purposes only
and do not imply an endorsement by the American Academy of Pediatrics (AAP). The AAP is not responsible for the
content of external resources. Information was current at the time of publication.
The publishers have made every effort to trace the copyright holders for borrowed material. If they have inadvertently
overlooked any, they will be pleased to make the necessary arrangements at the first opportunity.
This publication has been developed by the American Academy of Pediatrics. The authors, editors, and contributors are
expert authorities in the field of pediatrics. No commercial involvement of any kind has been solicited or accepted in the
development of the content of this publication. Disclosures: Dr Ariel Berlinski disclosed an advisor relationship with IPAC-
RS and a financial relationship with Therapeutics Development Network, NIH, Cystic Fibrosis Foundation, and Vertex. Dr
Lee Brooks disclosed a financial relationship with Astra Zeneca. Dr Thomas Ferkol disclosed a financial relationship with
ReCode Therapeutics, Translate Bio, Arrowhead Pharmaceuticals, and NIH; and a principal investigator relationship with
Parion Sciences. Dr Christopher Harris has disclosed a financial relationship with Enata Pharmaceuticals and Vertex
Pharmaceuticals. Dr Jordana Hoppe disclosed a financial relationship with Vertex Pharmaceuticals. Dr Susanna McColley
disclosed a financial relationship with Vertex Pharmaceuticals. Dr Kenneth Olivier disclosed a financial relationship with
AN2 Therapeutics, Insmed Inc./Kaplan, Mannkind Corporation, and Spero Therapeutics. Dr Michael Schecter disclosed a
financial relationship with Astra Zeneca, Vertex Pharmaceuticals, and Sanofi. Dr Jade Tam-Williams disclosed a financial
relationship with Merck. Any relevant disclosures have been mitigated through a process approved by the AAP Board of
Directors.
Every effort has been made to ensure that the drug selection and dosages set forth in this publication are in accordance
with the current recommendations and practice at the time of publication. It is the responsibility of the health care
professional to check the package insert of each drug for any change in indications or dosage and for added warnings and
precautions.
Every effort is made to keep Pediatric Pulmonology consistent with the most recent advice and information available from
the American Academy of Pediatrics.
Please visit www.aap.org/errata for an up-to-date list of any applicable errata for this publication.
Special discounts are available for bulk purchases of this publication. Email Special Sales at
nationalaccounts@aap.org for more information.
© 2024 American Academy of Pediatrics
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form
or by any means—electronic, mechanical, photocopying, recording, or otherwise—without prior written permission from
the publisher (locate title at https://publications.aap.org/aapbooks and click on © Get Permissions; you may also fax the
permissions editor at 847/434-8780 or email permissions@aap.org). First edition published 2011.
Printed in the United States of America
3-363/1123 1 2 3 4 5 6 7 8 9 10
MA1077
ISBN: 978-1-61002-652-9
eBook: 978-1-61002-653-6
Cover and publication design by LSD DESIGN LLC
Library of Congress Control Number: 2022901614
00 FM PP 2ND ED.indd 2 11/7/23 8:03 AM

American Academy of Pediatrics Reviewers
Board of Directors Reviewer
Madeline M. Joseph, MD, FAAP
Committees, Councils, and Sections

Committee on Hospital Care
Committee on Infectious Diseases
Committee on Native American Child Health
Committee on Pediatric and Adolescent HIV
Committee on Substance Use and Prevention
Council on Children With Disabilities
Council on Genetics
Council on Immigrant Child and Family Health
Council on Injury, Violence, and Poison Prevention
Section on Anesthesiology and Pain Medicine
Section on Endocrinology
Section on Epidemiology, Public Health, and Evidence
Section on Gastroenterology, Hepatology, and Nutrition
Section on Hematology/Oncology
Section on Hospice and Palliative Medicine
Section on Hospital Medicine
Section on Infectious Diseases
Section on Minority Health, Equity, and Inclusion
Section on Neurology
Section on Oral Health
Section on Radiology
Section on Rheumatology
III
00 FM PP 2ND ED.indd 3 11/7/23 8:03 AM

American Academy of Pediatrics
Section on Pediatric Pulmonology and Sleep Medicine
2022–2023
Executive Committee
Chairperson
Charlottesville, VA
Rajeev Bhatia, MD, FAAP

Scottsdale, AZ
Lauren Elizabeth (L.E.) Faricy, MD, FAAP

Burlington, VT
Theresa Guilbert, MD, FAAP

Cincinnati, OH
Brooke Gustafson, MD, FAAP

Fellowship Trainee Member
Columbus, OH
Binal Kancherla, MD, FAAP

Sugar Land, TX
Rebekah Nevel, MD, FAAP

Columbia, MO
Christopher Oermann, MD, FAAP

Kansas City, MO
Andrew Sokolow, MD, FAAP

Nashville, TN

Immediate Past Chairperson
New Orleans, LA
Staff
Laura Laskosz, MPH
Manager, Committees and Sections
00 FM PP 2ND ED.indd 5 11/7/23 8:03 AM

Contributors
Editors in Chief
Michael J. Light, MD, FAAP
Orlando Pediatric Pulmonary and Sleep Associates
Orlando, FL
Ochsner Hospital for Children
New Orleans, LA
Associate Editors
Professor of Pediatrics
Rowan University
School of Osteopathic Medicine
Stratford, NJ
Clinical Professor of Pediatrics
Division of Pediatric Pulmonology
NYU–Long Island School of Medicine
Mineola, NY
President, Boston Children’s Health Physicians
Associate Physician-in-Chief
Maria Fareri Children’s Hospital at WMCHealth
Professor of Pediatrics and Clinical Public Health
New York Medical College
Valhalla, NY
Professor Emeritus of Pediatrics, Physiology, and Neuroscience
Keck School of Medicine of USC
Children’s Hospital Los Angeles
Los Angeles, CA
VII
00 FM PP 2ND ED.indd 7 11/7/23 8:03 AM

VIII
Contributors

Division Chief, Division of Pediatric Respiratory Medicine
University of Virginia School of Medicine
Charlottesville, VA
Shruti M. Paranjape, MD, FAAP
Eudowood Division of Pediatric Respiratory Sciences
Johns Hopkins University
Baltimore, MD
Professor and Chief
Division of Pulmonary Medicine
Department of Pediatrics
Virginia Commonwealth University
Children’s Hospital of Richmond at VCU
Richmond, VA
Rush University
Chief, Division of Pediatric Pulmonology
Director, Rush Cystic Fibrosis Center
Rush University Medical Center
Chicago, IL
Dennis C. Stokes, MD, MPH, FAAP
Vanderbilt University School of Medicine
Division of Allergy, Immunology, and Pulmonary Medicine
Monroe Carell Jr Children’s Hospital at Vanderbilt
Nashville, TN
00 FM PP 2ND ED.indd 8 11/7/23 8:03 AM

IX
Contributors
Chapter Authors
Mutasim Abu-Hasan, MD
Senior Attending Physician
Sidra Medicine
Doha, Qatar
Jennifer Accardo, MD, MSCE
Associate Professor of Pediatrics and Neurology
Virginia Commonwealth University School of Medicine
Richmond, VA
Suzanne E. Beck, MD
Professor of Clinical Pediatrics
Perelman School of Medicine at the University of Pennsylvania
Division of Pulmonary and Sleep Medicine
Children’s Hospital of Philadelphia
Philadelphia, PA
Ariel Berlinski, MD, FAAP, FAARC
Division of Pediatric Pulmonology and Sleep Medicine
University of Arkansas for Medical Sciences
Pediatric Aerosol Research Laboratory
Arkansas Children’s Research Institute
Little Rock, AR
Shyall Bhela, MD
Boston Children’s Health Physicians
Maria Fareri Children’s Hospital
Westchester Medical Center
Westchester, NY
Ellen K. Bowser, MS, RDN, LDN, RN, FAND
Associate in Pediatrics
Codirector and Nutrition Faculty
Pediatric Pulmonary Center Leadership Training Program
Pediatric Pulmonary Division
University of Florida
Gainesville, FL
00 FM PP 2ND ED.indd 9 11/7/23 8:03 AM

X
Contributors
John S. Bradley, MD, FAAP

Distinguished Professor
Division of Infectious Diseases
UCSD School of Medicine
Rady Children’s Hospital San Diego
San Diego, CA
Deborah M. Brooks, MD
Assistant Professor of Child and Adolescent Psychiatry
University of Maryland School of Medicine
Baltimore, MD
Pi Chun Cheng, MD, MS
Assistant Professor of Pediatrics
Division of Pediatric Pulmonology, Allergy, and Sleep Medicine
Riley Hospital for Children
Indiana University School of Medicine
Indianapolis, IN
Christopher M. Cielo, DO, MS
University of Pennsylvania
Division of Pulmonary & Sleep Medicine
Philadelphia, PA
Robyn T. Cohen, MD, MPH
Division of Pediatric Pulmonary and Allergy
Boston Medical Center
Associate Professor of Pediatrics
Chobanian and Avedisian Boston University School of Medicine
Boston, MA
Carol Conrad, MD
Director, Pediatric Lung Transplant Program
Stanford University
Palo Alto, CA
Zarmina Ehsan, MD, FAAP
University of Missouri–Kansas City
Division of Pulmonary and Sleep Medicine Children’s Mercy–Kansas City
Kansas City, MO
00 FM PP 2ND ED.indd 10 11/7/23 8:03 AM

XI
Contributors
Laurie C. Eldredge, MD, PhD

University of Washington School of Medicine
Seattle Children’s Hospital
Seattle, WA
Harold J. Farber, MD, MSPH, FAAP
Professor of Pediatrics, Pulmonary Division
Baylor College of Medicine
Texas Children’s Hospital
Houston, TX
David Fedele, PhD, ABPP
Associate Professor
Department of Clinical and Health Psychology
Gainesville, FL
Thomas W. Ferkol, MD
Division of Pulmonology
University of North Carolina at Chapel Hill
Chapel Hill, NC
Julie L. Fierro, MD, MPH
Assistant Professor
Philadelphia, PA
Edward W. Fong, MD
Assistant Clinical Professor of Pediatrics
University of Hawaii
Kapiolani Medical Center for Women and Children
Honolulu, HI
Emily S. Gillett, MD, PhD, FAAP
Assistant Professor of Clinical Pediatrics
Los Angeles, CA
00 FM PP 2ND ED.indd 11 11/7/23 8:03 AM

XII
Contributors
Samuel B. Goldfarb, MD
Codirector, Pediatric Cystic Fibrosis Program
Codirector, University of Minnesota Cystic Fibrosis Center
Division of Pediatric Pulmonary and Sleep Medicine
University of Minnesota
Minneapolis, MN
Madeleine Grigg-Damberger, MD
Professor of Neurology
University of New Mexico School of Medicine
Medical Director, Pediatric Sleep Medicine Services
Associate Director, University of New Mexico Neurodiagnostic Laboratory
Associate Director, Clinical Neurophysiology Fellowship Program
University of New Mexico
Albuquerque, NM
Pallav Halani, MD, FAAP
Fellow, Division of Pediatric Pulmonology
University of North Carolina
Chapel Hill, NC
Karen Ann Hardy, MD, FATS
Clinical Professor
Division of Pediatric Pulmonary, Asthma, and Sleep Medicine
Stanford University
Palo Alto, CA
Christopher E. Harris, MD, FAAP
Medical Director
Enanta Pharmaceuticals
Watertown, MA
Leslie Hendeles, PharmD
Professor Emeritus, College of Pharmacy
Courtesy Professor of Pediatrics (Pulmonary)
Gainesville, FL
Jordana E. Hoppe, MD, MSCS
University of Colorado School of Medicine
Aurora, CO
00 FM PP 2ND ED.indd 12 11/7/23 8:03 AM

XIII
Contributors
Paul Houin, MD
Senior Instructor
Department of Pediatric Pulmonology and Sleep Medicine
University of Colorado School of Medicine Anschutz Medical Campus
Pediatric Pulmonologist
Children’s Hospital Colorado
Aurora, CO
Caitlin Hurley, MD
Assistant Member
Division of Critical Care Medicine and Department of Bone Marrow
Transplantation and Cellular Therapy
Medical Director, Continuing Medical Education
St. Jude Children’s Research Hospital
Memphis, TN
Manju S. Hurvitz, MD, FAAP
Fellow, Pediatric Pulmonology
Division of Respiratory Medicine
University of California San Diego
San Diego, CA
Maki Ishizuka, MD
Philadelphia, PA
Jay Jin, MD, PhD
Assistant Professor of Clinical Pediatrics
Section of Allergy and Immunology
Riley Hospital for Children at Indiana University Health
Indianapolis, IN
Katharine Kevill, MD, MHCDS, FAAP
Stony Brook Children’s Hospital
Stony Brook, NY
00 FM PP 2ND ED.indd 13 11/7/23 8:03 AM

XIV
Contributors
T. Bernard Kinane, MD
Massachusetts General Hospital for Children
Harvard Medical School
Boston, MA
Sankaran Krishnan, MD, MPH
Associate Professor of Pediatrics and Public Health
Division Chief, Pediatric Pulmonology, Allergy, Immunology, and Sleep
Medicine
Maria Fareri Children’s Hospital at Westchester Medical Center
Valhalla, NY
Patricia Lenhart-Pendergrass, MD, PhD
Division of Respiratory Medicine
San Diego, CA
Evans M. Machogu, MBChB, MS, FAAP
Section of Pediatric Pulmonology, Allergy, and Sleep Medicine
Indiana University School of Medicine
Riley Hospital for Children
Indianapolis, IN
Stacey L. Martiniano, MD
Section of Pediatric Pulmonology and Sleep Medicine
University of Colorado Denver
Aurora, CO
Oscar Henry Mayer, MD
Medical Director, Pulmonary Function Testing Laboratory
The Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
00 FM PP 2ND ED.indd 14 11/7/23 8:03 AM

XV
Contributors
Susanna A. McColley, MD, FAAP

Associate Director for Child Health
Northwestern University Clinical and Translational Sciences Institute
Scientific Director, Interdisciplinary Research Partnerships
Stanley Manne Children’s Research Institute
Ann & Robert H. Lurie Children’s Hospital of Chicago
Professor of Pediatrics in Pulmonary and Sleep Medicine
Northwestern University Feinberg School of Medicine
Chicago, IL
Peter H. Michelson, MD, MS
Medical Director, Clinical Development
Vertex Pharmaceuticals, Inc
Boston, MA
Kenneth N. Olivier, MD, MPH
Michael E. Hatcher Distinguished Professor
Department of Medicine
Division of Pulmonary Diseases and Critical Care Medicine
University of North Carolina at Chapel Hill
Chapel Hill, NC
Brian P. O’Sullivan, MD
Geisel School of Medicine at Dartmouth
Hanover, NH
Howard B. Panitch, MD
Director, Technology Dependence Center
The Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
Madhuri Penugonda, MD
University of Florida College of Medicine
Pensacola, FL
00 FM PP 2ND ED.indd 15 11/7/23 8:03 AM

XVI
Contributors
Iris A. Perez, MD, FAAP

Associate Professor of Clinical Pediatrics
Los Angeles, CA
Yehudit Pollack, MD
Division of Pediatric Pulmonology, Allergy, Immunology, and
Sleep Medicine
Valhalla, NY
Priya Prashad, MD, MSCE, DABSM
Division of Pediatric Pulmonology, Allergy, Immunology, and
Sleep Medicine
Valhalla, NY
Courtney M. Quinlan, DO, MS
University of South Florida College of Medicine
Lehigh Valley Reilly Children’s Hospital
Allentown, PA
Nanda Ramchandar, MD, MPH, FAAP
Uniformed Services University
Voluntary Assistant Clinical Professor of Pediatrics
San Diego, CA
Clement L. Ren, MD, MBA
Professor of Pediatrics and Richard B. Johnston Jr Chair in Pediatrics
University of Pennsylvania Perelman School of Medicine
Cystic Fibrosis Center Director
Philadelphia, PA
00 FM PP 2ND ED.indd 16 11/7/23 8:03 AM

XVII
Contributors
Bruce K. Rubin, MEngr, MD, MBA, FRCPC, FAAP

Jessie Ball duPont Distinguished Professor, Department of Pediatrics
Professor and Chair Emeritus of Pediatrics
Professor of Biomedical Engineering
Virginia Commonwealth University School of Medicine
Richmond, VA
Danieli B. Salinas, MD, MS
Associate Professor of Pediatrics and Preventive Medicine
Associate Director, Cystic Fibrosis Center
Los Angeles, CA
Adrienne P. Savant, MD, MS
Service Line Chief, Pediatric Pulmonology
Children’s Hospital of New Orleans
Chief, Pediatric Pulmonology
Tulane University School of Medicine
New Orleans, LA
Mark H. Sawyer, MD
Rady Children’s Hospital San Diego
San Diego, CA
James W. Schroeder Jr, MD, MBA, FACS, FAAP
Vice Chair of Education–Department of Surgery
Ann & Robert H. Lurie Children’s Hospital of Chicago
Professor
Departments of Otolaryngology Head and Neck Surgery and
Medical Education
Northwestern University Feinberg School of Medicine
Chicago, IL
00 FM PP 2ND ED.indd 17 11/7/23 8:03 AM

XVIII
Contributors
Marianna Martin Sockrider, MD, DrPH, FAAP

Professor of Pediatrics, Pulmonary Division
Baylor College of Medicine
Chief of Pulmonary Clinics
Texas Children’s Hospital
Houston, TX
Paul C. Stillwell, MD, FAAP
Senior Instructor, Department of Pediatrics
University of Colorado School of Medicine Anschutz Medical Campus
Pediatric Pulmonologist
Children’s Hospital Colorado
Aurora, CO
Jade B. Tam-Williams, MD, FAAP
Assistant Professor of Pediatric Pulmonology
Children’s Mercy–Kansas City
Kansas City, MO
Danna Tauber, MD, MPH
University of Pennsylvania School of Medicine
Philadelphia, PA
Nadav Traeger, MD, DABSM, FCCP, FAAP
Associate Professor of Clinical Pediatrics
Valhalla, NY
Timothy J. Vece, MD
Director, Rare and Genetic Lung Disease Program
University of North Carolina–Chapel Hill
Chapel Hill, NC
00 FM PP 2ND ED.indd 18 11/7/23 8:03 AM

XIX
Contributors
Nico W. Vehse, MD
Associate Professor, UMass Chan Medical School–Baystate
Chief, Pediatric Pulmonology
Medical Director, CF Center
Medical Director, Pediatric Respiratory Care
Baystate Children’s Hospital
Springfield, MA
Karen Z. Voter, MD, FAAP
University of Rochester School of Medicine
Rochester, NY
Mary H. Wagner, MD
Division of Pediatric Pulmonary and Sleep Medicine
Gainesville, FL
Miles Weinberger, MD, FAAP
Professor Emeritus
University of Iowa
Visiting Clinical Professor of Pediatrics
Rady Children’s Hospital
San Diego, CA
Pnina Weiss, MD, MHPE, FAAP
Vice Chair for Education
Section on Pulmonology, Allergy, Immunology, and Sleep Medicine
Yale School of Medicine
New Haven, CT
John Welter, MD
00 FM PP 2ND ED.indd 19 11/7/23 8:03 AM

XX
Contributors
Valhalla, NY
Amy S. Whigham, MD, MS-HPEd
Associate Professor
Department of Otolaryngology–Head and Neck Surgery
Division of Pediatric Otolaryngology
Vanderbilt University School of Medicine
Nashville, TN
Eric D. Zee, MD
Clinical Associate Professor of Pediatrics
Stanford University School of Medicine
Palo Alto, CA
00 FM PP 2ND ED.indd 20 11/7/23 8:03 AM

Equity, Diversity, and Inclusion Statement
The American Academy of Pediatrics is committed to principles of equity,
diversity, and inclusion in its publishing program. Editorial boards, author
selections, and author transitions (publication succession plans) are designed
to include diverse voices that reflect society as a whole. Editor and author
teams are encouraged to actively seek out diverse authors and reviewers at all
stages of the editorial process. Publishing staff are committed to promoting
equity, diversity, and inclusion in all aspects of publication writing, review, and
production.
XXI
00 FM PP 2ND ED.indd 21 11/7/23 8:03 AM

Contents
Preface..................................................................................................................................... XXIX
Part 1. Foundation....................................................................................... 1
Chapter 1. Anatomy of the Lung............................................................................................ 3
Michael J. Light, MD
Chapter 2. Pulmonary Physiology........................................................................................15
Chapter 3. Applied Pulmonary Physiology....................................................................... 39
Maki Ishizuka, MD, and Christopher M. Cielo, DO, MS
Chapter 4. Taking the Pulmonary History........................................................................ 55
Chapter 5. The Pulmonary Physical Examination......................................................... 65
Chapter 6. Pulmonary Function Testing.......................................................................... 77
Carol J. Blaisdell, MD, and Allen J. Dozor, MD, FAAP
Chapter 7. Pulmonary Imaging........................................................................................... 101
Michael J. Light, MD; Julieta M. Oneto, MD; and Ricardo Restrepo, MD
Chapter 8. Bronchoscopy......................................................................................................141
Pi Chun Cheng, MD, MS, and Samuel B. Goldfarb, MD
Part 2. Allergic Conditions.................................................................... 163

Chapter 9. Allergic Bronchopulmonary Aspergillosis................................................ 165
Chapter 10. Hypersensitivity Pneumonitis.................................................................... 183
Chapter 11. Eosinophilic Pneumonia................................................................................ 197
Chapter 12. Asthma................................................................................................................ 207
Miles Weinberger, MD, FAAP; Mutasim Abu-Hasan, MD; and Leslie Hendeles,
PharmD
XXIII
00 FM PP 2ND ED.indd 23 11/7/23 8:03 AM

XXIV
Contents
Part 3. Anatomical Disorders................................................................................. 239

Chapter 13. Congenital Abnormalities of the Upper Airway.................................... 241
James W. Schroeder Jr, MD, MBA, FACS, FAAP; Susanna A. McColley, MD, FAAP;
and Mary Bono Cataletto, MD, FAAP
Chapter 14. Congenital Lung Anomalies......................................................................... 253
Brian P. O’Sullivan, MD, and T. Bernard Kinane, MD
Chapter 15. Chest Wall and Spinal Deformities.......................................................... 279
Julie L. Fierro, MD, MPH, and Oscar Henry Mayer, MD
Part 4. Upper Airway Infections........................................................................... 309

Chapter 16. Croup, Epiglottitis, and Bacterial Tracheitis.......................................... 311
Part 5. Lower Airway Infections............................................................................327

Chapter 17. Bronchiectasis................................................................................................... 329
Jordana E. Hoppe, MD, MSCS, and Paul C. Stillwell, MD, FAAP
Chapter 18. Bronchiolitis...................................................................................................... 341
Chapter 19. Viral Pneumonia (Including COVID-19)................................................. 353
Michael J. Light, MD; Paul C. Stillwell, MD, FAAP; Nanda Ramchandar, MD, MPH,
FAAP; and Mark H. Sawyer, MD
Chapter 20. Nonviral Pneumonia...................................................................................... 365
Chapter 21. Complications of Pneumonia...................................................................... 387
Chapter 22. Recurrent Pneumonia....................................................................................401
Paul Houin, MD, and Paul C. Stillwell, MD, FAAP
Chapter 23. Tuberculosis.......................................................................................................411
Carol Conrad, MD
Chapter 24. Nontuberculous Mycobacteria................................................................... 453
Stacey L. Martiniano, MD; Patricia Lenhart-Pendergrass, MD, PhD;
and Kenneth N. Olivier, MD, MPH
00 FM PP 2ND ED.indd 24 11/7/23 8:03 AM

XXV
Contents
Part 6. Noninfectious Pulmonary Disorders................................................ 467

Chapter 25. Atelectasis......................................................................................................... 469
Chapter 26. Respiratory Disorders Associated With Systemic Inflammatory
Diseases...................................................................................................................................... 481
Paul C. Stillwell, MD, FAAP, and Eric D. Zee, MD
Chapter 27. Interstitial Lung Disease...............................................................................505
Pallav Halani, MD, FAAP; Timothy J. Vece, MD; and Adrienne P. Savant, MD, MS
Chapter 28. Bronchopulmonary Dysplasia..................................................................... 521
Laurie C. Eldredge, MD, PhD, and Susanna A. McColley, MD, FAAP
Chapter 29. Pleural Effusion (Noninfectious).............................................................. 541
Chapter 30. Pneumothorax and Pneumomediastinum............................................. 553
Chapter 31. Pulmonary Hemorrhage................................................................................ 563
Evans M. Machogu, MBChB, MS, FAAP, and Karen Z. Voter, MD, FAAP
Part 7. Pediatric Sleep Medicine.......................................................................... 579

Chapter 32. Development and Maturation of Sleep................................................... 581
Chapter 33. Obstructive Sleep Apnea Syndrome........................................................ 603
Courtney M. Quinlan, DO, MS, and Suzanne E. Beck, MD
Chapter 34. Sleep Testing in the Laboratory and Home........................................... 617
Deborah M. Brooks, MD, and Lee J. Brooks, MD, FAAP
Chapter 35. Sleep-Related Movement Disorders......................................................... 633
Chapter 36. Insomnia............................................................................................................. 643
Chapter 37. Parasomnias....................................................................................................... 651
Chapter 38. Narcolepsy and Other Disorders of Excessive Somnolence............659
00 FM PP 2ND ED.indd 25 11/7/23 8:03 AM

XXVI
Contents
Chapter 39. Sudden Infant Death Syndrome and Brief, Resolved,

Unexplained Events............................................................................................................... 671
Chapter 40. Congenital Central Hypoventilation Syndrome.................................. 681
Iris A. Perez, MD, FAAP; Emily S. Gillett, MD, PhD, FAAP; and Thomas G. Keens,
MD, FAAP
Part 8. Other Pulmonary Issues........................................................................... 697

Chapter 41. Acute Aspiration and Chronic Aspiration–Related
Lung Disease............................................................................................................................ 699
Chapter 42. Lung Transplantation.................................................................................... 721
Carol Conrad, MD
Chapter 43. Asthma and Other Respiratory Disorders Associated
With Obesity............................................................................................................................. 747
Mutasim Abu-Hasan, MD, and David Fedele, PhD, ABPP
Chapter 44. Functional Respiratory Disorders............................................................. 763
Miles Weinberger, MD, FAAP; Manju S. Hurvitz, MD, FAAP;
and Mutasim Abu-Hasan, MD
Part 9. Genetic Disorders......................................................................................... 779

Chapter 45. Cystic Fibrosis.................................................................................................. 781
Chapter 46. Cystic Fibrosis Newborn Screening and CFTR-Related
Metabolic Syndrome............................................................................................................. 807
Danieli B. Salinas, MD, MS, and Clement L. Ren, MD, MBA
Chapter 47. Primary Ciliary Dyskinesia and Other Genetic Lung Diseases....... 817
Madhuri Penugonda, MD; Nico W. Vehse, MD; Thomas W. Ferkol, MD; and
Part 10. Lung Disease Associated With Systemic Disorders.............. 849

Chapter 48. Respiratory Considerations in Children With Cardiac Disease..... 851
Yehudit Pollack, MD, and Sankaran Krishnan, MD, MPH
Chapter 49. Lung Disease Associated With Endocrine Disorders........................ 869
Michael J. Light, MD, and Martin Draznin, MD
Chapter 50. Pulmonary Complications of Gastrointestinal Diseases.................. 875
Edward W. Fong, MD
00 FM PP 2ND ED.indd 26 11/7/23 8:03 AM

XXVII
Contents
Chapter 51. Pulmonary Complications of Sickle Cell Disease................................ 891

Chapter 52. Pulmonary Manifestations of Oncologic Disease
and Treatment.......................................................................................................................... 913
Mary Bono Cataletto, MD, FAAP, and Caitlin Hurley, MD
Chapter 53. Pulmonary Complications of Immunologic Disorders..................... 929
Jay Jin, MD, PhD, and Clement L. Ren, MD, MBA
Chapter 54. Pulmonary Complications of Neuromuscular Disorders.................947
Part 11. Treating and Managing Pulmonary Disease...............................969

Chapter 55. Airway Clearance Techniques..................................................................... 971
Chapter 56. Aerosol Delivery of Medication.................................................................. 991
Chapter 57. Bronchodilators............................................................................................. 1005
John Welter, MD; H. William Kelly, PharmD; and Leslie Hendeles, PharmD
Chapter 58. Antibiotics for Pulmonary Conditions.................................................. 1019
Michael J. Light, MD; Nanda Ramchandar, MD, MPH, FAAP; and John S. Bradley,
MD, FAAP
Chapter 59. Nutritional Aspects of Pulmonary Conditions...................................1045
Ellen K. Bowser, MS, RDN, LDN, RN, FAND, and Mary H. Wagner, MD
Chapter 60. Oxygen Therapy............................................................................................ 1061
Shyall Bhela, MD, and Sankaran Krishnan, MD, MPH
Chapter 61. Nicotine and Tobacco..................................................................................1083
Harold J. Farber, MD, MSPH, FAAP, and Marianna Martin Sockrider, MD, DrPH,
FAAP
Chapter 62. Tracheostomy.................................................................................................. 1111
Chapter 63. Home Ventilation...........................................................................................1125
Howard B. Panitch, MD, and Thomas G. Keens, MD, FAAP
Index.............................................................................................................................1145
00 FM PP 2ND ED.indd 27 11/7/23 8:03 AM

Preface
We are pleased to present the second edition of Pediatric Pulmonology. While
the first edition was intended for primary care physicians, many pediatric
pulmonologists have come to rely on “the blue book” as an excellent refer-
ence. In the second edition, we attempted to provide a broad-based reference
that would be useful to subspecialists while still being a most useful reference
for primary care physicians, residents, and students. Recognizing that an
ever-growing number of pulmonology sections and practices include sleep
medicine specialists, this edition dedicates a full section to pediatric sleep
medicine—expanding beyond apparent life-threatening events (now termed
brief, resolved, unexplained events) and sleep-disordered breathing to include
information on normal sleep, sleep-related movement disorders, sleep-wake
disorders, and disorders of excessive somnolence.
As with the first, this edition begins by covering the fundamental topics of
lung anatomy, pulmonary physiology, and the basics of eliciting a thorough
pulmonary history and physical examination. Among the many updates
throughout the book, the chapters on cystic fibrosis and cystic fibrosis trans-
membrane conductance regulator (CFTR)-related metabolic syndrome are
significantly different, as they reflect the many developments and advances in
the treatment of these disorders since the first edition was published in 2011.
In addition, the section on lower airway infections was updated and expanded
with more in-depth coverage of pneumonia and the complications of pneumo-
nia, including pneumonia caused by COVID-19.
Dr Light, editor in chief of the first edition, returns to lend his experience and
expertise to this revision, collaborating this time with Dr Van Hook, past chair
of the American Academy of Pediatrics (AAP) Section on Pediatric Pulmon-
ology and Sleep Medicine, as well as an esteemed team of associate editors.
This update would not have been possible without the tireless efforts of Chris
Wiberg, our liaison with American Academy of Pediatrics Publishing; we are
indebted to him for his assistance. We would also like to thank the authors of
the individual chapters, who spent countless hours researching and revising
their individual contributions to make this book possible.
XXIX
00 FM PP 2ND ED.indd 29 11/7/23 8:03 AM

PART
1
Foundation
Chapter 1. Anatomy of the Lung........................................................... 3

Chapter 2. Pulmonary Physiology........................................................15

Chapter 3. Applied Pulmonary Physiology........................................39

Maki Ishizuka, MD, and Christopher M. Cielo, DO, MS
Chapter 4. Taking the Pulmonary History......................................... 55

Chapter 5. The Pulmonary Physical Examination............................65

Chapter 6. Pulmonary Function Testing...........................................77

Carol J. Blaisdell, MD, and Allen J. Dozor, MD, FAAP
Chapter 7. Pulmonary Imaging.......................................................... 101

Michael J. Light, MD; Julieta M. Oneto, MD; and Ricardo Restrepo, MD
Chapter 8. Bronchoscopy....................................................................141
Pi Chun Cheng, MD, MS, and Samuel B. Goldfarb, MD
01 PP 2ND ED - PO 01_001-002.indd 1 11/7/23 8:08 AM

CHAPTER
1
Anatomy of the Lung
Introduction
Knowledge of the development of the lungs helps us to understand congenital
pulmonary anomalies. The lungs develop after 22 to 24 weeks with the ulti-
mate purpose of sustaining life after delivery of the newborn. This occurs by
oxygen from the atmosphere being inhaled into the lungs and carbon dioxide
being exhaled. Oxygen provides the fuel to allow the human body to function.
In this chapter, the gross anatomy of the lung, rather than microscopic
anatomy, is described.
Embryology of the Lungs

The 3 laws of development of the lungs according to Hislop and Reid1 are
as follows:
1. The bronchial tree is developed by the 16th week of intrauterine life.
2. Alveoli develop at 28 weeks, increasing in number until 5 to 8 years
of age, and increasing in size until growth of the chest wall finishes
with adulthood.
3. The pre-acinar vessels (arteries and veins) follow the development of the
airways; development of the intra-acinar vessels follows that of the alveoli.
Muscularization of the intra-acinar arteries does not keep pace with the
appearance of new arteries.
There are 5 phases or periods of lung development (Figure 1-1). Before
3 weeks of gestation, a pouch arises from the primitive foregut, at which
time the embryo is 3 mm long. This period constitutes the embryonic phase.
The lung bud divides into right and left, which will become the right and left
lungs. By the end of the embryonic period, there will be 5 additional branches,
which are the major bronchi, and the lung buds will have elongated into
primary lung sacs. Developmental anomalies at this stage will result in
anomalies of the major airways, including atresia (closed or undeveloped)
and tracheoesophageal fistula.
02 PP 2ND ED - CHAPTER 01_003-014.indd 3 9/12/23 8:47 AM

4
The glandular period (also called pseudoglandular) starts at the end of the fifth
week of gestation and continues to the 16th week as the conducting airways
are formed by dichotomous branching. This period is called pseudoglandular
because the airways are blind tubes lined by columnar or cuboidal epithelium.
The terminal bronchioles are formed, and primitive acinar (terminal airway)
structures are developing. If there is a diaphragmatic hernia, there is the
potential for a reduction in the number of branches formed on the side of
the hernia with a resultant hypoplastic lung.
The canalicular period is from the 16th week until the 24th week. During
this period, the terminal bronchioles will have divided to produce a number
of respiratory bronchioles, and the capillary bed is forming so that toward the
end of this stage gas exchange can occur and potentially life can be sustained,
even though the alveoli have not yet formed.
The airways from the trachea to the 19th generation are the conducting
airways, and the gas-exchanging units are from the 20th to 27th generation
and are the terminal respiratory units. From the major bronchi at the eighth
generation to the 20th are the nonrespiratory bronchioles, and the respiratory
bronchioles are from 20th to 23rd generation (Figure 1-1).
The saccular period extends from the end of the canalicular phase until birth
and overlaps with the alveolar period, which extends to 5 to 8 years of age. The
terminal respiratory unit comprises the respiratory bronchiole and the alveolar
ducts, including the alveoli, and the unit is also known as the acinus. Alveoli
Embryonic period Fetal period
Alveolar
Saccular
Canalicular
Birth
Pseudoglandular
Embryonic Surfactant
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
Weeks
Generations 0 2 4 6 8 10 12 14 16 17 18 19 20 21 22 23
Bronchi Bronchioles Terminal Respiratory Alveolar ducts Alveolar

bronchioles bronchioles sac
Conducting zone Transitional and respiratory zones
Figure 1-1. The 5 phases of embryonic development, which are approximate and overlapping.

5
Chapter 1—Anatomy of the Lung
are lined by both type 1 and type 2 pneumocytes. Type 2 pneumocytes are
cuboidal and synthesize surfactant. They are able to divide and undergo repair.
Eventually, most of them flatten out to form type 1 pneumocytes, which are
supportive in function. Type 1 pneumocytes cover most of the alveolar surface
and compose 95% of alveolar cells. They are not able to divide or be repaired.
If damaged, they are replaced by transformation of the type 2 cells into type 1
cells. The primitive airways, before birth, contain lung fluid, which drains into
the amniotic fluid.
In the postnatal period, alveoli continue to develop until 5 to 8 years of age
and enlarge through adolescence. The term infant has between 20 million and
50 million alveoli at birth, and this number increases to about 300 million at
age 8 years. The alveolar surface area is approximately 2.8 m2 at birth, 32 m2
at 8 years of age, and 75 m2 at adulthood. This last number is often equated
to the size of a tennis court.
The Bony Thorax

The bony thorax provides protection to the heart and lungs (Figure 1-2).
The components are the 12 paired ribs, the sternum, and the bodies of the
thoracic vertebrae.
The ribs 1 through 7 are true ribs connecting to the sternum by costal cartilage.
Ribs 8 through 10 are false ribs connecting to the seventh rib by costal carti-
lage. Ribs 11 and 12 are floating because they are unattached. The sternum
is in 3 parts: the manubrium is where the clavicles and first rib attach. The
sternal body articulates directly with ribs 2 through 7 and indirectly with ribs
8 through 10. The xiphoid process is an attachment site for part of the rectus
abdominis muscle. The ribs have a groove on the inferior surface, which is
the site of the neu-
rovascular bundle.
Between the ribs
and attached to them
are the intercostal
muscles, internal
and external. The
thoracic vertebrae
are numbered T1
through T12, and
the corresponding
pairs of ribs to which
they are attached
are numbered
1 through 12.
Figure 1–2. The bony thorax.

6
Blood Supply
During the embryonic and glandular periods, the development of the pulmo-
nary arteries parallels that of the branching airways. During this same period,
the bronchial vessels are close to the pulmonary vessels. The bronchial arteries
supply blood for the nutrition of the lung; they are derived from the thoracic
aorta or from the upper aortic intercostal arteries. The conducting airways
receive their blood supply from the bronchial vessels, and the terminal respira-
tory units receive their blood from the pulmonary vessels. The pulmonary
veins form from the capillary network and join together to form the 4 main
pulmonary veins, which drain oxygenated blood into the left atrium. The
pulmonary artery pressures are high at birth and decrease in response to
higher oxygen levels over the next days and weeks. The bronchial arterial
circulation is at systemic pressures.
Pulmonary Lymphatics
The lymphatics draining from the lung comprise lymph ducts, lymph nodes,
and the thoracic duct. At birth, the pulmonary lymphatics are vital for the
removal of amnionic fluid. There are 2 lymphatic networks: the pleural and
parenchymal
networks. Most
drainage is toward the
hilum, and, because of
the valves in the
lymph channels, the
flow moves in one
direction. Fully
formed lymph nodes
are not seen until birth
and further develop in
infancy. The main
right lymphatic ducts
follow the right side
of the trachea, join-
ing the venous sys-
tem at the junction
of the right jugular
and subclavian veins.
Figure 1-3. Pulmonary lymphatics.
On the left side, the
Reprinted with permission of the American Thoracic Society. Copyright ©
2022 American Thoracic Society. All rights reserved. Stump B, Cui Y, veins follow the tra-
Kidambi P, Lamattina AM, El-Chemaly S. Lymphatic changes in respiratory chea and empty into
diseases: more than just remodeling of the lung? Am J Respir Cell Mol Biol.
2017;57(3):272–279. The American Journal of Respiratory Cell and Molecular the thoracic duct,
Biology is an official journal of the American Thoracic Society. which drains into

7
the veins on the left side of the neck. Pulmonary lymphatic drainage is
complex and highly variable from individual to individual (Figure 1-3).
Nerve Supply
The nerve supply of the lungs is from branches of the thoracic sympathetic
ganglia and the vagus nerve. The upper 3 to 5 branches of the sympathetic
ganglia supply the lungs, and the lower branches supply the intercostal nerves.
Almost all of the afferent (sensory) pathways are through the vagus nerve.
Figure 1-4 shows the efferent (motor) component. The efferent fibers control
the caliber of the conducting airways, the activity of bronchial glands, and the
caliber (constricted or dilated) of the pulmonary vessels. The parietal pleura
is richly innervated with pain fibers. The visceral pleura has no pain fibers.
The phrenic nerves supply the diaphragm, originating from the third to fifth
cervical roots (C3–C5) (Figure 1-4).
Figure 1-4. Efferent nervous system of the lungs and innervation of the diaphragm, intercostal
muscles, and lungs. The efferent (motor) systems are shown. The afferent (sensory) system is
mainly in the vagus nerve.

8
Gross Anatomy of the Lung

The lungs are within the thoracic cavity, separated by the heart and mediasti-
num (Figure 1-5). The airways terminate in the acinus where gas exchange
occurs. The whole lung is spongelike and pink in the early years, gradually
becoming grayer with age. The apex extends into the root of the neck, and the
base is concave, resting on the convexity of the diaphragm. The right lung has
3 lobes and 2 fissures (the minor or horizontal fissure between the right upper
and middle lobes and the major or oblique fissure between the right middle
and lower lobes), and the left lung has 2 lobes and 1 fissure (the major or
oblique fissure). The lobes of the lung are further divided into segments,
and these are shown diagrammatically in Figures 1-6 and 1-7.
Trachea
Ascending aorta
Arch of aorta
Pulmonary artery Left auricula
Right lung Left lung
Right ventricle Left ventricle
Figure 1-5. A, Front

view of the lungs and
Innominate artery
heart (anterior borders
of the lungs retracted).
B, Mediastinal surface
of the right lung.
Eparterial bronchus
Pulmonary artery
Hyparterial bronchus
Pulmonary veins
Cardiac
impression
Base

9
Apical 1-2 Apical

Post.
Post.
Ant. 3
6
6 Ant.
6
4 4
4
7
5 5
8 7 8 10
5
9 10 10 8
9
9
1
1 1-2
2
2
3 6 3
3
6
Lat. 6
4 Lat.
7
Med. 5 10
8 7 8 8 Med.
9 10 10
9 9
1 1-2
1
2 2
3 3
Apical
Apical 3
4 6
4
5 5 4
M. Basal
A. Basal 8
M. Basal 10
L. Basal 9 5
P. Basal
P. Basal
A. Basal
L. Basal
Figure 1-6. A, Upper lobe, anterior view. B, Right upper lobe, lateral view. Dashed lines indicate
lateral and horizontal fissures. C, Right middle lobe, anterior view. D, Right middle lobe, lateral
view. Dashed lines indicate lateral and horizontal fissures. E, Right lower lobe, anterior view.
F, Right lower lobe, lateral view. Dashed lines indicate lateral and horizontal fissures.
Abbreviations: A.Basal, anterior basal; Ant., anterior; L.Basal, lateral basal; Lat., lateral; M.Basal, medial
basal; Med., medial; P.Basal, posterior basal; Post., posterior.

10
Apico-Post.
1 Apico-post.
2
3 Ant.
6
Ant.
6
6
4 Sup. L. Sup. L.
5
8 7 Inf. L.
Inf. L.
9 10 10 8 10
9
9
1 1-2 1-2
3 3
6 3 Apical
4 4 4
Apical
5 5
8 7 5
10 P. Basal A. Basal A. Basal
9
L. Basal L. Basal
P. Basal
Figure 1-7. A, Left upper lobe (includes lingula), anterior view. B, Left upper lobe (includes
lingula), lateral view. C, Left lower lobe, anterior view. D, Left lower lobe, lateral view.
Abbreviations: A.Basal, anterior basal; Ant., anterior; Apico-Post., apicoposterior; Inf. L., inferior lingual;
L.Basal, lateral basal; P.Basal, posterior basal; Sup. L., superior lingual.
The lungs are covered by the visceral pleura (also called pulmonary pleura),
and this membrane extends into the fissures. The parietal pleura lines the
inner surface of the thoracic cavity, and the visceral and parietal pleurae
join at the root of the lung (hilum). There is an expandable space between
the 2 layers that contains a small amount of pleural fluid.
Mediastinum
The mediastinum lies within the thoracic cavity between the pleurae of the
2 lungs, with the anterior boundary of the sternum and posterior border of
the vertebral column. The superior mediastinum is above the pericardium
and contains the thymus, trachea, esophagus, and upper great vessels.

11
Below the pericardium there are 3 parts. In front of the pericardium is the
anterior mediastinum, which contains the thymus; the middle mediastinum
contains the heart and pericardium; and the posterior mediastinum is behind
the heart and contains the esophagus (Figure 1-5B).
The hila of the lungs are where the structures of the lung enter from the
mediastinum. The usual level of the hilum is anterior to the third to fourth
costal cartilage and posterior to the fifth to seventh thoracic vertebrae.
Intercostal Muscles and Diaphragm

The muscles of respiration are the intercostals and the diaphragm. The anatomy
of the diaphragm is shown in Figure 1-8. The right hemidiaphragm overlies
the liver and is higher than the left hemidiaphragm, which overlies the stomach
and spleen. There are 3 major openings in the diaphragm, including the inferior
vena cava at thoracic vertebral level T12, the esophagus at T10, and the aorta at
T12. The diaphragm’s anterior opening is the foramen of Morgagni, and the
diaphragm’s posterior opening is the foramen of Bochdalek. These 2 foramina
are the sites of diaphragmatic hernia, with the Bochdalek hernia being the most
common and known as the posterolateral diaphragmatic hernia (it is mostly
[80%–85%] on the left). The Bochdalek hernia tends to be more severe and
may be associated with pulmonary hypoplasia and pulmonary hypertension.
Xiphoid process
Vena cava Central tendon

foramen
Esophageal
hiatus
Aortic hiatus
Figure 1-8. View of the diaphragm from below, showing the important
openings.

12
It is important to understand the surface anatomy of the lungs, which is

shown in Figure 1-9. Knowing the area of the lung below the surface while
percussing and auscultating the lungs is important in localizing disease. The
diaphragm is attached to the lower costal margin, and the muscular leaves are
dome shaped. With inspiration, the diaphragm flattens and the lower border
of the lungs correspondingly descends. This movement results in a different
level of the lower lung border, which changes by several centimeters during
deep breathing.
Figure 1-9. A–B, The lung images on the surface of the chest wall indicate the lobes and lungs
at full inspiration. With tidal breathing and full expiration, the images will be moderately smaller
and much smaller, respectively. C–D, The lung images on the surface of the chest wall indicate
the lobes and lungs at full inspiration. With tidal breathing and full expiration, the images will
be moderately smaller and much smaller, respectively.

13
key points
} Lung development occurs in 5 phases. Extrauterine life can be sustained at
20 to 22 weeks of gestation.
} The airways branch from the trachea. The first 19 branches are the conduction
airways, and the 20th to 27th branches are the gas-exchanging units.
} It is important to know the surface position of lung anatomy to aid in localizing
lung diseases.
Reference
1. Gould SJ. The respiratory system. In: Keeling JW, ed. Fetal and Neonatal Pathology. Springer;
1993:403–428

CHAPTER
2
Pulmonary Physiology
Introduction
The primary function of the respiratory system is to provide oxygen to arterial
blood to nourish the body’s tissues and to remove carbon dioxide from the
returning venous blood. Gas exchange takes place at the level of the alveoli
surrounded by a network of thin capillaries. Oxygen and carbon dioxide move
between the air and blood by a process of diffusion. Air is brought to the alveoli
by branching bronchi and bronchioles. The muscles of respiration act as a pump
to move air in and out of the lungs. Elastic properties of the lung and chest wall
and airway resistance affect the work and efficiency of the system. Disease
processes that alter these relationships can lead to respiratory failure, defined
as failure of the lungs to oxygenate and/or ventilate adequately.
Gas Exchange
The tensions or pressures of dissolved oxygen or carbon dioxide in the blood are
designated as Po2 and Pco2 (individual partial pressures of the gases), respec-
tively. Table 2-1 shows the partial pressures of gases in the atmosphere and the
lung. Dry atmospheric air is composed primarily of nitrogen. Oxygen consti-
tutes 20.93% of the atmosphere; there is a minimal amount of carbon dioxide.1
Table 2‑1. Partial Pressure of Gases in the Atmosphere and the Lung
Gas Air (mm Hg) Humidified Air (mm Hg) Alveoli (mm Hg)
Oxygen 159 149 104
Carbon dioxide 0.3 0.3 40
Nitrogen 600.6 564 569
Water vapor 0 47 47
Adapted with permission from Levitzky M. Pulmonary Physiology. 4th ed. McGraw-Hill, Inc; 1995:74–75.
Dry atmospheric air is humidified as it travels down the airways into the lungs.
The Po2 in the alveoli is determined by the balance between the amount that
flows in and the amount that is removed by the pulmonary capillaries. It will
be decreased if barometric pressure is low (ie, high altitude), if there is no
fresh supply of air (ie, atelectasis), or if Pco2 is elevated (ie, hypoventilation).
15

16
As gas moves in and out of the alveolus, blood flows through the pulmonary
capillary vessels, which provide a large surface for gas exchange. Figure 2-1
depicts how gas exchange occurs in the alveolus. The driving force for gas
exchange is the difference in pressures of Po2 and Pco2 between the venous
blood and alveoli. Under normal conditions, the gases equilibrate fully, and
the Po2 and Pco2 of pulmonary capillary blood equal those of the alveoli.2
PO2 = 149
PCO2 = 0.3
Alveolus
PO2 = 104
PCO2 = 40
Venous Arterial
blood blood
PO2 = 100
PCO2 = 40
PO2 = 40
PCO2 = 45 Pulmonary capillary blood
Figure 2-1. Gas exchange in the alveolus (values in mm Hg). Oxygen and carbon dioxide diffuse
across the alveolar-capillary membrane. There is little carbon dioxide in the atmosphere. The Po2
in the alveolus is high, and oxygen diffuses into the capillary blood. Pco2 is high in the venous
blood, and carbon dioxide diffuses into the alveolus.
Oxygen Consumption and Carbon Dioxide Production
The total amount of oxygen taken up by the body in 1 minute is called the
oxygen consumption, and the amount of carbon dioxide produced is the
carbon dioxide production. Oxygen consumption and carbon dioxide pro-
duction increase with exercise. The ratio between them is known as the
respiratory quotient and is approximately 0.8. The respiratory quotient
increases (ie, more carbon dioxide is produced for each molecule of oxygen
consumed) on a high carbohydrate diet. For patients in respiratory failure,
low carbohydrate and high lipid formulas are suggested to decrease the
respiratory quotient and decrease carbon dioxide production.3

17
Chapter 2—Pulmonary Physiology
Ventilation
The process of ventilation brings air in and out of the lungs. During inspira-
tion, the size of the thoracic cavity increases and air moves into the lungs.
The fresh air is carried through conducting airways to the alveoli, which
are responsible for gas exchange.
Alveolar and Dead Space Ventilation

The volume of a breath is known as the tidal volume.2 However, only part of
the breath is used for gas exchange. Only the air that reaches the alveolus is
involved in gas exchange; this is known as alveolar volume and is shown in
Figure 2‑2. The conducting airways are not involved in gas exchange, and
the volume of air in them is known as dead space. About 30% of each breath
ends up in dead space.4 In some disease processes, the dead space volume
increases, and less air is available in each breath for gas exchange.
Dead
space
Tidal
volume
Alveolar
volume
Venous
blood
Pulmonary
capillary
Figure 2‑2. The relationship of tidal volume to dead space and alveolar volume. In each breath
(tidal volume), some of the air goes into the alveoli (alveolar volume) and is available for gas
exchange. The rest remains in the conducting airways and is known as dead space.
Total ventilation is the total volume of fresh air that reaches the lung each
minute. It is determined by the volume of each breath multiplied by the
number of breaths per minute. The relationship of tidal volume, respira-
tory rate, and total ventilation is shown in Figure 2‑3. If a child has a tidal
volume of 100 mL and is breathing 15 breaths/min, then the total ventilation
is 1,500 mL/min. Alveolar ventilation is the total volume of air that reaches
the alveoli and is available for gas exchange each minute. Thus, if a disease
process decreases the respiratory rate and/or the volume of each breath or
increases the dead space, it will decrease the effective ventilation. Total

18
ventilation is easy to quantify because tidal volume is easily measured;

alveolar ventilation is more difficult to quantify because dead space is more
difficult to measure.
Tidal 100
volume mL
15 breaths/min Dead space
Alveolar
ventilation
1,000 mL
Total
ventilation
1,500 mL
Dead space
ventilation
500 mL
Figure 2‑3. Components of total ventilation: tidal volume, respiratory rate, alveolar ventilation,
and dead space ventilation. Total ventilation is determined by the volume of each breath
multiplied by the number of breaths per minute. In this diagram, dead space is one-third of
total volume.
Relationship of Ventilation to Arterial Pco2

The removal of carbon dioxide from the blood depends on alveolar ventilation.
If alveolar ventilation increases, then the elimination of carbon dioxide in-
creases, and its concentration in the arterial blood decreases.1 This relationship
is shown in Figure 2‑4. If alveolar ventilation decreases, then the elimination
of carbon dioxide decreases, and it accumulates in the arterial blood. There is
an inverse relationship between the alveolar ventilation and the arterial carbon
dioxide concentration: if alveolar ventilation doubles, the arterial carbon
dioxide concentration is halved. If the alveolar ventilation decreases by
50%, then the arterial carbon dioxide concentration doubles.
The effect of changes in respiratory rate, tidal volume, and dead space on
ventilation and arterial carbon dioxide level are depicted in Table 2‑2. A wide
variety of factors can cause decreased alveolar ventilation with an increase in
arterial carbon dioxide tension. A decrease in respiratory rate or tidal volume
can result from drugs such as opiates, benzodiazepines, or alcohol; central
nervous system infection; trauma; seizures; or sepsis. Preterm infants can
have cessation of breathing or apnea of prematurity. In congenital central hypo-
ventilation syndrome, children have a decreased central drive to breathe and,
consequently, hypoventilation. Children with obstructive sleep apnea have a

19
relative decrease in their tidal volume because they cannot effectively breathe
in. Chest wall trauma or deformity, neuromuscular weakness, and lung
disease can also decrease the tidal volume and impair ventilation. Disease
processes, such as acute respiratory distress syndrome, scoliosis, pulmonary
embolus, or general anesthesia, can increase the dead space and thus impair
the proportion of effective ventilation.
150 Figure 2‑4. The relationship
between ventilation and carbon
dioxide levels in the lung.
Increases in alveolar ventilation
100 will decrease carbon dioxide
PACO2 (mm Hg)
levels; conversely, decreases in

ventilation will increase
carbon dioxide levels. Paco2
50 is the Pco2 in the alveolus.
Adapted from Lumb AB. Nunn’s Applied
Respiratory Physiology.
5th ed. Edinburgh, Scotland:
0 Butterworth Heinemann;
0 2 4 6 8 10 2000, with permission.
Alveolar Ventilation (L/min)
Table 2‑2. Effect of Changes in Respiratory Rate, Tidal Volume, and Dead Space on Total
Ventilation and Arterial Carbon Dioxide Level
Respiratory Rate Tidal Dead Total Arterial
(breaths/min) Volume Space Ventilation Pco2 Causes
Medications, alcohol,
 ↔ ↔ ↓ ↑ central nervous system
infections, seizures, apnea
Chest wall trauma,
↔  ↔ ↓ ↑ neuromuscular weakness,
lung disease
Acute respiratory distress
↔ ↔  ↔ ↑ syndrome, scoliosis,
pulmonary embolus
Metabolic acidosis,
 ↔ ↔ ↑ ↓ salicylate overdose,
anxiety, pain
Metabolic acidosis,
↔  ↔ ↑ ↓ salicylate overdose,
anxiety, pain
↔ ↔  ↔ ↓
Mechanical ventilation,
deep breathing
The primary events are shown in bold arrows; the effects on total ventilation and arterial PCO2 are listed.
Decreases in respiratory rate and tidal volume decrease total ventilation and increase arterial carbon dioxide
tension. Increases in respiratory rate and tidal volume increase total ventilation and decrease arterial carbon
dioxide tension. Changes in dead space do not affect total ventilation; they will, however, affect alveolar
ventilation and carbon dioxide levels.

20
Increased alveolar ventilation results in a decrease in Pco2. Causes for

increasing respiratory rate and tidal volume are depicted in Table 2‑2. The
most common causes include metabolic acidosis, salicylate ingestion, anxiety,
central nervous system disorders, and pain. There are also some instances in
which the dead space can be decreased.
Regulation of Arterial Pco2

The arterial carbon dioxide concentration reflects a balance between carbon
dioxide production and elimination. More carbon dioxide is produced when
the metabolic rate is increased. Fever or increased muscle activity (shivering,
seizures) produces more carbon dioxide and can produce elevations in arterial
carbon dioxide levels unless ventilation is increased.
Ventilation is controlled by sensors called chemoreceptors, which are located
in the brain and aortic bodies (at the common carotid artery and aortic arch,
respectively). These receptors sense changes in arterial carbon dioxide concen-
tration. They respond by activating effectors that alter ventilation to keep
arterial carbon dioxide concentration normal.
Acid-Base Status
Carbon dioxide is transported in the blood in 3 forms: dissolved, bicarbonate,
and combined with proteins such as carbamino compounds. In arterial blood,
most carbon dioxide is carried as bicarbonate (90%).5
Carbonic Anhydrase
↓
CO2 + H2O D H2CO3 D H+ + HCO-3
Carbon dioxide and water are converted to carbonic acid by the enzyme car-
bonic anhydrase in red blood cells. Carbonic acid spontaneously dissociates
into hydrogen ions (acid) and bicarbonate.
The pH of the blood depends on the relationship of bicarbonate and carbon
dioxide. As the arterial Pco2 increases, the pH decreases, which is known as
respiratory acidosis. As the arterial Pco2 decreases, the pH increases, which
is known as respiratory alkalosis.
The lungs regulate the concentration of carbon dioxide, and the kidneys control
the bicarbonate concentration. In response to respiratory acidosis, the kidneys
will compensate over 3 to 5 days by conserving bicarbonate and will create a
secondary metabolic alkalosis. Table 2‑3 provides a list of primary acid-base
disorders and their secondary compensation. In contrast, in response to
respiratory alkalosis, the kidneys will eliminate excess bicarbonate and
create a secondary metabolic acidosis in compensation.
03 PP 2ND ED - CHAPTER 02_015-038.indd 20 11/6/23 2:31 PM

21
Table 2‑3. Primary Acid-Base Disorders and Compensation

Carbon Dioxide Bicarbonate
Disorder Level pH Level
Acute respiratory acidosis
Chronic respiratory acidosis
Acute respiratory alkalosis
Chronic respiratory alkalosis
Metabolic acidosis
Metabolic alkalosis
The primary events are shown in bold arrows; the secondary effects are listed, and the arrow lengths
are proportional to the magnitude of the change. For example, in acute respiratory acidosis, the primary
event is an elevation in arterial Pco2. There is a concomitant decrease in pH and a very small increase in
bicarbonate. In chronic respiratory acidosis, there is renal compensation and bicarbonate increases. As
a result, the Pco2 is still elevated, but the pH is not as dramatically low as in acute respiratory acidosis.
It is possible to determine the primary acid-base disorder and the compensa-

tion by plotting the values on a nomogram as exemplified in Figure 2‑5.6
In general, for acute respiratory acidosis, an increase in Pco2 of 10 mm Hg
will decrease the pH by 0.08 and the bicarbonate by 1 mmol/L (1 mEq/L).
In chronic respiratory acidosis, after renal compensation, the bicarbonate
will increase by a total of 4 mmol/L (4 mEq/L) for each increase in Pco2 of
10 mm Hg. In acute and chronic respiratory alkalosis, similar changes in the
opposite direction occur. Remembering the relationship between change in
Pco2 and pH can be useful in determining whether a patient has compensated,
partially compensated, or uncompensated respiratory acidosis. For example,
a patient with a severe acute asthma exacerbation may present to the emergen-
cy department with a pH of 7.24, Pco2 of 60 mm Hg, and bicarbonate level of
22 mmol/L (22 mEq/L), which indicates acute uncompensated respiratory
acidosis. If the patient’s ventilation does not improve, over the course of 2 to
3 days the kidneys will start to compensate, and a follow-up blood gas mea-
surement may have a pH of 7.30, Pco2 of 60 mm Hg, and bicarbonate level of
25 mmol/L (25 mEq/L), which reflects partial compensation. In contrast, an
infant with bronchopulmonary dysplasia who has chronic respiratory failure
may have a blood gas measurement with a pH of 7.35, Pco2 of 60 mm Hg, and
bicarbonate level of 28 mmol/L (28 mEq/L), which indicates compensated
respiratory acidosis.

22
A B
Figure 2‑5. Nomogram of acid-base abnormalities. From this nomogram, the primary acid-
base abnormality can be determined. A. Patient A has a pH of 7.18, Pco2 of 80 mm Hg, and
bicarbonate (HCO-3) of 26 mmol/L, which is consistent with acute respiratory acidosis.
B. Patient B has a pH of 7.3, Pco2 of 80 mm Hg, and HCO-3 of 37 mmol/L, which is consistent
with chronic respiratory acidosis.
Adapted from DuBose TD. Disorders of acid-base balance. In: Brenner BM, ed. Brenner and Rector’s The Kidney.
Philadelphia, PA: Saunders Elsevier; 2007, with permission from Elsevier.
Oxygenation
Oxygen reaches the alveoli through the conducting airways, where it diffuses
across the very thin membrane to the capillary blood. Under normal circum-
stances, oxygen composes approximately 21% of air. The amount of oxygen
in the alveolus is determined by the presence of other gases such as carbon
dioxide, a supply of fresh air, and changes in barometric pressure. The Po2
decreases when the Pco2 increases. The Po2 depends on a fresh flow of air; if
there is no airflow, such as in cases of mucous plugging, atelectasis, or apnea,
then the Po2 in the alveolus decreases. In addition, the Po2 depends on the
atmospheric pressure. At high altitudes, the atmospheric pressure is lower,

23
and there is less oxygen available, which accounts for the development of
hypoxemia, or low arterial oxygen level, at Mount Everest or when flying.
Oxygen is primarily bound to hemoglobin in the red blood cell; a small
amount is dissolved in plasma. A red blood cell takes about three-quarters of
a second to transverse the pulmonary capillary bed; under normal conditions,
it takes about one-quarter of a second for oxygen to be transferred fully to the
red blood cell.2 If the capillary membrane is thickened, then transfer may take
longer and may not be complete by the end of its transit time. This delay may
be aggravated by exercise; as the blood moves more quickly through the
lungs, it may not have adequate time to become fully saturated.7
Mechanisms of Hypoxemia
The primary processes that contribute to hypoxemia are hypoventilation;
diffusion impairment; shunt; ventilation/perfusion (V̇/Q̇) mismatch; and,
under some conditions, low venous blood saturation.8 These processes are
depicted in Figure 2‑6. In addition, as mentioned in the prior section,
hypoxemia may result from low inspired Po2 , which may occur at high
altitudes or in the laboratory under experimental conditions.
Hypoventilation
If ventilation is inadequate, the Pco2 in the alveoli increases and the Po2
decreases. Inadequate ventilation may be caused by depressed respiratory
drive (medications, sepsis, brain trauma), damage to the chest wall, or
weakness of the respiratory muscles.
The relationship between the increase in arterial carbon dioxide and decrease
in oxygen tension can be seen from the alveolar gas equation, which is often
simplified as follows:
Pao2 = Pio2 – Paco2/R,
where Pao2 is the alveolar Po2 , Pio2 is the inspired Po2 , Paco2 is the arterial
Pco2 , and R is the respiratory exchange ratio of carbon dioxide and oxygen,
which is estimated to be 0.8 for the whole lung. Therefore, every increase
in alveolar Pco2 of 10 mm Hg would decrease the Po2 by approximately
12.5 mm Hg. For example, if a child without lung disease with a resting
Pco2 of 40 mm Hg and Po2 of 100 mm Hg has an episode of apnea and
the Pco2 increases to 80 mm Hg, the Po2 will decrease to 50 mm Hg.

24
↑PCO2
↑PCO
↑P CO2
↓PO2 ↑PCO2 2 ↑PCO2
↓POO2
↓P
↓PO2 ↓PO2 PO2
↓↓PO2 ↓PO2 2 ↓↓PO2 ↓PO2
↓↓POO2 ↓POO2 ↓↓POO2 PPOO22 ↓PO
↓↓P ↓P ↓↓P PO2 PO↓P
2 O22
↓↓PO2 2 ↓↓PO2 ↓PO2 2 ↓PO2 2
↓↓PO2 ↓↓PO2 ↓PO2 ↓PO2
A. Hypoventilation B. Diffusion impairment
A.Hypoventilation
A. Hypoventilation B.Diffusion
B. Diffusionimpairment
impairment
A. Hypoventilation
A. Hypoventilation B. Diffusion
B. Diffusion
impairment
impairment
x x
xxx x xxx xPO
x x x
xx x
2 PO2
↓↓PO2 xx ↓↓PO2
↓↓PPOO22 ↓↓POO2
↓↓PO2
↓↓POO2
↓↓P
↓
PO2
↓↓PO2 2 ↓↓PO2
↓↓
↓
PPOO22
PPOO22
PO2
PO2
PO2
↓
PPOO22
PO2 OP2O2
↓↓P PO2
↓↓POO2
↓↓P
↓↓ ↓↓P 2 ↓P O
↓↓PO2 2 ↓↓PO2
↓↓PO2 ↓↓PO2 ↓↓PO2 ↓↓PO2 2
C. Shunt D. Ventilation/perfusion mismatch
↓POO2
↓P
C. Shunt ↓PO2 2 ↓P
D.Ventilation/perfusion
Ventilation/perfusion O2
mismatch
C. Shunt D. mismatch
C. Shunt
C. Shunt D. Ventilation/perfusion
D. Ventilation/perfusion
mismatch
mismatch
PO2
PPOO22
PO2 PO2
↓↓↓PO2 ↓PO2
↓↓↓POO2
↓↓↓P ↓POO2
↓P
↓↓↓PO2P↓↓↓P
E. Low venous 2O O2 ↓PO2 2 ↓PO2
2
E.Low
E. Lowvenous
venousPPOO2
Figure 2‑6. Causes of hypoxemia. A, Hypoventilation:
E. Low E.
venous PO2 2 Ventilation
Low venous PO2 is decreased, and Pco2 is
increased. Consequently, the Po2 in the alveolus decreases. B, Diffusion impairment: Diffusion
across the alveolar-capillary membrane to the hemoglobin in the red blood cells is decreased.
C, Shunt: Pulmonary venous blood bypasses the lung without being oxygenated. This may
occur in congenital cardiac disease or arteriovenous malformation where there is a right-to-left
shunt. D, Ventilation/perfusion mismatch: Some areas of the lung are nonfunctional and poorly
oxygenate the venous blood. Blood from functioning alveolar units mixes with the venous
blood. E, Low venous Po2: The Po2 in the venous blood may be abnormally low because of
anemia, fever, or decreased cardiac output. In the presence of lung disease, shunt, or exercise,
the venous blood may not be fully oxygenated as it completes its course through the lung.
Diffusion Defects
Pediatric patients can have problems with diffusion. Diffusion of a gas through
tissues depends on the cross-sectional area, the partial pressure difference
across the tissue and the thickness of the tissue, and inherent characteristics
of the gas (its solubility and molecular weight). Diffusion can be impaired if the
surface area of the lung is decreased (such as in a lobectomy or emphysema) or

25
the capillary basement membrane is thickened (such as in pulmonary edema or

interstitial fibrosis). Problems with diffusion can be detected by using carbon
monoxide as a surrogate marker and testing the diffusing capacity of the lung
for carbon monoxide (Dlco). The Dlco may be low in the aforementioned
conditions and also with reduced thoracic blood volume or reduced hemoglobin.
Infants and children have lower diffusion capacities, related to their smaller body
length and lung volumes, than adults do. Infants and children with chronic lung
disease of prematurity have a decrease in Dlco likely related to arrested alveolar-
ization and decreased surface area.9–11 Despite immature alveolarization, it does
not appear as though prematurity per se is associated with a decrease in Dlco.12
Shunt
Shunt occurs when deoxygenated blood bypasses the lungs and flows directly
into the arterial circulation.2 Small shunts exist under normal physiological
conditions. Deoxygenated blood
from the bronchial arteries drains
directly into the pulmonary veins,
and the coronary veins drain directly
into the left ventricle through the
Thebesian veins. In some circum-
stances, there can be an abnormal
connection between the veins and
arteries (arteriovenous malformation).
In addition, a right-to-left shunt
can occur with congenital heart
disease (eg, pulmonary atresia with
ventriculoseptal defect, pulmonary
hypertension with an atrial septal
defect or patent foramen ovale).
The amount of blood going through
the shunt can be calculated from the
following equation:
Q̇ s = Cc'o2 – Cao2
Q̇ t Cc'o2 – Cv̄ o2
Figure 2‑7. Effect of changing inspired oxygen

where Q̇ s/Q̇ t is the fraction of blood
concentration on arterial Po2 in lungs with shunts going through the shunt, Cc'o2 is the
of varying degrees from 10% to 50%. In larger pulmonary capillary oxygen content,
shunts, administering supplemental oxygen Cao2 is the arterial oxygen content,
has little effect on arterial Po2. Addition of
100% oxygen has little effect on arterial Po2 and Cv̄ o2 is the mixed venous oxy-
when the shunt is greater than 30%. gen content. Shunt fractions can also
From Dantzker DR. Gas exchange in the adult respiratory be calculated from nomograms
distress syndrome. Clin Chest Med. 1982;3:57–67, with
permission from Elsevier. (Figure 2‑7).

26
A shunt will result in decreased oxygen concentration but does not usually pro-
duce elevated arterial carbon dioxide levels. The chemoreceptors normally sense
the elevation of arterial carbon dioxide and respond by increasing ventilation.
Mismatch
V̇ /Q̇ mismatch is one of the most difficult of the causes of hypoxemia to
understand. If blood flow and ventilation are not matched in areas of the lung,
then inadequate gas exchange occurs. If an area of the lung is perfused but not
ventilated, as in the case of pneumonia or atelectasis (lung collapse), then it acts Sho
like a small shunt. Deoxygenated blood goes through the nonfunctional lung new
without being oxygenated and then mixes with blood from other areas of the 2-8
lung that are oxygenated.
ack
A shunt can be distinguished from V̇ /Q̇ mismatch by the hyperoxia test. In
the case of the latter, addition of 100% oxygen will increase the arterial oxygen
lue
saturation. However, if a true shunt exists, the supplemental oxygen will raise
the arterial saturation by only a small amount (usually < 5%).2
Low Venous Po2
The normal Po2 of venous blood is 45 mm Hg and has a saturation of 75%. If
venous blood has an unusually low Po2, then the blood may not be fully oxygen-
ated by the time it finishes its course through the pulmonary capillaries. Low
venous Po2 may result when the body extracts more oxygen from the blood than
usual, such as in anemia, fever, and low cardiac output. Normally, the lung can
compensate for the abnormally low venous Po2. However, it may not during exer-
cise or if there is another superimposed problem, such as V̇ /Q̇ mismatch, shunt,
or diffusion impairment.
Oxygen Transport
Oxygen is primarily carried in the blood bound to hemoglobin; a very small
amount is dissolved in plasma. The total amount carried by the blood is called
the oxygen content. The maximum amount of oxygen that can be combined
with hemoglobin is called the oxygen capacity. One gram of hemoglobin can
combine with 1.34 mL of oxygen.2 The oxygen capacity for a normal child
with a hemoglobin concentration of 14 g/100 mL is 19.5 mL oxygen/100 mL
of blood.
The oxygen saturation is the percentage of binding sites of hemoglobin that
have oxygen attached. The normal oxygen saturation is 98% for arterial blood
and 75% for venous blood. In general, oxygen saturation increases as the Po2
of the blood increases. The dissociation curve for oxygen is S-shaped and is
shown in Figure 2-8. Between an oxygen tension of 20 and 75 mm Hg, there
is a sharp, linear increase in oxygen saturation. After that, large increases in
arterial Po2 cause small increases in oxygen saturation. The P50 is the oxygen
tension at which 50% of the hemoglobin is saturated.

27
At high oxygen tension, relatively large

changes in PO2 will lead to only small
changes in SpO2 (flat part of the curve)
100
90
↑ pH
↓ DPG
80
↓ Temp
Oxyhemoglobin (% Saturation)
70 ↓ pH
↑ DPG
60 ↑ Temp
At SpO2 90% or lower, small reduction

50 in SpO2 may result in dangerous falls
in PO2 (steep part of the curve)
40
30
20
10
0
0 10 20 30 40 50 60 70 80 90 100
PO2 (mmHg)
Figure 2‑8. Oxygen dissociation curve. The oxygen dissociation curve is shown for a pH of
7.4, Pco2 of 40 mm Hg, temperature of 37 °C, and hemoglobin concentration of 15 g/100 mL
(dashed line). Many factors can shift the oxygen dissociation curve to the right and cause
oxygen to bind less avidly to hemoglobin (dotted line): increased temperature, acidosis,
hypercarbia, and increased 2,3-diphosphoglycerate (2,3-DPG) levels. Conversely, decreased
temperature, alkalosis, low carbon dioxide levels, and decreased 2,3-DPG levels shift the
curve to the left (solid line); thus, oxygen binds more avidly to the hemoglobin, and the effect
is decreased delivery to the tissues. Spo2, oxygen saturation as measured by pulse oximetry. P50 is
the oxygen tension when hemoglobin is 50% saturated with oxygen. When hemoglobin-
oxygen affinity increases, the oxyhemoglobin dissociation curve shifts to the left and decreases
P50. When hemoglobin-oxygen affinity decreases, the oxyhemoglobin dissociation curve shifts
to the right and increases P50.
Adapted from Krishnan S. Oximetry and capnography. In: Stokes DC, Dozor AJ, eds. Pediatric Pulmonology, Asthma,
and Sleep Medicine: A Quick Reference Guide. Itasca, IL: American Academy of Pediatrics; 2018: 63–67.

28
Factors That Alter the Affinity of Hemoglobin for Oxygen

Many factors can affect the affinity of hemoglobin for oxygen. Acidosis,
hypercarbia, hyperthermia, and increased 2,3-diphosphoglycerate (2,3-DPG)
levels can decrease the affinity. The result is a shift in the oxygen dissociation
curve to the right, which is shown in Figure 2‑8. As a result, the hemoglobin
is less saturated at a given oxygen tension. The converse is also true: alkalosis,
hypocarbia, hypothermia, and decreased 2,3-DPG levels shift the oxygen
dissociation curve to the left, and the hemoglobin has a higher saturation
at a given oxygen tension.
Another common reason for altered oxygen affinity is alterations in the
hemoglobin itself. The hemoglobin in patients with sickle cell disease has
less affinity for oxygen than that in those with normal hemoglobin, so patients
with sickle cell disease may have a lower oxygen saturation in room air.13,14
In contrast, fetal hemoglobin or red blood cells that have been stored in a
blood bank have a higher affinity for oxygen because of a decreased level
of 2,3-DPG.15 The saturation of oxygen can also be lower because it is
bound by other molecules, such as in carbon monoxide poisoning
or methemoglobinemia.
Decreases in oxygen capacity and, consequently, impaired oxygen delivery
to tissues can be caused by a decrease in oxygen saturation or anemia. As
previously described, decreases in oxygen saturation can be caused by
decreases in arterial oxygen concentration (pneumonia, atelectasis, lung
disease, high altitude), decreases in affinity of hemoglobin for oxygen,
or sites on the hemoglobin being bound by other molecules.
Assessment of Oxygenation and Ventilation

It is extremely difficult to assess the adequacy of oxygenation and ventilation
by means of physical examination. The most specific sign of impaired oxygen-
ation is cyanosis, which can usually be detected at an oxyhemoglobin satura-
tion of 80%.16 However, it may be difficult to assess in children with anemia
or dark-colored skin. Signs of hypoxemia include tachypnea and tachycardia,
and progression may be associated with confusion, motor incoordination, and
agitation. Impaired ventilation is even more difficult to determine. Certainly,
when a patient is apneic or has an extremely low respiratory rate, an impair-
ment of ventilation is likely. Tidal volume is difficult to determine from
examination of chest excursion; dead space cannot be assessed.17 Other late
signs of impaired ventilation are hypotension, flushed skin, diaphoresis,
tachycardia, and lethargy.
Noninvasive Monitoring of Oxygen and Carbon Dioxide
Both oxygenation and ventilation can be assessed noninvasively. Pulse oxi-
metry is the most common way to assess oxygenation and is based on the
principle that oxyhemoglobin and reduced hemoglobin have different light

29
absorption spectra. Pulse oximetry detects arterial pulsations and measures the
arterial oxygen saturation. However, it has a few deficiencies. It is insensitive to
changes at high arterial Po2 (because of the shape of the oxygen dissociation
curve) and inaccurate at low arterial oxygen saturation (Sao2). Pulse oximetry
may be less sensitive to hypoxemia in patients with more darkly pigmented
skin. There is also a delay in response to changes in Sao2, particularly when the
oximeter is placed on an extremity. In addition, a number of factors can give
spurious results; these factors are listed in Box 2‑1.18,19
Box 2‑1
Causes of Inaccuracies in Pulse Oximetry
Carboxyhemoglobin Intravenous dyes
Methemoglobin ū Methylene blue
High-intensity ambient light ū Indigo carmine
ū Indocyanine green
Impaired perfusion
Nail polish and artificial nails
End-tidal carbon dioxide monitoring (capnography) can be used to assess

ventilation.20 The carbon dioxide in exhaled air is measured by means of in-
frared light absorption or mass spectrometry. A representative capnograph is
shown in Figure 2‑9. In healthy individuals, the carbon dioxide in the exhaled
50
End-tidal CO2
40
30
PCO2 mm Hg
20
10
0
0 1 2 3 4 5
Expiration Inspiration
starts starts
Time (sec)
Figure 2‑9. Normal capnograph. Carbon dioxide is measured in the exhaled air. The beginning
of the breath is filled with dead space volume. At the end of the breath, the end-tidal Pco2
reflects alveolar Pco2. It is a noninvasive way of monitoring arterial Pco2.
From Levitzky M. Pulmonary Physiology. 4th ed. New York: McGraw-Hill, Inc; 1995:73, with permission.

30
air will be slightly less than the arterial Pco2. Larger differences may occur in
disease states in which there is more dead space, such as in patients who are
anesthetized or those with pulmonary embolism.21
Another noninvasive method to estimate arterial Po2 and Pco2 is by using
a transcutaneous monitor, which measures skin-surface Po2 and Pco2. The
transcutaneous monitor increases the local temperature of the skin, produc-
ing hyperperfusion, and determines the Po2 and Pco2 by using a sensor.22
Because of the widespread use of pulse oximetry and the potential risk of
thermal injury, the transcutaneous monitor is usually used only to estimate
arterial Pco2 and is referred to as transcutaneous Pco2 (TcPco2). This tech-
nique has advantages and disadvantages. TcPco2 values are typically higher
than the true arterial Pco2. Inaccurate readings may occur in patients with
hyperoxemia, hypoperfusion, or skin edema and from improper electrode
placement.22 However, TcPco2 values may provide a better estimate of arterial
Pco2 than does end-tidal Pco2 , particularly in neonates and preterm infants in
whom end-tidal Pco2 measurements often lead to underestimation of the true
arterial Pco2.23 Transcutaneous Pco2 monitoring is especially useful in
neonatal and pediatric intensive care units, sleep laboratories, and operating
rooms.22–25
Arterial Blood Gas Analysis
The gold standard for assessing both oxygenation and ventilation is arterial
blood gas analysis.26 The actual value of measured arterial Po2 is important.
However, in patients with hypoventilation or receiving supplemental oxygen,
it is also useful to compare it with what it should ideally be. The difference
between the predicted arterial Po2 , calculated from the alveolar Po2 (Pao2),
and what is measured is known as the alveolar-arterial (A-a) gradient; it is
usually less than 10 mm Hg.27 The Pao2 can be calculated from the simplified
alveolar gas equation as follows:
Pao2 = Pio2 – Paco2/R,
and because Pio2 = Fio2 (Patm – Ph2o),
Pao2 = Fio2 (Patm – Ph2o) – Paco2/R,
where Pao2 is the alveolar Po2 , Pio2 is the inspired Po2 , Paco2 is the arterial
Pco2 , and R is the respiratory exchange ratio of carbon dioxide and oxygen
(which is estimated to be 0.8 for the whole lung). Fio2 is the percentage of
oxygen, Patm is atmospheric pressure (760 mm Hg at sea level), and Ph2o is
water vapor pressure (47 mm Hg at 37° C). So, for example, a patient breath-
ing 40% oxygen with an arterial Pco2 of 35 mm Hg has a Po2 of 100 mm Hg.
However, on the basis of the equation, the patient should have an arterial
Po2 of 240 mm Hg at sea level. The A-a gradient is extremely elevated at
140 mm Hg. There are other ways to assess impairment of oxygenation by
using the Pao2 as well as other variables27–31 (Table 2‑4).

31
The adequacy of ventilation can be assessed by measuring arterial blood

gas; there is an inverse correlation between ventilation and the arterial Pco2.
However, the number must be assessed in the context of the clinical picture.
For example, a patient with asthma who is in severe distress with a respiratory
rate of 60 breaths/min has a Pco2 of 40 mm Hg. Although this is a normal
value, it implies impending respiratory failure in a patient with this degree
of tachypnea and work of breathing.
Measurement of arterial blood gases is invasive and may be technically diffi-
cult and painful. Surrogate measures involve using either a venous or a capil-
lary blood sample. In the latter, a finger or toe is pierced with a lancet and the
blood collected. Neither measure is useful for assessing arterial oxygenation
because the samples are mixed with venous blood. Because venous blood has
a higher Pco2 , both samples will lead to overestimation of the true arterial
Pco2 (and indicate the worst-case scenario). In cases of cardiac arrest, the
discrepancy between the 2 values widens.32
Table 2‑4. Measures of Impairment in Oxygenation

Name of Index Equation Normal Values
A-a oxygen gradient Pao2 – Pao2 < 10 mm Hg
A-a oxygen ratio Pao2/Pao2 > 0.75
Pao2:Fio2 ratio Pao2/Fio2 300–500 mm Hg
Oxygenation index Fio2 × mean airway pressure × 100/Pao2 <5
Oxygen saturation index Fio2 × mean airway pressure × 100/Spo2 < 6.5
Normal values are from references 27–31.
Mechanics of Breathing
The muscles of respiration act like a pump to move air in and out of the lungs.
The efficiency of the pump is determined by the elastic properties of the chest
wall and lungs and the resistance of the airways. Disease processes can alter
these relationships and lead to respiratory failure.
Muscles of Breathing
The muscles of breathing are depicted in Figure 2‑10. The diaphragm is the
primary muscle of inspiration. It is a dome-shaped muscle and is responsible
for two-thirds of the air that enters the lungs during quiet breathing. When
it contracts, it forces the abdominal contents down and widens the rib cage.
When it is paralyzed, as in the case of phrenic nerve or cervical spine injury,
it moves up instead of down during inspiration. Other muscles of inspiration
are the external intercostal muscles and other accessory muscles, such as the
scalene and sternocleidomastoid muscles.

32
In normal quiet breathing, expiration is passive; the recoil of the lungs forces
the air out. However, in active breathing, such as with exercise, coughing, or
singing, or in lower airway obstruction, expiratory muscles are recruited.1
The muscles of expiration are the abdominal and internal intercostal muscles.
Neuromuscular disease, abdominal muscle weakness, or postoperative
abdominal pain may impair cough, leading to a decreased ability to
clear secretions.
INSPIRATION ACTIVE EXPIRATION
Accessory
muscles
External
intercostals
Internal
intercostals
Diaphragm
Abdominal
muscles
Posterior Anterior
Figure 2‑10. Muscles of breathing. The inspiratory muscles are

the diaphragm, external intercostals, and accessory muscles such
as the sternocleidomastoid and scalene. Expiration with quiet
breathing is passive. Active expiration requires the use of the
abdominal and internal intercostal muscles.

33
Elastic Properties of the Lung and Chest Wall

The interaction of the lungs and chest wall determines the effectiveness
of the pump. The lungs and individual alveoli act like balloons. Pressure is
required to inflate the lungs; without it, they would tend to collapse. At low
volumes, it is difficult to overcome the elastic forces and to inflate the lung;
high pressures are required. At medium volumes, less pressure is required to
inflate the lungs. At high volumes, it is again more difficult, and higher pres-
sures are required. The ease with which the lungs can be stretched is known
as compliance. Reduced lung compliance can be seen in conditions such as
fibrosis, pulmonary edema, and acute respiratory distress syndrome. Increased
lung compliance is seen in emphysema and aging. One of the important func-
tions of surfactant, a phospholipid produced by the lung, is to increase lung
compliance by reducing the surface tension of the alveoli. Consequently, in
preterm neonates in whom there is a developmental decrease in surfactant
production, there is a decrease in lung compliance and the development of
neonatal respiratory distress syndrome.
The chest wall has elastic properties and its own compliance. Its inherent
tendency is to expand, which counterbalances the tendency of the lungs to
collapse. The relationship between the forces of the chest wall and lung
volume is shown in Figure 2‑11. The resting lung volume (functional residual
capacity) represents the equilibrium between the 2 forces (Figure 2‑11A).
Lung volumes are smaller if the compliance of either the chest wall
(Figure 2‑11B) or the lung (Figure 2‑11C) is decreased.
A B C
Figure 2‑11. Interactions of the chest wall and lung. A, In the normal lung, the outward recoil
of the chest wall balances the inward recoil of the lung. The final volume of the lung depends
on the equilibrium between them. B, If the chest wall becomes less compliant and more stiff,
there is less outward force to balance out the inward recoil of the lungs. The result is a smaller
lung volume. Examples include obesity, neuromuscular weakness, and trauma to or defects in
the chest wall. C, If the lungs become less compliant, they overcome the outward force of the
chest wall and have a smaller resting volume. Examples include pulmonary edema, interstitial
fibrosis, and acute respiratory distress syndrome.

34
Airway Resistance
Resistance is the force that opposes the forward motion of the airflow.
Approximately 25% to 40% of the total resistance to airflow is located in the
upper airway: nose and mouth passages and larynx.1,5 The airways and lung
tissue provide the remainder of the resistance. Air flows through the airways
as if they were tubes. In some areas, the flow is very orderly and is known as
laminar flow. In some places, such as in narrowed or branch points, it is dis-
organized and is known as turbulent flow. In laminar flow, resistance is directly
proportional to the radius4 of the airways. Consequently, if the radius of an air-
way is narrowed by one-half, the resistance increases by 16-fold. In an infant’s
or child’s airway, which is already narrow relative to an adult’s, small changes
in caliber produce large changes in the degree of obstruction. Turbulent flow
depends on gas density. Thus, gases with a low density, such as helium, are
administered to decrease resistance in patients with airway obstruction.33
Work of Breathing
The work involved in breathing is proportional to the tidal volume and the
change in pressure required to move the air. The work of breathing increases
when the compliance of the chest wall or lung is decreased; more negative
pressure is required to breathe. In addition, the work of breathing increases
with increased airway resistance, such as with asthma or upper airway
obstruction. Infants and young children are at a mechanical disadvantage;
their respiratory system works less efficiently than an adult’s. Their chest
walls are more compliant, and their diaphragms are flatter and more likely
to fatigue, which predisposes them to respiratory failure.
Assessment of Lung Mechanics

An alteration in lung mechanics may result in signs of respiratory distress.
Decreases in lung and chest wall compliance are usually heralded by tachy-
pnea. Increased effort of breathing is manifested by recruitment of accessory
muscles, such as the sternocleidomastoid or scalene muscles. Retractions,
bowing in of the muscle and soft tissue of the chest wall with inspiration,
indicate that high pressures are generated to move air through the airways.
They can be seen subcostally, intercostally, and in the suprasternal notch.
The higher the retractions, the more severe the respiratory distress. Nasal
flaring is an attempt to decrease the resistance of breathing by decreasing
the resistance of the nasal passages.
Airflow, lung volumes, and airway resistance can be measured by means
of pulmonary function testing and will be further described in Chapter 6,
Pulmonary Function Testing.

35
key po ints
Gas Exchange
} The Po2 in the alveoli is determined by the balance between the amount that
flows in and the amount that is removed in the pulmonary capillaries.
Ventilation
} In each breath (tidal volume), some of the air goes into the alveoli (alveolar
volume) and is available for gas exchange, while the rest remains in the
conducting airways and is known as dead space.
} The arterial Pco2 is inversely proportional to alveolar ventilation.
} Increases in arterial Pco2 can be caused by decreased tidal volume, decreased
respiratory rate, increased dead space, or increased carbon dioxide production.
} In chronic respiratory acidosis, after renal compensation, the bicarbonate will
increase by a total of 4 mEq/L for each 10-mm increase in Pco2.
} Arterial Pco2 can be approximated noninvasively by end-tidal carbon dioxide or
transcutaneous carbon dioxide monitoring.
Oxygenation
} Hypoxemia, or low arterial Po2, may be caused by low inspired partial pressure of
oxygen (ie, high altitude), hypoventilation, diffusion impairment, shunt, V/Q
mismatch, and abnormally low venous blood saturation (under certain conditions).
} Oxygen is primarily carried in the blood bound to hemoglobin; a very small
amount is dissolved in plasma.
} The P50 is the oxygen tension at which 50% of the hemoglobin is saturated.
} The affinity of hemoglobin for oxygen can by altered by changes in blood pH,
Pco2, temperature, and 2,3-DPG levels.
} Arterial oxygen saturation can be approximated noninvasively by using pulse
oximetry.
} The degree of impairment in oxygenation can be assessed by calculating the
A-a oxygen gradient or other indexes such as A-a oxygen ratio, Pao2:Fio2 ratio,
oxygenation index, and oxygen saturation index.
} The diaphragm is the primary muscle of inspiration.
} The ease with which the lungs can be stretched is known as compliance, which
is decreased in conditions such as pneumonia, pulmonary edema, and acute
respiratory distress syndrome.
} In laminar airflow, which normally occurs only in small airways, resistance is
directly proportional to the radius4 of the airways, and small changes in the
airway caliber produce large changes in resistance.
} The work of breathing increases when the compliance of the chest wall or lung
is decreased or airway resistance is increased.
} Infants and young children are at higher risk of respiratory failure in part
because their chest walls are more compliant and their diaphragms are flatter
and more prone to fatigue.

36
References
1. Levitzky MG. Pulmonary Physiology. 4th ed. McGraw-Hill, Inc; 1995:12–54, 73–80, 130–186
2. West JB. Respiratory Physiology: The Essentials. 8th ed. Lippincott Williams & Wilkins;
2008:13–34, 55–122, 126–129
3. Angelillo VA, Bedi S, Durfee D, Dahl J, Patterson AJ, O’Donohue WJ Jr. Effects of low and
high carbohydrate feedings in ambulatory patients with chronic obstructive pulmonary disease
and chronic hypercapnia. Ann Intern Med. 1985;103(6 (Pt 1)):883–885 PMID: 3933397
https://doi.org/10.7326/0003-4819-103-6-883
4. Kerr AA. Dead space ventilation in normal children and children with obstructive airways
disease. Thorax. 1976;31(1):63–69 PMID: 1257940 https://doi.org/10.1136/thx.31.1.63
5. Lumb AB. Nunn’s Applied Respiratory Physiology. 6th ed. Elsevier/Butterworth Heinemann;
2006:25–54, 76–91, 148–155, 189–200
6. DuBose TD. Disorders of acid-base balance. In: Brenner BM, ed. Brenner and Rector’s The
Kidney. Saunders Elsevier; 2007:505–520
7. Presson RG Jr, Graham JA, Hanger CC, et al. Distribution of pulmonary capillary
red blood cell transit times. J Appl Physiol (1985). 1995;79(2):382–388 PMID: 7592192
https://doi.org/10.1152/jappl.1995.79.2.382
8. Dantzker DR. Pulmonary gas exchange. In: Dantzker D, ed. Cardiopulmonary Critical Care.
Grune &Stratton, Inc; 1986:25–46
9. Bancalari E, Claure N, Sosenko IR. Bronchopulmonary dysplasia: changes in pathogenesis,
epidemiology and definition. Semin Neonatol. 2003;8(1):63–71 PMID: 12667831
https://doi.org/10.1016/S1084-2756(02)00192-6
10. Balinotti JE, Chakr VC, Tiller C, et al. Growth of lung parenchyma in infants and toddlers
with chronic lung disease of infancy. Am J Respir Crit Care Med. 2010;181(10):1093–1097
PMID: 20133928 https://doi.org/10.1164/rccm.200908-1190OC
11. Chang DV, Assaf SJ, Tiller CJ, Kisling JA, Tepper RS. Membrane and capillary components
of lung diffusion in infants with bronchopulmonary dysplasia. Am J Respir Crit Care Med.
2016;193(7):767–771 PMID: 26566056 https://doi.org/10.1164/rccm.201506-1219OC
12. Assaf SJ, Chang DV, Tiller CJ, et al. Lung parenchymal development in premature infants
without bronchopulmonary dysplasia. Pediatr Pulmonol. 2015;50(12):1313–1319
PMID: 25462113 https://doi.org/10.1002/ppul.23134
13. Needleman JP, Setty BN, Varlotta L, Dampier C, Allen JL. Measurement of hemoglobin
saturation by oxygen in children and adolescents with sickle cell disease. Pediatr Pulmonol.
1999;28(6):423–428 PMID: 10587417 https://doi.org/10.1002/
(SICI)1099-0496(199912)28:6<423::AID-PPUL7>3.0.CO;2-C
14. Rackoff WR, Kunkel N, Silber JH, Asakura T, Ohene-Frempong K. Pulse oximetry and factors
associated with hemoglobin oxygen desaturation in children with sickle cell disease. Blood.
1993;81(12):3422–3427 PMID: 7685205 https://doi.org/10.1182/blood.V81.12.3422.3422
15. Watkins GM, Rabelo A, Pizak LF, Sheldon GF. The left shifted oxyhemoglobin curve in
sepsis: a preventable defect. Ann Surg. 1974;180(2):213–220 PMID: 4842983
https://doi.org/10.1097/00000658-197408000-00015
16. Comroe JH Jr, Botelho S. The unreliability of cyanosis in the recognition of arterial
anoxemia. Am J Med Sci. 1947;124(1):1–6 PMID: 20250015
https://doi.org/10.1097/00000441-194707000-00001
17. Mithoefer JC, Bossman OG, Thibeault DW, Mead GD. The clinical estimation of alveolar
ventilation. Am Rev Respir Dis. 1968;98(5):868–871 PMID: 5683481
18. Brockway J, Hay WW Jr. Prediction of arterial partial pressure of oxygen with pulse
oxygen saturation measurements. J Pediatr. 1998;133(1):63–66 PMID: 9672512
https://doi.org/10.1016/S0022-3476(98)70179-9
19. Brown M, Vender J. Noninvasive oxygen monitoring. In: Vender J, ed. Intensive Care
Monitoring. WB Saunders; 1988:493–509
20. Stock MC. Noninvasive carbon dioxide monitoring. In: Vender J, ed. Intensive Care Monitoring.
WB Saunders; 1988:511–526
21. Nunn JF, Hill DW. Respiratory dead space and arterial to end-tidal carbon dioxide tension
difference in anesthetized man. J Appl Physiol. 1960;15(3):383–389 PMID: 14427915
22. Restrepo RD, Hirst KR, Wittnebel L, Wettstein R. AARC clinical practice guideline:
transcutaneous monitoring of carbon dioxide and oxygen: 2012. Respir Care.
2012;57(11):1955–1962 PMID: 23107301 https://doi.org/10.4187/respcare.02011

37
23. Trevisanuto D, Giuliotto S, Cavallin F, Doglioni N, Toniazzo S, Zanardo V. End-tidal

carbon dioxide monitoring in very low birth weight infants: correlation and agreement
with arterial carbon dioxide. Pediatr Pulmonol. 2012;47(4):367–372 PMID: 22102598
https://doi.org/10.1002/ppul.21558
24. Bhalla AK, Khemani RG, Hotz JC, Morzov RP, Newth CJ. Accuracy of transcutaneous
carbon dioxide levels in comparison to arterial carbon dioxide levels in critically ill children.
Respir Care. 2019;64(2):201–208 PMID: 30254042 https://doi.org/10.4187/respcare.06209
25. Karlsson V, Sporre B, Ågren J. Transcutaneous PCO2 monitoring in newborn infants during
general anesthesia is technically feasible. Anesth Analg. 2016;123(4):1004–1007 PMID: 27464976
https://doi.org/10.1213/ANE.0000000000001462
26. Shapiro BA. Arterial blood gas monitoring. In: Vender J, ed. Intensive Care Monitoring.
WB Saunders; 1988:479–492
27. Filley GF, Gregoire F, Wright GW. Alveolar and arterial oxygen tensions and the significance of
the alveolar-arterial oxygen tension difference in normal men. J Clin Invest. 1954;33(4):517–529
PMID: 13152191 https://doi.org/10.1172/JCI102922
28. Covelli HD, Nessan VJ, Tuttle WK III. Oxygen derived variables in acute respiratory failure.
Crit Care Med. 1983;11(8):646–649 PMID: 6409506
https://doi.org/10.1097/00003246-198308000-00012
29. Gilbert R, Keighley JF. The arterial-alveolar oxygen tension ratio: an index of gas exchange
applicable to varying inspired oxygen concentrations. Am Rev Respir Dis. 1974;109(1):142–145
PMID: 4809154 https://doi.org/10.1164/rccm.201705-0956LE
30. Thomas NJ, Shaffer ML, Willson DF, Shih MC, Curley MA. Defining acute lung disease in
children with the oxygenation saturation index. Pediatr Crit Care Med. 2010;11(1):12–17
PMID: 19561556 DOI: 10.1097/PCC.0b013e3181b0653d
31. Muniraman HK, Song AY, Ramanathan R, et al. Evaluation of oxygen saturation index
compared with oxygenation index in neonates with hypoxemic respiratory failure. JAMA Netw
Open. 2019;2(3):e191179 PMID: 30924897 https://doi.org/10.1001/jamanetworkopen.2019.1179
32. Adrogué HJ, Rashad MN, Gorin AB, Yacoub J, Madias NE. Assessing acid-base status in
circulatory failure: differences between arterial and central venous blood. N Engl J Med.
1989;320(20):1312–1316 PMID: 2535633 https://doi.org/10.1056/NEJM198905183202004
33. Gupta VK, Cheifetz IM. Heliox administration in the pediatric intensive care unit:
an evidence-based review. Pediatr Crit Care Med. 2005;6(2):204–211 PMID: 15730610
https://doi.org/10.1097/01.PCC.0000154946.62733.94

CHAPTER
3
Applied Pulmonary Physiology
Maki Ishizuka, MD
Christopher M. Cielo, DO, MS
Exercise Physiology
Understanding exercise physiology in children is important because of the
increasing participation of young children in competitive sports. The energy
to power skeletal muscle depends on adenosine triphosphate (ATP). Combined
with water, hydrolysis splits one of the phosphate groups, which results in the
formation of adenosine diphosphate. To replenish the limited stores of ATP,
phosphorylation adds a phosphate group to adenosine diphosphate. If phosphor-
ylation occurs in the presence of oxygen, the reaction is aerobic metabolism;
in the absence of oxygen, the reaction is anaerobic metabolism.
The ventilatory response to exercise results from increased demand for oxygen
and excretion of carbon dioxide (CO2). Exercise results in an almost immediate
increase in oxygen consumption, and without oxygen stores in the body, the
carotid chemoreceptors register hypoxemia. Ventilation appears to increase
before there is hypoxemia and is probably driven by a neural response. Hypox-
emia results in higher minute ventilation, which is the tidal volume (the volume
of air inspired and expired during a passive breath) multiplied by the number
of breaths per minute (frequency). Both tidal volume and frequency increase
in response to increased metabolic demands. There is also an increase in blood
flow to the lungs and an increase in lung diffusion capacity, which is a measure
of the transport of oxygen passing from the alveolus across the alveolar-capillary
membrane into the pulmonary circulation. The frequency increases from the
resting rate of 12 to 15 breaths/min to 45 to 70 breaths/min depending on age.
The tidal volume increases to levels that may reach 50% to 60% of the vital
capacity, which is the largest active breath than can be inspired and expired.
As the degree of exercise increases, there is a linear increase in tidal volume
that reaches a maximum, and increased minute ventilation then results from
an increase in the frequency of breathing.
The cardiac responses to exercise are increased heart rate and stroke volume,
which increase cardiac output. Cardiac output increases more slowly than does
ventilation during exercise. Resting heart rate averages 60 to 80 beats/min and
39

40
increases in direct proportion to the degree of exercise to a maximum that

is approximately 220 minus the age in years. Stroke volume also increases
with exercise intensity, and training can increase this volume significantly.
The increase in cardiac output results in increased pulmonary arterial and
venous pressure, which accounts for the recruitment and distention of
pulmonary capillaries.
The point at which the oxygen consumption does not increase with increasing
exercise intensity is V̇ o2max, which is also known as maximal oxygen uptake
or aerobic capacity, expressed as milliliters of oxygen per kilogram of body
weight per minute. The expression relative to weight or body surface area is
useful in comparing a child with other children (and adults of different sizes).
There is a great deal of variety in V̇ o2max, and genetics plays a major role in
these differences.1 Responders to training make substantial improvement, and
nonresponders make little or no progress in V̇ o2max. Maximal ventilation
increases to some extent with training, but at submaximal levels of exercise,
ventilation is consistently lower after training.2 In children, both aerobic and
anaerobic work capacity increase with training as measured by increase in
V̇ o2max and decreased lactate production for a given workload.3
High-Altitude Illness
Ascending to high altitude (ie, > 1,500 m [5,000 ft]) results in hypoxia because
the Po2 of inspired air decreases with ascent. Mild altitude elevation is con-
sidered to be higher than 1,500 m (5,000 ft); moderate, 2,000 to 3,500 m
(6,700–11,700 ft); very high, 3,500 to 5,500 m (11,700–18,300 ft); and extreme,
higher than 5,500 m (18,300 ft). Table 3‑1 shows the approximate alveolar
oxygen (ie, the oxygen concentration at the level of the gas exchange portion
of the lung) at different altitudes. The physiological effect of the reduced
inspired oxygen depends principally on the rate of ascent and to a lesser
extent on the medical history of the individual. High-altitude illness is a spec-
trum of cerebral and pulmonary syndromes induced by the hypoxic stress of
high altitude. The susceptibility of children to altitude illness is comparable
with that of adults. However, children with a history of cardiopulmonary
conditions, at increased risk of pulmonary hypertension, or with a recent
upper respiratory illness should not travel to high altitude. Such travel should
also be avoided for infants during the first 4 to 6 weeks after birth, or longer
for those born prematurely, especially those with lung diseases.

41
Chapter 3—Applied Pulmonary Physiology
Table 3-1. Altitude and Oxygen Tensions

Approximate Alveolar
Altitude Meters (Feet) Oxygen Tension (mm Hg)
Sea level 0 100
Mild elevation 1,500–2,000 (5,000–6,700) 80
Moderate elevation 2,000–3,500 (6,700–11,700) 60
Very high elevation 3,500–5,500 (11,700–18,300) 40
Extreme elevation > 5,500 (> 18,300) < 40
Acclimatization
The percentage (fraction) of oxygen in inspired air remains approximately
21% (0.21), but during ascent the Po2 decreases with the decrease in baro-
metric pressure. Compensatory responses to acute hypobaric hypoxia are
known as acclimatization. The physiological response to hypoxia occurs both
immediately and over time. The immediate response is an increase in minute
ventilation when the carotid and aortic bodies register the hypoxemia. As
alveolar ventilation increases, there is resultant decrease in Paco2 , which
causes a mild respiratory alkalosis and a reduction in the degree of hyper-
ventilation. Over time, renal compensation for the respiratory alkalosis
causes excretion of bicarbonate, which normalizes the pH. This ventilatory
acclimatization takes place over 3 to 4 days. After a rapid and sustained
increase in altitude, circulatory changes involving systemic, cerebral, and
pulmonary vasculature occur. Sympathetic activity increases cardiac output,
blood pressure, heart rate, and venous tone. Hypoxia causes pulmonary
vasoconstriction and an increase in cerebral blood flow.
Hemoconcentration results from reduction in plasma volume caused by fluid
shifts and diuresis, which improves the oxygen-carrying capacity of the blood.
Hypoxemia stimulates the production of erythropoietin, resulting in increased
red blood cell production over time.
Acute Mountain Sickness

Acute mountain sickness (AMS) is a clinical syndrome characterized by
headache plus 1 of several other symptoms including anorexia, nausea,
dizziness, malaise, and sleep disturbance. Symptom onset tends to be 6 to
12 hours after ascent greater than 2,000 m (6,700 ft) but can be as early as
1 to 2 hours or as late as 24 hours. There are no approved clinical measures
for diagnosing AMS, but several tools have been studied in a research context.
The simplest screening tool for assessing AMS is the Clinical Functional
Score; the 2018 Lake Louise Acute Mountain Sickness Score may be used
to assess the severity of AMS as shown in Box 3-1.4 Children are at risk for
AMS but not necessarily more than adults are.

42
Box 3-1
AMS Scores
Clinical Functional Score
Overall, if you had AMS symptoms, how did they affect your activities?
0 Not at all
1 Symptoms present, but did not force any change in activity or itinerary
2 My symptoms forced me to stop the ascent or to go down on my own power
3 Had to be evacuated to a lower altitude
2018 Lake Louise Acute Mountain Sickness Score
Headache
0 None at all
1 Mild headache
2 Moderate headache
3 Severe headache, incapacitating
Gastrointestinal symptoms
0 Good appetite
1 Poor appetite or nausea
2 Moderate nausea or vomiting
3 Severe nausea and vomiting, incapacitating
Fatigue and/or weakness
0 Not tired or weak
1 Mild fatigue/weakness
2 Moderate fatigue/weakness
3 Severe fatigue/weakness, incapacitating
Dizziness/light-headedness
0 No dizziness/light-headedness
1 Mild dizziness/light-headedness
2 Moderate dizziness/light-headedness
3 Severe dizziness/light-headedness, incapacitating
An AMS Clinical Functional Score of 2 or higher indicates AMS. On the basis of the
2018 Lake Louise Acute Mountain Sickness Score, AMS is indicated if the sum of
the scores is 3 points or higher, including headache (mild AMS, 3–5 points;
moderate AMS, 6–9 points; severe AMS, 10–12 points).
Abbreviation: AMS, acute mountain sickness.

From Roach RC, Hackett PH, Oelz O, et al; Lake Louise AMS Score Consensus Committee. The 2018 Lake Louise
Acute Mountain Sickness Score. High Alt Med Biol. 2018;19(1):4–6.

43
High-Altitude Cerebral Edema

High-altitude cerebral edema (HACE) may be associated with AMS or high-
altitude pulmonary edema. The major symptoms are ataxia and altered
consciousness; HACE is essentially the severe form of AMS. The cerebral
edema may cause papilledema or retinal hemorrhage and even cranial
nerve palsy. Drowsiness is followed by stupor. Death may occur from
brainstem herniation.
High-Altitude Pulmonary Edema

High-altitude pulmonary edema (HAPE) is a noncardiogenic pulmonary
edema. As noted previously, hypoxia causes pulmonary vasoconstriction, and
pulmonary hypertension results. The combination of increased pressure and
hypoxia-related increased capillary permeability leads to leakage of fluid in
the lungs. Some children may have a genetic predisposition to HAPE. Genes
affecting the renin-angiotensin-aldosterone system pathway, the nitric oxide
pathway, and the hypoxia-inducible factor pathway may all be associated with
increased susceptibility to HAPE.5 In addition, the presence of preexisting
pulmonary hypertension before the ascent exacerbates the effect of hypoxia.
The risk of HAPE is increased by exercise because of the increased cardiac
output and oxygen deficit. Travel to high altitude should be avoided during
the first 4 to 6 weeks after birth in children with a history of cardiopul-
monary conditions or Down syndrome, at increased risk for pulmonary
hypertension, or with a recent upper respiratory illness. In children with
a history of prematurity, travel to altitude should be done with caution,
even at older ages.
High-altitude pulmonary edema usually occurs 2 to 4 days after the ascent
and tends to be worse at night. The primary symptom is cough with progres-
sive dyspnea. In children, HAPE manifests as increasing respiratory distress
over 1 to 2 days, but it may develop more precipitously. Cough and decreased
exercise ability are usually the first symptoms to manifest, and only late in the
illness does production of frothy bloodstained sputum occur. Young children
may develop only pallor and depressed consciousness or other nonspecific
symptoms such as increased fussiness, crying, decreased appetite, decreased
playfulness, disrupted sleep, and possibly vomiting. Low-grade fever may
be present, so a diagnosis of pneumonia may be incorrectly considered. In
children with HAPE, chest radiography typically shows unilateral or bilateral
patchy infiltrates with a normal heart size.
Reentry HAPE occurs when persons who live at high altitude leave for a
time and then return. Children are more susceptible than adults. Symptoms
develop as rapidly as 24 hours after returning. It is diagnosed and managed
the same as HAPE.

44
It is important to recognize HAPE because it has the potential to be life-

threatening within a few hours. The Lake Louise Consensus Definition for
HAPE is summarized in Box 3-2.6 Fifty percent of people with HAPE have
AMS, and 14% have HACE.
Box 3-2
Lake Louise Consensus Definition for HAPE
At least 2 of the following symptoms and at least 2 of the following signs are
necessary for diagnosis.
Symptoms
Weakness or decreased exercise ability
Cough
Dyspnea at rest
Chest tightness or congestion
Signs
Crackles or wheezing in at least 1 lung field
Central cyanosis or arterial oxygen desaturation relative to altitude
Tachycardia
Tachypnea
Abbreviation: HAPE, high-altitude pulmonary edema.

Derived from Hackett PH, Oelz O. The Lake Louise Consensus on the definition and quantification of altitude
illness. In: Sutton JR, Houston CS, Coates G, eds. Hypoxia and Mountain Medicine. Queen City Press; 1992:327–330.
Chronic Mountain Sickness

Chronic mountain sickness (CMS) occurs with persons born at high altitude
as well as lowlanders who spend a prolonged period at high altitude. The
symptoms are related to polycythemia and include headache, dizziness,
lethargy, difficulty sleeping, and impaired mentation and memory. The
disorder is incompletely understood because actual hematocrit levels tend
to be higher than expected considering the oxygen saturation. In addition,
there is hypoventilation and blunted hypoxic ventilatory response. Pulmonary
hypertension may develop. The first consideration is to descend to a lower
altitude, but this may not be practical. The management of CMS is lowering
the red blood cell volume by means of phlebotomy. Low-flow oxygen may
be beneficial.7
Management of Altitude Sickness

Descent remains the single best treatment for AMS, HACE, or HAPE.
Symptoms of AMS may improve with a descent as small as 500 to 1,000 m
(1,700–3,300 ft). The first treatment of AMS is supplemental oxygen to raise
peripheral capillary oxygen saturation greater than 90%. Symptoms can be
reduced with acetazolamide, effective within 24 hours. Dexamethasone is

45
equivalently effective, with a response within about 12 hours. Acetazolamide

is also used as a preventive treatment, especially in those with a history of
AMS or HAPE, but it is not used in the treatment of HAPE. The headache
associated with AMS responds well to ibuprofen; however, ibuprofen is not
proved to improve the full spectrum of AMS symptoms. Nifedipine should be
used for HAPE treatment when descent is delayed or access to supplemental
oxygen is limited. Nifedipine can be also used for HAPE prevention for
susceptible individuals. Early diagnosis of HAPE is essential because it is
the cause of most deaths from high-altitude illness. It is important not to
exacerbate hypoxia during the descent by additional exertion. Table 3-2
presents medical therapies for high-altitude sickness, but caution is necessary
for children because data are limited. Supplemental oxygen to keep
peripheral capillary oxygen saturation greater than 90% may be used to
treat AMS, HACE, or HAPE. Portable hyperbaric chambers are effective
for treating severe altitude illness. A rapid pressurization of the patient
simulates a descent of about 1,500 to 2,500 m (5,000–8,300 ft). However,
use of a portable hyperbaric chamber should not delay descent.
Table 3-2. Therapy for High-Altitude Illness

Agent Indication Route Dosage
Acetazolamide AMS, HACE Oral 125 mg every 12 h
prevention Pediatrics: 2.5 mg/kg every 12 h
AMS Oral 250 mg every 12 h
treatment Pediatrics: 2.5 mg/kg every 12 h
(Maximum: 125 mg per dose)
Dexamethasone AMS, HACE Oral 2 mg every 6 h or 4 mg every 12 h
prevention Pediatrics: Should not be used
for prophylaxis
AMS, HACE Oral, AMS: 4 mg every 6 h
treatment IV, IM HACE: 8 mg once, then 4 mg every 6 h
Pediatrics: 0.15 mg/kg every 6 h
(Maximum: 4 mg per dose)
Ibuprofen AMS Oral 600 mg every 8 h
prevention
Nifedipine HAPE Oral 30 mg extended-release every 12 h
prevention or 20 mg extended-release every 8 h
HAPE Oral 30 mg extended-release every 12 h
treatment or 20 mg extended-release every 8 h
Abbreviations: AMS, acute mountain sickness; HACE, high-altitude cerebral edema; HAPE, high-altitude
pulmonary edema; IM, intramuscular; IV, intravenous.
Adapted from Luks AM, Auerbach PS, Freer L, et al. Wilderness Medical Society clinical practice guidelines for the
prevention and treatment of acute altitude illness: 2019 update. Wilderness Environ Med. 2019;30(4S):S3–S18.

46
Underwater Medicine
Shallow Water Blackout
Hyperventilation before diving lowers CO2 levels, which reduces the stimu-
lus to breathe and prolongs the breath-holding time, but it can be dangerous.
It occurs when free diving because as the diver descends, alveolar Po2 and
Pco2 increase, but CO2 is so soluble that it diffuses into the tissues. The Po2
increases artificially, prolonging the breath-holding time, and then when the
diver ascends, the Po2 decreases dramatically so that unconsciousness may
occur before the diver reaches the surface. The risk is increased because
of simultaneous hypocapnic vasoconstriction of the cerebral vessels. This
combination is thought to explain many of the accidents that occur in
swimming pools. Advice to parents should include telling children not
to hyperventilate before swimming underwater and to avoid prolonged
breath holding.
Thoracic Squeeze
This condition results during breath-hold diving, also known as free diving.
Taking a full breath and free diving to 10 m (33 ft) would cause the lungs to
be one-half of their original size. At 20 m (66 ft), they would be one-third,
and at 30 m (99 ft) they would be one-fourth. The air within the lungs is
compressed during descent, and it is possible to compress to a volume smaller
than the residual volume of the lungs. The chest wall will not be able to be
compressed further, and the squeeze results in blood being forced into the
alveoli because of the negative pressure within the lungs. The result is wheez-
ing and hemoptysis. Free divers attempt to improve their ability to dive to
deeper levels by packing or stacking, which consists of glossopharyngeal
breathing whereby the tongue and pharynx force air into the lung to exceed
total lung capacity. A nontrained free diver risks lung injuries, blackouts, and
potentially drowning, so training specific to free diving should be considered
to improve safety.
Scuba Diving
Scuba is an acronym for self-contained underwater breathing apparatus, and
the sport of scuba diving is very popular. There are limits of lower age set by
the 2 major certifying agencies in North America. The Professional Associa-
tion of Diving Instructors (PADI) requires that a child be 10 years or older to
take the certification course. Students younger than 15 will receive the PADI
Junior Open Water Diver certification, which can then be upgraded to PADI
Open Water Diver certification on reaching age 15. The minimum age for the
National Association of Underwater Instructors’ course is also 10 years.
The effect of underwater pressure on gases is described by Boyle’s law,
which states that as the pressure of a gas increases, the volume decreases

47
proportionately. By going from the surface (1 atm) to 10 m (33 ft) (2 atm), the
volume of air within the lungs is halved. This law helps explain the principles
behind diving-related barotrauma and air embolism. Charles’s law states
that if the pressure is constant, the volume of gas alters with temperature,
expanding with heating and contracting with cooling. This means that when a
scuba tank is filled, it will have less air if it is filled at a high temperature and
later cools than will a tank that is filled at a low temperature. Charles’s law
is important when nitrogen in the tissues is expelled as gas in the lungs. If a
diver is close to the bends (see Decompression Sickness later in this chapter)
and is warmed, there will be increased risk of the bends. If a scuba tank is left
in a hot car, it is more at risk for bursting (as the temperature increases, with
the volume constant, the pressure increases). Also important is Dalton’s law,
which states that in a mixture of gases, the total gas pressure is equal to the
sum of the individual pressures, implying that as air is compressed into
the scuba tank, the percentages of each gas will remain the same. Many of
the complications of diving are related to Henry’s law, which states that the
amount of gas that dissolves in a liquid is a function of the partial pressure of
the gas and how easily the liquid absorbs gas. As a result, when a diver is at
great depths, the amount of nitrogen absorbed into blood and tissues increases
because of the increased pressure, which explains in part why the risk of
decompression sickness (DCS) and nitrogen narcosis is greater at depths
of 30 m (100 ft) than 10 m (33 ft).
Complications of Scuba Diving

Nitrogen Narcosis
Nitrogen narcosis is caused by an increased partial pressure of nitrogen.
Symptoms include euphoria, difficulty concentrating, and poor judgment.
Because it happens at depths greater than 30 m (100 ft), this can be a dan-
gerous situation for the diver. It is called rapture of the deep because the
symptoms are similar to the effects of alcohol. It resolves very quickly
during the ascent.
Oxygen Toxicity
Oxygen toxicity is caused by exposure to high-pressure oxygen during diving
and can manifest as both respiratory and central nervous system symptoms,
including cough, shortness of breath, tremor and seizure, nausea, and tunnel
vision. These effects may not occur until lower depths if the diver is using
nitrox, a blend of oxygen and nitrogen. The advantage of nitrox is that there
is less risk of nitrogen narcosis and DCS because the percentage of nitrogen
decreases as the percentage of oxygen increases.
Decompression Sickness
During descent, nitrogen under pressure is absorbed into tissues throughout
the body. The amount is increased more in adipose tissues and tissues with

48
good blood flow and less in other tissues, such as cartilage and tendons.
During ascent, the nitrogen is released again; with slow ascent, the nitrogen
travels to the lung and is exhaled. If the ascent is too rapid, the nitrogen forms
bubbles in the blood that can block circulation in blood vessels, producing
symptoms, commonly known as the bends, that result from blockage in
the small veins of joints, especially the elbow, knee, and shoulder joints.
Type I DCS is the nonneurogenic form, which causes itching, rashes, joint
pains, fatigue, and vertigo. Type II DCS is the more severe form, when the
bubbles interfere with the cerebral and spinal circulation resulting in weak-
ness, paralysis, and behavioral changes. Decompression sickness occurs
within a short time after the dive. Thalmann8 reported 42% within 1 hour,
60% within 3 hours, and 98% within 24 hours, so that later symptoms are
unlikely to be due to DCS.
Preventing Decompression Sickness
Good diving practice is the most important way to prevent DCS, although
there are differences in age, body size and shape, and degree of fitness that
may make certain individuals more susceptible. Dive tables indicate how
much time can be spent at a certain depth, and dive computers are helpful
to define these depths, particularly if multiple dives are attempted. The rate
of ascent is very important, and decompression stops should be routine,
including a stop at one-half of the maximum dive and a safety stop at 5 m
(15 ft). Divers should wait 12 to 48 hours before flying, depending on
number of dives.
Treating Decompression Sickness
The treatment for DCS includes administration of 100% oxygen and hydra-
tion. Positioning the patient in the left decubitus and mild Trendelenburg
positions prevents preferential entry of bubbles into cerebral circulation.
Hyperbaric oxygen therapy is the gold standard treatment for DCS.9 The
recompression dissolves the bubbles, which can then be gradually eliminated
by slow decompression.
Barotrauma
As every diver is aware, breath holding during ascent is extremely dangerous.
Air in the lung expands, especially in the last 10 m (30 ft), and if it is unable
to escape can produce an arterial gas embolism, pneumothorax, pneumo-
mediastinum, or subcutaneous emphysema. These complications are more
likely to occur if there is air trapping. The presence of lung bullae or cysts,
cystic fibrosis, pulmonary fibrosis, or a history of pneumothorax or pneu-
momediastinum should be considered absolute contraindications to diving.
Arterial gas embolism is the most serious complication, whereby the alveolar
sacs rupture and air enters the pulmonary capillary circulation. Bubbles travel
to the left ventricle and then into the systemic circulation. The bubbles form

49
an embolus with ischemia distal to the obstruction. Immediate recompression

is necessary to reduce the size of the bubble causing the obstruction.
Diving and Asthma
Not uncommonly, parents and patients will inquire about the safety of under-
water sports for children with asthma. Several factors occurring naturally in
the course of undertaking scuba diving may put individuals with increased
airway hyperresponsiveness at risk of acute asthma exacerbation. These
include the inspiration of cold and dry gas, increased airway resistance,
increased inspired Po2 , possible gas contamination with allergens and
irritants, saltwater aspiration, and extreme exertion.10 Airway obstruction
may be localized to the distal airways, preventing gas elimination. Uncon-
trolled expansion of the distal airway may result in pulmonary barotrauma.
Epidemiological studies do not seem to show a greater risk of barotrauma,
DCS, or arterial gas embolism in patients with asthma.11
Patients with severe asthma should not dive, and only those with well-
controlled asthma should be considered for clearance to dive. Patients with
asthma should not dive within 48 hours of having asthma symptoms or need-
ing to use a rescue bronchodilator. The Undersea and Hyperbaric Medical
Society in the United States recommends that children with exercise-induced
bronchospasm should not dive. All divers with asthma should have an annual
review of their fitness for diving. The diver with asthma should not dive
until peak flow measurement is within 10% of the best values. Patients with
normal lung function and well-controlled asthma should be able to scuba
dive successfully.12
Drowning
Drowning is a process resulting in primary respiratory impairment from
submersion or immersion in a liquid medium.13 The spectrum of drowning
ranges from brief entry of liquid into the airways resulting in minor tempo-
rary injury to prolonged presence of liquid in the lungs resulting in pulmonary
dysfunction, hypoxia, neurological and cardiac abnormalities, and death.
Fatal drowning results in death, and nonfatal drowning occurs when the
person is rescued. The highest rate of drowning occurs in 1- to 4-year-olds
left unattended in or near swimming pools. Worldwide, more than 500,000
deaths occur annually from drowning, and it is the leading cause of death
in boys 5 to 14 years old. The prognosis for cerebral recovery is dependent on
the pH upon arrival in the emergency department.
The composition of the body usually allows individuals to float in water with
about 3% of their volume above the surface. If a breath is taken, then more of
the body can be above water; conversely, on deep expiration, the body will sink
somewhat. This is one of the reasons that shouting while drowning may cause
a person to sink. In addition, restrictive lung disease will reduce buoyancy.

50
An important factor relating to drowning is the temperature of the water.

Immersion in cold water results in hypothermia, which may have the poten-
tial to prolong survival. The mammalian dive reflex results from immersion
of the face in cold water. This dive reflex leads to an immediate response
with reduced physiological functioning of various body systems, including
the respiratory, cardiac, and nervous systems, entering a state of near
suspended animation.
The sequence of events in a drowning accident is usually immersion followed
by a sharp inspiration, initially resulting in a spasm of the larynx preventing
water from entering the lungs. Hypoxia leads to unconsciousness, with sub-
sequent laryngeal relaxation allowing water to enter the lungs. The major
contribution to mortality and morbidity is the degree and duration of hypoxia
with resultant cerebral injury. The pulmonary effects are from aspiration.
The amount of aspirated fluid is usually small, and the distinction between
salt water and fresh water drowning is no longer considered important. Aspi-
rated fluid can wash out surfactant and cause alveolar instability. Decreased
surfactant levels result in decreased lung compliance, ventilation/perfusion
(V̇ /Q̇ ) mismatching, and intrapulmonary shunting, leading to hypoxemia.
Acute respiratory distress syndrome is an important complication of drown-
ing. Bronchospasm is often seen in those who experience nonfatal drowning,
and most cases rapidly improve with inhaled β-adrenergic agonists. Pneumo-
nia complicates recovery from drowning, especially when the submersion is
in stagnant or polluted water and the organisms responsible for infection may
be unusual, including Burkholderia pseudomallei, Chromobacterium viola-
ceum, and Pseudallescheria boydii, as well as the more expected Escherichia
coli, Streptococcus pneumoniae, and Haemophilus influenzae. There is no
good evidence to support the routine use of glucocorticoids, prophylactic
antibiotics, or exogenous surfactant in nonfatal drowning patients. The initial
management should focus on reversing anoxia from submersion through
the use of rescue breaths or bag-mask ventilation with 100% oxygen and
rewarming if there is hypothermia.
The cause of drowning needs to be evaluated because other injuries may
be present including traumatic injury (intentional, or perhaps unintentional,
head injury), seizures, syncope, or cardiac disease. Hypoglycemia or alcohol
intoxication may also have been involved.
Inhalation Injury
Inhalation of Products of Combustion
Inhalation injury most commonly occurs during the inhalation of smoke
containing chemicals and particulates and/or steam from fires but also may
occur with the inhalation of oils or corrosive chemicals. For pediatric patients

51
with a severe burn injury, inhalation injury significantly increases mortality

and affects approximately 20% to 30% of patients.14 A multicenter review of
pediatric burn patients with inhalation injury showed that overall mortality was
16% and that most patients died from pulmonary dysfunction and sepsis.15
Injury from inhalation is caused by both chemical and thermal exposures,
with most of the thermal injury occurring in the upper airway. The exception
to this is steam, which can carry thermal injury to the lower airways because
of its large heat capacity. Tracheobronchial damage below the vocal cords
occurs owing to chemical injury, which results from incomplete products of
combustion and release of various substances that may combine with water
vapor to form corrosive substances. These include compounds such as nitrous
oxide and sulfur dioxide forming nitric and sulfuric acids. Children are
at risk of airway compromise because of the small size of the airway, and the
threshold for intubation should be low. Stridor from upper airway edema and
increased airway hyperreactivity with reflex bronchoconstriction increase
airway resistance, significantly increasing the work of breathing.
Damage to the lung parenchyma is delayed and usually manifests at least
24 hours after the initial injury. Small airway damage may occur directly
or as a result of the effects of hypoxemia and hypotension. Edema of the
interstitium, alveoli, and alveolar vessels can occur, and acute pulmonary
edema often ensues owing to increased vascular permeability. Atelectasis
from both obstruction of small airways and loss of pulmonary surfactant,
and loss of hypoxic vasoconstriction may complicate V̇ /Q̇ mismatching,
leading to significant hypoxemia. Patients who die from acute injury have
severe necrotizing bronchitis and bronchiolitis, intra-alveolar hemorrhage,
hyaline membrane formation, and massive pulmonary edema.16
Bronchoscopic evaluation, especially in children and youth with facial burns,
can reveal the extent and level of the thermal injury and may also provide a
means to clear debris from the airway and enhance ventilation and oxygen-
ation. The pathological lesions encountered include bronchial erythema with
vascular engorgement, edema, and epithelial necrosis, with formation of
obstructing bronchial casts composed of sooty debris, exudated fibrin, and
other circulatory-derived products, including inflammatory cells. Super-
infection may eventually affect both the damaged airways and lungs.
Significant airway injury may require endotracheal intubation and mechanical
ventilation with positive end-expiratory pressure to reduce pulmonary edema
from vascular leak. Awake and cooperative patients with lesser pulmonary
involvement and few facial burns may benefit from noninvasive ventilation
with continuous positive airway pressure devices. Attention to fluid manage-
ment and antibiotics as needed for superinfection is important. The long-term

52
prognosis after thermal, chemical, and smoke inhalation injury is guarded.

Inhalation injury limits exercise endurance and leads to reduced lung
function for 3 to 8 years after injury.17,18
Carbon Monoxide Toxicity

Carbon monoxide (CO) and cyanide toxicity are early and immediate causes
of morbidity and mortality due to hypoxia. Carbon monoxide is the most
common gas resulting from incomplete combustion of carbon-containing
materials such as wood. It is responsible for 50% of fire-related fatalities
and should be an immediate concern for caregivers of people who have been
burned. Carbon monoxide combines with great affinity to hemoglobin (with
approximately 250 times the affinity of oxygen), forming carboxyhemoglobin
(COHb). COHb shifts the oxyhemoglobin dissociation curve to the left, im-
pairing release of oxygen at the tissues and use of oxygen in mitochondria,
leading to tissue hypoxia. It is important to understand that the oxygen
content of the blood is reduced, but the Po2 on a blood gas measurement will
not reflect this. In addition, pulse oximetry will be inaccurate, as it measures
both saturated normal hemoglobin and COHb; co-oximetry is needed to dis-
tinguish between them. The CO level measured in blood can indicate the
severity of exposure, with expected associated symptoms as outlined in
Table 3-3. Treatment consists of administration of 100% oxygen, which
reduces the half-life of COHb from 120 to 200 minutes to 30 minutes. Patients
should continue 100% oxygen until COHb levels return to normal. Hyper-
baric oxygen has been used to treat CO poisoning in children; however,
evidence for its use in children is inconclusive.19
Table 3-3. Signs and Symptoms Associated With Carbon Monoxide Intoxication
Carboxyhemoglobin Level (%) Signs and Symptoms
Mild (< 20%) Headache, slight dyspnea, decreased visual acuity,
decreased coordination, slowed thinking
Moderate (20%–40%) Irritability, nausea, decreased vision, impaired judgment,
rapid fatigue
Severe (> 40%) Confusion, hallucination, ataxia, coma
Critical (> 60%) Death
Hydrogen Cyanide Toxicity

If synthetic materials are also burned in the fire, hydrogen cyanide is released
and may be a significant component of the inhaled smoke. Cyanide also pro-
duces hypoxia at the cellular level; however, the mechanism is different from
that of CO. Cyanide disrupts mitochondrial generation of ATP through bind-
ing of ferric ions in cytochrome c oxidase. Cyanide poisoning is difficult to
confirm because the symptoms are nonspecific and cyanide levels usually

53
cannot be measured quickly enough to be clinically meaningful. For treat-

ment, hydroxocobalamin has shown some efficacy in lowering cyanide
levels; however, current evidence remains limited.20
Effect of Pregnancy on Pulmonary Function

Normal pregnancy is associated with a 20% increase in oxygen consump-
tion and a 15% increase in metabolic rate. When the uterus expands, the
diaphragm is displaced as much as 4 cm (1.6 in) higher in the thoracic cavity.
The function of the diaphragm remains normal. The thoracic cavity expands
at its lower level by increasing circumference. The major physiological effect
on pulmonary function is reduction in the functional residual capacity by
about 20% during the latter one-half of pregnancy. This results from reduc-
tion in both expiratory reserve volume and residual volume. The changes in
vital capacity tend to be small, and the forced expired volume in 1 second is
essentially unchanged.
The minute volume increases by nearly 50% at term as a result of increased
tidal volume with respiratory rates that do not increase. This effect is thought
to be related to increased levels of progesterone. The change in minute volume
is associated with a corresponding decrease in arterial Pco2 , which tends to be
about 30 mm Hg at term, and an increase in Pao2 because of reduced alveolar
CO2 levels.
key points
} The definitive treatment of AMS, HACE, and HAPE is descent to lower altitude.
} Individuals may be particularly susceptible to AMS, HACE, and HAPE and can
experience recurrence on ascent to altitude.
} Shallow water blackout can occur with hyperventilation before swimming and
diving; children and adolescents should be warned against this practice.
} Qualified diving instruction and good diving practice help prevent DCS.
} Scuba diving is contraindicated in patients with a history of pulmonary blebs or
bullae, moderate to severe persistent asthma, and acute asthma symptoms
with abnormal pulmonary function.
} Children are at high risk of upper airway obstruction from thermal inhalation
injury.
} Pulse oximetry is inaccurate in measuring CO toxicity; oxygen should be
administered for suspected cases of CO toxicity to reduce COHb.
} Compensatory increase in minute volume prevents hypoxemia in pregnancy
because of reduction in functional residual capacity.

54
References
1. Bouchard C, Dionne FT, Simoneau JA, Boulay MR. Genetics of aerobic and anaerobic
performances. Exerc Sport Sci Rev. 1992;20:27–58 PMID: 1623888
2. Homnick DN. Chest and pulmonary conditions. In: Patel DR, Greydanus DE, Baker RJ, eds.
Pediatric Practice Sports Medicine. McGraw-Hill Medical; 2009:119–131
3. Sjödin B, Svedenhag J. Oxygen uptake during running as related to body mass in
circumpubertal boys: a longitudinal study. Eur J Appl Physiol Occup Physiol.
1992;65(2):150–157 PMID: 1396639 doi: 10.1007/BF00705073
4. Roach RC, Hackett PH, Oelz O, et al; Lake Louise AMS Score Consensus Committee.
The 2018 Lake Louise Acute Mountain Sickness Score. High Alt Med Biol. 2018;19(1):4–6
PMID: 29583031 doi: 10.1089/ham.2017.0164
5. Luo Y, Zou Y, Gao Y. Gene polymorphisms and high-altitude pulmonary edema susceptibility:
a 2011 update. Respiration. 2012;84(2):155–162 PMID: 22508396 doi: 10.1159/000336625
6. Hackett PH, Oelz O. The Lake Louise Consensus on the definition and quantification of
altitude illness. In: Sutton JR, Houston CS, Coates G, eds. Hypoxia and Mountain Medicine.
Queen City Press; 1992:327–330
7. West JB. High-altitude medicine. Am J Respir Crit Care Med. 2012;186(12):1229–1237 PMID:
23103737 doi: 10.1164/rccm.201207-1323CI
8. Thalmann ED. Phase II Testing of Decompression Algorithms for Use in the US Navy
Underwater Decompression Computer. Navy Experimental Diving Unit; 1984:1–84
doi: 10.21236/ADA142470
9. Pollock NW, Buteau D. Updates in decompression illness. Emerg Med Clin North Am.
2017;35(2):301–319 PMID: 28411929 doi: 10.1016/j.emc.2016.12.002
10. Cirillo I, Vizzaccaro A, Crimi E. Airway reactivity and diving in healthy and
atopic subjects. Med Sci Sports Exerc. 2003;35(9):1493–1498 PMID: 12972867
doi: 10.1249/01.MSS.0000084424.67486.5B
11. Muller A, Rochoy M. [Diving and asthma: literature review]. Rev Pneumol Clin.
2018;74(6):416–426 PMID: 30442511 doi: 10.1016/j.pneumo.2018.10.002
12. Coop CA, Adams KE, Webb CN. SCUBA diving and asthma: clinical recommendations
and safety. Clin Rev Allergy Immunol. 2016;50(1):18–22 PMID: 25666876
doi: 10.1007/s12016-015-8474-y
13. Idris AH, Bierens JJLM, Perkins GD, et al. 2015 Revised Utstein-style recommended guidelines
for uniform reporting of data from drowning-related resuscitation: an ILCOR advisory
statement. Circ Cardiovasc Quai Outcomes. 2017;10(7):e000024 PMID: 28716971
doi: 10.1161/HCQ.0000000000000024
14. Jeschke MG, Herndon DN. Burns in children: standard and new treatments. Lancet.
2014;383(9923):1168–1178 PMID: 24034453 doi: 10.1016/S0140-6736(13)61093-4
15. Palmieri TL, Warner P, Mlcak RP, et al. Inhalation injury in children: a 10 year experience
at Shriners Hospitals for Children. J Burn Care Res. 2009;30(1):206–208 PMID: 19060756
doi: 10.1097/BCR.0b013e3181923ea4
16. Lee AS, Bye MR, Mellins RB. Lung injury from hydrocarbon aspiration and smoke
inhalation. In: Chernick V, Boat TF, Wilmott RW, Bush A, eds. Kendig’s Disorders
of the Respiratory Tract in Children. WB Saunders; 2006:653–660
doi: 10.1016/B978-0-7216-3695-5.50049-3
17. Lee AS, Mellins RB. Lung injury from smoke inhalation. Paediatr Respir Rev.
2006;7(2):123–128 PMID: 16765298 doi: 10.1016/j.prrv.2006.03.003
18. Mlcak R, Desai MH, Robinson E, Nichols R, Herndon DN. Lung function following thermal
injury in children—an 8-year follow up. Burns. 1998;24(3):213–216 PMID: 9677023
doi: 10.1016/S0305-4179(98)00012-6
19. Buckley NA, Juurlink DN, Isbister G, Bennett MH, Lavonas EJ. Hyperbaric oxygen for
carbon monoxide poisoning. Cochrane Database Syst Rev. 2011;2011(4):CD002041
PMID: 21491385
20. Shepherd G, Velez LI. Role of hydroxocobalamin in acute cyanide poisoning.
Ann Pharmacother. 2008;42(5):661–669 PMID: 18397973 doi: 10.1345/aph.1K559

CHAPTER
4
Taking the Pulmonary History
Pulmonary History
In the evaluation of children with respiratory concerns, it is crucial to obtain
a complete and thorough history. This history should be considered a supple-
ment to the general pediatric history, a guide to which can be found in several
comprehensive texts.1,2 The pulmonary history is an information-gathering
process; sensitivity is key to the formation of a good therapeutic relationship.
Parents and other care providers are often under great stress, especially when
dealing with a chronic illness. Multiple people may care for the patient, and,
with appropriate parental or guardian consent, attention should be given to get-
ting information from grandparents, teachers, and others in the child’s life to
obtain a clear picture of the symptom complex. Sensitivity and humility must
also be shown to cultural aspects of the child and family. This may include the
nuances of language that trained translators can provide. Finally, ingrained
beliefs about conditions are often present and may influence how a parent or
care provider is able to understand and trust the information given. For
instance, parents may not believe that their active child has asthma because of a
long-held idea that asthma causes children to be sickly and inactive. Assurance
that persons with asthma may be Olympic-class athletes helps dispel this idea.
History of Present Illness

As in the general pediatric history of present illness, determining onset
(gradual or acute), duration (chronic ≥ 3 weeks), recurrence (periods of well-
ness alternating with periods of illness) or persistence, and triggers (eg, viral
upper respiratory infection, activity) is essential, all obtained in chronological
fashion. Because the lungs are in constant contact with the external environ-
ment, the environmental history is particularly important. Indoor exposures
(environmental tobacco smoke [ETS], woodstoves, pets, stuffed animals in the
bedroom, etc) and outdoor exposures (animals, cold air, industrial pollutants,
etc) must be carefully sought. Exposure to ETS will adversely affect children’s
lung health. Parents and other caregivers should be questioned about tobacco
use, with a strong recommendation to quit, with use of a brief intervention,
or, at minimum, removing all secondhand smoke from a child’s environment
55

56
(eg, not smoking in the house or car, sitting in nonsmoking areas of restau-
rants, avoiding family gatherings where smoke cannot be avoided, or asking
family members to smoke away from the child). Teen smoking is a growing
problem, and all teens and preteens, starting in the middle school years, should
be questioned about primary smoking. Also, information about the use of
electronic nicotine delivery systems (vape devices such as JUUL, SMOK
Infinix, or Suorin Air) must be carefully sought. (See Chapter 61, Nicotine and
Tobacco.) Additional environmental inquiry should include the age of the
home; type of construction; and sources of heating, cooling, and ventilation.
Family History
Family history of respiratory illness is very important because many diseases
manifesting in childhood have a genetic basis. Various conditions result in
pulmonary abnormalities. The Mendelian defects are single gene defects that
may be autosomal dominant, autosomal recessive, X-linked dominant, and
X-linked recessive. In addition, there are chromosome and multifactorial
disorders that may result in pulmonary abnormalities. Some examples are
shown in Box 4-1. If there appears to be a genetic basis for disease, an
extended family tree may be useful.
Box 4-1
Genetic or Chromosomal Defects That Result in Pulmonary Disorders
Dominant X-linked Other (multifactorial)
Marfan syndrome Dominant Cleft lip and palate
Neurofibromatosis 1 ū Rett syndrome Asthma
Achondroplasia Recessive Allergic rhinitis
Familial pulmonary ū Duchenne muscular Gastroesophageal reflux
fibrosis dystrophy Autoimmune disorders
Recessive ū Hemophilia Diabetes mellitus type 1
Cystic fibrosis Chromosomal Heart disease
Primary ciliary Down syndrome Interstitial lung disease
dyskinesia Other trisomy
Sickle cell disease
Mucopolysaccharidoses
Spinal muscular atrophy
Medical History
The neonatal history may indicate a reason for persistent or recurrent respira-
tory disease, especially in infancy, although even teens may have chronic
airway obstruction as a result of neonatal disease such as infant respiratory
distress syndrome or bronchopulmonary dysplasia. Precise details of the
antenatal history and clinical course after delivery are key to providing

57
Chapter 4—Taking the Pulmonary History
rational and appropriate care. Attention should be paid to birth weight and
gestational age, both of which are known antecedents to neonatal lung disease.
The pregnancy history should include maternal use of tobacco and other sub-
stances. Other important points include maternal complications during preg-
nancy, such as pregnancy-induced hypertension or diabetes mellitus. Problems
at the time of delivery are relevant because they may immediately place the
neonate at risk for lung disease and injury. For instance, a prolonged labor
increases the risk for fetal distress and the antenatal passage of meconium.
With sufficient stress, meconium aspiration syndrome may occur, which can
be associated with significant lung injury and pulmonary hypertension. In
addition, details of treatment in the intensive care nursery aid in understanding
how severely the child’s lungs may have been affected by both antenatal factors
and postnatal treatment. Certainly the neonate born with transient tachypnea
of the newborn and a 12-hour intubation is very different from the 500-g
neonate born at 26 weeks’ gestation who underwent intubation and mechanical
ventilation for weeks. Finally, the total length of oxygen therapy can provide
information regarding the degree of lung injury.
Surgical History
Surgical procedures relevant to the respiratory tract, including cardiac, gastro-
intestinal, otolaryngological, orthopedic, and urological and renal procedures,
may be a clue to persistent respiratory problems. For example, repair of a
tracheoesophageal fistula may leave significant residual airway problems in
the form of localized tracheomalacia. Tympanostomy (ear tubes) or tonsillec-
tomy and adenoidectomy may not be declared without prompting the parent
or caretaker.
A history of contact with the medical system and the use of medical resources
can give valuable information about the severity, chronicity, and control of a
respiratory condition. For example, hospitalizations and emergency department
visits provide important information about the patient’s history.
Quality health care includes efficient use of resources and limiting unnecessary
repeat studies. Many times, a few precisely directed calls will yield valuable
information regarding previous studies and investigations that can be summa-
rized quickly. This information will often obviate the need for repeating some
studies, allowing further diagnostic testing to be streamlined, lowering cost,
and lessening the burden of health care visits on the family. In some cases,
however, repeat studies are necessary. For example, if a sweat chloride test for
cystic fibrosis (CF) is not performed according to Cystic Fibrosis Foundation
standards by experienced personnel (most often found in a CF care center), the
results may be suspect, and the test should be repeated. Similarly, relying solely
on the result of a newborn screening test for CF may miss the diagnosis of a
case caused by less common mutations.

58
The past response to various therapeutic trials is also helpful information for
pediatricians and other physicians. For example, if a child has chronic cough
that fails to respond to oral antibiotics but that responds well after a several
day course of corticosteroid, then a diagnosis of asthma is supported. Alter-
natively, if the cough responds well to oral antibiotics, then conditions such
as chronic sinusitis, CF, bronchiectasis, or possible aspirated foreign body are
more likely. Medication delivery information is also critical because inade-
quate delivery may lead to a lack of response to therapy. For example, it is
appropriate to inquire whether nebulized medications were administered
with a blow-by method rather than with a properly fitted mask. Furthermore,
was there an attempt to give a metered-dose inhaler to a small child who
lacks the skill or proper equipment to use it?
Social History
Additional social history will supplement the environmental history. For exam-
ple, an appropriate social history should determine whether a child spends time
in different households. Exposure to ETS in one home may make asthma con-
trol difficult, and education of all caregivers is essential. Other questions to
ask include the following:
X Who is caring for the child or youth?
X Is there an adult in the home who can supervise administration of
medication and provide for early medical intervention when symptoms
are exacerbated?
X Is the child receiving treatments as prescribed, or are there any challenges
to adhering to recommended treatment?
X Does the family have any barriers to follow-up appointments?
X Are there financial barriers that prevent adherence to a therapeutic regimen
or that may promote emergency department use rather than primary or
subspecialty follow-up care?
X Is there a history of any medical or mental illness of the caregiver that could
interfere with adherence to therapeutic recommendations?
X Are there educational or language barriers that prevent the family from
reading and understanding educational and instructional information
regarding illness treatment and prevention?
A medical social worker can help sort through possible barriers to quality
care and help families obtain the resources necessary to treat respiratory
conditions with minimal stress.
As in the general pediatric history, immunization and specific medication
allergy history are important to record. The child with chronic respiratory
disease is at particular risk from influenza, so yearly influenza vaccination
should be administered as recommended by the Centers for Disease Control
and Prevention and the American Academy of Pediatrics. Occasionally, travel

59
may expose a patient to an infectious agent that is not common in a local area.
Certain fungal pathogens have a particular propensity for a geographic region,
so it is helpful to know about a patient’s travel history. Foreign travel can
increase risk for Mycobacterium tuberculosis exposure with varying degrees
of susceptibility to antimicrobials.
Copies of previous medical records, including imaging studies, will help
avoid unnecessary tests, confirm response or lack thereof to medication or
other therapeutic trials, and confirm the severity and frequency of symptoms
and chronicity of a condition. A list of elements of the pediatric pulmonary
history is found in Box 4-2.
Box 4-2
Elements of the Pediatric Pulmonary History
Present Illness Allergen exposure
Onset ū Age and condition of the house and
Duration the child’s bedroom
Recurrence ū Stuffed toys
Persistence ū Pets
Triggers ū Heat source, humidifiers, air filters
Medical History ū Other environments including a
second household and child care
Birth history
ū Attempts at allergy reduction
Immunizations
Travel
Medication and environmental allergy
Social History
Hospitalizations and ED visits
Family dynamics
Response to therapeutic interventions
ū Who are the caregivers?
Imaging and laboratory test results
ū Is the child supervised in taking
Family History medications?
Allergy or allergic rhinitis, bronchitis, ū Educational and reading level
asthma, cystic fibrosis, sinus diseases,
pneumonia, tuberculosis, inflamma- ū Barriers to treatment such as lan-
tory bowel disease, childhood cancer, guage, transportation, caregiver
HIV or immune problems, eczema, illness, or health literacy
congenital heart disease, juvenile- Financial Support
onset diabetes mellitus, early-onset Are medications affordable to the
emphysema, liver disease patient and family?
Environmental History Are follow-up visits avoided because of
Smoke and other toxic exposures finances or other logistic problems
ū Primary and secondhand environ- (eg, co-pays or lack of transportation)?
mental tobacco smoke exposure ED use because of financial hardship
ū Woodstoves
ū Industrial and household aerosols
ū Dust, mold, construction dust,
and debris
ū Other toxins
Abbreviation: ED, emergency department.

60
Review of Systems
A complete review of systems is always necessary for the thorough evalua-
tion of a new patient. The review of systems relevant to the respiratory tract
is listed in Box 4-3. Important information not otherwise gleaned in the
history of present illness may become evident here and may shed light on
the current illness.
Box 4-3
Review of Systems Relevant to the Respiratory Tract
Constitutional
Fever, weight loss or gain, night sweats, fatigue, pain
Skin
Eczema, other rashes, urticaria
Head, Eyes, Ears, Nose, Throat
Sinusitis, otitis media, congestion
Respiratory
Cough, wheeze, stridor, shortness of breath, chest discomfort or pain, hemoptysis,
sputum production, chest tightness, symptoms with exercise, pneumonia
diagnosis
Cardiovascular
Congenital heart disease, hypertension, syncope, previous surgery
Gastrointestinal
Stool volume and consistency, constipation, diarrhea, regurgitation or
gastroesophageal reflux disease, choking or gagging with feedings, food
intolerance, hematochezia
Genital and Urinary
Urinary anomalies, poly- or oligohydramnios, renal disease, recurrent infection
Neurological
Known neuromuscular disease, known developmental disabilities, choking or
gagging, stridor
Musculoskeletal
Scoliosis, chest wall deformity, previous chest wall surgery, muscle weakness,
joint pain or swelling, chest wall pain or discomfort
Allergy and Immunology
Wheezing or known asthma, chronic cough, chronic congestion, itching and
sneezing, recurrent infection, HIV infection or other viral exposures, skin or
serum test results
Blood Disorders
Sickle cell disease, coagulopathies, bleeding, cancer, other blood dyscrasias,
transfusion history
Endocrine
Diabetes, thyroid, parathyroid disease, growth parameters

61
Common Symptoms Related to the Pulmonary System

Pediatricians commonly encounter symptoms that include cough, wheezing
and stridor, chest pain, dyspnea (shortness of breath), and cyanosis. Although
considerable overlap may occur, the causes of these symptoms may vary by
the child’s age. Details about the various causes presented here can be found in
the specific diseases discussed in other chapters of this book and in other
pediatric pulmonary texts.3
Cough
Coughing arises from an irritation of the airways where receptors are concen-
trated at airway bifurcations. It occurs in a phased sequence involving a deep
inspiration, closure of the glottis and relaxation of the diaphragm along with
contraction of muscles of expiration, and sudden opening of the glottis with
forceful expired airflow. Cough can be classified as acute or, if symptoms
continue beyond 3 weeks, chronic.
Cough during infancy most commonly accompanies infection, usually viral,
and is productive of thin, white mucus resolving over about 10 days. Croup syn-
drome produces a brassy, seal-like cough as part of an upper airway infection.
Exposure to irritants such as ETS and woodstoves may produce acute cough
in infants. Chronic cough in infants requires a more extensive and comprehen-
sive evaluation. Causes include CF, infections (Bordetella pertussis, Chlamydia,
Mycoplasma), aspiration due to developmental disabilities or traumatic birth
injury (suck-swallow discoordination, recurrent laryngeal nerve injury, com-
plications of neonatal intubation), gastroesophageal reflux disease (GERD),
the sequelae of neonatal lung injury (bronchopulmonary dysplasia), and con-
genital lung malformations (bronchogenic cyst, congenital pulmonary airway
malformation, congenital hyperlucent lung, and pulmonary sequestration).
Cough in childhood, like in infancy, is most often caused by infectious agents.
Cystic fibrosis may manifest with cough at this age, although newborn screen-
ing usually allows for this diagnosis to be determined earlier. Foreign body
aspiration becomes a more common cause of acute cough in early childhood.
Chronic causes of cough include infections (tuberculosis if exposed to infected
individuals), primary ciliary dyskinesia, chronic sinusitis, aspiration (especially
with developmental disabilities), GERD, ETS and other toxic exposures, con-
genital lung and airway malformations, and the use of angiotensin-converting
enzyme inhibitor drugs. Functional or habit cough (psychogenic cough) may
begin in late childhood but is more common in adolescents. Asthma may
manifest only as cough (cough variant asthma) at almost any age and can be
proved with a bronchial challenge, such as methacholine, or by response to
a trial of asthma treatment. Acute cough in adolescents is also most often
caused by infectious agents but may result from acute toxic exposures, such
as primary smoking and exposure to ETS or other aerosols. Postnasal drip

62
and chronic sinusitis are a cause of throat clearing and nighttime–early

morning cough. In adolescents with cough, a history of exposure to irritating
inhalants should be sought if substance use is suspected; certainly the recent
surge of cases of e-cigarette, or vaping, product use-associated lung injury
has raised awareness of these dangerous products. Occasionally, a congenital
malformation, such as a bronchogenic cyst, will not become evident until
the teen years when recurrent or chronic infection occurs.
Wheezing and Stridor

Stridor and wheezing due to respiratory infections (bronchiolitis and croup)
are very common during infancy, although CF may also manifest with
chronic wheezing. Infants with disabilities may aspirate silently, so a strong
index of suspicion should be maintained when recurrent pulmonary symp-
toms occur in this group of infants. Gastroesophageal reflux disease with
retrograde aspiration can occur and may be found with congenital causes of
stridor, such as laryngomalacia. When tracheomalacia or bronchomalacia is
present, chronic coarse expiratory wheeze also occurs. Rarely, airway lesions,
such as laryngeal hemangiomas, laryngeal webs, subglottic stenosis, and
laryngo-esophageal clefts, cause stridor in infancy. Intermittent stridor beyond
early childhood most often occurs in children with atopic dermatitis and is
termed spasmodic croup. Allergy is a rare cause of wheezing in infancy but
is a more common cause in childhood. Other causes of wheezing in children
include aspirated foreign body, CF, inhalation injury, bronchiectasis from
any cause, aspiration syndromes, and mediastinal and airway malformations
or neoplasms. Stridor with or without expiratory wheezing is a common
finding in vocal cord dysfunction (see Chapter 44, Functional Respiratory
Disorders), which is transient, not life-threatening, often associated with
exercise, and most common in adolescents. Adolescents can also experience
the other causes mentioned for children, although asthma and wheezing as a
result of intentional or nonintentional inhalation of irritating aerosols or
smoke are more common in adolescents.
Chest Pain
Chest pain can originate in chest wall structures or within the lung as a result
of inflammation of the lung-covering membranes (pleura). Infants clearly
cannot express specific pain, but tenderness on palpation along with skin
changes that might be related to trauma can be elicited and noted during a
careful examination. Chest wall pain is commonly associated with prolonged
and vigorous coughing and is commonly found in children with CF who are
experiencing a pulmonary exacerbation. Other causes of chest pain in children
include pleurisy, most often associated with coxsackievirus B (pleurodynia)
and bacterial pneumonias. Occasionally, both GERD and asthma will be
causes of chest pain or discomfort in children and adolescents; certainly the

63
acute chest pain associated with sickle cell crisis is well known in pediatrics
and must be treated aggressively. Adolescents in athletic activities such as
weight lifting can present with acute or chronic chest wall pain localized
over the costochondral junctions (costochondritis). Rib fractures caused by
chest wall trauma or vigorous activities such as competitive rowing can occur
in teens. Although spontaneous pneumothorax as a cause of chest pain can
occur at other ages, it is most common in adolescents and should be suspected
when an otherwise healthy teen complains of sudden onset of sharp, unilateral
chest pain with shortness of breath (dyspnea). Herpes zoster as a cause of
chest wall pain is readily identifiable by its characteristic rash found along
a chest wall dermatome. Rarely, previously undiagnosed coronary artery
anomalies and mitral valve prolapse, as well as myocarditis, can manifest in
this age group as well as in younger children.
Dyspnea
Increased depth of respiration, often with increased respiratory rate (tachypnea),
can occur at any age and is produced by both pulmonary and nonpulmonary
causes. Any cause of airway obstruction in infancy can lead to dyspnea,
although sudden onset is more likely caused by infection or cardiac disease.
Acidosis is a cause of nonpulmonary dyspnea and may occur with inborn
errors of metabolism or with dehydration. Rarely in infants but more com-
monly in children and adolescents, dyspnea is associated with ketoacidosis as
an initial manifestation of diabetes mellitus or with inadequate diabetic control
leading to severe hyperglycemia. In childhood as well as adolescence, acute
asthma becomes a common cause of dyspnea, and acute toxic ingestion (eg,
salicylates) can also manifest as dyspnea. Cyanosis and hemoptysis, along
with dyspnea, often occur with pulmonary embolism due to traumatic lower
extremity injury, heart disease, or other coagulopathy. Anxiety (hyperventila-
tion with panic attacks—see Chapter 44, Functional Respiratory Disorders)
and substance ingestion (eg, suicide attempt with salicylates) are more common
in adolescents.
Cyanosis
Central cyanosis (blue mucous membranes) should be distinguished from
peripheral cyanosis (blue extremities) because the former is associated with
important cardiopulmonary disease. Any pulmonary disease that causes sig-
nificant mismatching of lung ventilation and perfusion or reduced functional
residual capacity (expiratory reserve volume plus residual volume) will lead
to oxygen desaturation and, eventually, visible central cyanosis. In newborns,
this occurs during infant respiratory distress syndrome (hyaline membrane
disease), which reduces functional residual capacity, and any significant lung
inflammation, such as neonatal pneumonia or meconium aspiration. Space-
occupying lesions, such as lung malformations (congenital hyperlucent lung,

64
congenital pulmonary airway malformation, pulmonary sequestration,

bronchogenic cyst, gastroenteric cyst, etc), may compress acutely on the
ipsilateral healthy portion of the lung or the contralateral lung, leading to
decreased ventilation and perfusion. If present prenatally, lung malforma-
tions and oligohydramnios can lead to lung hypoplasia, which may cause
cyanosis. Any right-to-left shunt caused by vascular malformation or intrin-
sic cardiac disease may lead to cyanosis. In older children and adolescents,
cyanosis is most commonly associated with acute pulmonary disease (eg,
acute asthma or pneumonia). Cyanosis is a late manifestation of chronic,
destructive pulmonary disease such as is found in CF. Because of increased
survival of children with CF, cyanosis is unusual in infancy or childhood.
Cyanosis is also a late finding of degenerative neurological disease such as
Duchenne muscular dystrophy. Acute inhalation of smoke or other toxic sub-
stances, such as hydrocarbons, can lead to cyanosis stemming from severe
acute lung inflammation. A space-occupying thoracic neoplasm may produce
enough pressure on surrounding lung or airways to compromise ventilation
and perfusion significantly, producing cyanosis.
key points
} Careful questioning and listening, with cultural sensitivity and humility, lead to
an accurate picture of the patient’s condition and how it affects individual and
family ability to adapt to the respiratory illness.
} Genetics and environment play a large role in childhood respiratory disease.
} Information about onset, duration, recurrence, persistence, and triggers helps
lead the diagnostician first to determine acuteness and chronicity and, second,
to determine a likely cause of a pediatric respiratory condition.
} Toxic exposures, particularly ETS or primary smoking, are important causes of
acute and chronic respiratory conditions as children age.
} Asthma is a common cause of chronic cough as well as wheeze.
} Response to previous therapeutic interventions, including medications, can be
a valuable clue to the cause of an underlying pulmonary condition.
References
1. Homnick D. The respiratory system. In: Greydanus DE, Feinberg AN, Patel DR, Homnick DN,
eds. The Pediatric Diagnostic Examination. McGraw-Hill; 2007:189–226
2. Zitelli BJ, McIntire SC, Nowalk AJ. Zitelli and Davis’ Atlas of Pediatric Physical Diagnosis.
7th ed. Elsevier; 2017
3. Wilmott R, Deterding R, Li A, et al, eds. Kendig’s Disorders of the Respiratory Tract in
Children. 9th ed. Elsevier; 2019

CHAPTER
5
The Pulmonary Physical Examination
Introduction
Every clinical encounter must begin with a thorough history. As outlined in
Chapter 4, Taking the Pulmonary History, details of the present condition,
its time course and past management, other medical and surgical conditions,
and family history should be completely reviewed. Social, environmental,
and immunization histories and a complete review of systems are necessary
to completely evaluate a child with a pulmonary concern.
The pediatric physical examination should vary according to the age and
developmental stage of the child. In young children, the passive examination,
where possible, is always more productive; for example, a child should be
lying down to bring out wheezing by lowering lung volumes and thus reduc-
ing airway caliber. Examinations such as the heart and lungs that are more
difficult in a crying child should be done first, and the less tolerated examina-
tions, such as ears and throat, should be saved for last. Young children often
are most comfortable when seated in the lap of a parent or caretaker. The
time- honored principles of inspection, palpation, auscultation, and percussion
apply well to the pulmonary examination of children and youth at any age.1–3
Upper Airway
The head, ears, nose, and throat examination is an important part of the
respiratory tract examination. Chronic otitis media may be a first sign of
immune deficiency and is often present in children with primary ciliary
dyskinesia. Nasal examination is also very important in children presenting
with respiratory diseases. Children with allergic conditions, such as allergic
rhinitis, often have mucosal pallor or edema along with the presence of clear
secretions. Aggressive treatment of upper airway allergies may improve
lower airway signs and symptoms.4 Sinusitis may also be a common problem
in children presenting with chronic cough. Because the paranasal sinuses
are lined by pseudostratified columnar epithelium (the same cells lining the
airway), it stands to reason that conditions affecting the airway may also
affect the sinuses.5 For example, chronic sinusitis is nearly universal in
65

66
children with cystic fibrosis (CF) and primary ciliary dyskinesia. Patients with
allergic rhinitis may also have mucosal edema, preventing the sinus ostia from
draining readily. Nasal polyps may also complicate both allergic rhinitis and
CF. Polyps, which have a characteristic clear to white bulbous appearance,
may be quite large but cause the child relatively few symptoms, probably
because of the gradual nasal obstruction that occurs with polyp growth.
The diagnosis of sinusitis can be rather difficult to establish solely on clinical
grounds. Nasal secretions are usually thick and purulent. However, if post-
nasal drip is present, secretions may not be issuing from the nares. Therefore,
the oropharynx should be examined carefully for mucoid material draining
from above. A cobblestoned oropharynx may be noted with postnasal drip.
Sinus tenderness with palpation of the maxillary and frontal sinuses may be
helpful in diagnosing a sinus infection in older children. Reports of sinus
pressure, especially when the patient bends over, are also common with
sinus infections.
Examination of the mouth and oral cavity is important in respiratory medicine
because of congenital anomalies and other conditions that affect sleep. Many
dysmorphologies affect orofacial structures. Common examples include the
Pierre Robin sequence, Stickler syndrome, Treacher Collins syndrome, and
Crouzon syndrome. Infants with these conditions may present with cleft
palate, making early nutritional and feeding intervention of prime importance.
Conditions associated with relative or absolute macroglossia, such as Down
syndrome, congenital hypothyroidism, and glycogen storage diseases, may
place the child at risk of obstruction of the upper airway during sleep. Careful
questioning of the caretakers and a low threshold for referral for sleep evalua-
tion and polysomnography are needed in caring for these children. Tonsillar
size is also very important to assess in all children, especially during the
preschool years. Frequent infections of the upper respiratory tract during
these years cause the lymphoid tissues in the head and neck to proliferate.
This hyperplasia, along with the normal small size of the upper airway, puts
children at risk for sleep-disordered breathing, including obstructive sleep
apnea. In addition, the increasing prevalence of obesity among children
further contributes to increased risk for obstructive sleep apnea.6 Therefore,
careful inspection of tonsillar size and degree of oropharyngeal filling must
be noted in all children, especially for those with sleep-related concerns.
Characterization of the voice is another important part of the pulmonary
examination. Lesions in the area of the larynx may impede normal vocal fold
function and cause hoarse voice along with inspiratory stridor. For example,
respiratory papillomas caused by infection with human papillomavirus may
cause a hoarse voice. Also, injury to the nerves innervating the larynx may

67
Chapter 5—The Pulmonary Physical Examination
cause vocal disturbance and stridor. Repair of congenital heart defects,

especially ligation of the ductus arteriosus, may be associated with at least
temporary vocal cord paresis. Of much greater consequence are abnormalities
of the central nervous system (CNS) that may compress the brainstem and
cranial nerves. Arnold-Chiari malformations are well known to be associated
with bilateral vocal cord paralysis. Signs include a soft, breathy voice and
stridor. Demonstration of cough by the child should be elicited when there is
concern about laryngeal innervation. Stridor has different causes at different
ages and depends on whether it is intermittent or continuous. Inspiratory
stridor usually indicates lesions of the glottis or above, and expiratory coarse
wheeze or stridor indicates lesions below the level of the glottis. Biphasic
stridor may occur with severe glottic lesions. Causes of stridor in different
age groups are listed in Table 5-1.
Table 5-1. Causes of Stridor in Children and Adolescents
Patient Intermittent Persistent
Infant Aspiration Laryngeal anomaly
Viral croup Mediastinal mass
Electrolyte abnormality Vascular ring
Lung or gastrointestinal cyst
Intubation trauma
Neck or surgical trauma to RLN
Child Viral croup Vascular ring
Spasmodic croup Laryngeal anomaly
Aspiration Mediastinal mass
Vocal cord dysfunction (rare) Inhalation injury
Foreign body aspiration
Adolescent Vocal cord dysfunction Mediastinal mass
Spasmodic croup Inhalation injury
Foreign body aspiration
Glottic trauma
Abbreviation: RLN, recurrent laryngeal nerve.

68
Extremities
Examination of the extremities for clubbing and the Schamroth sign is also
important (Figure 5-1). These signs may be found in patients with chronic
lung, heart, and liver disease and are also a clue to the chronicity of a
respiratory condition in children. Potential causes of digital clubbing
are listed in Box 5-1.
Box 5-1
Causes of Clubbing
Pulmonary
Cystic fibrosis
Bronchiectasis
Pulmonary abscess
Empyema
Neoplasms
Interstitial lung disease
Alveolar proteinosis
Chronic pneumonia
Cardiac
Cyanotic congenital
heart disease
Bacterial endocarditis
Gastrointestinal and
Hepatic
Figure 5-1. Clubbing measuring methods. DIP, distal Inflammatory bowel
interphalangeal joint; DPD, distal phalangeal depth; IPD, disease (ulcerative
interphalangeal depth; NB, nail bed. colitis and Crohn
From van Manen MJG, Vermeer LC, Moor CC, Vrijenhoeff R, Grutters disease)
JC, Veltkamp M, Wijsenbeek MS. Clubbing in patients with fibrotic Polyposis
interstitial lung diseases. Respir Med. 2017;132:226–231, with
permission from Elsevier. Biliary cirrhosis
Biliary atresia
Thyrotoxicosis
Familial

69
Eupnea and Dyspnea

The chest and lung examination is of primary importance for patients with
respiratory concerns. Inspection of the chest should begin as soon as the
examiner enters the room. Findings of respiratory distress depend on the
patient’s age. Increased respiratory rate (tachypnea) is often the first indication
of respiratory distress at all ages; however, normal rates will vary over a wide
range according to age (Table 5-2). Normal respiratory rates are also highly
variable in infants and toddlers depending on sleep state and the presence of
fever. Breathing pattern is important: Hyperpnea (abnormally deep respira-
tion) may accompany acidosis and CNS dysfunction. Hypopnea can occur in
sleep-disordered breathing and again with CNS disease. Eupnea is normal,
unlabored breathing, and dyspnea is difficulty breathing.
Dyspnea, which is shortness of breath or difficulty “catching” one’s breath,
is found with true lung disease, such as acute asthma, but also occurs with
hyperventilation secondary to panic attack or panic disorder.
Table 5-2. Respiratory Rate by Age
Age Respiration (breaths/minute)

Newborn 30–60
1–6 weeks 30–60
6 months 25–40
1 year 20–40
3 years 20–30
6 years 12–25
10 years 12–20
Adapted from Burbulys DB. Respiratory distress. In: Berkowitz CD, ed.
Berkowitz’s Pediatrics: A Primary Care Approach. 6th ed. American Academy of
Pediatrics; 2021:501–505.

70
Lungs and Thorax

The highly compliant chest wall of the young infant leads to significant
retractions (suprasternal, intercostal, subcostal) with increased respiratory
effort. Retractions occur when the skin overlying the neck or chest is drawn
in during inspiration. Even with the patient clothed, retractions within the
suprasternal notch may be readily apparent in the older child and adolescent.
This group may also demonstrate intercostal retractions as well as use of
accessory muscles of respiration (sternocleidomastoid and scalene muscles)
during periods of respiratory distress. Infants may also demonstrate nasal
flaring with respiratory distress.
Inspection and palpation of the chest wall may reveal abnormalities. The
trachea should normally deviate slightly to the right when a finger is placed
in the suprasternal notch. Changes in the position of the trachea may provide
important information during the physical examination. In conditions in
which either air or liquid fills the pleural space, the lung may move away
from its normal position with the trachea also shifting in the same direction.
Conversely, in complete atelectasis of a lung, the trachea may shift toward the
side of collapse. In lung agenesis or hypoplasia, the trachea may deviate to the
affected side. Absence of a pectoralis muscle is seen in Poland syndrome, and
rib or thoracic vertebral anomalies may lead to chest wall asymmetry. Severe
scoliosis may lead to respiratory compromise due to restriction of normal lung
expansion, which may be accompanied by kyphosis, and both conditions may
be seen in children with neuromuscular disease. Pectus carinatum (pigeon
breast) or pectus excavatum are both common reasons for referral for eval-
uation, although they affect cardiopulmonary functioning only when severe
(Figure 5-2). Children with significant obstructive sleep apnea may develop
a Harrison groove, which is an indentation along the site of diaphragmatic
insertion of the anterior ribs. Furthermore, certain genetic syndromes may be
associated with a small thoracic cage. For example, Jeune syndrome, spinal
muscular atrophy type I, or other congenital myopathies may show a small
bony thorax.

71
Figure 5-2. Pectus carinatum (A)

and pectus excavatum (B).

72
Percussion of the chest gives the clinician vital information about underly-
ing structures (Figure 5-3). Percussion may be difficult in the small, un-
cooperative infant and may precipitate crying, so percussion and palpation
should always follow auscultation in this age group. Usually, normal lungs
will provide a resonant note with a low pitch and slightly long duration. When
pleural effusion, consolidating pneumonia, or an intrathoracic mass is present,
the note is flat with a high pitch and shorter duration. Conversely, when a
pneumothorax has occurred, one will find a high-pitched, loud note. Obstruc-
tive lung disease with air trapping, such as asthma or CF, may also produce
a hyperresonant pitch. In particular, when percussing the chest, always
remember to compare one side with the other.
Figure 5-3. Technique of chest percussion.
After percussion, auscultation of the lungs is performed during physical

assessment (except in the infant and small child, when auscultation should
precede percussion and palpation). With normal breathing and with larger
tidal volumes, normal breath sounds or adventitial sounds may be detectable.
Normal vesicular breath sounds are low-pitched and heard mostly throughout
inspiration, continuing approximately one-third of the way into exhalation.
During certain clinical conditions, other breath sounds may replace the nor-
mal vesicular breath sounds. Bronchial breath sounds are abnormal sounds
that are often louder than vesicular breath sounds; they may be shorter dur-
ing inspiration and longer during exhalation. In addition, they may be slightly
louder and more high-pitched during expiration. These are the sounds of large
airways transmitted through lung parenchyma that is consolidated or atelec-
tatic. Three different types of adventitious sounds are generally acknowledged
and agreed on in present medical teaching. First, crackles or rales are short,

73
intermittent sounds. Two types of crackles are described: Fine crackles are
similar to hairs being rubbed together near the ears; coarse crackles, as the
name implies, are louder and harsher, more like rubbing 2 pieces of tissue
paper together. Fine crackles are more commonly associated with interstitial
lung disease. Coarse crackles are often heard in pneumonia or CF. Wheeze,
the sound most commonly associated with asthma, is a continuous sound and
is often musical. Rhonchi are also continuous sounds but much lower in pitch
and may clear with coughing. These sounds are probably caused by secretions
in the large airways. A pleural rub may also occasionally be heard during
chest examination. More often heard during inspiration, these low-pitched
continuous sounds are the result of pleural inflammation. Often described
as a creaky noise, they may also sound like leather being stretched.
During auscultation is an opportune time to examine the cardiovascular
system, which begins with inspection of mucous membranes and nail beds for
signs of central cyanosis. Next is auscultation of the heart tones; children with
congenital heart disease may present with murmurs heard during the entire
cardiac cycle. Full characterization of murmurs may require evaluation by a
pediatric cardiologist. Dysrhythmias, both bradycardic and tachycardic, may
be noted during cardiac auscultation.
Additional Examinations
Additional systems may give important clues to chronic respiratory
disease. These include the abdominal, dermatologic, musculoskeletal, and
neurological systems.
The abdominal examination should include accurate assessment of liver
and spleen size. Hepatomegaly may occur in patients with CF and may be
a potentially life-threatening complication. Cirrhosis may occur because
of biliary tract obstruction, leading to hepatocyte damage and subsequent
fibrosis. Secondary splenic congestion due to hepatic insufficiency may also
occur occasionally and requires expert skill to ascertain fullness in the left
upper quadrant of the abdomen reliably. Any mass or fluid in the abdomen
may restrict thoracic excursion through elevation of the diaphragm and thus
lead to respiratory compromise.
Sequelae of neurological complications often affect the respiratory system.
Severe neurological dysfunction may interfere with respiratory control, lead-
ing to apnea or hypoventilation. Much more commonly, patients are seen with
more subtle neurological involvement, most frequently involving swallowing.
Patients with cerebral palsy often are at risk for aspiration pneumonia, and
particular care should be paid to the patient’s ability to handle oral secretions.
Evaluating the strength and duration of an elicited gag reflex may provide
clues to aspiration risk because both prolonged and absent gags are abnormal.

74
Silent aspiration can occur often in children with severe neurological deficits,
and a strong index of suspicion should be maintained; bronchoscopy and
radiographic deglutition studies (best with a physical or speech therapist
present) can help delineate aspiration risk. Any condition leading to thoracic
muscle weakness can lead to progressive respiratory compromise and, eventu-
ally, respiratory failure requiring support. At the first sign of sleep disturbance
or with recurrent respiratory infection, children with muscle weakness should
be referred for pulmonary and sleep evaluation.
Examining the skin may yield important clues to underlying systemic disease
with a respiratory component. Eczema in infancy may be associated with food
allergy and rarely is associated with respiratory disease. However, as children
age, eczema is more often associated with asthma, allergic rhinitis, and inha-
lation allergy. Severe asthma, with eczema and recurrent Staphylococcus
aureus infection, occurs with the immunodeficiency of the hyper-IgE syn-
drome. Cyanosis of nail beds and mucous membranes is always a significant
physical finding and should prompt a thorough investigation.
Assessing the musculoskeletal system is the final portion of the physical ex-
amination. Many patients with developmental delay or genetic conditions are
prone to kyphoscoliosis. Careful examination of the back is of prime impor-
tance in children of all ages. Key points to assess include the linearity of the
spine, asymmetry of the back and shoulders, and range of motion (flexion,
extension, and lateral bending). Digital clubbing, if not previously assessed,
should be evaluated at this time.
key points
} Respiratory rates in children vary over a wide range with activity and age;
this vital sign should be compared against standard tables.
} The heart and lung examinations are best performed first in young children to
increase the chance of an adequate examination.
} Characterization of breath sounds and their location can lead to efficient and
accurate diagnosis of acute or chronic pulmonary conditions.
} Children with developmental disabilities can aspirate silently, leading to
recurrent pneumonia; therefore, a strong index of suspicion with appropriate
testing is in order.
} Other systems affect or are affected by the lungs, including the cardiovascular,
neurological, dermatologic, and musculoskeletal systems; these must be
evaluated along with the pulmonary tract during the complete physical
evaluation, which is especially important in the preparticipation examination
for children and teens seeking to undertake athletics. This examination is
discussed in detail in the American Academy of Pediatrics publication
Preparticipation Physical Evaluation.7

75
References
1. Homnick DN. The respiratory system. In: Greydanus DE, Feinberg AN, Patel DR,
Homnick DN, eds. The Pediatric Diagnostic Examination. McGraw-Hill; 2007:189–226
2. Zitelli BJ, McIntire SC, Nowalk AJ. Zitelli and Davis’ Atlas of Pediatric Physical Diagnosis.
7th ed. Elsevier; 2017
3. Wilmott RW, Deterding R, Li A, et al, eds. Kendig’s Disorders of the Respiratory Tract
in Children. 9th ed. Elsevier; 2019
4. Fireman P. Rhinitis and asthma connection: management of coexisting upper airway allergic
diseases and asthma. Allergy Asthma Proc. 2000;21(1):45–54 PMID: 10748952
https://doi.org/10.2500/108854100778248935
5. Slavin RG. The upper and lower airways: the epidemiological and pathophysiological
connection. Allergy Asthma Proc. 2008;29(6):553–556 PMID: 19173781
https://doi.org/10.2500/aap.2008.29.3169
6. Tauman R, Gozal D. Obesity and obstructive sleep apnea in children. Paediatr Respir Rev.
2006;7(4):247–259 PMID: 17098639 https://doi.org/10.1016/j.prrv.2006.08.003
7. Bernhardt DT, Roberts WO, eds. Preparticipation Physical Evaluation. 5th ed.
American Academy of Pediatrics; 2019

CHAPTER
6
Pulmonary Function Testing
Carol J. Blaisdell, MD
Pulmonary function tests (PFTs) offer clinicians useful objective functional

information that can aid in the diagnosis and management of known or
suspected lung or respiratory system disease in children. Symptoms of
shortness of breath (dyspnea), chest pain, cough, and wheezing have many
potential causes. As part of a clinician’s evaluation, the choice of an appro-
priate objective and reproducible test of pulmonary function may confirm a
working diagnosis. Many children are prescribed asthma medications with
potential adverse effects for years or even decades. Pulmonary function tests
can assure patients, parents, and clinicians that the diagnosis is correct. In
addition, PFTs are important in assessing the progression of known lung
disease and response to therapy. Some tests are readily available in the
primary care office, while others are most often restricted to pulmonary
function laboratories or, more recently, the offices of pediatric pulmonolo-
gists. Procedures should follow American Thoracic Society1 guidelines
referenced to healthy populations. Indications are listed in Box 6-1.
Box 6-1
Indications for Pulmonary Function Tests
ū To determine the nature of the respiratory dysfunction (obstructive versus
restrictive disease)
ū To evaluate respiratory function associated with signs and symptoms
ū To quantify the extent or progression of known pulmonary disease
ū To provide an objective measure to determine the appropriateness of reducing
therapy for asthma
ū To measure the effect of occupational exposure
ū To identify benefits, adverse effects, or consequences of withdrawal or
step-down of therapy
ū To assess the presence of airway hyperreactivity
ū To assess preoperative lung function
ū To use as a research objective or measure
77

78
Peak Expiratory Flow Rate

Peak expiratory flow rate (PEFR) is a useful measure for monitoring lung
function in the primary care management of obstructive lung diseases, particu-
larly asthma. It is inexpensive and can be used at the patient’s home or work-
place, at the clinician’s office, and in the acute care setting of the emergency
department (ED) and hospital. However, there are important limitations.2
To use a peak flow meter, the child should blow out as quickly as possible
from maximal inhalation with his or her mouth closed tightly on the mouth-
piece. The highest of 3 attempts should be recorded. The performance of
PEFR depends highly on effort and is affected by large-airway dysfunction.
Patients who do not keep a tight seal on the mouthpiece will produce a falsely
low PEFR, and those who put their tongue in the mouthpiece while exhaling
(essentially performing a “blow-dart” maneuver) may have falsely elevated
PEFR measurements. Consistency of the values with 3 trials at a time suggests
reproducible results that can be interpreted. If variability is greater than 20%
with 3 efforts performed at one time, the clinician should suspect that there is a
problem with the patient’s technique.
Normative PEFR data based on standing height are available to assess flow
limitation compared with that in healthy control subjects; however, these data
are fairly old and vary with the PEFR devices used.2–4 If the values are less
than 80% of the expected or the patient’s personal best PEFR (discussed in the
next paragraph), airflow obstruction should be suspected. This result could
be consistent with subjective concerns of a patient with asthma or may be
unexpected in a patient with poor perception of his or her disease.
Like all PFTs, PEFR is much more useful in detecting changes over time than
in asking the question, “Is this normal?” In a patient with poorly controlled
asthma who frequently accesses acute care in an ED, PEFR can be used to set
criteria for contacting the clinician for impending asthma exacerbations. The
asthma action plan, which defines adjustment in home asthma management in
response to early symptoms of asthma (cough, dyspnea, chest pain), may also
document the target PEFR for each individual.5 The convention is to determine
the patient’s personal best PEFR when asthma is under best control in the clini-
cian’s office or with home monitoring and to review these data with the provider.
Using a peak expiratory flow meter to determine whether there is significant
airflow obstruction in adolescents who complain of exercise-induced dyspnea
can be useful. A 20% change in the PEFR between before and after exercise
that elicits dyspnea is consistent with exercise-induced asthma. Peak expira-
tory flow rate values greater than 80% of the personal best or expected for
height usually suggest reasonable control if symptoms are absent. When
PEFR decreases to less than 80% of personal best or there is greater than
20% variability from morning to evening PEFR measurements on the same

79
Chapter 6—Pulmonary Function Testing
day, then adjustments to asthma medications should be considered. Adjust-

ments could include initiating short-acting β-agonist therapy, such as albuterol;
increasing the dose of inhaled corticosteroids; adding a long-acting β-agonist,
such as salmeterol or formoterol to inhaled corticosteroids; or adding a leu-
kotriene receptor antagonist such as montelukast. If PEFR measurements
decrease to less than 50% of predicted or personal best, and a dose of short-
acting β-agonist does not resolve the symptoms and increases the PEFR to
50%, patients should contact a physician. Evaluation and management in
an urgent care setting are often needed, and a short course of systemic
corticosteroids will most likely be necessary.
Spirometry
Unlike PEFR, spirometry is helpful in inferring lung volumes as well as a
measure of flows. It is the most useful test for determining whether respiratory
symptoms are attributable to underlying obstructive versus restrictive lung
disease, although confirmation when restrictive disease is suspected usually
requires measurement of complete lung volumes. Abnormal spirometry results
do not provide a specific diagnosis; rather, they place a patient in a specific
physiological category. The most common obstructive lung disease in children
is asthma, affecting about 10% of the US population.6,7 Cystic fibrosis (CF) is
also an obstructive lung disease that often presents to the clinician as recurrent
cough, bronchitis, or pneumonia. Restrictive lung diseases include chronic lung
diseases that decrease effective lung volumes (eg, bronchopulmonary dysplasia,
sickle cell disease), chest wall disorders (eg, pectus deformities, scoliosis), and
neuromuscular disorders (eg, Duchenne muscular dystrophy). Normal spirome-
try results do not exclude lung disease, but they can provide reassurance that
the disease is not significantly limiting pulmonary function at rest.
Most children as young as 6 years can perform spirometry adequately for
interpretation, and, with practice, some can perform adequately even younger.
Preschoolers may be able to perform simple maneuvers with good coaching
from staff who help the child feel comfortable and motivated to perform the
test.8 It is possible to obtain reproducible forced expiratory maneuvers in
infants, but this is technically challenging and possible only in pediatric PFT
laboratories with experience in this specialized technique. The raised volume
rapid thoracoabdominal compression technique produces forced expiratory
maneuvers in infants that simulate adult-type flow-volume curves. Forced
expiratory flows measured with raised volume rapid thoracoabdominal com-
pression in infants with CF are often lower than those in healthy infants and
appear to be useful for early detection of CF airway dysfunction.9,10
Measures of forced vital capacity (FVC), forced expiratory volume in the first
second of expiration (FEV1), and the ratio of these 2 (FEV1/FVC) are a useful
start in distinguishing between obstructive and restrictive lung disorders.

80
Patterns of spirometry results are listed in Table 6-1. The vital capacity is the
largest volume of air that a person can inspire or expire from the lungs. The
maneuver required to measure FVC involves taking a maximal inhalation and
forcefully exhaling with the mouth tightly closed around a mouthpiece with the
nose closed with a nose clip until the entire lung volume is exhaled. The volume
exhaled in the first second is the FEV1 (Figure 6-1) and is decreased compared
with normal if there is obstruction to exhaled airflow (as with asthma and CF).
Flows in the midportion of the forced-exhalation maneuver, a forced expiratory
flow between 25% and 75% of the FVC (FEF25%–75%), are sensitive to small-
airway function in children and are the first affected in obstructive lung
diseases such as asthma and CF.
Table 6-1. Patterns of Spirometry Results
Measure Obstructive Restrictive
FVC Normal or increased Reduced
FRC Increased Normal or reduced
TLC Increased Reduced
FEV1 Decreased Normal or decreased
FEV1/FVC Decreased Normal or decreased
FEF25%–75% Decreased Normal or decreased
Abbreviations: FEF25%–75%, forced expiratory flow between 25% and 75% of the FVC; FEV1, forced expiratory
volume in 1 second; FRC, functional reserve capacity; FVC, forced vital capacity; TLC, total lung capacity.
3
Exp. Volume (L)
2
FEV1 FVC
0
0 1 2 3 4
Time (s)
Figure 6-1. What spirometry measures. Abbreviations: FEV1, forced expiratory volume in 1 second;
FVC, forced vital capacity.

81
The results of the expiratory maneuver that generates the measurements

of FEV1 and FVC are displayed most commonly as a flow-volume loop
or can be displayed as a volume-versus-time graph (Figure 6-2).
Figure 6-2. Flow-volume loop and volume-versus-time graph of a spirogram. There was good
patient effort on the maneuvers, American Thoracic Society criteria were met, and 2 puffs of
albuterol were administered with a holding chamber.
Abbreviations: Pre, before bronchodilator; pred, predicted; post, after bronchodilator.
In obstructive lung diseases, there may be a reduced rate of airflow at any

given lung volume, and the FEV1/FVC is lower than normal. Criteria for
assessing for
Box 6-2
an adequate
Characteristics of Flow-Volume Loops flow-volume
Acceptable flow-volume loop loop include
Instantaneous start of exhalation and rapid increase in flow (1) instantaneous
to peak start of exhalation
Normal sharp peak, indicating maximal effort and no large and rapid increase
conducting central airway obstruction in flow to peak;
Smooth, continuous exhalation to residual volume (2) normal sharp
Reproducible results peak, indicating
Unacceptable flow-volume loop maximal effort;
Poor start of exhalation with slow or erratic increase to peak (3) smooth, con-
tinuous exhalation
Broad or flat peak, which may indicate less-than-optimal
effort; if it is smooth and reproducible, it may indicate to zero flow; and
central conducting airway obstructions (4) reproducible
Erratic exhalation with cough or abrupt flow changes results (Box 6-2,
Exhalation not complete (ie, flow decreases abruptly to zero
Figure 6-3).
without a gradual return to zero)
Curve features not reproducible

82
Figure 6-3. Acceptable flow-volume loop:

rapid increase during expiration, a normal
sharp peak, smooth exhalation, and gradual
return to zero flow.
An unacceptable flow-volume curve is shown in Figure 6-4, which demon-

strates erratic flows during exhalation that are attributable to coughing. With-
out a reliable flow-volume loop, the results of the spirometric maneuver should
be questioned. Careful inspection of the expiratory flow-volume curve provides
a more sensitive indication of small-airway obstruction than does evaluating
only the quantitative measurements. The early reduction of flow and the flatten-
ing of the slope are characteristic of obstruction, which appears as a concave
expiratory flow tracing (Figure 6-5). Pulmonary function laboratories should
always follow standards set by the American Thoracic Society, and PFTs in
children are more likely to be reproducible and useful when obtained in
laboratories or other settings with significant experience with children.
Spirometry has become so ubiquitous that it may seem as if it is the only PFT
available. It is relatively inexpensive and easy to perform and has become the
primary end point for almost all clinical trials. However, there are many
limitations, particularly in children.

83
Figure 6-4. Unacceptable

flow-volume loop: poor start,
erratic exhalation with cough
that led to inhalation during
expiratory phase, and abrupt
return to zero.
Abbreviations: Pre, before
bronchodilator; pred, predicted;
post, after bronchodilator.
Figure 6-5. Severe airflow

Flow obstruction. The flow-volume
8 loop demonstrates flow limitation
Pre at all lung volumes, with concave
tracings on the expiratory loop.
Post There was no improvement
6
in flows after use of a
bronchodilator.
4 Abbreviations: Pre, before
bronchodilator; post, after
bronchodilator.
–2
–4
–6
–1 0 1 2 3 4
Volume

84
Reference Values
Pulmonary function test results may indicate patterns of lung function
consistent with obstructive or restrictive lung disease. The results should
be compared with reference values from healthy populations. Norms and
standards for interpretation11,12 should be chosen from a study in a healthy
population similar to the patient. It is important to obtain an accurate stand-
ing height (or arm span if the patient cannot stand or has significant scoliosis)
because the interpretation of normal versus abnormal is based on height in
addition to age, sex, and race. If the pulmonary function laboratory does not
provide a qualitative interpretation of the data, then fixed-percent predicted
cutoffs of less than 80%, 80%, and 60% are reasonable for identifying abnor-
malities of FVC, FEV1, and FEF25%–75% , respectively. Grades of impairment
compared with predicted norms are shown in Table 6-2. An FEV1 or FVC
of less than 80% of that predicted has generally been considered abnormal,
though recently more expert bodies, including the American Thoracic Society,
recommend moving to calculation of z scores and considering a z score less
than −2 (2 SDs below the normal mean) to be abnormal. As a general rule,
spirometric measurements are considered mildly abnormal if they are
between 70% and 79% of predicted values, though a healthy child younger
than 12 years usually has an absolute FEV1/FVC ratio of 0.85 or greater.
Table 6-2 includes one classification of severity of obstruction based on spi-
rometric values expressed as percentage of predicted values, though these
are not universally accepted. An example of how predicted values can vary
depending on the reference group used for comparison is represented in
Table 6-3. For the spirometric data in the same patient, according to National
Health and Nutrition Examination Survey III references,4 FVC and FEV1 were
64% of that predicted, or moderately abnormal. According to the European
Respiratory Society 1993 standards,13 which do not include Black counter-
parts, the FVC and FEV1 were 56% and 57% of that predicted, respectively,
or moderate to severely abnormal.
The development of reference ranges for PFTs, particularly spirometry
and diffusing capacity, has improved significantly. One of the more vexing
problems for pediatricians has been the lack of a single set of reference
equations that can be used for children of all ages. In the past, clinicians had
to switch reference ranges midway through childhood, which could result in
significant confusion and misinterpretation. Now, there are internationally
accepted equations for patients of all ages (from age 3 years and up) for
spirometry and diffusing capacity. An international group of experts devel-
oped these equations as part of the Global Lung Function Initiative (GLI),
as nicely summarized in the review article by Cooper et al.14 Not all current
spirometers have these newer equations built into their memory, but

85
continued advocacy efforts for their wide adoption are critical to achieve
health equity. However, although GLI is a step in the right direction to
eliminate race-based medicine, the normative values on which it relies remain
limited by small sample sizes of African Americans, particularly children, as
well as many other ethnic groups and nationalities throughout the world.
Using race-based reference equations for the interpretation of pulmonary
function tests in Black patients (see Table 6-3) can result in underdiagnosing
lung disease, which can perpetuate health disparities in many respiratory
diseases and respiratory complications of several diseases, such as sickle cell
disease.15–18 When comparing results in an individual patient over time, it is
important to compare absolute volumes and flows and examine which
reference values were used to report the predicted volumes and flows. The
use of appropriate references is required not only for spirometry but also for
measures of lung volumes and diffusion capacity.
Table 6-2. Grades of Impairment

FEV1 or FVC FEF25%–75%, FEV1/FVC,
Grade % Predicted % Predicted Absolute Ratio
Normal > 80 > 70 > 0.80
Mild < 80–70 < 70–60 < 0.80–0.60
Moderate < 70–55 < 60–40 < 0.60–0.40
Severe < 55–30 < 40–15 < 40–0.25
Extreme < 30 < 15 < .25
Table 6-3. Differences of Percent-Predicted Values on Spirometry for

a 15-Year-Old Black Boy
% %
Parameter Results Referencea Predicteda Referenceb Predictedb
FVC, L 2.69 4.18 64 4.83 56
FEV1, L 2.29 3.59 64 3.98 57
FEV1/FVC, absolute ratio 0.85 0.86 — 0.83 —
FEF25%–75%, L/s 2.48 4.00 62 5.08 49
Abbreviations: FEF25%–75%, forced expiratory flow between 25% and 75% of the FVC; FEV1, forced expiratory
volume in 1 second; FVC, forced vital capacity.
a
National Health and Nutrition Examination Survey III; www.cdc.gov/nchs/nhanes.htm.
b
European Community Respiratory Health Survey; www.ecrs.org.

86
Lung Volumes
When the FVC on a spirometry test is low (< 80% of that predicted) and the
FEV1/FVC ratio is normal or elevated (> 80%), a restrictive defect in pulmo-
nary function is suggested. When the FVC is less than 80% and the ratio of
FEV1/FVC is less than 80%, an obstructive defect is suggested. To confirm a
restrictive versus obstructive disease pattern, measure complete lung volumes,
(ie, residual volume [RV], functional reserve capacity [FRC], and total lung
capacity) (Figure 6-6). With spirometry, only lung volumes and flow rates
within the FVC are measurable—the volume of air that is exhaled or inhaled
from maximal inhalation to maximal exhalation, such as the FVC, FEV1, and
FEF25%–75%. Because RV is the volume of air that cannot be exhaled from the
lungs even after maximal exhalation, it must be measured indirectly. The most
common methods for measuring lung volumes are helium dilution, nitrogen
washout, and body plethysmography (the body box). In practice, the FRC is
measured, and RV and TLC are calculated from the FRC by measuring the
Figure 6-6. Spirogram. Lung volumes: RV, residual volume—amount of air that cannot be
exhaled from the lung; ERV (expiratory reserve volume), volume that can be exhaled starting
from FRC to RV; FRC, the volume of air in the lungs at the end of the tidal breath, and a combina-
tion of ERV and RV; TLC, the total volume of air in the lung on full inspiration.
From Whitmer KH. Assessment of pulmonary function: spirometry. In: A Mixed Course-Based Research
Approach to Human Physiology. Iowa State University Digital Press. Accessed August 30, 2022. https://
iastate.pressbooks.pub/curehumanphysiology/chapter/pulmonary-function/.

87
expiratory reserve volume and vital capacity. The helium dilution and nitro-
gen washout methods rely on the mixing of known concentrations of gas with
the patient’s lung volume at the start of the test, which by convention starts at
FRC. If a patient has severe obstructive lung disease, this method is not very
accurate because the gases mix too slowly to reflect accurate volumes or not
at all in regions of the lung that have significant air trapping. In this case, use
of the body box is more accurate. Almost all body boxes today are referred
to as pressure boxes, in which pressure changes at the mouth with the patient
inside a closed box permit calculation of FRC. The body box can provide
useful information about air trapping (high FRC or RV) in patients with CF
but cannot be used successfully if obesity prevents the patient from fitting
in the closed box or the patient depends on supplemental oxygen.
When a restrictive lung disease is suspected, such as a neuromuscular dis-
order or sickle cell disease, measuring lung volumes can provide more detail
about the severity of the restrictive changes. These studies take more time
than spirometry and usually can be performed only in a pulmonary function
laboratory with standardized protocols that follow American Thoracic Society
guidelines. These techniques require little or no effort on the part of the
patient but depend greatly on the skill and experience of the technician.
Carbon Monoxide Diffusing Capacity

Diffusing capacity of the lung for carbon monoxide (Dlco) is the measure-
ment of carbon monoxide (CO) transfer from inspired gas into the pulmonary
capillary. The transfer of CO into the blood depends on many variables, in-
cluding alveolar capillary interface (thickness), capillary volume, hemoglobin
concentration, and the reaction rates between CO and hemoglobin.19 In
patients with lung disease, the Dlco correlates with disease severity and
arterial blood oxygenation, particularly during exercise.20 Measuring Dlco
over time may be useful for patients with the potential for progressive loss of
alveolar surface area, such as those with sickle cell disease (Figure 6-7),
those under-going chemotherapy or radiation therapy, and those who have
undergone lung resection. The Dlco is diminished in young adults with a
history of being born preterm, regardless of whether they had a diagnosis of
bronchopulmonary dysplasia.21 This diminished Dlco likely reflects inade-
quate or abnormal growth of the alveoli after preterm birth. Normative data
for Dlco are not as comprehensively available for different racial and ethnic
groups and young ages as are data for spirometry19; but the new GLI reference
ranges discussed earlier in spirometry are excellent.14 Generally speaking, a
Dlco of 60% and up to the lower limits of normal for the reference popula-
tion is considered mildly abnormal, 40% to 60% is considered moderately
abnormal, and less than 40% is considered severely abnormal. The clinician
can evaluate trends over time for an individual patient to determine whether

88
Age: 15 Height(in): 70 Race: Black Gender: Male Weight(lb): 127

Diagnosis: Sickle cell/asthma Medication:
Dyspnea Rest: No Dyspnea Exercise: No Cough: No Productive(cc):
Persistent: No Smoker: No How Long(pk/yrs): Stopped(yrs):
Cigarettes: No Cigars: No Temp: 22 PBar: 757
PULMONARY FUNCTION ANALYSIS

Flow
8 Spirometry Ref Pre Pre Post Post Post
6 Meas % Ref Meas % Ref % Chg
4 FVC Liters 4.83 2.69 56 2.89 60 7
2 FEV1 Liters 3.98 2.29 57 2.53 64 11
0 FEV1/FVC % 89 85 87
-2 FEF25-75% L/sec 5.08 2.48 49 3.02 60 22
-4 PEF L/sec 7.92 5.26 66 5.74 72 9
-6 FET100% Sec 5.67 6.41 13
-1 0 1 2 3 4
Lung Volume FIVC Liters 4.83 2.55 63 2.03 42 -21
FIF50% L/sec 2.51 1.52 -35
MVV L/min
10 TLC Lung Volumes

8 ERV
VC Liters 4.76 2.89 61
RV TLC Liters 6.04 3.96 65
6
RV Liters 1.26 1.06 65
4 RV/TLC % 23 27
FRC N2 Liters 2.97 2.35 79
2
ERV Liters 0.55
0
Ref Meas
Diffusion Hb: 8.8
DLCO mL/mmHg/min 29.4 17.9 61
DL Adj mL/mmHg/min 35.1 22.2 61
VA Liters 7.14 3.76 53
DLCO/VA mL/mmHg/min/L 5.06 4.77 94
DL/VA Adj mL/mmHg/min/L 5.06 5.91 117
IVC Liters 2.35
Figure 6-7. Example of pulmonary function test: sickle cell disease. Moderate restrictive defect
shown with spirometry is suspected from decreased FVC and normal FEV/FEV1 and confirmed
with lung volumes with an FVC of 56% predicted and TLC of only 65% predicted. The Dlco is
decreased to 61%, corrected for the patient’s anemia (with a Hb level of 8.8). This patient has
had multiple episodes of acute chest syndrome.
Abbreviations: Adj, adjusted; Chg, change; DL, lung diffusion; Dlco, carbon monoxide diffusing capacity;
ERV, expiratory reserve volume; FEF25–75%, forced expiratory flow between 25% and 75% of the FVC;
FET100%, forced expiratory time; FEV1, forced expiratory volume in 1 second; FIF50%, forced inspiratory
flow; FIVC, forced IVC; FRC, functional reserve capacity; FVC, forced vital capacity; FVL, flow-volume loop;
Hb, hemoglobin; IVC, inspiratory vital capacity; Meas, measure; MVV, maximum voluntary ventilation;
PEF, peak expiratory flow; Ref, reference; RV, residual volume; TLC, total lung capacity; VA, alveolar volume;
VC, vital capacity.

89
there is progressive loss of alveolar or capillary surface area for gas exchange
in certain disease states that require close monitoring, such as those in patients
undergoing chemotherapy for cancer, patients with sickle cell hemoglobinopa-
thy, and patients with interstitial lung disease. Whole-lung irradiation can lead
to mild, moderate, and severe changes in Dlco,22 so monitoring the effects of
cancer therapy in children is very important.
Assessing Airway Reactivity

Children who have asthma or a history of early neonatal lung injury
(eg, bronchopulmonary dysplasia, bronchiolitis, aspiration syndromes,
prolonged mechanical ventilation) may have increased bronchial reactivity.
In addition, children with symptoms of dyspnea or chest pain with normal
physical findings and normal spirometry test results at rest may be evaluated
by using tests of airway reactivity.23
Bronchodilator Testing
Spirometry before and after the use of an aerosolized bronchodilator can
help evaluate the usefulness of bronchodilator therapy for a patient with
known obstructive lung disease or who is suspected of having obstructive
lung disease (Figure 6-8).24 Asthma is the most common reversible obstruc-
tive airway disease, and if it is suspected as the cause of a patient’s signs and
symptoms, bronchodilator testing can help confirm the diagnosis. For patients
with neuromuscular disease, the usefulness of bronchodilators can be assessed
with spirometry before and after albuterol use. As shown in Figure 6-9, a 13-
year-old boy with Duchenne muscular dystrophy had worse expiratory flows
after albuterol use (17% worsening of FEV1 and 67% worsening of FEF25%–75%),
showing that albuterol is not useful in his treatment. A lack of response to
a bronchodilator in a patient with an obstructive pattern at spirometry may
indicate long-standing airway inflammation and raise the question of other
diagnoses, such as CF (Figure 6-10). Spirometry performed at rest can be
repeated 10 to 15 minutes after a standard dose of an inhaled bronchodilator if
the patient has not used any bronchodilators for at least 4 hours before testing.
Albuterol administered with a metered-dose inhaler (2–4 puffs) with a spacer
for adequate dose delivery or 2.5 to 5.0 mg of nebulized albuterol should be
adequate for assessing bronchodilation. As a general rule, an increase in FVC
or FEV1 of 12% would be considered a significant bronchodilator response
and compatible with a diagnosis of asthma regardless of whether the baseline
spirometry test result demonstrated obstruction or was normal compared
with reference values.

90
Hospital for Children

Pediatric Pulmonary Function Lab
Gender: Male
Age: 15 Race: Black
Height(in): 65 Weight(lb): 132
Diagnosis:
Spirometry Ref Pre % Ref Post % Ref % Chg
FVC Liters 3.39 4.10 121 4.17 123 2

FEV1 Liters 2.96 2.02 68 2.68 91 33
FEV1/FVC % 86 49 64
FEF25-75% L/sec 3.50 0.94 27 1.81 52 93
PEF L/sec 6.98 4.37 63 6.52 94 49
Vol Extrap Liters 0.01 0.04 600
Flow
8
PRED
6 PRE
POST Volume PRED PRE POST
4
8
2
Liters
6
Liters
0 4
-2 2
-4 0
-1 0 1 2 3 4 5 6 7 8
-6 Liters/Second
-1 0 1 2 3 4
Liters/Second Time
Volume
Comments:
Interpretation:
Forced expiration demonstrates a moderate obstructive ventilatory defect.
There is an immediate response to aerosolized bronchodilator. Spirogams
plateau normally. Flow volume loops reveal decreased expiratory flow rates
at low lung volumes consistent with airway obstruction.
Figure 6-8. Example of pulmonary function test: severe airflow obstruction attributable to
asthma due to FEV1/FVC % of only 49% before bronchodilator with improved but not quite
normalized flows after bronchodilator response: FEV1/FVC % of 64%.
Abbreviations: Chg, change; FEF25–75%, forced expiratory flow between 25% and 75% of the FVC; FEV1, forced
expiratory volume in 1 second; FVC, forced vital capacity; FVL, flow-volume loop; PEF, peak expiratory flow;
Post, after bronchodilator; Pre, before bronchodilator; Pred, predicted; Ref, reference; Vol Extrap,
extrapolated volume.

91
DUCHENNE MUSCULAR DYSTROPHY
Age: 13 years ?????TL3097134

Sex/Race: Male/Caucasian Room: Out
Height: 63 in 161 cm
Weight: 142 lbs 65 kg
Pre-RX Post-RX
Spirometry (BTPS) PRED BEST %PRED BEST %PRED %CHG
FVC Liters 3.69 0.90 26 0.95 26 –1
FEV1 Liters 3.17 0.90 38 0.75 29 –17
FEV1/FVC % 94 79 –16
FEF25-75% L/Sec 3.33 2.00 38 0.66 19 –67
FEF25% L/Ses 1.34 1.19 –53
FEF50% L/Sec 2.18 0.72 –67
FEF75% L/Sec 1.55 0.41 –47
PEF L/Sec 2.26 2.73 38 1.48 18 –49
FIVC Liters ? 0.99 27 0.98 41 1
PIF L/Sec 2.24 2.63 0
Figure 6-9. Example of pulmonary function test: Duchenne muscular dystrophy. A severe
restrictive pattern is shown, with FVC at only 0.90 L or 26% of that predicted, FEV1 at 0.90 L
or 28% of that predicted, and FEV1/FVC at 94%, with worsening after use of a bronchodilator
(FEV1 decreased by 17%).
Abbreviations: CHG, change; BTPS, body temperature, ambient pressure, and gas saturated with water
vapor; FEF, forced expiratory flow; FEV1, forced expiratory volume in 1 second; FIVC, forced inspiratory vital
capacity; FVC, forced vital capacity; PEF, peak expiratory flow; PIF, peak inspiratory flow; Post-Rx, after
bronchodilator; Pred, predicted; Pre-Rx, before bronchodilator.

92
CYSTIC FIBROSIS
Age: 21 Years
Sex/Race: Female/Caucasian
Height: 59 in 150 cm
Weight: 86 lbs 39 kg
Pre-RX Post-RX
Spirometry (BTPS) PRED BEST %PRED BEST %PRED %CHG
FVC Liters 3.31 1.45 # 44# 1.52 # 46# 5
FEV1 Liters 3.01 0.91 # 30# 0.94 # 31# 3
FEV1/FVC % 91 63 # 69# 62 # 68# –2
FEF25-75% L/Sec 4.02 0.48 # 12# 0.46 # 11# –4
FEF25% L/Sec 1.48 1.63 10
FEF50% L/Sec 0.54 0.56 4
FEF75% L/Sec 0.20 0.16 –20
PEF L/Sec 2.60 2.75 6
FIVC Liters 3.31 1.33 # 40# 1.37 # 41# 3
PIF L/Sec 2.38 2.64 11
# = Outside 95% Confidence Interval # = Outside Normal Range
4 Flow/Volume
( Pre–Rx )
3 ( Post–Rx )
1
Liters
0 .5 1 1.5 2 2.5 3 3.5 4 4.5

Liters/Second
Figure 6-10. Example of pulmonary function test: cystic fibrosis. Shown are severe airflow
obstruction (FEV1 at 30% of that predicted) and a severe restrictive pattern (FVC at 44% of that
predicted), with no improvement after bronchodilator administration. Flow limitation is worse
with forced exhalation compared with tidal breathing at rest.
Abbreviations: CHG, change; BTPS, body temperature, ambient pressure, and gas saturated with water vapor;
FEF, forced expiratory flow; FEV1, forced expiratory volume in 1 second; FIVC, forced inspiratory vital capacity;
FVC, forced vital capacity; PEF, peak expiratory flow; PIF, peak inspiratory flow; Post-Rx, after bronchodilator;
Pred, predicted; Pre-Rx, before bronchodilator.

93
Bronchial Challenge Testing

For patients with a history or physical examination findings suggestive of
asthma (eg, cough, dyspnea, chest pain, wheezing), it is not uncommon for a
clinician to prescribe a trial of bronchodilator or an anti-inflammatory therapy.
However, continued use of a therapy for an unconfirmed diagnosis of asthma
can expose a child to unnecessary adverse effects. When an adolescent with
unexplained dyspnea, chest pain, or cough has normal spirometric results
and an unclear response to bronchodilators, bronchial challenge testing can
be used to diagnose airway hyperreactivity. Airway hyperreactivity is a more
sensitive objective marker of asthma in children than is PEFR or spirometry
at rest or after bronchodilator use.25
Inhalation of methacholine is frequently used to determine whether airway
hyperreactivity is present. Children with asthma will respond to methacho-
line with a pattern of airway obstruction at spirometry at a lower dose than do
children who do not have asthma. In addition to asthma, factors that increase
bronchial hyperresponsiveness include exposure to environmental antigens,
occupational sensitizers, respiratory infections, air pollutants, cigarette smoke,
and chemical irritants.26 After baseline spirometry is measured, the patient
inhales increasing doses of methacholine. A change in FEV1 is the primary
outcome measure for methacholine challenge testing. Provocative concen-
tration 20 (PC20) is defined as the exact concentration of methacholine that
causes a 20% decrease in FEV1 from the baseline FEV1. A positive test result
is one in which the PC20 occurs at less than 4.0 mg/mL22 (Table 6-4). A patient
with a PC20 of less than 1.0 mg/mL has moderate to severe bronchial hyper-
reactivity. If doses of greater than 16 mg/mL methacholine do not cause a 20%
decrease in FEV1, then the patient’s result is considered normal, and another
cause for the reported symptoms should be sought. Approximately 30% of
patients without asthma who have allergic rhinitis have a PC20 in the border-
line range (4.0–16 mg/mL). Approximately 90% to 98% of patients with asthma
Table 6-4. Methacholine Challenge Interpretation
are hyperreactive to metha-
of Bronchial Hyperresponsiveness choline or histamine, another
PC20 a
Interpretation inhalation challenge agent.27
Methacholine challenge test-
> 16 mg/mL Normal
ing should be performed in a
4–16 mg/mL Borderline pulmonary function laboratory
1–4 mg/mL Mild with experienced personnel
< 1 mg/mL Moderate to severe because of the risk of serious
a
Provocative concentration of methacholine causing a airflow obstruction.
20% decrease in forced expiratory volume in 1 second.

94
Exercise Challenge Testing

Although a little less sensitive than methacholine testing, bronchial challenge
testing can also be accomplished by using exercise on a treadmill or bicycle.
The test may be particularly useful for a patient whose respiratory concerns
occur primarily with exercise to confirm a suspected diagnosis of exercise-
induced bronchospasm (EIB). Bronchial challenge can also be used to deter-
mine the ability of an adolescent to perform demanding or lifesaving work
and to determine the effectiveness of therapy to prevent symptoms. As many
as 95% of children and adolescents with asthma have EIB.28,29 A child or
adolescent suspected of having EIB whose respiratory symptoms are not pre-
vented by treatment with an inhaled bronchodilator given 15 to 20 minutes
before exercise and who has no other manifestations of asthma should be
referred for exercise challenge testing to confirm the diagnosis.23
Patients are asked to walk or run on a treadmill to reproduce symptoms
experienced with exercise. The standard is a minimum of 4 minutes at the
target heart rate: heart rate is 80% to 90% of the predicted maximum, calcu-
lated as 220 minus age in years, or ventilation at 40% to 60% of the predicted
maximum voluntary ventilation, estimated as FEV1 × 35.26 For the bicycle
ergometer to produce an adequate test, a target work rate to achieve the target
ventilation must be sustained for at least 4 to 6 minutes. Only 50% to 70%
of children demonstrate significant bronchoconstriction with cycling, so the
treadmill is more likely to provide confirmation of airway hyperreactivity.
As with methacholine challenge testing, the change in FEV1 is the primary
outcome variable. Repeated measures of spirometry are obtained immediately
after exercise and then serially 5, 10, 15, and 20 minutes after completing the
exercise. If the FEV1 is not back to a baseline level by 20 minutes, then another
measure at 30 minutes should be obtained. Response to a bronchodilator may
be assessed if the patient experiences significant dyspnea or the FEV1 has not
returned to within 10% of baseline at 30 minutes. A 10% decrease from the
baseline FEV1 is generally accepted as abnormal,29,30 although a decrease of
15% is considered by some to be more diagnostic of EIB.23,31
Cardiopulmonary Exercise Testing

Cardiopulmonary exercise testing (CPET) involves assessing cardiac and
pulmonary function during incremental exercise and includes measuring gas
exchange (oxygen consumption, CO production, minute ventilation), per-
forming electrocardiography, and measuring blood pressure.32 The clinician
requests CPET for patients who report shortness of breath, dyspnea on exer-
tion, or exercise intolerance without a clear cause or response to thera-
peutic trials. It may also be used to assess cardiopulmonary fitness. If the
patient has chest pain or symptoms suggestive of cardiovascular disease,
a cardiologist should perform a cardiac stress test. Exercise challenge testing

95
is more appropriate if the patient complains of chest tightness and wheezing

during or after exercise (see Exercise Challenge Testing). Cardiopulmonary
exercise testing is useful for a child or adolescent who feels limited by exer-
cise. Limitation can be attributable to impaired lung function; impaired
cardiac, pulmonary, or peripheral circulation; or poor conditioning. Patients
with asthma, chronic lung disease, or sickle cell disease may have limitations
to their oxygenation or ventilatory responses to exercise. See Box 6-3 for
indications for CPET.
Box 6-3
Indications for Cardiopulmonary Exercise Testing
ū To determine exercise capacity or the cause of any exercise impairment
ū To identify abnormal responses to exercise
ū To stratify risk and exercise response for training and rehabilitation
ū To evaluate results of treatment
ū For preoperative assessment
ū To evaluate impairment or disability
ū To evaluate unexplained dyspnea
Pulse Oximetry
Pulse oximetry is a convenient, in vivo, noninvasive technique for measuring
oxygen saturation. Oxygen saturation is determined by the ratio of oxyhemo-
globin to the sum of oxyhemoglobin and reduced hemoglobin. Pulse oxime-
ters perform optical measurements across a pulsating arterial bed (on the
finger or ear) at only 2 wavelengths of light to discriminate oxygenated and
deoxygenated hemoglobin. Carboxyhemoglobin and methemoglobin also
absorb light at the wavelengths measured by the pulse oximeter and, if
abundant, can affect the accuracy of the pulse oximeter. These devices
are calibrated by means of healthy volunteers with insignificant amounts
of dysfunctional hemoglobins.33
Pulse oximetry is used widely to assess arterial oxygenation and provides
a useful estimate of hypoxia. Oxygen saturations of less than 93% predict a
partial pressure of oxygen of less than 70 mm Hg. The pulse oximeter has
been validated in various cohorts of patients with presumably normal hemo-
globin levels, such as neonates, and in patients with cyanotic heart disease34;
however, a retrospective review of simultaneous pulse oximetry and arterial
blood gas analysis data obtained in patients with sickle cell disease in the ED
suggested that the pulse oximeter did not predict hypoxemia well.35 Results
from a prospective study in children and adolescents with sickle cell hemoglo-
bin demonstrated that pulse oximetry led to overestimation of the number of
children with hypoxia and could have led to inappropriate treatment with

96
supplemental oxygen.36 Pulse oximetry may be less sensitive to hypoxemia in

patients with more darkly pigmented skin.
One cannot rely on the pulse oximeter for assessing oxygenation in an
adolescent or young adult with potential smoke inhalation. Carbon monoxide
bound to hemoglobin has wavelength-absorption characteristics similar
to those of oxygenated hemoglobin, and patients with smoke inhalation will
have a falsely normal pulse oximetry value. In the evaluation of a patient with
potential smoke exposure, measuring carboxyhemoglobin directly from an
arterial blood sample is essential. Methemoglobin causes the pulse oximeter
readout to tend toward 85%. If the clinician is aware of the presence of dyshe-
moglobins in a patient’s blood, correlation of an arterial blood sample with
pulse oximetry is advisable. Normal oxygen saturation of the blood does not
ensure adequate oxygen delivery to the tissues, especially in patients with
anemia, patients in heart failure, or patients in shock.
Arterial Blood Gas

Arterial blood gas measurements are used to assess oxygenation and
ventilation. This subject is covered in Chapter 2, Pulmonary Physiology.
When to Refer
X Spirometry should be used to confirm a suspected diagnosis of asthma
(reversible airways obstruction) and periodically used to monitor progres-
sion of the disease and its response to therapy. If a primary care office does
not have access to spirometry, children and adolescents who have asthma
or other chronic pulmonary disease should be referred to a pediatric
pulmonologist for evaluation at some point in their course.
X If spirometry is performed, referral to a pediatric pulmonologist or to a
pediatric pulmonary function laboratory should be considered if there is:
ū Any suggestion of restriction
ū Severe degree of obstruction
ū Nonresponsiveness or ambiguous response to bronchodilators
ū Unexplained inability to perform acceptable or reproducible forced
expiratory maneuvers
ū Clinical history inconsistent with pulmonary function findings.

97
key points
} Spirometry is useful to distinguish restrictive from obstructive lung disease to
develop a differential diagnosis in children with chronic respiratory symptoms.
} Using PFTs can provide objective evidence of the severity of pulmonary disease,
changes over time, and response to therapies (eg, in disorders such as asthma,
CF, sickle cell disease, and muscular dystrophy).
} Although some children can perform spirometry as young as age 3 years,
consistent results are more likely after the age of 6 years.
} Measurement of RV requires more sophisticated testing than simple spirometry
and should be performed in a pulmonary function laboratory with experience
testing in children.
} Pulmonary function testing may be useful in the primary care office, but
oversight and interpretation by the pediatric pulmonologist is helpful and using
appropriate normative data for comparison is essential.
} If the primary care office performs PFTs, it is important that there is a mecha-
nism in place to ensure that studies are performed to American Thoracic Society
guidelines, which implies that there is a medical director responsible for
oversight of the testing.
} Exercise challenge should be used for evaluating exercise-related symptoms,
particularly if lung function measures are normal at rest and there is little or no
response to therapy.
} Cardiopulmonary exercise testing can be used to evaluate fitness or the cause
of exercise limitations.
} Pulse oximetry is a useful, noninvasive test to measure arterial oxygen
saturation, but it has limitations (eg, normal adult hemoglobin is assumed).
References
1. American Thoracic Society. Pulmonary function testing. Accessed October 6, 2021.
https://www.thoracic.org/statements/pulmonary-function.php
2. National Heart, Lung, and Blood Institute of the National Institutes of Health. Guidelines
for the diagnosis and management of asthma 2007 (EPR–3). Accessed March 15, 2022.
https://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm
3. Hsu KH, Jenkins DE, Hsi BP, et al. Ventilatory functions of normal children and young
adults—Mexican-American, white, and black. I. Spirometry. J Pediatr. 1979;95(1):14–23
PMID: 479997 doi: 10.1016/S0022-3476(79)80075-X
4. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the
general U.S. population. Am J Respir Crit Care Med. 1999;159(1):179–187 PMID: 9872837
doi: 10.1164/ajrccm.159.1.9712108
5. Radeos MS, Camargo CA Jr. Predicted peak expiratory flow: differences across formulae
in the literature. Am J Emerg Med. 2004;22(7):516–521 PMID: 15666252
doi: 10.1016/j.ajem.2004.08.018
6. New NHLBI guidelines for the diagnosis and management of asthma. National Heart, Lung and
Blood Institute. Lippincott Health Promot Lett. 1997;2(7):1, 8–9 PMID: 9300898
7. Mannino DM, Homa DM, Akinbami LJ, Moorman JE, Gwynn C, Redd SC. Surveillance for
asthma—United States, 1980-1999. MMWR Surveill Summ. 2002;51(1):1–13 PMID: 12420904
8. Beydon N, Davis SD, Lombardi E, et al; American Thoracic Society/European Respiratory
Society Working Group on Infant and Young Children Pulmonary Function Testing. An official
American Thoracic Society/European Respiratory Society statement: pulmonary function
testing in preschool children. Am J Respir Crit Care Med. 2007;175(12):1304–1345
PMID: 17545458 doi: 10.1164/rccm.200605-642ST

98
9. Turner DJ, Lanteri CJ, LeSouef PN, Sly PD. Improved detection of abnormal respiratory
function using forced expiration from raised lung volume in infants with cystic fibrosis.
Eur Respir J. 1994;7(11):1995–1999 PMID: 7875271
10. Davis S, Jones M, Kisling J, Howard J, Tepper RS. Comparison of normal infants and infants
with cystic fibrosis using forced expiratory flows breathing air and heliox. Pediatr Pulmonol.
2001;31(1):17–23 PMID: 11180670
doi: 10.1002/1099-0496(200101)31:1<17::AID-PPUL1002>3.0.CO;2-8
11. Pattishall EN. Pulmonary function testing reference values and interpretations in pediatric
training programs. Pediatrics. 1990;85(5):768–773 PMID: 2330239 doi: 10.1542/peds.85.5.768
12. Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests.
Eur Respir J. 2005;26(5):948–968 PMID: 16264058 doi: 10.1183/09031936.05.00035205
13. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault J-C. Lung volumes
and forced ventilatory flows. Eur Respir J. 1993;6(suppl 16):5–40 PMID: 24576915
doi: 10.1183/09041950.005s1693
14. Cooper BG, Stocks J, Hall GL, et al. The Global Lung Function Initiative (GLI) Network:
bringing the world’s respiratory reference values together. Breathe (Sheff). 2017;13(3):e56–e64
PMID: 28955406 doi: 10.1183/20734735.012717
15. Ramsey NB, Apter AJ, Israel E, et al. Deconstructing the way we use pulmonary function test
race-based adjustments. J Allergy Clin Immunol Pract. 2022;10(4):972–978 PMID: 35184982
doi: 10.1016/j.jaip.2022.01.023
16. Schluger NW, Dozor AJ, Jung YEG. Rethinking the race adjustment in pulmonary
function testing. Ann Am Thorac Soc. 2022;19(3):353–356 PMID: 34784493
doi: 10.1513/AnnalsATS.202107-890PS
17. Schluger NW. The vanishing rationale for the race adjustment in pulmonary function test
interpretation. Am J Respir Crit Care Med. 2022;205(6):612–614 PMID: 35085469
doi: 10.1164/rccm.202112-2772ED
18. Wright JL, Davis WS, Joseph MM, Ellison AM, Heard-Garris NJ, Johnson TL; AAP Board
Committee on Equity. Eliminating race-based medicine. Pediatrics. 2022;150(1):e2022057998
PMID: 35491483 doi: 10.1542/peds.2022-057998
19. Macintyre N, Crapo RO, Viegi G, et al. Standardisation of the single-breath determination of
carbon monoxide uptake in the lung. Eur Respir J. 2005;26(4):720–735 PMID: 16204605
doi: 10.1183/09031936.05.00034905
20. Zapletal A, Houstĕk J, Samánek M, Copová M, Paul T. Lung function in children and
adolescents with idiopathic interstitial pulmonary fibrosis. Pediatr Pulmonol. 1985;1(3):154–166
PMID: 3877269 doi: 10.1002/ppul.1950010307
21. Vrijlandt EJ, Gerritsen J, Boezen HM, Grevink RG, Duiverman EJ. Lung function and exercise
capacity in young adults born prematurely. Am J Respir Crit Care Med. 2006;173(8):890–896
PMID: 16456146 doi: 10.1164/rccm.200507-1140OC
22. Weiner DJ, Maity A, Carlson CA, Ginsberg JP. Pulmonary function abnormalities in children
treated with whole lung irradiation. Pediatr Blood Cancer. 2006;46(2):222–227
PMID: 15926160 doi: 10.1002/pbc.20457
23. Abu-Hasan M, Tannous B, Weinberger M. Exercise-induced dyspnea in children and
adolescents: if not asthma then what? Ann Allergy Asthma Immunol. 2005;94(3):366–371
PMID: 15801248 doi: 10.1016/S1081-1206(10)60989-1
24. Miller MR, Hankinson J, Brusasco V, et al; ATS/ERS Task Force. Standardisation of
spirometry. Eur Respir J. 2005;26(2):319–338 PMID: 16055882
doi: 10.1183/09031936.05.00034805
25. Ulrik CS, Postma DS, Backer V. Recognition of asthma in adolescents and young adults:
which objective measure is best? J Asthma. 2005;42(7):549–554 PMID: 16169787
doi: 10.1080/02770900500215715
26. Crapo RO, Casaburi R, Coates AL, et al; American Thoracic Society. Guidelines for
methacholine and exercise challenge testing—1999. This official statement of the American
Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit
Care Med. 2000;161(1):309–329 PMID: 10619836
27. Chai H, Farr RS, Froehlich LA, et al. Standardization of bronchial inhalation challenge
procedures. J Allergy Clin Immunol. 1975;56(4):323–327 PMID: 1176724
doi: 10.1016/0091-6749(75)90107-4
28. Godfrey S. Exercise-induced asthma—clinical, physiological, and therapeutic implications.
J Allergy Clin Immunol. 1975;56(1):1–17 PMID: 805807 doi: 10.1016/0091-6749(75)90029-9

99
29. Backer V, Ulrik CS. Bronchial responsiveness to exercise in a random sample of 494 children
and adolescents from Copenhagen. Clin Exp Allergy. 1992;22(8):741–747 PMID: 1525692
doi: 10.1111/j.1365-2222.1992.tb02813.x
30. Cropp GJ, Schmultzler IJ. Relative sensitivity of different pulmonary function tests in the
evaluation of exercise-induced asthma. Pediatrics. 1975;56(5 pt-2)(suppl):860–867
PMID: 1187276 doi: 10.1542/peds.56.5S.860
31. Haby MM, Anderson SD, Peat JK, Mellis CM, Toelle BG, Woolcock AJ. An exercise challenge
protocol for epidemiological studies of asthma in children: comparison with histamine challenge.
32. American Thoracic Society; American College of Chest Physicians. ATS/ACCP statement on
cardiopulmonary exercise testing [published correction appears in Am J Respir Crit Care Med.
2003:1451–1452]. Am J Respir Crit Care Med. 2003;167(2):211–277 PMID: 12524257
doi: 10.1164/rccm.167.2.211
33. Yelderman M, New W Jr. Evaluation of pulse oximetry. Anesthesiology. 1983;59(4):349–352
PMID: 6614545 doi: 10.1097/00000542-198310000-00015
34. Poets CF, Southall DP. Noninvasive monitoring of oxygenation in infants and children:
practical considerations and areas of concern. Pediatrics. 1994;93(5):737–746 PMID: 8165071
doi: 10.1542/peds.93.5.737
35. Goepp J, Murray C, Walker A, Simone E. Oxygen saturation by pulse oximetry in patients
with sickle cell disease: lack of correlation with arterial blood gas measurements [abstract].
Pediatr Emerg Care. 1991;7:387
36. 35. Blaisdell CJ, Goodman S, Clark K, Casella JF, Loughlin GM. Pulse oximetry is a poor
predictor of hypoxemia in stable children with sickle cell disease. Arch Pediatr Adolesc Med.
2000;154(9):900–903 PMID: 10980793 doi: 10.1001/archpedi.154.9.900

CHAPTER
7
Pulmonary Imaging
Julieta M. Oneto, MD
Ricardo Restrepo, MD
Radiation Exposure in Children

A clinician ordering an imaging test must be familiar with the indications
and contraindications of multiple imaging modalities and their alternatives,
taking into consideration factors such as radiation exposure, cost, and goal of
imaging. A major concern with imaging in children is the child’s exposure to
ionizing radiation. Pediatric radiologists modify imaging parameters to mini-
mize radiation by following standard protocols, particularly for computed
tomography (CT) scans. Pediatric radiologists keep in mind the concept of
as low as reasonably achievable in terms of a child’s exposure to radiation
during imaging. The Image Gently campaign1 is an initiative of the Alliance
for Radiation Safety in Pediatric Imaging. The campaign goal is to change
practice by increasing the awareness of the opportunities to lower radiation
dose while performing imaging in children.
Ionizing radiation is used in plain radiography, fluoroscopy, and CT scanning.
The effective dose is a calculated age- and sex-averaged value that is used as a
measure of the potential risk of cancer and hereditary effects due to exposure
to ionizing radiation by comparing that value with those of other sources of
exposure such as background radiation or air travel.
The biological effect of ionizing radiation is represented in the unit of Sieverts,
which is the product of the absorbed dose and a weighting factor. The weight-
ing factor is a function of the type of radiation and the tissue involved.2
Ionizing radiation has the potential to alter DNA directly or by generating
free radicals. In the extreme, ionizing radiation causes cell death. In addition,
high doses of ionizing radiation are carcinogenic. Medical imaging accounts
for an increasing amount of radiation exposure to the general population.
In the United States, imaging accounts for about 50% of the total radiation
exposure; of this amount, 50% is accounted for by CT scanning. Children
are 2 to 10 times more susceptible to radiation of all kinds than are adults.
101

102
The risk of cancer from radiation has not been defined, and clinical studies
have not been performed to define the risk-versus-benefit ratio. The theoretical
risk of radiation exposure from medical imaging has been suggested from
the studies of cancer incidence in survivors of the Hiroshima atomic bomb.
Moderate or severe exposure (> 100–150 mSv) is clearly a cancer risk, but lower
levels are less obvious. The difference in effect on the body between acute and
chronic exposure is not fully understood, but it is clear that exposures over a
lifetime are cumulative.
The dose of a single chest radiograph is approximately 0.1 mSv, which is
equivalent to the natural background radiation that the population is exposed
to in 10 days. In an effort to decrease radiation, pediatric radiologists have
developed a low-dose protocol that can reduce the radiation dose in children.2,3
Recently, ultralow-dose protocols have been developed for patients with chronic
conditions, such as cystic fibrosis (CF), that require continuous follow-up. Such
ultralow-dose protocols can have an effective dose as low as 0.14 mSv.4 Chil-
dren with chronic conditions have a longer life expectancy than in the recent
past, and their exposure to medical imaging is higher as well.
Imaging Approach
Several modalities are available to evaluate the chest and its structures in
children. In general, chest radiography is the initial imaging approach when
a chest anomaly is suspected. General suggestions on choosing an imaging
technique are found in Table 7‑1.
Table 7‑1. Imaging Approach According to Condition or Suspected Condition
Indication Imaging Modality
Suspected foreign body Expiratory radiography, or bilateral lateral
decubitus if patient cannot breathe on
command (due to age or developmental delay)
Suspected pneumothorax Lateral radiography with suspected side up
Ultrasonography
Suspected fluid in pleural space Lateral decubitus and radiography
Ultrasonography
Visualized structural anomalies (chest wall, MDCT scanning, with or without contrast
vascular, tracheobronchial tree, lung material
parenchyma)
Anomalies of the tracheobronchial tree, CT virtual bronchoscopy
evaluate lumen and pulmonary infiltrates
that fail to resolve in 10 to 14 days
Chronic unexplained respiratory symptoms CT virtual bronchoscopy
with low suspicion for foreign body
Pleural effusion Ultrasonography

103
Chapter 7—Pulmonary Imaging
Table 7‑1. Imaging Approach According to Condition or Suspected Condition (continued)

Indication Imaging Modality
Lung abscess CT scanning
Suspected vascular rings Swallow study or CT angiography
Visualized vascular rings MRI
Characterized vasculature of MRI
developmental lung malformations
Chronic interstitial process HRCT scanning
Airspace disease CT scanning
Bronchiectasis HRCT scanning
Asthma complications CT or HRCT scanning
Measuring airway thickness MDCT scanning
Uncomplicated pneumonia No imaging is required
Complicated pneumonia Chest radiography as an initial step; CT
scanning as clinically indicated
Anterior or middle mediastinal mass CT scanning, PET scanning for lymphoma
Posterior mediastinal mass MRI
Abbreviations: CT, computed tomography; HRCT, high-resolution CT; MDCT, multidetector CT;
MRI, magnetic resonance imaging; PET, positron emission tomography.
Chest Radiography
The posteroanterior (PA) and lateral views are the standard order for chest
radiography. Although a single view saves cost, it has not been shown to be
useful because the diaphragm obscures much of the lung field in the PA view,
particularly the bases. The radiograph is obtained at full inspiration, which may
be difficult to time in the young child. Full inspiration typically results in the
diaphragm being at the level of the eighth to tenth posterior rib or the fifth to
sixth anterior rib. Whenever possible, the patient should undergo imaging in the
upright position. On occasion—for example, in evaluating for a foreign body or
pneumothorax—an expiratory radiograph may be ordered. The anteroposterior
(AP) portable radiograph, obtained with the patient in bed, may not present as
clear an image as that taken in the radiology department, but it is of great value
in imaging patients who are critically ill. A lateral decubitus radiograph may
be ordered to evaluate layering of fluid in the pleural space; however, this
radiograph has been largely replaced by ultrasonography because ultrasonogra-
phy does not involve radiation, can be performed at the bedside, and allows
evaluation of the pleural effusion’s characteristics. The dependent lung in the
lateral decubitus radiograph should show increase in density because atelectasis
results from the weight of the mediastinum. Failure to show increased density
suggests that there is air trapping, which is useful to know if a foreign body is
suspected. A lordotic view is obtained to view the apices of the lungs.

104
Multidetector CT Scanning
Multidetector CT (MDCT) scanning is considered the best modality to
characterize in detail the chest wall, vascular structures, tracheobronchial
tree, and lung parenchyma. The different postprocessing techniques, 2- and
3-dimensional reformations, virtual bronchoscopy (VB), and maximum
intensity projections allow detailed characterization of structural anomalies
(Figure 7-1). Computed tomography provides accurate information about
the location and extent of involvement, as well as anatomical landmarks
and relationship to the abnormality in question.
Figure 7‑1. B, Three-dimensional volume

rendered image, also known as virtual bron-
choscopy, showing laryngeal papillomatosis
(arrows).
Figure 7‑1. A, Computed tomography scan
of the neck showing laryngeal papillomatosis
(arrow).
Figure 7‑1. C, Computed tomography scan

showing the tracheal bronchus (arrows).

105
Virtual bronchoscopy is a relatively new technique that provides an internal

rendering of the tracheobronchial walls and lumen.5 Despite the use of a low-
tube-current technique and rapid table speed, the major disadvantage of CT
scanning and VB is radiation exposure. Indications for VB include pulmonary
infiltrates that fail to resolve in the usual time (10–14 days) and chronic, un-
explained respiratory symptoms in a patient who has a low suspicion for
foreign body aspiration and normal or nonspecific chest radiographic results.
The advantages of VB are the ability to evaluate tortuous structures and
segmental and subsegmental bronchi, which are hard to evaluate with con-
ventional bronchoscopy given the small size of airways in children. Virtual
bronchoscopy also allows evaluation distal to the obstruction and proper
visualization of upper lobe bronchi that arise at an acute angle from
the major bronchi.6,7
Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) is appropriate in certain circumstances;
however, the evaluation of the lung parenchyma with this technique is limited.
Magnetic resonance imaging may help characterize the vasculature of devel-
opmental lung malformations or vascular rings. A magnetic resonance (MR)
angiogram provides a very detailed map of the vasculature (Figure 7-2).3
Magnetic resonance
imaging is accurate in
evaluating chest wall
masses and depicting
intraspinal extension
of neurogenic lesions
in the posterior media-
stinum, a feature that
helps in the differential
diagnosis and treatment.
Disadvantages of MRI
include its availability
and the length of the
studies that in some
cases require sedation.8
Figure 7‑2. A, Plain chest radiograph showing scimitar

syndrome, also known as hypogenetic lung syndrome. The
arrow shows the vein that drains into the inferior vena cava.

106
Figure 7‑2. B, Magnetic resonance

image showing scimitar syndrome.
The thick arrows show the pulmonary
vein draining into the inferior vena
cava (IVC).
Abbreviation: RLPV, right lower pulmonary vein
(thin arrow).
Figure 7‑2. C, Three-dimensional

reconstruction of Figure 7-2B. The
long arrows show the pulmonary vein
draining into the inferior vena cava
(IVC; short arrow).

107
Ultrasonography
Although ultrasonography has not replaced the stethoscope, it is increasingly
used to evaluate the lungs (and heart) in the emergency department and inten-
sive care unit. For imaging the fetus, ultrasonography is of particular value
when bronchopulmonary foregut malformations or diaphragmatic hernias are
suspected. Ultrasonography is very helpful in evaluating pleural effusions,
providing the best detail
of the fluid consistency
and demonstrating septa-
tions, solid components,
or debris that cannot
be well characterized
on radiographs or CT
scans (Figure 7-3).9
Assessing mediastinal
vascular structures and
the thymus is possible
with ultrasonography by
using the correct acoustic
window. For superficial
chest wall lesions, ultra-
sonography also can
provide information
regarding the cystic or
Figure 7‑3. A, Radiograph showing hydropneumothorax.
Note the central trachea. The upper arrow shows the lung solid nature of a mass,
margin, and the lower arrow shows the air-fluid interface. the presence of fat or
calcification, and the
margins and size of a
lesion if confined to
the superficial tissues,
which helps narrow the
differential diagnosis
and provides guidance
regarding a therapeutic
approach. The advan-
tages of ultrasonography
include no need for seda-
tion, cost savings when
compared with CT scan-
ning, portability, and
lack of radiation.10
Figure 7‑3. B, Ultrasonographic image showing the pleural
effusion in Figure 7.3A.

108
Angiography
Traditionally, angiography was the technique of choice for imaging vascular
anomalies, particularly when vascular rings, pulmonary sequestration, or
hypogenetic lung syndrome is suspected and surgical treatment is considered.
Currently, MDCT scanning has replaced conventional angiography because
of its exquisite spatial resolution, noninvasiveness, and multiplanar reforma-
tion capabilities allowing the characterization of other tissues (Figure 7-4).
Figure 7‑4. A, Multidetector

computed tomography scan
showing a vessel (arrow)
supplying sequestration.
Figure 7‑4. B, Computed tomography

reconstruction of Figure 7-4A. The
arrows show the vessel supplying
the sequestered lobe.

109
Ventilation/Perfusion Scanning
Ventilation/perfusion scanning indicates the degree of vascular perfusion of
different lobes of the lung and the distribution of ventilation. Ventilation scan-
ning is performed as the child inhales xenon through a mask. The perfusion
study is performed by injecting nuclear particles that produce microemboli
in the parenchyma of the lung, which can indicate the degree of vascular
perfusion of the different lobes of the lung. The results are expressed as
percentages of ventilation and perfusion.
Chest Radiograph Report

The radiology report is a consultation between the radiologist and the physi-
cian who orders the study. It is helpful for the ordering physician to view
the images rather than rely only on the written or oral report. It is not only
a good exercise but also a good practice because the referring physician has
knowledge of the entire clinical history and may aid in the final diagnosis. If
necessary, the radiologist can be contacted in person or by phone to explain
the findings in greater detail. The written report is part of the medical record
and, as such, may be written in language that requires interpretation. It may
be useful to discuss the findings with the radiologist, who may provide
additional information that is not in the report. A good example is the state-
ment, “these findings are consistent with the diagnosis of pneumonia,”
which may mean that this is likely a case of pneumonia or alternatively that
pneumonia is in the differential diagnosis. Two different radiologists might
report the same radiograph as “pneumonia in the right lower lobe” and “there
is an infiltrate in the right lower lobe.” It is good practice for radiologists
to describe the findings and in the conclusion to include a brief summary
followed by a differential diagnosis in descending order of possibility. The
radiologist should be able to provide insight to help refine the physician’s
decision for treatment or perhaps recommend additional imaging.
Reading the Chest Radiograph

The first step in evaluating the radiograph is to identify the name and the
date of birth or medical record number and note the date of the radiograph,
although the widespread use of picture archiving and communication systems
obviates this step. If prior studies are available, comparison of the findings
with previous radiographs helps to identify acute versus chronic abnormalities
and change over time.
Radiologists are trained to evaluate the quality and the technique of the study.
An appropriate depth of penetration is important for a good radiograph. The
thoracic spine should be visible on the PA radiograph above the carina and
almost invisible behind the heart. The position of the chest is also important.
If there is rotation, the lucency of the 2 lungs will be unequal and will need

110
to be differentiated from alterations in aeration of the lungs. Also in a

rotated radiograph, one pulmonary hilum is more exposed and may be
misinterpreted as a perihilar opacity. The degree of rotation is assessed by
looking for symmetry of the ribs and the position of the ends of the clavicles.
Landmarks and Structures

The chest radiograph is a 2-dimensional picture, so objects outside the chest
may be superimposed, including monitor leads, jewelry, hair plaits, and other
objects that may confuse the picture. An initial broad view should be taken to
include the mediastinum and the position of the trachea and the great vessels.
The cardiothoracic ratio should be less than 50% in the upright PA view, but
the heart will appear larger than in the PA view if the image was obtained
with a supine or AP view or by using portable radiography. These factors
must be considered before making a diagnosis of cardiomegaly, particularly
from an AP radiograph. The physician should review the lung fields from the
apices to the costophrenic angles while comparing the right lung to the left
lung. The right diaphragm is typically higher than the left diaphragm, and the
outline should be clear and continuous. The costophrenic angles should be
sharp; if they are blunted, it may indicate a pleural effusion or sometimes
pleural thickening. When a pleural effusion is small, it may be obscured by
the overlying lung in an upright radiograph. When a pleural effusion is large
enough and free-floating, a meniscus sign typically is visible. On a supine
radiograph, a free-floating pleural effusion will layer, and the involved
hemithorax will appear diffusely hazy.
A deviation or shifting of the position of the heart and mediastinum toward
one side of the chest may suggest volume loss on that side. If the mediastinum
shifts away from the lesion, this suggests a space-occupying lesion or pleural
effusion. A large tension pneumothorax will shift the mediastinum toward
the other side of the chest.
If the hilum is enlarged, it may be because of enlarged pulmonary vessels,
enlarged lymph nodes, or a mass in the area. Peribronchial thickening (or
cuffing) is caused by inflammation or edema of the airways and is a common
finding in children with reactive airway disease, especially in preschoolers or
in patients with viral lower respiratory infections. Pulmonary edema is also a
cause of peribronchial cuffing.
Silhouette Sign
The silhouette sign was first described by Dr Ben Felson and is useful to
locate the anatomical position of an abnormality.11 The silhouette sign is
the elimination of the lung and soft-tissue interface and is caused by fluid or
a mass in the lung. The most common example of this sign is the presence of

111
a right middle lobe opacity that obscures the border of the right side of the
heart. If the opacity was in the right lower lobe, the border of the right side
of the heart would be visible (Figure 7-5). Another example of the silhouette
sign is the lingular opacity overlying and obscuring the border of the left side
of the heart. The silhouette sign is applicable to the heart, aorta, chest wall,
and diaphragm.
Figure 7‑5. Radiographs showing right middle lobe pneumonia obscuring the border of
the right side of the heart and demonstrating a positive silhouette sign. (A) Arrow shows the
horizontal fissure. (B) The upper arrow shows the horizontal fissure, and the lower arrow
shows the oblique fissure.
Fluoroscopy
Fluoroscopy is used for dynamic airway assessment to evaluate the following:
X Diaphragmatic motion
X Tracheomalacia and laryngomalacia
X Airway obstruction in suspected foreign bodies
Fluoroscopy is also used for a swallow function study.

X Generally performed by a radiologist with an experienced speech pathologist
X Performed to evaluate the mechanics and efficiency of swallowing
X Can be used to identify aspiration during ingestion of liquids or solids

112
Other Specific Findings

The following terms are words radiologists commonly use to describe
findings to reach a differential diagnosis. The Fleischner Society unified
this thoracic imaging terminology most recently in 2008.12
A bronchogram refers to the outline of the airway made visible by
filling the alveoli with cells or fluid. The air bronchogram is seen in the
following situations:
X Any condition causing lung consolidation, most commonly pneumonia
X Atelectasis
X Neonatal respiratory distress syndrome
X Acute lung injury (adult respiratory distress syndrome)
X Some neoplasms
X Normal expiration
Atelectasis is collapse or incomplete expansion of the lung or part of the lung
and is described in Chapter 25, Atelectasis. It can be lobar, segmental, or
subsegmental, depending on the extension, and passive or postprogressive
according to the pathophysiological characteristics. Atelectasis appears as an
increased density on the chest radiograph and is in the differential diagnosis
of a parenchymal consolidation.
Infiltrate is a term formerly used to describe an ill-defined opacity in the lung
field that almost by definition is not diagnostic of any specific abnormality
and should be interpreted with caution. Even though some radiologists still
frequently use the term to refer to pneumonia, it is not synonymous with this
condition. The use of the term infiltrate is currently discouraged; the correct
term to be used is opacity or airspace disease.
A consolidation is characteristic of lobar pneumonia, and the area may
increase in size. If the involved area is airless and decreased in size, it is
described as collapse. Areas of consolidation may be seen with pulmonary
hemorrhage and vasculitic disorders in addition to the diagnosis of pneumo-
nia. Lobar consolidation is classically seen in pneumococcal pneumonia.
Interstitial as a descriptor has fallen out of favor. By definition, the intersti-
tium is a continuum of connective tissue throughout the lung, including the
bronchovascular, the parenchymal and acinar, and the subpleural connective
tissue. The correct terms to be used are reticular pattern and reticulonodular
pattern. A reticular pattern usually indicates interstitial lung disease (ILD).
Interstitial pneumonia is more commonly seen with atypical organisms or
viral pneumonia. A nodular pattern is characterized on chest radiographs by
the presence of myriad tiny round opacities ranging from 2 to 10 mm that are

113
usually widespread. When a reticular pattern is combined with a nodular

pattern, it is known as a reticulonodular pattern. Recognition of these
patterns is critical because each is associated with a subset of diseases
that is useful when generating a differential diagnosis.
An opacity should be characterized by noting the size and shape, the number
and location, the margins, and the homogeneity. Comparison with a previous
radiograph is important. Ground-glass opacities are partially filled airspaces
(with fluid or cells) and interstitial thickening. At CT scanning, this finding
is seen as hazy lung parenchyma that is not opaque enough to obscure the
adjacent interstitial prominence, as opposed to a consolidation. Ground-glass
opacities are seen in patients with pulmonary edema, pulmonary hemorrhage,
pneumocystis pneumonia, and alveolar proteinosis, among many other entities
(Figure 7‑6). They are also seen in those with chronic ILDs and even as
an incidental finding in the dependent portion of the lungs as the result of
blood flow redistribution in the horizontal position. In cases of ILD, they
are considered a marker of active disease and suggest inflammation or
alveolitis, which are potentially treatable.13
A micronodule is a discrete opacity in the lung measuring less than 3 mm,
whereas nodules are rounded opacities, well- or ill-defined, measuring
up to 3 cm in diameter, without regard for contour, border, or intensity. The
term mass implies a solid or partially solid lesion that may be caused by infec-
tion, by a granuloma
such as tuberculosis
(TB), or by a tumor
(benign or malignant).
Vascular anomalies
may have the appear-
ance of a nodule and
may be caused by
arteriovenous mal-
formation and lung
infarct, Wegener
granulomatosis, or
rheumatoid arthritis.
Figure 7‑6. Plain chest radiograph showing a ground-glass

appearance.

114
The rate of a nodule’s enlargement is helpful in diagnosis. If the lesion doubles

in size within a month, the diagnosis is likely infection, vascular lesion, or
infarction. If the doubling time is 6 to 18 months, it is likely a benign tumor
or malignant granuloma; if the doubling time is more than 24 months, then
a benign nodule is likely. The presence of multiple nodules may indicate
various causes, as shown in Box 7‑1.
Box 7‑1
Causes of Multiple Nodules
ū Infection: tuberculosis, fungal infection
ū Neoplasm: lymphoma, hamartoma, metastatic lesions
ū Rheumatoid: Wegener granulomatosis
ū Granuloma: systemic lupus erythematosus
A cavity is essentially a hole in the lung caused by destruction of lung

parenchyma. The most common cause in children is infection, known as
necrotizing pneumonia. Pneumococcus is the most common cause of necro-
tizing pneumonia. Other microorganisms potentially causing cavitation
include Staphylococcus aureus, Mycobacterium tuberculosis, gram-negative
bacteria (especially Klebsiella), group A Streptococcus, anaerobic bacteria,
and fungi. It is also seen in nontuberculous mycobacteria in children with
CF. Cavitation also can occur in those with septic emboli or vasculitis, such
as Wegener granulomatosis.
Cystic changes in the lung are seen in the late stages of pulmonary fibrosis,
also known as honeycomb lung. Cysts are also seen with bronchiectasis,
especially saccular bronchiectasis.
A pneumatocele is an air-filled, thin-walled space that is most commonly
associated with prior history of pneumonia or trauma. The pathophysiological
mechanism is unclear but is believed to be due to either focal overinflation or
parenchymal necrosis, with a check valve mechanism that may allow it to
grow. In most cases, it resolves spontaneously.14
A bleb is a small gas-containing space smaller than 1 cm within the visceral
pleura or subpleural lung, and a bulla is 1 cm or larger; however, the distinc-
tion is of little clinical significance. They can be associated with other signs
of pulmonary emphysema. The cause of blebs and bullae is not known, but
they are still meaningful because the possibility of rupture or air leakage
may result in pneumothorax.
A cyst is a gas-filled round space, which also may be fluid filled or solid,
surrounded by a thin wall (< 2 mm) and without evidence of emphysema.
Cysts are seen in patients with Langerhans cell histiocytosis or in

115
lymphangioleiomyomatosis. Thicker-walled cysts are seen in the development

of end-stage fibrosis (honeycomb lung).
Bronchiectasis is usually considered irreversible localized or diffuse bron-
chial dilatation secondary to bronchial wall destruction. Three types are
described: cystic, cylindrical, and saccular. Cases of reversible or temporary
bronchiectasis are related to the re-expansion of a lung that has been collapsed
due to infection or atelectasis,15 as well as in cases of acute pneumonia, bron-
chitis, and allergic bronchopulmonary aspergillosis (ABPA). Its distribution
is also important in narrowing the cause. Upper lobe bronchiectasis is more
common in patients with CF and chronic mycotic and mycobacterial infec-
tions, the lower lobes are more commonly involved in idiopathic cases, and
perihilar or central bronchiectasis is frequently seen in those with ABPA.16
Reading the CT Scan

In CT scanning, the scan is axial and is reconstructed so that 3 planes—
coronal, sagittal, and oblique—can be viewed. The usual chest CT scan is
viewed as a cross-section, which implies a horizontal section from the neck
to the abdomen if someone is standing. The standard CT scan of the chest pro-
vides continuous images of sections of the lung, whereas a high-resolution CT
(HRCT) scan has thin sections with skipped areas between the sections. The
parameters used at HRCT scanning are meant to optimize spatial resolution
to assess fine parenchymal patterns. The images obtained will be representa-
tive of the overall lung parenchyma but only cover skipped areas and may not
reveal small isolated findings (eg, isolated cavity or nodule, consolidation). It
is best used to evaluate diffuse parenchymal disease. Examples of diseases
well assessed with HRCT scanning are bronchiectasis, CF, immotile cilia
syndrome, asthma, Langerhans cell histiocytosis, interstitial pneumonias,
ABPA, recurrent aspiration, and pulmonary infections.17
The range of normal findings has considerable overlap with disease, and
care must be taken to avoid overinterpretation, particularly for the ground-
glass appearance.5 Computed tomography scanning has become very sophis-
ticated and provides images that are not overlaid by tissues, as occurs with
2-dimensional radiography, and results in much clearer CT images. Instant
reformation in different planes allows the review of the examination on the
axial and coronal planes and can help sort out findings that are merely normal
structures. The mediastinal structures, especially the vessels, can be evaluated
only with intravenous contrast material. The indications for using intravenous
contrast material are many, but in general it is administered to evaluate neo-
plasms in the mediastinum, lung, and chest wall; pulmonary and chest wall
abscesses; pleural effusions; congenital developmental lung malformations;
and adenopathy.

116
Ground-glass attenuation is a hazy attenuation of the lung parenchyma and is

caused by alveolar filling, interstitial thickening, or both.18 The appearance is
visible on chest radiographs but is more obvious on CT scans.
It is seen with infant respiratory distress syndrome, pulmonary edema, inter-
stitial pneumonitis, idiopathic pulmonary fibrosis, and alveolar proteinosis
(Figure 7‑7). The tree-in-bud pattern, seen on thin-section CT scans, is the
finding of linear branching opacities of similar caliber connecting to small
centrilobular nodules of soft tissue and indicating bronchiolar luminal impac-
tion with mucus, pus, or fluid, which makes the normally invisible peripheral
airways visible (Figure 7‑8). A tree-in-bud pattern is not visible on the chest
radiograph. It is indicative of inflammation and is nonspecific, although cer-
tain conditions are associated with the finding. Originally, it was used as
an indicator of endobronchial spread of TB, but any infectious organism—
bacterial, viral, fungal, or
parasitic—may cause the
pattern.6 It has also been
noted in bronchogenic
dissemination of atypical
mycobacteria and is seen
in conditions that result
in bronchiectasis, in-
cluding CF and primary
ciliary dyskinesia. The
tree-in-bud finding is
also seen in ABPA and
Figure 7‑7. Axial computed tomography images in lung connective tissue dis-
window show ground-glass airspace opacities within the right
lower lobe. Consolidation of the left lower lobe is also noted.
orders. Less commonly,
certain malignancies,
Courtesy of Mariangeles Medina Perez, MD.
including gastric, breast,
and renal cancer, can
produce this pattern.19
Figure 7‑8. Computed tomography scan showing tree-in-bud

appearance at the arrows and elsewhere.

117
Imaging for Specific Conditions

Allergic Bronchopulmonary Aspergillosis
Allergic bronchopulmonary aspergillosis usually manifests in children
with long-standing asthma or CF. Aspergillosis infection can be divided
into 5 categories according to manifestation: (1) saprophytic aspergillosis
(aspergilloma in a preexisting cavity), (2) semi-invasive (chronic necrotizing
consolidations), (3) hypersensitivity reaction (ABPA), (4) airway-invasive
aspergillosis (tracheobronchitis, bronchopneumonia), and (5) angioinvasive
aspergillosis. Radiologically, ABPA may manifest with a normal chest radio-
graph or mild hyperinflation. The earlier changes typically are single or
multiple ill-defined opacities and tubular finger-in-glove areas of increased
density in a bronchial distribution in the upper lobes. The later stages include
bronchiectasis with fibrotic changes.
In children with debilitating chronic illness, aspergillosis may manifest in
a semi-invasive form with segmental unilateral or bilateral consolidations
with or without cavitation; however, the course of the disease takes years
and is most commonly seen in adulthood. Airway-invasive and angioinvasive
aspergillosis are more common in patients who are immunocompromised.
Airway-invasive disease manifests as acute tracheobronchitis with bron-
chiolitis (tree-in-bud pattern on CT scans) and bronchopneumonia in a
peribronchial distribution. Angioinvasive disease manifests as nodules
surrounded by a halo of ground-glass attenuation (halo sign).20
Hypersensitivity Pneumonitis
Hypersensitivity pneumonitis, also called extrinsic allergic alveolitis, is
the immunologic response to allergens from organic dust of plant or animal
origin or chemicals. Acute hypersensitivity pneumonitis may manifest with a
normal chest radiograph or as airspace consolidations. The subacute form also
may manifest with a normal chest radiograph, but ground-glass opacities and
nodules, and sometimes air trapping, can be observed on HRCT scans. The
chronic manifestation is fibrosis that mostly spares the lung bases, as opposed
to other causes of fibrosis (idiopathic pulmonary fibrosis, interstitial pneumo-
nias), with other associated findings from the acute or subacute form.21,22
Eosinophilic Pneumonia
Acute eosinophilic pneumonia results in diffuse alveolar or alveolar-interstitial
opacities with chest radiography. Computed tomography scanning shows
bilateral patchy areas of ground-glass opacity with septal thickening. There
may be additional areas of consolidation or ill-defined nodules.23,24 The
appearance may be similar to that of hydrostatic pulmonary edema without
cardiomegaly. Chronic eosinophilic pneumonia has CT findings of airspace
opacities predominantly in the upper lobes and peripheral lung fields ranging

118
from ground-glass opacities to consolidations with air bronchograms.

The most distinctive radiographic feature is the photographic negative of
pulmonary edema, which is infrequent and not specific.25
Asthma
Most patients can have asthma diagnosed clinically by means of medical
history and physical examination and tend to respond rapidly to bronchodila-
tor therapy. Therefore, chest radiography is not needed for the diagnosis in
most children. The value of chest radiography is in diagnosing complications,
establishing a precipitating cause for the asthma episode, and excluding
alternate diagnoses that resemble asthma (Box 7‑2).
Hyperinflation is the most common abnormality and is identified radio-
graphically as hyperexpansion, flattening of the diaphragms, increased retro-
sternal lucency, anterior bowing of the sternum, and bulging of the intercostal
rib spaces. There is poor correlation between the degree of hyperinflation and
the severity of the asthma attack or the patient’s responsiveness to therapy.
Hyperinflation can persist even after symptoms resolve in up to 15%
of patients.
The finding of hypoinflation at chest radiography significantly correlates with
hospital admission for children aged 6 to 17 years (but not younger children);
thus, hypoinflation is a poor prognostic sign and may indicate the need for
more aggressive therapy.26 Hypoinflation may result in clinically significant
hypoxemia, possibly because children with asthma exacerbations may begin
to lose their respiratory drive or may exhaust their accessory muscles of
respiration. Bronchial wall thickening is usually transient and is more
common in patients with asthma and superimposed acute viral infections
and in those with persistent asthma.
Box 7-2
Indications for Chest Radiography in Children With Asthma
ū Severe respiratory distress
ū Unequal breath sounds (to exclude pneumothorax)
ū Fever (to exclude pneumonia)
ū Detection of complications such as atelectasis or pneumomediastinum
ū No response to routine treatment
ū When other causes of wheezing are suspected, such as a foreign body,
endobronchial lesion, vascular ring, or cystic fibrosis

119
Atelectasis secondary to thickened airway secretions is common and may be

lobar, segmental, or subsegmental. The next most common finding in children
with complicated asthma is pneumonia. The reported radiographic incidence
of pneumonia ranges from 0% to 30%.
Pneumothorax is an uncommon complication in children with asthma, with a
reported incidence of 0% to 3%.27 It is an important complication of mechani-
cal ventilation in children with asthma and should be suspected if there is
acute deterioration. The reported incidence of pneumomediastinum in chil-
dren with asthma ranges from 0% to 15% and may be underreported. There
is a bimodal distribution, peaking at ages 4 to 6 and 13 to 18 years. The extent
of the pneumomediastinum involved correlates with the severity of the attack.
The diagnosis requires a high level of suspicion because up to 30% of cases
may be missed initially with radiography.28
High-resolution CT scanning in children with asthma provides additional
information about lung disease, including bronchial wall thickening,
narrowing of the bronchial lumen, regions of decreased attenuation and
vascularity on inspiratory scans and air trapping on expiratory scans,
bronchiectasis, emphysema, atelectasis, pneumonia, and mucus impaction.
A combination of inspiratory and expiratory CT scans reveals the major
physiological consequences of small airway diseases. Advanced findings
include bronchiectasis, bronchial wall thickening (because this is caused by
inflammation or remodeling rather than only bronchoconstriction), fibrotic
reactions, and emphysema.29
Airway remodeling refers to the thickening of the airway walls because of
the hypertrophy of smooth muscle, infiltration with inflammatory cells, and
mucous gland hyperplasia. Airway wall thickening has been related to the
severity of the disease and airflow obstruction. Airway thickness can be
measured with HRCT scanning; therefore, the effects of various stimuli
and treatments on remodeling can be monitored longitudinally.30
Bronchiolitis
Although chest radiography is not indicated for children with acute respira-
tory syncytial virus bronchiolitis, the most typical findings are hyperinflation
with flattened diaphragms, increased AP diameter of the chest, and increased
lucency in the anterior clear space. There may be prominent peribronchial
markings and small opacities, particularly in the lower lobes (Figure 7‑9).
Pleural effusion does not occur. Changing atelectasis, especially of the right
upper lobe, may result from inflammation of the airway.

120
Figure 7‑9. A, Plain radiograph

showing bronchiolitis and flattened
diaphragms (black arrows). There is
peribronchial thickening. Note the
herniation of the right lung into the
anterior mediastinum (white arrow).
Figure 7‑9. B, Lateral view

of Figure 7-9A showing flat
diaphragms (black arrows)
and lung in the anterior
mediastinum (white arrow).
Arrowhead shows air trapping.

121
Bronchiectasis
The finding of parallel lines (“tram tracks”) radiating from the hilum is the
hallmark of bronchiectasis on the chest radiograph. The CT scan provides
significantly improved images of the degree and extent of bronchiectasis.
Ring shadows indicate enlarged thickened airways, which may extend well
into the lung parenchyma. Cystic bronchiectasis is often accompanied by
mucus-filled cysts, which may have air-fluid levels. Multiple nodular
densities represent mucous plugging of the peripheral airways.
There are 3 patterns of bronchiectasis that can be identified on CT scan.
Cylindrical bronchiectasis is the earliest change, with dilatation of the
airway and mucous plugging. Varicose bronchiectasis involves increased
dilatation, with ballooning of the airway and reduction of the number of
branching airways to the sixth or seventh generation. The most severe
form of bronchiectasis is cystic or saccular bronchiectasis. Clusters of
cysts may be seen, and on occasion there is a honeycomb appearance.
Congenital Anomalies
Airway Compression Caused by Vascular Anomalies
Vascular rings are congenital anomalies that encircle the esophagus and
trachea and typically compress these structures. They are classified as true
rings (anatomically complete) or partial rings, though both can have similar
clinical manifestations. Types of complete vascular rings include the double
aortic arch and right aortic arch with aberrant left subclavian and left ligamen-
tum arteriosum. Incomplete rings include innominate artery compression and
pulmonary artery sling.31
A double aortic arch is the most common symptomatic vascular ring. It causes
respiratory symptoms earlier in life more frequently than do other vascular
rings. The second most common vascular ring is the right-sided aortic arch
with aberrant left subclavian artery and left-sided ligamentum arteriosum.
Other less commonly encountered rings include a right aortic arch with mirror
image branching and left-sided ligamentum arteriosum, left aortic arch with
aberrant right subclavian artery and right-sided ligamentum arteriosum, and
circumflex aorta (the descending aorta crosses behind the esophagus to the
opposite side of the arch) with a ligamentum arteriosum on the contralateral
side of the arch. The pulmonary artery sling is the anomalous origin of the
left pulmonary artery from the right pulmonary artery coursing between the
trachea and esophagus to reach the left pulmonary hilum. Pulmonary slings
are associated with complete O-shaped tracheal rings in 40% to 50% of cases,
which narrow the trachea. Other airway abnormalities include the bridging
bronchus and tracheal bronchus. Multidetector CT angiography as well as MR
angiography offer exquisite detail of the vascular anatomy. Association with
ipsilateral lung agenesis has been reported.

122
Posteroanterior and lateral chest radiographs may be useful for screening for
vascular rings. Right-sided or double aortic arch, tracheal narrowing, anterior
bowing, and increased retrotracheal soft tissues are the most common find-
ings. At least 1 of these findings is reported in more than 95% of cases.
Therefore, the importance of frontal and lateral chest radiographs cannot be
underestimated because a normal chest radiograph significantly decreases
the likelihood of finding a vascular ring in a patient with symptoms.
Barium esophagography was previously considered the most useful study to
confirm the diagnosis of a vascular ring. A posterior indentation suggests an
aberrant subclavian artery. Bilateral indentation on the AP view suggests a
double arch. Anterior pulsatile indentation of the esophagus is virtually
pathognomonic of pulmonary artery sling.
Computed tomography and MR angiography are now preferred for confirma-
tion of the vascular ring.32 Multidetector CT scanning has advantages in that
it is widely available and has a short scanning time that can obviate sedation.
Computed tomography can be used to evaluate the tracheobronchial tree and
lung parenchyma. Magnetic resonance imaging is advantageous in that its
multiplanar capabilities depict precisely the vascular anatomy.
Lung Malformations
Congenital developmental lung malformations have been described as a
spectrum of disease from lung parenchymal abnormalities with relatively
normal vascularity at one end of the spectrum to vascular abnormalities with
relatively preserved parenchyma at the other end.33,34
Computed tomography angiography provides the more comprehensive
approach because some of these lesions may have arterial, parenchymal,
and tracheobronchial tree abnormalities. Characterizing these structures
is important not only for establishing the diagnosis but also for surgical
planning and evaluation of complications, such as superimposed infections.
Pulmonary Agenesis or Hypoplasia
Radiographically, pulmonary agenesis mimics pneumonectomy. There is
hyperinflation of the remaining lung, mediastinal shift, diaphragmatic
elevation, and sometimes chest wall deformity.
Bronchial Atresia
Bronchial atresia is thought to be due to intrauterine interruption of bronchial
arterial supply. The distal branches can develop normally.

123
Congenital Lobar Hyperinflation

In children with congenital lobar hyperinflation, previously known as
congenital lobar emphysema, the left upper and right middle lobes are the
most commonly affected. Radiographically, this manifests as overinflation
with air trapping during expiration (Figure 7‑10).
Congenital Pulmonary Airway Malformation
Congenital pulmonary airway malformation, previously known as congenital
cystic adenomatoid malformation, makes up 25% of all congenital lung ano-
malies. It consists of adenomatoid proliferation of bronchioles that form cysts
instead of normal alveoli. There are 3 most commonly described types: Type
1 cysts are the most common and measure 2 to 10 cm, type 2 cysts are 0.5 to
2 cm, and type 3 solid-appearing lesions are formed by microscopic cysts
(Figure 7‑11).
Figure 7‑10. Axial computed tomography scan showing lobar

emphysema (arrows).
Figure 7‑11. Axial computed tomography

image in lung window demonstrating a
multicystic lucent lesion within the right
lower lobe with macrocyts and microcysts.
Courtesy of Mariangeles Medina Perez, MD..

124
Bronchogenic Cysts
A bronchogenic cyst is usually an incidental finding on a chest radiograph and
is in the differential diagnosis of a mediastinal mass. Both CT scanning and
MRI help to differentiate, but the MRI is more specific. The cyst contains fluid
of water density, but, on occasion, the mass is of soft-tissue density, which
makes differentiation from lymph nodes or other solid lesions more difficult.
The cyst is derived from the foregut and is typically in the aortopulmonary
window. More than 65% are mediastinal; when located in the lung parenchyma,
they are usually in the lower lobes. Bronchogenic cysts can be asymptomatic
or manifest because of superimposed infection simulating a lung abscess.
Pulmonary Sequestration
Pulmonary sequestration is defined as a segment of lung tissue that is separate
from the tracheobronchial tree and receives its blood supply from a systemic
artery rather than from the pulmonary artery.35,36 There are 2 types of
pulmonary sequestration: intralobar and extralobar (Table 7‑2).
Because pulmonary sequestration may manifest as a consolidation, a history
of repeated pneumonias in the same location should raise the suspicion of
possible intralobar sequestration. Computed tomography is a useful method
for measuring the volume of pulmonary sequestration.
Table 7‑2. Characteristics of Intralobar and Extralobar Pulmonary Sequestration

Characteristic Intralobar Extralobar
Frequency ~75% ~25%
Location Posterior basal Between lower lobe and diaphragm,
also within the diaphragm, lung, hilum,
Left > right—2:1
mediastinum, retroperitoneum, upper
abdomen, etc
Left > right
Arterial Descending thoracic aorta, Aorta, less commonly from splenic,
supply upper abdominal aorta, gastric subclavian, intercostal or
splenic or celiac arteries pulmonary arteries
Venous > 80% to left atrium Systemic
drainage
Chest Normal Usually manifests as a solid
radiograph mass because it rarely connects
Postobstructive hyperinflation
to bronchi
(ventilation by collateral
channels)
Mucoid impaction surrounded
by hyperinflated lung
Solid mass, if infected
Visceral pleura Within the lobe Separated visceral pleura
Bronchial Often present Sometimes present
communication

125
Dysmorphic Lung Syndrome

Dysmorphic lung syndrome, which includes scimitar syndrome, is character-
ized by arrested development of either a whole lung (lung agenesis-hypoplasia
complex) or a lobe (lobar agenesis-aplasia complex). Absence of a lobe may
be associated with other abnormalities.
Three forms of lobar agenesis have been described: pulmonary agenesis,
aplasia, and hypoplasia. Although complete agenesis of a lung has been reported
to be twice as common on the left side as it is on the right, in general, hypo-
genetic lung is considered to be almost exclusively on the right (Figure 7‑12).
Hypogenetic lung is part of the congenital pulmonary venolobar syndrome.
The major components include hypogenetic lung, partial anomalous pulmo-
nary venous return, absence of a pulmonary artery, pulmonary sequestration,
systemic arterialization of the lung, absence of the inferior vena cava, and
accessory diaphragm.37
Figure 7‑12. B, Computed

tomography scan showing
hypoplastic right lung
posterior to the heart.
Figure 7‑12. A, Radiograph showing the right lung

volume loss with the mediastinal shift to the right and
crowded ribs. The arrow points to the hemidiaphragm,
which is still visible due to some aerated lung at the base.
Absence of Main Pulmonary Artery

In a child with absence of the main pulmonary artery, the peripheral pulmonary
arteries are usually intact and supplied by systemic collateral circulation, which
most often arises from the bronchial arteries. It is more common on the right
side. At imaging, the lung and hilum are small; the pulmonary vascularity is
decreased, rendering a radiolucent lung. Serrated pleural thickening with
subpleural bands may indicate the systemic collateral vessels.
Pulmonary Arteriovenous Malformation
Pulmonary arteriovenous malformations can be solitary or multiple, as in
children with hereditary hemorrhagic telangiectasia or Osler-Weber-Rendu

126
disease. The lesions tend to be recognized with increased age because time
is needed for the flow effects to manifest.
Pneumonia
Chest radiography should not be performed routinely in the outpatient treat-
ment of children suspected of having pneumonia. Radiological findings are
accepted as the reference standard for defining pneumonia, but it is not clear to
what extent chest radiographs alter the outcome of childhood pneumonia even
though they frequently are used to confirm the presence, site, and extent of
pulmonary infiltrates.38 Swingler et al39 observed that undergoing chest radio-
graphy significantly increased the likelihood of being prescribed antibiotics.
Accepted clinical indications for chest radiography are severe disease and
confirmation of nonspecific clinical findings, as well as assessment of compli-
cations and exclusion of other thoracic causes of respiratory symptoms.40
Computed tomography is not indicated in uncomplicated pneumonia. Com-
puted tomography scans provide more information than do plain radiographs
for complicated pneumonias and for assessment before procedures. In patients
who are immunocompromised and hospitalized, CT scanning has a higher
accuracy than plain radiography in detecting early fungal and Pneumocystis
jirovecii pneumonia.
Ultrasonography has an advantage over CT scanning in the identification of,
characterization of, and management decisions about complicated effusions.
Ultrasonography also has an established role in the imaging-guided drainage
of pleural fluid. The decision of whether a fluid collection needs to be drained
is clinical and is indicated if the collections are increasing in size or respira-
tory function is compromised.41 If thrombolytic therapy is contemplated, CT
scanning should be considered if a bronchopleural fistula is suspected because
a fistula is a contraindication to thrombolytic therapy.
Round Pneumonia
Round pneumonia occurs in children younger than 8 years because young
children have poorly developed pathways of collateral ventilation (eg, pores
of Kohn, canals of Lambert), more closely apposed connective tissue septa,
and smaller alveoli than do adolescents and adults42 (Figure 7‑13). Round
pneumonias clinically manifest with cough, tachypnea, and malaise followed
by an acute febrile illness. Round pneumonias on chest radiographs character-
istically are located posteriorly in the lower lobes and touching the pleura or a
fissure. Satellite lesions are not seen in children, whereas satellite lesions are
found in more than 50% of round pneumonias in adults.43 In a child younger
than 8 years with the typical clinical findings of pneumonia and a typical

127
radiographic appearance, the diagnosis is almost always round pneumonia.

Round pneumonias are diagnosed on radiographs and, if all the criteria are
met, all that is needed is follow-up chest radiography to ensure resolution.
Figure 7‑13. A, Radiograph showing
round pneumonia (arrow) in the right
lower lobe. Note the negative silhou-
ette sign (border of the right side of
the heart is visible) and horizontal
fissure parallel to the arrow.
Figure 7‑13. B, The arrows delineate

the edges of the round pneumonia.

128
Aspiration
Aspiration is of great concern in children because of the frequency with
which they place foreign objects in their mouths or noses and the frequency
with which young children choke on food items. The most common organic
aspirated foreign bodies include peanuts, seeds, and nuts; blades of grass;
and bone fragments. The most common inorganic bodies are plastic objects
(toy fragments, pen caps, dental prostheses) or metal objects (hairpins, pins,
steel filaments). Chest
radiography is the first
imaging study performed
when aspiration is
suspected.44 Because less
than 10% of aspirated
foreign bodies are radi-
opaque, the inhaled object is
usually not visible, but
indirect findings may assist
in supporting the diagnosis.
Radiological findings in the
event of an acute aspiration
include hyperinflation, air
trapping, regional oligemia,
atelectasis, or consolidation.
The airway is usually either
Figure 7‑14. A, Radiographs showing aspirated foreign
body. B, The left lateral decubitus view shows persistent unobstructed or partially
expansion of the left lung (white arrows). obstructed during inspira-
tion but completely
obstructed during expiration
because the physiological
expiratory decrease in
bronchial diameter results in
air trapping. To improve the
accuracy of radiographs, the
physician may order
inspiratory and expiratory
views in cooperative
children and lateral decubi-
tus radiographs in younger
children (Figures 7–14).44
However, radiographs are
still negative in up to 30% of
Figure 7‑14. B, The right lung normally deflates in the cases of aspiration.
right lateral decubitus position (black arrow).

129
Multidetector CT scanning is more accurate than chest radiography in the

detection of radiolucent foreign bodies, and it is suggested in patients with a
low clinical suspicion of foreign body aspiration in whom chest radiography
results are negative.45 Multidetector CT scanning, as opposed to single-section
CT scanning, allows rapid acquisition of volumetric data sets, essential to
reduce radiation exposure in children and to avoid sedation. Multidetector CT
scanning also can be helpful in children after bronchoscopy when residual
foreign bodies are suspected. Although this is a relatively uncommon compli-
cation, retained foreign bodies are described in 1% to 18% of cases. Computed
tomography in these children can offer a description of the pattern of residual
obstruction, which would help in future decisions as to whether repeat
bronchoscopy is indicated.45
Complications of Pneumonia
Pleural Effusion
The chest radiograph may show pneumonia before the effusion is evident. The
earliest sign is blunting of the costophrenic angle, which will be evident on
a radiograph obtained with the patient in an erect position but not on a radio-
graph obtained with the patient in a supine position. A radiograph obtained
with the patient in a lateral decubitus position with the affected side down
may be helpful in showing small amounts of fluid. If the fluid does not shift
with the lateral decubitus position, it implies loculation of the fluid. If there is
an air-fluid level, there is both an effusion and pneumothorax, which is called
hydropneumothorax. The presence of hydropneumothorax in the absence of a
recent intervention is suggestive of a bronchopleural fistula. Empyemas on
chest radiographs, because of the intrapleural location, tend to have obtuse
angles superiorly and inferiorly on the frontal view. On the lateral view, a
distinguishing feature of pulmonary abscess is the decrease in diameter
when compared with the frontal view. Lung abscesses tend to have the
same AP and transverse diameter on both frontal and lateral views.
Ultrasonography is the best imaging modality to characterize pleural fluid. It
can depict fluid before it is evident on a chest radiograph and can easily help
distinguish between free and loculated fluid. Pleural effusions at ultrasono-
graphy are classified as simple or complex. Simple effusions are anechoic or
black and in most cases indicate a transudate. Complex effusions indicate an
exudate. Features that make an effusion complex include internal septations,
debris, honeycombing, and pleural thickening, all of which are easily depicted
at ultrasonography.9 Ultrasonography may also be helpful in defining the best
site for thoracentesis and the need for intrapleural fibrinolysis or video-assisted
thoracoscopic surgery (Figure 7‑15A–B). Computed tomography scanning is
not more helpful than ultrasonography in defining a pleural effusion but does
have a place in detecting abnormalities in the lung parenchyma.

130
Figure 7‑15. A, Radiograph

showing a complicated
effusion. The left arrow
shows the displaced trachea.
The right arrow shows
whiteout of left thorax.
Figure 7‑15. B, Ultrasonographic image

showing septations (arrows) in an effusion.
Lung Abscess
A lung abscess is a thick-walled cavity that contains purulent material as a
result of a pulmonary infection that has led to suppurative necrosis of the
involved lung parenchyma. Lung abscesses in the early stages manifest as
consolidation; however, unlike necrotizing pneumonia, abscesses tend to be
spherical and well-defined, and the diagnosis is more obvious when there is a
connection between the abscess and a draining bronchus because an air-fluid
level will be present. The air-fluid level will be evident only on a radiograph
obtained with the patient in a lateral decubitus or erect position.46 The presence
of an air-fluid level is not pathognomonic of an abscess, given that an air-fluid
level can be seen in developmental lung malformations or pneumatoceles with

131
superimposed infection, cavitary pneumonia, cavitary septic emboli, Wegener

granulomatosis, and other conditions. For distinguishing a lung abscess from
other conditions, contrast-enhanced CT scanning of the chest is the imaging
modality of choice (Figure 7‑16).47 Lung abscess caused by aspiration typically
is located in the posterior segments of the upper lobes or superior segments of
the lower lobes. When in a subpleural location, lung abscesses and any consoli-
dation can be identified at ultrasonography. In this location, ultrasonography
can be used as a guiding tool for percutaneous drainage.
Figure 7‑16. Computed tomography scan showing a lung

abscess with an air-fluid level (arrow).
Necrotizing Pneumonia
Necrotizing pneumonia is a complication of severe pneumonia that produces
cavities by means of tissue necrosis in the area of pneumonic consolidation.
The chest radiograph may show the cavities, but a significant number of chil-
dren who have CT findings of cavities have no evidence of necrosis on plain
radiographs. If the cavity contains air, the chest radiograph may show the
cavity, but if it is fluid filled, the plain radiograph may show only consoli-
dation. Unlike a pulmonary abscess, the cavities of necrotizing pneumonia
tend to be multiple, tubular or round, and more irregular. In addition, the
borders of the consolidation are less distinct. Air bronchograms can be
present (Figure 7‑17).

132
Figure 7‑17. A, Coronal computed

tomography scan showing necrotizing
pneumonia. The arrowheads show pleural
effusion, and the arrows point to cavities.
Figure 7‑17. B, Plain radio-

graph showing necrotizing
pneumonia, suggestive of
bronchopleural fistula. The
arrows point to cavitation
necrosis.
Figure 7‑17. C, Computed

tomography scan showing
necrotizing pneumonia and
bronchopleural fistula. The
arrows point to cavitation
necrosis.

133
Tuberculosis
Primary Pulmonary TB
The radiographic findings in primary TB are nonspecific. The plain radio-
graph may be normal, but more commonly there is an area of segmental or
lobar consolidation with hilar adenopathy in the adjacent area. Hilar adeno-
pathy is an important finding because it is unusual to see lymphadenopathy
in postprimary TB. The lung opacity of primary TB tends to become smaller
over time, calcify, and be apparent as a calcified granuloma.
Airway involvement is common in primary TB, and airway compression
by the lymphadenopathy may result in atelectasis, which may result in con-
solidation of the right upper or middle lobe. One of the life-threatening
manifestations of TB is miliary TB, most common in infants and toddlers.
It manifests as small nodules (usually < 2 mm) with uniform distribution
in the lungs.
Postprimary Pulmonary TB
Pleural effusion is an important manifestation of postprimary TB in adoles-
cents. Miliary TB results from hematogenous spread so that there are diffuse,
small (1–2 mm) nodules scattered throughout the lung fields. The characteris-
tic finding of postprimary TB is upper lobe consolidation with cavitation. The
findings are usually evident at chest radiography, but CT scanning is useful
to define the extent of disease, in particular the degree of cavitation.
Pulmonary Nontuberculous Mycobacteria

The radiological findings of nontuberculous mycobacteria are nonspecific and
similar to those of TB, fungal infections, and other granulomatous processes.
The typical imaging features are as follows:
X Multiple small nodules
X Multilobe bronchiectasis
X Tree-in-bud pattern (see Reading the CT Scan, earlier in this chapter)
X Progressive fibrosis
Most children with pulmonary nontuberculous mycobacteria are those with
HIV infection or CF.
Systemic Lupus Erythematosus
Pleural effusion is the most common pulmonary manifestation of systemic
lupus erythematosus, and the effusions are typically small. There may be an
associated pericardial effusion. The greatest pulmonary imaging challenge
in children with systemic lupus erythematosus is differentiating pneumonia,
pulmonary hemorrhage, and lupus pneumonitis. Computed tomography
findings with lung disease, either pneumonia or lupus pneumonitis, include

134
patchy consolidation, especially in the lower lobes, often with a pleural effu-
sion. Lupus pneumonitis has the potential to develop into chronic interstitial
pneumonitis with irreversible lung disease and pulmonary fibrosis. Acute
alveolitis, recognized by a ground-glass appearance, has the potential
to be improved by steroids and should be treated promptly to prevent
chronic changes.
Interstitial Lung Disease

Chest radiography is the usual imaging modality to diagnose ILD in children.
It is not specific and therefore usually requires additional imaging studies,
especially HRCT scanning. The plain chest radiograph may reveal character-
istic patterns, including ground-glass opacities, reticular or nodular opacities,
and honeycombing. Ground-glass opacities are seen with active alveolitis,
and honeycombing is seen with advanced disease. The findings are often
described as interstitial even though the disease is primarily alveolar.
High-resolution CT scanning is better than chest radiography for defining
the extent of pulmonary disease, and tree-in-bud patterns and patterns of
differential aeration may be evident.
Cystic Fibrosis
Chest radiography is not important in diagnosing CF but does allow longitu-
dinal assessment of the progression of pulmonary disease. The findings of
CF clearly overlap with those of other disorders of chronic lung disease;
nevertheless, bronchiectasis of unknown cause is an indication to evaluate
for CF. The usefulness of the chest radiograph during an exacerbation of
CF is unclear. In this situation, the advantage of the chest radiograph is to
exclude a pneumothorax, pneumonia, or atelectasis.
More recently, the use of CT scanning to evaluate inflammation and early
lung damage has been confirmed. High-resolution CT scanning allows
demonstration of mucous plugging and bronchiectasis to the fifth or sixth
generation of bronchi.
Bronchial arteriography is the preferred technique to evaluate major hemo-
ptysis, and the technique is to view all of the bronchial vessels in preparation
for embolization. The vessels that are bleeding may not be identified; there-
fore, all vessels should be embolized, because if only the bleeding vessels are
embolized, other nonembolized vessels will likely bleed at a later date.
The most widely used CF scoring system in the United States is the Brasfield
scoring system, also called the Birmingham system, which was developed in
1979.48 Five elements are evaluated as shown in Table 7‑3.

135
Several additional scoring systems have been reviewed and attempts made to
provide radiological and clinical correlation. One of the reasons for deriving
scores is to reduce interobserver differences and permit longitudinal following
of the clinical course.
Computed tomography findings of CF include air trapping, early evidence
of airway inflammation, or bronchiectasis. Mucous plugging, centrilobular
nodules, and peribronchial thickening are potentially reversible findings in
patients with symptoms. Because children are more sensitive to radiation-
induced cancer than are adults, special care should be taken, particularly
when multiple radiological examinations in a lifetime will be needed.
Computed tomography scanning is used to assess the following conditions:
X ABPA
X Atypical mycobacterial infection
X Unexplained clinical deterioration
X Pulmonary embolism
X Severe hemoptysis
X Sinus disease
Table 7‑3. Components of the Brasfield Scoring System

Category Definition Scoring
I. Air Generalized pulmonary overdistension as 0 = absent; 1–4 for
trapping sternal bowing, depression of the diaphragm, increasing severity
and/or thoracic kyphosis (4, most severe)
II. Linear Line densities due to prominence of bronchi as 0 = absent; 1–4 for
markings parallel line densities, sometimes branching, increasing severity
or as end-on circular densities with thickening (4, most severe)
of bronchial wall
III. Nodular Multiple, discrete, small, rounded densities, 0 = absent; 1, 2, 3, or 4
cystic ≥ 0.5 cm, with either radiopaque or radiolucent for involvement of
lesions centers (does not refer to irregular linear 1, 2, 3, or 4 quadrants
markings); confluent nodules not classified
as large lesions
IV. Large Segmental or lobar atelectasis or 0 = absent; 3 if segmental
lesions consolidation; includes acute pneumonia or lobar; 5 if large
V. General Impression of overall severity of changes 0 = normal; 1–4 for increasing
severity on radiographs severity of abnormalities;
only cardiac enlargement or
pneumothorax require 5
Points are subtracted from a total possible score of 25, so that 25 is without abnormality and 3 is the
most severe.
From Brasfield D, Hicks G, Soong S, Tiller RE. The chest roentgenogram in cystic fibrosis: a new scoring
system. Pediatrics. 1979;63(1):24–29.

136
Mediastinal Masses
The location of mediastinal masses in children is shown in Box 7‑3.
Box 7-3
Location and Types of Mediastinal Masses
Anterior mediastinum (about 40%) Posterior mediastinum (34%)
Thymus Neurogenic mass: neuroblastoma
Lymphoma Ganglioneuroblastoma, ganglioneuroma
Germ cell tumors Schwannoma, neurofibroma
Middle mediastinum (about 20%)
Bronchogenic cyst
Enteric and neurenteric cysts
Mediastinal lymphadenopathy
Pericardial cyst
Anterior Mediastinal Masses

More than 40% of mediastinal masses are anterior mediastinal masses, with
most of them arising from the thymus or mediastinal lymph nodes.
Thymus
There is extensive variability in the configuration and radiographic appear-
ance of thymic tissue, including the possibility of manifesting in an ectopic
location. It can usually be recognized at chest radiography—microlobulated
borders, ability to see the normal pulmonary architecture through it, and
absence of mass effect. If the diagnosis remains uncertain, CT scanning or
MRI can aid in its recognition.
The thymus can change in shape and size within hours. An external stimulus,
commonly seen in patients who are hospitalized, can dramatically reduce the
size of the thymus. Likewise, thymic rebound is the enlargement or hyper-
plasia of the thymus in response to withdrawal of myelosuppressive therapy.
It typically occurs 6 to 12 months after suspension of therapy but cases as
early as 1 week after suspension of therapy have been described.49
Lymphoma
Lymphoma (Hodgkin and non-Hodgkin) is the most common true anterior
mediastinal mass in children. Mediastinal lymphoma appears as a hypo-
attenuating lobulated, nonhomogeneous, mediastinal, soft-tissue mass.
Hilar lymphadenopathy is associated with Hodgkin lymphoma. In Hodgkin
lymphoma, bulky mediastinal disease has a worse prognosis than in cases
in which there is a small tumor volume. In non-Hodgkin lymphoma, tumor
bulk does not appear to influence outcome.

137
Positron emission tomography (PET)/CT scanning is a valuable tool to use

for the initial staging, to monitor interim treatment response, and to assess
complete response to treatment. Substantial evidence supports that the
addition of PET scanning to current staging investigations in lymphoma
increases the accuracy of staging and results in change in management.
An International Harmonization Project released consensus recommenda-
tions50 in 2007 to standardize clinical trial parameters for the use of PET
scanning. At initial staging, CT scanning should be performed either alone
or in combination with PET scanning. Most commonly, the combination is
preferred to reduce the amount of radiation delivered. If hepatic or splenic
disease is also present, then intravenous contrast material should be
administered to improve the assessment.
Germ Cell Tumors

Germ cell tumors account for up to 20% of anterior mediastinal masses in
children. Germ cell tumor can be diagnosed definitely when the characteristic
CT scanning or MRI findings of a complex mass with cystic and solid areas
containing fat and irregular calcifications are observed.
Middle Mediastinal Masses

Middle mediastinal masses account for about 20% of mediastinal masses.
Foregut duplication cysts include bronchogenic, enteric, and neurenteric cysts,
which are developmental malformations of the embryonic foregut. Computed
tomography or MRI can be used to confirm the diagnosis and characterize
the mass. These masses are relatively well marginated, round, or oval with
homogeneous water or soft-tissue attenuation or signal intensity (because
of proteinaceous material) without internal contrast enhancement.49
The extension of lymphoma into the middle mediastinum is common.
Other causes of lymphadenopathy include metastatic disease, infection or
inflammation from granulomatous diseases, or Langerhans cell histiocytosis.
Posterior Mediastinal Masses

Posterior mediastinal masses account for 34% of mediastinal masses, and
most (~90%) are neurogenic in origin.49 Most neurogenic masses, including
neuroblastoma, ganglioneuroblastoma, and ganglioneuroma, arise from gan-
glion cells in the paravertebral sympathetic chain. The remaining masses are
nerve sheath tumors, such as schwannoma and neurofibroma. Chest radio-
graphic findings include a well-circumscribed posterior mediastinal mass
with calcifications or adjacent bone erosion (Figure 7‑18). Imaging does not
allow differentiation among the tumor types, so biopsy is needed. Evaluation
of the extent of disease, particularly looking for intraspinal extension, should
be performed, and MRI is the modality of choice (Figure 7‑19).

138
Figure 7‑18. Radiograph showing a

posterior mediastinal mass (arrow), with
the diaphragm and border of the right
side of the heart visible.
Figure 7‑19. Magnetic resonance image

showing ganglioneuroma (arrow).
References
1. Sidhu M, Goske MJ, Connolly B, et al. Image gently, step lightly: promoting radiation safety in
pediatric interventional radiology. AJR Am J Roentgenol. 2010;195(4):W299–W301
PMID: 20858793 doi: 10.2214/AJR.09.3938
2. Mettler FA Jr, Huda W, Yoshizumi TT, Mahesh M. Effective doses in radiology and diagnostic
nuclear medicine: a catalog. Radiology. 2008;248(1):254–263 PMID: 18566177
doi: 10.1148/radiol.2481071451
3. Huda W. Radiation doses and risks in chest computed tomography examinations. Proc Am
Thorac Soc. 2007;4(4):316–320 PMID: 17652493 doi: 10.1513/pats.200611-172HT
4. O’Connor OJ, Vandeleur M, McGarrigle AM, et al. Development of low-dose protocols for
thin-section CT assessment of cystic fibrosis in pediatric patients. Radiology.
2010;257(3):820–829 PMID: 20876388 doi: 10.1148/radiol.10100278
5. Heyer CM, Nuesslein TG, Jung D, et al. Tracheobronchial anomalies and stenoses: detection
with low-dose multidetector CT with virtual tracheobronchoscopy—comparison with flexible
tracheobronchoscopy. Radiology. 2007;242(2):542–549 PMID: 17255423
doi: 10.1148/radiol.2422060153
6. Lee EY, Boiselle PM, Cleveland RH. Multidetector CT evaluation of congenital lung anomalies.
Radiology. 2008;247(3):632–648 PMID: 18487532 doi: 10.1148/radiol.2473062124
7. Lee EY, Siegel MJ. Large airways. In: Boiselle PM, Lynch DA, eds. CT of the Airways.
Humana; 2008:351–379 doi: 10.1007/978-1-59745-139-0_15
8. Knisely BL, Broderick LS, Kuhlman JE. MR imaging of the pleura and chest wall. Magn Reson
Imaging Clin N Am. 2000;8(1):125–141 PMID: 10730239 doi: 10.1016/S1064-9689(21)00045-3

139
9. Kim OH, Kim WS, Kim MJ, Jung JY, Suh JH. US in the diagnosis of pediatric chest diseases.
Radiographics. 2000;20(3):653–671 PMID: 10835119
doi: 10.1148/radiographics.20.3.g00ma05653
10. Coley BD. Pediatric chest ultrasound. Radiol Clin North Am. 2005;43(2):405–418
PMID: 15737376 doi: 10.1016/j.rcl.2004.12.003
11. Felson B, Felson H. Localization of intrathoracic lesions by means of the postero-anterior
roentgenogram: the silhouette sign. Radiology. 1950;55(3):363–374 PMID: 14781343
doi: 10.1148/55.3.363
12. Hansell DM, Bankier AA, MacMahon H, McLoud TC, Müller NL, Remy J. Fleischner Society:
glossary of terms for thoracic imaging. Radiology. 2008;246(3):697–722 PMID: 18195376
doi: 10.1148/radiol.2462070712
13. Remy-Jardin M, Remy J, Giraud F, Wattinne L, Gosselin B. Computed tomography assessment
of ground-glass opacity: semiology and significance. J Thorac Imaging. 1993;8(4):249–264
PMID: 8246323 doi: 10.1097/00005382-199323000-00001
14. Quigley MJ, Fraser RS. Pulmonary pneumatocele: pathology and pathogenesis. AJR Am
J Roentgenol. 1988;150(6):1275–1277 PMID: 3259364 doi: 10.2214/ajr.150.6.1275
15. Field CE. Bronchiectasis in childhood: clinical survey of 160 cases. Pediatrics. 1949;4(1):21–46
PMID: 18146463
16. Reiff DB, Wells AU, Carr DH, Cole PJ, Hansell DM. CT findings in bronchiectasis: limited
value in distinguishing between idiopathic and specific types. AJR Am J Roentgenol.
1995;165(2):261–267 PMID: 7618537 doi: 10.2214/ajr.165.2.7618537
17. Garcia-Peña P, Lucaya J. HRCT in children: technique and indications. Eur Radiol.
2004;14(suppl 4):L13–L30 PMID: 14762683 doi: 10.1007/s00330-003-2223-y
18. Hansell DM. Thin-section CT of the lungs: the Hinterland of normal. Radiology.
2010;256(3):695–711 PMID: 20720066 doi: 10.1148/radiol.10092307
19. Rossi SE, Franquet T, Volpacchio M, Giménez A, Aguilar G. Tree-in-bud pattern at thin-section
CT of the lungs: radiologic-pathologic overview. Radiographics. 2005;25(3):789–801
PMID: 15888626 doi: 10.1148/rg.253045115
20. Franquet T, Müller NL, Giménez A, Guembe P, de La Torre J, Bagué S. Spectrum of pulmonary
aspergillosis: histologic, clinical, and radiologic findings. Radiographics. 2001;21(4):825–837
PMID: 11452056 doi: 10.1148/radiographics.21.4.g01jl03825
21. Flors L, Domingo ML, Leiva-Salinas C, Mazón M, Roselló-Sastre E, Vilar J. Uncommon
occupational lung diseases: high-resolution CT findings. AJR Am J Roentgenol.
2010;194(1):W20–W26 PMID: 20028886 doi: 10.2214/AJR.09.2593
22. Silva CI, Müller NL, Lynch DA, et al. Chronic hypersensitivity pneumonitis: differentiation
from idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia by using thin-section
CT. Radiology. 2008;246(1):288–297 PMID: 18096541 doi: 10.1148/radiol.2453061881
23. Daimon T, Johkoh T, Sumikawa H, et al. Acute eosinophilic pneumonia: thin-section CT
findings in 29 patients. Eur J Radiol. 2008;65(3):462–467 PMID: 17537607 doi: 10.1016/j.
ejrad.2007.04.012
24. Cheon JE, Lee KS, Jung GS, Chung MH, Cho YD. Acute eosinophilic pneumonia: radiographic
and CT findings in six patients. AJR Am J Roentgenol. 1996;167(5):1195–1199 PMID: 8911179
doi: 10.2214/ajr.167.5.8911179
25. Marchand E, Cordier JF. Idiopathic chronic eosinophilic pneumonia. Orphanet J Rare Dis.
2006;1(1):11 PMID: 16722612 doi: 10.1186/1750-1172-1-11
26. Spottswood SE, Allison KZ, Lopatina OA, et al. The clinical significance of lung hypoexpansion
in acute childhood asthma. Pediatr Radiol. 2004;34(4):322–325 PMID: 14767624
doi: 10.1007/s00247-003-1083-6
27. Woodring JH, Reed JC. Types and mechanisms of pulmonary atelectasis. J Thorac Imaging.
1996;11(2):92–108 PMID: 8820021 doi: 10.1097/00005382-199621000-00002
28. Caceres M, Ali SZ, Braud R, Weiman D, Garrett HE Jr. Spontaneous pneumomediastinum:
a comparative study and review of the literature. Ann Thorac Surg. 2008;86(3):962–966
PMID: 18721592 doi: 10.1016/j.athoracsur.2008.04.067
29. de Blic J, Scheinmann P. The use of imaging techniques for assessing severe childhood asthma.
J Allergy Clin Immunol. 2007;119(4):808–810 PMID: 17289134 doi: 10.1016/j.jaci.2006.12.657
30. Aysola RS, Hoffman EA, Gierada D, et al. Airway remodeling measured by multidetector CT
is increased in severe asthma and correlates with pathology. Chest. 2008;134(6):1183–1191
PMID: 18641116 doi: 10.1378/chest.07-2779
31. Subramanyan R, Venugopalan P, Narayan R. Vascular rings: an important cause of persistent
respiratory symptoms in infants and children. Indian Pediatr. 2003;40(10):951–957
PMID: 14581732

140
32. Browne LP. What is the optimal imaging for vascular rings and slings? Pediatr Radiol.
2009;39(suppl 2):S191–S195 PMID: 19308384 doi: 10.1007/s00247-008-1118-0
33. Newman B. Congenital bronchopulmonary foregut malformations: concepts and controversies.
Pediatr Radiol. 2006;36(8):773–791 PMID: 16552585 doi: 10.1007/s00247-006-0115-4
34. Panicek DM, Heitzman ER, Randall PA, et al. The continuum of pulmonary developmental
anomalies. Radiographics. 1987;7(4):747–772 PMID: 3448653
doi: 10.1148/radiographics.7.4.3448653
35. Yucel O, Gurkok S, Gozubuyuk A, et al. Diagnosis and surgical treatment of pulmonary
sequestration. Thorac Cardiovasc Surg. 2008;56(3):154–157 PMID: 18365974 doi:
10.1055/s-2007-965572
36. Caradonna P, Bellia M, Cannizzaro F, Regio S, Midiri M, Bellia V. Non-invasive diagnosis
in a case of bronchopulmonary sequestration and proposal of diagnostic algorithm.
Monaldi Arch Chest Dis. 2008;69(3):137–141 PMID: 19065849
37. Woodring JH, Howard TA, Kanga JF. Congenital pulmonary venolobar syndrome revisited.
Radiographics. 1994;14(2):349–369 PMID: 8190958 doi: 10.1148/radiographics.14.2.8190958
38. Ranganathan SC, Sonnappa S. Pneumonia and other respiratory infections. Pediatr Clin
North Am. 2009;56(1):135–156, xi PMID: 19135585 doi: 10.1016/j.pcl.2008.10.005
39. Swingler GH, Hussey GD, Zwarenstein M. Randomised controlled trial of clinical outcome
after chest radiograph in ambulatory acute lower-respiratory infection in children. Lancet.
1998;351(9100):404–408 PMID: 9482294 doi: 10.1016/S0140-6736(97)07013-X
40. Westra SJ, Choy G. What imaging should we perform for the diagnosis and management of
pulmonary infections? Pediatr Radiol. 2009;39(suppl 2):S178–S183 PMID: 19308382
doi: 10.1007/s00247-009-1159-z
41. Calder A, Owens CM. Imaging of parapneumonic pleural effusions and empyema in children.
42. Kim YW, Donnelly LF. Round pneumonia: imaging findings in a large series of children.
43. Restrepo R, Palani R, Matapathi UM, Wu YY. Imaging of round pneumonia and
mimics in children. Pediatr Radiol. 2010;40(12):1931–1940 PMID: 20686763
doi: 10.1007/s00247-010-1767-7
44. Pinto A, Scaglione M, Pinto F, et al. Tracheobronchial aspiration of foreign bodies: current
indications for emergency plain chest radiography. Radiol Med (Torino). 2006;111(4):497–506
PMID: 16779536 doi: 10.1007/s11547-006-0045-0
45. Koşucu P, Ahmetoğlu A, Koramaz I, et al. Low-dose MDCT and virtual bronchoscopy in
pediatric patients with foreign body aspiration. AJR Am J Roentgenol. 2004;183(6):1771–1777
PMID: 15547227 doi: 10.2214/ajr.183.6.01831771
46. Emanuel B, Shulman ST. Lung abscess in infants and children. Clin Pediatr (Phila).
1995;34(1):2–6 PMID: 7720324 doi: 10.1177/000992289503400101
47. Patradoon-Ho P, Fitzgerald DA. Lung abscess in children. Paediatr Respir Rev. 2007;8(1):77–84
PMID: 17419981 doi: 10.1016/j.prrv.2006.10.002
48. Brasfield D, Hicks G, Soong S, Tiller RE. The chest roentgenogram in cystic fibrosis: a new
scoring system. Pediatrics. 1979;63(1):24–29 PMID: 440798
49. Lee EY. Evaluation of non-vascular mediastinal masses in infants and children: an evidence-
based practical approach. Pediatr Radiol. 2009;39(suppl 2):S184–S190 PMID: 19308383
doi: 10.1007/s00247-008-1108-2
50. Juweid ME, Stroobants S, Hoekstra OS, et al; Imaging Subcommittee of International
Harmonization Project in Lymphoma. Use of positron emission tomography for response
assessment of lymphoma: consensus of the Imaging Subcommittee of International
Harmonization Project in Lymphoma. J Clin Oncol. 2007;25(5):571–578 PMID: 17242397
doi: 10.1200/JCO.2006.08.2305

CHAPTER
8
Bronchoscopy
Pi Chun Cheng, MD, MS
Samuel B. Goldfarb, MD
CASE REPORT 8-1

A 6-month-old infant had vibratory inspiratory stridor since the age of 1 month.
He fed poorly and had gasping respiration, neck hyperextension, and intermit-
tent upper airway obstruction during sleep. Results of flexible bronchoscopy
with the patient under light sedation and with his head in a neutral position
demonstrated foreshortening of the aryepiglottic folds and prolapse of the
arytenoid cartilages during inspiration, causing almost complete obstruction
of the glottis. The dynamic airway events correlated with the infant’s stridor
and clinical airway obstruction. Evaluation results for the rest of the airway to
the level of the segmental bronchi were normal. Severe laryngomalacia was
diagnosed. The infant was referred to an otolaryngologist who performed
an aryepiglottoplasty, removing some redundant tissue from the arytenoid
cartilages. The infant’s stridor and obstructive sleep apnea markedly improved,
as did his growth. By the age of 12 months, his stridor had resolved completely,
and both growth and development were normal.
Introduction
Until relatively recently, direct evaluation of a young child’s airway required
the skills of a surgeon versed in rigid (open tube) bronchoscopy, with the child
under general anesthesia. Flexible bronchoscopy became routinely available
in the United States in 1969, but use of the technique was restricted in chil-
dren because of the instruments’ size limitations. By 1980, a commercially
available scope that was 3.5 mm in diameter with an integral suction channel
and a tip that could be directed was being used to evaluate newborns.1 With
improvements in fiberoptic technology, thinner (eg, 2.8 mm) bronchoscopes
could be made without sacrificing functionality or image quality. More
recently, digital technology has been applied to bronchoscopic images, and
a 2.8-mm or 3.8-mm pediatric bronchoscope with a video chip in the tip
provides high- resolution digital images in an instrument that can be used in
141

142
most newborns through adolescents. There are also ultrathin scopes ranging
from 1.8 to 2.2 mm, but these have neither suction channels nor angulation
capabilities, so their use
is limited to evaluation of the trachea and proximal main bronchi in children
with established artificial airways (endotracheal or tracheostomy tubes).
Choosing Between Flexible and Rigid Bronchoscopy

General Considerations
The flexible bronchoscope complements, but does not replace, the rigid
bronchoscope. Each has strengths and weaknesses that must be considered
when deciding on the approach to a particular patient. Table 8-1 lists some
of the relative advantages of each type of procedure. Flexible bronchoscopy is
usually performed via a transnasal approach. This approach allows the patient’s
head to be kept in a neutral position, and there is no distortion of upper airway
structures as the bronchoscope follows the normal contour of the nasopharynx,
oropharynx, and hypopharynx. Thus, dynamic events that occur in this part of
the airway can be observed without altering tissue relationships. In contrast,
direct laryngoscopy with a rigid bronchoscope or laryngoscope requires hyper-
extension of the neck and suspension of the base of the tongue for optimal
visualization. In this situation, structures that cause noisy breathing could be
elevated and the cause of airway obstruction missed.
The transnasal approach, however, causes the flexible bronchoscope to be
angulated anteriorly as it approaches the glottis. Although anterior structures
of the glottis are easily examined, it is more difficult to obtain a thorough
evaluation of the intra-arytenoid portion of the glottis, and posterior lesions
might be missed. Thus, if a lesion like a laryngoesophageal cleft is being
considered, rigid bronchoscopy is the preferred technique. Similarly, the
subglottic space is better evaluated using a rigid scope than a flexible scope.
The flexible bronchoscope can be advanced more distally in the tracheobron-
chial tree, allowing for better peripheral evaluation of the airway. The diag-
nostic capabilities of flexible bronchoscopy are broadened when combined
with techniques like bronchoalveolar lavage (BAL), bronchial brushing, and,
in select circumstances, transbronchial biopsy. All of these techniques are
better accomplished with a flexible scope than a rigid scope.

143
Chapter 8—Bronchoscopy
Table 8‑1. Relative Advantages of Flexible and Rigid Bronchoscopy

Site or Procedure Flexible Rigid
Nasopharynx ++ −/+
Hypopharynx ++ +
Larynx ++ ++
Laryngeal function ++ −
Subglottis +/− ++
Trachea ++ ++
Main bronchi ++ ++
Lobar bronchi ++ +
Segmental and subsegmental bronchi ++ +/−
Foreign body − ++
Bronchoalveolar lavage ++ +
Control of bleeding − ++
Mucosal biopsy ++ ++
Transbronchial biopsy ++ +
Abbreviations: ++, most likely to provide optimal diagnostic and therapeutic outcome; +, likely to provide
optimal diagnostic and therapeutic outcome; +/-, uncertain diagnostic and therapeutic value; -, unlikely to
provide diagnostic and therapeutic outcome.
Foreign Body
When a retained foreign body in the airway is suspected, the procedure of
choice is rigid bronchoscopy with the patient under general anesthesia. The
rigid bronchoscope has a larger working channel than does the flexible scope,
allowing for a wide range of instruments specially designed for the safe
retrieval of a foreign body. Furthermore, the child’s airway and ventilation are
carefully monitored and controlled, maximizing the safety of the procedure.
Continual communication with the anesthesiologist is critical to ensure ade-
quate depth of anesthesia and patient stability. A combined approach with
flexible bronchoscopy is often taken to allow exploration of the distal airway
for further debris. Although there are reports of retrieving a foreign body
from the respiratory tract of young children by means of flexible bronchos-
copy,2 this approach should be performed by a skilled bronchoscopist with the
option for a rigid scope should flexible bronchoscopy not be successful. The
greatest risk of using flexible bronchoscopy to remove a foreign body is the
accidental lodging of the foreign body in the larynx with total occlusion of the
airway. However, if the presence of a retained foreign body is considered as a
differential diagnosis but not the most probable diagnosis, it is reasonable to
perform flexible bronchoscopy as an initial procedure.3 If a foreign body is in
fact present, either flexible or rigid bronchoscopy can subsequently be used
to remove it.

144
Hemoptysis and Pulmonary Hemorrhage

Bronchoscopy is occasionally performed in the evaluation and treatment
of hemoptysis and pulmonary hemorrhage. When conducted as part of the
evaluation of pulmonary bleeding, the procedure should occur after acute
bleeding has subsided to maximize the diagnostic yield. If no bleeding site
is immediately obvious, or if the diagnosis of pulmonary hemorrhage is
uncertain, BAL can be performed to look for hemosiderin-laden macro-
phages. However, if bronchoscopy is being entertained to help manage an
episode of massive hemoptysis, the procedure of choice is rigid bronchoscopy.
In this situation, control of the airway is paramount, and bleeding may be so
brisk that visualization will be impaired unless large amounts of blood can
be suctioned quickly. Depending on the size of the patient, larger scopes with
a 2.0- to 2.3-mm working channel may allow for better removal of blood and
identification of the source of bleeding. Smaller children who cannot accom-
modate a larger scope may require a rigid scope that would better facilitate
clearance of the airway, but the 1.2-mm channel of the pediatric bronchoscope
cannot. If the area of bleeding can be identified, a solution of cold saline or
topical epinephrine can be used to achieve hemostasis. In addition, a balloon-
tipped catheter can be placed under direct visualization in the airway from
which blood is emanating to isolate the source and protect other regions of
the lung from being soiled.4
Indications for Flexible Bronchoscopy

Flexible bronchoscopy is used for diagnostic, therapeutic, and research
purposes (Box 8-1).5–7 It is commonly chosen to evaluate chronic stridor or
wheezing and chronic or recurrent pulmonary opacities seen on radiographs
Box 8‑1
Indications for Flexible Bronchoscopy
ū Noisy breathing ū Retained foreign body
• Stridor ū Hemoptysis
• Chronic wheezing (especially ū Interstitial lung disease
homophonous) ū Pneumonia in an
• Voice disturbance (hoarse, immunocompromised host
decreased amplitude) ū Tracheostomy evaluation
ū Persistent moist cough ū Post–lung transplant evaluation
ū Persistent radiographic abnormality ū Examination of lungs to determine
ū Congenital anomaly suitability for donation for lung
ū Recurrent pneumonia transplant
ū Atelectasis

145
in children or to determine the cause of pneumonia in children with compro-

mised immune function. The procedure is also used to evaluate hemoptysis,
recurrent aspiration, and chronic cough, and it can be used to examine the
airways in children with tracheostomies.
The most common indications for bronchoscopy are stridor or noisy breath-
ing, followed in no particular order by chronic wheezing, atelectasis, and
recurrent radiographic opacities.8–12 The frequency and distribution of indica-
tions vary with the characteristics of the programs that use bronchoscopy. For
example, a program involved in lung transplantation will frequently evaluate
patients for airway stenosis at the anastomosis site and perform transbron-
chial biopsies to assess for signs of rejection, whereas programs associated
with large cardiac centers would commonly evaluate patients for airway
compression associated with cardiac or pulmonary vascular enlargement.
When the decision to use flexible bronchoscopy as a diagnostic modality is
made, the yield is quite good but varies depending on the indication for the
procedure. For instance, Wood12 found that an abnormality relevant to the
primary indication for the procedure was present in 97% of subjects with
stridor but in only 46% of those with chronic or recurrent pneumonia. When
considering all indications for the procedure, findings related to the primary
indication were present in 76% of the 1,000 procedures reviewed. Godfrey
et al10 found the diagnostic yield of bronchoscopy in children younger than
18 years to be 67% of the 200 consecutive procedures reviewed. The groups
most likely to have relevant findings included those with noisy breathing
(96.2%) and atelectasis (76%). The ability to determine a diagnosis related to
the indication for bronchoscopy can be enhanced with the addition of BAL or
biopsy. When cytological examination and bacterial or fungal culture results
were added to findings on inspection, the incidence of clinically meaningful
findings increased to 90.5%.10
Flexible bronchoscopy can be used therapeutically to remove mucous plugs
that cause atelectasis (Figure 8-1) or to instill agents directly into the airway,
like deoxyribonuclease in patients with cystic fibrosis who have a high-DNA
mucous burden.13 Relief of atelectasis is more likely to occur when no air
bronchograms are visible in the atelectatic region, suggesting the presence
of a central mucous plug (Figure 8-2). In contrast, if air bronchograms are
present (Figure 8-3), it is likely that there are multiple distal mucous plugs
that will not be easy to retrieve via bronchoscopy.
Bronchoscopy with BAL has been used as a research tool for evaluating early
changes in the lungs in infants with cystic fibrosis.14 Similarly, results from
BAL and endobronchial biopsies are shedding new light on the pathophysio-
logical characteristics of bronchiolitis, asthma, and childhood interstitial lung
disease in the pediatric population.15,16

146
Figure 8‑1. Plastic bronchitis cast of the right lower lobe bronchi removed from a patient with
congenital heart disease and respiratory compromise. The cast was a mixed formation of fibrin,
mucin, and cells.

147
Figure 8‑2. A, Chest radiograph in a girl with VACTERL association and acute respiratory
failure from adenovirus pneumonia. Note the abrupt ending of an air bronchogram in the
distal left main bronchus, together with left lung atelectasis. B, The same patient 24 hours
after bronchoscopic removal of a mucous plug from the left main bronchus.
Figure 8‑3. Chest radiograph in a 4-year-old boy with myotubular

myopathy and left lower lobe atelectasis. Note the air bronchograms
within the area of atelectasis, reflecting multiple distal sites of airway
obstruction rather than a central mucous plug.

148
Contraindications for Bronchoscopy

It has been said that the only time bronchoscopy is truly contraindicated
is when the information or therapeutic objective can be obtained in a less
invasive fashion.11 There are, however, relative contraindications for which
the risk of the procedure must be balanced against the information or thera-
peutic benefit to be derived. Generally, an uncorrected bleeding diathesis like
thrombocytopenia or clotting dysfunction, profound hypoxemia before the
procedure, moderate or severe pulmonary hypertension, or severe airway
obstruction all should be carefully weighed so that the added risk of the pro-
cedure is worth the anticipated outcome to the patient. Occasionally, these
very conditions are the reason to perform bronchoscopy (eg, if hypoxemia is
the result of massive atelectasis or if removing a mucous plug can potentially
reverse a condition).11
Pathophysiological and Clinical Features

in Diagnostic Bronchoscopy
When diagnostic bronchoscopy is performed to evaluate abnormal noises,
the diagnostic yield is enhanced if the child creates the noise during the pro-
cedure, which may require the examiner to reproduce the situation in which
the noise occurs. Thus, if the noise is heard mostly when the child sleeps, as
in cases of obstructive sleep apnea, examining the child during sedated quiet
sleep is more likely to recreate the airway obstruction and enable the exam-
iner to determine its origin than if the child were minimally sedated. Alterna-
tively, if the noise occurs with increased breathing effort, the child should be
only lightly sedated to accentuate breathing effort. Having the patient emerge
from anesthesia with the bronchoscope positioned in the nasopharynx often
is used to assess the upper airway dynamics at the end of the procedure.
CASE REPORT 8-2

A young athlete was evaluated for possible exercise-related vocal cord
dysfunction. To recreate the situation, he was told to hyperventilate with a
bronchoscope in place, but this did not reveal any abnormalities. The only
time he reported symptoms, however, was during indoor swimming practice
and competitions. The examination was repeated while he smelled chlorine
bleach, and he quickly demonstrated paradoxical vocal fold motion within
a few breaths.
Extrathoracic Airway
Intraluminal airway pressure is subatmospheric during inspiration, giving
structures in the extrathoracic airway the propensity to collapse. Thus, any
dynamic lesion will be louder during inspiration. Fixed lesions (ie, those that
do not result in a respiratory phase–dependent change in airway caliber, like

149
subglottic stenosis) can cause biphasic noise. The noise created by dynamic
lesions depends on the magnitude of the intraluminal pressure decrease and the
tone or stiffness (compliance) of the airway structures. It may also be positional,
as neck hyperextension places longitudinal traction on the extrathoracic airway
and can stiffen it to some degree.
Flexible bronchoscopy offers the advantages of examining the extrathoracic
airway from the nostril onward, so that any structure in the extrathoracic airway
that might cause obstruction or airway vibration should be visible. Furthermore,
the patient is examined while the head is in a neutral position. Because the flexi-
ble scope follows the contours of the nasopharynx, it does not distort the anatomy
of the airway.17 Sedation can be made lighter or deeper so that the conditions
under which the noise or obstruction is usually present can be replicated.
Extrathoracic lesions that cause noisy breathing or obstruction are identified in
most children who undergo bronchoscopy.10,12 When stridor is the indication for
evaluation, in the absence of a known history of prolonged airway intubation,
the cause is usually a congenital lesion.7,10,17 Of these, laryngomalacia is the most
common condition, followed by vocal cord paralysis.7,12,17 The finding of laryn-
gomalacia during laryngoscopy does not obviate the need to look below the
vocal cords: 15% to 21% of patients will have a second airway abnormality
noted during more distal evaluation of the airways.12,17 Severe stenosis should
generally not be examined below the lesion with flexible bronchoscopy because
of the risk of worsening swelling and edema; it is better accomplished with a
combined procedure.
Excessive sedation or breathing effort can lead to erroneous diagnoses. The
presence of large airway collapse in an infant making heroic efforts to breathe
because of inadequate sedation may be mistaken for tracheomalacia or bron-
chomalacia. Excessive sedation or the application of lidocaine to the larynx18
can result in dynamic collapse of laryngeal structures and be mistaken for true
laryngomalacia. If there is no preprocedure history of wheezing in the former
case or stridor
Box 8‑2 in the latter
Lesions Associated With Noisy Breathing case, such
Stridor Wheezing findings are
ū Laryngomalacia ū Tracheomalacia or bronchomalacia likely artifac-
ū Subglottic stenosis ū Tracheal stenosis tual. A list
ū Vocal cord paralysis ū Airway compression of common
ū Hemangioma • Vascular lesions that
ū Vocal cord dysfunction • Lymph nodes lead to noisy
• Mediastinal mass breathing
ū Bronchitis is shown
ū Endobronchial tumor in Box 8-2.

150
Not all children with noisy breathing, however, require airway evaluation.
Bronchoscopy should be reserved for children whose noisy breathing is pro-
gressive, leads to episodes of apnea, and is associated with feeding difficulty
and poor growth or sleep disruption and impaired development, or when the
history and physical examination results raise the possibility of a lesion other
than congenital laryngomalacia.7 Bronchoscopy might also be considered in
an infant with laryngomalacia when parental anxiety regarding the noise is so
great that confirmation of the diagnosis is necessary to allow for reassurance
regarding the natural history of the disorder.
Intrathoracic Airway
Diagnostic bronchoscopy is performed to evaluate chronic wheezing or cough
unresponsive to medical therapy, persistent or recurrent radiographic opacities
in the lung, atelectasis, localized hyperinflation, hemoptysis, suspected re-
current aspiration, or possible retained foreign body. When bronchoscopy is
combined with techniques like BAL or transbronchial biopsy, information
can also be gleaned about processes in small airways and alveolar spaces.
In addition, biopsies of the airway wall can yield disease-specific information
(eg, ciliary ultrastructure and function or the type of inflammatory cells and
presence of rejection after lung transplant).
Evaluating Intrathoracic Airway Collapse
As with evaluation of the extrathoracic airway, the degree of respiratory
effort must be considered when evaluating intrathoracic airway collapse. In
contrast to extrathoracic obstruction, the forces acting across intrathoracic
airway walls favor their narrowing during exhalation. Excessive expiratory
effort will cause invagination of the posterior membrane of the trachea and
main bronchi; oversedation or paralysis will minimize the collapsing pres-
sures exerted across the airway wall. This situation makes the diagnosis of
primary intrathoracic tracheomalacia or bronchomalacia exceedingly difficult
because all patients can demonstrate some degree of airway collapse with
excessive expiratory effort or cough. Furthermore, visual estimates of airway
narrowing are highly subjective, and no universally agreed-on definition
based on magnitude of airway narrowing exists.19 When tracheomalacia
occurs secondary to another condition, like tracheoesophageal fistula, there
is often a larger than normal ratio of posterior membrane to anterior cartilage;
this is not necessarily true in primary tracheomalacia or tracheomalacia
acquired after prolonged mechanical ventilation.
Evaluating Narrowed Intrathoracic Airway
When an intrathoracic airway is narrowed, the endoscopist must determine
(1) if the obstruction is dynamic or fixed, (2) if the lesion is intrinsic (web,
tumor, mucosal lesion, etc) or if the narrowing is from extrinsic compression,
and (3) whether the compression is pulsatile. Location of the narrowing often
is an important clue in determining extrinsic compression; the left pulmonary

151
artery crosses over the left main bronchus and proceeds behind the left lower
lobe and left upper lobe bronchi, and the right pulmonary artery crosses over
the bronchus intermedius (because the right upper lobe bronchus is superior
to its attendant pulmonary artery, it is never compressed by it). The aorta will
cause a pulsatile compression of the left anterior tracheal wall on its ascent,
and the descending aorta can compress the left main bronchus posteriorly.20
Enlarged lymph nodes encircling the right middle lobe bronchus can narrow
the bronchus intermedius; bronchogenic cysts, which are often subcarinal,
can cause compression of the main bronchi or widening of the main carina.
Interpreting Other Intrathoracic Bronchoscopic Findings
Often, when bronchoscopy is undertaken for evaluation and treatment of
atelectasis, there are no secretions for removal. Absence of such a finding
still may be critical for care decisions (Figure 8-4). Similarly, absence
of a suspected retained foreign body is as important as finding one. It may be
difficult to interpret BAL findings when that modality is used to determine the
cause of infection in children with chronic or recurrent radiographic opacities
or with a compromised immune system. The bronchoscope is passed through
the nose and mouth, compromising the sterility of the samples. Efforts to avoid
suctioning the airway until the scope is below the vocal cords can reduce, but
not eliminate, the risk of contaminating the specimens. Combining the visual
findings from bronchoscopic examination (presence or absence of airway
inflammation and secretions) with cell count, cytological examination, and
quantitative bacterial culture will strengthen the interpretation of the findings
(see Diagnostic Procedures, later in this chapter). If the proportion of squamous
cells is high, or if cultures return showing polymicrobial flora, upper airway
contamination of the specimen is likely. If the central airways are inflamed and
there are large amounts of secretions in those airways, however, the cells and
bacteria may be there because the child chronically aspirates oral secretions.
Figure 8-4. A, Computed tomographic reconstruction of the chest in a 16-year-

old boy with Duchenne muscular dystrophy and chronic right lower lobe
atelectasis. The air bronchogram ends abruptly, suggesting a mucous plug. B,
Bronchoscopic evaluation demonstrates airway narrowing and distortion resulting
from the patient’s severe scoliosis and chest wall deformity but no mucous plug.

152
Airway Management and Examination

There are several different ways to examine the pediatric airway by using
flexible bronchoscopy. These methods include transnasally or transorally
or via face mask, laryngeal mask airway, endotracheal tube, or tracheostomy
tube. The mode of airway entry should take into account the clinical context
and the reason for the procedure (Table 8‑2).9
Table 8‑2. Advantages and Disadvantages of Different Airway Entry Techniques

Technique Advantages Disadvantages
Natural • Inspect entire airway • More difficult to monitor ventilation
airway • Assess airway dynamics • Laryngospasm
(transnasal • May allow for the use of
or transoral a larger bronchoscope
approach) • Allows for airway evaluation
with a rigid scope
Face • Inspect entire airway • More difficult to monitor ventilation
mask • Assess airway dynamics • Laryngospasm
• Does not limit size of • May limit movement of broncho-
bronchoscope scope
Laryngeal • Is easy to place • Cannot assess upper airway
mask airway • Is a relatively secure airway • Cannot accurately assess vocal cord
• Can assist ventilation with movement
positive pressure • May limit size of bronchoscope
• May hinder passage of bronchoscope
• Requires deeper sedation than
natural
airway
• Can mask lower airway dynamics
• Does not completely protect airway if
vomiting occurs during the procedure
Endotracheal or • Is easy to place • Cannot assess upper airway
tracheostomy • Secures the airway • Cannot assess vocal cord anatomy
tube • Is easy and quick to reinsert and movement
bronchoscope if needed • Cannot assess airway dynamics
• Enables positive pressure • May limit size of bronchoscope
ventilation • Requires deeper sedation than
• Prevents contamination of natural airway
lower airway specimens by
upper airway secretions

153
Diagnostic Procedures
Bronchoalveolar Lavage Testing
Bronchoalveolar lavage is used to sample the alveoli for different cell types,
including migrated leukocytes and macrophages, invading bacteria, and other
infectious pathogens. Analysis can also be performed to evaluate acellular
components, including viral particles, cytokines, and proteins. The flexible
bronchoscope is advanced into progressively more distal airways until it is
wedged or unable to be advanced further. The lavage is performed first by
instilling normal saline through the working channel of the bronchoscope
into the distal airways and airspaces and then by withdrawing it by means of
suction. The amount of saline used for a lavage varies from center to center,
from 0.5 to 3.0 mL/kg per aliquot with a maximum of 4 aliquots taken at
1 procedure. Typically, a protocol is used to limit the total amount of saline
that is instilled. In many centers, the first sample is discarded because it is
believed not to represent alveolar sampling, but rather sampling of bronchial
cells. A return of at least 30% to 40% of the aliquot used in the lavage
is considered a good sample.7,9,21 Bronchoalveolar lavage is performed in
the most affected area as determined with radiographic imaging or direct
visualization with the bronchoscope. If there is no identified affected area,
the lavage is performed in the right middle lobe or lingula in children,
and the lavage is performed in the right lower lobe in infants to optimize
fluid recovery.9,21
Normal Cell Types
Bronchoalveolar lavage is a diagnostic tool used to evaluate cellular counts of
the lavage fluid (Table 8‑3). The absolute number of nucleated cells and red
blood cells can be detected, and the different types of white blood cells can
also be analyzed. In healthy lungs, alveolar macrophages make up roughly
80% to 90% of the cells in the BAL fluid, and lymphocytes and neutrophils
make up roughly 2% to 12% and 0% to 5% of the BAL fluid, respectively.22
There are subtle age-dependent differences in the BAL fluid. A slight increase
in the number of neutrophils is observed in patients younger than 12 months
when compared with those in children aged 12 to 36 months. Younger chil-
dren also can have a greater number of total cells when compared with those
in the adult population.23 Squamous epithelial cells, when detected in BAL,
suggest either contamination by oropharyngeal secretions because of poor
technique in performing the BAL or aspiration of upper airway secretions
by the patient.

154
Table 8‑3. Cell Types in Bronchoalveolar Lavage Fluid

Normal Percentage Disease Associated With Abnormal Cell Type
Cell Types in Healthy Patients or Number
Alveolar 80%–90% Lipid-laden macrophages: aspiration,
macro- gastroesophageal reflux
phages
Hemosiderin-laden macrophages: idiopathic
pulmonary hemosiderosis, vasculitis and collagen
vascular disease, infections, pulmonary vascular
disease, drug-associated increase
Lymphocytes 2%–12% Increased CD4+ cells: sarcoidosis, Crohn disease
Increased CD8+ cells: hypersensitivity pneumonia,
histiocytosis X, drug-induced pneumonitis, ILD,
bronchiolitis obliterans organizing pneumonia
Eosinophils 0%–1% Increased eosinophils: asthma, ILD,
drug-associated increase
Idiopathic increases: Churg-Strauss syndrome,
eosinophilic lung disease
Neutrophils 0%–5% Increased neutrophils: ILD, infection, asthma,
chronic bronchitis
Abbreviations: CD4+, cluster of differentiation 4 positive; CD8+, cluster of differentiation 8 positive;
ILD, interstitial lung disease.
Abnormal Cell Differentials

The BAL fluid can be examined for pathological cell types to enhance diag-
nostic yield. The number of different abnormal cell types and analysis of the
ratio of different cell types can be informative. For example, elevated numbers
of lipid-laden macrophages, in the proper clinical context, may be associated
with aspiration from swallowing dysfunction or from gastroesophageal reflux
disease (GERD). Similarly, hemosiderin-laden macrophages reflect a history
of pulmonary bleeding. The presence of increased numbers of normal cell
types is often nonspecific but can guide further investigation. Thus, increased
numbers of eosinophils in the BAL can be associated with multiple disorders,
including eosinophilic lung diseases, asthma, Churg-Strauss syndrome, drug
reaction, allergic bronchopulmonary aspergillosis, and interstitial lung disease.
Increased numbers of neutrophils can be found in infections, asthma, and
some interstitial lung diseases. In contrast, an increase in absolute numbers
of lymphocytes and variation in T-cell subpopulation ratios (particularly the
CD4:CD8 ratio, which is elevated in sarcoidosis and Crohn disease) can help
to identify specific diseases. An increase in CD8 lymphocyte populations is
associated with hypersensitivity pneumonitis, histiocytosis X, drug-induced
pneumonitis, interstitial lung disease associated with collagen vasculitis, and
cryptogenic organizing pneumonia (Table 8-3).21,22
In addition to cultures and cell types, BAL fluid can be analyzed for other
contents. For example, markers that suggest GERD with microaspiration can

155
be detected in BAL fluid. Investigators in several studies have attempted to

correlate the presence of pepsin and bile acids in BAL fluid with lung disease
from GERD. In patients with lung transplants, detection of either marker has
been an important finding because an elevation of either of these indexes
correlates with the onset of bronchiolitis obliterans.24 Bronchoalveolar lavage
fluid can also be analyzed for cytokines. Although such measurements cur-
rently are largely relegated to research investigations, they can help to assess
the effect of different pharmacological therapies on various lung diseases,
particularly inflammatory disease of either infectious or noninfectious origins.
For example, a reduction in measured cytokines in BAL fluid from patients
with asthma or cystic fibrosis might be demonstrated after a pharmacological
intervention.25,26 Investigators in some studies have measured immunoglobu-
lin levels in the BAL fluid. Patients with chronic disease had higher levels of
immunoglobulin G than did healthy control subjects.27 Although measure-
ments of cytokines or immunoglobulins are not routinely performed in the
pediatric patient population, their analysis underscores the importance of
the BAL fluid and its usefulness in both research and clinical care.
Microbiology
Testing for bacteria should include direct visualization of the BAL fluid
specimen by using the Gram stain. Such screening provides not only a rapid
clue to the type of bacteria that might be present but also some qualitative
assessment of the adequacy of the specimen. Fluid that contains large num-
bers of squamous cells, for instance, is likely to indicate contamination by
mouth flora. In contrast, the presence of large numbers of neutrophils supports
a diagnosis of acute infection. On the basis of a patient’s clinical history, BAL
fluid can be cultured for bacteria, acid-fast bacilli, fungi, and molds. Quanti-
tative cultures that yield greater than 105 colony-forming units per milliliter
offer insight into predominant strains of bacteria present in the lavage fluid
and help to eliminate contaminated samples.
Screening for viruses can also be performed. Polymerase chain reaction
detection to augment antigen detection and viral cultures has increased the
sensitivity of discovering viruses in the lower airways. As an adjunct to these
techniques, or if polymerase chain reaction or rapid antigen detection tech-
niques are not available, cytological examination of the BAL fluid can also
help identify viral infection of the lung.9 Inclusion bodies in the cytoplasm or
nucleus, balloon cells, syncytial cells, and smudge cells are pathognomonic
for agents like herpesvirus, cytomegalovirus, varicella, respiratory syncytial
virus, or adenovirus. In addition to using the Gram stain to detect gram-
positive or gram-negative organisms, other special stains can be used to find
specific pathogens. The Gomori methenamine silver stain is used to detect
fungal organisms and Pneumocystis jirovecii, and the Ziehl-Neelsen stain is
used to detect acid-fast bacilli.

156
The keys to effective anaerobic bacterial cultures include collecting a

contaminant-free specimen and protecting it from oxygen exposure. Bron-
choalveolar lavage fluid is aspirated using a sterile syringe that is then tightly
capped to prevent entry of air. The specimens should be plated as rapidly as
possible onto specially prepared anaerobic culture media. Cultures should be
placed in an environment that is free of oxygen at 35° C (95° F) for at least
48 hours before the plates are examined for growth.
Special Studies
Transbronchial Biopsy
Transbronchial biopsies are used in select pediatric populations. By far the
largest experience is in the population with lung transplants. Transbronchial
biopsy is the gold standard for the diagnosis of acute cellular rejection, a
common complication in the first 12 months after lung transplant. The
procedure is performed under fluoroscopic guidance by using 1.2-mm or
2.0-mm forceps that are passed though the working channel of the bron-
choscope. Six to 12 samples are taken for evaluation. These samples can
be examined histologically to evaluate for different cell types to establish a
diagnosis.28 Samples can also be cultured if infection is being considered.
Ciliary Biopsy
Ciliary biopsy is an important diagnostic tool for evaluating for primary
ciliary dyskinesia.29 To diagnose primary ciliary dyskinesia, the physician
can take samples from the upper and lower airways. Sampling from the upper
airway through nasal brushing often yields false-positive findings second-
ary to inflammation from respiratory infections, exposure to tobacco smoke,
and allergic rhinitis. Sampling from the lower airway will improve overall
yield by eliminating these secondary changes. Bronchoscopic sampling in
the lower airway is performed by using a cytology brush and sampling the
bronchial membrane at the main carina or in close proximity to it. Samples
are fixed in glutaraldehyde and sent for evaluation with electron microscopy
to assess ciliary ultrastructure. Some centers will also grow or culture cilia
samples or take samples for direct microscopic evaluation of ciliary motion.
Examination of ciliary ultrastructure with electron microscopy requires a
pathologist experienced in this area.
Therapeutic Bronchoscopy
Medication can be administered via a flexible bronchoscope. Epinephrine
can be instilled topically to help control bleeding in patients with pulmonary
hemorrhage.4 Although the drug is often administered blindly through an
endotracheal tube, localized deposition to a specific area of concern offers a
more directed therapeutic intervention. Dornase alfa also can be administered
via flexible bronchoscope. This mucolytic agent has been used in patients with

157
cystic fibrosis to target the DNA polymer network in the airway. It can improve
mucous clearance and pulmonary function in patients with cystic fibrosis.13
Mechanical removal of mucous plugs can also be achieved bronchoscopically.
In some instances, particularly in the intensive care unit setting, frequent
bronchoscopy can be used for airway clearance. This technique is useful to
clear proximal airways, if a chest radiograph shows an abrupt ending of an air
bronchogram (Figure 8-2). The technique is not an effective method of airway
clearance for processes in which air bronchograms are seen throughout an area
of atelectasis or consolidation (Figure 8-3), as discussed previously. Simple
saline washes of the airway through the bronchoscope can also help remove
tenacious, thick mucous plugs.
Removal of other foreign bodies is traditionally accomplished with rigid bron-
choscopes. Although some investigators have described foreign body removal
with a flexible bronchoscope, the general consensus is that rigid bronchoscopy
is a safer and more efficient mode for removing foreign bodies from the
airway, with decreased risk of airway obstruction when removing the
foreign body.2
Therapeutic Lavage
Pulmonary alveolar proteinosis is a disease for which whole lung lavage is a
therapeutic treatment option. This rare disease that occurs in both children
and adults is the result of an abnormality in surfactant homeostasis and meta-
bolism, resulting in abnormal accumulation of surfactant in the alveoli, which
in turn leads to abnormal gas exchange. Whole lung lavage, whereby each
lung sequentially undergoes lavage in a controlled manner to remove the
proteinaceous material filling the airspaces, is a treatment option generally
effective at ameliorating symptoms, and it is used along with other therapies
in this patient population.30
Endoscopic Intubation
Endoscopic intubation, in which an endotracheal tube is passed over the
flexible bronchoscope to guide its placement under direct visualization, can
be used when the standard approach to visualizing the larynx is not feasible
or possible. Thus, patients with cervical injuries, craniofacial abnormalities,
temporomandibular joint limitation, or known previous difficult airway
intubations can benefit from this approach.31
Stent Placement
Endobronchial stents can be positioned bronchoscopically in the central air-
ways, as distal as the lobar bronchi. There is limited indication for airway
stent placement in the pediatric population, typically involving severe cases
of airway narrowing that are not candidates for surgical intervention. Patients

158
with severe tracheomalacia, bronchomalacia, or stenosis can benefit from

airway stent placement when there is clinically significant respiratory com-
promise. Children with lung transplants are the population in which stent
placement has been used most commonly. This cohort can benefit from tempo-
rary placement of stents when there is stenosis or malacia at the anastomosis
site while it is healing. It is theorized that the temporary placement of a stent
can help reshape the area of concern.32 Limitations of the procedure in the
pediatric population include stent sizing and complications from the stent
placement. Some stents may be easily dislodged with coughing, and others
are difficult to remove because of clinically significant growth of granulation
tissue.32,33 Another concern is poor airway clearance of secretions in the area
of the stent.
Balloon Dilation of the Airway

Balloon dilation is performed with special balloon catheters. They can be
introduced into the affected region through the working channel of the bron-
choscope, after which the balloon is inflated under pressure to expand the area.
Balloon catheters come in a variety of dimensions and levels of rigidity and
can be used in patients with either congenital or acquired airway stenosis.
Often this procedure needs to be repeated at regular intervals to maintain
airway patency.33
Laser Therapy and Electrosurgery

Laser bronchoscopy uses laser energy delivered via standard bronchoscopes
to treat endobronchial disorders. Laser therapy is a tool widely used in adults,
in whom the incidence of endobronchial lesions is greater because of a higher
prevalence of carcinomas.34 However, in the pediatric population, this tech-
nique is helpful in the treatment of bronchial lesions, such as hemangiomas
and papillomas, or for the removal of granulation tissue. Another method of
treating these obstructions is endobronchial electrosurgery (also known as
electrocautery or diathermy), which uses high-frequency electrical current
through a probe to coagulate or vaporize tissue.
Endobronchial Ultrasonography
Endobronchial ultrasonography is a diagnostic technique for visualizing the
tracheobronchial wall and the immediate surrounding structures. Ultrasound
waves are transmitted to anatomical structures, and the reflected echoes are
transformed into electrical signals, which are converted to a visual image on
the monitoring screen. Endobronchial ultrasonography with ultrasound-guided
biopsy is used in the adult population, particularly in diagnosing tumors.35 In
2020, endobronchial ultrasonography was reported to be safely and success-
fully performed in more than 20 pediatric patients with reported increased
yield in diagnosis compared with that at standard bronchoscopy. The youngest
patient in this cohort was aged 2.5 years.36

159
Electromagnetic Navigational Bronchoscopy

Electromagnetic navigational bronchoscopy is a navigational system using
electromagnetic technology to guide a bronchoscope through the airways
for accurate targeting of lesions for biopsy that were previously inaccessible.
Using a virtual, 3-dimensional bronchial map from a computed tomography
scan of the chest and a catheter with a sensor probe, bronchoscopists are able
to navigate to a desired location for diagnostic biopsy and therapeutic treat-
ment.37 These techniques are currently limited to adult pulmonary centers
with expertise. This technology has the potential to expand the scope of
pediatric bronchoscopy in the future.
Complications of Flexible Bronchoscopy

Flexible bronchoscopy is a safe procedure in practiced hands, but some
complications occur with low frequency.9 Direct trauma to airway mucosa
can result in epistaxis or bronchial bleeding; these are typically minor and
self-limited problems. Crying, coughing, or phonating while the broncho-
scope is positioned between the vocal cords can lead to hoarseness or stridor
that is also mild and self-limited, and inadequate topical laryngeal anesthesia
can cause laryngospasm. Airway obstruction by the bronchoscope and seda-
tion can impair gas exchange, leading to hypoxemia and hypercapnia.9
Administration of supplemental oxygen during the procedure usually pre-
vents significant hypoxemia, allowing the procedure to be completed safely,
and the bronchoscope can be withdrawn quickly from a narrowed airway if
its presence causes critical obstruction. Airway instrumentation can elicit
vagal responses and cause bradycardia, but this problem is easily avoided
by using a topical application of lidocaine. Passage of the scope through an
infected upper airway (ie, if the procedure is performed when the patient has
an acute upper respiratory infection) can predispose a child to lower respira-
tory infection; similarly, meticulous cleaning of equipment is mandatory
between procedures to prevent a contaminated scope from infecting other
patients. Fever commonly occurs after flexible bronchoscopy, but it is usually
transient and resolves after a single dose of an antipyretic. Its persistence may
indicate significant infection.
Some complications are more likely when procedures like BAL or transbron-
chial biopsy are also performed. Persistent fever after BAL, especially in the
setting of bronchitis, may reflect transient bacteremia or local extension of
infection. Sepsis after bronchoscopy, however, is a rare complication. The
risk of pneumothorax is increased when transbronchial biopsy is performed;
therefore, any patient undergoing the procedure must be monitored for several
hours for the complication.

160
key po ints
} Fiberoptic bronchoscopy can be used at any age as a diagnostic or therapeutic
procedure.
} Foreign body removal usually requires rigid bronchoscopy.
} The most common indication for fiberoptic bronchoscopy is evaluation of noisy
breathing.
} Bronchoalveolar lavage is useful to define lower airway microbiological and
cytological characteristics.
} Extensive experience has demonstrated that flexible bronchoscopy is safe in
the hands of experienced bronchoscopists.
} The usefulness of diagnostic and therapeutic flexible bronchoscopy continues
to expand in parallel with technological advances.
References
1. Wood RE, Sherman JM. Pediatric flexible bronchoscopy. Ann Otol Rhinol Laryngol.
1980;89(5 pt 1):414–416 PMID: 7436241 doi: 10.1177/000348948008900506
2. Ramírez-Figueroa JL, Gochicoa-Rangel LG, Ramírez-San Juan DH, Vargas MH. Foreign body
removal by flexible fiberoptic bronchoscopy in infants and children. Pediatr Pulmonol.
2005;40(5):392–397 PMID: 16130115 doi: 10.1002/ppul.20242
3. Righini CA, Morel N, Karkas A, et al. What is the diagnostic value of flexible bronchoscopy in
the initial investigation of children with suspected foreign body aspiration? Int J Pediatr
Otorhinolaryngol. 2007;71(9):1383–1390 PMID: 17580093 doi: 10.1016/j.ijporl.2007.05.012
4. Karmy-Jones R, Cuschieri J, Vallières E. Role of bronchoscopy in massive hemoptysis.
Chest Surg Clin N Am. 2001;11(4):873–906 PMID: 11780301
5. Schellhase DE. Pediatric flexible airway endoscopy. Curr Opin Pediatr. 2002;14(3):327–333
PMID: 12011674 doi: 10.1097/00008480-200206000-00009
6. Midulla F, de Blic J, Barbato A, et al; ERS Task Force. Flexible endoscopy of paediatric airways.
7. Nicolai T. Pediatric bronchoscopy. Pediatr Pulmonol. 2001;31(2):150–164 PMID: 11180692
doi: 10.1002/1099-0496(200102)31:2<150::AID-PPUL1024>3.0.CO;2-6
8. Barbato A, Magarotto M, Crivellaro M, et al. Use of the paediatric bronchoscope, flexible
and rigid, in 51 European centres. Eur Respir J. 1997;10(8):1761–1766 PMID: 9272916
doi: 10.1183/09031936.97.10081761
9. Faro A, Wood RE, Schechter MS, et al; American Thoracic Society Ad Hoc Committee on
Flexible Airway Endoscopy in Children. Official American Thoracic Society technical
standards: flexible airway endoscopy in children. Am J Respir Crit Care Med.
2015;191(9):1066–1080 PMID: 25932763 doi: 10.1164/rccm.201503-0474ST
10. Godfrey S, Avital A, Maayan C, Rotschild M, Springer C. Yield from flexible bronchoscopy
in children. Pediatr Pulmonol. 1997;23(4):261–269 PMID: 9141111
doi: 10.1002/(SICI)1099-0496(199704)23:4<261::AID-PPUL3>3.0.CO;2-P
11. Wood RE. Spelunking in the pediatric airways: explorations with the flexible fiberoptic
bronchoscope. Pediatr Clin North Am. 1984;31(4):785–799 PMID: 6462800
doi: 10.1016/S0031-3955(16)34645-4
12. Wood RE. The diagnostic effectiveness of the flexible bronchoscope in children.
Pediatr Pulmonol. 1985;1(4):188–192 PMID: 4069807 doi: 10.1002/ppul.1950010404
13. Kamin W, Klär-Hlawatsch B, Truebel H. Easy removal of a large mucus plug with a flexible
paediatric bronchoscope after administration of rhDNase (Pulmozyme). Klin Padiatr.
2006;218(2):88–91 PMID: 16506110 doi: 10.1055/s-2005-836608

161
14. Khan TZ, Wagener JS, Bost T, Martinez J, Accurso FJ, Riches DW. Early pulmonary
inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med. 1995;151(4):1075–1082
PMID: 7697234
15. Kim ES, Kim SH, Kim KW, et al. Basement membrane thickening and clinical features of
children with asthma. Allergy. 2007;62(6):635–640 PMID: 17508967
doi: 10.1111/j.1398-9995.2007.01375.x
16. Kuo CS, Young LR. Interstitial lung disease in children. Curr Opin Pediatr. 2014;26(3):320–327
PMID: 24752172 doi: 10.1097/MOP.0000000000000094
17. Wood RE, Boesch RP. Bronchoscopy and bronchoalveolar lavage in pediatric patients.
In: Wilmott RW, Boat TF, Bush A, Chernick V, Deterding RR, Ratjen F, eds. Kendig and
Chernick’s Disorders of the Respiratory Tract in Children. 8th ed. Elsevier Saunders;
2012:131–144 doi: 10.1016/B978-1-4377-1984-0.00009-7
18. Nielson DW, Ku PL, Egger M. Topical lidocaine exaggerates laryngomalacia during
flexible bronchoscopy. Am J Respir Crit Care Med. 2000;161(1):147–151 PMID: 10619812
doi: 10.1164/ajrccm.161.1.9811043
19. Masters IB, Chang AB. Tracheobronchomalacia in children. Expert Rev Respir Med.
2009;3(4):425–439 PMID: 20477332 doi: 10.1586/ers.09.29
20. Goldman SA, Rimell FL, Meza MP, Newman B. Diagnosis and management of left main stem
bronchus compression. Ann Otol Rhinol Laryngol. 1997;106(6):461–465 PMID: 9199603
doi: 10.1177/000348949710600603
21. de Blic J, Midulla F, Barbato A, et al; European Respiratory Society. Bronchoalveolar lavage
in children. ERS Task Force on bronchoalveolar lavage in children. Eur Respir J.
2000;15(1):217–231 PMID: 10678650
22. Ratjen F, Bredendiek M, Brendel M, Meltzer J, Costabel U. Differential cytology of
bronchoalveolar lavage fluid in normal children. Eur Respir J. 1994;7(10):1865–1870
PMID: 7828697 doi: 10.1183/09031936.94.07101865
23. Midulla F, Villani A, Merolla R, Bjermer L, Sandstrom T, Ronchetti R. Bronchoalveolar lavage
studies in children without parenchymal lung disease: cellular constituents and protein levels.
24. Palmer SM, Miralles AP, Howell DN, Brazer SR, Tapson VF, Davis RD. Gastroesophageal
reflux as a reversible cause of allograft dysfunction after lung transplantation. Chest.
2000;118(4):1214–1217 PMID: 11035701 doi: 10.1378/chest.118.4.1214
25. Cetin I, Ozçelik U, Goçmen A, Kiper N, Doğru D, Yalçin E. BALF nitrite as an indicator of
inflammation in children with cystic fibrosis. Respiration. 2004;71(6):625–629 PMID: 15627874
doi: 10.1159/000081764
26. Gelfand EW, Cui ZH, Takeda K, Kanehiro A, Joetham A. Fexofenadine modulates T-cell
function, preventing allergen-induced airway inflammation and hyperresponsiveness.
J Allergy Clin Immunol. 2002;110(1):85–95 PMID: 12110826 doi: 10.1067/mai.2002.124770a
27. Kitz R, Ahrens P, Zielen S. Immunoglobulin levels in bronchoalveolar lavage fluid of children
with chronic chest disease. Pediatr Pulmonol. 2000;29(6):443–451 PMID: 10821726
doi: 10.1002/(SICI)1099-0496(200006)29:6<443::AID-PPUL6>3.0.CO;2-M
28. McWilliams TJ, Williams TJ, Whitford HM, Snell GI. Surveillance bronchoscopy in lung
transplant recipients: risk versus benefit. J Heart Lung Transplant. 2008;27(11):1203–1209
PMID: 18971092 doi: 10.1016/j.healun.2008.08.004
29. Shapiro AJ, Davis SD, Polineni D, et al; American Thoracic Society Assembly on Pediatrics.
Diagnosis of primary ciliary dyskinesia. An official American Thoracic Society clinical
practice guideline. Am J Respir Crit Care Med. 2018;197(12):e24–e39 PMID: 29905515
doi: 10.1164/rccm.201805-0819ST
30. de Blic J. Pulmonary alveolar proteinosis in children. Paediatr Respir Rev. 2004;5(4):316–322
PMID: 15531257 doi: 10.1016/j.prrv.2004.07.001
31. Elizondo E, Navarro F, Pérez-Romo A, Ortega C, Muñoz H, Cicero R. Endotracheal intubation
with flexible fiberoptic bronchoscopy in patients with abnormal anatomic conditions of the
head and neck. Ear Nose Throat J. 2007;86(11):682–684 PMID: 18225630
doi: 10.1177/014556130708601122
32. Antón-Pacheco JL, Cabezalí D, Tejedor R, et al. The role of airway stenting in pediatric
tracheobronchial obstruction. Eur J Cardiothorac Surg. 2008;33(6):1069–1075 PMID: 18299200
doi: 10.1016/j.ejcts.2008.01.034
33. Törer B, Gülcan H, Oğuzkurt L, Oğuzkurt P, Tarcan A. Use of balloon-expandable metallic
stent in a premature infant with congenital tracheobronchial stenosis. Pediatr Pulmonol.
2008;43(4):414–417 PMID: 18286549 doi: 10.1002/ppul.20788

162
34. Wahidi MM, Herth FJF, Ernst A. State of the art: interventional pulmonology. Chest.
2007;131(1):261–274 PMID: 17218585 doi: 10.1378/chest.06-0975
35. Haas AR, Vachani A, Sterman DH. Advances in diagnostic bronchoscopy. Am J Respir Crit
Care Med. 2010;182(5):589–597 PMID: 20378726 doi: 10.1164/rccm.201002-0186CI
36. Bouso JM, Yendur O, Hysinger E, et al. Endobronchial ultrasound-guided biopsy is feasible,
safe, and improves diagnostic yields in immunocompromised children. Am J Respir Crit Care
Med. 2020;201(3):384–386 PMID: 31626557 doi: 10.1164/rccm.201907-1372LE
37. Gildea TR, Cicenia J. Electromagnetic navigation bronchoscopy. In: Mehta A, Jain P, eds.
Interventional Bronchoscopy: A Clinical Guide. Humana Press; 2013:107–120
doi: 10.1007/978-1-62703-395-4_6

PART
2
Allergic Conditions
Chapter 9. Allergic Bronchopulmonary Aspergillosis................... 165

Chapter 10. Hypersensitivity Pneumonitis..................................... 183

Chapter 11. Eosinophilic Pneumonia................................................ 197

Chapter 12. Asthma............................................................................. 207

Miles Weinberger, MD, FAAP; Mutasim Abu-Hasan, MD; and Leslie Hendeles,
PharmD
163
10 PP 2ND ED - PO 02_163-164.indd 163 11/6/23 8:05 AM

10 PP 2ND ED - PO 02_163-164.indd 164 10/20/23 2:39 PM
CHAPTER
9
Allergic Bronchopulmonary Aspergillosis
Introduction
Allergic bronchopulmonary aspergillosis (ABPA) is a T-helper 2 (Th2 cell) and
immunoglobulin E (IgE)–mediated allergic reaction to the mold Aspergillus
fumigatus. This ubiquitous mold is usually of little consequence in the immu-
nocompetent host. In patients with an immunodeficiency, however, this mold
can infect the lung, leading to an overwhelming infection. Patients with asthma
and cystic fibrosis (CF) can become colonized with this organism, and while no
actual infection is present, the body’s immune system mounts a Th2 inflam-
matory response marked by increased expression of interleukin (IL) 5 (IL-5)
and IL-13, leading to eosinophil recruitment to the lung and increased produc-
tion of IgE. This can lead to asthma that is difficult to control, and, in patients
with CF, increased pulmonary exacerbations and worsened bronchiectasis.
Failure to recognize this condition can lead to progressive lung disease with
significantly decreased pulmonary function and, ultimately, bronchiectasis
and pulmonary fibrosis.
The Aspergillus species represents a family of molds often found in soil
and decaying plant matter.1–3 More than 300 species have been described,
with A fumigatus the most common in human infections.3 Transmission via
inhalation is the most common method of inoculation. No human-to-human
spread occurs.1,2 The conidia (spore) form is infectious, while the hyphae
form is what is seen in invasive disease.4
Aspergillus infections can take on 1 of 5 forms, 3 of which predominate:
allergic, saprophytic, and invasive (with allergic sinusitis and chronic
pulmonary aspergillosis less commonly seen).1,5 Allergic forms include
ABPA, hypersensitivity pneumonitis, and severe asthma with Aspergillus
colonization in immunocompetent hosts. The saprophytic form includes
aspergillomas, a situation in which the mold grows within preexisting
pulmonary cysts or cavities. This represents a nonallergic situation in an
immunocompetent host. Finally, the invasive form of the disease is the most
severe and life-threatening. These cases are seen in immunocompromised
165

166
hosts, such as those with prolonged neutropenia (ie, patients with cancer or
those undergoing transplantation; graft-versus-host disease) or impaired
phagocytosis (eg, chronic granulomatous disease).
Etiology
The immunologic cause of ABPA is complicated and not fully elucidated.
While several animal models are available to study this allergic-mediated
disease, they do not exactly mimic what is seen in humans. Many patients
with asthma and CF are sensitized to A fumigatus. Approximately 20% to
25% of patients with asthma and up to 60% of patients with CF are skin
test positive.6–8 Up to 80% of patients with CF have immunoglobulin G (IgG)
antibodies to Aspf14, and 60% to 80% may at one time grow A fumigatus in
their sputum culture.4,7,9 Despite this, not all of these patients develop ABPA.
Allergic bronchopulmonary aspergillosis is thought to be a Th2-mediated
disease, with IL-4, IL-5, IL-13, and IgE being important mediators of disease
progression.4,6,8 The working disease model for ABPA is outlined here1,2,4,6,10–12
and in Figure 9-1.10
1. Aspergillus fumigatus spores are inhaled. The spores become trapped in
the airway surface mucus and eventually germinate.
2. Airway clearance is compromised by the underlying disease
(asthma or CF).
3. Aspergillus fumigatus releases virulence factors, allergens (especially Af1),
and proteases in genetically susceptible patients, which
• disrupt and break down airway epithelial barriers.
• impair fungicidal proteins and complement.
• inhibit phagocytotic killing cells (macrophages and neutrophils).
4. The immune system is activated.
• Cytokines recruit CD4+ Th2 cells.
• Interleukin-5 production increases and IL-10 production decreases
with subsequent eosinophil infiltration.
• Interleukin-8 production increases with subsequent neutrophil
infiltration.
5. A specific humoral adaptive response occurs with elevation of IgG,
immunoglobulin A (IgA), and IgE to A fumigatus as well as IL-4 produc-
tion and nonspecific IgE elevation.
Aspergillus fumigatus spores demonstrate increased binding to inflammatory
proteins. In particular, the Aspergillus antigens cross-link with the IgE on the
mast cells, releasing mediators such as histamine, leukotrienes, and platelet-
activating factor, which increase vascular permeability and cause smooth
muscle constriction. Mast cell cytokines are chemoattractants for eosinophils.

167
Chapter 9—Allergic Bronchopulmonary Aspergillosis
Thus, a cycle of antigen-mediated stimulation and inflammation is created,

ultimately leading to the development of bronchiectasis.
Genetic predisposition
Trapping of A fumigatus spores in the viscid secretions
Growth of hyphae
Release of antigens and exoproteases
Abnormal mucociliary clearance Antigen presenting cells

Damage to airway epithelial barrier
Activation of the innate immune system
Release of cytokines
and chemokines
Th2 – Th1 T-cell responses

Release of IL-4, IL-5, IL-13
Influx of inflammatory cells
Propagation of
Early and late phase reactions inflammation
Cytokines, chemokines, Eosinophils, mast cells, neutrophils

growth factors T-cells, airway epithelium
• Increased IgE levels (total and A fumigatus specific)

• Pulmonary eosinophilic inflammation
• Tissue damage partially mediated by eosinophils
• Airway remodeling
Figure 9-1. Immunology of allergic bronchopulmonary aspergillosis.

Abbreviations: A fumigatus, Aspergillus fumigatus; IgE, immunoglobulin E; IL, interleukin.
Reprinted from Agarwal R. Allergic bronchopulmonary aspergillosis. Chest. 2009;135:805–826. © 2009.
Reproduced with permission from the American College of Chest Physicians.

168
Risk Factors
Certain genetic factors may increase a patient’s risk from merely possessing
A fumigatus sensitivity to developing ABPA. In particular, the presence of
HLA-DR2 and DR5 restrictions, IL-4Rα single nucleotide polymorphisms,
and IL-10 promoter mutations is associated with the development of ABPA.5
In a small case series, patients with asthma who were heterozygous for CFTR
mutations had a higher risk for the development of ABPA, suggesting that
this gene has some effect on the organism’s immunogenicity.6,8,11,13
There are several other factors that put one at risk for the development of
ABPA. In patients with CF, the acquisition of Pseudomonas aeruginosa
has been associated with a higher incidence of ABPA.9 Pseudomonas
aeruginosa is thought to heighten the Th2 response to A fumigatus antigens.
Airway acquisition of P aeruginosa often precedes the sensitization with
A fumigatus.9
Atopy is also associated with a higher risk of developing ABPA. Approxi-
mately 22% of patients with CF and atopy have ABPA, while 2% of patients
with CF who do not also have atopy develop ABPA.6,11 Aspergillus fumigatus
colonization is greater in patients with ABPA than in those with just atopy.6
Sensitization to A fumigatus is a key factor in the development of ABPA. In
patients sensitized to A fumigatus, the B cells of those with ABPA release
more IgE than the B cells of patients without ABPA. Different Aspergillus
antigens are associated with different clinical effects. Patients with ABPA
develop IgE to antigens Asp2, Asp4, or Asp6, while atopic patients develop
IgE to antigens Asp1 or Asp3.6,14
High levels of Aspergillus antibodies are thought to be produced because the
Aspergillus proteases disrupt the epithelial lining, exposing bronchoalveolar
lymph tissue to Aspergillus antigens, thus generating a potent immune
response.12 In those with CF, the abnormal mucus traps the spores more
effectively, further increasing the antigenic load.
Epidemiology
The prevalence of ABPA is difficult to determine because studies use varying
criteria to determine the diagnosis. The rate for patients with asthma is about
1% to 2%.10,11 It is much more common in people with CF, with prevalence
varying between 2% and 15%.4,6,10,11 Several large epidemiologic studies in
those with CF have further attempted to define the prevalence. In a report
from the Epidemiologic Study of Cystic Fibrosis published in 1999, the preva-
lence of ABPA among 14,210 patients in the United States and Canada was
2%,7 similar to a rate of 2.2% reported in a Cystic Fibrosis Foundation Patient
Registry analysis published in 199515 and the Registry analysis published in

169
2020,16 with a rate of 2.2% in patients younger than 18 years (though the rate
for older patients was higher at 7.4%, with an overall rate of 5%). In the United
States, there appears to be regional variation in the CF population, with the
highest rate in the West (4.0%) and the lowest rate in the Southwest (0.9%).7
Different criteria used to assign the diagnosis of ABPA, and the extent to
which this diagnosis was sought, may explain these regional variations, as
well as the lower prevalence rates when compared with other studies. Other
confounding features, such as environmental factors, could also not be ruled
out. The European Registry of Cystic Fibrosis, published in 2000, covered 9
European countries and 12,447 patients and reported an ABPA prevalence of
7.8%.17 This prevalence varied by country, with the highest rate (13.6%) found
in Belgium and the lowest rate (2.1%) found in Sweden. All 3 of these studies
demonstrated higher rates of ABPA in patients older than 5 to 6 years with
lower FEV1 values (<70% of predicted), Pseudomonas colonization, and a
history of wheezing.
Clinical Presentation
The classic presentation of ABPA is a triad of reversible airway obstruction,
recurrent pulmonary infiltrates, and central bronchiectasis. Common symp-
toms seen in patients with ABPA include wheezing, coughing, and increased
mucus production.5 Other symptoms that may be present include anorexia,
malaise, fever, and the expectoration of mucus with brown to black plugs.5,10
Hemoptysis has also been reported. In patients with asthma, their asthma fre-
quently becomes more difficult to control, while those with CF usually have
an increased number of pulmonary exacerbations and experience a significant
deterioration in pulmonary function. Weight loss is often reported. Allergic
bronchopulmonary aspergillosis may be easily confused with an exacerbation
of the patient’s underlying disease process; thus, a high degree of suspicion is
required to avoid missing the diagnosis of ABPA.
The results of the physical examination are typical for an exacerbation of
the patient’s underlying illness. Wheezing and a productive cough are often
found.5,11 Clubbing (reports up to 16%) can be seen in patients with ABPA.5,10
The chest wall can be hyperinflated.5
The differential diagnosis of ABPA is broad and includes illnesses that are
similar to both asthma and CF.5,10 These illnesses include acute processes such
as pneumonia (viral or bacterial) or a retained foreign body in the airways.
Allergy or inflammatory-mediated illnesses include eosinophilic pneumonia,
pulmonary infiltrates with eosinophilia, hypersensitivity pneumonitis, Churg-
Strauss syndrome, and sarcoidosis. The differential diagnosis also includes
chronic infectious tuberculosis, as well as disorders associated with
bronchiectasis, such as ciliary dyskinesia.

170
Evaluation
No single test can definitively establish the diagnosis of ABPA. Several
tests may return abnormal results in patients with ABPA; however, each
of these studies is insufficient to establish the diagnosis. To further com-
plicate matters, in select patients, many of these test results may actually
be normal despite clear evidence that the patient has ABPA. Accordingly,
the diagnosis is ultimately established through a combination of history,
physical examination findings, select laboratory study findings, and clinical
judgment. Various diagnostic algorithms have been proposed, and these
are discussed in Diagnostic Criteria later in this chapter. Microscopic iden-
tification of the mold can be accomplished with 10% potassium hydroxide
on a wet mount. For pathologic examination of tissue, silver staining (using
Gomori-methenamine or periodic acid–Schiff stains) is helpful but may be
negative in cases of ABPA. Affected tissue may demonstrate black staining
with dichotomously branching (at a 45-degree angle) hyphae.1,3 In the airways
of patients with ABPA, large mucus plugs (plastic bronchitis3) are often found.
On examination of these plugs, one can see a variety of inflammatory cells
or their breakdown products, including fibrin, Curschmann spirals, Charcot-
Leyden crystals, eosinophils, other inflammatory cells, and mold hyphae.2,10
Examination of the airway tissue itself demonstrates infiltration of the
bronchial walls with eosinophils, lymphocytes, and plasma cells.5 In more
severe or chronic cases, proximal bronchiectasis, especially of the upper
lobes, will be evident.5
Skin Testing
Because ABPA features an exaggerated IgE-mediated immune response
to the presence of A fumigatus, a positive immediate skin test result (type 1
reaction) is seen as essential for diagnosis in all patients. Various studies
consider a positive skin test finding to be a wheal 4 mm or larger, while others
accept a wheal of 3 mm or larger.6 This disagreement over the appropriate
wheal size likely contributes to regional differences in reported ABPA pre-
valence. When the skin test is properly performed in patients with ABPA, an
immediate wheal and erythema begins within 1 minute, reaches a maximal
size in 10 to 20 minutes, and then resolves within 1 to 2 hours.5,10 A delayed
reaction (type 3) can also be seen 4 to 8 hours later and can occur in 33% of
patients.5,10 As with any type of skin testing, precautions need to be taken to
ensure accurate testing, such as avoidance of antihistamines and steroids,
which could lead to a diminished wheal and flare reaction, prior to testing.
As stated earlier, A fumigatus is a ubiquitous organism, and many people
have been sensitized to it. Approximately 20% to 25% of people with asthma
are skin test positive to this mold,6,7,18 as are 60% of patients with CF.6–9,18

171
Consequently, a positive skin test result by itself is insufficient to establish

the diagnosis. On the other hand, a properly performed skin test with negative
results makes the diagnosis highly unlikely.5
Serologic Testing
Serum IgE is a key marker of ABPA, both in helping to make the diagnosis
as well as assessing for exacerbations. Total serum IgE is markedly elevated
in cases of ABPA, with levels often greater than 1,000 IU/mL in untreated
individuals. Lower levels (200–500 IU/mL) in patients with CF can be sugges-
tive of ABPA, and the test should be repeated in 1 to 3 months to assess for
persistent elevation. Repeated testing of serum IgE levels ideally should be
performed while the patient is not being treated with steroids.6 Decreasing IgE
levels are a good indication of effective therapy, with levels dropping 35% to
50% within several days of instituting therapy.10 Doubling of baseline levels is
seen in relapses of ABPA. While most patients with ABPA have elevated IgE
levels, a small subset may have normal IgE levels despite obvious ABPA. This
is thought to be secondary to IgE isotype switching.9
IgE and IgG antibodies specific to Aspergillus are also useful diagnostic
tests. In particular, IgE-specific antibodies are very sensitive markers for
ABPA.14 IgG-precipitating antibodies to Aspergillus antigens, although a
less sensitive test and highly dependent on the antigens used in the assay,
are also useful if positive (although a negative study finding does not
eliminate the diagnosis).10
Eosinophilia is another nonspecific blood test finding used in making the
diagnosis of ABPA. Patients with ABPA often have an elevated eosinophil
count of greater than 1,000 cells/µL.
Culture
Allergic bronchopulmonary aspergillosis represents a hypersensitivity reaction
to A fumigatus, which colonizes the airways of affected patients. Accordingly,
a sputum sample can often yield A fumigatus on culture. Because colonization
does not always lead to hypersensitivity, a positive sputum culture is not
diagnostic for ABPA.14
Radiologic Studies
Abnormalities on chest radiographs are often seen in active cases of ABPA.5,10
Transient or fixed pulmonary infiltrates are the classic finding. Central bron-
chiectasis may also be detected. Large bronchial mucus plugs are a pathologic
finding of ABPA and manifest themselves on chest radiographs as “finger in
glove” opacities or “toothpaste shadows.” Tram lines (fine parallel lines
radiating from the hila) are another common radiologic finding of ABPA.
These infiltrates often improve or resolve with appropriate therapy.6,19

172
Chest computed tomographic (CT) scans provide more detail than plain radio-
graphs, but this extra detail is not always needed for diagnosis. Computed
tomographic scans demonstrate the central bronchiectasis of ABPA, which can
be varicose, cylindrical, or cystic in nature, with the varicose and cystic forms
typically seen in ABPA.14 Mucoid impaction can be seen as high-attenuation
mucus plugs. The sine qua non of ABPA on CT scans is central bronchiectasis
and peripheral tapering of the bronchi.10,19 Other findings include centrilobular
nodules and tree-in-bud opacities.
Pulmonary Function Testing

Pulmonary function testing demonstrates obstructive airway disease.10 This
is a nonspecific finding, however, because asthma and CF by themselves
manifest as obstructive airway disease on pulmonary function tests; however,
a significant decline in pulmonary function should raise concern of ABPA,
particularly if usual interventions are not effective.
Diagnostic Criteria
Because there is no single diagnostic test for ABPA, various authors use
different criteria to determine the diagnosis. This makes for difficulty in
conducting epidemiologic studies as well as comparing various treatment
regimens. In 2003, a consensus statement was created to guide the physician
in diagnosing ABPA.6 Algorithms were created for diagnosis (Figure 9-2)
and determining the occurrence of an exacerbation.10
The criteria for diagnosing classic ABPA are listed in Box 9-1. The first
5 criteria should be present.6,11,19
In patients with CF, 5 criteria are present in classic cases (Box 9-2).4,6,11
Because all 5 criteria are not always present, minimum criteria for diag-
nosing ABPA in patients with CF have been established (Box 9-2).6 In
assessing for these criteria, the physician must make sure that ABPA is the
cause of the problem rather than the symptoms representing an exacerbation
of the underlying asthma or CF. This can be quite challenging because of the
large degree of overlap in these conditions. Confusion can arise both when
determining the initial diagnosis and when determining if an exacerbation
of ABPA (vs asthma or CF) is occurring. Therefore, referral to a pulmonary
or allergy specialist should be considered when the diagnosis of ABPA
is suspected.

173
All patients with bronchial asthma
Aspergillus skin test
Positive Negative
IgE levels Follow up with repeat

skin test every 2 years
>1,000 IU/mL 500-1,000 IU/mL <500 IU/mL
• Chest radiograph IgG/IgE specific Yearly follow-up

• High resolution CT to A fumigatus with IgE levels
chest
• IgG/IgE specific to A
fumigatus
• Absolute eosinophil
count
• Precipitins to A More than 2-fold compared
fumigatus to Aspergillus-hypersensitive No
• Spirometry asthmatics
Yes
Close follow-up with IgE

levels every 6 weeks
If increasing to >1,000
IU/mL
Treatment for ABPA
Figure 9-2. Algorithm for the diagnosis of allergic bronchopulmonary aspergillosis (ABPA).
Abbreviations: CT, computed tomography; Ig, immunoglobulin.
Reprinted from Agarwal R. Allergic bronchopulmonary aspergillosis. Chest. 2009;135:805–826. © 2009.
Reproduced with permission from the American College of Chest Physicians.

174
Box 9-1
Criteria for Diagnosing Classic Allergic Bronchopulmonary
Aspergillosis in Patients With Asthmaa
1 Underlying diagnosis of asthma
2 Proximal (central) bronchiectasis
3 Positive skin test to Aspergillus fumigatus
4 Elevated total immunoglobulin (Ig) E (>417 IU/mL or >1,000 ng/mL)b
5 Elevated IgE and/or IgG to A fumigatus
6 Infiltrates on chest radiograph
7 Positive precipitins to A fumigatus
8 Eosinophilia
9 Sputum containing A fumigatus
The first 5 criteria should be present.
a
b
Other literature suggests >1,000 IU/mL or 2,400 ng/mL.10
Staging of ABPA has been developed and can be used in patients with
asthma,10,11,20 though it is not used in patients with CF.6 Of note, one does
not need to pass from stage 1 through stage 5 directly; rather, there can
be transitioning back and forth between stages 1 through 3. Staging is
summarized in Table 9-1.19
To help determine if ABPA is developing or if an exacerbation is occurring,
serial monitoring of IgE levels is advisable, especially in patients with CF.
Annual measurement of IgE levels should be performed. In patients with
no history of ABPA, if the IgE level is greater than 500 IU/mL, a more
formal evaluation for ABPA should be undertaken, including skin testing
or IgE-specific testing for Aspergillus.6,11 If the test results are positive, a
diagnosis of ABPA can be considered using the minimal criteria outlined in
Box 9-2. If IgE levels are lower (200–500 IU/mL) and a diagnosis of ABPA
or a flare-up is still being entertained, further diagnostic tests (skin testing
for Aspergillus, IgE and/or IgG specific for Aspergillus, precipitins, chest
radiographs) should be considered.

175
Box 9-2
Diagnostic Criteria for Allergic Bronchopulmonary
Aspergillosis (ABPA) in Patients With Cystic Fibrosis (CF)
Classic Diagnostic Criteria
1 Acute or subacute clinical deterioration (cough, wheeze, and other pulmonary
symptoms) not explained by another etiology
2 Serum total immunoglobulin (Ig) E levels >1,000 IU/mL
3 Immediate cutaneous reactivity to Aspergillus or presence of serum IgE
antibody to Aspergillus fumigatus
4 Precipitating antibodies to A fumigatus or serum IgG antibody to A fumigatus
5 New or recent abnormalities on chest radiograph or chest computed
tomographic (CT) scan that have not cleared with antibiotics and standard
physiotherapy
Minimal Diagnostic Criteria
1 Acute or subacute clinical deterioration (cough, wheeze, and other pulmonary
symptoms) not explained by another etiology
2 Total serum IgE levels >500 IU/mL (if total IgE level is 200–500 IU/mL, repeat
testing in 1 to 3 months is recommended)
3 Immediate cutaneous reactivity to Aspergillus or presence of serum IgE
antibody to A fumigatus
4 One of the following: (1) precipitins to A fumigatus or demonstration of
IgG antibody to A fumigatus or (2) new or recent abnormalities on chest
radiograph or chest CT scan that have not cleared with antibiotics and
standard physiotherapy
Screening for ABPA in Patients With CF
1 Maintain a high level of suspicion for ABPA in patients with CF.
2 Determine the total serum IgE levels annually. If the total serum IgE
level is >500 IU/mL, perform A fumigatus skin test or use an IgE antibody
to A fumigatus. If results are positive, consider diagnosis based on
minimal criteria.
3 If the total serum IgE level is 200 to 500 IU/mL, repeat the measurement if
there is increased suspicion for ABPA and perform further diagnostic tests
(immediate skin test reactivity to A fumigatus, IgE antibody to A fumigatus,
A fumigatus precipitins, or serum IgG antibody to A fumigatus and chest
radiography).
Adapted from Stevens DA, Moss RB, Kurup VP, et al. Allergic bronchopulmonary aspergillosis in cystic
fibrosis—state of the art: Cystic Fibrosis Foundation Consensus Conference.
Clin Infect Dis. 2003;37(suppl 3):S225–S264, by permission of the Infectious Diseases Society of America.

176
Table 9-1. Staging of Allergic Bronchopulmonary Aspergillosis

Stage Description Radiographic Infiltrates Total Serum IgE
I Acute Upper lobes or middle lobe Sharply elevated
II Remission No infiltrate and patient off prednisone Elevated or normal
for >6 months
III Exacerbation Upper lobes or middle lobe Sharply elevated
IV Corticosteroid- Often without infiltrates, but intermittent Elevated or normal
dependent infiltrates might occur
asthma
V End stage Fibrotic, bullous, or cavitary lesions Might be normal
Abbreviations: CT, computed tomography; IgE, immunoglobulin E; PFT, pulmonary function test.
Reprinted from Greenberger PA. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol.
2002;110:685–692 . © 2002 with permission from Elsevier.
Therapy
Treatment for ABPA is directed at modulating the Th2-mediated immune
response to A fumigatus. While several treatment modalities have been used,
steroids appear to be the most effective at downregulating the hyperimmune
reaction. Steroids are thought to work by inhibiting phospholipase A2 activity
and arachidonic acid metabolism, thus diminishing chemotaxis and tissue
infiltration of inflammatory cells. This results in a decrease in IgE levels,
lessened eosinophilia, and clearing of pulmonary infiltrates.6
Although a number of different regimens are reported, they have several
features in common, including aggressive treatment for the first couple of
weeks of therapy, slow tapering of the steroid dose over the next several weeks
to months, and a universal improvement in the patient’s clinical course.6,14
Immunoglobulin E levels, in general, quickly decrease by 35% to 50% over
the first few weeks of therapy.10,11,19 Infiltrates on chest radiographs resolve, or
at least improve, over the first 1 to 2 months of therapy. Pulmonary function
(particularly FEV1) improves during this time.
The 2003 consensus statement recommends the following steroid dosing
schedule: prednisone at 0.5 to 2.0 mg/kg/d (with a maximum dose of 60 mg/d)
for 1 to 2 weeks, followed by tapering to every-other-day dosing for 1 to
2 weeks, and then tapering the dose over the next 2 to 3 months as clinically
able.6 Dose elevation might be needed if symptoms start to worsen. Often,
increasing the steroid dose back to the previously effective dosage will bring
symptoms under control. Serial IgE levels and follow-up chest radiographs
are useful for monitoring the progress of the treatment plan.

177
Steroids treat the patient’s inflammatory burden but do nothing to decrease

the antigen load to which the patient’s immune system is being exposed.
Various antifungal regimens have been used to eradicate, or at least decrease,
the disease burden of A fumigatus. Unfortunately, these regimens have met
with limited success. Only a few studies have been attempted, and most were
small in number.21,22 The most successful agent used has been itraconazole.
This drug has been found to be effective as a steroid-sparing agent.23 It acts by
inhibiting ergosterol synthesis in the fungal cell membrane, which decreases
the organism’s growth. In combination, itraconazole and oral steroids are
useful at treating exacerbations or relapses of ABPA.6,21,22
As with oral steroids, several dosing regimens have been published for anti-
fungal agents, though they have similar limitations to those discussed in the
steroid studies. The 2003 consensus statement6 recommends itraconazole at
5 mg/kg (up to 200 mg/dose) once per day. If more than 200 mg/d is indicated,
the dose should be split into a twice-per-day schedule (with a maximum dose
of 400 mg/d). Treatment with itraconazole is typically continued for 3 to
6 months or longer if symptoms persist or IgE levels remain elevated. A
search for and elimination of continued exposure to Aspergillus may be
helpful in patients with persistently high IgE levels.
Itraconazole has many adverse effects as well as several drug-drug interac-
tions. Hepatic toxicity is problematic, so close monitoring of liver function
is warranted. Liver function tests should be obtained before starting therapy
and then repeated after 1 month of treatment. Liver function also should be
monitored every 3 to 6 months while the patient is receiving therapy or if
any liver-related toxicity appears. Levels should also be checked if there is
no clinical response to therapy, if there are possible drug-drug interactions,
or if there are concerns regarding poor drug absorption or poor adherence
to the medication regimen.6
Common side effects of itraconazole include gastrointestinal upset, fever,
rash, headaches, dizziness, and fatigue. Concomitant use of drugs that lower
stomach acid (such as histamine-2 blockers or proton pump inhibitors) can
decrease absorption. Taking the medication with an acidic drink such as
orange juice may aid absorption. Grapefruit juice, however, should be avoided
because it interferes with the liver’s CYP3A4 enzyme, which can have an
effect on itraconazole metabolism.6 The treatment protocols presented in
the consensus statement are summarized in Table 9-2.6

178
Table 9-2. Treatment Protocol for Allergic Bronchopulmonary Aspergillosis (ABPA)

Treatment, Factor Explanation
Corticosteroids
Indications All patients except those with steroid toxicity
Initial 0.5–2.0 mg/kg/day po prednisone equivalent, maximum
60 mg/day, for 1–2 weeks
Begin taper 0.5–2 mg/kg/day every other day
for 1–2 weeks
Taper off Attempt to taper off within 2–3 months
Relapse Increase corticosteroids, add itraconazole, taper corticosteroids
when clinical parameters improve
Itraconazole
Indications Slow or poor response to corticosteroids, relapse, corticosteroid-
dependent, or corticosteroid toxicity
Dosing 5 mg/kg/day, maximum dose 400 mg/day po unless itraconazole
levels determined; bid dosing required
Duration 3–6 months
Monitor Liver function tests for all cases; itraconazole serum concentrations
if concern of adequate absorption, lack of response, possible
drug- drug interaction; serum concentrations of concomitant
drugs with potential for drug-drug interaction
Adjunctive therapy
Inhaled corticosteroids, No evidence for use in ABPA; may be used for the asthma
bronchodilators, component of ABPA
other anti-asthma
drugs
Environmental Attempt to search for and modify mold spore exposure in
manipulation refractory cases
Abbreviations: bid, twice a day; po, orally.
Reprinted from Stevens DA, Moss RB, Kurup VP, et al. Allergic bronchopulmonary aspergillosis in cystic
fibrosis—state of the art: Cystic Fibrosis Foundation Consensus Conference.
Clin Infect Dis. 2003;37(suppl 3):S225–S264, by permission of the Infectious Diseases Society of America.

179
Other medications have been used, with anecdotal evidence of improvement.

Several case reports using omalizumab (a humanized anti-IgE monoclonal
antibody) have been published demonstrating clinical improvement, fewer
respiratory exacerbations, reduced need for oral steroids, and lower IgE levels.
These studies, however, were observational in design with low numbers of
enrolled patients. No large, well-controlled study has been completed to date.
Case reports assessing the efficacy of other medications (such as inhaled
amphotericin as well as voriconazole and posaconazole) have been published,
with preliminarily promising results; however, larger studies confirming their
efficacy remain to be undertaken. For now, oral steroids, with the potential
addition of itraconazole, remain the standard of care.24
In addition to the use of oral steroids and itraconazole, supportive care for
the underlying disease processes (asthma and CF) is needed. Long-term
anti-inflammatory therapy for asthma is required. Although use of inhaled
steroids (such as budesonide or fluticasone) has been attempted to treat the
ABPA, with questionable success, their use in treating the underlying asthma
is not questioned. Supportive care for CF is required and includes nutritional
support (pancreatic enzymes and vitamins), aggressive airway clearance
(mucolytic agents and chest physiotherapy), and treatment with suppressive
antibiotics (inhaled tobramycin or aztreonam). Oral or intravenous antibio-
tics are warranted if a pulmonary exacerbation is occurring. Distinguish-
ing between a classic CF exacerbation and an ABPA flare can be difficult.
If there is no overwhelming evidence that the symptoms are due to an
ABPA flare, then aggressive use of antibiotics is indicated. If the patient’s
condition does not improve, then an ABPA flare needs to be addressed
and appropriately treated.
Prognosis
Allergic bronchopulmonary aspergillosis is a chronic and recurrent disease
that can often mimic the asthma and/or CF with which it is frequently asso-
ciated. While therapy is available to successfully treat ABPA, it is not curative
and may lead to significant adverse effects because of the long-term therapy
often required. When ABPA is aggressively treated early in its course, the
chance is minimized that the disease will progress to end-stage fibrosis.5,14
Lifelong monitoring is required to prevent complications and achieve
the most beneficial outcome.

180
key points
} The physician should consider the possibility of ABPA in patients with poorly
controlled asthma or CF.
} Suspect ABPA in children with asthma when asthma is under poor control
despite the patient’s being on an appropriate treatment plan.
➤ Infiltrates are seen on chest radiography.
➤ Atopic dermatitis is present.
➤ Elevated IgE levels are present.
} Suspect ABPA in patients with CF who have
➤ increasing numbers of pulmonary exacerbations.
➤ unexplained deterioration in pulmonary function.
➤ new onset of wheezing.
➤ increasing IgE levels measured at annual studies.
} No single diagnostic test is sufficient to establish the diagnosis. Many patients
might have positive ABPA-related test results but do not have the illness, while
a smaller number of patients might have negative study findings and have the
illness. History, physical examination findings, laboratory study findings, and
clinical judgment are needed to establish the diagnosis.
} Because of the challenges inherent in diagnosing ABPA and its overall low
prevalence, all suspected cases are best evaluated and managed by a
pediatric pulmonologist.
} Annual screening for ABPA with yearly measurement of IgE levels is advisable.
IgE levels should also be routinely measured during exacerbations of CF that
require intravenous antibiotics to make sure an ABPA exacerbation is not
being overlooked.
} Therapy consists of
➤ Oral steroids (prednisone)
➤ Antifungal therapy (itraconazole)
➤ Supportive care
ū In children with asthma: chronic anti-inflammatory therapy
ū In children with CF: nutritional support, airway clearance, appropriate use
of antibiotics
References
1. American Academy of Pediatrics. Aspergillosis. In: Kimberlin DW, Barnett ED, Lynfield R,
Sawyer MH, eds. 2021–2024 Red Book: Report of the Committee on Infectious Diseases.
32nd ed. American Academy of Pediatrics; 2021:211–215
2. Wark PA, Gibson PG. Allergic bronchopulmonary aspergillosis: new concepts of
pathogenesis and treatment. Respirology. 2001;6(1):1–7 PMID: 11264756
doi: 10.1046/j.1440-1843.2001.00289.x
3. Kradin RL, Mark EJ. The pathology of pulmonary disorders due to Aspergillus spp. Arch Pathol
Lab Med. 2008;132(4):606–614 PMID: 18384212 doi: 10.5858/2008-132-606-TPOPDD
4. Rapaka RR, Kolls JK. Pathogenesis of allergic bronchopulmonary aspergillosis in cystic
fibrosis: current understanding and future directions. Med Mycol. 2009;47(suppl 1):S331–S337
PMID: 18668399 doi: 10.1080/13693780802266777

181
5. Knutsen AP, Amin RS, Temprano J, Wilmott RW. Hypersensitivity pneumonitis and
eosinophilic pulmonary diseases. In: Chernick V, Boat TF, Wilmott RW, Bush A, eds. Kendig’s
Disorders of the Respiratory Tract in Children. 7th ed. Saunders Elsevier; 2006:686–704
doi:10.1016/B978-0-7216-3695-5.50053-5
6. Stevens DA, Moss RB, Kurup VP, et al; Participants in the Cystic Fibrosis Foundation
Consensus Conference. Allergic bronchopulmonary aspergillosis in cystic fibrosis—
state of the art: Cystic Fibrosis Foundation Consensus Conference. Clin Infect Dis.
2003;37(suppl 3):S225–S264 PMID: 12975753 doi: 10.1086/376525
7. Geller DE, Kaplowitz H, Light MJ, Colin AA; on behalf of the Scientific Advisory Group,
Investigators, and Coordinators of the Epidemiologic Study of Cystic Fibrosis. Allergic
bronchopulmonary aspergillosis in cystic fibrosis: reported prevalence, regional distribution, and
patient characteristics. Chest. 1999;116(3):639–646 PMID: 10492265 doi: 10.1378/chest.116.3.639
8. Knutsen AP, Slavin RG. Allergic bronchopulmonary aspergillosis in asthma and cystic fibrosis.
Clin Dev Immunol. 2011;2011:843763 PMID: 21603163 doi: 10.1155/2011/843763
9. Hartl D. Immunological mechanisms behind the cystic fibrosis-ABPA link. Med Mycol.
2009;47(suppl 1):S183–S191 PMID: 18651306 doi: 10.1080/13693780802189938
10. Agarwal R. Allergic bronchopulmonary aspergillosis. Chest. 2009;135(3):805–826
PMID: 19265090 doi: 10.1378/chest.08-2586
11. Moss RB. Pathophysiology and immunology of allergic bronchopulmonary aspergillosis.
Med Mycol. 2005;43(suppl 1):S203–S206 PMID: 16110813 doi: 10.1080/13693780500052255
12. Knutsen AP, Bellone C, Kauffman H. Immunopathogenesis of allergic bronchopulmonary
aspergillosis in cystic fibrosis. J Cyst Fibros. 2002;1(2):76–89 PMID: 15463812
doi: 10.1016/S1569-1993(02)00033-4
13. Miller PW, Hamosh A, Macek M Jr, et al. Cystic fibrosis transmembrane conductance regulator
(CFTR) gene mutations in allergic bronchopulmonary aspergillosis. Am J Hum Genet.
1996;59(1):45–51 PMID: 8659542
14. Thia LP, Balfour Lynn IM. Diagnosing allergic bronchopulmonary aspergillosis in children
with cystic fibrosis. Paediatr Respir Rev. 2009;10(1):37–42 PMID: 19203743
doi: 10.1016/j.prrv.2009.01.001
15. FitzSimmons SC. Cystic Fibrosis Foundation Patient Registry: 1995 Annual Data Report.
Cystic Fibrosis Foundation; 1996
16. Cystic Fibrosis Foundation. Patient Registry 2020: Annual Data Report. Cystic Fibrosis
Foundation; 2021. Accessed May 25, 2022. https://www.cff.org/sites/default/files/2021-11/
Patient-Registry-Annual-Data-Report.pdf
17. Mastella G, Rainisio M, Harms HK, et al; Epidemiologic Registry of Cystic Fibrosis.
Allergic bronchopulmonary aspergillosis in cystic fibrosis: a European epidemiological study.
Eur Respir J. 2000;16(3):464–471 PMID: 11028661 doi: 10.1034/j.1399-3003.2000.016003464.x
18. Schwartz HJ, Greenberger PA. The prevalence of allergic bronchopulmonary aspergillosis in
patients with asthma, determined by serologic and radiologic criteria in patients at risk. J Lab
Clin Med. 1991;117(2):138–142 PMID: 1993855
19. Greenberger PA. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol.
2002;110(5):685–692 PMID: 12417875 doi: 10.1067/mai.2002.130179
20. Patterson R, Greenberger PA, Radin RC, Roberts M. Allergic bronchopulmonary aspergillosis:
staging as an aid to management. Ann Intern Med. 1982;96(3):286–291 PMID: 7059089
doi: 10.7326/0003-4819-96-3-286
21. Wark PA, Gibson PG, Wilson AJ. Azoles for allergic bronchopulmonary aspergillosis associated
with asthma. Cochrane Database Syst Rev. 2004;(3):CD001108 PMID: 15266440
doi: 10.1002/14651858.CD001108.pub2
22. Elphick HE, Southern KW. Antifungal therapies for allergic bronchopulmonary aspergillosis in
people with cystic fibrosis. Cochrane Database Syst Rev. 2016;(11):CD002204 PMID: 27820955
doi: 10.1002/14651858.CD002204.pub4
23. Stevens DA, Schwartz HJ, Lee JY, et al. A randomized trial of itraconazole in allergic
bronchopulmonary aspergillosis. N Engl J Med. 2000;342(11):756–762 PMID: 10717010
doi: 10.1056/NEJM200003163421102
24. Janahi IA, Rehman A, Al-Naimi AR. Allergic bronchopulmonary aspergillosis in patients
with cystic fibrosis. Ann Thorac Med. 2017;12(2):74–82 PMID: 28469716
doi: 10.4103/atm.ATM_231_16

CHAPTER
10
Hypersensitivity Pneumonitis
CASE REPORT 10-1

A 12-year-old boy presented to the primary care clinic with a 3-month history
of cough and shortness of breath when he played soccer. In addition, he had
lost 3.18 kg (7 lb) during this time and had had intermittent fevers. The physical
examination revealed tachypnea with bibasilar crackles and oxygen saturation
of 89%. He was admitted to the hospital and treated with antibiotics. His
symptoms improved, and he returned home. Within a short time, his cough
and dyspnea recurred, and he was referred to a pulmonologist. Pulmonary
function testing revealed a restrictive pattern, and chest radiographs showed
increased interstitial markings. An in-depth history revealed that his symptoms
started shortly after the family had moved into a house with pigeons nesting
in the garden.
Introduction
Hypersensitivity pneumonitis (HP) is a complex disorder with variable
clinical presentation, intensity of symptoms, and natural history. It results
from immunologically mediated inflammation of the lung parenchyma in
response to an array of inhaled antigens.1 Hypersensitivity pneumonitis is also
known as extrinsic allergic alveolitis1 and has been described as a “group of
granulomatous, interstitial, bronchiolar, and alveolar-filling pulmonary
diseases.”2 Initially, HP was thought to be an adult disease resulting from
occupational exposure to environments such as moldy hay ( farmer’s lung),
moldy maple bark (maple bark stripper’s lung), and pigeon breeding. Hyper-
sensitivity pneumonitis was first reported in children in 1967 as pigeon
breeder’s lung. The children who were affected had severe interstitial
pneumonitis and presented with chronic symptoms of cough, progressive
dyspnea, and weight loss, as well as acute symptoms of fever and chest pain.
The children had had prolonged exposure to pigeons.3 In the decades since,
no universally accepted definition of HP has emerged, and its mechanism
remains incompletely described. Hypersensitivity pneumonitis has continued
to be a rare diagnosis in pediatrics. However, the incidence of HP diagnosis
183

184
in children could increase sharply in the future. It has been described as a

manifestation of e-cigarette or vaping use–associated lung injury, a problem
tracked by the Centers for Disease Control and Prevention as an outbreak in
the summer of 2019.4–6
Clinical Manifestations
The clinical and pathological manifestations of HP vary with the chronicity
of symptoms, with the intensity of the exposure to the offending antigens, and
with the host response to the antigen. It has been described in acute, chronic,
and recurrent forms.1,7 In the pediatric literature, HP is described via a series
of case reports, many of which describe children who have had symptoms for
months or years. Regardless of the duration of symptoms, most adults and
children with an ultimate diagnosis of HP present with symptoms of cough,
dyspnea, decreased exercise tolerance, and fever. Fatigue and weight loss
are common. Crackles are heard during examination in most patients with
tachypnea and hypoxemia, and in chronic cases clubbing of the fingers is
seen. Wheezing may be heard. Hemoptysis and pneumothorax have also been
described at presentation in children. The severity of disease can vary from
asymptomatic to severe, leading to pulmonary fibrosis and even death.
Most children with HP have abnormalities seen on plain chest radiographs,
often with reticulonodular shadowing or increased interstitial markings sug-
gestive of interstitial lung disease.1 High-resolution computed tomography of
the chest is more sensitive than plain radiography for detecting parenchymal
lung disease. Pediatric case reports have described ground-glass opacities,
centrilobular nodules, and air trapping,8–12 as well as honeycombing in a
case diagnosed late in the disease.13
Investigators in most pediatric cases with pulmonary function studies
describe restrictive lung disease manifested as decreased lung volumes
and often decreased diffusing capacity for carbon monoxide (Dlco). Inves-
tigators in 2 large case series of HP that included adults and children found a
restrictive pattern in the majority of patients (53% to 77%), with a substantial
minority (9% and 13%) of patients having a purely obstructive pattern14,15;
26% of patients had air trapping as indicated by an increased residual volume;
and 85% had a decreased Dlco.15 Reversible pulmonary artery hypertension
has been described in some children with HP.11,16 See Table 10‑1 for a
summary of common and uncommon symptoms.

185
Chapter 10—Hypersensitivity Pneumonitis
Table 10‑1. Occurrence of Signs and Symptoms in Patients With Hypersensitivity

Pneumonitis
Characteristic Occurrence
Usually Often Sometimes Late in Disease
Symptoms Cough Weight loss Hemoptysis —
Dyspnea Fever
Fatigue
Signs Crackles Tachypnea Wheezing —
Hypoxemia Clubbing
Pulmonary Restrictive pattern — Obstructive —
function only pattern only
Decreased diffusing Mixed obstructive
capacity for carbon and restrictive
monoxide pattern
Plain Reticulonodular — — —
radiography pattern
findings Increased interstitial
markings
High-resolution Nodules in a — Ground-glass Honeycombing
computed centrilobular opacities Traction
tomography distribution bronchiectasis
of the chest
findings Lobar volume
loss
Other — — Pulmonary artery —
complications hypertension
Congestive heart
failure
Pneumothorax
Epidemiology and Etiology

Few articles address the epidemiology of HP in children. It is considered
a rare, but underreported, condition. Most information about pediatric HP
comes from case reports in small series of patients, which included approxi-
mately 95 cases reported between 1960 and 2005.1 Although most pediatric
cases of HP have been reported in school-age children, it has also been
reported in infants and in young children.17,18 Investigators in a retrospective
Danish study identified children with HP from a national cohort of children
with interstitial lung disease, all of whom underwent lung biopsy; they found
HP in 26% of the cohort of 73 pediatric patients with interstitial lung disease,
for a point prevalence of 4/1,000,000 Danish children.19 Investigators in
a German study found the incidence of new cases of diffuse parenchymal

186
lung disease in children to be 1.32 new cases per 1 million children per year;
HP was the final diagnosis in 11 of the 38 cases (29%) described.20
The epidemiology of HP reported in the general population varies greatly
with age, location, and occupation. A claims-based cohort in the United States
that included 150 million people had 7,498 cases of HP over a 10-year period,
for an annual incidence of 1.28 to 1.94 cases per 100,000 individuals; the
prevalence increased with age from 0.95 per 100,000 in the 0- to 9-year-old
age group to 11.2 per 100,000 in the 65 years or older group.21 A retrospec-
tive Danish study’s results showed an incidence of interstitial lung disease of
4.1 per 100,000 inhabitants per year, with HP being 7% of those cases.19 By
contrast, investigators in a prospective study identified 1,084 new cases of
interstitial lung disease from 19 Indian cities and found final diagnoses of HP
in 47% of the cases.22 In England and Finland, the prevalence of farmer’s lung
has been estimated to range from 10 to 200 per 100,000 inhabitants.23
More than 200 antigens are known to provoke HP. The antigens are often
tied to occupational exposure, with the name of the disease reflecting the
profession or hobby of the patient: farmer’s lung, bird fancier’s lung, malt
worker’s lung, hot tub lung, wind instrument alveolitis.24 Antigens can be
divided into 6 categories—bacteria, fungi, mycobacteria, proteins, chemicals,
and metals.24,25 However, the causal antigen is not identified in 30% to 60%
of cases. Reported cases of HP related to e-cigarette use highlight the diffi-
culty of pinpointing a specific antigen.5,6 In pediatric reports, most cases are
attributed to proteins in the serum or droppings of birds, including pigeons,
doves, parakeets, budgerigars, canaries, and cockatoos. In these cases, dura-
tion of exposure ranged from weeks to years, with location of exposure often
within the house itself or a nearby pigeon coop. A source of HP in children
can be exposure to a variety of molds, especially Aspergillus species, found
in locations such as hay in a barn,26 grain dryers kept near the home on a
farm,17 a basement shower,8 and standing water under the house.10
The immunologic pathogenesis of HP is complex and remains incom-
pletely understood. In 1967, Stiehm et al3 described features of both immune
complex–mediated (type III) and T-cell–mediated (type IV) reactions in
their cohort. There is no evidence of a role for either immediate-type hyper-
sensitivity (type I) or cytotoxic-mediated (type II) allergic reactions in the
pathogenesis of HP. People with atopic tendencies are not affected more
frequently than those without atopic tendencies.27,28 The incidence of HP is
lower in smokers than in nonsmokers,29 and current cigarette smokers had
lower levels of serum immunoglobulin (Ig) G against pigeon antigens than
did pigeon fanciers who did not smoke.30 The inhibitory effect of nicotine on
alveolar macrophages has been suggested as a potential mechanism.29 A key
unanswered question regarding the pathogenesis of HP is why relatively few
individuals develop the disease given the universal presence of the instigating

187
antigens. Selman et al31 depicted a 2-hit hypothesis in which “antigen

exposure acts as the inducing factor, and genetic or environmental factors
act as promoting risk factors” (Figure 10-1).
Figure 10‑1. Proposed mechanisms in the pathogenesis of hypersensitivity pneumonitis. Most

exposed individuals develop an immune tolerance, and the antigen inhalation may result at
most in a mild increase of local lymphocytes, without clinical consequences. The coexistence
of genetic or environmental promoting factors provokes the development of an exaggerated
immune reaction that results in marked lung inflammation. The generation of the granuloma-
tous inflammation requires, among others, the expression of Th1 cytokines, including tumor
necrosis factor-α, IL-12, and interferon-γ, as well as a toll-like receptor 9–mediated dendritic
cell response, which is believed to promote Th1 skewing and prevent Th2 skewing during the
development of the adaptive immune response. Subsequently, in the presence of progressing
factors (ie, further exposure) or genetic predisposition, critical immunopathological changes
occur in the lung microenvironment.
Reprinted with permission of the American Thoracic Society. Copyright © 2012 American Thoracic Society. All
rights reserved. From Selman M, Pardo A, King TE Jr. Hypersensitivity pneumonitis: insights in diagnosis and
pathobiology. Am J Respir Crit Care Med. 2012;186(4):314–324. doi: 10.1164/rccm.201203-0513CI. The American
Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

188
Differential Diagnosis and Evaluation

Diagnosing HP in children can be difficult because it is a relatively rare
disease with variable manifestations and environmental triggers. Many of the
signs and symptoms overlap with those of a range of infectious and respiratory
illnesses (Box 10-1). Diagnosis depends on a high index of suspicion. The
diagnosis of HP should be entertained in any child with fulminant respiratory
symptoms with hypoxemia and restrictive physiology that resolves in the
hospital and then recurs after discharge, prolonged respiratory symptoms of
unknown cause, restrictive lung disease
Box 10‑1
or interstitial lung disease without a
Differential Diagnosis clear cause, or a history of vaping.
of Hypersensitivity
Pneumonitis in Children There is no definitive test for HP. Multiple
diagnostic criteria have been proposed,
Infectious
ū Bacterial pneumonia
but currently there is no universally
accepted definition.1,7,32 The 4 major cri-
ū Blastomycosis
teria Richerson et al7 detailed are among
ū Brucellosis
the more commonly used: (1) history
ū Coccidioidomycosis and physical examination findings and
ū Histoplasmosis pulmonary function findings indicate
ū HIV infection interstitial lung disease, (2) radiographic
ū Legionella infection findings are consistent with HP, (3) there
ū Mycoplasma infection is exposure to a recognized cause, and
ū Psittacosis (4) there is antibody to the causative
antigen. However, the causative agent
ū Tuberculosis
is not always known. In a large case series,
Respiratory
Hanak et al14 did not identify the cause in
ū Allergic bronchopulmonary
aspergillosis 25% of cases of HP. A common practice is
integration of the clinical, radiological, and
ū Asthma
histological findings by a multidisciplinary
ū Bronchiolitis obliterans
organizing pneumonia team that reaches a consensus. Algorithms
have been proposed for subacute or chro-
ū Cystic fibrosis
nic HP.32,33 Uncommonly, HP has been
ū E-cigarette or vaping
use–associated lung injury diagnosed at explant in adult patients
ū Interstitial lung disease of
undergoing transplant for progressive
childhood of unknown cause interstitial lung disease.34
ū Recurrent pneumonia Given the prevalence of both respiratory
Other infections and asthma in children, it is
ū Immune deficiency not surprising that many children ulti-
ū Malignancy mately receiving a diagnosis of HP are
ū Sarcoidosis first treated with antibiotics or asthma
ū Systemic lupus erythematosus
medications. Recurrence of symptoms
or failure to improve with time and

189
treatment differentiates HP from most acute respiratory illnesses and from

asthma. Restrictive lung disease, clubbing, and reduced Dlco are frequent
findings in children with HP but rare in those with asthma. A prolonged course
of illness, weight loss, and fevers may prompt an evaluation for tuberculosis,
HIV, malignancy, or immune deficiency. A false-positive enzyme-linked
immunosorbent assay for HIV has been reported in a boy with symptoms
of cough, progressive dyspnea, and weight loss who eventually had HP
diagnosed.35 Cystic fibrosis and allergic bronchopulmonary aspergillosis
(ABPA) are often considered in these patients. Sweat chloride quantitation
and genetic studies permit evaluation for cystic fibrosis. Allergic bronchopul-
monary aspergillosis occurs primarily in those with asthma or cystic fibrosis
and is always associated with allergen-specific IgE to Aspergillus detectable
with an allergy skin test or an in vitro blood test.36 Although a positive test
for precipitins to Aspergillus fumigatus can be found in both HP and ABPA,
eosinophilia is present in ABPA but not in HP. Allergic bronchopulmonary
aspergillosis typically has a pattern of obstructive lung disease in contrast to
that of HP, which usually manifests as restrictive lung disease. The sequela
of ABPA is bronchiectasis of the proximal airways, whereas long-standing
or recurring HP can lead to pulmonary fibrosis.
Evaluation of any patient suspected of having HP should include a detailed
history, with specific inquiries about exposure to known sources of HP, such
as birds, hay, and e-cigarettes. A thorough physical examination is important,
with particular evaluation for weight loss, tachypnea, hypoxemia, crackles,
and clubbing. Pulmonary function studies, including spirometry, total lung
volumes, and Dlco should be performed if the child is able to cooperate. A
chest radiograph will usually demonstrate findings consistent with interstitial
lung disease. High-resolution computed tomography is more sensitive, but
not specific. Depending on the clinical presentation, one may choose to
evaluate the patient for pulmonary artery hypertension, which has been
described in HP.12,16
Laboratory evaluation for HP may reveal neutrophilia or lymphopenia after
acute exposure, but eosinophilia is not expected.7 Elevated levels of IgG, IgM,
or IgA subtypes; erythrocyte sedimentation rate; or C-reactive protein levels
occasionally occur. These findings are not specific and are consistent with
acute and chronic inflammation. An elevated IgE level does not indicate HP
because an elevated IgE level accompanies a type I allergic process, whereas
HP is characterized by type III inflammation and an elevated IgG level.37
Positive precipitating antibodies specific to the suspected agent confirm
adequate exposure to the agent to generate a humoral immune response and
are supportive of a diagnosis but do not indicate disease.7 People who have
been exposed but do not have symptoms may have positive precipitins to a
given antigen.30,38 Although commercial tests for common serum precipitins

190
are available (Figure 10-2), nega-

tive test results do not rule out the
diagnosis of HP. Commercial tests
have been inaccurate in some cases
and may not include the source of
exposure.9,10 In 2017, Rouzet et al39
identified 2 biomarkers of bird fan-
cier’s lung that discriminate between
those who have been exposed and
those with disease with good sen-
sitivity and specificity, and they
proposed using these markers for
future diagnosis.
Figure 10‑2. Precipitin test. The patient’s
serum is in the center well. The peripheral When the evaluation results provide a
wells contain (1) pigeon droppings, (2) pigeon
high probability of an HP diagnosis,40
serum, (3) chicken serum, (4) canary serum,
(5) parakeet serum, and (6) parrot serum. proceeding to bronchoscopy or lung
Wells 1 and 2 are positive. biopsy is not needed. When broncho-
scopy is performed, the broncho-
alveolar lavage fluid of patients with HP demonstrates lymphocytosis.10,15,41
The cellular profile may depend on the timing of exposure to the antigen, with
CD8 cells predominating after recent exposure.15 The lung biopsy histological
findings in children 3,12,13 are consistent with the characteristic findings of
bronchiolocentric interstitial inflammation, composed mostly of lymphocytes.1
Interstitial nonnecrotizing granulomas are found in many cases.1,42 In individu-
als with interstitial lung disease of unknown cause, lung biopsy results can be
essential for diagnosing HP (see Case Report 10-2).8,42
Provocation tests, in which the suspected antigen is administered in an
aerosolized form, have been used to aid in diagnosing HP and to confirm
the environmental trigger. After the exposure, the patient is observed for
recurrence of symptoms. The use of this type of test is limited by lack of
standardized antigens, the possibility of contamination of the aerosol by non-
specific irritants, and the need to administer the test in a specialized center.1
In some patients, purposeful exposure to the environment in question can be
helpful diagnostically, as can a trial period during which the patient is not
exposed to the suspected trigger.7
Treatment and Prognosis

The usual treatment for HP is removing the suspected antigen from the
patient’s environment. Corticosteroids are indicated for clinically significant
symptoms. Outcomes in adults and children depend on cessation of exposure
to the trigger. Studies document improvement after the exposure to the antigen
in question was halted but continued or recurrent deterioration in respiratory

191
CASE REPORT 10-2

A 10-year-old boy presented with symptoms of fever, night sweats, chronic
cough, and wheezing. No environmental history of exposure to birds, farm
animals, or farm materials was obtained. Chest radiography and pulmonary
function testing indicated restrictive lung disease. Commercial serum precipitin
tests were negative. The boy had many features consistent with sarcoidosis,
including restrictive lung disease, decreased diffusing capacity, increased
angiotensin-converting enzyme levels, suggestive gallium scanning results,
and a positive response to corticosteroids. Lung biopsy results revealed pre-
dominant lymphoid interstitial infiltrate with features that distinguished
hypersensitivity pneumonitis from sarcoidosis. There was a noncaseating
granuloma that was peribronchiolar rather than interstitial in location and
composed of poorly organized aggregates of giant cells rather than the large,
discrete granulomas characteristic of sarcoidosis. The lung biopsy results
prompted further environmental evaluation and ultimately yielded discovery
of the inciting antigen.
status when exposure continued.8,43 Antigens can remain in the home even
18 months after removal of the source, and, in some cases, families have
moved from their homes to halt exposure.13,17 Prognosis ranges from complete
resolution of symptoms3 to death.44 Risk factors for worse prognosis include
pulmonary fibrosis documented at lung biopsy at the time of diagnosis,45,46
increased levels of the chitinase-like protein YKL-40,47 and coexisting
autoimmune disease.48 Patients who undergo lung transplant because of HP
have a reduced risk of posttransplant death than do patients with idiopathic
pulmonary fibrosis.34
Few studies address the efficacy of systemic corticosteroid treatment in HP.
Available data suggest that corticosteroids hasten the recovery from acute
HP but have no beneficial effect on long-term prognosis.49,50 A case report
describes clinical efficacy of inhaled corticosteroid for a patient’s recurrent
HP, but not for her initial presentation of HP, which was more severe than the
recurrent episodes.51
There are no clinical trials that address the merits of treatment with corti-
costeroids for HP in children, in either the short or long term. Prednisone is
the corticosteroid most frequently used, with treatment duration ranging from
weeks to months. The usual starting dose would be 1 to 2 mg/kg for 2 weeks
and subsequent doses depending on response. Monthly methylprednisolone
has also been used, as well as other immunosuppressive drugs.52 Investiga-
tors in a retrospective, single-center Danish study described the outcomes
in 19 children with biopsy-confirmed HP who were not treated with a
standardized protocol but who all were treated with monthly high-dose

192
intravenous methylprednisolone. Multiple lung function parameters, including

FEV1, FVC, total lung capacity, Dlco, and the ratio of Dlco to alveolar volume,
improved in all children at 3 and 6 months of treatment.19 In a cross-sectional,
follow-up study of this cohort, 47% of 22 patients had a low lung clearance
index, but 90% had normal spirometry results.52
key points
} Hypersensitivity pneumonitis is a complex disorder with variable
manifestation.
} Consider a diagnosis of HP in any child with
➤ Restrictive lung disease.
➤ Interstitial lung disease without a clear cause.
➤ Fulminant respiratory symptoms that resolve in the hospital and then recur.
➤ Unexplained persistent respiratory symptoms or recurrent pneumonia.
➤ Bronchiolitis obliterans organizing pneumonia without an underlying
risk factor.
➤ A history of vaping.
} Take an environmental history and consider an unknown or not yet described
environmental trigger.
} Hypersensitivity pneumonitis is not mediated via IgE; normal IgE levels or
negative results of a skin prick test to a specific antigen are not relevant for
the diagnosis.
} If pediatric interstitial lung disease is without a clear cause, a lung biopsy may
prove essential to ascertain the diagnosis.
} A timely HP diagnosis can have a substantial effect on outcomes.
➤ Lack of diagnosis and continued exposure to the antigen can lead to
end-stage lung disease from pulmonary fibrosis and even death.
➤ Prompt diagnosis and removal from exposure to the antigen can result in
complete recovery.
} Consider consultation with a pediatric pulmonologist in the evaluation of any
child in whom HP is suspected or in any child treated for asthma whose
symptoms do not improve as expected.
} Expect to see this diagnosis more often in the future.
➤ The underdiagnosis of HP is likely to change as diagnostic criteria become
more clear.
➤ The epidemiology of HP may change with increased exposure of the
pediatric population to inhaled antigens contained in e-cigarettes and
other sources.

193
References
1. Fink JN, Ortega HG, Reynolds HY, et al. Needs and opportunities for research in hypersensitivity
pneumonitis. Am J Respir Crit Care Med. 2005;171(7):792–798 PMID: 15657460
doi: 10.1164/rccm.200409-1205WS
2. Adams TN, Newton CA, Batra K, et al. Utility of bronchoalveolar lavage and transbronchial
biopsy in patients with hypersensitivity pneumonitis. Lung. 2018;196(5):617–622
PMID: 29959521 doi: 10.1007/s00408-018-0139-1
3. Stiehm ER, Reed CE, Tooley WH. Pigeon breeder’s lung in children. Pediatrics.
1967;39(6):904–915 PMID: 4165212
4. Centers for Disease Control and Prevention. Outbreak of lung injury associated with the use of
e-cigarette, or vaping, products. Page last reviewed August 3, 2021. Accessed March 14, 2022.
https://www.cdc.gov/tobacco/basic_information/e-cigarettes/
severe-lung-disease.html?s_cid=osh-stu-home-spotlight-006.
5. Sommerfeld CG, Weiner DJ, Nowalk A, Larkin A. Hypersensitivity pneumonitis and acute
respiratory distress syndrome from e-cigarette use. Pediatrics. 2018;141(6):e20163927
PMID: 29773665 doi: 10.1542/peds.2016-3927
6. Nair N, Hurley M, Gates S, et al. Life-threatening hypersensitivity pneumonitis secondary
to e-cigarettes. Arch Dis Child. 2020;105(11):1114-1116 PMID: 31712273
doi: 10.1136/archdischild-2019-317889
7. Richerson HB, Bernstein IL, Fink JN, et al. Guidelines for the clinical evaluation of
hypersensitivity pneumonitis. Report of the Subcommittee on Hypersensitivity
Pneumonitis. J Allergy Clin Immunol. 1989;84(5 pt 2):839–844 PMID: 2809034
doi: 10.1016/0091-6749(89)90349-7
8. Hogan MB, Patterson R, Pore RS, Corder WT, Wilson NW. Basement shower
hypersensitivity pneumonitis secondary to Epicoccum nigrum. Chest. 1996;110(3):854–856
PMID: 8797443 doi: 10.1378/chest.110.3.854
9. Yalçin E, Kİper N, Göçmen A, OzçelIk U, Doğru D, Misirligİl Z. Pigeon-breeder’s disease
in a child with selective IgA deficiency. Pediatr Int. 2003;45(2):216–218 PMID: 12709156
doi: 10.1046/j.1442-200X.2003.01691.x
10. Temprano J, Becker BA, Hutcheson PS, Knutsen AP, Dixit A, Slavin RG. Hypersensitivity
pneumonitis secondary to residential exposure to Aureobasidium pullulans in 2 siblings.
Ann Allergy Asthma Immunol. 2007;99(6):562–566 PMID: 18219839
doi: 10.1016/S1081-1206(10)60387-0
11. Ceviz N, Kaynar H, Olgun H, Onbaş O, Misirligil Z. Pigeon breeder’s lung in childhood:
is family screening necessary? Pediatr Pulmonol. 2006;41(3):279–282 PMID: 16400661
doi: 10.1002/ppul.20297
12. Lee SK, Kim SS, Nahm DH, et al. Hypersensitivity pneumonitis caused by Fusarium
napiforme in a home environment. Allergy. 2000;55(12):1190–1193 PMID: 11117278
doi: 10.1034/j.1398-9995.2000.00650.x
13. Farber HJ, Budson D. A pediatric case of severe chronic interstitial lung disease presenting
as spontaneous pneumothorax: blame it on the birds. Pediatr Asthma Allergy Immunol.
2000;14(1):75–85 doi: 10.1089/pai.2000.14.75
14. Hanak V, Golbin JM, Ryu JH. Causes and presenting features in 85 consecutive patients
with hypersensitivity pneumonitis. Mayo Clin Proc. 2007;82(7):812–816 PMID: 17605960
doi: 10.4065/82.7.812
15. Morell F, Roger À, Reyes L, Cruz MJ, Murio C, Muñoz X. Bird fancier’s lung: a series of
86 patients. Medicine (Baltimore). 2008;87(2):110–130 PMID: 18344808
doi: 10.1097/MD.0b013e31816d1dda
16. Balasubramaniam SK, O’Connell EJ, Yunginger JW, McDougall JC, Sachs MI. Hypersensitivity
pneumonitis due to dove antigens in an adolescent. Clin Pediatr (Phila). 1987;26(4):174–176
PMID: 3829561 doi: 10.1177/000992288702600402
17. Thorshauge H, Fallesen I, Ostergaard PA. Farmer’s lung in infants and small children. Allergy.
1989;44(2):152–155 PMID: 2719181 doi: 10.1111/j.1398-9995.1989.tb02238.x
18. Wolf SJ, Stillerman A, Weinberger M, Smith W. Chronic interstitial pneumonitis in a 3-year-old
child with hypersensitivity to dove antigens. Pediatrics. 1987;79(6):1027–1029 PMID: 3588126
19. Buchvald F, Petersen BL, Damgaard K, et al. Frequency, treatment, and functional outcome in
children with hypersensitivity pneumonitis. Pediatr Pulmonol. 2011;46(11):1098–1107
PMID: 21618714 doi: 10.1002/ppul.21479
20. Griese M, Haug M, Brasch F, et al. Incidence and classification of pediatric diffuse parenchymal
lung diseases in Germany. Orphanet J Rare Dis. 2009;4(1):26 PMID: 20003372
doi: 10.1186/1750-1172-4-26

194
21. Fernández Pérez ER, Kong AM, Raimundo K, Koelsch TL, Kulkarni R, Cole AL. Epidemiology
of hypersensitivity pneumonitis among an insured population in the United States: a claims-
based cohort analysis. Ann Am Thorac Soc. 2018;15(4):460–469 PMID: 29236517
doi: 10.1513/AnnalsATS.201704-288OC
22. Singh S, Collins BF, Sharma BB, et al. Interstitial lung disease in India. Results of a
prospective registry. Am J Respir Crit Care Med. 2017;195(6):801–813 PMID: 27684041
doi: 10.1164/rccm.201607-1484OC
23. Demedts M, Wells AU, Antó JM, et al. Interstitial lung diseases: an epidemiological overview.
Eur Respir J Suppl. 2001;32:2s–16s PMID: 11816822
24. Nogueira R, Melo N, Novais E Bastos H, et al. Hypersensitivity pneumonitis: antigen
diversity and disease implications. Pulmonology. 2019;25(2):97–108 PMID: 30126802
doi: 10.1016/j.pulmoe.2018.07.003
25. Lacasse Y, Girard M, Cormier Y. Recent advances in hypersensitivity pneumonitis. Chest.
2012;142(1):208–217 PMID: 22796841 doi: 10.1378/chest.11-2479
26. Hughes WF, Mattimore JM, Arbesman CE. Farmer’s lung in an adolescent boy. Am J Dis Child.
1969;118(5):777–780 PMID: 5348378 doi: 10.1001/archpedi.1969.02100040779018
27. Terho EO, Husman K, Vohlonen I. Prevalence and incidence of chronic bronchitis and farmer’s
lung with respect to age, sex, atopy, and smoking. Eur J Respir Dis Suppl. 1987;152:19–28
PMID: 3499342
28. McSharry C, Banham SW, Lynch PP, Boyd G. Skin testing and extrinsic allergic alveolitis.
Clin Exp Immunol. 1983;54(1):282–288 PMID: 6616972
29. Blanchet MR, Israël-Assayag E, Cormier Y. Inhibitory effect of nicotine on experimental
hypersensitivity pneumonitis in vivo and in vitro. Am J Respir Crit Care Med.
2004;169(8):903–909 PMID: 14701707 doi: 10.1164/rccm.200210-1154OC
30. Carrillo T, Rodriguez de Castro F, Cuevas M, Diaz F, Cabrera P. Effect of cigarette smoking
on the humoral immune response in pigeon fanciers. Allergy. 1991;46(4):241–244
PMID: 1897684 doi: 10.1111/j.1398-9995.1991.tb00580.x
31. Selman M, Pardo A, King TE Jr. Hypersensitivity pneumonitis: insights in diagnosis and
pathobiology. Am J Respir Crit Care Med. 2012;186(4):314–324 PMID: 22679012
doi: 10.1164/rccm.201203-0513CI
32. Morisset J, Johannson KA, Jones KD, et al; HP Delphi Collaborators. Identification of diagnostic
criteria for chronic hypersensitivity pneumonitis: an international modified Delphi survey.
Am J Respir Crit Care Med. 2018;197(8):1036–1044 PMID: 29172641
doi: 10.1164/rccm.201710-1986OC
33. Lacasse Y, Selman M, Costabel U, et al; HP Study Group. Classification of hypersensitivity
pneumonitis: a hypothesis. Int Arch Allergy Immunol. 2009;149(2):161–166 PMID: 19127074
doi: 10.1159/000189200
34. Kern RM, Singer JP, Koth L, et al. Lung transplantation for hypersensitivity pneumonitis. Chest.
2015;147(6):1558–1565 PMID: 25412059 doi: 10.1378/chest.14-1543
35. Karakurum M, Doraswamy B, Bennuri SS. Index of suspicion. Case 1. Hypersensitivity
pneumonitis. Pediatr Rev. 1999;20(2):53–54 PMID: 9989111
36. Greenberger PA, Bush RK, Demain JG, Luong A, Slavin RG, Knutsen AP. Allergic
bronchopulmonary aspergillosis. J Allergy Clin Immunol Pract. 2014;2(6):703–708
PMID: 25439360 doi: 10.1016/j.jaip.2014.08.007
37. Bogaert P, Tournoy KG, Naessens T, Grooten J. Where asthma and hypersensitivity pneumonitis
meet and differ: noneosinophilic severe asthma. Am J Pathol. 2009;174(1):3–13 PMID: 19074616
doi: 10.2353/ajpath.2009.071151
38. Banham SW, McSharry C, Lynch PP, Boyd G. Relationships between avian exposure, humoral
immune response, and pigeon breeders’ disease among Scottish pigeon fanciers. Thorax.
1986;41(4):274–278 PMID: 3738847 doi: 10.1136/thx.41.4.274
39. Rouzet A, Reboux G, Dalphin JC, et al. An immunoproteomic approach revealed antigenic
proteins enhancing serodiagnosis performance of bird fancier’s lung. J Immunol Methods.
2017;450:58–65 PMID: 28760669 doi: 10.1016/j.jim.2017.07.012
40. Lacasse Y, Selman M, Costabel U, et al; HP Study Group. Clinical diagnosis of hypersensitivity
pneumonitis. Am J Respir Crit Care Med. 2003;168(8):952–958 PMID: 12842854
doi: 10.1164/rccm.200301-137OC
41. Ratjen F, Costabel U, Griese M, Paul K. Bronchoalveolar lavage fluid findings in children
with hypersensitivity pneumonitis. Eur Respir J. 2003;21(1):144–148 PMID: 12570123
doi: 10.1183/09031936.03.00035703a
42. Yee WF, Castile RG, Cooper A, Roberts M, Patterson R. Diagnosing bird fancier’s disease in
children. Pediatrics. 1990;85(5):848–852 PMID: 2330249

195
43. Dinda P, Chatterjee SS, Riding WD. Pulmonary function studies in bird breeder’s lung. Thorax.
1969;24(3):374–378 PMID: 5817840 doi: 10.1136/thx.24.3.374
44. Bang KM, Weissman DN, Pinheiro GA, Antao VC, Wood JM, Syamlal G. Twenty-three years
of hypersensitivity pneumonitis mortality surveillance in the United States. Am J Ind Med.
2006;49(12):997–1004 PMID: 17096370 doi: 10.1002/ajim.20405
45. Vourlekis JS, Schwarz MI, Cherniack RM, et al. The effect of pulmonary fibrosis on survival in
patients with hypersensitivity pneumonitis. Am J Med. 2004;116(10):662–668 PMID: 15121492
doi: 10.1016/j.amjmed.2003.12.030
46. Wang P, Jones KD, Urisman A, et al. Pathologic findings and prognosis in a large prospective
cohort of chronic hypersensitivity pneumonitis. Chest. 2017;152(3):502–509 PMID: 28223152
doi: 10.1016/j.chest.2017.02.011
47. Long X, He X, Ohshimo S, et al. Serum YKL-40 as predictor of outcome in hypersensitivity
pneumonitis. Eur Respir J. 2017;49(2):1501924 PMID: 27836954
doi: 10.1183/13993003.01924-2015
48. Adegunsoye A, Oldham JM, Demchuk C, Montner S, Vij R, Strek ME. Predictors of survival in
coexistent hypersensitivity pneumonitis with autoimmune features. Respir Med. 2016;114:53–60
PMID: 27109811 doi: 10.1016/j.rmed.2016.03.012
49. Kokkarinen JI, Tukiainen HO, Terho EO. Effect of corticosteroid treatment on the recovery
of pulmonary function in farmer’s lung. Am Rev Respir Dis. 1992;145(1):3–5 PMID: 1731594
doi: 10.1164/ajrccm/145.1.3
50. Mönkäre S, Haahtela T. Farmer’s lung—a 5-year follow-up of eighty-six patients. Clin Allergy.
1987;17(2):143–151 PMID: 3581462 doi: 10.1111/j.1365-2222.1987.tb02332.x
51. Tanaka H, Tsunematsu K, Nakamura N, et al. Successful treatment of hypersensitivity
pneumonitis caused by Grifola frondosa (Maitake) mushroom using a HFA-BDP extra-fine
aerosol. Intern Med. 2004;43(8):737–740 PMID: 15468977 doi: 10.2169/internalmedicine.43.737
52. Sisman Y, Buchvald F, Blyme AK, Mortensen J, Nielsen KG. Pulmonary function and fitness
years after treatment for hypersensitivity pneumonitis during childhood. Pediatr Pulmonol.
2016;51(8):830–837 PMID: 26678017 doi: 10.1002/ppul.23360

CHAPTER
11
Eosinophilic Pneumonia
Introduction
Eosinophilia is found in a wide variety of respiratory illnesses, but eosino-
philic pneumonia is a specific condition characterized primarily by infiltration
of eosinophils into the lung parenchyma.1,2 Eosinophilic pneumonia can be
further divided into acute and chronic eosinophilic pneumonia based on the
duration of symptoms and the response to therapy.3,4 Although no specific
causative agent has been determined, acute eosinophilic pneumonia (AEP)
has been reported following exposures to multiple agents, including medi-
cations, industrial agents, high dust exposure, and tobacco smoke.5 Environ-
mental contaminants have been reported with AEP described in US military
personnel in Iraq6 as well as in rescue workers exposed following the
September 11, 2001, terrorist attack on the World Trade Center.7
Case series of AEP suggest that more than 80% of patients present with
acute onset fever, severe hypoxemia, dyspnea, and cough.8 Diffuse pulmo-
nary infiltrates are seen on chest radiography; high-resolution computed
tomography (CT) scanning reveals ground-glass opacity in most patients.9–11
In children, the onset of symptoms is rapid, with progression to respiratory
failure requiring mechanical ventilation.12 Since this condition so closely
simulates acute respiratory distress syndrome, aggressive therapeutic
interventions should be undertaken concurrently with the initial diag-
nostic steps.5 Fluid stabilization, ventilatory support, and the initiation
of broad-spectrum antibiotics are usually warranted. Bronchoscopy and
bronchoalveolar lavage (BAL) can be used to document eosinophilia in a
lower airway sample.13,14
Chronic eosinophilic pneumonia (CEP) is less commonly seen in pediatrics
and differentiated by its female predominance (2:1 female to male ratio),
older age of disease onset (mean age 45 years), and increased incidence of
both asthma and atopy.1,15–17 Symptoms of CEP are similar to AEP in presenta-
tion but progress more slowly, often extending months from the initial
presentation. Bronchoalveolar lavage examination is also indicated to evaluate
for CEP and has replaced open lung biopsy as the predominant diagnostic
197

198
procedure. If there is concern about associated extrapulmonary involvement,

then the systemic eosinophilic syndromes need to be considered.18
Presentation
Patients with AEP predominantly present with acute onset fever, dyspnea,
hypoxemia, and cough.5,19 The age at presentation ranges from adolescence
to young adult; the average onset of symptoms prior to diagnosis is approxi-
mately 4 days.20 In addition to the acuity of presentation, the severity of the
hypoxemia and the lack of a confirmed diagnosis of the respiratory distress
are features of AEP. Pope-Harman et al proposed diagnostic criteria14 that
included (1) acute onset (< 7 days of symptoms); (2) fever; (3) bilateral infil-
trates on chest radiograph; (4) severe hypoxemia (arterial Po2 on room air
≤ 60 mm Hg); (5) lung eosinophilia; and (6) no other evidence of infection,
hypersensitivity to drugs, or other known causes of acute eosinophilic lung
disease. More recent recommendations, the modified Philit criteria, suggest
“definite” AEP can be diagnosed by (1) acute respiratory illness of ≤ 1 month
duration; (2) infiltrates on either chest radiograph or CT; (3) pulmonary
eosinophilia, as demonstrated by either ≥ 25% eosinophils in BAL fluid or
eosinophilic pneumonia on lung biopsy; and (4) absence of other specific
eosinophilic lung diseases.3,20 To assess for lung eosinophilia, bronchoscopy
with BAL is needed to document a differential of ≥ 25%, which has been
proposed to be one of the diagnostic criteria for AEP, as well as to confirm
no other infectious etiology.14,21,22 The approach to evaluation of AEP is
shown in Box 11‑1.
The age range at presentation for AEP has been reported with a mean of
30 years; patient series have reported pediatric patients, aged 15 to 20 years,5
with a maximum reported age of 86 years. Presentations are typical across all
age ranges with no consistent association of asthma and only an inconsistent
history of atopy. Tobacco use has been commonly linked to AEP, with some
studies reporting up to two-thirds of patients having a history of tobacco use,
many with recent initiation of smoking. In considering the rate of tobacco
usage contrasted with the rarity of AEP, a direct causative relationship is
unlikely, but further investigation of this link is needed.23 More likely, lung
injury, perhaps enhanced by or associated with tobacco use, contributes to
the development of AEP.24 Case reports have linked e-cigarette use to AEP25;
however, vaping-related acute lung injury (VpALI) and e-cigarette or vaping
use-associated lung injury (EVALI) appear to be more frequently consistent
with either a toxic inhalation injury or lipoid pneumonia.26–28
Outdoor exposures to dust and other triggers have been reported to result
in AEP.3 These exposures include tear gas, workplace renovations, fungal
spores, and medications.9 Triggers resulting in AEP have also included

199
Chapter 11—Eosinophilic Pneumonia
firefighters exposed to debris and dust from the destruction of New York
City’s World Trade Center7 and military personnel exposed to sand and other
possible toxins while serving in the Middle East.6 Similarities to hypersensi-
tivity pneumonitis also need to be considered in the differential diagnosis, as
similar exposures are noted, but the diagnostic criteria should differentiate
between these 2 conditions.25,29
In contrast, CEP presents in a more progressive fashion over a period of
months.2 Symptoms at presentation include chest pain, dyspnea, and cough,
with a history of atopy and asthma reported in as many as two-thirds of
patients.24 The mean
Box 11-1
age at presentation
Algorithm for the Evaluation of is in the fifth decade;
Acute Eosinophilic Pneumonia there is a 2:1 female
A. History predisposition9; the
1. Previously healthy individual majority of patients
2. Acute onset dyspnea report little to no
3. Recent outdoor activity with extensive dust exposure history of tobacco
4. Possible recent tobacco use use; and relapse
B. Presentation can occur in up
1. Cough to 50% of cases.30
2. Fever
3. Chest pain
4. Tachypnea
5. Tachycardia
6. Crackles on physical examination
C. Laboratory evaluation
1. Bilateral infiltrates on chest radiography
2. Computed tomography with ground-glass opacities
3. Room air Pao2 < 60 mm Hg
4. Bronchoalveolar lavage eosinophilia ≥ 25%
5. Negative infectious workup
D. Diagnostic criteria
1. Acute onset of symptoms within 7 days of presentation
2. Fever
3. Bilateral infiltrates on chest radiography
4. Severe hypoxemia
5. Bronchoalveolar lavage or pulmonary eosinophilia
6. No other known cause of acute eosinophilia
E. Treatment
Systemic steroids

200
Diagnostic Testing
Across all series, chest radiography findings are consistent. Bilateral infil-
trates with alveolar, interstitial, or mixed alveolar and interstitial infiltrates
have all been reported.3 Pleural effusions are not uncommon and persist
during the recovery period. Although CT findings of nodular infiltrates with
ground-glass opacities have been frequently reported,13,24 these findings are
not required to confirm the diagnosis. The radiologic differential diagnosis
includes conditions such as viral or atypical bacterial pneumonia, pulmonary
hemorrhage, and diffuse alveolar damage (DAD).
Neither elevation of the peripheral white blood cell count nor isolated
eosinophilia has been consistently reported.5 Obtaining BAL is critical
to examine for lower airway eosinophilia. Cell differential examination of
the BAL is needed to establish the diagnosis with eosinophil differential
counts up to and in excess of 50%. Diagnostic criteria require a differential
of ≥ 25% eosinophilia, which can preclude the need for open lung biopsy.14
Eosinophilia has also been shown to persist in the pleural fluid and sputum.9
Characterization of the oxygen requirement, either by pulse oximetry or
arterial blood gas, is needed in addition to chest radiography, BAL cell count,
and differential and examination findings to meet the established diagnostic
requirements. Unfortunately, until bronchoscopy cultures are completed
and negative for infectious pathogens, AEP can only be implicated but
not confirmed.3
In contrast, the workup of CEP is altered by its slow onset of symptoms.
In this condition, pulmonary function testing may be indicated and a more
complete assessment of the extrapulmonary manifestations is advisable.
Bronchoalveolar lavage and sputum examination for eosinophils as well as
for markers of eosinophil degranulation will help to confirm the diagnosis.18,31
Additional laboratory characteristics reported in CEP include elevated
erythrocyte sedimentation rate and C-reactive protein, as well as a marked
increase in IgE, which is seen in approximately half of patients.24
Lung function may be practical in only the mildest of presentations. Most
commonly reported are mild restrictive changes, with a reduced diffusing
capacity for carbon monoxide and obstructive features in patients with CEP,
especially with a previously reported history of asthma or atopy.1,14

201
Pathophysiology
The histologic presentation of AEP is similar to that of DAD, with features
of interstitial and alveolar eosinophilic infiltration.13 Like DAD, the acute
phase is notable for hyaline membranes, interstitial edema, and microthrombi.
More chronic histology demonstrates organizing exudates with prominent
type II pneumocyte hyperplasia.32 Because the eosinophilic infiltration is so
responsive to corticosteroids, patients who receive steroids prior to diagnostic
evaluation may have reduced or incomplete eosinophilic predominance that
may obscure these findings.3,4
The respiratory distress and respiratory failure associated with AEP seems
to be most directly related to the influx of eosinophils.33 Although peripheral
eosinophilia is not universally present, eosinophilic infiltration into the lung
parenchyma is what is responsible for the hypoxemia and radiographic
findings characteristic of AEP.34 The immunologic response appears to
involve both lymphocyte and eosinophilic recruitment, as demonstrated by
Katoh et al.35 Activated T lymphocytes secrete IL-5 and IL-33, together with
multiple other cytokines. Chemokines help to both recruit eosinophils and
inhibit their apoptosis.19,36,37 Once localized to the pulmonary interstitium,
these cells degranulate further, releasing inflammatory mediators and toxic
products such as major basic protein, eosinophilic cationic protein, and leuko-
trienes.38 These products have been implicated in causing the histopathologic
findings (Figure 11-1) of interstitial infiltration, airway inflammation, and
exudate deposition.39,40
Figure 11-1. Histopathology of a patient with acute eosinophilic pneumonia. Note the diffuse
airway inflammation, hyaline membrane formation with many eosinophils within the alveolar
spaces. H&E stain, 100X.
From Leslie KO. My approach to interstitial lung disease using clinical, radiological and histopathological patterns.
J Clin Pathol. 2009;62(5):387–401. © Leslie 2009.

202
Treatment
Effective treatment of AEP is aimed at the underlying cause. Corticosteroids
have been shown to provide rapid successful resolution of the pulmonary
pathology.14 Either oral prednisolone or intravenous methylprednisolone is
most commonly prescribed for a duration of 1 month after resolution of
symptoms and radiographic findings.5 More recent data support shorter
courses of steroids, even less than 2 weeks, especially with patients who
respond more dramatically to initiation of anti-inflammatory therapy.11,41
Additional treatment options have included inhaled corticosteroids and
bronchodilators, especially if the symptoms involve airflow obstruction.39
Supportive therapy, including supplemental oxygen and fluid management, is
part of initial therapy for AEP.5,39 If respiratory failure ensues as a result of
advanced involvement, ventilator support, initially with bilevel positive
airway pressure, progressing to intubation and ventilation, is indicated. With
rapid responses to corticosteroids reported, there is rarely a need for long
periods of mechanical ventilator support.3
Most treatment regimens begin with intravenous corticosteroids with
doses up to 1 g/d. Steroid dosing is usually tapered once symptoms resolve,
but the duration of treatment may extend up to 3 months.5 Relapse has not
been reported in AEP responsive to corticosteroids. Chronic eosinophilic
pneumonia is similarly responsive to the initial course of treatment; how-
ever, relapses24 require reinitiation of steroid therapy with chronic mainte-
nance dosing. Targeting therapies with newly available biologics, such as
mepolizumab, a human monoclonal antibody to IL-5, have been trialed
in some patients with CEP with some success in reducing corticosteroid
adverse effects.42
Conclusions
Idiopathic eosinophilic pneumonias are the result of localized eosinophilic
recruitment and activation. Eosinophilic degranulation-damaged lung tissue
may result in hypoxemic respiratory failure, which may be life-threatening.
Recognition of this condition and early treatment with corticosteroids is
highly effective, and in most cases the prognosis is good with minimal
clinical sequelae.8

203
key points
} Acute eosinophilic pneumonia is marked by its acute onset, the severity of the
hypoxemia, the presence of eosinophils on BAL, and lack of other causes
of the respiratory failure.
} Acute eosinophilic pneumonia is characterized by the short duration of
symptoms prior to presentation and the rapid deterioration to respiratory
failure, which may require mechanical ventilation.
} Treatment for AEP is high-dose steroids, which lead to good clinical response;
recovery is rapid with no clinical sequelae.
} Acute eosinophilic pneumonia is distinguished from CEP by its rapid
progression, the severity of the hypoxemia, and the lack of history of
hypersensitivity to medications or atopy.
} Chronic eosinophilic pneumonia differs from AEP in its infrequent need for
mechanical ventilation and the high frequency of relapse upon the withdrawal
of corticosteroids.
References
1. Cottin V. Eosinophilic lung diseases. Clin Chest Med. 2016;37(3):535–556 PMID: 27514599
doi: 10.1016/j.ccm.2016.04.015
2. Wechsler ME. Pulmonary eosinophilic syndromes. Immunol Allergy Clin North Am.
2007;27(3):477–492 PMID: 17868860 doi: 10.1016/j.iac.2007.07.005
3. Philit F, Etienne-Mastroïanni B, Parrot A, Guérin C, Robert D, Cordier J-F. Idiopathic
acute eosinophilic pneumonia: a study of 22 patients. Am J Respir Crit Care Med.
2002;166(9):1235–1239 PMID: 12403693 doi: 10.1164/rccm.2112056
4. Allen J, Wert M. Eosinophilic pneumonias. J Allergy Clin Immunol Pract. 2018;6(5):1455–1461
PMID: 29735405 doi: 10.1016/j.jaip.2018.03.011
5. Janz DR, O’Neal HRJ Jr, Ely EW. Acute eosinophilic pneumonia: A case report and
review of the literature. Crit Care Med. 2009;37(4):1470–1474 PMID: 19242348
doi: 10.1097/CCM.0b013e31819cc502
6. Shorr AF, Scoville SL, Cersovsky SB, et al. Acute eosinophilic pneumonia among US military
personnel deployed in or near Iraq. JAMA. 2004;292(24):2997–3005 PMID: 15613668
doi: 10.1001/jama.292.24.2997
7. Rom WN, Weiden M, Garcia R, et al. Acute eosinophilic pneumonia in a New York City
firefighter exposed to World Trade Center dust. Am J Respir Crit Care Med. 2002;166(6):797–800
PMID: 12231487 doi: 10.1164/rccm.200206-576OC
8. Suzuki Y, Suda T. Eosinophilic pneumonia: A review of the previous literature, causes, diagnosis,
and management. Allergol Int. 2019;68(4):413–419 PMID: 31253537 doi: 10.1016/j.alit.2019.05.006
9. Cottin V, Cordier JF. Eosinophilic pneumonias. Allergy. 2005;60(7):841–857 PMID: 15932372
doi: 10.1111/j.1398-9995.2005.00812.x
10. Allen JN, Pacht ER, Gadek JE, Davis WB. Acute eosinophilic pneumonia as a reversible cause
of noninfectious respiratory failure. N Engl J Med. 1989;321(9):569–574 PMID: 2761601
doi: 10.1056/NEJM198908313210903
11. Rhee CK, Min KH, Yim NY, et al. Clinical characteristics and corticosteroid treatment
of acute eosinophilic pneumonia. Eur Respir J. 2013;41(2):402–409 PMID: 22599359
doi: 10.1183/09031936.00221811
12. Alp H, Daum RS, Abrahams C, Wylam ME. Acute eosinophilic pneumonia: a cause of reversible,
severe, noninfectious respiratory failure. J Pediatr. 1998;132(3 Pt 1):540–543 PMID: 9544919
doi: 10.1016/S0022-3476(98)70038-1
13. Jeong YJ, Kim K-I, Seo IJ, et al. Eosinophilic lung diseases: a clinical, radiologic, and pathologic
overview. Radiographics. 2007;27(3):617–637 PMID: 17495282 doi: 10.1148/rg.273065051
14. Pope-Harman ALDW, Davis WB, Allen ED, Christoforidis AJ, Allen JN. Acute eosinophilic
pneumonia. A summary of 15 cases and review of the literature. Medicine (Baltimore).
1996;75(6):334–342 PMID: 8982150 doi: 10.1097/00005792-199611000-00004

204
15. Wubbel C, Fulmer D, Sherman J. Chronic eosinophilic pneumonia: a case report and national
survey. Chest. 2003;123(5):1763–1766 PMID: 12740299 doi: 10.1378/chest.123.5.1763
16. O’Sullivan BP, Nimkin K, Gang DL. A fifteen-year-old boy with eosinophilia and pulmonary
infiltrates. J Pediatr. 1993;123(4):660–666 PMID: 8410525 doi: 10.1016/S0022-3476(05)80973-4
17. Cottin V, Cordier JF. Eosinophilic lung diseases. Immunol Allergy Clin North Am.
2012;32(4):557–586 PMID: 23102066 doi: 10.1016/j.iac.2012.08.007
18. Durieu J, Wallaert B, Tonnel AB. Long-term follow-up of pulmonary function in chronic
eosinophilic pneumonia. Groupe d´Etude en Pathologie Interstitielle de la Société de
Pathologie Thoracique du Nord. Eur Respir J. 1997;10(2):286–291 PMID: 9042622
doi: 10.1183/09031936.97.10020286
19. De Giacomi F, Vassallo R, Yi ES, Ryu JH. Acute eosinophilic pneumonia. Causes, diagnosis,
and management. Am J Respir Crit Care Med. 2018;197(6):728–736 PMID: 29206477
doi: 10.1164/rccm.201710-1967CI
20. Oermann CM, Panesar KS, Langston C, et al. Pulmonary infiltrates with eosinophilia syndromes
in children. J Pediatr. 2000;136(3):351–358 PMID: 10700692 doi: 10.1067/mpd.2000.103350
21. Ogawa H, Fujimura M, Matsuda T, Nakamura H, Kumabashiri I, Kitagawa S. Transient wheeze.
Eosinophilic bronchobronchiolitis in acute eosinophilic pneumonia. Chest. 1993;104(2):493–496
PMID: 8339639 doi: 10.1378/chest.104.2.493
22. Hayakawa H, Sato A, Toyoshima M, Imokawa S, Taniguchi M. A clinical study of idiopathic
eosinophilic pneumonia. Chest. 1994;105(5):1462–1466 PMID: 8181338
doi: 10.1378/chest.105.5.1462
23. Uchiyama H, Suda T, Nakamura Y, et al. Alterations in smoking habits are associated
with acute eosinophilic pneumonia. Chest. 2008;133(5):1174–1180 PMID: 18263675
doi: 10.1378/chest.07-2669
24. Eosinophilic lung disease of undetermined cause. In: Mason RJ, Broaddus VC, Murray JF,
Nadel J, eds. Murray and Nadel’s Textbook of Respiratory Medicine 4th ed. Saunders; 2005
PMID: 29773665 doi: 10.1542/peds.2016-3927
26. Kalininskiy A, Bach CT, Nacca NE, et al. E-cigarette, or vaping, product use associated lung
injury (EVALI): case series and diagnostic approach. Lancet Respir Med. 2019;7(12):1017–1026
PMID: 31711871 doi: 10.1016/S2213-2600(19)30415-1
27. Moritz ED, Zapata LB, Lekiachvili A, et al; Lung Injury Response Epidemiology/Surveillance
Group; Lung Injury Response Epidemiology/Surveillance Task Force. Update: characteristics
of patients in a national outbreak of e-cigarette, or vaping, product use-associated lung injuries -
United States, October 2019. MMWR Morb Mortal Wkly Rep. 2019;68(43):985–989
PMID: 31671085 doi: 10.15585/mmwr.mm6843e1
28. Fonseca Fuentes X, Kashyap R, Hays JT, et al. VpALI-vaping-related acute lung injury:
a new killer around the block. Mayo Clin Proc. 2019;94(12):2534–2545 PMID: 31767123
doi: 10.1016/j.mayocp.2019.10.010
29. Iwami T, Umemoto S, Ikeda K, Yamada H, Matsuzaki M. A case of acute eosinophilic
pneumonia. Evidence for hypersensitivity-like pulmonary reaction. Chest. 1996;110(6):1618–1621
PMID: 8989089 doi: 10.1378/chest.110.6.1618
30. Marchand E, Reynaud-Gaubert M, Lauque D, Durieu J, Tonnel AB, Cordier JF. Idiopathic chronic
eosinophilic pneumonia. A clinical and follow-up study of 62 cases. The Groupe d’Etudes et de
Recherche sur les Maladies “Orphelines” Pulmonaires (GERM“O”P). Medicine (Baltimore).
1998;77(5):299–312 PMID: 9772920 doi: 10.1097/00005792-199809000-00001
31. Jederlinic PJ, Sicilian L, Gaensler EA. Chronic eosinophilic pneumonia. A report of 19 cases
and a review of the literature. Medicine (Baltimore). 1988;67(3):154–162 PMID: 3285120
doi: 10.1097/00005792-198805000-00002
32. Tazelaar HD, Linz LJ, Colby TV, Myers JL, Limper AH. Acute eosinophilic pneumonia:
histopathologic findings in nine patients. Am J Respir Crit Care Med. 1997;155(1):296–302
PMID: 9001328 doi: 10.1164/ajrccm.155.1.9001328
33. Sarnaik AP, Heidemann SM. Acute eosinophilic pneumonia: a treatable cause of severe
acute respiratory failure. Crit Care Med. 1999;27(9):2069–2070 PMID: 10507665
doi: 10.1097/00003246-199909000-00081
34. Nakagome K, Shoda H, Shirai T, et al. Eosinophil transendothelial migration induced by the
bronchoalveolar lavage fluid of acute eosinophilic pneumonia. Respirology. 2017;22(5):913–921
PMID: 28139852 doi: 10.1111/resp.12982
35. Katoh S, Matsumoto N, Fukushima K, et al. Elevated chemokine levels in bronchoalveolar lavage
fluid of patients with eosinophilic pneumonia. J Allergy Clin Immunol.
2000;106(4):730–736 PMID: 11031344 doi: 10.1067/mai.2000.109827

205
36. Taniguchi H, Kadota J, Fujii T, et al. Activation of lymphocytes and increased interleukin-5
levels in bronchoalveolar lavage fluid in acute eosinophilic pneumonia. Eur Respir J.
1999;13(1):217–220 PMID: 10836352 doi: 10.1034/j.1399-3003.1999.13a40.x
37. Nakahara Y, Hayashi S, Fukuno Y, Kawashima M, Yatsunami J. Increased interleukin-5 levels
in bronchoalveolar lavage fluid is a major factor for eosinophil accumulation in acute
eosinophilic pneumonia. Respiration. 2001;68(4):389–395 PMID: 11464086
doi: 10.1159/000050532
38. Godding V, Bodart E, Delos M, et al. Mechanisms of acute eosinophilic inflammation in a case
of acute eosinophilic pneumonia in a 14-year-old girl. Clin Exp Allergy. 1998;28(4):504–509
PMID: 9641579 doi: 10.1046/j.1365-2222.1998.00231.x
39. Katz U, Shoenfeld Y. Pulmonary eosinophilia. Clin Rev Allergy Immunol. 2008;34(3):367–371
PMID: 18197481 doi: 10.1007/s12016-007-8053-y
40. Leslie KO. My approach to interstitial lung disease using clinical, radiological and
histopathological patterns. J Clin Pathol. 2009;62(5):387–401 PMID: 19398592
doi: 10.1136/jcp.2008.059782
41. Jhun BW, Kim SJ, Kim K, Lee JE. Outcomes of rapid corticosteroid tapering in acute
eosinophilic pneumonia patients with initial eosinophilia. Respirology. 2015;20(8):1241–1247
PMID: 26333129 doi: 10.1111/resp.12639
42. To M, Kono Y, Yamawaki S, et al. A case of chronic eosinophilic pneumonia successfully
treated with mepolizumab. J Allergy Clin Immunol Pract. 2018;6(5):1746–1748.e1741

CHAPTER
12
Asthma
Introduction
What is asthma? Can it be defined?1 This question is of importance in evaluat-
ing respiratory disease in the child for whom euphemisms for asthma have
been commonly used, including reactive airway disease (RAD), wheezy
bronchitis, obstructive bronchitis, recurrent bronchiolitis, and others. More-
over, the symptoms associated with asthma—wheezing, cough, and
dyspnea—are not unique to asthma. They can also be associated with other
respiratory disorders.2 Asthma is a heterogeneous disorder that includes
various phenotypes and endotypes that share a common final pathway,
reversible airway narrowing from bronchial smooth muscle spasm, and
airway mucosal inflammation. Treatment decisions and counseling of
families regarding the expected outcome often relate to the specific pheno-
type, and future treatment may target specific endotypes.
Asthma, in its various phenotypes, is the most common medical diagnosis
among children hospitalized in the United States. Asthma has accounted
for more than 5% of nonsurgical admissions to the hospital in children and
adolescents.3 Asthma is also a leading cause for emergency care visits;
a leading cause for missed school; and a cause of considerable morbidity,
disability, and occasional mortality at all ages.4
A National Asthma Education and Prevention Program (NAEPP) was ini-
tiated in 1989 to address asthma as a national health problem. The NAEPP
provided a venue for stakeholders with an interest in improving asthma
management. Guidelines for asthma management were published by the
NAEPP in 1991, 1997, 2002, and 2007. A focused update was published in
2020.5 Asthma guidelines were also published by the Global Initative for
Asthma (GINA) as the Global Strategy for Asthma Management, first in
2002 and then with annual updates. Comparisons of the NAEPP and GINA
guidelines show similarities and some differences.6 Despite these excellent
published guidelines, outcome of asthma continues to be concerning.7
207

208
Convincing data indicate that failure of asthma management is not generally

due to lack of adequate therapeutic options but more commonly is due to
ineffective delivery of appropriate medical care.8 Asthma specialty programs,
which provide patients with continuity of care, an evidence-based treatment
plan, and effective patient education, result in improved asthma outcomes.9 In
this chapter, we will discuss the challenges of asthma diagnosis in children,
the different asthma phenotypes, and their clinical characteristics. Finally,
we will discuss the different treatments available for asthma and outline a
preventive and therapeutic approach to children with asthma on the basis of
their clinical phenotype.
Diagnosis of Asthma
Asthma diagnosis should be considered when children have 1 or more of the
following symptoms:
X Recurrent or chronic wheezing, with or without shortness of breath
X Recurrent or chronic coughing
X Repeated diagnoses of bronchitis or bronchiolitis
X Repeated diagnoses of pneumonia not clinically consistent with
pyogenic infection
In this section, we discuss how asthma should be confirmed and when
alternate diagnoses should be considered when the clinician is presented
with a child who has any combination of these symptoms or diagnoses.
Asthma is characterized by hyperresponsiveness of the airways to various
stimuli resulting in airway obstruction that is reversible to a substantial degree
either spontaneously or because of treatment. The airway obstruction is a
result of varying degrees of bronchospasm and inflammation (Figure 12-1).
Besides causing bronchospasm, airway inflammation also results in mucosal
edema and mucous hypersecretion, which further contributes to airway
obstruction. The diagnosis of asthma, therefore, is most efficiently confirmed
in patients with suggestive symptoms by demonstrating improvement of
symptoms and/or spirometric measurements of airway obstruction after
use of an inhaled β2-agonist or after treatment of airway inflammation with
a 5- to 10-day course of oral corticosteroids.10
In children who still have symptoms after a course of oral corticosteroids
or who do not have substantial reversal of airway obstruction with these
measures, a disorder other than asthma should be suspected. For example,
obstruction of an airway from bronchomalacia, bronchial compression from
a vascular ring, or foreign body aspiration can cause wheezing and result in
an incorrect diagnosis and inappropriate treatment. Also, chronic airway

209
Chapter 12—Asthma
infection and inflammation due to poor airway clearance such as in cystic

fibrosis and primary ciliary dyskinesia or immune deficiency can manifest
with asthma-like symptoms. Because of the chronic and recurrent nature
of the disease process and its symptoms, it is prudent to avoid assigning the
definitive diagnosis of asthma until there have been several distinct episodes
of wheezing or prolonged cough with at least 1 definite response to anti-
asthma medications.
The diagnosis of asthma has no lower age limit; however, in young children,
the diagnosis of asthma has been particularly associated with controversy.11
Symptoms resulting from airway inflammation associated with asthma are
frequently misdiagnosed as pneumonia, bronchitis, and recurrent bronchiol-
itis, which can result in ineffective and unnecessary use of antibiotics. How-
ever, persistent wheezing in infants may be caused by airway malacia, chronic
aspiration, and unusual congenital abnormalities such as vascular rings, and
these children often receive asthma medications with little benefit. Alterna-
tive terminology for asthma, such as reactive airway disease, adds to the
confusion.12 Both overdiagnosis and underdiagnosis of asthma in children
can result in unnecessary and ineffective treatment.13,14
Inflammed swollen
bronchial mucosa
Bronchial mucosa
Mucus secretion
Bronchial smooth muscle
Muscle spasm
Mucus
secretions
Figure 12-1. The 2 components of airway obstruction in asthma—bronchospasm and

inflammation with mucosal edema and mucous secretions illustrated on the right. The normal
airway is illustrated on the left.
Clinical Characterization of Phenotypic

Patterns of Asthma
Because of the heterogeneous nature of asthma, simply establishing the
diagnosis of asthma is not sufficient for development of the most appropriate
treatment plan. Planning effective and efficient strategies for managing
asthma requires identifying the clinical pattern of disease. These clinical
patterns or phenotypes can generally be determined by obtaining a brief

210
history that addresses the age of onset and pattern of symptoms, as well as
the nature of triggers. The following questions are specifically helpful:
X What was the age of onset of lower respiratory symptoms?
X Are symptoms of asthma associated only with the clinical symptoms of a
viral respiratory infection?
X Are there extended periods between episodes of respiratory symptoms
when there is no cough or wheeze?
X Is there a seasonal variation in symptoms, and does the season match
those of inhalant allergens for which the patient has allergen-specific
immunoglobulin E (IgE)?
X Are respiratory symptoms related to specific environmental exposures?
X Do lower respiratory symptoms occur daily for extended periods?
From the responses to those questions, 3 distinct clinical patterns of asthma
can be identified—intermittent asthma, persistent asthma, and seasonal
allergic asthma.
Intermittent Asthma
Intermittent asthma is characterized by episodic symptoms with absence of
active asthma symptoms between episodes. This common asthma phenotype
is triggered primarily by viral respiratory tract infections. More importantly,
patients with intermittent asthma are both completely without symptoms and
without airway obstruction during the periods between episodes. Typically,
parents will say, “Every time my child gets a cold, it goes into the chest.”
This pattern of asthma generally begins in the first 1 or 2 years after birth.
The typical course starts with the onset of coryza from a common cold virus
followed by cough, wheezing, and respiratory distress of varying severity
that progresses over the next 1 to 2 days. The duration of symptoms without
effective intervention can be days or weeks. During asymptomatic periods
between episodes, patients with this pattern of asthma have no evidence of
airway inflammation when examined with bronchoalveolar lavage.15
The absence of allergen-specific IgE in an infant or toddler in association
with a clinical pattern of intermittent viral respiratory tract infection–induced
asthma is generally predictive of a reduced frequency of symptoms or remis-
sion over time. Although most infants and toddlers with asthma have this
intermittent viral respiratory infection–induced pattern, allergy testing can
identify those who are at risk for more persistent symptoms in the future.16
Preschool-age children average 7 colds per year, with 15% of children experi-
encing 12 or more colds per year.17 For some children, that can result in the
appearance of almost continuous symptoms. Summer is generally associated
with an abatement of symptoms in these children. Distinguishing asthma

211
Chapter 12—Asthma
limited to viral respiratory infections from a chronic or seasonal allergic

pattern is important because, unlike with the latter, the most effective of
maintenance therapies will not reliably prevent the viral respiratory infection–
induced asthma that characterizes this common intermittent pattern.18–20
Persistent Asthma
Children with persistent asthma experience year-round chronic symptoms
and, in the absence of effective maintenance therapy, do not have extended
symptom-free periods. Most children with a persistent pattern of asthma
have an allergic component to the asthma. Symptoms in these children may
have begun with a viral respiratory infection–induced intermittent pattern
of symptoms. Those who develop IgE-mediated allergy (ie, atopy) are at risk
for more persistent symptoms. The early presence of allergen-specific IgE is
predictive of more persistent symptoms.21
Contrary to the belief of some, there is no age limitation for allergy testing,
and some children can have evidence of inhalant allergy contributing to
asthma even in infancy (Figure 12-2).
Seasonal Allergic Asthma

Children with seasonal allergic asthma experience persistent symptoms only
during an inhalant allergy season. For example, in the North Central United
States, this is most commonly from an outdoor mold, Alternaria, which
grows on decaying vegetation from early spring through late fall, with peaks
particularly in the spring and fall, when it has been associated with near-
fatal asthma exacerbations.22 In the valley areas of the Pacific Northwest and
Northern California, grass pollens are the major allergens causing seasonal
allergic asthma, generally accompanied by symptoms of allergic rhinocon-
junctivitis.23 Because allergens and seasonal patterns vary with the geographic
region, seasonal symptoms in other regions may be from molds, pollens,
flying insects, or a combination of those airborne allergens. The physician
caring for a child with asthma needs to have some knowledge of the local
aerobiological environment to establish a correct diagnosis.
Additional Phenotypes
Besides these main 3 common phenotypes of asthma in children, there are
other less common phenotypes. Late-onset allergic asthma can follow aller-
gic rhinitis. Nonallergic persistent asthma, common in adults, also occurs
occasionally in children. Catamenial asthma, characterized by exacerbations
associated with menses in adult women, is seen occasionally in female adoles-
cents. These phenotypes and sudden asphyxic asthma in adolescents and
preadolescents are discussed in a previous publication.24 Notably, there is
potential overlap among all clinical patterns of asthma. For example, patients
with persistent disease often have intermittent exacerbations from viral

212
respiratory illness and may have seasonal allergic exacerbations. Identification

of the clinical pattern in each patient contributes to a rational and optimally
effective therapeutic strategy for that patient.
Figure 12-2. Allergy skin testing in an 11-month-old infant. He was hospitalized aged 9 months
with severe acute asthma preceded by rhinoconjunctivitis during the peak of the grass pollen
season in a Northern California valley area, where grass pollen is a major inhalant allergen. The
typical wheal and flare of the multiple related species of grass pollen native to that area are on
the left side of the infant’s back. They are much larger than the histamine control (H) with no
reactivity to the diluent control (C). Skin tests on the right side of the back to other common
inhalant allergens were all negative. Although immunotherapy using injections of allergenic
extracts is rarely indicated at this age, this infant illustrates a striking exception for whom
benefit could reasonably be expected.
From Weinberger M. Pediatric asthma and related allergic and nonallergic diseases: patient-oriented
evidence-based essentials that matter. Pediatric Health. 2008;2(5):631–650.

213
Chapter 12—Asthma
Exacerbations of Asthma
An exacerbation of asthma may be nothing more than transient broncho-
spasm from exercise or a specific exposure. Rapid response to a bronchodila-
tor such as an albuterol aerosol from a metered dose inhaler (MDI) may then
be sufficient to end that type of exacerbation. However, a more prolonged
exacerbation generally involves mucosal edema and mucous secretions. While
that is sometimes self-limited, a corticosteroid may be necessary to prevent
that exacerbation from progressing and to end the increase in symptoms.
Viral respiratory infections are common causes of more severe exacerbations.
Common cold viruses exacerbate all asthma phenotypes, possibly because of
a defect in innate immunity related to mucosal interferon.25 While common
cold viral infections affect only the upper respiratory mucosa in those without
asthma, infection and inflammation of the lower airways occur in those with
asthma. The frequency of common colds in preschoolers is usually higher for
those who attend child care or have siblings in school. Symptoms of asthma
exacerbations parallel the seasonal pattern of cold viruses that begin with
the onset of the school year and its associated increase in contact with other
children and continue throughout the fall, winter, and spring (Figure 12-3).26
3.5
2 to 4
5 to 15
16 to 49
3
2.5
Multiple of Mean
1.5
0.5
5
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
Figure 12-3. Typical autumnal increase in asthma at the beginning of the school year with the
younger school-age children beginning first followed by their older and younger siblings.
Reprinted from Johnston NW, Johnston SL, Norman GR, Dai J, Sears MR. The September epidemic of
asthma hospitalization: school children as disease vectors. J Allergy Clin Immunol. 2006;117(3):557–562.
Copyright © 2006 American Academy of Allergy, Asthma and Immunology.

214
Assessing Asthma Severity

Asthma can vary in severity from mild symptoms of cough and wheezing
to life-threatening symptoms of respiratory distress and respiratory failure.
Symptoms can also vary in frequency. Questions to assess severity include
the following:
X Do respiratory symptoms interfere with activity?
X Do respiratory symptoms interfere with sleep?
X What is the frequency of intermittent medication use with bronchodilator
and systemic corticosteroids?
X With what frequency is urgent care required—a physician’s office? Or the
emergency department? What is the frequency of hospitalization?
X How often has there been a requirement for intensive care?
X Has there been a requirement for ventilatory assistance?
X Have there been acute life-threatening events?
Treatment of Asthma
Intervention Medication (“Rescue” Medications)
Intervention medications are those used for acute symptoms (Table 12-1).
A short-acting inhaled β2-agonist is typically the initial intervention for acute
symptoms. Older children generally can successfully use these medications
with a metered-dose inhaler (MDI). In younger children and infants, nebuliz-
ers were a previous method for delivering aerosol. An MDI with a valved
holding chamber has generally replaced the nebulizer for delivery of aerosol
medications for asthma. The simplicity, more rapid administration, lower cost,
and greater portability of the MDI with an antistatic valved holding chamber
has made this the method of choice for aerosol administration in younger
children with asthma. Nebulized medication takes longer to deliver and is
associated with more adverse effects such as tachycardia and jitteriness
because of the much higher dose. An exception for use of a nebulizer for a
bronchodilator is the use of continuous nebulized albuterol for treatment of
severe acute asthma in the intensive care setting.
A valved holding chamber with a mask provides lung delivery from an MDI
for a patient too young to be able to form a seal with their mouth on a holding
chamber. This method of drug administration has proven efficacy for young
children, even in the emergency care setting.27 Parents and patients must
be properly instructed for whatever device is used for aerosol delivery and
should demonstrate appropriate use of these devices when prescribed
(Figure 12-4).

Table 12–1. Intervention Medication: Dosage and Decisions for Usual Treatment of Acute Symptoms of Asthma
Medication Dosage When to Use
Albuterol or levalbuterol 2–4 inhalations, up to 6 inhalations, can be used at a time As needed for cough, wheezing, labored
metered-dose inhaler breathing. Scheduled use has no advantage
Albuterol dry powder inhaler over as-needed use and may be deleterious
and dry powder digital inhaler for some patients. Repeated need during
exacerbations warrants consideration for
a short course of an oral corticosteroid.
Prednisone, prednisolone, Prednisone, prednisolone, methylprednisolone doses to obtain maximal effect in When bronchodilator subresponsiveness is
14 PP 2ND ED - CHAPTER 12_207-238.indd 215

methylprednisolone, and asthmatic airways identified by means of incomplete
dexamethasone as tablets resolution of symptoms and signs from
Infants—15 mg twice a day
Liquid formulations and oral repeated use of the bronchodilator.
1–3 years of age—20 mg twice a day Re-evaluate if not improving within 5 days
disintegrating tablets of pred-
nisolone for young children 3–13 years of age—30 mg twice a day or asymptomatic within
(Parenteral forms indicated 10 days. Do not taper.
> 13 years of age—40 mg twice a day
only in the case of concern
about oral retention) Because dose-response data are insufficient to support recommendations based
on weight or body size, these are empirical doses based solely on experience
that lower doses less reliably provide complete cessation of symptoms with the
goal of a short course (5–7 days). Lower doses almost certainly are adequate for
some patients, and minor adverse effects justify limiting dosage in some
patients to once daily in the morning only. There is no reason to taper short
courses.
Dexamethasone dose—one-fifth the milligrams of prednisone or prednisolone
dose is considered equivalent in effect, but dexamethasone is longer acting.
Ipratropium metered-dose 0.5 mg with 2.5–5 mg albuterol by nebulizer Indicated only for severe acute asthma
inhaler: ipratropium exacerbation in the emergency department
combined with albuterol in when response to β2-agonist is inadequate
soft-mist inhaler and for relief of respiratory distress.
ipratropium solution added to
albuterol solution for use in
nebulizer
Chapter 12—Asthma
215
9/12/23 9:13 AM
216
Figure 12-4. Various ways to deliver an aerosol to children from a metered-dose inhaler (MDI).
(A) A school-age boy being instructed by the doctor on proper use. (B) A 5-year-old girl who
used the MDI but did not inhale it as evidenced when she opened her mouth and the aerosol
mist was visibly expelled. (C) An infant receiving an aerosol from an MDI via a valved holding
chamber. (D) How to hold the chamber mask so that the hand of the adult moves with the
child maintaining the mask in contact with the face to avoid leakage of the aerosol.
Images A and C from Alamy Images. Images B and D from Weinberger M. Pediatric asthma and related
allergic and nonallergic diseases: patient-oriented evidence-based essentials that matter. Pediatric Health.
2008;2(5):631–650.
Albuterol is the most common β2-agonist used for acute bronchodilata-

tion in North America; terbutaline, less potent on a microgram basis than
albuterol, is commonly used in Northern Europe. Albuterol is a racemic
mixture of 2 optical isomers with levalbuterol being the therapeutically
active moiety. Although levalbuterol is available as the sole isomer, it is
therapeutically equivalent in both efficacy and toxicity to the racemic
preparation when administered in a dosage equivalent to the levalbuterol
component of racemic albuterol (ie, one-half of the milligram quantity of
racemic albuterol is levalbuterol).28 Despite initial marketing claims and
continued factitious beliefs, there is no evidence for any pharmacological
effect of the inactive moiety of racemic albuterol, and there is therefore no
therapeutic difference in efficacy or toxicity between levalbuterol alone
or in racemic albuterol.

217
Chapter 12—Asthma
Because β2-agonists do not alter the inflammatory component of airway

obstruction, anti-inflammatory therapy is essential to relieve that component.
Inflammation contributing to airway obstruction can be identified clinically
by increased frequency of using albuterol with decreasing clinical response.
Early aggressive use of systemic steroids provides impressive clinical benefit
for children having an acute exacerbation of asthma.29 Administration of oral
corticosteroids during the early symptoms of a viral respiratory infection
appears to prevent progression to severe acute asthma in children who have
previously required hospitalization. Earlier discharge after hospitalization for
acute asthma results from early administration of systemic corticosteroids,30
and prompt administration of systemic steroids in the emergency department
decreases the likelihood of subsequent admission of patients seen for emer-
gency care for asthma.31,32 Administration of a short course of a systemic
corticosteroid also prevents progression of asthma exacerbations in patients
who are ambulatory and have a history indicating a risk for requiring urgent
care (dosage is indicated in Table 12-1).33,34 Tapering is not indicated for
a short duration of systemic corticosteroid.35 Although care should be taken
to avoid excessive systemic corticosteroid exposure, no evidence of adverse
effects on bone metabolism, bone mineralization, or adrenal suppression
was seen in a study in 48 children who received a median of 4 courses of
oral glucocorticoids (range, 3–11 courses) compared with 35 similar children
who had not received corticosteroids in the preceding year.36
The most appropriate place to treat acute symptoms of asthma is where
they occur—at home, at school, or at play. The issue for many children is not
whether they will have another exacerbation, but when they will have one;
and that “when” is not predictable. Treatment in the doctor’s office, emergency
department, or hospital is stressful and disruptive for patients and parents and
should generally be considered damage control for a treatment failure. The
measures for treating acute asthma are inhaled β2-adrenergic bronchodilators
and systemic corticosteroids, usually administered orally. These measures are
most effective when used before the need for urgent medical care, rather than
waiting until presentation to the emergency department, clinic, or physician’s
office.29 Thus, for patients closely followed up by the physician managing the
child’s asthma, having the oral corticosteroid available at home to be used at
the early signs and symptoms of asthma exacerbation is most appropriate.37
When questioned, parents frequently can identify the early signs of previous
exacerbations. That information can be used to identify when a future oral
corticosteroid should be started before the need for urgent medical care.38

218
Box 12‑1
Measures to Maximize Benefit and Minimize Risk for Home Use of
Oral Corticosteroids to Treat an Asthma Exacerbation
ū Prescribe a dose sufficient for 1 week with no refills.
ū Instruct the patient and family on how to recognize an impending exacerbation;
questioning them regarding previous experience can provide useful guidance.
ū Provide an adequate dose; the absence of reliable dose–response data for
children suggests that erring high may be more likely to prevent urgent care.
ū The oral corticosteroid should be continued until the increase in symptoms
stops, whether 3, 5, or 7 days, so long as progressive improvement is occurring.
Tapering is not indicated.
ū The patient or family should contact the prescribing physician if symptoms do
not begin to improve within the first 2–3 days or are not gone by 7 days.
ū Adjust the dose if there are minor adverse effects from the corticosteroid
dose used.
ū Provide verbal and written instructions regarding the appropriate use of the
oral corticosteroid; repeat verbal instructions at scheduled follow-up.
ū Review the appropriateness and effect of corticosteroids after each use through
communication before refill—no refills without contact.
ū The prescribing physician is responsible for adequate follow-up to review
patient and family understanding and management of exacerbations. We all
learn from repetition.
Specific measures that can maximize benefit and minimize risk in the
home use of oral corticosteroids are given in Box 12-1.
For children with intermittent asthma, as-needed inhaled corticosteroids have
been suggested as an alternative to an oral corticosteroid.39 While earlier studies
have questioned the efficacy of inhaled corticosteroids for acute asthma,11,18–20
very early use of inhaled corticosteroids at the beginning of an exacerbation
may be sufficiently effective for some patients. This is discussed in a point/
counterpoint discussion published in Chest.40–43
A strategy for very early use of an inhaled corticosteroid in an exacerbation is
to combine an inhaled corticosteroid with a bronchodilator so that each use of
a bronchodilator for acute symptoms ensures the early use of additional doses
of inhaled corticosteroid. This approach is known as single maintenance and
reliever therapy (SMART). A combination of an inhaled corticosteroid with
formoterol, a rapid-onset, long-acting inhaled bronchodilator,44 or albuterol,45
for both maintenance and intervention has been shown to decrease the fre-
quency of exacerbations.46 While oral corticosteroids may still be needed for
some exacerbations, guidelines have now included this strategy as useful for
some children.39,47,48 Concerns have been expressed regarding the practicality

219
Chapter 12—Asthma
of this practice based on product labeling as mandated by the US Food and

Drug Administration at the time of this writing.49,50
In the emergency care setting, ipratropium, an anticholinergic aerosol, poten-
tially can add value to inhaled albuterol in treating severe acute asthma not
fully responsive to albuterol alone. Results of an early study showed decreased
risk of hospitalization for the children with more severe disease manifested
by an FEV1 less than 60%.51 A later Cochrane review of 20 studies consisting
of 2,697 children aged 1 to 18 years who were randomly assigned came to a
similar conclusion that benefit was most evident among the patients with more
severe disease.52 Ipratropium has no documented clinical role in patients who
are ambulatory. Repeated use of ipratropium also has no apparent value in the
outcome of patients hospitalized with acute asthma.53 Intravenous magnesium
has been used for severe acute asthma, but data generally show minimal
added clinical effect.54
Early during acute asthma, hypoxemia is common because obstruction
of small airways decreases oxygen uptake while perfusion is maintained.
The hypoxemia from this ventilation/perfusion (V̇ /Q̇ ) mismatching can be
corrected with oxygen. However, hypoxemia also can occur from respiratory
failure, which is associated with an increase in Pco2 as airway obstruction
progresses in severity. Measuring blood gas to measure pH and Pco2 (capillary
or venous is sufficient) is essential when hypoxemia is present to distinguish
hypoxemia caused by V̇ /Q̇ mismatching from hypoxemia caused by ventilatory
insufficiency. Supplementary oxygen is appropriate treatment for hypoxemia
from V̇ /Q̇ mismatching, but an increasing Pco2 indicates inadequate ventila-
tion. This hypercarbia (ie, elevated Pco2) indicates the potential for impending
ventilatory failure and the possible need for assisted ventilation. An initially
normal Pco2 should be carefully interpreted in the context of the clinical pic-
ture because the Pco2 may have been previously low, and increased work
of breathing from worsening airway obstruction can result in decreased
ventilation and an increasing Pco2.
Maintenance Medication
Maintenance medications are indicated for patients with persistent asthma and
for those with prolonged seasonal allergic asthma to treat frequent symptoms
and, ideally, prevent exacerbations (Table 12-2). The goal of maintenance
treatment for asthma is to use acceptably safe daily medication that effectively
suppresses asthmatic symptoms, prevents exacerbations, and maintains normal
lung function. Inhaled corticosteroids are the most effective medications for
children with prolonged periods of symptomatic asthma. These agents can be
effectively delivered with an MDI. A valved holding chamber decreases oral
deposition and consequent systemic absorption. Use of a tight-fitting mask with
a valved holding chamber provides effective delivery of aerosol medication to

220
Table 12-2. Maintenance Medications for Asthma

Medication
Type Formulation (Brand Name in Italics) When to Use
ICS MDIs First-line medication for
• Fluticasone propionate persistent symptoms; for
(Flovent HFA 44, 110, or 220 mcg) infants and toddlers use
• Mometasone furoate the MDI devices with a VHC
(Asmanex HFA 50, 100, or 200 mcg) and mask—many can use
• Ciclesonide a VHC without a mask by
(Alvesco 80 or 160 mcg) age 4 years; most can use
the breath-actuated MDI
Breath-actuated MDI and DPI formulations
• Beclomethasone dipropionate HFA effectively
(QVAR RediHaler 40 or 80 mcg) by age 6 years.
DPIs
• Budesonide
(Pulmicort Flexhaler 90 or 180 mcg)
• Fluticasone furoate
(Arnuity Ellipta 50, 100, or 200 mcg)
• Fluticasone propionate
(Flovent Diskus 50, 100, or 250 mcg;
ArmonAir Respiclick and Digihaler 55, 113,
or 232 mcg)
• Mometasone furoate
(Asmanex Twisthaler 110 or 220 mcg)
Leukotriene Montelukast An alternative to an ICS for
receptor (Singulair 4-mg sprinkle, 4- or 5-mg mild persistent symptoms;
antagonist chewable tablets, or 10-mg tablets) modest additional benefit
as add-on to inhaled
cortico-steroids. Black box
warning regarding mood
disorders.
Combination MDIs Use when an ICS does
ICS/LABA • Budesonide/formoterol fumarate dihydrate not maintain control and a
(Symbicort 80/4.5 or 160/4.5 mcg) LABA is added; occasionally
• Fluticasone propionate/salmeterol a patient’s condition may
(Advair HFA 45/21, 115/21, or 230/21 mcg) be made worse from the
• Mometasone furoate/formoterol fumarate addition of a LABA.
(Dulera 50/5, 100/5, or 200/5 mcg) Improved lung function,
DPIs but did not reduce exacer-
• Fluticasone furoate/vilanterol bation rates in patients with
(Breo Ellipta 100/25 or 200/25 mcg) moderate to severe asthma
• Fluticasone propionate/salmeterol compared to ICS/LABA
(Advair Diskus 100/50, 250/50, or 500/50 mcg; treatment
AirDuo Respiclick and Digihaler 55/14, 113/14,
or 232/14 mcg; Wixela Inhub 100/50, 250/50,
or 500/50 mcg)
• Fluticasone furoate/umeclidinium/
vilanterol inhaled
(Trelegy Ellipta 100 mcg/62.5 mcg/25 mcg per
puff, 200 mcg/62.5 mcg/25 mcg per puff)

221
Chapter 12—Asthma
Table 12-2. Maintenance Medications for Asthma (continued)

Medication
Type Formulation (Brand Name in Italics) When to Use
Long-acting Tiotropium bromide May be substituted for LABA.
muscarinic (Spiriva Respimat, Spiriva HandiHaler) Add on when control not
antagonist maintained with ICS/LABA
that improves FEV1 but does
not decrease need for
systemic corticosteroids.
Biologic Anti-IgE Omalizumab is used for
• Omalizumab poorly controlled asthma
(Xolair) from allergen-specific
IgE-mediated symptoms.
Anti-IL-5
• Mepolizumab Anti-IL-5 products are used
(Nucala) for poorly controlled severe
• Reslizumab asthma with an eosinophilic
(Cinqair) phenotype.
• Benralizumab Dupilumab is effective for
(Fasenra) atopic dermatitis, asthma,
and nasal polyps.
Anti-IL-4/IL-13
• Dupilumab Tezepelumab does not
(Dupixent) require eosinophilic
phenotype or demonstra-
Anti-TSLP tion of biomarkers.
• Tezepelumab
(Tezspire)
Abbreviations: DPI, dry powder inhaler; HFA, hydrofluoroalkane; ICS, inhaled corticosteroid;
IgE, immunoglobulin E; IL, interleukin; LABA, long-acting β2-agonist; MDI, metered-dose inhaler;
TSLP, thymic stromal lymphopoietin; VHC, valved holding chamber.
infants and toddlers (Figure 12-4). Because static charge reduces drug delivery
substantially, an antistatic chamber should be used. Comfortable tidal breathing
is essential for effective aerosol delivery; a crying child receives little delivery of
the medication to the lungs.55
Although inhaled corticosteroid is available as a nebulizer solution, there is no
evidence that this formulation offers any therapeutic advantage over the simpler
and more rapid administration with a pressurized MDI with a valved holding
chamber.56 Older children can use a dry powder inhaler (Table 12-2) for which
no assist device such as a valved holding chamber is needed. However, specific
instruction is needed because patients are required to generate high inspiratory
airflow when using a dry powder inhaler to aerosolize the powder. Whichever
inhaled corticosteroid preparation is used, individualized and clear instructions
with direct demonstration of their use to patients and parents is important.
There is evidence for dose-related systemic effects from most inhaled corti-
costeroids.57 Ciclesonide, however, has been reported to have little or no dose-
related systemic effect.58 Conventional low doses of all of the currently marketed

222
inhaled corticosteroids have an established safety record.59 Measurable but

small transient effects on height growth velocity have been reported for most
inhaled corticosteroids.60 Ciclesonide is an exception and is preferred if growth
slows while a child is receiving one of the other inhaled corticosteroids.61
Ciclesonide is highly protein bound, allowing less free corticosteroid to
circulate, and it may be metabolized more rapidly than other inhaled cortico-
steroids. Monitoring growth for children receiving inhaled corticosteroids,
therefore, should be a standard of care.
Montelukast, a leukotriene receptor inhibitor, is an orally administered drug
that has some clinical benefit for patients with mild persistent asthma, as
compared with placebo, and has some potential additive effect with inhaled
corticosteroids.62 However, the clinical benefit of adding montelukast to an
inhaled corticosteroid does not appear to be as great as is seen with an inhaled
long-acting β2-agonist (LABA).62 Although montelukast is generally well
tolerated, postmarketing study results have shown serious neuropsychiatric
adverse drug reactions.63 Consequently, the US Food and Drug Administration
has added a boxed warning.
Adding a LABA to an inhaled corticosteroid is generally more effective than
using a higher dose of the inhaled steroid in patients who continue to have
symptoms with use of initial doses of inhaled steroids.64 A small subset of
patients appears to be at risk from downregulation of the β2-adrenergic
receptors with continued use of LABAs alone or even with inhaled steroids.65
A particularly dramatic example was seen in 2 boys who had life-threatening
asthma exacerbations that were documented to be from salmeterol.66 This
uncommon adverse effect of LABAs is best recognized by clinical worsening
of asthma symptoms when a LABA is added or by clinical improvement when
discontinued. Careful monitoring of the patient with regularly scheduled
return visits is important to identify the patient who worsens rather than the
more usual benefit seen from the addition of a LABA.
Tiotropium, a long-acting muscarinic receptor antagonist, has less bronchodi-
latation than does a β2-agonist. In addition to the effect on airway smooth
muscle relaxation, inhibition of mucous gland secretion may also contribute
to a therapeutic role in asthma. Clinical trials in children and adolescents
have shown increased FEV1 but no improvement in frequency of exacerba-
tions when treatment with tiotropium is added in patients with asthma not
adequately controlled with inhaled corticosteroids and LABA.67
Immunotherapy (allergy shots) can reduce asthma symptoms in highly
selected cases in which the symptoms can be convincingly related to a limited
number of well-defined inhalant allergens to which immunotherapy has been
of benefit.68 In recent years, a number of new medications called biologics have
been developed for use in patients with asthma not adequately controlled with

223
Chapter 12—Asthma
Figure 12-5. Schematic of biologics that interfere with the inflammatory pathways of asthma.
Abbreviations: DP2R, prostaglandin D2 receptor; IgE, immunoglobulin E; IL, interleukin; ILC-2,
type 2 innate lymphoid cell; Th, T helper; TSLP, thymic stromal lymphopoietin.
Reprinted from Krings JG, McGregor MC, Bacharier LB, Castro M. Biologics for severe asthma: treatment-
specific effects are important in choosing a specific agent. J Allergy Clin Immunol Pract. 2019;7(5):1379–1392.
Copyright © 2019 American Academy of Allergy, Asthma & Immunology.
inhaled corticosteroid, LABA, and long-acting muscarinic receptor antagonist

medications (Table 12-2). The first of these, omalizumab, a monoclonal
anti-IgE agent, prevents allergen-specific free IgE from binding to mast cells
and releasing mediators from those mast cells.69,70 Other current and possibly
future biologics have been developed for severe asthma (Figure 12-5).71–75
Environmental Considerations
Identification and avoidance of asthma triggers are important components of
asthma management. The physician providing asthma care should assess the
child’s environment and its role in contributing to asthma symptoms. Both
the macro- and microenvironmental aspects need to be considered. Cigarette
smoke exposure, whether primary, secondary, or tertiary, is a strong irri-
tant for the sensitive airways of a child with asthma.76 Indoor fireplaces
and outdoor bonfires or leaf burning77 are also important nonallergenic
major irritants that contribute to asthmatic symptoms.

224
Children with allergen-specific IgE to common mold aeroallergens can have

intense exposure to outdoor molds during procedures that stir up decaying
vegetation, such as raking leaves or harvesting. Very old homes may be
plagued by indoor mold, especially if there is a basement with dampness
or water leakage. Forced air heating can distribute aeroallergens throughout
the home but also provides an opportunity to use a high-efficiency air filter to
minimize aeroallergens in the indoor environment. Pets can be a contributing
factor to asthma, but those family members should not be blamed for causing
symptoms without the patient demonstrating allergen-specific IgE to the spe-
cies and the physician obtaining a convincing history that exposure contributes
to morbidity. However, pet exposure in early infancy may prevent subsequent
allergy.78,79 Clinically important aeroallergens vary with the region and the
living area. They include pollens, outdoor and indoor molds, animal dander,
cockroaches, rodents, flying insects, and dust mites. Knowledge of allergen-
specific IgE in the patient and the aerobiological characteristics of the patient’s
environment are essential to assess the importance of environmental factors.
Exercise-Induced Asthma
Bronchospasm induced by exercise is a common component of active asthma.
However, exercise-induced asthma tends to be overdiagnosed as a cause of
exercise-induced dyspnea. If baseline pulmonary function is normal or near
normal, either naturally or with maintenance medication, exercise-induced
bronchospasm can be readily prevented for most patients by pretreating with
an inhaled bronchodilator, such as albuterol. If that does not block exercise-
induced dyspnea, then alternative diagnoses should be pursued.80,81 An
uncommon but serious reason for losing the bronchoprotective effect from
adrenergic bronchodilators is the regular use of LABA bronchodilators.66
Treating Difficult Asthma

Asthma may be difficult to control because of several factors. Before assuming
that it is the asthma that is intractable and adding yet more medications, the
physician should consider the following: (1) poor adherence to the prescribed
medications, (2) improper inhaler technique resulting in suboptimal delivery
of the medication to the airways, (3) poor choice of medications, (4) exposure
to irritants such as cigarette smoke, (5) presence of other comorbidities such
as obesity, or (6) incorrect diagnosis (ie, the child does not have asthma).2
The most common cause of poorly controlled asthma is that the medications
are not being taken or are not being taken properly. Besides asking patients
about the frequency of taking medications, the number of puffs used can
be determined on the dose counters of various inhaler devices. Calling the
patient’s pharmacy for the number of refills can help determine whether a
prescription is being filled with appropriate frequency.82 If poor adherence is

225
Chapter 12—Asthma
established, address the possible obstacles that prevent patients from taking
medications. Simplification of treatment regimen or switching the medication
to one with a lower co-pay may improve adherence. Also, there is evidence
that in patients with asthma that is severe and poorly controlled due to lack
of treatment adherence, administration of asthma medications by a school
nurse can improve outcome.83
Emergency Department and Hospitalization

The decision to hospitalize is usually made when dyspnea or hypoxemia is
not responsive to home or emergency care. However, this decision may be
influenced by social factors in addition to the severity of the physiological
abnormality. Asthma is the leading medical cause of hospitalization for chil-
dren, and these hospitalizations are mostly preventable. The treatment admin-
istered during hospitalization is essentially the same as treatment that would
have prevented most hospitalizations had the treatment been performed earlier
(ie, aerosol bronchodilators and systemic corticosteroids). Chest radiographs
are of limited value for the child with asthma in the emergency department
or hospital and infrequently influence management.84
Hospitalization is primarily to ensure that oxygen can be administered if
needed and that respiratory failure, if it occurs, can be managed with assisted
ventilation. Hospitalization is also an opportunity to provide intensive patient
education and plan for appropriate ambulatory care. Adequate doses of sys-
temic corticosteroids should be administered in any child with asthma that
requires an emergency department visit or hospitalization for asthma. Inhaled
albuterol can be administered for an increase in the work of breathing. Contin-
uous nebulization of albuterol can decrease the need for assisted ventilation.85
Discharge from the hospital should occur once the level of care is such that it
can be continued at home. There is no need to continue hospitalization until
all symptoms are completely gone unless there are social concerns regard-
ing continuing medication at home. Once improvement is well established,
deterioration is highly unlikely with continued medication, and appropriate
ambulatory care can begin.
Treating Comorbidities
Treating comorbidities may benefit the control of chronic asthma. Although
rhinitis, often called sinusitis, and gastroesophageal reflux are often associated
with asthma, the evidence that asthma control benefits from their treatment
is anecdotal only and inconsistent with published evidence.86,87 Symptoms
attributed to sinusitis are predominantly those of rhinitis, and there is little
correlation between radiological evidence of sinusitis and clinical symptoms.88
Although chronic allergic rhinitis should be treated with topical nasal steroids,
and gastroesophageal reflux should be treated in those experiencing the

226
associated symptoms of heartburn, regurgitation, and substernal discomfort,

there is little reason to expect clinically important benefit for the asthma itself.89
Obesity is a potential comorbidity associated with poor asthma control.90
Obesity and asthma are treated more extensively in Chapter 43, Asthma and
Other Respiratory Disorders Associated With Obesity. Nighttime asthma
symptoms can easily overlap with symptoms of obstructive sleep apnea, and
a strong correlation between the 2 illnesses has been suggested. In one study
in which investigators examined the relationship between asthma and obstruc-
tive sleep apnea, the authors concluded that sleep-disordered breathing was a
risk factor for poor control of asthma in children.91
Monitoring the Clinical Course

Successful management of asthma does not stop with providing patients
with prescriptions. Physicians need to ensure that patients and parents have
developed self-sufficiency in managing the disease and its exacerbations.
Ideally, there should rarely be a need to see the patient during acute symp-
toms because the patient or family should have been taught with oral and
written instructions regarding the key components of successful management
at home. These include the use of maintenance medications as a preventive
measure for persistent and seasonal allergic asthma, the use of an inhaled
bronchodilator for acute symptom relief, and early intervention with a short
course of systemic corticosteroid for acute exacerbations. Regular scheduled
return visits are essential to review
Box 12‑2 adherence to the treatment plan, to
check inhaler technique, to assess
Criteria for Asthma Control
if the patient meets criteria for
ū Absence of hospitalization
asthma control (Box 12-2), and to
ū Absence of urgent care requirements adjust treatment when appropriate
ū Absence of interference with sleep to meet those criteria with the least
ū Absence of interference with activity amount of medication.
ū Infrequent use of inhaled β2-agonists Measuring pulmonary function
for acute symptoms with office spirometry should be a
ū Infrequent use of oral corticosteroids routine standard of care in order to
ū Normal or near normal pulmonary identify airway obstruction not
function as measured with spirometry detected with routine stethoscopic
ū Infrequent school absences because auscultation.92 Total airway
of asthma resistance and its components,
Reprinted from Weinberger M. Pediatric asthma proximal large airway resistance,
and related allergic and nonallergic diseases: and peripheral small airway
patient-oriented evidence-based essentials that
matter. Pediatric Health. 2(5):631–650. https:// resistance are obtained.
www.futuremedicine.com/doi/
full/10.2217/17455111.2.5.631 There is increasing evidence
regarding the importance of

227
Chapter 12—Asthma
assessing small airway dysfunction in the lung periphery that is not readily
identified with spirometry.93,94 In addition to identifying peripheral small
airway dysfunc-tion, impulse oscillometry does not require the effort of
spirometry. Only tidal voluming is needed. Consequently, even 3- and
4-year-old children, or anyone unable to perform the maximal effort of
spirometry, can perform impulse oscillometry.
Although use of a peak flow meter has been proposed as a tool to monitor
asthma and guide its therapy, the weight of evidence indicates that symp-
tom monitoring is as good as or even better than the meter.95 Measuring peak
flow depends on patient effort and technique. If the value is low while symp-
toms are absent, the result can be unnecessarily increased patient and parent
anxiety, overuse of asthma medications, and overuse of the health care system.
The only situations in which a home peak flow meter or portable spirometer
is useful are for those who occasionally under- or overperceive asthmatic
symptoms. An objective measure of disease severity can help distinguish
anxiety-induced dyspnea or nonperception of airway obstruction. Even in
these clinical situations, using handheld spirometers, which are now becom-
ing more available and increasingly less expensive, is a better alternative
than using the iconic peak flow meter.
There is current interest in the use of exhaled nitric oxide (FeNO) as a marker
of eosinophilic airway inflammation in asthma.96 A review of studies in chil-
dren concluded that the use of FeNO to guide asthma therapy in children
may be beneficial in a subset of children, but it cannot be universally recom-
mended for all children with asthma.97 A conditional recommendation for
use was the conclusion of an official American Thoracic Society Clinical
Practice Guideline.98
General medical care for asthma should include routine immunizations. The
varicella vaccine is particularly important because of the small but serious
risk of disseminated varicella that has been reported when varicella occurs
during a course of high-dose systemic corticosteroids as may be necessary for
an asthma exacerbation.99 A COVID-19 vaccine and yearly influenza vaccine
are recommended for children and are especially appropriate for children with
asthma.100 Little risk from current influenza vaccines is present for those
with allergy to eggs, and egg allergy is not a contraindication for influenza
vaccination.101 Also, an egg-free recombinant flu vaccine is readily available.
The best decision-making by the physician can fail unless the family or
patient is adequately educated about the benefits and risks, if any, of each
medication and the implementation of the treatment plan. Particularly import-
ant is having a simple written action plan that deals with periods of increased
symptoms and exacerbations (Box 12-3). There is no advantage to complex
plans with visual aids such as traffic light cartoon illustrations.102

228
Box 12‑3
Intervention Action Plan Handout for an Acute Exacerbation of Asthma
Acute symptoms of asthma including cough, wheeze, or shortness of breath should be
dealt with promptly. They are particularly likely to be triggered by a viral respiratory
infection (common cold). Increasing cough after a day of a runny nose is often the first
sign of asthma triggered by a viral respiratory infection. Medication taken daily as
maintenance often does not prevent the acute flare of asthma from a viral respiratory
infection. Prompt intervention can shorten the course and generally prevent the need
for urgent medical care or hospitalization.
First: Use your inhaled bronchodilator.
If symptoms are not completely relieved: Repeat use of your inhaled bronchodi-
lator.
If symptoms stop completely: Repeat use of your inhaled bronchodilator when
necessary; consider a short course of oral corticosteroid after the third dose for
acute symptoms within 8 hours or if you have more than 4 in 24 hours (other than
for preventive use before exercise).
If symptoms are still not completely relieved: A short course of oral corticoste-
roids may be needed. If uncertain what to do, call your physician for advice.
Otherwise, take a first dose of oral corticosteroid and notify your physician.
(Dosage and instructions should already be on hand.) The response to oral
corticosteroids is slow. For patients who have required emergency care or
hospitalization, the oral corticosteroid should be started well before symptoms
become severe.
Once corticosteroids are started, use of your inhaled bronchodilator can be repeated
when needed. Maintenance medications should be continued.
Continued increase in the frequency of inhaled bronchodilator use or continued
difficulty breathing may require hospitalization. Call your doctor or go to the
emergency department of a hospital if you have continued difficulty breathing.
Frequent intervention treatment for episodes of asthma requires reassessment
of the management plan.
Natural History of Asthma

Parents frequently ask if their child will ever outgrow asthma. In the
preschool- age child with episodic symptoms of asthma, the presence of
atopy identified by the presence of allergen-specific IgE is predictive of
continued symptoms throughout childhood, whereas those with no pres-
ence of a potential allergic component are likely to have marked reduction

229
Chapter 12—Asthma
or cessation of asthmatic symptoms by school age (Figure 12-6).103 The

long-term clinical course of asthma in young children was examined in a
prospective study with repeated evaluations for more than 35 years (Figure
12-7).104 On the basis of that survey, overall community prevalence for
asthma symptoms in childhood was estimated to be about 20% in Australia,
a rate similar to that described in the United States.105 Continued asthma as an
adult was related to the pattern of asthma in early childhood. Although
inhaled corticosteroids are highly effective for decreasing symptoms of
persistent asthma, the long-term disease course is not influenced. Attempts to
modify the course of subsequent asthma by early use of inhaled corticoste-
roids have been unsuccessful.106
Figure 12-6. Influence of atopy on likelihood of experiencing continued symptoms of asthma

from birth to age 13 years in children.
Reprinted from Illi S, von Mutius E, Lau S, Niggemann B, Grüber C, Wahn U; Multicentre Allergy Study (MAS)
group. Perennial allergen sensitisation early in life and chronic asthma in children: a birth cohort study.
Lancet. 2006;386(9537):766. Copyright © 2006, with permission from Elsevier.

230
100
80
Percent of Patients
60
40
20
0
5 w VRI 5 w VRI w/o VRI Chronic
Childhood pattern of asthma at age 7
Persistent asthma
Frequent episodic asthma
Infrequent episodic asthma
No recent asthma
Figure 12-7. Clinical expression of childhood asthma at age 42 years among patients initially
evaluated at age 7 years, with varying patterns and severity of asthma: < 5 w VRI were those
who had a previous history of less than 5 viral respiratory infection–induced asthma symptoms
before age 6 years. 5+ w VRI were those who had a history of having 5 or more viral respiratory
infection–induced asthma symptoms before age 6 years. w/o VRI were those who had symp-
toms of asthma before age 6 years not limited to viral respiratory infection. Chronic were those
identified at age 10 years with persistent asthma since before age 3 years. Each of these groups
had about 100 children.
Reprinted from Phelan PD, Robertson CF, Olinsky A. The Melbourne Asthma Study: 1964–1999. J Allergy Clin
Immunol. 2002;109(2):189–194. Copyright © 2002 American Academy of Allergy, Asthma and Immunology.
Asthma Disparities
There are disparities in asthma treatment and outcomes for some populations
of color and those living in underresourced communities. These disparities
have been present for decades and continue to occur throughout the United

231
Chapter 12—Asthma
States.107 Higher morbidity and mortality due to asthma are reported in Black,
Indigenous American, and Hispanic children of Caribbean origin, compared
with those in children of European descent. Black children have rates of
hospitalization and emergency department visits 2 to 3 times higher than
those of non-Hispanic white children and face a fivefold to tenfold higher
asthma mortality rate.108 These asthma disparities are primarily explained
and driven by social factors.109 A review of the literature on the effect of social
determinants of health and discrimination is beyond the scope of this discus-
sion, but numerous individual- and system-level factors combine to contribute
to asthma disparities. Children in resource-limited communities have greater
exposure to asthma triggers (eg, indoor and outdoor irritants, indoor allergens,
stress).110 They are also less likely to receive asthma treatments appropriate to
their level of disease severity.111 Interacting barriers include transportation,
time, health literacy, food and housing insecurity, finances, and cultural
alienation from pediatricians and other physicians. The result is difficulty
in accessing optimal care and suboptimal use of the care received.112,113
The sensitivity and attention of pediatricians and other physicians to the
challenges of caring for patients with asthma in these populations can
improve outcomes.114,115 Interventions are most likely to be successful when
they involve a comprehensive multifocal approach that may go beyond the
resources of individual physicians.116 Comprehensive specialty clinic–based
care should include evidence-based decisions and education to promote under-
standing of the disease and its treatment by the patient and family. The most
successful programs are those using specialty care and employing case
managers and social service workers to assist with transportation, housing
quality, and food insecurity. Adverse childhood experiences as well as mental
health disorders in both patients and their caregivers should be identified.
Community health workers can help educate and mentor families. Alliances
with medical and legal resources can ensure landlord compliance with hous-
ing codes and assist with other legal challenges. School nurses with whom
children spend most of their days can review medication use and treatment
of acute symptoms.117–121

232
key points
General
} Asthma is one of the most common chronic diseases of children.
} Asthma causes more hospitalizations than any other medical problem in children.
} Asthma is associated with rhinitis and atopic dermatitis as important comorbidities.
Clinical Characteristics of Asthma
} Asthma is both underdiagnosed and overdiagnosed.
} Intermittent asthma is most commonly a viral respiratory infection–induced
phenotype in preschool-age children but is seen at all ages.
} The persistent asthma phenotype is characterized by the absence of extended
symptom-free periods.
} The seasonal allergic phenotype is characterized by being limited to seasons that
correspond to allergen-specific IgE to seasonal inhalant allergens.
Severity of Asthma
} Severity of asthma can be assessed on the basis of
➤ Interference with activity from exercise limitation.
➤ Interference with sleep from repeated nocturnal awakening.
➤ Frequency of requirements for intervention measures, inhaled bronchodilators,
and oral corticosteroids.
➤ Urgent care visits or hospitalizations.
Management of Asthma
} Intervention measures for relief of acute symptoms are albuterol and oral
corticosteroids.
} Maintenance medications for those with chronic or extended seasonal
symptoms include inhaled corticosteroids, inhaled corticosteroids with long-
acting bronchodilators, leukotriene modifiers, immunotherapy, and biologics.
Monitoring the Clinical Course of Asthma
} The patient’s awareness of symptoms is essential to early intervention to prevent
progression of exacerbations.
} Scheduled follow-up appointments for assessment and education are required to
evaluate treatment adequacy and assess adherence to the treatment plan.
Evaluating and Managing Difficult Asthma
} Distinguishing between poor adherence and incorrect diagnosis may require
calling the patient’s pharmacy for a refill history of maintenance medication and
observation of the patient’s inhaler technique, as well as family education.
Natural History of Asthma
} Although some children will experience remission, many will continue to have
symptoms of asthma well into adulthood.
} Children who have symptoms of asthma not limited to a viral respiratory infection
have a greater likelihood of asthma symptoms persisting into adulthood.

233
Chapter 12—Asthma
References
1. Gross NJ. What is this thing called love?—or, defining asthma. Am Rev Respir Dis.
1980;121(2):203–204 PMID: 7362129
2. Weinberger M, Abu-Hasan M. Pseudo-asthma: when cough, wheezing, and dyspnea are not
asthma. Pediatrics. 2007;120(4):855–864 PMID: 17908773 doi: 10.1542/peds.2007-0078
3. Keren R, Shah SS. Editorial. JAMA Pediatrics hospital medicine theme issue. JAMA Pediatr.
2013;167(5):485–487 PMID: 23529674 doi: 10.1001/jamapediatrics.2013.384
4. Pate CA, Zahran HS, Qin X, Johnson C, Hummelman E, Malilay J. Asthma Surveillance -
United States, 2006-2018. MMWR Surveill Summ. 2021;70(5):1–32 PMID: 34529643
doi: 10.15585/mmwr.ss7005a1
5. Avery C, Perrin EM, Lang JE. Updates to the pediatrics asthma management guidelines.
JAMA Pediatr. 2021;175(9):966–967 PMID: 34096987 doi: 10.1001/jamapediatrics.2021.1494
6. Chipps BE, Murphy KR, Oppenheimer J. 2020 NAEPP guidelines update and GINA
2021–Asthma Care Differences, Overlap, and Challenges. J Allergy Clin Immunol Pract.
2022;10(1S):S19–S30 PMID: 34718214 doi: 10.1016/j.jaip.2021.10.032
7. Bush A, Pavord ID. Forthcoming UK asthma guidelines: an opportunity to improve asthma
outcomes. Lancet. 2021;398(10314):1856–1858 PMID: 34656285
doi: 10.1016/S0140-6736(21)02244-3
8. Weinberger M. Time for a new paradigm for asthma management. Mayo Clin Proc.
2016;91(4):405–407 PMID: 26944838 doi: 10.1016/j.mayocp.2016.02.007
9. Weinberger M. Why clinical practice guidelines hinder rather than help. Invited editorial
commentary. Paediatr Respir Rev. 2018;25:85–87 PMID: 27091766 doi: 10.1016/j.
prrv.2016.03.005
10. Doan T, Patterson R, Greenberger PA. Cough variant asthma: usefulness of a diagnostic-
therapeutic trial with prednisone. Ann Allergy. 1992;69(6):505–509 PMID: 1471782
11. Weinberger M, Abu-Hasan M. Asthma in the preschool-age child. In: Wilmott RW, Boat TF,
Bush A, Chernick V, Deterding RR, Ratjen F, eds. Kendig and Chernick’s Disorders of the
Respiratory Tract in Children. 8th ed. Elsevier Saunders; 2012:686–698
12. Fahy JV, O’Byrne PM. “Reactive airways disease”. A lazy term of uncertain meaning that should
be abandoned. Am J Respir Crit Care Med. 2001;163(4):822–823 PMID: 11282751
doi: 10.1164/ajrccm.163.4.2005049
13. Joseph CL, Foxman B, Leickly FE, Peterson E, Ownby D. Prevalence of possible undiagnosed
asthma and associated morbidity among urban schoolchildren. J Pediatr. 1996;129(5):735–742
PMID: 8917242 doi: 10.1016/S0022-3476(96)70158-0
14. Aaron SD, Boulet LP, Reddel HK, Gershon AS. Underdiagnosis and overdiagnosis of asthma.
doi: 10.1164/rccm.201804-0682CI
15. Maclennan C, Hutchinson P, Holdsworth S, Bardin PG, Freezer NJ. Airway inflammation
in asymptomatic children with episodic wheeze. Pediatr Pulmonol. 2006;41(6):577–583
PMID: 16617454 doi: 10.1002/ppul.20415
16. Sherrill D, Stein R, Kurzius-Spencer M, Martinez F. On early sensitization to allergens and
development of respiratory symptoms. Clin Exp Allergy. 1999;29(7):905–911 PMID: 10383590
doi: 10.1046/j.1365-2222.1999.00631.x
17. Rosenstein N, Phillips WR, Gerber MA, Marcy SM, Schwartz B, Dowell SF. The common
cold—principles of judicious use of antimicrobial agents. Pediatrics. 1998;101(suppl 1):181–184
doi: 10.1542/peds.101.S1.181
18. Wilson N, Sloper K, Silverman M. Effect of continuous treatment with topical corticosteroid on
episodic viral wheeze in preschool children. Arch Dis Child. 1995;72(4):317–320 PMID: 7763063
doi: 10.1136/adc.72.4.317
19. McKean M, Ducharme F. Inhaled steroids for episodic viral wheeze of childhood. Cochrane
Database Syst Rev. 2000;2000(2):CD001107 PMID: 10796596 doi: 10.1002/14651858.CD001107
20. Doull IJ. Limitations of maintenance therapy for viral respiratory infection-induced asthma.
J Pediatr. 2003;142(2 suppl):S21–S25 PMID: 12584516 doi: 10.1067/mpd.2003.22
21. Wright AL. Epidemiology of asthma and recurrent wheeze in childhood. Clin Rev Allergy
Immunol. 2002;22(1):33–44 PMID: 11803801 doi: 10.1007/s12016-002-0004-z
22. 22. O’Hollaren MT, Yunginger JW, Offord KP, et al. Exposure to an aeroallergen as a possible
precipitating factor in respiratory arrest in young patients with asthma. N Engl J Med.
1991;324(6):359–363 PMID: 1987459 doi: 10.1056/NEJM199102073240602
23. Reid MJ, Moss RB, Hsu YP, Kwasnicki JM, Commerford TM, Nelson BL. Seasonal asthma in
northern California: allergic causes and efficacy of immunotherapy. J Allergy Clin Immunol.
1986;78(4 pt 1):590–600 PMID: 3771951 doi: 10.1016/0091-6749(86)90076-X

234
24. Weinberger M. Pediatric bronchial hyperresponsiveness and asthma phenotypes. Ann Allergy
Asthma Immunol. 2018;121(4):387–388 PMID: 30290892 doi: 10.1016/j.anai.2018.07.035
25. Johnston SL. Innate immunity in the pathogenesis of virus-induced asthma exacerbations.
Proc Am Thorac Soc. 2007;4(3):267–270 PMID: 17607011 doi: 10.1513/pats.200701-030AW
26. Johnston NW, Johnston SL, Norman GR, Dai J, Sears MR. The September epidemic of asthma
hospitalization: school children as disease vectors. J Allergy Clin Immunol. 2006;117(3):557–562
PMID: 16522453 doi: 10.1016/j.jaci.2005.11.034
27. Delgado A, Chou KJ, Silver EJ, Crain EF. Nebulizers vs metered-dose inhalers with spacers for
bronchodilator therapy to treat wheezing in children aged 2 to 24 months in a pediatric
emergency department. Arch Pediatr Adolesc Med. 2003;157(1):76–80 PMID: 12517199
doi: 10.1001/archpedi.157.1.76
28. Weinberger M. Is there any advantage to using levalbuterol in the treatment of asthma?
Clin Pulm Med. 2004;11(3):129–134 doi: 10.1097/01.cpm.0000127196.53489.f1
29. Bhogal SK, McGillivray D, Bourbeau J, Benedetti A, Bartlett S, Ducharme FM. Early
administration of systemic corticosteroids reduces hospital admission rates for children
with moderate and severe asthma exacerbation. Ann Emerg Med. 2012;60(1):84.e3–91.e3
PMID: 22410507 doi: 10.1016/j.annemergmed.2011.12.027
30. Storr J, Barrell E, Barry W, Lenney W, Hatcher G. Effect of a single oral dose of prednisolone
in acute childhood asthma. Lancet. 1987;1(8538):879–882 PMID: 2882288
doi: 10.1016/S0140-6736(87)92857-1
31. Tal A, Levy N, Bearman JE. Methylprednisolone therapy for acute asthma in infants and
toddlers: a controlled clinical trial. Pediatrics. 1990;86(3):350–356 PMID: 2201941
32. Scarfone RJ, Fuchs SM, Nager AL, Shane SA. Controlled trial of oral prednisone in the
emergency department treatment of children with acute asthma. Pediatrics. 1993;92(4):513–518
PMID: 8414819 doi: 10.1542/peds.92.4.513
33. Harris JB, Weinberger MM, Nassif E, Smith G, Milavetz G, Stillerman A. Early intervention
with short courses of prednisone to prevent progression of asthma in ambulatory patients
incompletely responsive to bronchodilators. J Pediatr. 1987;110(4):627–633 PMID: 3559814
doi: 10.1016/S0022-3476(87)80567-X
34. Brunette MG, Lands L, Thibodeau LP. Childhood asthma: prevention of attacks with short-term
corticosteroid treatment of upper respiratory tract infection. Pediatrics. 1988;81(5):624–629
PMID: 3357723
35. O’Driscoll BR, Kalra S, Wilson M, Pickering CA, Carroll KB, Woodcock AA. Double-blind
trial of steroid tapering in acute asthma. Lancet. 1993;341(8841):324–327 PMID: 8094111
doi: 10.1016/0140-6736(93)90134-3
36. Ducharme FM, Chabot G, Polychronakos C, Glorieux F, Mazer B. Safety profile of frequent
short courses of oral glucocorticoids in acute pediatric asthma: impact on bone metabolism,
bone density, and adrenal function. Pediatrics. 2003;111(2):376–383 PMID: 12563067
doi: 10.1542/peds.111.2.376
37. Weinberger M, Hendeles L, Abu-Hasan M. Oral corticosteroids should be available on-hand
at home for the next asthma exacerbation! Ann Allergy Asthma Immunol. 2018;121(1):18–21
PMID: 29653237 doi: 10.1016/j.anai.2018.04.004
38. Rivera-Spoljaric K, Chinchilli VM, Camera LJ, et al; Childhood Asthma Research and
Education (CARE) Network. Signs and symptoms that precede wheezing in children with a
pattern of moderate-to-severe intermittent wheezing. J Pediatr. 2009;154(6):877.e4–81.e4
PMID: 19324370 doi: 10.1016/j.jpeds.2008.12.029
39. Cloutier MM, Baptist AP, Blake KV, et al; Expert Panel Working Group of the National Heart,
Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education
and Prevention Program Coordinating Committee (NAEPPCC). 2020 Focused Updates to the
Asthma Management Guidelines: A Report from the National Asthma Education and Prevention
Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol.
2020;146(6):1217–1270 PMID: 33280709 doi: 10.1016/j.jaci.2020.10.003
40. Farber HJ. POINT: Is escalation of the of the inhaled corticosteroid dose appropriate for acute
loss of asthma control in an attempt to reduce need for oral corticosteroids in children? Yes.
Chest. 2016;150(3):488–490 PMID: 27426479 doi: 10.1016/j.chest.2016.06.024
41. Weinberger M. COUNTERPOINT: Is escalation of the of the inhaled corticosteroid dose
appropriate for acute loss of asthma control in an attempt to reduce need for oral corticosteroids
in children? No. Chest. 2016;150(3):490–492 PMID: 27426480 doi: 10.1016/j.chest.2016.06.026
42. Farber HJ. Rebuttal from Dr Farber. Chest. 2016;150(3):493 PMID: 27426478
doi: 10.1016/j.chest.2016.06.027
43. Weinberger M. Rebuttal from Dr Weinberger. Chest. 2016;150(3):494 PMID: 27426477
doi: 10.1016/j.chest.2016.06.025

235
Chapter 12—Asthma
44. Lin J, Zhou X, Wang C, Liu C, Cai S, Huang M. Symbicort® Maintenance and Reliever Therapy
(SMART) and the evolution of asthma management within the GINA guidelines. Expert Rev
Respir Med. 2018;12(3):191–202 PMID: 29400090 doi: 10.1080/17476348.2018.1429921
45. Papi A, Chipps BE, Beasley R, et al. Albuterol–budesonide fixed-dose combination rescue
inhaler for asthma. N Engl J Med. 2022;386(22):2071–2083 PMID: 35569035
doi: 10.1056/NEJMoa2203163
46. Rogliani P, Beasley R, Cazzola M, Calzetta L. SMART for the treatment of asthma: A network
meta-analysis of real-world evidence. Respir Med. 2021;188:106611 PMID: 34536699
doi: 10.1016/j.rmed.2021.106611
47. Reddel HK, Bacharier LB, Bateman ED, et al. Global Initiative for Asthma Strategy 2021:
Executive Summary and Rationale for Key Changes. Am J Respir Crit Care Med.
2022;205(1):17–35 PMID: 34658302 doi: 10.1164/rccm.202109-2205PP
48. Crossingham I, Turner S, Ramakrishnan S, et al. Combination fixed-dose beta agonist and
steroid inhaler as required for adults or children with mild asthma. Cochrane Database Syst Rev.
2021;5(5):CD013518 PMID: 33945639
49. Hendeles L, Blake KV, Galbreath A. A Single Inhaler Combining a Corticosteroid and
Long-Acting Beta-2 Agonist for Maintenance with Additional Doses for Reliever Therapy
(SMART): Obstacles for Asthma Patients in the USA. Pediatr Allergy Immunol Pulmonol.
2021;34(2):73–75 PMID: 34143685 doi: 10.1089/ped.2021.0052
50. Norris MR, Modi S, Al-Shaikhly T. SMART - is it practical in the United States? Curr Opin
Pulm Med. 2022;28(3):245–250 PMID: 35131990 doi: 10.1097/MCP.0000000000000862
51. Beck R, Robertson C, Galdès-Sebaldt M, Levison H. Combined salbutamol and ipratropium
bromide by inhalation in the treatment of severe acute asthma. J Pediatr. 1985;107(4):605–608
PMID: 2931507 doi: 10.1016/S0022-3476(85)80033-0
52. Griffiths B, Ducharme FM. Combined inhaled anticholinergics and short-acting beta2-agonists
for initial treatment of acute asthma in children. Cochrane Database Syst Rev.
2013;(8):CD000060 PMID: 23966133 doi: 10.1002/14651858.CD000060.pub2
53. Craven D, Kercsmar CM, Myers TR, O’riordan MA, Golonka G, Moore S. Ipratropium bromide
plus nebulized albuterol for the treatment of hospitalized children with acute asthma. J Pediatr.
2001;138(1):51–58 PMID: 11148512 doi: 10.1067/mpd.2001.110120
54. Knightly R, Milan SJ, Hughes R, et al. Inhaled magnesium sulfate in the treatment of
acute asthma. Cochrane Database Syst Rev. 2017;11(11):CD003898 PMID: 29182799
doi: 10.1002/14651858.CD003898.pub6
55. Iles R, Lister P, Edmunds AT. Crying significantly reduces absorption of aerosolised drug in
infants. Arch Dis Child. 1999;81(2):163–165 PMID: 10490528 doi: 10.1136/adc.81.2.163
56. Castro-Rodriguez JA, Rodrigo GJ. beta-agonists through metered-dose inhaler with valved
holding chamber versus nebulizer for acute exacerbation of wheezing or asthma in children
under 5 years of age: a systematic review with meta-analysis. J Pediatr. 2004;145(2):172–177
PMID: 15289762 doi: 10.1016/j.jpeds.2004.04.007
57. Eid N, Morton R, Olds B, Clark P, Sheikh S, Looney S. Decreased morning serum cortisol
levels in children with asthma treated with inhaled fluticasone propionate. Pediatrics.
2002;109(2):217–221 PMID: 11826198 doi: 10.1542/peds.109.2.217
58. Szefler S, Rohatagi S, Williams J, Lloyd M, Kundu S, Banerji D. Ciclesonide, a novel
inhaled steroid, does not affect hypothalamic-pituitary-adrenal axis function in patients
with moderate-to-severe persistent asthma. Chest. 2005;128(3):1104–1114 PMID: 16162694
doi: 10.1378/chest.128.3.1104
59. Kelly HW, Nelson HS. Potential adverse effects of the inhaled corticosteroids. J Allergy Clin
Immunol. 2003;112(3):469–478 PMID: 13679801 doi: 10.1016/S0091-6749(03)01870-0
60. Kelly HW, Sternberg AL, Lescher R, et al; CAMP Research Group. Effect of inhaled
glucocorticoids in childhood on adult height. N Engl J Med. 2012;367(10):904–912
PMID: 22938716 doi: 10.1056/NEJMoa1203229
61. Liddell BS, Oberlin JM, Hsu DP. Inhaled corticosteroid related adrenal suppression detected by
poor growth and reversed with ciclesonide. J Asthma. 2017;54(1):99–104 PMID: 27284755
doi: 10.1080/02770903.2016.1196370
62. Ram FSF, Cates CJ, Ducharme FM. Long-acting beta2-agonists versus anti-leukotrienes as
add-on therapy to inhaled corticosteroids for chronic asthma. Cochrane Database Syst Rev.
2005;(1):CD003137 PMID: 15674901 doi: 10.1002/14651858.CD003137.pub2
63. Benard B, Bastien V, Vinet B, Yang R, Krajinovic M, Ducharme FM. Neuropsychiatric adverse
drug reactions in children initiated on montelukast in real-life practice. Eur Respir J.
2017;50(2):1700148 PMID: 28818882 doi: 10.1183/13993003.00148-2017

236
64. Woolcock A, Lundback B, Ringdal N, Jacques LA. Comparison of addition of salmeterol to

inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med.
1996;153(5):1481–1488 PMID: 8630590 doi: 10.1164/ajrccm.153.5.8630590
65. Weinberger M. Combination of inhaled corticosteroid and a long-acting β-agonist:
proceed with caution. Ann Allergy Asthma Immunol. 2019;122(3):350 PMID: 30798852
doi: 10.1016/j.anai.2018.11.019
66. Weinberger M, Abu-Hasan M. Life-threatening asthma during treatment with salmeterol.
N Engl J Med. 2006;355(8):852–853 PMID: 16929006 doi: 10.1056/NEJMc066282
67. Murphy KR, Chipps BE. Tiotropium in children and adolescents with asthma. Ann Allergy
Asthma Immunol. 2020;124(3):267.e3–276.e3 PMID: 31805357 doi: 10.1016/j.anai.2019.11.030
68. Roberts G, Hurley C, Turcanu V, Lack G. Grass pollen immunotherapy as an effective therapy
for childhood seasonal allergic asthma. J Allergy Clin Immunol. 2006;117(2):263–268
PMID: 16461125 doi: 10.1016/j.jaci.2005.09.054
69. Walker S, Monteil M, Phelan K, Lasserson TJ, Walters EH. Anti-IgE for chronic asthma in
adults and children. Cochrane Database Syst Rev. 2006;(2):CD003559 PMID: 16625585
doi: 10.1002/14651858.CD003559.pub3
70. Busse WW, Morgan WJ, Gergen PJ, et al. Randomized trial of omalizumab (anti-IgE) for
asthma in inner-city children. N Engl J Med. 2011;364(11):1005–1015 PMID: 21410369
doi: 10.1056/NEJMoa1009705
71. Ortega HG, Liu MC, Pavord ID, et al; MENSA Investigators. Mepolizumab treatment in patients
with severe eosinophilic asthma. N Engl J Med. 2014;371(13):1198–1207 PMID: 25199059
doi: 10.1056/NEJMoa1403290
72. Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with
elevated blood eosinophil counts: results from two multicentre, parallel, double-blind,
randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3(5):355–366
PMID: 25736990 doi: 10.1016/S2213-2600(15)00042-9
73. FitzGerald JM, Bleecker ER, Nair P, et al; CALIMA study investigators. Benralizumab, an
anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe,
uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled
phase 3 trial. Lancet. 2016;388(10056):2128–2141 PMID: 27609406 doi: 10.1016/S0140-
6736(16)31322-8
74. Rabe KF, Nair P, Brusselle G, et al. Efficacy and safety of dupilumab in glucocorticoid-
dependent severe asthma. N Engl J Med. 2018;378(26):2475–2485 PMID: 29782224
doi: 10.1056/NEJMoa1804093
75. Abrams EM, Becker AB, Szefler SJ. Current state and future of biologic therapies in the
treatment of asthma in children. Pediatr Allergy Immunol Pulmonol. 2018;31(3):119–131
PMID: 30283711 doi: 10.1089/ped.2018.0901
76. Burke H, Leonardi-Bee J, Hashim A, et al. Prenatal and passive smoke exposure and incidence
of asthma and wheeze: systematic review and meta-analysis. Pediatrics. 2012;129(4):735–744
PMID: 22430451 doi: 10.1542/peds.2011-2196
77. Curtis L. The health hazards of leaf burning. Am J Public Health. 1994;84(10):1696
PMID: 7943505 doi: 10.2105/AJPH.84.10.1696
78. Platts-Mills T, Vaughan J, Squillace S, Woodfolk J, Sporik R. Sensitisation, asthma, and a
modified Th2 response in children exposed to cat allergen: a population-based cross-sectional
study. Lancet. 2001;357(9258):752–756 PMID: 11253969 doi: 10.1016/S0140-6736(00)04168-4
79. Stokholm J, Chawes BL, Vissing N, Bønnelykke K, Bisgaard H. Cat exposure in early life
decreases asthma risk from the 17q21 high-risk variant. J Allergy Clin Immunol.
2018;141(5):1598–1606 PMID: 29102067 doi: 10.1016/j.jaci.2017.07.044
80. Weinberger M, Abu-Hasan M. Perceptions and pathophysiology of dyspnea and
exercise intolerance. Pediatr Clin North Am. 2009;56(1):33–48, ix PMID: 19135580
doi: 10.1016/j.pcl.2008.10.015
PMID: 15801248 doi: 10.1016/S1081-1206(10)60989-1
82. Sherman J, Hutson A, Baumstein S, Hendeles L. Telephoning the patient’s pharmacy to assess
adherence with asthma medications by measuring refill rate for prescriptions. J Pediatr.
2000;136(4):532–536 PMID: 10753254 doi: 10.1016/S0022-3476(00)90019-2
83. Pertzborn MC, Prabhakaran S, Hardy A, Baker D, Robinson MA, Hendeles L. Direct observed
therapy of inhaled corticosteroids for asthma at school or daycare. Pediatr Allergy Immunol
Pulmonol. 2018;31(4):226–229 PMID: 30595951 doi: 10.1089/ped.2018.0912

237
Chapter 12—Asthma
84. Allie EH, Dingle HE, Johnson WN, et al. ED chest radiography for children with asthma
exacerbation is infrequently associated with change of management. Am J Emerg Med.
2018;36(5):769–773 PMID: 29137905 doi: 10.1016/j.ajem.2017.10.009
85. Phumeetham S, Bahk TJ, Abd-Allah S, Mathur M. Effect of high-dose continuous albuterol
nebulization on clinical variables in children with status asthmaticus. Pediatr Crit Care Med.
2015;16(2):e41–e46 PMID: 25560428 doi: 10.1097/PCC.0000000000000314
86. Zimmerman B, Stringer D, Feanny S, et al. Prevalence of abnormalities found by sinus
x-rays in childhood asthma: lack of relation to severity of asthma. J Allergy Clin Immunol.
1987;80(3 pt 1):268–273 PMID: 3624681 doi: 10.1016/0091-6749(87)90029-7
87. Gibson PG, Henry RL, Coughlan JL. Gastro-oesophageal reflux treatment for asthma in
adults and children. Cochrane Database Syst Rev. 2003;(2):CD001496 PMID: 12804410
doi: 10.1002/14651858.CD001496
88. Weinberger M. Whither sinusitis? Clin Pediatr (Phila). 2018;57(9):1013–1019 PMID: 29562756
doi: 10.1177/0009922818764927
89. Holbrook JT, Wise RA, Gold BD, et al; Writing Committee for the American Lung Association
Asthma Clinical Research Centers. Lansoprazole for children with poorly controlled asthma:
a randomized controlled trial. JAMA. 2012;307(4):373–381 PMID: 22274684
doi: 10.1001/jama.2011.2035
90. Papamichael MM, Katsardis C, Tsoukalas D, Erbas B, Itsiopoulos C. Weight status and
respiratory health in asthmatic children. Lung. 2019;197(6):777–782 PMID: 31522248
doi: 10.1007/s00408-019-00273-w
91. Ginis T, Akcan FA, Capanoglu M, et al. The frequency of sleep-disordered breathing in children
with asthma and its effects on asthma control. J Asthma. 2017;54(4):403–410 PMID: 28060556
doi: 10.1080/02770903.2016.1220012
92. Schifano ED, Hollenbach JP, Cloutier MM. Mismatch between asthma symptoms and
spirometry: implications for managing asthma in children. J Pediatr. 2014;165(5):997–1002
PMID: 25175496 doi: 10.1016/j.jpeds.2014.07.026
93. Shi Y, Aledia AS, Galant SP, George SC. Peripheral airway impairment measured by
oscillometry predicts loss of asthma control in children. J Allergy Clin Immunol.
2013;131(3):718–723 PMID: 23146376 doi: 10.1016/j.jaci.2012.09.022
94. Weinberger M. Editorial: should you be doing impulse oscillometry in your young patients
with asthma? Ann Allergy Asthma Immunol. 2021;127:287–288 PMID: 34479729
doi: 10.1016/j.anai.2021.04.031
95. Chan-Yeung M, Chang JH, Manfreda J, Ferguson A, Becker A. Changes in peak flow, symptom
score, and the use of medications during acute exacerbations of asthma. Am J Respir Crit Care
Med. 1996;154(4 pt 1):889–893 PMID: 8887581 doi: 10.1164/ajrccm.154.4.8887581
96. Pike K, Selby A, Price S, et al. Exhaled nitric oxide monitoring does not reduce exacerbation
frequency or inhaled corticosteroid dose in paediatric asthma: a randomised controlled trial.
Clin Respir J. 2013;7(2):204–213 PMID: 22747899 doi: 10.1111/j.1752-699X.2012.00306.x
97. Petsky HL, Kew KM, Chang AB. Exhaled nitric oxide levels to guide treatment for children
with asthma. Cochrane Libr. 2016;11(11):CD011439 PMID: 27825189
doi: 10.1002/14651858.CD011439.pub2
98. Khatri SB, Iaccarino JM, Barochia A, et al; American Thoracic Society Assembly on Allergy,
Immunology, and Inflammation. Use of fractional exhaled nitric oxide to guide the treatment
of asthma: an official American Thoracic Society clinical practice guideline. Am J Respir Crit
Care Med. 2021;204(10):e97–e109 PMID: 34779751 doi: 10.1164/rccm.202109-2093ST
99. Silk HJ, Guay-Woodford L, Perez-Atayde AR, Geha RS, Broff MD. Fatal varicella in
steroid-dependent asthma. J Allergy Clin Immunol. 1988;81(1):47–51 PMID: 3339190
doi: 10.1016/0091-6749(88)90219-9
100. Simon AE, Ahrens KA, Akinbami LJ. Influenza vaccination among US children with asthma,
2005–2013. Acad Pediatr. 2016;16(1):68–74 PMID: 26518382 doi: 10.1016/j.acap.2015.10.006
101. Fung I, Spergel JM. Administration of influenza vaccines to patients with egg-induced
anaphylaxis. J Allergy Clin Immunol. 2012;129(4):1157–1159 PMID: 22236726
doi: 10.1016/j.jaci.2011.11.038
102. Gibson PG, Powell H. Written action plans for asthma: an evidence-based review of the key
components. Thorax. 2004;59(2):94–99 PMID: 14760143 doi: 10.1136/thorax.2003.011858
103. Illi S, von Mutius E, Lau S, Niggemann B, Grüber C, Wahn U; Multicentre Allergy Study
(MAS) group. Perennial allergen sensitisation early in life and chronic asthma in children:
a birth cohort study. Lancet. 2006;368(9537):763–770 PMID: 16935687
doi: 10.1016/S0140-6736(06)69286-6

238
104. Phelan PD, Robertson CF, Olinsky A. The Melbourne Asthma Study: 1964–1999. J Allergy Clin
Immunol. 2002;109(2):189–194 PMID: 11842286 doi: 10.1067/mai.2002.120951
105. Yawn BP, Wollan P, Kurland M, Scanlon P. A longitudinal study of the prevalence of asthma in a
community population of school-age children. J Pediatr. 2002;140(5):576–581 PMID: 12032525
doi: 10.1067/mpd.2002.123764
106. Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool
children at high risk for asthma. N Engl J Med. 2006;354(19):1985–1997 PMID: 16687711
doi: 10.1056/NEJMoa051378
107. Grant EN, Lyttle CS, Weiss KB. The relation of socioeconomic factors and racial/ethnic
differences in US asthma mortality. Am J Public Health. 2000;90(12):1923–1925
PMID: 11111268 doi: 10.2105/AJPH.90.12.1923
108. Centers for Disease Control and Prevention. AsthmaStats. Accessed January 30, 2021.
https://www.cdc.gov/asthma/asthma_stats/default.htm
109. Cazzola M, Calzetta L, Matera MG, Hanania NA, Rogliani P. How does race/ethnicity influence
pharmacological response to asthma therapies? Expert Opin Drug Metab Toxicol.
2018;14(4):435–446 PMID: 29528249 doi: 10.1080/17425255.2018.1449833
110. Pacheco CM, Ciaccio CE, Nazir N, et al. Homes of low-income minority families with
asthmatic children have increased condition issues. Allergy Asthma Proc. 2014;35(6):467–474
PMID: 25584914 doi: 10.2500/aap.2014.35.3792
111. Halterman JS, Auinger P, Conn KM, Lynch K, Yoos HL, Szilagyi PG. Inadequate therapy
and poor symptom control among children with asthma: findings from a multistate sample.
Ambul Pediatr. 2007;7(2):153–159 PMID: 17368410 doi: 10.1016/j.ambp.2006.11.007
112. Canino G, McQuaid EL, Rand CS. Addressing asthma health disparities: a multilevel challenge.
113. 113. Bryant-Stephens T. Asthma disparities in urban environments. J Allergy Clin lmmunol.
2009;123(6):1199–1206 PMID: 19501229 doi: 10.1016/j.jaci.2009.04.030
114. Brown R, Bratton SL, Cabana MD, Kaciroti N, Clark NM. Physician asthma education program
improves outcomes for children of low-income families. Chest. 2004;126(2):369–374
PMID: 15302719 doi: 10.1378/chest.126.2.369
115. Ogbogu PU, Capers Q 4th, Apter AJ. Disparities in asthma and allergy care: what can
we do? J Allergy Clin Immunol Pract. 2021;9(2):663–669. PMID: 33317817
doi: 10.1016/j.jaip.2020.10.030
116. Volerman A, Chin MH, Press VG. Solutions for asthma disparities. Pediatrics.
2017;139(3):e20162546 PMID: 28228500 doi: 10.1542/peds.2016-2546
117. Butz AM, Matsui EC, Breysse P, et al. A randomized trial of air cleaners and a health coach
to improve indoor air quality for inner-city children with asthma and secondhand smoke
exposure. Arch Pediatr Adolesc Med. 2011;165(8):741–748 PMID: 21810636
doi: 10.1001/archpediatrics.2011.111
118. Margellos-Anast H, Gutierrez MA, Whitman S. Improving asthma management among
African-American children via a community health worker model: findings from a
Chicago-based pilot intervention. J Asthma. 2012;49(4):380–389 PMID: 22348448
doi: 10.3109/02770903.2012.660295
119. Stempel H, Federico MJ, Szefler SJ. Applying a biopsychosocial model to inner city asthma:
recent approaches to address pediatric asthma health disparities. Paediatr Respir Rev.
2019;32:10–15 PMID: 31678039 doi: 10.1016/j.prrv.2019.07.001
120. Klein MD, Beck AF, Henize AW, Parrish DS, Fink EE, Kahn RS. Doctors and lawyers
collaborating to HeLP children--outcomes from a successful partnership between professions.
J Health Care Poor Underserved. 2013;24(3):1063–1073 PMID: 23974381
doi: 10.1353/hpu.2013.0147
121. Lemanske RF Jr, Kakumanu S, Shanovich K, et al. Creation and implementation of SAMPRO™:
a school-based asthma management program. J Allergy Clin Immunol. 2016;138(3):711–723
PMID: 27596707 doi: 10.1016/j.jaci.2016.06.015

PART
3
Anatomical Disorders
Chapter 13. Congenital Abnormalities of the Upper Airway........ 241

James W. Schroeder Jr, MD, MBA, FACS, FAAP; Susanna A. McColley, MD, FAAP;
and Mary Bono Cataletto, MD, FAAP
Chapter 14. Congenital Lung Anomalies......................................... 253

Brian P. O’Sullivan, MD, and T. Bernard Kinane, MD
Chapter 15. Chest Wall and Spinal Deformities..............................279

Julie L. Fierro, MD, MPH, and Oscar Henry Mayer, MD
239
15 PP 2ND ED - PO 03_239-240.indd 239 11/6/23 8:15 AM

15 PP 2ND ED - PO 03_239-240.indd 240 9/12/23 9:21 AM
CHAPTER
13
Congenital Abnormalities of the Upper Airway
James W. Schroeder Jr, MD, MBA, FACS, FAAP
Introduction
Obstructive lesions of the upper airway create turbulent airflow, which follows
the laws of fluid dynamics. Rapidly flowing air moving across a narrowed
segment of the respiratory tract creates vibrations that produce distinctive
sounds, which are diagnostically useful to the clinician. The location of the
obstruction in the airway will affect the phase, tone, and timing of the sound.
The clinician can use this information to create a differential diagnosis. Stertor
describes the low-pitched inspiratory snoring sound typically produced by
nasal or nasopharyngeal obstruction. Stridor typically originates from the
larynx, upper trachea, or hypopharynx. Wheezing is the expiratory sound
produced by the turbulent flow of air through constricted lower airways
(trachea and bronchi). This sound is similar to, and frequently mistaken for,
other intrathoracic conditions such as bronchomalacia, tracheomalacia, or
foreign bodies in the tracheobronchial tree.1
The timing of the noisy breathing can be particularly useful in determining
the location of a congenital abnormality of the upper airway. As outlined in
Holinger’s laws of airway obstruction,2 the severity of the noisy breathing in
relation to the sleep-wake cycle is important. In general, when the noise is
worse during sleep, the obstruction is nasal or pharyngeal, especially with
tonsil and adenoid obstruction. If the symptoms are worse when the child
is awake or if they are exacerbated by exertion, the obstruction is typically
laryngeal, tracheal, or bronchial. These clues are helpful during the initial
assessment. However, they are generalizations, and like most rules they have
exceptions. For example, the initial presentation of a child with recurrent
respiratory papillomatosis of the larynx is progressive upper airway obstruc-
tion during sleep rather than during exertion. In addition, infants with
laryngomalacia may have inspiratory stridor with sleep.
The phase of breathing during which the sound occurs can also be diagnos-
tic. Stertor is typically an inspiratory sound that occurs because of turbulent
241

242
airflow over a fixed or positional obstruction in the nasal cavity or pharynx. In

infants, who are obligate nasal breathers, this turbulence will be greatest
during inhalation. During exhalation, the infant will be able to use the oral
cavity or will be able to displace nonfixed lesions and decrease or bypass the
obstruction. Therefore, the noise will be less noticeable or nonexistent during
exhalation. Stridor is most often an inspiratory sound. Based on the Bernoulli
principle, a narrowing at the level of the larynx will cause the air flowing
through the narrowing to increase in speed and therefore decrease the
pressure in this area, which in turn causes the narrowed area to narrow even
further, increasing the obstruction and the stridor. During exhalation, the
opposite occurs. The non-fixed laryngeal lesion is forced laterally, opening
the obstruction and decreasing the noise. However, if the laryngeal lesion is
fixed, such as in the subglottis where the cricoid cartilage forms a complete
ring, the lesion will not move during exhalation, and there will be a biphasic
(inspiratory and expiratory) stridor. Intrathoracic lesions (tracheomalacia and
bronchomalacia) create an expiratory sound (wheezing) owing to the exagger-
ated collapse of the airways during exhalation when the pleural pressure
increases and compresses the bronchioles. During inhalation, when the
pleural pressure decreases, the bronchioles enlarge, and no sound is produced.
Assessment
When assessing a child suspected of having a congenital anomaly of the upper
airway, it is important to determine the severity and location of the obstruc-
tion. The severity of mild to moderate chronic persistent obstruction must be
assessed in the presence of acute symptoms of respiratory distress (increased
work of breathing, retractions, nasal flaring, and cyanosis). The mnemonic
SPECS-R3 (Box 13-1) is a useful tool to organize history taking and to deter-
mine the need for endoscopy in the operating room. This technique incorpo-
rates the parents’ subjective interpretation of the child’s obstruction along with
a more objective measurement of the child’s eating and sleeping behavior.
Radiography is also a helpful tool in assessing obstruction in these children.
Box 13‑1
Subjective Interpretation of Airway Obstruction
S: Severity—parents’ subjective impression
P: Progression of the obstruction over time
E: Eating or feeding difficulties, aspiration, failure to thrive
C: Cyanotic episodes, apparent life-threatening events
S: Sleep obstruction so severe that retractions occur during sleep
R: Radiology-specific abnormalities detected on radiographs
Derived from Holinger LD. Diagnostic endoscopy of the pediatric airway. Laryngoscope.
1989;99(3):346–348.

243
Chapter 13—Congenital Abnormalities of the Upper Airway
Congenital Nasal Anomalies

Newborns are obligate nasal breathers. Therefore, an obstructive lesion of the
nasal cavity can cause clinically significant respiratory distress in a neonate.
The symptoms do not vary based on the location of the lesion in the nasal
cavity. In general, the respiratory distress caused by nasal obstruction is worse
at rest and can be relieved with crying because the oral cavity is open. Some
common congenital nasal anomalies are listed in Box 13‑2.
Box 13‑2
Congenital Anomalies of the Upper Airway
Congenital Nasal Anomalies Congenital Lesions of the Tongue
Pyriform aperture stenosis Macroglossia
Choanal atresia Vascular malformations
Nasolacrimal duct cyst Tumors (rhabdomyosarcoma)
Nasal dermoid, glioma, encephalocele Tongue base
Cleft lip nasal deformity Ectopic thyroid
Craniofacial Abnormalities Lingual thyroid
Crouzon syndrome Thyroglossal duct cyst
Apert syndrome Congenital Laryngeal Anomalies
Pierre Robin sequence Laryngomalacia
Down syndrome Laryngocele
Saccular cysts
Subglottic stenosis
Vocal cord paralysis
Pyriform Aperture Stenosis

Pyriform aperture stenosis, also called anterior nasal stenosis, is caused
by prenatal overgrowth of the medial maxilla, which narrows the pyriform
aperture at the front of the nasal cavity. This condition is often not readily
noticed at physical examination and can be diagnosed by means of a cranio-
facial computed tomography (CT) scan demonstrating a narrowed pyriform
aperture in relation to the posterior choanae.4,5 This stenosis can also be
seen in conjunction with a mega-incisor, which may be associated with
holoprosencephaly.6 These children should be evaluated with neuroimaging
and for other endocrine abnormalities associated with an abnormal hypotha-
lamic-pituitary-adrenal axis. Conservative therapy with topical decongestants
and steroids is helpful in infants with mild symptoms. The use of noninvasive
airway support (such as positive airway pressure) may also be considered for
infants with clinically significant obstructive symptoms. Pyriform aperture
stenosis causing clinically significant respiratory distress can be corrected
surgically through a sublabial incision.

244
Choanal Atresia
Choanal atresia is an uncommon disorder that is the most common cause
of complete nasal obstruction in the neonate. It occurs when the posterior
choanae fail to develop properly. The published incidence varies from 1 in
5,000 to 1 in 8,000 live births.7 Both sexes are affected, but reports suggest
a female predominance of 2 to 1; unilateral cases are more common than
bilateral cases and may not be diagnosed until later in life.8,9 Bony atresia
(90%) is more common than membranous atresia (10%); however, some
investigators suggest that mixed bony-membranous anomalies may have the
highest incidence.10 One way to screen for this condition is to attempt to pass
a flexible catheter through each of a newborn’s nasal cavities. Failure to pass
a 6F catheter successfully more than 32 mm (1.3 inch) past the anterior nares
requires further workup. Axial CT scanning of the nasal cavity and/or nasal
endoscopy can help confirm the diagnosis. Orotracheal intubation or an oral
airway device must be used to relieve the obstruction until the patient is a
candidate for surgery. Unilateral atresia may not be noticed until later in
life and most often manifests with persistent unilateral rhinorrhea. Choanal
atresia is associated with other congenital anomalies 43% to 72% of the time.11
It is most commonly seen as part of the CHARGE association—coloboma of
the eye, heart defects, atresia (choanal), restricted growth and development,
genitourinary hypoplasia, and ear anomalies. Nonsyndromic choanal atresia
is usually sporadic and most likely multifactorial. Surgical correction can be
performed via a transoral transpalatal approach or, more commonly, through
a transnasal endoscopic approach that often requires postoperative stent
placement followed by repeat dilations.
Nasolacrimal Duct Cyst

If the nasolacrimal duct is not patent at birth, it will typically become patent
during the first month after birth.12 If the nasolacrimal apparatus fails to
canalize, a nasolacrimal duct cyst can develop and expand into the nose
from under the inferior turbinate and enter the inferior meatus, causing nasal
airway obstruction. The cyst can occasionally be seen via anterior rhinoscopy,
but the diagnosis is confirmed by means of nasal endoscopy after nasal
decongestion and/or CT scanning or magnetic resonance imaging (MRI) of
the sinuses.5 The cyst can become infected and cause swelling and erythema
of the medial canthus and purulent orbital discharge. Treatment consists of
endoscopic marsupialization and nasolacrimal duct probing.
Nasal Dermoid, Glioma, and Encephalocele

Nasal dermoids, gliomas, and encephaloceles are congenital midline nasal
lesions that are believed to result from abnormal closure of the anterior neuro-
pore. All encephaloceles and many dermoids and gliomas communicate with
the central nervous system. Therefore, no congenital nasal mass or polyp in

245
a child should be manipulated until intracranial communication is ruled out.

Computed tomography and MRI are required for diagnosis and surgical plan-
ning.8 Dermoid sinuses and cysts generally occur in the nasal midline and
can manifest as a fistulous tract or a mass anywhere from the nasal tip to the
glabella.13 Hair or sebaceous material may protrude from the pit, and patients
may present with drainage. Gliomas and encephaloceles are similar in clinical
appearance and histological characteristics. Gliomas are unencapsulated col-
lections of glial cells that may retain attachments to the dura. Encephaloceles
are herniations of the meninges with or without brain tissue through the skull
base and communicate with the subarachnoid space.14 They usually manifest
early in life but can be unrecognized until adulthood. Unlike dermoids, they do
not routinely occur in the midline, nor do they connect via a sinus tract to the
skin. These lesions are surgically removed jointly by an otolaryngologist and
neurosurgeon using a combination of external and endoscopic approaches.
Cleft Lip Nasal Deformity

The incidence of clefts of the lip and/or palate is approximately 1 in 800 live
births.15 The nasal deformity resulting from flattening of the nasal bridge and
ala can be associated with clinically significant nasal obstruction. The nasal
deformity is corrected surgically after the cleft lip is repaired.8
Craniofacial Abnormalities
Craniofacial abnormalities can be associated with airway compromise by
obstructing the nose, nasopharynx, oropharynx, or hypopharynx (Box 13‑2).
Crouzon syndrome (craniofacial dysostosis) is defined by craniosynostosis and
maxillary hypoplasia. The resulting midface hypoplasia and high-arched palate
can lead to nasal obstruction. Severe cases can warrant intubation or trach-
eostomy. Apert syndrome (acrocephalosyndactyly) is also marked by severe
maxillary hypoplasia resulting in proptosis and relative prognathism. The
underdeveloped nose and high-arched palate result in clinically significant nasal
obstruction. Apert syndrome is also associated with syndactyly of the hands,
which differentiates it from Crouzon syndrome. Pierre Robin sequence (cleft
palate, micrognathia, and glossoptosis) can cause severe pharyngeal airway
obstruction at birth. In mild cases, prone positioning can help. In more severe
cases, placement of an oral airway device or an intubation may be needed to
bypass the obstruction caused by the base of the tongue. Mandibular distraction
can eliminate the obstruction by pulling the tongue base forward and relieving
the glossoptosis. A tracheostomy is occasionally needed until the distraction
is completed or the mandible has grown sufficiently. This sequence can be
associated with Stickler syndrome, and genetic workup is required.
Down syndrome (trisomy 21) occurs in approximately 1 in 722 live births and
is the most common congenital chromosomal anomaly.16 There are multiple
head and neck morphological abnormalities in these children that predispose

246
them to disease. These abnormalities include midface hypoplasia, which is

characterized by malformation of the eustachian tube, a shortened palate,
macroglossia, and a narrowing of the oropharynx and nasopharynx.17 In
combination with systemic hypotonia, these abnormalities underlie the high
incidence of recurrent otitis media and obstructive sleep apnea in children with
Down syndrome. Obstructive sleep apnea is the most common cause of upper
airway obstruction in children older than 1 year. Nearly 50% of parents of
these children do not report a sleep disturbance despite abnormal findings
during a sleep study. The true incidence of obstructive sleep apnea is unknown,
and a high level of suspicion should be maintained. Laryngomalacia is seen in
approximately 50% of children with Down syndrome. Tracheomalacia occurs
in about one-third, most of whom have congenital heart disease.16
Congenital Lesions of the Tongue

Macroglossia
Beckwith-Wiedemann syndrome is the most common cause of macroglossia
in children.18 Macroglossia can also be seen with trisomy 21, congenital
hypothyroidism, vascular malformations, muscular enlargement, and tumors.
Lymphangiomas or hemangiomas of the tongue may cause clinically significant
airway obstruction present at birth. Lymphangiomas are most common and are
apparent at birth in 60% of cases.19 Symptoms include dysphagia; drooling;
disarticulation; and a dried, fissured tongue. In cases of severe obstruction,
intubation or tracheostomy may be required, followed by surgical reduction of
part of the tongue. In children, tumors of the tongue are rare, but rhabdomyo-
sarcoma can occur, and 20% of these tumors that occur in the head and neck
occur in the tongue (Box 13‑2).19
Congenital Lesions of the Base of the Tongue

Congenital lesions of the base of the tongue are rare and include ectopic thyroid
tissue, most commonly a lingual thyroid, and thyroglossal duct cysts. A lingual
thyroid can manifest with upper airway obstruction in a newborn or as part of
the workup for congenital hypothyroidism. Seventy percent to 100% of children
with ectopic thyroid tissue in the tongue have no other thyroid tissue.20,21 The
diagnosis can be confirmed with CT scanning, ultrasonography, or MRI. Radio-
nuclide scans will help localize functioning thyroid tissue. The ectopic thyroid
tissue is subject to the same pathological changes as normal thyroid tissue
(including cancer), but it is usually associated with hypothyroidism. Treatment
includes suppression therapy to prevent enlargement, hypothyroidism, and
malignancy.20–22 Radioactive iodine-131 ablation has also been described.20
However, when the obstruction is not corrected with suppression therapy or
if malignancy is suspected, surgical excision is the treatment of choice and
can be accomplished through transoral and transcervical approaches.

247
Thyroglossal Duct Cysts

Thyroglossal duct cysts are the most common malformations found in the
neck and account for 70% of congenital cervical abnormalities. Although they
can manifest at any age, most are detected in the first 2 decades, making them
primarily a pediatric disease.23 Thyroglossal duct cysts usually manifest as
a midline cervical mass that lies either directly above the hyoid bone or just
below it. The mass typically moves with protrusion of the tongue. Besides the
cosmetic deformity associated with these lesions, they can become recurrently
infected; therefore, surgical excision is the treatment of choice. The cyst is
removed through a midline cervical incision, along with the central portion
of the hyoid bone, as well as the associated tract in the base of tongue. This is
called the Sistrunk procedure.
Congenital Laryngeal Anomalies

Laryngomalacia
Laryngomalacia is the most common cause of inspiratory stridor in infants.24
Symptoms typically begin 1 to 3 weeks after birth and usually progress over
several months. It is caused, in part, by decreased laryngeal tone leading to
supraglottic collapse during inspiration.24–26 Gastroesophageal reflux disease
and neurological disease influence the severity of the disease and, thereby,
the clinical course.24–26 Greater disease severity is associated with low Apgar
scores at birth. The diagnosis is established primarily based on symptoms
that include stridor, dysphagia, apnea, cyanosis, and failure to thrive. The
stridor associated with laryngomalacia is inspiratory and can be worsened
by the patient’s agitation and while feeding. It can also be worsened when the
infant is supine and in a relaxed state and therefore can be heard during sleep.
Flexible fiberoptic laryngoscopy with the patient awake is used to confirm
the diagnosis and to differentiate the cause of the stridor from other glottic
disease. In otherwise healthy children, laryngomalacia typically resolves
by 1 year of age without surgical intervention. However, in 15% to 20%
of patients, symptoms are severe enough to cause progressive respiratory dis-
tress, cyanosis, or failure to thrive.27,28 In these patients, supraglottoplasty is
considered. This procedure may be performed using cold knife instrumenta-
tion, carbon dioxide laser, or microdebrider techniques. All techniques focus
on directed removal of the redundant cuneiform cartilages, the lysis of tight
aryepiglottic folds, and the occasional removal of obstructing portions of
the epiglottis. Potential complications include persistent airway obstruction
requiring further surgery, supraglottic stenosis, dysphasia, aspiration, and
death.29 Supraglottoplasty is more than 90% successful in relieving upper
airway obstruction caused by severe laryngomalacia.29

248
Laryngocele and Saccular Cysts

A laryngocele is an abnormal dilatation or herniation of the laryngeal saccule,
which rises vertically between the false vocal cords, the base of the epiglottis,
and the inner surface of the thyroid cartilage. It communicates with the lumen
of the larynx and is filled with air. An internal laryngocele is confined to the
interior of the larynx and extends posterosuperiorly into the area of the false
vocal cords and aryepiglottic folds, causing a mass that can be seen by means
of direct or indirect laryngoscopy. An external laryngocele extends cephalad to
protrude laterally into the neck through the thyrohyoid membrane, manifesting
as a neck mass.30 A laryngocele may be solely congenital; it may be a congeni-
tal defect made apparent or exacerbated by habitual, increased intralaryngeal
pressure; or it may be acquired solely on the basis of prolonged increased
intralaryngeal pressure. A saccular cyst is distinguished from a laryngocele in
that the lumen is isolated from the interior of the larynx and it does not contain
air. These cysts result from a developmental failure of the saccular orifice to
maintain patency.30 Inflammation, trauma, and tumors may occlude the orifice
as well. Therefore, saccular cysts can be congenital or acquired.
In infants and children, laryngoceles cause hoarseness and dyspnea that may in-
crease with crying. Saccular cysts cause respiratory distress and stridor. Laryngo-
cele is diagnosed by means of a soft-tissue posteroanterior radiograph of the neck.
If the laryngocele is not distended at the time the image is obtained, the image
of the larynx will be normal. Saccular cysts are diagnosed by means of direct
laryngoscopy. Cysts can be treated endoscopically with repeat needle aspiration
or with excision through marsupialization and unroofing. External excision
through a lateral horizontal cervical incision can be used in recurrent cases.30
Congenital Subglottic Stenosis

Congenital subglottic stenosis is the second most common cause of stridor in
neonates.1 The subglottis is the narrowest part of the upper airway in a child.
Subglottic stenosis is a narrowing of the subglottic larynx, which is the space
extending from the undersurface of the true vocal cords to the inferior margin of
the cricoid cartilage. It typically causes respiratory distress and biphasic stridor.
In mild cases, the child may present with recurrent croup before the age of 1 year.
The edema and thickened secretions of the common cold further narrow an
already marginal airway, leading to crouplike symptoms. The stenosis can be
caused by abnormally shaped cricoid cartilage; by a tracheal ring that becomes
trapped underneath the cricoid cartilage; or by soft-tissue thickening caused by
ductal cysts, submucosal gland hyperplasia, or fibrosis.31 The diagnosis can
be established by means of posteroanterior and lateral airway radiographs and
confirmed by means of endoscopic examination. During diagnostic laryngoscopy
and bronchoscopy, the subglottic larynx is visualized directly and sized objec-
tively by using an endotracheal tube. The percentage of stenosis is determined by
comparing the size of the patient’s larynx to a standard of laryngeal dimensions

249
based on age.32 The degree of stenosis will help dictate treatment. Children with
stenosis greater than 50% tend to have more symptoms and more often require
treatment. Surgical options include bronchoscopy with balloon dilation, laryngo-
tracheal reconstruction, and cricotracheal resection. Laryngotracheal reconstruc-
tion involves augmenting the subglottis with an anterior or posterior cartilage
graft placed in the cricoid cartilage. This reconstruction can be performed via an
open technique through a cervical neck incision or endoscopically through the
oral cavity, depending on the type and degree of stenosis. A cricotracheal resec-
tion involves removing most of the stenosed cricoid cartilage and re-anastomosing
the trachea to the larynx. The postoperative care is critical and often requires
multiple bronchoscopies to ensure patency and prevent repeat stenosis.
Vocal Cord Paralysis

Vocal cord paralysis in infants is the third most common cause of stridor in
infants, after laryngomalacia and subglottic stenosis.1 In approximately 40% of
cases, bilateral vocal cord paralysis in infants is the result of central congenital
anomalies.33 It is found most commonly in association with myelomeningocele,
Arnold-Chiari malformation, and hydrocephalus. Unilateral vocal cord paraly-
sis is most often iatrogenic as a result of surgical treatment for gastrointestinal
(tracheoesophageal fistula) and cardiovascular (patent ductus arteriosus repair)
anomalies. Unilateral vocal cord paralysis is seen most often on the left because
of the longer course of the recurrent laryngeal nerve on this side. Internal trauma,
such as with an endotracheal tube or nasogastric tube, and external trauma,
including birth trauma, strangulation injury, or motor vehicle accidents, may
lead to vocal cord paralysis.
Bilateral vocal cord paralysis manifests with a high-pitched, inspiratory stridor
and respiratory distress similar to the manifestation of laryngomalacia. How-
ever, in this case, it is the vocal cords that are drawn together during inspiration
causing stridor rather than the supraglottic structures. The vocal cords are pushed
apart during exhalation, relieving the obstruction. Children with unilateral vocal
cord paralysis can experience aspiration leading to cough and a weak, breathy
cry. Airway obstruction and stridor are less common in these patients because
the paralyzed vocal cords tend to stay fixed in a lateral position. The diagnosis
is confirmed using flexible fiberoptic laryngoscopy without anesthesia. Once
the diagnosis is established, determining the cause should include pediatric
otolaryngology, neurology, and cardiology consultations and may include
chest and neurological imaging, depending on the patient’s history.
Vocal cord paralysis resolves spontaneously within 6 to 12 months in 48% to
62% of infants.34 If it does not resolve within 2 to 3 years, it is unlikely to do so.33
Treatment is based on the severity of the patient’s symptoms. In patients with
bilateral vocal cord paralysis and respiratory distress, a trial of intubation may
be warranted to allow a chance for spontaneous recovery. If this does not occur,
surgical intervention may be considered. Procedures that widen the posterior

250
glottis to relieve the obstruction include laryngotracheal reconstruction by using

an endoscopically placed posterior glottic cartilage graft, arytenoidectomy, or
arytenoid lateralization. These procedures are successful in reducing the obstruc-
tion. However, they may worsen the patient’s voice quality, and they may result
in aspiration that can become severe. Tracheostomy is sometimes necessary. In
cases of unilateral vocal cord paralysis in which aspiration and a hoarse cry are
the main symptoms, vocal cord medialization is often used, most commonly per-
formed endoscopically through an injection technique. A temporary injectable
material, such as absorbable gelatin sponge or endogenous fat, may be injected
into the larynx to medialize the vocal cord and decrease aspiration. The material
will absorb in 3 to 6 months and, if it was successful, another injection with a
more permanent substance can be used. The main complication is overinjection,
leading to postoperative respiratory distress, which is most often temporary.
key points
} Stertor is the low-pitched inspiratory, snoring sound typically produced by
nasal or nasopharyngeal obstruction.
} Stridor is an inspiratory sound (occasionally biphasic) that typically originates
from the larynx, upper trachea, or hypopharynx.
} Wheezing is the expiratory sound produced by the turbulent flow of air
through constricted bronchioles.
} Pyriform aperture stenosis seen in conjunction with a mega-incisor may be
associated with holoprosencephaly.
} Choanal atresia should be suspected by the failure to pass a 6F catheter more
than 32 mm (1.3 inch) past the anterior nares.
} The Crouzon and Apert syndromes are defined by craniosynostosis and
maxillary hypoplasia, which can result in severe upper airway obstruction.
} The Pierre Robin sequence (cleft palate, micrognathia, and glossoptosis) can
cause severe pharyngeal airway obstruction that is present at birth.
} Lymphangiomas are the most common cause of macroglossia in children and
are apparent at birth in 60% of cases.
} Thyroglossal duct cysts are the most common malformations found in the neck
and account for 70% of congenital cervical abnormalities.
} Laryngomalacia is the most common cause of inspiratory stridor in infants and
typically begins 1 to 3 weeks after birth and resolves by about 1 year of age.
} Subglottic stenosis is the second most common cause of stridor in neonates.
➤ It typically manifests with respiratory distress and biphasic stridor.
➤ In mild cases, the child may present with recurrent croup before the
age of 1 year.
} Paralysis of the vocal cords is the third most common cause of stridor in infants.
Bilateral paralysis in infants is the result of central congenital anomalies in
approximately 40% of cases.

251
References
1. Holinger LD. Etiology of stridor in the neonate, infant and child. Ann Otol Rhinol Laryngol.
1980;89(5 pt 1):397–400 PMID: 7436240 doi: 10.1177/000348948008900502
2. Holinger LD. Evaluation of stridor and wheezing. In: Holinger LD, ed. Pediatric Laryngology
& Bronchoesophagology. Lippincott–Raven; 1997:28–41
3. Holinger LD. Diagnostic endoscopy of the pediatric airway. Laryngoscope. 1989;99(3):346–348
PMID: 2918809 doi: 10.1288/00005537-198903000-00023
4. Bignault A, Castillo M. Congenital nasal piriform aperture stenosis. AJNR Am J Neuroradiol.
1994;15(5):877–878 PMID: 8059654
5. Otteson TD, Wang T. Upper airway lesions in the neonate. In: Martin RJ, Fanaroff AA,
Walsh MC, eds. Fanaroff and Martin’s Neonatal-Perinatal Medicine: Diseases of the Fetus
and Infant. Vol II. 11th ed. Elsevier; 2020:1244
6. Cohen MM Jr. Perspectives on holoprosencephaly: part I. Epidemiology, genetics, and
syndromology. Teratology. 1989;40(3):211–235 PMID: 2688166 doi: 10.1002/tera.1420400304
7. Gujrathi CS, Daniel SJ, James AL, Forte V. Management of bilateral choanal atresia in the
neonate: an institutional review. Int J Pediatr Otorhinolaryngol. 2004;68(4):399–407
PMID: 15013604 doi: 10.1016/j.ijporl.2003.10.006
8. Smith MM, Ishman SL. Pediatric nasal obstruction. Otolaryngol Clin North Am.
2018;51(5):971–985 PMID: 30031550 doi: 10.1016/j.otc.2018.05.005
9. Moreddu E, Rizzi M, Adil E, et al. International Pediatric Otolaryngology Group (IPOG)
consensus recommendations: diagnosis, pre-operative, operative and post-operative pediatric
choanal atresia care. Int J Pediatr Otorhinolaryngol. 2019;123:151–155 PMID: 31103745
doi: 10.1016/j.ijporl.2019.05.010
10. Sadek SA. Congenital bilateral choanal atresia. Int J Pediatr Otorhinolaryngol.
1998;42(3):247–256 PMID: 9466228 doi: 10.1016/S0165-5876(97)00142-0
11. Stahl RS, Jurkiewicz MJ. Congenital posterior choanal atresia. Pediatrics. 1985;76(3):429–436
PMID: 4034303
12. Lusk RP, Muntz HM. Nasal obstruction in the neonate secondary to nasolacrimal duct cysts.
Int J Pediatr Otorhinolaryngol. 1987;13(3):315–322 PMID: 3679686
doi: 10.1016/0165-5876(87)90112-1
13. Frodel JL, Larrabee WF, Raisis J. The nasal dermoid. Otolaryngol Head Neck Surg.
1989;101(3):392–396 PMID: 2508011 doi: 10.1177/019459988910100314
14. Hengerer A. Congenital Anomalies of the Nose: Their Embryology, Diagnosis and Management
[monograph]. American Academy of Otolaryngology Head and Neck Surgery; 1987
15. Rahimov F, Jugessur A, Murray JC. Genetics of nonsyndromic orofacial clefts. Cleft Palate
Craniofac J. 2012;49(1):73–91 PMID: 21545302 doi: 10.1597/10-178
16. Alsubie HS, Rosen D. The evaluation and management of respiratory disease in children
with Down syndrome (DS). Paediatr Respir Rev. 2018;26:49–54 PMID: 29033214
doi: 10.1016/j.prrv.2017.07.003
17. Mitchell RB, Call E, Kelly J. Ear, nose and throat disorders in children with Down syndrome.
Laryngoscope. 2003;113(2):259–263 PMID: 12567079 doi: 10.1097/00005537-200302000-00012
18. Brioude F, Kalish JM, Mussa A, et al. Expert consensus document: clinical and molecular
diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international
consensus statement. Nat Rev Endocrinol. 2018;14(4):229–249 PMID: 29377879
doi: 10.1038/nrendo.2017.166
19. Weiss LS, White JA. Macroglossia: a review. J La State Med Soc. 1990;142(8):13–16
PMID: 2230521
20. Maddern BR. Lingual thyroid in a young infant presenting as airway obstruction:
report of a case. Int J Pediatr Otorhinolaryngol. 1990;19(1):79–80 PMID: 2341237
doi: 10.1016/0165-5876(90)90199-2
21. Kansal P, Sakati N, Rifai A, Woodhouse N. Lingual thyroid. Diagnosis and treatment. Arch
Intern Med. 1987;147(11):2046–2048 PMID: 3675109 doi: 10.1001/archinte.1987.00370110174028
22. Wassner AJ, Brown RS. Congenital hypothyroidism: recent advances. Curr Opin Endocrinol
Diabetes Obes. 2015;22(5):407–412 PMID: 26313902 doi: 10.1097/MED.0000000000000181
23. Maddalozzo J, Venkatesan TK, Gupta P. Complications associated with the Sistrunk procedure.
Laryngoscope. 2001;111(1):119–123 PMID: 11192879 doi: 10.1097/00005537-200101000-00021
24. Thompson DM. Abnormal sensorimotor integrative function of the larynx in congenital
laryngomalacia: a new theory of etiology. Laryngoscope. 2007;117(6 pt 2)(suppl 114):1–33
PMID: 17513991 doi: 10.1097/MLG.0b013e31804a5750
25. Scott BL, Lam D, MacArthur C. Laryngomalacia and swallow dysfunction. Ear Nose Throat J.
2019;98(10):613–616 PMID: 31119989 doi: 10.1177/0145561319847459

252
26. Carter J, Rahbar R, Brigger M, et al. International Pediatric ORL Group (IPOG) laryngomalacia
consensus recommendations. Int J Pediatr Otorhinolaryngol. 2016;86:256–261 PMID: 27107728
doi: 10.1016/j.ijporl.2016.04.007
27. Olney DR, Greinwald JH Jr, Smith RJ, Bauman NM. Laryngomalacia and its treatment.
Laryngoscope. 1999;109(11):1770–1775 PMID: 10569405
doi: 10.1097/00005537-199911000-00009
28. Isaac A, Zhang H, Soon SR, Campbell S, El-Hakim H. A systematic review of the evidence on
spontaneous resolution of laryngomalacia and its symptoms. Int J Pediatr Otorhinolaryngol.
2016;83:78–83 PMID: 26968058 doi: 10.1016/j.ijporl.2016.01.028
29. Schroeder JW Jr, Thakkar KH, Poznanovic SA, Holinger LD. Aspiration following CO(2)
laser-assisted supraglottoplasty. Int J Pediatr Otorhinolaryngol. 2008;72(7):985–990
PMID: 18448173 doi: 10.1016/j.ijporl.2008.03.007
30. Holinger LD, Barnes DR, Smid LJ, Holinger PH. Laryngocele and saccular cysts. Ann Otol
Rhinol Laryngol. 1978;87(5 pt 1):675–685 PMID: 718065 doi: 10.1177/000348947808700513
31. Holinger PH, Johnson KC, Schiller F. Congenital anomalies of the larynx. Ann Otol Rhinol
Laryngol. 1954;63(3):581–606 PMID: 13208076 doi: 10.1177/000348945406300302
32. Myer CM III, O’Connor DM, Cotton RT. Proposed grading system for subglottic stenosis
based on endotracheal tube sizes. Ann Otol Rhinol Laryngol. 1994;103(4 pt 1):319–323
PMID: 8154776 doi: 10.1177/000348949410300410
33. Holinger LD, Holinger PC, Holinger PH. Etiology of bilateral abductor vocal cord paralysis:
a review of 389 cases. Ann Otol Rhinol Laryngol. 1976;85(4 pt 1):428–436 PMID: 949150
doi: 10.1177/000348947608500402
34. Jabbour J, Martin T, Beste D, Robey T. Pediatric vocal fold immobility: natural history and
the need for long-term follow-up. JAMA Otolaryngol Head Neck Surg. 2014;140(5):428–433
PMID: 24626342 doi: 10.1001/jamaoto.2014.81

CHAPTER
14
Congenital Lung Anomalies
Brian P. O’Sullivan, MD
T. Bernard Kinane, MD
Congenital lung malformations are a spectrum of disorders arising from errors

in formation of the airways or vascular supply of the lung. Although major con-
genital lung malformations are often presented as separate entities, there is
great overlap between these abnormalities, and a single congenital abnormality
may not fit neatly into one category.
The wheel theory of airway and vessel malinosculations (Figure 14-1) helps
to understand the malformations.1 In this approach, the developmental inter-
actions of bronchial, acinar, and vascular components are interpreted along
a continuum. A congenital abnormality may be isolated to large airways
(eg, tracheomalacia), involve abnormalities in both bronchial and vascular
development (eg, pulmonary sequestration), or involve the vasculature only
with secondary airway involvement (eg, vascular rings). Recently, the unifying
term congenital pulmonary airway malformation (CPAM) has been adopted to
describe these malformations. However, in practice, many clinicians still refer
to the malformations by specific names, and this chapter uses that approach to
describe variations in clinical presentation and treatment. To appreciate these
differences, a basic review of lung development is useful.
Lung Growth and Development

Prenatal lung development occurs in 5 stages: embryonic (0–5 weeks after
conception), pseudoglandular (6–16 weeks), canalicular (17–24 weeks), saccu-
lar (24–38 weeks), and alveolar (38 weeks to years) (Figure 14‑2).2,3 There is
tremendous interaction between the developing endoderm and mesoderm as
airways and acini develop, and errors in regulation of differentiation depend on
the 3 Cs: communication, complexity, and critical timing. For example, differ-
entiation of the bronchial tree is complete by the end of the pseudoglandular
period (16 weeks of gestation). Thus, events that disrupt the complex communi-
cation between genetic promotors and regulators at critical points in develop-
ment (ie, before 16 weeks of gestation) will affect airway development, whereas
events occurring after 16 weeks will affect development of terminal respiratory
bronchioles and alveoli (the acinus). See also Chapter 1, Anatomy of the Lung.
253

254
3
Systemic supply to
“normal” lung
Theoretical
“insult”
Dividing bronchus
2 4
Local lesion Pulmonary artery Systemic supply to
Systemic abnormal lung
plexus
1 5
Agenesis Normal pulmonary artery
supply to abnormal lung
Figure 14‑1. Wheel theory of abnormal lung development: (1) agenesis of lung segment,
(2) budding lesion of airway (eg, bronchogenic cyst), (3) systemic blood supply to normal
lung segment, (4) systemic blood supply to abnormal lung segment (eg, sequestration),
and (5) normal blood supply to abnormal lung segment.
Reprinted from Clements BS, Warner JO. Pulmonary sequestration and related congenital bronchopulmonary-
vascular malformations: nomenclature and classification based on anatomical and embryological considerations.
Thorax. 1987;42(6):401–408, with permission from BMJ Publishing Group Ltd.

255
Chapter 14—Congenital Lung Anomalies
Fetal and postnatal lung development and growth
Normal growth period

Stage of microvascular maturation
Alveolar stage
Saccular stage
Canalicular stage
Pseudoglandular stage
Embryonic period
Lung development Lung growth
10 20 30 3 6 9 1 2 3 4 5 6 7
Weeks Months Years
Fertilization Birth Age
Figure 14‑2. Intrauterine stages of lung development. Airway branching is complete by the
end of the pseudoglandular phase (16 weeks after conception).
Reprinted from Zeltner TB, Burri PH. The postnatal development and growth of the human lung. II. Morphology.
Respir Physiol. 1987;67(3):269–282, with permission from Elsevier.
Laryngomalacia
See Chapter 13, Congenital Abnormalities of the Upper Airway, for a
discussion of laryngomalacia.
Tracheobronchial Abnormalities
Disorders of the large airways include tracheobronchomalacia, tracheomegaly,
and tracheal bronchus. Of these, tracheal bronchus, an aberrant lobar bronchus
arising above the carina, which supplies 1 or all 3 of the right upper lobe seg-
ments, is most common, occurring in up to about 2% of people (Figure 14‑3).4
In most instances, tracheal bronchus is a benign variant of no clinical signi-
ficance. However, if the orifice of the tracheal bronchus is small and easily
plugged, it can lead to recurrent right upper lobe atelectasis or infection.
Similarly, obstruction of the tracheal bronchus by an endotracheal tube
can lead to problems in patients requiring mechanical ventilation.

256
Figure 14‑3. Coronal oblique computed

tomography minimal intensity projection
reformat image demonstrating tracheal
takeoff of the right upper lobe bronchus
(tracheal bronchus).
Tracheomalacia refers to an excess in compliance of the airway that predis-

poses the trachea to dynamic collapse. Tracheomalacia and bronchomalacia
may be primary or secondary to other congenital anomalies. Mass lesions,
such as vascular rings and bronchogenic cysts, can cause indentation and
malacia of the developing tracheobronchial tree with resultant airway collapse
and shifts in intraluminal pressure during the respiratory cycle. Primary tra-
cheobronchomalacia occurs in about 1 in 2,000 infants and may be misdiag-
nosed initially as asthma.5,6 Because of the increased compliance, the malacic
airway is prone to narrowing during expiration when intrathoracic pressure
is increased. A wheeze caused by narrowing of a single large intrathoracic
airway during expiration differs from the wheezing of someone with asthma.
The child with asthma has many small airways involved, all to a differing
degree, such that the wheeze will be orchestral (polyphonic) and vary in pitch
and intensity during auscultation of different chest regions. The child with
tracheobronchomalacia has narrowing of a single large airway during expira-
tion (when pleural pressure exceeds intraluminal pressure), leading to a
monophonic wheeze that has the same characteristics throughout the chest.
In contrast to tracheomalacia, a fixed lesion causing constant large airway
narrowing that does not vary with changes in pleural pressure will cause
noisy breathing during inspiration and expiration. The diagnosis can often be
established by means of history and physical examination, but bronchoscopy
is the gold standard for diagnosis. More recently, multidetector 2-dimensional
and 3-dimensional computed tomography (CT) scans have been used to
demonstrate dynamic airway collapse and offer a noninvasive diagnostic
modality at the cost of increased exposure to ionizing radiation.
Common symptoms for tracheomalacia and bronchomalacia include a brassy
or barking cough, monophonic wheeze, noisy breathing, recurrent pulmonary
infections due to ineffective airway clearance, apnea, and episodes of pallor
and apnea (ie, “dying spells”).7 Treatment consists of supportive care, includ-
ing optimizing airway clearance, because dynamic collapse with cough may

257
lead to obstruction and infection. Use of bronchodilators such as albuterol

can cause further collapse owing to relaxation of supporting musculature.
Ipratropium bromide may help by decreasing airway secretions and increasing
airway tone. Tracheomalacia is often associated with congenital abnormalities
such as a tracheoesophageal fistula (TEF) or vascular ring and will not resolve
spontaneously; however, growth of the trachea leads to an increased lumen,
and a moderate degree of collapse will become less important over time.
Surgery is required in cases associated with other anomalies such as TEF.
In the case of primary tracheomalacia, surgery is reserved for the most severe
cases and generally consists of procedures that lift major vessels away from
the trachea or tether the trachea posteriorly.8
A much less common tracheal abnormality is tracheobronchomegaly,
known more familiarly as Mounier-Kuhn syndrome, which results from
absence or atrophy of elastic fibers and smooth muscle in the wall of the
airways. The loss of tracheal wall support leads to dilatation and develop-
ment of diverticula. Mounier-Kuhn syndrome has been seen in association
with other disorders of connective tissue, including Ehlers-Danlos syndrome
and cutis laxa.9 Mounier-Kuhn syndrome usually manifests in the third or
fourth decade of life, which has led to some debate as to whether it is a con-
genital or an acquired anomaly. The weakened and dilated walls of the large
airways collapse during forced exhalation (cough), decreasing mucociliary
clearance and increasing the probability of repeated infections.9 Involvement
of smaller, more peripheral airways will lead to bronchiectasis. Acquired
forms of tracheomegaly result from intubation and high-pressure ventilation
in neonates. Plain chest radiographs may lead to suspicion of the diagnosis,
but CT scanning with comparison to normal tracheal diameter for age is
necessary to establish the diagnosis. A CT scan is diagnostic if the trachea
is more than 3 SDs above mean reference values.10
Tracheoesophageal Fistula
Tracheoesophageal fistula is an early embryological defect in foregut differen-
tiation. The incidence of these malformations is approximately 1 in 3,000
births.11 The rate is increased in multiple birth pregnancies and white babies.
A genetic basis is plausible, and the reoccurrence rate is about 2% in children
of an affected parent. Most cases of TEF, however, are sporadic. Tracheo-
esophageal fistula can occur in association with chromosomal abnormalities
such as trisomies (18 and 21) and deletions of 22q11, and an increased inci-
dence occurs in DiGeorge syndrome, Pierre Robin syndrome, Holt-Oram
syndrome, and Feingold syndrome.

258
There are several types of TEF (Figure 14‑4). Esophageal atresia with distal
TEF accounts for 86% of cases. In this form, the proximal esophagus is dilated
and usually ends high in the mediastinum. The distal esophagus is usually
much smaller in diameter and usually communicates with the distal trachea
via a fistula to a point about 2 cm proximal to the carina (Figure 14‑4A). The
distance between the proximal pouch and distal esophagus can vary. Isolated
esophageal atresia without fistula accounts for 10% of cases. In this formation,
the proximal esophagus ends high in the posterior mediastinum. The distal
esophagus usually ends low in the mediastinum just above the diaphragm.
The distance between the 2 ends is substantial and usually does not allow for
a primary repair (Figure 14‑4E).
H-type TEF accounts for approximately 4% of cases. In H-type TEF, both
the esophagus and trachea are continuous cephalad to caudad, but there is
a fistulous connection between the 2 tubular structures. The fistula is very
narrow and usually is found in the lower cervical region. Usually there is a
single fistula, but multiple fistulas have been described (Figure 14‑4D).
The mechanism that underlies tracheoesophageal malformation is a subject
of intensive investigation. Formation of the trachea is a multistage process.
Initially, a groove forms in the posterior foregut, the sulcus laryngotrachealis,
then a septum separates the groove, thus forming the primitive trachea and
esophagus.3 Both genetic and environmental factors are likely to contribute
to developmental abnormalities affecting this separation and subsequent forma-
tion of a normal trachea and esophagus. Fifty percent or more of infants with
tracheoesophageal malformation have at least 1 other congenital abnormality.12
Esophageal atresia without a fistula has the highest incidence of associated
abnormalities, and H-type fistula has the lowest. Tracheoesophageal fistula
has been associated with a number of syndromes including the VATER asso-
ciation (vertebral, anorectal, tracheoesophageal, and renal or radial abnormali-
ties), VACTERL association (C cardiac, L limb), and the CHARGE association
(coloboma, heart defects, atresia [choanal], restricted growth and development,
genital hypoplasia, and ear deformities).
The classic presentation of a child with esophageal atresia is coughing, chok-
ing, and aspiration during the first feeding. These infants also have excessive
salivation because their saliva pools in the esophageal pouch. A plain radio-
graph of the chest is usually diagnostic and should show the tip of a nasogastric
catheter curled up in the upper pouch at the level of thoracic vertebrae. Associ-
ated findings on the radiograph provide insight into which type of malforma-
tion is present. If air is present in the stomach, a distal TEF is probable (Figure
14‑4C). Alternatively, the lack of gastrointestinal air suggests isolated atresia.
H-type fistulas may not manifest until a child is several months old and has
chronic coughing or choking with feeding and recurrent pneumonia. A

259
persistently distended abdomen caused by air migrating from the trachea

into the intestinal tract may also occur. The diagnosis is established by
performing a barium study with contrast material infused through a nasogas-
tric tube under gentle pressure to distend the esophagus in the distal to
proximal direction (Figure 14‑5).
A.
B.
C. D.
F.
E.
Figure 14‑4. Types of tracheoesophageal fistulas. A, Proximal esophageal pouch with distal
fistula. B, Proximal fistula with distal isolated esophagus. C, Disrupted esophagus with proximal
and distal fistula. D, H-type fistula. E, Esophageal atresia without fistula. F, Upper and lower
fistula without esophageal atresia.

260
Figure 14‑5. Lateral esophagram image

demonstrating H-type tracheoesophageal
fistula. Note the contrast in the distended
esophagus with contrast material crossing
across the fistula and outlining the trachea.
Surgical correction of the esophageal abnormality is mandatory. Preoperative

management is critical. A suction tube (Replogle catheter) should be placed in
the upper pouch to prevent aspiration. Likewise, the child should be positioned
upright to prevent reflux into the trachea through the distal fistula. Surgery
can normally be performed electively. The exception is when an infant with
a distal fistula is in severe respiratory distress requiring ventilatory support.
High-pressure gas delivered to the trachea can cross the fistula and may lead
to dangerous inflation of the stomach with possible gastric rupture. In such
cases, surgery should be performed emergently.
Most defects can be corrected in a single procedure. A number of strategies
have been developed to facilitate a primary anastomosis and ligation of the
fistula. In children with pure esophageal atresia, there may be a long gap
between the 2 esophageal remnants, necessitating a modified approach. Many
procedures have been developed to apply tension on the esophageal ends over
a period of 6 to 10 days to approximate the pouches and allow a primary
anastomosis. Rarely, patients require the placement of a large-bowel graft
known as colonic interposition.
Postoperative complications are common, including anastomosis leakage,
anastomotic stricture, and recurrent fistulas. Leaks occur in about 20%
of cases, and one-third of these events leads to a major disruption and may
require emergency surgery. Anastomotic strictures occur in about one-third
of patients who require dilation. Recurrent TEF occurs in about 10% of cases
and should be considered if the infant has respiratory symptoms during
feeding or has recurring pneumonia after initial corrective surgery.
Tracheoesophageal fistula is not simply an anatomical malformation manage-
able with corrective surgery. Residual postsurgical issues should be expected
because of the abnormal tracheal and esophageal development in utero.
Among these are gastroesophageal reflux, tracheomalacia, and esophageal
dysmotility. Long-term respiratory complications are common, with 40%
of patients having wheezing and brassy cough at 15 years of age.13,14 Tracheo-
malacia occurs in at least 15% of cases. Results from 2 long-term studies have
shown that respiratory morbidity and pulmonary function abnormalities are

261
common in children and adolescents after TEF repair. These studies’ results
have shown both obstructive and restrictive issues. Birth weight, interpouch
distance, and postoperative complications are important predictors of
longer-term outcomes.15,16
Pulmonary Agenesis or Hypoplasia

The most severe form of lung malformation is agenesis of both lungs. This
malformation is believed to be a result of loss of development of the trachea
or the main pulmonary arteries. Complete pulmonary agenesis is incompati-
ble with life. However, lesser degrees of agenesis, such as absence of 1 lung or
1 lobe, occur. Complete agenesis of the right lung carries a worse prognosis
than agenesis of the left lung because of greater displacement of the media-
stinum and heart, with increased torsion on the great vessels and remaining
bronchus. Pulmonary agenesis of single lobes is uncommon but when present
is predominantly a right-sided event, with the right upper lobe and right middle
affected together.17 Pulmonary agenesis is often associated with other congeni-
tal abnormalities, particularly cardiac defects, and a diagnosis of agenesis
should trigger a careful
assessment for other
somatic malformations.
Hypoplasia of the right
lung or agenesis of a
lobe therein with anoma-
lous pulmonary venous
blood flow to the inferior
vena cava is known as
scimitar syndrome, the
name deriving from the
curved, scimitar sword-
like appearance of the
vein descending through
the diaphragm to the vena
cava (Figure 14‑6). This
syndrome may manifest
with a variety of vascular
anomalies, including sys-
temic arterial supply to the
right lower lobe, agenesis
Figure 14‑6. Scimitar syndrome (hypoplastic lung with of the right pulmonary
partial anomalous venous return). Frontal chest radiograph artery, and congenital
showing that the right lung is smaller than the left, resulting
in rightward mediastinal deviation, and a large anomalous heart defects. Two forms,
pulmonary vein (arrowheads) draining the right lung to the infantile and adult, have
subdiaphragmatic inferior vena cava.

262
been reported, the distinction based on age of manifestation. The infantile

form is diagnosed in the first months after birth and is associated with more
severe cardiac defects or congestive heart failure due to high output failure
through the systemic vessels feeding the right lung, whereas the adult form
with pulmonary hypoplasia and aberrant venous drainage may be asymptom-
atic and only discovered serendipitously.18,19 Immediate attention to the
underlying cardiac problems is essential with manifestation in the newborn
period. Older children or adults in whom the scimitar syndrome is diagnosed
as an incidental finding may not require any intervention at all.
Generalized pulmonary hypoplasia is more common than agenesis of a
single lung or lobe. It is associated with a variety of intrauterine insults,
including (1) hydrops fetalis; (2) renal anomalies; (3) hernia, including dia-
phragmatic hernia and omphalocele; (4) skeletal anomalies; and (5) amniotic
fluid abnormalities, particularly oligohydramnios.20 Mild pulmonary hypo-
plasia may cause tachypnea without serious associated lung disease, which
may improve over time as the lungs achieve “catch-up” growth. More severe
pulmonary hypoplasia may necessitate aggressive ventilatory support in the
newborn period.
Of particular interest is the association between amniotic fluid abnormalities
and pulmonary hypoplasia. Abnormalities that result in reduced or absent
urine formation (renal agenesis) or oligohydramnios (eg, premature rupture
of membranes) lead to physical restriction of fetal breathing movements
and limited chest wall development. The earlier in gestation these problems
occur, the more severe the pulmonary hypoplasia. Premature rupture of
membranes late in pregnancy may have little or no effect on pulmonary
function, whereas extremely early rupture of membranes will result in severe
pulmonary compromise. The degree of pulmonary hypoplasia depends on the
degree of oligohydramnios, its duration, and the gestational age (stage of lung
development) at which it occurs. The most severe form of oligohydramnios and
pulmonary hypoplasia is Potter syndrome, named for Edith Potter who in 1946
described the association of renal agenesis, unusual flattened facies, talipes,
intrauterine growth restriction, and pulmonary hypoplasia.21
Bronchogenic Cysts
Bronchogenic cysts are the most common cysts of infancy, accounting for
about 5% of mediastinal masses in infants and children. These are foregut-
derived cystic malformations of the respiratory tract, usually located within
the mediastinum if formed in an early stage of development or in the lung
parenchyma if formed at a later stage. However, they can be in ectopic
locations anywhere along the developmental pathway of the foregut.

263
Many bronchogenic cysts remain asymptomatic and are detected only

incidentally later in life, so the true incidence of these cysts is unknown.
Bronchogenic cysts are formed when a piece of bronchial tissue separates
from the developing airway. In most cases there is no connection between the
bronchogenic cyst and the normal airway, but such a connection can occur and
may lead to chronic, recurrent infection of the cyst.22 There is overlap between
bronchogenic and esophageal cysts, given that both are anomalies in foregut
differentiation. A cleft develops between the developing trachea and esopha-
gus at approximately day 28 after conception. Anomalies in budding around
this time can result in cysts with both bronchial and esophageal characteris-
tics. Generally, bronchogenic cysts are thin walled and lined with ciliated
respiratory epithelium. The cysts may contain mucoid material and frequently
have cartilage in their walls (Figure 14‑7).
Bronchogenic cysts may be asymptomatic, be minimally symptomatic, or
cause extreme respiratory distress. The degree of symptoms depends on the
location and size of the cyst. Infants have compressible tracheobronchial
cartilage, and a space-occupying lesion in the peritracheal area will cause
airway narrowing and noisy breathing. Compression of the esophagus can
lead to concomitant feeding problems. More peripheral bronchogenic cysts
will cause fewer symptoms but may cause recurrent infections, especially if
there is communication with the bronchial tree. Rare cases of compression
of vascular structures, including coronary arteries, have been reported.23
Bronchogenic cysts do not have a known association with other congenital
malformations but may be seen in conjunction with other malformations of
lung development. Diagnosis is generally established by means of a barium
esophagram or CT scan of the chest (Figure 14‑7A and B).
Therapy for a bronchogenic cyst that is causing symptoms consists of surgical
removal of the cyst. Therapy for asymptomatic cysts, often detected inciden-
tally, is less clear. Many experts believe that surgical resection of asymptom-
atic cysts is indicated for pathological examination because there is a chance
that the cyst may cause future symptoms, including infection and hemorrhage,
and that the lesion poses an inherent oncogenic risk. There have been several
case reports of different types of cancer being detected within bronchogenic
cysts, including large cell carcinoma, bronchoalveolar carcinoma, and carci-
noid tumor.24–27 Other experts believe that not all mediastinal cysts need to
be treated surgically, citing concerns regarding the reliability of some of
the reports of malignant transformation and putting into perspective the low
incidence of malignancies in simple cysts.28 A definitive answer to the ques-
tion of what to do with a bronchogenic cyst is not available because of the
rarity of the lesion and the reports of only small series of patients. At present,
surgical excision remains the most common way to deal with these lesions.

264
Figure 14‑7. A, Frontal esophagram image

demonstrating compression of the esophagus
by a bronchogenic cyst. B, Axial computed
tomography image showing the bronchogenic
cyst (BC) compressing the trachea (T) and
esophagus (E). C, Photomicrograph of a
bronchogenic cyst demonstrating cartilage
(black arrow) in the cyst wall with lung
remnants (blue arrow) within the cyst.
Congenital Pulmonary Airway Malformation

Congenital pulmonary airway malformations consist of a group of lesions
previously known as congenital cystic adenomatoid malformations. Congeni-
tal pulmonary airway malformations are characterized by the hamartomatous
proliferation of terminal respiratory bronchioles forming a multicystic lung
mass. The incidence of CPAM is not well known and has been described
as being as rare as 1 in 27,000 live births and as common as 1 in 7,200 live
births.29 Congenital pulmonary airway malformation is one of the most com-
mon lung lesions diagnosed prenatally. It is usually sporadic and isolated with
no familial recurrence. The genetic causes of CPAM are not known, but a
number of different genes and promoters have been implicated.30
Congenital pulmonary airway malformations are thought to be an overgrowth
of bronchi at various stages in lung development. The size of the cyst offers
insight into the pathogenesis. When known as congenital cystic adenomatoid
malformations, these malformations were classified by Stocker et al31 into
3 histological types.
X Type I, the most common form, is composed of variable-sized cysts, with
at least 1 dominant cyst greater than 2 cm in diameter.
X Type II contains multiple cysts less than 2 cm in diameter and forms a
smaller fraction of cases.
X Type III is the solid, adenomatoid form and is a rarer manifestation.

265
The CPAM designation has been broadened to include types 0 through IV,32
similar to the original description with the addition of a type 0 defect, which is
acinar dysplasia, and type IV, which is an unlined cystic lesion. Type I is thought
to arise from bronchial overgrowth, type II is bronchiolar in origin, type III is
bronchiolar or alveolar in origin, and type IV is distal acinar in origin.
Congenital pulmonary airway malformations are rare. These lesions are almost
always unilateral, although bilateral lesions occur in approximately 10% of cases.
They affect the left and right sides equally. Associations with other congenital
malformations have been described, in particular with congenital heart disease
and congenital diaphragmatic hernia (CDH).
In the era of near-universal prenatal ultrasonographic examinations, CPAMs
are increasingly recognized prenatally. There are reports of regression of these
masses at sequential examinations and near disappearance at birth. However,
residual small masses of abnormal tissue may be detectable on postnatal chest CT
scans. In addition, they may manifest as an incidental finding, as an unresolving
pneumonia, or as pneumothorax later in life. Congenital pulmonary airway
malformations have to be differentiated from other cystic-appearing lesions,
including diaphragmatic hernia, cystic hygroma, bronchogenic and enteric cysts,
bronchopulmonary sequestration, and pleuropulmonary blastoma (PPB). Pleuro-
pulmonary blastoma is a malignancy that may be indistinguishable from CPAM
on radiographic studies; however, a genetic predisposition and a family history of
malignancy are often present in patients with PPB and help identify the at-risk
population.33 Pleuropulmonary blastoma is less likely than CPAM to be detected
with prenatal ultrasonography and is associated with the DICER1 family of
neoplasms. Genetic testing for DICER1 mutations can help differentiate PPB
from CPAM preoperatively.34 However, differentiation of CPAM from PPB may
only be possible at pathological examination after resection.
Overall, the prognosis of prenatal CPAMs is based on size and growth charac
teristics. Seventy percent resolve or decrease in size before birth, 10% remain
unchanged, and 20% increase in size. About 10% of infants with a prenatal
diagnosis of CPAM develop hydrops fetalis and have a poor outcome. There
is no doubt that infants with symptoms and large lesions should undergo
surgical resection. However, there is no simple answer as to the approach to
asymptomatic CPAM. The lifelong risk of infection and malignant transfor-
mation is not known with certainty. Many think that removal before compli-
cations occur is the most prudent approach, but others think that performing
what may be unnecessary surgery is not warranted. In the past, it has been
argued that the denominator—the number of people with asymptomatic
CPAM that never came to light—was unknown, but that is changing as
universal prenatal ultrasonography is adopted. Risk of malignancy is greatest
in type I and type IV CPAMs, and PPB should be removed, which has led to
a greater tendency to remove masses of uncertain tissue type early in life to

266
avoid later complications or malignancy. If the child does not have symp-
toms, surgery can be delayed until the child is older (larger) and the
surgery is easier and better tolerated.
The mortality with CPAM with hydrops if left untreated approaches 100%
and is an indication for fetal intervention. The approach depends on the type
of lesion. In those in which there is a dominant cyst, hydrops may respond
to cyst aspiration and, if it recurs, to thoracoamniotic shunt placement. In a
solid type of CPAM, open fetal surgery for resection of the CPAM may be
indicated. The survival rate of such surgeries is 61%.35 A report of prenatal
sclerotherapy showed 50% survival in a cohort of 8 patients.36
Congenital Lobar Emphysema

Strictly speaking, the term congenital lobar emphysema (CLE) is a misnomer,
and this condition is better referred to as an infantile large, hyperlucent lobe or
congenital lobar overexpansion. (See Figure 14-8). The exact cause of this
lesion remains obscure. The lung parenchyma is not truly emphysematous
because there is no destruction of alveolar walls, nor is the condition uniformly
present antenatally, although it likely has its
origins in a prenatal condition. Abnormalities of
the bronchi leading to partial obstruction or
collapse at expiration, with a resultant ball-valve
effect and air or amniotic fluid trapping in the
peripheral lung, are often invoked as a causative
feature, but, in fact, such bronchial defects are
identified in no more than one-third of children
with CLE.37,38 Microscopic evaluation of excised
lobar emphysema tissue shows 1 of 2 patterns.
In classic CLE, there is a hyperexpanded lobe
with a normal number of enlarged alveoli. In
about 30% of cases, CLE manifests with a
polyalveolar lobe, which consists of an enlarged
lobe containing many more than the normal
number of alveoli.38,39 Congenital lobar emphy-
sema most frequently affects the left upper lobe,
followed by the right middle lobe and right
upper lobe.37,38 The lower lobes are rarely
involved. Multiple lobes may be enlarged, but it
Figure 14‑8. Axial and coronal
is extremely unusual to have bilateral lesions.
computed tomography images in
lung window show hyperlucency Clinically, CLE manifests in the immediate
of the left upper lobe with
oligemia in a child with congenital
newborn period in most cases, with symptoms
lobar emphysema. typical of a space-occupying mass: tachypnea,
Courtesy of Mariangeles Medina dyspnea, decreased breath sounds on the
Perez, MD. affected side, and wheezing. More than

267
one-half of all cases manifest in the first week after birth because of respira-
tory distress, and more than 80% will manifest by 6 months of age. Occasion-
ally, a child will not have symptoms, and CLE will be diagnosed incidentally
when a chest radiograph is obtained for an unrelated reason. In the newborn
period, CLE may resemble neonatal pneumothorax or CPAM. The lesion may
manifest as a fluid-filled mass that then becomes hyperlucent as retained fetal
lung liquid is cleared. Delayed clearance of lung fluid is most common in the
polyalveolar form of CLE.38,39 In older children, the differential diagnosis
should include foreign body aspiration with postobstructive hyperinflation.
Radiographic studies show hyperinflation of a lobe with compression of the
ipsilateral lung and herniation of the emphysematous lung across the anterior
mediastinum. The contralateral lung may be
compressed and atelectatic due to the mass
effect of the hyperinflated lung. The diagnosis
depends on being able to recognize which
lung is abnormal. The small lung may be
hypoplastic or atelectatic with compensatory
hyperinflation of the other normal lung.
Alternately, the large lung may be emphysem-
atous with corresponding compression of the
Figure 14‑9. Axial computed
tomography image obtained with a
smaller lung. Although this distinction is not
lung window showing hyperlucen- always easy, CT or ventilation/perfusion
cy and decreased lung markings in scans can be helpful in distinguishing the
the right lower lobe lesion. healthy from the affected lung (Figure 14‑9).
With the increased use of prenatal ultrasonography and fetal magnetic
resonance imaging (MRI), there has been an increase in detecting CLE
during fetal life. Follow-up shows spontaneous resolution in some cases,
although postpartum symptoms may occur even in children whose lesions
seem to have disappeared before birth.40 Knowing that CLE can regress
spontaneously has led to a more conservative management approach. Previ-
ously, it was thought that, once detected, an emphysematous lobe must be
removed to relieve respiratory distress and to allow the healthy lobes to grow
normally. Surgery remains the treatment of choice for the child with severe
respiratory distress; however, it is increasingly apparent that infants with mild
to moderate symptoms can be treated medically. Some infants with symptoms
at birth do not require surgery.41
Congenital Diaphragmatic Hernia

Congenital diaphragmatic hernia (Figure 14-10) is a major congenital defect,
and the classic hernia, Bochdalek hernia, is through a posterolateral defect in
the diaphragm. Investigators in a 2003 population-based study from Atlanta
place the incidence at approximately 2.4 per 10,000 live births,42 with in-
creased frequency in premature and male neonates. Eighty percent of CDHs

268
are on the left side, and 20% are on the right side.
The expected recurrence risk in a first-degree
relative is slightly greater than 2%. At present, a
genetic cause can be identified in only approxi-
mately 30% of cases. The ability to identify more
genetic determinants of CDH could have
far-reaching implications for prenatal diagnosis
and treatment.43 The incidence of associated ab-
normalities is about 30%, with skeletal and car-
diac abnormalities being the most common.44,45
Figure 14‑10. Frontal chest Cardiac malformations tend to affect the outflow
radiograph shows indistinct tracts and include tetralogy of Fallot and transpo-
left hemidiaphragm with
partial opacification of the left sition of the great vessels. Congenital diaphrag-
hemithorax by multiple matic hernia occurs in the context of a number of
air-filled bowel loops. There is syndromes, including trisomies 21, 18, and 13;
mass effect on the mediasti-
Fryns syndrome; Beckwith-Wiedemann syn-
num, which is shifted towards
the right side. drome; and Goldenhar syndrome.
The pathophysiological nature of CDH is complex.
Courtesy of Mariangeles Medina
Perez, MD.
The diaphragm is formed in 2 stages. The septum
transversum forms from the area of the inferior
portion of the pericardial cavity. This septum separates the peritoneal and
thoracic cavities and ultimately forms the central tendon. However, lateral
foramina persist and are called pleuroperitoneal canals. Normally, these
canals are closed by pleuroperitoneal membranes. It is through these canals
that the usual Bochdalek hernia protrudes. The left-sided hernia may
contain stomach, small bowel, spleen, and even kidney.
The hernia is covered by a membrane in 10% of cases. The extension of the
abdominal viscera into the thoracic cavity results in clinically significant lung
hypoplasia by virtue of the space-occupying effect. If the hernia occurs before
16 weeks of gestation, there will be a reduction in the number of bronchial
branches. Whether early or late, the hernia decreases acinar development of
both the ipsilateral and contralateral lung, and thus gas-exchange surface
area is reduced. Vascular abnormalities are striking, with reduced numbers
of pulmonary arterial branches and muscular thickening of the arteries.
These vascular abnormalities increase the risk of the affected infant having
pulmonary hypertension and developing persistent fetal circulation.
The diagnosis of CDH is considered when respiratory distress occurs at birth.
The degree of distress depends on the degree of pulmonary hypertension and
hypoplasia. In infants in whom a great deal of abdominal viscera is displaced
into the thorax, the abdomen is flat (scaphoid) and there is asymmetrical dis-
tention of the chest. Respiratory distress may increase as the gastrointestinal

269
tract fills with swallowed air. The presence of bowel sounds over the thorax
and the absence of breath sounds on the affected side are frequently described.
The diagnosis is often determined during a routine prenatal ultrasonographic
examination. Ultrasonography can depict CDHs as early as 12 weeks of ges-
tation, but they are usually found at 24 weeks of gestation. The severity of
CDH can be estimated prenatally by using observed-to-expected lung–head
ratios (at ultrasonography) and total fetal lung volumes (at MRI).46 Polyhy-
dramnios is reported in 75% of cases. After birth, the diagnosis is confirmed
by means of plain chest radiography. Common findings are bowel in the chest
cavity and deviation of the mediastinum. The diagnosis is usually obvious,
but other diagnoses should be considered, including congenital cystic disease
of the lung and agenesis of the lung. Once the diagnosis is confirmed, it is
important to screen for associated anomalies by using echocardiography
and ultrasonography of the head and kidneys.
Early therapy is directed at improving respiratory status. Although defects
in surfactant have been described, a role for prenatal steroid therapy or
surfactant administration at birth has not been established.47,48 Fetal surgery
to enhance lung development is no longer used because recent study results
demonstrated no benefit.49 Initial resuscitation should involve endotracheal
intubation and placement of a nasogastric tube to abrogate expansion of
the stomach and small bowel by swallowed air. Once intubation has been
performed, mechanical ventilation is used as a bridge to surgical repair. A
number of ventilatory strategies can keep the preductal arterial Po2 greater
than 60 mm Hg, including varying from high rates with low positive end-
expiratory pressure to lower rates with higher positive end-expiratory pres-
sure. Central to most strategies is the use of pressure-cycled ventilators
with strict monitoring of tidal volume and preductal oxygen saturations.
The need for extensive support suggests that lung hypoplasia or pulmonary
hypertension is substantial. A number of indices have been established to
quantify this support and thus help predict ultimate outcome. These indexes
include a ventilatory index and an oxygenation index. High-frequency oscilla-
tory ventilation has been used with success, but results from a 2016 study
showed similar rates of mortality and morbidity between use of conventional
mechanical ventilation and use of high-frequency oscillatory ventilation.50
This latter therapy should be considered in patients in whom conventional
mechanical ventilation fails. Nitric oxide is a successful therapy for pulmo-
nary artery hypertension, but in children with CDH, the results are mixed;
however, a therapeutic trial is appropriate when pulmonary artery hyper-
tension is clinically significant.51 Extracorporeal membrane oxygenation
is indicated if conventional or high-frequency oscillatory ventilation and
nitric oxide therapies are not beneficial.

270
Surgery for CDH is no longer considered an emergency intervention. Results

from 2 randomized controlled trials did not demonstrate an advantage to either
early or late repair.52,53 With advances in intensive care medicine, surgery can
be elective, allowing for appropriate time to look for other congenital abnor-
malities that may alter the surgical approach. If the diaphragmatic defect is
large, it may be closed with a prosthetic patch or a local flap from the chest
wall or abdominal wall. The abdominal cavity may be hypoplastic due to
relocation of the bowel into the thorax during development. With return of the
viscera, it may not be possible to close the abdomen. In these cases, the skin is
approximated, and after a few months, the abdominal wall defect can be
closed. The minimally invasive surgery approach for CDH repair is gaining
acceptance in selective cases. Minimally invasive surgery was associated with
decreased length of stay and incidence of small-bowel obstruction but higher
recurrence rates.54
Outcomes of CDH have improved dramatically in recent years, and survival
rates of 80% to 90% are frequently described.55 Pulmonary function test
results are frequently abnormal but improve over time; at long-term follow-up,
50% of patients had normal lung function by 10 years of age.56 Increased
bronchial reactivity, as demonstrated by wheezing with respiratory tract
infections, can be a persistent problem. Neurodevelopmental abnormalities are
common, particularly when extracorporeal membrane oxygenation has been
used. In addition, gastroesophageal reflux is frequently seen and needs to be
addressed medically.
The Morgagni hernia is a less common form of CDH. This hernia occurs at
either side of the midline just behind the sternum, where the septum transver-
sum joins the chest wall. Occasionally, these hernias are bilateral and give
rise to a large central defect. Morgagni hernias are rarely symptomatic and
can manifest at any age. These hernias may be associated with other abnor-
malities, particularly malrotation of the gut. Operative repair is relatively
straightforward via a transverse upper abdominal incision, where the dia-
phragm is attached to the posterior rectal sheath. These hernias may also
be manageable with laparoscopic and thoracoscopic approaches.
Eventration of the diaphragm is another frequently seen diaphragmatic defect.57
In congenital eventration, there is a thin, membranous diaphragm with some
protrusion into the thoracic cavity. Although usually benign, a large eventra-
tion may manifest with symptoms similar to those of CDH. In the acquired
form, the phrenic nerve is paralyzed owing to either birth trauma or surgical
trauma. The distribution of the muscle fibers in the diaphragm is normal in
the acquired form; however, in the congenital form, the muscle is distributed
around the rim of the diaphragm. Generally, eventrations are identified as an
incidental finding or because of mild respiratory symptoms during respira-
tory tract infections. Occasionally, there is intolerance of rigorous exercise.

271
The diagnosis is confirmed with fluoroscopy of the chest. At fluoroscopy,

there is paradoxical movement, with the diaphragm on the affected side
rising during inspiration. Most eventrations are small, and surgical repair
is not necessary. When the defect is large or symptomatic, plication of the
thinned-out diaphragm can optimize lung growth and development.
Pulmonary Sequestration
Of all the lesions discussed in this chapter, pulmonary sequestration is
perhaps the most complex, least clear, and most controversial in terminol-
ogy, origin, and description. Classic extralobar pulmonary sequestration
consists of an isolated segment of lung tissue with no connection to the
tracheobronchial tree, invested in its own pleura, fed by a systemic artery,
and drained via a systemic vein.58 However, pulmonary sequestration is
often associated with multiple variants of this schema and may be seen in
combination with other pulmonary anomalies, such as CPAM, bronchogenic
cyst, and scimitar syndrome.59 Intralobar sequestration was initially thought
to be an acquired lesion consisting of neovascularization via a systemic
artery to an area of chronically inflamed lung parenchyma (generally caused
by recurrent infection). However, intralobar sequestration can be a congeni-
tal problem unrelated to recurrent infection.
According to the malinosculation classification of Clements and Warner,1
pulmonary sequestration can be seen as a spectrum of diseases and can
involve any or all 4 of the major components of lung tissue: airways, arterial
blood supply, venous drainage, and lung parenchyma. Thus, in classic extra-
lobar sequestration, all 4 components are abnormal, whereas in intralobar
sequestration, the arterial blood supply may be the only abnormality, although
pulmonary disease is generally also present. Given the myriad variations of
sequestration, and given the frequent association with other intrapulmonary
lesions, some experts believe a more proper name for pulmonary sequestra-
tion is congenital bronchopulmonary foregut malformation. The more specific
term is used with the understanding that each lesion has its own variations
and associated anomalies.
Extralobar sequestrations of the lung are predominantly on the left side (65%)
and are usually found between the lower lobe and the diaphragm, but they
can be located anywhere in the thorax and occasionally even subdiaphrag-
matically.57 Blood supply is directly from the thoracic or abdominal aorta in
80% of cases and arises from branches of smaller systemic vessels in the
remainder. Venous drainage is generally to the right atrium, creating a left-
to-right shunt. On cut sections, the sequestrum contains irregularly formed
bronchi, alveolar ducts, and alveoli and may even have cystic elements,
confirming the maldevelopment of lung parenchyma in addition to the
airway and blood vessel abnormalities.

272
Extralobar sequestrations appear as triangular opacities and can be seen on chest

radiographs in the retrocardiac area. Computed tomography angiography and
magnetic resonance angiography allow for much better characterization of the
lesions and frequently demonstrate the abnormal systemic blood supply to the
area.60,61 However, feeder vessels may not be visible if their diameter is below the
scanning technique’s limit of resolution. Resolution is improved in the current
generation of CT scanners and postprocessing workstations, which allows
visualization of even small aortic branches. Any imaging study should be
performed with contrast enhancement to elucidate feeding vessels better.
Extralobar sequestrations may be incidental findings consisting of a retrocardiac
mass on a chest radiograph obtained for other reasons, may manifest as respira-
tory distress in the newborn period, or may become infected at some time after
the newborn period. Infection is generally due to hematogenous spread of
bacteria unless there is a connection to a bronchus or to the esophagus. Repeat
infection or abscess formation may occur and is an indication for surgical
resection. Tachypnea in the newborn period may be due to mass effect,
high-output cardiac failure, or associated cardiac or pulmonary congenital
defects. Treatment for an extralobar sequestration is usually surgical removal,
given the need to confirm the lesion histologically, prevent future infection or
bleeding, and allow for normal lung growth. Treatment with arterial emboliza-
tion and recognition of spontaneous involution of some lesions have led to
questioning the need for surgery in all cases.62,63
Vascular Rings
Vascular rings are a wide spectrum of abnormalities that frequently include the
aortic arch, pulmonary arteries, and brachiocephalic vessels. Most infants with
vascular rings do not have symptoms, but if symptoms arise they relate to the
degree of compression of the respiratory and gastrointestinal tracts. If vascular
rings cause symptoms, they manifest in the first few months after birth in most
infants. Symptoms can be variable, including stridor, arching of the neck,
unusual postures during sleep, a brassy or seal-like cough, and apnea. These
symptoms are not unique to vascular rings and, accordingly, infants with rings
frequently initially receive a diagnosis of esophageal reflux, laryngotracheom-
alacia, or reactive airways disease. Dysphagia occurs when the child transitions
to solid foods if constriction of the esophagus is severe, and an infant may refuse
solid foods. Dysphagia can manifest later in life when the arteries calcify.
The overall incidence of vascular rings is unknown, given that many may remain
asymptomatic and go undiagnosed, but they are thought to constitute 1% to 2%
of congenital heart defects. Vascular rings are classified into complete rings,
incomplete rings, and pulmonary slings. These vascular abnormalities usually
occur in isolation, but 10% to 15% are associated with congenital heart disease.64

273
There are a number of types of complete rings, including a double aortic arch
and right arch with the ring formed by ligamentum arteriosum, ductus arterio-
sus, or aberrant left subclavian branching. A double aortic arch occurs when
the right dorsal aortic arch does not
regress. Thus, the 2 arches encircle
the trachea and the esophagus
RS (Figure 14‑11, Figure 14-12). The
LS right arch is predominant in about
RCC
75% of cases. This form usually
LCC manifests in infancy and is
confirmed by means of echocardi-
LD ography and CT scanning.
Although MRI is superior for
RPA vascular imaging, it has a long
scanning time and requires
sedation, making CT scanning a
more appropriate choice for
infants. Surgery is indicated when
the child has symptoms. Surgery
involves ligation of the nondomi-
nant arch while preserving
brachiocephalic blood flow. There
is often associated tracheomalacia
from in utero compression of the
trachea, and many infants have
Figure 14‑11. Double aortic arch encircling the
trachea and esophagus. persistent respiratory symptoms
Abbreviations: LCC, left common carotid artery; LD, after surgery.
ligamentum arteriosum; LS, left subclavian artery; RPA, right
pulmonary artery; RS, right subclavian artery.
Figure 14‑12. Axial computed tomography

angiography shows symmetric double aortic
arch surrounding the trachea and thoracic
esophagus.

274
A right-sided aortic arch may occur in isolation or may form part of a ring. In
one ring formation (Figure 14‑13), the right arch traces around the back of the
esophagus, and there is an aberrant left subclavian artery from the descend-
ing aorta. The ring is closed by the ligamentum arteriosum, which bridges the
pulmonary artery and the left subclavian artery. In another form of right-sided
arch ring, called mirror imaging, an aberrant left innominate artery reaches
across the front of the trachea. The arch still traces behind the aorta, and the
ring is completed by the ligamentum arteriosum arising from the descending
aorta rather than the aberrant subclavian artery to the pulmonary artery. Another
form of vascular ring maintains a less complete ring in which the ligamentum
arteriosum arises from the mirror image left subclavian or innominate artery
to the pulmonary artery. These arches may be complicated by a Kommerell
diverticulum at the site where the ligamentum arteriosum joins the aorta.
Surgery is generally necessary if the vascular anomaly is causing symptoms
such as noisy breathing or dysphagia. It involves ligation of the ligamentum
arteriosum. If a Kommerell diverticulum is present, then a resection or
aortopexy surgery may
be required.
Incomplete vascular LS
rings do not form closed, RS
constricting lesions but
may still impinge on the RCC LCC
airway or esophagus. LDAR
Anomalous innominate Innom
A
LD
artery compression is LPA
considered to exist if the
artery arises from the
LS
aortic arch to the left of
midline and causes
tracheal compression.
Usually this causes no or LCC
mild symptoms, and no
surgery is indicated.
Only when symptoms
are severe should
PT
surgery be considered
because, in most
untreated cases, symp-
toms ameliorate over Figure 14‑13. Isolated right aortic arch with ductus arteriosus
time. Another simple arising from diverticulum of Kommerell.
ring involves an aber- Abbreviations: Innom A, innominate artery; LCC, left common carotid artery;
LD, ligamentum arteriosum; LDAR, left dorsal aortic root (diverticulum of
rant right subclavian Kommerell); LPA, left pulmonary artery; LS, left subclavian artery; RCC, right
artery. It arises from the common carotid artery; RS, right subclavian artery.

275
descending aorta and traces

behind the esophagus. It rarely
LS causes symptoms but can be
RS associated with feeding problems.
RCC LCC
Pulmonary slings are an unusual
form of vascular compression. In
To left
this condition, the left pulmonary
lung artery arises from the right
pulmonary artery and travels
RPA between the trachea and esopha-
gus (Figure 14‑14). Pulmonary
slings are associated with
PT
complete tracheal rings and
tracheal stenosis in about
one-third of cases.65 Surgery is
usually indicated and may involve
tracheal reconstruction. Gener-
ally, the long-term prognosis after
surgical correction is favorable.
However, after surgery, there is
usually some tra-cheomalacia
that results in a lingering cough
Figure 14‑14. Pulmonary sling. The left pulmonary and noisy breathing, which
artery arises from the right pulmonary artery and should improve in time.
courses behind the trachea and in front of the
esophagus.
Abbreviations: LCC, left common carotid artery; LS, left
subclavian artery; RCC, right common carotid artery; RPA,
right pulmonary artery; RS, right subclavian artery.
key points
} Pulmonary congenital malformations arise from errors in fetal lung develop-
ment.
} Pulmonary malformations can involve the airways, pulmonary parenchyma,
blood vessels, or any combination of the 3.
} Lung abnormalities that arise from developmental issues before 16 weeks of
gestation affect airway development; those that arise after 16 weeks affect
acinar development.
} Some pulmonary lesions detected by means of prenatal ultrasonography
resolve spontaneously.
} Symptomatic congenital pulmonary abnormalities require surgical intervention.
} Although there have been reports of malignant transformation within some of
these lesions, the absolute risk of cancer associated with congenital lung
malformations is unknown.

276
References
1. Clements BS, Warner JO. Pulmonary sequestration and related congenital bronchopulmonary-
vascular malformations: nomenclature and classification based on anatomical and embryological
considerations. Thorax. 1987;42(6):401–408 PMID: 3660297 doi: 10.1136/thx.42.6.401
2. Cardoso WV, Lü J. Regulation of early lung morphogenesis: questions, facts and controversies.
Development. 2006;133(9):1611–1624 PMID: 16613830 doi: 10.1242/dev.02310
3. Kinane TB. Lung development and implications for hypoplasia found in congenital
diaphragmatic hernia. Am J Med Genet C Semin Med Genet. 2007;145C(2):117–124
PMID: 17436303 doi: 10.1002/ajmg.c.30124
4. O’Sullivan BP, Frassica JJ, Rayder SM. Tracheal bronchus: a cause of prolonged atelectasis in
intubated children. Chest. 1998;113(2):537–540 PMID: 9498980 doi: 10.1378/chest.113.2.537
5. Finder JD. Primary bronchomalacia in infants and children. J Pediatr. 1997;130(1):59–66
PMID: 9003852 doi: 10.1016/S0022-3476(97)70311-1
6. Boogaard R, Huijsmans SH, Pijnenburg MW, Tiddens HA, de Jongste JC, Merkus PJ.
Tracheomalacia and bronchomalacia in children: incidence and patient characteristics. Chest.
2005;128(5):3391–3397 PMID: 16304290 doi: 10.1378/chest.128.5.3391
7. Wallis C, Alexopoulou E, Antón-Pacheco JL, et al. ERS statement on tracheomalacia
and bronchomalacia in children. Eur Respir J. 2019;54(3):1900382 PMID: 31320455
doi: 10.1183/13993003.00382-2019
8. Panitch HB, Keklikian EN, Motley RA, Wolfson MR, Schidlow DV. Effect of altering smooth
muscle tone on maximal expiratory flows in patients with tracheomalacia. Pediatr Pulmonol.
1990;9(3):170–176 PMID: 1980538 doi: 10.1002/ppul.1950090309
9. Benesch M, Eber E, Pfleger A, Zach MS. Recurrent lower respiratory tract infections
in a 14-year-old boy with tracheobronchomegaly (Mounier-Kuhn syndrome).
Pediatr Pulmonol. 2000;29(6):476–479 PMID: 10821730
doi: 10.1002/(SICI)1099-0496(200006)29:6<476::AID-PPUL10>3.0.CO;2-R
10. Griscom NT, Wohl MEB. Dimensions of the growing trachea related to age and gender.
AJR Am J Roentgenol. 1986;146(2):233–237 PMID: 3484568 doi: 10.2214/ajr.146.2.233
11. Torfs CP, Curry CJ, Bateson TF. Population-based study of tracheoesophageal fistula and
esophageal atresia. Teratology. 1995;52(4):220–232 PMID: 8838292
doi: 10.1002/tera.1420520408
12. Spitz L. Oesophageal atresia. Orphanet J Rare Dis. 2007;2(1):24 PMID: 17498283
doi: 10.1186/1750-1172-2-24
13. Kovesi T, Rubin S. Long-term complications of congenital esophageal atresia and/or
tracheoesophageal fistula. Chest. 2004;126(3):915–925 PMID: 15364774
doi: 10.1378/chest.126.3.915
14. Malmström K, Lohi J, Lindahl H, et al. Longitudinal follow-up of bronchial inflammation,
respiratory symptoms, and pulmonary function in adolescents after repair of esophageal
atresia with tracheoesophageal fistula. J Pediatr. 2008;153(3):396–401 PMID: 18534205
doi: 10.1016/j.jpeds.2008.03.034
15. Ditrich R, Stock P, Rothe K, Degenhardt P. Pulmonary outcome of esophageal atresia patients
and its potential causes in early childhood. J Pediatr Surg. 2017;52(8):1255–1259
PMID: 28094013 doi: 10.1016/j.jpedsurg.2016.12.025
16. Donoso F, Hedenström H, Malinovschi A, Lilja HE. Pulmonary function in children and
adolescents after esophageal atresia repair. Pediatr Pulmonol. 2020;55(1):206–213
PMID: 31535483 doi: 10.1002/ppul.24517
17. Felson B. Pulmonary agenesis and related anomalies. Semin Roentgenol. 1972;7(1):17–30
PMID: 5056777 doi: 10.1016/0037-198X(72)90027-2
18. Dupuis C, Charaf LAC, Brevière GM, Abou P, Rémy-Jardin M, Helmius G. The “adult”
form of the scimitar syndrome. Am J Cardiol. 1992;70(4):502–507 PMID: 1642189
doi: 10.1016/0002-9149(92)91198-D
19. Dupuis C, Charaf LAC, Brevière GM, Abou P. “Infantile” form of the scimitar syndrome
with pulmonary hypertension. Am J Cardiol. 1993;71(15):1326–1330 PMID: 8498375
doi: 10.1016/0002-9149(93)90549-R
20. Nakamura Y, Harada K, Yamamoto I, et al. Human pulmonary hypoplasia. Statistical,
morphological, morphometric, and biochemical study. Arch Pathol Lab Med.
1992;116(6):635–642 PMID: 1616425
21. Potter EL. Bilateral renal agenesis. J Pediatr. 1946;29:68–76 PMID: 20992008
doi: 10.1016/S0022-3476(46)80241-5
22. Abel RM, Bush A, Chitty LS, Harcourt J, Nicholson AG. Congenital lung disease. In: Chernick
V, Boat TF, Wilmott RW, Bush A, eds. Kendig’s Disorders of the Respiratory Tract in Children.
Saunders Elsevier; 2006:280–316 doi: 10.1016/B978-0-7216-3695-5.50021-3

277
23. Azeem F, Finlay M, Rathwell C, Awad WI. A near fatal presentation of a bronchogenic cyst
compressing the left main coronary artery. J Thorac Cardiovasc Surg. 2008;135(6):1395–1396
PMID: 18544397 doi: 10.1016/j.jtcvs.2007.09.082
24. Jakopovic M, Slobodnjak Z, Krizanac S, Samarzija M. Large cell carcinoma arising in
bronchogenic cyst. J Thorac Cardiovasc Surg. 2005;130(2):610–612 PMID: 16077456
doi: 10.1016/j.jtcvs.2004.12.022
25. Servais E, Paul S, Port JL, Altorki NK, Lee PC. Carcinoid tumor nested within a bronchogenic
cyst. J Thorac Cardiovasc Surg. 2008;136(1):227–228 PMID: 18603086
doi: 10.1016/j.jtcvs.2008.02.042
26. Endo C, Imai T, Nakagawa H, Ebina A, Kaimori M. Bronchioloalveolar carcinoma arising
in a bronchogenic cyst. Ann Thorac Surg. 2000;69(3):933–935 PMID: 10750790
doi: 10.1016/S0003-4975(99)01402-2
27. Okada Y, Mori H, Maeda T, Obashi A, Itoh Y, Doi K. Congenital mediastinal bronchogenic
cyst with malignant transformation: an autopsy report. Pathol Int. 1996;46(8):594–600
PMID: 8893229 doi: 10.1111/j.1440-1827.1996.tb03659.x
28. Ponn RB. Simple mediastinal cysts: resect them all? Chest. 2003;124(1):4–6 PMID: 12853491
doi: 10.1378/chest.124.1.4
29. Lau CT, Kan A, Shek N, Tam P, Wong KKY. Is congenital pulmonary airway malformation
really a rare disease? Result of a prospective registry with universal antenatal screening program.
Pediatr Surg Int. 2017;33(1):105–108 PMID: 27770196 doi: 10.1007/s00383-016-3991-1
30. Swarr DT, Peranteau WH, Pogoriler J, et al. Novel molecular and phenotypic insights into
congenital lung malformations. Am J Respir Crit Care Med. 2018;197(10):1328–1339
PMID: 29328793 doi: 10.1164/rccm.201706-1243OC
31. Stocker JT, Madewell JE, Drake RM. Congenital cystic adenomatoid malformation of the lung.
Classification and morphologic spectrum. Hum Pathol. 1977;8(2):155–171 PMID: 856714
doi: 10.1016/S0046-8177(77)80078-6
32. Stocker JT. Cystic lung disease in infants and children. Fetal Pediatr Pathol. 2009;28(4):155–184
PMID: 19842869 doi: 10.1080/15513810902984095
33. Priest JR, Williams GM, Hill DA, Dehner LP, Jaffé A. Pulmonary cysts in early childhood
and the risk of malignancy. Pediatr Pulmonol. 2009;44(1):14–30 PMID: 19061226
doi: 10.1002/ppul.20917
34. Thunders M, Delahunt B. Gene of the month: DICER1: ruler and controller. J Clin Pathol.
2021;74(2):69–72 PMID: 33293352 doi: 10.1136/jclinpath-2020-207203
35. Crombleholme TM, Coleman B, Hedrick H, et al. Cystic adenomatoid malformation volume
ratio predicts outcome in prenatally diagnosed cystic adenomatoid malformation of the lung.
J Pediatr Surg. 2002;37(3):331–338 PMID: 11877643 doi: 10.1053/jpsu.2002.30832
36. Chon AH, Korst LM, Abdel-Sattar M, Llanes A, Ouzounian JG, Chmait RH. Types II and III
congenital pulmonary airway malformation with hydrops treated in utero with percutaneous
sclerotherapy. Prenat Diagn. 2018;38(7):493–498 PMID: 29665020 doi: 10.1002/pd.5266
37. Ozçelik U, Göçmen A, Kiper N, Doğru D, Dilber E, Yalçin EG. Congenital lobar emphysema:
evaluation and long-term follow-up of thirty cases at a single center. Pediatr Pulmonol.
2003;35(5):384–391 PMID: 12687596 doi: 10.1002/ppul.10240
38. Mani H, Suarez E, Stocker JT. The morphologic spectrum of infantile lobar emphysema:
a study of 33 cases. Paediatr Respir Rev. 2004;5(suppl A):S313–S320 PMID: 14980289
doi: 10.1016/S1526-0542(04)90056-5
39. Cleveland RH, Weber B. Retained fetal lung liquid in congenital lobar emphysema: a possible
predictor of polyalveolar lobe. Pediatr Radiol. 1993;23(4):291–295 PMID: 8414757
doi: 10.1007/BF02010918
40. Olutoye OO, Coleman BG, Hubbard AM, Adzick NS. Prenatal diagnosis and management of
congenital lobar emphysema. J Pediatr Surg. 2000;35(5):792–795 PMID: 10813352
doi: 10.1053/jpsu.2000.6084
41. Mei-Zahav M, Konen O, Manson D, Langer JC. Is congenital lobar emphysema a surgical
disease? J Pediatr Surg. 2006;41(6):1058–1061 PMID: 16769334
doi: 10.1016/j.jpedsurg.2006.02.011
42. Dott MM, Wong LY, Rasmussen SA. Population-based study of congenital diaphragmatic
hernia: risk factors and survival in Metropolitan Atlanta, 1968–1999. Birth Defects Res A Clin
Mol Teratol. 2003;67(4):261–267 PMID: 12854661 doi: 10.1002/bdra.10039
43. Katz OL, Wild KT, McEldrew D, et al. Molecular mechanisms contributing to the etiology of
congenital diaphragmatic hernia: a review and novel cases. J Pediatr. 2022;246:251–265.e2
PMID: 35314152 doi: 10.1016/j.jpeds.2022.03.023
44. Migliazza L, Xia H, Diez-Pardo JA, Tovar JA. Skeletal malformations associated with congenital
diaphragmatic hernia: experimental and human studies. J Pediatr Surg. 1999;34(11):1624–1629
PMID: 10591556 doi: 10.1016/S0022-3468(99)90630-9

278
45. Migliazza L, Otten C, Xia H, Rodriguez JI, Diez-Pardo JA, Tovar JA. Cardiovascular
malformations in congenital diaphragmatic hernia: human and experimental studies.
J Pediatr Surg. 1999;34(9):1352–1358 PMID: 10507428 doi: 10.1016/S0022-3468(99)90010-6
46. Knox E, Lissauer D, Khan K, Kilby M. Prenatal detection of pulmonary hypoplasia in fetuses
with congenital diaphragmatic hernia: a systematic review and meta-analysis of diagnostic
studies. J Matern Fetal Neonatal Med. 2010;23(7):579–588 PMID: 20085507
doi: 10.3109/14767050903551400
47. Ford WD, Kirby CP, Wilkinson CS, Furness ME, Slater AJ. Antenatal betamethasone and
favourable outcomes in fetuses with ‘poor prognosis’ diaphragmatic hernia. Pediatr Surg Int.
2002;18(4):244–246 PMID: 12021971 doi: 10.1007/s003830100685
48. Kay S, Laberge JM, Flageole H, Richardson S, Belanger S, Piedboeuf B. Use of antenatal
steroids to counteract the negative effects of tracheal occlusion in the fetal lamb model.
Pediatr Res. 2001;50(4):495–501 PMID: 11568293 doi: 10.1203/00006450-200110000-00012
49. Harrison MR, Keller RL, Hawgood SB, et al. A randomized trial of fetal endoscopic tracheal
occlusion for severe fetal congenital diaphragmatic hernia. N Engl J Med.
2003;349(20):1916–1924 PMID: 14614166 doi: 10.1056/NEJMoa035005
50. Snoek KG, Capolupo I, van Rosmalen J, et al; CDH EURO Consortium. Conventional
mechanical ventilation versus high-frequency oscillatory ventilation for congenital
diaphragmatic hernia: a randomized clinical trial (the VICI-trial). Ann Surg.
2016;263(5):867–874 PMID: 26692079 doi: 10.1097/SLA.0000000000001533
51. Kinsella JP, Ivy DD, Abman SH. Pulmonary vasodilator therapy in congenital diaphragmatic
hernia: acute, late, and chronic pulmonary hypertension. Semin Perinatol. 2005;29(2):123–128
PMID: 16052736 doi: 10.1053/j.semperi.2005.04.008
52. de la Hunt MN, Madden N, Scott JE, et al. Is delayed surgery really better for congenital
diaphragmatic hernia? A prospective randomized clinical trial. J Pediatr Surg.
1996;31(11):1554–1556 PMID: 8943121 doi: 10.1016/S0022-3468(96)90176-1
53. Nio M, Haase G, Kennaugh J, Bui K, Atkinson JB. A prospective randomized trial of delayed
versus immediate repair of congenital diaphragmatic hernia. J Pediatr Surg. 1994;29(5):618–621
PMID: 8035269 doi: 10.1016/0022-3468(94)90725-0
54. Putnam LR, Tsao K, Lally KP, et al; Congenital Diaphragmatic Hernia Study Group and the
Pediatric Surgery Research Collaborative. Minimally invasive vs open congenital diaphragmatic
hernia repair: is there a superior approach? J Am Coll Surg. 2017;224(4):416–422
PMID: 28147253 doi: 10.1016/j.jamcollsurg.2016.12.050
55. Weber TR, Kountzman B, Dillon PA, Silen ML. Improved survival in congenital diaphragmatic
hernia with evolving therapeutic strategies. Arch Surg. 1998;133(5):498–502 PMID: 9605911
doi: 10.1001/archsurg.133.5.498
56. Muratore CS, Kharasch V, Lund DP, et al. Pulmonary morbidity in 100 survivors of congenital
diaphragmatic hernia monitored in a multidisciplinary clinic. J Pediatr Surg. 2001;36(1):133–140
PMID: 11150452 doi: 10.1053/jpsu.2001.20031
57. Deslauriers J. Eventration of the diaphragm. Chest Surg Clin N Am. 1998;8(2):315–330
PMID: 9619307
58. Stocker JT. Sequestrations of the lung. Semin Diagn Pathol. 1986;3(2):106–121 PMID: 3303232
59. Bratu I, Flageole H, Chen MF, Di Lorenzo M, Yazbeck S, Laberge JM. The multiple facets of
pulmonary sequestration. J Pediatr Surg. 2001;36(5):784–790 PMID: 11329590
doi: 10.1053/jpsu.2001.22961
60. Au VW, Chan JK, Chan FL. Pulmonary sequestration diagnosed by contrast enhanced
three-dimensional MR angiography. Br J Radiol. 1999;72(859):709–711 PMID: 10624331
doi: 10.1259/bjr.72.859.10624331
61. Ko SF, Ng SH, Lee TY, et al. Noninvasive imaging of bronchopulmonary sequestration.
AJR Am J Roentgenol. 2000;175(4):1005–1012 PMID: 11000154 doi: 10.2214/ajr.175.4.1751005
62. García-Peña P, Lucaya J, Hendry GMA, McAndrew PT, Duran C. Spontaneous involution
of pulmonary sequestration in children: a report of two cases and review of the literature.
Pediatr Radiol. 1998;28(4):266–270 PMID: 9545486 doi: 10.1007/s002470050348
63. Nayar PM, Thakral CL, Sajwani MJ. Congenital lobar emphysema and sequestration—
treatment by embolization. Pediatr Surg Int. 2005;21(9):727–729 PMID: 15995872
doi: 10.1007/s00383-005-1462-1
64. van Son JA, Julsrud PR, Hagler DJ, et al. Surgical treatment of vascular rings: the Mayo Clinic
experience. Mayo Clin Proc. 1993;68(11):1056–1063 PMID: 8231269
doi: 10.1016/S0025-6196(12)60898-2
65. Berdon WE, Baker DH, Wung JT, et al. Complete cartilage-ring tracheal stenosis associated
with anomalous left pulmonary artery: the ring-sling complex. Radiology. 1984;152(1):57–64
PMID: 6729137 doi: 10.1148/radiology.152.1.6729137

CHAPTER
15
Chest Wall and Spinal Deformities
Julie L. Fierro, MD, MPH
Oscar Henry Mayer, MD
Inspiration Versus Exhalation
The act of breathing is sometimes compared with the movement of a piston
because of the cyclical cephalad and caudad motion of the diaphragm, and the
chest wall is seen as a passive participant; however, this view is too simplistic.
The chest wall is very dynamic during breathing and is critical in maintaining
resting lung volume, optimizing lung mechanics, allowing normal respiratory
growth, and protecting the thoracic organs.
In healthy children, inspiration begins from functional residual capacity
(FRC), which is the point in the respiratory cycle when the outward recoil
of the rib cage and the inward recoil of the lungs are equal and opposite. The
diaphragm contracts and moves caudally, increasing intra-abdominal pressure
and displacing the abdominal contents and the lower edges of the rib cage
outward. This caudad motion of the diaphragm, along with outward and
cephalad rotation of the ribs, produces increasingly negative intrathoracic
pressure and a gradient favoring airflow down the respiratory tract from
the mouth to the alveoli (Figure 15‑1A).
Inspiration is an active process, but exhalation is largely passive. After the
muscles of inspiration relax, the inward recoil of the lungs produces positive
pressure in the alveoli that favors expiratory flow down the pressure gradient
to the mouth, as the lung volume decreases to FRC (Figure 15‑1B).
Area of Apposition
The extent of the diaphragm’s downward excursion depends on the area of
apposition of the diaphragm to the rib cage, or the portion of the diaphragm
aligned vertically along the inner surface of the chest wall (Figure 15‑2).
As the portion of the diaphragm in the area of apposition contracts, the
diaphragm moves caudally. The area of apposition constitutes one-quarter
to three-quarters of the total surface area of the rib cage in adults.1
279

280
- -
- -
-
-
- - - -
- - - -
- - - -
- -
- - -
- -
FRC Inspiration
FRC Inspirat
- -
- + -
+
+ +
- -
+ +
- - -
- -
FRC Inspiration
FRC Inspiration
Figure 15-1. Representation of the motion of Figure 15-2. Area of apposition at
the alveoli, diaphragm, and chest wall during functional residual capacity (FRC) and
inspiration (A) and exhalation (B). during inspiration.
Courtesy of Oscar Henry Mayer, MD. Courtesy of Oscar Henry Mayer, MD.
It is somewhat less in children and substantially less in infants. In a child

with clinically significant lung disease with hyperinflation, the diaphragm
will be positioned in a lower and flatter position, and the area of apposition
can be much smaller. Furthermore, with a smaller area of apposition, the
diaphragm becomes flatter with a larger radius of curvature (Figure 15‑3).
By the law of Laplace, the force-generating capacity of the diaphragm will
be lower with a larger radius of curvature.

281
Chapter 15—Chest Wall and Spinal Deformities
R2
R2
R1
R1
R1 > R2
Figure 15-3. Radius of curvature (R) of the diaphragm in 2 different diaphragm orientations with
R1 > R2. R1 > R2
Courtesy of Oscar Henry Mayer, MD.
Thoracoabdominal Mechanics
During restful breathing in a healthy child, the abdominal and rib cage ex-
cursion are nearly coincident (Figure 15‑4A). With respiratory disease,
such as increased airway resistance or chest wall compliance, the abdominal
excursion will lead the chest wall excursion (thoracoabdominal asynchrony).
This asynchrony is easily visible during a respiratory examination and can
increase to the far end of the spectrum to completely asynchronous or para-
doxical respiration, with
the abdomen moving out-
ward as the chest wall is
moving inward (Figure
15‑4B).
When airway resistance
increases, the pressure gra-
dient needed to overcome
the resistance and generate
flow is higher, and it takes
longer to generate outward
chest wall motion. A highly
compliant rib cage will
move inward while the
abdomen moves outward
at the onset of inspiration
because of the progres-
sively negative intrathoracic
Figure 15-4. Thoracoabdominal motion during inspiration
from functional residual capacity with synchronous pressure (Figure 15‑4B).
conditions (A) and asynchronous conditions (B).

282
This condition can be seen in some neonates and young infants; children
with neuromuscular disease, especially spinal muscular atrophy type 1;
and children with chest wall disorders.
To increase inspiration, the diaphragm will contract more caudally, and the
scalene and sternocleidomastoid muscles will contract to elevate the superior
rib cage further. With forceful exhalation from total lung capacity (TLC),
such as coughing, the abdominal muscles contract, pushing the abdominal
contents inward and upward elevating the diaphragm, while the internal
intercostal muscles contract to augment the inward recoil of the chest wall
and lungs.
Pathophysiology
Structural Changes Resulting From Growth and Development
In neonates, lung compliance is low and chest wall compliance is high
compared with those in older children and adults.2–6 In addition, the ribs
are more horizontal in infants than in children and adults, in whom the ribs
slope more caudally.7
Through early childhood, lung compliance increases as the alveoli develop
and lung volume increases; however, lung compliance and lung volume
increase at roughly the same rate such that when lung compliance is normal-
ized for lung growth it remains constant.8 Chest wall compliance normalized
to lung volume decreases through childhood as the chest stiffens owing to a
combination of rib ossification and increasing chest wall muscle mass.9,10 In
adulthood, chest wall compliance decreases further as the costal cartilage also
progressively calcifies.10
Functional Consequences of Developmental and Structural Changes

A highly compliant chest wall has clear advantages in the birthing process
by allowing distortion during the movement through the birth canal. In neo-
nates and infants, this high degree of chest wall compliance creates mechani-
cal disadvantages. First, the negative intrathoracic pressure produced during
inspiration can move the highly compliant chest wall inward (Figure 15‑4B).
Second, infants have low lung compliance relative to their chest wall com-
pliance, which produces a lower FRC relative to that in older children and
adults. The lower FRC may be at or below the point when airways close and
atelectasis occurs (the closing volume). If closing volume occurs during tidal
breathing, before any inspiratory flow can occur, pressure needs to be applied
to the respiratory system to raise lung volume above the closing volume to
open the closed airways. This increases work of breathing without benefit
because the energy used to inflate the lung above closing volume does not
produce inspiratory flow.

283
To compensate for this mechanical inefficiency, infants will often breathe

at a higher respiratory rate, allowing for less time to exhale, and use glottic
narrowing, ending at an end-expiratory lung volume higher than FRC and
above the closing volume.11,12 Actively maintaining the end-expiratory lung
volume above FRC and closing volume minimizes the work of breathing.
Finally, a highly compliant chest wall may move outward during cough
owing to the highly positive intrathoracic pressure during a forced exhalation,
thereby decreasing cough efficiency.
Under normal circumstances, the outward excursion of the rib cage provides
about 35% of the volume of inspiration in a newborn,13 with the remainder
coming from abdominal excursion. The relative rib cage excursion increases
to the adult value of 65% of inspiratory volume early in the second year
after birth.13
Although a chest wall with high compliance may move inward during
inspiration (Figure 15‑4B), a chest wall with low compliance moves very
little. To maintain an acceptable tidal volume, the diaphragm will contract
further, and the lungs will expand more caudally and less outward, which
can cause a number of problems.
First, the inspiratory reserve volume, the volume that can be recruited during
a maximal inspiration, will be lower (Figure 15‑5), as will forced vital capa-
city (FVC), the volume of air that can move through the lungs during maximal
inspiration and expiration. Second, because the diaphragm is contracting more
during inspiration, it
a b c is working harder and
is at risk of fatigue.
Third, cough and air-
way clearance can be
IRV compromised because
IRV
FVC the FVC and inspira-
tory reserve volume
IRV VT will be lower, which
TLC
FRC
VT limits how deeply air
ERV is inhaled into the
ERV VT
lungs and beyond
ERV airway secretions.
RV
RV
RV
Figure 15-5. Lung volumes in normal condition (A), restrictive

lung disease (B), and obstructive lung disease (C).
Abbreviations: ERV, expiratory reserve volume; FRC, functional residual
capacity; IRV, inspiratory reserve volume; RV, residual volume; TLC, total
lung capacity; VT, tidal volume.
Tuesday, May 12, 2009

284
Methods for Assessing Chest Wall Function

Physical Examination
It is very important to assess chest wall function qualitatively by means
of observation.
Spine
Scoliosis is often thought of as a uniplanar defect with a curve that is in the
coronal plane on the basis of its radiographic appearance; however, there can
also be more complicated multiplanar kyphoscoliosis and rotational scoliosis.
It is important first to assess the back statically and look for gross asymmetry.
Scoliosis can often be seen by visually examining the spine and tracing it with
a finger while a patient is standing upright. Shoulder asymmetry and unilateral
scapular or rib bulging can be a sign of scoliosis with substantial spinal rota-
tion. Examining the spine with the patient bending at the waist and reaching
for his or her toes can show more subtle scoliosis and right-to-left asymmetry.
It is then important to evaluate the extent and symmetry of thoracoabdominal
excursion. This can be qualitatively assessed using the thumb excursion test14
by placing the fingers of each hand on the left and right scapula with the
thumbs placed on either side of the spine. In a patient without scoliosis, the
thumbs should move laterally the same amount. Auscultation of the right
and left lungs can be used to discriminate asymmetrical aeration due to
airway compression or atelectasis.
Chest Wall
The relative excursion of the convex and concave chest is variable and is
based on the mobility of the chest wall and the position and extent of lung
compression.15,16 Thoracoabdominal asynchrony, the difference in timing
between chest wall and abdominal excursion, is also important to assess and
is a measure of overall respiratory mechanics.17,18 With a poorly compliant
or stiff chest wall, the abdomen moves outward, and there is a delay before
outward chest wall movement. It takes more intra-abdominal pressure to move
the lower chest wall and more accessory inspiratory muscle contraction to
expand the chest wall.
Diaphragm
In unilateral diaphragm dysfunction caused by paralysis or eventration, the
contralateral side of the chest should move normally while the ipsilateral
side of the chest may move very little, if at all, because of asymmetrical
diaphragm motion. In complete unilateral diaphragm paralysis, the epigastric
abdominal wall may move upward and toward the side of the lesion during
deep inspiration. With a flail chest, there will be a marked asymmetry in chest
wall excursion; the unaffected side will move outward during inspiration, and
the affected side will move inward.

285
Diaphragm fatigue, dysfunction, or unilateral paralysis can limit the caudad

movement of the diaphragm during inspiration. To compensate, the chest wall
excursion is greater, can occur before any abdominal motion, and will be more
important in inspiration than typical. Depending on its severity, a patient
may have asynchronous respiration with outward chest wall motion coin-
cident with inward abdominal motion, which can occur because of negative
intrathoracic pressure pulling the diaphragm cephalad during inspiration.
Abdomen
A highly compliant abdomen will have a greater outward excursion during
inspiration but still should lead the thorax on inspiration. On forced expira-
tion, the abdominal contraction can be irregular based on the characteristics
of the initial defect (as with gastroschisis and omphalocele), the subsequent
repair, and the amount of residual muscle mass.
Quantitative Assessment of Chest Wall Motion

The qualitative assessment of thoracoabdominal motion performed during
the observation portion of the physical examination can be quantitated using
respiratory inductance plethysmography. During respiratory inductive ple-
thysmography, thoracoabdominal motion is measured by timing the maximal
thoracic and abdominal excursion during respiration by using inductance
bands that measure the cross-sectional area of the chest wall and abdomen.17–19
The exact delay between abdominal and thoracic excursion and the relative
excursion of each compartment can be measured.17–19
Lung Function Testing

Conventional lung function testing can be stratified into 2 different types:
(1) forced flow measurements with spirometry to evaluate for obstructive
lung disease and (2) static lung volume measurement with plethysmography
or gas dilution to evaluate for restrictive respiratory disease (see Chapter 6,
Pulmonary Function Testing). In children with obstructive lung disease,
the FEV1, FEF25%–75%, and FEV1/FVC can be low. In those with restrictive
respiratory disease, however, the FEV1/FVC is normal, and there is always
a low TLC. Although FVC is expected to be low in children with restrictive
respiratory disease, it can be low in those with obstructive lung disease
because of air trapping due to airway closure during exhalation leading to
an increased residual volume. Therefore, a low TLC is needed to diagnose
restrictive respiratory disease definitively. Thereafter, FVC can be moni-
tored as an index of severity.
In patients with scoliosis, TLC decreases as the spinal curvature increases;
however, TLC can be within the normal range.20 Patients with more compli-
cated rotational kyphoscoliosis or constrictive scoliosis, such as in thoracic
insufficiency syndrome (TIS), can have a marked restrictive defect.21 When

286
evaluating the lung function of a patient with scoliosis, it is important to

normalize the results by using arm span as a surrogate for height to avoid
underrepresenting the restrictive defect (Figure 15‑6A). There are well-
documented tables with normal values for the ratio of the upper body to the
lower body.22 This ratio is abnormal in patients with chest wall or spinal
disease, with the upper body being shorter relative to the lower body. Because
the height of a patient with scoliosis may be shorter than the idealized height
because of the curve and a shorter spine, the use of height to normalize lung
volume will give an inappropriate (low) normal value, and lung volume as
a percentage of that predicted will then be falsely high (Figure 15‑6B).
Because arm span is not affected by spinal growth, it will more accurately
represent the potential, idealized height and metabolic demand. However,
lung volume normalized to height can still be useful. This correction will
normalize for chest size and, if low, is consistent with an intrinsic restrictive
lung disease, separate from any external compression.
Age: 9 BMI: 11.9

Gender: Female Height: 158 cm Weight: 29.6 kg
Race: African American
Note: Height and/or Weight and/or BMI is <3% tile or >97% tile for age.
Spirometry (BTPS) ATS
Ref Pre % Ref Z-score
FVC L 2.66 1.37 52 -3.16
FEV1 L 2.31 1.29 56 -2.92
FEV1/FVC % 90 94 104 0.67
FEF25-75 L/s 2.70 2.25 83 -0.57
PEFR L/s 5.27 3.22 61 -1.78
FET sec 3.07
FIF50 L/s 1.92
FEF50/FIF50 1.36
FEV.5 L 1.57 1.10 70
Back Volume 0.05
Lung Volumes (Box) ATS
TLC L 3.51 1.99 57 -3.61
VC L 2.59 1.37 53 -0.87
FRC L 1.83 1.00 55 -2.67
ERV L 0.91 0.38 42
RV L 0.92 0.62 67 -1.16
RV/TLC % 26 31 119 0.36
Figure 15-6. Spirometry and static lung volume measurements in a child with scoliosis with
normalization by means of arm span (A) or height (B).

287
Age: 9 DOB: 10/11/1999 BMI: 20.6

Gender: Female Height: 120 cm Weight: 29.6 kg
Race: African American
Note: Height and/or Weight and/or BMI is <3% tile or >97% tile for age.
Spirometry (BTPS) ATS
FVC L 1.23 1.37 111 0.59
FEV1 L 1.16 1.29 111 0.65
FEV1/FVC % 90 94 104 0.67
FEF25-75 L/s 1.79 2.25 126 1.01
PEFR L/s 3.19 3.22 101 0.05
FET sec 3.07
FIF50 L/s 1.92
FEF50/FIF50 1.36
FEV.5 L 0.96 1.10 115
Back Volume 0.05
Lung Volumes (Box) ATS
TLC L 1.79 1.99 111 0.93
VC L 1.21 1.37 113 0.24
FRC L 0.99 1.00 101 0.6
ERV L 0.41 0.38 93
RV L 0.58 0.62 107 0.25
RV/TLC % 32 31 97 -0.06
Figure 15-6, (continued)
Abbreviations: ATS, American Thoracic Society; BTPS, body temperature and pressure, saturated; DOB, date
of birth; ERV, expiratory reserve volume; FEF25–75, forced expiratory flows between 25% and 75% of the FVC;
FEF50 , forced expiratory flow at 50% of FVC; FET, forced expiratory time; FEV.5, forced expiratory volume in
0.5 seconds; FIF50, forced inspiratory flow at 50% of FVC; FRC, functional reserve capacity; FVC, forced vital
capacity; PEFR, peak expiratory flow rate; Pre, before; Ref, reference; RV, residual volume; TLC, total lung
capacity; VC, vital capacity.
Respiratory Muscle Strength

Respiratory muscle strength is measured by recording the maximal inspira-
tory pressure and maximal expiratory pressure by means of manometry.
The maximal inspiratory pressure is the maximal sustained pressure that
can be maintained for 1 second when inhaling maximally against a closed
shutter from residual volume or from FRC. It is critical to measure at the
same volume, or the comparisons will not be accurate. The maximal expira-
tory pressure is the maximal sustained pressure that can be maintained for
1 second when exhaling maximally against a closed shutter from TLC. In

288
adolescents with scoliosis, inefficient coupling between the muscle and chest
wall reduces respiratory muscle strength. The degree of weakness partly
depends on the severity of the curve.23 Children with severe scoliosis have an
activation of respiratory muscles similar to that of children with respiratory
failure caused by obstructive lung disease.24
Structural Abnormalities
A list of structural abnormalities of the chest wall is found in Box 15-1.
Box 15-1
Structural Abnormalities of the Chest Wall
Pectus Deformity ū Hypoplastic chest wall
Pectus excavatum • Jeune syndrome
Pectus carinatum • Jarcho-Levin syndrome
Scoliosis • Ellis-van Creveld syndrome
Spinal deformity • Achondroplasia
Rib cage deformity • Campomelic dysplasia
ū Flail chest • Osteogenesis imperfecta
ū Rib fusion • Hypophosphatemia
ū Neuromuscular disease (eg, spinal Neuromuscular scoliosis
muscular atrophy) ū Hypotonic
Idiopathic • Spinal muscular atrophy
Thoracic Insufficiency Syndrome • Congenital muscular dystrophies
Congenital constricted chest wall ū Hypertonic
syndrome • Static encephalopathy
ū Progressive congenital scoliosis and • Flail chest
spinal disorders ū Absent ribs
• Hemivertebrae ū Iatrogenesis or trauma
• Wedge vertebrae • Rib resection
• Bar vertebrae
• Segmental fusion
• Fused ribs
Pectus Excavatum and Carinatum

Clinical Features
Pectus excavatum accounts for about 90% of chest wall defects,25 with an
incidence of between 1 in 400 and 1 in 1,000.26 Although abnormal lung
function is rare in most patients with pectus excavatum, subjective reports of
pulmonary difficulty are much more common.27 Patients with pectus
excavatum commonly have cardiac deviation to the left and occasionally have

289
conduction abnormalities as a result of the distortion.26 Exercise testing is more

effective in diagnosing cardiopulmonary limitation,26,28 which is still a rare
concern. However, when there is exertional limitation, it is typically caused
by cardiac limitation as opposed to pulmonary limitation.29–31 Pectus
excavatum is usually sporadic26 but is associated with connective tissue
defects, such as Marfan syndrome, Ehlers-Danlos syndrome, and osteogenesis
imperfecta,32 and progressive neuromuscular defects, such as spinal muscu-
lar atrophy. Although pectus excavatum can manifest early in life, it
commonly worsens through adolescence.33
Pectus carinatum is less common. Pulmonary, cardiac, or exercise limitation is
extremely rare, and physical appearance is by far the most common concern.34
As with pectus excavatum, there are a number of associated disorders that
can be present with pectus carinatum, such as Marfan syndrome, Noonan
syndrome, and osteogenesis imperfecta.35
Diagnostic Evaluation
Computed tomography (CT) scans of the chest can be very helpful in clearly
defining the defect and the severity. Haller et al36 developed criteria for eval-
uating the severity of pec-tus excavatum via chest CT scanning by using the
ratio of the lateral chest diameter to the distance from the sternum to the
spine, known as the Haller index or the pectus severity index (Figure 15‑7). In
pectus excavatum, a pectus severity index of 2.5 or less is considered
B normal;
A
the higher the pectus severity index, the worse the defect. Patients with an
index ratio of 3.25 or higher are likely to undergo corrective surgery.37
Computed tomography scanning has also been used to define the amount of
cardiac distortion from the pectus defect.38 If there is cardiac distortion, then it
is important for the patient to undergo echocardiography and a thorough cardiac
evaluation. HI = 2.0
B
A A B
HI = 2.0 HI = 2.8
Figure 15-7. Haller index (HI) for grading pectus excavatum. The index is the ratio of the
transverse rib-to-rib diameter (A) to the distance between the spine and sternum (B).
A B

290
In pectus carinatum, chest CT scanning is also useful in defining the defect.

Conversely to pectus excavatum, the lower the pectus severity index (< 2.0),
the more severe the disease,39 given that the defect is one of protrusion rather
than invagination.
Pulmonary function testing is indicated to assess for restrictive pulmonary
disease in patients with moderate to severe pectus excavatum or those with
respiratory symptoms. Although most patients with pectus excavatum may have
pulmonary symptoms, pulmonary function abnormalities are found in about
one-third of patients.40 Exercise testing is indicated for patients with moderate
to severe pectus excavatum or those with respiratory symptoms.28Additional
routine testing for patients with pectus carinatum is not typically indicated.
Medical Management
Chest bracing is not used for patients with pectus excavatum, but physical
therapy has been used in conjunction with surgery for patients with clinically
significant postural abnormalities.41,42 Part of the challenge in using nonsurgical
repair is that the defect is an invagination as opposed to a protuberance, as
with pectus carinatum. Alternately, pectus carinatum can respond well to
bracing, and this may obviate the need for surgery.43,44
Surgical Management
The effect of pectus excavatum on lung function is variable, as is the im-
provement in lung function after surgical correction. There are 2 main surgical
procedures for correcting pectus excavatum—the modified Ravitch procedure
and the Nuss procedure.
In the modified Ravitch procedure, a number of cartilage segments are resected,
leaving the perichondrium in place.26 A sternal support, usually a metallic strut,
is placed between the anterior edges of the rib cage and through the sternum,
with the sternum repositioned normally. After 2 to 3 years, the strut is removed.
In the past, aggressive and extensive cartilage resection and sternal remodeling
were performed. This practice has since been substantially modified owing to
cases of severe asphyxiating thoracic dystrophy, believed to be caused by the
disruption of sternum and cartilage growth, thereby limiting future chest wall
growth.44 However, limiting cartilage resection and performing the procedure
in children older than 8 years have largely eliminated this concern.
The Nuss procedure, or minimally invasive pectus excavatum repair, involves
using a titanium rod that is bent to the corrected contour of the chest wall. It is
inserted into the pleural space through a small axillary thoracotomy, passed
through the retrosternal space anterior to the heart, and through the contra-
lateral chest at the same level as the entry point. It is then rotated anteriorly

291
Figure 15-8. Pectus excavatum repair by means of the Nuss procedure with antero-
posterior (A) and lateral (B) chest radiographs before insertion and anteroposterior (C)
and lateral (D) chest radiographs after insertion.
to press the sternum outward at the level of the maximal invagination and
is sutured in place on the outside of the chest wall (Figure 15‑8).45 The rod
is kept in place as a brace until the sternum has remolded and usually is
removed after 2 years, usually with a permanent repair.

292
Although data from some centers demonstrate a modest increase in lung

function after pectus repair, the results are quite variable.28–31,39,45 For patients
not deemed to be surgical candidates, periodic physical examinations and
imaging should be performed, particularly during periods of rapid growth,
because the deformity and associated symptoms may progress.46
Scoliosis
Clinical Features
Scoliosis can decrease chest wall compliance and lung compliance in the con-
cave chest, thereby worsening respiratory mechanics. As scoliosis progresses,
the convex chest can become hyperexpanded because of the lateral rotation
of the chest and stretching of the intercostal muscles (Figure 15‑9), further
limiting chest wall excursion and worsening chest wall compliance.
More complex scoliosis with clinically significant transverse chest wall rota-
tion (Figure 15‑10) can substantially distort the chest wall in the transverse
plane. In doing so, the diaphragm can rotate radially and flatten and increase
the radius of curvature; however, the clinical significance of this has not been
Figure 15-9. Scoliosis. Anteroposterior radiograph showing the compression of the

lung and chest wall on the concave side of the chest and the hyperexpansion of the
chest on the convex side in a teenager with spinal muscular atrophy type 2.

293
Figure 15-10. Transverse computed tomography scans showing the

rotation of the spine and diaphragm in complicated scoliosis from the
level of the apex of the lung (A), the carina (B), the lower thorax (C), and
the lower edge of the liver (D). Gray arrows indicate the rotational axis
of the spine.
demonstrated. Bronchial compression can also occur because of compression

by the rotated anterior edge of the vertebral body.47
The cause of scoliosis can be described in 1 of 3 ways (1) spinal instability or
abnormality with asymmetrical growth; (2) rib cage deformity with absence of
ribs, rib fusion, or general lateral instability from muscle weakness; or (3)
idiopathic scoliosis, in which there is no clear cause.
In children with hemivertebrae or asymmetrical vertebrae, such as wedge or
bar vertebrae, scoliosis will serve as a nidus for the curve because spinal integ-
rity is disrupted at that point (Figure 15‑11). A bar vertebra or unilateral fusion
provides a tethering point around which vertical spinal growth is asymmetrical
and produces scoliosis (Figure 15‑11). In children with absent ribs, lateral chest
wall support will be deficient, and the lateral chest wall will collapse, creating
an ipsilateral scoliosis (Figure 15‑12A). Rib fusion that causes a tethering point
around which the spine will grow asymmetrically can cause scoliosis (Figure
15‑12B). In children with neuromuscular disease, the biomechanics of the
thorax are abnormal, often with weak rib-to-rib support and eventual unilateral
or bilateral collapse, with severe caudad rotation of the ribs in the convex chest,
as is often seen in spinal muscular atrophy type 1 (Figure 15‑13). Finally, idio-
pathic scoliosis can occur in children with no clear underlying musculoskeletal
abnormality. Often the scoliosis is asymptomatic and noticed incidentally as
part of a health supervision visit or on a chest radiograph.

294
Figure 15-11. Anteroposterior

chest radiograph demonstrating
scoliosis caused by an underlying
spinal disorder with hemiverte-
brae (H), bar vertebra (B), and
rib fusion (F).
Figure 15-12. A, Anteroposterior radiograph showing scoliosis caused by rib fusion (F) and rib
absence (A). B, Anteroposterior radiograph showing scoliosis caused by rib fusion.

295
Figure 15–13. Anteroposterior radiograph showing neuromuscular scoliosis caused by spinal

muscular atrophy type 1 with caudad rotation of the ribs in the right side of the chest.
Medical Management
Before surgery is considered, bracing can be used to align the spine in a more
favorable midline position, or as close to it as possible. Although in many
situations bracing is seen as a temporizing procedure and not a cure,48 it can
be successful in preventing scoliosis curve progression in patients who are
skeletally immature and have curves of less than 40°48,49 and occasionally
may obviate the need for surgery.48
Surgical Management
The decision to treat scoliosis is made on the basis of clinical symptoms, sever-
ity of scoliosis, and rapidity of progression, with 50° of curve being the point
at which surgical intervention is often considered.48 The definitive surgical
treatment is placement of spinal fusion rods along each edge of the spine with
use of metal suture material to connect to the spinal laminae (Figure 15‑14),
pedicle screws placed into the vertebral bodies, or laminar hooks over the spinal
laminae. Although this treatment provides mechanical stability, it prevents
further spine growth within the fused region and limits FVC commensurate
with both the length of the fusion and the height of the superior fusion point.50
This growth prevention clearly limits the usefulness of the procedure in
younger children. In these children, growth can be maintained with non-
surgical interventions, such as bracing the abdomen and part of the thorax
intermittently to keep the spine aligned properly.

296
Figure 15-14. Anteroposterior radiographs showing a child with spinal

muscular atrophy type 2 before (A) and after (B) spinal fusion.

297
The longitudinal pulmonary outcome of scoliosis surgery is determined

chiefly by the preoperative FVC and, to a lesser extent, by the surgical approach,
with the posterior approach without thoracotomy being more favorable than the
anterior approach via thoracotomy.20 Among a number of potential complicating
factors is the potential for a secondary lordosis, or “crankshaft” abnormality,
with posterior-only spinal fusion because of continued anterior spinal growth
and arrested posterior spinal growth. The alternative of a thoracotomy and
anterior fusion has been associated with a decrease in lung function.38
It is hard to make a definitive statement about the usefulness of spinal fusion in
correcting lung function because lung function is not the only outcome measure.
In addition, there should not be an expectation of substantial improvement in
vital capacity as a percentage of that predicted after scoliosis surgery because
the act of fusion limits further spine growth and worsening of scoliosis at
the expense of lung growth and, in some situations, loss of lung function.38,51
Therefore, the decision to perform spinal fusion is a balance between
supporting growth and minimizing the further loss of lung function.
A separate approach is to use growing rods (Figure 15-15) along the spine to
support the spine, as is done with spinal fusion, but with serial lengthening of
the rods commensurate with expected spine growth.52 Although spine growth
can be kept in the normal range,52 the effect on future lung function is not yet
known. These rods must be transitioned to a static rod to fuse the spine after
growth is complete. Definitive spinal fusion may be more challenging in this
approach because of residual perispinal scarring from the growing rods.
Figure 15-15. Radiographs showing growing rods in a child with scoliosis in the anteroposterior
(A) and lateral (B) projections.
Courtesy of Robert Campbell, MD.

298
Thoracic Insufficiency Syndrome

Clinical Features
Thoracic insufficiency syndrome encompasses a wide range of complex tho-
racospinal disorders in which the chest wall and spine cannot support normal
respiration and lung growth.14 Thoracic insufficiency syndrome is different
from idiopathic scoliosis in that patients with TIS typically have a more rapid
loss of lung function that can cause severe pulmonary morbidity or respiratory
failure if untreated. Although TIS encompasses a number of disparate condi-
tions, there are 3 phenotypic categories of TIS—congenital constricted chest
wall syndrome, progressive spinal deformity, and flail chest.53
Congenital constricted chest wall syndrome has 2 subtypes—progressive
congenital thoracic scoliosis and hypoplastic thorax disorders.14,53 Progressive
congenital thoracic scoliosis can result from abnormal rib segmentation,
or rib fusion (Figure 15-12B), with or without a skeletal abnormality.14,53 In
congenital cases, clinical symptoms can occur quite early and may be severe.
Primary rib defects, such as
rib fusion, can also occur.
Hypoplastic thorax disorders can
occur owing to defects in cartilage
(achondroplasia, campomelic
dysplasia), costal growth abnormali-
ties (Ellis-van Creveld syndrome,
Jeune syndrome [Figure 15-16]), or
spinal growth abnormalities (Jarcho-
Levin syndrome [Figure 15-17]).14,53
Similarly, the thorax can be hypo-
plastic with osteogenesis imperfecta
type 2 and with hypophosphatemia
owing to undermineralized bone
causing easy fracture, disrupted
healing, and poor thoracic growth.
Over time, the chest does not grow
with the rest of the body and the
increasing metabolic need.
Figure 15-16. Anteroposterior radiograph

showing hypoplastic thorax in Jeune syndrome.

299

showing Jarcho-Levin syndrome.
Progressive spinal deformity is progressive scoliosis caused by neuromus-

cular disease (Figure 15-13) or a primary vertebral abnormality, such as bar
vertebrae, segmental fusion, hemivertebrae, or wedge vertebrae (Figure
15-11),14,53 without rib abnormalities. In congenital cases, clinical symptoms
can occur quite early and may be severe.
Flail chest can occur because of a congenital defect with absent ribs (Figure
15-12A) and may also be associated with a variety of different spinal defects.
It can also occur as a result of chest wall surgery to remove a portion of the
chest wall or as a result of trauma.
Medical Management
Although there is no medical therapy that can effectively treat TIS, nutritional
support and noninvasive or invasive ventilation can be critical in helping a
patient grow to the point at which surgery would be most feasible. With chest
wall expansion and spinal straightening, as described in the next section,
proper soft-tissue mass is needed to close the newly expanded chest wall and
cover the inserted supportive hardware.53 If this is not done, there can be a
higher risk for complications, such as skin and soft-tissue breakdown at the
site of the repair.
Surgical Management
Thoracic insufficiency syndrome poses surgical challenges that go well
beyond stabilizing the spine, and with the early age at which many patients
with TIS present, fusion is not a viable option. The combination of early
onset of thoracospinal disease with TIS spurred the development of the
vertical expandable prosthetic titanium rib (VEPTR). This model provides
spinal support and is expandable to allow normal longitudinal growth, as with
the growing rod model. However, the VEPTR has the additional advantage of

300
lateral support in a variety of different ways based on the placement of the

devices (Figure 15-18).14 It can also be used to correct rotational scoliosis and a
variety of types of complicated thoracospinal disorders,53 such as flail chest;
scoliosis with fused ribs or with absent ribs; and scoliosis with major vertebral
abnormalities that destabilize the spine, such as bar vertebrae, hemivertebrae,
or wedge vertebrae. The expansions are typically performed every 6 to 8
months during a day- surgery procedure to maintain a normal spinal growth
velocity while providing spinal and thoracic stability.52 A magnetically
controlled growing rod inserts similarly to the VEPTR but lengthens nonsurgi-
cally and during an outpatient visit. It uses telescoping rods containing an
internal magnet that are lengthened from an external actuator, thereby elimi-
nating the need for anesthesia.54,55 Long-term data comparing outcomes among
the main growth-sparing procedures are not yet available.
Figure 15-18. Anteroposterior radiographs showing vertical expandable prosthetic titanium rib
placement in the rib-to-rib (right) and rib-to–iliac crest (left) (A) and rib-to-spine (B) orientations.

301
Because TIS is a constellation of heterogeneous conditions that have similar

morbidity, optimal timing for correction is based on a combination of the
severity of the underlying thoracospinal defect and the associated respiratory
morbidity. Thus, the ideal insertion time of the VEPTR is variable and individ-
ualized to the patient. Although there is clearly a benefit in surgically treating
TIS early to minimize progression, there are no data that give a clear link
between age of surgery and long-term prognosis.
The VEPTR can be used in patients with a hypoplastic chest, such as with
Jarcho-Levin syndrome and Jeune syndrome. With Jarcho-Levin syndrome, the
VEPTR supports the spine and places a longitudinal traction force to encourage
growth (Figure 15-19). In Jeune syndrome, the VEPTR pro-vides a lateral
tethering point for the rib cage to expand after a series of rib osteotomies and
outward traction leaving the periosteum in place (Figure 15-20). There is also
Figure 15-19. Anteroposterior radiographs showing Jarcho-Levin syndrome before (A) and after
(B) repair with the vertical expandable prosthetic titanium rib.

302
an alternative approach, a lateral thoracic expansion technique, in which

there are a series of staggered rib osteotomies with fusion of the alternating
longer lengths of rib to expand the chest wall circumference (Figure 15-21).56
Unlike the VEPTR, in which the device is lengthened about every 6 months,
the lateral thoracic expansion technique is a single procedure that is not
repeated and does not allow for growth over time.
There are substantial challenges in obtaining reliable pulmonary function
testing results given the young age of the patient at the time of surgery. In a
cohort of older patients with TIS, pulmonary function testing showed that
VEPTR insertion does not result in an improvement in lung function but rather
in a decrease in FVC and an increase in residual volume, which suggest that
the role of surgical correction is to prevent further decline in pulmonary
function.21 However, advanced imaging techniques, including dynamic
magnetic resonance imaging, have shown increases in lung volume and
diaphragm excursion after VEPTR placement.57
Figure 15-20. Anteroposterior radiographs showing Jeune syndrome before (A) and after
(B) vertical expandable prosthetic titanium rib insertion.

303

showing Jeune syndrome repair by means of the
lateral thoracic expansion technique, with arrows
pointing to the free rib segments with growth of
new bone.
Muscular Abnormalities
A list of muscular abnormalities is found in Box 15-2. Diaphragm weak-
ness is common in Duchenne muscular dystrophy. Chest wall weakness
and abnormal mechanics are prominent in both spinal muscular atrophy
and Duchenne muscular dystrophy, can be seen in the congenital muscular
dystrophies, and can
Box 15-2
lead to clinically sig-
Muscular Abnormalities nificant thoracospinal
ū Congenital diaphragmatic hernia disease. These condi-
ū Abdominal wall defects tions are discussed in
ū Gastroschisis Chapter 54, Pulmonary
Complications of Neuro-
ū Omphalocele
muscular Disorders.
ū Prune belly syndrome (Eagle-Barrett syndrome)
Congenital Diaphragmatic Hernia

Congenital diaphragmatic hernia (CDH) occurs when the pleuroperitoneal
canal fails to close during early fetal development. The primary morbidity from
CDH is related to pulmonary hypoplasia or other organ system defects.58–60
Diaphragm function and muscle strength, on the basis of maximal inspiratory
pressures,61 are directly related to the size of the diaphragm defect and synthe-
tic patch needed for the repair. However, in a cohort of 25 patients with CDH,
diaphragm function was adequate for unsupported respiration, even considering
the associated pulmonary hypoplasia and airway disease.61
Abdominal wall defects and CDHs are repaired surgically; however, the
chronic respiratory failure and pulmonary hypertension that are often seen
coincidently can require substantial medical therapy, both before and after
definitive surgical repair.

304
Gastroschisis and Omphalocele

Gastroschisis and omphalocele cause lateral and midline defects, respectively,
in the abdominal musculature; after successful closure, the abdomen is devoid
of muscle and highly compliant. Prune belly syndrome, also known as Eagle-
Barrett syndrome, has a similar outcome but is associated with urinary tract
obstruction and massive dilatation of the urinary tract and abdomen, affecting
mesenchymal development and abdominal muscle structure. These defects can
affect respiration in 2 ways. First, the high abdominal compliance means that
caudad diaphragm movement during inspiration will displace the abdominal
contents outward more, with less resistance from the abdominal wall. As a
result, there will be a smaller increase in intra-abdominal pressure and less
outward excursion of the lower rib cage. Second, the paucity of abdominal
muscle limits forceful exhalation and reduces cough effectiveness.
key points
} Normal respiration involves coordination between diaphragm contraction and
abdominal and chest wall motion. Chest wall abnormalities can substantially
compromise respiratory system function by interfering with these functions.
} The central tenet of treating thoracospinal defects is to prevent their progres-
sion, stabilize the chest and spine, and support normal growth. Although the
likelihood of a clinically significant improvement in lung function remains low,
it is possible to prevent or minimize further decline in lung function.
References
1. de Troyer A, Loring S. Action of the respiratory muscles. In: Maklem PT, Mead J, eds.
Handbook of Physiology: Mechanics of Breathing. American Physiological Society;
1986:443–461.
2. Davis GM, Coates AL, Papageorgiou A, Bureau MA. Direct measurement of static chest wall
compliance in animal and human neonates. J Appl Physiol (1985). 1988;65(3):1093–1098
PMID: 3182479 https://doi.org/10.1152/jappl.1988.65.3.1093
3. Gerhardt T, Bancalari E. Chestwall compliance in full-term and premature infants. Acta Paediatr
Scand. 1980;69(3):359–364 PMID: 7376862 https://doi.org/10.1111/j.1651-2227.1980.tb07093.x
4. Reynolds RN, Etsten BE. Mechanics of respiration in apneic anesthetized infants. Anesthesiology.
1966;27(1):13–19 PMID: 5901117 https://doi.org/10.1097/00000542-196601000-00004
5. Richards CC, Bachman L. Lung and chest wall compliance of apneic paralyzed infants.
J Clin Invest. 1961;40(2):273–278 PMID: 13741257 https://doi.org/10.1172/JCI104253
6. Papastamelos C, Panitch HB, England SE, Allen JL. Developmental changes in chest wall
compliance in infancy and early childhood. J Appl Physiol (1985). 1995;78(1):179–184
PMID: 7713809 https://doi.org/10.1152/jappl.1995.78.1.179
7. Openshaw P, Edwards S, Helms P. Changes in rib cage geometry during childhood. Thorax.
1984;39(8):624–627 PMID: 6474391 https://doi.org/10.1136/thx.39.8.624
8. Gerhardt T, Hehre D, Feller R, Reifenberg L, Bancalari E. Pulmonary mechanics in normal
infants and young children during first 5 years of life. Pediatr Pulmonol. 1987;3(5):309–316
9. Davidson MB. The relationship between diaphragm and body weight in the rat. Growth.
1968;32(3):221–223 PMID: 5696255

305
10. Mittman C, Edelman NH, Norris AH, Shock NW. Relationship between chest wall
and pulmonary compliance and age. J Appl Physiol. 1965;20(6):1211–1216
11. Chernick V, England SJ, Haddad GG. Laryngeal function and respiratory system neural reflexes.
In: Haddad GG, Abman SH, Chernick V, eds. Chernick-Mellins Basic Mechanisms of Pediatric
Respiratory Disease. BC Decker; 2002
12. Kosch PC, Hutchinson AA, Wozniak JA, Carlo WA, Stark AR. Posterior cricoarytenoid and
diaphragm activities during tidal breathing in neonates. J Appl Physiol (1985).
1988;64(5):1968–1978 PMID: 3391897 https://doi.org/10.1152/jappl.1988.64.5.1968
13. Hershenson MB, Colin AA, Wohl ME, Stark AR. Changes in the contribution of the rib cage to
tidal breathing during infancy. Am Rev Respir Dis. 1990;141(4 pt 1):922–925 PMID: 2139308
https://doi.org/10.1164/ajrccm/141.4_Pt_1.922
14. Campbell RM Jr, Smith MD, Mayes TC, et al. The characteristics of thoracic insufficiency
syndrome associated with fused ribs and congenital scoliosis. J Bone Joint Surg Am.
2003;85(3):399–408 PMID: 12637423 https://doi.org/10.2106/00004623-200303000-00001
15. Delelis D, Basse-Cathalinat B, Arnaud D, Lavignolle B. [Xenon 133 pulmonary scintigraphy.
Its significance in the preoperative evaluation of pulmonary function in adolescents with
kyphoscoliosis prior to vertebral arthrodesis] [in French]. Anesth Analg (Paris).
1977;34(5):929–942 PMID: 613865
16. Grau M, Leisner B, Rohloff R, et al. [Functional scintigraphy of pulmonary ventilation with
133Xe in juvenile scoliosis (author’s transl)] [in German]. Nuklearmedizin. 1981;20(4):178–182
PMID: 7279684 https://doi.org/10.1055/s-0037-1620736
17. Allen JL, Greenspan JS, Deoras KS, Keklikian E, Wolfson MR, Shaffer TH. Interaction
between chest wall motion and lung mechanics in normal infants and infants with
bronchopulmonary dysplasia. Pediatr Pulmonol. 1991;11(1):37–43 PMID: 1833720
18. Allen JL, Wolfson MR, McDowell K, Shaffer TH. Thoracoabdominal asynchrony in infants
with airflow obstruction. Am Rev Respir Dis. 1990;141(2):337–342 PMID: 2137313
https://doi.org/10.1164/ajrccm/141.2.337
19. Mayer O, Clayton R, Jawad AF, McDonough J, Allen J. Respiratory inductance plethysmography
in healthy three to five year old children. Chest. 2003;124:1812–1819
20. Newton PO, Perry A, Bastrom TP, et al. Predictors of change in postoperative pulmonary
function in adolescent idiopathic scoliosis: a prospective study of 254 patients. Spine.
2007;32(17):1875–1882 PMID: 17762296 https://doi.org/10.1097/BRS.0b013e31811eab09
21. Mayer OH, Redding G. Early changes in pulmonary function after vertical expandable prosthetic
titanium rib insertion in children with thoracic insufficiency syndrome. J Pediatr Orthop.
2009;29(1):35–38 PMID: 19098643 https://doi.org/10.1097/BPO.0b013e3181929c8b
22. Turan S, Bereket A, Omar A, Berber M, Ozen A, Bekiroglu N. Upper segment/lower segment
ratio and armspan-height difference in healthy Turkish children. Acta Paediatr.
2005;94(4):407–413 PMID: 16092452 https://doi.org/10.1111/j.1651-2227.2005.tb01909.x
23. Laghi F, Tobin MJ. Disorders of the respiratory muscles. Am J Respir Crit Care Med.
2003;168(1):10–48 PMID: 12826594 https://doi.org/10.1164/rccm.2206020
24. Estenne M, Derom E, De Troyer A. Neck and abdominal muscle activity in patients with
severe thoracic scoliosis. Am J Respir Crit Care Med. 1998;158(2):452–457 PMID: 9700120
https://doi.org/10.1164/ajrccm.158.2.9710116
25. Fokin AA, Steuerwald NM, Ahrens WA, Allen KE. Anatomical, histologic, and genetic
characteristics of congenital chest wall deformities. Semin Thorac Cardiovasc Surg.
2009;21(1):44–57 PMID: 19632563 https://doi.org/10.1053/j.semtcvs.2009.03.001
26. Fonkalsrud EW. 912 open pectus excavatum repairs: changing trends, lessons learned:
one surgeon’s experience. World J Surg. 2009;33(2):180–190 PMID: 19002739
https://doi.org/10.1007/s00268-008-9793-4
27. Bay V, Farthmann E, Naegele U. Unoperated funnel chest in middle and advances age:
evaluation of indications for operation. J Pediatr Surg. 1970;5(6):606–609 PMID: 5502888
https://doi.org/10.1016/S0022-3468(70)80004-5
28. Malek MH, Berger DE, Marelich WD, Coburn JW, Beck TW, Housh TJ. Pulmonary function
following surgical repair of pectus excavatum: a meta-analysis. Eur J Cardiothorac Surg.
2006;30(4):637–643 PMID: 16901712 https://doi.org/10.1016/j.ejcts.2006.07.004
29. Malek MH, Fonkalsrud EW, Cooper CB. Ventilatory and cardiovascular responses to exercise
in patients with pectus excavatum. Chest. 2003;124(3):870–882 PMID: 12970011
https://doi.org/10.1378/chest.124.3.870

306
30. Quigley PM, Haller JA Jr, Jelus KL, Loughlin GM, Marcus CL. Cardiorespiratory function
before and after corrective surgery in pectus excavatum. J Pediatr. 1996;128(5 pt 1):638–643
PMID: 8627435 https://doi.org/10.1016/S0022-3476(96)80128-4
31. Borowitz D, Cerny F, Zallen G, et al. Pulmonary function and exercise response in patients with
pectus excavatum after Nuss repair. J Pediatr Surg. 2003;38(4):544–547 PMID: 12677562
https://doi.org/10.1053/jpsu.2003.50118
32. Williams AM, Crabbe DC. Pectus deformities of the anterior chest wall. Paediatr Respir Rev.
2003;4(3):237–242 PMID: 12880759 https://doi.org/10.1016/S1526-0542(03)00053-8
33. Nuss D, Kelly RE Jr. Minimally invasive surgical correction of chest wall deformities
in children (Nuss procedure). Adv Pediatr. 2008;55(1):395–410 PMID: 19048741
https://doi.org/10.1016/j.yapd.2008.07.012
34. Robicsek F. Surgical treatment of pectus carinatum. Chest Surg Clin N Am.
2000;10(2):357–376, viii PMID: 10803339
35. Kotzot D, Schwabegger AH. Etiology of chest wall deformities—a genetic review
for the treating physician. J Pediatr Surg. 2009;44(10):2004–2011 PMID: 19853763
https://doi.org/10.1016/j.jpedsurg.2009.07.029
36. Haller JA Jr, Kramer SS, Lietman SA. Use of CT scans in selection of patients for pectus
excavatum surgery: a preliminary report. J Pediatr Surg. 1987;22(10):904–906 PMID: 3681619
https://doi.org/10.1016/S0022-3468(87)80585-7
37. Nakagawa Y, Uemura S, Nakaoka T, Yano T, Tanaka N. Evaluation of the Nuss procedure
using pre- and postoperative computed tomographic index. J Pediatr Surg. 2008;43(3):518–521
PMID: 18358292 https://doi.org/10.1016/j.jpedsurg.2007.10.033
38. Kim HC, Park HJ, Ham SY, et al. Development of automatized new indices for radiological
assessment of chest-wall deformity and its quantitative evaluation. Med Biol Eng Comput.
2008;46(8):815–823 PMID: 18612670 https://doi.org/10.1007/s11517-008-0367-2
39. Fonkalsrud EW. Surgical correction of pectus carinatum: lessons learned from
260 patients. J Pediatr Surg. 2008;43(7):1235–1243 PMID: 18639675
https://doi.org/10.1016/j.jpedsurg.2008.02.007
40. Redding GJ, Kuo W, Swanson JO, et al. Upper thoracic shape in children with pectus
excavatum: impact on lung function. Pediatr Pulmonol. 2013;48(8):817–823 PMID: 22912067
41. Schoenmakers MA, Gulmans VA, Bax NM, Helders PJ. Physiotherapy as an adjuvant to the
surgical treatment of anterior chest wall deformities: a necessity? A prospective descriptive
study in 21 patients. J Pediatr Surg. 2000;35(10):1440–1443 PMID: 11051146
42. Egan JC, DuBois JJ, Morphy M, Samples TL, Lindell B. Compressive orthotics in the treatment
of asymmetric pectus carinatum: a preliminary report with an objective radiographic marker.
J Pediatr Surg. 2000;35(8):1183–1186 PMID: 10945691 https://doi.org/10.1053/jpsu.2000.8724
43. Frey AS, Garcia VF, Brown RL, et al. Nonoperative management of pectus carinatum. J Pediatr
Surg. 2006;41(1):40–45 PMID: 16410105 https://doi.org/10.1016/j.jpedsurg.2005.10.076
44. Haller JA Jr, Colombani PM, Humphries CT, Azizkhan RG, Loughlin GM. Chest wall
constriction after too extensive and too early operations for pectus excavatum. Ann Thorac Surg.
1996;61(6):1618–1624 PMID: 8651758 https://doi.org/10.1016/0003-4975(96)00179-8
45. Nuss D, Kelly RE Jr, Croitoru DP, Katz ME. A 10-year review of a minimally invasive technique
for the correction of pectus excavatum. J Pediatr Surg. 1998;33(4):545–552 PMID: 9574749
https://doi.org/10.1016/S0022-3468(98)90314-1
46. Felts E, Jouve JL, Blondel B, Launay F, Lacroix F, Bollini G. Child pectus excavatum:
correction by minimally invasive surgery. Orthop Traumatol Surg Res. 2009;95(3):190–195
PMID: 19376762 https://doi.org/10.1016/j.otsr.2009.03.001
47. Colin AA, Allen JL, Berde CB, Griscom NT, Hall JE, Young LW. Radiological case of the
month. Bronchial compression and ventilatory dysfunction in scoliosis. Am J Dis Child.
1988;142(5):545–546 PMID: 3358398
48. Shaughnessy WJ. Advances in scoliosis brace treatment for adolescent idiopathic
scoliosis. Orthop Clin North Am. 2007;38(4):469–475, v PMID: 17945126
https://doi.org/10.1016/j.ocl.2007.07.002
49. Jarvis J, Garbedian S, Swamy G. Juvenile idiopathic scoliosis: the effectiveness of
part-time bracing. Spine. 2008;33(10):1074–1078 PMID: 18449040
https://doi.org/10.1097/BRS.0b013e31816f6423
50. Karol LA, Johnston C, Mladenov K, Schochet P, Walters P, Browne RH. Pulmonary function
following early thoracic fusion in non-neuromuscular scoliosis. J Bone Joint Surg Am.
2008;90(6):1272–1281 PMID: 18519321 https://doi.org/10.2106/JBJS.G.00184

307
51. Wong CA, Cole AA, Watson L, Webb JK, Johnston ID, Kinnear WJ. Pulmonary function
before and after anterior spinal surgery in adult idiopathic scoliosis. Thorax. 1996;51(5):534–536
PMID: 8711684 https://doi.org/10.1136/thx.51.5.534
52. Thompson GH, Akbarnia BA, Campbell RM Jr. Growing rod techniques in early-onset
scoliosis. J Pediatr Orthop. 2007;27(3):354–361 PMID: 17414025
https://doi.org/10.1097/BPO.0b013e3180333eea
53. Campbell RM Jr, Smith MD. Thoracic insufficiency syndrome and exotic scoliosis.
J Bone Joint Surg Am. 2007;89(suppl 1):108–122 PMID: 17272428
https://doi.org/10.2106/00004623-200701001-00013
54. Dannawi Z, Altaf F, Harshavardhana NS, El Sebaie H, Noordeen H. Early results of a remotely-
operated magnetic growth rod in early-onset scoliosis. Bone Joint J. 2013;95-B(1):75–80
PMID: 23307677 https://doi.org/10.1302/0301-620X.95B1.29565
55. Akbarnia BA, Cheung K, Noordeen H, et al. Next generation of growth-sparing
techniques: preliminary clinical results of a magnetically controlled growing rod in
14 patients with early-onset scoliosis. Spine. 2013;38(8):665–670 PMID: 23060057
https://doi.org/10.1097/BRS.0b013e3182773560
56. Davis JT, Long FR, Adler BH, Castile RG, Weinstein S. Lateral thoracic expansion for
Jeune syndrome: evidence of rib healing and new bone formation. Ann Thorac Surg.
2004;77(2):445–448 PMID: 14759413 https://doi.org/10.1016/S0003-4975(03)01340-7
57. Udupa JK, Tong Y, Capraro A, et al. Understanding respiratory restrictions as a function
of the scoliotic spinal curve in thoracic insufficiency syndrome: a 4D dynamic MR
imaging study. J Pediatr Orthop. 2020;40(4):183–189 PMID: 32132448
doi: 10.1097/BPO.0000000000001258 PMID: 30247181
58. Chatrath RR, el-Shafie M, Jones RS. Fate of hypoplastic lungs after repair of congenital
diaphragmatic hernia. Arch Dis Child. 1971;46(249):633–635 PMID: 5118051
https://doi.org/10.1136/adc.46.249.633
59. Lally KP. Congenital diaphragmatic hernia. Curr Opin Pediatr. 2002;14(4):486–490
PMID: 12130916 https://doi.org/10.1097/00008480-200208000-00022
60. Rottier R, Tibboel D. Fetal lung and diaphragm development in congenital diaphragmatic
hernia. Semin Perinatol. 2005;29(2):86–93 PMID: 16050526
https://doi.org/10.1053/j.semperi.2005.04.004
61. Panitch H, Hedrick H, Rintoul N, Weiner D. Pulmonary function in infants with congenital
diaphragmatic hernia. Proc Am Thorac Soc. 2005;2:A187

PART
4
Upper Airway Infections
Chapter 16. Croup, Epiglottitis, and Bacterial Tracheitis..............311

309
19 PP 2ND ED - PO 04_309-310.indd 309 11/6/23 8:17 AM

19 PP 2ND ED - PO 04_309-310.indd 310 9/12/23 9:26 AM
CHAPTER
16
Croup, Epiglottitis, and Bacterial Tracheitis
Croup
CASE REPORT 16-1
A 2-year-old boy with a history of mild upper respiratory symptoms for 2 days
develops sudden onset of a barky, croupy cough at 2:00 am. His voice is hoarse.
When taken to the emergency department (ED), he develops intermittent inspi-
ratory stridor when agitated. He is afebrile and tachycardic. His oxyhemoglobin
saturation in room air is normal, and he has minimal retractions and no cyano-
sis. Lung auscultation reveals good and equal air exchange bilaterally, with
coarse sounds but no wheeze or crackles. There is a history of similar symptoms
2 months ago, and, as his parents prepared to take to him to the ED, there was
sudden resolution of symptoms during the car trip. That time, he was observed
for a short time in the ED before being discharged. A diagnosis of croup is
suspected.
Introduction
Croup, or acute laryngotracheobronchitis, is an early childhood viral syn-
drome characterized by acute laryngeal and subglottic swelling resulting in the
sudden onset of a barky cough, inspiratory stridor, hoarse voice, and respira-
tory distress. Onset of these symptoms in a young child with acute worsening,
usually in the early hours of the morning, and associated disruption of family
routine may lead to substantial anxiety in both the child and the caretaker.
Causes
The cause of croup is primarily parainfluenza type 1.1 Other viruses
implicated in the cause are parainfluenza types 2 and 3; influenza A and B;
adenovirus; respiratory syncytial virus; rhinovirus; measles; human metap-
neumovirus; and coronavirus, including SARS-CoV-2, the virus causing
COVID-19.2,3 Most patients presenting with mild symptoms and mild fever
have acute laryngotracheitis. Presence of a high-grade fever, substantial
respiratory distress, and toxemia point to a bacterial cause, such as bacterial
tracheitis or laryngotracheobronchitis.4
311

312
Pathophysiology
Mild cases involve noninflammatory edema in the subglottic region. More
severe cases (acute laryngotracheitis) involve
inflammation and edema of the subglottic area and
lateral wall of the trachea, which is characterized by
cellular infiltration with lymphocytes, neutrophils,
histiocytes, and plasma cells. The inflammation and
edema of the subglottic region result in narrowing
and clinical presentation of barky, brassy cough;
hoarse voice; stridor; and respiratory distress with
retractions. Subglottic and upper tracheal narrowing
is responsible for the typical steeple sign on radio-
graphs (Figure 16-1). The fluctuation in symptom
severity, nocturnal worsening, and tendency of
some children to develop severe and recurrent
Figure 16-1. Frontal
radiograph of the airway of a episodes of croup may be related to whether the
5
patient presenting with croup. child is agitated or calm, low levels of endogenous
Note the typical steeple sign 6
cortisol, and tendency of some children for having
due to upper tracheal and
subglottic narrowing. an intrinsically narrower subglottic space.7 Host
Courtesy of Mariangeles Medina
factors, such as allergies, may play a role in recur-
Perez, MD. rent croup.8
Epidemiology
Most patients with viral croup are younger than 6 years and more typically are
between 3 months and 3 years of age. The incidence in boys is 1.5 times higher,
and the disease tends to occur most commonly from September to December in
the northern hemisphere. The incidence has been reported to correlate with
parainfluenza virus prevalence.9 Up to 6% of children with croup may require
hospitalization.10 CD14 gene polymorphism (C/C variant of CD14 [C-159T])
has been reported to be associated with reduced prevalence of croup.11
Clinical Features
Typically, the child with croup has mild upper respiratory symptoms for
12 to 48 hours before the abrupt onset of the characteristic barky cough, res-
piratory distress, stridor, and hoarse voice. The onset of these symptoms is
usually during the early hours of the morning. The symptoms are generally
short-lived, and most children have resolution of the barky cough within
48 hours. The symptoms are worse if the child is agitated. There may be
diminished breath sounds, rhonchi, and scattered crackles.
Differential Diagnosis
The differential diagnosis of croup includes retropharyngeal or peritonsillar
abscess, which is identified by a typical swelling of the local area. Other

313
Chapter 16—Croup, Epiglottitis, and Bacterial Tracheitis
diagnoses to rule out include angioneurotic edema, allergic reaction, and

foreign body, which are identified by a corroborative history and sudden onset.
Tracheitis and epiglottitis, though rare, should be considered in the presence
of toxic appearance, fever, and rapidly worsening course.
Unlike viral croup, spasmodic croup (laryngismus stridulus) usually involves
the croup-like cough that occurs in an older age group, tends to be recurrent,
and is thought to be allergic in origin. It is treated with corticosteroids and
tends to be benign even though it can be persistent. Recurrent croup is diag-
nosed in patients with tracheomalacia who present with prominent cough with
each upper respiratory infection episode that results in a visit to urgent care or
the emergency department. Investigators in a retrospective study of recurrent
croup reported a 47% incidence of gastroesophageal reflux.12
Modern vaccination practices have resulted in a drastic reduction in the preva-
lence of laryngeal diphtheria, a highly contagious infection that should be con-
sidered in patients with possible exposure who are unimmunized. It can affect
all ages. There is usually a prodromal phase of pharyngitis, and the illness is
characterized by hoarseness, barking cough, usually dysphagia, minimal to
severe inspiratory stridor, fever, and membranous pharyngitis. Corynebacterium
diphtheriae is identified on smear and culture of the membrane.
Assessment of Severity
Table 16‑1 summarizes the classification of clinical features in mild, moderate,
and severe croup.
Table 16-1. Classification of Croup Severity

Clinical Feature Severity
Mild Moderate Severe
Cough Occasional barking Frequent barking Frequent barking
Stridor None at rest Audible at rest Prominent inspiratory
Retractions None or mild Suprasternal Marked sternal
Agitation None None or little Substantial with distress
Investigations
Radiography is not usually indicated because the clinical picture is straight-
forward and there is appropriate response to treatment. Moreover, the child may
be more agitated during a visit to the radiology department, resulting in further
worsening of clinical condition. In the event that there is an atypical clinical
picture and the diagnosis is uncertain, anteroposterior and lateral soft-tissue
neck radiographs show a typical steeple sign that is consistent with the diagno-
sis of croup (Figure 16-1) or that differentiates it from an alternative diagnosis,
such as epiglottitis.13 Soft-tissue neck radiographs are not routinely used in

314
patients with croup; however, if performed to exclude other causes of upper

airway obstruction, they will show tracheal narrowing, which has been
correlated with the severity and outcome in patients with croup.14
Management
General
Effort should be taken to make the child comfortable and to reduce agitation
because agitation can substantially worsen the condition. Sitting the child
comfortably in the lap of a parent or caregiver is usually the best way to
examine the child.
Figure 16-2 shows an algorithm to treat croup in pediatric practice. Children
who have a compromised airway, such as a subglottic stenosis, may experience
worse symptoms and may require endotracheal intubation or tracheotomy.
Mild croup Moderate croup Severe croup

No stridor or significant Stridor, retractions, Stridor, persistent
respiratory distress or retractions no agitation agitation, lethargy
• Oral dexamethasone Minimize interventions, • Minimize intervention, unnecessary

0.6 mg/kg body weight eg, avoid unnecessary exam investigations, separation from
• Reassure and educate exam & investigations, parents to reduce distress and
parents regarding anticipated separating child from agitation
benign course, when to come parents. • “Blow-by oxygen” if hypoxia
back, and what to look for at • Oral/IM dexamethasone
home 0.6 mg/kg body weight
• Nebulized epinephrine (racemic:
2.25%, 0.5 ml, or L-epinephrine
• Nebulized epinephrine (racemic:
1:1000, 5 ml)
Discharge home 2.25%, 0.5 ml, or L-epinephrine
1:1000, 5 ml)
• Oral/IM dexamethasone
0.6 mg/kg body weight
• General care like in mild case. If good response, If poor response,
• Observe for improvement Observe for 2 hours repeat epinephrine,
admit to PICU. If poor
response to second
dose, look for
If improvement with If no or minimal alternative diagnoses
no stridor or retractions, improvement by
discharge home after 4 hours, consider
educating parents about hospitalization If severe symptoms
the possible course, persist or distress
when to come back, and recurs, repeat
what to look for nebulized epinephrine
If only mild symptoms persist,
ie, croupy cough, no recurrence
of stridor or retraction,
Discharge home treat like patient with mild stridor
and reassure, educate parents If poor response to
second treatment with
nebulized epinephrine,
Discharge home hospitalize and consider
alternate diagnosis
Figure 16-2. Algorithm for the management of croup.

315
Corticosteroids
Corticosteroids are routinely used in the treatment of croup. Investigators in a
meta-analysis of 24 studies in which corticosteroids were used to treat croup
concluded that dexamethasone and budesonide are effective in relieving the
symptoms of croup as early as 6 hours after treatment; fewer co-interventions
were used, and the length of hospital stay was reduced in patients treated with
corticosteroids.15 A recent Cochrane Database review reported the glucocorti-
coids improved symptoms at 2 hours, reduced length of stay, and led to fewer
return visits.16
In children with mild croup, oral dexamethasone in a dose of 0.6 mg per
kilogram of body weight results in consistent, small, but clinically signifi-
cant improvement.17 If the child is vomiting, intramuscular dexamethasone
is indicated.
In moderately severe cases of croup, a single dose of intramuscular dexameth-
asone of 0.6 mg per kilogram of body weight or nebulized budesonide 4 mg
resulted in statistically significant reduction in hospitalization. Dexamethasone
was associated with greater clinical improvement at 5 hours.18
Results from a systematic review of 43 studies in which investigators used
dexamethasone (0.6 mg/kg administered orally) or nebulized budesonide
(2–4 mg) involving more than 4,500 children from North America, Europe,
Asia, and Australia showed that glucocorticoids reduced croup symptoms
at 2 hours, shortened hospital stays, and reduced the rate of return visits.16
A lower dose of dexamethasone, 0.15 mg/kg, has had a similar effect and is
gaining wider acceptance.19Administration of a single dose of dexamethasone
to treat croup does not affect endogenous corticosteroid levels.20
Epinephrine
Although nebulized racemic epinephrine traditionally has been used to treat
croup, nebulized epinephrine 1/1,000 is as effective and safe.21 The usual
dose is 0.05 mL/kg of 2.25% racemic epinephrine or 5 mL (or 0.5 mL/kg) of
1/1,000 epinephrine via nebulizer. Authors of a systematic review of 8 studies
(225 subjects), with the limitation of the number of relevant studies and
subjects, reported statistically significant, albeit transient, improvement
in croup symptoms within 30 minutes of epinephrine administration.22
Therefore, children with croup who have received epinephrine should
continue to be monitored for recurrence of symptoms and can be discharged
home if the symptoms do not recur within 2 to 4 hours after treatment.23,24
Symptoms that occur once the epinephrine wears off are not likely a rebound
phenomenon but a recurrence of the original symptoms. If more than 2 doses
of epinephrine are needed, the child likely should be hospitalized. Over-
the-counter epinephrine metered-dose inhalers have been used for home
treatment of recurrent croup; however, oral dexamethasone or nebulized

316
budesonide (see Corticosteroids earlier in this chapter) are gaining wider

acceptance and obviate epinephrine use–related adverse effects.
Oxygen Supplementation
Oxygen supplementation may be used in the unlikely situation of hypoxia.
Because croup is caused by airway obstruction rather than ventilation/
perfusion mismatch, a patient with croup who is hypoxic is probably also
hypercarbic. The clinical practice guidelines developed by the Alberta
Clinical Practice Guideline Working Group recommend blow-by oxygen
in children with respiratory distress.13
Humidified Air
Although it has been used for a long time, there is no published evidence to
suggest that administration of humidified air results in substantial improve-
ment. Authors of a systematic review and meta-analysis of 3 studies25 con-
cluded that there is no statistically significant improvement in the croup score
of children with mild to moderate croup treated in an emergency setting and
that evidence is insufficient to exclude either a small beneficial or a harmful
effect with its use. Severe burns due to steam inhalation used for respiratory
infection have been reported.26,27
Heliox
Heliox is a combination of inert gas helium with oxygen. Because low-density
helium (as opposed to the nitrogen present in the air) converts turbulent flow
into laminar flow through a narrow airway, some have advocated its use.
Heliox was reported to provide no benefit compared with results with stan-
dard treatment in older studies,7,28 especially in patients with moderate to
severe croup, but more recent research has shown that heliox may be benefi-
cial in the short term for children with moderate to severe croup treated with
dexamethasone. The effect may be similar to 100% oxygen administered
with 1 or 2 doses of adrenaline.29
Other Medications
Other medications, such as decongestants, short-acting β2 agonists, antitus-
sives, and analgesics, have no physiological basis for their use. Sedatives
should not be prescribed.
When to Refer
X Cases of croup associated with excessive tachycardia may be associated
with impending respiratory failure.
X In addition, persistence of symptoms for several days may merit referral for
ear, nose, and throat specialist or pediatric pulmonologist evaluation and to
rule out underlying structural airway abnormality. Similarly, patients with
recurrent croup or croup in children with a history of airway manipulation
or facial hemangioma warrant a referral.

317
When to Admit
X Severe respiratory distress, particularly if there is hypoxia (hypoxia is
unusual in benign croup)
X Inability to eat or drink
X Acute care requiring 2 or more nebulizations of epinephrine
Epiglottitis
CASE REPORT 16-2
A 4-year-old boy who was previously healthy and received all immunizations
expected for his age is brought into the emergency department for evaluation
of fever and sore throat. He refuses to eat or talk. He has a temperature of
39.5°C (103.1°F) and oxygen saturation of 94% while breathing room air. He
appears ill, is drooling, and prefers to sit alone and prop himself up and forward
onto his hands in a tripod position. The examination reveals inspiratory stridor
and suprasternal retractions.
The differential diagnosis is short, and clinical suspicion for impending
respiratory failure due to acute epiglottitis should be quite high. In this case,
consultation with the otolaryngology and anesthesiology teams should be
initiated, and the child should be taken to the operating room for endotracheal
intubation. Ideally, a protocol for team mobilization for this situation should be
determined in advance and standardized as an interdisciplinary policy.
Introduction
Acute epiglottitis, also known as supraglottitis, is a potentially life-threatening
infection of the supraglottic structures that can lead to sudden, fatal airway
obstruction if treatment is delayed. Classically, the disease does not involve
the subglottic or tracheal mucosa. If treatment is delayed, it may rapidly
progress to complete airway obstruction with cardiorespiratory arrest.
Epidemiology
Historically, acute epiglottitis was described as a disease of adults, but in the
1960s it was recognized primarily as a pediatric disease. Since the introduc-
tion of the Haemophilus vaccination, the incidence has decreased significantly
to 0.63 cases per 100,000 per year in the United States.30 Invasive disease due
to Haemophilus influenzae occurred at a rate of 116 cases per 100,000 children
in 1986, and this is the organism most often cultured in children with epiglot-
titis. After the introduction of the conjugate vaccine against H influenzae
type b (Hib) in 1985, the incidence of invasive disease due to H influenzae
decreased dramatically,31 and there was a concomitant and dramatic decline
in the incidence of acute epiglottitis in children.32–34 Epiglottitis is now more
frequently seen in adults than in children, and respiratory pathogens other
than H influenzae are typically implicated.35

318
Causative Organisms
As the frequency of Hib disease has decreased, the cause of epiglottitis has
shifted toward other causative organisms. Today, most cases are thought to
be caused by other bacteria, such as Streptococcus pneumoniae and other
Streptococcus species, Staphylococcus aureus, Moraxella catarrhalis, Pseudo-
monas species, Candida albicans, Klebsiella pneumoniae, Pasteurella multo-
cida, and Neisseria species.33,36 Bacterial superinfection of viral infections
also occurs, particularly with herpes simplex, parainfluenza, varicella zoster,
and Epstein-Barr.34,36
Epiglottitis tends to occur throughout the year but mainly during the 6-month
period from December to May in the northern hemisphere. It previously oc-
curred equally in male and female patients, with a slight male predominance
between the ages of 2 and 6 years,37 but more recently has shifted toward
substantially older patients38 and should be a consideration at any age.
The onset of epiglottitis is usually abrupt, preceded by a minor upper respira-
tory infection in some cases. The onset is characterized by high fever, toxic
appearance, and sore throat that progresses over a few hours to dysphagia,
drooling, and respiratory distress. The patient appears anxious and irritable.
Stridor is a late finding. Breathing becomes noisy, and the voice and cry
are muffled as swelling of the aryepiglottic folds and supralaryngeal mucosa
obstructs the glottic inlet. The patient tends to sit forward in the sniffing
position with the neck hyperextended to increase airway patency. Complete
airway obstruction may occur at any time without any preceding deterioration
in clinical signs.
Diagnosis
A very high index of suspicion must be maintained, and epiglottitis should be
considered in every child with apparent acute upper airway obstruction who
has a high fever and sore throat, especially when those signs have developed
over a few hours. A lateral neck radiograph can be helpful, though it should
be attempted only if the patient is stable and the diagnosis is in doubt, because
the disease can progress rapidly. Therapeutic trials of inhaled medicines, such
as corticosteroids or racemic epinephrine, should not be initiated because time
is wasted and it may irritate the child, leading to complete obstruction of
the airway. In addition, direct visualization of the epiglottis should not be
performed until the child is undergoing tracheal intubation.

319
Epiglottitis must be differentiated from other causes of acute upper airway

obstruction, including viral croup (laryngotracheobronchitis), spasmodic
croup, and bacterial tracheitis. Any patient with stridor, sore throat, and
fever should be referred to a specialist for confirmation of the diagnosis.
Trauma and accidental causes are easily ruled out by the history. Foreign
body aspiration should be considered as well, and this diagnosis may be
suggested by a history of choking while eating or of playing with small
objects in the mouth, the absence of fever, or visualization of an object
in the airway on inspection.
Management
Most fatalities occur within the first few hours after the patient has arrived at
the hospital. All deaths result from complete airway obstruction. Once the
diagnosis is determined, there should be no delay in establishing an artificial
airway. If there is time, the child should undergo intubation in the operating
room under general anesthesia by personnel who can perform emergency
tracheostomy in case intubation fails. Corticosteroids and epinephrine have
been used in the past; however, there is no solid evidence that these
medications are helpful in cases of epiglottitis.
Approximately 10% to 25% of cases may be managed by observation, though
these are older patients with larger airways, and mortality is a risk. Box 16-1
describes an appropriate treatment protocol.
Box 16-1
Management When Epiglottitis Is Suspected
ū Avoid disturbance until an airway is secured. Allow the child to sit up and stay
in a parent’s arms to avoid agitation.
ū Provide 100% oxygen via blow-by administration.
ū Perform a radiological lateral neck study only if the child appears stable and
the diagnosis of epiglottitis is in doubt.
ū Notify and assemble the epiglottitis team (eg, intensivist; ear, nose, and throat
specialist; anesthetist; and pediatric pulmonologist).
ū Perform intubation in the operating room or tracheotomy if intubation is
not possible.
ū Provide sedation (after intubation) or critical care (if tracheostomy is required).
ū Administer intravenous antibiotics, which may effectively control inflammation
and infection. Antibiotics are usually prescribed to treat the most common
types of bacteria. Blood cultures are usually obtained with the premise that
any organism found growing in the blood can be attributed as the cause of
the epiglottitis, even though Hemophilus influenzae (which has a recovery rate
of 80%–100% from the blood) is now a very uncommon cause of epiglottitis.

320
When to Refer
As soon as epiglottitis is suspected, the child should be referred to the
nearest pediatric emergency department with surgical and anesthesia
expertise available.
When to Admit
All children suspected of having epiglottitis should be admitted to the hospital
for intravenous antibiotic treatment and intensive care monitoring. The surgical
specialist (eg, pediatric ear, nose, and throat specialist; pediatric surgeon) and
anesthesiologist should be contacted immediately. In some institutions, rapid
responders may include a skilled flexible bronchoscopist. The medical and
surgical team should be ready to place an endotracheal tube emergently and
also be ready for emergent tracheotomy. It is best for the surgeons to visualize
the airway when in the operating room.
Bacterial Tracheitis
CASE REPORT 16-3
A 4-year-old-boy arrives in the emergency department with cyanosis and a
very productive cough. His history reveals a mild case of croup 1 week prior.
The previous day, he developed a high fever with rapidly progressive symp-
toms of cough and respiratory distress. Respiratory failure is diagnosed. He
undergoes intubation, and purulent secretions are aspirated from the airway.
A diagnosis of bacterial tracheitis is assigned.
Introduction
Bacterial tracheitis is a serious and potentially life-threatening cause of acute
upper airway obstruction. Bacterial tracheitis has also been referred to as
membranous croup, bacterial croup, and pseudomembranous croup.
Epidemiology
Until recently, viral croup and epiglottitis have been considered the main causes
of infectious upper airway obstruction.39 Immunization against H influenzae40
and treatment of viral croup with nebulized or systemic corticosteroids15–18
have changed the incidence, morbidity, and mortality of upper airway obstruc-
tion. Bacterial tracheitis has assumed predominance over epiglottitis as the
most common cause of acute upper airway obstruction in children older than
2 years. However, it is still uncommon, the estimated annual incidence being
0.1 in 100,000 children. The manifestation may vary between a mild upper
respiratory infection and a typical bacterial tracheitis.41 The authors of an

321
article published in 2020 reported a higher incidence of tracheitis in patients

with tracheostomy.42
Bacterial tracheitis generally affects children between 4 weeks and 13 years
of age, with a mean age of 4 years. The number of cases increases during the
fall and winter when viral croup is more prevalent.
Causative Organisms
The pathogenesis of bacterial tracheitis remains controversial. It often occurs
as a secondary bacterial infection complicating a preexisting viral infection,
including parainfluenza, adenovirus, and influenza A or B. Bacteria can gain
access to the tracheal epithelium after a viral infection compromises epithelial
integrity. Tracheal epithelial inflammation causes mucosal damage and pre-
disposes the patient to bacterial adherence to the compromised epithelial cells
of the trachea. The usual protective and defensive response of the epithelial
cells is weakened and results in mucous hypersecretion as well as inflamma-
tory cell chemotaxis, allowing for thick mucopurulent secretions to accumu-
late, sometimes forming a pseudomembrane. Thick secretions and sloughed
mucosa may result in tracheal obstruction, which may also involve main-
stem bronchi.43 Before 1985, when the Hib conjugate vaccine was introduced,
H influenzae was one of the primary causative organisms, but since 1997,
the most commonly implicated organism has been S aureus, followed by
M catarrhalis, Streptococcus species, and oral anaerobes.44 In patients admit-
ted to a pediatric intensive care unit, ventilator-associated tracheobronchitis
has been associated with an increase in the length of stay and mortality,45
and a reduction in the incidence has been reported when an evidence-based
approach for prevention is used.46
Presentation
Bacterial tracheitis can be distinguished from croup by patient age and
symptom severity (Table 16-2).47 Children with bacterial tracheitis tend
to be older (preschoolers) than are those with viral croup (toddlers). A sign
more characteristic of bacterial tracheitis is toxic appearance and high fever.
Patients with both bacterial tracheitis and viral croup can present with a
prodrome of fever, barky cough, and stridor. In contrast to croup symptoms,
bacterial tracheitis symptoms worsen over time. The presenting symptoms
are shown in Box 16-2.

322
Table 16-2. Comparison of Epiglottitis, Viral Croup, and Bacterial Tracheitis

Factor Epiglottitis Viral Croup Bacterial Tracheitis
Age 2–6 years 3 months–3 years 4 weeks–13 years
Organism Various Parainfluenza 1, 3 Staphylococcus aureus
Streptococcus species
Moraxella catarrhalis
Season All year Late spring, late fall All year
Clinical Child sitting Child lying down Toxic appearance
presentation Toxic appearance Nontoxic appearance Barking cough
Drooling Barking cough
Dysphagia Hoarseness
Muffled voice
Onset Rapid; over a few Variable; a few hours Variable; a few hours
prodrome hours to 4 days to 5 days
Stridor Less common Common Common
Fever High Low High
Chest Less common Common Common
retractions
Lateral Swollen epiglottis Subglottic narrowing Pseudomembrane
neck radiograph
Progression Rapid Usually slow Usually slow
Recurrence Rare Common Rare
Box 16-2
Presentation of a Patient With Bacterial Tracheitis
ū Fever, which may be high
ū Stridor, inspiratory; may also be expiratory
ū Seal-like brassy cough
ū Hoarseness
ū Dyspnea with retractions, nasal flaring
ū Cyanosis
ū May progress rapidly to respiratory failure

323
Tracheostomy and Tracheitis

Patients with tracheostomy are more likely to have other complex issues48,49
and bacterial colonization of the trachea and contiguous airways. Such patients
tend to have a higher incidence of tracheitis,42,50 which is diagnosed and treated
early because there is likely to be a low threshold for direct visualization of
the trachea with use of a bronchoscope. Viral coinfection is associated with
poorer outcome.
Diagnosis
Lateral and anteroposterior radiographs of the neck and chest may be helpful
in diagnosis. Findings on plain-film radiographs include subglottic narrowing,
a ragged edge to the usually smooth tracheal air column, and a hazy shadow
within the tracheal lumen. The epiglottis and supraglottic structures appear
normal on neck radiographs. The steeple sign characteristically seen in croup
may also be evident.
The most definitive procedure is to visualize the trachea endoscopically.
The supraglottic structures will appear normal, but subglottic edema is the
prominent feature, and ulcerations and copious purulent secretions will be
present. These secretions should be cultured so that the causative agent may
be treated effectively with antibiotics.
Management
Children with bacterial tracheitis must be monitored very closely; often,
tracheal intubation with mechanical ventilation is necessary in the event of
respiratory failure or an inability to mobilize secretions effectively. Using an
endotracheal tube 1 size smaller than usual can reduce trauma to the subglot-
tic area. Careful attention to the suctioning and mobilization of secretions is
essential. Occlusion of the endotracheal tube has been reported as the most
frequent cause of death in children with bacterial tracheitis who have under-
gone intubation and mechanical ventilation. Some otolaryngologists have
advocated for expectant placement of tracheotomy tubes in children with
bacterial tracheitis for this reason. Humidification of the inspired air helps
prevent mucous plugging of the endotracheal tube. Antibiotics and suppor-
tive care are essential for full recovery. Antibiotics should be initiated with
nafcillin or oxacillin (200 mg/kg per day divided every 6 hours for either
agent) in conjunction with a third-generation cephalosporin, such as ceftri-
axone (50 mg/kg daily). The addition of vancomycin should be considered
if resistant organisms are present in the local community or if there is
multisystem involvement.

324
Complications
Complications associated with bacterial tracheitis include toxic shock syn-
drome, septic shock, postintubation pulmonary edema, acute respiratory
distress syndrome, and subglottic stenosis.51 Most children recover, and there
is no reason to suspect an underlying immunodeficiency. It is rare for a child
to have a second episode of bacterial tracheitis.
key points
} The differential diagnosis for children who have stridulous breathing should
include croup, epiglottitis, and bacterial tracheitis.
} Most patients with croup can be treated as outpatients.
} When symptoms are severe, croup should be differentiated from alternative
causes, such as epiglottitis or bacterial tracheitis.
} Corticosteroids are the established treatment of choice for croup.
} If epiglottitis is suspected, the child should be admitted to the hospital.
A pediatric otolaryngologist or anesthesiologist should be contacted imme-
diately and should be the only physician to attempt to visualize the airway.
} Children who have croup tend to have a sudden onset of hoarseness and
barking cough, but do not appear toxic, as do those who have epiglottitis
or bacterial tracheitis.
} Children with bacterial tracheitis have high fever and typically require endotra-
cheal intubation and mechanical ventilation.
References
1. Henrickson KJ, Hoover S, Kehl KS, Hua W. National disease burden of respiratory
viruses detected in children by polymerase chain reaction. Pediatr Infect Dis J.
2004;23(1)(suppl):S11–S18 PMID: 14730265 doi: 10.1097/01.inf.0000108188.37237.48
2. Venn AMR, Schmidt JM, Mullan PC. Pediatric croup with COVID-19. Am J Emerg Med.
2021;43:287.e1–287.e3 PMID: 32980228 doi: 10.1016/j.ajem.2020.09.034
3. Pitstick CE, Rodriguez KM, Smith AC, Herman HK, Hays JF, Nash CB. A curious case
of croup: laryngotracheitis caused by COVID-19. Pediatrics. 2021;147(1):e2020012179
PMID: 32913132 doi: 10.1542/peds.2020-012179
4. Cherry JD. Clinical practice. Croup. N Engl J Med. 2008;358(4):384–391 PMID: 18216359
doi: 10.1056/NEJMcp072022
5. Johnson D, Williamson J. Croup; duration of symptoms and impact on family functioning.
Pediatr Res. 2001;49:83A
6. Geelhoed GC. Croup. Pediatr Pulmonol. 1997;23(5):370–374 PMID: 9168511
doi: 10.1002/(SICI)1099-0496(199705)23:5<370::AID-PPUL9>3.0.CO;2-O
7. Bjornson CL, Johnson DW. Croup. Lancet. 2008;371(9609):329–339 PMID: 18295000
doi: 10.1016/S0140-6736(08)60170-1
8. Arslan Z, Cipe FE, Ozmen S, Kondolot M, Piskin IE, Yöney A. Evaluation of allergic
sensitization and gastroesophageal reflux disease in children with recurrent croup. Pediatr Int.
2009;51(5):661–665 PMID: 19419517 doi: 10.1111/j.1442-200X.2009.02859.x
9. Marx A, Török TJ, Holman RC, Clarke MJ, Anderson LJ. Pediatric hospitalizations for croup
(laryngotracheobronchitis): biennial increases associated with human parainfluenza virus 1
epidemics. J Infect Dis. 1997;176(6):1423–1427 PMID: 9395350 doi: 10.1086/514137
10. Klassen TP. Croup. A current perspective. Pediatr Clin North Am. 1999;46(6):1167–1178
PMID: 10629679 doi: 10.1016/S0031-3955(05)70180-2

325
11. Rennie DC, Karunanayake CP, Chen Y, et al. CD14 gene variants and their importance for
childhood croup, atopy, and asthma. Dis Markers. 2013;35(6):765–771 PMID: 24347797
doi: 10.1155/2013/434920
12. Waki EY, Madgy DN, Belenky WM, Gower VC. The incidence of gastroesophageal reflux
in recurrent croup. Int J Pediatr Otorhinolaryngol. 1995;32(3):223–232 PMID: 7665269
doi: 10.1016/0165-5876(95)01168-B
13. Worrall G. Croup. Can Fam Physician. 2008;54(4):573–574. PMID: 18411388
14. Yang WC, Hsu YL, Chen CY, et al. Initial radiographic tracheal ratio in predicting
clinical outcomes in croup in children. Sci Rep. 2019;9(1):17893 PMID: 31784540
doi: 10.1038/s41598-019-54140-y
15. Ausejo M, Saenz A, Pham B, et al. The effectiveness of glucocorticoids in treating croup:
meta-analysis. BMJ. 1999;319(7210):595–600 PMID: 10473471 doi: 10.1136/bmj.319.7210.595
16. Gates A, Gates M, Vandermeer B, et al. Glucocorticoids for croup in children. Cochrane Libr.
2018;(8):CD001955. Accessed March 30, 2022 PMID: 30133690
doi: 10.1002/14651858.CD001955.pub4
17. Bjornson CL, Klassen TP, Williamson J, et al; Pediatric Emergency Research Canada Network.
A randomized trial of a single dose of oral dexamethasone for mild croup. N Engl J Med.
2004;351(13):1306–1313 PMID: 15385657 doi: 10.1056/NEJMoa033534
18. Johnson DW, Jacobson S, Edney PC, Hadfield P, Mundy ME, Schuh S. A comparison of
nebulized budesonide, intramuscular dexamethasone, and placebo for moderately severe croup.
N Engl J Med. 1998;339(8):498–503 PMID: 9709042 doi: 10.1056/NEJM199808203390802
19. Petrocheilou A, Tanou K, Kalampouka E, Malakasioti G, Giannios C, Kaditis AG. Viral croup:
diagnosis and a treatment algorithm. Pediatr Pulmonol. 2014;49(5):421–429 PMID: 24596395
doi: 10.1002/ppul.22993
20. Gill N, Sirizzotti N, Johnson D, et al. Endogenous glucocorticoid response to single-dose
dexamethasone for croup in children: a pharmacodynamic study. Pediatr Emerg Care.
2020;36(1):50–56 PMID: 28398936
21. Waisman Y, Klein BL, Boenning DA, et al. Prospective randomized double-blind study
comparing L-epinephrine and racemic epinephrine aerosols in the treatment of laryngotracheitis
(croup). Pediatrics. 1992;89(2):302–306 PMID: 1734400 doi: 10.1542/peds.89.2.302
22. Bjornson C, Russell K, Vandermeer B, Klassen TP, Johnson DW. Nebulized epinephrine for
croup in children. Cochrane Database Syst Rev. 2013;(10):CD006619 PMID: 24114291
23. Kelley PB, Simon JE. Racemic epinephrine use in croup and disposition. Am J Emerg Med.
1992;10(3):181–183 PMID: 1375027 doi: 10.1016/0735-6757(92)90204-B
24. Corneli HM, Bolte RG. Outpatient use of racemic epinephrine in croup. Am Fam Physician.
1992;46(3):683–684 PMID: 1514465
25. Moore M, Little P. Humidified air inhalation for treating croup: a systematic review and
meta-analysis. Fam Pract. 2007;24(4):295–301 PMID: 17602176 doi: 10.1093/fampra/cmm022
26. Al Himdani S, Javed MU, Hughes J, et al. Home remedy or hazard? Management and costs of
paediatric steam inhalation therapy burn injuries. Br J Gen Pract. 2016;66(644):e193–e199
PMID: 26917659 doi: 10.3399/bjgp16X684289
27. Murphy SM, Murray D, Smith S, Orr DJA. Burns caused by steam inhalation for
respiratory tract infections in children. BMJ. 2004;328(7442):757 PMID: 15044293
doi: 10.1136/bmj.328.7442.757
28. Weber JE, Chudnofsky CR, Younger JG, et al. A randomized comparison of helium-oxygen
mixture (Heliox) and racemic epinephrine for the treatment of moderate to severe croup.
Pediatrics. 2001;107(6):E96 PMID: 11389294 doi: 10.1542/peds.107.6.e96
29. Moraa I, Sturman N, McGuire TM, van Driel ML. Heliox for croup in children.
Cochrane Database Syst Rev. 2018;(10):CD006822 PMID: 30371952
30. Guldfred LA, Lyhne D, Becker BC. Acute epiglottitis: epidemiology, clinical presentation,
management and outcome. J Laryngol Otol. 2008;122(8):818–823 PMID: 17892608
doi: 10.1017/S0022215107000473
31. Broadhurst LE, Erickson RL, Kelley PW. Decreases in invasive Haemophilus influenzae
diseases in US Army children, 1984 through 1991. JAMA. 1993;269(2):227–231 PMID: 8417240
doi: 10.1001/jama.1993.03500020061032
32. Kessler A, Wetmore RF, Marsh RR. Childhood epiglottitis in recent years. Int J Pediatr
Otorhinolaryngol. 1993;25(1-3):155–162 PMID: 8436460 doi: 10.1016/0165-5876(93)90049-9
33. Wenger JD. Epidemiology of Haemophilus influenzae type b disease and impact of Haemophilus
influenzae type b conjugate vaccines in the United States and Canada. Pediatr Infect Dis J.
1998;17(9)(suppl):S132–S136 PMID: 9781746 doi: 10.1097/00006454-199809001-00008

326
34. Senior BA, Radkowski D, MacArthur C, Sprecher RC, Jones D. Changing patterns in
pediatric supraglottitis: a multi-institutional review, 1980 to 1992. Laryngoscope.
1994;104(11 pt 1):1314–1322 PMID: 7968159 doi: 10.1288/00005537-199411000-00002
35. Baird SM, Marsh PA, Padiglione A, et al. Review of epiglottitis in the post Haemophilus
influenzae type-b vaccine era. ANZ J Surg. 2018;88(11):1135–1140 PMID: 30207030
doi: 10.1111/ans.14787
36. Ward MA. Emergency department management of acute respiratory infections. Semin Respir
Infect. 2002;17(1):65–71 PMID: 11891520 doi: 10.1053/srin.2002.31692
37. Baxter JD. Acute epiglottitis in children. Laryngoscope. 1967;77(8):1358–1367 PMID: 6034859
doi: 10.1288/00005537-196708000-00011
38. Shah RK, Roberson DW, Jones DT. Epiglottitis in the Hemophilus influenzae type B
vaccine era: changing trends. Laryngoscope. 2004;114(3):557–560 PMID: 15091234
doi: 10.1097/00005537-200403000-00031
39. Hopkins A, Lahiri T, Salerno R, Heath B. Changing epidemiology of life-threatening upper
airway infections: the reemergence of bacterial tracheitis. Pediatrics. 2006;118(4):1418–1421
PMID: 17015531 doi: 10.1542/peds.2006-0692
40. Centers for Disease Control and Prevention (CDC). Progress toward elimination of Haemophilus
influenzae type b invasive disease among infants and children—United States, 1998–2000.
MMWR Morb Mortal Wkly Rep. 2002;51(11):234–237 PMID: 11925021
41. Casazza G, Graham ME, Nelson D, Chaulk D, Sandweiss D, Meier J. Pediatric bacterial
tracheitis—a variable entity: case series with literature review. Otolaryngol Head Neck Surg.
2019;160(3):546–549 PMID: 30348058 doi: 10.1177/0194599818808774
42. Ni JS, Kohn J, Shah UK, Levi JR. Acute pediatric tracheitis: distinguishing the disease by
tracheostomy status. Int J Pediatr Otorhinolaryngol. 2020;130:109800 PMID: 31884048
doi: 10.1016/j.ijporl.2019.109800
43. Stroud RH, Friedman NR. An update on inflammatory disorders of the pediatric airway:
epiglottitis, croup, and tracheitis. Am J Otolaryngol. 2001;22(4):268–275 PMID: 11464324
doi: 10.1053/ajot.2001.24825
44. Brook I. Aerobic and anaerobic microbiology of bacterial tracheitis in children. Pediatr Emerg
Care. 1997;13(1):16–18 PMID: 9061728 doi: 10.1097/00006565-199702000-00005
45. Wheeler DS, Whitt JD, Lake M, Butcher J, Schulte M, Stalets E. A case-control study on the
impact of ventilator-associated tracheobronchitis in the PICU. Pediatr Crit Care Med.
2015;16(6):565–571 PMID: 25850864 doi: 10.1097/PCC.0000000000000405
46. Muszynski JA, Sartori J, Steele L, et al. Multidisciplinary quality improvement initiative to
reduce ventilator-associated tracheobronchitis in the PICU. Pediatr Crit Care Med.
2013;14(5):533–538 PMID: 23628838 doi: 10.1097/PCC.0b013e31828a897f
47. Bernstein T, Brilli R, Jacobs B. Is bacterial tracheitis changing? A 14-month experience in a
pediatric intensive care unit. Clin Infect Dis. 1998;27(3):458–462 PMID: 9770140
doi: 10.1086/514681
48. Lee JH, Smith PB, Quek BH, Laughon MM, Clark RH, Hornik CP. Risk factors and in-hospital
outcomes following tracheostomy in infants. J Pediatr. 2016;173:39.e1–44.e1 PMID: 26944265
doi: 10.1016/j.jpeds.2016.01.072
49. Zenk J, Fyrmpas G, Zimmermann T, Koch M, Constantinidis J, Iro H. Tracheostomy in young
patients: indications and long-term outcome. Eur Arch Otorhinolaryngol. 2009;266(5):705–711
PMID: 18766359 doi: 10.1007/s00405-008-0796-4
50. Esianor BI, Jiang ZY, Diggs P, Yuksel S, Roy S, Huang Z. Pediatric tracheostomies in patients
less than 2 years of age: analysis of complications and long-term follow-up. Am J Otolaryngol.
2020;41(2):102368 PMID: 31859007 doi: 10.1016/j.amjoto.2019.102368
51. Burns JA, Brown J, Ogle JW. Group A streptococcal tracheitis associated with toxic shock
syndrome. Pediatr Infect Dis J. 1998;17(10):933–935 PMID: 9802646
doi: 10.1097/00006454-199810000-00024

PART
5
Lower Airway Infections
Chapter 17. Bronchiectasis.................................................................329

Jordana E. Hoppe, MD, MSCS, and Paul C. Stillwell, MD, FAAP
Chapter 18. Bronchiolitis.................................................................... 341

Chapter 19. Viral Pneumonia (Including COVID-19).................... 353

Chapter 20. Nonviral Pneumonia..................................................... 365

Chapter 21. Complications of Pneumonia.......................................387

Chapter 22. Recurrent Pneumonia...................................................401

Paul Houin, MD, and Paul C. Stillwell, MD, FAAP
Chapter 23. Tuberculosis.....................................................................411

Carol Conrad, MD
Chapter 24. Nontuberculous Mycobacteria.................................... 453

Stacey L. Martiniano, MD; Patricia Lenhart-Pendergrass, MD, PhD;
and Kenneth N. Olivier, MD, MPH
327
21 PP 2ND ED - PO 05_327-328.indd 327 11/6/23 8:24 AM

21 PP 2ND ED - PO 05_327-328.indd 328 9/12/23 9:38 AM
CHAPTER
17
Bronchiectasis
Jordana E. Hoppe, MD, MSCS
Introduction
Bronchiectasis is the dilatation of bronchi and bronchioles associated
with airway wall thickening.1,2 The most common cause among children in
North America is cystic fibrosis (CF), but there are numerous other potential
underlying causes (Table 17-1). The most commonly identified causes have
considerable geographic variability based on the risk of serious infections
and the particular diagnostic expertise of regional medical centers.3 A 2014
study demonstrated that in most, but not all, children a cause of non-CF
bronchiectasis can be identified, with infection, primary immunodeficiency,
aspiration, and primary ciliary dyskinesia being the most common causes.4
The end result of airway injury that is associated with both acute and chronic
inflammation, bronchiectasis perpetuates ongoing airway injury. It can occur
in 1 or a few lung segments, or it can be generalized throughout all segments.
If the airway injury is severe or recurrent, the airway damage becomes
irreversible and self-sustaining.
The child with bronchiectasis has a chronic “wet” or productive cough
and recurrent chest infections. Some children may have recurrent wheez-
ing. A small percentage may have hemoptysis.2,3 Recurrent or persistent
pneumonia can also be a presenting feature of bronchiectasis. The results of
the chest examination in the child with bronchiectasis may be normal until
significant airway abnormalities are present. As the disease advances, the
intensity of breath sounds may be decreased and inspiratory crackles may
be present. Expiratory wheezing may be present when severe airway damage
has occurred. The examination findings may be more prominently abnormal
during acute exacerbations of the bronchiectasis, and less so after resolution.
The abnormal findings may be localized if the bronchiectasis is segmental.
Other examination findings may be present depending on the underlying
cause of the bronchiectasis (eg, failure to thrive in patients with CF; ear,
nose, and throat abnormalities in patients with primary ciliary dyskinesia
329

Table 17-1. Disease Processes Associated With Bronchiectasis and Potential Evaluations
330
Disease Process Possible Diagnosis Evaluation

Impaired mucociliary clearance Cystic fibrosis Sweat test, DNA analysis
Primary ciliary dyskinesia Ciliary biopsy (electron microscopy), DNA analysis, nasal nitric oxide
Infections Mycobacterium tuberculosis Skin test, acid-fast stain and culture, interferon-γ release assay
Atypical mycobacteria Acid-fast stain and culture

Measles Serology

Pertussis Direct fluorescent-antibody serology
Mycoplasma Polymerase chain reaction (PCR), serology
HIV PCR, serology
Varicella PCR, serology
Adenovirus PCR, serology
Severe bacterial pneumonia Cultures
Necrotizing pneumonia Cultures
Immunodeficiency Humoral or cellular immunodeficiency Immunoglobulins, complement levels, cell-mediated immunity tests, genetic
testing
Neutrophil dysfunction Dihydrorhodamine or nitroblue tetrazolium tests, genetics
Airway injury or toxin Dysphagia with aspiration Video-assisted swallow study, functional endoscopic evaluation of swallowing
Esophageal reflux Contrast esophagram, pH/impedance probe, milk scan
Inhalational injury History
Immunologic Allergic bronchopulmonary aspergillosis Specific immunoglobulin (Ig) E and IgG, total IgE
Connective tissue disease Various (see Chapter 26)
Inflammatory bowel disease GastrointestinaI endoscopy, bronchoscopy
9/12/23 9:40 AM
Disease Process Possible Diagnosis Evaluation
Congenital/connective Tracheobronchomegaly Computed tomographic (CT) scan, bronchoscopy
tissue abnormality Airway cartilage deficiency CT scan, bronchoscopy
Marfan syndrome Clinical criteria, genetic testing
Yellow nail syndrome Clinical criteria

Young syndrome Sperm count, negative cystic fibrosis test results
Alpha-1 antitrypsin deficiency Alpha-1 antitrypsin levels; Pi type
Obstructed airways Retained foreign body Imaging, bronchoscopy
Endobronchial tumor Imaging, bronchoscopy
Extrinsic compression CT scan, bronchoscopy
Severe asthma Pulmonary function testing, history
Chapter 17—Bronchiectasis
331
9/12/23 9:40 AM
332
or primary immunodeficiency). Digital clubbing can occur with moderate

and severe bronchiectasis regardless of the etiology.
Pulmonary function testing (PFT) performed in children old enough to
cooperate may show an obstructive pattern, a restrictive pattern, or a combina-
tion of both.5 The spirometric abnormalities in children with bronchiectasis
due to CF are generally correlated with disease severity and progression,6 but
the utility of spirometry in monitoring non-CF bronchiectasis is less certain.7
Because of ready availability and absence of risk, PFT is commonly used to
monitor the airway function in children with bronchiectasis. However, the
abnormalities that may be present with bronchiectasis are not specific to this
diagnosis. An evaluation for bronchiectasis should be considered for children
with persistent or progressive PFT abnormalities. Figure 17-1 shows an
example of flow-volume loops in a child with severe non-CF bronchiectasis.
4
F/V ex Pre
Post
3
0 Vol (L)
0.5 1.0 1.5 2.0 2.5 3.0
1
Reference Pre-Pre %% z Z-scorePost- Post bd % %z %Z-score % change

Reference Bronchodilator Predicted
Predictedscore Bronchodilator Predicted score change
Predicted
FVC (L)
FVC (L) 2.18
2.18 1.91
1.91 8888 −1.08
–1.08 2.16 2.16 99 99 −0.08 +13
–0.08 +13
FEV1 (L)
FEV1 (L) 1.89
1.89 1.34
1.34 7171 −2.54
–2.54 1.49 1.49 79 79 −1.86 +11
–1.86 +11
FEV1/FVC
FEV1/FVC
87
87
70
70 — −2.34
–2.34
69 69 — −2.49 —
–2.49
FEF 2.24 0.99 44 −2.95 1.05 47 −2.76 +6
FEF 25–75
25–75 2.24 0.99 44 –2.95 1.05 47 –2.76 +6
(L/s)
(L/s)
PEFR 248.2 1.62 66 −2.45 2.04 82 −1.27 +25
PEF
(L/min) 248.2 1.62 66 –2.45 2.04 82 –1.27 +25
(L/min)
Figure 17-1. Example of a flow-volume loop in bronchiectasis (with volume on the horizontal
axis and flow on the vertical axis). Expiratory flow is above the volume axis and inspiratory flow is
below the volume axis. The expiratory loop is concave with regard to the volume axis, indicating
an airflow obstruction, without a significant bronchodilator improvement. When such an
obstructive abnormality occurs in a child with chronic cough, the differential diagnosis should
be expanded beyond asthma. A bronchodilator response of ≥ 12% in FEV1 would be more typical
of asthma.
Abbreviations: FEF25–75, forced expiratory flow between 25% and 75% of the vital capacity; FEV1, forced
expiratory volume in 1 second; FVC, forced vital capacity; PEFR, peak expiratory flow rate.

333
The chest radiograph (Figure 17-2) may show increased interstitial markings
but may also appear normal until the bronchiectasis is extensive. A definitive
diagnosis of bronchiectasis is established using high-resolution computed
tomography (HRCT), which has supplanted bronchograms as a diagnostic
tool.1 The radiographic findings on chest radiography and HRCT are outlined
in Box 17-1.8 Airway changes used to diagnose bronchiectasis on HRCT
include an airway diameter that is larger than the diameter of the accompany-
ing pulmonary artery (signet ring sign), lack of normal bronchial tapering,
and visualization of peripheral airways (within 1 cm of the pleura).9,10 The
Figure 17-2. Chest radiograph, frontal (A) and lateral (B), in a 13-year-old with severe
bronchiectasis from an underlying immunodeficiency (T and B cell). There are diffuse
increased interstitial markings, multiple thin-walled cavitary lesions, and overinflation.
Box 17‑1
Radiographic Findings in Bronchiectasis
Chest Radiographic Findings
Increased interstitial markings
Thickened airway walls
Dilated airway lumen
Hyperinflation
High-resolution Chest Computed Tomographic Findings
Airway lumen greater than adjacent blood vessel (“signet ring”)
Tram-track markings
Extension of airway markings to periphery
Lack of tapering of airways toward periphery
Mucus plugging and centrilobular opacities (“tree in bud”)
Mosaic pattern of perfusion
Focal air-trapping (best seen on expiratory views)
Mucus plugging

334
Figure 17-3. High-resolution computed tomographic scans showing cylindrical bronchiectasis.

The patient is a 2-year-old with neutrophil dysfunction.
Figure 17-4. High-resolution computed tomographic scans demonstrating cystic bronchiecta-

sis. The patient is a 10-year-old boy with an immunodeficiency resulting in bronchiectasis.
Figure 17-5. High-resolution

computed tomographic scan of a
cystic (saccular) bronchiectasis. The
patient is a 13-year-old with saccular
bronchiectasis due to an underlying
immunodeficiency and chronic
aspiration.
3 types of bronchiectasis—cylindrical, varicose, and cystic—are also

defined by their appearance on HRCT.9 Cylindrical bronchiectasis (Figure
17-3) has a tubular appearance with smooth walls, is the least severe form, and
may be reversible.9 In varicose bronchiectasis, the airway has an irregular
appearance, with alternating portions of more dilated airway next to more
narrowed portions.9 Finally, cystic bronchiectasis is the most severe form,
with larger, saccular dilatation of the airways (Figure 17-4, Figure 17-5).9

335
A chest CT scan should be considered to evaluate for bronchiectasis in

children with persistent productive cough, persistently abnormal chest
radiographic findings, persistently abnormal chest auscultation findings, or
persistent PFT abnormalities. Additionally, children with severe asthma can
be at risk for the development of bronchiectasis.11
Pathophysiology
The initial airway injury leading to bronchiectasis can result from a variety
of causes, but the most common is an infection.1 A mucosal injury, severely
impaired mucociliary clearance, or an underlying immunodeficiency allows
an initial infection, and perpetuation of the host inflammatory response
eventually leads to airway damage. The cellular response is predominantly
neutrophilic, and ongoing inflammation produces increased mucus secretion,
thickened mucus, and airway edema. Higher levels of neutrophil elastase are
associated with greater disease severity and an increased risk of exacerbations
in patients with bronchiectasis.1 It is unclear in most cases why the enhanced
host response persists (unlike acute bronchitis, which resolves), unless there
is repeated injury such as that which may occur with repeated chronic aspira-
tion or repeated airway infections. The combination of dilated airway walls,
mucosal inflammation, and thickened secretions impairs mucociliary clear-
ance, which impairs clearance of the infection and increases the risk of
subsequent infection. Eventually, the airway damage becomes irreversible
and self-perpetuating.1,2
Microscopic examination of the bronchiectatic airway reveals thickened
airway walls, mucosal gland enlargement, cellular (usually neutrophilic)
infiltration, dilated cross-sectional airway lumen, and excessive secretions.1
If the infection has not been treated with antibiotics, bacteria may be evident
on special stains. Excessive proinflammatory mediators are present in
bronchoalveolar lavage (BAL) fluids.1
Evaluation
Once bronchiectasis is documented, an underlying cause should be sought
(Table 17-1). If the history or examination findings suggest a specific cause,
the initial evaluation can be targeted toward that cause (eg, sweat test if
steatorrhea is present). More commonly, several tests are necessary and are
usually performed from least invasive to most invasive. All children with
bronchiectasis should undergo a sweat chloride test to assess for CF (even if
newborn screening results were negative). Screening for immunodeficiency
should include quantitative immunoglobulins, white blood cell counts with
differential, and measurement of total complement levels. More advanced
immune studies include assessment of response to immunizations, evaluation
of cell-mediated immunity, neutrophil function tests, and genetic testing.

336
Allergic bronchopulmonary aspergillosis and connective tissue diseases can be

assessed by means of specific immunologic studies. Mycobacterium tuberculo-
sis infection can be assessed with a skin test, an interferon-γ release assay in
those older than 5 years, and stains and culture at the time of bronchoscopy. A
video-assisted swallow study can be conducted to assess swallowing coordina-
tion and risk of aspiration. An upper gastrointestinal barium contrast study can
assess for gastroesophageal reflux. Other tests to evaluate the risks for aspira-
tion include the functional endoscopic evaluation of swallowing, esophageal
pH/impedance probe, and radionuclide milk scans. Primary ciliary dyskinesia
can be evaluated by means of electron microscopy of ciliary ultrastructure,
DNA analysis, nasal nitric oxide measurement, and ciliary wave form analysis;
these tests are usually performed at a referral center. Flexible bronchoscopy
allows assessment of airway anatomy and obstruction, visual inspection of
the airway mucosa, and collection of airway secretions and BAL fluid. The
BAL fluid can be analyzed with stains and cultures for a variety of infections,
as well as cell counts with differential and other specialized stains.
Management
Once the clinical suspicion of bronchiectasis is confirmed by HRCT scan,
an evaluation for the specific underlying disease should be undertaken
(Table 17-1). If a specific disease can be identified, therapy directed at that
process should be initiated or intensified. Therapeutic options for CF have
undergone sophisticated evaluation to help direct appropriate management
choices12 (see Chapter 45, Cystic Fibrosis), but randomized clinical prospec-
tive studies of non-CF bronchiectasis in children are just beginning. Much of
the treatment offered for non-CF bronchiectasis is extrapolated from data
acquired in patients with CF.13
Antibiotics targeting bacteria isolated from sputum or bronchoscopy samples
are likely beneficial in treating exacerbations of bronchiectasis,14 similar to
treatment for CF airway infections. The most common bacteria isolated in
non-CF bronchiectasis include Streptococcus pneumoniae, Haemophilus
influenzae, Moraxella catarrhalis, and Staphylococcus aureus. However, less is
known about the microbiome of bronchiectasis, and its impact on disease
severity and exacerbations, in patients who do not have CF compared with
those who do.15 Patients with CF have a greater risk of developing Pseudomo-
nas aeruginosa airway infection than patients with non-CF bronchiectasis.
Antibiotic treatment for acute exacerbations of bronchiectasis is documented
to help reverse the acute illness.1,13 The role of long-term antibiotic therapy
for non-CF bronchiectasis is not well established.1,13 Inhaled antibiotics have
documented benefit for patients with CF and may have benefit in non-CF
bronchiectasis as well, depending on the organisms in the airway.1,12,13 Airway
clearance therapy using a variety of techniques is commonly prescribed, with

337
perceived anecdotal benefit (see Chapter 55, Airway Clearance Techniques).

Some individuals may respond to inhaled bronchodilators, and even if there
is no documented increase in airflow on PFT, the bronchodilator may have a
positive effect on mucociliary clearance.1,13 Inhaled corticosteroids have shown
some benefit in adults with non-CF bronchiectasis,1,13 but their role in CF has
been challenged, with conflicting evidence.12 Despite limited evidence of the
benefits of inhaled corticosteroids, high rates of use are observed in patients
with bronchiectasis.16 Other anti-inflammatory treatments show promise in CF,
but there is limited evidence of benefit in non-CF bronchiectasis, particularly
in children.13 Several studies have suggested that oral macrolide therapy, used
as an anti-inflammatory rather than as an antibiotic, has reduced the frequency
of exacerbations in non-CF bronchiectasis.17
Mucolytic treatments with rhDNase have had documented benefit for patients
with CF,12 but they may have a detrimental effect in patients with non-CF
bronchiectasis (based on a single adult study).18 Nebulized hypertonic saline
has been shown to benefit patients with CF.12 Although less is known regarding
the benefits of hypertonic saline in non-CF bronchiectasis, studies have
suggested that it decreases the viscosity of sputum, leading to an increase
in expectorated sputum, and may decrease hospitalizations and improve
lung function.19
Hospitalization to intensify antibiotic therapy and airway clearance might
be indicated for an exacerbation in patients with non-CF bronchiectasis,
an approach that has documented benefit for patients with CF. Anecdotal
evidence suggests that the same benefit can be achieved for children with
non-CF bronchiectasis. Patients with large volumes of hemoptysis, hypoxia, or
rapidly declining pulmonary function require hospitalization.
Surgical resection of limited or segmental bronchiectasis may be necessary if
massive hemoptysis occurs, but recent evidence suggests that, in the absence of
hemoptysis, aggressive medical management can result in similar improvement
to that of surgical intervention in non-CF bronchiectasis.20 Double lung
transplantation may be an option for patients with severe progressive bronchi-
ectasis that does not respond well to medical management.13 Lung transplanta-
tion has commonly been offered as an option for end-stage bronchiectatic
lung disease due to CF, with short- and long-term outcomes similar to those
in other diseases for which transplantation is often performed.21
Prognosis
The prognosis for non-CF bronchiectasis is not as well studied as that for CF,
but generally survival has been longer for patients with non-CF bronchiectasis
than for those with CF.22 This may change as improved understanding of CF
lung disease and new treatment options have steadily increased the median

338
age of survival.12,23 The rate of progression of non-CF bronchiectasis and

prognosis for survival are likely primarily related to the underlying cause and
treatment options.1,13 However, persons with bronchiectasis have a high rate
of health care utilization and disease burden,24 which likely has an adverse
effect on their quality of life. The presence of chronic P aeruginosa airway
infection negatively affects the survival of patients with both CF and
non-CF bronchiectasis.1,13
key points
} Bronchiectasis in children can be the result of a wide variety of underlying causes.
} When no cause is found, these cases are considered idiopathic.
} Bronchiectasis should be suspected if a child has a chronic wet cough and
recurrent chest infections.
} An HRCT scan should be performed to definitively establish the diagnosis of
bronchiectasis.
} Once bronchiectasis is confirmed, an underlying cause should be sought.
} The management of patients with non-CF bronchiectasis has largely been
determined by expert opinion and data extrapolated from CF studies.
References
1. McShane PJ, Tino G. Bronchiectasis. Chest. 2019;155(4):825–833 PMID: 30403962
doi: 10.1016/j.chest.2018.10.027
2. Chang AB, Bush A, Grimwood K. Bronchiectasis in children: diagnosis and treatment. Lancet.
2018;392(10150):866–879 PMID: 30215382 doi: 10.1016/S0140-6736(18)31554-X
3. Li AM, Sonnappa S, Lex C, et al. Non-CF bronchiectasis: does knowing the aetiology
lead to changes in management? Eur Respir J. 2005;26(1):8–14 PMID: 15994383
doi: 10.1183/09031936.05.00127704
4. Brower KS, Del Vecchio MT, Aronoff SC. The etiologies of non-CF bronchiectasis in childhood:
a systematic review of 989 subjects. BMC Pediatr. 2014;14(1):299 PMID: 25492164
doi: 10.1186/s12887-014-0299-y
5. Pifferi M, Caramella D, Bulleri A, et al. Pediatric bronchiectasis: correlation of HRCT,
ventilation and perfusion scintigraphy, and pulmonary function testing. Pediatr Pulmonol.
2004;38(4):298–303 PMID: 15334506 doi: 10.1002/ppul.20110
6. VanDevanter DR, Rasouliyan L, Murphy TM, et al; Investigators, Coordinators of the
Epidemiologic Study of Cystic Fibrosis. Trends in the clinical characteristics of the U.S. cystic
fibrosis patient population from 1995 to 2005. Pediatr Pulmonol. 2008;43(8):739–744
PMID: 18613041 doi: 10.1002/ppul.20830
7. Twiss J, Stewart AW, Byrnes CA. Longitudinal pulmonary function of childhood bronchiectasis
and comparison with cystic fibrosis. Thorax. 2006;61(5):414–418 PMID: 16467074 doi: 10.1136/
thx.2005.047332
8. Rossi UG, Owens CM. The radiology of chronic lung disease in children. Arch Dis Child.
2005;90(6):601–607 PMID: 15908625 doi: 10.1136/adc.2004.051383
9. Juliusson G, Gudmundsson G. Diagnostic imaging in adult non-cystic fibrosis bronchiectasis.
Breathe (Sheff). 2019;15(3):190–197 PMID: 31508157 doi: 10.1183/20734735.0009-2019
10. Schäfer J, Griese M, Chandrasekaran R, Chotirmall SH, Hartl D. Pathogenesis, imaging and
clinical characteristics of CF and non-CF bronchiectasis. BMC Pulm Med. 2018;18(1):79
PMID: 29788954 doi: 10.1186/s12890-018-0630-8

339
11. Lo D, Maniyar A, Gupta S, Gaillard E. High prevalence of bronchiectasis on chest CT in a

selected cohort of children with severe asthma. BMC Pulm Med. 2019;19(1):136 PMID: 31349825
doi: 10.1186/s12890-019-0900-0
12. Flume PA, O’Sullivan BP, Robinson KA, et al; Cystic Fibrosis Foundation, Pulmonary Therapies
Committee. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung
health. Am J Respir Crit Care Med. 2007;176(10):957–969 PMID: 17761616
doi: 10.1164/rccm.200705-664OC
13. Rosen MJ. Chronic cough due to bronchiectasis: ACCP evidence-based clinical practice
guidelines. Chest. 2006;129(1)(suppl):122S–131S PMID: 16428701
doi: 10.1378/chest.129.1_suppl.122S
14. Goyal V, Grimwood K, Ware RS, et al. Efficacy of oral amoxicillin-clavulanate or azithromycin
for non-severe respiratory exacerbations in children with bronchiectasis (BEST-1): a multicentre,
three-arm, double-blind, randomised placebo-controlled trial. Lancet Respir Med.
2019;7(9):791–801 PMID: 31427252 doi: 10.1016/S2213-2600(19)30254-1
15. Richardson H, Dicker AJ, Barclay H, Chalmers JD. The microbiome in bronchiectasis.
Eur Respir Rev. 2019;28(153):190048
16. Henkle E, Aksamit TR, Barker AF, et al. Pharmacotherapy for non-cystic fibrosis bronchiectasis:
results from an NTM Info & Research patient survey and the Bronchiectasis and NTM Research
Registry. Chest. 2017;152(6):1120–1127 PMID: 28479113 doi: 10.1016/j.chest.2017.04.167
17. Hill AT. Macrolides for clinically significant bronchiectasis in adults: who should receive this
treatment? Chest. 2016;150(6):1187–1193 PMID: 27591924 doi: 10.1016/j.chest.2016.08.1451
18. O’Donnell AE. Bronchiectasis. Chest. 2008;134(4):815–823 PMID: 18842914
doi: 10.1378/chest.08-0776
19. Máiz Carro L, Martínez-García MA. Nebulized hypertonic saline in noncystic fibrosis
bronchiectasis: a comprehensive review. Ther Adv Respir Dis. 2019;13:1–15 PMID: 31390940
doi: 10.1177/1753466619866102
20. Karadag B, Karakoc F, Ersu R, Kut A, Bakac S, Dagli E. Non-cystic-fibrosis bronchiectasis in
children: a persisting problem in developing countries. Respiration. 2005;72(3):233–238
21. UNOS. Data. Accessed June 10, 2022. https://UNOS.org/data
22. Redondo M, Keyt H, Dhar R, Chalmers JD. Global impact of bronchiectasis and cystic fibrosis.
Breathe (Sheff). 2016;12(3):222–235 PMID: 28210295 doi: 10.1183/20734735.007516
23. Gentzsch M, Mall MA. Ion channel modulators in cystic fibrosis. Chest. 2018;154(2):383–393
PMID: 29750923 doi: 10.1016/j.chest.2018.04.036
24. Lovie-Toon YG, Grimwood K, Byrnes CA, et al. Health-resource use and quality of life in
children with bronchiectasis: a multi-center pilot cohort study. BMC Health Serv Res.
2019;19(1):561 PMID: 31409413 doi: 10.1186/s12913-019-4414-5

CHAPTER
18
Bronchiolitis
Introduction
Bronchiolitis usually manifests as an isolated episode, mostly a viral lower
respiratory tract infection in an infant with symptomatic airway obstruction.
Most patients are younger than 1 year; however, bronchiolitis can occur beyond
infancy. It is characterized by acute inflammation, edema and necrosis of the
epithelial lining of small airways, and mucus production. An infant with
bronchiolitis typically presents with increased work of breathing manifested
by retractions and associated with polyphonic wheeze, which may be heard
without a stethoscope.
Epidemiology
As many as 3% of all US infants are hospitalized annually for bronchiolitis,
making this clinical problem the leading cause of hospitalization during the
first year after birth.1 Although respiratory syncytial virus (RSV types A
and B) predominates (50%–80%) as a cause of bronchiolitis, many other
respiratory viruses have been detected in the nasopharyngeal secretions
of children hospitalized with bronchiolitis. These include, in descending
order of frequency, human rhinovirus (groups A, B, and C) (5%–25%),2
parainfluenza virus (most commonly type 3), human metapneumovirus
(subgroups A and B), coronavirus, adenovirus, influenza (A and B) virus,
and enterovirus (echovirus and coxsackievirus).3
Authors of a systematic review and remodeling study estimated 33.1 million
episodes of RSV caused acute lower respiratory infections globally in 2015,
resulting in 3.2 million hospitalizations and 27,300 in-hospital deaths.4
Regardless of the viral cause, a predictable seasonal pattern occurs for
bronchiolitis, although there is some variability from year to year5,6 and
by region.7
341

342
The prodrome of bronchiolitis is a typical-appearing upper respiratory tract
infection, with mild rhinorrhea and occasionally a low-grade fever. Progres-
sion then occurs over 1 to 2 days to cough, retractions (Figure 18-1), tachy-
pnea, and prolonged expiratory phase with wheezing and inspiratory crackles.
The tachypnea and increased work of breathing can result in poor feeding.
The extent of poor feeding is related to the degree of respiratory distress.
In a mild case, the infant is able to finish the usual amount of food but takes
longer to finish because of interruptions. More severe respiratory distress
results in reduced quantities of food taken along with an increase in time to
finish. Finally, the infant may not be interested in feeding owing to severe
respiratory distress. Reduced feeding with increasing respiratory distress may
result in dehydration manifested by poor tearing, dry mucous membranes,
and poor skin turgor.
A varying degree of hypoxemia can occur, and hypercapnia may be found in
severe cases.
Crackles and wheezing may be present at auscultation. Wheezing may be
audible without a stethoscope.
Suprasternal retractions
Intercostal retractions
Substernal retractions
Subcostal retractions
Figure 18-1. Retractions in infants and young children. The location of retractions is an impor-
tant clue to the cause and severity of respiratory distress. Suprasternal retractions predominate
when infants have extrathoracic obstruction. Subcostal and substernal retractions usually result
from lower respiratory tract disorders. Suprasternal retractions occur in upper respiratory tract
disorders. Alone, mild intercostal retractions may be normal. However, intercostal retractions
accompanied by subcostal and substernal retractions may indicate moderate respiratory
distress. Deep suprasternal retractions typically indicate severe distress.

343
Chapter 18—Bronchiolitis
The term bronchiolitis should not be applied to repeated episodes of wheezing.
The following conditions, manifesting as nonisolated or repeated wheezing,
should be differentiated from a typical case of bronchiolitis.
Asthma
Authors of a 2020 article have attempted to differentiate bronchiolitis with its
neutrophil-mediated airway inflammation, secretions, and associated airway
obstruction from asthmatic airway obstruction with bronchoconstriction and
airway inflammation.8 An asthmatic episode may mimic bronchiolitis; how-
ever, a history of recurrent of bronchospastic symptoms, presence of triggers
such as physical activity, typical nocturnal asthmatic symptoms and eczema,
allergic rhinitis symptoms, and family history should help. Asthma can mani-
fest as clinically nondiscernible from bronchiolitis, even in infants. The future
course and follow-up may help to differentiate bronchiolitis from asthma.
Conditions Causing Focal Wheeze

Lobar pneumonia, congenital lung anomalies such as congenital pulmonary
airway malformations, sequestration, and focal airway obstruction due to
lobar emphysema may mimic bronchiolitis; however, the presence of focal
clinical signs, corroborative findings on investigations, and other features
such as high persistent fever in pneumonia may help differentiate these from
typical bronchiolitis. Foreign body aspiration may cause focal or generalized
wheeze. However, in a child who is previously healthy and without symptoms
who presents with sudden respiratory distress, a typical history (if witnessed)
and clinical and radiological findings may help differentiate.
Recurrent Wheeze With Other Causes

Children with chronic conditions such as bronchomalacia, craniofacial
malformations, upper airway obstruction due to such causes as a vascular
ring, gastroesophageal reflux, oropharyngeal incompetence, and dysphagia
(extreme prematurity) may develop recurrent wheeze with upper respiratory
infections and may have bronchiolitis diagnosed. However, the diagnosis
of an associated condition and history of recurrent wheeze with an upper
respiratory tract infection may help differentiate the diseases. Conditions
such as congestive heart failure and interstitial lung disease may manifest
with persistent crackles, tachypnea, and low oxygen saturation. However,
the presence of clinical features specific to the disorder and the absence of
the typical bronchiolitis picture may help differentiate these conditions
from bronchiolitis.

344
Pathophysiology
The virus initially replicates in the epithelium of the upper respiratory tract,
but in the susceptible young infant, it spreads rapidly to the lower airways.
The pathological findings in bronchiolitis are primarily in the respiratory
epithelium with generalized involvement. Inflammatory changes of variable
severity are observed in most small bronchi and bronchioles. Peribronchiolar
infiltration, mostly with mononuclear cells, and edema of the submucosa and
adventitia occur. Necrosis and sloughing of the bronchiolar epithelium occur
with gradual recovery. Plugs of necrotic material and fibrin may completely
or partially obstruct the small airways. Smooth muscle constriction does not
appear to be important in the obstruction.
Infants are particularly vulnerable to obstruction because mucosal inflamma-
tion causes relatively greater compromise of their small-lumen airways, and
changes in resistance are proportional to the cube of changes in the radius
of the airway (the Poiseuille law). Therefore, small airway obstruction in
an infant with bronchiolitis results in a larger increase in work of breathing.
In areas peripheral to sites of partial obstruction, air becomes trapped by a
process similar to a ball-valve mechanism. The negative intrapleural pres-
sure exerted during inspiration allows air to flow beyond the point of partial
obstruction. However, during expiration, the size of the lumen decreases with
the positive intrathoracic pressure, thereby resulting in increased obstruction
and hyperinflation. Thus, although airflow is impeded during both inspiration
and expiration, the latter is more affected and prolonged. In areas peripheral
to complete obstruction, the trapped air eventually becomes absorbed, which
results in multiple areas of atelectasis. This absorptive atelectasis is greatly
accelerated when the infant is breathing a high concentration of oxygen. A
presumed reason why infants have increased susceptibility to the develop-
ment of atelectasis or hyperinflation is that collateral channels that maintain
alveolar expansion in the presence of airway obstruction are not well
developed early in life.
Natural History
Viral bronchiolitis is most commonly caused by RSV. Virtually all infants
contract RSV during the first 2 years after birth, most during the first year. An
estimated 20% develop bronchiolitis from an RSV infection, whereas others
develop upper respiratory symptoms, coryza, or the symptoms of a common
cold. Of those with bronchiolitis, most do not require hospitalization. None-
theless, bronchiolitis is the leading cause of hospitalization during the first
year beyond the neonatal period.
An estimated 25% to 50% of patients with bronchiolitis have subsequent
recurrence of similar symptoms triggered by viral respiratory infections,
as in the case of patients with asthma developing bronchospastic symptoms

345
triggered by viral respiratory infections.9,10 Those who develop bronchiolitis

appear to differ from those who do not in genetic factors that involve innate
immunity.11–13 Thus, although all children get viral respiratory infections, it
is primarily genetic susceptibility that contributes to both bronchiolitis and
recurrent symptoms of asthma exacerbations from viral respiratory infections.
Exposure to tobacco smoke during pregnancy and after birth appears to be an
environmental contributing factor that increases the risk of bronchiolitis.14–16
Laboratory and Radiological Findings

Bronchiolitis is a clinical diagnosis. Investigations apart from antigen
tests, pulse oximetry, and, in a patient with severe hypoxia, blood gas
measurements are not valuable.
Antigen tests of nasal washings provide rapid (usually within 30 minutes)
and accurate (sensitivity, 87%–91%; specificity, 96%–100%) detection of
RSV during the peak season. Respiratory viral panels, cultures for RSV or
other viruses, or detection by means of direct fluorescent antibody or poly-
merase chain reaction may be useful for epidemiological and educational
purposes. However, they add to the cost and provide no useful information
for patient care.
Pulse oximetry can be used to identify the presence of sufficient hypox-
emia to warrant supplemental oxygen. Blood gas measurements can indicate
the Pco2 , which is essential to distinguish hypoxia caused by ventilation/
perfusion mismatching from that caused by hypoventilation and hypercarbic
respiratory failure.
A complete blood cell count is seldom useful because the white blood cell
count is usually within normal limits. Urine specific gravity testing may
provide useful information regarding fluid balance and possible dehydration.
Serum chemistry is not affected directly by the infection but may aid in
assessing and managing dehydration.
Radiological findings are nonspecific and typically demonstrate hyperinfla-
tion with flattened diaphragms and increased anteroposterior diameter with
precordial air from air trapping. Patchy infiltrates and focal atelectasis may
also be present. None of those findings alters therapy. Consequently, chest
radiography is not routinely necessary when the clinical presentation is typical
of bronchiolitis.17 However, it may be considered if complications such as
secondary bacterial infection are suspected.
Management
American Academy of Pediatrics (AAP) clinical practice guidelines do not
recommend use of inhaled bronchodilators for a patient with typical viral
bronchiolitis.18 Nebulized hypertonic saline may be tried in patients who are

346
hospitalized; however, AAP clinical practice guidelines do not recommend

its regular use in the emergency department.18 The AAP guidelines also
recommend using supplemental oxygen when oxygen saturation is less than
90%.18 Supportive management to maintain adequate hydration, by using
nasogastric or intravenous fluids when oral hydration is not possible, is
recommended in AAP clinical practice guidelines.18 Current study results
do not support the use of antibiotics to treat persistent cough or wheeze
after acute bronchiolitis.19
Prophylaxis
Passive immunity is used for at least partial prophylaxis of bronchiolitis in
infants at high risk of developing the disease. Results of double-blind studies
of palivizumab have shown reduction in severe RSV infections by 55% and
reduction in hospitalizations by about 50% for infants at high risk because
of prematurity, chronic lung disease, or congenital heart disease. The AAP
clinical practice guidelines recommend 5 monthly doses of palivizumab
(15 mg/kg per dose) during the RSV bronchiolitis season in the appropriate
high-risk population—those with a gestational age less than 29 weeks, during
the first year in infants with hemodynamically significant heart disease, or
those with chronic lung disease of prematurity (premature babies < 32 weeks
requiring supplemental oxygen for more than 28 days after birth).18
Palivizumab is a humanized monoclonal immunoglobulin G1 antibody that
recognizes the RSV F protein. Agents targeting different proteins within the
RSV virion, such as SH protein, which causes inhibition of cell apoptosis
through inhibition of the tumor necrosis factor-α pathway; M2–2 protein,
which mediates the transition from transcription to RNA replication; NS2
protein, which inhibits host cellular antiviral type 1 interferon induction and
interferon response; and N protein, are undergoing clinical trials. A phase 3
clinical trial of motavizumab for the prevention of RSV disease in healthy
Navajo and Apache infants showed an 87% relative reduction in the pro-
portion of infants admitted with RSV20; however, because it lacks greater
clinical efficacy compared with that of palivizumab and because of reports
of cutaneous hypersensitivity in some treated infants, it did not receive
US Food and Drug Administration approval.
Hospitalization
Because bronchiolitis is generally a self-limited illness for which specific
treatments are of unclear effectiveness, the primary reasons for admission
are poor oral intake, dehydration, and concern that the degree of respiratory
distress may result in respiratory failure and the need for assisted ventilation.
If the caretakers are unable to assess the severity of illness or there is con-
cern about their reliability to monitor the infant, then hospitalization may

347
be indicated. Assessing the degree of feeding difficulty, described in the

Clinical Presentation section, may help in deciding which patients need
hospitalization. The frequent use of pulse oximetry in the office or emer-
gency department assessment has been associated with an increase in the
frequency of hospitalization for bronchiolitis because of the perceived
need for supplemental oxygen.
If there is a concern regarding the potential for respiratory failure, a facility
with a pediatric intensive care unit is the preferred site for hospitalization. The
potential for respiratory failure can be assessed by means of the presence of
hypoxemia detected with pulse oximetry and a blood gas (capillary or venous)
measurement indicating an increased Pco2. Assessing Pco2 is essential to
distinguish ventilation/perfusion mismatching from respiratory failure that
may require assisted ventilation.
In-Hospital Management
Because there is little documented evidence that pharmacological measures
have any clinically important effect on symptoms, length of stay, or duration
of symptoms, treatment is mainly supportive.21,22 Treatment includes oxygen-
ation, hydration, and ventilation if needed. Nebulized hypertonic saline may
be tried in patients who are hospitalized.18
Use of a high-flow nasal cannula in children with bronchiolitis is reported to
be safe23,24 and may decrease the rate of treatment failure compared with use
of only supplemental oxygen. However, no statistically significant benefit is
seen compared with results with standard therapy using supplemental oxygen
and continuous positive airway pressure (CPAP),24 and a higher failure rate of
the high-flow nasal cannula compared with that of CPAP or bilevel positive
airway pressure has been reported in infants admitted to the pediatric inten-
sive care unit.25 Using CPAP may reduce the respiratory rate in children with
acute bronchiolitis more than does standard therapy but has no effect on
length of hospital stay.26 Furthermore, investigators in a large, multicenter
database study of infants with acute bronchiolitis reported that the infants
initially receiving noninvasive positive pressure ventilation required invasive
ventilation at a higher rate than did infants initially receiving respiratory
support with a high-flow nasal cannula.27 Authors of a 2021 meta-analysis
of the comparative efficacy of bronchiolitis interventions concluded, with low
confidence, that nebulized hypertonic saline and nebulized hypertonic saline
plus epinephrine reduced hospital length of stay but that treatment with a
high-flow nasal cannula did not.28
Routine chest radiography results do not influence treatment and are
unnecessary. Testing for RSV antigen is also unnecessary because the
clinical course and treatment are independent of which respiratory virus
is causing the bronchiolitis.18,29

348
Evaluation for bacterial infection is rarely indicated but may be considered

in select situations, such as in patients with a temperature greater than 38°C
(100.4°F), particularly in infants younger than 2 months. Some study inves-
tigators have reported clinical benefits with use of chest physiotherapy.30
However, authors of a Cochrane review31 concluded that these techniques
cannot be used as standard clinical practice, in line with AAP clinical prac-
tice guidelines.18 Use of cool mist is not indicated. The scheduled use of
bronchodilators, routine use of antibiotics, routine use of corticosteroids
via any route, antihistamines, and decongestants are not indicated. Cardio-
respiratory monitoring should be considered for all patients during the
acute stage. Monitoring, including continuous pulse oximetry, may help in
decisions about the use of supplemental oxygen18 and may be discontinued
as status improves because excessive monitoring does not improve outcome
and can prolong hospitalization.32 Respiratory and contact isolation should
be routine to prevent nosocomial spread of infection.
Discharge
Infants may be discharged when they are sufficiently comfortable with
improved respiratory distress, do not require frequent suctioning, are able
to take full oral feedings for at least 12 hours, have oxygenation of at least
90% when checked with pulse oximetry, and have a social situation that raises
no concerns about care. Family members and caregivers should be educated
about the adverse effects of smoke exposure; smoking cessation; and the
importance of hand hygiene before and after direct contact with the patient,
objects in contact with the patient, and even after taking off gloves.18 Dis-
charge instructions should include advice regarding tobacco smoke exposure
and the risk of recurrent similar respiratory symptoms, especially if there is a
family history of asthma or recurrent episodes of prolonged lower respiratory
symptoms, cough, or labored breathing in the parents or siblings during
preschool-age years.

349
key points
} Bronchiolitis may manifest with respiratory distress in the form of tachypnea,
retractions, and cyanosis.
} The decision to hospitalize an infant with bronchiolitis is based on the presence
of severe respiratory distress, hypoxemia, and poor oral intake, as well as social
situation.
} Treatment and monitoring
➤ Measure pulse oximetry until clinically stable, followed by spot checks with
vital signs.
➤ Bronchodilators, if administered, may be albuterol or racemic epinephrine
as a trial, but only with physician assessment of respiratory distress level
before and after; if there is improvement, the bronchodilator can be
repeated as needed.
➤ Routine scheduled bronchodilators are not indicated.
➤ Hydration and nutrition should be provided as needed.
} Criteria for discharge
➤ Oxygen saturation stable with breathing room air of at least 90% with
normal to low Pco2
➤ Good oral intake
➤ No social contraindications (distance from medical care and parental
capability may delay discharge)
} Discharge planning should include
➤ Counseling regarding smoking cessation if needed
➤ Counseling regarding risk for recurrent episodes (influenced by family
history)
References
1. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-associated
hospitalizations among US children, 1980–1996. JAMA. 1999;282(15):1440–1446
PMID: 10535434 doi: 10.1001/jama.282.15.1440
2. Hasegawa K, Jartti T, Bochkov YA, et al. Rhinovirus species in children with severe
bronchiolitis: multicenter cohort studies in the United States and Finland. Pediatr Infect Dis J.
2019;38(3):e59–e62 PMID: 30001231 doi: 10.1097/INF.0000000000002141
3. Meissner HC. Viral bronchiolitis in children. N Engl J Med. 2016;374(1):62–72 PMID: 26735994
doi: 10.1056/NEJMra1413456
4. Shi T, McAllister DA, O’Brien KL, et al; RSV Global Epidemiology Network. Global, regional,
and national disease burden estimates of acute lower respiratory infections due to respiratory
syncytial virus in young children in 2015: a systematic review and modelling study. Lancet.
2017;390(10098):946–958 PMID: 28689664 doi: 10.1016/S0140-6736(17)30938-8
5. Holman RC, Curns AT, Cheek JE, et al. Respiratory syncytial virus hospitalizations among
American Indian and Alaska Native infants and the general United States infant population.
Pediatrics. 2004;114(4):e437–e444 PMID: 15466069 doi: 10.1542/peds.2004-0049
6. Canducci F, Debiaggi M, Sampaolo M, et al. Two-year prospective study of single infections and
co-infections by respiratory syncytial virus and viruses identified recently in infants with acute
respiratory disease. J Med Virol. 2008;80(4):716–723 PMID: 18297694 doi: 10.1002/jmv.21108
7. Fowlkes AL, Fry AM, Anderson LJ; Centers for Disease Control and Prevention (CDC).
Brief report: respiratory syncytial virus activity—United States, 2005–2006. MMWR Morb
Mortal Wkly Rep. 2006;55(47):1277–1279 PMID: 17136023

350
8. Douros K, Everard ML. Time to say goodbye to bronchiolitis, viral wheeze, reactive airways
disease, wheeze bronchitis and all that. Front Pediatr. 2020;8:218 PMID: 32432064
doi: 10.3389/fped.2020.00218
9. Weinberger M. Clinical patterns and natural history of asthma. J Pediatr.
2003;142(2 suppl):S15–S19 PMID: 12584515 doi: 10.1067/mpd.2003.21
10. Weinberger M, Solé D. The natural history of childhood asthma. In: Pawankar R, Holgate S,
Rosenwaser L, eds. Allergy Frontiers: Epigenetics to Future Perspectives. Vol 5.
Springer; 2010:511–530
11. Janssen R, Bont L, Siezen CLE, et al. Genetic susceptibility to respiratory syncytial virus
bronchiolitis is predominantly associated with innate immune genes. J Infect Dis.
2007;196(6):826–834 PMID: 17703412 doi: 10.1086/520886
12. Smyth RL. Innate immunity in respiratory syncytial virus bronchiolitis. Exp Lung Res.
2007;33(10):543–547 PMID: 18075829 doi: 10.1080/01902140701756711
13. See H, Wark P. Innate immune response to viral infection of the lungs. Paediatr Respir Rev.
2008;9(4):243–250 PMID: 19026365 doi: 10.1016/j.prrv.2008.04.001
14. Gürkan F, Kiral A, Dağli E, Karakoç F. The effect of passive smoking on the development of
respiratory syncytial virus bronchiolitis. Eur J Epidemiol. 2000;16(5):465–468 PMID: 10997834
doi: 10.1023/A:1007658411953
15. Bradley JP, Bacharier LB, Bonfiglio J, et al. Severity of respiratory syncytial virus bronchiolitis is
affected by cigarette smoke exposure and atopy. Pediatrics. 2005;115(1):e7–e14 PMID: 15629968
doi: 10.1542/peds.2004-0059
16. Carroll KN, Gebretsadik T, Griffin MR, et al. Maternal asthma and maternal smoking are
associated with increased risk of bronchiolitis during infancy. Pediatrics. 2007;119(6):1104–1112
PMID: 17545377 doi: 10.1542/peds.2006-2837
17. Schuh S, Lalani A, Allen U, et al. Evaluation of the utility of radiography in acute bronchiolitis.
J Pediatr. 2007;150(4):429–433 PMID: 17382126 doi: 10.1016/j.jpeds.2007.01.005
18. Ralston SL, Lieberthal AS, Meissner HC, et al; American Academy of Pediatrics. Clinical practice
guideline: the diagnosis, management, and prevention of bronchiolitis. Pediatrics.
2014;134(5):e1474–e1502 PMID: 25349312 doi: 10.1542/peds.2014-2742
19. McCallum GB, Plumb EJ, Morris PS, Chang AB. Antibiotics for persistent cough or wheeze
following acute bronchiolitis in children. Cochrane Database Syst Rev. 2017;8(8):CD009834
PMID: 28828759 doi: 10.1002/14651858.CD009834.pub3
20. O’Brien KL, Chandran A, Weatherholtz R, et al; Respiratory Syncytial Virus (RSV) Prevention
study group. Efficacy of motavizumab for the prevention of respiratory syncytial virus disease in
healthy Native American infants: a phase 3 randomised double-blind placebo-controlled trial.
Lancet Infect Dis. 2015;15(12):1398–1408 PMID: 26511956 doi: 10.1016/S1473-3099(15)00247-9
21. American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis.
Diagnosis and management of bronchiolitis. Pediatrics. 2006;118(4):1774–1793 PMID: 17015575
doi: 10.1542/peds.2006-2223
22. Yanney M, Vyas H. The treatment of bronchiolitis. Arch Dis Child. 2008;93(9):793–798
PMID: 18539685 doi: 10.1136/adc.2007.128736
23. Dadlez NM, Esteban-Cruciani N, Khan A, et al. Safety of high-flow nasal cannula outside the
ICU for previously healthy children with bronchiolitis. Respir Care. 2019;64(11):1410–1415
PMID: 30914486 doi: 10.4187/respcare.06352
24. Lin J, Zhang Y, Xiong L, Liu S, Gong C, Dai J. High-flow nasal cannula therapy for children
with bronchiolitis: a systematic review and meta-analysis. Arch Dis Child. 2019;104(6):564–576
PMID: 30655267 doi: 10.1136/archdischild-2018-315846
25. Habra B, Janahi IA, Dauleh H, Chandra P, Veten A. A comparison between high-flow nasal
cannula and noninvasive ventilation in the management of infants and young children with
acute bronchiolitis in the PICU. Pediatr Pulmonol. 2020;55(2):455–461 PMID: 31922360
doi: 10.1002/ppul.24553
26. Jat KR, Mathew JL. Continuous positive airway pressure (CPAP) for acute bronchiolitis in
children. Cochrane Database Syst Rev. 2019;1(1):CD010473 PMID: 30701528
doi: 10.1002/14651858.CD010473.pub3
27. Clayton JA, McKee B, Slain KN, Rotta AT, Shein SL. Outcomes of children with bronchiolitis
treated with high-flow nasal cannula or noninvasive positive pressure ventilation. Pediatr Crit Care
Med. 2019;20(2):128–135 PMID: 30720646 doi: 10.1097/PCC.0000000000001798
28. Elliott SA, Gaudet LA, Fernandes RM, et al. Comparative efficacy of bronchiolitis interventions
in acute care: a network meta-analysis. Pediatrics. 2021;147(5):e2020040816 PMID: 33893229
doi: 10.1542/peds.2020-040816

351
29. Wrotek A, Czajkowska M, Jackowska T. Chest radiography in children hospitalized with

bronchiolitis. Adv Exp Med Biol. 2019;1222:55–62 PMID: 31529287 doi: 10.1007/5584_2019_435
30. Van Ginderdeuren F, Vandenplas Y, Deneyer M, Vanlaethem S, Buyl R, Kerckhofs E.
Effectiveness of airway clearance techniques in children hospitalized with acute bronchiolitis.
31. Roqué i Figuls M, Giné-Garriga M, Granados Rugeles C, Perrotta C, Vilaró J. Chest physiotherapy
for acute bronchiolitis in paediatric patients between 0 and 24 months old. Cochrane Database
Syst Rev. 2016;2(2):CD004873 PMID: 26833493 doi: 10.1002/14651858.CD004873.pub5
32. Schroeder AR, Marmor AK, Pantell RH, Newman TB. Impact of pulse oximetry and oxygen
therapy on length of stay in bronchiolitis hospitalizations. Arch Pediatr Adolesc Med.

CHAPTER
19
Viral Pneumonia (Including COVID-19)
Mark H. Sawyer, MD
In a prospective, multisite comprehensive evaluation of children hospitalized

with radiographically documented community-acquired pneumonia, 1 or more
viruses alone were responsible for 66% of the pneumonia.1 The most common
viruses were respiratory syncytial virus (RSV; 28%), human rhinovirus/
enterovirus (27%), human metapneumovirus (13%), adenovirus (11%), human
parainfluenza virus (7%), influenza A and B (7%), and seasonal coronavirus
(5%). Coinfection with 2 or more viruses was common. The isolation of RSV
was most common in those 4 years or younger, as was human metapneumo-
virus. Influenza, human rhinovirus/enterovirus, and coronavirus were present
in similar percentages in all age groups. Although each virus tends to have
a seasonal pattern, the pattern is most pronounced for RSV, human meta-
pneumovirus, influenza, and coronavirus. Similar findings were identified
in a large study in Africa and Asia.2
Viral infections are the most common cause of symptomatic disease in chil-
dren. The number of respiratory infections per year may be 5 to 10 or even
more, with most being upper respiratory infections. Most cases of pneumonia
are diagnosed clinically, but there is an increasing ability to find a causative
agent as new biotechnology facilitates the diagnosis of viral infections. As
noted in Chapter 20, Nonviral Pneumonia, depending on the age of the child
and viral pathogen responsible, secondary bacterial infection occurs in about
one-third of cases of viral pneumonia.3,4 Although children who are immuno-
compromised are at higher risk of opportunistic infections, such as cytomega-
lovirus and varicella-zoster virus, they are also at risk of seasonal pneumonias,
including RSV, influenza, and parainfluenza. The symptoms of viral pneumo-
nia are similar to those of bacterial pneumonia, although there is less in terms
of chest pain or rigors with viral pneumonia.
353

354
Coronavirus
Coronavirus made headlines in 2003 when the severe acute respiratory
distress syndrome (SARS) was a cause of life-threatening pneumonia. The
virus (SARS-CoV) quickly spread from China to the rest of the world,
affecting 8,000 patients in 29 countries, and caused 774 deaths. As a result
of intensive infection control measures, the global transmission was halted
in 2003. It was speculated that subsequent variant strains of coronavirus
would likely cause increased cases of pneumonia in the future. There are
7 coronaviruses, of which 4 typically only cause mild upper respiratory
illness. The others are SARS-CoV from China; Middle East respiratory
syndrome from the Middle East; and SARS-CoV-2, which was responsible
for the COVID-19 pandemic.
COVID-19
The COVID-19 pandemic originated in December 2019 in Wuhan, China, and
spread throughout the world. The virus was named SARS-CoV-2, which is the
causative agent; COVID-19 is the disease. Mutations of viruses are typical,
and the changes may affect the course of the disease. Variants of concern of
SARS-CoV-2 have resulted in spikes of cases, including (as of publication)
beta, delta, and omicron, with anticipation of future mutations.
The pulmonary complications, although variable, are overall less serious
in children than adults. Although the incubation period may vary from 1 to
15 days, the average is 3 to 7 days. The clinical classification of severity is
shown in Box 19-1, and the symptoms are shown in Box 19-2.
SARS-CoV-2 results in an acute viral infection of both the upper and lower
respiratory tract. The virus is transmitted primarily via droplets. Close
proximity with both children and adults who are infected permits rapid
spread.
When SARS-CoV-2 reaches the lower airway, the viral spike protein binds
with high affinity to the angiotensin-converting enzyme 2 cellular trans-
membrane receptor principally found on the apical membrane of type II
pneumocytes. The receptor and virus are transported inside the cell and
subsequently replicate. The immune response has 2 phases. Initially, an
immunoreactive phase is characterized by activation of a cytokine storm.
The second phase depends on the immune system, and subsequent progres-
sion may result in cell damage with release of cytokines and chemokines
(IL-6, IL-10, and interferon) and recruitment of inflammatory cells, which
mediate lung damage.

355
Chapter 19—Viral Pneumonia (Including COVID-19)
Box 19‑1
Classification of COVID-19 Severity in Children
Asymptomatic: Positivity of the RT-PCR buffer to SARS-CoV-2 or positive serology
in the absence of any symptoms of illness.
Mild: Symptoms are mild and mainly affect the upper airways (nasal obstruction,
sneezing), sometimes associated with fever, cough, and gastrointestinal
symptoms.
Moderate: Symptoms are more critical, and fever and cough (mainly dry)
are almost always present and are associated with breathing difficulties. It is
characterized radiologically by lung anomalies compatible with interstitial
pneumonia.
Severe: It is characterized by the presence of hypoxemia (SpO2 < 92%) with signs of
respiratory distress (tachypnea, groaning, wing flaps, sags), cyanosis, neurological
signs and symptoms, refusal to eat, and signs of dehydration.
Critical: Disease progression to ARDS with onset of respiratory failure requiring
mechanical ventilation, signs of shock, or multiorgan failure.
Abbreviations: ARDS, acute respiratory distress syndrome; RT-PCR, reverse transcriptase–polymerase

chain reaction; SpO2, oxygen saturation as measured by pulse oximetry.
Derived from Miao H, Li H, Yao Y, et al. Update on recommendations for the diagnosis and treatment of
SARS-CoV-2 infection in children. Eur J Clin Microbiol Infect Dis. 2020;39(12):2211–2223.
Box 19‑2
Symptoms of COVID-19 in Children
ū Fever or chills ū Fatigue
ū Nasal congestion or runny nose ū Headache
ū Cough ū Muscle aches or body aches
ū Sore throat ū Nausea or vomiting
ū Loss of smell or taste ū Diarrhea
ū Shortness of breath or difficulty
breathing
Clinical Features
In children, there is considerable variation in symptoms; they tend to be less
severe than in adults. Absence of symptoms is not uncommon.
The pulmonary features of COVID-19 in children vary from asymptomatic
to respiratory failure. Respiratory management dominates the clinical picture
of children who are hospitalized. Hospital admission is decided based on
symptoms and pulse oximetry results. Deterioration of the clinical picture
with increasing dyspnea, cyanosis, and the onset of acute respiratory distress
syndrome occurs 8 to 10 days after onset of infection, which potentially may
lead to multiple organ failure and death.5

356
Chest Imaging
If COVID-19 is diagnosed and symptoms are mild, chest radiography is not
necessarily indicated. If there are moderate or severe symptoms, chest radiog-
raphy may assist in characterizing the extent of disease. Computed tomogra-
phy is indicated if the symptoms are worsening or if there is suspicion for
pulmonary embolus.6 Findings may be unilateral or bilateral (55% and 45%,
respectively) and include peribronchial thickening and ground-glass opacities.
These findings are seen in adults and are milder in children than in adults. One
finding that is present in children but not in adults is the halo sign that appears
early. There is a central opacity that blocks out underlying lung structure with
a ringlike, surrounding hazy area (ground-glass opacities) (Figure 19-1A).
The halo sign has also been reported in infectious aspergillosis and other
fungal infections.
Authors from Boston Children’s Hospital7 developed recommendations on
when to conduct imaging studies for COVID-19 in children. They do not
recommend imaging as a screening tool or when symptoms are mild. The
decision depends on symptom severity, and chest radiography or computed
tomography is indicated if results may affect patient care. The decision to
order imaging is affected by the conditions shown in Box 19-3.
As the disease progresses, so do the radiological findings. Figure 19-1 shows
the progression that can be expected if there is worsening.
Ultrasonography has the advantage of portability and no radiation. Findings
in children with COVID-19 have shown the ability to follow the progress of
pulmonary findings. Musolino et al7 reported 10 children with COVID-19
showing B lines (70%), pleural irregularities (60%), white lung (10%), and
subpleural thickening (10%).
Box 19‑3
Imaging Considerations for COVID-19 in Children
ū Disease severity: mild or moderate/ • Cancer
severe • Prematurity-related lung disease
ū Disease prevalence: low or high • Chronic infection (eg, tuberculosis
ū Presence of underlying health or HIV)
conditions like: ū Travel history to area of known high
• Asthma COVID-19 prevalence
• Cystic fibrosis ū Constrained health resources
• Congenital heart disease
Derived from Foust AM, Phillips GS, Chu WC, et al. International expert consensus statement on chest
imaging in pediatric COVID-19 patient management: imaging findings, imaging study reporting, and
imaging study recommendations. Radiol Cardiothorac Imaging. 2020;2(2):e200214.

357
Figure 19–1. Axial lung window computed tomography images showing 3 phases (early, pro-
gressive, and developed) of COVID-19 pneumonia in 3 pediatric patients. A, Early phase of
pediatric COVID-19 pneumonia in a 14-year-old female adolescent with Hodgkin lymphoma and
a positive COVID-19 RT-PCR (reverse transcriptase–polymerase chain reaction) test result who
presented with fever and cough. The image shows a rounded ground-glass opacity (arrow) with
a subtle area of central consolidation in keeping with the halo sign that is often seen in the early
phase of pediatric COVID-19 pneumonia. B, Progressive phase of pediatric COVID-19 pneumonia
in a 15-year-old female adolescent with traveling history in an endemic area in Europe and a
positive COVID-19 RT-PCR test result who presented with increasing cough and shortness of
breath. The image shows rounded ground-glass opacities (arrows) with a subtle area of central
consolidation. Between these areas, ground-glass opacities (*) have started to fill the lung
parenchyma. C, Developed phase of pediatric COVID-19 pneumonia in a 16-year-old female
adolescent with a positive COVID-19 RT-PCR test result who presented with severe shortness
of breath. The image shows predominantly confluent consolidation (arrow) in the posterior
left lower lobe.
From Foust AM, Phillips GS, Chu WC, et al. International expert consensus statement on chest imaging in
pediatric COVID-19 patient management: imaging findings, imaging study reporting, and imaging study
recommendations. Radiol Cardiothorac Imaging. 2020;2(2):e200214. Published online April 23, 2020. DOI:
10.1148/ryct.2020200214. © Radiological Society of North America.
Persistence of Pulmonary Symptoms

Long COVID-19
Long COVID-19 or long-haul COVID-19 is when symptoms persist for a
period of months. Most children have symptoms for only a short time. Symp-
toms that may last more than 4 weeks include fatigue, fever in children aged 5
to 11 years, headache, and sore throat in adolescents aged 12 to 17 years. Other
symptoms that have been reported include brain fog or difficulty thinking or
concentrating, chest pain, cough, depression or anxiety, and loss of smell or
taste. There is no specific test for long COVID-19, and it can be expected to
improve over time.
Pediatric Inflammatory Multisystem Syndrome and Multisystem
Inflammatory Syndrome in Children
The inflammatory response to SARS-CoV-2 may be exaggerated, resulting in
pediatric inflammatory multisystem syndrome (PIMS) or multisystem inflam-
matory syndrome in children (MIS-C). The 2 conditions are essentially the

358
same but have different criteria for diagnosis. Multisystem inflammatory

syndrome in children is a postinfectious exaggerated inflammatory response
that is rare but can occur 2 to 6 weeks after the acute infection. Criteria
include confirmation of SARS-CoV-2 infection and evidence of inflamma-
tion with involvement of multiple systems with an illness that manifests
like Kawasaki disease. Evidence of inflammation may include an elevated
C-reactive protein, erythrocyte sedimentation rate, fibrinogen, procalcitonin,
ferritin, d-dimer, elevated neutrophils, and reduced lymphocytes. This inflam-
mation may progress to more severe illness with multisystem involvement,
including cardiac involvement and shock. Treatment of MIS-C is primarily
with anti-inflammatory or immunomodulatory medications such as
corticosteroids and intravenous immunoglobulin.
Management
Isolation is necessary, as is adequate fluid and calorie intake. Fever is
managed preferably with acetaminophen rather than ibuprofen. Children
hospitalized with hypoxemia require administration of oxygen via nasal
cannula or mask to keep the saturation at 92% or higher and should be moni-
tored closely for clinical worsening. High-flow nasal oxygen or continuous
positive airway pressure may be indicated in such cases. High-flow nasal
oxygen should be administered in single or negative pressure rooms to
protect health care workers.
The National Institutes of Health recommendations for treating COVID-19
in children are that steroids should be used when the patient requires supple-
mental oxygen, high-flow oxygen, nonmechanical ventilation, mechanical
ventilation, or extracorporeal membrane oxygenation. The effectiveness of
other treatments, including antibiotics, is unclear.
Remdesivir, a nucleoside antiviral, previously used to treat Ebola, has been
approved for children 28 days or older and adults hospitalized with COVID-
19. At one point in the pandemic, several monoclonal antibody combinations
showed a benefit as therapy, particularly in mild infection in individuals at
high risk of severe disease; however, they are no longer authorized as
currently the overall prevalence of non-susceptible variants is high. This is a
rapidly evolving area of investigation; for the most up to date recommenda-
tions, see https://www.aap.org/en/pages/2019-novel-coronavirus-covid-19
-infections/clinical-guidance/outpatient-covid-19-management-strategies
-in-children-and-adolescents/.
In December 2021, nirmatrelvir and ritonavir (Paxlovid, Pfizer) received
emergency use authorization from the US Food and Drug Administration
(FDA) for use in patients 12 years or older with COVID-19 who are at risk
of progression to severe disease.

359
Respiratory Syncytial Virus

Respiratory syncytial virus is the most important cause of lower respiratory
infection in children younger than 2 years. By age 2 years, more than 94%
of children will have serological evidence of RSV infection. During the
RSV season, RSV is the cause of hospitalization in more than 90% of infants
hospitalized with bronchiolitis. The differentiation between bronchiolitis
and pneumonia can be difficult, so the designation of lower respiratory tract
infection due to RSV may be easier than trying to define whether there is one
or both diagnoses. Infants with RSV pneumonia tend to have less wheezing,
less hyperinflation, and more crackles.
The clinical scenario of pneumonia is similar to that of bronchiolitis (see
Chapter 18, Bronchiolitis), with an upper respiratory prodrome followed by
worsening cough and increasing respiratory distress. As noted, wheezing
tends to be less prominent, and there may be crackles during examination.
The radiographic appearance of lobar consolidation (especially in the
right upper lobe) or a bronchopneumonia pattern supports the diagnosis
of pneumonia.
Most infants with RSV pneumonia recover in a few days, but a small percent-
age progress to respiratory failure. Infants younger than 2 months and those
with clinically significant respiratory distress or apnea should be hospitalized.
Severe lower respiratory tract infection is a concern for former preterm
infants with bronchopulmonary dysplasia and cyanotic heart disease
and also for infants with pulmonary hypertension.
Influenza Virus
The influenza virus is a single-stranded RNA virus that is a common cause of
pneumonia, especially in the very young and very old. It occurs in epidemic
form in the winter months, and children who are chronically ill are at more
risk for serious illness. Pandemics in the past 110 years include the 1918–1919
Spanish pandemic (influenza virus subtype H1), the 1957 pandemic (subtype
H2N2), the 1968–1969 pandemic (Hong Kong subtype H3N2), and the novel
influenza A (H1N1) pandemic of 2009–2010. The incubation period is 1 to
5 days after exposure to the virus.
The manifestation of influenza is characteristic with high fever, chills, muscle
aches, and headache, although young children may have more nonspecific
symptoms. The illness starts as an upper respiratory infection with rhinitis,
pharyngitis, and initially nonproductive cough. Young children may also have
conjunctivitis and gastrointestinal symptoms. Pneumonia is associated with
increasing respiratory symptoms and hypoxemia. Secondary bacterial
infection is common after influenza pneumonia.

360
Positivity for A or B influenza virus can be determined by means of immuno-

fluorescence or hemagglutination techniques, although during the 2009–2010
H1N1 pandemic, these tests were not very helpful in diagnosis. A polymerase
chain reaction assay of respiratory specimens has both high sensitivity and
high specificity for detection of influenza virus.
Symptoms last for several days and are treated with over-the-counter medica-
tions. Aspirin should be avoided because of the association with Reye syndrome.
Oral oseltamivir may be used in persons 2 weeks or older with influenza A or
B who have had symptoms for no more than 2 days. Oseltamivir may also be
used for prophylaxis of influenza infection for patients older than 3 months
who have been exposed.7,8 Baloxavir marboxil is approved by the FDA for
uncomplicated influenza in persons 12 years or older and is administered
as a single dose orally within 48 hours of symptom onset. Study results have
shown safe use of baloxavir marboxil in children as young as 1 year of age.
Human Parainfluenza Virus

Human parainfluenza virus (HPIV) 1, HPIV-2, and HPIV-3 cause croup;
HPIV-1 and HPIV-3 cause lower respiratory tract infection, including bron-
chiolitis, bronchitis, and pneumonia. Outbreaks of HPIV-3 occur during spring
and summer. Almost all children have been infected, and, because immunity
is short-lived, repeated infections occur. Human parainfluenza virus is spread
via droplet and fomite exposure.
Morbidity and mortality from HPIV lower respiratory tract infection is
uncommon in the United States. It is a substantial cause of mortality in under-
resourced countries, especially after secondary bacterial infection in children
who are malnourished.
Adenovirus
Adenovirus is an enveloped DNA virus that causes both upper and lower
respiratory infection. Most cases are mild, self-limited upper respiratory
infections. The population at risk for severe disease is the immunocompro-
mised, including patients who have received transplants, especially patients
who have received hematopoietic stem cell as well as solid organ transplants.
Treatment is to relieve symptoms. Cidofovir has been used in patients who are
severely ill and immunocompromised. There is a small risk of developing
bronchiectasis after adenovirus lower respiratory tract infection.
Human Metapneumovirus
Human metapneumovirus was first described in the Netherlands in 2001. It is
in the same family as RSV and HPIV (the Paramyxoviridae family). In the
pediatric population, the infections are similar to those with RSV, although

361
the illness tends to be milder and the children tend to be older. The symptoms
include rhinorrhea, cough, tachypnea, and wheeze. The signs include retrac-
tions, crackles, and wheeze. The clinical manifestations are similar to those
of RSV bronchiolitis, but pneumonia and respiratory failure may occur.
Varicella-zoster Virus
Varicella-zoster virus is a herpesvirus that causes chicken pox and has the
potential to reactivate as shingles. Risk factors for varicella pneumonia
include high-dose steroids (1–2 mg/kg/day for >2 weeks), malignancy (includ-
ing leukemia), and other immunocompromised states (including HIV infec-
tion). Varicella pneumonia causes substantial mortality and is associated with
severe invasive group A streptococcal disease. The viremia is treated with
acyclovir, and children with varicella pneumonia should be hospitalized.
Varicella-zoster immune globulin is indicated for immunocompromised
patients without evidence of immunity and newborn infants whose mothers
have signs of varicella 5 days before and 2 days after delivery.
Measles Virus
Measles virus is another member of the Paramyxoviridae family. It causes a
febrile illness with morbilliform rash; pneumonia can occur. Children who are
unvaccinated, malnourished, or immunocompromised are at risk for severe
lower respiratory tract infection.
Cytomegalovirus
Cytomegalovirus is a virus in the herpes group. Cytomegalovirus pneumonia
is a major cause of pneumonia in children who are immunocompromised,
including those with transplant, HIV, and malignancy. The typical scenario is
that 2 to 3 months after transplant, there is cough and fever; severe dyspnea
and hypoxia result. The symptoms are nonspecific, and the lung involvement
is an interstitial pneumonia. The chest radiograph shows bilateral interstitial
infiltrates. Pulmonary symptoms may be accompanied by gastrointestinal
disease, especially hepatitis and diarrhea, and chorioretinitis.
Ganciclovir is used as prophylaxis in patients at risk after transplant (eg, when
the donor is seropositive and the recipient is seronegative). It is also beneficial
for patients with pneumonia who have symptoms.
Supportive Care
For most patients with viral pneumonia, supportive care is all that is required
to make sure they have satisfactory oxygenation and hydration. Hospitaliza-
tion may be necessary for more severe illness and is most common in children
younger than 2 years. If influenza is identified, then appropriate antiviral
therapy might shorten the duration of the illness. Oseltamivir is commonly

362
selected because it is usually effective for both A and B strains. The Centers
for Disease Control and Prevention (CDC) regularly checks for resistance to
the recommended antiviral drugs, and amantadine is no longer recommended
because of lack of effectiveness for influenza B and a high percentage of resis-
tance with influenza A. Inhaled zanamivir may be used for children 5 years
or older provided they can use the device correctly and are not at risk for
bronchospasm. Intravenous peramivir is available for children 2 years or
older, and baloxavir is available for children 12 years or older.
Prevention of Viral Pneumonia

The CDC recommends that all individuals 6 months or older get a seasonal
flu vaccine. The seasonal flu vaccine protects against influenza viruses that
research indicates will be most common during the upcoming season. The
CDC also recommends that people in contact with certain groups of children
get a seasonal flu vaccine the better to protect the child (or children) in their
lives from the flu.
The CDC recommends that the following contacts of children receive
seasonal influenza vaccination:
X Close contacts of children younger than 5 years (people who live with
them), especially those younger than 6 months
X Out-of-home caregivers (nannies, child care providers, etc) of children
younger than 5 years
X People who live with or have other close contact with a child or children
of any age with a chronic health problem (asthma, diabetes, etc)
X All health care workers, to keep from spreading the flu to their patients
When to Refer
Most children with viral pneumonia will not require consultation. If there are
complications, such as pleural effusion, acute respiratory failure, or prolonged
hypoxia, consultation with a pulmonologist may be indicated. If the child has
a chronic illness, consultation with the specialist who is involved in the child’s
long-term care may be helpful. Consultation with infectious diseases or allergy
specialists is indicated if patients have allergies, comorbid conditions, or
unresponsiveness to antibiotics.
When to Admit
Children with pneumonia and a chronic illness, for example if they are
immunocompromised, may require hospitalization. If the degree of respira-
tory distress is clinically significant, if there is hypoxia, and if they appear
septic, they may require hospitalization. Currently, validated screening

363
systems do not exist to help predict which children with pneumonia should be
hospitalized. Hospitalization is indicated with the following:
X Oxygen saturation consistently less than 90%
X Moderate or severe respiratory distress
X Severe dehydration
X A home circumstance or social situation that raises concerns
key points
} The cause of pneumonia is closely related to the age of the child.
} Imaging studies do not help differentiate viral from bacterial lower respiratory
tract infections.
} Chest radiography is not necessary to establish the diagnosis of pneumonia.
} Computed tomography is indicated for evaluating complications of pneumonia.
} Ultrasonography is useful to characterize pleural effusion or empyema.
} Treatment depends on the age of the child and the likely diagnosis and severity
of illness.
References
1. Jartti T, Söderlund-Venermo M, Hedman K, Ruuskanen O, Mäkelä MJ. New molecular virus
detection methods and their clinical value in lower respiratory tract infections in children.
Paediatr Respir Rev. 2013;14(1):38–45 PMID: 23347659 doi: 10.1016/j.prrv.2012.04.002
2. O’Brien KL, Baggett HC, Brooks WA, et al; Pneumonia Etiology Research for Child Health
(PERCH) Study Group. Causes of severe pneumonia requiring hospital admission in children
without HIV infection from Africa and Asia: the PERCH multi-country case-control study.
Lancet. 2019;394(10200):757–779 PMID: 31257127 doi: 10.1016/S0140-6736(19)30721-4
3. Chonmaitree T, Trujillo R, Jennings K, et al. Acute otitis media and other complications of
viral respiratory infection. Pediatrics. 2016;137(4):e20153555 PMID: 27020793
doi: 10.1542/peds.2015-3555
4. Uhari M, Hietala J, Tuokko H. Risk of acute otitis media in relation to the viral etiology of infections
in children. Clin Infect Dis. 1995;20(3):521–524 PMID: 7756470 doi: 10.1093/clinids/20.3.521
5. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in
Wuhan, China. Lancet. 2020;395(10223):497–506 PMID: 31986264
doi: 10.1016/S0140-6736(20)30183-5
6. Musolino AM, Supino MC, Buonsenso D, et al; Roman Lung Ultrasound Study Team for Pediatric
COVID-19 (ROMULUS COVID Team). Lung ultrasound in children with COVID-19: preliminary
findings. Ultrasound Med Biol. 2020;46(8):2094–2098 PMID: 32409232
doi: 10.1016/j.ultrasmedbio.2020.04.026
7. Foust AM, McAdam AJ, Chu WC, et al. Practical guide for pediatric pulmonologists on imaging
management of pediatric patients with COVID-19. Pediatr Pulmonol. 2020;55(9):2213–2224
PMID: 32462724 doi: 10.1002/ppul.24870
8. Maldonado YA, O’Leary ST, Ardura MI, et al; American Academy of Pediatrics Committee
on Infectious Diseases. Recommendations for prevention and control of influenza in children,
2021–2022. Pediatrics. 2021;148(4):e2021053744 PMID: 34493537 doi: 10.1542/peds.2021-053744

CHAPTER
20
Nonviral Pneumonia
Mark H. Sawyer, MD
Introduction
Pneumonia is a serious global health issue. It is the second leading cause of
death in children younger than 5 years and the leading cause of death in this
age group in certain geographic areas.1,2 Death from pneumonia is closely
linked to poverty, with the highest mortality occurring in the most economi-
cally disadvantaged areas.3 The story is quite different in resource-rich coun-
ties: the incidence of community-acquired pneumonia (CAP) in the United
States is about 35 to 40 per 1,000 children 4 years or younger and decreases
to 10 per 1,000 in teenagers and adolescents; less than 1% die.4
There are several different ways pneumonia may be classified to identify
the suspected organism, determine the best management, and predict the
outcome. There are multiple causative agents, both nonviral and viral. These
include gram-positive and gram-negative bacteria, atypical bacteria, and
fungal, parasitic, and chemical agents. Classification based on the clinical
scenario includes CAP or health care–related (including ventilator-associated
pneumonia), immunocompromised versus immunocompetent host, patient
age, and geographic and exposure risks.5,6 Classification based on the appear-
ance of radiographic images includes bronchopneumonia, lobar (or multilobar)
pneumonia, and interstitial pneumonia.6 Complicated pneumonia is defined as
a pulmonary parenchymal infection complicated by parapneumonic effusions,
multilobar disease, abscesses or cavities, necrotizing pneumonia, empyema,
pneumothorax, or bronchopleural fistula or as pneumonia that is a complica-
tion of bacteremic disease that includes other sites of infection (see Chapter
21, Complications of Pneumonia).7 Not one of these classifications has a strong
predictive value as to the specific cause. Despite various classification
schemes, the specific microorganisms responsible for the pneumonia may be
difficult to determine.7 Therefore, it is common practice to prescribe antibiotic
therapy, despite lack of a documented bacterial infection, “just in case.”8
365

366
Common Clinical Presentations

Children with pneumonia, regardless of the cause, may have a constellation of
symptoms, including fever, cough, chest pain, and dyspnea. Other systemic
symptoms such as nausea and vomiting are also common.2 The findings at
auscultation vary with the extent of the pneumonia but commonly include
tachypnea, inspiratory crackles, and decreased intensity of breath sounds.8
Expiratory wheezing suggests a viral or atypical bacterial cause. If a pleural
effusion is present, there may be dullness to percussion over the affected area.
Small children with compliant chest walls often have retractions. The oxygen
saturation is commonly reduced, although cyanosis may be evident only with
severe levels of desaturation (Table 20-1).
Table 20-1. Findings Suggestive of Pneumonia

Finding Method ≤2 months 2–12 months 1–5 years >5 years
Respiratory rate ≥60/min ≥50/min ≥40/min ≥30/min
WHO threshold
Symptoms and Cough Cough Cough Cough
signs Poor feeding Fever Fever Fever
Apnea Poor feeding Rhinorrhea Headache
Tachypnea Tachypnea Chest pain Pleuritic pain
Grunting Grunting Tachypnea Abdominal pain
Nasal flaring Rhinorrhea Retractions Tachypnea
Retractions Nasal flaring Retractions
Retractions
Auscultation Crackles Wheeze Crackles Crackles
Wheeze Crackles Wheeze Wheeze
Pleural rub Pleural rub
Abbreviation: WHO, World Health Organization.
Evaluation of Suspected Pneumonia

Imaging
Pneumonia can be diagnosed on clinical grounds without documentation with
a chest radiograph (CXR).2,5,9–12 In countries with limited resources, identify-
ing children with fever and elevated respiratory rate as needing a higher level
of care and antibiotics has reduced the mortality from pneumonia. However,
results from a study in which the investigators compared pneumonia diagnosed
simply by means of World Health Organization clinical criteria, especially
elevated respiratory rate, showed that a majority of the children who were
considered as having pneumonia actually had a normal CXR.13

367
Chapter 20—Nonviral Pneumonia
In resource-rich areas, a CXR is commonly obtained to help diagnose pneu-

monia for children with fever, cough, and adventitious pulmonary sounds
aside from wheezing.10 This is particularly true for children taken to the
emergency department or admitted to the hospital. Although it is possible to
have pneumonia without abnormal radiographic findings, an abnormal CXR
is usually the gold standard for diagnosing pneumonia. A negative CXR has a
high predictive value of the patient not having pneumonia and not developing
pneumonia in the near future, unless it is obtained very early in the illness.9,10
Standard practice is to obtain a posteroanterior CXR (or anteroposterior if
the patient is younger than 4 years). A lateral view is also advisable for
children who are hospitalized.
Chest computed tomography is seldom required for CAP and is reserved
for helping evaluate and define complicated pneumonias (see Chapter 21,
Complications of Pneumonia). Ultrasonography is useful with pleural
effusions, and there is interest in its use for CAP as well, which may be
important in resource-limited areas when chest radiography and computed
tomography are not readily available.2,5
Laboratory Evaluation of Pneumonia

Which laboratory tests are ordered for a child with pneumonia often depends
on the severity of the illness and whether hospitalization is being considered.2
For a child with mild CAP who was previously healthy, perhaps no laboratory
studies are indicated. For a child who is more seriously ill who will be admit-
ted to the hospital, a complete blood cell count (CBC) with a white blood cell
(WBC) differential count and inflammatory markers (C-reactive protein
[CRP] level, erythrocyte sedimentation rate, procalcitonin [PCT] level) and
a basic metabolic panel are commonly ordered.14,15 Certain patterns of results
may suggest a specific type of organism, but the predictive value is not high.
If the WBC count is higher than 15,000/μL (15.00 × 109/L) with a shift toward
immature neutrophils, bacterial infection may be suspected.14,15 The CRP and
PCT levels are more sensitive and specific for bacterial infections.16–19 If the
WBC count is normal or low and there is a lymphocyte predominance, viral
infection is suspected, especially if accompanied by a modestly elevated or
normal CRP or PCT level. In infants, if the WBC count is high with a marked
lymphocyte predominance, Bordetella pertussis is suspected. If the WBC
differential count has excessive eosinophils, parasitic or fungal infection is
suspected. In infants, peripheral eosinophilia may suggest Chlamydia tracho-
matis pneumonia. Another benefit of the CBC is checking the hemoglobin
level to make sure there is satisfactory oxygen-carrying capacity for oxygen
delivery to the tissues. Electrolyte disturbance such as hyponatremia may
raise concern for inappropriate antidiuretic hormone secretion. Elevated liver
enzyme levels may be found with adenovirus or Mycoplasma infections.

368
Microbiology
Advances in laboratory techniques have increased the ability to make a
specific microbiological diagnosis in many cases of pneumonia.7 Polymerase
chain reaction (PCR) detection with a rapid turnaround time is now available
for a wide range of viruses and some bacteria from the upper respiratory
tract.16 Studies using this technology in children hospitalized with pneumonia
in the United States identified a viral cause in 66%, a bacterial cause in 8%,
and mixed bacterial and viral causes in 7% of the 81% in which a specific
cause was identified.4 A similar study in younger children hospitalized with
pneumonia in Africa and Asia identified a viral cause in 61%, a bacterial
cause in 27.3%, and Mycobacterium tuberculosis in nearly 6%; bacterial
infection was more common in these children with “very severe” pneumonia
compared with “severe” pneumonia.17 The multiplex PCR technology has
largely supplanted other testing modes such as direct fluorescent antibody
testing and serial serological testing; some types of rapid influenza detection
tests use immunofluorescence but are less sensitive and less specific than
molecular tests.7
Although multiplex PCR testing has greatly improved the ability to identify
evidence of specific organisms, it has also created concern whether some of
these organisms are the source of the pneumonia or found incidentally in the
patient’s nasal and oral secretions.18 According to a comparison of patients
with CAP versus control subjects without symptoms, detection of influenza,
respiratory syncytial virus (RSV), and human metapneumovirus is probably
indicative of cause, whereas the detection of parainfluenza, coronavirus,
rhinovirus, and adenovirus is less clearly indicative of cause. A positive PCR
result for rhinovirus may occur for several weeks after an infection. These
concerns also apply to more recently discovered potential pathogens such as
bocavirus among others.18
A sputum sample for Gram stain and culture is not usually indicated in CAP
but may be valuable, provided the sample is good quality and not predomi-
nantly upper airway secretions and squamous epithelial cells. Predominance
of a single type of bacteria in large numbers suggests this is the pathogen
responsible for the pneumonia.14,15 Mixed flora in lower density usually does
not correctly identify the pathogen. Blood cultures in patients with simple
CAP are infrequently positive and are not cost-effective; they are more likely
to be positive in patients hospitalized with complicated pneumonia.19 When
a pleural effusion is present, sampling the pleural fluid to find a specific
pathogen may be helpful; however, the result is often negative, particularly
if the patient has already received antibiotics.8,15 Recent development of
metagenomic next-generation sequencing rapid tests is likely to greatly
improve the ability to identify bacterial infections and resistance patterns
of bacterial pathogens.20

369
Indirect tests such as urinary antigen testing are useful in some causes of
pneumonia such as histoplasmosis but have had less use with bacterial pneu-
monia such as Streptococcus pneumoniae. Serum antibody testing is very
helpful in patients who are immunocompromised and have fungal pneumonia
for which culturing an organism in the laboratory can be slow and challenging.
Markers of fungal cell wall elements such a β-D-glucan and galactomannan
can be helpful if present in blood or bronchoalveolar lavage specimens,
especially in a patient who is immunocompromised.
Pathology
The pathology of pneumonia is described as follows:
X Lobar
X Bronchopneumonia
X Interstitial
X Miliary
Lobar pneumonia has 4 stages. The initial stage is congestion, when the
alveoli are filled with fibrinous fluid, neutrophils, and bacteria. This stage
occurs within 24 hours of infection. The second stage usually occurs on days
2 to 3 and is called red hepatization. The lung reddens and is of the consis-
tency of liver. The alveoli are filled with fibrinous inflammatory exudates
with increased numbers of neutrophils and red blood cells that contribute to
the color. The consolidated lobe is airless and evident on a CXR. The pleura
is usually thickened, and a pleural rub may be heard. The next stage is called
gray hepatization, when the alveoli are filled with fibrin threads and neutro-
phils and the red blood cells are much fewer in number. The lung is still stiff,
and the alveolar walls are thickened and fibrosed. The fourth stage is that of
resolution as the inflammatory exudates are resorbed.
Bronchopneumonia is patchier, and, as the name suggests, there is suppurative
inflammation of the bronchi and surrounding alveoli. The exudates fill bronchi
and bronchioles and affect the adjacent alveoli, while the distant alveoli may
be free of exudates. The patchy consolidation may affect one or several lobes
and is usually bilateral. The lobes more involved include the dependent lung
zones and the bases.
Interstitial pneumonia results from inflammation within the alveolar wall
rather than in the alveolar airspace. The infiltrate tends to be lymphocytes
and macrophages, and hyaline membranes may line the alveolar spaces.
Miliary pneumonia occurs with hematogenous spread to the lung, which leads
to multiple discrete lesions, often throughout both lungs.
Bacterial pneumonia often follows a viral upper respiratory infection (URI).
Lobar pneumonia is most commonly bacterial, including atypical bacteria.

370
Bronchopneumonia may be bacterial, atypical, or viral. Interstitial pneumonia

may result from HIV, measles, and pertussis, as well as from noninfectious
causes, including aspiration. Miliary pulmonary infection is most commonly
seen in tuberculosis, histoplasmosis, and coccidioidomycosis. Patients who are
immunocompromised are at risk for cytomegalovirus or varicella-zoster virus
and other opportunistic infections.
Diagnosis
The microbiological diagnosis of pneumonia is difficult to prove in many
cases without extensive investigation. The age of the child will suggest the
most likely cause, and it is also helpful to be aware of which organisms are
in the community at the time. Pneumonia in the pediatric population is most
common in infants and toddlers and least common in adolescents.
Box 20-1 lists the more likely causes of pneumonia on the basis of age.
Box 20‑1
Age-Related Causes of Pneumonia in the
Child Who Is Immunocompetent
≤ 2 Months 1–4 Years
Group B Streptococcus Pneumococcus
Pneumococcus Parainfluenza
Staphylococcus aureus Influenza
Chlamydia trachomatis Adenovirus
Listeria monocytogenes RSV
2–12 Months hMPV
Pneumococcus Mycoplasma
RSV 5–12 Years
Parainfluenza Mycoplasma
Influenza Pneumococcus
Adenovirus Group A Streptococcus
hMPV Viruses
C trachomatis ≥ 12 Years
Pertussis Mycoplasma
Chlamydia pneumoniae
Pneumococcus
Group A Streptococcus
Viruses
Abbreviations: hMPV, human metapneumovirus;

RSV, respiratory syncytial virus.

371
Infants to School Age (1 Month–4 Years)

After children reach 1 month of age, cough is the most common manifesta-
tion of pneumonia. A viral upper respiratory illness commonly precedes
the pneumonia. If the pneumonia is bacterial, a clinically significant fever
is usually present, whereas in viral or atypical infections, the fever may be
low-grade. Generally, the height of the fever is a poor indicator of cause.
Most cases of pneumonia are viral, and RSV is the most common pathogen.
Although RSV principally causes bronchiolitis, it is also a common cause of
pneumonia. After children reach 2 years of age, RSV does not typically cause
lower respiratory tract infection except in patients who are immunocompro-
mised (especially transplant recipients). Human parainfluenza type 3 occurs
year-round, with peaks in the spring, and types 1 and 2 are typically seen
in the fall.
From 5 Years of Age to Adolescence

The most common cause of bacterial pneumonia is S pneumoniae, but
Mycoplasma is increasingly being diagnosed as the cause of CAP. Group A
Streptococcus is also increasingly being diagnosed. Various viruses cause
pneumonia, including adenovirus, influenza, parainfluenza, and RSV
(in patients who are immunocompromised or have received transplants).
Bacterial Pneumonia
In one study, bacteria were isolated as a cause of CAP in less than 10%
of children hospitalized for pneumonia, and an additional 7% had mixed
bacterial and viral infections.4 A bacterial pathogen alone was infrequent
in children younger than 2 years, and the incidence increased through child-
hood and adolescence.4 S pneumoniae was the most common typical bacteria
identified and only in less than 5% of the patients. Other bacteria identified in
lower frequency included Staphylococcus aureus (both methicillin resistant
and methicillin sensitive), Streptococcus pyogenes, viridans streptococci,
and Haemophilus influenzae. Only a very small number of gram-negative
organisms were identified. Atypical bacteria (Mycoplasma and Chlamydia)
are discussed separately later.
Bacterial pneumonia is an important cause of death if untreated, especially in
underresourced countries. Although most children with bacterial pneumonia
improve without sequelae, children with a preexisting condition may be at
increased risk for morbidity, including subsequent infections because of
scarring in the lungs. The immune status of the child also affects the risk of
mortality and morbidity.

372
Gram-Positive Bacteria
Pneumococcus
S pneumoniae was the most common bacterial cause of lower respiratory
infection before the institution of the pneumococcal vaccine in 2000. Since
2000, there has been a reduction of invasive pneumococcal disease by 80%
for children younger than 2 years, and this finding may increase since the
13-valent pneumococcal conjugate vaccine (PCV13) replaced PCV7 in the
routine childhood immunization schedule and became available in 2010.6
Surveillance is also indicated for nonvaccine serotypes. Although invasive
pneumococcal disease has decreased, complicated pneumonia has increased
significantly across the United States,7 and these cases tend to be due to
nonvaccine serotypes.
Pneumococci are gram-positive diplococci, and the upper respiratory tract
is colonized in many people. Transmission is by droplet, and the incubation
period is short (sometimes 1–3 days). Populations at more risk for invasive
pneumococcal disease (pneumonia, meningitis, and sepsis) are shown
in Box 20-2.
Pneumococcal pneumonia may be preceded by a mild URI. Infants may
present with a sudden increase in fever, possibly a seizure, and diarrhea and
vomiting. Cough may be absent, but evidence of respiratory distress includes
tachypnea, nasal flaring, and perioral cyanosis. Older children usually present
with fever, chills, dyspnea, and pleuritic chest pain. Older children may have
sputum production, and streaks of blood may be apparent in the sputum.
Chest examination results may not be abnormal in infants and small children.
Older children will usually have crackles and dullness to percussion with
bronchial breathing over the involved lobe. Friction rub is not often elicited.
Abdominal pain is a common symptom in an older child.
Box 20‑2
Children at Increased Risk of Invasive Pneumococcal Disease
ū Children younger than 36 months
ū Children with sickle cell disease
ū Children with asplenia
ū Children with HIV
ū Children with cochlear implants
ū Children with chronic disease including asthma, immune deficiency
(including transplants), cardiac disease, pulmonary disease, renal
insufficiency, and diabetes mellitus are at presumed high risk, but
the data are insufficient to calculate rates.

373
Laboratory findings also are not consistent. Although not usually obtained
in the outpatient setting, a WBC count higher than 15,000/μL (15.00 × 109/L)
with the clinical picture of pneumonia is certainly suggestive of pneumo-
coccal disease. The yield from blood culture is low, but, when an adequate
specimen is obtained, the sputum findings of many polymorphonuclear leuko-
cytes with gram-positive diplococci are almost diagnostic. Young age is a
barrier to sputum collection. Antigen detection is not considered useful for
diagnosis except for pleural fluid.
Chest radiography in children with pneumococcal pneumonia may initially
demonstrate a lobar pattern and then extend beyond the lobar boundaries. It
is the most common cause of the round pneumonia pattern. On occasion, the
markings may be patchy or interstitial. As discussed in Chapter 7, Pulmonary
Imaging, chest radiography is not consistently able to help confirm the diagno-
sis of a bacterial or viral pneumonia because of overlap between findings.
The clinical course of pneumococcal pneumonia is usually rapid, with response
to antibiotics causing reduction of fever within a few hours. For outpatient
treatment in children with CAP that has been proven to be or is suspected to
be of bacterial origin, amoxicillin or amoxicillin-clavulanate is the therapy
of choice. In school-aged children (>5 years), the addition of a macrolide for
coverage of atypical organisms may be warranted. In children ill enough to
warrant hospitalization, the empirical use of penicillin or ampicillin and the
addition of a macrolide may be appropriate, and decisions for therapy should
take into account local resistance patterns and immunization history. Use of
third-generation cephalosporins is reserved for infants and children who are
hospitalized and not fully immunized in areas with a higher incidence of inva-
sive pneumococcal strains and high-level penicillin resistance or in children
with severe infection. Empirical therapy with a third-generation parenteral
cephalosporin (ceftriaxone or cefotaxime) should be prescribed for infants
and children who are hospitalized and not fully immunized; in regions where
local epidemiology of invasive pneumococcal strains documents high-level
penicillin resistance; or for infants and children with life-threatening infec-
tion, including those with empyema. Complications may be systemic, with
meningitis, carditis, peritonitis, and septic arthritis resulting from bacteremia.
Pulmonary complications include pleural effusion and empyema. Inappropri-
ate secretion of antidiuretic hormone is common and may cause a clinically
significant reduction of serum sodium.
Group A Streptococcus
Also known as S pyogenes, Group A β-hemolytic Streptococcus is an
uncommon cause of pneumonia. It is important because the clinical course
is aggressive and may result in necrotizing pneumonia. The clinical appear-
ance of the child includes fever, chills, lethargy, cough, and dyspnea. The
most common radiographic pattern is a patchy bronchopneumonia, but in a

374
minority of cases there is lobar consolidation. Cavitation may occur, as well

as pleural effusion with progression to fibrinopurulent empyema.
The response to antibiotics tends to be slow, even with selection of an
appropriate agent such as penicillin or ampicillin. Clindamycin, a ribosomal
agent, may be added as an adjunct in toxin-mediated disease. Penicillin is the
treatment of choice, although ampicillin is an alternative. Complications are
common and include pneumothorax, pneumatoceles, bronchiectasis, and
bronchopleural fistula.
Staphylococcal Pneumonia
S aureus is an uncommon cause of pneumonia in children who are immuno-
competent, but it does occur in infancy. It also occurs more commonly after
influenza infection and other viral URIs. Staphylococci are gram-positive
organisms that occur in clusters. Pneumonia results from inhalation of organ-
isms or from bacteremic spread. The clinical picture varies from a mild
respiratory infection with fever, cough, and tachypnea to a rapidly progres-
sive illness with dyspnea, cyanosis, and septic shock. The initial radiographic
appearance is multiple nodular infiltrates, usually unilateral, which in a few
days become cavitary, and pneumatoceles subsequently form. Pneumothorax
is common, especially in infants receiving ventilation, and empyema is present
in most cases.
The scenario described in the previous paragraph would be likely diagnosed as
S aureus in an infant, but if the same findings were present in an older child,
other organisms would be more likely, such as Escherichia coli, Pseudomonas,
or Klebsiella. It is likely that the relative prevalence from pneumococcus to
S aureus is increasing in older children and that there are increasing numbers
of children with pneumonia caused by methicillin-resistant S aureus.8
If staphylococcal pneumonia is suspected, the increased prevalence of
methicillin-resistant S aureus may require vancomycin or clindamycin for
initial treatment until the sensitivities are known. Alternative agents include
trimethoprim/sulfamethoxazole and ceftaroline fosamil, which has been
shown to be an effective agent for treatment of pediatric CAP, and linezolid.
Daptomycin is inactivated by surfactant and should therefore not be used to
treat pneumonia.
Gram-Negative Bacteria
Pseudomonas aeruginosa
Pseudomonas is a gram-negative bacterium that has a predilection to moist
environments. It is common to acquire Pseudomonas, with colonization in
more than 50% of humans, and Pseudomonas often causes nosocomial
infection. It is an unusual cause of pneumonia in children who are healthy.

375
Pneumonia caused by Pseudomonas is a common complication in patients

with endotracheal tubes or tracheostomy. It is the dominant organism in
cystic fibrosis (CF). It occurs more frequently in children with HIV infection,
neutropenia, and complement deficiency10 and those who are immunosup-
pressed. It is the most common cause of pneumonia in the intensive care
environment. It also has been reported after exposure in hot tub spas.
Although the typical color of sputum produced in pseudomonal pneumonia
is green, this color may be seen with pneumococcal and Haemophilus
infections. The progression of Pseudomonas pneumonia to necrotizing
bronchopneumonia may be rapid if untreated. Pleural effusion is common,
and the pneumonia may have a lobar or diffuse bilateral bronchopneumonia
radiographic pattern.
For children with chronic Pseudomonas infection, especially those with CF,
there is a major problem of resistance when therapy with a single antibiotic is
used. Therefore, the use of 2 antibiotics (a semisynthetic penicillin along with
an aminoglycoside) is often indicated.
Burkholderia cepacia
Pseudomonas cepacia was described initially by Walter Burkholder in 1949
and is now named B cepacia. It is an important pathogen in causing pneumo-
nia in patients with CF and has been reported to cause pneumonia in patients
who are immunocompromised. B cepacia does not typically cause pneumonia
in children who are healthy.
Klebsiella pneumoniae
K pneumoniae is a gram-negative rod-shaped bacillus and is clinically
the most important member of the Klebsiella genus of Enterobacteriaceae.
Pneumonia as a result of K pneumoniae is typically a nosocomial infection.
It may also be community acquired, although this is rare in children who
are otherwise healthy. Pneumonia tends to occur in children who are immu-
nocompromised or debilitated. Pneumonia as a result of K pneumoniae is
associated with an acute onset with fever and chills. The cough is productive
and yields abundant thick sputum that is typically tinged with blood and is
known as red currant jelly sputum. Pneumonia is usually complicated, and
abscess formation, cavitation, and empyema are common. Infection is more
commonly unilateral, occurring typically in the upper lobes. Hospitalization
is indicated, including for CAP, because even with treatment, there is clini-
cally significant mortality. Many Klebsiella organisms are resistant to
various antimicrobials, and empirical therapy should take this into account.
The potential choice is wide, including third-generation cephalosporins
(eg, cefotaxime or ceftriaxone), cefepime, carbapenems (eg, meropenem),
aminoglycosides, and quinolones. Infectious disease consultation is
advisable.

376
Legionella pneumophila
Legionnaires’ disease was first recognized in 1976 at an American Legion
convention in Philadelphia. The organism that caused an outbreak of pneumo-
nia was identified as a gram-negative bacillus, L pneumophila. Although an
unusual cause of pneumonia in children, it is important to recognize. It is more
common in children who are immunosuppressed, and more than one-third of
pediatric cases have been in children younger than 1 year. Transmission occurs
via aerosolization and inhalation or aspiration of water containing the organ-
ism. It has been linked to contaminated water in hospitals and respiratory
therapy equipment, as well as cooling towers; central air conditioning systems;
evaporative coolers; hot water systems, including showers and hot tub spas;
and ice-making machines. The disease is particularly prevalent in hotels, cruise
ships, and hospitals that have outdated cooling systems. The incubation period
is 2 to 10 days; for milder disease, known as Pontiac fever, the incubation
period is 1 to 2 days.
Clinical Features
Legionnaires’ disease manifests with fever, chills, and cough, which is initially
nonproductive. Constitutional symptoms include headache, muscle ache, and
sometimes ataxia (loss of coordination) and diarrhea or vomiting. The lung
examination typically reveals crackles.
Blood testing may reveal abnormal hepatic or renal function, and hyponatremia
is common. A CXR typically shows unilateral or bilateral bronchopneumonia.
Management
Clues to the diagnosis are the constitutional symptoms and the laboratory test
abnormalities, including hyponatremia. Detection of L pneumophila serogroup
1 is aided by detecting Legionella antigen in the urine.
Azithromycin is the drug of choice for children suspected of or confirmed as
having Legionella pneumonia. Azithromycin should initially be administered
intravenously, converting to orally when the child responds.
Anaerobic Organisms
The most common anaerobic gram-negative bacilli (AGNB) to cause pneumo-
nia are the pigmented Prevotella species. The Prevotella species are important
components of the bacterial flora of the mouth, nose, and nasopharynx. They
are not often cultured because of the difficulty in specimen collection and
growing in the microbiology laboratory. Anaerobic organisms are common
causes of chronic sinusitis, chronic mastoiditis, chronic otitis media, and
retropharyngeal abscess.
Pneumonia caused by anerobic organisms results from aspiration of upper
airway or gastric secretions. Severe gingival disease is a risk factor for aspira-
tion. After aspiration, there may be progression from pneumonia to necrotizing

377
pneumonia, and AGNB is an important cause of lung abscess.11 Frequently,

AGNB may be recovered in culture along with Enterobacteriaceae,
Pseudomonas, and S aureus.
The Prevotella species are resistant to penicillin and typically susceptible to
amoxicillin/clavulanate, clindamycin, metronidazole, and carbapenems.
Atypical Pneumonia
The term atypical pneumonia is applied because the causative organism is an
atypical bacteria or virus. The agents that cause atypical pneumonia include
Mycoplasma pneumoniae, C trachomatis, Chlamydia pneumoniae, and
Chlamydia psittaci.
M pneumoniae
M pneumoniae is the most common cause of CAP in children older than
5 years and is often called walking pneumonia. It is common in children
younger than 5 years.12 The true incidence is unknown because many cases
are treated empirically without confirmation of the diagnosis. There are
no geographic limitations, and infection occurs year-round. There may be
epidemics every 3 to 7 years, and outbreaks occur in schools and universities.
M pneumoniae is called Mycoplasma because of the plasticity of the bacterial
forms, which resemble fungal elements. Instead of a cell wall there is a cell
membrane containing sterols, which are not present in other bacteria or
viruses. Unlike viruses, they do not require a cell to replicate and can
grow in cell-free media, and they contain both RNA and DNA.
Clinical Features
M pneumoniae infections usually start with a URI with pharyngitis, cough,
headache, and myalgias. There may be fever, which is usually less than 39°C
(102°F). The cough is initially nonproductive and can be severe and debilitat-
ing. Blood streaking of the sputum is not uncommon, and the coughing may
cause chest pain that is nonpleuritic. In 5% to 10% of children, the URI pro-
gresses to bronchitis or pneumonia. Small pleural effusions can occur in
5% to 20% of patients. Cutaneous manifestations are common and include
maculopapular rash and erythema nodosum. Extrapulmonary symptoms are
not uncommon and include bullous myringitis, which supports the diagnosis
of Mycoplasma.
In sickle cell disease, a Mycoplasma infection may be severe and is consid-
ered an important cause of acute chest syndrome. It also can be severe in
Down syndrome, especially in those with congenital cardiac disease. Both
Mycoplasma and Chlamydia cause exacerbations of asthma in children and
adolescents.

378
The physical examination usually reveals oropharyngeal inflammation. The

chest examination results may be relatively benign, with few crackles and
rhonchi, at the same time that a CXR shows clinically significant findings
of pneumonia. Wheezing may occur, particularly if the child has asthma.
Laboratory
Cold agglutinins should not be used to confirm the diagnosis because they are
nonspecific (only about 75% are positive). Mycoplasma immunoglobulins M
and G may be useful to confirm the diagnosis, with a sensitivity of approxi-
mately 98% if both are measured. Immunoglobulin M results may be negative
in the first week of illness and may be indicative of past infection. A PCR test
is highly sensitive, but the results may reflect colonization when the sample is
obtained from the nasopharynx.
Imaging
Infiltrates are more likely to be bilateral than unilateral. There may be lobar,
multifocal, or diffuse disease with reticular infiltrates.11 Pleural effusions
are present in about 20% of cases (though they tend to be small), and hilar
adenopathy is seen in 7% to 22%.
Management
First-line treatment for M pneumoniae is macrolide antibiotics, although there
are now reports of macrolide resistance. Tetracycline is active, in particular
doxycycline, and can be used for adolescents; if administered to children
younger than 8 years, the duration should be 21 days or fewer. The newer
fluoroquinolones are effective, but not as effective as macrolides. The lack of
cell wall predicts that β-lactams are not effective, nor is trimethoprim. Most
cases of CAP improve in a matter of days with no residual findings.
C trachomatis
C trachomatis is an important cause of sexually transmitted infection and
trachoma. Although uncommon in the United States, trachoma is the most
common cause of blindness in the world. C trachomatis causes pneumonia,
especially in infants. Approximately 5% to 22% of pregnant women have
C trachomatis of the cervix, and 30% to 50% of these will show culture
evidence of infection. The infection in the newborn is conjunctivitis with or
without nasopharyngitis, which in some cases results in neonatal pneumonia.
Clinical Features
Most infants with C trachomatis pneumonia have a history of conjunctivitis,
nasal stuffiness, and cough with tachypnea. This pneumonia is characteristi-
cally afebrile. The chest examination reveals scattered crackles; wheezing
is absent.

379
Imaging
The CXR shows either a lobar or interstitial pattern.
Management
The first-line therapy to treat infants with C trachomatis pneumonia is
erythromycin 50 mg/kg/day divided every 6 hours for 14 days. Azithromycin
is an alternative.
C psittaci
C psittaci causes psittacosis or ornithosis after exposure to infected birds.
Ornithosis is the preferred name because it can be caused by any bird, includ-
ing parrots, chickens, ducks, turkeys, pigeons, and sparrows. It is transmitted
from birds to humans by either direct contact or aerosolization. It is much less
common since the imposition of a quarantine for 30 days for imported birds
and the introduction of bird feed laced with antibiotics.
It is quite difficult to diagnose, and it is possible that it is more common than
appreciated. The most common disease is a mild pneumonia, but it can pro-
duce a more fulminant illness. There is fever without elevation of the pulse,
which is usually associated with fever. Clues to the diagnosis include spleno-
megaly; a blanching erythematous maculopapular rash; and signs of hepatitis,
disseminated intravascular coagulation, or meningoencephalitis, any of which
may be present. C psittaci is sensitive to both macrolides and tetracyclines.
Because the antibiotic only kills the organism when it is active, the bird
should be treated for 45 days.
C pneumoniae
C pneumoniae causes a mild pneumonia or bronchitis in older children,
adolescents, and adults. Approximately 50% of young adults have serological
evidence of prior infection. C pneumoniae has been reported to cause 10%
to 20% of CAP, but this is likely an overestimate. It is transmitted from
person to person by respiratory secretion transfer. The incubation period
is approximately 3 to 4 weeks.
Initially there is a URI, and many patients have no further symptoms. The
symptoms can be prolonged, and helpful in the diagnosis is the presence
of hoarseness and headache; fever is uncommon. The physical examination
reveals crackles and rhonchi. Even with treatment, C pneumoniae tends to
respond more slowly than does Mycoplasma, which may also be a clue to
the diagnosis. Many cases are self-limiting and mild. Recommendations
for treatment include macrolides as first-line treatment, with tetracyclines or
fluoroquinolones as alternatives. Therapy duration depends on symptoms and
typically is 10 to 14 days. Mortality of 9.8% has been reported in patients with
sickle cell disease.13
Table 20-2 provides a template for management of CAP.

380
Table 20-2. Antibiotics for Community-Acquired Pneumonia

Age Typical Bacterial Pneumonia Atypical Bacterial Pneumonia
Outpatient: Amoxicillin (orally) Azithromycin (orally)
younger than
5 years Alternative: amoxicillin + Alternatives: clarithromycin,
clavulanate (orally) erythromycin (orally)
Outpatient: Amoxicillin (orally) Azithromycin (orally)
5 years or
older Alternative: amoxicillin + Alternatives: clarithromycin,
clavulanate (orally) erythromycin, doxycycline
(<21 days) (orally), levofloxacin
Inpatient: Ampicillin or penicillin G Azithromycin + β-lactam
all ages
Alternative: ceftriaxone, Alternatives: clarithromycin,
erythromycin, doxycycline
(<21 days), levofloxacin
If MRSA suspected:
add vancomycin or clindamycin
Abbreviation: MRSA, methicillin-resistant Staphylococcus aureus.
Other Causes of Bacterial Pneumonia

Tularemia, anthrax, and plague are uncommon bacterial syndromes in which
pneumonia may be a prominent feature. They should raise the suspicion
of bioterrorism.
When selecting initial empirical antibiotics for a child with CAP, it is import-
ant to consider the child’s age and immunization status as well as treatment
locale (Table 20-2).8 Because S pneumoniae is the most common bacterial
organism, empirical therapy is initially targeted at that organism.
Previously, the recommended dosing interval for amoxicillin was twice daily,
but administering the antibiotic 3 times per day significantly increases the
active time kill.15 Local microbiological and epidemiological information
should be considered when selecting empirical antibiotic therapy in both the
inpatient and outpatient settings. If a specific organism is identified, the antibi-
otic choice can be directed more specifically.15 Additional antibiotic dosing and
schedules can be found in Chapter 58, Antibiotics for Pulmonary Conditions.
Fungal Pneumonia
The most common endemic fungal pneumonias include histoplasmosis, coc-
cidioidomycosis, blastomycosis, and cryptococcosis (caused by Cryptococcus
gatii, not Cryptococcus neoformans). These infections are predominantly
geographically restricted and can occur in those who are healthy as well
as those who are immunocompromised (Table 20-3). With a more mobile
population, the pneumonia might be discovered after return to home from
travel to an endemic area, emphasizing the importance of a travel history.

381
The initial infection appears similar to CAP, and constitutional symptoms

are frequent. The severity of infection ranges from barely noticeable to life-
threatening acute respiratory distress syndrome. Other organ systems are
commonly affected with dissemination of the infection (Table 20-4).
Table 20-3. Summary of Geographically Restricted Fungal Pneumonia

Chest
Geographic High-Risk Radiographic Notable
Organism Area Exposures Findings (Acute) Features
Histoplasmosis Mississippi Old buildings Mediastinal Popcorn
and Ohio Chicken coops or hilar calcifications
River adenopathy
Bird roosts
Valleys Diffuse or focal
Caves
opacity
Wood piles
Coccidioidomycosis Desert Deserts Diffuse or focal Eosinophilia
Southwest Archeological opacity Prolonged
digs fatigue
Dust storms
Prairie dog
habitat
Blastomycosis Upper Rivers and Diffuse or focal ARDS in
Midwest wetlands opacity 50%–70%
and Wooded areas (high
Southeast mortality)
Buildings with
bat
droppings
Abbreviation: ARDS, acute respiratory distress syndrome.
Adapted from Stillwell PC. Fungal pneumonia. In: Stokes DC, Dozor AJ, eds. Pediatric Pulmonology, Asthma,
and Sleep Medicine: A Quick Reference Guide. American Academy of Pediatrics; 2018:421–426.
Table 20-4. Organs Commonly Infected With Geographically Restricted Fungal Diseases
Disease/Organism
Cryptococcal
Organ Coccidioidomycosis Histoplasmosis Blastomycosis Infection
Lung +++ +++ ++ ++
Brain and
++ − − +++
meninges
Bone marrow
and lymph − +++ +++ −
nodes
Skin, bone, −
++ − +++
and joints
Abbreviations: −, uncommon; ++, common; +++, very common.
Adapted from Stillwell PC. Fungal pneumonia. In: Stokes DC, Dozor AJ, eds. Pediatric Pulmonology, Asthma,
and Sleep Medicine: A Quick Reference Guide. American Academy of Pediatrics; 2018:421–426.

382
The diagnosis of endemic fungal pneumonia can be challenging without a

high index of suspicion because initially it appears similar to any other CAP
and the organisms are often not identified with standard microbiological
testing.21 The patient’s area of residence, travel history, and recreational or
occupational activities can be suggestive of a fungal source. Radiographically,
nodular opacities and hilar adenopathy can also offer clues to the nature of the
infection. Acute histoplasmosis can have a radiographic appearance similar
to those of tuberculosis or nontuberculous mycobacteria. Cavitary lesions are
common with coccidioidomycosis. During the healing phase of these granulo-
matous infections, calcifications are common. Confirmation of the specific
fungal organism can be established by means of culture, characteristic appear-
ance with staining, serological testing, and antigen testing (Table 20-5).21
More recently, Aspergillus PCR testing has been used for patients who are
critically ill and suspected of having invasive Aspergillus pneumonia, and
serum antibody testing for blastomycosis has become available to aid with
the diagnosis of Blastomyces (anti-Blastomyces adhesin 1).21
Table 20-5. Aids in Establishing the Diagnosis of Fungal Pneumonia

Serological
Disease/Organism Culture Stains Testing Antigen Testing
Histoplasmosis +++ + ++ +++
(blood and (especially urine)
bone marrow)
Coccidioidomycosis ++ +++ +++ ++
(blood test
not used often)
Blastomycosis +++ +++ ++ +++
(especially urine)
Candida albicans +++ ++ Not yet Not yet
Cryptococcus +++ ++ ++ ++
neoformans
Aspergillus fumigatus +++ ++ + +++
(invasive) (galactomannan)
Abbreviations: +, uncommon; ++, common; +++, very common.
Adapted from Stillwell PC. Histoplasmosis and other endemic fungal pneumonias. In: Stokes DC, Dozor AJ,
eds. Pediatric Pulmonology, Asthma, and Sleep Medicine: A Quick Reference Guide. American Academy of
Pediatrics; 2018:427–432.
Because spontaneous resolution is likely, treatment for endemic fungal pneu-

monia may be limited to observation if the patient experiences few symptoms
and is at low risk for dissemination. Traditionally, itraconazole has been used
for histoplasmosis and blastomycosis, and fluconazole has been used for
coccidioidomycosis, but posaconazole and voriconazole have also been

383
effective against Coccidioides. For central nervous system infections or severe

dissemination, amphotericin B may be required. Consultation with infectious
disease experts is helpful in selecting the appropriate agent and duration of
therapy and determining the success of therapy.
Children who are immunocompromised are at risk of developing pneumonia
with opportunistic fungal organisms that typically do not infect those who
are healthy (see Chapter 53, Pulmonary Complications of Immunologic
Disorders, and Chapter 52, Pulmonary Manifestations of Oncologic Disease
and Treatment), as well as pneumonia from organisms that do occur in those
who are healthy. These opportunistic organisms include (but are not limited
to) Aspergillus fumigatus (most common) and Aspergillus species, Pneumo-
cystis jirovecii, Candida albicans and other Candida species, C neoformans,
Mucormycetes, Rhizopus, Scedosporium, Bipolaris, and Curvularia. Prophy-
laxis against P jirovecii with trimethoprim/sulfamethoxazole can substantially
reduce the incidence of this pneumonia. Children who are immunocompro-
mised and have these fungal infections are usually very sick and may require
intensive care. The correct diagnosis can be elusive and may require multiple
methods of detection, including tissue biopsy.21
Prevention of Pneumonia in Children

The risk of pneumonia from many organisms can be reduced or eliminated
by using the childhood immunization schedule recommended by the Centers
for Disease Control and Prevention (CDC). Invasive pulmonary infections
with H influenzae type B, S pneumoniae, B pertussis, varicella, and measles
have been reduced substantially or prevented by immunizations.22 Influenza
immunization, recommended for all children 6 months or older, can reduce
the number of children infected and reduce the severity of the infection for
those who get influenza despite vaccination. COVID-19 vaccination is
recommended by the CDC for all children 6 months and older, including
getting boosters if eligible. Having the children in a community robustly
immunized can help reduce the incidence of pneumonia by herd immunity.
Attempts at reducing RSV infections by means of vaccination have been
somewhat more difficult than for other organisms. The prophylaxis currently
available consists of only palivizumab, and revised guidelines to optimize
patient outcomes balanced with cost-effectiveness limit its widespread use.
Reducing adverse environmental exposures such as tobacco smoke and
infectious contacts can help reduce the risk of developing pneumonia. Reliev-
ing unsanitary or crowded living conditions should also reduce the risk of
pneumonia. Although a cleaner air policy has improved children’s overall
respiratory health, there are challenges to establish that cleaner breathing
conditions can specifically reduce the occurrence of childhood pneumonia.

384
In 2000, the CDC recommended PCV7 for children in the United States
to reduce the incidence of pneumococcal pneumonia. The original vaccine,
which contained 7 serotypes, was highly effective, but two-thirds of the
invasive pneumococcal disease was caused by 6 serotypes not included in
this vaccine. Subsequently, PCV13 was approved in February 2010 and is
recommended for all children from 2 months through 5 years of age. Pneu-
movax-23 is approved for use in persons 50 years of age or older and persons
younger than 2 years who are at increased risk of pneumococcal disease.
The CDC recommends that all individuals 6 months or older get a seasonal
flu vaccine. The seasonal flu vaccine protects against 4 influenza viruses that
research indicates will be most common during the upcoming season. The
CDC also recommends that people in contact with certain groups of children
get a seasonal flu vaccine the better to protect the child (or children) in their
lives from the flu.
The CDC recommends that the following contacts of children receive
seasonal influenza vaccination:
X Close contacts of children younger than 5 years (people who live with them),
especially those younger than 6 months
X Out-of-home caregivers (nannies, child care providers, etc) of children
younger than 5 years
X People who live with or have other close contact with a child or children
of any age with a chronic health problem (asthma, diabetes, etc)
X All health care workers, to keep from spreading the flu to their patients
Additional considerations are H influenzae type B vaccine and varicella
vaccine.
When to Refer
Most children with CAP will not require a consultation. If there are
complications, such as pleural effusion or prolonged hypoxia, consultation
with a pulmonologist may be indicated. If the child has a chronic illness,
consultation with the specialist who is involved in the child’s long-term care
may be helpful. Consultation with infectious diseases or allergy specialists is
indicated for children with allergies, comorbid conditions, or unresponsiveness
to antibiotics.
When to Admit
Children with pneumonia and a chronic illness—for example, if they are
immunocompromised—may require hospitalization. If the degree of respira-
tory distress is clinically significant, if there is hypoxia, and if they appear
septic, they may require hospitalization. Currently, validated screening

385
systems do not exist to help predict which children with pneumonia should be
hospitalized. Hospitalization is indicated with the following:
X Oxygen saturation consistently less than 90% (definite)
X Suspected sepsis (definite)
X Severe dehydration (definite)
X Inability to drink fluids (possible)
X Moderate or severe respiratory distress (possible)
X Failure of outpatient antibiotic treatment (clinical judgment)
X Home circumstance or social situation raising concerns (likely)
X Infants younger than 6 months (unless ideal caretaker)
key points
} The cause of pneumonia is closely related to the age of the child.
} Imaging studies do not help differentiate viral from bacterial lower respiratory
tract infections.
} Chest radiography is not necessary to diagnose pneumonia.
} Computed tomography is indicated for evaluation of complications
of pneumonia.
} Ultrasonography is useful to characterize pleural effusion or empyema.
} Management depends on the age of the child and the likely diagnosis.
} Preventive immunization should follow CDC guidelines.
References
1. Watkins K, Sridhar D. Pneumonia: a global cause without champions. Lancet.
2018;392(10149):718–719 PMID: 30191817 doi: 10.1016/S0140-6736(18)31666-0
2. Zar HJ, Andronikou S, Nicol MP. Advances in the diagnosis of pneumonia in children. BMJ.
2017;358:j2739 PMID: 28747379 doi: 10.1136/bmj.j2739
3. The Lancet Global Health. The disgraceful neglect of childhood pneumonia. Lancet Glob Health.
2018;6(12):e1253 PMID: 30420022 doi: 10.1016/S2214-109X(18)30495-9
4. Jain S, Williams DJ, Arnold SR, et al; CDC EPIC Study Team. Community-acquired
pneumonia requiring hospitalization among U.S. children. N Engl J Med. 2015;372(9):835–845
PMID: 25714161 doi: 10.1056/NEJMoa1405870
5. Schooler GR, Davis JT, Parente VM, Lee EY. Children with cough and fever: up-to-date imaging
evaluation and management. Radiol Clin North Am. 2017;55(4):645–655 PMID: 28601173
doi: 10.1016/j.rcl.2017.02.007
6. Franquet T. Imaging of community-acquired pneumonia. J Thorac Imaging. 2018;33(5):282–294
PMID: 30036297 doi: 10.1097/RTI.0000000000000347
7. Lee GE, Lorch SA, Sheffler-Collins S, Kronman MP, Shah SS. National hospitalization trends
for pediatric pneumonia and associated complications. Pediatrics. 2010;126(2):204–213
PMID: 20643717 doi: 10.1542/peds.2009-3109
8. Bradley JS, Byington CL, Shah SS, et al; Pediatric Infectious Diseases Society and the Infectious
Diseases Society of America. Executive summary: the management of community-acquired
pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the
Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect
Dis. 2011;53(7):617–630 PMID: 21890766 doi: 10.1093/cid/cir625

386
9. Lipsett SC, Monuteaux MC, Bachur RG, Finn N, Neuman MI. Negative chest radiography
and risk of pneumonia. Pediatrics. 2018;142(3):e20180236 PMID: 30154120
doi: 10.1542/peds.2018-0236
10. Garber MD, Quinonez RA. Chest radiograph for childhood pneumonia: good, but not good
enough. Pediatrics. 2018;142(3):e20182025 PMID: 30154121 doi: 10.1542/peds.2018-2025
11. Florin TA, Ambroggio L, Brokamp C, et al. Reliability of examination findings in suspected
community-acquired pneumonia. Pediatrics. 2017;140(3):e20170310 PMID: 28835381
doi: 10.1542/peds.2017-0310
12. Ayalon I, Glatstein MM, Zaidenberg-Israeli G, et al. The role of physical examination in
establishing the diagnosis of pneumonia. Pediatr Emerg Care. 2013;29(8):893–896
PMID: 23903669 doi: 10.1097/PEC.0b013e31829e7d6a
13. Hazir T, Nisar YB, Qazi SA, et al. Chest radiography in children aged 2–59 months diagnosed
with non-severe pneumonia as defined by World Health Organization: descriptive multicentre
study in Pakistan. BMJ. 2006;333(7569):629 PMID: 16923771 doi: 10.1136/bmj.38915.673322.80
14. Iroh Tam PY. Approach to common bacterial infections: community-acquired pneumonia.
Pediatr Clin North Am. 2013;60(2):437–453 PMID: 23481110 doi: 10.1016/j.pcl.2012.12.009
15. Messinger AI, Kupfer O, Hurst A, Parker S. Management of pediatric community-acquired
bacterial pneumonia. Pediatr Rev. 2017;38(9):394–409 PMID: 28864731
doi: 10.1542/pir.2016-0183
16. Koster MJ, Broekhuizen BD, Minnaard MC, et al. Diagnostic properties of C-reactive protein
for detecting pneumonia in children. Respir Med. 2013;107(7):1087–1093 PMID: 23672994
doi: 10.1016/j.rmed.2013.04.012
17. Florin TA, Ambroggio L, Brokamp C, et al. Biomarkers and disease severity in children with
community-acquired pneumonia. Pediatrics. 2020;145(6):e20193728 PMID: 32404432
doi: 10.1542/peds.2019-3728
18. Elemraid MA, Rushton SP, Thomas MF, Spencer DA, Gennery AR, Clark JE. Utility of
inflammatory markers in predicting the aetiology of pneumonia in children. Diagn Microbiol
Infect Dis. 2014;79(4):458–462 PMID: 24857169 doi: 10.1016/j.diagmicrobio.2014.04.006
19. Stockmann C, Ampofo K, Killpack J, et al. Procalcitonin accurately identifies hospitalized
children with low risk of bacterial community-acquired pneumonia. J Pediatric Infect Dis Soc.
2018;7(1):46–53 PMID: 28158460 doi: 10.1093/jpids/piw091
20. Schlaberg R, Queen K, Simmon K, et al. Viral pathogen detection by metagenomics and
pan-viral group polymerase chain reaction in children with pneumonia lacking identifiable
etiology. J Infect Dis. 2017;215(9):1407–1415 PMID: 28368491 doi: 10.1093/infdis/jix148
21. Hage CA, Carmona EM, Epelbaum O, et al. Microbiological laboratory testing in the diagnosis
of fungal infections in pulmonary and critical care practice. An official American Thoracic
Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2019;200(5):535–550
PMID: 31469325 doi: 10.1164/rccm.201906-1185ST
22. Griffin MR, Zhu Y, Moore MR, Whitney CG, Grijalva CG. U.S. hospitalizations for
pneumonia after a decade of pneumococcal vaccination. N Engl J Med. 2013;369(2):155–163
PMID: 23841730 doi: 10.1056/NEJMoa1209165

CHAPTER
21
Complications of Pneumonia
Introduction
Community-acquired pneumonia (CAP) is a serious global health issue
and a common cause of mortality in underserved areas of the world.1 The
prevalence of CAP in the United States is approximately 35 to 40 per 1,000
children younger than 4 years and about 10 per 1,000 in teenagers; fewer than
1% die of CAP.2 A full recovery is the expected outcome for most children,
with or without antibiotic therapy. Complications are not frequent but are a
major source of morbidity when they occur. Complications of CAP include
parapneumonic effusion, empyema, abscess, necrotizing pneumonia,
bronchopleural fistula, and pneumatocele formation.3–5
Parapneumonic Effusion
Pleural effusions are an abnormal collection of fluid in the pleural space.6 The
most common etiology in children is a parapneumonic effusion, which occurs
in approximately 13% of CAP cases.2,7 While a wide variety of organisms are
associated with parapneumonic effusions, Streptococcus pneumoniae and
Staphylococcus aureus are the most common (Box 21-1).4,7,8
The evolution of a parapneumonic effusion occurs in 3 stages. The initial
effusion, which is the exudative phase, is thin fluid with a yellow color. It is
an inflammatory response of the pleura to the underlying parenchymal infec-
tion. The fluid is free flowing in the pleural space and is usually exudative in
nature according to Light’s criteria, which, while not validated in pediatrics,
are often helpful in assessing effusions.6 This phase lasts 2 to 5 days and is
followed by the fibrinopurulent phase, which occurs 5 to 10 days after the
onset of the pneumonia. Fibrin strands limit the flow of fluid in the pleural
space, causing loculations. This phase often involves an empyema with a high
white blood cell count and perhaps even pus in the pleural space. The third
phase is the organizing phase, usually occurring during the second week of
illness, when a thick fibrous peel forms in the pleural space; this is the last
step in healing. If the fibrous peel does not resolve with progressive healing,
a trapped lung may occur.
387

388
Box 21‑1
Infections Associated With
Parapneumonic Effusions in Children
Bacterial Causes Nonbacterial Infectious Causes
ū Aerobic ū Viral
• Streptococcus pneumoniae • Adenovirus
• Staphylococcus aureus • Influenza
• Streptococcus pyogenes • Parainfluenza viruses
ū Anaerobic ū Parasitic
• Bacteroides species • Paragonimus species
• Peptostreptococcus species • Cysticercus species
• Peptococcus species • Entamoeba histolytica
• Fusobacterium species ū Fungal
ū Atypical • Coccidioides immitis
• Mycoplasma pneumoniae
• Actinomyces species
• Nocardia species
ū Mycobacteria tuberculosis
From Kupfer O, Stillwell PC. Complications of pneumonia: pleural effusions. In: Stokes DC,
Dozor AJ, eds. Pediatric Pulmonology, Asthma, and Sleep Medicine: A Quick Reference Guide.
American Academy of Pediatrics; 2018:433–438.
The usual clinical presentation of a parapneumonic effusion or an empyema is
a child with CAP (see Chapter 19, Viral Pneumonia, and Chapter 20, Nonviral
Pneumonia) who has progressive respiratory deterioration with ongoing fevers,
increased work of breathing, and chest pain.3,7 This may progress despite the
initiation of antibiotic treatment. Examination reveals decreased-intensity
breath sounds over the affected side and dullness to percussion. Inspiratory
crackles may be present above the area of the effusion but may not be
appreciated directly over the effusion.
Diagnostic Considerations
If a parapneumonic effusion is suspected, the usual initial evaluation is a
chest radiograph, both frontal and lateral views (Figure 21-1). Typically,
there is an opacity representing the pneumonia and a fluid margin tracking
up the chest wall (meniscus sign). A lateral decubitus film (affected side
down; Figure 21-2) will clearly show the effusion if the fluid is free flowing;
if there are loculations, this may not be evident.9

389
Chapter 21—Complications of Pneumonia
Figure 21-1. Frontal and lateral chest radiographic

images of an 8-year-old with a right lower lobe
pneumonia and a right-sided parapneumonic
effusion.
Reproduced with permission from PREP Pulmonology.
Figure 21-2. Right-side-down

lateral decubitus radiograph
shows the pleural fluid extending
cephalad in the pleural space.
Reproduced with permission from
PREP Pulmonology.

390
Ultrasonography (US) is an excellent, nontraumatic, radiation-free method of

evaluating children for a parapneumonic effusion. It can approximate the size
of the effusion, document whether the fluid is freely flowing or loculated, and
determine the fluid’s echogenicity. In addition, US can help guide the best
location for a successful thoracentesis.10 (Figure 21-3)
A chest computed tomographic (CT) scan will provide more exquisite detail of
the lung and pleural space than either chest radiography or US (Figure 21-4).
However, a CT scan is not often needed if the US is fully informative and
satisfactory for managing the effusion.9
Sampling the effusion may help delineate a specific infectious etiology.6 This
can be done by thoracentesis or at the time a chest tube is inserted. The likeli-
hood of a positive bacterial culture is reduced if the child has already received
antibiotic therapy. Studies commonly obtained include white blood cell count
with differential (see Chapter 29, Pleural Effusion [Noninfectious]), Gram
stain, bacterial culture, pH, lactate dehydrogenase, and total protein. The use
of Light’s criteria to assess exudate versus transudate has not been validated
in children and may not be helpful if the fluid is clearly pus; however, Light’s
Figure 21-3. Pleural effusion. Longitudinal

ultrasonographic image of the right chest
demonstrates a septated, mixed echo-
genicity collection in the right pleural space,
indicating complex effusion. Some of the
echogenicity is due to opacified lung with
pneumonia.
Image courtesy of Jason Weinman, MD,
Department of Radiology, University of
Colorado School of Medicine Anschutz
Medical Campus and Children’s Hospital
Colorado.
Figure 21-4. Axial (A) and coronal (B) computed tomography in soft tissue window with left
lower lobe pneumonia and loculated left pleural effusion with peripheral contrast enhance-
ment, consistent with empyema.

391
criteria may be helpful with effusions of unknown etiology.6,11 Patients with

CAP and effusions are more likely to have positive blood culture findings, but
the yield from a blood culture remains only about 20% to 30%.3,4,7 The use of
polymerase chain reaction to detect streptococcal infection in the pleural space
may increase the ability to specify the offending organism.7
The parapneumonic effusion is considered an empyema if there is pus visible
in the pleural fluid, if the Gram stain is positive, or if the white blood cell
count is greater than 15,000/µL. The incidence of empyema-complicating
CAP in hospitalized children is between 0.6% and 2%.3,4,7 The incidence of
complex pneumonia seems to be increasing despite the widespread introduc-
tion of pneumococcal conjugate vaccine.12,13 The presence of an empyema
usually mandates more aggressive drainage than that needed for a simple
parapneumonic effusion.
Management
There are several potential approaches to managing the parapneumonic effu-
sion, including simply treating with antibiotics,14 antibiotics with chest tube
drainage, antibiotics with repeated thoracenteses, antibiotics with chest tube
drainage and fibrinolytics, or video-assisted thoracoscopic surgery (VATS).15–17
Simple observation with antibiotic treatment and antibiotics with repeated
thoracenteses are rarely used in tertiary care children’s hospitals in current
practice. The decision regarding chest tube insertion is based on the acuity
of illness and the size of the effusion. Drainage is mandated if the effusion is
large enough to compromise ventilation or cardiac output by compressing vital
structures. With increased use of antibiotics along with chest tube insertion
and fibrinolytics, the need for VATS has decreased.15–18
Prognosis for Complex or Complicated Community-Acquired Pneumonia

Most patients return to their usual state of health in 4 to 8 weeks. Findings on
follow-up chest radiographs in 3 to 6 months are usually normal.19 Typically,
otherwise healthy children with no previous bacterial infections will not
require a full immune workup. Children who do not recover quickly or who
have atypical medical histories may require further evaluation.
Lung Abscess
The incidence of lung abscess has decreased with the use of more potent and
broad-spectrum antibiotics.20,21 Children at risk for pulmonary abscess often
have had a period of altered consciousness, either transiently from anesthesia,
seizure, or intoxication or as part of a more global neurologic deficit such as
that which may be present with spastic quadriplegia and intellectual disability
or traumatic brain injury.20,21 The most common organisms are presented
in Box 21-2.22

392
Box 21‑2
Organisms Associated With Aspiration Pneumonia
and Pulmonary Abscess
Aerobes Anaerobes
ū Pseudomonas aeruginosa ū Peptostreptococcus spp
ū Streptococcus pneumoniae ū Prevotella
ū Escherichia coli ū Porphyromonas spp
ū Klebsiella pneumoniae ū Fusobacterium nucleatum
ū Staphylococcus aureus ū Bacteroides fragilis
ū Alpha hemolytic Streptococcus ū Bacteroides spp
ū Haemophilus influenzae ū Bifidobacterium spp
Many of these organisms are anaerobic mouth flora, which should be taken
into account when selecting the antibiotic strategy. Occasionally, a patient with
underlying lung disease or immunodeficiency will have a lung abscess as a
result of impaired healing from CAP.17,22
Fever and cough are the most common symptoms, followed by dyspnea, chest
pain, anorexia, purulent sputum, rhinorrhea, and malaise/lethargy. If the infec-
tion is anaerobic, the breath may smell fetid and the fevers may be only low
grade.22 There may be few findings on examination since a single abscess is
usually isolated away from the chest wall surface and is not communicating
well with the airways.
Chest radiography usually identifies a round-shaped opacity, often in an upper
lobe distribution, that may or may not have an air-fluid level (Figure 21-5A).
The CT scan provides additional detail to support the diagnosis of pulmonary
abscess (Figure 21-5B).17 Ultrasonography can be a useful complement to
chest radiography.10
Infections with Mycobacterium tuberculosis or atypical mycobacteria and
vasculitic disease such as granulomatosis with polyangiitis may have a
similar radiographic appearance and should be considered in the differen-
tial diagnosis of pulmonary abscesses (see Chapter 23, Tuberculosis;
Chapter 24, Nontuberculous Mycobacteria; and Chapter 26, Respiratory
Disorders Associated With Systemic Inflammatory Diseases).17

393
Figure 21-5. Frontal chest radiograph (A) and chest computed tomographic (CT) scan (B) of
a 17-year-old experiencing chest pain after sedation for an orthodontic procedure. The chest
radiograph shows a round opacity with central lucency in the left upper lobe. The CT scan
confirms the presence of a thick-walled abscess in the left upper lobe, most likely from
aspiration of bacteria during the procedure.
Management
Treatment of a pulmonary abscess is usually successful with antibiotic
therapy alone.17,20–22 The decision regarding hospitalization should be based
on the severity of illness; many children with pulmonary abscesses are well
enough to be treated on an outpatient basis. Surgical intervention or interven-
tional radiology is seldom required unless the course of antibiotic therapy is
not successful. The empiric antibiotics selected usually include anaerobic
coverage (eg, clindamycin or amoxicillin) and a cephalosporin. The choice
of oral or intravenous antibiotic depends on the severity of the illness and
the likelihood of successful oral administration.20 The duration of treatment
is not well known, but it is often 2 weeks or longer.22
Prognosis
Limited data are available regarding the outcome of lung abscesses in children.
The prognosis is generally very good for full and complete recovery unless
there is underlying lung disease or immunodeficiency. Resolution of the
radiographic abnormality may take weeks to months.20
Necrotizing Pneumonia and Bronchopleural Fistulas

Necrotizing pneumonia occurs when the CAP is not successfully contained
and significant parenchymal damage occurs.23–25 The most commonly identi-
fied organism is S pneumoniae and occasionally S aureus (usually methicillin
resistant).23,24 When air leaks are present, they often heal very slowly and a
bronchopleural fistula persists, which can result in a prolonged need for
chest tube drainage.25

394
Clinical Presentation and Diagnosis

Children with necrotizing pneumonia have presenting signs and symptoms
that are similar to those in uncomplicated pneumonia, except their illness
progresses without improvement and they usually become severely ill.23–25
The chest radiograph shows a large opacity involving many lung segments,
and chest CT is usually required to demonstrate the multiple cavitary lesions
within the consolidation characteristic of necrotizing pneumonia23–25 (Figure
21-6, Figure 21-7). If a bronchopleural fistula is present, there will be
evidence of a pneumothorax and an ongoing air leak in the water seal compo-
nent of the chest tube apparatus (Figure 21-8).
Figure 21-6. A, Frontal radiograph of a previously healthy 2-year-old with progressive

respiratory symptoms 10 days after respiratory syncytial virus and entero/rhinovirus upper
respiratory tract infection. B is from the same patient 3 days later, showing near complete
opacification of the right hemithorax and suggestions of lucencies, consistent with necrotizing
pneumonia.
Figure 21-7. Axial computed tomography images in soft tissue and lung window show
necrotizing pneumonia of the right lower lobe and a right posterior empyema.

395
Figure 21-8. Chest radiograph of a

5-year-old with complications from
necrotizing pneumonia shows a persistent
pneumothorax due to a bronchopleural
fistula.
Management
Because most children with necrotizing pneumonia are very sick, treatment
is typically initiated in the intensive care unit setting with intravenous anti-
biotics.23 If an infecting organism has been identified, antibiotics targeting that
organism should be selected. Often, no specific organism can be identified
so the antibiotic therapy is targeted toward resistant S pneumoniae as well as
S aureus.23,24 It is common to insert a chest tube for drainage of associated
empyemas, drainage of the pneumothorax, or both. The optimal duration of
treatment is not known, but often several weeks of antibiotics are needed.23,24
Prognosis
The mortality rate for necrotizing pneumonia is higher than that for other
complicated pneumonia and may reach as high as 5.5% to 7%.23 Children
who survive necrotizing pneumonia often return to baseline with normal
pulmonary function test results and normal chest radiographic findings.
Pneumatocele
A pneumatocele is a thin-walled cyst located in the lung parenchyma. It can be
a single cyst or can encompass several cysts. Pneumatoceles most commonly
occur as a pneumonia heals, but they can also occur after hydrocarbon inhala-
tion, trauma, or lung injury from mechanical ventilation.26,27 It is possible that
pneumatoceles, which are rare in adults and occur more frequently in younger
children, are more common in developing lungs. One theory is that the pores
of Kohn, which allow collateral ventilation, are not fully developed, and
therefore air cannot escape from an obstructed region.
Pneumatoceles are more common in children younger than 3 years. Although
bacteria are not always recovered, S aureus is frequently determined to be the
responsible organism.

396
Patients with pneumatoceles secondary to pneumonia may not have any
additional findings. The pneumatoceles are usually identified as the primary
pneumonia is healing and do not cause any additional symptoms.26
Pneumatoceles typically can be diagnosed with plain radiographs
(Figure 21-9).
Figure 21–9. Pneumatoceles in the right middle lung zone following successful therapy for a
right upper lobe pneumonia and right parapneumonic effusion in a 7-year-old.
Image courtesy of Jason Weinman, MD, Department of Radiology, University of Colorado School of
Medicine Anschutz Medical Campus and Children’s Hospital Colorado.
Management
Most pneumatoceles caused by infection will resolve within 2 to 6 months
with successful treatment of the underlying pneumonia.26 Children with
uncomplicated cases who have few clinical complaints, minimal atelectasis,
and involvement of less than 50% of the hemithorax can be observed with the
expectation of spontaneous clinical improvement.26 If the pneumatocele is
complicated by a large size, an increasing size, or an infection, surgical
intervention may be required.26,27 A growing pneumatocele is a risk for
pneumothorax.

397
Prognosis
Simple pneumatoceles have an excellent prognosis and typically resolve
without treatment. Typically, there are no visible sequelae on radiographs
in 2 months, though some patients may require as long as 6 months to
fully recover.
When to Refer
Children with complex or complicated pneumonias are often quite ill and may
require input from several specialists, including pulmonologists, infectious
disease consultants, pediatric surgeons, and intensive care specialists. There-
fore, early referral to a tertiary care children’s facility should be considered
as soon as it is recognized that the pneumonia is not a simple CAP.
When to Admit
Many of the complications of pneumonia are diagnosed in patients who have
experienced failed outpatient therapy or in those who are already hospitalized.
All of these patients should be treated with intravenous antibiotics, and many
will require further medical and/or surgical treatment. Experienced pediatric
interventional radiologists or surgeons should be involved in the care of any
patient who may need chest tube placement or surgical intervention, such as
VATS. Pediatric surgeons, interventional radiologists, pediatric pulmonolo-
gists, and pediatric infectious disease specialists should, as a team, help
determine the best approach for the patient.
key points
} Complications of pneumonia typically require hospitalization.
} Complications are usually associated with the most common causes of CAP.
} Complications frequently require multidisciplinary care at a tertiary
children’s hospital.
} Even in very ill children, the long-term prognosis is generally very good.

398
References
1. Watkins K, Sridhar D. Pneumonia: a global cause without champions. Lancet.
2018;392(10149):718–719 PMID: 30191817 doi: 10.1016/S0140-6736(18)31666-0
2. Jain S, Williams DJ, Arnold SR, et al; CDC EPIC Study Team. Community-acquired
pneumonia requiring hospitalization among U.S. children. N Engl J Med. 2015;372(9):835–845
PMID: 25714161 doi: 10.1056/NEJMoa1405870
3. Erlichman I, Breuer O, Shoseyov D, et al. Complicated community acquired pneumonia in
childhood: different types, clinical course, and outcome. Pediatr Pulmonol. 2017;52(2):247–254
PMID: 27392317 doi: 10.1002/ppul.23523
4. Hendaus MA, Janahi IA. Parapneumonic effusion in children: an up-to-date review. Clin Pediatr
(Phila). 2016;55(1):10–18 PMID: 26054782 doi: 10.1177/0009922815589917
5. Corcoran JP, Wrightson JM, Belcher E, DeCamp MM, Feller-Kopman D, Rahman NM.
Pleural infection: past, present, and future directions. Lancet Respir Med. 2015;3(7):563–577
PMID: 26170076 doi: 10.1016/S2213-2600(15)00185-X
6. Feller-Kopman D, Light R. Pleural disease. N Engl J Med. 2018;378(8):740–751 PMID: 29466146
doi: 10.1056/NEJMra1403503
7. Krenke K, Urbankowska E, Urbankowski T, Lange J, Kulus M. Clinical characteristics of
323 children with parapneumonic pleural effusion and pleural empyema due to community
acquired pneumonia. J Infect Chemother. 2016;22(5):292–297 PMID: 26919911
doi: 10.1016/j.jiac.2016.01.016
8. Walker W, Wheeler R, Legg J. Update on the causes, investigation and management of empyema
in childhood. Arch Dis Child. 2011;96(5):482–488 PMID: 20736395 doi: 10.1136/adc.2009.165357
9. Calder A, Owens CM. Imaging of parapneumonic pleural effusions and empyema in children.
10. Mong A, Epelman M, Darge K. Ultrasound of the pediatric chest. Pediatr Radiol.
2012;42(11):1287–1297 PMID: 22526284 doi: 10.1007/s00247-012-2401-7
11. McGraw MD, Robison K, Kupfer O, Brinton JT, Stillwell PC. The use of light’s criteria in
hospitalized children with a pleural effusion of unknown etiology. Pediatr Pulmonol.
2018;53(8):1101–1106 PMID: 29806196 doi: 10.1002/ppul.24065
12. Li S-TT, Tancredi DJ. Empyema hospitalizations increased in US children despite pneumococcal
conjugate vaccine. Pediatrics. 2010;125(1):26–33 PMID: 19948570 doi: 10.1542/peds.2009-0184
13. Dorman RM, Vali K, Rothstein DH. Trends in treatment of infectious parapneumonic effusions
in U.S. children’s hospitals, 2004-2014. J Pediatr Surg. 2016;51(6):885–890 PMID: 27032611
doi: 10.1016/j.jpedsurg.2016.02.047
14. Carter E, Waldhausen J, Zhang W, Hoffman L, Redding G. Management of children with
empyema: pleural drainage is not always necessary. Pediatr Pulmonol. 2010;45(5):475–480
PMID: 20425855 doi: 10.1002/ppul.21200
15. Islam S, Calkins CM, Goldin AB, et al; APSA Outcomes and Clinical Trials Committee,
2011-2012. The diagnosis and management of empyema in children: a comprehensive review
from the APSA Outcomes and Clinical Trials Committee. J Pediatr Surg. 2012;47(11):2101–2110
16. Marhuenda C, Barceló C, Fuentes I, et al. Urokinase versus VATS for treatment of empyema:
a randomized multicenter clinical trial. Pediatrics. 2014;134(5):e1301–e1307 PMID: 25349313
doi: 10.1542/peds.2013-3935
17. Raymond D. Surgical intervention for thoracic infections. Surg Clin North Am.
2014;94(6):1283–1303 PMID: 25440124 doi: 10.1016/j.suc.2014.08.004
18. Cremonesini D, Thomson AH. How should we manage empyema: antibiotics alone, fibrinolytics,
or primary video-assisted thoracoscopic surgery (VATS)? Semin Respir Crit Care Med.
2007;28(3):322–332 PMID: 17562502 doi: 10.1055/s-2007-981653
19. Kontouli K, Hatziagorou E, Kyrvasilis F, Roilides E, Emporiadou M, Tsanakas J. Long-term
outcome of parapneumonic effusions in children: lung function and exercise tolerance. Pediatr
Pulmonol. 2015;50(6):615–620 PMID: 24777950 doi: 10.1002/ppul.23054
20. Brook I. Anaerobic pulmonary infections in children. Pediatr Emerg Care. 2004;20(9):636–640
PMID: 15599270 doi: 10.1097/01.pec.0000139751.63624.0b
21. Desai H, Agrawal A. Pulmonary emergencies: pneumonia, acute respiratory distress syndrome,
lung abscess, and empyema. Med Clin North Am. 2012;96(6):1127–1148 PMID: 23102481
doi: 10.1016/j.mcna.2012.08.007
22. Bartlett JG. How important are anaerobic bacteria in aspiration pneumonia: when should they
be treated and what is optimal therapy. Infect Dis Clin North Am. 2013;27(1):149–155
PMID: 23398871 doi: 10.1016/j.idc.2012.11.016

399
23. Hacimustafaoglu M, Celebi S, Sarimehmet H, Gurpinar A, Ercan I. Necrotizing

pneumonia in children. Acta Paediatr. 2004;93(9):1172–1177 PMID: 15384879
doi: 10.1111/j.1651-2227.2004.tb02744.x
24. McCarthy VP, Patamasucon P, Gaines T, Lucas MA. Necrotizing pneumococcal
pneumonia in childhood. Pediatr Pulmonol. 1999;28(3):217–221 PMID: 10495339
doi: 10.1002/(SICI)1099-0496(199909)28:3<217::AID-PPUL9>3.0.CO;2-R
25. Nicolaou EV, Bartlett AH. Necrotizing pneumonia. Pediatr Ann. 2017;46(2):e65–e68
PMID: 28192581 doi: 10.3928/19382359-20170120-02
26. Imamoğlu M, Çay A, Koşucu P, et al. Pneumatoceles in postpneumonic empyema:
an algorithmic approach. J Pediatr Surg. 2005;40(7):1111–1117 PMID: 16034754
doi: 10.1016/j.jpedsurg.2005.03.048
27. Gerdung CA, Ross BC, Dicken BJ, Bjornson CL. Pneumonectomy in a child with multilobular
pneumatocele secondary to necrotizing pneumonia: case report and review of the literature.
Case Rep Pediatr. 2019;2019:2464390 PMID: 31396429 doi: 10.1155/2019/2464390

CHAPTER
22
Recurrent Pneumonia
Paul Houin, MD
Introduction
Recurrent pneumonia is defined as 3 or more episodes of pneumonia in a
lifetime or 2 episodes within a 12-month period.1–3 In pediatric practice, the
diagnosis of pneumonia is commonly established based on clinical history and
physical examination findings alone without chest radiographs, despite recom-
mendations for radiographic confirmation in community-acquired pneumonia
in adults.4 Diagnosing a pneumonia based on clinical findings alone is challeng-
ing in the pediatric population because the signs and symptoms of pneumonia,
asthma, and bronchiolitis often overlap in infants.4 Clinicians often neglect to
obtain a follow-up radiograph to document resolution of the pneumonia if the
patient returns to their usual state of health, making it difficult to determine if
there actually has been recurrent pneumonia or whether the problem is persis-
tent rather than recurrent.3 Documenting resolution of pneumonia is important
because the differential diagnosis of a persistent radiographic abnormality can
be different than recurrent pneumonia. The lack of consistent radiographic
confirmation for each episode can make it difficult to ascertain whether the
abnormality recurs in the same lung segments or in a variety of different
segments.3 In under-resourced countries, where pneumonia is a major cause
of childhood mortality and radiographs may be more difficult to obtain, the
clinical findings of lower chest wall indrawing and rapid respiratory rate are
sufficient to diagnose pneumonia and institute appropriate intervention.5 The
British Thoracic Society guidelines support the diagnosis and management
of a mild, uncomplicated acute lower respiratory tract infection without using
a radiograph to confirm whether a pneumonia is present.6 Despite the British
Thoracic Society guidelines, a clinician should consider radiographic confirma-
tion for patients who seem to have frequent lower respiratory tract symptoms.
Recurrent pneumonia can lead to persistent lung injury, such as bronchiectasis,
if not prevented. Early identification of a potential underlying cause of recurring
pneumonia may be beneficial for long-term lung health by allowing for
initiation of a more targeted therapy earlier in the course of the disease.1–3 (See
Figure 22-1.)
401

402
Figure 22-1. Chest computed tomography

scan of an adolescent showing bronchiectasis
and severe lung damage as a result of long-
standing aspiration and immunodeficiency
(PI3Kδ syndrome type 1 [APDS1] due to a
deleterious mutation in PIK3CD).
Pathophysiology
Box 22-1 categorizes conditions causing recurrent pneumonia in children. A
careful history, physical examination, and review of the radiographs will help
tailor the investigation to identify the underlying cause.1–3 Several risk factors
for recurrent pneumonia have been established, including a history of broncho-
pulmonary dysplasia, atopy with either allergic rhinitis or eczema, tobacco
exposure, overcrowding, and air pollution (both indoor and outdoor).1
Because of the high frequency of asthma in developed countries, a clinician
should evaluate for signs of asthma as the cause of recurrent acute lower respi-
ratory tract infections.3 The mechanism of recurrent pneumonia in the child
with asthma is likely mucus plugging during acute asthma exacerbations. The
usual trigger is a viral upper respiratory tract infection, which may cause a
fever as well. The constellation of fever, respiratory difficulty, abnormal aus-
cultation, and an abnormal chest radiograph leads the clinician to the diagno-
sis of pneumonia. If asthma is the cause of recurrent pneumonia, patients will
often have recurrent cough and acute wheeze with upper respiratory infections.
The symptoms are usually worse at night; they may also have cough, wheeze,
or respiratory difficulty apart from viral infections (eg, allergen, irritant, or
exercise triggers). Improved asthma control often eliminates or reduces the
episodes of pneumonia if asthma is the cause.3
Immunodeficiency syndromes, although overall uncommon, are a common
cause of recurrent pneumonia in children and can be familial.3,7 Associated
signs and symptoms of infections in other systems usually provide a clue to
the underlying diagnosis. Poor B-cell function often leads to predominantly
respiratory tract infections such as otitis media, sinusitis, and pneumonia
caused by common respiratory tract pathogens. Immunoglobulin (Ig) G defi-
ciency, IgG subclass deficiency, and IgA deficiency are B-cell−related deficien-
cies associated with recurrent sinopulmonary infections. If the child has poor
growth and serious infections in other organ systems, the immunodeficiency is
more likely to be in the T-cell−mediated system or in the phagocytic portion
(eg, neutropenia or chronic granulomatous disease) of the immune system.

403
Chapter 22—Recurrent Pneumonia
Box 22‑1
Conditions Leading to Recurrent Pneumonia in Children
Impaired Mucociliary Clearance
ū Asthma
ū Cystic fibrosis
ū Primary ciliary dyskinesia
ū Tracheomalacia/bronchomalacia
ū Restricted chest wall (weakness, immobility, uncoordinated cough)
Mechanical Abnormalities
ū Aspiration
ū Intrinsic obstruction (tumor, retained foreign body)
ū Extrinsic compression (tumor, adenopathy, enlarged cardiac structure)
Immune Deficiency (congenital or acquired)
ū Abnormal cell-mediated immunity (T cell)
ū Hypogammaglobulinemia (or B-cell deficiency)
ū Neutrophil/macrophage dysfunction
ū Mucosal surface immunodeficiency (immunoglobulin [Ig] A deficiency,
IgG subclass deficiency)
ū Syndromes associated with immunodeficiency
Systemic and Immune-Mediated Diseases
ū Hypersensitivity pneumonitis
ū Collagen vascular disease
ū Idiopathic hemosiderosis
ū Renal-pulmonary syndromes
ū Granulomatous diseases (tuberculosis, congenital, sarcoidosis)
ū Allergic bronchopulmonary aspergillosis
ū Pulmonary alveolar proteinosis
ū Acute chest syndrome (in sickle cell disease)
Congenital Anomaly
ū Bronchogenic cyst
ū Sequestration
ū Esophageal duplication cyst
ū Congenital pulmonary airway malformation
ū Congenital lobar overdistention
ū Tracheal bronchus (or other abnormal tracheobronchial branching)
Non-Pulmonary Causes
ū Pulmonary edema
ū Lymphangiectasis
ū Diaphragmatic hernia
ū Mediastinal mass
ū Anomalous pulmonary venous return

404
These infections can be due to common respiratory pathogens or opportunistic

pathogens. Complement pathway deficiencies are the rarest type of immunode-
ficiency and can lead to pyogenic pneumonia.3,7 (See Chapter 53, Pulmonary
Complications of Immunologic Disorders.)
Persistent pneumonia or recurrent pneumonia in one particular lung lobe
should prompt the clinician to consider congenital anomalies such as a congen-
ital pulmonary airway malformation or an airway obstruction from a foreign
body, adjacent lymphadenopathy, or tumor.8 (See Figure 22-2.)
Children with cystic fibrosis (CF) may present with a history of recurrent
pneumonia.9 Cystic fibrosis should be considered as the cause of recurrent
pneumonia if there is associated steatorrhea, recurrent productive cough, or
failure to thrive. It is important to know that approximately 10% to 15% of
patients with CF are pancreatic sufficient; therefore, a patient with CF may
not have growth failure.10 Although CF occurs most commonly in white indi-
viduals, it should be considered in other races and ethnicities as well. Since
2010, all states in the United States have newborn screening for CF, which
should identify 95% or more of the patients with CF shortly after birth.11
Because the newborn screen can have false-negative results, if the clinician
suspects CF as a possibility with recurrent pneumonia, the patient should have
the gold-standard diagnostic sweat chloride measurement at a Cystic Fibrosis
Foundation–accredited site.10,11 (See Chapter 45, Cystic Fibrosis.)
Patients with primary ciliary dyskinesia (PCD) may have recurrent pneumonia.
A patient with PCD usually has unexplained respiratory distress starting in the
neonatal period; this should prompt consideration of this diagnosis as a cause
Figure 22–2. (A) Chest radiograph of an adolescent with post-obstructive pneumonia and
atelectasis of the right lower lobe. (B) Chest computed tomography scan of the same patient
showing near complete obstruction of the proximal right lower lobe bronchi by an endobron-
chial tumor (arrow).

405
of recurrent pneumonia.12 Approximately 50% of patients will have associated

dextrocardia and abdominal situs inversus. Chronic cough, neonatal respiratory
distress, nasal congestion, and recurrent otitis media occur in more than 80% of
patients with PCD. The diagnosis is often difficult to confirm and is usually
established by a combination of respiratory cilia abnormalities on electron
micrographs, reduced exhaled nasal nitric oxide, and recently improving
techniques and sensitivities of DNA analysis.12 (See Chapter 47, Primary
Ciliary Dyskinesia and Other Genetic Lung Diseases.)
Children with reduced cough efficiency may have recurrent pneumonia
because they have poor control or clearance of normal secretions. This occurs
commonly in children with neurologic disorders (eg, cerebral palsy) and
weakness (eg, muscular dystrophy), but it also can occur in children with other
types of chest wall restriction, such as kyphoscoliosis.3 Excessive dynamic
collapse of the trachea or main stem bronchi (tracheomalacia/bronchomalacia)
may also impair mucus clearance. In addition to recurrent pneumonia, these
children may have stridor or wheezing. The etiology of tracheomalacia and
bronchomalacia is usually unknown, and the collapse usually improves with
age, although patients with prior surgery for a tracheoesophageal fistula
commonly have dynamic airway collapse that persists into adulthood.13,14
Dysphagia and aspiration are common causes of recurrent pneumonia in
children.3 Aspiration can occur while swallowing directly or after esopha-
geal reflux. Children with neurologic disorders are at increased risk because
of hypotonia of the swallowing muscles as well as poor mucus clearance,
although neurologically normal children can aspirate as well. Any child
with gastroesophageal reflux (GER) is at risk for aspiration during periods
of decreased consciousness (such as sleep) and while recumbent.15 It is con-
troversial whether aspiration of normal oral secretions causes recurrent pneu-
monia, but signs of airway inflammation can be seen on bronchoscopy of
patients that aspirate.16 Laryngeal clefts and H-type tracheoesophageal
fistulas are rare causes of aspiration.15
Evaluation of the Child With Recurrent Pneumonia

A careful history and physical examination should lead to a concise differential
diagnosis, and the subsequent laboratory evaluation can then be tailored for the
most likely underlying condition. Box 22-2 lists common diagnostic tools that
often help in evaluating the child with recurrent pneumonia.1–3
The first step is to gather all the chest radiographs for review. It is helpful to
have the radiographs interpreted by a pediatric radiologist who has access to
all the images at the same time and has a clinical summary. Certain patterns
may suggest other tests or simply a different therapeutic approach. For exam-
ple, a child whose chest radiographs repeatedly show overinflation, diffuse

406
Box 22‑2
Diagnostic Evaluation of the Child With Recurrent Pneumonia
ū Pulmonary function testing
• Flow-volume loops before and after bronchodilator
• Lung volume studies
• Diffusion capacity
• Challenge tests (exercise, methacholine, cold air)
ū Videofluoroscopic swallow study (with speech therapist present)
ū Fiberoptic endoscopic evaluation of swallowing
ū Flexible bronchoscopy with bronchoalveolar lavage
ū Screening for immunodeficiency
ū Testing for cystic fibrosis (sweat chloride test, DNA analysis)
ū Testing for primary ciliary dyskinesia (electron microscopy studies,
DNA analysis, fractional nasal exhaled nitric oxide)
ū Chest computed tomography with expiratory images
ū Esophagram and upper gastrointestinal series
ū Other tests for reflux and aspiration
• Gastric emptying study
• Radioactive lung scintiscan
• Esophagogastroduodenoscopy with gastroenterologist
• pH/impedance probe
increased peribronchial markings, and subsegmental atelectasis with normal

findings in between may not need additional studies but may need more
aggressive asthma management.
If a defect in the immune system is suspected, initial screening studies
should be considered, such as a complete blood cell count; white cell differ-
ential including lymphocyte differentiation; quantitative immunoglobulins
(IgG, IgM, and IgA); antibody response to Streptococcus pneumoniae,
Haemophilus influenzae type b, and tetanus immunizations; total comple-
ment; human immunodeficiency virus serology; and measurement of
neutrophil function with oxidative burst assay.1–3
The gold-standard test for CF is the sweat chloride measurement. Even if
the newborn screen was negative for CF, a sweat test should be performed
for any child with recurrent pneumonia unless there is a clear alternative
explanation. DNA analysis is another available diagnostic test for CF and
should be performed to confirm the diagnosis and potentially direct specific
gene-targeted treatments. Specialized tests, such as the mucosal electrical
potential difference, are not commonly available.10
The traditional test for PCD is electron microscopic evaluation of the ciliary
ultrastructure. Cilia from respiratory mucosa can be obtained with mucosal

407
biopsy by brushing the mucosa with a cytology brush or curette scraping of

the nasal mucosa. Patients with PCD have a decreased exhaled nasal nitric
oxide level, and this can be diagnostic when CF testing is negative.17 DNA
analysis for PCD mutations has recently become more extensive and useful in
diagnosis with new panels reporting over 75% to 80% sensitivity for diagno-
sis. Assessment of the ciliary waveform and beat frequency by microscopic
examination on live cilia can also document ciliary dyskinesia, but this
test is not commonly available.12
Aspiration can be identified with certainty only if contrast material is identified
in the airway during a videofluoroscopic swallow study, fiberoptic endoscopic
evaluation of swallowing, or upper gastrointestinal contrast study. If GER is
identified without evidence of aspiration, additional testing may be pursued
to determine if there is a link between GER and recurrent pneumonia. Milk
scintiscan is one test that can document aspiration after reflux, but it is insen-
sitive.18 The use of the lipid index (semi-quantification of lipid-laden macro-
phages obtained during bronchoalveolar lavage) to document aspiration
is controversial.19
Computed tomography of the chest is helpful in identifying congenital lung
anomalies; chronic airway damage, such as bronchiectasis; bronchial obstruc-
tion; and tracheobronchial branching pattern abnormality.20 Because of the
high radiation exposure with computed tomography scanning, this test should
be ordered after prudent consideration and performed with pediatric-specific
algorithms to reduce the total radiation dose.20
Flexible bronchoscopy is useful for identifying airway abnormalities, obtaining
lower airway and alveolar samples to stain and culture for infection, and muco-
sal biopsy for ciliary electron microscopy to assess PCD. Bronchoalveolar
lavage is useful to assess acute and chronic infection, including opportunistic
infection in the immunocompromised patient, and assess for hemosiderin or
lipid-laden macrophages.
Treatment
If a specific underlying etiology for the recurrent pneumonia can be identified,
therapy should be directed at that etiology. If the underlying etiology is asthma,
comprehensive and aggressive management of the asthma should stop the
recurrence of the pneumonia. Similarly, preventing aspiration from occurring
usually prevents the recurrence of the pneumonia. Some children will be at
risk for recurring pneumonia despite appropriate therapy, such as a child
with a neurological disability with impaired secretion control. Assisting these
patients with airway clearance techniques may minimize the frequency of
their pneumonia. There are several options for assisting airway clearance,
such as inhaled bronchodilators and corticosteroids, chest physical therapy
with postural drainage, high-frequency chest wall oscillation, and cough assist

408
devices. There are some pharmacologic treatments targeted for patients with
CF that have not been extensively studied in other lung diseases, such as
nebulized antibiotics, dornase alfa, and hypertonic saline. New cystic fibrosis
transmembrane regulator (CFTR) conductance gene correctors and highly
effective modulators continue to be developed to improve CF care as well.
Other preventive lung-protective strategies should be recommended, includ-
ing complete childhood immunization, annual influenza immunization, and
avoidance of toxicities, such as environmental tobacco poisoning.
key points
} A careful history and physical examination, coupled with radiographic
documentation of suspected lower respiratory tract infections, allow a directed
evaluation to discover an underlying cause for the recurrent pneumonia.
} Treatment is tailored to a specific cause once identified. Every effort should be
made to protect and preserve lung function.
References
1. Montella S, Corcione A, Santamaria F. Recurrent pneumonia in children: reasoned diagnostic
approach and a single centre experience. Int J Mol Sci. 2017;18(2):296 PMID: 28146079
doi: 10.3390/ijms18020296
2. Patria MF, Esposito S. Recurrent lower respiratory tract infections in children: a practical
approach to diagnosis. Paediatr Respir Rev. 2013;14(1):53–60 PMID: 23347661
doi: 10.1016/j.prrv.2011.11.001
3. Vaughan D, Katkin JP. Chronic and recurrent pneumonias in children. Semin Respir Infect.
2002;17(1):72–84 PMID: 11891521 doi: 10.1053/srin.2002.31693
4. Jain S, Williams DJ, Arnold SR, et al; CDC EPIC Study Team. Community-acquired pneumonia
requiring hospitalization among U.S. children. N Engl J Med. 2015;372(9):835–845
PMID: 25714161 doi: 10.1056/NEJMoa1405870
5. World Health Organization. Revised WHO classification and treatment of childhood
pneumonia at health facilities: Evidence Summaries. 2014
https://apps.who.int/iris/bitstream handle/10665/137319/9789241507813_eng.pdf.
Accessed June 3, 2022
6. Harris M, Clark J, Coote N, et al; British Thoracic Society Standards of Care Committee.
British Thoracic Society guidelines for the management of community acquired pneumonia
in children: update 2011. Thorax. 2011;66(66)(suppl 2):ii1–ii23 PMID: 21903691
doi: 10.1136/thoraxjnl-2011-200598
7. Baumann U, Routes JM, Soler-Palacín P, Jolles S. The lung in primary immunodeficiencies:
new concepts in infection and inflammation. Front Immunol. 2018;9:1837 PMID: 30147696
doi: 10.3389/fimmu.2018.01837
8. Thacker PG, Rao AG, Hill JG, Lee EY. Congenital lung anomalies in children and adults: current
concepts and imaging findings. Radiol Clin North Am. 2014;52(1):155–181 PMID: 24267716
doi: 10.1016/j.rcl.2013.09.001
9. Zemanick ET, Hoffman LR. Cystic fibrosis: microbiology and host response. Pediatr Clin
North Am. 2016;63(4):617–636 PMID: 27469179 doi: 10.1016/j.pcl.2016.04.003
10. Farrell PM, White TB, Ren CL, et al. Diagnosis of cystic fibrosis: consensus guidelines from
the Cystic Fibrosis Foundation. J Pediatr. 2017;181S:S4–S15.e1 PMID: 28129811
doi: 10.1016/j.jpeds.2016.09.064

409
11. Rosenfeld M, Sontag MK, Ren CL. Cystic fibrosis diagnosis and newborn screening. Pediatr
Clin North Am. 2016;63(4):599–615 PMID: 27469178 doi: 10.1016/j.pcl.2016.04.004
12. Leigh MW, Ferkol TW, Davis SD, et al. Clinical Features and Associated Likelihood of Primary
Ciliary Dyskinesia in Children and Adolescents. Ann Am Thorac Soc. 2016;13(8):1305–1313
13. Hysinger EB, Panitch HB. Paediatric Tracheomalacia. Paediatr Respir Rev. 2016;17:9–15
PMID: 25962857
14. DeBoer EM, Prager JD, Ruiz AG, et al. Multidisciplinary care of children with repaired
esophageal atresia and tracheoesophageal fistula. Pediatr Pulmonol. 2016;51(6):576–581
PMID: 26422584 doi: 10.1002/ppul.23330
15. Hu X, Lee JS, Pianosi PT, Ryu JH. Aspiration-related pulmonary syndromes. Chest.
2015;147(3):815–823 PMID: 25732447 doi: 10.1378/chest.14-1049
16. Jaoude PA, Knight PR, Ohtake P, El-Solh AA. Biomarkers in the diagnosis of aspiration
syndromes. Expert Rev Mol Diagn. 2010;10(3):309–319 PMID: 20370588 doi: 10.1586/erm.10.7
17. Shapiro AJ, Josephson M, Rosenfeld M, et al. Accuracy of nasal nitric oxide measurement as a
diagnostic test for primary ciliary dyskinesia. A systematic review and meta-analysis. Ann Am
Thorac Soc. 2017;14(7):1184–1196 PMID: 28481653 doi: 10.1513/AnnalsATS.201701-062SR
18. Ravelli AM, Panarotto MB, Verdoni L, Consolati V, Bolognini S. Pulmonary aspiration
shown by scintigraphy in gastroesophageal reflux-related respiratory disease. Chest.
2006;130(5):1520–1526 PMID: 17099032 doi: 10.1378/chest.130.5.1520
19. Colombo JL, Hallberg TK. Pulmonary aspiration and lipid-laden macrophages: in search of
gold (standards). Pediatr Pulmonol. 1999;28(2):79–82 PMID: 10423305
doi: 10.1002/(SICI)1099-0496(199908)28:2<79::AID-PPUL1>3.0.CO;2-A
20. Franquet T. Imaging of community-acquired pneumonia. J Thorac Imaging. 2018;33(5):282–294
PMID: 30036297 doi: 10.1097/RTI.0000000000000347

CHAPTER
23
Tuberculosis
Carol Conrad, MD
Introduction
Tuberculosis (TB) is an infectious disease that has coevolved with humans and
has been described in human records at least since Neolithic times, 10,000 BCE,
when the development of farming began. Tuberculosis is typically caused by
Mycobacterium tuberculosis and occasionally by Mycobacterium bovis and
Mycobacterium africanum. The most frequently infected organs are the lungs,
although other modes of infection with M tuberculosis can occur by contamina-
tion of an open wound, such as an insect bite or an abrasion of the skin. Congen-
ital infection occurs either transplacentally or by inhalation of infected amniotic
fluid at the time of delivery. Infection by M bovis results primarily from inges-
tion of unpasteurized milk or dairy products that contain it. M bovis infections
most commonly localize in extrapulmonary sites, causing cervical lymphadeni-
tis, gastrointestinal disease, and meningitis, although latent infection can
progress to pulmonary disease. Infection by M bovis, representing about 1% to
2% of TB cases, is more likely to occur in developing countries where control of
TB in cattle and pasteurization of milk are not available and may occur in
children of families entering the United States from countries where TB is
endemic or those who may have traveled for extended stays to countries where
TB is endemic.
Tuberculosis is one of the leading causes of death from infectious disease
globally. It is estimated that 2 billion persons are infected with M tuberculosis.
In a report released by the Centers for Disease Control and Prevention (CDC)
National Tuberculosis Surveillance System in 2019, the number of TB cases
reported in the United States increased 20% during the period from 1985 to
1992 after having shown a decrease for nearly 30 years previously. In 2009, the
TB rate (3.8 cases per 100,000 population) was the lowest that had been
recorded in the United States since 1953. Annually, the percentage change in
rate slowed from an average decrease of 6.7% during the period from 2007 to
2012 to an average decrease of 2.2% between 2012 and 2017 but has remained
frustratingly stable during those years. In 2019, 8,920 new cases were reported,
and 70.9% of these new cases were detected in patients not born in the United
States, but the rate of new cases had decreased by 1.5%. Overall, the TB rate
411

412
among patients not born in the United States (14.6%) was nearly 15 times the
rate of people infected with TB who were born in the United States (Figure
23-1).1
Figure 23‑1. Number and rate of tuberculosis (TB) cases in the United States from 1993 to
2020 among persons born in the United States and those born elsewhere according to the
year reported.
From Deutsch-Feldman M, Pratt RH, Price SF, Tsang CA, Self JL. Tuberculosis—United States, 2020. MMWR Morb
Mortal Wkly Rep. 2021;70(12):409–414.
Approximately 10 million people globally developed TB disease in 2019, with

about one-tenth of those being children. Tuberculosis infection (TBI) caused
nearly 1.2 million deaths among people who were HIV negative in 2019 and
an additional 208,000 deaths among people who were HIV positive, which
indicates a slight decrease compared with 2018 statistics.2
The global number of new and relapse TB cases per 100,000 population have
both been decreasing between 2014 and 2019 but not quickly enough to reach
the #EndTB goals put forth by the World Health Organization (WHO). The
cumulative reduction from 2014 to 2019 was 9%, rather than the expected
decrease of 20% by 2020.2
Drug-resistant TB species pose the greatest obstacle to achieving control of
TB disease and are most concerning in southern Africa, China, India, and
countries of the former Soviet Union. Multidrug-resistant TB (MDR-TB) is
defined as TB having resistance to at least isoniazid (or isonicotinic acid
hydrazide [INH]) and rifampin (RIF). Extensively drug-resistant TB (XDR-
TB) is a type of MDR-TB that demonstrates resistance to both a fluoroquino-
lone and a second-line injectable agent (amikacin, kanamycin, and/or
capreomycin). The term pre-XDR-TB is used to identify MDR-TB with
additional resistance to either, but not both, of those classes of drugs.3

413
Chapter 23—Tuberculosis
In 2020, the WHO published an updated global surveillance report that

included the incidence of MDR-TB and XDR-TB. At least 30% of people with
new and previously treated TB in 2017 had RIF-resistant TB. Globally, that
accounted for 718,684 cases of MDR-TB, which was at least double the
incidence reported in 2016. Of those, more than 8% were estimated to be
infected with XDR-TB. Nearly one-half of the XDR-TB cases were detected
in China and India. As of early 2018, 127 countries confirmed having at least
1 case of XDR-TB.2
According to the CDC, the incidence of TB among children and adolescents
in the United States is low and continues to decrease, but continued challenges
are presented to the health care system. From 2010 to 2017, 6,072 TB cases in
children and adolescents were documented. In the United States, 3,520 (68%)
of 5,175 cases occurred among children who were born in the United States,
including 2,977 (76%) of 3,896 children and 543 (42%) of 1,279 adolescents.
However, the incidence rate among children and adolescents decreased by
47.8% between 2007 and 2017. Children and adolescents of color are dispro-
portionately infected with TB, as are those living in islands affiliated with
the United States and children born in, or to parents from, TB-endemic
countries.4,5 Factors such as poverty and crowded housing likely contribute to
these disparites.
Almost all cases of TB are acquired through person-to-person contact via
droplet nuclei formed by sneezing, coughing, or phonating. The tubercle
bacilli establish infection in the lung after droplets containing 2 or 3 bacilli
(small enough [5–10 µm] to reach the alveolar space) are inhaled. If the
bacterial clusters contain more bacilli, the droplets are larger and will not
cause infection because the droplet will be cleared quickly by the mucociliary
transport defense mechanisms of the larger airways. Whether a particle that
reaches the alveoli will cause infection or disease depends on the virulence of
the bacilli and the killing capacity of the host macrophages.
Primary Infection
The initial host defense in the alveoli involves phagocytosis by the macro-
phages. However, a tubercle bacillus can multiply slowly within the macro-
phage without being killed. Once bacterial numbers are large enough (103–
104 organisms), a cellular response is elicited by macrophage activation. At
the slow rate of replication by M tuberculosis, this process takes about 4 to
8 weeks. A tubercle, or granuloma, is a formation of an epithelioid cluster of
macrophages with phagocytosed bacilli and is the primary focus of infection.
The infection spreads through the lymphatic vessels to the hilar lymph nodes.
A Ghon complex consists of the primary focus, lymphangitis, and the regional
hilar lymph node inflammation associated with it. Ghon complexes are
generally located in the middle or lower lobes of the lungs. The spread of

414
infection is contained by stimulation of cell-mediated immunity processes.

The granuloma will proceed to fibrosis and calcification and produce an
isolated, calcified spot seen on a chest radiograph.
Dissemination
Bacilli can escape before the innate defense system of the host is able to
respond or if it cannot mount an effective cell-mediated response to eliminate
the infection. The bacilli multiply inside alveolar macrophages and kill the
infected cells. Dying cells release TB bacilli into the surrounding lung
parenchyma and cause progressive destruction of the lung. Bacilli can spread
locally by erosion of the caseating lesions into the lung airways or instead can
form cavities in the injured tissue. Once bacilli are present within the
airspaces, the host becomes infectious to others, and infection is spread via
droplet nuclei created when coughing. In a person who is infected, bacilli may
also spread hematogenously and seed other portions of the lungs or other
organs, which can result in the formation of numerous small granulomas.
These have the appearance of small nodules on chest radiographs and indicate
the presence of miliary TB. Symptomatic hematogenous spread is rare, except
in patients who are immunocompromised.
As cell-mediated immunity develops, TBI is more reliably detected. For
example, the reaction to the skin test occurs as a result of delayed-type
hypersensitivity, in which sensitized T-helper (CD4+) cells move to the site of
antigen deposition and release lymphokines, which results in the characteris-
tic indurated area created in the purified protein derivative (PPD) skin test.
The skin test reaction and other tests for TBI are discussed in detail later in
this chapter (see “Diagnosis”).
The nature of pathological findings in persons who are infected is relative to
the antigen load and the degree of hypersensitivity elicited. If few antigens are
present and hypersensitivity is active, the classic tubercle develops, character-
ized by the presence of organized lymphocytes, macrophages, Langerhans
giant cells, and fibroblasts that result in the formation of the classic tubercu-
lous granuloma. A large bacterial load can overwhelm the immune system.
The resulting hypersensitivity reaction can be destructive to cells and
surrounding tissues. In some of the granulomas, incomplete necrosis occurs.
Caseation is a process that occurs through the release of hydrolytic, destruc-
tive enzymes; reactive oxygen species; and cytotoxic lymphokines, producing
the classic caseating granuloma seen at pathological examination. The TB
bacillus can replicate at a very high rate in a liquefaction process such as this,
which further increases antigen load and the destructive response by the host
immune system. Healing can occur only when growth of the tubercle bacilli is
inhibited. With caseous, liquefied cavities, the body isolates lesions with a
primarily fibrotic process.

415
Primary Pulmonary Disease
Tuberculous infection is different from tuberculous disease. Most initial
infections are asymptomatic and controlled by cell-mediated immunity. When
infection is present, the child has a positive test for TBI (skin test or blood-
based test), but there is no clinical, radiographic, or laboratory evidence that
indicates organ involvement. Approximately 10% of children who become
infected with M tuberculosis develop manifestations of disease, but nearly
one-half of infants younger than 12 months infected with TB will develop
disease after infection, and postpubertal adolescents are also at high risk of
developing disease.
Pulmonary disease is the most common manifestation of TB in children.
Fever is the most frequent symptom of disease; cough is less commonly
present. Symptoms are highly variable in children and also include weight
loss or poor weight gain, night sweats, and chills. Pulmonary disease due to
TB should be considered if a fever of 100.4°F (38°C) has persisted for at least
2 weeks, and other causes have been treated or excluded, or if a child develops
a chronic unremitting cough that does not improve with treatment and has
lasted more than 3 weeks. In addition, if weight loss or failure to thrive is
notable at examination, TB should be considered because growth delay may
be a manifestation of disease.3 These signs and symptoms are nonspecific, so
a history of an exposure to a person who is infected and a positive skin test
will direct the differential diagnosis toward TB. However, a negative test for
TBI (skin test or blood-based test) does not rule out TB. If other features are
suggestive of TB, the diagnosis should be considered, even if the test for TBI
is negative. These findings, along with the characteristic abnormalities of a
pulmonary infiltrate associated with hilar lymph node enlargement seen on
chest radiographs, nearly confirms the diagnosis. However, children have
infiltrates at radiographic evaluation less frequently than do adults, but
children more frequently have regional lymphadenopathy, lymphohematoge-
nous spread, and calcified lesions than do adults. Approximately one-third of
all patients develop a pleural effusion that is visible on a chest radiograph in
addition to the Ghon complex previously described. Lymphadenopathy may
be robust and can cause bronchial compression with resultant atelectasis of the
associated bronchial segment. In short, any child who is treated for pneumo-
nia, pleural effusion, cavitary lesion, or mass lesion in the lung that does not
improve with standard antibacterial therapy should be assessed for TBI.
Once infected, infants younger than 1 year are at highest risk of developing
disseminated TB (10%–20%) as well as pulmonary TB (30%–40%). The risk
for dissemination decreases as the age increases, with the 5- to 10-year-old

416
age group having the least risk of developing disease (Table 23-1).6–8 Infants
and children who develop disseminated disease will develop symptoms related
to the organ affected. The most common sites of extrapulmonary disease in
children are the superficial lymph nodes and the central nervous system.
Neonates are at the highest risk for progression of TB disease with meningeal
involvement and are likely to present with seizures or stroke associated with
high fevers.6
Approximately 5% of individuals who are infected develop disease within the
first 5 years of infection if it is not treated. The likelihood of developing disease
decreases as time passes, but another 5% of individuals who are infected will
develop disease after the first 5 years, particularly if immunocompetence is
lost.5,8 Thorough evaluation of infants and young children is important because
of their higher rate of progression to TB disease. Disease in other organs
appears to follow a specific timetable of manifestation characteristic to the
organ: meningitis usually occurs within 3 to 6 months after the initial infection,
pleuritis develops within 3 to 9 months, bone and joint disease develops within
1 to 3 years, and renal disease develops within 5 to 25 years.
After TBI, several factors can influence whether it remains latent or progresses
to active disease. These include age,8 nutritional status,9 previous vaccination,10
and, importantly, baseline immune function.11 Studies in animal and human
hosts have shown reduced microbial killing and diminished monocyte recruit-
ment to the site of infection in infants compared with those in adults.6 The
relative immaturity of the innate immune defenses of the neonate and infant
allow M tuberculosis to establish infection before initiation of an antigen-specific
immune response. Data from areas where infection rates are high but there is
little available antibiotic treatment suggest that most children younger than
2 years (60%–80%) have detectable radiological abnormalities after infection.12
Table 23-1. Risk of Pulmonary and Extrapulmonary Disease in Children After Infection
With Mycobacterium tuberculosis
Age Risk of Disease After Primary Infection
Disseminated TB or TB
Meningitis Pulmonary TB No Disease
<1 y 10%–20% 30%–40% 50%
1–2 y 2%–5% 10%–20% 75%–80%
2–5 y 0.5% 5% 95%
5–10 y < 0.5% 2% 98%
> 10 y < 0.5% 10%–20% 80%–90%
Abbreviation: TB, tuberculosis.
Derived from Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intra-thoracic tuberculosis: a critical
review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis. 2004;8(4):392–402.

417
Latent TB
A minority of individuals infected with TB will ever develop TB disease.
Although the biological mechanisms that permit persistence of the bacillus have
been studied extensively, it is unpredictable who will develop signs of clinical
disease. The latent or dormant state of the M tuberculosis bacillus is maintained
by activated macrophages and interferon (IFN) γ–producing T cells.
Reactivation Disease
Reactivation of latent disease is primarily a phenomenon that occurs in
adolescents and adults. Reactivation TB results when the persistent bacteria in
a host begin to proliferate. Patients who are immunosuppressed are at high risk
for reactivation TB, but the immunologic factors that actively suppress the
reactivation are not known. The infection can remain latent for several years,
and the trigger for release of the latent state has not been defined (Box 23-1).
Primary TB usually resolves spontaneously, but reactivation disease can recur
in 50% to 60% of patients who have not received a course of antibiotic therapy
to prevent development of TB disease. Reactivation TB begins insidiously over
a period of weeks to months. Cough is common, with a slow increase in
sputum production, and is often accompanied with constitutional symptoms
including fever, weight loss, anorexia, and night sweats. Episodes of streaky
hemoptysis are not unusual in this stage. Reactivation appears to be related to
bacillus replication, rupture of dormant lesions, and the release of caseating
material into the bronchi and parenchyma, which causes cavity formation. This
form of TB is the classic upper lobe, cavitating disease.
In contrast to the manifestation of primary disease, reactivation TB is more
often localized and often not associated with regional lymph node involve-
ment, and the caseating process is generally less prominent. The lesion
typically occurs at the lung apexes. Unless the host is severely immunosup-
pressed, dissemination does not often occur.
Box 23-1
Immunosuppressive
Conditions Associated With
Reactivation Tuberculosis
ū HIV infection and AIDS
ū Solid organ transplant
ū Diabetes mellitus
ū Lymphoma
ū Corticosteroid use
ū Diminution in cell-mediated immunity

418
Chronic Disease
Ten percent of children with acute M tuberculosis infection who develop TB
disease will recover spontaneously, but a fraction of those will develop
chronic disease. However, in more recent decades, with aggressive detection
programs and treatment being more available, the proportion of children who
will develop chronic disease is unknown. Chronic disease caused by TBI is
characterized by repeated episodes of reactivation, eventually controlled by
the host with a fibrotic healing response surrounding the lesions. In the
process, tissue is destroyed bit by bit. Successful healing through spontaneous
eradication of the bacilli rarely, if ever, occurs. Unchecked bacterial growth
and the resultant tissue damage can lead to disseminated TB by means of
hematogenous spread.
Extrapulmonary Disease
Approximately 15% of patients with active TB also present with TB disease
in an extrapulmonary site; the risk is increased in patients who are immuno-
compromised as well as in children younger than 2 years.11,13 The most
commonly involved sites include, in order of frequency, the lymph nodes,
pleural space, heart, skin, genitourinary tract, bone and joint sites, menin-
ges, and peritoneal-gastrointestinal tract.12
Diagnosis
Screening Tests
A diagnosis of TB (pulmonary or extrapulmonary) in a child is suspected
with the classic triad of (1) recent close contact with a known infectious index
case, (2) a positive tuberculin skin test (TST) or IFN-γ release assay (IGRA)
result, and (3) findings at imaging or physical examination that are suggestive
of TB.
The American Thoracic Society, Infectious Diseases Society of America, and
CDC suggest using the following approach for evaluation of a child suspected
of having TB14:
X Careful history (including history of TB contact and symptoms consistent
with TB)
X Clinical examination (including growth assessment)
X Tuberculin skin test and/or IGRA (if both tests are available, the sensitivity
and specificity of the IGRA supersede those of the TST, so IGRA is the
preferred method)15–17
X Bacteriologic confirmation whenever possible

419
X Evaluation for all organ involvement with relevant imaging and functional
studies
X HIV testing (in areas with a high HIV prevalence or populations at risk)
All data, including thorough history, physical examination, and diagnostic
testing, must be considered carefully. A history of recent close contact with an
infectious (positive sputum smear) case of TB is a critical factor in establish-
ing the diagnosis of TB in children, especially for those younger than 5 years.
Skin Testing
In a situation in which an IGRA cannot reliably be performed, the American
Academy of Pediatrics (AAP) suggests that a TST be used to assess for TBI if
any of the following are true3:
X Contact with confirmed or suspected contagious TB (contact investigation)
X Radiographic or clinical findings that suggest TB disease
X Consumption of unpasteurized milk or unpasteurized cheese
X Recent immigration from areas with TB-endemic infection (eg, Asia,
Middle East, Africa, Latin America, countries of the former Soviet Union),
including international adoptees
X Recent history of travel to countries with TB-endemic infection and/or
substantial contact with people from those countries
X HIV-infected children and incarcerated adolescents
X Before initiation of immunosuppressive therapy, which includes prolonged
steroid administration or use of tumor necrosis factor α antagonists in
children treated for collagen vascular disorders or candidates for organ
transplant who will receive immunosuppressive therapy
Before the IGRA was developed, the TST was the only practical tool for
diagnosing TBI in children without symptoms. For children of all ages,
IGRAs are available (see “Improving Immunologic Diagnosis”) and are the
preferred method for testing. The preferred skin test is the Mantoux test,
which contains 5 tuberculin units of PPD injected intradermally.16 The
sensitivity of TSTs ranges from 80% to 96% if read within 48 to 72 hours
after placement, but they are falsely positive in children who have received the
bacille Calmette-Guérin (BCG) vaccine. The TST is correctly read by
measuring the largest diameter of induration surrounding the injection site
(not redness) and is best performed by experienced health care professionals.
However, fewer people are properly trained to read TSTs, and there are many
causes of both false-positive and false-negative results (Box 23-2), so IGRA
should be performed whenever possible.15,17,18

420
Box 23-2
Causes of False-Negative TST Reactions
ū Infections (eg, early TB infection [< 12 weeks], active TB, HIV, measles, varicella,
typhoid fever, brucellosis, typhus, leprosy, blastomycosis)
ū Live virus vaccines can suppress tuberculin reactivity for 4 to 6 weeks. Live virus
vaccines can be administered concomitantly with the TST, but if not administered
on the same day, they should be separated by at least 6 weeks.
ū Medical conditions (eg, chronic renal failure, malignancies, sarcoidosis, poor
nutrition) and glucocorticoid therapy (if initiated before the TST was placed)
ū Technical factors (eg, inadequate dose, improper storage, failure to administer
intradermally, improperly timed reading)
Abbreviations: TB, tuberculosis; TST, tuberculin skin test.
False-positive TST reactions can result if the patient has prior exposure to
nontuberculous mycobacteria or has received whole-blood transfusions from
donors with positive TSTs or if the individual reading the test is inexperienced
or biased. Furthermore, vaccines against TB are in early phases of develop-
ment, and the vaccines are designed to create a T-cell response. Some infants
and children may have false-positive reactions, but this result does not last
long, and repeat testing in 6 to 8 weeks is merited in a patient who does not
have symptoms or is at low risk. False-positive reactions also may occur in
children who have received BCG vaccine.15,16 Although the TST can be
affected by receipt of the BCG vaccine,19 interpretation of the TST depends on
the child’s risk factors.20
Interpreting Skin Test Results
A wide spectrum of PPD skin testing results occurs in the general population.
Reactions depend in part on the type of exposure to TB among tested popula-
tions. People with a history of contact and subsequent TBI frequently have a
prominent reaction to the skin test. In this population, the median diameter of
induration is 16 to 17 mm, and there are few reactions smaller than 10 mm. In
comparison, the general population without a significant history of TB contact
has a different distribution of reactivity, with reactions varying from none (no

421
Figure 23‑2. Positive skin

test for tuberculosis.
infection) to reactions with induration less than 10 mm. Cross-reaction to

other Mycobacteria is commonly associated with this type of reaction
(Figure 23-2).
Because of these potential confounding elements, the CDC recommends
using different criteria to determine whether a positive reaction is present.
These are based on the prior likelihood of true TBI (Box 23-3). Figure 23-3 is
a flowchart that assists in the evaluation of a child exposed to a known
positive contact.

422
Box 23-3
Definition of Positive TST Results in Infants, Children, and Adolescentsa,b
Induration 5 mm or Greater
Children in close contact with people who are known to be or are suspected of
being contagious with TB disease
Children suspected of having TB disease
ū Findings on chest radiograph consistent with active or previous TB disease
ū Clinical evidence of TB diseasec
Children receiving immunosuppressive therapyd or with immunosuppressive
conditions, including HIV infection
Children at increased risk of disseminated TB disease
ū Children younger than 4 years
ū Children with other medical conditions, including Hodgkin disease, lymphoma,
diabetes mellitus, chronic renal failure, or malnutrition
ū Children with likelihood of increased exposure to TB disease
ū Children born in high-prevalence regions of the world
ū Children with significant travele to high-prevalence regions of the world
ū Children frequently exposed to adults who are HIV infected, homeless, users of
illicit drugs, residents of nursing homes, incarcerated or institutionalized, or
migrant farm workers
Children without any risk factors
Abbreviations: TB, tuberculosis; TST, tuberculin skin test .

a
See www.cdc.gov/tb/publications/guidelines/pdf/ciw778.pdf.
b
These definitions apply regardless of previous bacille Calmette-Guérin immunization; erythema alone at
a TST site does not indicate a positive test result. Tests should be read 48 to 72 hours after placement.
c
Evidence by physical examination or laboratory assessment that would include TB in the working
differential diagnosis (eg, meningitis).
d
These include immunosuppressive doses of corticosteroids or tumor necrosis factor α antagonists or
blockers or immunosuppressive drugs used in recipients of transplants.
e
Some experts define significant travel as travel or residence in a country with an elevated TB rate for at
least 1 month.
From American Academy of Pediatrics. Tuberculosis. In: Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH, eds. Red
Book: 2021–2024 Report of the Committee on Infectious Diseases. 32nd ed. American Academy of Pediatrics;
2021:786–814.

423
Age ≥2 yrs
No Yes
BCG
vaccinated?
No Yes
Likely to return for

TST reading?
Yes
No
TST TST acceptable,
preferred but so is an IGRA
Negative result: Positive result: Negative result: Positive result:

Testing complete Testing complete Testing complete Testing complete
unless criteria A* unless criteria B** unless criteria A* unless criteria B**
met, then IGRA are met, then IGRA met, then IGRA are met, then
IGRA preferred
*Criteria A
1) High clinical suspicion for
TB disease and/or Negative result: Positive result:
Indeterminate
2) High risk for infection, testing complete testing complete
progression, or poor
outcome
Repeat IGRA
**Criteria B
1) Additional evidence needed
to ensure adherence and/or
2) child healthy and at low
risk and/or Negative result: Positive result:
3) NTM suspected testing complete testing complete
Figure 23-3. Evaluation of a child exposed to a person with contagious TB. Guidelines for the
use of either the TST or IGRA in children older than 2 years with 1 or more risk factor.
Abbreviations: BCG, bacille Calmette-Guérin; IGRA, interferon γ release assay; NTM, nontuberculous
mycobacteria; TB, tuberculosis; TST, tuberculin skin test.
From American Academy of Pediatrics. Tuberculosis. In: Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH, eds. Red
Book: 2021–2024 Report of the Committee on Infectious Diseases. 32nd ed. American Academy of Pediatrics;
2021:786–814.

424
Effect of BCG Vaccine

Bacille Calmette-Guérin vaccination often results in tuberculin conversion;
most recipients of the vaccine develop tuberculin reactions 10 mm or greater
within 8 to 12 weeks after vaccination. However, for infants who receive BCG
vaccination during the neonatal period, the TST reactions diminish fairly
rapidly; among more than 1,000 individuals who received vaccination in the
first year after birth, no effect on tuberculin reactions 10 mm or greater could
be detected after 10 to 25 years.19
For individuals who receive the BCG vaccine after the first year after birth or
those who receive a second dose of BCG vaccine, however, tuberculin
reactions wane more slowly. In a study that included more than 1,000 individ-
uals with history of BCG vaccination, those vaccinated between the ages of 6
and 10 years had a higher rate of persistent tuberculin reaction than did those
vaccinated at the ages of 2 and 5 years (20%–25% vs 10%–15%, respec-
tively).19 Nevertheless, a history of previous BCG vaccination is not a valid
reason to dismiss a positive TST reaction. Positive results should prompt
evaluation for infection, preferably with an IGRA according to the interpreta-
tion guidelines outlined previously.18 Repeated PPD testing or 2-step testing
can boost BCG vaccine–induced sensitivity. If the TST reaction is positive, an
IGRA is the preferred test to distinguish reactivity caused by BCG vaccine
sensitization versus that from TBI (see “Improving Immunologic Diagnosis”
later in this chapter). The usefulness of the IGRA has not been verified in
children younger than 2 years, but studies have been published that demon-
strate its high sensitivity and specificity.3 In addition, a search for the organ-
ism in sputum, gastric aspirates, or bronchoalveolar lavage fluid may be
necessary if the source of infection cannot be verified.
Positive Response to the TST
A person infected with M tuberculosis will react to the TST with a delayed-
type hypersensitivity T-lymphocyte response. Activated T cells and other
recruited immune cells infiltrate the site and create maximal induration 48 to
72 hours after inoculation with the TST. Skin test conversion occurs within 2
to 12 weeks after primary infection. The ability to respond to a TST is often
maintained for many years after the primary infection, although the intensity
of the reaction can wane over time.
Sputum Analysis
It is somewhat difficult to establish a diagnosis of TB in children, given that
they tend to be unable to expectorate and the bacterial load within the sputum
is low, because there is a generally low incidence of cavitary disease in the
pediatric population. However, if endobronchial caseating lesions are present
and caseating lymph nodes have eroded into a bronchus, the bacterial load and
likelihood of smear positivity increases. Nonetheless, children tend to swallow

425
sputum rather than expectorate it, so, in general, the bacteriologic specimens
must be collected by obtaining early morning gastric aspirate washings. This
method requires overnight fasting with collection on 3 consecutive days and
is often best performed during a hospitalization. Even so, the rate of positive
confirmation with acid-fast bacilli staining using this method is only 10% to
15%, and cultures are negative approximately 70% of the time.21 All speci-
mens obtained should be sent for bacteriologic evaluation, and nontubercu-
lous mycobacteria should also be considered with a positive smear. If gastric
specimens do not yield positive acid-fast bacilli test results, bronchoscopy for
lavage of airways where there might be endobronchial granulomas can often
increase the detection of M tuberculosis. Polymerase chain reaction (PCR)
detection of TB should always be performed because this method is much
more sensitive. Tissue biopsy can be performed on endobronchial lesions,
and the specimens can be stained for acid-fast bacilli testing and quantitative
PCR testing. Nevertheless, for 25% of infants and 50% of children with
pulmonary TB diagnosed, no organism is isolated, even with the most
optimal culture techniques. Without definitive diagnosis, treatment is based
on exposure history, results of the cultures obtained from the infection
source, clinical features, the TST and/or IGRA results, and radiographic
results.
Improving Analysis of Specimens Obtained

Sputum can be obtained successfully by means of induction procedures with
nebulization of hypertonic saline in children who are old enough to cooperate
with huff coughs and expectoration maneuvers. However, this is a procedure
that can also generate aerosol of bacterial particles, so it is impractical if tried
outside of hospital settings. Avoiding infection of the person performing the
procedure requires strict adherence to infection control procedures.22
Detection of M tuberculosis With Sequencing-Based Techniques

Molecular methods for detecting M tuberculosis have been developed that
concomitantly identify both the presence of the bacterium and RIF resistance.
These methods include PCR techniques that can be performed on samples of
sputum, gastric aspirate, bronchoalveolar lavage and/or pleural fluid, nasopha-
ryngeal swabs, stool, and tissue biopsy specimens20 and are highly sensitive
and specific. The most frequent PCR test in use is the GeneXpert MTB/RIF
assay (Cepheid, Inc, Sunnyvale, CA). It is an automated test that is substan-
tially more sensitive than smear microscopy.23 Real-time PCR testing ampli-
fies specific DNA targets in M tuberculosis and is combined with the use of
specific fluorogenic hybridization probes that bind directly with both M
tuberculosis DNA and resistance mutations in the rpoB and katG genes
associated with MDR-TB. Study results demonstrated a sensitivity of 91% for
BD MAX (Beckton, Dickinson and Company, Franklin Lakes, NJ) and 90%

426
for Xpert on processed sputum samples.23,24 Sensitivity and specificity for RIF
resistance compared with those for phenotypic drug sensitivity testing were
90% and 95%, respectively.24 The Xpert Ultra cartridge is a more recent
iteration of the BD MAX technology and is a more sensitive method of
detection in specimens with low numbers of bacilli.25,26 Sputum, nasopharyn-
geal aspirate, gastric aspirate, and stool specimens can be tested with the
Xpert Ultra cartridges.27
The Xpert Ultra cartridges are easily modified to include detection of resis-
tance genes to several antibiotics used in XDR-TB treatment regimens. These
antibiotics include INH, fluoroquinolones, ethionamide, amikacin, kanamy-
cin, and capreomycin, with sensitivities of 94%, 94%, 54%, 73%, 86%, and
61%, respectively, and 98% specificity for those same antibiotics, and perfor-
mance was equivalent to that of line probe assays in a head-to-head compari-
son study by Penn-Nicholson et al26 in 2021.
New sequencing technologies, compared with the rapid molecular tests, are
better able to provide detailed information about resistance mutations for
multiple gene regions. Line probe assays are designed to detect closely spaced
resistance genes of the M tuberculosis chromosome. Line probe assays require
the use of complex DNA-based assays and are limited to use in experienced
reference laboratories.28
Urine-based testing that detects the mycobacterial lipoarabinomannan antigen
is available to detect TB in people infected with HIV. Because these tests have
low sensitivity, they are unsuitable to use as a general screening test for TB,
but they have demonstrated improved sensitivity for diagnosing TB among
individuals coinfected with HIV with low T-lymphocyte counts, on which the
quantitative IGRAs depend (see the next section, “Improving Immunologic
Diagnosis”). Lipoarabinomannan testing is associated with a decrease in
mortality in people living with HIV by providing an earlier diagnosis, thus
allowing treatment to start sooner.29
Improving Immunologic Diagnosis

Blood-based IGRAs are the preferred method and, since 2019, have replaced
the TST, which is neither sensitive nor specific. The IGRAs rely on stimula-
tion of host T lymphocytes with M tuberculosis–specific antigens and
measure the consequent production of IFN-γ in response. These are
termed T-cell–based IGRAs. Two principal IGRAs are used to detect TBI: the
QuantiFERON-TB Gold (Qiagen, Hilden, Germany) and the T-SPOT.TB
(Oxford Diagnostic Laboratories, Oxfordshire, United Kingdom) assays. The

427
former has been validated for use in children older than 2 years and can be
used to increase the sensitivity for detecting TBI, particularly in younger
children.30 T-cell assays are more specific (not affected by BCG vaccine) than
are TSTs but, like the TSTs, do not distinguish between active disease and
TBI. In addition, the IGRA cannot distinguish among infection by M tubercu-
losis, Mycobacterium kansasii, Mycobacterium szulgai, or Mycobacterium
marinum. Interpretation therefore depends on the clinical context and culture
results from sputum or other infected samples or the source of infection.20,31–33
At this time, the TST is no longer considered the gold standard for diagnosing
TBI. The AAP recommendations for using IGRAs in children are as follows3:
X For children 2 years or older who are immunocompetent, IGRAs can be
used in place of TSTs to confirm cases of TBI and likely will yield fewer
false-positive test results.
X Children with a positive IGRA result should be considered infected with M
tuberculosis complex. A negative IGRA result cannot universally be
interpreted as absence of infection.
X Because of their higher specificity and lack of cross-reaction with BCG
vaccine, IGRAs are the preferred diagnostic method for TBI in children
who have received the BCG vaccine. A child with a false-positive TST
reaction caused by the BCG vaccine will have a positive TST but a negative
IGRA result.
X Interferon-γ release assays can be used in children older than 2 years and
have a sensitivity similar to that of TSTs.33,34
X Indeterminate IGRA results do not exclude TBI. Further diagnostic
procedures should be performed to guide clinical decisions.
IGRAs can improve the ability to detect TBI, especially in settings where
resources are scarce, which is where better and more sensitive tests are needed
the most.
Treatment of TBI (Positive IGRA/TST Results and Negative

Chest Radiographs)
With no evidence of active disease, TBI in a patient at low risk can be treated
with single-drug therapy. Isoniazid is the drug of choice and is prescribed for
a minimum of 6 months. For patients unable to take INH or who are known to
have been exposed to INH-resistant M tuberculosis, RIF daily for 4 months is
an alternative therapy (Table 23-2).

Table 23-2. Treatment of Tuberculosis Infection Without Evidence of Disease
428
Duration,
Agents Dosage and Age Group Administration mo Age Restriction Comments
INH + Rifapentine Age ≥ 12 y Weekly (SAT or DOT) 3 Not for children < 2 y Take with food, containing
(3HP) INH: 15 mg/kg, rounded up to fat if possible; pyridoxine
nearest 50 or 100 mg (max 900 mg) for selected patientsa
Rifapentine (by weight):

10–14 kg: 300 mg
14.1–25 kg: 450 mg
25.1–32 kg: 600 mg

32.1–49.9 kg: 750 mg
≥ 50.0 kg: 900 mg
Age 2–11 y
INH: 25 mg/kg, rounded up to nearest 50 or 100 mg
(max 900 mg)
Rifapentine: see above
Rifampin (4R) Adult: 10 mg/kg (max 600 mg) Daily (SAT) 4 None Drug–drug interactions
Child: 15–20 mg/kg (max 600 mg)
INH + Rifampin Same doses as when drugs are used individually Daily (SAT) 3 None Not considered unless 3HP
or 4R are not feasible
INH Adult: 5 mg/kg (max dose 300 mg) Daily (SAT) 6 or 9 None Seizures with overdose;
Child: 10–15 mg/kg (max 300 mg) pyridoxine for selected
Adult: 15 mg/kg (max dose 900 mg) Twice weekly (DOT) patientsa
Child: 20–30 mg/kg (max 900 mg)
Abbreviations: DOT, directly observed therapy; INH, isoniazid; max, maximum; SAT, self-administered therapy.
a
Infants who were exclusively breastfed and children and adolescents with meat- and milk-deficient diets; children with nutritional deficiencies, including all children with symptoms
living with HIV infection; and pregnant adolescents and women.
Adapted from Nolt D, Starke JR. Tuberculosis infection in children and adolescents: testing and treatment. Pediatrics. 2021;148(6):e2021054663.
10/23/23 11:52 AM
429
Treatment of TB Disease
Tuberculosis infection in infants and children younger than 4 years has a high
likelihood of dissemination, so treatment should begin as soon as test results
support the diagnosis. Children who do not have symptoms who have a
positive IGRA or PPD skin test result and an abnormal chest radiograph
should receive combination chemotherapy with the quadruple drug regimen
of INH, RIF, pyrazinamide, and ethambutol daily or 3 times per week as
initial therapy for 2 months. The subsequent 4 months of therapy with INH
and RIF is prescribed in drug-susceptible isolates or if the risk of MDR-TB is
low. Directly observed therapy (DOT) (as described later) should be estab-
lished to avoid emergence of drug-resistant TB in the setting of incomplete
adherence to the drug regimen.3
Careful consideration must be given to the risk group to which the individual
belongs before deciding on a treatment regimen. Tuberculosis that originates
in the United States is unlikely to be caused by MDR-TB or XDR-TB strains.
The risk of infection due to MDR-TB is much higher in most other countries,
particularly for immigrants from southern Africa, China, India, and countries
of the former Soviet Union. The decision-making process for effective
treatment is complex but can be aided by the use of molecular and well-tested
diagnostic assessments that can quickly help determine susceptibility to the
first-line drug regimen. The use of second-line drugs may create certain
morbidities and toxicities. The decision to use them for prolonged treatment
durations must balance these factors with the drugs’ potential benefits. In
these situations, consultation should be sought with a TB expert when
suspicion is high for MDR-TB. Experts can be found through CDC-supported
TB Centers of Excellence at (https://www.cdc.gov/tb/education/tb_coe/default.
htm) and through local health department TB control programs (https://www.
cdc.gov/tb/links/tboffices.htm) in the United States. Online sources of expert
advice and information can also be obtained through the British Thoracic
Society MDR-TB Clinical Advice Service (http://mdrtb.brit-thoracic.org.uk).
All children from another country who have no known contact with an index
case with known drug susceptibility should begin treatment with the recom-
mended 5-drug MDR-TB regimen as is recommended for adults (Table 23-3).
To avoid toxicities and morbidities, physicians should try to obtain culture of
the organism and its antibiotic sensitivities.
The American Thoracic Society, in a joint publication with the CDC, Euro-
pean Respiratory Society, and Infectious Diseases Society of America, has
recommendations in the approach to treating MDR-TB.35 These MDR-TB
guidelines are noted in Box 23-4.

430
Table 23-3. Recommended Treatment Regimens for Drug-Susceptible TB Disease in

Infants, Children, and Adolescents
Infection or
Disease Category Regimen Remarks
M tuberculosis
infection (posi-
tive TST or IGRA
result, no
disease)a
Isoniazid 12 weeks of isoniazid plus Most experts consider isoniazid-
susceptible rifapentine, once a week rifapentine to be the preferred
regimen for treatment of TBI for
children 2 years or older, and
some experts prefer isoniazid-
rifapentine therapy for TBI in
children 2 years or older.
OR
4 mo of rifampin, once a day Continuous daily therapy is
required. Intermittent therapy
even with DOT is not recom-
mended.
OR
3 mo of isoniazid plus rifampin, To be considered if more than
once a day 2 regimens are not feasible
OR
6 or 9 mo of isoniazid, once a day If daily therapy is not possible,
DOT twice a week can be used;
medication doses differ with
daily and twice-weekly
regimens.
Isoniazid 4 mo of rifampin, once a day Continuous daily therapy is
resistant required. Intermittent therapy
even with DOT is not recom-
mended.
Isoniazid- Consult a TB specialist. Moxifloxacin or levofloxacin
rifampin resistant with or without ethambutol
or pyrazinamide are most
commonly used.

431
Table 23-3. Recommended Treatment Regimens for Drug-Susceptible TB Disease in

Infants, Children, and Adolescents (continued)
Infection or
Disease Category Regimen Remarks
Pulmonary and 2 mo of rifampin, isoniazid, Some experts recommend a
extrapulmo- pyrazinamide, and ethambutol 3-drug initial regimen (isoniazid,
nary disease (RIPE) daily or 3 times per week, rifampin, and pyrazinamide) if
(except followed by 4 mo of isoniazid the risk of drug resistance is low;
meningitis)b and rifampinc with DOTd for DOT is highly desirable.
drug-susceptible M tuberculosis If there is only hilar adenopathy
and the risk of drug resistance is
low, a 6-mo course of isoniazid
and rifampin is sufficient.
Directly observed therapy is
required for intermittent
regimens.
Drugs can be administered daily
or 3 times per week; 2 times per
week is acceptable if DOT
resources are scarce.
At least 9 mo of isoniazid and
rifampin for Mycobacterium
bovis susceptible to these drugs
Meningitis 2 mo of isoniazid, rifampin,
pyrazinamide, and ethionamide,
if possible, or an aminoglycosidee
or capreomycin, once a dayf,g;
followed by 4–10 mo of isoniazid
and rifampin, once a day or 3
times per week (9–12 mo total)
for drug-susceptible M
tuberculosis
At least 12 mo of therapy without
pyrazinamide for M bovis sus-
ceptible to isoniazid and
rifampin
Abbreviations: DOT, directly observed therapy; IGRA, interferon γ release assay; TB, tuberculosis; TBI, TB
infection; TST, tuberculin skin test.
a
See the current edition of the American Academy of Pediatrics Red Book for comments and additional
acceptable and alternative regimens.
b
Duration of therapy may be longer for people living with HIV infection, and additional drugs and dose
administration intervals may be indicated.
c
Medications should be administered daily for the first 2 weeks to 2 months of treatment and then can be
administered daily or 3 times per week with DOT; twice weekly is acceptable if resources for DOT are
limited. Intermittent therapy is not recommended for people living with HIV infection.
d
If the initial chest radiograph shows pulmonary cavities and/or sputum culture results after 2 months of
therapy remain positive, the continuation phase is extended to 7 months, for a total treatment duration of
9 months.
e
Parenteral streptomycin, kanamycin, or amikacin.
f
Many experts add a fluoroquinolone to this initial regimen.
g
When susceptibility to first-line drugs is established, the ethionamide, aminoglycoside (or capreomycin),
and/or fluoroquinolone can be discontinued.
From American Academy of Pediatrics. Tuberculosis. In: Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH,
eds. Red Book: 2021–2024 Report of the Committee on Infectious Diseases. 32nd ed. American Academy
of Pediatrics; 2021:797–798.

432
Box 23-4
Selection of Effective MDR-TB Treatment Regimen and Duration
ū Use at least 5 drugs in the intensive first phase of treatment and 4 drugs in the
continuation phase of treatment.
ū Intensive phase duration of treatment should be 5 to 7 months after culture
conversion.
ū Total treatment duration should be for 15 to 21 months after culture conversion.
ū In patients with pre-XDR-TB and XDR-TB, total treatment duration should be 15
to 24 months after culture conversion.
Abbreviations: MDR-TB, multidrug-resistant TB; XDR-TB, extensively drug–resistant.

Derived from Nahid P, Mase SR, Migliori GB, et al. Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/
ERS/IDSA Clinical Practice Guideline. Am J Respir Crit Care Med. 2019;200(10):e93–e142. Erratum in: Am J Respir
Crit Care Med. 2020;201(4):500–501.
For patients with drug intolerance or who are infected with minimally
resistant organisms, alternative regimens can be substituted. Mycobacteria
can develop drug resistance rapidly, particularly when single-drug regimens
are used. Thus, a 2-drug combination is the minimum recommended by the
WHO and the CDC for treatment of disease and is recommended only for
patients who absolutely cannot tolerate a more rigorous regimen.2,3 See Table
23-4, Table 23-5, and Box 23-5 for dose administration regimens, alternate
regimens, and medication toxicities.
Therapies for TB tend to be associated with multiple toxicities. Isoniazid and
RIF are often associated with hepatic toxicity, so laboratory evaluation for
evidence of hepatitis should be performed at least once in the first month of
treatment, and more frequently for patients who have a history of hepatitis or
renal insufficiency (those who are treated with streptomycin or other amino-
glycosides). However, routine monitoring of transaminase levels in children

Table 23-4. Treatment of TB Disease in Patients at Low Risk (Suspects/Cases) for Susceptible and Isoniazid-Resistant Mycobacterium tuberculosis
Consult CDC guidelines for the treatment of active TB disease with alternative anti-TB regimens.
Drug Dose Interval Adverse Effects Monitoring Comments
INH Adults: 300 mg Every day Hepatitis, peripheral LFTs (transaminases) once; Administer pyridoxine 25–50 mg/day
neuropathy, mild CNS more if history of chronic to prevent neuropathy in elderly,
Children: 10–15 mg/kg

effects, skin rash, liver disease or other IDDM, nutritional deficiency,
up to 300 mg
increased phenytoin hepatotoxic drugs; not pregnancy, HIV, and renal disease; in
levels, increased tacrolim- normally needed for children infants exclusively breastfed; and in
us levels unless signs of hepatitis children with meat
occur during therapy and milk-deficient diets.
Disease caused by an INH-resistant but rifampin- and pyrazinamide-susceptible strain can be treated with a 6-month regimen of rifampin,
pyrazinamide, and ethambutol.
Rifampin Adults: 10 mg/kg Every day Orange discoloration of Baseline CBC count; Warn patient about orange discoloration
up to 600 mg secretions, cholestatic LFTs once; more if history of urine and other body secretions,
hepatitis, febrile (flu-like of chronic liver disease or such as tears. Can discolor contact
reaction), thrombocyto- other hepatotoxic drugs lenses. Induces hepatic microsomal
up to 600 mg; for < 45
kg, use 450 mg penia, drug interactions, enzymes.
skin rash
Ethambutol Adults: 15–25 mg/kg Every day Optic neuritis very rare at Red-green color discrimination Dose adjustment needed for
15 mg/kg if renal function and visual acuity should be renal disease.
is normal checked at baseline and
(2.5-g max for all ages)
Reversible if discontinued monthly.
Skin rash
Pyrazinamide Adults: 20–25 mg/kg Every day Hepatitis, GI upset, LFTs at start and monthly, Dose adjustment needed for
hyperuricemia, arthralgia, uric acid if renal disease renal disease.
photosensitive dermatitis
(2-g max for all ages) Safety is not established in pregnancy.
433
Abbreviations: CBC, complete blood cell; CDC, Centers for Disease Control and Prevention; CNS, central nervous system; GI, gastrointestinal; IDDM, insulin-dependent diabetes mellitus;
INH, isoniazid; LFT, liver function test; max, maximum; TB, tuberculosis;.
9/12/23 9:43 AM
Table 23-5. Treatment of Multidrug-Resistant Tuberculosis Disease in Children of All Ages
434
Drug Dose Interval Adverse Effects Monitoring

Amikacin Children: 15–30 mg/kg (IV Every day Auditory and vestibular toxic effects, nephrotoxic Creatinine check initially, then weekly
or IM) up to 1 g effects Audiological testing at initiation and in 6 months,
Max dose 1 g all ages then annually
Capreomycin Children: 15–30 mg/kg IM Every day Auditory and vestibular toxic effects, nephrotoxic Creatinine check initially, then weekly
Max dose 1 g all ages effects Audiological testing at initiation and in 6 months,
then annually

Cycloserine 10–20 mg/kg/day orally, Twice a day Psychosis, personality changes, seizures, rash Clinical follow-up
administered in 2 divided
doses
Max dose 1 g all ages
Ethionamide 15–30 mg/kg/day 3 times a GI disturbances, hepatotoxic effects, hypersensitivi- LFTs at start and monthly
Max dose 1 g all ages day ty reactions, hypothyroidism
Kanamycin 15–30 mg/kg/day Every day Auditory and vestibular toxic effects, nephrotoxic Creatinine check initially, then weekly
then annually
Levofloxacin 15–20 mg/kg Every day Possible effect on growing cartilage, tendinitis, GI Preinitiation radiological evaluation of growth
Max dose 1 g all ages disturbances, cardiac disturbances, peripheral plates, ECG, clinical follow-up
neuropathy, rash, headache, restlessness,
confusion
Linezolid < 10 y: 10 mg/kg/day Twice a day Bone marrow suppression CBC count at initiation, and weekly or monthly
> 10 y: 10 mg/kg/day Every day
Max dose 600 mg all ages
Streptomycin 20–40 mg/kg/day Every day Auditory and vestibular toxic effects, nephrotoxic Creatinine check initially, then weekly
then annually
Abbreviations: CBC, complete blood cell; ECG, electrocardiogram; GI, gastrointestinal; IM, intramuscular; IV, intravenous; LFT, liver function test; max, maximum.
9/12/23 9:43 AM
435
Box 23-5
Priority-Ordered Groups of Medicines Recommended
by the World Health Organization for Use in Longer Multidrug-
Resistant Tuberculosis Regimens
Group A = levofloxacin or moxifloxacin, with bedaquiline and linezolid
Group B = clofazimine and either cycloserine or terizidone
Group C = ethambutol, delamanid, pyrazinamide, imipenem-cilastatin or
meropenem, amikacin or streptomycin, ethionamide or prothionamide, and
p-aminosalicylic acid
From World Health Organization. WHO consolidated guidelines on tuberculosis, Module 4: treatment—
drug-resistant tuberculosis treatment. 2020. Accessed May 4, 2022. https://www.who.int/publications/i/
item/9789240007048.
taking INH alone is not recommended by the AAP,3 except in the case of
severe and disseminated disease. In addition, RIF may accelerate elimination
of drugs metabolized by the cytochrome P450 complex in the liver, resulting
in the need to alter dose administration regimens of those medications.
Rifampin will discolor urine and tears orange; patients should be cautioned
that soft contact lenses will be permanently stained. Ethambutol is associated
with optic neuritis in addition to the aforementioned other typical toxicities, so
follow-up to assess changes in visual acuity may be necessary. Finally, these
medications are not generally available in liquid or suspension form, leading
to a potential for decreased adherence to the regimen in younger children.
Development of New Antibiotics and Recycling

Older Antibiotics
New drugs active against TB are urgently required. Novel drugs that can both
reduce the number of drugs and the duration of treatment are needed to treat
drug-susceptible TB and MDR-TB effectively. As of 2018, the WHO reported

436
clinical trials in phase 1, 2, or 3 with 20 drugs for the treatment of drug-

susceptible TB, MDR-TB, and latent TBI. There are several new compounds
under development, including bedaquiline, delamanid, GSK3036656, preto-
manid, and SQ109. Bedaquiline, delamanid, and pretomanid are the most
advanced in development for the treatment of MDR-TB (Table 23-6). Each is
highly effective and well tolerated; the WHO indications for treatment include
RIF-resistant MDR-TB in children but are limited to children 3 years or older
for delamanid and 6 years or older for bedaquiline.45,46 Which regimen
provides the best outcomes with fewest adverse drug reactions remains under
investigation. These agents can be associated with QT prolongation, which
must be further addressed. Other known antibiotics are being repurposed
including clofazimine, linezolid, levofloxacin, moxifloxacin, rifampicin (high
dose), and rifapentine (Table 23-6). Few of these drugs have been tested in
randomized, placebo-controlled studies in children, so dose administration
regimens are not included in this chapter, but the WHO has determined that
bedaquiline may be used in children 6 years or older who have infection with
INH-resistant M tuberculosis.
Investigators in several phase 2 or 3 trials in progress are testing various
combination regimens with new or repurposed drugs (Table 23-6). Preto-
manid is a novel drug that potentially shortens the duration of treatment in
both drug-susceptible and drug-resistant TB.37,44 The TB Alliance in South
Africa has implemented the NiX-TB trial to test the safety and efficacy of a
6-month all-oral regimen combining bedaquiline, pretomanid, and linezolid
in patients with XDR-TB, patients intolerant of standard MDR-TB treatment,
and patients for whom the MDR-TB regimen was not effective. The primary
end point was bacteriologic failure, relapse, or clinical failure during the 6
months after completion of treatment. This trial had a cure rate of 87% for the
first 15 patients enrolled.41 A follow-on trial, ZeNix, is an ongoing clinical trial
to evaluate the efficacy, safety, and tolerability of various doses and durations
of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in
participants with pulmonary XDR-TB, pre-XDR-TB, or treatment-intolerant
or nonresponsive MDR-TB, and lower doses and shorter durations of linezolid
are used to minimize toxicity. The study remains active.47

437
In a phase 2c/3 clinical trial with delamanid completed in patients who had
either drug-susceptible TB or MDR-TB, investigators targeted the primary
end point as culture conversion at 2 months after having concluded a phase 2b
safety study of the bedaquiline, pretomanid, moxifloxacin, and pyrazinamide
regimen with delamanid (a bactericidal drug) added. In it, the investigators
found almost 100% culture conversion at 2 months in patients with
MDR-TB.43
The open-label single-center NixTB study included 109 patients with
XDR-TB and MDR-TB41 and was designed to evaluate the safety and efficacy
of the combination of bedaquiline, pretomanid, and linezolid for 26 weeks in
patients with XDR-TB and MDR-TB previously not responsive to treatment or
for whom the medication regimen was not well tolerated and discontinued.
The results at 6 months after finishing the regimen demonstrated good
bacteriologic outcome (remained culture negative) in 90% of the 109 patients
enrolled. In 10% of the subjects, severe adverse events occurred related to
neurological and optic nerve toxicity, but the WHO has determined that all
patients with MDR-TB would likely benefit from this all-oral regimen, and
similar patients should be treated under observed and monitored conditions.
Table 23-6 lists these and other trials that have been completed to a phase 1
or 2 level.36–44
These worldwide, multicenter antibiotic trials have resulted in a dramatic shift
in treatment for MDR-TB and XDR-TB. The WHO has published recommen-
dations for treatment of drug-resistant TB (Box 23-5).

438
Table 23-6. Medications Under Clinic Trial for Use in MDR-TB

Agent NCT ID, Phase, Type, Date Initiated Class of Drug End Date Results
OPC-16783236 NCT03678688a Carbostyril derivative, affects cell-wall Result pending 4/2021

9/2018 synthesis
A phase 1/2, active-controlled, randomized,

open-label trial to evaluate the safety,
tolerability, pharmacokinetics, and efficacy of
multiple oral doses of OPC-167832 tablets in
subjects with uncomplicated, smear-positive,
drug-susceptible pulmonary tuberculosis
Bedaquiline37,38 NCT02365623b Diarylquinoline 9/2019
2/2015 Inhibits the proton pump of mycobacterial Tolerated, but increased incidence of SAEs,
An open-label study of safety, efficacy, and PK in ATP synthase, an enzyme that is risk for prolonged QTc interval.
Japanese patients with pulmonary MDR-TB for essential for the generation of energy in Effective in sputum culture conversion of
24 weeks in combination with 5 of the Mycobacterium tuberculosis. MDR-TB (58%) and XDR-TB (72%) by 24
following: PZA, ETH, streptomycin, kanamycin, weeks of treatment.
ethionamide, cycloserine, p-aminosalicylic acid,
amikacin, or levofloxacin or other fluoroquino-
lone
SQ109 added NCT01785186c SQ109, Ethylenediamine Phase 2
to Rifafour + 4/2013 Inhibitor of MmpL3, a mycolic acid Study was terminated early for lack of additive
moxifloxacin transporter required for incorporation of or synergistic efficacy compared with the
Multiple-arm, multiple-stage, open-label,
randomized, controlled clinical trial to compare mycolic acid into the M tuberculosis cell standard of care.
the efficacy and safety of SQ109 added to wall 9/2017
standard control regimen in patients with
smear-positive, pulmonary TB
9/12/23 9:43 AM
GSK303665639 NCT03557281d GSK3036656 selectively inhibits the Expected 2/2022
Phase 2a open-label study of the early bactericid- enzyme leucyl-transfer RNA synthetase
al activity, safety, and tolerability of in M tuberculosis and suppresses
GSK3036656 in patients infected with protein synthesis.
drug-sensitive M tuberculosis
Telacebec40 NCT03563599e Imidazopyridine amide targets the 9/2019
Phase 2a, open-label, randomized study in cytochrome bcc complex, a variant of Increasing doses of telacebec were associated

patients who were treatment naive and had the cytochrome bc1 complex (complex with greater reductions in viable mycobac-
smear-positive, drug-sensitive pulmonary TB to III) of the respiratory chain of mycobacterial sputum load.
assess the early bactericidal activity of teria.
telacebec. Targets M tuberculosis cellular energy
Begun 6/2018 production through inhibition of
cytochrome bc1 complex.
In vitro, depletion of ATP synthesis
resulted in cell death regardless of the
replication status of the bacteria.
Comparative study with Rifafour.
Sutezolid41 NCT03959566f Oxazolidinone antibiotic Last update 9/2021
5/2019 No results posted
Different doses of sutezolid in combination with
bedaquiline, delamanid, and moxifloxacin in
adults with newly diagnosed, uncomplicated,
smear-positive, drug-sensitive pulmonary TB
Pretomanid37 NCT01498419g,h Nitroimidazooxazine drug that inhibits 7/2013
3/2012 synthesis of mycolic acid Completed.
Phase 2, open-label partially randomized trial It is active against both replicating and
207 patients with newly diagnosed drug-sensi- nonreplicating M tuberculosis.
tive or MDR-TB, smear-positive TBI taking a
combination of moxifloxacin, pretomanid, and
PZA orally daily for 8 weeks versus standard
439
4-drug regimen of Rifafour

(continued)
11/6/23 8:36 AM
440
Table 23‑6. Medications Under Clinic Trial for Use in MDR-TB (continued)
Agent NCT ID, Phase, Type, Date Initiated Class of Drug End Date Results
42 i,j
Pretomanid NCT02333799 Nitroimidazooxazine drug that inhibits 11/2020

1/2015 synthesis of mycolic acid Complete and attained the approval of the US
109 patients with XDR-TB taking pretomanid in Food and Drug Administration in August
combination with bedaquiline and linezolid had 2019 for adults with pulmonary XDR-TB or
a favorable outcome at 6 months after the end treatment-intolerant or nonresponsive
of treatment. MDR-TB.
Activity of pretomanid, moxifloxacin, and PZA
was superior to standard treatment on daily
change in colony-forming units and time to
culture conversion in rifampicin-susceptible
TB.
Nix-TB41 NCT02333799k Pretomanid is a nitroimidazooxazine drug 8/2020
Pretomanid, 3/2015 that inhibits synthesis of mycolic acid 98 patients (90%; 95% CI, 82.7%–94.9%) had a
bedaquiline, and thus cell-wall synthesis favorable outcome at 6 months after the
109 patients
and linezolid Bedaquiline is a diarylquinoline that end of treatment.
26-week safety and efficacy of bedaquiline plus
inhibits the proton pump of mycobacte- Linezolid toxicities of peripheral neuropathy
pretomanid plus linezolid in adult subjects with
rial ATP synthase, an enzyme that is (81% of patients) and myelosuppression
pulmonary MDR-TB
essential for the generation of energy in (48% of patients) were managed by
M tuberculosis. reductions of dose and/or interruptions in
Linezolid is an oxazolidinone that inhibits linezolid.
bacterial protein synthesis.
11/7/23 9:50 AM
Pretomanid43 NCT03338621l Nitroimidazole inhibits mycolic acid Study concluded 2/2022
Evaluate the efficacy, safety, and tolerability at 8 synthases and is bactericidal.
weeks (2 months), 52 weeks (12 months), and
104 weeks (24 months) after the start of the
following treatment regimens in participants
with drug-sensitive TB(BPaMZ for 17 weeks vs

standard HRZE/HR for 26 weeks) and patients
with drug-resistant TB: (BPaMZ for 26 weeks or
6 months)
Delamanid38,43,44 NCT01859923m Nitroimidazole inhibits mycolic acid 11/2020
(extension of NCT01856634)n synthases and is bactericidal. Well-tolerated, QTc prolongation potential
Phase 2, open-label, dose-finding study in 37
pediatric patients with MDR-TB infection
treated with levofloxacin, bedaquiline, linezolid,
clofazimine (optimized baseline regimen, WHO)
Abbreviations: ATP, adenosine triphosphate; BPaMZ, bedaquiline, pretomanid, moxifloxacin, and pyrazinamide; ETH, ethionamide; HRZE/HR, isoniazid (H), rifampin (R), pyrazinamide
(Z), and ethambutol (E)/isoniazid (H) and rifampin (R); MDR-TB, multidrug-resistant TB; MmpL3, mycobacterial membrane protein Large 3; NCT, National Clinical Trial; PK,
pharmacokinetics; PZA, pyrazinamide; SAE, serious adverse event; TB, tuberculosis; TBI, TB infection; XDR-TB, extensively drug–resistant; WHO, World Health Organization.
a https://clinicaltrials.gov/ct2/show/NCT03678688.
b https://clinicaltrials.gov/ct2/show/NCT02365623.
c https://clinicaltrials.gov/ct2/show/NCT01785186.
d https://clinicaltrials.gov/ct2/show/NCT03557281.
e https://clinicaltrials.gov/ct2/show/NCT03563599.
f https://clinicaltrials.gov/ct2/show/NCT03959566.
g https://clinicaltrials.gov/ct2/show/NCT01498419?term=NCT01498419&draw=2&rank=1.
h Deb U, Biswas S. Pretomanid: the latest USFDA-approved anti-tuberculosis drug. Indian J Tuberc. 2021;68(2):287–291.
i https://clinicaltrials.gov/ct2/show/NCT02333799?term=pretomanid&draw=2&rank=12.
j
Conradie F, Diacon AH, Ngubane N, et al; Nix-TB Trial Team. Treatment of highly drug-resistant pulmonary tuberculosis. N Engl J Med. 2020;382(10):893–902.
k https://clinicaltrials.gov/ct2/show/NCT02333799.
l https://clinicaltrials.gov/ct2/show/NCT03338621.
m https://clinicaltrials.gov/ct2/show/NCT01859923.
441
n https://clinicaltrials.gov/ct2/show/NCT01856634.
9/12/23 9:43 AM
442
Directly Observed Therapy

Because TB is highly contagious, the mortality rate due to TB is high, and
poor adherence to the multidrug regimen can lead to multidrug resistance,
DOT medication administration systems have been developed. With DOT, a
health care worker is assigned to watch the patient swallow every dose. It is
generally accepted that DOT is the most optimal means of ensuring that
children receive TB therapy. Directly observed therapy can be accomplished
by trained personnel in many settings, including medical clinics, public health
facilities, the home, and school. Frequently, proper administration of anti-TB
medications necessitates using crushed pills and suspensions to attain correct
doses. Tolerance of the medications must be monitored closely, and children
may resist taking their prescribed medications. Parents should not be relied on
to supervise DOT. If a patient experiences toxicity from the medications, this
can be detected early with routine blood tests. Directly observed therapy is
also helpful to allow and encourage ongoing patient education. In some
patients, the multidrug regimen for TB can be administered 3 times weekly
rather than daily. Directly observed therapy services increase the likelihood of
successful treatment of TB, decreasing mortality due to TB, and preventing
the spread of MDR-TB in the United States. This system has proved success-
ful in other countries where access to medical care is limited.
Prognosis
In general, the prognosis for patients infected with TB is good, but mortality
rates increase when patients have comorbidities such as malnutrition, dissemi-
nated disease, or immunodeficiency (especially HIV), and mortality rates
increase dramatically in patients infected with MDR-TB. Globally, the mortality
rate for positive cases of MDR-TB in the HIV-negative population in 2008 was
estimated at about 26%, though the range varied between 16% and 58%.2 The
high mortality rate due to MDR-TB can eventually be addressed if resources to
provide adequate prevention, diagnosis, treatment, and care are present. In the
United States, although a substantial portion of the population is medically and
economically indigent, most cases are likely detected at some point in the
disease course. Conversely, most cases of people who are infected in China and
Africa go undetected, and these patients do not receive adequate treatment and
have high mortality. A global decrease in MDR-TB mortality can be effected
with appropriate antibiotic coverage and as DOT programs expand. Infection
control measures that have been considered and systematically instituted can
potentially reduce transmission throughout the populations most at risk, and
mortality due to MDR-TB will eventually be reduced, if not eliminated.
Control of TB
Control of TB requires a concerted and consistent public health effort involv-
ing state and local health departments, individual health care providers, and

443
other institutions, including hospitals and incarceration units. The local health
department often plays an important role in the following areas once a TB
case is identified:
X Thoroughly investigating contacts of an index case and ensuring that
contacts receive appropriate testing for evidence of infection
X Ensuring that the index case receives appropriate standard therapy or
therapy for MDR-TB on the basis of laboratory evaluation and that all
infected contacts receive appropriate evaluation, monitoring, and therapy
X Providing a mechanism so that all patients receive DOT for TB
X Ensuring that all patients receive regular monitoring for secondary effects
of anti-TB therapy
X Ensuring that high-risk groups such as individuals who are incarcerated,
individuals who are HIV positive, and health care workers receive regular
screening for TB
X Ensuring that children and adults return to school and the workplace as
soon as able after treatment for TB is initiated
Most children younger than 10 years are not contagious, primarily because of
the rare occurrence of cavitary disease in children. However, children with (1)
cavitary pulmonary TB; (2) positive sputum acid-fast bacilli smears; (3)
laryngeal involvement; (4) extensive pulmonary infection; or (5) congenital
TB who are undergoing oropharyngeal procedures, such as endotracheal
intubation, can infect others. Precautions should always be taken when
treating these types of pediatric patients.
Vaccine Development
Most countries outside the United States provide the BCG vaccination as an
element of the routine childhood vaccinations according to the epidemiological
characteristics of TB for each country; 158 countries vaccinated their pediatric
population in 2017, and most reported that their effort covered approximately
90% of children.2 The WHO’s #EndTB strategy to eliminate TB by 2035
challenges these countries to reach this goal, but further research and develop-
ment must proceed at an aggressive pace as well.2 Although many break-
throughs have been announced, the programs must be accelerated so that many
more breakthroughs are achieved. By 2025, TB cases must decrease by at least
17% per year, not the current rates of less than 5%. Vaccine development is a
priority to reduce the risk of infection, but the effect of the BCG vaccine wanes
within a few years. New vaccine and new drug development must be supported.
As of 2020, 12 vaccine trials were begun and some have been completed and
are in various stages of development (Table 23-7).48–59 Some are safety and
dose-ranging trials (phases 1 and 2); others have progressed to phase 3
placebo-controlled trials designed to either prevent disease from developing in
people with TBI or improve the outcomes of those with TB disease.60,61

444
Table 23-7. Results of Vaccine Trials to Prevent TB Dissemination

Vaccine/Phase/ Composition Mechanism of Efficacy Results
48,49 +
DAR-901/2b Induces CD4 T-cell cytokine profiles that correlate A 3-dose series of 1 mg DAR-901 was safe and well
Inactivated whole-cell TB booster vaccine in with protection tolerated but did not prevent initial or persistent
adolescents who are BCG vaccine primed IGRA conversion. Recipients of DAR-901 with
(NCT02712424) IGRA conversion had enhanced immune respons-

es to ESAT-6.
Phase 2a completed 5/2021
M72/AS01E/3 RDBPC50,51 Induces M72-specific antibodies and increases the The vaccine efficacy at month 36 was 54% to
Vaccine contains a recombinant fusion protein frequencies of M72-specific CD4+ T cells. prevent active pulmonary TB disease according
derived from 2 Mycobacterium tuberculosis Efficacy of M72/AS01E to prevent active pulmonary to the case definition.
antigens (Mtb32A and Mtb39A) combined with the TB disease according to the first case definition Future steps: GlaxoSmithKline outsourced M72/
AS01E adjuvant system. (NCT01755598) (bacteriologically confirmed pulmonary TB) AS01E to the Gates Medical Research Institute for
A phase 2b study completed in men aged 18 to 50 followed for 3 years after the second dose. continued development and potentially for use
years with TBI defined by positive IGRA results of the vaccine candidate in countries with high
without evidence of active TB disease at centers in TB burdens.
Kenya, South Africa, and Zambia, with 1:1 ratio to
receive 2 doses of either M72/AS01E or placebo,
administered 1 month apart, in participants who
were HIV negative
NCT04556981a Start date 11/2020 Results pending
M72/AS01E randomized, placebo-controlled, 402 participants with HIV who were virally
observer-blind, phase 2 study to evaluate safety suppressed and treated with HAART
and immunogenicity of the investigational M72/
AS01E M tuberculosis vaccine
9/12/23 9:43 AM
NCT01378312b Randomized 2:1 to receive 2 intramuscular CD8+ T-cell responses were induced and dominat-
AERAS-402 is a replication-deficient Ad35 vaccine injections of either AERAS-402 or placebo on ed by cells that coexpressed IFN-γ, tumor
that encodes a fusion protein of the M tuberculosis study days 0 and 28. Safety and immunogenicity necrosis factor α, and IL-2 (polyfunctional cells)
antigens 85A, 85B, and TB10.52 parameters were evaluated for up to 182 days and were more robust than CD4+ T-cell
after the second injection. responses.
Phase 1
Immunogenicity was assessed with a flow
Healthy male participants aged 18–45 years with a
cytometry–based intracellular cytokine staining

negative QFT.
assay and transcriptional profiling.
12 participants enrolled
NCT0241482853 Phase 2 randomized, placebo-controlled, Study ended 4/2016
Phase 1 RDBPC dose-escalation study in adults double-blind dose-escalation study in an adult AERAS-402 candidate TB vaccine administered in
recently treated for pulmonary TB South African cohort (n = 72) that was HIV participants with current or previous pulmonary
negative with active pulmonary TB (receiving TB induced a robust immune response, but
72 participants
treatment for 1–4 mo) or pulmonary TB treated at analysis of the vaccine-induced CD8+ T cells
Single or booster doses least 12 months before study entry and revealed that the induced cells did not recognize
considered cured the M tuberculosis–infected cell.
NCT0119836654 487 infants aged 16–26 weeks Antibodies directed against Ag85A and Ag85B
Phase 2 Received 2–3 doses IM vaccine or placebo were detected. Low magnitude CD4+ and CD8+
polyfunctional T-cell responses were observed at
RDBPC, multicenter study to evaluate the safety and Follow-up for 24 months
all dose levels. The addition of a third dose of
immunogenicity of AERAS-402 in infants who were
AERAS-402 at the highest dose level did not
BCG vaccinated, HIV uninfected, and without
increase frequency or magnitude of antibody or
evidence of TB
CD8+ T-cell responses.
South Africa National Clinical Trial Register (DOH-27- AERAS-402 in infants, administered as a boost after AERAS-402 is safe in healthy infants previously
0209-2655)55 a prime with BCG vaccine vaccinated with BCG vaccine and induces
Phase 2 RDBPC, dose-escalation trial, in 57 infants dose-dependent CD4+ and CD8+ T-cell responses.
aged 6–9 months who were BCG vaccinated and
sequentially randomly assigned to receive an
increasing dose strength of AERAS-402 or placebo
445
(continued)
11/6/23 8:38 AM
Table 23-7. Results of Vaccine Trials to Prevent TB Dissemination (continued)
446
Vaccine/Phase/ Composition Mechanism of Efficacy Results

c,56
NCT01113281 Promotes phagolysosomal maturation and The immunogenicity of VPM1002 as measured
Phase 1 study VPM1002, a recombinant BCG vaccine impedes the survival of mycobacteria inside the with IFN-γ release by T cells was dose dependent.
in which the urease C gene is replaced by the macrophage VPM1002 induced multifunctional CD4+ and
listeriolysin O gene from Listeria monocytogenes CD8+ T-cell subsets that play a role in protection
against TBI.
NCT01479972d,57 This is the first investigation of VPM1002 in Safe, well-tolerated, and efficacious vaccine
Phase 2 open-label, randomized, controlled study to newborns.

evaluate safety and immunogenicity of VPM1002 in
comparison with BCG in newborns who were HIV
unexposed and BCG vaccine naive in South Africa
NCT03152903e,58 A 2,000-participant 3-arm multicenter RPC phase Expected end date 5/2022
A multicenter, RDBPC phase 2/3 trial in adults with a 2/3 trial to assess the ability of VPM1002 or
single dose of VPM1002 or placebo to determine Immunovac/MIP to prevent disease in contacts of
efficacy of the vaccine against recurrent TB patients with sputum-positive pulmonary TB
diagnosed in India
Immunovac/MIP59 Evaluated the immunotherapeutic potential of MIP Immunovac/MIP was safe with no adverse effects.
RDBPC in 890 participants with smear-positive as an adjunct to treatment in patients with Although sputum smear conversion did not show
pulmonary TB smear-positive pulmonary TB any statistically significant difference, a signifi-
cantly higher number of patients in the MIP group
achieved sputum culture conversion at fourth
week compared with results in the placebo group
(67% vs 57%), suggesting a role of MIP in
clearance of bacilli.
Abbreviations: Ad35, adenovirus serotype 35; BCG, bacille Calmette-Guérin; CD, cluster of differentiation; ESAT, early secretory antigenic target; HAART, highly active antiretroviral
therapy; IFN-γ, interferon γ; IGRA, IFN-γ release assay; IL-2,interleukin 2; IM, intramuscular; MIP, Mycobacterium indicus pranii; NCT, National Clinical Trial; QFT, QuantiFERON-TB Gold
(Qiagen, Hilden, Germany); RDBPC, randomized, double-blind, placebo-controlled; TB, tuberculosis.
a https://clinicaltrials.gov/ct2/show/NCT04556981.
b https://clinicaltrials.gov/ct2/show/NCT01378312.
c https://clinicaltrials.gov/ct2/show/NCT01113281.
d https://clinicaltrials.gov/ct2/show/NCT01479972.
e https://clinicaltrials.gov/ct2/show/NCT03152903.
11/7/23 9:57 AM
447
When to Refer
X All patients suspected of having active TBI should be reported to the local
health department according to state statute (usually within 1 working day).
X In many areas, young children with latent TBI should be reported to the
local health department, according to local regulations.
X Ideally, a pediatrician experienced in TB should manage TB disease in
children. If a specialist is not available, close and ongoing consultation with
a pediatric TB expert should be established.
When to Admit
X Children suspected of having a TBI should be admitted to the hospital for
culture collection. Early-morning gastric aspirates have the highest yield
when obtained from gastric secretions after a nasogastric tube is placed the
night before and the child has not yet arisen or eaten.
X Patients with increased work of breathing, meningitis, or complicating
simultaneous conditions should be admitted to the hospital for supportive
and aggressive care.
key points
} Only children who have a new risk for TB exposure since the last TST or who
have features suggestive of TB disease should undergo testing with a TST or
IGRA.
} Interferon-γ release assay testing is the first line of testing in most patients aged
2 years or older.
} All children with latent TBI diagnosed should be treated and monitored for
adherence and toxicity.
} Tuberculosis disease is diagnosed clinically and radiographically in children,
often without the benefit of culture confirmation.
} Vaccines are in development, but none have yet been developed that prevent
TBI (Table 23-6).

448
References
1. Deutsch-Feldman M, Pratt RH, Price SF, Tsang CA, Self JL. Tuberculosis—United States, 2020.
MMWR Morb Mortal Wkly Rep. 2021;70(12):409–414 PMID: 33764959 doi: 10.15585/mmwr.
mm7012a1
2. World Health Organization. Global Tuberculosis Report 2020. World Health Organization; 2020.
https://www.who.int/publications/i/item/9789240013131
3. American Academy of Pediatrics. Tuberculosis. In: Kimberlin DW, Barnett ED, Lynfield R,
Sawyer MH, eds. Red Book: 2021–2024 Report of the Committee on Infectious Diseases. 32nd
ed. American Academy of Pediatrics; 2021:786–814
4. Cowger TL, Wortham JM, Burton DC. Epidemiology of tuberculosis among children and
adolescents in the USA, 2007–17: an analysis of national surveillance data. Lancet Public Health.
2019;4(10):e506–e516 PMID: 31446052 doi: 10.1016/S2468-2667(19)30134-3
5. Centers for Disease Control and Prevention. Latent tuberculosis infection resources. Updated
March 24, 2022. Accessed May 4, 2022. https://www.cdc.gov/tb/publications/ltbi/ltbiresources.
htm
6. Mandalakas AM, Starke JR. Current concepts of childhood tuberculosis. Semin Pediatr Infect
Dis. 2005;16(2):93–104 PMID: 15825140 doi: 10.1053/j.spid.2005.01.001
7. Jenmalm MC. The mother–offspring dyad: microbial transmission, immune interactions and
allergy development. J Intern Med. 2017;282(6):484–495 PMID: 28727206 doi: 10.1111/
joim.12652
8. Beyers N, Gie RP, Schaaf HS, et al. A prospective evaluation of children under the age of 5 years
living in the same household as adults with recently diagnosed pulmonary tuberculosis. Int J
Tuberc Lung Dis. 1997;1(1):38–43 PMID: 9441057
9. Balinda IG, Sugrue DD, Ivers LC. More than malnutrition: a review of the relationship between
food insecurity and tuberculosis. Open Forum Infect Dis. 2019;6(4):ofz102 PMID: 30949541 doi:
10.1093/ofid/ofz102
10. Colditz GA, Brewer TF, Berkey CS, et al. Efficacy of BCG vaccine in the prevention of
tuberculosis: meta-analysis of the published literature. JAMA. 1994;271(9):698–702 PMID:
8309034 doi: 10.1001/jama.1994.03510330076038
11. Barnes PF, Bloch AB, Davidson PT, Snider DE Jr. Tuberculosis in patients with human
immunodeficiency virus infection. N Engl J Med. 1991;324(23):1644–1650 PMID: 2030721 doi:
10.1056/NEJM199106063242307
12. Marais BJ, Gie RP, Schaaf HS, et al. The clinical epidemiology of childhood pulmonary
tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis.
2004;8(3):278–285 PMID: 15139465
13. Dodd PJ, Prendergast AJ, Beecroft C, Kampmann B, Seddon JA. The impact of HIV and
antiretroviral therapy on TB risk in children: a systematic review and meta-analysis. Thorax.
2017;72(6):559–575 PMID: 28115682 doi: 10.1136/thoraxjnl-2016-209421
14. Lewinsohn DM, Leonard MK, LoBue PA, et al. Official American Thoracic Society/Infectious
Diseases Society of America/Centers for Disease Control and Prevention clinical practice
guidelines: diagnosis of tuberculosis in adults and children. Clin Infect Dis. 2017;64(2):e1–e33
PMID: 27932390 doi: 10.1093/cid/ciw694
15. Cruz AT, Reichman LB. The case for retiring the tuberculin skin test. Pediatrics.
2019;143(6):e20183327 PMID: 31147487 doi: 10.1542/peds.2018-3327
16. Centers for Disease Control and Prevention. What you need to know about the tuberculosis skin
test. 2015. www.cdc.gov/tb/publications/pamphlets/tb_skin_test.pdf
17. Ahmed A, Feng PI, Gaensbauer JT, et al; Tuberculosis Epidemiologic Studies Consortium.
Interferon-γ release assays in children <15 years of age. Pediatrics. 2020;145(1):e20191930
PMID: 31892518 doi: 10.1542/peds.2019-1930
18. Kay AW, Islam SM, Wendorf K, Westenhouse J, Barry PM. Interferon-γ release assay
performance for tuberculosis in childhood. Pediatrics. 2018;141(6):e20173918 PMID: 29728429
doi: 10.1542/peds.2017-3918
19. Menzies R, Vissandjee B. Effect of bacille Calmette-Guérin vaccination on tuberculin reactivity.
Am Rev Respir Dis. 1992;145(3):621–625 PMID: 1546843 doi: 10.1164/ajrccm/145.3.621
20. Hauk L. Tuberculosis: guidelines for diagnosis from the ATS, IDSA, and CDC. Am Fam
Physician. 2018;97(1):56–58 PMID: 29365230
21. Goussard P, Gie RP, Kling S, et al. Bronchoscopic assessment of airway involvement in children
presenting with clinically significant airway obstruction due to tuberculosis. Pediatr Pulmonol.
2013;48(10):1000–1007 PMID: 23281247 doi: 10.1002/ppul.22747

449
22. Zar HJ, Hanslo D, Apolles P, Swingler G, Hussey G. Induced sputum versus gastric lavage for
microbiological confirmation of pulmonary tuberculosis in infants and young children: a
prospective study. Lancet. 2005;365(9454):130–134 PMID: 15639294 doi: 10.1016/S0140-
6736(05)17702-2. Erratum in: Lancet. 2005;365(9475):1926
23. Walters E, Goussard P, Bosch C, Hesseling AC, Gie RP. GeneXpert MTB/RIF on
bronchoalveolar lavage samples in children with suspected complicated intrathoracic
tuberculosis: a pilot study. Pediatr Pulmonol. 2014;49(11):1133–1137 PMID: 24339262 doi:
10.1002/ppul.22970
24. Shah M, Paradis S, Betz J, et al. Multicenter study of the accuracy of the BD MAX multidrug-
resistant tuberculosis assay for detection of Mycobacterium tuberculosis complex and mutations
associated with resistance to rifampin and isoniazid. Clin Infect Dis. 2020;71(5):1161–1167
PMID: 31560049 doi: 10.1093/cid/ciz932
25. Nicol MP, Workman L, Isaacs W, et al. Accuracy of the Xpert MTB/RIF test for the diagnosis of
pulmonary tuberculosis in children admitted to hospital in Cape Town, South Africa: a
descriptive study. Lancet Infect Dis. 2011;11(11):819–824 PMID: 21764384 doi: 10.1016/
S1473-3099(11)70167-0
26. Penn-Nicholson A, Georghiou SB, Ciobanu N, et al; Xpert XDR Trial Consortium. Detection of
isoniazid, fluoroquinolone, ethionamide, amikacin, kanamycin, and capreomycin resistance by
the Xpert MTB/XDR assay: a cross-sectional multicentre diagnostic accuracy study. Lancet
Infect Dis. 2022:22(2)242–249. PMID: 34627496 doi: 10.1016/S1473-3099(21)00452-7
27. World Health Organization. WHO consolidated guidelines on tuberculosis. Module 3:
diagnosis—rapid diagnostics for tuberculosis detection. 2021 update. Accessed May 4, 2022.
https://apps.who.int/iris/rest/bitstreams/1354562/retrieve
28. Desikan P, Panwalkar N, Mirza SB, et al. Line probe assay for detection of Mycobacterium
tuberculosis complex: an experience from central India. Indian J Med Res. 2017;145(1):70–73
PMID: 28574017 doi: 10.4103/ijmr.IJMR_831_14
29. Nathavitharana RR, Lederer P, Chaplin M, Bjerrum S, Steingart KR, Shah M. Impact of
diagnostic strategies for tuberculosis using lateral flow urine lipoarabinomannan assay in people
living with HIV. Cochrane Database Syst Rev. 2021;8(8):CD014641 PMID: 34416013 doi:
10.1002/14651858.CD014641
30. Pai M, Riley LW, Colford JM Jr. Interferon-gamma assays in the immunodiagnosis of
tuberculosis: a systematic review. Lancet Infect Dis. 2004;4(12):761–776 PMID: 15567126 doi:
10.1016/S1473-3099(04)01206-X
31. World Health Organization. Technical report on critical concentrations for drug susceptibility
testing of medicines used in the treatment of drug-resistant tuberculosis. 2018. Accessed May 4,
2022. https://www.who.int/publications/i/item/WHO-CDS-TB-2018.5
32. Kay AW, González Fernández L, Takwoingi Y, et al. Xpert MTB/RIF and Xpert MTB/RIF Ultra
assays for active tuberculosis and rifampicin resistance in children. Cochrane Database Syst Rev.
2020;8(8):CD013359 PMID: 32853411 doi: 10.1002/14651858.CD013359.pub2
33. Auguste P, Tsertsvadze A, Pink J, et al. Accurate diagnosis of latent tuberculosis in children,
people who are immunocompromised or at risk from immunosuppression and recent arrivals
from countries with a high incidence of tuberculosis: systematic review and economic
evaluation. Health Technol Assess. 2016;20(38):1–678 PMID: 27220068 doi: 10.3310/hta20380
34. Meier NR, Volken T, Geiger M, Heininger U, Tebruegge M, Ritz N. Risk factors for
indeterminate interferon-gamma release assay for the diagnosis of tuberculosis in children: a
systematic review and meta-analysis. Front Pediatr. 2019;7:208 PMID: 31192175 doi: 10.3389/
fped.2019.00208
35. Nahid P, Mase SR, Migliori GB, et al. Treatment of drug-resistant tuberculosis: an official ATS/
CDC/ERS/IDSA clinical practice guideline. Am J Respir Crit Care Med. 2019;200(10):e93–e142
PMID: 31729908 doi: 10.1164/rccm.201909-1874ST. Erratum in: Am J Respir Crit Care Med.
2020;201(4):500–501
36. Hariguchi N, Chen X, Hayashi Y, et al. OPC-167832, a novel carbostyril derivative with potent
antituberculosis activity as a DprE1 inhibitor. Antimicrob Agents Chemother.
2020;64(6):e02020–e19 PMID: 32229496 doi: 10.1128/AAC.02020-19
37. Tweed CD, Dawson R, Burger DA, et al. Bedaquiline, moxifloxacin, pretomanid, and
pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or
drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b
trial. Lancet Respir Med. 2019;7(12):1048–1058 PMID: 31732485 doi: 10.1016/S2213-
2600(19)30366-2

450
38. Pecora F, Dal Canto G, Veronese P, Esposito S. Treatment of multidrug-resistant and extensively
drug-resistant tuberculosis in children: the role of bedaquiline and delamanid. Microorganisms.
2021;9(5):1074 PMID: 34067732 doi: 10.3390/microorganisms9051074
39. Tenero D, Derimanov G, Carlton A, et al. First-time-in-human study and prediction of early
bactericidal activity for GSK3036656, a potent leucyl-tRNA synthetase inhibitor for tuberculosis
treatment. Antimicrob Agents Chemother. 2019;63(8):e00240–e19 PMID: 31182528 doi: 10.1128/
AAC.00240-19
40. de Jager VR, Dawson R, van Niekerk C, et al. Telacebec (Q203), a new antituberculosis agent. N
Engl J Med. 2020;382(13):1280–1281 PMID: 32212527 doi: 10.1056/NEJMc1913327
41. Conradie F, Diacon AH, Ngubane N, et al; Nix-TB Trial Team. Treatment of highly drug-
resistant pulmonary tuberculosis. N Engl J Med. 2020;382(10):893–902 PMID: 32130813 doi:
10.1056/NEJMoa1901814
42. Deb U, Biswas S. Pretomanid: the latest USFDA-approved anti-tuberculosis drug. Indian J
Tuberc. 2021;68(2):287–291 PMID: 33845969 doi: 10.1016/j.ijtb.2020.09.003
43. World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis
treatment. 2019. https://apps.who.int/iris/handle/10665/311389
44. Shah I, Gandhi S, Shetty NS. Bedaquiline and delamanid in children with XDR tuberculosis:
what is prolonged QTc? Pediatr Infect Dis J. 2020;39(6):512–513 PMID: 32032176 doi: 10.1097/
INF.0000000000002601
45. World Health Organization. WHO consolidated guidelines on tuberculosis, Module 4:
treatment—drug-resistant tuberculosis treatment. 2020. Accessed May 4, 2022. https://www.
who.int/publications/i/item/9789240007048
46. World Health Organization. Rapid communication on updated guidance on the management of
tuberculosis in children and adolescents. 2021. Accessed May 4, 2022. https://www.who.int/
publications/i/item/9789240033450
47. US National Library of Medicine. Safety and Efficacy of Various Doses and Treatment Durations
of Linezolid Plus Bedaquiline and Pretomanid in Participants With Pulmonary, XDR-TB,
Pre- XDR-TB or Non-responsive/Intolerant MDR-TB (ZeNix). Accessed May 4, 2022. https://
clinicaltrials.gov/ct2/show/NCT03086486
48. Munseri P, Said J, Amour M, et al. DAR-901 vaccine for the prevention of infection with
Mycobacterium tuberculosis among BCG-immunized adolescents in Tanzania: a randomized
controlled, double-blind phase 2b trial. Vaccine. 2020;38(46):7239–7245 PMID: 33004239 doi:
10.1016/j.vaccine.2020.09.055
49. Masonou T, Hokey DA, Lahey T, et al. CD4+ T cell cytokine responses to the DAR-901 booster
vaccine in BCG-primed adults: a randomized, placebo-controlled trial. PLoS One.
2019;14(5):e0217091 PMID: 31120957 doi: 10.1371/journal.pone.0217091
50. Van Der Meeren O, Hatherill M, Nduba V, et al. Phase 2b controlled trial of M72/AS01E vaccine
to prevent tuberculosis. N Engl J Med. 2018;379(17):1621–1634 PMID: 30280651 doi: 10.1056/
NEJMoa1803484
51. Tait DR, Hatherill M, Van Der Meeren O, et al. Final analysis of a trial of M72/AS01E vaccine to
prevent tuberculosis. N Engl J Med. 2019;381(25):2429–2439 PMID: 31661198 doi: 10.1056/
NEJMoa1909953
52. van Zyl-Smit RN, Esmail A, Bateman ME, et al. Safety and immunogenicity of adenovirus 35
tuberculosis vaccine candidate in adults with active or previous tuberculosis: a randomized trial.
Am J Respir Crit Care Med. 2017;195(9):1171–1180 PMID: 28060545 doi: 10.1164/rccm.201603-
0654OC
53. Nyendak M, Swarbrick GM, Duncan A, et al. Adenovirally-induced polyfunctional T cells do
not necessarily recognize the infected target: lessons from a phase I trial of the AERAS-402
vaccine. Sci Rep. 2016;6:36355 PMID: 27805026 doi: 10.1038/srep36355
54. Tameris M, Hokey DA, Nduba V, et al. A double-blind, randomised, placebo-controlled,
dose-finding trial of the novel tuberculosis vaccine AERAS-402, an adenovirus-vectored fusion
protein, in healthy, BCG-vaccinated infants. Vaccine. 2015;33(25):2944–2954 PMID: 25936724
doi: 10.1016/j.vaccine.2015.03.070
55. Kagina BM, Tameris MD, Geldenhuys H, et al; 018-402 Clinical Lab study team. The novel
tuberculosis vaccine, AERAS-402, is safe in healthy infants previously vaccinated with BCG,
and induces dose-dependent CD4 and CD8T cell responses. Vaccine. 2014;32(45):5908–5917
PMID: 25218194 doi: 10.1016/j.vaccine.2014.09.001
56. Gengenbacher M, Nieuwenhuizen N, Vogelzang A, et al. Deletion of nuoG from the vaccine
candidate Mycobacterium bovis BCG ΔureC::hly improves protection against tuberculosis.
mBio. 2016;7(3):e00679–16 PMID: 27222470 doi: 10.1128/mBio.00679-16

451
57. Loxton AG, Knaul JK, Grode L, et al. Safety and immunogenicity of the recombinant
Mycobacterium bovis BCG vaccine VPM1002 in HIV-unexposed newborn infants in South
Africa. Clin Vaccine Immunol. 2017;24(2):e00439–16 PMID: 27974398 doi: 10.1128/CVI.00439-
16
58. US National Library of Medicine. Study to Check the Efficacy and Safety of Recombinant BCG
Vaccine in Prevention of TB Recurrence. Accessed May 4, 2022. https://clinicaltrials.gov/ct2/
show/NCT03152903
59. Sharma SK, Katoch K, Sarin R, et al. Efficacy and safety of Mycobacterium indicus pranii as an
adjunct therapy in category II pulmonary tuberculosis in a randomized trial. Sci Rep.
2017;7(1):3354 PMID: 28611374 doi: 10.1038/s41598-017-03514-1
60. Weerasuriya CK, Clark RA, White RG, Harris RC. New tuberculosis vaccines: advances in
clinical development and modelling. J Intern Med. 2020;288(6):661–681 PMID: 33128834 doi:
10.1111/joim.13197
61. Sable SB, Posey JE, Scriba TJ. Tuberculosis vaccine development: progress in clinical
evaluation. Clin Microbiol Rev. 2019;33(1):e00100–19 PMID: 31666281 doi: 10.1128/
CMR.00100-19

CHAPTER
24
Nontuberculous Mycobacteria
Stacey L. Martiniano, MD
Patricia Lenhart-Pendergrass, MD, PhD
Kenneth N. Olivier, MD, MPH
CASE REPORT 24-1

A 14-year-old girl who has been followed in the cystic fibrosis center for several
years underwent computed tomography scanning because the usual therapy
for a pulmonary exacerbation failed. She reported recent weight loss and night
sweats. The computed tomography scan showed 2 cavities in the right upper
lobe. She produced minimal sputum, so bronchoscopy with bronchoalveolar
lavage was performed, and a smear revealed acid-fast bacilli. Mycobacterium
abscessus subspecies abscessus was cultured, and she was treated with intra-
venous amikacin, intravenous imipenem, oral azithromycin, and oral linezolid.
Subsequent therapy will be decided based on response to treatment and
sensitivity patterns.
Introduction
All species of mycobacteria, with the exception of Mycobacterium tuberculosis,
Mycobacterium leprae, and Mycobacterium ulcerans, can be categorized as
nontuberculous mycobacteria (NTM). More than 200 different species of NTM
have been reported in the literature to date,1 but only a small subset are associ-
ated with human disease. Nontuberculous mycobacteria are found ubiquitously
in the environment, including soil, dust, and water sources such as tap water
and even hospital water sources.2 Unlike M tuberculosis infections, NTM
infections are almost exclusively caused by direct acquisition from the environ-
ment, although results from whole-genome sequencing studies suggest that
direct or indirect transmission between patients has occurred.3 Nontuberculous
mycobacteria infections can occur in both the immunocompetent and the
immunocompromised host. Pulmonary disease from NTM most commonly
occurs in hosts with underlying pulmonary conditions, such as cystic fibrosis
(CF), primary ciliary dyskinesia, or other non-CF bronchiectasis, and is rare in
453

454
healthy children. Other pulmonary manifestations include thoracic or

endobronchial nodal disease and hypersensitivity pneumonitis. Extrapulmo-
nary manifestations include lymphadenitis, skin and soft-tissue infections,
and catheter-associated infections. Disseminated disease can be seen in hosts
with primary immunodeficiency or secondary immune suppression. Diagnos-
ing NTM infection can be challenging, and treatment strategies remain
complex.
Pathophysiology
Acquisition of NTM most commonly occurs through exposure to environmen-
tal sources. Inhalation into the respiratory tract is thought to be the source for
pulmonary parenchymal disease, as well as endobronchial and mediastinal
disease. Although person-to-person spread is thought to present a low risk,
incidences of person-to-person spread of NTM in patients with CF have been
reported.3,4 The oropharyngeal mucosa is the likely portal of entry in patients
with cervical lymphadenitis. Direct inoculation can occur through abrasions or
via surgical incisions and central catheters. Entry through the gastrointestinal
tract can be associated with disseminated disease. Infection tends to remain
localized to the site or organ of infection, but dissemination can occur in
patients with HIV infection and in patients with congenital immune defects
of the interleukin 12 (IL-12)/interferon γ (IFN- γ) axis.5
Nontuberculous mycobacteria are acid-fast bacteria that require special
media to grow in the laboratory and can be classified by their speed of growth.
Appropriately identifying organisms in children with CF requires working
with a knowledgeable microbiology laboratory that is adept at isolating these
pathogens and at using proper isolation techniques (eg, Pseudomonas aerugi-
nosa can overgrow NTM in culture).6 Nontuberculous mycobacteria that
grow rapidly (within 1 week) and are commonly associated with lung disease
include the Mycobacterium abscessus species (which includes subspecies
abscessus, massiliense, and bolletii), Mycobacterium fortuitum, and Myco-
bacterium chelonae.7 Slow-growing NTM typically take weeks to grow and
include Mycobacterium avium complex (MAC; which includes the species
M avium, Mycobacterium intracellulare, and Mycobacterium chimaera,
among others), Mycobacterium kansasii, Mycobacterium xenopi, and Myco-
bacterium simiae. Most human pulmonary disease is caused by a limited
number of NTM, so identifying the species (and subspecies for M abscessus
species) helps determine whether the isolated species is pathogenic and,
therefore, guides therapy. Because NTM are ubiquitous, environmental
contamination can occur in the laboratory. For example, Mycobacterium
gordonae is thought to be the least pathogenic of all mycobacteria, and
isolation is typically regarded as a contaminant. Thus, interpretation of single

455
Chapter 24—Nontuberculous Mycobacteria
isolates of NTM needs to include the context of the clinical presentation and
ideally repeat isolation from additional samples. Nontuberculous mycobacteria
species identification is ideally performed using specific DNA probes, poly-
merase chain reaction techniques, or DNA sequence analysis. Some study
results have shown that matrix-assisted laser desorption ionization–time of
flight mass spectrometry may be useful in providing rapid species identifica-
tion of many NTM species, but not all species can be identified reliably with
this method.8–10
Clinical Features
Pulmonary Disease
Pulmonary NTM isolation rates in the general population range from 6 to
22 per 100,000 in North America.11 In children, NTM infection is most com-
monly associated with CF. The prevalence of pulmonary NTM infection in
children with CF increases with age; NTM infection in the first decade of
life is less common, with a prevalence of about 5% to 10%, increasing to a
prevalence of 6% to 19% among adults with CF.11–13 Pulmonary NTM is also
associated with other syndromes affecting the mucociliary clearance that lead
to bronchiectasis, such as primary ciliary dyskinesia and certain immunodefi-
ciency conditions such as autosomal dominant hyperimmunoglobulin E (Job)
syndrome.14,15 In these other disorders of mucociliary clearance, incidence of
NTM infection also increases with age and is less likely in young children.
Isolation rates for NTM are increasing over time among those with CF12,16,17
and in the general population18 for reasons that are uncertain but that may
relate to improving surveillance and culture techniques. M avium complex is
the most frequently recovered NTM in the United States, but rapid growers,
typically M abscessus species, are also common. The prevalence and species
of NTM vary geographically across the United States, which may be related in
part to atmospheric water vapor pressure and other environmental factors.19,20
Symptoms can include an increase in respiratory symptoms such as cough,
sputum production, and hemoptysis. A decrease in FEV1 can occur. Systemic
symptoms such as fever, night sweats, or weight loss may be present. Imag-
ing findings can include the development of nodules; tree-in-bud opacities;
segmental consolidation; and, at times, cavitary lesions.21 Unlike MAC and
M abscessus species, M kansasii is a rare pathogen in children and adoles-
cents and is seen more frequently in older men; however, it can occur in
individuals with underlying lung disease. M kansasii infection most closely
mimics tuberculosis (TB). Hot tub lung, a rare, diffuse pulmonary disease
that occurs after exposure to aerosolized MAC droplets, occurs typically
with poorly drained indoor hot tubs and manifests as a hypersensitivity-like
pneumonitis with fever, dyspnea, and cough.22

456
Localized lymphadenitis is the most common manifestation of NTM infection
in children, particularly those in the preschool age range. The most commonly
affected nodes are in the cervicofacial region, most often unilateral. The pre-
sentation is typically subacute, occurring over the course of weeks, and the
child often appears well without systemic symptoms. A positive NTM culture,
histopathological test result, or polymerase chain reaction result from a tissue
specimen of the affected node can establish the diagnosis.23 M avium complex
is the most common group of NTM identified in lymphadenitis.
Isolated thoracic node or endobronchial disease likely has a pathogenesis
similar to that of cervical node disease and most commonly results from
MAC. Manifestation typically occurs within the first few years of life, often
with persistent wheeze or stridor unresponsive to bronchodilator therapy.
Similar to findings in patients with NTM lymphadenitis, systemic findings
such as fever are reported but are not always present, and children with these
findings often appear well. Given that cross-reactivity between MAC and
TB may occur, findings may also be identified incidentally on chest images
obtained as evaluation for a positive purified protein derivative test result. The
diagnosis is typically determined after chest computed tomography or bron-
choscopy is performed for the persistent pulmonary findings. Results from
biopsy of the node or endobronchial lesion show granulomatous inflammation,
and acid-fast bacteria may be seen on smears and grow in culture.24
Skin and soft-tissue infections can occur both in individuals who are healthy
and in those who are immunocompromised. These infections can be caused
by M abscessus species and other rapidly growing NTM species, as well as
Mycobacterium marinum and M ulcerans. Infections can be superficial, but
abscess formation can occur, especially with the rapidly growing species.
Nontuberculous mycobacteria should be suspected in infections that fail
to respond to typical antibiotic treatment regimens.25
Disseminated NTM may manifest with pulmonary disease (typically consoli-
dation or miliary nodular involvement) and extrapulmonary disease and is
associated with immunodeficiency. Individuals typically present with fever,
night sweats, and weight loss. Lymphadenopathy and hepatosplenomegaly
may be present at physical examination, and HIV should be excluded in
individuals with disseminated NTM.26 Inherited and acquired immunodefi-
ciency or disorders of the IFN-γ/IL-12 pathway, such as defects of the IFN-γ
receptor, defects of IL-12 or IL-12 receptor, GATA2 deficiency, and defects of
nuclear factor-κB essential modulator operon, may also cause patients to be
susceptible to NTM infections, including disseminated disease.5,27

457
Diagnosis
Pulmonary Disease
Pulmonary NTM in children and adolescents occurs most frequently in the
setting of underlying bronchiectasis from CF, primary ciliary dyskinesia,
or other underlying diseases. Nontuberculous mycobacteria should be consid-
ered in the setting of a pulmonary exacerbation unresponsive to treatment
of typical pathogens or with unexpected clinical decline.28,29 A high index of
suspicion for mycobacteria is necessary because symptoms may not differ
much from those of pulmonary exacerbation from other pathogens. Routine
screening for NTM infection is also an important aspect of diagnosis. The
Cystic Fibrosis Foundation and European Cystic Fibrosis Society have pub-
lished guidelines on managing NTM in CF and recommend surveillance
mycobacterial cultures be performed annually in patients who can expectorate
spontaneously and have a stable clinical course.30 In the absence of clinical
features that suggest NTM pulmonary disease, patients who do not produce
sputum do not require routine screening. Cultures should be obtained from
sputum and not from oropharyngeal swabs.30 Because of these practices,
many NTM infections are initially detected as part of routine screening, in
the absence of clinical features. In patients who have clinical symptoms
suggestive of NTM, additional cultures from spontaneously expectorated
or induced sputum should be obtained. The usefulness of gastric aspirates in
children unable to produce sputum for diagnosing NTM pulmonary infection
is not well delineated, and diagnosis by means of bronchoscopy with bronchial
wash, bronchoalveolar lavage, or biopsy should be strongly considered in
patients who have symptoms but cannot expectorate.
The diagnosis of NTM pulmonary disease requires a combination of clinical,
radiographic, and microbiological evidence of disease. The American Tho-
racic Society, European Respiratory Society, European Society of Clinical
Microbiology and Infectious Disease, and Infectious Diseases Society of
America have compiled specific criteria for diagnosing NTM pulmonary
disease (Box 24-1).7 The Cystic Fibrosis Foundation and European Cystic
Fibrosis Society guidelines also support the use of these criteria for diagnosis
in patients with CF.30 Although these guidelines have been developed for
adults, they likely can be applied to children and adolescents who are capable
of sputum production. Consultation with a pulmonologist or infectious
diseases physician with experience in diagnosing NTM disease is advisable.
Evaluating pulmonary disease should include clinical assessment; examination
of the chest by means of radiography (Figure 24-1) or computed tomography
(Figure 24-2); obtaining at least 3 sputum samples for culture of acid-fast

458
Box 24‑1
Criteria for Diagnosis of Nontuberculous Mycobacteria Pulmonary Disease
Clinical and Radiographic Criteria
ū Pulmonary or systemic symptoms, AND
ū Compatible chest imaging results, including nodular or cavitary opacities on
chest radiographs or bronchiectasis with multiple small nodules on chest
computed tomography scans, AND
ū Exclusion of other diagnoses
Microbiological Criteria
ū Positive culture from at least 2 sputum samples, OR
ū Positive culture from at least 1 bronchial wash or bronchoalveolar lavage, OR
ū Transbronchial or other lung biopsy results with mycobacterial histo-
pathological features (granulomatous inflammation or acid-fast bacilli)
and positive culture for nontuberculous mycobacteria from biopsy,
sputum, or bronchial washing
Adapted from Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis,
treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med.
2007;175:367–416. © American Thoracic Society
Figure 24-1. Mycobacterium abscessus species in a patient with

cystic fibrosis. Frontal chest radiograph shows the lungs are
hyperinflated, and there is extensive peribronchial thickening.
Scattered lucencies due to bronchiectasis and nodular foci due
to mucous plugging are seen throughout the lungs.
From Stillwell PC, Martiniano S. Nontuberculous mycobacterial
pulmonary disease. In: Stokes DC, Dozor AJ, eds. Pediatric
Pulmonology, Asthma, and Sleep Medicine: A Quick Reference Guide.
American Academy of Pediatrics; 2018:415–419.

459
Figure 24-2. Mycobacterium

abscessus species infection in a
patient with cystic fibrosis.
Computed tomography axial scan
reveals scattered nodules due to
mucous plugging (arrow),
bronchiectasis, cavity formation,
and tree-in-bud opacities
(arrowhead).
From Stillwell PC, Martiniano S.
Nontuberculous mycobacterial
pulmonary disease. In: Stokes DC,
Dozor AJ, eds. Pediatric Pulmonology,
Asthma, and Sleep Medicine: A Quick
Reference Guide. American Academy
of Pediatrics; 2018:415–419.
bacilli; and exclusion of other entities, such as TB. Microbiological criteria

require positive cultures from 2 or more sputum samples; a positive culture
from bronchoalveolar lavage or bronchial wash; or a lung biopsy with myco-
bacterial histological features, which include granulomatous inflammation or
acid-fast bacilli; and at least 1 positive NTM culture from a respiratory source.
In individuals with CF and other causes of underlying bronchiectasis, the
diagnosis can be confounded by overlap of similar clinical symptoms and
radiographic features related to coinfection with other bacterial isolates
(eg, P aeruginosa or Staphylococcus aureus) or because of comorbidities
(eg, CF-related diabetes or allergic bronchopulmonary aspergillosis).31 Aggres-
sive treatment of other coinfections isolated in CF may help determine the
clinical significance of NTM. If the patient continues to have symptoms of
a pulmonary exacerbation despite aggressive treatment, NTM pulmonary
disease should be considered and appropriate cultures obtained. Because the
presentation is largely subacute or chronic, there is typically time to collect
this information before initiating therapy to ensure evidence of NTM pulmo-
nary disease exists. On average, 40% of patients with CF who are infected
with NTM ultimately have NTM pulmonary disease diagnosed.31
A diagnosis of nodal or endobronchial NTM disease is typically established
through positive culture of a biopsy or needle aspirate specimen in the con-
text of a compatible clinical presentation. Results from biopsy of the node or
endobronchial lesion show granulomatous inflammation, and acid-fast bacteria
may be seen on smears and grow in culture.24 For extrapulmonary or dissemi-
nated disease, a single positive biopsy or blood culture result is sufficient to
establish the diagnosis and initiate treatment.

460
Management
Proper identification of the NTM infection to the species level is critical
for antibiotic selection. In addition, identification to the subspecies level for
M abscessus species can provide additional clinical and epidemiological infor-
mation to help guide treatment.7 For example, culture conversion to negative is
less likely to occur in patients infected with M abscessus subspecies abscessus
than in those with M abscessus subspecies massiliense, likely related to the
presence of a functional erm(41) gene in subspecies abscessus, which results
in inducible macrolide resistance.32 Thus, patients infected with subspecies
abscessus (or subspecies bolletii) typically require additional antibiotics in their
regimen. Consensus guidelines recommend susceptibility-based treatment for
macrolides and amikacin over empiric therapy for MAC and M abscessus
species pulmonary disease.7 Beyond macrolides and amikacin, there is little
correlation between results from in vitro susceptibility tests and clinical
response for other antibiotics in the treatment of NTM.33–35
Treating pulmonary NTM disease requires combination antibiotic drug
regimens to prevent resistance (Table 24-1). The choice of antibiotics requires
knowledge of species-specific regimens, as well as the antibiotic history of the
specific patient. In addition, drug–drug interactions and adverse events need
to be considered on an individual basis. Given the complexity of these regi-
mens, consultation with a pulmonologist or infectious disease specialist who is
experienced in managing NTM infections is advisable. Lung resection surgery
can be a beneficial adjunctive treatment in selected patients with localized or
refractory disease.7,36 The decision to proceed with lung resection should be
weighed against risks and should be performed by a surgeon experienced in
mycobacterial surgery.7,37 Notably, lung resection is generally not performed in
patients with CF or in pediatric populations.30 The decision to treat and timing
of treatment require a careful assessment of the morbidity of the illness and
the patient’s ability to commit to a prolonged, combination antimicrobial
course. Because individuals with parenchymal NTM disease often have
comorbidities (eg, bronchiectasis, concomitant pulmonary pathogens), objective
data that can be tracked to assist in treatment response are necessary. Inflam-
matory markers, pulmonary function tests, semiquantitative sputum acid-fast
bacilli smears and cultures, and imaging studies may help assess response to
therapy. In addition, airway clearance measures, such as use of chest percus-
sion or postural drainage, a percussion vest, handheld oscillatory or positive
expiratory pressure devices, and inhaled hypertonic saline treatments, should
be initiated or continued to augment medical treatment.
Consensus guidelines recommend that the treatment regimen for macrolide-
susceptible pulmonary MAC infection is a 3-drug oral regimen that includes
a macrolide (azithromycin preferred over clarithromycin).7 Typical regimens

461
Table 24-1. Example Treatment Regimens of Typical Nontuberculous Mycobacteria

Infection (With Consultation of an Expert)
Organism Example Antimicrobial Regimens
Mycobacterium avium • Oral azithromycin or clarithromycin, rifampin, and ethambutol
complex • For macrolide-resistant, cavitary, or severe disease, addition of an
IV aminoglycoside course
Mycobacterium Initial phase (3 or more drugs) Continuation phase (2 or more)
abscessus group, • IV amikacin • Inhaled amikacin
macrolide susceptible • IV imipenem or cefoxitin • Oral azithromycin
• Oral azithromycin • Oral clofazimine or linezolid
Mycobacterium Initial phase (4 or more drugs) Continuation phase (2 or more)
abscessus group, • IV amikacin • Inhaled amikacin
mutational or • IV imipenem or cefoxitin • Oral clofazimine
inducible macrolide • Oral clofazimine • Oral linezolid
resistant • Oral linezolid
Mycobacterium kansasii • Oral rifampin, isoniazid or macrolide, and ethambutol
Abbreviation: IV, intravenous.
include a macrolide plus ethambutol and rifampin. In the setting of macrolide

resistance or cavitary, advanced, or severe disease, addition of an intravenous
(IV) aminoglycoside (amikacin or streptomycin) may be included in the initial
regimen.7 Drug–drug interactions need to be assessed in all patients. Interac-
tions occur most commonly with rifamycins, in particular in patients with
CF who are prescribed medications containing ivacaftor. Amikacin liposome
inhalation suspension is a treatment of refractory MAC approved by the US
Food and Drug Administration for use in adults. Clofazimine is also an option
to be used in combination therapy for initial or refractory MAC.38 Fluoro-
quinolones have previously been included as a treatment option; however,
when combined with a macrolide, there may be an increased incidence of
macrolide resistance than is seen with the combination of macrolides with
ethambutol and a rifamycin.33 The first treatment course has the best chance of
response; therefore, multidrug therapy is very important. In adults with
macrolide-susceptible, noncavitary, nodular or bronchiectatic MAC pulmo-
nary disease, treatment may be condensed into thrice-weekly dosages.7
However, little is known of the efficacy of these regimens for children, and
daily treatment regimens are required for patients with CF.30
M kansasii responds well to rifamycin-containing regimens, with a typical
regimen (similar to that used for TB) consisting of rifampin, ethambutol, and
isoniazid or a macrolide. In patients with rifampicin-resistant M kansasii or
intolerance to first-line antibiotics, a fluoroquinolone (eg, moxifloxacin) can
be used.7 Three-times weekly regimens can be used for rifampicin-sensitive,

462
noncavitary M kansasii treated with rifampin, ethambutol, and a macrolide.

Isoniazid-containing regimens should be administered daily.7 For all regi-
mens, toxicities need to be reviewed, and a strict monitoring plan is required
(Table 24-2). For MAC and M kansasii, optimal length of therapy is not well
defined, but a typical regimen is 12 months of therapy beyond the date of
conversion to a negative sputum culture.7,39
Treatment of M abscessus species requires an initial phase of treatment
including IV antibiotics followed by a continuation phase with a combina-
tion of oral and/or inhaled agents.7,39 Because of the usual severity of infection
and potential for drug resistance, treatment of M abscessus species requires
multidrug therapy, typically 3 or more active drugs, guided by in vitro sus-
ceptibility.7 Specific drug selection and duration of treatment should follow
published guidelines7 and be managed by an expert in treating patients with
M abscessus species pulmonary disease. M abscessus strains develop macro-
lide resistance through chromosomal mutations in the 23S ribosomal RNA
(rrl) gene, as well as through the presence of a functional erm(41) gene that
causes inducible macrolide resistance.7 In M abscessus species strains without
inducible or mutational resistance, the most reliably effective antimicrobial
is a macrolide (azithromycin and clarithromycin), which should be included
in the treatment regimen. In strains with resistance, macrolides may be inclu-
ded for immunomodulatory purposes but should not be counted as an active
drug in the treatment regimen.7 Other antibiotics that generally have activity
against M abscessus species and can be used in a multidrug treatment regi-
men include parenteral agents such as amikacin, imipenem, tigecycline, and
cefoxitin; oral clofazimine or linezolid; and inhaled amikacin.7 Newer tetra-
cyclines, including omadacycline (IV or oral),40 may have a role in clinical
management in the future. The role of bedaquiline, an agent developed for the
treatment of multidrug-resistant TB, is still unknown for the treatment of NTM
disease.41
Published dosage guidelines for NTM antibiotics are available.7 An optimal
NTM drug dosage in children is not well described, and consultation with
an expert is advisable. Therapeutic drug monitoring is indicated when using IV
amikacin to reduce toxicities and may be helpful for other antibiotics
in patients with refractory disease or in patients with medical conditions
(eg, reduced renal function or CF) that are suspected to lead to subtherapeutic
or toxic drug concentrations.7,42 The antibiotics used to treat M abscessus
species are frequently associated with adverse reactions and toxicities; there-
fore, education of patients and a close monitoring plan should be established
at the beginning of treatment (Table 24-2).7

463
Table 24–2. Antimicrobial Toxicities and Monitoring

Monitoring, in Addition
Drug Major Adverse Effects to Clinical Symptoms
Amikacin Vestibular toxicity or ototoxicity, Audiograms, periodic renal
nephrotoxicity function tests, drug levels
Amikacin liposome Dysphoria, vestibular toxicity Audiograms, periodic renal
inhalation or ototoxicity, nephrotoxicity, function tests, drug levels
suspension cough, dyspnea
Azithromycin, Gastrointestinal disturbance, Periodic liver function tests,
clarithromycin hepatotoxicity, decreased audiograms,
hearing, QT interval electrocardiograms
prolongation
Cefoxitin Drug hypersensitivity, Periodic complete blood cell
cytopenias counts
Clofazimine Discoloration of skin and body Periodic liver function tests,
secretions, hepatotoxicity, electrocardiograms
QT interval prolongation
Ethambutol Optic neuritis (loss of red–green Visual acuity and color
discrimination and acuity), discrimination
peripheral neuropathy
Imipenem Hypersensitivity (rash), Periodic complete blood cell
cytopenias, nephrotoxicity counts, renal function tests
Isoniazid Hepatitis, peripheral neuropathy Periodic liver function tests
Linezolid Cytopenias, peripheral Periodic complete blood cell
neuropathy, optic neuritis counts, visual acuity and color
discrimination
Moxifloxacin Tendinitis, hepatotoxicity, Electrocardiograms, periodic liver
QT interval prolongation function tests
Rifampin Orange discoloration of body Periodic complete blood cell
secretions, hypersensitivity, counts, liver function tests
hepatotoxicity, cytopenias,
drug–drug interactions
Tigecycline Tooth staining < 8 years old, Periodic liver function tests,
gastrointestinal disturbance, amylase and lipase levels
hepatitis or pancreatitis
Other pulmonary manifestations of NTM infection, such as hot tub lung,

can be treated by removal of the source of exposure and administration of
steroids. Antibiotic treatment is rarely necessary. Lymphadenitis does not
always require treatment; in mild cases, observation for spontaneous resolu-
tion may be appropriate. If treatment is required, complete surgical excision

464
of the affected node is considered the definitive therapy, with or without anti-
biotics directed at the primary pathogen. Appropriate antibiotic therapy, with
or without surgical excision, is also used in the treatment of endobronchial
NTM infections.24 Skin and soft-tissue infections also typically require
treatment with multidrug antibiotic regimens.25 Treatment of NTM infec-
tions associated with defects in the IFN-γ/IL-12 axis, typically disseminated
disease, may include immunomodulatory therapy. If response to INF-γ is
predicted by the defect, or documented in vitro, this therapy may augment
antimicrobial therapy. Consultation with an immunologist or infectious disease
expert is advisable.
References
1. Parte AC. LPSN—list of prokaryotic names with standing in nomenclature (bacterio.net),
20 years on. Int J Syst Evol Microbiol. 2018;68(6):1825–1829 PMID: 29724269
doi: 10.1099/ijsem.0.002786
2. Feazel LM, Baumgartner LK, Peterson KL, Frank DN, Harris JK, Pace NR. Opportunistic
pathogens enriched in showerhead biofilms. Proc Natl Acad Sci USA. 2009;106(38):16393–16399
PMID: 19805310 doi: 10.1073/pnas.0908446106
3. Bryant JM, Grogono DM, Greaves D, et al. Whole-genome sequencing to identify transmission
of Mycobacterium abscessus between patients with cystic fibrosis: a retrospective cohort study.
Lancet. 2013;381(9877):1551–1560 PMID: 23541540 doi: 10.1016/S0140-6736(13)60632-7
4. Aitken ML, Limaye A, Pottinger P, et al. Respiratory outbreak of Mycobacterium abscessus
subspecies massiliense in a lung transplant and cystic fibrosis center [letter]. Am J Respir
Crit Care Med. 2012;185(2):231–232 PMID: 22246710 doi: 10.1164/ajrccm.185.2.231
5. Freeman AF, Holland SM. Persistent bacterial infections and primary immune disorders.
Curr Opin Microbiol. 2007;10(1):70–75 PMID: 17208513 doi: 10.1016/j.mib.2006.11.005
6. Whittier S, Olivier K, Gilligan P, Knowles M, Della-Latta P. Proficiency testing of clinical
microbiology laboratories using modified decontamination procedures for detection of
nontuberculous mycobacteria in sputum samples from cystic fibrosis patients. The
Nontuberculous Mycobacteria in Cystic Fibrosis Study Group. J Clin Microbiol.
1997;35(10):2706–2708 PMID: 9316943 doi: 10.1128/jcm.35.10.2706-2708.1997
7. Daley CL, Iaccarino JM, Lange C, et al. Treatment of nontuberculous mycobacterial pulmonary
disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline. Clin Infect Dis.
2020;71(4):905–913 PMID: 32797222 doi: 10.1093/cid/ciaa1125
8. Saleeb PG, Drake SK, Murray PR, Zelazny AM. Identification of mycobacteria in solid-culture
media by matrix-assisted laser desorption ionization–time of flight mass spectrometry. J Clin
Microbiol. 2011;49(5):1790–1794 PMID: 21411597 doi: 10.1128/JCM.02135-10
9. van Eck K, Faro D, Wattenberg M, de Jong A, Kuipers S, van Ingen J. Matrix-assisted laser
desorption ionization–time of flight mass spectrometry fails to identify nontuberculous
mycobacteria from primary cultures of respiratory samples. J Clin Microbiol.
2016;54(7):1915–1917 PMID: 27147723 doi: 10.1128/JCM.00304-16
10. Alcaide F, Amlerová J, Bou G, et al. How to: identify non-tuberculous Mycobacterium species
using MALDI-TOF mass spectrometry. Clin Microbiol Infect. 2018;24(6):599–603
PMID: 29174730 doi: 10.1016/j.cmi.2017.11.012
11. Prevots DR, Marras TK. Epidemiology of human pulmonary infection with nontuberculous
mycobacteria: a review. Clin Chest Med. 2015;36(1):13–34 PMID: 25676516
doi: 10.1016/j.ccm.2014.10.002
12. Olivier KN, Weber DJ, Wallace RJ Jr, et al. Nontuberculous mycobacteria. I: multicenter
prevalence study in cystic fibrosis. Am J Respir Crit Care Med. 2003;167(6):828–834
PMID: 12433668 doi: 10.1164/rccm.200207-678OC
13. 2020 Annual Data Report. Cystic Fibrosis Foundation Patient Registry; 2021.
https://www.cff.org/sites/default/files/2021-11/Patient-Registry-Annual-Data-Report.pdf
14. Noone PG, Leigh MW, Sannuti A, et al. Primary ciliary dyskinesia diagnostic and phenotypic
features. Am J Respir Crit Care Med. 2004;169(4):459–467 PMID: 14656747
doi: 10.1164/rccm.200303-365OC

465
15. Melia E, Freeman AF, Shea YR, Hsu AP, Holland SM, Olivier KN. Pulmonary nontuberculous
mycobacterial infections in hyper-IgE syndrome [letter]. J Allergy Clin Immunol.
2009;124(3):617–618 doi: 10.1016/j.jaci.2009.07.007
16. Bar-On O, Mussaffi H, Mei-Zahav M, et al. Increasing nontuberculous mycobacteria infection in
cystic fibrosis. J Cyst Fibros. 2015;14(1):53–62 PMID: 24917112 doi: 10.1016/j.jcf.2014.05.008
17. Adjemian J, Olivier KN, Prevots DR. Epidemiology of pulmonary nontuberculous mycobacterial
sputum positivity in patients with cystic fibrosis in the United States, 2010–2014. Ann Am Thorac
Soc. 2018;15(7):817–826 PMID: 29897781 doi: 10.1513/AnnalsATS.201709-727OC
18. Prevots DR, Shaw PA, Strickland D, et al. Nontuberculous mycobacterial lung disease
prevalence at four integrated health care delivery systems. Am J Respir Crit Care Med.
2010;182(7):970–976 PMID: 20538958 doi: 10.1164/rccm.201002-0310OC
19. Adjemian J, Olivier KN, Prevots DR. Nontuberculous mycobacteria among patients with
cystic fibrosis in the United States: screening practices and environmental risk. Am J Respir
Crit Care Med. 2014;190(5):581–586 PMID: 25068291 doi: 10.1164/rccm.201405-0884OC
20. Donohue MJ. Epidemiological risk factors and the geographical distribution of eight
Mycobacterium species. BMC Infect Dis. 2021;21(1):258 PMID: 33706712
doi: 10.1186/s12879-021-05925-y
21. Olivier KN, Weber DJ, Lee JH, et al. Nontuberculous mycobacteria. II: nested-cohort study of
impact on cystic fibrosis lung disease. Am J Respir Crit Care Med. 2003;167(6):835–840
PMID: 12433669 doi: 10.1164/rccm.200207-679OC
22. Marras TK, Wallace RJ Jr, Koth LL, Stulbarg MS, Cowl CT, Daley CL. Hypersensitivity
pneumonitis reaction to Mycobacterium avium in household water. Chest. 2005;127(2):664–671
PMID: 15706013 doi: 10.1378/chest.127.2.664
23. Willemse SH, Oomens MAEM, De Lange J, Karssemakers LHE. Diagnosing nontuberculous
mycobacterial cervicofacial lymphadenitis in children: a systematic review. Int J Pediatr
Otorhinolaryngol. 2018;112:48–54 PMID: 30055739 doi: 10.1016/j.ijporl.2018.06.034
24. Freeman AF, Olivier KN, Rubio TT, et al. Intrathoracic nontuberculous mycobacterial infections
in otherwise healthy children. Pediatr Pulmonol. 2009;44(11):1051–1056 PMID: 19824053
doi: 10.1002/ppul.21069
25. Gonzalez-Santiago TM, Drage LA. Nontuberculous mycobacteria: skin and soft tissue
infections. Dermatol Clin. 2015;33(3):563–577 PMID: 26143432 doi: 10.1016/j.det.2015.03.017
26. Jones D, Havlir DV. Nontuberculous mycobacteria in the HIV infected patient. Clin Chest Med.
2002;23(3):665–674 PMID: 12371002 doi: 10.1016/S0272-5231(02)00015-1
27. Spinner MA, Sanchez LA, Hsu AP, et al. GATA2 deficiency: a protean disorder of
hematopoiesis, lymphatics, and immunity. Blood. 2014;123(6):809–821 PMID: 24227816
doi: 10.1182/blood-2013-07-515528
28. Martiniano SL, Nick JA, Daley CL. Nontuberculous mycobacterial infections in cystic fibrosis.
Clin Chest Med. 2016;37(1):83–96 PMID: 26857770 doi: 10.1016/j.ccm.2015.11.001
29. Richards CJ, Olivier KN. Nontuberculous mycobacteria in cystic fibrosis. Semin Respir Crit
Care Med. 2019;40(6):737–750 PMID: 31659731 doi: 10.1055/s-0039-1693706
30. Floto RA, Olivier KN, Saiman L, et al. US Cystic Fibrosis Foundation and European Cystic
Fibrosis Society consensus recommendations for the management of non-tuberculous
mycobacteria in individuals with cystic fibrosis: executive summary. Thorax. 2016;71(1):88–90
PMID: 26678435 doi: 10.1136/thoraxjnl-2015-207983
31. Martiniano SL, Nick JA, Daley CL. Nontuberculous mycobacterial infections in cystic fibrosis.
Thorac Surg Clin. 2019;29(1):95–108 PMID: 30454926 doi: 10.1016/j.thorsurg.2018.09.008
32. Koh WJ, Jeon K, Lee NY, et al. Clinical significance of differentiation of Mycobacterium
massiliense from Mycobacterium abscessus. Am J Respir Crit Care Med. 2011;183(3):405–410
PMID: 20833823 doi: 10.1164/rccm.201003-0395OC
33. Griffith DE, Brown-Elliott BA, Langsjoen B, et al. Clinical and molecular analysis of macrolide
resistance in Mycobacterium avium complex lung disease. Am J Respir Crit Care Med.
2006;174(8):928–934 PMID: 16858014 doi: 10.1164/rccm.200603-450OC
34. Jeon K, Kwon OJ, Lee NY, et al. Antibiotic treatment of Mycobacterium abscessus lung disease:
a retrospective analysis of 65 patients. Am J Respir Crit Care Med. 2009;180(9):896–902
PMID: 19661243 doi: 10.1164/rccm.200905-0704OC
35. Kobashi Y, Yoshida K, Miyashita N, Niki Y, Oka M. Relationship between clinical efficacy of
treatment of pulmonary Mycobacterium avium complex disease and drug-sensitivity testing
of Mycobacterium avium complex isolates. J Infect Chemother. 2006;12(4):195–202
PMID: 16944258 doi: 10.1007/s10156-006-0457-8

466
36. Yu JA, Weyant MJ, Mitchell JD. Surgical treatment of atypical mycobacterial infections.
Thorac Surg Clin. 2012;22(3):277–285 PMID: 22789593 doi: 10.1016/j.thorsurg.2012.05.004
37. Mitchell JD, Bishop A, Cafaro A, Weyant MJ, Pomerantz M. Anatomic lung resection
for nontuberculous mycobacterial disease. Ann Thorac Surg. 2008;85(6):1887–1893
38. Martiniano SL, Wagner BD, Levin A, Nick JA, Sagel SD, Daley CL. Safety and effectiveness
of clofazimine for primary and refractory nontuberculous mycobacterial infection. Chest.
2017;152(4):800–809 PMID: 28483608 doi: 10.1016/j.chest.2017.04.175
39. Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis,
treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med.
2007;175(4):367–416 PMID: 17277290 doi: 10.1164/rccm.200604-571ST
40. Bax HI, de Vogel CP, Mouton JW, de Steenwinkel JEM. Omadacycline as a promising new agent
for the treatment of infections with Mycobacterium abscessus. J Antimicrob Chemother.
2019;74(10):2930–2933 PMID: 31236595 doi: 10.1093/jac/dkz267
41. Kim DH, Jhun BW, Moon SM, et al. In vitro activity of bedaquiline and delamanid against
nontuberculous mycobacteria, including macrolide-resistant clinical isolates. Antimicrob Agents
Chemother. 2019;63(8): e00665-19 PMID: 31182533 doi: 10.1128/AAC.00665-19
42. Martiniano SL, Wagner BD, Brennan L, et al. Pharmacokinetics of oral antimycobacterials and
dosing guidance for Mycobacterium avium complex treatment in cystic fibrosis. J Cyst Fibros.
2021;20(5):772–778 PMID: 34030986 doi: 10.1016/j.jcf.2021.04.011

PART
6
Noninfectious Pulmonary Disorders
Chapter 25. Atelectasis........................................................................469

Chapter 26. Respiratory Disorders Associated With Systemic

Inflammatory Diseases....................................................................... 481
Paul C. Stillwell, MD, FAAP, and Eric D. Zee, MD
Chapter 27. Interstitial Lung Disease...............................................505

Pallav Halani, MD, FAAP; Timothy J. Vece, MD; and Adrienne P. Savant, MD, MS
Chapter 28. Bronchopulmonary Dysplasia...................................... 521

Laurie C. Eldredge, MD, PhD, and Susanna A. McColley, MD, FAAP
Chapter 29. Pleural Effusion (Noninfectious).................................541

Chapter 30. Pneumothorax and Pneumomediastinum................. 553

Chapter 31. Pulmonary Hemorrhage................................................ 563

Evans M. Machogu, MBChB, MS, FAAP, and Karen Z. Voter, MD, FAAP
467
30 PP 2ND ED - PO 06_467-468.indd 467 11/6/23 8:44 AM

30 PP 2ND ED - PO 06_467-468.indd 468 9/12/23 9:54 AM
CHAPTER
25
Atelectasis
CASE REPORT 25-1

A 14-year-old boy with congenital muscular dystrophy and history of marked
weakness, chronic respiratory insufficiency, tracheostomy, and assisted ventila-
tion is brought to the emergency department with shortness of breath and low
pulse oximeter readings. He has not used the cough assist device prescribed in
the neuromuscular pulmonary clinic. Physical examination results are remark-
able for diminished air entry in the left lower zone posteriorly. Venous blood
gas has worsened since the last blood gas measurement, with evidence of
hypercarbia and hypoxia, and the chest radiograph showed left lower
lobe opacity with reduced intercostal spaces. Left lower lobe atelectasis
is diagnosed.
Introduction
Atelectasis refers to a loss of lung volume owing to collapse of part or all of
the lung. Usually the magnitude of the collapsed alveolar spaces is severe
enough to appear on a plain chest radiograph. Patients with conditions asso-
ciated with increased and more viscid secretions, such as cystic fibrosis (CF),
are more likely to develop atelectasis, which may result in transient hypox-
emia due to ventilation/perfusion mismatching. Secondary infection of the
atelectatic lung and bronchiectasis in the atelectatic portion of a chronically
infected lung may occur.
Epidemiology
Atelectasis is almost always a secondary phenomenon, occurring more
frequently in young children because their airways are small and thus prone
to blockage. In the newborn lung, the interalveolar holes (pores of Kohn) are
either absent or few in number, thereby preventing collateral communication.
Therefore, infants are more prone to developing atelectasis than are older chil-
dren or adults.1 The incidence of atelectasis varies according to the cause and
background conditions. The most common cause is asthma, but there are no
incidence data in children. Patients with CF tend to develop atelectasis (up to
469

470
5%).2 A much higher incidence is reported in patients postoperatively (up to

23%)3 and in patients with neuromuscular disorders (up to 85%).4 In children
with congenital heart disease, extrinsic compression of the airways owing to
enlarged heart chambers or dilated blood vessels can lead to atelectasis,
especially postoperatively. Patients in the intensive care unit after they have
undergone intubation and are using a ventilator have a tendency to develop
atelectasis because of secretions blocking the airways and inability to cough.
Shallow breathing, associated with sedation, anesthesia, mode of ventilation
such as oscillatory ventilation, and extracorporeal membrane oxygenation,
may lead to the development of atelectasis. Medications such as anticholiner-
gics may increase the viscosity of the airway secretions, impairing the
mucociliary clearance. The current emphasis on airway clearance in
children with conditions such as primary ciliary dyskinesia,5 neuromuscular
disorders,6,7 and CF,8 and in patients postoperatively after various surgeries,9
should result in a lower incidence of atelectasis (see Chapter 55, Airway
Clearance Techniques). Airway obstruction due to plastic bronchitis in
patients who have undergone a Fontan procedure may cause clinically
significant airway obstruction, atelectasis, and increased need for assisted
ventilation.10
Etiology
Atelectasis can result from either obstructive or nonobstructive causes
(Box 25‑1).
Obstructive Atelectasis
Obstructive atelectasis involves a loss of communication between alveoli and
the trachea, resulting in reabsorption of the gas from the alveoli. There is lack
of ventilation in the area distal to the obstruction. The pores of Kohn, which
normally provide collateral communication between the adjacent alveoli, are
absent in young infants11 and may not form for the first 3 to 4 years.12 The air
from the airways, distal to the obstruction, is absorbed by the circulating
blood, leading to collapse of the corresponding alveoli. In the early stages,
blood perfusion in this area continues, resulting in ventilation/perfusion
mismatching and arterial hypoxemia.13 Because oxygen from the airways is
absorbed more rapidly than is the nitrogen in room air (within minutes versus
hours), atelectasis develops more rapidly during ventilation with a high
inspired oxygen fraction.12 The alveolar spaces may be filled with secretions,
thereby preventing complete collapse of the atelectatic lung. There may be
compensatory distention of the uninvolved surrounding lung tissue. When
there is a large area of atelectasis, there can be a shift of the heart and the
mediastinum toward the atelectasis, the diaphragm may be elevated, and the
chest wall may flatten. These findings can appear within a period of a few
hours if there is an extensive area of atelectasis, and removal of the obstruction

471
Chapter 25—Atelectasis
Box 25-1
Causes of Atelectasis
Intrinsic Obstruction of the Airways Incomplete Expansion of the
ū Asthma Alveoli and Collapse
ū Bronchiolitis ū Hypoventilation due to muscle
ū Aspiration weakness in neuromuscular
disorders
ū Endobronchial lesions (tuberculosis)
ū Postoperative period
ū Foreign body
ū Splinting of the chest wall because
ū Cystic fibrosis (viscid secretions) of painful lesions resulting in
Extrinsic Compression of the Airways hypoventilation
ū Enlarged lymph nodes ū Drug-induced hypoventilation
ū Tumors ū Cicatrization atelectasis due to
ū Enlarged heart or vasculature severe parenchymal scarring
Compression of Lung Tissue Lack of Surfactant
ū Decoupling of the inward recoil of ū Lack of production
the lung and outward recoil of the (prematurity, acute respiratory
chest wall because of the presence distress syndrome)
of air, blood, pus, or chyle in the ū Inactivation
pleural space (radiation pneumonitis,
ū Pneumothorax blunt trauma to the lung)
ū Hemothorax ū Surfactant washout
(drowning, pulmonary edema)
ū Pyothorax
ū Chylothorax
ū Compression due to causes other than
pleural space disease
ū Intrathoracic abdominal mass
ū Chest wall mass
ū Enlarged heart
ū Overdistended adjacent lung tissue
ū Space-occupying lesions of the lung
ū Skeletal deformities of the chest wall
leads to return to a normal state. In a protracted case of atelectasis, such as that

caused by the viscid secretions in patients with CF, chronic aspiration, or
undiagnosed foreign body, infection may occur. Persistent, untreated infection
can lead to bronchiectasis.
The site of obstruction dictates the extent and distribution of atelectasis;
for example, the obstruction of a lobar bronchus will cause lobar atelectasis.
Intrinsic obstruction of the airways is the most common cause of atelectasis in
children, and asthma is the most common predisposing disorder. Children with
airway inflammation caused by asthma may have thicker secretions, which, in
conjunction with airway narrowing, result in subsegmental or lobar atelectasis.

472
This situation poses a diagnostic dilemma when children with asthma present
with an exacerbation, an abnormal radiograph, and a possible diagnosis of
pneumonia. Some other common causes of obstruction are bronchiolitis
aspiration from any cause, including gastroesophageal reflux and oropharyn-
geal incompetence; foreign body aspiration; and airway obstruction due to
viscid secretions (eg, in CF).
Extrinsic compression of the airway from enlarged lymph nodes or an
enlarged heart compressing the left main or left lower lobe bronchus, as
well as airway wall thickening caused by edema and inflammation, may
be causative factors. The right middle lobe is particularly susceptible to
atelectasis; this is described as middle lobe syndrome or Brock syndrome.
The right middle lobe bronchus is surrounded by lymph nodes that drain
the right middle and lower lobes. The middle lobe syndrome was originally
described in association with tuberculosis; however, it may be seen with other
conditions such as CF and asthma. Patients having reduced lung expansion
and lung recruitment associated with muscle weakness, splinting of the chest
wall because of postoperative pain after thoracoabdominal surgery (Figure
25‑1), hypoventilation due to narcotic medications, and musculoskeletal
deformities are predisposed to developing atelectasis if there is poor airway
clearance and pooling of secretions in the airways.
Figure 25-1. Left lower lobe atelectasis with volume loss and shift of the mediastinum.

473
Nonobstructive Atelectasis
The loss of contact between the visceral and parietal pleura is the primary
cause of nonobstructive atelectasis. Normally, there is a balance between the
factors responsible for the inward recoil of the lung and the outward recoil of
the chest wall to reduce the potential for lung or alveolar collapse. In addition,
surfactant protein produced by type II alveolar epithelial cells lowers the sur-
face tension in the alveoli and prevents alveoli from collapsing. As alveolar
volume decreases with expiration, surface tension increases to the extent that,
without surfactant, the alveolus will collapse completely. Surfactant deficiency
can lead to adhesive atelectasis. Dependent atelectasis is almost always present
in patients receiving sedation for procedures such as computed tomography
(CT) scanning unless measures such as endotracheal intubation and ventilation
to maintain a large tidal volume are used. Atelectasis is also caused by com-
pression of lung tissue owing to pleural effusion (pneumothorax, hemothorax,
empyema, or chylothorax), space-occupying lesions of parenchyma, and
hyperinflated adjacent lung parenchyma. Cicatrization atelectasis is caused
by severe parenchymal scarring.
Clinical Features
Small areas of atelectasis often are detected only when a chest radiograph is
obtained for other reasons. Microatelectasis, common in patients with neuro-
muscular disorders, may not be visible on chest radiographs. With larger areas
of atelectasis, there may be tachypnea as the patient tries to compensate for
decreased tidal volume by increasing the frequency of respiration. A child
may grunt while attempting to create an auto-positive end-expiratory pres-
sure, and sudden hypoxia may develop as evidenced by a sudden or rapid
decrease in oxyhemoglobin saturation. Physical examination may not reveal
any additional findings in children with small areas of atelectasis. In
children with larger areas of involvement, such as lobar involvement or
complete lung collapse, breath sounds are diminished, there is increased
dullness on chest percussion, and a mediastinal shift may be present.
Diagnosis
Chest Radiography
Clinically unrecognized atelectasis may be revealed by a chest radiograph.
There may be a displacement of fissures and opacification of the collapsed
lobe. The site of obstruction will dictate the portion or area of the atelectasis,
which can be the entire lung or 1 or more lobes (Figure 25‑2). Other indirect
signs, such as hilar displacement, mediastinal shift toward the side of collapse,
loss of volume in the corresponding area or ipsilateral hemithorax, crowding
of the ribs, compensatory hyperinflation of the adjacent area, or obliteration
of the cardiac borders or diaphragm, may be visible on chest radiographs.

474
Examination of air bronchograms on chest radiographs may help determine

whether proximal or distal airways are obstructed.
Figure 25-2. Right upper lobe atelectasis with volume loss.
Lung Ultrasonography
Lung ultrasonography has good sensitivity, specificity, and accuracy to
diagnose postoperative atelectasis in children14; therefore, it has been
suggested for use in diagnosing atelectasis in children with neuromuscular
disorders.15 Lung ultrasonography was found to be more effective than
conventional therapies in preventing intraoperative atelectasis.16
Magnetic Resonance Imaging of the Lung

Magnetic resonance imaging of the lung is being tried in the diagnosis of
various pulmonary disorders17 and may be used to diagnose atelectasis.18 In
small children, for whom voluntary breath holding is not possible, sedation
or general anesthesia has been used for a satisfactory examination. However,
because of the risks associated with anesthesia, including dorsal atelectasis,

475
respiratory navigation (radiofrequency-tracking pulses to detect physical

motion) during magnetic resonance imaging is being used19 to obviate
the need for sedation or general anesthesia.20
Computed Tomography
Chest CT may help evaluate airway compression, detect underlying disease,
and reveal diffuse disease undetected with chest radiography. Because of
the inherent additional risk of a patient developing atelectasis during general
anesthesia, ultrafast chest CT using respiratory navigation during free breath-
ing21 is gaining wider acceptance at various centers in the United States. The
best way to avoid iatrogenic atelectasis caused by sedation is by performing
the examination with the child having undergone intubation and ventilation
with high tidal volumes.22
Management
Some measures may prevent the formation of atelectasis (Table 25‑1). These
include aggressive and regular chest physical therapy (CPT) and postural
drainage in patients with CF23 and primary ciliary dyskinesia.5 Patients with
neuromuscular disorders, such as Duchenne muscular dystrophy,6,7 may
benefit from breathing exercises and preventive airway clearance techniques.
Adequate pain management, early ambulation, and frequent position changes
postoperatively to prevent splinting of the chest may reduce the incidence of
atelectasis. Apart from some anecdotal reports, there is no evidence, such as
double-blinded placebo-controlled trials, to support the routine use of dornase
alfa hypertonic or normal saline, N-acetylcysteine, heparin, sodium bicarbon-
ate, or bronchoscopy in patients with atelectasis. See Figure 25‑3 for steps in
managing possible atelectasis.
Table 25-1. Preventive Measures to Reduce Atelectasis

Clinical Condition Preventive Measures
Cystic fibrosis, primary ciliary dyskinesia Chest physical therapy and postural drainage
Neuromuscular disorder Use of cough assist device
Postoperative period Chest physical therapy
Pain control
Early ambulation
Frequent position changes
Ultrasound-guided lung recruitment maneuver

476
Sudden, unexpected clinical worsening In patients with Cystic fibrosis

Hypoxia predisposing Ventilated patients
Focal findings conditions Neuromuscular disorder
Mediastinal shift Postoperative patients
Confirm diagnosis by
chest radiograph
Ensure airway clearance using

bronchodilators, chest physical therapy
If no response, use special agents and devices

eg, dornase alfa in cystic fibrosis
(nebulized or local instillation via bronchoscope)
cough-assist device in patients with neuromuscular disorders
If persistent, focal atelectasis suspected due to

mucus pug, consider referral for bronchoscopy
Figure 25-3. Management of suspected atelectasis.
Chest Physical Therapy

Although CPT has traditionally been the first-line therapy to prevent
atelectasis, evidence for its efficacy is lacking.24 In one study, postextubation
CPT in neonates did not prevent postextubation atelectasis.25
Aggressive airway clearance is the attempt to clear mucus and secretions
from the trachea and bronchial tree and includes nebulized or inhaled bron-
chodilators (β2-agonists such as albuterol) followed by CPT and postural
drainage. However, evidence is lacking to support using a bronchodilator
as a component of an airway clearance regimen.26 Chest physical therapy
may be provided by using hand percussion and postural drainage or by using
a mechanical method, the choice of which will depend on the underlying
disorder. For example, the cough assist device used in patients with neuro-
muscular disorders6 may not be appropriate for patients with CF who will
be better served by a high-frequency chest wall oscillation device.27 Other
positive expiratory oscillation devices, such as the FLUTTER mucus
clearance device (Axcan Scandipharm, Inc) or the acapella Vibratory
PEP Therapy System (Smiths Medical), may also be used for airway
clearance (see Chapter 55, Airway Clearance Techniques).

477
Intrapulmonary Percussive Ventilation

Intrapulmonary percussive ventilation is a form of CPT delivered by a per-
cussive pneumatic device that delivers high-flow jets of gas to the airways
by means of a pneumatic flow interrupter at a rate of 100 to 300 cycles per
minute. The duration of percussion is controlled by the patient or the therapist.
The driving pressure and peak airway pressure are adjustable. Intrapul-
monary percussive ventilation maintains lung volume in a state of partial
inspiration while the airways are internally percussed. It has been used
in patients with CF and neuromuscular disorders.28,29
Recombinant Human DNase

Dornase alfa is a recombinant human DNase that when nebulized or directly
instilled into the airways reduces the viscoelasticity of purulent secretions,
especially in patients with CF. The Cystic Fibrosis Foundation recommends
regular use of dornase alfa by children with CF, 6 years or older, with moder-
ate to severe lung disease.27 There have been reports of successful use of bron-
choscopically administered dornase alfa for the treatment of lobar atelectasis
in patients with CF,30 but prospective controlled trials are lacking (see Chapter
55, Airway Clearance Techniques). Evidence is lacking to support its use in
the neonatal or pediatric intensive care unit with non-CF causes of atelectasis
or other lung diseases.
Oximetry and Blood Gas Measurement

Atelectasis may be associated with a decrease in oxyhemoglobin saturation or
evidence of hypoxia on a blood gas profile.
When to Refer
For bronchoscopy:
X Bronchoscopy with therapeutic lavage should be considered when obstruc-
tion due to a mucous plug is considered to be causing atelectasis and there
is no response to noninvasive airway clearance.6
X Patients with CF with persistent lobar atelectasis may benefit from lavage
with local administration of recombinant human DNase.28
X Atelectasis caused by a foreign body requires bronchoscopy.
When to Admit
X Massive atelectasis
X Hypoxia
X Suspected foreign body

478
key points
} Extrinsic compression of the airways or lung tissue and intrinsic airway
obstruction are some of the common causes of atelectasis.
} Clinically unrecognized atelectasis may be diagnosed by using chest
radiography.
} Appropriate preventive measures to assist effective cough, airway secretion
mobilization, and drainage by means of CPT and postural drainage may help
prevent development of atelectasis.
} Atelectasis may be associated with a decrease in oxyhemoglobin saturation
or evidence of hypoxia on a blood gas profile.
References
1. Ochs M, O’Brodovich H. The structural and physiologic basis of respiratory disease.
In: Wilmott RW, Deterding R, Li A, Ratjen F, Sly P, Zar HJ, Bush A, eds. Kendig’s Disorders
of the Respiratory Tract in Children. 9th ed. Elsevier; 2019: 63–100
2. Stern RC, Boat TF, Orenstein DM, Wood RE, Matthews LW, Doershuk CF. Treatment and
prognosis of lobar and segmental atelectasis in cystic fibrosis. Am Rev Respir Dis.
1978;118(5):821–826 PMID: 736353
3. Hasegawa S, Mori K, Inomata Y, Murakawa M, Yamaoka Y, Tanaka K. Factors associated with
postoperative complications in pediatric liver transplantation from living-related donors.
Transplantation. 1996;62(7):943–947 PMID: 8878388 doi: 10.1097/00007890-199610150-00012
4. Schmidt-Nowara WW, Altman AR. Atelectasis and neuromuscular respiratory failure. Chest.
1984;85(6):792–795 PMID: 6723392 doi: 10.1378/chest.85.6.792
5. Sharma GD. Primary ciliary dyskinesia. Medscape. Updated October 17, 2017. Accessed
April 22, 2022. https://emedicine.medscape.com/article/1002319-overview
6. Finder JD, Birnkrant D, Carl J, et al; American Thoracic Society. Respiratory care of the patient
with Duchenne muscular dystrophy: ATS consensus statement. Am J Respir Crit Care Med.
2004;170(4):456–465 PMID: 15302625 doi: 10.1164/rccm.200307-885ST
7. Miske LJ, Hickey EM, Kolb SM, Weiner DJ, Panitch HB. Use of the mechanical in-exsufflator
in pediatric patients with neuromuscular disease and impaired cough. Chest.
2004;125(4):1406–1412 PMID: 15078753 doi: 10.1378/chest.125.4.1406
8. Flume PA, Robinson KA, O’Sullivan BP, et al; Clinical Practice Guidelines for Pulmonary
Therapies Committee. Cystic fibrosis pulmonary guidelines: airway clearance therapies.
Respir Care. 2009;54(4):522–537 PMID: 19327189
9. Birnkrant DJ, Panitch HB, Benditt JO, et al. American College of Chest Physicians consensus
statement on the respiratory and related management of patients with Duchenne muscular
dystrophy undergoing anesthesia or sedation. Chest. 2007;132(6):1977–1986 PMID: 18079231
doi: 10.1378/chest.07-0458
10. Harteveld LM, Blom NA, Hazekamp MG, Ten Harkel ADJ. Treatment and outcome of plastic
bronchitis in single ventricle patients: a systematic review. Interact Cardiovasc Thorac Surg.
2020;30(6):846–853 PMID: 32451550 doi: 10.1093/icvts/ivaa032
11. Macklem PT. Airway obstruction and collateral ventilation. Physiol Rev. 1971;51(2):368–436
PMID: 4928122 doi: 10.1152/physrev.1971.51.2.368
12. Carlsen KH, Crowley S, Smevik B. Atelectasis. In: Wilmott RW, Deterding R, Li A, Ratjen F,
Sly P, Zar HJ, Bush A, eds. Kendig’s Disorders of the Respiratory Tract in Children. 9th ed.
Elsevier; 2019: 1027–1033
13. West JB. Pulmonary Pathophysiology—The Essentials. Williams & Wilkins; 2008:165–167
14. Acosta CM, Maidana GA, Jacovitti D, et al. Accuracy of transthoracic lung ultrasound for
diagnosing anesthesia-induced atelectasis in children. Anesthesiology. 2014;120(6):1370–1379
PMID: 24662376 doi: 10.1097/ALN.0000000000000231
15. Ullmann N, D’Andrea ML, Gioachin A, et al. Lung ultrasound: a useful additional tool in
clinician’s hands to identify pulmonary atelectasis in children with neuromuscular disease.

479
16. Lee JH, Choi S, Ji SH, et al. Effect of an ultrasound-guided lung recruitment manoeuvre on
postoperative atelectasis in children: a randomised controlled trial. Eur J Anaesthesiol.
2020;37(8):719–727 PMID: 32068572 doi: 10.1097/EJA.0000000000001175
17. Hirsch FW, Sorge I, Vogel-Claussen J, et al. The current status and further prospects for lung
magnetic resonance imaging in pediatric radiology. Pediatr Radiol. 2020;50(5):734–749
PMID: 31996938 doi: 10.1007/s00247-019-04594-z
18. Fraioli F, Serra G, Ciarlo G, et al. Chest MR imaging in the follow-up of pulmonary alterations
in paediatric patients with middle lobe syndrome: comparison with chest X-ray. Radiol Med.
2013;118(3):444–455 PMID: 23090250 doi: 10.1007/s11547-012-0889-3
19. Liu YL, Riederer SJ, Rossman PJ, Grimm RC, Debbins JP, Ehman RL. A monitoring, feedback,
and triggering system for reproducible breath-hold MR imaging. Magn Reson Med.
1993;30(4):507–511 PMID: 8255201 doi: 10.1002/mrm.1910300416
20. Rosenzweig S, Scholand N, Holme HCM, Uecker M. Cardiac and respiratory self-gating in
radial MRI using an adapted singular spectrum analysis (SSA-FARY). IEEE Trans Med Imaging.
2020;39(10):3029–3041 PMID: 32275585 doi: 10.1109/TMI.2020.2985994
21. Kino A, Zucker EJ, Honkanen A, et al. Ultrafast pediatric chest computed tomography:
comparison of free-breathing vs. breath-hold imaging with and without anesthesia in young
children. Pediatr Radiol. 2019;49(3):301–307 PMID: 30413857 doi: 10.1007/s00247-018-4295-5
22. Brody AS, Guillerman RP. Ten rules for ordering chest CTs. Pediatr Pulmonol.
2021;56(7):1868–1871 PMID: 33852774 doi: 10.1002/ppul.25399
23. Pryor JA, Main E, Agent P, Bradley JM. Physiotherapy. In: Cystic fibrosis in the 21st century.
Bush A, Alton EWFW, Davies JC, Griesenbach U, Jaffe A, eds. Progress in Respiratory
Research. Vol 34. Karger; 2006: 301–308
24. Al-Alaiyan S, Dyer D, Khan B. Chest physiotherapy and post-extubation atelectasis
in infants. Pediatr Pulmonol. 1996;21(4):227–230 PMID: 9121851
doi: 10.1002/(SICI)1099-0496(199604)21:4<227::AID-PPUL4>3.0.CO;2-L
25. Sharma GD. Cystic fibrosis. Medscape. Updated September 28, 2020. Accessed
April 22, 2022. https://emedicine.medscape.com/article/1001602-overview
26. Schindler MB. Treatment of atelectasis: where is the evidence? Crit Care. 2005;9(4):341–342.
PMID: 16137380 doi: 10.1186/cc3766
27. Flume PA, O’Sullivan BP, Robinson KA, et al; Cystic Fibrosis Foundation, Pulmonary
Therapies Committee. Cystic fibrosis pulmonary guidelines: chronic medications for
maintenance of lung health. Am J Respir Crit Care Med. 2007;176(10):957–969
PMID: 17761616 doi: 10.1164/rccm.200705-664OC
28. Birnkrant DJ, Pope JF, Lewarski J, Stegmaier J, Besunder JB. Persistent pulmonary
consolidation treated with intrapulmonary percussive ventilation: a preliminary report.
doi: 10.1002/(SICI)1099-0496(199604)21:4<246::AID-PPUL8>3.0.CO;2-M
29. Yen Ha TK, Bui TD, Tran AT, Badin P, Toussaint M, Nguyen AT. Atelectatic children treated
with intrapulmonary percussive ventilation via a face mask: clinical trial and literature overview.
Pediatr Int. 2007;49(4):502–507 PMID: 17587276 doi: 10.1111/j.1442-200X.2007.02385.x
30. Slattery DM, Waltz DA, Denham B, O’Mahony M, Greally P. Bronchoscopically administered
recombinant human DNase for lobar atelectasis in cystic fibrosis. Pediatr Pulmonol.
2001;31(5):383–388 PMID: 11340685 doi: 10.1002/ppul.1062

CHAPTER
26
Respiratory Disorders Associated With
Systemic Inflammatory Diseases
Eric D. Zee, MD
Introduction
The lungs are at risk for involvement in systemic inflammatory disorders
because of their enormous vascular network, both systemic and pulmonary;
extensive immunologic network; and vast structural framework. Systemic
inflammatory diseases such as collagen vascular (or rheumatic) diseases,1,2
vasculitidies,3,4 and granulomatous diseases5 may all have respiratory system
involvement. Because most of these systemic diseases occur relatively infre-
quently in children, much of what we know about the lung involvement is
extrapolated from adult literature. With national and international registries
for pediatric-specific diseases, there is a growing body of information
regarding the pediatric experience.
Systemic inflammatory diseases may present with a limited number of organs
involved or multiple organ systems involved. Frequent constitutional complaints
include fevers, malaise, fatigue, and arthralgias. Lung involvement might be
an initial presenting feature, or the lungs may become involved as the primary
underlying disease process evolves. Common pulmonary complaints include
cough, dyspnea, exercise intolerance, chest pain, and hemoptysis. The findings
on the pulmonary examination will vary according to the type of lung involve-
ment. With pleural effusions, the breath sound intensity is decreased, as is the
percussion note. With interstitial disease and pneumonia, crackles are common.
If pulmonary hypertension is present, the pulmonic component of the second
heart sound may be accentuated. Examination of other systems may lend a clue
as to the underlying diagnosis, such as the distribution of the arthritis, pattern
and type of skin involvement, digital clubbing, peripheral edema, weakness,
nasal deformity, and ocular involvement.
481

482
A plain chest radiograph is often the initial imaging, but high-resolution com-
puted tomography (HRCT) of the chest or computed tomography angiography
provides more detailed information regarding the nature of the respiratory
involvement.6,7 Ultrasonography is helpful in assessing pleural disease and
effusions, particularly if there is concern for infection in the pleural space.
While the radiographic patterns can be highly suggestive of a specific under-
lying diagnosis, there is considerable overlap between the systemic inflam-
matory diseases and the appearance of infectious complications of the
inflammatory disease or its treatment. Therefore, the imaging pattern may
be highly suggestive of a specific disease process, but it is seldom diagnostic
without additional studies.
A pulmonary function test (PFT) can be an integral part of the evaluation as
well as a noninvasive mechanism to follow the pulmonary disease progression
or improvement. The spirometry pattern varies with the specific underlying
disease and pulmonary involvement, but it commonly shows a restrictive
pattern. Restriction should be confirmed with lung volume measurements
rather than relying solely on the spirometric data. If restriction is documented,
the respiratory muscle strength should be assessed with maximal inspiratory
and expiratory pressures to be sure that the restriction is not from weakness.
If bronchiectasis or bronchiolitis obliterans is present, there may be an obstruc-
tive pattern on the spirometry and air trapping evident on the lung volumes.
The diffusing capacity is typically low unless alveolar hemorrhage has
occurred, which elevates the diffusing capacity.
Flexible fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) is helpful
in assessing airway anatomy and appearance as well as differentiating among
infections, inflammation, and alveolar hemorrhage, which can be a presenting
problem for several systemic inflammatory diseases. Transbronchial biopsy
can be useful to identify the noncaseating granulomas in sarcoidosis, but the
small tissue sample can often miss the most significant pathology in other
diseases of this nature. Therefore, if lung tissue is needed for diagnostic
purposes, a video-assisted thoracoscopic lung biopsy is usually preferred.
Diagnostic criteria are established for each of these diseases to help provide
correct classification and to unify disease identification between institutions.
Despite specific criteria, some patients do not fit perfectly into a disease
category, and occasionally the specific disease will be recognized at a later
date after evolution of the primary disease process. The pattern of organ
involvement can vary widely within a specific disease process, so in addition
to the clinical presentation, both imaging and laboratory investigation are
usually required to establish the correct diagnosis. The use of a variety of

483
Chapter 26—Respiratory Disorders Associated With Systemic Inflammatory Diseases
antibody and antigen markers as well as other pertinent laboratory tests

frequently allows a specific and accurate diagnosis to be determined.8,9
Pathologic examination of a tissue biopsy specimen can be very supportive
when a disease-specific location and abnormal histologic appearance are
present. Treatments for the primary disease process may cause a lung
problem or risk for opportunistic pulmonary infection, further confounding
the correct diagnosis.10
A multidisciplinary team often participates in the diagnosis and management
of patients with systemic inflammatory diseases. Key members may include
clinicians from rheumatology, pulmonology, infectious disease, intensive
care, and nephrology. Pediatric surgery is often called on to obtain biopsy
specimens. Other specialists may be valuable depending on the specific organ
system affected. Because of the complexity of multisystem disease and the
challenges in establishing a diagnosis, referral to an experienced specialist
early in the disease process is appropriate. The decision regarding hospitali-
zation is determined by the severity and acuity of the initial presentation and
subsequently by the response to therapy and potential complications. Many of
these disease processes seem to have an ethnic predisposition. Reasons for this
are not well understood, with more research for some diseases than for others.
Regardless, these diseases are clearly affected by socioeconomic factors,
inequities, and barriers to care.11
Rheumatic Diseases
For most patients, the constellation of symptoms, examination findings,
and laboratory study results allows for a specific categorization of the disease
process.8,9 However, some children have a constellation of rheumatic and der-
matologic problems that do not fit easily into a discrete diagnostic category.
These diagnoses are termed mixed connective tissue diseases or overlap
diseases; they comprise features of systemic lupus erythematosus (SLE),
systemic sclerosis, dermatomyositis, and juvenile idiopathic arthritis (JIA).
These patients seem to have a similar risk for pulmonary involvement, with
the same respiratory disease processes that occur in systemic sclerosis
and dermatomyositis.
The uncommon conditions of systemic sclerosis (scleroderma) and idiopathic
inflammatory myositis (dermatomyositis and polymyositis) are associated
with a higher risk for pulmonary disease than the most commonly occurring
pediatric rheumatic disease, JIA, in which pulmonary disease occurs relatively
infrequently (Table 26-1).12–16 In SLE, a relatively common rheumatic disease,
diverse lung involvement occurs frequently (Table 26-2).17,18

484
Table 26-1. Relative Frequency of Rheumatic Diseases and Associated Pulmonary Disease
Systemic
Characteristic JIA SLE JSS JDM
Incidence (per 10 ) 5
1 0.3–0.9 Unknown 0.2–0.4
Age at onset Variable Adolescence Unknown 7y
Antibody associations None ANA, ANA, anti-Scl-70; ANA,
anti-dsDNA anti-centromere myositis-
(in CREST syndrome) specific
antibodies
Pulmonary involvement + +++ +++ ++
Female-to-male ratio 1:1 4–5:1 ≤ age 8 y > age 8 y 2–4:1
1:1 3:1
Ethnic prevalence a
None African American, African American, No
Hispanic, Native Native American
American, Asian
Abbreviations: ANA, antinuclear antibody; anti-dsDNA, anti-double stranded DNA; anti-Scl-70, anti-scleroderma-70
antibodies; CREST, calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia; JDM,
juvenile dermatomyositis; JIA, juvenile idiopathic arthritis; JSS, juvenile systemic
sclerosis; SLE, systemic lupus erythematosus; +, occasional occurrence; ++, common or significant;
+++, quite frequent or very significant.
a
Reasons for apparent ethnic prevalence are not well understood; these diseases are clearly affected
by socioeconomic factors, inequities, and barriers to care.
Table 26-2. Common Pulmonary Involvement Associated With Collagen Vascular Disease
Pulmonary Involvement JIA SLE MCTD jSS jDM SjS
Pleuritis/effusion + + ++ — — —
ILD +/− ++ +++ +++ + +
DAH — +++ + + — —
Abnormal PFT +/− +++ + ++ ++ +
Abnormal Dlco — ++ ++ ++ ++ +
Pneumonitis + +++ +/− ++ ++ +
Weakness — — + ++ ++ —
Dysphagia/aspiration — — — +++ +++ —
PH — ++ — +++ + +
PAP +/− — — — — —
Thrombosis/PE — ++ — — — —
Bronchiectasis + + + + — —
Other MAS — — — — LIP;NHL
Abbreviations: DAH, diffuse alveolar hemorrhage; Dlco, diffusing capacity for carbon monoxide;
ILD, interstitial lung disease; jDM, juvenile dermatomyositis; JIA, juvenile idiopathic arthritis; jSS, juvenile systemic
sclerosis; LIP, lymphoid interstitial pneumonitis; MAS, macrophage activation syndrome; MCTD, mixed connective
tissue disease; NHL, non-Hodgkins lymphoma; PAP, pulmonary alveolar proteinosis;
PE, pulmonary embolism; PFT, pulmonary function test; PH, pulmonary hypertension; SjS, juvenile Sjögren syndrome;
SLE, systemic lupus erythematosus; —, rare or infrequent; +/−, some occurrence; +, occasional occurrence; ++,
common or significant; +++, quite frequent or very significant.

485
Chapter 26—Respiratory Disorders Associated With Systemic Inflammatory Disease
Juvenile Idiopathic Arthritis

Formerly known as juvenile rheumatoid arthritis, JIA is the most common
rheumatologic disease of childhood.12,13 It consists of 7 subtypes: oligoarthritis,
rheumatoid factor (RF)–negative polyarthritis, RF-positive polyarthritis,
systemic arthritis, psoriatic arthritis, enthesitis-related arthritis, and undifferen-
tiated arthritis. The classification depends on clinical manifestations, articular
and extra-articular involvement, number of joints affected, and RF and human
leukocyte antigen (HLA)-B27 positivity.
Joint stiffness and swelling are the most common presenting symptoms.
These symptoms tend to improve over the course of the day with increased
activity and warm showers. Children with JIA can have worse symptoms in
the morning and an abnormal gait (walking like an “old person”). Joint pain
is typically mild and at times absent. Pulmonary-specific symptoms are
relatively rare.12
Pulmonary Evaluation
Pulmonary involvement is more common with systemic JIA13; it is rarer in
patients with polyarticular JIA. As with many other rheumatologic causes
of pulmonary disease, serositis and pleuritis are the most common presenta-
tions. Clinical presentations most commonly include cough, dyspnea, chest
pain (with or without pleurisy and effusion), and increased pulmonary infec-
tions. Rarer but more severe pulmonary-related findings of interstitial lung
disease (ILD), alveolar proteinosis, and pulmonary hypertension are suggestive
of uncontrolled systemic disease. Pulmonary function test abnormalities may
precede the onset of arthritis. Pulmonary function testing, plain chest
radiography, and HRCT can be helpful in the initial evaluation of pulmonary
involvement (Figure 26-1). Bronchoalveolar lavage can be helpful in deter-
mining if an inflammatory process is present and in ruling out infection with
neutrophils predominating. However, lung biopsy remains the gold standard.
Management
Historically, treatment consisted of nonsteroidal anti-inflammatory drugs
(NSAIDs); first-line treatment has been transitioning to disease-modifying
antirheumatic drugs (DMARDs).12,13,19 NSAIDs are still used for shorter time
frames (1–2 months) or when the diagnosis of JIA has not been firmly estab-
lished. Systemic steroids are used less often for long-term treatment, given
their adverse effects, although intra-articular glucocorticoids continue to be
a common component of the treatment plan. Methotrexate has been the most
common DMARD used in JIA. Other DMARDs include leflunomide and
sulfasalazine. Biologic DMARDs include tumor necrosis factor inhibitors

486
Figure 26-1. Seven-year-old with systemic juvenile idiopathic arthritis

and secondary pulmonary alveolar proteinosis. Frontal (A) and lateral (B)
chest radiographs and axial computed tomography images (C, D) show
diffuse centrilobular interstitial thickening with ground-glass opacities.
such as etanercept, adalimumab, and infliximab; interleukin-1 (IL-1) receptor

antagonist anakinra; interleukin-6 (IL-6) inhibitor tocilizumab; and T-cell
co-stimulation inhibitor abatacept.19
New concerns have arisen regarding novel parenchymal lung disease in
patients with JIA consisting of septal thickening and ground-glass opacities
on CT scan, with pathologic changes of pulmonary alveolar proteinosis or
endogenous lipoid pneumonia. A 2019 study suggested there was increased
risk in children with Down syndrome; in those with young age of onset of
JIA; and in those with exposure to IL-1 and IL-6 inhibitors, although severity
might have been caused by the underlying disease process itself. Preliminary
concern is for macrophage dysfunction as the etiology.20
Systemic Lupus Erythematosus

Systemic lupus erythematosus in children is a multisystem autoimmune
disease with great variability of symptoms.14,17 The diagnosis is based on the
presence of at least 4 of 11 criteria from the American College of Rheumatol-
ogy classification criteria, or more recently the Systemic Lupus International
Collaborating Clinics Classification. Systemic lupus erythematosus rarely
occurs before 5 years of age, and its incidence varies by sex and ethnicity;
groups with a higher incidence include female, Hispanic, Black, Native
American, and Asian individuals.14

487
Children with SLE can have more severe organ involvement with worse
outcomes than adults. Many systems can be involved in children with SLE,
including musculoskeletal (arthritis), skin (malar or photosensitive rash),
neuropsychiatric (cognitive dysfunction, headaches), hematologic (cytopenia),
cardiac (pericarditis, pericardial effusion, and premature atherosclerosis),
renal (nephritis or nephrosis), and lung disease.
Pulmonary disease has a wide range of clinical severity, from asymptomatic
PFT abnormalities14,18 to severe life-threatening pulmonary hemorrhage.21
Systemic lupus erythematosus–related lung disease consists of acute and
chronic findings. Acute findings with chest pain and respiratory distress can
revolve around serositis with pneumonitis and pleuritis. Simultaneous infec-
tious pneumonia may complicate the clinical picture. Chronic findings consist
of more severe disease, including pulmonary hemorrhage, pulmonary fibrosis,
and pneumothorax.21 Less common findings include diaphragmatic involve-
ment (shrinking lung syndrome, phrenic nerve paralysis), vasculitis, chronic
thromboembolic pulmonary hypertension with secondary antiphospholipid
antibody syndrome, and pulmonary embolus. Pulmonary hypertension usually
occurs late in the disease process and suggests poor prognosis; treatment with
vasodilators (prostacyclins or inhaled nitric oxide) has not been shown to be
effective. Chronic ILD also can present, with crackles and nonproductive
cough; imaging often reveals scattered nodular densities. Cryptogenic
organizing pneumonia is a rare complication.21
Plain chest radiographs help to differentiate the clinical patterns seen: pleurisy
with effusion, pleuropericarditis with diaphragm thickening or elevation, and
fibrosing alveolitis.6 High-resolution computed tomography is indicated if
the plain radiograph does not explain the symptoms and signs. Additional
pulmonary investigations include bronchoscopy, bronchoalveolar lavage,
and lung biopsy, especially to differentiate between SLE and infection.21
Distinguishing lupus-induced pulmonary disease from infection can be a
diagnostic challenge.
Pleural fluid in active SLE is exudative (protein > 3 g/dL, pH > 7.35), although
it may be transudative on occasion. The fluid typically has an elevated white
blood cell count (2,500–5,000 cells/mm3) with mononuclear and lymphocyte
predominance; LE cells may be present, and the positive antinuclear antibody
titer is usually greater than the patient’s serum titer.22 Pulmonary function
test results are abnormal in two-thirds of patients, with obstruction of small
airways and decreased carbon dioxide diffusing capacity (Dlco) the most
prevalent complications.21

488
Management
Treatment for SLE should be handled in conjunction with a pediatric
rheumatologist. NSAIDs provide symptomatic relief of mild pleuritis if the
patient is not at risk for hemorrhage or experiencing decreased renal function.
Hydroxychloroquine has also become a mainstay of therapy in decreasing
rates of flare, organ damage, and thrombotic effects. Failure to respond may
lead to a trial of an immunosuppressive agent or a biological response modifier,
such as anti-CD19 monoclonal antibodies (rituximab) or an anti–B lymphocyte
stimulator (belimumab).19 Corticosteroids, including high-dose pulse therapy,
are the treatment for severe acute pulmonary disease. Treatment may also be
needed for specific processes, such as pulmonary hemorrhage and pulmonary
hypertension. Patients with SLE often are immunocompromised, which
increases their risk of developing pulmonary infections.10,21
Juvenile Dermatomyositis
Juvenile dermatomyositis (JDM) is an autoimmune disorder that occurs much
less frequently than either JIA or SLE,15,16 but it seems to be associated with a
high risk of pulmonary involvement.23 Although JDM occurs infrequently, it is
one of the more easily identifiable of the systemic inflammatory myopathies.24
Nonspecific symptoms predominate, including malaise, fever, rash, and fatigue.
Proximal muscle weakness and elevated muscle enzymes are frequently seen. It
is important to be aware of musculoskeletal and cutaneous manifestations
(heliotrope discoloration of the eyelids and Gottron papules); these can present
before pulmonary involvement.23 As many as one-third of patients will have
pulmonary signs or symptoms sometime during the course of their disease.23
Although the disease initially may be asymptomatic, the most common clinical
manifestations are dyspnea and cough. Interstitial lung disease is commonly
seen with JDM and is associated with significant morbidity. Because of proxi-
mal muscle weakness, patients may have impaired secretion control and
increased susceptibility to pneumonia. They are also at risk for aspiration
because of pharyngeal weakness. Children are also at risk for hypoventilation.
Clinicians need to be vigilant for opportunistic lung infections secondary to
immunosuppressive therapies.10
Pulmonary disease in JDM may occur less often than in adult disease.
Anti-RNA synthetases, anti-Jo-1 antibody, and anti-MDA-5 are strong
predictive factors in development of ILD. Rapidly progressive and fatal ILD
with JDM has been associated with positive anti-MDA-5 antibody.25 Pulmo-
nary function testing is useful; even children without respiratory symptoms
can have abnormalities, with restrictive pulmonary disease and reduced

489
Chapter 26—Respiratory Disorders Associated With Systemic Inflammatory Disease
diffusion capacity. High-resolution computed tomography has been less

helpful in establishing the diagnosis in children. Children still may require a
lung biopsy to establish the diagnosis of ILD.1,23
Management
Pharmacological treatment is centered around glucocorticoids combined at
times with methotrexate or cyclosporin. For children with more severe disease
or pulmonary involvement, high-dose pulse methylprednisolone has been
used. There also have been case reports involving use of cyclophosphamide
and rituximab.19
Juvenile Systemic Sclerosis

Localized scleroderma and juvenile systemic sclerosis (JSS) are thought to
be 2 separate entities rather than a spectrum of the same disease process.9,14,16
Juvenile systemic sclerosis is associated with hardening of the skin (morphea)
and diffuse organ fibrosis and vasculopathy within the heart, lung, GI tract,
and kidneys. It occurs in girls 3 times more commonly than in boys after age
8 years. Before 8 years of age, JSS is exceedingly rare and the incidence is
similar for boys and girls.
Diagnostic criteria for JSS require skin thickening proximal to the metacarpo-
phalangeal joints and at least 2 additional minor criteria consisting of specific
organ involvement (including pulmonary fibrosis, decreased Dlco, and
pulmonary hypertension) and positivity to certain autoantibodies. Cardiopul-
monary disease occurs in 30% to 50% of children with systemic sclerosis.
It is a primary cause of morbidity and mortality.26 Interstitial lung disease
and pulmonary hypertension result from associated vasculopathy with
endothelial damage.26
If possible, all patients should be screened with PFT, which can reveal reduced
forced vital capacity, restrictive lung disease, and reduced diffusion capacity.
Those with abnormal PFT results should undergo chest HRCT to evaluate for
ground-glass appearance, pulmonary nodules, and bronchiectasis, as well as
to reveal a nonspecific interstitial pneumonia pattern. Affected patients are at
increased risk for aspiration secondary to dysphagia, esophageal dysmotility,
and reflux.26
Management
Treatment for JSS depends on the organs affected. For the lung, cyclophospha-
mide is frequently used for ILD. Alternatively, mycophenolate mofetil and
rituximab have also been used. For pulmonary hypertension, phosphodiester-
ase inhibitors, endothelin-1-receptor antagonists, and, if required, intravenous

490
prostacyclins may be used.19 Lung transplantation may be necessary for those

refractory to treatment.26
Mixed Connective Tissue Disease and Sjögren Syndrome

Mixed connective tissue disease (MCTD) and Sjögren syndrome are auto-
immune diseases with immune dysregulation and multisystem organ
involvement.26,27 Clinically, they share many of the same features as SLE.
The incidence and prevalence are not known but are thought to be lower
than those seen with SLE.
Multiple aspects of the lung may be involved including airways, parenchyma,
vasculature, and pleura.6 For both entities, pulmonary-related symptoms
depend on the presence of serositis culminating in chest pain, pleuritis,
fibrosis, and pulmonary hypertension. Interstitial lung disease and organizing
pneumonias have also been described.
Criteria for the diagnosis in children are not as rigorously validated as those in
adults. The criteria for MCTD include either Raynaud phenomenon or hand
and finger swelling in addition to high-titer anti-U1 RNP antibody and
1 sign from at least 2 of the following: SLE, systemic sclerosis, and polymyo-
sitis. No single laboratory test is diagnostic for MCTD. For Sjögren syndrome,
earlier detection with anti-Sjögren syndrome A (Ro) and anti-Sjögren
syndrome C (La) is possible.9 Computed tomography of the chest can reveal
ground-glass appearance with septal thickening and subpleural honeycombing.
Pulmonary artery dilatations and pleural effusions also can be seen on CT.6
Management
Coordination between pediatric subspecialists is paramount. Treatment for
MCTD is similar to that for SLE, with glucocorticoids, hydroxychloroquine,
methotrexate, and NSAIDs. Serositis and pleuritis may require immunosup-
pressives such as cyclophosphamide. If pulmonary hypertension is present,
prostacyclins and endothelin-1-receptor antagonists may also be needed.26 For
Sjögren syndrome, glucocorticoids continue to be a mainstay of therapy.27
Vasculitic Diseases
Granulomatosis With Polyangiitis
Granulomatosis with polyangiitis (GPA), formerly known as Wegener
granulomatosis, is a rare necrotizing, granulomatous, small- to medium-sized
vasculitis.28–31 It has a pediatric incidence of 0.1 per 100,000 in the US popula-
tion younger than 20 years, with involvement of the upper airways, lungs,

491
and kidneys. Pulmonary disease is associated with up to 75% of GPA cases.1

The cause of GPA remains unknown.31 In vitro studies show that cytoplas-
mic antineutrophil cytoplasmic antibodies (c-ANCA) interact with protein-
ase-3 (PR3) to activate proinflammatory pathways.31
To establish a diagnosis of GPA, a patient should have at least 2 of 4 predefined
criteria (nasal or oral inflammation, abnormal findings on chest radiograph,
abnormal urinary sediment, and granulomatous inflammation on biopsy),
per the American College of Rheumatology.32 The presence of any 2 or more
criteria yields a sensitivity of 88% and a specificity of 92%.29 More than 90%
of patients with GPA initially seek medical attention for upper or lower airway
symptoms.33 Sinusitis is the most frequent presenting symptom, followed by
fever, arthralgias, cough, rhinitis, and hemoptysis. In the upper airway, GPA
is commonly associated with subglottic stenosis and nasal deformities (nasal
septum perforation and saddle nose deformity).28 Subglottic stenosis often
occurs independently of other GPA symptoms. In the lower airway, tracheo-
bronchostenosis is possible and can involve clinical symptoms of cough,
hoarseness, stridor, dyspnea, and wheezing. Stenosis of the airways may
require surgical intervention.34 Diffuse alveolar hemorrhage and massive
hemoptysis can be life-threatening conditions. Pulmonary fibrosis, pleurisy,
and pneumothorax are less common.
Evaluation
Evaluation for GPA can be complicated. Routine laboratory test results are
generally nonspecific, with increased generalized markers of inflammation.
The diagnosis often can be established with elevated c-ANCA levels (detect-
able in 70%–90% of patients with active GPA), PR3-ANCA, and potentially
kidney and lung biopsies.35 Children should be monitored and evaluated for
signs of upper airway and lower airway obstruction. Often part of presenting
symptoms, pneumonia and sinusitis may also mask the diagnosis.28,29
Although one-third of chest radiographs in children with GPA show abnor-
malities, these children may be asymptomatic. Findings include densities,
cavitation, and nodules, which become more severe over time without treat-
ment. Less frequently, atelectasis, pneumothorax, pleural effusion, pulmonary
hemorrhage, and mediastinal or hilar lymphadenopathy are found. Plain chest
radiography can detect these abnormalities, but HRCT provides more detail,
especially in detecting airway stenosis, pulmonary nodules, granulomas, and
cavitations (Figure 26-2). Following a diffuse alveolar bleed, a septal thicken-
ing pattern, sometimes termed crazy paving, can be seen. Bronchoscopy may
be necessary to evaluate airway lesions fully. Pulmonary function testing

492
Figure 26-2. Radiograph (A, B) and chest computed tomographic scans (C, D) in a child with
granulomatosis with polyangiitis; note the diffuse infiltrate, nodules, and granulomas.
reveals obstructive or restrictive lung disease as well as lower Dlco. Histo-

pathologic evaluation with lung biopsy can reveal necrosis, vasculitis, and/or
granulomatous inflammation.35
Management
Initial treatment with glucocorticoids and cyclophosphamide induces remis-
sion in more than 90% of patients.35 This treatment may be continued for at
least 1 year after disease control or remission and then gradually reduced.
Alternatively, methotrexate or azathioprine may be used after an initial 4- to
6-month tapering course of cyclophosphamide.35 Rituximab is a promising new
option in both induction remission and maintenance therapies. Unfortunately,
subglottic stenosis related to GPA does not usually improve with systemic
medical treatment. Serial intratracheal dilation and injection of long-acting

493
glucocorticoids provide a safe and effective treatment, commonly mitigat-

ing the need for tracheostomy.34 Clinicians should be aware of the risk of
opportunistic infections. Prophylaxis against Pneumocystis jiroveci with
trimethoprim-sulfamethoxazole is now commonplace for children undergo-
ing treatment for GPA.35
Microscopic Polyangiitis
Microscopic polyangiitis (MPA) is another ANCA-positive systemic vasculitis
that shares many of the same clinical and pathophysiologic features as GPA.36
The great challenge of the MPA diagnosis is differentiating it from GPA. Given
significant clinical overlap and lack of standardized definitions and distinct
classification, diagnosing MPA has been difficult. It occurs at a slightly younger
age than GPA, and girls are affected about 3 times more often than boys.36
Previous classification systems have been inadequate; thus, rheumatologists
have been validating new ways to identify MPA.3,35
The kidneys and lungs remain the most affected organs. Children can still
present with tachypnea and hemoptysis, but, unlike GPA, pulmonary manifes-
tations are typically less severe in MPA. Pathologically, MPA is differentiated
from GPA by the absence of granuloma formations. Pulmonary nodules, fixed
infiltrates, and cavitation are not seen in MPA; if present, they tend to steer the
diagnosis toward GPA. Pleural effusions, along with fibrosis, septal thickening,
and pneumothorax, are less common. Children with MPA frequently do not
have sinusitis, subglottic stenosis, and tracheobronchomalacia, as seen in
GPA.3,29 More recent classification systems exclude upper airway disease
and airway stenosis from the diagnosis of MPA.3
Typical of other types of vasculitis, markers of inflammation are elevated.
pANCA/MPO-ANCA is often positive with MPA, and occasionally patients
will test positive for both MPO-ANCA and PR3-ANCA; as many as one-
quarter will have negative ANCA test results.3 Radiographic evaluation of
the chest can show effusions, fibrosis, and pneumothorax, but, overall, there
are far fewer abnormalities compared to those in GPA.
Management
Treatment is similar to that for GPA. Corticosteroids with cyclophosphamide
are often used for induction. Maintenance and remission therapy also includes
DMARDs such as azathioprine, methotrexate, azathioprine, and rituximab.
Other therapies may include plasmapheresis or intravenous immunoglobulin.19,29

494
Eosinophilic Granulomatosis With Polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as
Churg-Strauss syndrome) is an exceedingly rare condition in childhood that is
characterized by development of eosinophilic vasculitis involving sinopulmo-
nary and gastrointestinal tracts, heart, nervous system, and skin.37 The disease
is defined by pulmonary eosinophilic granulomatous inflammation of small- to
medium-sized vessels, pneumonia, and necrotizing vasculitis with associated
asthma and eosinophilia.37 The cause of EGPA is unknown.21 The incidence
and prevalence in the pediatric population are unknown. The prominence of
allergic features, such as elevated levels of serum immunoglobulin (Ig) E, and
the presence of immune complexes, rheumatoid factor, and c-ANCA suggest
an autoimmune origin.31
Eosinophilic granulomatosis with polyangiitis consists of 3 stages: asthma and
rhinitis, tissue eosinophilia (including eosinophilic pneumonia), and extrapul-
monary eosinophilic vasculitis.37 Similar to many eosinophilic syndromes, con-
stitutional symptoms, including fever, weight loss, and generalized myalgias,
are common in EGPA. Prodrome is characterized by atopic disease, allergic
rhinitis, and asthma. The eosinophilic phase includes blood eosinophilia and
infiltration of multiple organs, especially the lung and gastrointestinal tract.
Rarely, a life-threatening systemic vasculitis is associated with vascular and
extravascular granulomatosis.
Because of its rarity in children, the incidence of pediatric EGPA is unknown.
The diagnosis of EGPA in childhood remains challenging. A strong clinical
suspicion coupled with pathologic confirmation can expedite the diagnosis.
The diagnosis often is not established until the abdomen, heart, and nervous
system become involved. Reports of EGPA occurring in children are limited
and generally consist of single case reports. Asthma is almost always present
in EGPA. Ear, nose, and throat disease includes chronic sinusitis and nasal
polyps. Laboratory evaluation includes complete blood cell count with differen-
tial, c-ANCA, p-ANCA, and total IgE. Antineutrophil cytoplasmic antibodies
are common but seem to have less specificity in children.35,38 Pulmonary
function testing has shown mostly obstructive disease, but restrictive and
mixed lung disease patterns are possible. Bronchoalveolar lavage often shows
eosinophil predominance. Chest radiograph abnormalities are common and
consist of bilateral, nonsegmental alveolar or interstitial infiltrates. Computed
tomographic chest findings include reticulonodular disease without cavitation
(unlike GPA) and bronchial wall thickening, with less common findings of

495
Figure 26-3. Fourteen-year-old with eosinophilic granulomatosis with

polyangiitis and hemoptysis; note the reticulonodular disease on the
radiograph (A) and corresponding computed tomographic scan (B) of the
chest.
ground-glass opacities and tree and bud patterns (Figure 26-3).37 A biopsy
to evaluate for an eosinophilic inflammatory process or vasculitis remains the
gold standard for diagnosis.38
Management
Corticosteroids are the mainstay of treatment, often with striking results.35
Although cytotoxic agents, such as cyclophosphamide, do not improve
survival rates, their use is associated with a reduced incidence of relapse.
Other successful therapies have included intravenous Ig infusions, azathio-
prine, methotrexate, interferon-α, infliximab, and mepolizumab. Laboratory
markers, such as serum eosinophils, often normalize within 2 weeks of treat-
ment initiation. Clinical improvement can also be seen within 2 to 4 weeks,
but often residual respiratory symptoms may require the continuation of
low-dose prednisone therapy for longer periods. Since immunosuppressive
therapies increase the risk of opportunistic infection, prophylaxis with
trimethoprim-sulfamethoxazole should be provided.35
Anti-glomerular Basement Membrane Disease

Anti-glomerular basement membrane (AGBM) disease, previously known
as Goodpasture disease, is an organ-specific small vessel vasculitis causing
rapidly progressive glomerulonephritis and alveolar hemorrhage. Immunoglob-
ulin G antibodies to the α-3 chain of type IV collagen deposit in the basement
membranes of both the renal and pulmonary circulation.39
It is an uncommon cause of pulmonary-renal syndromes in children
(Table 26-3). Rarely, alveolar hemorrhage occurs in the absence of renal
involvement; it is more common to have renal disease without alveolar

496
Table 26-3. Most Common Alveolar Hemorrhage Syndromes

Characteristic SLE GPA MPA AGBM EGPA
Blood markers ANA, c-ANCA p-ANCA Anti-GBM Eosinophilia
anti-dsDNA antibody
Renal disease +++ +++ +++ +++ +
Skin involvement +++ + + − +
ENT involvement + +++ + − ++
Arthritis +++ ++ + − −
Radiographic ILD, Nodules, ILD, Hemorrhage Increased
findings hemorrhage cavities, hemorrhage peribronchial
hemorrhage markings
Abbreviations: −, rare occurrence; +, occasional occurrence; ++, common or significant; +++, quite
frequent or very significant; AGBM, anti-glomerular basement membrane; ANA, antinuclear antibody;
anti-dsDNA, anti-double stranded DNA; c-ANCA, cytoplasmic antineutrophil cytoplasmic antibody (also
antiprotease antibody); EGPA, eosinophilic granulomatosis with polyangiitis; ENT, ear, nose, and throat;
GPA, granulomatosis with polyangiitis; ILD, interstitial lung disease; MPA, microscopic polyangiitis;
p-ANCA, perinuclear antineutrophil cytoplasmic antibody; SLE, systemic lupus erythematosus.
hemorrhage. Although alveolar and renal manifestations occur concomitantly,

alveolar hemorrhage may occur prior to the onset of renal disease.
The diagnosis is established by the presence of circulating anti-glomerular
basement membrane antibodies or linear immunofluorescent deposits of IgG
on the renal basement membrane, which also can be seen on the alveolar
basement membranes should a lung biopsy be performed.39 This immunofluo-
rescence pattern is less consistent on lung biopsy compared to renal biopsy.
The linear pattern differentiates AGBM disease from immune-complex
deposits causing the renal disease. In up to 30% of patients with AGBM
disease, the ANCA may also be positive in addition to the AGBM antibodies
(so-called double positive); MPO-ANCA is more common than PR3-ANCA.
Management
The goals of therapy are to remove the circulating antibodies, prevent the pro-
duction of more antibodies, and attempt to identify and resolve any triggering
agent. Initial treatment with plasmapheresis is often successful at removing the
circulating AGBM antibodies. Intravenous methylprednisolone, cyclophos-
phamide, and, more recently, rituximab are used for immunosuppression.
Survival should be anticipated, but prognosis is guarded if end-stage renal
disease is present; renal transplantation may be necessary.39

497
Henoch-Schönlein Purpura (IgA Vasculitis)/

Kawasaki Disease/Polyarteritis Nodosa
The most common vasculitidies in children are Henoch-Schönlein purpura,
Kawasaki disease, and polyarteritis nodosa.40,41 Henoch-Schönlein purpura
involves the small vessels, while Kawasaki disease and polyarteritis nodosa
are predominantly medium vessel diseases. Takayasu arteritis is a granulo-
matous arteritis predominantly affecting the aorta and its major branches.
Pulmonary involvement with these more commonly occurring vasculidities
in childhood is extremely uncommon.
Granulomatous Lung Disease

Most of the granulomatous lung diseases in pediatrics are caused by infec-
tions (Box 26-1) and are discussed elsewhere in this book or elsewhere in this
chapter (Table 26-3).5 This section will focus on noninfectious, systemic
inflammatory diseases with granulomatous pathology.
The chest radiographs or CT images often reveal nodules and adenopathy,
which raises concern for malignancy. While malignancy is exceedingly rare
when assessing a child with pulmonary nodules, the risk of cancer should
be considered. Small nodules and nodules with calcification are unlikely to
be malignant and can be observed, but larger or growing nodules without a
determined etiology should be biopsied or excised.
Sarcoidosis
Sarcoidosis is a multisystem disease of unknown etiology.42 Sarcoidosis is a
granulomatous response to an unknown antigen or antigens characterized by
a T lymphocyte infiltration, granuloma formation, and distortion of normal
microarchitecture. These noncaseating granulomas have a core composed of
activated macrophages (epithelioid cells), multinucleated giant cells, and CD4
type 1 helper T lymphocytes. Angiotensin-converting enzyme is produced by
the activated macrophages in the granuloma. In adults, pulmonary involve-
ment occurs in approximately 85% of patients; pulmonary involvement may
be slightly less common in children. In the United States, sarcoidosis is more
prevalent and more severe in the African American population. Socioeco-
nomic factors, barriers to care, and occupational exposure are all implicated in
racial disparities. Furthermore, certain medications may be better tolerated
than others but are inaccessible because of insurance coverage rules. For
example, corticosteroids may be associated with significant adverse effects,
but steroid-sparing medications may not be as readily covered. Inequitable

498
Box 26-1
Differential Diagnosis of Granulomatous Lung Disease
Noninfectious Causes Infectious Causes
ū Autoimmune disease ū Viruses
• Primary systemic vasculitidies • Epstein-Barr virus
X Granulomatosis with polyangiitis • Herpes
X Eosinophilic granulomatosis • Rubella
with polyangiitis • Cytomegalovirus
• Systemic lupus erythematosus • Measles
• Inflammatory bowel disease • Coxsackie B
(Crohn disease) • Parainfluenza
• Primary biliary cirrhosis ū Fungi
ū Bronchocentric granulomatosis • Histoplasma
ū Primary immunodeficiencies • Aspergillus
• Chronic granulomatous disease • Coccidioides immitis
(see Chapter 53, Pulmonary
Complications of Immunologic • Blastomycosis
Disorders) • Cryptococcus
• Common variable immune ū Protozoa
deficiency • Toxoplasma
• Hypogammaglobulinemia • Leishmania
ū Histiocytosis X ū Metazoa (Schistosoma)
ū Hypersensitivity pneumonitis ū Bacteria
• Farmer’s lung • Yersinia
• Bird fancier’s lung • Borrelia
ū Neoplasms • Brucella
• Carcinomas • Mycobacteria
• Sarcomas X Mycobacterium tuberculosis
• Lymphomas X Mycobacterium leprae
ū Sarcoidosis X Nontuberculous mycobacteria
(and necrotizing sarcoidosis)

ū Drug-induced granulomas
access to medications and therapies results in potentially negative impacts

on quality of life.43
Symptoms may be absent or sparse and include cough, dyspnea, and fatigue.42
The diagnosis is often delayed and requires documentation of granulomatous
involvement of at least 2 organ systems. A tissue biopsy should be performed
from the most easily accessible site. Sarcoidosis is a diagnosis of exclusion,
and alternative explanations such as fungal infection, mycobacterial infection,
and lymphoma must be excluded. An elevated angiotensin-converting

499
enzyme (ACE) level is not pathognomonic of sarcoidosis. The ACE testing

sensitivity is fair but not specific. The positive predictive value is higher but
with a less helpful negative predictive value.
Pulmonary function testing may show a restrictive pattern with impaired
diffusion capacity, but an obstructive pattern may also be present, as well as
bronchial reactivity.42 Radiographically, pulmonary involvement is identified
by bilateral hilar adenopathy; interstitial infiltrates and pulmonary nodules
may also be seen. Progression to end-stage fibrotic disease is possible but not
frequent in children. Bronchoalveolar lavage is not a reliable tool to establish
the diagnosis of sarcoidosis, although it is commonly performed at the time
of bronchoscopy for transbronchial biopsy; noncaseating granulomas are
found in more than 90% of biopsy specimens. Lymphocytosis on BAL may be
present, with a T cell CD4:CD8 ratio elevated above 3.5. The ACE level also is
often elevated in BAL fluid, as are several cytokines. The primary utility of
BAL in sarcoidosis is to exclude fungal, mycobacterial, atypical mycobacte-
rial infection, or other infectious processes as the explanation for the patient’s
symptoms and radiographic findings.
Treatment
Management of children with sarcoidosis depends on presentation, clinical
picture, and number and severity of organ systems involved. Rarely, asymp-
tomatic children with hilar adenopathy may not need to be treated. Treatment
should be considered for children with multisystem disease, dyspnea, worsen-
ing lung function, and worsening radiologic findings. Corticosteroids remain
the mainstay of treatment. For pulmonary disease, 6 to 18 months of therapy
may be reasonable, but no time course has been well established for other
organ systems. Immunosuppressives include methotrexate, hydroxychloro-
quine, azathioprine, cyclophosphamide, and infliximab. There is no guideline
regarding optimal follow-up in children.42
Langerhans Cell Histiocytosis

Langerhans cell histiocytosis (LCH) encompasses conditions with abnormal
differentiation and proliferation of mononuclear phagocytes.44 It is considered
a myeloid neoplastic disorder. The granulomatous lesions are most commonly
found in bone, skin, the lungs, and the pituitary. It can occur as a single indo-
lent lesion or as an aggressive multisystem disease. Children with liver, spleen,
or bone marrow involvement are considered at high risk for a poor outcome,
even with chemotherapy. In the past, isolated pulmonary involvement was
labeled “eosinophilic granuloma,” which occurred primarily in adolescent
boys and young men and was associated with cigarette smoking.
Pathologically, the lung lesions start as discrete bronchiolocentric nodules with
a mix of Langerhans cells, lymphocytes, eosinophils, and plasma cells. The

500
Langerhans cells stain positive for langerin, CD1a, E-cadherin, and S100.
Electron microscopy reveals Birbeck granules in the Langerhans cells. As the
lesions progress, they coalesce and form cysts, creating the risk of sponta-
neous pneumothoraces, which may be the presenting symptom.
Therapy for LCH is stratified based on the number of organ systems involved
and the risk of mortality. For isolated pulmonary LCH, smoking cessation
alone may be the only therapy required.
Inflammatory Bowel Disease

Crohn disease presents more frequently with extraintestinal manifestations
than ulcerative colitis.45 Case reports have identified pulmonary nodules in
patients with inflammatory bowel disease, which raises concern regarding
infection complicating the therapy for the underlying bowel disease. These
pulmonary nodules are noncaseating epithelioid granulomas similar to those
seen in sarcoidosis (Figure 26-4). Before treatment with tumor necrosis factor
α blockers is initiated in patients with inflammatory bowel disease, they should
be checked for latent tuberculosis infection. When the pulmonary nodules
are related to the inflammatory bowel disease, they commonly respond to
treatment of the bowel disease.45
Figure 26-4. Pulmonary nodules incidentally found

on a computed tomographic scan of the abdomen in
a patient with Crohn disease.

501
key points
} Systemic inflammatory diseases may present with a limited number of organs
involved or multiple organ systems involved. Lung involvement might be an
initial presenting feature, or the lungs may become involved as the primary
underlying disease process evolves.
} Initial respiratory symptomatology and constitutional complaints may be very
similar through this very diverse collection of diseases.
} Diagnosis and management are often challenging and optimally include a
multidisciplinary team from rheumatology, pulmonology, infectious diseases,
intensive care, and nephrology.
} Results of pulmonary testing with chest radiography, chest CT, pulmonary
function testing, and flexible fiberoptic bronchoscopy with bronchoalveolar
lavage (BAL) may be highly suggestive of a specific disease process, but these
tests are seldom diagnostic without additional studies.
} Diagnostic criteria (clinical presentation, imaging, and laboratory investigation)
are established for each of these diseases to help provide correct classification
and to unify disease identification between institutions.
References
1. Richardson AE, Warrier K, Vyas H. Respiratory complications of the rheumatological
diseases in childhood. Arch Dis Child. 2016;101(8):752–758 PMID: 26768831
2. Kusmirek JE, Kanne JP. Thoracic manifestations of connective tissue diseases. Semin
Ultrasound CT MR. 2019;40(3):239–254 PMID: 31200872 doi: 10.1053/j.sult.2018.12.003
3. Iudici M, Puéchal X, Pagnoux C, et al; French Vasculitis Study Group. Childhood-onset systemic
necrotizing vasculitides: long-term data from the French Vasculitis Study Group Registry.
Arthritis Rheumatol. 2015;67(7):1959–1965 PMID: 25808634 doi: 10.1002/art.39122
4. Lally L, Spiera RF. Pulmonary vasculitis. Rheum Dis Clin North Am. 2015;41(2):315–331
PMID: 25836645 doi: 10.1016/j.rdc.2015.01.004
5. Ohshimo S, Guzman J, Costabel U, Bonella F. Differential diagnosis of granulomatous
lung disease: clues and pitfalls. Eur Respir Rev. 2017;26(145):170012 PMID: 28794143
doi: 10.1183/16000617.0012-2017
6. Ahuja J, Arora D, Kanne JP, Henry TS, Godwin JD. Imaging of pulmonary manifestations of
connective tissue diseases. Radiol Clin North Am. 2016;54(6):1015–1031 PMID: 27719973
doi: 10.1016/j.rcl.2016.05.005
7. Navallas M, Inarejos Clemente EJ, Iglesias E, Rebollo-Polo M, Antón J, Navarro OM. Connective
tissue disorders in childhood: are they all the same? Radiographics.
2019;39(1):229–250 PMID: 30620697 doi: 10.1148/rg.2019180078
8. Tzouvelekis A, Karampitsakos T, Bouros E, Tzilas V, Liossis SN, Bouros D. Autoimmune
biomarkers, antibodies, and immunologic evaluation of the patient with fibrotic lung disease. Clin
Chest Med. 2019;40(3):679–691 PMID: 31376900 doi: 10.1016/j.ccm.2019.06.002
9. Mohan C, Assassi S. Biomarkers in rheumatic diseases: how can they facilitate diagnosis and
assessment of disease activity? BMJ. 2015;351:h5079 PMID: 26612523 doi: 10.1136/bmj.h5079
10. Higgins GC. Complications of treatments for pediatric rheumatic diseases. Pediatr Clin North
Am. 2018;65(4):827–854 PMID: 30031500 doi: 10.1016/j.pcl.2018.04.008

502
11. Anderson NB, Armstead CA. Toward understanding the association of socioeconomic status and
health: a new challenge for the biopsychosocial approach. Psychosom Med. 1995;57(3):213–225
PMID: 7652122 doi: 10.1097/00006842-199505000-00003
12. Crayne CB, Beukelman T. Juvenile idiopathic arthritis: oligoarthritis and polyarthritis.
13. Lee JJY, Schneider R. Systemic juvenile idiopathic arthritis. Pediatr Clin North Am.
2018;65(4):691–709 PMID: 30031494 doi: 10.1016/j.pcl.2018.04.005
14. Tarvin SE, O’Neil KM. Systemic lupus erythematosus, Sjögren syndrome, and mixed connective
tissue disease in children and adolescents. Pediatr Clin North Am. 2018;65(4):711–737
PMID: 30031495 doi: 10.1016/j.pcl.2018.04.001
15. Huber AM. Juvenile idiopathic inflammatory myopathies. Pediatr Clin North Am.
2018;65(4):739–756 PMID: 30031496 doi: 10.1016/j.pcl.2018.04.006
16. Li SC. Scleroderma in children and adolescents: localized scleroderma and systemic sclerosis.
17. Huggins JL, Holland MJ, Brunner HI. Organ involvement other than lupus nephritis in
childhood-onset systemic lupus erythematosus. Lupus. 2016;25(8):857–863 PMID: 27252262
doi: 10.1177/0961203316644339
18. Veiga CS, Coutinho DS, Nakaie CMA, et al. Subclinical pulmonary abnormalities in childhood-
onset systemic lupus erythematosus patients. Lupus. 2016;25(6):645–651 PMID: 26849883
doi: 10.1177/0961203316629554
19. Mehta J, Beukelman T. Biologic agents in the treatment of childhood-onset rheumatic disease.
J Pediatr. 2017;189:31–39 PMID: 28711176 doi: 10.1016/j.jpeds.2017.06.041
20. Saper VE, Chen G, Deutsch GH, et al; Childhood Arthritis and Rheumatology Research
Alliance Registry Investigators. Emergent high fatality lung disease in systemic juvenile
arthritis. Ann Rheum Dis. 2019;78(12):1722–1731. Published correction appears in Ann Rheum
Dis. 2022;81(2):e35. PMID: 31562126 doi: 10.1136/annrheumdis-2019-216040
21. Amarnani R, Yeoh S-A, Denneny EK, Wincup C. Lupus and the lungs: the assessment and
management of pulmonary manifestations of systemic lupus erythematosus. Front Med
(Lausanne). 2021;7:610257 PMID: 33537331 doi: 10.3389/fmed.2020.610257
22. Choi BY, Yoon MJ, Shin K, Lee YJ, Song YW. Characteristics of pleural effusions in systemic
lupus erythematosus: differential diagnosis of lupus pleuritis. Lupus. 2015;24(3):321–326
PMID: 25318967 doi: 10.1177/0961203314555171
23. Long K, Danoff SK. Interstitial lung disease in polymyositis and dermatomyositis. Clin Chest
Med. 2019;40(3):561–572 PMID: 31376891 doi: 10.1016/j.ccm.2019.05.004
24. Dalakas MC. Inflammatory muscle diseases. N Engl J Med. 2015;372(18):1734–1747
PMID: 25923553 doi: 10.1056/NEJMra1402225
25. Jablonski R, Bhorade S, Strek ME, Dematte J. Recognition and management of myositis-
associated rapidly progressive interstitial lung disease. Chest. 2020;158(1):252–263
PMID: 32059958 doi: 10.1016/j.chest.2020.01.033
26. Perelas A, Arrossi AV, Highland KB. Pulmonary manifestations of systemic sclerosis and
mixed connective tissue disease. Clin Chest Med. 2019;40(3):501–518 PMID: 31376887
doi: 10.1016/j.ccm.2019.05.001
27. Natalini JG, Johr C, Kreider M. Pulmonary involvement in Sjögren syndrome. Clin Chest Med.
2019;40(3):531–544 PMID: 31376889 doi: 10.1016/j.ccm.2019.05.002
28. Bohm M, Gonzalez Fernandez MI, Ozen S, et al. Clinical features of childhood granulomatosis
with polyangiitis (Wegener’s granulomatosis). Pediatr Rheumatol Online J. 2014;12:18
PMID: 24891844 doi: 10.1186/1546-0096-12-18
29. Cabral DA, Canter DL, Muscal E, et al; ARChiVe Investigators Network within the PedVas
Initiative. Comparing presenting clinical features in 48 children with microscopic polyangiitis
to 183 children who have granulomatosis with polyangiitis (Wegener’s). Arthritis Rheumatol.
2016;68(10):2514–2526 PMID: 27111558 doi: 10.1002/art.39729
30. Filocamo G, Torreggiani S, Agostoni C, Esposito S. Lung involvement in childhood onset
granulomatosis with polyangiitis. Pediatr Rheumatol Online J. 2017;15:28 PMID: 28410589
doi: 10.1186/s12969-017-0150-8
31. Jarrot PA, Kaplanski G. Pathogenesis of ANCA-associated vasculitis: an update. Autoimmun Rev.
2016;15(7):704–713 PMID: 26970490 doi: 10.1016/j.autrev.2016.03.007
32. Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria
for the classification of Wegener’s granulomatosis. Arthritis Rheum. 1990;33(8):1101–1107
PMID: 2202308 doi: 10.1002/art.1780330807

503
33. Morishita KA, Moorthy LN, Lubieniecka JM, et al; ARChiVe Investigators Network within
the PedVas Initiative. Early outcomes in children with antineutrophil cytoplasmic antibody-
associated vasculitis. Arthritis Rheumatol. 2017;69(7):1470–1479 PMID: 28371513
doi: 10.1002/art.40112
34. Terrier B, Dechartres A, Girard C, et al; French Vasculitis Study Group. Granulomatosis with
polyangiitis: endoscopic management of tracheobronchial stenosis—results from a multicentre
experience. Rheumatology (Oxford). 2015;54(10):1852–1857 PMID: 26001634 doi: 10.1093/
rheumatology/kev129
35. Thompson GE, Specks U. Update on the management of the respiratory manifestations
of the antineutrophil cytoplasmic antibodies-associated vasculitides. Clin Chest Med.
2019;40(3):573–582 PMID: 31376892 doi: 10.1016/j.ccm.2019.05.012
36. Wang H, Sun L, Tan W. Clinical features of children with pulmonary microscopic
polyangiitis: report of 9 cases. PLoS One. 2015;10(4):e0124352 PMID: 25923706
doi: 10.1371/journal.pone.0124352
37. Cottin V, Bel E, Bottero P, et al; the Groupe d’Etudes et de Recherche sur les Maladies
Orphelines Pulmonaires (GERM“O”P). Respiratory manifestations of eosinophilic
granulomatosis with polyangiitis (Churg-Strauss). Eur Respir J. 2016;48(5):1429–1441
PMID: 27587545 doi: 10.1183/13993003.00097-2016
38. Fina A, Dubus JC, Tran A, et al. Eosinophilic granulomatosis with polyangiitis in children: data
from the French RespiRare cohort. Pediatr Pulmonol. 2018;53(12):1640–1650 PMID: 29943913
doi: 10.1002/ppul.24089
39. Gulati K, McAdoo SP. Anti-glomerular basement membrane disease. Rheum Dis Clin North Am.
2018;44(4):651–673 PMID: 30274629 doi: 10.1016/j.rdc.2018.06.011
40. Weiss PF. Pediatric vasculitis. Pediatr Clin North Am. 2012;59(2):407–423 PMID: 22560577
doi: 10.1016/j.pcl.2012.03.013
41. Barut K, Sahin S, Kasapcopur O. Pediatric vasculitis. Curr Opin Rheumatol. 2016;28(1):29–38
PMID: 26555448 doi: 10.1097/BOR.0000000000000236
42. Nathan N, Sileo C, Calender A, et al; French Sarcoidosis Group (GSF); Silicosis Research Group.
Paediatric sarcoidosis. Paediatr Respir Rev. 2019;29:53–59 PMID: 30917882
43. Sharp M, Eakin MN, Drent M. Socioeconomic determinants and disparities in sarcoidosis. Curr
Opin Pulm Med. 2020;26(5):568–573 PMID: 32732595 doi: 10.1097/MCP.0000000000000704
44. Allen CE, Merad M, McClain KL. Langerhans-cell histiocytosis. N Engl J Med.
2018;379(9):856–868 PMID: 30157397 doi: 10.1056/NEJMra1607548
45. Papanikolaou I, Kagouridis K, Papiris SA. Patterns of airway involvement in inflammatory
bowel diseases. World J Gastrointest Pathophysiol. 2014;5(4):560–569 PMID: 25400999
doi: 10.4291/wjgp.v5.i4.560

CHAPTER
27
Pallav Halani, MD, FAAP
Timothy J. Vece, MD
Adrienne P. Savant, MD, MS
CASE REPORT 27-1

An infant born at 37 weeks had tachypnea, retractions, and hypoxemia at her
4-month checkup. She had a previous history of respiratory syncytial virus–
negative bronchiolitis at 2 months of age; however, the patient’s mother stated
she never fully recovered from her previous illness. Because of her hypoxemia in
the office, she was transferred to a local emergency department and adminis-
tered an albuterol treatment that did not help. She was admitted to the general
pediatric team, and a pulmonary consultation was obtained. Test results for viral
respiratory pathogens were negative. Chest radiography was performed and
showed only hyperinflation. A computed tomography scan of the chest showed
ground-glass opacities in the right middle lobe, lingula, and paramedian por-
tions of the upper and lower lobes bilaterally with sparing of the periphery.
Results of genetic studies for surfactant protein mutations were negative. Lung
biopsy results showed no evidence of clinically significant inflammation and
clusters of bombesin-positive cells in the bronchioles, consistent with neuro-
endocrine cell hyperplasia of infancy. Supportive therapy was provided.
Introduction
The term interstitial lung disease (ILD) encompasses a group of rare, hetero-
geneous disorders characterized by diffuse pulmonary disease and disordered
gas exchange.1 Although a strict definition implies an abnormality of the inter-
stitium, there are some diseases that have minimal interstitial defect but have
pathological abnormalities in the airspaces and distal airway that are considered
under the broad term of ILD.2 For this reason, some authors prefer the term
diffuse lung disease (DLD). In this chapter, children’s ILD will be used to refer
to children’s diffuse and interstitial lung disease. Although individual children’s
ILD entities are rare, group estimates of disease prevalence range from 0.13 to
16.2 cases per 100,000, depending on disease definitions and inclusion criteria,
which would make these ILDs nearly as common as cystic fibrosis in the
United States.3
505

506
Previously, description and management of children’s ILD were largely

based on case reports and small series. The classification of children’s ILD
was fit to match adult classification schemes; however, there were clinically
significant differences in clinical outcomes and responses to treatment,4
leading to the recognition that new classifications were required (Boxes 27-1
and 27-2). Guidelines have been developed, with both the American Thoracic
Society clinical practice guideline (ATS CPG) focusing on children younger
than 2 years5 and European protocols focusing on all childhood ages.6
The manifestations of these diseases are within a developing lung, leading to a
more tailored, child-centered approach to care. This chapter focuses on the clini-
cal presentation, pathophysiological characteristics, and diagnostic approach
to children’s ILD. Some of the common children’s ILDs, management, and
prognosis are also discussed.
Age at presentation results in varied clinical appearances, with distinctly differ-
ent disorders in patients younger than 2 years and those aged 2 to 18 years. The
severity of the disease at presentation correlates with prognosis.7 Neonatal
presentation often occurs shortly after birth in term infants who have sub-
stantial respiratory distress leading to rapidly progressive respiratory failure
requiring mechanical ventilation. If an infant born preterm has respiratory
distress that does not follow the anticipated course for their level of prematurity,
children’s ILD should also be considered.6
Presentation after the neonatal period is nonspecific, with a variety of pul-
monary symptoms such as tachypnea, cough, wheeze, digital clubbing, hypoxia,
retractions, and crackles; however, auscultation results may be normal.6 Failure
to thrive can also be seen as a comorbidity. Respiratory syncytial virus bron-
chiolitis that does not seem to resolve may be an indication of ILD.6 In older
children (2–18 years of age), in addition to these signs and symptoms,
exercise-induced shortness of breath may be the presentation.
When a patient presents in a manner that suggests ILD, a systematic approach
to evaluation is essential to distinguish between primary pediatric ILD and
other conditions. A thorough medical history and physical examination will
often provide clues to an underlying diagnosis. A family history is most likely
to be positive in infants because many forms of ILD have a genetic basis.8 In a
retrospective analysis, 10% of case siblings were affected by similar diseases,9
and up to 34% of patients had a family history of lung disease in another study.10
It is also important to obtain information about exposures, such as to radiation,
birds, or toxins. In one report, only 25% of the clinicians’ initial diagnoses
based on patient history were correct except in cases in which a history of a
bird exposure led to a diagnosis of hypersensitivity pneumonitis.2 A thorough
review of systems, focusing on joints, skin, kidneys, sinuses, eyes, and nervous

507
Chapter 27—Interstitial Lung Disease
system, may raise suspicion of known causes of ILD, such as collagen vascular
diseases.8 In addition, pulmonary hypertension, reflux, and aspiration should
be excluded.11 Testing should be tailored based on the patient’s presentation
and the severity of the respiratory disorder. Regardless of the presentation,
common causes of the clinical symptoms should be excluded, such as cystic
fibrosis, congenital or acquired immunodeficiency, congenital heart disease,
bronchopulmonary dysplasia, pulmonary infection, primary ciliary dyskinesia
manifesting with newborn respiratory distress, and recurrent aspiration.
Once the common diseases have been eliminated, the rubric of children’s ILD
can be applied if the patient has at least 3 of 4 criteria: (a) respiratory symp-
toms, (b) respiratory signs, (c) hypoxemia, and (d) diffuse radiographic
abnormalities (Box 27-3).5
Box 27‑1
Children’s Interstitial Lung Disease More Prevalent in Infancy
(Ages 0–2 Years)
Diffuse developmental disorders Specific conditions of undefined cause
ū Acinar dysplasia ū Neuroendocrine cell hyperplasia
ū Congenital alveolar dysplasia of infancy
ū Alveolar capillary dysplasia with ū Pulmonary interstitial glycogenosis
misalignment of pulmonary veins Surfactant dysfunction disorders
Growth abnormalities reflecting ū Surfactant protein B (SFTPB)
deficient alveolarization mutations
ū Pulmonary hypoplasia ū Surfactant protein C (SFTPC)
ū Chronic neonatal lung disease mutations
• Prematurity-related chronic lung ū ABCA3 mutations
disease (bronchopulmonary ū Histological findings consistent
dysplasia) with surfactant dysfunction
• Acquired chronic lung disease in disorder without yet recognized
term infants genetic cause
ū Structural pulmonary changes with
chromosomal abnormalities
• Trisomy 21, others
ū Abnormalities associated with
congenital heart disease in children
with normal chromosomes
Derived from Kurland G, Deterding RR, Hagood JS, et al; American Thoracic Society Committee on
Childhood Interstitial Lung Disease (chILD) and the chILD Research Network. An official American Thoracic
Society clinical practice guideline: classification, evaluation, and management of childhood interstitial lung
disease in infancy. Am J Respir Crit Care Med. 2013;188(3):376–394; and Deutsch GH, Young LR, Deterding RR,
et al; Pathology Cooperative Group; ChILD Research Co-operative. Diffuse lung disease in young children:
application of a novel classification scheme. Am J Respir Crit Care Med. 2007;176(11):1120–1128.

508
Box 27‑2
Children’s Interstitial Lung Disease More Prevalent
in Childhood and Adolescence (Ages 2–18 Years)
Disorders of the normal host Disorders related to systemic disease
ū Infections and postinfectious process
processes ū Immune-related disorders
ū Disorders related to environmental ū Storage disease
agents: hypersensitivity pneumonia, ū Sarcoidosis
toxic inhalation ū Langerhans cell histiocytosis
ū Aspiration syndromes ū Malignant infiltrates
ū Eosinophilic pneumonias ū COVID-19 (COVID-ILD)
Disorders of the immunocompromised Disorders masquerading as interstitial
host lung disease
ū Opportunistic infections ū Arterial hypertensive vasculopathy
ū Disorders related to therapeutic ū Congestive vasculopathy
intervention
ū Lymphatic disorders
ū Disorders related to transplant
and rejection ū Congestive changes related to cardiac
dysfunction
ū Diffuse alveolar damage of
unknown cause Unclassified
Derived from Kurland G, Deterding RR, Hagood JS, et al; American Thoracic Society Committee on Childhood
Interstitial Lung Disease (chILD) and the chILD Research Network. An official American Thoracic Society clini-
cal practice guideline: classification, evaluation, and management of childhood interstitial lung disease in
infancy. Am J Respir Crit Care Med. 2013;188(3):376–394; and Fan LL, Dishop MK, Galambos C, et al; Children’s
Interstitial and Diffuse Lung Disease Research Network (chILDRN). Diffuse lung disease in biopsied children 2
to 18 years of age: application of the chILD classification scheme. Ann Am Thorac Soc. 2015;12(10):1498–1505.
Box 27‑3
Criteria for Diagnosis of Children’s Diffuse and Interstitial Lung Disease
Presence of 3 of the following, in absence of an identified cause:
ū Respiratory symptoms (cough, rapid and/or difficult breathing, and exercise
intolerance)
ū Respiratory signs (tachypnea, adventitious sounds, retractions, digital clubbing,
and failure to thrive)
ū Hypoxemia
ū Diffuse abnormalities at radiography or computed tomography
From Kurland G, Deterding RR, Hagood JS, et al; American Thoracic Society Committee on Childhood Inter-
stitial Lung Disease (chILD) and the chILD Research Network. An official American Thoracic Society clinical
practice guideline: classification, evaluation, and management of childhood interstitial lung disease in
infancy. Am J Respir Crit Care Med. 2013;188(3):376–394. © 2013 American Thoracic Society.

509
Pathophysiology
Interstitial lung disease is characterized by a pathological process affecting
the interstitial space in the lung. In the normal lung, the interstitium, the area
between the alveolar space and the capillary, is approximately 1 cell thick.
However, in patients with ILD, this area becomes thickened. Diffusion of
oxygen across the alveolus to the capillary is proportional to the thickness
of the area. In patients with ILD, oxygen takes longer to diffuse across the
thickened interstitium. This delay in diffusion leads to a compensatory
increase in minute ventilation that is clinically manifest by tachypnea. Thus,
tachypnea without desaturation is often the earliest symptom of ILD, espe-
cially in infants. When severe enough, the diffusion impairment cannot be
overcome by increasing minute ventilation, and hypoxemia ensues.
The thickened interstitium likely occurs because inflammation leads to the
deposition of connective tissue that forms areas of fibrosis. In some forms
of ILD, there is little or no inflammation visible on lung histopathological
studies, and treatment with anti-inflammatory agents does not consistently
lead to clinical improvement. Thus, inflammation is not the sole mechanism
for ILD. A second mechanism involves epithelial injury, leading to abnormal
repair of the lung.12 In children, the process of interstitial thickening is affected
by age-specific lung growth and development. Children’s lungs continue to
grow beyond infancy, so alterations in normal growth occur from the under-
lying disease. In addition, genetic variations can modulate susceptibility and
response to various injuries.9
Evaluation
The ATS CPG strongly recommends that diagnostic testing be performed
to determine the exact form of ILD.5 The order of diagnostic testing depends
on the clinical presentation and severity. If the clinical presentation is more
slowly progressive, a stepwise approach to diagnostic evaluation can be used.
In addition to ruling out common diseases that manifest in a manner similar
to that of ILD, this section will discuss specific evaluation of children’s ILD,
although the order of evaluation may vary for each patient.
Echocardiography
Pulmonary vascular disease and structural heart disease can masquerade
as ILD; therefore, the ATS CPG strongly recommends an echocardiogram.5
In addition, patients with ILD with pulmonary hypertension have a
worse prognosis.5
Genetic Testing
Single gene defects can result in children’s ILD, so genetic testing can help to
provide a diagnosis, reduce or eliminate the need for invasive testing such as

510
lung biopsy, and provide prognostic information. However, results from

genetic testing often take time, thereby limiting use in rapidly progressive
cases, and interpretation is not always straightforward. Regardless, patients
with a family history of ILD should undergo genetic testing.
Clinical presentation can guide genetic testing. For example, patients with
refractory pulmonary hypertension and associated congenital abnormali-
ties should be tested for the FOXF1 deletions as a cause of alveolar capil-
lary dysplasia, a weak recommendation from the ATS CPG.5 Patients with
hypothyroidism and/or neurological abnormalities, such as hypotonia and
developmental delay, should undergo analysis for NKX2.1 mutations, a strong
recommendation from the ATS CPG.5 Older children who present with chil-
dren’s ILD are strongly recommended to be assessed for surfactant mutations
ABCA3 and SFTPC and are weakly recommended to be assessed for receptors
for granulocyte-macrophage colony–stimulating factor (GM-CSF), CSF2RA,
and CSFR2B, along with serum levels for GM-CSF.5 The ATS CPG strongly
recommends newborns with children’s ILD and severe, rapidly progressive
disease or a family history be tested for genetic abnormalities associated
with neonatal ILD, such as SFTPB, SFTPC, and ABCA3.5
Radiography
Radiographic evaluation of a child suspected of having ILD should begin
with a chest radiograph. Although 10% of chest radiographs in adults with
ILD can be normal, findings are usually abnormal in children with ILD.2,4
The chest radiograph of a child with ILD (Figure 27-1) reveals diffuse
pulmonary infiltrates or specific patterns described as reticular, nodular,
ground-glass, or honeycombing.
To delineate parenchymal abnormalities further, a high-resolution computed
tomography (HRCT) scan of the chest should be obtained (Figure 27-2). The
ATS CPG weakly recommends obtaining a thin-section computed tomography
(CT) scan of the chest at a center with expertise in pediatric chest CT and
strongly recommends using the lowest radiation dose.5 Computed tomography
scans help to characterize the nature and distribution of the disease optimally.
For some children’s ILD diagnoses, the radiographic appearance can be diag-
nostic, thereby reducing the need for further diagnostic evaluation, but others
have nonspecific findings that may provide guidance for further testing.13 In
a review of 20 children with ILD proved by means of biopsy, 56% of the con-
fident first-choice diagnoses from HRCT were correct.1,14 High-resolution CT
scans of the chest can help evaluate the parenchyma of these children and help
the surgeon determine the optimal site for biopsy.
In adults and older children, patients perform a voluntary breath hold at
full inspiration and expiration during radiography. However, infants and
young children cannot cooperate with breath holding, and respiratory motion

511
Figure 27-1. Chest radiographs. Frontal (A)

and lateral (B) chest radiographs show
bilateral interstitial and alveolar opacities in a
child with juvenile rheumatoid arthritis and
biopsy-diagnosed follicular bronchiolitis.
Frontal chest radiograph (C) shows hyperinfla-
tion with coarse, diffuse bilateral thickened
interstitial markings in a child with an ABCA3
gene mutation.
Figure 27-2. Axial high-resolution computed tomography images. A, Extensive diffuse

ground-glass alveolar filling, with associated interstitial thickening. There are also multi-
ple small- to moderate-sized cysts present within both lungs. B, Mosaic pattern with areas of
denser and of more lucent lung in all lobes—the patient has abnormality in the ABCA3 gene.
C, Peripheral intralobular interstitial and interlobular septal thickening—this patient has juvenile
dermatomyositis.

512
produces motion artifacts that limit the quality of the imaging study.14 The
alternative is to use anesthesia with intubation to obtain acceptable images.
Long and colleagues15 developed a method that uses sedation combined with
controlled ventilation, as used in infant pulmonary function tests (iPFTs), to
provide a controlled pause in respiration.14 During this procedure, hyperventi-
lation of a child with a face mask produces a respiratory pause that is long
enough (6–12 seconds) to scan the entire lung. Images can thus be obtained at
full inspiration at 25 cm H2O and at full expiration at 0 cm H2O. It is important
to obtain high-quality scans, such as those obtained with controlled ventilation
HRCT, because false-positive cases have been found with conventional scans.14
Radiographic findings for children’s ILD can vary based on the specific illness.
Patients with surfactant-related disorders may have ground-glass opacities and
thickening of the interlobular septae.13 In addition, the term crazy paving has
been applied to the pattern seen in interlobular thickening.16 Patients with
ABCA3 and SFTPC abnormalities also had parenchymal cysts.5 Pathogno-
monic findings of neuroendocrine cell hyperplasia of infancy (NEHI) at chest
CT include geographic ground-glass opacities located centrally in the right
middle lobe and lingula.17 (See Figure 27-3.) With a compatible clinical
picture, chest CT scans are now considered sufficient to diagnose NEHI
without performing lung biopsy.18 Postinfectious bronchiolitis obliterans
also has characteristic CT findings, including mosaic perfusion, vascular
attenuation, and central bronchiectasis that are diagnostic and that correlate
with the approximate clinical history.19 Further specific radiographic evalua-
tions for various forms of children’s ILD continue to be investigated.
Physiological Testing
Pulmonary function tests are sometimes able to indicate functional patterns
that aid in distinguishing different disorders and correlate with radiography
Figure 27-3. High-resolution axial (A) and coronal (B) computed tomography images in lung
window demonstrate geographic ground-glass opacities with a right middle lobe and lingular
predominance, as well as less confluent central involvement of the right lower, left lower, right
upper, and left upper lobes.

513
and histological findings.1 Pulse oximetry and blood gas analysis are important
to determine the degree of hypoxemia. Most patients will be normoxemic but
may desaturate with sleep or exercise.1 Exercise tolerance studies or evalua-
tion of 6-minute walk distance may be of clinical use. Spirometry will reveal
a pattern of restrictive lung disease, with decreased lung volumes sometimes
with an obstructive component of air trapping.1 Diffusion capacity will be
low, although it may normalize when corrected for alveolar volume.1
Infant pulmonary function testing provides a physiological assessment and
aids in diagnosis. The ATS CPG weakly recommends iPFTs for better charac-
terization of physiological alterations.5 Spirometry and plethysmography can
now be used in infants at many major medical centers. Results from several
reports show that iPFTs can help distinguish disease, correlate with radio-
graphic and histological findings, and be used for assessment of therapy.1,20 The
usefulness of iPFTs in diagnosing ILD in infants is limited by the inability to
perform this test routinely in patients who require ventilatory support and the
limited number of centers that perform the test. To classify the characteristics
of the various forms of ILD better, more iPFT data need to be obtained.
Bronchoalveolar Lavage
Pathological evaluation with bronchoalveolar lavage (BAL) is important to rule
out infections and aid in the diagnosis of ILD. The entire aspirate is recovered
and sent for cell count, infectious studies (microbiology and polymerase chain
reaction–based assays), and lipid and hemosiderin stains. Cytological findings
can support specific diagnoses, such as infections, aspiration, and pulmonary
hemorrhage; alveolar proteinosis; lysosomal storage disorders; and histio-
cytosis.1 In a prospective series of ILD cases, a specific diagnosis was deter-
mined from the BAL in 17% of cases.21 When evaluated retrospectively, the
diagnosis was determined in 30% of patients. Although the usefulness of
BAL is limited, the ATS CPG weakly recommends BAL to exclude infection
or airway abnormalities.5
Lung Biopsy
Lung biopsy is the gold standard in diagnosing ILD. Lung biopsies were well
tolerated in one review, even during use of mechanical ventilation with extra-
corporeal membrane oxygenation, with no mortality and minimal morbidity.22
The ATS CPG strongly recommends lung biopsy via video-assisted thoraco-
scopic surgery (VATS) in neonates and infants with children’s ILD who have
not had disease identified by means of other tests or when there is clinical
urgency.5 Even in small infants, VATS can dramatically reduce the morbidity
associated with open thoracotomy.5 A transthoracic procedure has a shorter
operating time, a lower incidence of chest tube placement, and a shorter hospi-
talization,23 although it requires a surgeon who is familiar with the technique.
Current recommendations are to perform biopsies in more than 1 lobe,
including 1 area that is clearly affected and 1 area that is newly evolving or

514
with an unaffected appearance on CT scans.24 In a review of a small series of

cases, there was no increase in complications when biopsy was performed in
more than 1 lobe.23
Once the specimen has been obtained, proper processing of the tissue is critical
for a comprehensive diagnostic evaluation. The ATS CPG recommends follow-
ing published protocols to minimize improper handling and ensure uniform
processing.5 Tissue should be obtained for culture, light microscopy, immuno-
histochemistry (for surfactant proteins), and electron microscopy analyses.
Useful stains include hematoxylin and eosin, trichrome, pentachrome, and
periodic acid–Schiff with diastase.24 Other immunostains, such as bombesin
in NEHI and vimentin in pulmonary interstitial glycogenosis (PIG), have been
described as diagnostic aids for specific causes of ILD. Electron microscopy
shows distinctive type II cell abnormalities in specific surfactant gene muta-
tions.25 Other characteristic ultrastructural findings may indicate the presence
of a metabolic disorder or PIG.26
Specific Diseases in Infancy

It is not practical to discuss all forms of children’s ILD; however, a brief discus-
sion of the newer entities, especially those that manifest in infancy, is provided
here. Additional causes of children’s ILD are continually being discovered and
include coatomer-associated protein complex subunit α mutations leading to
COPA syndrome, FOXF1 mutations in alveolar capillary dysplasia with
misalignment of the pulmonary veins, lipopolysaccharide-responsive beige-like
anchor protein deficiency from mutations in the LRBA gene, FLNA mutations
leading to abnormal filamin A, and TMEM173 mutations leading to stimulator of
interferon genes–associated vasculopathy with onset in infancy.3,5,18,27
Surfactant is a mixture of proteins and phospholipids that prevent atelectasis
at end expiration. Both surfactant protein B and surfactant protein C are
important in lowering the surface tension in the alveoli.11 The ABCA3 protein
is believed to play a role in surfactant processing and transport within the
alveolar type II cell.28 Transcription for surfactant proteins is under the con-
trol of the gene NKX2.1.29 Once surfactant has been produced, it is cleared
by macrophages under the control of GM-CSF. Mutations in any of these
components can lead to ILD.
Surfactant protein B deficiency is a rare disorder, with clinical estimates of
1 per million live births.11 These infants typically present within the first few
hours after birth with respiratory failure. The neonates are clinically similar to
infants with respiratory distress syndrome (RDS), except that they are born at
term and the RDS does not resolve. The only treatment for these patients is
lung transplant, without which the disease is fatal.11
Surfactant protein C deficiency has a variable manifestation. The onset of
symptoms often occurs in term neonates who present with clinical symptoms

515
similar to those of RDS, but symptoms can occur later in childhood and even
in adulthood, when manifestation is typical for later-onset ILD. Treatment is
supportive, and many general ILD treatments have been used. Outcomes cover
a wide spectrum, with some children requiring lung transplant and others
improving enough over time that they no longer require supplemental
oxygen.11
A deficiency of ABCA3 protein also has a varied manifestation and clinical
outcome. ABCA3 deficiency manifests in the neonatal period with respiratory
distress. Treatment is generally supportive. Outcome ranges from death in the
newborn period to survival into the teenage years, with occasional survival
until the patient’s 20s or 30s.28 Reports of children with mild disease suggest
that some ABCA3 protein variants may lead to a milder course with
prolonged survival.28
Mutations and deletions of NKX2.1 have been seen in children with pulmo-
nary disease, neurological findings (such as hypotonia), and hypothyroidism,
with variable manifestations such that not all 3 organ systems are affected.29
Because of the disruption of surfactant transcription, patients may present
with severe respiratory distress in the neonatal period, but there is significant
phenotypic variation, with neurological manifestations being subtle or
occurring later in life.30 Patients also can have recurrent infections.30
Patients with mutations in the receptors for GM-CSF, CSF2RA, and CSF2RB
have pulmonary alveolar proteinosis in which surfactant accumulates in the
alveoli.31 Patients at any age can present with pulmonary symptoms of dyspnea;
cough; fatigue; weight loss; and, less commonly, sputum production and fever.31
Pulmonary interstitial glycogenosis is a form of ILD that also manifests in
the neonatal period and has been described in both term and preterm infants.
There is an association with alveolar simplification, pulmonary hypertension,
and structural heart disease.32 These infants are typically tachypneic and
hypoxic with crackles at physical examination and hyperinflation at radio-
graphic evaluation. This illness is postulated to be caused by a developmental
disorder of pulmonary mesenchymal cells, not an inflammatory or reactive
process. Experts believe this is the same entity as cellular interstitial pneumo-
nitis of infants. The long-term outcome is favorable in most patients.26
Neuroendocrine cell hyperplasia of infancy was referred to as persistent
tachypnea of infancy before the characteristic histopathological findings were
described.33 Children with NEHI have an onset of symptoms usually in the
first year after birth, with tachypnea, failure to thrive, and need for supple-
mental oxygen, but NEHI can manifest at later ages.27 These patients have
persistent tachypnea, hypoxia, and crackles. Radiographic evaluation reveals
hyperexpansion of the lungs and characteristic CT findings. Treatment is
mainly supportive, often including oxygen supplementation for several years.
Neuroendocrine cell hyperplasia of infancy has a favorable outcome with a

516
waxing and waning course but slow and steady improvement, often over
several years, with no known associated mortality.33
Management
Treatment of ILD is limited. The mainstay of treatment is supportive, specifi-
cally with oxygen. Most children with ILD have difficulty with diffusion
of oxygen across the alveolar–capillary barrier and become tachypneic to
maintain oxygen saturations. Administration of oxygen leads to less tachypnea.
If the underlying disease is known, then treatment toward the specific cause
should help the lung disease. Additional therapeutic recommendations from
both the Children’s Interstitial Lung Disease Research Network and chILD-EU
include maintaining adequate nutrition, treating underlying gastroesophageal
reflux or aspiration during feeding, immunizing against respiratory pathogens,
treating intercurrent illnesses aggressively, and avoiding environmental
tobacco smoke and other pollutants.5,6 Furthermore, patients may require
treatment with noninvasive and invasive ventilation.18
Close attention to growth parameters is important because failure to thrive is a
common complication of ILD. Many children with ILD have increased calorie
needs because of tachypnea and inflammation, so they require close monitoring
and, sometimes, interventions. In some cases, addition of supplemental
oxygen will reduce tachypnea and improve weight gain, but many children
need high-calorie formulas or supplemental feeding to augment caloric intake.
Evaluation for supplemental enteral feeding via nasogastric or gastrostomy
tube should be considered in addition to evaluation for other causes of failure to
thrive, including aspiration and gastroesophageal reflux.
Infants and children with ILD are at risk of developing respiratory decompen-
sation caused by viral respiratory infections. Many will have limited respira-
tory reserve and will require hospitalization for monitoring, hydration, and
management of supplemental oxygen during such illnesses. Some, especially
those with more severe forms of ILD, may require mechanical ventilation.
Good communication between the primary care professional and the
pulmonologist facilitates optimal care.
Beyond supportive care and disease-specific treatment, many modalities have
been tried. Treatment effect can be judged by decreases in cough and dyspnea
and by improvements in pulmonary function test results and saturation; how-
ever, radiographic changes do not occur quickly enough to follow frequently.9
Therapeutic agents for ILD can include immunomodulating agents, especially
corticosteroids, which have a highly variable response. The ATS CPG states:
“Given the limited evidence of a beneficial effect on clinical outcomes and the
well-known side effects of immunosuppressive medications, the decision about
whether or not to initiate trial of immunosuppressive therapy must be made on
a case-by-case basis.”5

517
Various immunomodulating treatment regimens have been used, ranging

from daily oral doses to monthly intravenous pulses of steroids. The opti-
mal dose, frequency, and duration of therapy, as well as when to initiate or
discontinue therapy and the relative harm compared with adverse effects,
remains unclear.12 Therefore, using Delphi methodology, the European
protocols developed consensus regarding treatment approaches for recom-
mended dosages and response rates, as well as ongoing monitoring via
improvements in physiological parameters.6 Hydroxychloroquine therapy
has been successful in the treatment of some cases, but the clinical response
is highly variable. Other steroid-sparing agents have been tried, such as
azathioprine, cyclophosphamide, methotrexate, cyclosporine, and intra-
venous immunoglobulin.1 However, many reports of treatment are from
case series that predate the current histological classification of pediatric
ILD. There is a substantial need for research in this area.18
Azithromycin has also been used, although as with the remainder of children’s
ILD, evidence is limited, often via case reports.34–37 Azithromycin not only is
anti-infective but also has anti-inflammatory properties.38 The European
protocols included azithromycin in their treatment consensus.6
Lung transplant is an option for progressive ILD with respiratory failure. The
ATS CPG strongly recommends referral to a pediatric lung transplant center
for infants with severe, life-threatening disease.5 Although the median post-
transplant survival rate for children is 7.6 years,39 some children survive much
longer. Complications from lung transplant are common, with bronchiolitis
obliterans being the most common, as well as hypertension, renal dysfunction,
diabetes mellitus, and hyperlipidemia (see Chapter 42, Lung Transplantation).
Infants who receive lung transplants for surfactant protein B deficiency have
outcomes similar to those who receive transplants for other reasons.40 There
are some anecdotal reports of ILD recurrence in the transplanted lung.12
Prognosis
A prognosis based on clinical symptoms at initial evaluation can be deter-
mined using the severity of illness classification. The score includes the
following elements: presence or absence of symptoms; saturations at rest,
during sleep, or with activity; and evidence of pulmonary hypertension. The
higher the score, the higher the probability of decreased survival, with each
increase in score increasing the risk of death by an estimated 140%.1,7
The outcome for a child with ILD depends on the underlying cause. The
higher the illness severity on the basis of symptoms at initial presentation, the
higher the probability of mortality.1 Pulmonary hypertension is the greatest
predictor of mortality, with a 5-year survival of 38% compared with a 5-year
survival of 64% in those without pulmonary hypertension.7 In a retrospective
study of diffuse lung disease in children younger than 2 years, only 30.2%

518
died, and 50% had ongoing pulmonary symptoms at follow-up; however,

children with certain diseases, such as PIG and NEHI, had no mortality,
whereas children with diffuse developmental disorders of the lung had 100%
mortality.10 It is important to have an accurate diagnosis before discussing
the prognosis with the family.
When to Refer
Refer to a pediatric pulmonologist for the following:
X Hypoxia and tachypnea of unknown cause
X Radiographic findings of pulmonary ground-glass opacities
X Clubbing
X Chronic dry cough, tachypnea, dyspnea, retractions, cyanosis, clubbing,
and failure to thrive in some combination
X Unexplained failure to thrive (found in two-thirds of children with ILD)9,10
X Unexplained exercise intolerance or frequent respiratory infections
(crackles may or may not be present)
When to Admit
X Upper respiratory infection in a child with known ILD, especially with
increasing hypoxemia
X Prompt evaluation for any change in the patient’s baseline respiratory
health, such as increased tachypnea or dyspnea or a reduction from
baseline oxyhemoglobin saturation
key points
} Interstitial lung disease is a rare, heterogeneous group of disorders, mainly
pulmonary, and characterized by diffuse pulmonary disease with disordered
gas exchange.
} Interstitial lung disease is any entity that results in derangement of the
alveolar-capillary interface, often characterized clinically with tachypnea,
crackles, hypoxemia, or diffuse infiltrates.
} Diagnosis is one of exclusion of known causes; lung biopsy is the gold standard.
} Treatment may include supportive therapy with oxygen supplementation,
immunomodulating agents, or lung transplant, depending on the severity of
the symptoms.
} Close monitoring of nutritional status, with appropriate intervention, is
important.
} Outcomes vary widely, depending on the specific diagnosis, but are not
uniformly fatal.

519
References
1. Fan LL, Deterding RR, Langston C. Pediatric interstitial lung disease revisited. Pediatr Pulmonol.
2004;38(5):369–378 PMID: 15376335 https://doi.org/10.1002/ppul.20114
2. Fan LL, Langston C. Chronic interstitial lung disease in children. Pediatr Pulmonol.
1993;16(3):184–196 PMID: 8309744 https://doi.org/10.1002/ppul.1950160309
3. Vece TJ, Young LR. Update on diffuse lung disease in children. Chest. 2016;149(3):836–845
PMID: 26502226 https://doi.org/10.1378/chest.15-1986
4. Fan LL, Mullen AL, Brugman SM, Inscore SC, Parks DP, White CW. Clinical spectrum of
chronic interstitial lung disease in children. J Pediatr. 1992;121(6):867–872 PMID: 1447647
https://doi.org/10.1016/S0022-3476(05)80330-0
5. Kurland G, Deterding RR, Hagood JS, et al; American Thoracic Society Committee on Childhood
Interstitial Lung Disease (chILD) and the chILD Research Network. An official American
Thoracic Society clinical practice guideline: classification, evaluation, and management of
childhood interstitial lung disease in infancy. Am J Respir Crit Care Med. 2013;188(3):376–394
PMID: 23905526 https://doi.org/10.1164/rccm.201305-0923ST
6. Bush A, Cunningham S, de Blic J, et al; chILD-EU Collaboration. European protocols
for the diagnosis and initial treatment of interstitial lung disease in children. Thorax.
2015;70(11):1078–1084 PMID: 26135832 https://doi.org/10.1136/thoraxjnl-2015-207349
7. Fan LL, Kozinetz CA. Factors influencing survival in children with chronic interstitial
lung disease. Am J Respir Crit Care Med. 1997;156(3 pt 1):939–942 PMID: 9310017
https://doi.org/10.1164/ajrccm.156.3.9703051
8. Fauroux B, Epaud R, Clément A. Clinical presentation of interstitial lung disease in children.
Paediatr Respir Rev. 2004;5(2):98–100 PMID: 15135118 https://doi.org/10.1016/j.prrv.2004.01.003
9. Clement A,; ERS Task Force. Task force on chronic interstitial lung disease in immunocompetent
children. Eur Respir J. 2004;24(4):686–697 PMID: 15459150
https://doi.org/10.1183/09031936.04.00089803
10. Deutsch GH, Young LR, Deterding RR, et al; Pathology Cooperative Group; ChILD Research
Co-operative. Diffuse lung disease in young children: application of a novel classification scheme.
https://doi.org/10.1164/rccm.200703-393OC
11. Hamvas A. Inherited surfactant protein-B deficiency and surfactant protein-C associated disease:
clinical features and evaluation. Semin Perinatol. 2006;30(6):316–326 PMID: 17142157
https://doi.org/10.1053/j.semperi.2005.11.002
12. Clement A, Eber E. Interstitial lung diseases in infants and children. Eur Respir J.
2008;31(3):658–666 PMID: 18310399 https://doi.org/10.1183/09031936.00004707
13. Toma P, Secinaro A, Sacco O, et al. CT features of diffuse lung disease in infancy. Radiol Med.
2018;123(8):577–585 PMID: 29569218 https://doi.org/10.1007/s11547-018-0878-3
14. Brody AS. Imaging considerations: interstitial lung disease in children. Radiol Clin North Am.
2005;43(2):391–403 PMID: 15737375 https://doi.org/10.1016/j.rcl.2004.12.002
15. Long FR, Castile RG. Technique and clinical applications of full-inflation and end-exhalation
controlled-ventilation chest CT in infants and young children. Pediatr Radiol. 2001;31(6):413–422
PMID: 11436888 doi: 10.1007/s002470100462
16. Johkoh T, Itoh H, Müller NL, et al. Crazy-paving appearance at thin-section CT: spectrum
of disease and pathologic findings. Radiology. 1999;211(1):155–160 PMID: 10189465
https://doi.org/10.1148/radiology.211.1.r99ap10155
17. Brody AS, Guillerman RP, Hay TC, et al. Neuroendocrine cell hyperplasia of infancy: diagnosis
with high-resolution CT. AJR Am J Roentgenol. 2010;194(1):238–244 PMID: 20028928
https://doi.org/10.2214/AJR.09.2743
18. Deterding RR, DeBoer EM, Cidon MJ, et al. Approaching clinical trials in childhood
interstitial lung disease and pediatric pulmonary fibrosis. Am J Respir Crit Care Med.
2019;200(10):1219–1227 PMID: 31322415 https://doi.org/10.1164/rccm.201903-0544CI
19. Moonnumakal SP, Fan LL. Bronchiolitis obliterans in children. Curr Opin Pediatr.
2008;20(3):272–278 PMID: 18475095 https://doi.org/10.1097/MOP.0b013e3282ff62e9
20. Kerby GS, Wagner BD, Popler J, et al. Abnormal infant pulmonary function in young children with
neuroendocrine cell hyperplasia of infancy. Pediatr Pulmonol. 2013;48(10):1008–1015
21. Fan LL, Lung MC, Wagener JS. The diagnostic value of bronchoalveolar lavage in
immunocompetent children with chronic diffuse pulmonary infiltrates. Pediatr Pulmonol.
1997;23(1):8–13 PMID: 9035193
https://doi.org/10.1002/(SICI)1099-0496(199701)23:1<8::AID-PPUL1>3.0.CO;2-N

520
22. O’Reilly R, Kilner D, Ashworth M, Aurora P. Diffuse lung disease in infants less than 1 year of
age: histopathological diagnoses and clinical outcome. Pediatr Pulmonol. 2015;50(10):1000–1008
23. Fan LL, Kozinetz CA, Wojtczak HA, Chatfield BA, Cohen AH, Rothenberg SS. Diagnostic
value of transbronchial, thoracoscopic, and open lung biopsy in immunocompetent children with
chronic interstitial lung disease. J Pediatr. 1997;131(4):565–569 PMID: 9386660
https://doi.org/10.1016/S0022-3476(97)70063-5
24. Langston C, Patterson K, Dishop MK, et al; chILD Pathology Co-operative Group. A protocol for
the handling of tissue obtained by operative lung biopsy: recommendations of the chILD Pathology
Co-operative Group. Pediatr Dev Pathol. 2006;9(3):173–180 PMID:
16944976 https://doi.org/10.2350/06-03-0065.1
25. Edwards V, Cutz E, Viero S, Moore AM, Nogee L. Ultrastructure of lamellar bodies in
congenital surfactant deficiency. Ultrastruct Pathol. 2005;29(6):503–509 PMID: 16316951
https://doi.org/10.1080/01913120500323480
26. Canakis AM, Cutz E, Manson D, O’Brodovich H. Pulmonary interstitial glycogenosis: a new
variant of neonatal interstitial lung disease. Am J Respir Crit Care Med. 2002;165(11):1557–1565
PMID: 12045133 https://doi.org/10.1164/rccm.2105139
27. Nogee LM. Interstitial lung disease in newborns. Semin Fetal Neonatal Med. 2017;22(4):227–233
PMID: 28363760 https://doi.org/10.1016/j.siny.2017.03.003
28. Prestridge A, Wooldridge J, Deutsch G, et al. Persistent tachypnea and hypoxia in a 3-month-old
term infant. J Pediatr. 2006;149(5):702–706 PMID: 17095348
https://doi.org/10.1016/j.jpeds.2006.07.032
29. Nogee LM. Genetic causes of surfactant protein abnormalities. Curr Opin Pediatr.
2019;31(3):330–339 PMID: 31090574 https://doi.org/10.1097/MOP.0000000000000751
30. Hamvas A, Deterding RR, Wert SE, et al. Heterogeneous pulmonary phenotypes associated with
mutations in the thyroid transcription factor gene NKX2-Chest. 2013;144(3):794–804
PMID: 23430038 https://doi.org/10.1378/chest.12-2502
31. Suzuki T, Trapnell BC. Pulmonary alveolar proteinosis syndrome. Clin Chest Med.
2016;37(3):431–440 PMID: 27514590 https://doi.org/10.1016/j.ccm.2016.04.006
32. Liptzin DR, Baker CD, Darst JR, et al. Pulmonary interstitial glycogenosis: diagnostic
evaluation and clinical course. Pediatr Pulmonol. 2018;53(12):1651–1658 PMID: 30019520
33. Deterding RR, Pye C, Fan LL, Langston C. Persistent tachypnea of infancy is associated with
neuroendocrine cell hyperplasia. Pediatr Pulmonol. 2005;40(2):157–165 PMID: 15965897
34. Thouvenin G, Nathan N, Epaud R, Clement A. Diffuse parenchymal lung disease caused by
surfactant deficiency: dramatic improvement by azithromycin. BMJ Case Rep.
2013;2013:bcr2013009988 PMID: 23814005 https://doi.org/10.1136/bcr-2013-009988
35. Hayes D Jr, Lloyd EA, Fitch JA, Bush A. ABCA3 transporter deficiency. Am J Respir Crit Care
Med. 2012;186(8):807 PMID: 23071193 https://doi.org/10.1164/ajrccm.186.8.807
36. Kröner C, Wittmann T, Reu S, et al. Lung disease caused by ABCA3 mutations. Thorax.
2017;72(3):213–220 PMID: 27516224 https://doi.org/10.1136/thoraxjnl-2016-208649
37. Nattes E, Lejeune S, Carsin A, et al. Heterogeneity of lung disease associated with NK2
homeobox 1 mutations. Respir Med. 2017;129:16–23 PMID: 28732825
https://doi.org/10.1016/j.rmed.2017.05.014
38. Kanoh S, Rubin BK. Mechanisms of action and clinical application of macrolides as
immunomodulatory medications. Clin Microbiol Rev. 2010;23(3):590–615 PMID: 20610825
https://doi.org/10.1128/CMR.00078-09
39. Lancaster TS, Miller JR, Epstein DJ, DuPont NC, Sweet SC, Eghtesady P. Improved waitlist
and transplant outcomes for pediatric lung transplantation after implementation of the lung
allocation score. J Heart Lung Transplant. 2017;36(5):520–528 PMID: 27866928
https://doi.org/10.1016/j.healun.2016.10.007
40. Palomar LM, Nogee LM, Sweet SC, Huddleston CB, Cole FS, Hamvas A. Long-term
outcomes after infant lung transplantation for surfactant protein B deficiency related to
other causes of respiratory failure. J Pediatr. 2006;149(4):548–553 PMID: 17011330
https://doi.org/10.1016/j.jpeds.2006.06.004

CHAPTER
28
Bronchopulmonary Dysplasia
Laurie C. Eldredge, MD, PhD
Introduction
History of Bronchopulmonary Dysplasia
Northway, Rosan, and Porter first described bronchopulmonary dysplasia
(BPD) in 1967 as a severe respiratory distress syndrome (RDS) of late pre-
term infants who were treated with prolonged artificial ventilation and a
life-sustaining high fraction of inspired oxygen (0.8–1.0).1 In this landmark
publication, Northway and colleagues described 4 stages of this chronic
lung disease: acute RDS (stage 1), a period of regeneration (stage 2), and
then progression to chronic disease (stages 3 and 4). Bronchopulmonary
dysplasia was associated with substantial (59%) mortality from severe
respiratory failure and pulmonary vascular disease with cor pulmonale.
Despite the severity of BPD, Northway and colleagues highlighted that
there was some reversibility of the condition with continued development of
functional lung.1 Catch-up growth with neoalveolarization takes place in
childhood and throughout adolescence.2 To model BPD for mechanistic
studies, Northway and colleagues3 also demonstrated that hyperoxia-
induced lung injury in mice resembles histopathological aspects of BPD.
Since this original description of BPD, the survival of preterm infants has
increased owing to significant advances in neonatal care, including the use of
neonatal positive pressure ventilation (PPV), antenatal steroids, exogenous
surfactant, and further honing of respiratory support strategies.4
BPD Epidemiology
Concordant with advances during the past 50 years, the incidence of BPD
has increased as gestational age and birth weight of viable infants decrease.
Extremely low gestational age newborns born at less than 28 weeks and
extremely low birth weight (ELBW) infants born at less than 1,000 g are at
521

522
highest risk of developing BPD. However, even when separated according

to gestational age, the rate of BPD is still rising.5 For infants born at gesta-
tional ages 22 through 28 weeks across 26 centers in the Neonatal Research
Network, the diagnosis of BPD increased from 32% (295 of 911) in 1993 to
45% (547 of 1,213) in 2000 (adjusted relative risk, 1.05 [95% CI, 1.04–1.06])
and then decreased to 40% (498 of 1,230) in 2008.5 For 8 centers with com-
plete data across 20 years, BPD increased from 2009 through 2012 for all
gestational ages except for those born at 28 weeks: from 50% (130 of 258)
to 55% (164 of 297) for infants born at 26 weeks and from 33% (103 of 312)
to 40% (134 of 339) for infants born at 27 weeks.5 Overall, nearly 50,000
extremely low gestational age newborns are born each year in the United
States, and approximately 35% (18,000) of these children develop BPD.6
Bronchopulmonary dysplasia rates are variable, however. Using a composite
outcome of BPD or death, BPD rates varied from 17.7% to 73.4% between
centers (interquartile range, 38.7%–54.1%) in a large retrospective study
spanning 125 neonatal intensive care units (NICUs) in California.7 Results
from this study also demonstrated associations between BPD, lower Apgar
scores, younger gestational age, lower birth weight, and male sex. Moreover,
data from major cohort studies (Extremely Low Gestational Age Newborns,
Canadian Neonatal Network, Korean Neonatal Network, Vermont Oxford
Network, and Swiss Neonatal Network, as well as studies in China, Taiwan,
and India) similarly demonstrated varied BPD prevalence of 11% to 50%,
although cohort-specific differences in gestational age and birth weight
also affected these numbers.8–14
BPD Definition
In 2001, a National Institutes of Health workshop developed a comprehensive
clinical definition for BPD to include the requirement for supplemental oxy-
gen for 28 days with further designation of mild, moderate, or severe disease
according to respiratory support needs at 36 weeks’ corrected gestational age
(CGA) (Table 28-1).15 However, in the era of a changing BPD pathophysiology
with improved survival of extremely preterm infants that have severe alveolar
and vascular hypoplasia, several changes to the definition have been pro-
posed.6 These changes delineate the clinical significances of noninvasive
respiratory support such as continuous positive airway pressure (CPAP) or
high-flow nasal canula with variable supplemental oxygen content. One
strategy defines the need for invasive mechanical ventilation at 36 weeks’
CGA as severe type 2 BPD.16 More recently, Jensen and colleagues17
proposed a severity-graded definition of BPD that predicted severe respiratory
morbidity and mortality in 81% of study infants. On the basis of specific
respiratory support needs at 36 weeks, BPD severity was defined as grade 1
(nasal cannula ≤ 2 L), grade 2 (nasal cannula > 2 L or noninvasive positive
airway pressure), or grade 3 (invasive mechanical ventilation).17

523
Chapter 28—Bronchopulmonary Dysplasia
Table 28-1. Bronchopulmonary Dysplasia Definition With Severity Stratification

Bronchopulmonary Relative Postdischarge
Dysplasia Severity Definitiona Incidenceb Mortalityb
None O2 treatment < 28 days and 23.10% 1.80%
breathing room air at 36 weeks’
PMA or discharge home, whichever
comes first
Mild O2 treatment at least 28 days and 30.30% 1.50%
breathing room air at 36 weeks’
comes first
Moderate O2 treatment at least 28 days and 30.20% 2.00%
receiving < 30% O2 at 36 weeks’
comes first
Severe (type 1) O2 treatment at least 28 days 16.40% 4.80%
and receiving ≥ 30% O2 or nasal (all sBPD) (all sBPD)
CPAP/HFNC at ≥ 36 weeks’ PMA
Severe (type 2) O2 treatment at least 28 days and
receiving mechanical ventilation
at ≥ 36 weeks’ PMA
Abbreviations: CPAP, continuous positive airway pressure; HFNC, high-flow nasal cannula; PMA,
postmenstrual age; PPV, positive pressure ventilation; sBPD, severe BPD.
a
Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;163(7):1723–1729.
doi: 10.1164/ajrccm.163.7.2011060.
b
Ehrenkranz RA, Walsh MC, Vohr BR, et al; National Institutes of Child Health and Human Development
Neonatal Research Network. Validation of the National Institutes of Health consensus definition of
bronchopulmonary dysplasia. Pediatrics. 2005;116(6):1353–1360. doi: 10.1542/peds.2005-0249.
Reprinted from Abman SH, Collaco JM, Shepherd EG, et al; Bronchopulmonary Dysplasia Collaborative.
Interdisciplinary care of children with severe bronchopulmonary dysplasia. J Pediatr. 2017;181:12.e1–28.e1.
doi: 10.1016/j.jpeds.2016.10.082. © 2017, with permission from Elsevier.
Pathophysiology
Jobe describes BPD as “an injury syndrome superimposed on the essential
18
lung growth and maturation (development) required for survival.” The impor-
tance of lung maldevelopment in “new” BPD pathogenesis19 has become even
more important as the survival of extremely preterm and ELBW infants has
increased (survival for 25–28 week preterm infants without major morbidity
increased 2% per year between 1993 and 2012).5
The structure of preterm lungs makes them highly susceptible to alveolar
and microvascular injury.18 This immaturity, coupled with the need for
life-sustaining but injurious therapies such as mechanical ventilation and
supplemental oxygen, initiates pulmonary developmental arrest with disor-
dered lung repair and remodeling (Figure 28-1).6,18,19 Moreover, a complex
combination of variables spanning the time from preconception to the
postnatal years contributes to the risk of BPD development (Figure 28-2).6
Prematurity and low birth weight are the strongest risk factors for BPD, with

524
additional risk factors of male sex, intrauterine growth restriction, patent

ductus arteriosus, sepsis or infection, and maternal cigarette smoking.20–23
Early respiratory support needs may predict BPD, as preterm infants with a
respiratory severity score (product of mean airway pressure and fraction of
inspired oxygen) of 6 or more on their 30th day after birth had worse survival
Figure 28-1. A diagram of some of the factors that can contribute to BPD. The focus is on how
long development is modulated by multiple injuries and repair over time.
Abbreviations: ANS, antenatal steroids; BPD, bronchopulmonary dysplasia; SGA, small for
gestational age.
From Jobe AH. Mechanisms of lung injury and bronchopulmonary dysplasia. Am J Perinatol.
2016;33(11):1076–1078. © Georg Thieme Verlag KG.
Figure 28-2. Timeline and stages of bronchopulmonary dysplasia (BPD). The timeline indicates
variables that may modulate lung development, injury, and repair. Acute lung injury (days to
weeks) progresses to chronic lung injury (weeks to years) and is coupled with lung repair and
remodeling (months to years).
From Thébaud B, Goss KN, Laughon M, et al. Bronchopulmonary dysplasia. Nat Rev Dis Primers.
2019;5(1):78. © 2019 Springer Nature.

525
and longer ventilation courses.24 Multicenter research studies are underway to

characterize carefully the specific clinical signs and symptoms in infants who
will develop severe BPD.
Inflammation plays a central role in BPD pathogenesis. Pro-inflammatory
exposures in preterm infants, including exposure to supplemental oxygen,25
mechanical ventilation, postnatal infections, and pulmonary overcirculation
from a patent ductus arteriosus, increase the risk of developing BPD. Pre-
term infants may also be more susceptible to oxidative injury because of
incompletely developed antioxidant enzyme defenses.26 Inflammation in
these infants is often systemic, and multiorgan cross talk may also play a role
in BPD severity; for example, acute kidney injury has been associated with
worse pulmonary outcomes in preterm infants.27,28 Neonatal inflammation is
pathogenic, but immune-mediated mechanisms driving BPD pathogenesis
remain poorly understood.29–35 Much of what is known about BPD development
stems from animal models.30,36 Hyperoxia-induced lung injury37 recapitulates
some of the histopathological aspects of BPD and allows for dissection of
molecular pathways with genetically mutant mice. More than 60 genes
affecting the response to lung injury have been characterized in mouse
models of BPD.6,38
Prenatal inflammation from chorioamnionitis is present in 94% of placentas
delivered between 21 and 24 weeks’ gestation, compared with 3% to 5% of
placentas delivered at term.39 Chorioamnionitis has been associated with
Ureaplasma species, among other genital mycoplasmas, but the pathogenic
neutrophilic inflammation may also be sterile. Despite this correlation with
preterm birth, authors of a meta-analysis of 59 heterogeneous studies involv-
ing more than 15,000 patients were unable to show a definitive association
between chorioamnionitis and BPD once results were adjusted.40
While mechanical ventilation is a life-sustaining therapy for patients with
immature lungs, ventilator-induced lung injury is a source of inflammation in
the development of BPD.41 Selecting the least injurious ventilation strategy
possible is challenging because of changes in physiological characteristics
as lung injury progresses. It is difficult to balance the risks of lung expansion
and associated volutrauma (more injurious than barotrauma) with the risks of
underexpansion and atelectrauma. Volutrauma is lung stretch injury resulting
from localized overdistention of airways and alveoli.42,43 Atelectrauma42 is a
lung injury caused by alveolar collapse at end expiration, seen in the setting
of surfactant deficiency, as well as in inadequate inflation of an injured lung.
Alveolar derecruitment leads to loss of functional residual volume.
Overall, it is difficult to predict which infants will develop severe BPD.
Identification of useful biomarkers that predict BPD severity is challenging,
in part, because of the variety of phenotypes and diseases that are grouped

526
together as the clinical diagnosis of BPD. Investigators in a published study

of exome sequencing identified variants in immune-mediated and growth
factor pathways in patients with BPD44 as part of the multicenter Prematurity
and Respiratory Outcomes Program. This study’s results highlight the need
for multicenter collaborative science to increase statistical power and
generalizability of findings relevant to this heterogeneous disease.
Clinical Features
Bronchopulmonary dysplasia is a multifactorial and multicompartmental
cause of pediatric respiratory failure.45 It includes alveolar disease with
associated hypoxemia and hypercarbia, lower airway obstruction due to
structurally narrowed airways with superimposed airway inflammation,
pulmonary vascular maldevelopment, and variable central injury.46 Broncho-
pulmonary dysplasia parenchymal injury is heterogeneous and may include
fibrosis, emphysema, and hypoalveolarization.6
To preserve minute ventilation, infants with BPD are tachypneic, with
increased work of breathing. Respiratory support should be titrated to the
patient to ensure adequate linear growth and neurodevelopment despite
the abnormal respiratory mechanics and chronic respiratory demands.16
Survivors of BPD have lifelong obstructive lung disease with reduced FEV1
as adults19,47 and are an emerging population of individuals with chronic
obstructive pulmonary disease.48 Patients with BPD, therefore, should be
followed up longitudinally with consideration of pulmonary function
testing and/or imaging.
Comorbidities
Infants with BPD frequently have feeding issues, including dysphagia,
gastroesophageal reflux disease, and growth failure. Feeding, occupational
and physical therapy, and gastrointestinal specialists may be needed as
determined in the patient’s medical home.
Tracheobronchomalacia (TBM) is a comorbidity that occurs most often in
preterm infants who develop BPD and require prolonged PPV.49,50 Because
the airways are not functionally or structurally mature, positive pressure may
distend the abnormally compliant airways and result in acquired or secondary
TBM.51 Pulmonary consequences of TBM include decreased intrathoracic
airway flow, cyanotic episodes, difficulty weaning from PPV, and higher
mortality.49 Patients with BPD and TBM also have longer and more compli-
cated hospitalizations, with increased need for tracheostomy, gastrostomy
tube use, longer mechanical ventilation, and increased risk of developing
oral feeding difficulties.49,52

527
In 2016, the American Heart Association (AHA) and American Thoracic

Society (ATS) published guidelines for the diagnosis and management of
pediatric pulmonary hypertension (PH).53 Recommendations for infants with
BPD include the following: (1) screening for PH in infants with established
BPD (at 36 weeks’ postmenstrual age [PMA] for preterm infants who require
supplemental oxygen or positive pressure support or earlier in the presence of
severe respiratory distress or high levels of ventilatory support, oligohydram-
nios, intrauterine growth restriction, or extreme prematurity); (2) evaluation
and treatment of lung disease (hypoxemia, aspiration, and so on) in those with
BPD-PH before starting PH medications; and (3) including cardiac catheteri-
zation for diagnosis, identification of other cardiac factors such as pulmonary
vein stenosis, and acute vasodilator testing when evaluating for use of medi-
cation to treat PH. Treatment options for PH include supplemental oxygen,
inhaled nitric oxide, and a variety of oral, inhalational, subcutaneous, and
intravenous pharmacotherapies. The AHA/ATS and Pediatric Pulmonary
Hypertension Network guidelines also recommend that a multidisciplinary
team of neonatologists, pulmonologists, cardiologists, intensivists, and PH
specialists should be involved in the care of patients with BPD-PH.54 Because
intermittent or prolonged hypoxemia can delay resolution of PH, oxygen
saturation goals for patients with BPD are 92% to 94%.53
Systemic hypertension is common in infants with BPD.55–57 Management
includes use of a PMA-specific nomogram for blood pressure that indicates
severe hypertension is blood pressure greater than the 95th percentile and
requires pediatric nephrologic consultation. Blood pressure elevations may
be severe enough to require pharmacological treatment in approximately
one-half of patients.55–57 The mechanisms involved in the development of
systemic hypertension in patients with BPD are not fully understood but
may include neonatal kidney injury,27,28 as well as increased aortic thickness
and systemic arterial stiffness.58
Respiratory Management
Prenatal, Perinatal, and Preventive
Management begins in the prenatal period to decrease the risk of preterm
delivery, with maternal monitoring, interventions to decrease infection and
preterm labor and delivery, and maximizing fetal growth and nutrition. Antena-
tal steroids are administered to accelerate lung development, with effects on
alveolar epithelial cells, surfactant binding protein, and antioxidant produc-
tion.59 Preterm infants born to mothers who received antenatal steroids have
improved rates of mortality, RDS, intraventricular hemorrhage (IVH), and
necrotizing enterocolitis. However, antenatal steroids have not been shown

528
to decrease the risk of BPD developing,59 possibly because of decreased

total alveolar number,60 which has been documented in preterm nonhuman
primates whose mothers were treated with antenatal steroids. Resuscitation
efforts in the delivery room progress with high oxygen concentration and
positive pressure as needed for respiratory failure, according to well-researched
Neonatal Resuscitation Program protocols.61 Lung recruitment maneuvers in
the delivery room have been abandoned because of increased mortality in
the first 48 hours after birth.62
Noninvasive Respiratory Support

A meta-analysis of 30 trials found that mechanical ventilation is overall
inferior to noninvasive strategies in primary outcomes of death and BPD at
36 weeks’ CGA or secondary outcomes of death, BPD, IVH, and air leak.63
However, because of advanced noninvasive ventilation strategies,62–64 many
extremely preterm infants no longer require intubation and mechanical
ventilation and therefore do not acquire ventilator-associated lung injury.
Continuous positive airway pressure is an effective form of noninvasive
support that has been popular since its development in 197365 and has had
interval improvements in mask and cannula interfaces. High-amplitude
bubble nasal CPAP (Seattle-PAP) allows for increased ventilation greater
than that with other forms of CPAP.66 Lung stretch induced by CPAP has
been associated with improved lung growth after hyperoxic lung injury in
animals.67 Similarly, infants born at 32 weeks’ gestational age or younger
who required 24 hours or more of CPAP who received an additional 2 weeks
of CPAP (compared with those with discontinuation of CPAP) had greater
functional residual capacities, indicating improved lung volumes.68
Other noninvasive respiratory support modalities include neurally adjusted
ventilatory assist69; noninvasive PPV; heated, humidified high-flow nasal
cannula; and low-flow nasal cannula. More research is needed to determine
the optimal noninvasive respiratory strategies, with the goal of decreasing
the work of breathing and promoting growth and development in patients
with BPD.
Surfactant improves lung compliance and uniformity of lung expansion,
permits lower oxygen supplementation and ventilatory support, and protects
against volutrauma in animal models. Less invasive surfactant administration
(LISA),70 during which surfactant is delivered with feeding tubes or vascular
catheters by using laryngoscopes during CPAP-assisted breathing, has been
used to realize the benefits of surfactant without the injury seen with invasive
mechanical ventilation. Results from a randomized controlled trial (RCT)
of LISA versus conventional surfactant delivery via endotracheal intubation
showed LISA was associated with increased survival without major compli-
cations. In a meta-analysis of 30 RCTs, investigators compared noninvasive

529
ventilation and surfactant administration strategies within 24 hours after birth

for infants less than 33 weeks’ gestational age who had not undergone intuba-
tion, and the results showed that the use of LISA was associated with the
lowest likelihood of the composite outcome of BPD or death at 36 weeks’
PMA.63 Therefore, preterm infants often benefit from exogeneous surfactant
without invasive mechanical ventilation.
Invasive Mechanical Ventilation

Despite the use of noninvasive PPV, 44.7% of ELBW infants require some
invasive mechanical ventilation within the first 7 days after birth.71 For pre-
term infants who require invasive ventilation, the goal is to provide adequate
gas exchange while minimizing lung injury. Preterm infants with RDS,
before BPD is diagnosed, have poorly compliant lungs, but the lung disease
is relatively homogeneous. A gentle ventilation strategy is used to minimize
ventilator-associated lung injury with minimal peak pressures, adequate
positive end-expiratory pressure, and faster rates.16 In a Cochrane review of
20 randomized trials, compared with neonates receiving pressure-limited
ventilation, neonates receiving volume-targeted ventilation had reduced
rates of death or BPD, pneumothorax, and duration of ventilation.72
Approximately 16% of infants with BPD require mechanical ventilation at
36 weeks’ CGA and therefore have severe BPD.73 Data have not solidified
the superiority of a specific mode of ventilation for established BPD, and
there is considerable center-to-center variability in local ventilation practices.74
Determination of optimal ventilation strategies for BPD is an important and
open research question for future multicenter studies.
Specific Ventilation Strategies for Patients With Severe Type 2 BPD

With careful multidisciplinary care, infants with severe type 2 BPD (those
requiring invasive mechanical ventilation at 36 weeks’ PMA in comparison
with those with severe type 1, who require noninvasive ventilation) will pro-
gress through 4 stages of BPD: unstable (high fraction of inspired oxygen, low
ventilation/perfusion state), transitional, pro-growth, and convalescence.75 As
infants progress through these stages, different phenotypes become apparent,
including restrictive (tachypnea due to hypoplasia), obstructive (lower airway
obstruction and 74% likelihood of bronchodilator responsiveness), and mixed
(obstructive and restrictive).76 A high tidal volume, long inspiratory time, and
low rate strategy from multiple centers of excellence support these infants
with heterogeneous lung disease and severe BPD (Figure 28-3).6
Chronic Mechanical Ventilation

The typical disease course of BPD is slow, steady improvement in lung
disease and weaning of respiratory support over time. A small number of
patients with BPD do not wean from invasive ventilation and develop severe

530
(TC = Resistance × Compliance)

Low tidal volume
Short insp times
Adverse effects:
Normal C • Worse distribution of gas
Normal R • Increased dead space ventilation
• Higher PCO2
• Higher FiO2
• Progressive atelectasis
Low C • Regional overdistension
High R
High C
Low R
Normal C
High R
A
Higher tidal volume

Longer insp time
Benefits:
Normal C • Improved gas distribution
Normal R • Lower Vd/Vt
• Lower PCO2
• Lower FiO2
• Less atelectasis
Low C
High R
High C
Low R
Normal C
High R
B
Figure 28-3. Alternative ventilation strategies in the treatment of heterogeneous lung disease
and severe BPD.
Abbreviations: C, compliance; FiO2, fraction of inspired oxygen; R, resistance; VD, dead-space ventilation;
VT, tidal volume.
Reprinted from Abman SH, Nelin LD. Management of the infant with severe bronchopulmonary dysplasia.
In: Bancalari E, Polin RA, eds. The Newborn Lung: Neonatology Questions and Controversies. 2nd ed.
Elsevier Saunders; 2012:407–425. © 2012, with permission from Elsevier.

531
type 2 (Abman criteria) or grade 3 (Jensen criteria) BPD. These patients

are more prevalent in the NICU because of prolonged hospitalizations,
accounting for 41% of patients with severe BPD at 36 weeks’ CGA.77 Patients
with severe BPD as well as TBM are more likely to require and benefit from
tracheostomy and long-term ventilation.49 Tracheostomy promotes improved
neurodevelopment in infants with severe BPD and can facilitate transition
to chronic mechanical ventilator care at home or in a pediatric chronic ven-
tilatory care facility.78 Management for these patients requires a multidisci-
plinary team,78 and a standardized discharge process can decrease hospital
length of stay.79 An ATS clinical practice guideline recommends generalist
and subspecialist comanagement for these patients, in addition to the presence
of an awake, trained caregiver at all times and standardized equipment for
monitoring, emergency response, and airway clearance.80 A comprehensive
medical home is also essential for longitudinal and coordinated care for
these patients.
Medications
In a study in 3,252 infants with severe BPD hospitalized at 43 centers, there
was a median of 30 (interquartile range, 17–45) medication exposures per
infant, with marked center–center variation.81 Most of these medications have
unclear efficacy and safety in patients with BPD. Thiazide and loop diuretics,82
although commonly used in the inpatient setting to improve lung compliance,
have not been shown to improve preterm infants’ clinical outcomes, such as
duration of mechanical ventilation, NICU length of stay, or rates of BPD. In
addition, diuretics (especially furosemide) are associated with comorbidities
such as sensorineural hearing loss,83 nephrolithiasis,84 and metabolic bone
disease.85 Therefore, diuretic use should be sparing, such as in patients who
cannot be weaned from positive pressure despite mild fluid restriction.
Interventions to minimize lung injury in patients with BPD, and the level
of evidence supporting their use, are summarized in Table 28-2. Systemic
corticosteroids have been frequently used as effective anti-inflammatory
agents to prevent and treat BPD. Enthusiasm for steroids waned because
of association with serious adverse effects, including hypertension, hyper-
glycemia, adrenocortical axis suppression, poor weight gain, gastrointestinal
perforation, and adverse neurodevelopmental outcomes.86 However, evidence
supports the use of corticosteroids when there is a high risk of developing
BPD,87 although this risk may be difficult to determine. Steroid administra-
tion practices vary considerably across centers.77 Inhaled corticosteroids
(flunisolide, beclomethasone, budesonide, dexamethasone, fluticasone) have
the benefits of less systemic toxicity but with uncertain efficacy. A meta-
analysis including 16 trials found that inhaled corticosteroids were associated
with a statistically significant reduction in death or BPD at 36 weeks’ PMA,88

532
although long-term data were not available. A promising approach combines

surfactant and budesonide. A multicenter RCT of 265 very low birth weight
infants with severe RDS compared outcomes of administration of surfactant
and budesonide versus administration of surfactant alone and found that the
surfactant and budesonide group had a statistically significant decrease in
mortality and the incidence of BPD, as well as lower levels of intratracheal
cytokines interleukins 1, 6, and 8 in tracheal aspirates at 12 hours of age.89
Results from a 2018 meta-analysis of 4 studies (3 with intramuscular delivery
and 1 with oral delivery) demonstrated that vitamin A supplementation was
associated with reduced BPD in ELBW survivors at 36 weeks’ CGA, but
there was no reduction in death, oxygen use at 28 days after birth, duration
of mechanical ventilation, IVH, retinopathy of prematurity, or necrotizing
enterocolitis.90 Vitamin A is essential for normal lung growth and maintenance
of respiratory tract epithelium.91,92
Caffeine is a methylxanthine used to treat apnea of prematurity. Caffeine
reduces the risk of BPD developing in very low birth weight infants and is
associated with improved survival without neurodevelopmental disability
at 18 to 21 months of age, but it is not known whether caffeine affects
longer-term pulmonary outcomes.93,94
Inhaled bronchodilators such as albuterol and ipratropium treat increased air-
way resistance and are often used in patients with BPD and/or patients who
were born preterm with chronic wheeze or cough. In a study in 110 patients
with severe BPD during their initial hospitalization, pulmonary function
test results demonstrated that 74% of patients with obstruction and 63% of
patients with a mixed obstructive and restrictive phenotype were broncho-
dilator responsive (2–8 puffs albuterol).76 Another review of 21 studies in
preterm-born children aged 5 years and older found improvements in FEV1
after short-term administration of bronchodilators.95 Although there are no
studies showing long-term benefits of inhaled bronchodilators in BPD, they
may be helpful in select patients with an obstructive phenotype and/or with
viral illnesses causing lower airway obstruction.
Inhaled nitric oxide can be effective for treating established BPD and symp-
tomatic PH. Chronic PH secondary to BPD is managed according to AHA
and ATS pediatric pulmonary hypertension guidelines.53
Studies to evaluate long-term effects of therapies, such as inhaled bronchodila-
tors, diuretics, and steroids, in patients with BPD are retrospective and under-
powered. Further research on respiratory treatments for these patients is needed.

533
Table 28–2. Interventions to Minimize Lung Injury in Preterm Infants

Intervention Rationale Level of Evidence Clinical Implications
Caffeine Reduced time on High quality: large Use in extremely preterm
ventilator leading RCT with long-term infants with apnea of
to less lung follow-up prematurity
damage
Less invasive Avoids the risks Low quality: small Very promising, but more
surfactant associated with RCTs, imprecise research required
administration endotracheal estimates of safety
intubation and efficacy
Vitamin A Low levels seen in Moderate quality: Depends on local incidence
preterm infants; meta-analysis of BPD; trade-off between
vitamin A required suggests a small the modest reduction in
for normal lung reduction in rates BPD and acceptability of
growth of death or BPD intramuscular treatment
Dexamethasone Reduced Moderate quality: Low-dose, short courses
inflammation meta-analyses and that are useful for infants
allowing earlier meta-regression receiving ventilation at
extubation of numerous small highest risk of developing
trials BPD
Hydrocortisone Avoids adverse Moderate quality: Promising, but
neurodevelopmen- small RCTs, more research into
tal effects of imprecise estimates neurodevelopmental
dexamethasone of safety and outcomes is required
efficacy
Steroids Better distribution of Low quality: small Very promising, but more
administered steroids and RCTs, imprecise research is required
with surfactant reduced systemic estimates of safety
effects and efficacy
Abbreviations: BPD, bronchopulmonary dysplasia; RCT, randomized controlled trial.
Adapted from Thébaud B, Goss KN, Laughon M, et al. Bronchopulmonary dysplasia. Nat Rev Dis Primers.
2019;5(1):78. © 2019 Springer Nature.
Longitudinal Care for Patients With BPD

Infants with moderate to severe BPD (requiring respiratory support at 36 weeks’
CGA) have prolonged hospitalizations after birth. Interdisciplinary teams con-
sisting of pulmonologists; neonatologists; cardiologists; nurses; respiratory
therapists; dieticians; physical, occupational, and speech therapists; and social
workers are helpful for coordinated discharge and outpatient plans.16,96
The European Respiratory Society published a guideline in 2019 outlining long-
term management of BPD in children. The authors recommended the following:
(1) lung imaging only in patients with severe BPD or recurrent admissions;
(2) lung function monitoring with pulmonary function testing; (3) individualized
advice on child care attendance; (4) treatment with bronchodilators for subgroups

534
such as those with severe disease, asthma symptoms, recurrent admissions,

and/or exercise intolerance; (5) no long-term treatment with steroids; (6)
allowing patients to outgrow their diuretics gradually; and (7) saturation targets
of 90% to 95%.97 An example of imaging in a patient with severe type 2 BPD
is in Figure 28-4.16 In 2021, the American Thoracic Society also published a
guideline98 for outpatient management of post-prematurity respiratory disease
(PPRD), a more inclusive diagnosis defined by prematurity and chronic respi-
ratory symptoms. The guidelines address the outpatient use of medications
(bronchodilators, inhaled steroids, and diuretics) and diagnostics (swallow
studies, bronchoscopy, polysomnography, and CT imaging) in patients
with PPRD.
Oxygen supplementation may be required throughout hospitalization and con-
tinued after discharge. New oxygen guidelines recommend higher saturation
goals than those used previously because of the SUPPORT (Surfactant, Posi-
tive Pressure, and Oxygenation Randomized Trial) trial findings of increased
mortality with oxygen saturation less than 90%.99,100 Titrating oxygen therapy
to avoid extremes of low or high saturations and unnecessary exposure to
inflammatory oxygen is still an active research question,101 but additional
guidance has emerged with new ATS guidelines for home oxygen therapy.102
Standardized protocols for home oxygen weaning are being evaluated.103
Nutritional maximization plays an essential role in neonatal growth and
development, and early undernutrition is linked with increased BPD. Early
aggressive protein and calorie administration improves pulmonary outcomes.
Figure 28-4. Imaging in severe type 2 bronchopulmonary dysplasia.

Anterior-posterior chest radiograph (left) and coronal computed
tomography scan (right). Cystic lung disease is apparent on the
computed tomography scan.
Reprinted from Abman SH, Collaco JM, Shepherd EG, et al; Bronchopulmonary
Dysplasia Collaborative. Interdisciplinary care of children with severe
bronchopulmonary dysplasia. J Pediatr. 2017;181:12.e1–28.e1.
doi: 10.1016/j.jpeds.2016.10.082. © 2017, with permission from Elsevier.

535
Lung growth is proportional to linear and somatic growth,104 and linear growth
should be maintained as respiratory support is weaned. Patients with BPD
should be followed up regularly with a dietician who partners with the
pediatrician and/or pediatric pulmonologist.
The Future of BPD

Bronchopulmonary dysplasia is the most common morbidity after preterm
birth. Research is critical to understand the variety of phenotypes within the
broad clinical definition of BPD and to develop targeted therapies. The Bron-
chopulmonary Dysplasia Collaborative is a multicenter group of clinicians
with the goal of improving the care of patients with severe BPD through
research and standardization of team-based care.16
key points
} Bronchopulmonary dysplasia remains a common cause of neonatal morbidity
and mortality, and BPD rates are increasing.
} Prematurity and gestational age are the largest risk factors for the development
of BPD.
} Advanced noninvasive ventilation techniques allow for avoidance of invasive
surfactant administration and mechanical ventilation in many preterm infants.
} Patients with severe type 2 BPD have unique physiological characteristics with
high airway resistance treated with specific ventilator strategies.
} Longitudinal care of infants with BPD requires a multidisciplinary approach
with a medical home that facilitates frequent evaluation and monitoring.
} More research is needed to establish a more precise diagnosis for BPD,
investigate underlying pathophysiological mechanisms of severe BPD,
and target inflammatory pathways with future therapies.
References
1. Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of
hyaline-membrane disease: bronchopulmonary dysplasia. N Engl J Med. 1967;276(7):357–368
PMID: 5334613 doi: 10.1056/NEJM196702162760701
2. Narayanan M, Owers-Bradley J, Beardsmore CS, et al. Alveolarization continues during
childhood and adolescence: new evidence from helium-3 magnetic resonance. Am J Respir Crit
Care Med. 2012;185(2):186–191 PMID: 22071328 doi: 10.1164/rccm.201107-1348OC
3. Bonikos DS, Bensch KG, Ludwin SK, Northway WH Jr. Oxygen toxicity in the newborn.
The effect of prolonged 100 per cent O2 exposure on the lungs of newborn mice. Lab Invest.
1975;32(5):619–635 PMID: 1092910
4. Abman SH, Bancalari E, Jobe A. The evolution of bronchopulmonary dysplasia after 50 years.
doi: 10.1164/rccm.201611-2386ED
5. Stoll BJ, Hansen NI, Bell EF, et al. Trends in care practices, morbidity, and mortality of
extremely preterm neonates, 1993–2012. JAMA. 2015;314(10):1039–1051 PMID: 26348753
doi: 10.1001/jama.2015.10244

536
6. Thébaud B, Goss KN, Laughon M, et al. Bronchopulmonary dysplasia. Nat Rev Dis Primers.
2019;5(1):78 PMID: 31727986 doi: 10.1038/s41572-019-0127-7
7. Lapcharoensap W, Gage SC, Kan P, et al. Hospital variation and risk factors for
bronchopulmonary dysplasia in a population-based cohort. JAMA Pediatr. 2015;169(2):e143676
PMID: 25642906 doi: 10.1001/jamapediatrics.2014.3676
8. Adams M, Bassler D, Bucher HU, et al; Swiss Neonatal Network and the Vermont Oxford
Network. Variability of very low birth weight infant outcome and practice in Swiss and US
neonatal units. Pediatrics. 2018;141(5):e20173436 PMID: 29654158 doi: 10.1542/peds.2017-3436
9. Bhunwal S, Mukhopadhyay K, Bhattacharya S, Dey P, Dhaliwal LK. Bronchopulmonary
dysplasia in preterm neonates in a level III neonatal unit in India. Indian Pediatr.
2018;55(3):211–215 PMID: 29242415 doi: 10.1007/s13312-018-1319-z
10. Bose C, Van Marter LJ, Laughon M, et al; Extremely Low Gestational Age Newborn Study
Investigators. Fetal growth restriction and chronic lung disease among infants born before
the 28th week of gestation. Pediatrics. 2009;124(3):e450–e458 PMID: 19706590
doi: 10.1542/peds.2008-3249
11. Isayama T, Lee SK, Yang J, et al; Canadian Neonatal Network and Canadian Neonatal
Follow-Up Network Investigators. Revisiting the definition of bronchopulmonary dysplasia:
effect of changing panoply of respiratory support for preterm neonates. JAMA Pediatr.
2017;171(3):271–279 PMID: 28114678 doi: 10.1001/jamapediatrics.2016.4141
12. Lee JH, Noh OK, Chang YS; Korean Neonatal Network. Neonatal outcomes of very low birth
weight infants in Korean Neonatal Network from 2013 to 2016. J Korean Med Sci. 2019;34(5):e40
PMID: 30718992 doi: 10.3346/jkms.2019.34.e40
13. Lin HJ, Du LZ, Ma XL, et al. Mortality and morbidity of extremely low birth weight infants in
the mainland of China: a multi-center study. Chin Med J (Engl). 2015;128(20):2743–2750
PMID: 26481740 doi: 10.4103/0366-6999.167312
14. Su BH, Hsieh WS, Hsu CH, Chang JH, Lien R, Lin CH; Premature Baby Foundation of Taiwan
(PBFT). Neonatal outcomes of extremely preterm infants from Taiwan: comparison with
Canada, Japan, and the USA. Pediatr Neonatol. 2015;56(1):46–52 PMID: 25154794
doi: 10.1016/j.pedneo.2014.05.002
15. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med.
2001;163(7):1723–1729 PMID: 11401896 doi: 10.1164/ajrccm.163.7.2011060
16. Abman SH, Collaco JM, Shepherd EG, et al; Bronchopulmonary Dysplasia Collaborative.
Interdisciplinary care of children with severe bronchopulmonary dysplasia. J Pediatr.
2017;181:12.e1–28.e1 PMID: 27908648 doi: 10.1016/j.jpeds.2016.10.082
17. Jensen EA, Dysart K, Gantz MG, et al. The diagnosis of bronchopulmonary dysplasia in very
preterm infants: an evidence-based approach. Am J Respir Crit Care Med. 2019;200(6):751–759
PMID: 30995069 doi: 10.1164/rccm.201812-2348OC
18. Jobe AH. Mechanisms of lung injury and bronchopulmonary dysplasia. Am J Perinatol.
2016;33(11):1076–1078 PMID: 27603539 doi: 10.1055/s-0036-1586107
19. Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med.
2007;357(19):1946–1955 PMID: 17989387 doi: 10.1056/NEJMra067279
20. Ambalavanan N, Van Meurs KP, Perritt R, et al; NICHD Neonatal Research Network, Bethesda,
MD. Predictors of death or bronchopulmonary dysplasia in preterm infants with respiratory
failure. J Perinatol. 2008;28(6):420–426 PMID: 18337740 doi: 10.1038/jp.2008.18
21. Rojas MA, Gonzalez A, Bancalari E, Claure N, Poole C, Silva-Neto G. Changing trends in the
epidemiology and pathogenesis of neonatal chronic lung disease. J Pediatr. 1995;126(4):605–610
PMID: 7699543 doi: 10.1016/S0022-3476(95)70362-4
22. Marshall DD, Kotelchuck M, Young TE, Bose CL, Kruyer L, O’Shea TM; North Carolina
Neonatologists Association. Risk factors for chronic lung disease in the surfactant era:
a North Carolina population-based study of very low birth weight infants. Pediatrics.
1999;104(6):1345–1350 PMID: 10585987 doi: 10.1542/peds.104.6.1345
23. Stevenson DK, Verter J, Fanaroff AA, et al. Sex differences in outcomes of very low
birthweight infants: the newborn male disadvantage. Arch Dis Child Fetal Neonatal Ed.
2000;83(3):F182–F185 PMID: 11040165 doi: 10.1136/fn.83.3.F182
24. Malkar MB, Gardner WP, Mandy GT, et al. Respiratory severity score on day of life 30 is
predictive of mortality and the length of mechanical ventilation in premature infants with
protracted ventilation. Pediatr Pulmonol. 2015;50(4):363–369 PMID: 24616279
doi: 10.1002/ppul.23020
25. Wai KC, Kohn MA, Ballard RA, et al; Trial of Late Surfactant (TOLSURF) Study Group.
Early cumulative supplemental oxygen predicts bronchopulmonary dysplasia in high risk
extremely low gestational age newborns. J Pediatr. 2016;177:97.e2–102.e2 PMID: 27470692
doi: 10.1016/j.jpeds.2016.06.079

537
26. Thibeault DW. The precarious antioxidant defenses of the preterm infant. Am J Perinatol.
2000;17(4):167–181 PMID: 11041438 doi: 10.1055/s-2000-9422
27. Starr MC, Boohaker L, Eldredge LC, et al; Neonatal Kidney Collaborative. Acute kidney
injury is associated with poor lung outcomes in infants born ≥ 32 weeks of gestational age.
Am J Perinatol. 2020;37(2):231–240 PMID: 31739364 doi: 10.1055/s-0039-1698836
28. Starr MC, Boohaker L, Eldredge LC, et al; Neonatal Kidney Collaborative. Acute kidney injury
and bronchopulmonary dysplasia in premature neonates born less than 32 weeks’ gestation.
29. Ambalavanan N, Carlo WA, D’Angio CT, et al; Eunice Kennedy Shriver National Institute of
Child Health and Human Development Neonatal Research Network. Cytokines associated with
bronchopulmonary dysplasia or death in extremely low birth weight infants. Pediatrics.
2009;123(4):1132–1141 PMID: 19336372 doi: 10.1542/peds.2008-0526
30. Lignelli E, Palumbo F, Myti D, Morty RE. Recent advances in our understanding of the
mechanisms of lung alveolarization and bronchopulmonary dysplasia. Am J Physiol Lung Cell
Mol Physiol. 2019;317(6):L832–L887 PMID: 31596603 doi: 10.1152/ajplung.00369.2019
31. Bhandari V. Molecular mechanisms of hyperoxia-induced acute lung injury. Front Biosci.
2008;13:6653–6661 PMID: 18508685 doi: 10.2741/3179
32. Jobe AH. Glucocorticoids, inflammation and the perinatal lung. Semin Neonatol.
2001;6(4):331–342 PMID: 11972434 doi: 10.1053/siny.2001.0068
33. Jobe AH, Ikegami M. Antenatal infection/inflammation and postnatal lung maturation and
injury. Respir Res. 2001;2(1):27–32 PMID: 11686862 doi: 10.1186/rr35
34. Kotecha S. Cytokines in chronic lung disease of prematurity. Eur J Pediatr.
1996;155(suppl 2):S14–S17 PMID: 8839740 doi: 10.1007/BF01958074
35. Ryan RM, Ahmed Q, Lakshminrusimha S. Inflammatory mediators in the immunobiology of
bronchopulmonary dysplasia. Clin Rev Allergy Immunol. 2008;34(2):174–190 PMID: 18330726
doi: 10.1007/s12016-007-8031-4
36. Jobe AH. Animal models, learning lessons to prevent and treat neonatal chronic lung disease.
Front Med (Lausanne). 2015;2:49 PMID: 26301222 doi: 10.3389/fmed.2015.00049
37. Warner BB, Stuart LA, Papes RA, Wispé JR. Functional and pathological effects of prolonged
hyperoxia in neonatal mice. Am J Physiol Lung Cell Mol Physiol. 1998;275(1):L110–L117
PMID: 9688942 doi: 10.1152/ajplung.1998.275.1.L110
38. Surate Solaligue DE, Rodríguez-Castillo JA, Ahlbrecht K, Morty RE. Recent advances in our
understanding of the mechanisms of late lung development and bronchopulmonary dysplasia.
Am J Physiol Lung Cell Mol Physiol. 2017;313(6):L1101–L1153 PMID: 28971976
doi: 10.1152/ajplung.00343.2017
39. Kim CJ, Romero R, Chaemsaithong P, Chaiyasit N, Yoon BH, Kim YM. Acute chorioamnionitis
and funisitis: definition, pathologic features, and clinical significance. Am J Obstet Gynecol.
2015;213(4)(suppl):S29–S52 PMID: 26428501 doi: 10.1016/j.ajog.2015.08.040
40. Hartling L, Liang Y, Lacaze-Masmonteil T. Chorioamnionitis as a risk factor for
bronchopulmonary dysplasia: a systematic review and meta-analysis. Arch Dis Child Fetal
Neonatal Ed. 2012;97(1):F8–F17 PMID: 21697236 doi: 10.1136/adc.2010.210187
41. Kneyber MC, Zhang H, Slutsky AS. Ventilator-induced lung injury: similarity and differences
between children and adults. Am J Respir Crit Care Med. 2014;190(3):258–265 PMID: 25003705
doi: 10.1164/rccm.201401-0168CP
42. Clark RH, Gerstmann DR, Jobe AH, Moffitt ST, Slutsky AS, Yoder BA. Lung injury in neonates:
causes, strategies for prevention, and long-term consequences. J Pediatr. 2001;139(4):478–486
PMID: 11598592 doi: 10.1067/mpd.2001.118201
43. Hillman NH, Moss TJ, Kallapur SG, et al. Brief, large tidal volume ventilation initiates lung
injury and a systemic response in fetal sheep. Am J Respir Crit Care Med. 2007;176(6):575–581
PMID: 17641159 doi: 10.1164/rccm.200701-051OC
44. Hamvas A, Feng R, Bi Y, et al; PROP Investigators. Exome sequencing identifies gene variants
and networks associated with extreme respiratory outcomes following preterm birth. BMC
Genet. 2018;19(1):94 PMID: 30342483 doi: 10.1186/s12863-018-0679-7
45. Redding GJMJ, Rea C. Respiratory failure in childhood. In: Morray J, ed. Principles in Pediatric
Intensive Care. Appleton Century Crofts, P.S.; 1987:117–134
46. Collaco JM, McGrath-Morrow SA. Respiratory phenotypes for preterm infants, children, and
adults: bronchopulmonary dysplasia and more. Ann Am Thorac Soc. 2018;15(5):530–538
PMID: 29328889 doi: 10.1513/AnnalsATS.201709-756FR
47. Martinez FD. Early-life origins of chronic obstructive pulmonary disease. N Engl J Med.
2016;375(9):871–878 PMID: 27579637 doi: 10.1056/NEJMra1603287

538
48. McGrath-Morrow SA, Collaco JM. Bronchopulmonary dysplasia: what are its links to COPD?
Ther Adv Respir Dis. 2019;13:1753466619892492 PMID: 31818194 doi:
10.1177/1753466619892492
49. Hysinger EB, Friedman NL, Padula MA, et al; Children’s Hospitals Neonatal Consortium.
Tracheobronchomalacia is associated with increased morbidity in bronchopulmonary dysplasia.
Ann Am Thorac Soc. 2017;14(9):1428–1435 PMID: 28622012
50. Wu KY, Jensen EA, White AM, et al. Characterization of disease phenotype in very preterm
infants with severe bronchopulmonary dysplasia. Am J Respir Crit Care Med.
2020;201(11):1398–1406 PMID: 31995403 doi: 10.1164/rccm.201907-1342OC
51. Shaffer TH, Wolfson MR, Panitch HB. Airway structure, function and development in
health and disease. Paediatr Anaesth. 2004;14(1):3–14 PMID: 14717868
doi: 10.1046/j.1460-9592.2003.01207.x
52. Wallis C, Alexopoulou E, Antón-Pacheco JL, et al. ERS statement on tracheomalacia and
bronchomalacia in children. Eur Respir J. 2019;54(3):1900382 PMID: 31320455
doi: 10.1183/13993003.00382-2019
53. Abman SH, Ivy DD, Archer SL, Wilson K; AHA/ATS Joint Guidelines for Pediatric Pulmonary
Hypertension Committee. Executive summary of the American Heart Association and American
Thoracic Society joint guidelines for pediatric pulmonary hypertension. Am J Respir Crit Care
Med. 2016;194(7):898–906 PMID: 27689707 doi: 10.1164/rccm.201606-1183ST
54. Krishnan U, Feinstein JA, Adatia I, et al; Pediatric Pulmonary Hypertension Network (PPHNet).
Evaluation and management of pulmonary hypertension in children with bronchopulmonary
dysplasia. J Pediatr. 2017;188:24.e1–34.e1. PMID: 28645441
doi: 10.1016/j.jpeds.2017.05.029
55. Abman SH, Warady BA, Lum GM, Koops BL. Systemic hypertension in infants with
bronchopulmonary dysplasia. J Pediatr. 1984;104(6):928–931 PMID: 6547171
doi: 10.1016/S0022-3476(84)80501-6
56. Anderson AH, Warady BA, Daily DK, Johnson JA, Thomas MK. Systemic hypertension in
infants with severe bronchopulmonary dysplasia: associated clinical factors. Am J Perinatol.
1993;10(3):190–193 PMID: 8517893 doi: 10.1055/s-2007-994716
57. Alagappan A, Malloy MH. Systemic hypertension in very low-birth weight infants with
bronchopulmonary dysplasia: incidence and risk factors. Am J Perinatol. 1998;15(1):3–8
PMID: 9475679 doi: 10.1055/s-2007-993889
58. Sehgal A, Malikiwi A, Paul E, Tan K, Menahem S. Systemic arterial stiffness in infants with
bronchopulmonary dysplasia: potential cause of systemic hypertension. J Perinatol.
2016;36(7):564–569 PMID: 26914016 doi: 10.1038/jp.2016.10
59. Roberts D, Brown J, Medley N, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung
maturation for women at risk of preterm birth. Cochrane Database Syst Rev.
2017;3(3):CD004454 PMID: 28321847 doi: 10.1002/14651858.CD004454.pub3
60. Beck JC, Mitzner W, Johnson JW, et al. Betamethasone and the rhesus fetus: effect on lung
morphometry and connective tissue. Pediatr Res. 1981;15(3):235–240 PMID: 7220145
doi: 10.1203/00006450-198103000-00007
61. Weiner GM, Zaichkin J, eds. Textbook of Neonatal Resuscitation (NRP). 7th ed. American
Academy of Pediatrics; 2016
62. Glaser K, Speer CP, Wright CJ. Fine tuning non-invasive respiratory support to prevent lung
injury in the extremely premature infant. Front Pediatr. 2020;7:544 PMID: 31998672
doi: 10.3389/fped.2019.00544
63. Isayama T, Iwami H, McDonald S, Beyene J. Association of noninvasive ventilation strategies
with mortality and bronchopulmonary dysplasia among preterm infants: a systematic review and
meta-analysis. JAMA. 2016;316(6):611–624 PMID: 27532916 doi: 10.1001/jama.2016.10708
64. Doyle LW, Carse E, Adams AM, Ranganathan S, Opie G, Cheong JLY; Victorian Infant
Collaborative Study Group. Ventilation in extremely preterm infants and respiratory function at
8 years. N Engl J Med. 2017;377(4):329–337 PMID: 28745986 doi: 10.1056/NEJMoa1700827
65. Kattwinkel J, Fleming D, Cha CC, Fanaroff AA, Klaus MH. A device for administration of
continuous positive airway pressure by the nasal route. Pediatrics. 1973;52(1):131–134
PMID: 4579583 doi: 10.1542/peds.52.1.131
66. Welty SE. Continuous positive airway pressure strategies with bubble nasal continuous positive
airway pressure: not all bubbling is the same: the Seattle positive airway pressure system.
Clin Perinatol. 2016;43(4):661–671 PMID: 27837751 doi: 10.1016/j.clp.2016.07.004
67. Reyburn B, Di Fiore JM, Raffay T, et al. The effect of continuous positive airway pressure in a
mouse model of hyperoxic neonatal lung injury. Neonatology. 2016;109(1):6–13 PMID: 26394387
doi: 10.1159/000438818

539
68. Lam R, Schilling D, Scottoline B, et al. The effect of extended continuous positive airway
pressure on changes in lung volumes in stable premature infants: a randomized controlled trial.
J Pediatr. 2020;217:66.e1–72.e1 PMID: 31519441 doi: 10.1016/j.jpeds.2019.07.074
69. Gibu CK, Cheng PY, Ward RJ, Castro B, Heldt GP. Feasibility and physiological effects of
noninvasive neurally adjusted ventilatory assist in preterm infants. Pediatr Res.
2017;82(4):650–657 PMID: 28399118 doi: 10.1038/pr.2017.100
70. Kribs A, Roll C, Göpel W, et al; NINSAPP Trial Investigators. Nonintubated surfactant
application vs conventional therapy in extremely preterm infants: a randomized clinical trial.
JAMA Pediatr. 2015;169(8):723–730 PMID: 26053341 doi: 10.1001/jamapediatrics.2015.0504
71. Finer NN, Carlo WA, Walsh MC, et al; SUPPORT Study Group of the Eunice Kennedy Shriver
NICHD Neonatal Research Network. Early CPAP versus surfactant in extremely preterm
infants. N Engl J Med. 2010;362(21):1970–1979 PMID: 20472939 doi: 10.1056/NEJMoa0911783
72. Klingenberg C, Wheeler KI, McCallion N, Morley CJ, Davis PG. Volume-targeted versus
pressure-limited ventilation in neonates. Cochrane Database Syst Rev. 2017;10(10):CD003666
PMID: 29039883 doi: 10.1002/14651858.CD003666.pub4
73. Ehrenkranz RA, Walsh MC, Vohr BR, et al; National Institutes of Child Health and Human
Development Neonatal Research Network. Validation of the National Institutes of Health
consensus definition of bronchopulmonary dysplasia. Pediatrics. 2005;116(6):1353–1360
PMID: 16322158 doi: 10.1542/peds.2005-0249
74. McKinney RL, Napolitano N, Levin JJ, et al; BPD Collaborative. Ventilatory strategies in infants
with established severe bronchopulmonary dysplasia: a multicenter point prevalence study.
J Pediatr. 2021;242:248.e1–252.e1 PMID: 34710394 doi: 10.1016/j.jpeds.2021.10.036
75. Logan JW, Lynch SK, Curtiss J, Shepherd EG. Clinical phenotypes and management concepts
for severe, established bronchopulmonary dysplasia. Paediatr Respir Rev. 2019;31:58–63
PMID: 31076379 doi: 10.1016/j.prrv.2018.10.004
76. Shepherd EG, Clouse BJ, Hasenstab KA, et al. Infant pulmonary function testing and
phenotypes in severe bronchopulmonary dysplasia. Pediatrics. 2018;141(5):e20173350
PMID: 29622720 doi: 10.1542/peds.2017-3350
77. Guaman MC, Gien J, Baker CD, Zhang H, Austin ED, Collaco JM. Point prevalence, clinical
characteristics, and treatment variation for infants with severe bronchopulmonary dysplasia.
78. Baker CD. Long-term ventilation for children with chronic lung disease of infancy. Curr Opin
Pediatr. 2019;31(3):357–366 PMID: 31090577 doi: 10.1097/MOP.0000000000000757
79. Baker CD, Martin S, Thrasher J, et al. A standardized discharge process decreases length of stay
for ventilator-dependent children. Pediatrics. 2016;137(4):e20150637 PMID: 26966133 doi:
10.1542/peds.2015-0637
80. Sterni LM, Collaco JM, Baker CD, et al; ATS Pediatric Chronic Home Ventilation Workgroup.
An official American Thoracic Society clinical practice guideline: pediatric chronic home
invasive ventilation. Am J Respir Crit Care Med. 2016;193(8):e16–e35 PMID: 27082538
doi: 10.1164/rccm.201602-0276ST
81. Bamat NA, Kirpalani H, Feudtner C, et al. Medication use in infants with severe
bronchopulmonary dysplasia admitted to United States children’s hospitals. J Perinatol.
2019;39(9):1291–1299 PMID: 31227785 doi: 10.1038/s41372-019-0415-9
82. Stewart A, Brion LP, Ambrosio-Perez I. Diuretics acting on the distal renal tubule for preterm
infants with (or developing) chronic lung disease. Cochrane Database Syst Rev.
2011;(9):CD001817 PMID: 21901679 doi: 10.1002/14651858.CD001817.pub2
83. Ertl T, Hadzsiev K, Vincze O, Pytel J, Szabo I, Sulyok E. Hyponatremia and sensorineural
hearing loss in preterm infants. Neonatology. 2001;79(2):109–112 PMID: 11223652
doi: 10.1159/000047076
84. Chang HY, Hsu CH, Tsai JD, et al. Renal calcification in very low birth weight infants.
Pediatr Neonatol. 2011;52(3):145–149 PMID: 21703556 doi: 10.1016/j.pedneo.2011.03.004
85. Jensen EA, White AM, Liu P, et al. Determinants of severe metabolic bone disease in very
low-birth-weight infants with severe bronchopulmonary dysplasia admitted to a tertiary referral
center. Am J Perinatol. 2016;33(1):107–113 PMID: 26295968
86. Committee on Fetus and Newborn. Postnatal corticosteroids to treat or prevent chronic lung
disease in preterm infants. Pediatrics. 2002;109(2):330–338 PMID: 11826218
doi: 10.1542/peds.109.2.330
87. Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair JC. An update on the impact of
postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect
modification by risk of bronchopulmonary dysplasia. J Pediatr. 2014;165(6):1258–1260
PMID: 25217197 doi: 10.1016/j.jpeds.2014.07.049

540
88. Shinwell ES, Portnov I, Meerpohl JJ, Karen T, Bassler D. Inhaled corticosteroids for
bronchopulmonary dysplasia: a meta-analysis. Pediatrics. 2016;138(6):e20162511
PMID: 27940717 doi: 10.1542/peds.2016-2511
89. Yeh TF, Chen CM, Wu SY, et al. Intratracheal administration of budesonide/surfactant to prevent
bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2016;193(1):86–95
PMID: 26351971 doi: 10.1164/rccm.201505-0861OC
90. Araki S, Kato S, Namba F, Ota E. Vitamin A to prevent bronchopulmonary dysplasia in
extremely low birth weight infants: a systematic review and meta-analysis. PLoS One.
91. Takahashi Y, Miura T, Takahashi K. Vitamin A is involved in maintenance of epithelial cells on
the bronchioles and cells in the alveoli of rats. J Nutr. 1993;123(4):634–641 PMID: 8463864
doi: 10.1093/jn/123.4.634
92. Zachman RD. Role of vitamin A in lung development. J Nutr. 1995;125(6 suppl):1634S–1638S
PMID: 7782917 doi: 10.1093/jn/125.suppl_6.1634S
93. Schmidt B, Roberts RS, Davis P, et al; Caffeine for Apnea of Prematurity Trial Group. Caffeine
therapy for apnea of prematurity. N Engl J Med. 2006;354(20):2112–2121 PMID: 16707748
doi: 10.1056/NEJMoa054065
94. Schmidt B, Roberts RS, Davis P, et al; Caffeine for Apnea of Prematurity Trial Group.
Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med.
2007;357(19):1893–1902 PMID: 17989382 doi: 10.1056/NEJMoa073679
95. Kotecha SJ, Edwards MO, Watkins WJ, Lowe J, Henderson AJ, Kotecha S. Effect of
bronchodilators on forced expiratory volume in 1 s in preterm-born participants aged 5 and over:
a systematic review. Neonatology. 2015;107(3):231–240 PMID: 25721674 doi: 10.1159/000371539
96. Shepherd EG, Knupp AM, Welty SE, Susey KM, Gardner WP, Gest AL. An interdisciplinary
bronchopulmonary dysplasia program is associated with improved neurodevelopmental
outcomes and fewer rehospitalizations. J Perinatol. 2012;32(1):33–38 PMID: 21546943
doi: 10.1038/jp.2011.45
97. Duijts L, van Meel ER, Moschino L, et al. European Respiratory Society guideline on long-term
management of children with bronchopulmonary dysplasia. Eur Respir J. 2020;55(1):1900788
PMID: 31558663 doi: 10.1183/13993003.00788-2019
98. Cristea AI, Ren CL, Amin R, et al. outpatient respiratory management of infants, children, and
adolescents with post-prematurity respiratory disease: an official American Thoracic Society
clinical practice guideline. Am J Respir Crit Care Med. 2021;204(12):e115–e133 PMID: 34908518
doi: 10.1164/rccm.202110-2269ST
99. Carlo WA, Finer NN, Walsh MC, et al; SUPPORT Study Group of the Eunice Kennedy Shriver
NICHD Neonatal Research Network. Target ranges of oxygen saturation in extremely preterm
infants. N Engl J Med. 2010;362(21):1959–1969 PMID: 20472937 doi: 10.1056/NEJMoa0911781
100. Stenson BJ, Tarnow-Mordi WO, Darlow BA, et al; BOOST II United Kingdom Collaborative
Group; BOOST II Australia Collaborative Group; BOOST II New Zealand Collaborative Group.
Oxygen saturation and outcomes in preterm infants. N Engl J Med. 2013;368(22):2094–2104
PMID: 23642047 doi: 10.1056/NEJMoa1302298
101. Cummings JJ, Polin RA, Watterberg KL, et al; Committee on Fetus and Newborn.
Oxygen targeting in extremely low birth weight infants. Pediatrics. 2016;138(2):e20161576
PMID: 27456511 doi: 10.1542/peds.2016-1576
102. Hayes D Jr, Wilson KC, Krivchenia K, et al. Home oxygen therapy for children: an official
American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med.
2019;199(3):e5–e23 PMID: 30707039 doi: 10.1164/rccm.201812-2276ST
103. Procaskey A, White H, Simoneau T, et al. The optimization of home oxygen weaning in
premature infants trial: design, rationale, methods, and lessons learned. Contemp Clin Trials.
2018;75:72–77 PMID: 30107239 doi: 10.1016/j.cct.2018.08.001
104. Balinotti JE, Tiller CJ, Llapur CJ, et al. Growth of the lung parenchyma early in life. Am J Respir

CHAPTER
29
Pleural Effusion (Noninfectious)
Introduction
Pleural effusion is defined as an excessive amount (> 10–20 mL) of fluid in
the pleural space and is the result of excessive filtration or defective absorp-
tion of accumulated fluid. Normally, there is a balance between the influx
and outflow of fluid from the pleural space, resulting in a very small amount
(0.1–0.2 mL/kg) of sterile, colorless fluid.1 Nearly 90% of the amount of pleural
fluid filtered out of the arterial end of the capillaries is reabsorbed at the venous
end. The remaining 10% of the filtrate is returned via the lymphatic system.
The final direction of fluid transport depends on the balance between filtration
and absorption forces.2
The balance depends on several factors, including capillary filtration or hydro-
static pressure, capillary oncotic pressure (mainly due to albumin), pleural
capillary hydrostatic pressure, and pleural fluid oncotic pressure. Normally,
capillary hydrostatic or driving pressure is higher than pleural hydrostatic
pressure, and pleural oncotic pressure is lower than capillary oncotic pressure,
which results, along with lymphatic drainage, in no net accumulation of pleural
fluid. Alterations in fluid dynamics may occur with changes in hydrostatic or
oncotic pressure in the capillaries and the pleural cavity. Variants of pleural
effusion include empyema or pyothorax, hemothorax, and chylothorax,
which are due to collections of pus, blood, and lymph, respectively, in
the pleural space.
CASE REPORT 29-1

A 4-year-old boy with nephrotic syndrome developed sudden respiratory
distress, hypoxia while breathing room air, and abdominal distention.
Laboratory test results showed hyponatremia and anemia, and a chest
radiograph (Figure 29-1) showed density in the lower lobes. A pleural
effusion is suspected.
541

542
Figure 29-1. Bilateral pleural effusions, moderate on the left side and smaller on the right side,
in a 4-year-old boy with nephrotic syndrome.
Courtesy of E. Comiskey, MD, Rush University Medical Center.
Fluid Characteristics
On the basis of its chemical characteristics, pleural fluid can be transuda-
tive (due to congestive heart failure, atelectasis, or hypoalbuminemia) or
exudative (due to pleuropulmonary infections, circulating toxins, systemic
lupus erythematosus, rheumatoid arthritis, sarcoidosis, tumor, or pulmonary
infarction). Fluid characteristics, such as protein concentration and the ratio
of lactate dehydrogenase (LDH) between pleural fluid and plasma, can help
determine whether the pleural fluid is an exudate or a transudate (Table 29-1).2
Another way of describing pleural fluid is based on causative factors such as
hemorrhage or malignancy.
Table 29-1. Pleural Fluid Characteristics to Differentiate Between Transudates

and Exudates
Characteristic Transudate Exudate
Protein level < 3 g/dL (< 30 g/L) ≥ 3 g/dL (≥ 30 g/L)
Pleural fluid LDH versus serum LDH < 2/3 ≤ 2/3
(upper level of serum LDH)
Pleural fluid: serum protein < 0.5 ≥ 0.5
Pleural fluid: serum LDH < 0.6 ≥ 0.6
Abbreviation: LDH, lactate dehydrogenase.

543
Chapter 29—Pleural Effusion (Noninfectious)
Box 29‑1
Causes of Pleural Effusion According to Type of Fluid
Causes of transudative pleural effusion Causes of exudative pleural effusion
Hypoalbuminemia Parapneumonic effusion
Congestive heart failure (most common cause in children)
Atelectasis Pancreatitis
Nephrotic syndrome Collagen vascular disorders
Cirrhosis (rheumatoid arthritis, systemic
lupus erythematosus)
Peritoneal dialysis
Tuberculosis
Myxedema
Sarcoidosis
Constrictive pericarditis
Trauma (esophageal perforation,
after cardiac surgery)
Malignancy
Pulmonary embolism
Radiation pleuritis
Meigs syndrome and pseudo-Meigs
syndrome
Yellow nail syndrome
Transudative Pleural Effusion

Disequilibrium between hydrostatic and oncotic forces results in ultrafiltration
of plasma in the pleural space, causing transudative pleural effusion. Increased
microvascular pressure is the mechanism in congestive heart failure; increased
perimicrovascular pressure, in atelectasis; and decreased oncotic pressure, in
hypoalbuminemia (see Box 29-1 for a list of causes). Because of the systemic
nature of disorders causing transudative pleural effusion, pleural effusion
tends to occur bilaterally.
Exudative Pleural Effusion

Exudative pleural effusion can be caused by pleural or pulmonary inflamma-
tion, impaired lymphatic drainage from the pleural space, or transdiaphrag-
matic movement of inflammatory fluid from the peritoneal space. Infectious
pleural effusions tend to occur unilaterally.
Hemorrhagic Pleural Effusion

Hemorrhagic pleural effusion can be caused by trauma to the heart, the
great vessels, and the chest wall; postpericardiotomy syndrome; hemorrhagic
disorders such vitamin K deficiency; Henoch-Schönlein purpura; and malig-
nancy. Hemothorax has been reported with congenital cystic adenomatoid

544
malformation.3 Patients with hemorrhagic pleural effusion, depending on

the amount of bleeding, may have a reduced hematocrit level. Hemothorax
should be suspected if pleural fluid hematocrit is more than 50% of
peripheral blood hematocrit.
Pleural Effusion Associated With Malignancies

In malignancies such as lymphomas and Hodgkin disease, pleural effusion
can be caused by impaired pleural lymphatic flow secondary to pleural involve-
ment and thoracic duct obstruction. Enlarged mediastinal lymph nodes, fibrosis,
thickening of parietal pleura, and obstruction of the thoracic duct can result in
exudative pleural effusion.2 Pleural metastasis may result in increased permea-
bility or obstruction of the pleural lymphatic vessels, in turn resulting in pleural
effusion. Radiation-induced pleural fibrosis and malignancy-associated hypo-
proteinemia may also contribute to pleural effusion. Meigs syndrome is a triad
of ascites, pleural effusion, and benign ovarian fibroma and has been reported
even in prepubertal children. Presence of an ovarian tumor other than a
fibroma, ascites, and pleural effusion is called pseudo-Meigs syndrome. The
prognosis in Meigs syndrome is good because most tumors are benign.
Chylous Pleural Effusion (Chylothorax)

Chyle is lymphatic fluid enriched with fat secreted by intestinal cells. In chil-
dren, chylothorax is usually a postoperative complication of cardiac and thoracic
surgery; other causes are thrombosis of the subclavian vein and malformation
of the pulmonary or thoracic lymphatic system as described in trisomy 21 and
Noonan syndrome.4 Congenital chylothorax, the most common cause of pleural
effusion in the newborn, is reported to occur in 1 in 10,000 live births.5
Characteristics of chylous pleural fluid are milky appearance with triglyceride
levels greater than 97.4 mg/dL (1.1 mmol/L), with minimal oral fat intake; total
cell count greater than or equal to 1,000 cells/μL (1 × 109/L); and lymphocytic
fraction greater than 80%.6 In cases caused by postoperative complication,
there is a relationship between the time congenital chylothorax is diagnosed and
initiation of oral fat intake. A delay in oral feeding may delay the
appearance and diagnosis of chylothorax.
The presentation of pleural effusion ranges from an incidental radiological
finding to symptoms of respiratory distress and hypoxia requiring urgent
treatment and removal of fluid. The degree of dysfunction and associated
clinical picture is determined by the amount and rate of fluid collection, nature
of the underlying disorder, and patients’ cardiopulmonary reserve. With a very
small collection, no obvious change may be apparent; larger collections limit
lung inflation and may result in imbalance and decoupling of the normally

545
Box 29‑2 balanced inward recoil of the lung and

outward recoil of the chest wall, which
Drugs Associated With further deflates the lung. This imbal-
Pleural Effusion
ance may result in compressive lung
ū Amiodarone ū Mitomycin atelectasis; ventilation/perfusion
ū Bleomycin ū Nitrofurantoin mismatch; hypoxemia; or a clinical
ū Dantrolene ū Procainamide picture of a pleural space–occupying
ū Hydralazine ū Procarbazine lesion, such as physical examination
ū Methotrexate ū Quinidine showing chest wall bulge and mediasti-
nal shift with corresponding radiologi-
ū Methysergide
cal changes. Inspiratory muscles are
placed at a mechanical disadvantage,
which may compromise inspiratory efforts.
The clinical picture of a patient with pleural effusion depends on the underlying
disease, amount of pleural effusion, and rate at which the fluid accumulates in
the pleural space. Many patients with pleural effusion may not have symptoms
related to pleural effusion.
It is important to obtain a history of the drugs implicated in the cause of
pleural effusion. These include drugs that have been associated with lupus
syndrome and others that may cause pleural effusion (Box 29-2). The follow-
ing sections discuss some of the symptoms.
Chest Pain
Transudative pleural effusion is not associated with chest pain because there
is no inflammation of pleura in the disorders associated with transudates
(Box 29-1). Involvement and inflammation of parietal pleura, because only
parietal pleura has pain fibers, may result in pleuritic chest pain, which is
present or gets worse during inspiration or coughing. Usually the pain is
localized and coincides with the affected area of the pleura. The pain may
be mild or severe and is stabbing or sharp in nature. At times, the pain may
be referred to the abdomen or ipsilateral shoulder because of common nerve
supply. The pain may decrease in severity as the quantity of pleural effusion
increases because increased quantity of fluid between 2 layers of pleura
prevents rubbing of the 2 surfaces against each other.
Dyspnea
Dyspnea, or shortness of breath, may be the most common presenting symp-
tom. Mechanical inefficiency of respiratory muscles stretched by outward
movement of the chest wall and downward movement of the diaphragm
results in dyspnea. Dyspnea indicates a large amount of pleural fluid
collection. Underlying lung disease can also contribute to dyspnea.

546
Cough
Mild nonproductive cough is a less common symptom of pleural effusion.
Distortion of the lung may cause cough, but an underlying lung disorder may
also cause cough.
Physical Findings
Pleural rub may be the only finding in the early stages when the fluid amount
collected in the pleural space is very small. Pleural rub is present through-
out the respiratory cycle, loudest at end inspiration and early expiration. It
disappears when the patient holds their breath.
With increasing amounts of fluid, there may be decreased breath sounds,
increased dullness at percussion, decreased tactile fremitus, and egophony.
Large amounts of fluid are associated with contralateral mediastinal shift.
There may be fullness of intercostal spaces over the pleural effusion area.
Ipsilateral mediastinal shift may be present when there is endobronchial
obstruction by a foreign body or tumor.
Pleural effusion rarely may be associated with yellow nail syndrome (slow
growing and discolored nails), lymphedema, or chronic recurrent pleural
effusion.
Diagnostic Studies
Laboratory Studies
Conservative management with observation of the patient for complications
may be reasonable in cases of pleural effusion associated with congestive
heart failure, viral pleurisy, and postoperative pleural effusions. Thoracentesis
should be considered in patients with unexplained pleural effusion when fluid
quantity is sufficient to allow a safe procedure. Blood cell counts, erythrocyte
sedimentation rate, and C-reactive protein level estimation help to confirm or
rule out an infective or inflammatory cause for pleural effusion. The results
of pleural fluid analysis for pH and serum glucose, LDH, protein, triglyceride,
and electrolyte levels, as well as microbiological studies, are associated with
different causes and used to differentiate between exudate and transudate
(Table 29-1).7
Chest Radiography
Chest radiography helps to confirm the diagnosis of pleural effusion. Radio-
graphic features of pleural effusion are related to several factors,3 including
the amount of fluid, whether the fluid is free or loculated, presence of adjacent
parenchymal lung disease, and position of the patient relative to the x-ray
beam. A small amount of fluid (< 200 mL) may be detected as only blunting
of the costophrenic angle. A larger amount of fluid appears as homogeneous

547
density with a concave superior border on an upright posteroanterior (PA)

view or lateral view. This meniscus sign may not be present when the radio-
graph is obtained with the patient supine, as in a portable radiograph, and only
a nonspecific haze over the affected hemithorax may be visible because of the
fluid layers in the posterior area. In still larger fluid collections, the whole
hemithorax may be opacified, and there may be evidence of mediastinal shift
to the opposite side. The fluid may extend into major or minor fissures and
appear as thickened fissures on chest radiographs obtained in the PA or lateral
view. A subpulmonic pleural effusion with fluid between the inferior surface
of the lung and superior margin of the diaphragm may appear as apparent
elevation of the corresponding dome of the diaphragm. Lateral displacement
of the apex of the diaphragm, increased space between the air bubble of the
gastric fundus and the superior margin of apparent diaphragm, absence of
the lower lobe vessels normally visualized overlying the diaphragm on PA
radiographs, and sharp angulation of the anterior portion of the apparent
diaphragm may also be seen.8
Ultrasonography
Ultrasonography is effective for visualization of effusion and determining
whether the fluid is free flowing or loculated, and it may also be used to guide
thoracentesis.9 Ultrasonography can also help differentiate between solid
mass and effusion.
Computed Tomography
Unless an underlying mass is a concern, computed tomography (CT) of the
chest may not be necessary to diagnose a simple pleural effusion. Neverthe-
less, CT with contrast material may provide additional information, such as
underlying lung parenchymal information, necrotizing pneumonia, atelectasis,
hilar adenopathy, and lung abscess. It may also have a role in cases of
complicated effusion or those unresponsive to therapy.
Magnetic Resonance Imaging

Conventional pediatric chest magnetic resonance imaging (MRI) for diagnos-
ing pleural effusion10 and its modified version, dynamic contrast-enhanced
MRI,11 for diagnosing chylothorax have also been proposed. However, con-
ducting the MRI may be associated with multiple issues, such as difficulty in
transporting the patient to the MRI facility because it may mean interrupting
monitoring and other ongoing therapies, need for sedation and anesthesia,
and risk of dorsal atelectasis during general anesthesia.
In cases in which conventional chest radiography or ultrasonography is not
helpful in confirming the diagnosis of pleural effusion, use of the respiratory
navigator (use of radiofrequency pulses to detect physiological motion) during
MRI may be considered.12,13

548
Management
Treatment of nonbacterial pleural effusion is primarily treatment of the pri-
mary disorder (Box 29-3). Refer to Chapter 21, Complications of Pneumonia,
for the treatment of bacterial pleural effusion, such as parapneumonic
pleural effusion.
Box 29‑3
Treatment for a Pediatric Patient With Nonbacterial Pleural Effusion
ū Document the presence of pleural effusion.
ū Suspect pleural effusion in the presence of clinical disorders likely to be asso-
ciated with it, such as nephrotic syndrome, hypoalbuminemia, and congestive
heart failure, and postoperative cardiothoracic cases.
ū Take a history and conduct a physical examination for symptoms such as chest
pain, dyspnea, and cough and the presence of physical signs such as pleural rub,
decreased breath sounds, increased dullness, and mediastinal shift.
ū Confirm the presence and estimate the quantity of pleural effusion by means of
chest radiography, ultrasonography, or computed tomography.
ū Investigate for possible causes of the pleural effusion (blood cell counts,
erythrocyte sedimentation rate, C-reactive protein levels).
ū Use thoracentesis to diagnose the type of fluid (transudate vs exudate) and
possible cause.
ū Use thoracentesis when pleural effusion compromises the patient’s respiratory
status; bacterial causes of pleural fluid, such as empyema, tuberculosis, and
malignancy, may require thoracentesis for diagnostic and therapeutic reasons.8
ū Apart from thoracentesis for diagnostic purposes and to relieve respiratory
distress, treatment of the underlying disorder should be the goal of therapy.
Thoracentesis
Thoracentesis may be considered therapeutic or diagnostic.
Therapeutic Thoracentesis
Thoracentesis is indicated to relieve dyspnea in patients with large effusions8
and to prevent development of complicated parapneumonic effusions. As a
general rule, thoracentesis can be performed safely when the thickness of the
pleural fluid layer at lateral decubitus chest radiography is more than 10 mm
or loculated fluid is identified at ultrasonography or chest CT. Administering
supplemental oxygen during thoracentesis can prevent hypoxemia as a com-
plication of the procedure. It is important to withdraw enough fluid to improve
the dyspnea without withdrawing too much fluid and too rapidly, which can
cause reexpansion pulmonary edema and pneumothorax.9 A small and clini-
cally nonsignificant pneumothorax may be present after thoracentesis. The

549
pneumothorax, if large, may manifest with increased respiratory distress,

oxygen requirement, and clinical signs (see Chapter 30, Pneumothorax and
Pneumomediastinum) and can be confirmed with chest radiography.
Diagnostic Thoracentesis
Diagnostic thoracentesis is performed in patients with effusion with no clear
cause. The fluid can be tested to differentiate between transudates and exudates
(Table 29-1). The fluid can be examined for physical characteristics, such as
color, specific gravity, triglyceride levels, and chylomicron levels. Other tests
can be used to help diagnose a specific cause of pleural effusion; these include
total and differential blood cell counts, LDH levels, pH, protein levels, glucose
levels, Gram stain, mycobacterial studies, fungal stain and culture, and cyto-
logical testing.8 Levels of amylase more than twice the levels of serum amylase
suggest pancreatic disease, such as acute pancreatitis, pancreatic pseudocyst,
and malignancy. Esophageal rupture also increases amylase levels in pleural
fluid.
Management of Chylous Pleural Effusion

Chylous pleural effusion may be either acquired (postoperative) or congenital.
Usually, initial therapy for postoperative chylothorax is pleural space drainage,
use of medium chain triglyceride oil, fat-free oral feeding, or enteric rest with
total parenteral nutrition. Chylous effusions often persist for weeks. In neo-
nates with congenital chylothorax refractory to conservative management,
octreotide, a somatostatin analogue, administered as an intravenous infusion
(1 mcg/kg/h, gradually increased to 10 mcg/kg/hr)14 may reduce production
and accumulation of fluid.15 However, gastrointestinal intolerance, necrotizing
enterocolitis, and transient hypothyroidism have been reported as adverse
effects.15,16 Investigators in a 2017 retrospective study of chylothorax in neo-
nates reported no advantage of octreotide over a regimen of nothing by mouth
and total parenteral nutrition.17 Surgery in the form of pleurodesis of leaking
lymphatic vessels and ligation of the thoracic duct is usually indicated if the
effusion persists after more than 4 weeks of conservative treatment.4,18
Prognosis and When to Refer

The prognosis depends on the cause of pleural effusion, the rate of fluid
collected, and the quantity of fluid collected. Small pleural effusions detected
accidentally on chest radiographs and not associated with clinically significant
findings may not require major intervention, such as pleural drainage. Pleural
effusions with a large amount of rapidly collecting fluid and clinical signs,
especially respiratory distress, hypoxia, and mediastinal shift, require more
aggressive therapy and referral for possible surgical intervention for drainage.
Failure of conservative therapy and delay in initiation of specific therapy may
result in complications, such as respiratory failure.

550
key points
} Nonbacterial pleural effusion should be suspected when a patient with
underlying disorders, such as nephrotic syndrome, hypoalbuminemia, or
congestive heart failure, or postoperative cardiothoracic cases, develops
respiratory distress, increased oxygen requirement, and clinical signs
of effusion.
} A small pleural effusion may manifest as only an incidental finding at chest
radiography.
} Rapidly collecting large pleural effusions with respiratory distress require
therapeutic thoracentesis.
} Pleural effusions with no obvious underlying cause require diagnostic workup,
including diagnostic thoracentesis, investigations for the possible underlying
cause, and treatment according to the cause.
References
1. Zocchi L. Physiology and pathophysiology of pleural fluid turnover. Eur R\espir J.
2002;20(6):1545–1558 PMID: 12503717 doi: 10.1183/09031936.02.00062102
2. Prentice B, Jaffe A. Air and fluid in the pleural space. In: Wilmott RW, Deterding R, Li A,
Ratjen F, Sly P, Zar HJ, Bush A, eds. Kendig’s Disorders of Respiratory Tract in Children.
9th ed. Elsevier; 2019:1007–1026
3. Laberge JM, Puligandla P, Flageole H. Asymptomatic congenital lung malformations.
Semin Pediatr Surg. 2005;14(1):16–33 PMID: 15770585 doi: 10.1053/j.sempedsurg.2004.10.022
4. Chernick V, Reed MH. Pneumothorax and chylothorax in the neonatal period. J Pediatr.
1970;76(4):624–632 PMID: 5420804 doi: 10.1016/S0022-3476(70)80420-6
5. Bellini C, Ergaz Z, Boccardo F, et al. Dynamics of pleural fluid effusion and chylothorax in the
fetus and newborn: role of the lymphatic system. Lymphology. 2013;46(2):75–84 PMID: 24354106
6. Büttiker V, Fanconi S, Burger R. Chylothorax in children: guidelines for diagnosis and
management. Chest. 1999;116(3):682–687 PMID: 10492271 doi: 10.1378/chest.116.3.682
7. Light RW, ed. Clinical Manifestations and Useful Tests in Pleural Diseases. 5th ed.
Lippincott Williams & Wilkins; 2007:73
8. Jay SJ. Diagnostic procedures for pleural disease. Clin Chest Med. 1985;6(1):33–48
PMID: 2408811 doi: 10.1016/S0272-5231(21)00336-1
9. Grogan DR, Irwin RS, Channick R, et al. Complications associated with thoracentesis: a
prospective, randomized study comparing three different methods. Arch Intern Med.
1990;150(4):873–877 PMID: 2183735 doi: 10.1001/archinte.1990.00390160119023
10. Kapur S, Bhalla AS, Jana M. Pediatric chest MRI: a review. Indian J Pediatr. 2019;86(9):842–853
PMID: 30719641 doi: 10.1007/s12098-018-02852-w
11. Pimpalwar S, Chinnadurai P, Chau A, et al. Dynamic contrast enhanced magnetic resonance
lymphangiography: categorization of imaging findings and correlation with patient management.
Eur J Radiol. 2018;101:129–135 PMID: 29571786 doi: 10.1016/j.ejrad.2018.02.021
12. Liu YL, Riederer SJ, Rossman PJ, Grimm RC, Debbins JP, Ehman RL. A monitoring, feedback,
and triggering system for reproducible breath-hold MR imaging. Magn Reson Med.
1993;30(4):507–511 PMID: 8255201 doi: 10.1002/mrm.1910300416
13. Rosenzweig S, Scholand N, Holme HCM, Uecker M. Cardiac and respiratory self-gating in radial
MRI using an adapted singular spectrum analysis (SSA-FARY). IEEE Trans Med Imaging.
2020;39(10):3029–3041 PMID: 32275585 doi: 10.1109/TMI.2020.2985994
14. Bellini C, Cabano R, De Angelis LC, et al. Octreotide for congenital and acquired chylothorax in
newborns: a systematic review. J Paediatr Child Health. 2018;54(8):840–847 PMID: 29602276
doi: 10.1111/jpc.13889

551
15. Das A, Shah PS. Octreotide for the treatment of chylothorax in neonates. Cochrane Database
Syst Rev. 2010;(9):CD006388 PMID: 20824848 doi: 10.1002/14651858.CD006388.pub2
16. Chandran S, Agarwal A, Llanora GV, Chua MC. Necrotising enterocolitis in a newborn infant
treated with octreotide for chylous effusion: is octreotide safe? BMJ Case Rep. 2020;13(2):e232062
PMID: 32051156 doi: 10.1136/bcr-2019-232062
17. Church JT, Antunez AG, Dean A, et al. Evidence-based management of chylothorax in infants.
J Pediatr Surg. 2017;52(6):907–912 PMID: 28342580 doi: 10.1016/j.jpedsurg.2017.03.010
18. Bender B, Murthy V, Chamberlain RS. The changing management of chylothorax in the modern
era. Eur J Cardiothorac Surg. 2016;49(1):18–24 PMID: 25732972 doi: 10.1093/ejcts/ezv041

CHAPTER
30
Pneumothorax and Pneumomediastinum
Pneumothorax
Pneumothorax occurs when air enters the pleural space by means of a leak in
the parietal or visceral pleura. Pneumothorax can be spontaneous or traumatic.
Traumatic pneumothorax is the result of blunt or penetrating trauma to the
chest wall or an unintended injury from a medical procedure. Spontaneous
pneumothorax does not have a preceding trauma and can be categorized further
as primary or secondary spontaneous pneumothorax. In primary pneumotho-
rax, there is no known underlying lung disease that would lead to air leak.
Apical blebs of unknown cause can be seen at the time of surgery or computed
tomography (CT).1 Secondary pneumothorax occurs as a complication of
underlying lung disease, such as asthma or cystic fibrosis. Data are limited on
the exact incidence of spontaneous pneumothorax in the pediatric population,
but it appears to be higher between the ages of 13 and 16 years.2 Primary spon-
taneous pneumothorax typically occurs in patients who are tall or asthenic
and more commonly in male patients.3,4 Smoking increases the risk of
pneumothorax.5 Box 30-1 contains a list of causes of pneumothorax.
CASE REPORT 30-1

A 16-year-old adolescent presented to the emergency department with a 2-day
history of right-sided chest pain. The only other symptom was shortness of
breath on exertion. He has been in previously good health, is active, and partici-
pates in sports. The pain started when he was sitting quietly in the evening. His
vital signs were normal except for a respiratory rate of 18 breaths/min. Oxygen
saturation in room air was 97%. Physical examination revealed a tall and thin
youth with a normal chest configuration. The chest examination findings were
normal, and findings from auscultation of the heart and lungs were negative.
A chest radiograph revealed a small pneumothorax on the right. He was ob-
served in the emergency department for 4 hours, during which time computed
tomography (CT) was performed. The CT scan confirmed the pneumothorax
and showed small apical blebs in both lungs. He was discharged home with no
intervention, and arrangements were made for follow-up radiography in 2 days.
553

554
Box 30‑1
Causes of Pneumothorax
Traumatic
ū Penetrating or blunt chest trauma
Iatrogenic
ū Mechanical ventilation (barotrauma)
ū Central vein catheterization
ū Procedures on airways: intubation, endoscopy, transbronchial biopsy
ū Laparoscopic procedures
ū Percutaneous biopsies
Primary spontaneous
ū Asthenic body habitus
ū Idiopathic
ū Cocaine or marijuana inhalation
Secondary spontaneous
ū Airway disease: asthma, cystic fibrosis
ū Postinfection: measles, Pneumocystis jirovecii pneumonia, tuberculosis,
necrotizing pneumonia or abscess, parasitic (ecchinococcal)
ū Interstitial lung disease: sarcoidosis, Langerhans cell histiocytosis
ū Connective tissue disease: Marfan syndrome, Ehlers-Danlos syndrome,
rheumatoid arthritis, systemic lupus erythematosus, polymyositis,
dermatomyositis
ū Malignancy: lymphoma, metastasis
ū Aspiration: foreign body, meconium
ū Catamenial pneumothorax
Congenital malformations
Pathophysiology
The exact mechanism for pneumothorax remains unclear but is thought to
involve an interplay of a few factors. One proposed mechanism suggests
that large increases in transpulmonary pressure can cause alveolar distention
with high pressure gradients leading to alveolar rupture. Subpleural blebs
then form that can rupture directly into the pleural space. Another suggested
mechanism is that there is direct injury from underlying lung disease to the
visceral pleura that then leads to pneumothorax. There is a negative pressure
within the pleural space, relative to the alveoli, which helps keep the pleural
space intact. Spontaneous pneumothorax occurs when the visceral pleura is
ruptured. Traumatic pneumothorax may involve the parietal pleura (air
entering from the outside), visceral pleura (air entering from the lungs), or
both. Tension pneumothorax develops when air enters the pleural space dur-
ing inspiration but cannot exit during exhalation. This situation will lead to

555
Chapter 30—Pneumothorax and Pneumomediastinum
collapse of the affected lung and shift of the mediastinum away from the
affected side. Tension pneumothorax is uncommon following primary spon-
taneous pneumothorax but is a potential risk after traumatic pneumothorax
and secondary spontaneous pneumothorax, especially in patients who are
receiving positive-pressure–assisted ventilation. Air enters the pleural space
with each breath and is unable to escape so that the mediastinum becomes
shifted to the other side. Hypoxia results, and hemodynamic changes lead
to shock and death within a short period (sometimes minutes) if the
pneumothorax is not treated.
Clinical Features
The most common symptom of pneumothorax is the sudden onset of chest
pain. Additional symptoms include tachypnea, dyspnea, tachycardia, and
cyanosis. The volume of air in the pleural space, the suddenness of onset, and
the degree of respiratory compromise from underlying lung disease determine
the severity of symptoms. Pain can be localized to the retrosternal space or to
the ipsilateral shoulder or can be generalized pleuritic pain. Physical examina-
tion findings include decreased breath sounds, decreased chest wall movement,
and increased resonance during percussion on the affected side. In cases of
tension pneumothorax with shift of the mediastinum, the trachea will be dis-
placed, as will the point of maximal cardiac impulse. Air moving from areas
of lower resistance can create subcutaneous emphysema in the neck, upper
extremities, abdominal wall, and peritoneum. If the pneumothorax is small
or is picked up as an incidental finding on a chest radiograph, the patient
will frequently be asymptomatic.
Diagnostic Tests
Pneumothorax is most frequently diagnosed by means of chest radiography.
The characteristic findings at radiography are air in the pleural space out-
lining the visceral pleura (pleural line) and hyperlucency and attenuation of
vascular and lung markings on the affected side (Figures 30-1 and 30-2).
Chest CT can depict bullae and blebs in patients with recurrent pneumothorax
and in cases in which the radiograph is inconclusive.6,7 Blood gas measure-
ments can reveal hypoxemia, but hypercapnia is not typically seen in cases of
pneumothorax without underlying chronic lung disease.1 Electrocardiography
can demonstrate changes in amplitude of the QRS complex and the cardiac
axis in cases of severe tension pneumothorax when there is mediastinal shift.

556
Figure 30-1. Anteroposterior

radiograph showing the
spinnaker sail (angel wing)
sign (arrows) in a patient
with pneumomediastinum
and pneumothorax.
Figure 30-2. Axial computed

tomography scan revealing
both paraesophageal air and
pneumothorax in the same
patient seen in Figure 30–1.
Management
Treatment choice depends on a number of factors, including degree of respira-
tory distress, pneumothorax size, pneumothorax cause, and the presence
of underlying lung disease. The goals of treatment are removal of air from
the pleural space and prevention of recurrence.1,8 Treatment options include
observation with or without supplemental oxygen; needle aspiration; chest
tube placement; pleurodesis; and, in some cases, surgical resection of blebs
if present. A few recent studies have been published on management of
pediatric spontaneous pneumothorax, but pediatric-specific guidelines
are not currently available.9–11

557
Minimal Symptoms: Observation With or Without the Use of

Supplemental Oxygen
In patients without respiratory distress and a small pneumothorax (< 2 cm
[0.79 inches] distance between chest wall and lung at the apex), simple obser-
vation can be instituted.12,13 In a younger child, hospitalization is advisable.
Supplemental oxygen can be used during this period of observation. The rate
of resorption of air from the pleural space is increased with the use of sup-
plemental oxygen.14 The increased alveolar oxygen tension creates a large
gradient between capillary and pleural gas partial pressure of nitrogen,
resulting in faster resorption of intrapleural air (known as nitrogen washout).
Use of 100% oxygen via a nonrebreathing face mask has been suggested,
although this should not be continued for a long period. In the older child,
observation may be on an outpatient basis. The exception is traumatic pneu-
mothorax because of the potential for tension pneumothorax. Most cases of
traumatic pneumothorax should be treated with a chest tube, especially if
positive-pressure ventilation is used.
Patients With Symptoms
Needle Aspiration
Patients with symptoms with a small or large pneumothorax will need to
have the air evacuated, which may be accomplished with needle aspiration.
A large-bore intravenous catheter is attached to a large syringe with a 3-way
stopcock. Air is aspirated until no more can be drawn off. If air continues to
be withdrawn, this means that there is a persistent air leak, and tube thoracos-
tomy should be performed. If no more air can be aspirated, then the stopcock
is closed and the catheter is taped to the chest wall. After 4 hours of obser-
vation, chest radiography should be performed. If there is sufficient lung
re-expansion, then the catheter can be removed and the patient observed. If
the pneumothorax remains the same size or larger, then the patient requires
chest tube placement. Published success rates vary, although they point to
a higher success rate in small pneumothoraces.9 A 2020 study10 looked at
needle aspiration for children presenting with their first primary spontaneous
pneumothorax. The authors recommended that needle aspiration be used
as a test and that those in whom needle aspiration fails go on to early
video-assisted thoracoscopic surgery (VATS).
Thoracostomy Tube
Thoracostomy tube placement has been the initial treatment of choice
for pediatric patients with symptoms with large primary or secondary
pneumothoraces, for younger children, or for those with recurrent sponta-
neous pneumothorax.15 Tube placement involves the use of a 1-way Heimlich
valve or water seal device to prevent re-accumulation of air. In guidelines
from the American College of Chest Physicians,15 half of the panel members
recommended clamping of the tube 4 hours after the last evidence of an air

558
leak, and the other half recommended never clamping a chest tube. To avoid
developing tension pneumothorax, a bubbling chest tube should never be
clamped. Repeat chest radiography should be performed 5 to 12 hours after
the last evidence of an air leak in preparation for removal of the tube.
Pleurodesis
Pleurodesis is performed in cases of recurrent pneumothorax. It can be
achieved chemically or surgically. Chemical pleurodesis involves injection of
a sclerosing agent, such as talc, tetracycline, doxycycline, autologous blood
patches, or fibrin glue, at the time of thoracostomy tube placement. Surgical
pleurodesis is favored over chemical pleurodesis for persistent air leak.16 The
literature supports both mechanical pleurodesis achieved by direct abrasion
with gauze or laser or chemical pleurodesis with talc or doxycycline at the
time of surgery to prevent recurrent pneumothoraces.15
Surgical Intervention
Surgery is indicated to treat persistent air leaks and to prevent recurrence.
Surgery involves stapling or oversewing ruptured blebs (bullectomy) or tears
in the visceral pleura and resection of abnormal lung tissue if present. Surgery
can be performed via a mini thoracotomy, open thoracotomy, or VATS, with
VATS being the preferred method by many surgeons. The American College
of Chest Physicians recommends surgical intervention at the time of the first
occurrence of a secondary spontaneous pneumothorax15 and at the second
occurrence of a primary spontaneous pneumothorax.17
Prognosis
Data are limited regarding the prognosis after spontaneous pneumothorax in
children. Results from one reported series showed a 37% incidence of
recurrent spontaneous pneumothorax.18 In pediatric patients undergoing
surgery, the reported risk of recurrence was 6% to 9%.19,20 In another study,21
the authors found that patients who underwent VATS-directed bullectomy and
pleurodesis at the first presentation of spontaneous pneumothorax had a 29%
recurrence rate compared with 0% in the group of patients undergoing VATS
on the second occurrence. Although there is not yet consensus in the literature
regarding the best treatment strategy for initial presentation of spontaneous
pneumothorax, patients and caregivers should be made aware of the risk
for recurrence.22
Pneumomediastinum
Pneumomediastinum is defined as the presence of air in the mediastinum.
Cases of pneumomediastinum can be further subdivided into spontaneous
or secondary pneumomediastinum. Spontaneous pneumomediastinum does
not have an identifiable source. Secondary pneumomediastinum occurs in
children with asthma or foreign body aspiration and after chest trauma due to

559
endotracheal or endoesophageal procedures, mechanical ventilation, cardiac

catheterization, or thoracic surgery. Spontaneous pneumomediastinum is a
rare condition in young children. However, because of respiratory infections,
there is a peak incidence between 6 months and 3 years of age.23,24 Sponta-
neous pneumomediastinum is mostly seen in older children and adolescents,
with reported incidences of 1 in 800 to 1 in 42,000 patients presenting to a
hospital emergency department.25 Stack and Caputo23 found an incidence of
spontaneous pneumomediastinum in 0.3% of 12,000 children presenting to
a pediatric emergency department with asthma. Most investigators report a
slightly higher incidence in male patients.25,26
Pathophysiology
Alveolar rupture occurs owing to excess pressure (from overdistention) in
the alveolus compared with the surrounding tissue. The air leaks into the
interstitial tissues toward the hilum along the peribronchial and perivascular
sheaths. The air then spreads toward the mediastinum; the cervical region;
the upper limbs; and, in some cases, the retroperitoneum, peritoneum, spine,
pericardium, and pleura.25 In some cases of spontaneous pneumomediasti-
num, a trigger can be found, which often includes asthma, emesis, intense
physical activity, inhalation drugs, and situations involving a strong Valsalva
maneuver (eg, coughing, screaming).26 Pneumothorax may accompany
the pneumomediastinum.
Clinical Features
Patients typically present with retrosternal chest pain with radiation to the
shoulders, back, and arms. The pain is worsened with deep inhalation. Other
presenting symptoms include sore throat, dyspnea, swelling of the neck, torti-
collis, dysphagia, and abdominal pain. Physical examination findings include
subcutaneous emphysema and the classic Hamman sign, which is a precordial
systolic crepitation or crunching sound at auscultation of the chest. Esophageal
perforation must be excluded in cases of spontaneous pneumomediastinum
that occur after severe and violent emesis.25
Diagnostic Tests
The diagnosis of spontaneous pneumomediastinum can be confirmed with
chest radiography. A number of specific radiographic findings are seen in
pneumomediastinum.25,27 The spinnaker sail or angel wing sign (Figure 30-1)
is created by air lifting the thymus off the heart and major vessels. The con-
tinuous diaphragm sign is caused by air collecting between the diaphragm
and the pericardium. The vertical lucent streak is seen on the left side of the
heart because of air outlining the parietal pleura. Additional radiographic
findings include thoracic and cervical subcutaneous emphysema and associ-
ated pneumothorax. If esophageal perforation is suspected, then radiography

560
with contrast material should be performed, which can be combined with

CT. Esophageal endoscopy can also be used to identify cases of perforation
or radiotransparent foreign body. Electrocardiography can show diffuse
microvoltage, depressed ST interval, T-wave inversion, and axis deviation,
depending on the size and location of the pneumomediastinum.25
Management
In most cases, spontaneous pneumomediastinum is benign and resolves in
3 to 15 days without further sequelae.28 Management is usually supportive,
including rest, analgesia, and treatment of the underlying condition, if pre-
sent. Patients are advised to avoid maneuvers that lead to forceful exhalation
(measure of lung function, physical activity, and playing of wind instruments)
for a few months after the episode. As with pneumothorax, the use of nitrogen
washout with 100% inspired oxygen is frequently used; however, efficacy
has not been conclusively established.29,30 Follow-up radiographs are not
necessary.25 Recurrence of spontaneous pneumomediastinum is rare but
is likely linked to either the underlying diagnosis of asthma or a repeat of
the causal situation (emesis, strong Valsalva maneuver) that led to the
first pneumomediastinum.
key points
} Pneumothoraces manifest with the sudden onset of severe chest pain.
} Treatment of pneumothoraces depends on the size of the pneumothorax and
degree of respiratory distress, with small pneumothoraces being treated with
observation or supplemental oxygen and larger pneumothoraces requiring
thoracotomy tube placement.
} Further evaluation with chest CT is indicated with recurrent pneumothorax.
} Most cases of pneumomediastinum in children are spontaneous and occur
during an asthma exacerbation or after a strong Valsalva maneuver; the course
is typically benign, and treatment is supportive.
} Tension pneumothorax is a potentially life-threatening emergency requiring
immediate attention.

561
References
1. Sahn SA, Heffner JE. Spontaneous pneumothorax. N Engl J Med. 2000;342(12):868–874
PMID: 10727592 doi: 10.1056/NEJM200003233421207
2. Dotson K, Johnson LH. Pediatric spontaneous pneumothorax. Pediatr Emerg Care.
2012;28(7):715–720 PMID: 22766594 doi: 10.1097/PEC.0b013e31825d2dd5
3. Abolnik IZ, Lossos IS, Gillis D, Breuer R. Primary spontaneous pneumothorax in men. Am J
Med Sci. 1993;305(5):297–303 PMID: 8484388 doi: 10.1097/00000441-199305000-00006
4. Withers JN, Fishback ME, Kiehl PV, Hannon JL. Spontaneous pneumothorax. Suggested
etiology and comparison of treatment methods. Am J Surg. 1964;108(6):772–776
PMID: 14233755 doi: 10.1016/0002-9610(64)90030-3
5. Bense L, Eklund G, Wiman LG. Smoking and the increased risk of contracting spontaneous
pneumothorax. Chest. 1987;92(6):1009–1012 PMID: 3677805 doi: 10.1378/chest.92.6.1009
6. Mitlehner W, Friedrich M, Dissmann W. Value of computer tomography in the detection of
bullae and blebs in patients with primary spontaneous pneumothorax. Respiration.
1992;59(4):221–227 PMID: 1485007 doi: 10.1159/000196062
7. Choudhary AK, Sellars ME, Wallis C, Cohen G, McHugh K. Primary spontaneous
pneumothorax in children: the role of CT in guiding management. Clin Radiol.
2005;60(4):508–511 PMID: 15767109 doi: 10.1016/j.crad.2004.12.002
8. Baumann MH, Strange C. Treatment of spontaneous pneumothorax: a more aggressive
approach? Chest. 1997;112(3):789–804 PMID: 9315817 doi: 10.1378/chest.112.3.789
9. Robinson PD, Blackburn C, Babl FE, et al; Paediatric Emergency Departments International
Collaborative (PREDICT) research network. Management of paediatric spontaneous
pneumothorax: a multicentre retrospective case series. Arch Dis Child. 2015;100(10):918–923
10. Leys CM, Hirschl RB, Kohler JE, et al; Midwest Pediatric Surgery Consortium MWPSC.
Changing the paradigm for management of pediatric primary spontaneous pneumothorax:
a simple aspiration test predicts need for operation. J Pediatr Surg. 2020;55(1):169–175
11. Miscia ME, Lauriti G, Lisi G, Riccio A, Lelli Chiesa P. Management of spontaneous
pneumothorax in children: a systematic review and meta-analysis. Eur J Pediatr Surg.
2020;30(1):2–12 PMID: 31899922 doi: 10.1055/s-0039-3402522
12. Kirby TJ, Ginsberg RJ. Management of the pneumothorax and barotrauma. Clin Chest Med.
1992;13(1):97–112 PMID: 1582152
13. Paape K, Fry WA. Spontaneous pneumothorax. Chest Surg Clin N Am. 1994;4(3):517–538
PMID: 7953482
14. Northfield TC. Oxygen therapy for spontaneous pneumothorax. BMJ. 1971;4(5779):86–88
PMID: 4938315 doi: 10.1136/bmj.4.5779.86
15. Baumann MH, Strange C, Heffner JE, et al; AACP Pneumothorax Consensus Group.
Management of spontaneous pneumothorax: an American College of Chest Physicians Delphi
consensus statement. Chest. 2001;119(2):590–602 PMID: 11171742 doi: 10.1378/chest.119.2.590
16. Alfageme I, Moreno L, Huertas C, Vargas A, Hernandez J, Beiztegui A. Spontaneous
pneumothorax. Long-term results with tetracycline pleurodesis. Chest. 1994;106(2):347–350
PMID: 7774300 doi: 10.1378/chest.106.2.347
17. Baumann MH. Management of spontaneous pneumothorax. Clin Chest Med.
2006;27(2):369–381 PMID: 16716824 doi: 10.1016/j.ccm.2005.12.006
18. Shaw KS, Prasil P, Nguyen LT, Laberge JM. Pediatric spontaneous pneumothorax. Semin
Pediatr Surg. 2003;12(1):55–61 PMID: 12520473 doi: 10.1016/S1055-8586(03)70007-9
19. Poenaru D, Yazbeck S, Murphy S. Primary spontaneous pneumothorax in children. J Pediatr
Surg. 1994;29(9):1183–1185 PMID: 7807340 doi: 10.1016/0022-3468(94)90795-1
20. Cook CH, Melvin WS, Groner JI, Allen E, King DR. A cost-effective thoracoscopic treatment
strategy for pediatric spontaneous pneumothorax. Surg Endosc. 1999;13(12):1208–1210
PMID: 10594267 doi: 10.1007/PL00009622
21. Qureshi FG, Sandulache VC, Richardson W, Ergun O, Ford HR, Hackam DJ. Primary vs delayed
surgery for spontaneous pneumothorax in children: which is better? J Pediatr Surg.
2005;40(1):166–169 PMID: 15868579 doi: 10.1016/j.jpedsurg.2004.09.042
22. Lewit RA, Tutor A, Albrecht A, Weatherall YZ, Williams RF. Pediatric spontaneous
pneumothorax: does initial treatment affect outcomes? J Surg Res. 2021;259:532–537
PMID: 33189361 doi: 10.1016/j.jss.2020.10.008
23. Stack AM, Caputo GL. Pneumomediastinum in childhood asthma. Pediatr Emerg Care.
1996;12(2):98–101 PMID: 8859917 doi: 10.1097/00006565-199604000-00008

562
24. Bierman CW. Pneumomediastinum and pneumothorax complicating asthma in children. Am J

Dis Child. 1967;114(1):42–50 PMID: 4951525 doi: 10.1001/archpedi.1967.02090220048008
25. Chalumeau M, Le Clainche L, Sayeg N, et al. Spontaneous pneumomediastinum in children.
doi: 10.1002/1099-0496(200101)31:1<67::AID-PPUL1009>3.0.CO;2-J
26. Caceres M, Ali SZ, Braud R, Weiman D, Garrett HE Jr. Spontaneous pneumomediastinum:
a comparative study and review of the literature. Ann Thorac Surg. 2008;86(3):962–966
27. Bullaro FM, Bartoletti SC. Spontaneous pneumomediastinum in children: a literature review.
Pediatr Emerg Care. 2007;23(1):28–30 PMID: 17228218
doi: 10.1097/01.pec.0000248686.88809.fd
28. Dekel B, Paret G, Szeinberg A, Vardi A, Barzilay Z. Spontaneous pneumomediastinum in
children: clinical and natural history. Eur J Pediatr. 1996;155(8):695–697 PMID: 8839727
doi: 10.1007/BF01957155
29. Tutor JD, Montgomery VL, Eid NS. A case of influenza virus bronchiolitis complicated by
pneumomediastinum and subcutaneous emphysema. Pediatr Pulmonol. 1995;19(6):393–395
PMID: 7567221 doi: 10.1002/ppul.1950190614
30. Gasser CR, Pellaton R, Rochat CP. Pediatric spontaneous pneumomediastinum: narrative
literature review. Pediatr Emerg Care. 2017;33(5):370–374 PMID: 26855340
doi: 10.1097/PEC.0000000000000625

CHAPTER
31
Pulmonary Hemorrhage
Evans M. Machogu, MBChB, MS, FAAP
Karen Z. Voter, MD, FAAP
Introduction
Pulmonary hemorrhage is an acute episode of bleeding from the upper or
lower respiratory tract, including the trachea, bronchi, bronchioles, and alveoli.
The onset can be characterized by hemoptysis, which is the expectoration of
blood during coughing. Hemoptysis is uncommon in children, so it is import-
ant to consider the possibility of pulmonary hemorrhage in children with
cough, hypoxemia, or respiratory distress in the setting of anemia. Although
most episodes of hemoptysis are mild and short-lived, they cause anxiety
among parents and patients. Furthermore, there is the possibility that the
hemoptysis indicates a severe underlying condition or a potential for
life-threatening bleeding.
A report of “coughing up blood” may indicate the presence of blood from the
upper airway (nose and pharynx) or the lower airway, lung, or gastrointestinal
tract, or it may be spurious and related to expectoration of saliva tinted with
colored food or drink. A history sorting out the presence or absence of cough,
possible foreign body exposure, underlying infection, nasal or pharyngeal
trauma, and recent food consumption may help. Many people with pulmonary
bleeding report the sensation of gurgling or bubbling in an area of the lung. A
physical examination of the nose, pharynx, and mouth should be performed to
look for signs of bleeding that would direct attention to the upper airway. Evi-
dence of crackles, increased work of breathing, or localized wheezing would
direct attention to causes of bleeding in the lower airways. Studies, including
chest radiography, may help to localize the bleeding.
563

564
Etiology
There are multiple causes of hemoptysis in children.1 Most cases of airway
bleeding are from irritation of the airway mucosa (Box 31-1). Irritation of
the airway mucosa from infection or trauma should trigger assessment for
pneumonia, bronchitis, or foreign body aspiration, especially in children
with underlying conditions, such as cystic fibrosis (CF). Bleeding from a
tracheostomy is characteristic of airway irritation, which can occur from
dried secretions when there is inadequate humidification, minor suction
trauma when a suction catheter is placed too deeply in the airway, or mecha-
nical trauma from the tracheostomy tube itself. Airway bleeding from
infection may also be related to mucosal irritation.
Increased pressure within the vasculature is another cause of bleeding
(Box 31-1), which is seen in children with congenital heart disease or con-
genital vascular anomalies such as arteriovenous malformations.2 Pulmonary
hypertension from any cause can increase the risk for bleeding. Bronchial
arteries are under systemic pressure, and bleeding from these vessels may be
massive. Hemorrhage into the alveoli is more unusual than other causes of
airway bleeding. Alveolar hemorrhage is seen in children with autoimmune
disorders, such as granulomatosis with polyangiitis (GPA), formerly known
as Wegener granulomatosis; microscopic polyangiitis; or systemic lupus
Box 31‑1
Results of Select Studies of the Causes of Airway Bleeding
Godfrey Chart Reviewa Batra and Holinger Bronchoscopy Studiesb
Upper airway bleeding—29% Blood clots—37%
Tracheostomy complications—18% Purulence—21%
No cause—18% Mucosal inflammation—21%
Other causes—35% Tracheal abrasion—11%
Batra and Holinger Chart Reviewb Granulation tissue—5%
Infectious causes—29% Bronchial mass—5%
Tracheostomy complications—14% Coss-Bu Chart Reviewc
No cause—21% Cystic fibrosis—65%
Other causes—36% Congenital heart disease, including ven-
tricular septal defect, truncus arteriosus,
complex cyanotic heart disease, transposi-
tion of the great arteries, atrioventricular
canal, tetralogy of Fallot—16%
Other causes—18%
a
Godfrey S. Pulmonary hemorrhage/hemoptysis in children. Pediatr Pulmonol. 2004;37(6):476–484.
b
Batra PS, Holinger LD. Etiology and management of pediatric hemoptysis. Arch Otolaryngol Head
Neck Surg. 2001;127(4):377–382.
c
Coss-Bu JA, Sachdeva RC, Bricker JT, Harrison GM, Jefferson LS. Hemoptysis: a 10-year retrospective
study. Pediatrics. 1997;100(3):E7.

565
Chapter 31—Pulmonary Hemorrhage
erythematosus (SLE). Fungal infections are more likely than bacterial infec-
tions to cause alveolar bleeding. Idiopathic pulmonary hemosiderosis is
diagnosed when bleeding occurs without an identified cause.
General Evaluation of a Child With

Pulmonary Hemorrhage and Hemoptysis
The first step in evaluating hemoptysis is to determine the site of bleeding. It is
important to be aware that bleeding sources can occur from the upper airway
or gastrointestinal tract, although those processes will not be discussed here.
It is helpful to estimate the amount of bleeding because children with large
amounts of hemorrhage are likely to need hospitalization and rapid diagnostic
and therapeutic intervention.
The physical examination should initially focus on the degree of respiratory
distress present, which would include tachypnea or tachycardia, as well as any
increased work of breathing or fever. Regardless of the cause of the bleeding,
the most common finding at auscultation is crackles. These may be localized
in the context of a single focus of bleeding or can be diffuse if there is a
nonfocal process such as capillaritis.
It is important to differentiate between a single episode of hemoptysis and
repeated, possibly undiagnosed, episodes. Aspects of the history that can be
helpful would include evidence of other bleeding problems (including clinically
significant or recurrent epistaxis), recurrent or chronic respiratory or sinus
symptoms, anemia, skin rash, jaundice, and renal disorders. Individuals with
an acute episode of hemoptysis may have evidence of infection, such as fever,
malaise, or cough. It is important to ask about foreign travel or use of medica-
tions (oral contraceptives, warfarin, aspirin) that can affect the risk of throm-
bosis or bleeding. The environmental history should include specific questions
about areas of water damage or mold in the home environment.3 Parents may
notice dampness or a moldy smell. If the parents acknowledge water damage
or a moldy smell, inquire about the child’s exposures to floods and chronically
water-damaged, moldy environments. The social history may suggest risk
for abuse.
Imaging and Laboratory Evaluation

Individuals with known underlying processes such as a tracheostomy,
bronchiectasis, or congenital heart disease may need only a focused evalua-
tion (Table 31-1). Evaluating hemoptysis in children without underlying
cardiorespiratory problems can be more involved (Table 31-2).
Laboratory evaluation may help determine the cause of bleeding. If the child
can expectorate sputum, this can be analyzed for the presence of infection. A
complete blood cell count (CBC) can help determine the amount of blood loss

566
and the likelihood of infection. Clinically significant anemia may suggest

repeated episodes of bleeding or an acute, severe episode of bleeding. Clot-
ting studies can be helpful to determine whether an underlying coagulopathy,
vitamin K deficiency, or medication adverse effect is present. A chest radio-
graph may help discriminate between focal or diffuse processes and localize a
particular site of bleeding. In some situations, a computed tomography (CT)
scan may be helpful to determine whether a focal endobronchial lesion,
diffuse interstitial process, or arteriovenous malformation is involved.
Table 31-1. Evaluation of Airway Bleeding in the Setting of a Preexisting Condition

Preexisting Probable Cause
Condition of Bleeding Evaluation and Treatment
Tracheostomy Dried secretions Improve humidification
Purulent secretions Culture secretions, antibiotics
Granulation tissue in airway Ear, nose, throat, or pulmonary referral
Mucosal erosion Visualize airway
Alter suction protocol
Consider new tracheostomy tube size
Cystic fibrosis Infection or exacerbation Antibiotics, airway clearance
Bronchiectasis
Coagulopathy Check clotting studies
Vitamin K supplementation
Central line clot Ultrasonography or dye study to evaluate
the line
Pulmonary embolism
Remove central line
Consider anticoagulation
Massive hemorrhage Interventional radiology for dye study of
(> 240 mL/day) the bronchial arteries
Embolization of tortuous arteries
Decreased airway clearance and inhaled
hypertonic saline for a few days
Infection Bacterial Sputum culture
Fungal Chest radiography
Tuberculosis Consider bronchoscopy
Leptospirosis
Foreign body Chest radiography
Consider bronchoscopy
Congenital Pulmonary hypertension Chest radiography
heart disease Previous surgical repair Cardiology evaluation, consider
echocardiography or catheterization
Collateral vessels

567
Table 31-2. Evaluation of Airway Bleeding in the Absence of Preexisting Conditions

Evaluation Finding Possible Diagnosis
History Fever Infection, autoimmune process
Physical Weight loss Autoimmune process
examination
Skin rash (butterfly, vasculitis) Autoimmune process
Skin rash (petechiae) Infection, autoimmune process
Jaundice Infection (leptospirosis)
Nasal or sinus fullness Autoimmune process (GPA)
or inflammation
Arthralgias or arthritis Autoimmune process
(systemic lupus erythematosus, GPA)
Localized crackles Can be any process but may suggest focal
infection, foreign body, or idiopathic cause
Diffuse crackles Autoimmune process, capillaritis
Sputum Blood mixed with purulent Infection
sputum
Chest Normal Bleeding from a different site
radiograph Foreign body
Infection
Cleared episode of idiopathic pulmonary
hemosiderosis
Focal Foreign body
Infection
Autoimmune
Idiopathic cause
Diffuse Autoimmune
Idiopathic cause
Computed Vascular abnormalities Arteriovenous abnormalities
tomography
scan (chest) Interstitial prominence Autoimmune process
Alveolar filling Infection
Localization of blood
Computed Mucosal thickening Autoimmune process (GPA)
tomography
scan (sinus)
Urinalysis Blood or protein Autoimmune process
Abbreviation: GPA, granulomatosis with polyangiitis.

568
Bronchoscopy may be important to localize the site of hemorrhage. Cardiac

evaluation with either echocardiography or catheterization may be indicated,
especially if there is a history of previous cardiac disease. Ongoing bleeding
from tortuous bronchial arteries can be localized and treated with dye studies
and embolization of these vessels, usually by an interventional radiologist. In
some cases, lung biopsy is indicated to determine whether there is evidence of
capillaritis, immune complex deposition, or pulmonary hypertension. Susarla
and Fan4 suggested considering lung biopsy in any child with diffuse alveolar
bleeding of unknown cause.
General Management
Minor amounts of bleeding from infection, airway dehydration, or trauma
can often be managed on an outpatient basis if the cause of the bleeding is
established and a treatment plan initiated. In the case of clinically significant
pneumonia or exacerbation of bronchiectasis, intravenous (IV) antibiotics may
be indicated. If the cause of the hemoptysis is unknown, further evaluation
with CT scanning, bronchoscopy, cardiac assessment, or lung biopsy may be
needed. It is important to consider the availability of the studies to determine
whether admission or referral to specialists is indicated. Hemoptysis requires
a prompt evaluation because of the risk of increased bleeding, as well as the
sometimes transient nature of the findings. If the cause of the bleeding is not
known, it is important to consider the risk of additional, sometimes massive,
bleeding in the decision about hospitalization.
Massive hemorrhage can be managed with endotracheal intubation and
mechanical ventilation to raise the pressure in the airways. Transfusion of
packed red blood cells may be indicated to stabilize the patient. If tortuous
vessels are suspected, embolization of the vessels can promptly stop
the bleeding.
Causes of Hemoptysis
Pulmonary Hemorrhage Due to Infection
Infection in the lower respiratory tract is the most common cause of hemop-
tysis. In most cases, hemoptysis is mild and lasts less than 24 hours. In other-
wise healthy children, bacterial infections can cause irritation and friability of
the airway mucosa. There may be some streaking of the sputum in bacterial
tracheobronchitis or pneumonia, but true hemoptysis or massive hemorrhage
is rare in previously healthy children. Common infectious causes include
bacterial or viral pneumonia, bronchitis, pulmonary tuberculosis, pharyngitis
or laryngitis, and lung abscess. Features of the history and physical examina-
tion that suggest an infection include fever, cough, diminished appetite or
activity level, jaundice (leptospirosis), and exposure to other people who have

569
been sick. There may be localized or diffuse crackles, depending on the extent
of the infection.
A CBC may be helpful in determining the amount of blood loss and the likeli-
hood of infection. A chest radiograph can be helpful in assessing if the lesion
is focal, but it can be difficult to distinguish infection from blood in the lungs.
Opacity on a chest radiograph that resolves quickly is more likely to be
blood than infection.
Treating the infection usually results in resolution of the bleeding. Worldwide,
tuberculosis is probably the infection most associated with pulmonary bleed-
ing. Bleeding due to tuberculosis results from either endobronchial infection
or cavitary lesions.
CASE REPORT 31-1

A 19-year-old woman with cystic fibrosis has evidence of moderate lung
disease. She has needed intravenous antibiotics approximately twice yearly.
She has been able to continue her daily routine with airway clearance, inhaled
bronchodilators, inhaled deoxyribonuclease, and antibiotics inhaled every
other month.
She was sitting quietly watching TV when she noticed the abrupt onset of a
gurgling sensation in her right upper lung field. She coughed up approximately
1 cup of bright red blood. She was brought to the emergency department,
where she had 2 more episodes of massive hemoptysis.
Evaluation included a chest radiograph with a new opacity in the right upper
lobe. Her hematocrit was 29% (0.29). Her coagulation study results were normal.
She started on bed rest and oxygen and was administered vitamin K. She was
brought to the interventional radiology department, where an angiogram
demonstrated tortuous bronchial arteries in both upper lobes. The radiologist
embolized the tortuous vessels, and the patient was admitted for observation.
She continued on bed rest, and airway clearance measures were stopped for
24 hours, then gradually resumed. She was discharged 3 days later with
instructions to resume her usual routine gradually.
Cystic Fibrosis and Bronchiectasis

Clinical Features
Cystic fibrosis and non-CF bronchiectasis can be associated with either
small or massive amounts of bleeding. Small volumes of blood are seen
relatively frequently and are associated with infection and friability of the
airway mucosa. As the infection progresses, there can be invasion into the
airway with erosion into a bronchial artery. Massive hemoptysis is defined
as blood loss of greater than 240 mL per day and can be rapid enough to be
life-threatening.

570
Evaluation and Imaging

Sputum can be cultured to determine the cause of the infection so appro-
priate antibiotics are initiated. A new infiltrate on the chest radiograph may
help with localization of the bleeding and can help determine whether pneu-
monia is present. Clotting studies can be helpful to determine whether an
underlying coagulopathy, vitamin K deficiency, or medication adverse effect
is present. Individuals with CF are at risk for vitamin K deficiency because
of the malabsorption of fat-soluble vitamins and for coagulopathy if there is
associated liver disease.
Management
The Cystic Fibrosis Foundation developed guidelines for treatment of
hemoptysis in patients with CF in 2010, and this document was reviewed
and reaffirmed in 2019.5 If there is clinically significant bleeding in a child
with CF, it may be worth stopping or using less vigorous methods of airway
clearance for a day or 2 to minimize the risk of massive hemoptysis. If a
patient is receiving inhaled hypertonic saline or oral nonsteroidal anti-
inflammatory medications, they should be stopped, at least during a
clinically significant bleeding episode. Administering vitamin K can be helpful
in cases of coagulopathy. If the patient has a central line or has been inactive,
the possibility of a thrombus and pulmonary embolism must be considered.
If a patient is receiving bilevel positive airway pressure ventilation, it should
be withheld during episodes of massive hemoptysis.
Massive hemoptysis in this setting is usually related to erosion into a bron-
chial artery. The most definitive treatment of bleeding from tortuous vessels
is embolization of the arteries, which interventional radiologists perform with
the use of fluoroscopy. A catheter is introduced into the bronchial arteries from
the aorta, and dye is infused to try to isolate the individual bleeding artery,
which is then embolized. Many radiologists will embolize any bronchial artery
that appears tortuous because of the risk of recurrent bleeding. Although most
patients tolerate the procedure well, there are risks of embolizing vessels that
may supply other organs, including the spinal cord.
Tracheostomy
Clinical Features
Trauma to the airway is a common cause of bleeding in patients with a trache-
ostomy. Abrasion of the airway mucosa with either the tip of the tracheostomy
tube or suction catheter can cause small amounts of bleeding. Repeated epi-
sodes of these abrasions can stimulate the formation of granulation tissue,
which can be friable. Bleeding is worsened with dry secretions, and maintain-
ing adequate humidity is critical to controlling bleeding. Humidification of
secretions in children with a tracheostomy can be increased with use of a mist
collar, heat and moisture exchanger (HME) device, or frequent nebulized

571
saline treatments. Massive bleeding in the presence of a tracheostomy may

indicate erosion into the mucosa. Rarely, erosion into an anterior innominate
artery has caused massive hemoptysis.
Children with bleeding through a tracheostomy are likely to have localized
bleeding in the central airways. Thick or discolored secretions with small
amounts of blood may indicate an infection. A chest radiograph may be help-
ful in determining whether pneumonia is present. Secretions can be cultured
to determine the possible role of infection. Large amounts of blood or per-
sistent bleeding should be evaluated by visualizing the airway mucosa via
bronchoscopy, which can help identify areas of mucosal disruption, granula-
tion tissue, or erosion into the airway, which are potential causes of bleeding.
Massive bleeding episodes are sometimes preceded by smaller bleeding
episodes, referred to as sentinel bleeds.
Management
Bleeding caused by airway infection will usually respond to antibiotics. Small
amounts of blood with suctioning are likely to be related to dehydration of the
secretions. It is important to review the humidification and suctioning tech-
niques. The tracheostomy should always have some source of humidification.
Short-term management of dehydrated secretions can include nebulized or
instilled saline. If the child is also receiving ventilation, the temperature of
the humidification system may need to be adjusted to allow for maximal
humidification. The airway should be suctioned primarily to clear the tra-
cheostomy tube, not the lower airways. Limiting the depth of the suctioning
will minimize the risk of damage to the airway mucosa. If granulation tissue
has already become established, the child may need surgical evaluation.
Massive bleeding is a clinical emergency that requires surgical intervention.
Child Abuse
Trauma can be a cause of bleeding even in patients who do not have a trache-
ostomy. Southall et al6 found evidence of bleeding from the nose or mouth in
infants who had been under covert surveillance for evaluation of an apparent
life-threatening event that was suspected to be caused by nonaccidental suffo-
cation. Child abuse should be considered as a cause of reported hemoptysis in
children in whom no other cause is discovered.
Cardiac Abnormalities
Clinical Features
Bleeding related to cardiovascular problems can arise in several situations.
A thrombus or pulmonary embolism may occur, especially in the setting of
a clotting disorder or the use of oral contraceptives in women. Pulmonary
hypertension can be associated with pulmonary hemorrhage, especially if the

572
vessels have become tortuous or collateral vessels have developed.7 Pulmonary

hypertension can develop from many causes, including uncorrected congenital
heart disease (Eisenmenger syndrome), as well as other cardiac, pulmonary,
or systemic autoimmune processes. Those who have undergone surgical repair
of congenital heart disease may have leak from aneurysms at the site of the
previous repair. In some cases, such as with cor triatriatum, the congenital
anomaly is not suspected before the hemoptysis.8 Arteriovenous malformations
in the lungs can be seen in patients with hereditary hemorrhagic telangiectasia
or hepatopulmonary syndrome and can be a cause of hemorrhage as well.9
Individuals with known congenital heart disease or pulmonary hypertension
require reassessment of the pulmonary vasculature. Chest radiography or CT
scanning may help localize areas of aneurysms or arteriovenous malforma-
tions. These patients are usually seen by a cardiologist, who should be involved
in the evaluation and management of the bleeding. Many of these patients will
need echocardiography as well as catheterization of the vessels to identify
possible sites of bleeding. Patients with pulmonary hypertension without a
previously known cardiac, pulmonary, or systemic cause will need a thorough
evaluation to establish a diagnosis.
Management
Medications to decrease pulmonary hypertension may be helpful, but, in
some cases, surgical intervention is required to stop the bleeding. If pulmo-
nary hypertension is identified in the absence of congenital heart disease,
more evaluation is indicated to determine possible underlying causes. If
arteriovenous malformations are identified, embolization may be performed
at the time of cardiac catheterization.
Autoimmune Pulmonary Hemorrhage

Clinical Features
Diffuse alveolar hemorrhage is less common than other forms of pulmonary
hemorrhage but can be life-threatening. It can be seen in association with
pulmonary capillaritis in such processes as GPA, microscopic polyangiitis,
Goodpasture syndrome, and SLE.10,11 Other rare causes of capillaritis have
included autoimmune hepatitis, Crohn disease, and drug reactions. The cause
of disrupted capillaries is frequently autoimmune in nature.12
Evidence that the process is chronic includes poor growth and anemia. The
presence of a rash suggesting one of the collagen vascular diseases should
prompt further autoimmune evaluation. Petechiae can be related to the pre-
sence of autoimmune vasculitis but may also be associated with bleeding dis-
orders or infection. Nose and sinus involvement in a patient with pulmonary
hemorrhage suggests the possibility of GPA. Swelling and inflammation of
characteristic joints can be seen with autoimmune disorders, including SLE.13

573

Evaluation of these autoimmune causes of pulmonary bleeding includes tests
to find evidence of autoimmune dysfunction, including CBC (to look for
evidence of chronic anemia), Coombs test (to look for evidence of hemolysis),
screening for evidence of hematuria and proteinuria, and levels of antineutro-
phil cytoplasmic antibodies and myeloperoxidase and proteinase 3 antibodies.
Chest radiography may show a bilateral alveolar filling pattern. If the bleeding
is occult, bronchoalveolar lavage can be used to evaluate for hemosiderin-
laden alveolar macrophages, which would indicate the presence of blood in
the airways or alveoli. Diffuse bleeding at bronchoscopy is also useful in
excluding localized causes of hemorrhage. Many collagen vascular disorders
have associated renal involvement, so urinalysis may aid in the diagnosis.
Other laboratory evaluations useful in diagnosing collagen vascular diseases
include erythrocyte sedimentation rate and levels of C-reactive protein, anti-
nuclear antibodies, specific extractable nuclear antigens, antineutrophil cyto-
plasmic antibodies (which can have either perinuclear or cytoplasmic patterns),
D-dimer, von Willebrand factor antigen, antiglomerular basement membrane
antibodies, and antiphospholipid antibodies. The final diagnosis may require
a lung biopsy to help confirm disruption of the pulmonary capillaries.4
Management
Most autoimmune disorders respond to anti-inflammatory medications,
although the treatment course may last months or years. These medications
may include corticosteroids, rituximab, cyclophosphamide, azathioprine,
methotrexate, hydroxychloroquine, and IV immunoglobulin. Initial therapy
of alveolar hemorrhage with high doses of IV methylprednisolone is usually
successful in controlling the bleeding. Treatment often begins with high-dose
pulse steroids with 30 mg/kg methylprednisolone daily for 3 days, followed by
a taper to daily oral steroids. Susarla and Fan4 describe the use of IV methyl-
prednisolone 2 to 4 mg/kg/day divided every 6 hours as an initial therapy for
alveolar hemorrhage. As the bleeding stops, the corticosteroids can be tapered
to either prednisone or methylprednisolone 0.5 to 1 mg/kg every other day. An
alternative is pulse IV methylprednisolone 30 mg/kg (maximum 1 g) infused
over 1 hour daily for 3 consecutive days repeated monthly.4 After the initial
bleeding has subsided, therapy for the underlying disease is likely to decrease
the risk of recurrent bleeding. Some patients may need ongoing therapy with
corticosteroids for months to control exacerbations of hemorrhage.
Idiopathic pulmonary hemosiderosis is diagnosed when no other autoimmune
disease is identified. It can respond to steroids but is not typically treated with
the other immunomodulatory medications.

574
CASE REPORT 31-2

A 10-year-old boy returns for follow-up of his pulmonary hypertension and
history of pulmonary hemorrhage. He was born at 26 weeks’ gestation and
subsequently had bronchopulmonary dysplasia diagnosed. Although he was
discharged from the neonatal intensive care unit at 3 months of age, he
developed hypoxemia requiring long-term oxygen therapy at 7 months of age.
At the age of 14 months, he had an acute deterioration with respiratory distress
and hypoxemia and was admitted to the hospital for evaluation and treatment.
The evaluation included the following:
1. Cardiac catheterization, which revealed suprasystemic pulmonary
hypertension, right ventricular diastolic dysfunction, clinically significant
right pulmonary vein desaturation, atrial septal defect (right-to-left
shunting), and diffuse pulmonary interstitial disease
2. Bronchoscopy, which revealed diffusely hemorrhagic and friable
bronchial tissue
He was treated with intubation and mechanical ventilation. He developed
bright red blood from the endotracheal tube and was treated with increased
pressure on the ventilator. Lung biopsy results revealed changes consistent
with idiopathic pulmonary hemosiderosis. Allergy testing revealed sensitivity
to milk, eggs, and peanuts.
He was treated with high-dose intravenous methylprednisolone and inhaled
nitric oxide. He required numerous transfusions to maintain his hemoglobin
level. He gradually improved, tapered off inhaled nitric oxide, and was ready
for discharge 2 months after admission. Prednisone was tapered over approxi-
mately 2 years and was increased with subsequent viral infections. He had
1 episode of subsequent pulmonary hemorrhage, approximately 6 months
after his admission, but otherwise has not had evidence of further bleeding. He
maintains a milk-, egg-, and peanut-free diet. He continues with nighttime
oxygen and sildenafil to treat his pulmonary hypertension but is able to
attend school and participate in activities, including physical education.
Idiopathic Pulmonary Hemorrhage and Hemosiderosis

Clinical Features
Idiopathic pulmonary hemorrhage is characterized by alveolar bleeding with-
out capillaritis. This bleeding tends to be recurrent, and when no underlying
cause for repeated episodes of diffuse alveolar hemorrhage is determined,
the condition is referred to as idiopathic pulmonary hemosiderosis. Lung
biopsy results in these patients generally demonstrate erythrocytes and
hemosiderin-laden alveolar macrophages but no inflammation of the
capillaries. Acute idiopathic pulmonary hemorrhage (AIPH) of infancy is a
more acute variation of pulmonary bleeding that was first described in a
Cleveland-based study, associated with indoor exposure to molds, including

575
Stachybotrys chartarum.14 Young infants often present without frank hemopty-

sis, and the diagnosis can be suspected in the presence of respiratory distress,
opacities on chest radiographs, and anemia. Although the causal association
between exposure to mold and AIPH in infants is being further evaluated, the
Cleveland study, additional case series, case reports from independent
sources, and basic scientific studies in animal models have provided evidence
of plausibility.15 Clinicians should be aware of the high mortality of acute
pulmonary hemorrhage and ensure that infants are not returned to moldy
home environments. Results from epidemiological studies suggest that
exposure to secondhand cigarette smoke may be an additional risk factor.16
The appearance of an acute episode of pulmonary hemorrhage on a chest
radiograph is similar to that of pneumonia; however, the infiltrates are more
transient and tend to resolve in 1 to 2 days. Repeated testing of hemoglobin
and hematocrit can be useful in determining the severity of the bleeding.
Many of these children will need bronchoscopy and bronchoalveolar lavage
to document the presence of alveolar bleeding. Care should be taken in
children with active bleeding because there is some risk of accelerated
bleeding after bronchoscopy.
Management
Idiopathic pulmonary hemosiderosis has been associated with a poor prog-
nosis in the past, but aggressive anti-inflammatory therapy has improved this
prognosis, with recent 5-year survival rates greater than 80%.4
The American Academy of Pediatrics recommends that parents of infants with
AIPH try to find and eliminate sources of chronic moisture and mold growth
before the child returns to the home. Avoidance of exposure to secondhand
cigarette smoke is always recommended, but especially in cases of AIPH.17
Other Causes of Hemoptysis
Malignancy is a common cause of airway bleeding in adults. Although the
occurrence of airway tumors is much lower in children, between 2% and
6% of children with hemoptysis have masses.4,18 These include endobronchial
lesions such as carcinoid, adenoma, mucoepidermoid tumor, metastases, tera-
toma, carcinoma, and pseudotumor.19,20 Some airway lesions, such as carcinoid
and hemangioma, are highly vascularized, and caution should be used when
obtaining biopsy samples, especially through a flexible bronchoscope.
Obstruction of an airway by an endobronchial lesion will usually produce
atelectasis visible on a chest radiograph. It is important to differentiate atelec-
tasis from infiltrate by means of radiography to determine the appropriate
evaluation. The presence of an airway obstruction will need further evaluation
with CT scanning or bronchoscopy. Bronchoscopy will allow differentiation of

576
a foreign body from an airway mass. Determining the cause of the mass will
require pathological evaluation.
The location and pathological characteristics of the airway mass will determine
the management. Some lesions can be removed through the bronchoscope, but
other lesions may require surgical removal of the affected lobe.
key points
} Pulmonary bleeding can arise from a number of causes, ranging in importance
from minor irritations and infections to life-threatening hemorrhage.
} In many cases, the bleeding is related to an underlying condition and can easily
be evaluated and treated. Other times, the cause is more elusive and will
require careful radiological, bronchoscopic, and pathological evaluation to
determine the cause of the bleeding.
} Identify the location of the bleeding.
} Evaluate expected complications of known problems, such as tracheostomy, CF,
bronchiectasis, and congenital heart disease.
} Evaluation of the child’s home is sometimes indicated to assess whether it is a
water-damaged or moldy environment.
} Consider new problems:
➤ Acute or chronic infection, foreign body aspiration
➤ Pulmonary hypertension, pulmonary embolism, or thrombosis
➤ Arteriovenous malformation
➤ Autoimmune disorder, idiopathic diffuse alveolar hemorrhage
} Diligently work to establish the diagnosis via coagulation status evaluation,
imaging, sputum culture, bronchoscopy, echocardiography or cardiac
catheterization, lung biopsy, and autoimmune evaluation.
} Treatment begins with stabilizing the patient, if necessary (including intubation
and/or transfusion, if necessary).
} Specific treatment depends on the cause of the bleeding and may include
antibiotics, humidification, cardiac or thoracic surgery, or long-term anti-
inflammatory medications.
} Treat the underlying condition:
➤ Embolization of bronchial arteries for massive bleeding
➤ Anti-inflammatory therapy for autoimmune disease

577
References
1. Simon DR, Aronoff SC, Del Vecchio MT. Etiologies of hemoptysis in children:
a systematic review of 171 patients. Pediatr Pulmonol. 2017;52(2):255–259 PMID: 27575742
2. Sismanlar T, Aslan AT, Akkan K, Cindil E, Onal B, Ozcan B. Successful embolization in
childhood hemoptysis due to abnormal systemic arterial bleeding of the lung and review of the
literature. Clin Respir J. 2016;10(6):693–697 PMID: 25773166 https://doi.org/10.1111/crj.12289
3. Heseltine E, Rosen J, eds. WHO Guidelines for Indoor Air Quality: Dampness and Mould.
World Health Organization; 2009
4. Susarla SC, Fan LL. Diffuse alveolar hemorrhage syndromes in children. Curr Opin Pediatr.
2007;19(3):314–320 PMID: 17505192 https://doi.org/10.1097/MOP.0b013e3280dd8c4a
5. Flume PA, Mogayzel PJ Jr, Robinson KA, Rosenblatt RL, Quittell L, Marshall BC; Clinical
Practice Guidelines for Pulmonary Therapies Committee; Cystic Fibrosis Foundation Pulmonary
Therapies Committee. Cystic fibrosis pulmonary guidelines: pulmonary complications:
hemoptysis and pneumothorax. Am J Respir Crit Care Med. 2010;182(3):298–306
PMID: 20675678 https://doi.org/10.1164/rccm.201002-0157OC
6. Southall DP, Plunkett MC, Banks MW, Falkov AF, Samuels MP. Covert video recordings of
life-threatening child abuse: lessons for child protection. Pediatrics. 1997;100(5):735–760
PMID: 9346973 https://doi.org/10.1542/peds.100.5.735
7. Haroutunian LM, Neill CA. Pulmonary complications of congenital heart disease: hemoptysis.
Am Heart J. 1972;84(4):540–559 PMID: 4672656 https://doi.org/10.1016/0002-8703(72)90479-6
8. Sritippayawan S, Margetis MF, MacLaughlin EF, Achermann R, Wells WJ, Davidson Ward SL.
Cor triatriatum: a cause of hemoptysis. Pediatr Pulmonol. 2002;34(5):405–408 PMID: 12357491
9. Cartin-Ceba R, Swanson KL, Krowka MJ. Pulmonary arteriovenous malformations. Chest.
2013;144(3):1033–1044 PMID: 24008954 https://doi.org/10.1378/chest.12-0924
10. Nasser M, Cottin V. Alveolar hemorrhage in vasculitis (primary and secondary). Semin Respir
Crit Care Med. 2018;39(4):482–493 PMID: 30404115 https://doi.org/10.1055/s-0038-1668533
11. Martínez-Martínez MU, Oostdam DAH, Abud-Mendoza C. Diffuse alveolar hemorrhage in
autoimmune diseases. Curr Rheumatol Rep. 2017;19(5):27 PMID: 28397125
https://doi.org/10.1007/s11926-017-0651-y
12. Jiang T, Li QB. [Diffuse alveolar hemorrhage in children]. Zhongguo Dang Dai Er Ke Za Zhi.
2019;21(9):949–954 PMID: 31506159 doi: 10.7499/j.issn.1008-8830.2019.09.020
13. O’Sullivan BP, Erickson LA, Niles JL. Case records of the Massachusetts General Hospital.
Weekly clinicopathological exercises. Case 30-2002. An eight-year-old girl with fever,
hemoptysis, and pulmonary consolidations. N Engl J Med. 2002;347(13):1009–1017
PMID: 12324558 https://doi.org/10.1056/NEJMcpc020022
14. Centers for Disease Control and Prevention (CDC). Acute pulmonary hemorrhage/hemosiderosis
among infants—Cleveland, January 1993–November 1994. MMWR Morb Mortal Wkly Rep.
1994;43(48):881–883 PMID: 7969010
15. Thrasher JD, Hooper DH, Taber J. Family of 6, their health and the death of a 16 month old
male from pulmonary hemorrhage: identification of mycotoxins and mold in the home
and lungs, liver and brain of deceased infant.Glob J Med Res: K Interdiscip. 2014;14(5)
https://globaljournals.org/GJMR_Volume14/1-Family-of-Six-their-Health.pdf
16. Mazur LJ, Kim J; Committee on Environmental Health, American Academy of Pediatrics.
Spectrum of noninfectious health effects from molds. Pediatrics. 2006;118(6):e1909–e1926
PMID: 17142508 https://doi.org/10.1542/peds.2006-2829
17. Kim JJ, Mazur LJ; Committee on Environmental Health, American Academy of Pediatrics.
Spectrum of noninfectious health effects from molds. Pediatrics. 2006;118(6):2582–2586
PMID: 17142549 https://doi.org/10.1542/peds.2006-2828
18. Godfrey S. Hemoptysis in children. Pediatr Pulmonol Suppl. 2004;26(26):177–179
19. Al-Qahtani AR, Di Lorenzo M, Yazbeck S. Endobronchial tumors in children: institutional
experience and literature review. J Pediatr Surg. 2003;38(5):733–736 PMID: 12720182
20. Eggli KD, Newman B. Nodules, masses, and pseudomasses in the pediatric lung.
Radiol Clin North Am. 1993;31(3):651–666 PMID: 8497596

PART
7
Pediatric Sleep Medicine
Chapter 32. Development and Maturation of Sleep...................... 581

Chapter 33. Obstructive Sleep Apnea Syndrome........................... 603

Courtney M. Quinlan, DO, MS, and Suzanne E. Beck, MD
Chapter 34. Sleep Testing in the Laboratory and Home............... 617

Deborah M. Brooks, MD, and Lee J. Brooks, MD, FAAP
Chapter 35. Sleep-Related Movement Disorders............................ 633

Chapter 36. Insomnia..........................................................................643

Chapter 37. Parasomnias..................................................................... 651

Chapter 38. Narcolepsy and Other Disorders of Excessive

Somnolence..........................................................................................659
Chapter 39. Sudden Infant Death Syndrome and Brief, Resolved,

Unexplained Events............................................................................ 671
Chapter 40. Congenital Central Hypoventilation Syndrome...... 681

Iris A. Perez, MD, FAAP; Emily S. Gillett, MD, PhD, FAAP; and Thomas G. Keens,
MD, FAAP
579
38 PP 2ND ED - PO 07_579-580.indd 579 11/6/23 9:07 AM

38 PP 2ND ED - PO 07_579-580.indd 580 9/12/23 10:12 AM
CHAPTER
32
Development and Maturation of Sleep
Piaget1 thought play was the major “work” of children, while sleep is the
principal behavior state of infants and young children. Sleep has long been
recognized as the predominant behavioral state of the fetus, neonate, and
young infant, where important developmental work happens.2 Neonates
born preterm spend 97% of the time sleeping, and infants born term sleep
14 to 18 hours per 24 hours.3–7 By age 2 years, the average child has spent
10,000 hours asleep compared to 7,500 hours awake.
The more time infants spend sleeping is thought to reflect the essential role
sleep plays in early fetal and neonatal brain development.8 The percentage of
sleep time spent in rapid eye movement (REM) sleep is far greater in infants:
80% of sleep time when preterm, 50% at term, decreasing to 30% by age 1 year,
and reaching adult percentages of 20% to 25% of sleep time spent in REM by
ages 3 to 5 years. Before age 2.5 years, brain development is characterized by
exuberant neuroplasticity, ongoing synaptogenesis, and increasing myelination,
and most of this occurs during REM sleep.8–12 Whereas, after age 2.5, sleep
functions involve stabilizing brain network connectivity, increasing white
matter integrity, and optimizing synaptic efficiency; these occur preferentially
in non-rapid eye movement (NREM) sleep.10
Reduced time spent in REM sleep during early infancy has been shown to have
lasting effects on later neurocognitive functioning.13–15 In a prospective study of
81 infants born preterm, less REM sleep time in infants (32 to 36 weeks’
postmenstrual age [wPMA]) was associated with poorer developmental out-
comes on the Bayley II Scale of Infant and Toddler Development at 6 months.13
The infants who had longer periods of sustained sleep, more time spent in REM
sleep, and more periods of REM sleep with rapid eye movements had better
cognitive outcomes.
In 2015, the National Sleep Foundation16 published updated age-related sleep
duration recommendations for children: 14 to 17 hours for babies aged 0 to
3 months; 12 to 15 hours for infants aged 4 to 11 months; 10 to 13 hours for
preschoolers aged 3 to 5 years; 9 to 11 hours for schoolchildren aged 6 to
12 years; and 8 to 10 hours for teenagers (13 years or older). In 2016, the
581

582
American Academy of Sleep Medicine17 published (and the American

Academy of Pediatrics endorsed) age-related sleep duration recommenda-
tions for children: infants ages 4 to 12 months should sleep 12 to 16 hours
per 24 hours (including naps); children aged 1 to 2 years should sleep 11
to 14 hours per 24 hours (including naps); children aged 3 to 5 years should
sleep 10 to 13 hours per 24 hours (including naps); children aged 6 to 12 years
should sleep 9 to 12 hours per 24 hours; and teenagers aged 13 to 18 years
should sleep 8 to 10 hours per 24 hours.
Unfortunately, such recommendations are too often ignored. Insufficient sleep
is common in children at all ages. In 2018, the Centers for Disease Control and
Prevention18 surveyed 52,500 US schoolchildren and adolescents and found that
63% of children aged 6 to 12 years and 93% of those aged 13 to 18 years reported
sleeping less than 9 hours on school nights; 30% of adolescents averaged 7 hours,
23% averaged 6 hours, 13% averaged 5 hours, and 8% averaged 4 hours or less.
Insufficient sleep in adolescence can alter the ultimate developmental trajectory
of brain and behavior. Final brain development occurs across adolescence and
young adulthood (usually complete by age 25 years). The last parts of the brain
to develop are the medial prefrontal cortex (PFC) and anterior cingulate cortex.
The PFC is most involved in attention, behavior, judgment, moral reasoning,
planning, executive decision-making, cognitive control, and flexibility. The PFC
is the part of the brain most vulnerable to sleep loss.
Late bedtimes and sleep restriction in adolescents can impact final remodeling
of cortical circuitry for adult decision-making, cognition, impulse control,
social interaction, and regulation of emotion.19,20
How much sleep is too little for optimal final brain development in adolescents?
A 2011 survey of 15,364 US high school students found that the 17% who sleep
less than 5 hours per night were more likely to report various negative outcomes
compared to those sleeping 8 hours or more per night.21 High school students
who reported sleeping 7 hours or less on school nights were more likely to
report several injury-related risk behaviors (infrequent bicycle helmet use,
infrequent seatbelt use, riding with a driver who had been drinking, drinking
and driving, and texting while driving) compared with students who sleep
9 hours on school nights.22
This chapter provides a brief review of the development and maturation of
sleep in typically developing infants, children, and adolescents.
Emergence of Sleep as a Distinctive Behavior State

Fetal ultrasonographic studies show rest-activity cycles by 20 to 24 weeks’
gestational age (wGA).8,23 By 24 to 25 wGA, these cycles last 40 to 60 minutes
and are unrelated to those of the mother. As early as 25 wGA, rudimentary

583
Chapter 32—Development and Maturation of Sleep
sleep cycling, characterized by periods of rapid eye movements (suggestive

of active/REM sleep) and periods without them, are observed. Recordings of
fetal electroencephalogram (EEG) on infants born extremely preterm show
activity that consists of bursts lasting less than 60 seconds alternating with
quiescent periods (interburst intervals [IBIs]) lasting 20 to 25 seconds. This
EEG activity is called tracé discontinu. At this gestational age, the fetus ex-
hibits alternating periods of activity and rest, but variations in EEG are
inconsistently associated with behavior.24 Painful stimulations during
handling provoke limb-withdrawal movements, which cause muscle
artifacts on EEG but no change in the EEG.
By 28 to 29 wPMA, 3 behavioral states are identifiable: active/REM sleep,
quiet/NREM sleep, and active wakefulness. Active/REM sleep is best (and
perhaps only) identified by the presence of rapid eye movements, absent in
quiet/NREM sleep. The EEG is more “continuous” with more runs of EEG
activity now lasting up to 160 seconds, and IBIs shorter (≤ 30 seconds). Infants
this age spend very little time awake (≤ 3%), identified by open eyes and cry-
ing.8,24,25 Reactivity (change in EEG in response to varying forms of sensory
stimuli, including pain) is still inconstant and variable in expression.24
The EEG begins to help distinguish wakefulness from active/REM and
quiet/NREM sleep by 30 to 31 wPMA: continuous during active/REM sleep,
discontinuous in quiet/NREM sleep. The IBIs during quiet/NREM sleep are
shorter (≤ 20 seconds). Periods of quiet wakefulness are rare. Reactivity of the
EEG to sensory stimuli is now observed, characterized by the appearance of
delta EEG activity.
The EEG is continuous in both wakefulness and active/REM sleep at 32 to
35 wPMA (distinguished so these 2 states [wakefulness and active/REM]
can only be identified by behavioral [not the EEG] correlates).26
Behaviors in preterm (and later term) infants that, when observed, are sug-
gestive of active/REM sleep are (1) eyes closed with rapid eye movements;
(2) irregular respiration (sometimes with periods of tachypnea or periodic
breathing); and (3) a myriad of movements tend to occur (such as sucking,
facial grimaces, clonic jaw jerks, fine limb muscle twitches, tremors, intermit-
tent stretching, and large athetoid limb movements). Behaviors that suggest
quiet/NREM sleep in infants are (1) closed eyes, not moving; (2) regular
respiration; (3) reduced movements relative to wakefulness with occasional
startle and periodic sucking. Identifying wakefulness, particularly quiet
wakefulness, is especially difficult in preterm infants.27
At 32 wPMA, the EEG in quiet/NREM sleep remains discontinuous with
periods of no EEG activity (interburst intervals) which normally last
up to 15 seconds at 32 wPMA, and up to 10 seconds at 34 wPMA.

584
By 36 wPMA, 2 different EEG patterns of REM sleep are seen. Both are
continuous, but the EEG pattern before a period of NREM sleep contains
generous amounts of intermixed delta activity (high-amplitude slow [0.1–4
Hz] waves), whereas REM sleep after a period of NREM sleep is character-
ized by a predominance of theta (low-amplitude, 4–7 Hz) activity.26
At 27 to 34 wPMA, 40% to 45% of sleep is spent in active/REM sleep, 25%
to 30% in quiet/NREM, and 30% in indeterminate sleep. After 35 wPMA,
infants spend 55% to 65% of sleep in active/REM sleep, 20% in quiet/NREM
sleep, and 10% to 15% in indeterminate sleep. Term neonates spend 50% to
60% of sleep in active/REM sleep, 30% to 40% in quiet/NREM sleep, and
10% to 15% in transitional sleep. The duration of a sleep cycle is 30 minutes
for infants less than 35 wPMA, increasing to 50 to 65 minutes for infants 35
wPMA or more.
Sleep/Wake Patterns in Infants 0 to 2 Months of Age

By 37 to 38 wPMA (beginning maturational age for term infants), the EEG
in wake and REM sleep is characterized by a continuous mixture of different
frequencies (activité moyene). Because the EEG activity in wakefulness and
REM sleep are so similar in appearance, behavioral correlates are needed to
differentiate them (Table 32-1).
The EEG background most often observed at this maturational age is trace
alternant, characterized by synchronous symmetrical bursts of 1 to 3 Hz delta
on a continuous background of lower-amplitude activity (Figure 32-1). The
more mature EEG pattern in term infants is high-voltage slow (HVS) charac-
terized by 50 to 150 µV 1-3 Hz activity (Figure 32-2) generally first seen at 38
to 39wPMA. Figure 32-3 shows a 30-second epoch of REM sleep recorded
in an infant 46 wPMA.
Trace alternant usually disappears by 44 weeks’ to as late as 46 weeks’
chronological age (wCA), replaced by HVS. By 46 wCA, NREM sleep is
characterized by HVS, no eye movements, regular respiration and heart
rates, and periodic chin electromyogram activation related to sucking. REM
sleep is best identified by reduced chin electromyogram, rapid eye move-
ments, irregular respiration and heart rate, and continuous mixed frequen-
cies especially near 3 Hz. Table 32-1 summarizes the polysomnographic
characteristics and their behavioral correlates of wakefulness, NREM
sleep, and REM sleep in babies 0 to 2 months of age.

Table 32-1. Polysomnographic Sleep/Wake Characteristics in Infants 0 to 2 Months of Age

State Behavior Respiration EEG EOG Chin EMG
REM Eyes closed, REMs, sucking, grimacing, Irregular, some LVI or M Eyes closed with Low with or without
squirming, facial grimaces, fine limb central apneas or (rarely HVS) (and without) REMs transient motor
muscle twitches, chin, body and limb periodic breathing activity
tremors, intermittent stretching, large may be seen
athetoid body movements
NREM Eyes closed, few or no movements, Regular TA, HVS, M, Eyes closed with Present, could be
periodic sucking can occur or sleep spindles no eye movements lower than
wakefulness
Wakefulness Calm or active with eyes open, Irregular, rapid LVI or M Eye blinks, conjugate 0.5–1 Hz Present, movement
crying, feeding and shallow vertical eye movements, conjugate, artifact
irregular, sharply peaked REMs,
scanning lambda waves (sharply
contoured 250–350 ms waveforms
occipital regions), transient eye
closure, crying
Abbreviations: EEG, electroencephalogram; EMG, electromyogram; EOG, electro-oculogram; LVI, low-voltage intermixed; M, mixed; HVS, high-voltage slow waves; NREM, non–rapid
eye movement; REM, rapid eye movement; TA, trace alternant; W, wakefulness.
585
10/24/23 12:11 PM
586
Figure 32-1. A 30-second polysomnographic epoch showing trace alternant in an infant

40 weeks’ postmenstrual age.
Figure 32-2. A 30-second polysomnographic epoch of high-voltage slow non–rapid eye

movement sleep in an infant 48 weeks’ post-menstrual age.
Indeterminate Sleep in Babies Aged 0 to 2 Months

Many epochs of sleep until 3 months post-term are best scored as indeter-
minate or transitional sleep (stage T) even though the percentage of stage T
rapidly falls beginning after 36 wPMA. Parmelee et al7 reported that 67%
of total sleep time was best scored as indeterminate in an infant 30 wCA,
38% at 40 wCA, 29% at 3 months post term.7

587
Figure 32-3. A 30-second polysomnographic epoch of rapid eye movement sleep recorded in
an infant 46 weeks’ postmenstrual age. Note the irregular breathing and rapid eye movements.
Polyphasic Sleep in Babies Aged 0 to 2 Months

Sleep in term newborns is characterized by 5 to 6 periods of sleep across
24 hours, which can last 50 to 300 minutes; these alternate with wake periods
lasting 90 to 180 minutes. Hunger and satiety drive when a newborn sleeps
and wakes. Until approximately 44 wCA, sleep cycles repeat in a polyphasic
pattern across the 24-hour day, interrupted approximately every 3 to 4 hours
by an awakening for care and feeding.28,29 Non-rapid eye movement and REM
sleep are typically evenly distributed during the night, although sleep is often
more restless in the first half of the night.28 Bottle-fed babies sleep longer
(3–5 hours) than breastfed babies (2–3 hours): breast milk contains more
whey, which is easier to digest; whereas formula milk contains more casein,
which babies digest more slowly.
REM-NREM-REM sleep cycles typically last an average of 50 to 60 minutes
(range 30–70 minutes). Within a given sleep cycle, REM sleep lasts 10 to
45 (mean 25) minutes, NREM sleep near to 20 minutes, and indeterminate/
transitional sleep about 10 minutes.29,30 Wakefulness represents only 8% to
10% of a 24-hour day in infants up to 48 wPMA.29 Stage N after the first
period of stage R often begins with HVS for 3% to 5% of the cycle, then a
longer period of trace alternant for 25%. Transitional/indeterminate sleep
most often occurs at sleep onset, especially when sleep transitions from REM
to NREM sleep, or following arousals. The percentage of indeterminate sleep
lessens with increasing maturational age: 38% of sleep at 40 wPMA, 24% of
sleep at 3 months of age (largely disappearing by 6 months of age).31
Development of EEG Biomarkers of

Mature NREM and REM Sleep
The major polysomnographic biomarkers of drowsiness and sleep are
hypersynchrony, saw-tooth waves, sleep spindles, vertex sharp waves,
K-complexes, and slow-wave activity (SWA) of NREM 3 sleep.32

588
Hypnagogic hypersynchrony is a distinctive EEG pattern of drowsiness

and NREM 1 sleep characterized by paroxysmal runs or bursts of diffuse
synchronous 75 to 350 µV 3–4.5 Hz waves often maximal over the central,
frontal, or fronto-central EEG derivations. Hypnagogic hypersynchrony
often disappears with deeper stages of NREM sleep. It is seen in 30% of
infants at 3 months post term birth, and 95% between 6 months and 4 years.
Hypnagogic hypersynchrony gradually disappears (seen in 10% of children
aged 11 years; it is rare after ages 12 or 13 years).
Sawtooth waves are brief bursts of often notched 4- to 6-per-second waves
lasting 2 to 3 seconds, which are seen during phasic REM sleep when rapid
eye movements are present. They are usually maximal over the midline
central region.
Table 32-2 summarizes the age when distinctive polysomnographic features
of sleep and wake first appear.
Table 32-2. Age When Distinctive PSG Features of Sleep and Wake First Appear
Distinctive
Polysomnographic
Electroencephalographic
Feature Characteristics Age at First Appearance
Sleep spindles Brief (usually 0.5–1.5 sec) 6 weeks to 3 months
bursts with a frequency post-term; first appear
range of 11–16 Hz. These are maximal over midline
generated in the thalamus central (Cz) and shift from
and play an important role side to side (C3, C4).
in sensory processing and
long-term memory.
Sawtooth waves of rapid Brief bursts of often-notched As early as age 7 weeks
eye movement sleep 4- to 6-per-second waves post-term: prominent over
lasting 2–3 seconds, which the frontal (F3, F4, FZ) and
are seen during phasic rapid central (Cz, C3, C4) regions.
eye movement sleep when Typically 2–6 Hz.
rapid eye movements are
present. They are usually
maximal over the Cz.
Dominant posterior An EEG rhythm over the Dominant posterior rhythm
rhythm occipital regions during first appears at a slower
wakefulness, which is frequency of 3.5–4.5 Hz by
(1) best seen with eyes 3–4 months post-term;
closed during periods of increases to 5–6 Hz by 5–6
physical relaxation and months; 7.5–9.5 Hz by 3
relative mental inactivity years; mean 9 Hz by 9 years
and (2) “reactive” (ie, and 10 Hz by 15 years;
attenuated/blocked maximal over occipital
by attention). electrodes.

589
Table 32-2. Age When Distinctive PSG Features of Sleep and Wake First Appear (continued)
Distinctive
Polysomnographic
Electroencephalographic
Feature Characteristics Age at First Appearance
K-complexes A 50–100 μV surface First appear 3–6 months
electronegative wave post-term maximal over
lasting 200 msec, followed frontal regions. Usually
by a surface-positive present by age 5–6 months.
30–50 μV 300–500 msec Between ages 3 and 5 years,
wave maximal over the K-complexes are striking:
prefrontal and frontal very high amplitude,
scalp EEG derivations. primarily surface-electro-
negative, sharply con-
toured, occurring in runs of
3–8 in 1–3 seconds. By
adolescence, K-complexes
resemble those seen in
adults and repeat at rates of
one every 1–3 seconds.
Slow-wave activity of High amplitude (> 75, usually First appears 2–5 months
non-rapid eye movement 100–400 µV) 0.5–2 Hz post-term maximal over
(NREM) 3 sleep activity maximal frontal frontal regions.
regions slow-wave activity.
Hypnagogic Paroxysmal runs or bursts First appears 3–6 months
hypersynchrony of diffuse bisynchronous post-term. Seen in 30%
75 to 350 µV 3–4.5 Hz waves of infants at 3 months
maximal central, frontal, post-term, 95% between
or fronto-central regions 6 months and 4 years of
observed in NREM 1 sleep. age. Gradually disappears
Usually disappears with (seen in 10% of children
deeper NREM sleep. 11 years of age; rare after
ages 12 or 13 years).
Vertex sharp waves Monophasic EEG surface- Broad vertex waves over
(V-waves) negative sharp waves central region first appear
maximal central regions; by 6 months post-term.
last < 0.5 second (usually Vertex sharp waves, which
< 200 msec); occur in bursts resemble those seen in
or runs. Most often seen older children and adults,
in the transition to NREM 1 typically first appear 16
sleep but can occur in either months post term.
NREM 1 or NREM 2 sleep.
Sleep Spindles
The first major EEG feature of mature sleep to appear after birth is sleep spin-
dles,3 which are sometimes seen as early as 3 to 4 weeks in neonates following
birth.32–34 Sleep spindles are usually present by 6 to 8 weeks’ postnatal age,
reflecting development of the thalamocortical structures,3,35–37 and may develop
earlier in babies born prematurely.38 Initially, sleep spindles occur asynchro-
nously, shifting from side to side but, by 2 years of age, sleep spindles, when

590
seen, are bisynchronous. Across an entire recording of sleep, 50% of sleep

spindles will occur synchronously (bilaterally) at 6 and 9 months of age;
increases to 70% by 12 months, and, by 18 months to 2 years, sleep spindles
are typically synchronous.
Sleep spindles in children can occur independently at 2 different EEG fre-
quencies and maximal over 2 different scalp locations: frontally predominant
11–12.75 Hz spindles, and centroparietal 12–14.75 Hz spindles (Figure
32-4). Frontal spindles decrease in prevalence around age 13 years, although
they are seen in some young adults, especially early in a night of sleep.
Sleep spindles play an important role in memory processing, which occurs
preferentially during NREM 3 sleep.3,39–41 Sleep spindles are also thought to
facilitate thalamocortical sensory gating, synaptic plasticity, and somatosen-
sory development.42 Higher spindle density is associated with better cogni-
tion, memory, and social behavior in children.43,44 Delayed appearance or
abnormal-appearing sleep spindles are an early biomarker of metabolic
and/or brain abnormalities.45,46
Figure 32-4. Until age 13 years, sleep spindles in children often occur independently at
2 different electroencephalographic frequencies and maximal over 2 different scalp locations:
11–12.75 Hz maximal over the frontal and 12–14.75 Hz over the centroparietal regions.
Vertex Waves
Vertex waves are seen in later NREM 1 and NREM 2 sleep, maximal over the
central EEG derivations, and predominantly surface electronegative.
Vertex waves are thought to either be a direct response to an external stimulus
or a mechanism to maintain sleep after a stimulus.47 Functional magnetic reso-
nance imaging studies show spontaneous vertex waves localize to the primary
sensorimotor cortices.48 Vertex waves may serve a role in modulating aware-
ness of the external work during NREM sleep by gating neocortical sensory
function.48 Studies suggest NREM sleep transients (vertex sharp waves,
hypnagogic hypersynchrony, K-complexes, and sleep spindles) are usually
coupled with hippocampal ripples.49 Hippocampal ripples are 80 to 200 Hz
neocortical rhythms, which are particularly important in sleep-related
memory processing.

591
Infrequent, broad, immature vertex waves over the central derivations have
been observed as early as 6 months term. Vertex waves resembling those seen
in older children and adults first appear later at 16 months term.50 Begin-
ning around 30 months of age, vertex waves in young children often occur in
repetitive runs. Around 36 months of age, vertex waves are more often high
amplitude (> 250 μV) and sharply peaked, occasionally misidentified as
epileptiform (Figure 32-5). Between ages 3 and 13 years, vertex waves evolve
to sharply peaked, primarily surface waveforms similar to those seen in
adults.51,52
Figure 32-5. Around 36 months of age, vertex waves are more often high amplitude (> 250 μV)
and sharply peaked, occasionally misidentified as epileptiform.
K-complexes
K-complexes appear to play an important role in maintaining sleep but also
promoting arousal. K-complexes are thought to reflect the brain judging
whether a particular stimulus is harmless (keep sleeping) or potentially
dangerous (worthy of waking).53,54 K-complexes also appear to play roles
in memory consolidation and synaptic homeostasis.55
K-complexes, an EEG biomarker of NREM 2 sleep, are usually present by
age 5 to 6 months and, at this age, are characterized by a 50- to 100-μV
surface-electronegative wave lasting 200 msec, followed by a surface-
positive 30- to 50-μV wave lasting 300 to 500 msec, which is maximal in
amplitude over the prefrontal and frontal scalp. K-complexes usually follow
sleep spindles. K-complexes are most easily provoked by auditory stimulus (eg,
loud clap). They may or may not result in an arousal (less likely, awakening).
Between ages 3 and 5 years, K-complexes are striking: very high amplitude,
primarily surface-electronegative, sharply contoured, occurring in runs of
3 to 8 in 1 to 3 seconds. By adolescence, K-complexes resemble those seen
in adults and repeat at rates of 1 every 1 to 3 seconds.52,56,57
Slow-Wave Activity of NREM 3 Sleep

Slow-wave activity as seen in NREM 3 sleep may be seen as early as 4 to
4.5 months and is usually present by 5 to 6 months.2,36,58,59 Slow-wave activity
is often 300 μV or greater in amplitude in young children.4 A study recording

592
24-hour polysomnogram in 31 normal infants younger than 6 months found

that sleep spindles first appeared at approximately 8 to 12 weeks term and
“true slow wave with delta waves” of slow-wave sleep first appeared
between 3 and 6 months term.60 NREM 1, 2, and 3 sleep can usually be
distinguished between 4 and 6 months term.2,28,58,60–63
Non-rapid eye movement 3 serves an important role for storage of long-term
memories into the neocortex. Sleep spindles, slow oscillations, and hippo-
campal ripples during NREM sleep provide the neurobiological scaffold
for reactivating memory traces learned while awake, processing them, and
channeling them for integration in neocortical sites for long-term storage.
Memory processing during NREM 3 sleep works best if sleep spindles are
coupled to slow oscillations, and spindle-slow oscillation coupling improves
from childhood to adolescence.64,65 In a 2020 study, Hahn et al65 tested the
ability of children to store memories, retesting them later as adolescents. The
ability to recall a set of words was better after a full night’s sleep. Memory
recall was best when sleep spindles were coupled with slow oscillations
(called phase coupling). Children with better spindle-slow oscillation
coupling had improved memory formation once they became teenagers. Hahn
et al65 demonstrated that increases in spindle-slow oscillation coupling
strength occur across childhood and adolescence and better coupling is
associated with enhanced memory formation.
Developmental Changes in Sleep Architecture

The most conspicuous changes in sleep architecture during infancy and early
childhood are (1) decrease in total sleep time; (2) gradual consolidation of
periods of sleep at night and wakefulness in the day; (3) decrease in the
intensity (EEG power) of NREM 3 SWA; and (4) a steady decline in the
percentage of sleep time spent in REM sleep.66
Development of Circadian Rhythm and Sleep/Wake

Patterns in Babies and Young Children
In the last 10 weeks of gestation, the circadian rhythm of the fetus is syn-
chronized with the mother’s maternal rest-activity cycle, heart rate, cortisol,
melatonin, and body temperature rhythms.4 Newborns exhibit no rest-activity
circadian rhythm independent of their mother before about 1 month of age
(because it has not yet developed).
Neonates are born with low levels of maternally transferred melatonin, which
dissipates in a week, and endogenous rises in melatonin to detectable levels
are not observed until approximately 6 weeks following birth.67 The rise in
the core body temperature correlating with morning waking first occurs
around 6 weeks following birth. Circadian regulation of cortisol secretion

593
(which is lowest from midnight to 4:00 am, peaking early morning) develops
by age 6 months.
Development of circadian rhythms in the newborn is influenced by length
and timing of light exposure, feeding, and rest/activity cycles. By 5 to 6 weeks
following birth, sleep becomes more concentrated during the night and wake-
fulness more prevalent during the day.68 By 12 to 14 weeks, a diurnal pattern
is established with a long nocturnal sleep period, shorter daytime naps, and
1 to 3 hours of wakefulness preceding the nocturnal sleep period.
Using sleep questionnaires and actigraphy, a large study5 of 1,427 infants
found that the average percentage of daytime sleep decreased from 36 ± 9%
at 3 months of age to 26 ± 7% at 8 months of age. Infants who developed a
24-hour rhythm later than others (1) slept more hours per day; (2) had a later
sleep-wake rhythm; (3) experienced more difficulties in settling to sleep;
(4) had longer sleep-onset latency; and (5) were awake longer during the night.
Still, by 6 months of age, most typically developing infants display a circadian
pattern with period, amplitude, and phase activity similar to those of an adult.
The researchers found the photoperiod (hours of daylight per 24 hours) during
the first 3 months was related to the slower development of sleep/wake rhythm
at age 3 months.
Providing cycles of dark and light in neonatal intensive care units may
foster development of the rest-activity circadian rhythm.69,70 Neonates born
extremely preterm when exposed to timed light in the neonatal intensive care
unit show an earlier emergence of the 24-hour sleep/wake rhythm compared
to neonates born term.71
Infants aged 2 to 12 months typically sleep 9 to 12 hours per night and nap
2 to 4.5 hours per day. In infants aged 6 to 12 months, the longest continuous
sleep period is about 7 hours. Sleep consolidation is observed in 70% to 80%
of infants by age 9 months. Infants between 2 and 12 months of age normally
arouse 2 to 4 times a night. In some infants, arousals are brief and they are
able to return to sleep without parental intervention (“self-soothers”); others
alert their parent(s) by crying (“signalers”).
Between 25% and 50% of infants aged 6 to 12 months have what parents
regard as problematic night awakenings. Nocturnal awakenings often
increase during the second 6 months after birth. This “relapse” is thought
to be triggered by separation anxiety, a normal developmental stage, which
often peaks between ages 6 and 18 months, and can make it difficult for
children to separate at bedtime or self-soothe when they wake at night.67
Developmental issues have an impact on sleep in toddlers. Between 10% and
20% of children exhibit bedtime refusal/resistance, and 15% to 20% have
problematic night awakenings. The child’s transition from crib to bed usually

594
occurs at about age 2 to 3 years, often prompting them to visit the parents’
bed. A child’s drive for autonomy and independence may also lead to
increased bedtime resistance. Transitional objects are useful at this develop-
mental age, fostering independence and self-soothing. Regression to more
immature patterns of sleep is a common response to stress. Children aged
3 to 5 years often need 11 to 12 hours of sleep per 24 hours. Nighttime sleep
becomes consolidated into long periods of approximately 10 hours.
Daytime Napping
72
A longitudinal study found that 84% of infants were napping twice a day at
age 6 months and 16% of infants were napping 3 times a day. Most children
aged 15 to 24 months take only one afternoon nap, typically for 2 hours. A
2020 meta-analysis found that < 2.5% of children cease napping prior to age
2 years and 94% of children cease napping by age 5 years.73 By ages 3 to
5 years, naps often decrease from one to none. As sleep consolidates during
the night, the need for daytime sleep gradually disappears. Napping often
reappears in adolescence as a compensation for late bedtimes, insufficient
sleep, and sleep debt. (See Chapter 36, Insomnia.) Declarative, motor, and
emotional memory are better if a nap follows learning.74
Ultradian Distribution of NREM-REM Sleep Cycles

Ultradian biological rhythms are recurrent periods or cycles repeated
throughout a 24-hour day; circadian rhythms are one cycle completed daily;
and infradian rhythms are biorhythms that recur in periods longer than a
day (eg, human menstrual cycle). Until approximately 44 wCA, ultradian
cycles of REM-NREM-REM sleep last a mean of 50 to 60 minutes (range
30–70 minutes) and are interrupted approximately every 3 to 4 hours by an
awakening for care and feeding.29 Cycles of NREM and REM sleep are
typically evenly distributed across day and night, and 7 to 13 cycles may
occur during nocturnal sleep.28,75 Wakefulness represents only 8% to
10% of a 24-hour day in babies up to 8 weeks post-term.29
By age 6 months, NREM 3 sleep is preferentially present toward the begin-
ning of the night, and REM sleep in the later portion. Sleep cycle length varies
with age: an average of 55 minutes in babies at term; 58 minutes at 9 months;
71 minutes at age 2 years; 79 minutes at age 5 years; 85 to 115 minutes at ages
8 to 12 years, and 90 minutes in adults.36,76 The mean ultradian cycle length in
schoolchildren is approximately 85 to 90 minutes with 4 to 6 cycles of NREM-
REM sleep occurring across a night.77 Sleep efficiency (percentage of time
in bed spent sleeping) remains constant across infancy to adolescence.76,78
The longest sleep period by age 1 year is 8 to 9 hours, supplemented by
naps. By age 5 years, it is 10 hours, and this remains stable until puberty,
when it begins to decline.76,78

595
The percentage of sleep time spent in REM sleep falls to 30% by 12 months
of age and reaches adult percentages of 20% to 25% by age 5 years. The pro-
portion of sleep spent in NREM sleep increases while REM sleep decreases
such that NREM 3 sleep occupies a greater proportion of sleep time than
REM sleep at age 12 months. From ages 5 to 19 years, the percentage of
REM sleep remains relatively stable while the percentage of NREM 2
sleep increases with a concomitant decrease in NREM 3 sleep.76,78
Decrease in NREM 3 Slow Wave Activity

The massive decline in SWA with growth and maturation reflects extensive
elimination of unnecessary cortical synapses occurring during adolescence,
the final step in brain neurodevelopment. Parallel declines in synaptic density,
delta wave amplitude, and cortical metabolic rate during adolescence would
suggest this. The delta power of NREM 3 sleep activity decreases by more
than 60% between ages 10 and 20 years.79 The density of SWA also declines
across recurring periods of NREM sleep within a night. A longitudinal study
showed delta power of the sleep EEG begins to decrease around age 11.5 years,
reduced by 60% by age 16 years.79 The amplitude of SWA shows an inverted
U-shape development: initially increasing in childhood, peaking just before
puberty, and then decreasing in puberty and adolescence.79 The fall in delta
power begins earlier in girls than in boys (consistent with observed age-
related changes in gray matter volume) but then slows so that the overall
rate of decline is similar between girls and boys at age 16.79
Shift From REM to NREM Sleep Onsets

Until 50 to 52 wPMA, infants generally enter sleep through REM.80 Several
studies79,81,82 found two-thirds of sleep onsets were REM sleep in babies
3 weeks post term, but only 18% at age 6 months. REM latencies of 20 to
40 minutes are typical in infants aged 3 to 12 months.80 REM latencies
increase from 15 ± 20 minutes at age 3 months to 70 ± 29 minutes at age
24 months. REM latencies average 116 minutes in children aged 1 year, and
136 minutes in children aged 11 to 18 years. At least some of this may be due
to the longer sleep cycles in older children since, after infancy, REM usually
begins at the end of the second sleep cycle. The percentage of sleep spent in
REM sleep declines from 50% at birth to 40% at ages 3 to 5 months, and to
30% at ages 1 to 2 years, reaching adult percentages of 20% to 25%
by ages 3 to 5 years.
Decrease of Total Sleep Time

Total sleep time decreases across infancy, early childhood, and adolescence.
A seminal longitudinal study by Iglowstein et al37 followed 493 children from
birth to age 16 years and found total sleep duration decreased from an average
of 14.2 ± 1.9 hours at 6 months to 8.1 ± 0.8 hours at age 16 years. Also, the

596
variance (greater variability in sleep duration) was noted, showing a similar

declining trend: the interquartile range at age 6 months was 2.5 hours, and
1 hour at age 16 years. For example, 96% of all children slept 10.8 to
15.6 hours at age 2 years compared to 8 to 10.7 hours at age 12 years.37
A 2012 meta-analysis by Galland et al66 found mean sleep durations were
12.8 hours (range 9.7–15.9) in infants; 11.9 hours (9.9–13.8) in toddlers/
preschool-aged children; and 9.2 (7.6–10.8) in schoolchildren.
Socioeconomic Differences in Sleep Patterns

in Infants and Children
Although sleep is biologically driven, socioeconomic differences significantly
modulate sleep behavior in infants and children. A study83 that recorded
actigraphy at approximately 1 month and 6 months of age in 306 infants83
found racial and ethnic differences in sleep emerge in early infancy. Night-
time and 24-hour sleep durations increased less in Hispanic and Black infants
compared to white infants, with differences largely explained by socioeco-
nomic and environmental factors. Adjustment for maternal education and
household income attenuated all observed daytime and nighttime sleep dura-
tion differences other than in Asian infants and children, where persistently
reduced nighttime sleep at age 6 months was observed.
Other cross-sectional studies have found that boys, children from under-
resourced areas, and children of color had shorter sleep times than girls,
children from high-resource areas, and white children, respectively84; and
that children of racial or ethnic minority were more likely than white children
to have a bedtime of 11:00 pm or later.85
A 2021 study86 examined the impact of daily experiences of racial and ethnic
discrimination on sleep in 95 adolescents. They found that daily discrimina-
tion was a low-frequency but high-impact event that, when it occurred, was
associated with short sleep duration. Social support from friends was
associated with a negative impact on sleep duration; parental support
promoted sleep quality. Support from teachers protected adolescents from the
negative effects of discrimination on sleep duration.
Ontogeny of Dreaming in Children

Even though it has been established that REM sleep appears in utero and
infancy, there is no evidence regarding whether or not infants dream. A recent
review analyzing findings of different studies of the ontogeny of dreaming
found that different methods for collecting dreams in children often result
in highly variable and sometimes contradictory assessments and outcomes.87
Fairly consistent observations include (1) dream narratives in younger chil-
dren are often shorter and simpler than those reported by older children and

597
adults; (2) preschoolers, when reporting their dreams, often verbalize only one
relevant aspect of the dream and may have difficulty distinguishing between
internal and external events; and (3) the highest prevalence of nightmares
is between ages 6 and 10 years.88 Schoolchildren in whom nightmares are
reported to occur often are more likely to have emotional problems or anxiety.
key points
} Sleep, especially REM sleep in the fetus, neonate, and infant, fosters early brain
development and connects the body with the brain (embodiment) by
facilitating mapping of the somatosensory, visual, auditory, pain, and tactile
12
regions of the cerebral cortex.
} The EEG and polysomnographic features of sleep and wakefulness evolve
across infancy and early childhood as the brain develops.
} Insufficient or fragmented sleep, especially during infancy, can disrupt the
normal development of the brain, but also has an impact in later childhood
and adolescence.
References
1. Piers MW, Piaget J; Erikson Institute; Loyola University Chicago. School of Education.,
Loyola University Chicago. Department of Psychology. Play and development; a symposium.
Norton; 1972
2. Grigg-Damberger MM. The visual scoring of sleep in infants 0 to 2 months of age.
J Clin Sleep Med. 2016;12(3):429–445
3. MacLean JE, Fitzgerald DA, Waters KA. Developmental changes in sleep and breathing
across infancy and childhood. Paediatr Respir Rev. 2015;16(4):276–284 PMID: 26364005
doi: 10.1016/j.prrv.2015.08.002
4. Mirmiran M, Maas YG, Ariagno RL. Development of fetal and neonatal sleep and circadian
rhythms. Sleep Med Rev. 2003;7(4):321–334 PMID: 14505599 doi: 10.1053/smrv.2002.0243
5. Paavonen EJ, Morales-Muñoz I, Pölkki P, et al. Development of sleep-wake rhythms during
the first year of age. J Sleep Res. 2020;29(3):e12918 PMID: 31495031 doi: 10.1111/jsr.12918
6. Parmelee AH, Stern E, Harris MA. Maturation of respiration in prematures and young infants.
Neuropediatrics. 1972;3(3):294–304 PMID: 5067426 doi: 10.1055/s-0028-1091768
7. Parmelee AH Jr, Wenner WH, Akiyama Y, Schultz M, Stern E. Sleep states in premature infants.
Dev Med Child Neurol. 1967;9(1):70–77 PMID: 6031536 doi: 10.1111/j.1469-8749.1967.tb02212.x
8. Bourel-Ponchel E, Hasaerts D, Challamel MJ, Lamblin MD. Behavioral-state development and
sleep-state differentiation during early ontogenesis. Neurophysiol Clin. 2021; 51(1):89-98
PMID: 33148436
9. Dereymaeker A, Pillay K, Vervisch J, et al. Review of sleep-EEG in preterm and term neonates.
Early Hum Dev. 2017;113:87–103 PMID: 28711233 doi: 10.1016/j.earlhumdev.2017.07.003
10. Cao J, Herman AB, West GB, Poe G, Savage VM. Unraveling why we sleep: quantitative
analysis reveals abrupt transition from neural reorganization to repair in early development.
Sci Adv. 2020;6(38):eaba0398 PMID: 32948580 doi: 10.1126/sciadv.aba0398
11. Sokoloff G, Hickerson MM, Wen RY, Tobias ME, McMurray B, Blumberg MS.
Spatiotemporal organization of myoclonic twitching in sleeping human infants. Dev Psychobiol.
2020;62(6):697–710 PMID: 32037557 doi: 10.1002/dev.21954
12. Blumberg MS, Dooley JC, Sokoloff G. The developing brain revealed during sleep. Curr Opin
Physiol. 2020;15:14–22 PMID: 32864534
13. Arditi-Babchuk H, Feldman R, Eidelman AI. Rapid eye movement (REM) in premature neonates
and developmental outcome at 6 months. Infant Behav Dev. 2009;32(1):27–32 PMID: 18996599
doi: 10.1016/j.infbeh.2008.09.001

598
14. Geva R, Yaron H, Kuint J. Neonatal sleep predicts attention orienting and distractibility.
J Atten Disord. 2013; PMID: 23893532
15. Weisman O, Magori-Cohen R, Louzoun Y, Eidelman AI, Feldman R. Sleep-wake transitions in
premature neonates predict early development. Pediatrics. 2011;128(4):706–714 PMID: 21911350
doi: 10.1542/peds.2011-0047
16. Hirshkowitz M, Whiton K, Albert SM, et al. National Sleep Foundation’s updated sleep
duration recommendations: final report. Sleep Health. 2015;1(4):233–243 PMID: 29073398
doi: 10.1016/j.sleh.2015.10.004
17. Paruthi S, Brooks LJ, D’Ambrosio C, et al. Recommended amount of sleep for pediatric
populations: a consensus statement of the American Academy of Sleep Medicine.
J Clin Sleep Med. 2016;12(6):785–786 PMID: 27250809 doi: 10.5664/jcsm.5866
18. Wheaton AG, Jones SE, Cooper AC, Croft JB. Short sleep duration among middle school and
high school students - United States, 2015. MMWR Morb Mortal Wkly Rep. 2018;67(3):85–90
PMID: 29370154 doi: 10.15585/mmwr.mm6703a1
19. Volk C, Huber R. Sleep to grow smart? Arch Ital Biol. 2015;153(2-3):99–109 PMID: 26742664
20. Zhao Z, Zhao X, Veasey SC. Neural consequences of chronic short sleep: reversible or lasting?
Front Neurol. 2017;8:235 PMID: 28620347 doi: 10.3389/fneur.2017.00235
21. Meldrum RC, Restivo E. The behavioral and health consequences of sleep deprivation
among U.S. high school students: relative deprivation matters. Prev Med. 2014;63:24–28
PMID: 24631498 doi: 10.1016/j.ypmed.2014.03.006
22. Wheaton AG, Olsen EO, Miller GF, Croft JB. Sleep duration and injury-related risk behaviors
among high school students—United States, 2007-2013. MMWR Morb Mortal Wkly Rep.
2016;65(13):337–341 PMID: 27054407 doi: 10.15585/mmwr.mm6513a1
23. Nijhuis JG, Prechtl HF, Martin CB Jr, Bots RS. Are there behavioural states in the human fetus?
Early Hum Dev. 1982;6(2):177–195 PMID: 7094856 doi: 10.1016/0378-3782(82)90106-2
24. André M, Lamblin MD, d’Allest AM, et al. Electroencephalography in premature and
full-term infants. Developmental features and glossary. Neurophysiol Clin. 2010;40(2):59–124
PMID: 20510792 doi: 10.1016/j.neucli.2010.02.002
25. Wallois F, Routier L, Heberlé C, Mahmoudzadeh M, Bourel-Ponchel E, Moghimi S. Back to
basics: the neuronal substrates and mechanisms that underlie the electroencephalogram in
premature neonates. Neurophysiol Clin. 2021;51(1):5–33 PMID: 33162287
doi: 10.1016/j.neucli.2020.10.006
26. Bourel-Ponchel E, Gueden S, Hasaerts D, et al. Normal EEG during the neonatal period:
maturational aspects from premature to full-term newborns. Neurophysiol Clin.
2021; 51(1):61-88 PMID: 33239230 doi: 10.1016/j.neucli.2020.10.004
27. Grigg-Damberger MM. The visual scoring of sleep in infants 0 to 2 months of age.
28. Hoppenbrouwers T, Hodgman JE, Harper RM, Sterman MB. Temporal distribution of sleep
states, somatic activity, and autonomic activity during the first half year of life. Sleep.
1982;5(2):131–144 PMID: 7100744
29. Lamblin MD, Walls Esquivel E, André M. The electroencephalogram of the full-term newborn:
review of normal features and hypoxic-ischemic encephalopathy patterns. Neurophysiol Clin.
2013;43(5-6):267–287 PMID: 24314754 doi: 10.1016/j.neucli.2013.07.001
30. Monod N, Pajot N. [The sleep of the full-term newborn and premature infant. I. Analysis of the
polygraphic study (rapid eye movements, respiration and E.E.G.) in the full-term newborn].
Biol Neonat. 1965;8(5):281–307 PMID: 5885343
31. de Weerd AW, van den Bossche RA. The development of sleep during the first months of life.
Sleep Med Rev. 2003;7(2):179–191 PMID: 12628217 doi: 10.1053/smrv.2002.0198
32. Eisermann M, Kaminska A, Moutard ML, Soufflet C, Plouin P. Normal EEG in childhood:
from neonates to adolescents. Neurophysiol Clin. 2013;43(1):35–65 PMID: 22781497
33. Ellingson RJ, Peters JF. Development of EEG and daytime sleep patterns in normal full-term
infant during the first 3 months of life: longitudinal observations. Electroencephalogr Clin
Neurophysiol. 1980;49(1-2):112–124 PMID: 6159152 doi: 10.1016/0013-4694(80)90357-0
34. Ellingson RJ, Peters JF. Development of EEG and daytime sleep patterns in low risk premature
infants during the first year of life: longitudinal observations. Electroencephalogr Clin
Neurophysiol. 1980;50(1-2):165–171 PMID: 6159184 doi: 10.1016/0013-4694(80)90333-8
35. Louis J, Zhang JX, Revol M, Debilly G, Challamel MJ. Ontogenesis of nocturnal organization of
sleep spindles: a longitudinal study during the first 6 months of life. Electroencephalogr Clin
Neurophysiol. 1992;83(5):289–296 PMID: 1385085 doi: 10.1016/0013-4694(92)90088-Y
36. Jenni OG, Borbély AA, Achermann P. Development of the nocturnal sleep electroencephalogram
in human infants. Am J Physiol Regul Integr Comp Physiol. 2004;286(3):R528–R538
PMID: 14630625 doi: 10.1152/ajpregu.00503.2003

599
37. Iglowstein I, Jenni OG, Molinari L, Largo RH. Sleep duration from infancy to adolescence:
reference values and generational trends. Pediatrics. 2003;111(2):302–307 PMID: 12563055
doi: 10.1542/peds.111.2.302
38. Metcalf DR. The effect of extrauterine experience on the ontogenesis of EEG sleep spindles.
Psychosom Med. 1969;31(5):393–399 PMID: 5350298 doi: 10.1097/00006842-196909000-00005
39. Fernandez LMJ, Lüthi A. Sleep spindles: mechanisms and functions. Physiol Rev.
2020;100(2):805–868 PMID: 31804897 doi: 10.1152/physrev.00042.2018
40. Fang Z, Ray LB, Houldin E, Smith D, Owen AM, Fogel SM. Sleep spindle-dependent functional
connectivity correlates with cognitive abilities. J Cogn Neurosci. 2020;32(3):446–466
PMID: 31659927 doi: 10.1162/jocn_a_01488
41. Fogel SM, Smith CT. The function of the sleep spindle: a physiological index of intelligence and
a mechanism for sleep-dependent memory consolidation. Neurosci Biobehav Rev.
2011;35(5):1154–1165 PMID: 21167865 doi: 10.1016/j.neubiorev.2010.12.003
42. Lüthi A. Sleep spindles: where they come from, what they do. Neuroscientist. 20(3):243–256
doi: 10.1177/1073858413500854 PMID 23981852. S2CID 206658010
43. Brockmann PE, Damiani F, Pincheira E, et al. Sleep spindle activity in children with obstructive
sleep apnea as a marker of neurocognitive performance: A pilot study. Eur J paediatr neurol.
2018;22(3):434–439
44. Mikoteit T, Brand S, Perren S, et al. Visually detected non-rapid eye movement stage 2 sleep
spindle density at age five years predicted prosocial behavior positively and hyperactivity
scores negatively at age nine years. Sleep Med. 2018;48:101–106 PMID: 29879654
doi: 10.1016/j.sleep.2018.03.028
45. Farmer CA, Chilakamarri P, Thurm AE, Swedo SE, Holmes GL, Buckley AW. Spindle activity
in young children with autism, developmental delay, or typical development. Neurology.
2018;91(2):e112–e122 PMID: 29875224 doi: 10.1212/WNL.0000000000005759
46. Gruber R, Wise MS. Sleep spindle characteristics in children with neurodevelopmental
disorders and their relation to cognition. Neural Plast. 2016;2016:4724792 PMID: 27478646
doi: 10.1155/2016/4724792
47. Colrain IM, Campbell KB. The use of evoked potentials in sleep research. Sleep Med Rev.
2007;11(4):277–293 PMID: 17628317 doi: 10.1016/j.smrv.2007.05.001
48. Stern JM, Caporro M, Haneef Z, et al. Functional imaging of sleep vertex sharp transients.
Clin Neurophysiol. 2011;122(7):1382–1386 PMID: 21310653 doi: 10.1016/j.clinph.2010.12.049
49. Mooij AH, Frauscher B, Goemans SAM, Huiskamp GJM, Braun KPJ, Zijlmans M. Ripples in
scalp EEGs of children: co-occurrence with sleep-specific transients and occurrence across
sleep stages. Sleep. 2018;41(11)Error! Hyperlink reference not valid.
50. Hughes JR. The development of the vertex sharp transient. Clin Electroencephalogr.
1998;29(4):183–187 PMID: 9783093 doi: 10.1177/155005949802900411
51. Werner SS, Stockard JE, Bickford RG. The ontogenesis of the electroencephalogram of
prematures. In: Atlas of Neonatal Electroencephalography. Raven Press; 1977:47–91
52. Kellaway P. Ontogenetic evolution of the electrical activity of the brain in man and animal.
Acta Med Belg. 1957:141–154
53. Gandhi MH, Emmady PD. Physiology, K Complex. StatPearls; 2021
54. Jahnke K, von Wegner F, Morzelewski A, et al. To wake or not to wake? The two-sided
nature of the human K-complex. Neuroimage. 2012;59(2):1631–1638 PMID: 21945697
doi: 10.1016/j.neuroimage.2011.09.013
55. Tononi G, Cirelli C. Sleep function and synaptic homeostasis. Sleep Med Rev. 2006;10(1):49–62
PMID: 16376591 doi: 10.1016/j.smrv.2005.05.002
56. Metcalf DR, Mondale J, Butler FK. Ontogenesis of spontaneous K-complexes. Psychophysiology.
1971;8(3):340–347 PMID: 5093977 doi: 10.1111/j.1469-8986.1971.tb00464.x
57. Halász P. K-complex, a reactive EEG graphoelement of NREM sleep: an old chap in a new
garment. Sleep Med Rev. 2005;9(5):391–412 PMID: 16122950 doi: 10.1016/j.smrv.2005.04.003
58. Grigg-Damberger M, Gozal D, Marcus CL, et al. The visual scoring of sleep and arousal in
infants and children. J Clin Sleep Med. 2007;3(2):201–240
59. Ficca G, Fagioli I, Salzarulo P. Sleep organization in the first year of life: developmental trends
in the quiet sleep-paradoxical sleep cycle. J Sleep Res. 2000;9(1):1–4 PMID: 10733682
doi: 10.1046/j.1365-2869.2000.00172.x
60. Coons S, Guilleminault C. Development of sleep-wake patterns and non-rapid eye movement
sleep stages during the first six months of life in normal infants. Pediatrics. 1982;69(6):793–798
PMID: 7079046 doi: 10.1542/peds.69.6.793
61. Samson-Dolfuss D, Nogues B, Verdure-Poussin A, Mallevile F. Electroencephalogramme du
sommeil de l’enfant normal entre 5 mois et 3 ans. Rev Electroencephalogr Neurophysiol Clin.
1977;7:335–345

600
62. Lenard H. The development of sleep behavior in babies and small children. Electroencephalogr
Clin Neurophysiol. 1972;32:710
63. Tanguay PE, Ornitz EM, Kaplan A, Bozzo ES. Evolution of sleep spindles in childhood.
Electroencephalogr Clin Neurophysiol. 1975;38(2):175–181 PMID: 45948
doi: 10.1016/0013-4694(75)90227-8
64. Cowan E, Liu A, Henin S, Kothare S, Devinsky O, Davachi L. sleep spindles promote the
restructuring of memory representations in ventromedial prefrontal cortex through enhanced
hippocampal-cortical functional connectivity. J Neurosci. 2020;40(9):1909–1919
PMID: 31959699 doi: 10.1523/JNEUROSCI.1946-19.2020
65. Hahn MA, Heib D, Schabus M, Hoedlmoser K, Helfrich RF. Slow oscillation-spindle coupling
predicts enhanced memory formation from childhood to adolescence. Elife. 2020;9:e53730
doi:
66. Galland BC, Taylor BJ, Elder DE, Herbison P. Normal sleep patterns in infants and children:
a systematic review of observational studies. Sleep Med Rev. 2012;16(3):213–222
PMID: 21784676 doi: 10.1016/j.smrv.2011.06.001
67. Bathory E, Tomopoulos S. Sleep regulation, physiology and development, sleep duration and
patterns, and sleep hygiene in infants, toddlers, and preschool-age children. Curr Probl Pediatr
Adolesc Health Care. 2017;47(2):29–42 PMID: 28117135 doi: 10.1016/j.cppeds.2016.12.001
68. McMillen IC, Kok JS, Adamson TM, Deayton JM, Nowak R. Development of circadian
sleep-wake rhythms in preterm and full-term infants. Pediatr Res. 1991;29(4 Pt 1):381–384
PMID: 1852533 doi: 10.1203/00006450-199104000-00010
69. Erren TC, Trautmann K, Salz MM, Reiter RJ. Newborn intensive care units and perinatal
healthcare: on light’s imprinting role on circadian system stability for research and prevention.
J Perinatol. 2013;33(10):824–825.
70. Tsai SY, Thomas KA, Lentz MJ, Barnard KE. Light is beneficial for infant circadian
entrainment: an actigraphic study. J Adv Nurs. 2012;68(8):1738–1747 PMID: 22043963
doi: 10.1111/j.1365-2648.2011.05857.x
71. Guyer C, Huber R, Fontijn J, et al. Very preterm infants show earlier emergence of 24-hour
sleep-wake rhythms compared to term infants. Early Hum Dev. 2015;91(1):37–42
PMID: 25460255 doi: 10.1016/j.earlhumdev.2014.11.002
72. Weissbluth M. Naps in children: 6 months-7 years. Sleep. 1995;18(2):82–87 PMID: 7792496
doi: 10.1093/sleep/18.2.82
73. Staton S, Rankin PS, Harding M, et al. Many naps, one nap, none: A systematic review and
meta-analysis of napping patterns in children 0-12 years. Sleep Med Rev. 2020;50:101247
PMID: 31862445 doi: 10.1016/j.smrv.2019.101247
74. Spencer RMC. The role of naps in memory and executive functioning in early childhood.
Adv Child Dev Behav. 2021;60:139–158 PMID: 33641791 doi: 10.1016/bs.acdb.2020.08.004
75. Jenni OG, Carskadon MA. Spectral analysis of the sleep electroencephalogram during
adolescence. Sleep. 2004;27(4):774–783 PMID: 15283014
76. Lopp S, Navidi W, Achermann P, LeBourgeois M, Diniz Behn C. Developmental changes
in ultradian sleep cycles across early childhood. J Biol Rhythms. 2017;32(1):64–74
PMID: 28088873 doi: 10.1177/0748730416685451
77. Coble PA, Kupfer DJ, Taska LS, Kane J. EEG sleep of normal healthy children. Part I: findings
using standard measurement methods. Sleep. 1984;7(4):289–303 PMID: 6515246
doi: 10.1093/sleep/7.4.289
78. Feinberg I, Davis NM, de Bie E, Grimm KJ, Campbell IG. The maturational trajectories of
NREM and REM sleep durations differ across adolescence on both school-night and extended
sleep. Am J Physiol Regul Integr Comp Physiol. 2012;302(5):R533–R540 PMID: 22116514
doi: 10.1152/ajpregu.00532.2011
79. Campbell IG, Darchia N, Higgins LM, et al. Adolescent changes in homeostatic regulation of
EEG activity in the delta and theta frequency bands during NREM sleep. Sleep. 2011;34(1):83–91
PMID: 21203377 doi: 10.1093/sleep/34.1.83
80. Schulz H, Salzarulo P, Fagioli I, Massetani R. REM latency: development in the first year
of life. Electroencephalogr Clin Neurophysiol. 1983;56(4):316–322 PMID: 6193945
doi: 10.1016/0013-4694(83)90257-2
81. Anders TF, Keener M. Developmental course of nighttime sleep-wake patterns in full-term and
premature infants during the first year of life. I. Sleep. 1985;8(3):173–192 PMID: 4048734
doi: 10.1093/sleep/8.3.173
82. Coons S. Development of sleep and wakefulness during the first 6 months of life.
In: Guilleminault C, ed. Sleep and Its Disorders in Children. Raven Press; 1987:7–27

601
83. Yu X, Quante M, Rueschman M, et al. Emergence of racial/ethnic and socioeconomic

differences in objectively measured sleep-wake patterns in early infancy: results of the
Rise & SHINE study. Sleep. 2021;44(3):zsaa193 PMID: 33057653 doi: 10.1093/sleep/zsaa193
84. Biggs SN, Lushington K, James Martin A, van den Heuvel C, Declan Kennedy J. Gender,
socioeconomic, and ethnic differences in sleep patterns in school-aged children. Sleep Med.
2013;14(12):1304–1309 PMID: 24074692 doi: 10.1016/j.sleep.2013.06.014
85. Spilsbury JC, Storfer-Isser A, Drotar D, et al. Sleep behavior in an urban US sample of
school-aged children. Arch Pediatr Adolesc Med. 2004;158(10):988–994 PMID: 15466688
doi: 10.1001/archpedi.158.10.988
86. Chen S, Alers-Rojas F, Benner A, Gleason M. Daily experiences of discrimination and
ethnic/racial minority adolescents’ sleep: the moderating role of social support. J Res Adolesc.
2021 PMID: 34850482 doi: 10.1111/jora.12693
87. Sándor P, Szakadát S, Bódizs R. Ontogeny of dreaming: a review of empirical studies.
Sleep Med Rev. 2014;18(5):435–449 PMID: 24629827 doi: 10.1016/j.smrv.2014.02.001
88. Schredl M, Fricke-Oerkermann L, Mitschke A, Wiater A, Lehmkuhl G. Longitudinal study of
nightmares in children: stability and effect of emotional symptoms. Child Psychiatry Hum Dev.
2009;40(3):439–449 PMID: 19280336 doi: 10.1007/s10578-009-0136-y

CHAPTER
33
Obstructive Sleep Apnea Syndrome
Courtney M. Quinlan, DO, MS
Suzanne E. Beck, MD
Introduction
Obstructive sleep apnea syndrome (OSAS) in children is a sleep-related
breathing disorder characterized by partial and/or complete upper airway
obstruction that disrupts sleep architecture and normal ventilation during
sleep.1 It is a relatively common condition that, if left untreated, increases
morbidity and decreases quality of life in affected children.2
Guidelines published in 2012 by the American Academy of Pediatrics (AAP)
provide a structured outline of how primary care providers and pediatric
specialists may best screen, diagnose, manage, and treat pediatric patients
with OSAS.2 Although the knowledge surrounding pediatric OSAS has
expanded since the publication of these guidelines, many unanswered
questions remain, allowing for significant research opportunities.
Epidemiology of OSAS in Children

The prevalence of pediatric OSAS is estimated to be between 1% and 5%
of school-aged children.3 Risk factors include obesity, tobacco exposure,
and low family income.4,5
Although OSAS affects children of all ages, peak prevalence occurs between
the ages of 2 and 8 years, correlating with the peak of adenotonsillar size in
relation to the airway.6 In children younger than 2 years, an increased inci-
dence of OSAS is associated with male sex, trisomy 21, preterm birth, and
child care attendance.7 Other processes, such as craniofacial abnormalities,
neuromuscular disorders, and genetic and inflammatory conditions, also
predispose children to OSAS.
Pathophysiology
The pathophysiology of childhood OSAS is best conceptualized as the
classic triad depicting the interrelationship of upper airway narrowing,
reduced upper airway tone, and other factors such as obesity, genetics, and
603

604
metabolism (Box 33-1). Adenotonsillar hypertrophy is the most common

cause of OSAS in children, but other causes of upper airway narrowing may
also predispose a child to OSA, including craniofacial abnormalities such as
retrognathia, micrognathia, midface hypoplasia, and macroglossia. Children
with a more collapsible upper
Box 33‑1
airway are also at a higher risk
Factors Contributing to Obstructive for OSAS. Specific factors such
Sleep Apnea Syndrome as upper airway hypotonia,
ū Upper airway narrowing neuromotor weakness, and
• Adenotonsillar hypertrophy inflammation increase the
• Craniofacial structure collapsibility of a child’s upper
• Obesity airway. The combination of
upper airway narrowing and
ū Abnormal upper airway neuromotor tone
increased collapsibility may be
ū Genetic factors
present in a variety of disease
ū Hormonal factors processes, as discussed later
ū Obesity in this chapter.6,8
The 2012 AAP guidelines on the diagnosis and management of childhood
obstructive sleep apnea syndrome recommend that all children should be
screened for snoring by their general health care provider.2 Children who
habitually snore should undergo a focused evaluation for further signs and
symptoms associated with OSAS. Although snoring does not reliably pre-
dict whether a child has OSAS, almost all children with OSAS do snore.9,10
It should be noted that children and infants with cleft palate or muscle
weakness may not snore or may not be heard and, therefore, snoring may
be underreported. Although a physical examination may be helpful in eval-
uating children who would benefit from a polysomnographic study, such as
children with tonsillar hypertrophy, it is important to note that there are not
always significant physical examination findings in children with OSAS.
If the focused examination raises concern regarding OSAS, particularly inat-
tention or behavioral problems, providers should obtain a polysomnogram
or refer the patient to a sleep specialist for a more comprehensive evaluation.
Nonspecific examination findings include adenoidal facies, high arched palate,
micrognathia, retrognathia, large tongue, adenotonsillar hypertrophy, nasal
obstruction, abnormal muscle tone, and signs of right-sided heart failure. If
a child or parent does not report snoring, it is important to continue to screen
the child at each well visit since snoring may develop.
In addition to screening otherwise healthy appearing children for snoring and
other sleep-related symptoms, the pediatrician should ask about the child’s
daytime functioning. Younger children with OSAS may exhibit daytime

605
Chapter 33—Obstructive Sleep Apnea Syndrome
hyperactivity or behavioral problems,11 which often result in poor school

performance and difficulty paying attention. In teenagers, poor sleep quality
due to OSAS may result in daytime hyperactivity, but it also may resemble
the daytime sleepiness seen more frequently in adult populations.12
Children with obesity are particularly susceptible to OSAS. In 2011–2012,
16.9% of children aged 2 to 19 years had obesity.13 Children with obesity
who have OSAS have a higher risk of developing metabolic syndrome and
cardiovascular complications than do children with either condition individu-
ally. Though the cause of OSAS in children with obesity is multifactorial,
adenotonsillectomy should be considered in conjunction with weight loss
when adenotonsillar hypertrophy is present.
If a child is at high risk for OSAS and has a significant comorbidity (genetic
syndrome, neuromuscular disease, preterm infant, craniofacial abnormality),
the child should be referred to a pediatric sleep medicine specialist for
further evaluation.
OSAS in Special Populations

OSAS in Infants and Young Children
Obstructive sleep apnea syndrome in the infant population is distinct from
OSAS in older children. The infant airway structure and chest wall mechanics
predispose the infant to paradoxical breathing and intermittent hypoxemia,
which may mimic or intensify OSAS. Further, an increased amount of REM
sleep normally found in infants places them at heightened risk to develop
OSAS. Obstructive sleep apnea syndrome in infants is often associated with
comorbidities, such as genetic syndromes, failure to thrive, and prematurity.14
Unlike older children who often have obesity, infants and young children with
OSAS may have failure to thrive. This may be due to increased metabolic
demands secondary to untreated OSA.
Polysomnographic scoring in infants is problematic. In adults, an apnea or
a hypopnea is scored if its duration is 10 seconds or longer. Because of the
faster respiratory rate in children, an apnea in a child is scored if the child
misses 2 breaths.15 However, with the even faster respiratory rate of infants,
2 missed breaths represents only 2 to 3 seconds and may have no physiological
consequences. The increased compliance of the infant’s chest wall may lead
to paradoxical respirations, particularly in REM sleep, which is completely
normal. Thus, the physician must review the polysomnographic study findings
in infants with even greater care. Infants with mild OSAS, without hypercap-
nia or hypoventilation, may be managed with supplemental oxygen or simply
observation, while those with moderate to severe OSAS may benefit from
positive airway pressure (PAP) therapy or surgical intervention.16

606
Preterm infants are at higher risk of developing sleep-disordered breathing and

OSAS compared to those born at term because of risk factors such as immature
control of breathing, decreased upper airway muscle tone, and small upper air-
way caliber.17 In addition, infants with lung disease, such as bronchopulmonary
dysplasia, are at higher risk for OSAS because of increased work of breathing
and a propensity for oxyhemoglobin desaturation as a result of their position
on the oxyhemoglobin desaturation curve.18 Some preterm infants with severe
OSAS may need tracheostomy and/or noninvasive positive pressure ventilation
to overcome their upper airway obstruction.
OSAS in Genetic Conditions

Numerous genetic conditions, particularly those that affect upper airway
anatomy and/or compliance, may increase the risk of developing OSAS.
Some examples include trisomy 21, craniofacial abnormalities, sickle cell
disease, and neuromuscular disease.
The prevalence of OSAS in children with trisomy 21 is high, with some esti-
mates reaching 50% to 100%.19,20 Individuals with trisomy 21 have numerous
risk factors for OSAS, including hypotonia, midface hypoplasia, mandibular
hypoplasia, a small upper airway with superficially positioned tonsils, and
obesity. Most children with trisomy 21 benefit from adenotonsillectomy as a
first line of treatment despite other risk factors.21,22 Given the high prevalence
of OSAS in children with trisomy 21 and presentation with atypical symptoms,
the AAP recommends full overnight polysomnography by the age of 4 years.23
Patients with craniofacial abnormalities are also at a higher risk of develop-
ing OSAS, though they may not exhibit typical sleep-disordered breathing
symptoms such as snoring, daytime fatigue, or hyperactivity.24
Anatomic abnormalities may include mandibular hypoplasia, cleft palate,
retrognathia, micrognathia, midface hypoplasia, craniosynostosis, and head
and neck tumors, among others. The first line of treatment in patients with
craniofacial abnormalities is surgical correction of the underlying defect.
If this is not possible because of the patient’s age, the need for multistaged
surgery, or other reasons, the patient may respond to medical management,
noninvasive ventilation, and, rarely, tracheostomy. These children benefit
from referral to a multidisciplinary subspecialty team including speech
therapists, otolaryngologists, audiologists, plastic surgeons, pediatric
sleep or pediatric pulmonary physicians, and orthodontists.
Children with neuromuscular disease may have both upper airway obstruction
and nocturnal hypoventilation due to coexisting decreased respiratory drive,25
diffuse muscular weakness, and associated pharyngeal muscle weakness.
There is a bimodal presentation of sleep-related breathing disorders in patients
with Duchenne muscular dystrophy (DMD), with OSA found in the first
decade of life and hypoventilation more commonly seen at the beginning of

607
the second decade.26 Almost all children with DMD will develop nocturnal
hypoventilation and go on to require nocturnal positive pressure ventilation,
though this may soon change given new targeted biologics. Often, these chil-
dren experience nonobstructive nocturnal hypoventilation prior to demon-
strating any daytime symptoms. For patients with neuromuscular weakness,
polysomnography for sleep-disordered breathing should be considered when
the partial pressure of carbon dioxide (Paco2) is 45 mm Hg or higher on
arterial blood gas.27 The 2004 American Thoracic Society consensus state-
ment regarding respiratory care of patients with DMD recommends a review
of sleep quality and symptoms of sleep-disordered breathing at every patient
encounter, as well as annual polysomnography with continuous carbon dioxide
(CO2) monitoring from the time the patient is using a wheelchair or when
clinically indicated.28
Diagnosis
Polysomnography
Obstructive sleep apnea syndrome should be distinguished from primary snor-
ing, central apnea, fixed upper airway obstruction, nonobstructive alveolar
hypoventilation, and sleep-related epilepsy.29 Polysomnography is the gold
standard for diagnosing OSAS in the pediatric population.2
It is important to keep in mind that OSAS is the clinical syndrome associated
with repeated upper airway obstruction with interrupted sleep, and thus the
polysomnographic findings should always be put into clinical context. The
International Classification of Sleep Disorders, 3rd Edition,29 defines
pediatric OSAS as requiring all of the following:
A. Caregiver reports snoring, labored and/or obstructive breathing;
B. Caregiver reports observing at least one of the following:
paradoxical inward ribcage motion during inspiration, move-
ment arousals, diaphoresis, neck hyperextension, excessive
sleepiness, hyperactivity or aggressive behavior, slow rate of
growth, morning headaches, secondary enuresis;
C. Polysomnographic recording demonstrating one or more score-
able obstructive hypopnea or obstructive apnea per hour with at
least one of the following: frequent arousals from sleep associated
with increased respiratory effort, arterial oxygen desaturations
associated with apneas, hypercapnia during sleep, or markedly
abnormal esophageal pressure swings; or periods of hypercapnia,
desaturation, or both associated with snoring, paradoxical inward
ribcage motion during inspiration with frequent arousals or
esophageal pressure swings; and
D. The disorder is not better explained by another disorder,
medications, or substance.

608
Note that clinical signs and symptoms as well as polysomnographic findings

are required to establish the diagnosis. There are limited data to support the
apnea-hypopnea index (AHI, the number of respiratory events per hour of
sleep) with 1 as a cutoff. A total AHI less than 1.5 is often used to define a
statistical norm, and complications of OSA such as elevated blood pressure
are usually not seen at an AHI less than 5.30,31
In comparison to adult polysomnography, pediatric polysomnography also
measures carbon dioxide, uses video monitoring, and scores arousals with
respiratory events. Carbon dioxide is monitored using end-tidal CO2, transcu-
taneous CO2, or both to identify hypoventilation since prolonged partial upper
airway obstruction with hypoventilation is not uncommon in children. For the
purposes of polysomnography, hypoventilation is defined as Paco2 50 mm Hg
or greater for at least 25% of sleep time.30 Short central pauses in breathing
can be physiologically normal in children. Central apneas are not scored
unless they are greater than 20 seconds or at least the duration of 2 missed
breaths followed by arousal, desaturation, or bradycardia. The pulse oximeter
used in a sleep laboratory is typically more sensitive, with shorter averaging
times compared to those with blood oxygen saturation (SpO2) monitors used
on the hospital floors or at home. Figure 33-1 depicts a typical 2-minute
polysomnographic epoch of rapid eye movement (REM) sleep, with obstruc-
tive apnea resulting in oxyhemoglobin desaturations, hypercapnia, and
arousals.
Although it is the gold standard, in-laboratory polysomnography is expensive
and requires experienced technicians. In addition, access to polysomnography
is often limited because of the scarcity of pediatric tertiary care centers. Inter-
pretation of polysomnographic findings in children must be done by a sleep
professional using pediatric scoring criteria, as adult criteria miss 80% of
Figure 33-1. Polysomnogram: 2-minute epoch of rapid eye movement sleep shows obstructive
apnea with intermittent oxyhemoglobin desaturation, hypercapnia, and arousal in a 3-year-old
girl with adenotonsillar hypertrophy.

609
pediatric OSAS.32 The American Academy of Sleep Medicine requires that

pediatric criteria be used at least until the age of 13 years.33
Upper Airway Imaging

Upper airway imaging may be helpful to assess patients with complicated
upper airway anatomy and residual OSA. It is important to note that no upper
airway imaging modality can replace polysomnography in the diagnosis of
OSA; it can, however, be useful to direct treatment.
Lateral neck radiographs are useful to visualize the upper airway from
the nasopharynx to the upper thoracic trachea. They allow the evaluation
of the adenoids, tonsils, and prevertebral soft tissue’s effect on the airway.
Radiographs are easily obtained and relatively inexpensive, with low radiation
exposure, but they are not usually needed in routine evaluation of pediatric
OSAS. However, they can be helpful to assess adenoid regrowth.
Axial computed tomography (CT) is a quick, easily available mode of assess-
ing the 3-dimensional structure of the upper airway. This modality is ideal for
identifying soft tissue and bony abnormalities. Cone-beam CT is a technique
within CT that is much faster and uses less radiation than a conventional CT
scan. Dynamic 3-dimensional CT is another type of CT that creates a dyna-
mic, 3-dimensional image of the upper airway. However, young patients
may require sedation.
Magnetic resonance imaging (MRI) creates a 3-dimensional image of the
patient’s upper airway without exposing the child to ionizing radiation. It
allows precise measurement of the bony structures and soft tissues of the
upper airway. Unfortunately, MRI often requires sedation, which may alter
the collapsibility of a child’s upper airway.
Drug-Induced Sleep Endoscopy

Drug-induced sleep endoscopy (DISE) is a technique used to evaluate
collapsibility of the upper airway during periods of simulated sleep, allow-
ing the physician to directly visualize the area of upper airway obstruction
and therefore allowing individualization of surgical management.34 DISE
is typically indicated for children who have persistent OSA after adenotonsil-
lectomy, those with OSA but without tonsillar hypertrophy, children with
risk factors predisposing to multiple sites of obstruction, or when sleep-state–
dependent laryngomalacia is suspected.35 Like MRI, DISE requires sedation,
which may alter the upper airway anatomy and collapsibility.
Home Sleep Apnea Tests

The home sleep apnea test (HSAT) is a widely used resource among the adult
population to diagnose OSAS. The HSAT is a simplified monitoring system
that tracks parameters such as nasal air flow, oxyhemoglobin saturation, and

610
breathing effort overnight. It allows patients to complete a sleep study from

their home. Unfortunately, since the HSAT measures fewer variables than
in-lab polysomnography, there may be an underestimation of the severity
or presence of OSA. The American Academy of Sleep Medicine guidelines
released in 2017 stated that the use of an HSAT is not recommended for
diagnosis of OSAS in children.36 Previous studies have demonstrated that use
of the HSAT is technically feasible when trained clinicians are placing the
electrodes; however, the probability of these tests being successful is less
likely when the patient’s caregivers place the electrodes.37 The HSAT is
discussed more fully in Chapter 34, Sleep Testing in the Laboratory or Home.
Pediatric polysomnography not only confirms the diagnosis of OSA but also
establishes the severity of the disease. Children with severe OSA are less
likely to be cured with adenotonsillectomy38 and are at higher risk for peri-
operative respiratory complications.39 Therefore, children with severe OSA
should be treated and observed in a facility where pediatric intensive care is
available if needed.
Genetics
There is evidence of specific genetic markers among adults with OSAS.40
Research is emerging on the genetic landscape of pediatric OSAS.41 The
biologic relevance of specific genes may suggest the utility of novel
therapies to treat the underlying cause of OSAS.
Management and Treatment

Adenotonsillectomy
Adenotonsillectomy is generally considered the first line of treatment for
pediatric OSAS2 and usually results in remission of symptoms and normaliza-
tion of the AHI in mild to moderate cases.38 A large, randomized, single-blind
study showed that adenotonsillectomy resulted in improved behavior, quality
of life, and polysomnographic findings compared to “watchful waiting” but
did not significantly improve objective scores of attention and executive
function on neuropsychological testing.42
As in all surgeries, notable postoperative complications may arise from adeno-
tonsillectomy. Postoperative respiratory complications occur in 1.4% to 5% of
adenotonsillectomies.39 Early complications may include pulmonary edema,
laryngospasm, bronchospasm, hypoxemia, and hypercapnia. Late complica-
tions include dehydration and tonsillar bleeding. A prospective study of consec-
utive children undergoing adenotonsillectomy for OSAS within 12 months of
preoperative polysomnography showed that age younger than 3 years, SpO2
nadir less than 80%, SpO2 less than 90% for more than 1.1% of total sleep
time, and peak CO2 60 mm Hg or greater predicted early respiratory complica-
tions in a high-risk population.39

611
Because of the complex pathophysiology of OSA, residual OSA may exist

after surgical intervention or it may recur later in adolescence.8 Therefore, it is
best to view the underlying cause of OSAS in children as a dynamic process
resulting from a combination of structural and neuromotor abnormalities,
rather than from structural abnormalities alone.6 Follow-up for patients with
severe OSA or persistent symptoms is essential.
Positive Airway Pressure Therapy

If adenotonsillectomy is not effective or is not desired by the family or the
physician, PAP therapy may be effective. PAP is delivered through a mask
interface, which provides a “pneumatic splint” to maintain a patent upper
airway at the site of the obstruction by increasing the intraluminal pressure
to exceed the pressure at which there is pharyngeal collapse.1
Multiple types of PAP devices are available, including continuous positive
airway pressure, automatic positive airway pressure, bilevel positive airway
pressure, and average volume-assured pressure support. Continuous positive
airway pressure delivers a constant pressure from the machine to the patient’s
upper airway. This pressure usually ranges from 4 cm H20 to 20 cm H20 in
the pediatric population.
Automatic positive airway pressure, which is widely used in adults, may be
effective in a wide range of age groups, including infants.16,43 However, the
algorithms are proprietary and were developed for adults. The physician may
set a range of expiratory PAP settings, and the machine auto-titrates (based
on these proprietary algorithms) to the patient’s needs, maintaining a patent
airway while asleep. These devices seem to deliver pressures similar to those
derived from titration polysomnography, but because the algorithms were
derived for adults, there remains some concern about using them for
small children.
Average volume-assured pressure support works by delivering a range of
pressures (inspiratory PAP range and expiratory PAP range) with a set backup
rate to hit a specific target tidal volume with each breath; it should be reserved
for pediatric patients with difficult-to-treat OSAS and other lung pathologies.
If a decision is made to initiate PAP therapy in a child, the patient should
undergo a comprehensive evaluation, including interface fitting and demon-
stration of placing mask and headgear, education regarding the home machine,
detailed assessment of bedtime routine and sleep habits, rationale for PAP
therapy, expectations for use, and available support. Parental understanding
and cooperation are essential. Techniques to enhance adherence include
modeling and/or desensitization. This evaluation can be done on an outpatient
basis unless the child is very young, is medically fragile, or has severe gas
exchange abnormalities, in which case inpatient initiation should be consid-
ered. Close follow-up should occur to ensure that the patient is using and

612
benefiting from the PAP and to assess for side effects. Once the patient is
accustomed to the PAP therapy, they should undergo a PAP titration study to
ensure that therapeutic pressures have been reached.
Medications and Oral Appliance

Other methods of treatment include intranasal corticosteroids, oral anti-
leukotrienes, and oral appliances. For children with moderate to severe
adenoidal hypertrophy, intranasal corticosteroids may be beneficial in reduc-
ing the size of adenoidal tissue and improving OSAS.44 Oral antileukotriene
modifiers are also associated with improved breathing during sleep in patients
with mild OSAS.45 Though the benefits of oral leukotrienes and intranasal
steroids are widely accepted, there are conflicting reports as to the long-term
effects of anti-inflammatory medications with respect to efficacy and safety.
Oral appliances are another management option for children with OSA.
Though data are limited in children, oral appliances are effective in adults with
mild-to-moderate OSA.46 Because maxillary transverse deficiency (crossbite)
is often seen in children with OSAS, pediatric oral appliances usually focus on
rapid maxillary expansion. Rapid maxillary expansion increases the transverse
dimension of the upper arch as well as buccal movement of the posterior teeth
and alveolar processes. Multiple small studies have demonstrated a reduction
in OSAS severity after patients underwent this intervention; it may be a good
option for children with this orthodontic pathology, particularly if they are
nonadherent with PAP. The orthodontist must be experienced with the
procedure and be comfortable dealing with children.47,48
Sequelae of Untreated OSAS

Consequences of untreated or unrecognized OSAS include neurocognitive
deficits, behavioral problems, and cardiovascular and metabolic risks. Chil-
dren with untreated OSAS have a higher prevalence of daytime hyperactivity,11
poor school performance, and nocturnal enuresis.31,49,50 Up to one-third of chil-
dren with OSAS or loud frequent snoring may demonstrate characteristics
associated with hyperactivity and inattentiveness.51 Children who underwent
adenotonsillectomy have demonstrated improved attention and reduced
hyperactivity postoperatively.52
Children with OSAS are at increased risk for hypertension.31,53 Right heart
failure and pulmonary hypertension are well-documented outcomes of
OSAS.54 In addition to cardiovascular comorbidities, children with OSAS
have a higher incidence of metabolic syndrome. Specifically, they are at
greater risk of developing insulin resistance and dyslipidemias. These asso-
ciations not only increase morbidity and mortality in children with OSAS,
but they also increase their health care utilization.55

613
key points
} Obstructive sleep apnea syndrome is characterized by partial and/or complete
upper airway obstruction that disrupts sleep architecture and normal ventilation
during sleep.
} The prevalence of OSAS is approximately 1% to 5%, with peak prevalence
between 2 and 8 years of age.
} The gold standard for diagnosis of OSAS is polysomnography.
} AAP guidelines from 2012 recommend that all children should be screened for
snoring by their pediatrician at every well visit.
} Adenotonsillectomy is the most common initial treatment for children
with OSAS.
} Children with severe OSAS should undergo close perioperative monitoring.
} Medical treatments for OSAS include positive airway pressure, anti-inflammatory
medications, and oral appliances.
} Consequences of untreated or unrecognized OSAS include neurocognitive
deficits, behavioral problems, and cardiovascular and metabolic risks.
} Special attention should be given to specific populations such as infants,
preterm infants, and patients with trisomy 21, craniofacial abnormalities,
and neuromuscular disease.
References
1. Section on Pediatric Pulmonology, Subcommittee on Obstructive Sleep Apnea Syndrome.
American Academy of Pediatrics. Clinical practice guideline: diagnosis and management of
childhood obstructive sleep apnea syndrome. Pediatrics. 2002;109(4):704–712 PMID: 11927718
doi: 10.1542/peds.109.4.704
2. Marcus CL, Brooks LJ, Draper KA, et al; American Academy of Pediatrics. Diagnosis and
management of childhood obstructive sleep apnea syndrome. Pediatrics. 2012;130(3):576–584
PMID: 22926173 doi: 10.1542/peds.2012-1671
3. Bixler EO, Vgontzas AN, Lin HM, et al. Sleep disordered breathing in children in a general
population sample: prevalence and risk factors. Sleep. 2009;32(6):731–736 PMID: 19544748
doi: 10.1093/sleep/32.6.731
4. Redline S, Tishler PV, Schluchter M, Aylor J, Clark K, Graham G. Risk factors for sleep-
disordered breathing in children: associations with obesity, race, and respiratory problems.
Am J Respir Crit Care Med. 1999;159(5):1527–1532 PMID: 10228121 doi: 10.1164/
ajrccm.159.5.9809079
5. Mitchell RB, Kelly J. Outcome of adenotonsillectomy for obstructive sleep apnea in obese and
normal-weight children. Otolaryngol Head Neck Surg. 2007;137(1):43–48 PMID: 17599563
doi: 10.1016/j.otohns.2007.03.028
6. Marcus CL. Sleep-disordered breathing in children. Am J Respir Crit Care Med.
2001;164(1):16–30 PMID: 11435234 doi: 10.1164/ajrccm.164.1.2008171
7. Côté V, Ruiz AG, Perkins J, Sillau S, Friedman NR. Characteristics of children under 2 years of
age undergoing tonsillectomy for upper airway obstruction. Int J Pediatr Otorhinolaryngol.
2015;79(6):903–908 PMID: 25912628 doi: 10.1016/j.ijporl.2015.04.003
8. Guilleminault C, Partinen M, Praud JP, Quera-Salva MA, Powell N, Riley R. Morphometric
facial changes and obstructive sleep apnea in adolescents. J Pediatr. 1989;114(6):997–999
PMID: 2723918 doi: 10.1016/S0022-3476(89)80447-0

614
9. Nieminen P, Tolonen U, Löppönen H. Snoring and obstructive sleep apnea in children: a 6-month
follow-up study. Arch Otolaryngol Head Neck Surg. 2000;126(4):481–486 PMID: 10772301
doi: 10.1001/archotol.126.4.481
10. Mitchell RB. Adenotonsillectomy for obstructive sleep apnea in children: outcome evaluated
by pre- and postoperative polysomnography. Laryngoscope. 2007;117(10):1844–1854
PMID: 17721406 doi: 10.1097/MLG.0b013e318123ee56
11. O’Brien LM, Holbrook CR, Mervis CB, et al. Sleep and neurobehavioral characteristics of
5- to 7-year-old children with parentally reported symptoms of attention-deficit/hyperactivity
disorder. Pediatrics. 2003;111(3):554–563 PMID: 12612236 doi: 10.1542/peds.111.3.554
12. Owens JA, Babcock D, Weiss M. Evaluation and treatment of children and adolescents with
excessive daytime sleepiness. Clin Pediatr (Phila). 2020;59(4-5):340–351 PMID: 32167377
doi: 10.1177/0009922820903434
13. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity
in the United States, 2011-2012. JAMA. 2014;311(8):806–814 PMID: 24570244
doi: 10.1001/jama.2014.732
14. Qubty WF, Mrelashvili A, Kotagal S, Lloyd RM. Comorbidities in infants with obstructive sleep
apnea. J Clin Sleep Med. 2014;10(11):1213–1216 PMID: 25325583 doi: 10.5664/jcsm.4204
15. American Thoracic Society. Standards and indications for cardiopulmonary sleep studies
in children. Am J Respir Crit Care Med. 1996;153(2):866–878 PMID: 8564147
doi: 10.1164/ajrccm.153.2.8564147
16. Cielo CM, Hernandez P, Ciampaglia AM, Xanthopoulos MS, Beck SE, Tapia IE. Positive airway
pressure for the treatment of OSA in infants. Chest. 2021;159(2):810–817
17. Arens R, Marcus CL. Pathophysiology of upper airway obstruction: a developmental
perspective. Sleep. 2004;27(5):997–1019 PMID: 15453561 doi: 10.1093/sleep/27.5.997
18. McGrath-Morrow SA, Ryan T, McGinley BM, Okelo SO, Sterni LM, Collaco JM.
Polysomnography in preterm infants and children with chronic lung disease. Pediatr Pulmonol.
2012;47(2):172–179 PMID: 21815283 doi: 10.1002/ppul.21522
19. Maris M, Verhulst S, Wojciechowski M, Van de Heyning P, Boudewyns A. Prevalence of
obstructive sleep apnea in children with Down syndrome. Sleep. 2016;39(3):699–704
PMID: 26612391 doi: 10.5665/sleep.5554
20. Hill CM, Evans HJ, Elphick H, et al. Prevalence and predictors of obstructive sleep apnoea in
young children with Down syndrome. Sleep Med. 2016;27–28:99–106 PMID: 27938928
doi: 10.1016/j.sleep.2016.10.001
21. Maris M, Verhulst S, Wojciechowski M, Van de Heyning P, Boudewyns A. Outcome of
adenotonsillectomy in children with Down syndrome and obstructive sleep apnoea. Arch Dis
Child. 2017;102(4):331–336 PMID: 27484971 doi: 10.1136/archdischild-2015-310351
22. Brooks LJ, Olsen MN, Bacevice AM, Beebe A, Konstantinopoulou S, Taylor HG. Relationship
between sleep, sleep apnea, and neuropsychological function in children with Down syndrome.
Sleep Breath. 2015;19(1):197–204 PMID: 24801138 doi: 10.1007/s11325-014-0992-y
23. Bull MJ; Committee on Genetics. Health supervision for children with Down syndrome.
Pediatrics. 2011;128(2):393–406 PMID: 21788214 doi: 10.1542/peds.2011-1605
24. Cielo CM, Silvestre J, Paliga JT, et al. Utility of screening for obstructive sleep apnea syndrome
in children with craniofacial disorders. Plast Reconstr Surg. 2014;134(3):434e–441e
PMID: 25158720 doi: 10.1097/PRS.0000000000000484
25. Rialp G, Raurich JM, Llompart-Pou JA, Ayestarán I, Ibáñez J. Central respiratory drive in
patients with neuromuscular diseases. Respir Care. 2013;58(3):450–457 PMID: 22780920
doi: 10.4187/respcare.01873
26. Suresh S, Wales P, Dakin C, Harris MA, Cooper DG. Sleep-related breathing disorder in
Duchenne muscular dystrophy: disease spectrum in the paediatric population. J Paediatr Child
Health. 2005;41(9-10):500–503 PMID: 16150067 doi: 10.1111/j.1440-1754.2005.00691.x
27. Hukins CA, Hillman DR. Daytime predictors of sleep hypoventilation in Duchenne muscular
dystrophy. Am J Respir Crit Care Med. 2000;161(1):166–170 PMID: 10619815
doi: 10.1164/ajrccm.161.1.9901057
2004;170(4):456–465 PMID: 15302625 doi: 10.1164/rccm.200307-885ST
29. Sateia MJ. International Classification of Sleep Disorders-Third Edition. Chest.
2014;146:1387–1394 PMID: 25367475 doi: 10.1378/chest.14-0970
30. Brooks DM, Brooks LJ. Reevaluating norms for childhood obstructive sleep apnea. J Clin Sleep
Med. 2019;15(11):1557–1558 PMID: 31739843 doi: 10.5664/jcsm.8066

615
31. Brooks DM, Kelly A, Sorkin JD, et al. The relationship between sleep-disordered breathing,
blood pressure, and urinary cortisol and catecholamines in children. J Clin Sleep Med.
2020;16(6):907–916 PMID: 32043963 doi: 10.5664/jcsm.8360
32. Rosen CL, D’Andrea L, Haddad GG. Adult criteria for obstructive sleep apnea do not
identify children with serious obstruction. Am Rev Respir Dis. 1992;146(5 pt 1):1231–1234
PMID: 1443876 doi: 10.1164/ajrccm/146.5_Pt_1.1231
33. 33. Berry RB, Quan S, Abreu A, et al. The AASM Manual for the Scoring of Sleep and
Associated Events: Rules, Terminology and Technical Specifications. American Academy of
Sleep Medicine; 2015.
34. Truong MT, Woo VG, Koltai PJ. Sleep endoscopy as a diagnostic tool in pediatric obstructive
sleep apnea. Int J Pediatr Otorhinolaryngol. 2012;76(5):722–727 PMID: 22421163
doi: 10.1016/j.ijporl.2012.02.028
35. Wilcox LJ, Bergeron M, Reghunathan S, Ishman SL. An updated review of pediatric
drug-induced sleep endoscopy. Laryngoscope Investig Otolaryngol. 2017;2(6):423–431
PMID: 29299518 doi: 10.1002/lio2.118
36. Kirk V, Baughn J, D’Andrea L, et al. American Academy of Sleep Medicine position paper for
the use of a home sleep apnea test for the diagnosis of OSA in children. J Clin Sleep Med.
2017;13(10):1199–1203 PMID: 28877820 doi: 10.5664/jcsm.6772
37. Marcus CL, Traylor J, Biggs SN, et al. Feasibility of comprehensive, unattended ambulatory
polysomnography in school-aged children. J Clin Sleep Med. 2014;10(8):913–918
PMID: 25126039 doi: 10.5664/jcsm.3970
38. 38. Suen JS, Arnold JE, Brooks LJ. Adenotonsillectomy for the treatment of obstructive sleep
apnea in children. Arch Otolaryngol Head Neck Surg. 1995;121(5):525–530
39. Thongyam A, Marcus CL, Lockman JL, et al. Predictors of perioperative complications in
higher risk children after adenotonsillectomy for obstructive sleep apnea: a prospective study.
Otolaryngol Head Neck Surg. 2014;151(6):1046–1054 PMID: 25301788 doi:
10.1177/0194599814552059
40. Cade BE, Chen H, Stilp AM, et al. Genetic associations with obstructive sleep apnea traits in
Hispanic/Latino Americans. Am J Respir Crit Care Med. 2016;194(7):886–897 PMID: 26977737
doi: 10.1164/rccm.201512-2431OC
41. Quinlan CM, Chang X, March M, et al. Identification of novel loci in obstructive sleep apnea in
European American and African American children. Sleep. 2022;zsac182. PMID: 35902206 doi:
10.1093/sleep/zsac182
42. Marcus CL, Moore RH, Rosen CL, et al; Childhood Adenotonsillectomy Trial (CHAT).
A randomized trial of adenotonsillectomy for childhood sleep apnea. N Engl J Med.
2013;368(25):2366–2376 PMID: 23692173 doi: 10.1056/NEJMoa1215881
43. Palombini L, Pelayo R, Guilleminault C. Efficacy of automated continuous positive airway
pressure in children with sleep-related breathing disorders in an attended setting. Pediatrics.
2004;113(5):e412–e417 PMID: 15121982 doi: 10.1542/peds.113.5.e412
44. Kheirandish-Gozal L, Gozal D. Intranasal budesonide treatment for children with mild
obstructive sleep apnea syndrome. Pediatrics. 2008;122(1):e149–e155 PMID: 18595959
doi: 10.1542/peds.2007-3398
45. Goldbart AD, Greenberg-Dotan S, Tal A. Montelukast for children with obstructive sleep apnea:
a double-blind, placebo-controlled study. Pediatrics. 2012;130(3):e575–e580 PMID: 22869829
doi: 10.1542/peds.2012-0310
46. Doff MHJ, Hoekema A, Wijkstra PJ, et al. Oral appliance versus continuous positive airway
pressure in obstructive sleep apnea syndrome: a 2-year follow-up. Sleep. 2013;36(9):1289–1296
PMID: 23997361 doi: 10.5665/sleep.2948
47. Cistulli PA, Palmisano RG, Poole MD. Treatment of obstructive sleep apnea syndrome by rapid
maxillary expansion. Sleep. 1998;21(8):831–835 PMID: 9871945 doi: 10.1093/sleep/21.8.831
48. Pirelli P, Saponara M, Guilleminault C. Rapid maxillary expansion in children with obstructive
sleep apnea syndrome. Sleep. 2004;27(4):761–766 PMID: 15283012 doi: 10.1093/sleep/27.4.761
49. Brooks LJ, Topol HI. Enuresis in children with sleep apnea. J Pediatr. 2003;142(5):515–518
PMID: 12756383 doi: 10.1067/mpd.2003.158
50. Suratt PM, Barth JT, Diamond R, et al. Reduced time in bed and obstructive sleep-disordered
breathing in children are associated with cognitive impairment. Pediatrics. 2007;119(2):320–329
PMID: 17272622 doi: 10.1542/peds.2006-1969
51. Ali NJ, Pitson DJ, Stradling JR. Snoring, sleep disturbance, and behaviour in 4-5 year olds.
Arch Dis Child. 1993;68(3):360–366 PMID: 8280201 doi: 10.1136/adc.68.3.360
52. Ali NJ, Pitson D, Stradling JR. Sleep disordered breathing: effects of adenotonsillectomy on
behaviour and psychological functioning. Eur J Pediatr. 1996;155(1):56–62 PMID: 8750813
doi: 10.1007/BF02115629

616
53. Marcus CL, Greene MG, Carroll JL. Blood pressure in children with obstructive
sleep apnea. Am J Respir Crit Care Med. 1998;157(4):1098–1103 PMID: 9563725
doi: 10.1164/ajrccm.157.4.9704080
54. Yilmaz MD, Onrat E, Altuntaş A, et al. The effects of tonsillectomy and adenoidectomy on
pulmonary arterial pressure in children. Am J Otolaryngol. 2005;26(1):18–21 PMID: 15635576
doi: 10.1016/j.amjoto.2004.06.008
55. Tarasiuk A, Greenberg-Dotan S, Simon-Tuval T, et al. Elevated morbidity and health care use in
children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 2007;175(1):55–61
PMID: 17038661 doi: 10.1164/rccm.200604-577OC

CHAPTER
34
Sleep Testing in the Laboratory and Home
Deborah M. Brooks, MD
Introduction
Obstructive sleep apnea (OSA) is a disorder in which breathing starts and
stops repeatedly during sleep. Apneas, the cessation of breathing, can be
classified as either obstructive or central, depending on where the breathing
dysregulation originates. This chapter will briefly mention central sleep apnea
but will primarily focus on OSA in children.
Obstructive respiratory sleep disorders represent a continuum, ranging from
habitual, primary snoring (regular, non-pathologic) to OSA.1 Primary snoring,
as distinguished from OSA, is defined as snoring without significant obstruc-
tive apneas, frequent arousals from sleep, or gas exchange abnormalities. In
contrast, OSA is sleep characterized by recurrent episodes of complete or
partial airway obstruction associated with arousals, awakenings, and/or
oxyhemoglobin desaturation.2–5
Obstructive sleep apnea is the most common respiratory sleep abnormality in
children during the first 2 years after birth and is usually worse during rapid
eye movement (REM) sleep.6,7 Obstructive sleep apnea affects 1% to 4% of
children, and the main risk factors include adenotonsillar hypertrophy,
obesity, craniofacial abnormalities, and neuromuscular diseases.8,9 While
OSA occurs in children of all ages, it is thought to be most common in
preschool-aged children because the tonsils and adenoids are the largest in
comparison to the size of their airway. Primary snoring, in contrast, is even
more common and occurs in 3% to 12% of preschool-aged children.10
Children are typically brought to the pediatrician’s office when their parents
or siblings notice noisy breathing, snoring, cessation of breathing, increased
body movements during sleep, or increased nocturnal awakenings.3 Daytime
sleepiness and neurobehavioral problems can also be present.9–11
Obstructive sleep apnea is classified according to its severity, typically denoted
by the Apnea-Hypopnea Index (AHI), which measures the number of respira-
tory events per hour of sleep. The International Classification of Sleep
617

618
Disorders, Third Edition (ICSD-3), defines pediatric OSA as having an AHI 1

or greater or a pattern of obstructive hypoventilation defined as at least 25% of
total sleep time with elevated carbon dioxide (CO2) (Paco2 > 50 mm Hg) in
association with snoring, flattening of the nasal pressure waveform, or paradox-
ical respiratory efforts.6 However, there are few data to support this cutoff, and
a total AHI less than 1.5 is often used as a cutoff. Complications of OSA, such
as elevated blood pressure, are usually not seen at an AHI less than 5.12 Other
factors, notably the depth of hypoxemia, should also be taken into account.
Obstructive sleep apnea in children is associated with significant morbidity
(Box 34-1), which is why it is important to recognize and diagnose the
condition in a timely fashion.1,4,10,11,13 According to the American Academy of
Pediatrics Subcommittee on Obstructive Sleep Apnea, the goals of diagnosis
(Box 34-2) are to identify children at risk for adverse outcomes, avoid unneces-
sary interventions in patients not at risk for adverse outcomes, and evaluate
which children are at risk for complications so that appropriate precautions can
be taken. In children, upper airway obstruction is usually caused by hypertro-
phy of the tonsils and adenoids, and treatment with an adenotonsillectomy is
typically effective.11,14 Severe OSA is associated with increased perioperative
complications and even residual OSA after surgery, so accurate preoperative
assessment of the presence and
Box 34-1
severity of the OSA is imperative.5,15,16
Morbidities Associated With For children who are not surgical
Pediatric Obstructive Sleep Apnea candidates or who do not respond to
Periodic hypoxemia surgery, continuous positive airway
Hypercarbia pressure is an option.10 It is also
Increased respiratory effort important, especially in young
Intrathoracic pressure changes children, to know if central sleep
Neurocognitive impairment apnea is present, as this can change
Behavioral problems management.13 Appropriate treatment
Failure to thrive of OSA can result in improvements in
Cor pulmonale behavior and cognitive abilities.16 (See
Chapter 33, Obstructive Sleep Apnea
Box 34-2 Syndrome.)
Goals of Diagnosis for Diagnosing and monitoring OSA
Obstructive Sleep Apnea is different in children than it is in
Identify patients at risk for adverse adults. There is a plethora of monitor-
outcomes. ing devices (some of which will be
Avoid unnecessary intervention. discussed later in this chapter) that
Evaluate which patients are at risk work very well in adults, but not in
for complications. children. In general, home testing has
Determine if central sleep apneas been shown to be no less accurate
are present.
than in-laboratory polysomnography

619
Chapter 34—Sleep Testing in the Laboratory and Home
(PSG) in adults, but this is not the case in children.11 Children are fundamen-
tally different from adults, and they experience a different kind of OSA. In
children with OSA, partial airway obstruction is more common, and oxygen
desaturation less common, as compared to adults with OSA.2 These episodes
may be missed completely by oximetry-based monitoring.5 Additionally, the
cutoff for clinically significant OSA is higher in adults, thereby eliminating the
need for discrimination between low and very low AHI values.6 Scoring is
also different, as the pediatric scoring criteria allow the option to score an
hypopnea if the event is associated with an arousal, rather than just a 3%
oxygen desaturation, thereby making electroencephalogram (EEG) monitor-
ing essential.5 The lack of EEG or CO2 monitoring on some home testing
options may significantly underestimate the presence and severity of OSA in
children.5 Children also sleep differently and are notably more restless
during sleep, and children with OSA have more movement arousals than
age-matched controls, increasing artifact signal.2 Monitors with leads can pose
a risk of strangulation and entrapment with young children.17 Children are also
generally less tolerant of the machines, and their body habitus, as well as
cognitive and emotional maturity, can vary widely, making it more difficult
to predict who will be able to tolerate the sensors.5 In addition, the first-line
treatment for adults with OSA is continuous positive airway pressure, which is
generally noninvasive, while the treatment in children is usually surgery (See
Box 34-3.) The base-line AHI predicts
Box 34-3
the child’s response to surgery and
Treatment Options for Pediatric perioperative complications, so it is
Obstructive Sleep Apnea important to know the severity, not
Adenotonsillectomy just the presence, of OSA in children.15
Continuous positive airway pressure Home sleep apnea testing has made a
Craniofacial surgery significant impact in adult sleep
Hypoglossal nerve stimulation medicine, but as will be explained in
Tracheostomy this chapter, these results cannot be
extrapolated to children.
Steps in Diagnosis
The first step in evaluating OSA in children is a thorough sleep history and
physical examination. The sleep history should include any report of snoring,
labored breathing, observed apneas, restless sleep, diaphoresis, enuresis,
cyanosis, excessive daytime sleepiness, and behavioral or learning problems.
The best historian is the person who observes the child sleeping on a regular
basis, which may be a sibling who shares a room with the patient. Physical
examination should pay special attention to the anatomy of the pharynx,
including tonsillar size, and a thorough cardiovascular examination. Often-
times, findings on physical examination during wakefulness are normal
or nonspecific related to adenotonsillar hypertrophy. While adenotonsillar

620
hypertrophy is a major risk factor for OSA in children, numerous studies have
shown that there is no relation between the size of the tonsils on inspection
and the presence of OSA; it is the combination of the size and the neuromus-
cular tone of the upper airway that leads to OSA.18 While they add important
information, history and physical examination alone have a poor sensitivity
and specificity in diagnosing sleep apnea. A patient with any of the complica-
tions noted in this text is considered to have obstructive sleep apnea
syndrome.10,15,16
In addition to the standard history and physical examination, several question-
naires have been developed to screen for OSA, although they generally exhibit
low sensitivity and specificity.8 The Clinical Sleep Score is a composite score
derived from the physical examination, subjective symptoms, and clinical
history. This combination has been shown to correlate relatively well with
AHI on PSG.4 The overall performance of questionnaires supports their use
more as a screening tool than as a diagnostic agent, such that a negative score
would be unlikely to mislabel a child with OSA as being healthy, but a
positive score would be unlikely to accurately diagnose a particular
child with certainty.16
In-Laboratory PSG
An overnight in-laboratory polysomnogram is the gold standard for diagnos-
ing OSA in children.1,4,5,7–10 In-laboratory polysomnograms are preferred for
children because the test provides an objective measure of disturbances in
respiratory parameters and sleep architecture, can differentiate habitual snor-
ing from sleep apneas while determining the severity of the apneas, and can
differentiate OSA from other sleep disorders, including movement disorders
and parasomnias.4 (See Chapter 35, Sleep-Related Movement Disorders,
and Chapter 37, Parasomnias.) Polysomnography includes simultaneous
recordings of EEG, electro-oculogram, electrocardiogram, submental and leg
electromyogram, oronasal thermistor, nasal pressure, thoracic and abdominal
wall movement sensors, end-tidal and/or transcutaneous CO2, and pulse
oximetry, all under the continuous observation of a trained technician
(Table 34-1).6 These channels are used to measure the presence and severity
of obstructive, mixed, and central respiratory pauses, which are especially
important in children in whom hypoventilation is possible (particularly
patients with neuromuscular or central nervous system disorders).4,7,19 The
sensors can also determine partial airway obstruction, oxyhemoglobin
desaturations, and sleep architecture.7

621
Table 34-1. Polysomnography Components and Their Importance

Polysomnography
Component Measurement Importance
Electroencephalogram Sleep vs wakefulness; Can identify seizure activity; determines
sleep architecture total sleep time (which is denominator
for Apnea-Hypopnea Index); determines
if events happen during sleep or wake
(eg, baby crying may mimic apneas)
Electro-occulogram Eye movements Differentiates rapid eye movement
(REM), non-REM, and wakefulness
Submental electro- Pharyngeal muscles Determines atony, which indicates
myogram (genioglossus) REM sleep
Leg electromyogram Leg movements Measures periodic limb movements
during sleep
Oronasal thermistor Exhaled air Exhaled air has a higher temperature
temperature than inhaled air, shows presence
of airflow
Thoracic and Chest and abdominal Differentiates between obstructive
abdominal movement movement and central events
sensor
Pulse oximeter Oxyhemoglobin Measures extent and duration of
saturation hypoxemia; identifies hypopneas
Electrocardiogram Heart rate and rhythm Identifies bradycardia and more
severe arrhythmias
Video recording Body movements, Helps identify wakefulness from sleep,
extraneous events especially in infants; helps identify body
causing arousal movements including tonic-clonic
seizures and periodic limb movements
Nasal carbon dioxide CO2 Identifies hypoventilation
(CO2) capnograph or
transcutaneous CO2
monitor
Laryngeal microphone Snoring sounds Identifies presence of snoring
Despite their gold-standard designation, in-lab polysomnograms are expensive,

time-consuming, inconvenient, and limited in their availability, which can lead
to long wait times.1,2,4,5,9,13 To alleviate some of that burden, nap polysomnograms
are occasionally used, particularly in infants. Nap polysomnograms are com-
monly performed during the day. Even though they are more convenient, nap
polysomnograms generally underestimate sleep-disordered breathing in chil-
dren.3 Nap polysomnograms are useful if the result is strongly positive, but an
overnight polysomnogram is still required if the nap study is negative or incon-
clusive. Nap polysomnograms have lower predictive value as compared to the
overnight polysomnogram because of decreased total sleep time and particularly
decreased REM sleep, when respiratory events are most prevalent.6

622
If a full overnight in-laboratory polysomnogram is not available, and the

patient’s clinical presentation shows a high likelihood of OSA as opposed to
other sleep disorders, the clinician may order alternative diagnostic tests and
consider proceeding to a full polysomnogram if the results are inconclusive.
The 2017 American Academy of Sleep Medicine (AASM) guidelines do
not support the use of home sleep apnea testing for the diagnosis of OSA in
children, although they do permit the use of portable monitors as an alterna-
tive to PSG in certain situations based on the physician’s clinical judgment
(taking into account access to available diagnostic tools, individual patient
circumstances, and available treatment options).5,19,20 The European Respi-
ratory Society is somewhat more liberal and allows video PSG, nap PSG,
respiratory polygraphy, and nocturnal pulse oximetry as tools to diagnose
OSA, although it still lists in-laboratory PSG as the more preferable modality.1
Generally, portable apnea monitoring tends to be helpful if the results are
strongly positive, but it has a poor predictive value if the results are negative;
thus, children with a negative portable study should still undergo a more
thorough evaluation, including full in-laboratory PSG. Portable studies have
limited ability to evaluate the severity of OSA, which limits their ability to
predict perioperative morbidity.10,16
Despite their low sensitivity and specificity, portable apnea monitoring devices
do have some advantages.16 These studies are feasible and reproducible, but
not as accurate as full polysomnograms. Home studies are also less expensive,
more convenient, and more accessible, with theoretically less “first night effect”
(decreased sleep and sleep efficiency on the first night of testing).4 However,
these benefits might be mitigated by the need to repeat a full polysomnogram
because of inconclusive results or a technically inadequate study.
Monitoring Classifications
In 1994, the AASM Portable Monitoring Task force classified portable moni-
toring into 4 categories (Table 34-2, Table 34-3), of which types 2 through
4 are applicable to home testing.4
Type 1 Monitoring
Type 1 monitoring is a fully attended polysomnogram with 7 or more channels,
completed in a laboratory setting under the continuous observation of a trained
technologist.4 As discussed previously, this is considered the gold standard
for diagnosing OSA in children because it provides an objective quantitative
evaluation of sleep and respiratory disturbances.16 Type 1 polysomnograms
also allow patients to be stratified according to their severity, which helps
determine which children are at risk for perioperative complications.

Table 34-2. Comparison of Obstructive Sleep Apnea Monitoring Device Classifications
Type 1 Type 2 Type 3 Type 4
Components (In-Laboratory Polysomnography) (Unattended Polysomnography) (Respiratory Polygraphy) (1–2 Parameters)
Electroencephalogram X X
Electro-occulogram X X

Submental X X
electromyogram
Leg electromyogram X X
Oronasal thermistor X X X
Thoracic and abdominal X X X
movement sensor
Pulse oximetry X X X X
Electrocardiogram X X
Video X Can be included but usually not Can be included but usually not
Carbon dioxide: nasal or X Can be included but usually not Can be included but usually not
transcutaneous capnograph
Laryngeal microphone X X
623
9/12/23 10:16 AM
Table 34-3. Advantages and Limitations of Portable Monitoring Devices
624
Monitoring Type Advantages Limitations Guidance on Use

Type 1 “Gold standard”; can Expensive; labor-intensive “Gold standard” for a reason; best test, if available
(fully attended in-laboratory identify hypopneas,
polysomnography [PSG]) hypoventilation,
movement disorders
Type 2 More convenient for Expensive; labor-intensive; less May be useful in older children and adults when there is
(unattended PSG with families; theoretically less useful in young children; signals high clinical suspicion for straightforward, uncomplicated
≥7 channels, or “PSG in “first night effect”because can be lost overnight obstructive sleep apnea (OSA), but, if negative, may still need

the home”) child is sleeping at home an in-laboratory polysomnogram. Works best when a trained
professional goes to the house and places the sensors.
Type 3 More convenient for Less sensitive and specific; does May be useful in older children with strong history and
(respiratory polygraphy) families; theoretically less not typically measure carbon physical examination findings suggestive of severe OSA.
“first night effect”because dioxide so cannot determine Should not be used in children younger than 3 years, and
child is sleeping at home hypoventilation should be used sparingly in children younger than 12 years
because of high failure rate in these populations. It should
not be used in patients in whom hypoventilation is likely
or suspected, including those with Down syndrome or
neuromuscular, craniofacial, or skeletal syndromes. If
inconclusive, a conventional polysomnogram should be
performed. Results are improved if a trained professional
sets up the sensors at the beginning of the night.
Type 4 Inexpensive, small, Poor sensitivity overall; poor May be useful in prioritization of treatment. Cannot replace
(1–2 signal channels) convenient negative predictive value; cannot full PSG because of its poor sensitivity and is not sufficient for
differentiate obstructive from identification of OSA in otherwise healthy children. If negative,
central apneas a full polysomnogram is necessary.
9/12/23 10:16 AM
625
Type 2 Portable Monitoring

Type 2 monitoring consists of an unattended polysomnogram with 7 or more
channels.4 This is essentially a “polysomnogram in the home” and typically
includes EEG as well as respiratory monitoring. These ambulatory poly-
somnograms are appropriate and reliable in some adults, but they should not
be used for the exclusive evaluation of severe OSA in children, especially
preschool-aged children, because these monitoring systems rarely include
capnography.13,16 In adults and older children, there is no significant difference
in respiratory parameters compared to in-laboratory polysomnogram, but the
type 2 monitors had a high error rate in children younger than 5 years.4,6,16
Under research conditions, when trained staff go to the child’s home and
apply the sensors, there is a high degree of technically acceptable recording,
particularly in children older than 5 years.4,19
Type 2 studies are still quite labor intensive and expensive because a tech-
nologist must travel to the home to set up and take down the equipment. The
scoring is no different from in-laboratory polysomnograms.4 Video recordings
are not always included, nor is CO2 monitoring, which is especially important
in children in whom there is a concern for hypoventilation, such as those with
neuromuscular disease, underlying lung disease, or obesity hypoventilation.
Other limitations for in-home polysomnograms include potential interference
from siblings, lack of electrical outlets near the bed, signal artifact from home
technology, and insufficient battery life if the unit is unplugged (eg, for a bath-
room trip) and not replugged.4 In many cases, even if the caregivers noted that
sensors came off overnight, few attempted to replace them. Nasal cannula flow
signals are often suboptimal with no technologist continuously monitoring the
patient.4,21 Any cost advantage of type 2 monitoring may be mitigated by the
need for a technologist to set up the devices in the home and the not infrequent
need to conduct a full polysomnogram in the lab because of an inconclusive
home study. There is currently one US Food & Drug Administration-approved
device for type 2 monitoring in adults, but the AHI is not comparable to
PSG in children.11

Type 3 studies, also known as respiratory polygraphy (RP), are more limited
than types 1 and 2 and typically consist of only 4 to 7 monitoring channels,
generally without EEG monitoring of sleep stages.4,16 The AASM recommends
that an RP study include, at a minimum, airflow, respiratory efforts, and oxy-
hemoglobin saturation.20 Home RP is accepted and used effectively in adults
and is, in many cases, the preferred option for adult sleep medicine.8 The
research in children is more limited, although type 3 portable monitoring may
offer a viable alternative for the diagnosis of otherwise healthy children with
moderate to severe obstructive sleep apnea syndrome, particularly where

626
access to a full polysomnogram is limited.4 Respiratory polygraphy, especially

when set up by a sleep technologist at the home in a research setting, can
identify an AHI that highly correlates to a type 1 polysomnogram in older
children, aged 12 through 17.21 The correlation is likely to be lower in the
clinical setting. These devices also demonstrate relatively high sensitivity
and specificity to diagnose OSA when the AHI is greater than 10, but RP is
inferior to PSG in more mild or moderate cases of OSA. Similar to the other
portable monitors, the percentage of successful recordings is higher if the RP
is set up by trained staff. However, even under ideal conditions, these studies
tend to underestimate the AHI because hypopneas causing arousals are
missed (with no EEG) and the total sleep time is only an estimate without
EEG confirmation.4
Respiratory polygraphy is not helpful in certain special populations, including
children with Down syndrome, Prader-Willi syndrome, and neuromuscular
diseases, because hypoventilation is not detected using these monitors, which
lack capnography.6,19 Younger children often have difficulty tolerating the
sensors, and, even with detailed oral and written instructions, caregivers are
frequently unable to place the sensors adequately.14 Additionally, if a child is
sleeping poorly, a type 3 monitor, which cannot stage sleep, may miss obstruc-
tive events because those tend to cluster during REM sleep.4 As with type 2
monitoring, because of the high specificity but low sensitivity, a negative
test necessitates an in-laboratory polysomnogram.8 Other limitations of RP
include that total recording time, rather than total sleep time, is used for the
denominator for AHI.13
Research evaluations of RP devices have used the same equipment as the
polysomnogram (minus certain signals). Home RPs are designed to be porta-
ble, and, while similar, they are not the same as in-laboratory equipment and
may yield poorer results than even these studies suggest.4 Any cost advantage
of type 3 portable monitoring may be mitigated by the need for a technologist
to set up the devices in the home, and the not infrequent need to perform a
full polysomnogram because of an inconclusive home study.

Type 4 monitoring consists of only 1 or 2 signal channels, traditionally, but not
exclusively, with pulse oximetry as one of the measurements.4 The second
channel may be electrocardiogram/heart rate, peripheral arterial tonometry,
or chest wall movement. As with other portable monitoring systems, type 4
monitors have a good positive predictive value in patients where there is a high
suspicion for OSA, but the monitors also have a poor negative predictive value,
indicating that oximetry is useful when results are positive but if the test is
negative, the patient still requires a full in-laboratory polysomnogram.10,11
Overall, single-channel recording has not been shown to correlate well with

627
in-laboratory PSG for the diagnosis of OSA.2,11 Oximetry alone is generally

insufficient for the diagnosis of OSA because of the higher rate of inconclusive
test results, especially considering that children with OSA can experience
arousals and sleep fragmentation and not develop desaturations. Children
also tend to move around in their sleep, which can result in motion artifacts.16
Pulse oximetry alone cannot differentiate between obstructive and central
apneas.11 Type 4 monitoring can, however, be useful in the prioritization of
treatment and can play a more central role in places where polysomnograms
are not available.4 These monitors are most useful in children being treated
with home oxygen to determine the feasibility of stopping the oxygen therapy.
Other Monitoring Options

Since 1994 when the American Academy of Sleep Medicine developed
these classifications for portable monitoring, several newer technologies
have been developed. While some of these methods will be described briefly,
it is important to note that none can fully replace a full in-laboratory
polysomnogram for the diagnosis of OSA in children.
Radiologic Studies
Certain radiologic studies have been used to help diagnose OSA, such as the
presence of airway narrowing on a lateral neck radiograph, which increases
the probability of predicting OSA on PSG.16
Acoustic Pharyngometry
Acoustic pharyngometry uses reflected sound waves administered through
the mouth to assess the size of the pharynx; however, the accuracy is still
being studied. When sound waves are administered through the nose
(acoustic rhinometry), nasal resistance can be assessed. A high nasal
resistance suggests an increased risk for OSA.22,23
Snoring Evaluations
Snoring evaluations, independent from a history and physical examination,
generally do not correlate well with the severity of OSA because the loudness
of the snoring does not necessarily correlate with the degree of obstructive
apnea.16 Snoring may disappear following surgery such as adenotonsillectomy,
yet OSA may persist if the baseline OSA was severe.
Peripheral Arterial Tonometry

Studies have found changes in cardiovascular parameters, such as heart rate
variability, pulse transit time, and peripheral arterial tonometry, in children
with OSA, but the sensitivities and specificities of these assessments are
variable and generally are not used as a single measurement.16 Peripheral
arterial tonometry assesses changes in peripheral arterial volume as a measure

628
of transient elevations of sympathetic tone associated with nighttime arousals.

Peripheral arterial tonometry, combined with pulse oximetry and actigraphy,
provides a relatively high degree of correlation of sleep variables in adults,
and in children with severe OSA, as compared to PSG.4,24
Pulmonary Function Tests

Using pulmonary function tests, a “sawtoothed” pattern of the maximal
expiratory flow-volume loop (Figure 34-1) has been suggested to screen
for OSA in adults, but younger children may have difficulty performing
the maneuver.16
Figure 34-1. Sawtooth pattern on pulmonary function test flow-volume loop.

From Sahni S, Blood A, Paulus S, Talwar A. “Saw-Tooth Sign” in upper airway disorders—a case report.
Pneumonol Alergel Pol. 2015; 83: 140-143.

629
Proteomics Studies
Some studies have tried to use urinary or serum proteomics analysis for
screening for OSA; in a highly selected patient population, urinary proteins
did have a high sensitivity and specificity, although more studies are needed.16,25
Audio and Video Recording

Audio and video recording, facilitated by the near-universal presence of cell
phones, shows a lot of discrepancies in screening for and diagnosing OSA in
children.10 Home video may be a useful first step in the clinical evaluation of
children suspected of having OSA as it has a generally high sensitivity and
medium specificity. The most useful information gleaned from a recording
is differentiating snoring from other respiratory noises. Limitations of video
recordings include that neither the sleep state nor any other parameters are
monitored.3 Audio recording alone is inferior to video recording because it
notes only one variable: the presence of noisy breathing.
Investigators have attempted to use video game modalities to assess sleep in
the home, similar to, but more comprehensive than, traditional video record-
ing. The Microsoft Kinect video game system has been the subject of some
studies. The Kinect system has 3 optical sensors to provide body tracking, 3D
body reconstruction, skeletal tracking, and joint tracking to detect respiratory
activity, particularly visualizing paradoxical movements of the thorax and
abdomen and monitoring of limb movements. The system alone cannot detect
oxygen saturation levels, arousals, or changes in heart rate. One study showed
that the Kinect system can accurately measure respiratory movements under
low light conditions and, therefore, detect apneas even in young children,
although more studies are necessary.17
Radar
Radar has also been examined as a noncontact monitoring device for OSA;
however, to make use of the Doppler effect in sleep requires that the record-
ing system be within 1 meter of the patient. If radio frequency identification
technology is used, sensors are still required on the patient’s body, which may
be uncomfortable and prone to distortion by the patient’s movements and
signal interference.17
Thermal Cameras
Thermal video cameras have been used to detect CO2 emissions or to
determine skin temperature differences between inhalation and exhalation.
However, these measurements can be affected by head position, movement
artifact, and anything that might cover the face, such as a blanket.17

630
Image Sequence Analysis

Image sequence analysis uses the optical flow of the chest surface captured by
video camera, but lighting conditions are a major drawback and the data has
to be interpreted after the video is analyzed, so abnormal events cannot be
captured in real time. Three-dimensional surface information of the patient’s
chest, captured by time-of-flight cameras for detecting respiratory motion,
is also severely affected by noise and motion artifact, and the technique
is quite expensive.17
Capacitor-based Systems
Capacitor-based systems detect static charge contained within bedding
material and can discern breathing movements, but studies with children
so far have had limited success.4
Sheets and Mats

Sheets and mats with pressure, vibration, and sound sensors also exist,
although so far the vibration-sensing mat underestimates AHI in adults and
the pressure-sensing sheets can detect central apneas but not obstructive
ones.4 A newer device, the Sonomat, a mattress pad with both sound and
movement sensors, is showing some promise in identifying both obstructive
and central apneas in children.26
Biomotion Sensors
Noncontact biomotion sensors can use radio waves to measure movement
and respiration from the bedside table and have been useful in adults with
an AHI greater than 15.4 As yet, good studies in children are lacking.
Conclusion
While portable home monitoring of OSA is accepted and validated in adults, it
has significant deficiencies and is not regularly used in children. However,
the ultimate judgment regarding this, and any specific care, must be made by
the treating physician considering the individual circumstances of the patient.5
This is not to say that home monitoring will never be appropriate in children,
but given the few validated studies in youngsters and the conflicting results,
in-laboratory PSG remains the gold standard for diagnosing and evaluating
OSA in children.

631
key points
} Obstructive sleep apnea affects 1% to 4% of children and, undiagnosed and
untreated, can cause behavioral problems, poor school performance, and
daytime sleepiness. Obstructive sleep apnea in children is typically caused by
enlarged tonsils or adenoids and is corrected surgically.
} The gold standard for diagnosing OSA in children is with an in-laboratory
polysomnogram.
} Simpler and less expensive testing options are available, but they only
incorporate a fraction of the measurements that are recorded using
a polysomnogram.
References
1. Michelet M, Blanchon S, Guinand S, et al. Successful home respiratory polygraphy to
investigate sleep-disordered breathing in children. Sleep Med. 2020;68:146–152 PMID: 32036287
doi: 10.1016/j.sleep.2019.11.1264
2. Kirk VG, Bohn SG. Flemons; W Ward, Remmers JE. Comparison of Home Oximetry
Monitoring With Laboratory Polysomnography in Children. Chest. 2003;124 (5):1702–1708
3. Sivan Y, Kornecki A, Schonfeld T. Screening obstructive sleep apnoea syndrome by home
videotape recording in children. Eur Respir J. 1996;9(10):2127–2131 PMID: 8902478
doi: 10.1183/09031936.96.09102127
4. Tan HL, Kheirandish-Gozal L, Gozal D. Pediatric home sleep apnea testing slowly getting there!
Chest. 2015;148(6):1382–1395 PMID: 26270608 doi: 10.1378/chest.15-1365
5. Kirk V, Baughn J, D’Andrea L, et al. American academy of sleep medicine position paper for the
use of a home sleep apnea test for the diagnosis of OSA in children. J Clin Sleep Med.
2017;13(10):1199–1203 PMID: 28877820 doi: 10.5664/jcsm.6772
6. Kaditis AG, Alonso Alvarez ML, Boudewyns A, et al. ERS statement on obstructive sleep
disordered breathing in 1- to 23-month-old children. Eur Respir J. 2017;50(6):1700985
PMID: 29217599 doi: 10.1183/13993003.00985-2017
7. Morielli A, Ladan S, Ducharme FM, Brouillette RT. Can sleep and wakefulness be distinguished
in children by cardiorespiratory and videotape recordings? Chest. 1996;109(3):680–687
PMID: 8617076 doi: 10.1378/chest.109.3.680
8. Alonso-Álvarez ML, Terán-Santos J, Ordax Carbajo E, et al. Reliability of home respiratory
polygraphy for the diagnosis of sleep apnea in children. Chest. 2015;147(4):1020–1028
PMID: 25539419 doi: 10.1378/chest.14-1959
9. Pavone M, Cutrera R, Verrillo E, Salerno T, Soldini S, Brouillette RT. Night-to-night consistency
of at-home nocturnal pulse oximetry testing for obstructive sleep apnea in children. Pediatr
10. Section on Pediatric Pulmonology and Subcommittee on Obstructive Sleep Apnea Syndrome.
Clinical practice guideline: diagnosis and management of childhood obstructive sleep apnea
syndrome. American Academy of Pediatrics. Pediatrics. 2002;109(4):704–712
doi: 10.1542/peds.109.4.704
11. Scalzitti N, Hansen S, Maturo S, Lospinoso J, O’Connor P. Comparison of home sleep apnea
testing versus laboratory polysomnography for the diagnosis of obstructive sleep apnea in
children. Int J Pediatr Otorhinolaryngol. 2017;100:44–51 PMID: 28802385
doi: 10.1016/j.ijporl.2017.06.013
12. Brooks DM, Brooks LJ. Reevaluating norms for childhood obstructive sleep apnea.
13. Suzuki M, Furukawa T, Sugimoto A, Kotani R, Hosogaya R. Comparison of diagnostic
reliability of out-of-center sleep tests for obstructive sleep apnea between adults and children.
Int J Pediatr Otorhinolaryngol. 2017;94:54–58 PMID: 28167012 doi: 10.1016/j.ijporl.2017.01.015
14. Poels PJ, Schilder AG, van den Berg S, Hoes AW, Joosten KF. Evaluation of a new device for
home cardiorespiratory recording in children. Arch Otolaryngol Head Neck Surg.
2003;129(12):1281-1284. Ahttps://jamanetwork.com/

632
15. Suen JS, Arnold JE, Brooks LJ. Adenotonsillectomy for treatment of obstructive sleep apnea
in children. Arch Otolaryngol Head Neck Surg. 1995;121(5):525–530 PMID: 7727086
doi: 10.1001/archotol.1995.01890050023005
16. Marcus CL, Brooks LJ, Ward SD, Draper KA, et al. Diagnosis and management of childhood
obstructive sleep apnea syndrome. Pediatrics. 2012;130(3);e714‒755 doi: 10.1542/peds.2012-1672
17. Al-Naji A, Gibson K, Lee SH, Chahl J. Real time apnoea monitoring of children using the
Microsoft Kinect sensor: a pilot study. Sensors (Basel). 2017;17(2):286 PMID: 28165382
doi: 10.3390/s17020286
18. Brooks LJ, Stephens BM, Bacevice AM. Adenoid size is related to severity but not the number
of episodes of obstructive apnea in children. J Pediatr. 1998;132(4):682–686 PMID: 9580770
doi: 10.1016/S0022-3476(98)70360-9
19. Hassan F, D’Andrea LA. Best and safest care versus care closer to home. J Clin Sleep Med.
2018;14(12):1973–1974 PMID: 30518457 doi: 10.5664/jcsm.7514
20. Masoud AI, Patwari PP, Adavadkar PA, Arantes H, Park C, Carley DW. Validation of
the medibyte portable monitor for the diagnosis of sleep apnea in pediatric patients.
21. Bhattacharjee R. Ready for primetime? Home sleep apnea tests for children. J Clin Sleep Med.
2019;15(5):685–686 PMID: 31053225 doi: 10.5664/jcsm.7748
22. Okun MN, Hadjiangelis N, Green D, Hedli LC, Lee KC, Krieger AC. Acoustic rhinometry
in pediatric sleep apnea. Sleep Breath. 2010;14(1):43–49 PMID: 19641942
doi: 10.1007/s11325-009-0278-y
23. Brooks L. Acoustic reflectance. In: Marcus C, Carroll J, Donnely D, Loughlin G, eds. Sleep in
Children. Informa; 2008:553–563
24. Tanphaichitr A, Thianboonsong A, Banhiran W, Vathanophas V, Ungkanont K. Watch peripheral
arterial tonometry in the diagnosis of pediatric obstructive sleep apnea. Otolaryngol Head Neck
Surg. 2018;159(1):166–172 PMID: 29631515 doi: 10.1177/0194599818768215
25. Feliciano A, Torres VM, Vaz F, et al. Overview of proteomics studies in obstructive sleep apnea.
Sleep Med. 2015;16(4):437–445 PMID: 25770042 doi: 10.1016/j.sleep.2014.11.014
26. Norman MB, Pithers SM, Teng AY, Waters KA, Sullivan CE. Validation of the sonomat against
PSG and quantitative measurement of partial upper airway obstruction in children with
sleep-disordered breathing. Sleep. 2017;40(3):1–13. PMID: 28364431 doi: 10.1093/sleep/zsx017

CHAPTER
35
Sleep-Related Movement Disorders
Introduction
Pediatric pulmonologists have led the way in identification and treatment
of obstructive sleep apnea in children. However, pediatric sleep practice
requires knowledge of non-respiratory sleep disorders as well as respiratory
ones. Parents often voice concerns about children’s movements during sleep
and restless sleep. While these are often related to sleep-related breathing
disorders (see Chapter 33, Obstructive Sleep Apnea Syndrome), movements
may represent sleep disorders in their own right, sometimes but not always
comorbid with sleep-related breathing disorders.
Sleep-related movement disorders in children typically disrupt sleep at its ini-
tiation, with stereotyped, simple movements. The International Classification
of Sleep Disorders, 3rd Edition (ICSD-3) catalogs restless legs syndrome
(RLS; also known as Willis-Ekbom disease), periodic limb movement disorder
(PLMD), sleep-related leg cramps, sleep-related bruxism, sleep-related rhythmic
movement disorder, benign sleep myoclonus of infancy, and propriospinal myo-
clonus at sleep onset; as well as sleep-related movement disorders due to medical
disorder, medication or substance, or unspecified; and isolated symptoms and
normal variants such as excessive fragmentary myoclonus, hypnagogic foot
tremor and alternating leg muscle activation, and sleep starts (also known
as hypnic jerks).1 In addition, restless sleep disorder is a newly defined sleep
disorder not yet added to the classification.2 The most frequently discussed of
these entities, on which this chapter will focus, are RLS and PLMD.
Epidemiology
The American Academy of Sleep Medicine (AASM) defines a periodic limb
movement index (PLMI) of more than 5 periodic limb movements of sleep
(PLMS) per hour as abnormal.1 A large cross-sectional study of more than 10,000
subjects based on National Institutes of Health criteria for RLS revealed a
prevalence of 1.9% in children aged 8 to 11 years, and 2% in children aged 12 to
17 years. In these groups, 0.5% and 1% respectively reported moderate to severe
symptoms at least twice a week.3 A cross-sectional study of community-recruited
633

634
children aged 5 to 17 years who had polysomnography (PSG) performed for

research purposes noted 7.7% with PLMI more than 5 per hour, and 1.5% more
than 15 per hour.4
In terms of other sleep-related movement disorders, bruxism may affect 15% to
49% of typically developing children.5 Up to 3% of infants and toddlers identi-
fied through well child checks had sleep-related rhythmic movement disorders,
confirmed by videosomnography.6 Researchers estimate the prevalence of
restless sleep disorder at 7.7% of children clinically referred to a sleep center.7
Pathophysiology
Research implicates iron, a key mediator of the dopaminergic system, in the
pathophysiology of RLS and PLMD. A detailed description of these proposed
mechanisms is beyond the scope of this chapter but is available in several
published original research studies and reviews.8 Iron deficiency due to any
cause can lower the threshold for RLS/PLMD symptoms, even without
clinical anemia as measured by hemoglobin, and iron levels may not mea-
sure its availability to the central nervous system specifically. Serum ferritin
acts as a marker for bioavailability of iron in the cerebrospinal fluid. It should
be drawn on first morning fasting. Because serum ferritin acts as an acute
phase reactant and can remain elevated more than 5 weeks post-infection,
consider delaying laboratory work in the immediate aftermath of illness and
ordering an erythrocyte sedimentation rate or C-reactive protein to assess
for residual inflammation.8
Diagnosis
Clinical Features
Surface electrodes on the tibialis anterior muscle monitor the occurrence of
limb movements (LMs) during PSG, placed and filtered as per the most recent
version of The AASM Manual for the Scoring of Sleep and Associated Events.9
Rhythmic sequences of LMs constitute PLMS. Limb movements last 0.5 to
10 seconds, with a minimum 8 microvolt increase in voltage over resting
electromyography.9 Periodic limb movements of sleep consist of at least
4 LMs, each separated by 5 to 90 seconds, not scored if occurring within
0.5 seconds of the onset or offset of a respiratory event (see Figure 35-1).9
Periodic limb movement disorder manifests during sleep. Family members
may observe the patient to be kicking during sleep, but they may or may not
wake up. It is diagnosed when the following criteria are met: polysomno-
graphic documentation of PLMS occurringmore than 5 times per hour;
associated with disturbed sleep or impaired function; and not better
explained by another disorder, sleep or otherwise.1 Other movement variations
include alternating leg muscle activation and hypnogogic foot tremor.

635
Chapter 35—Sleep-Related Movement Disorders
Figure 35-1. Periodic limb movements of sleep on polysomnography during non-REM

sleep in a 16-year-old girl with 4 limb movements over the course of three 30-second epochs.
Note that these particular leg movements are not associated with arousals or alteration of
cardiopulmonary function.
Restless legs syndrome, in contrast, is a clinical diagnosis, not the result of

laboratory testing. Its symptoms occur during wakefulness and may interfere
with sleep onset. Successful diagnosis depends on history, which presents
a challenge in young children and children with communication disorders.
Restless legs syndrome and PLMD overlap and share pathophysiology, such
that their diagnosis is often entwined. In addition, diagnosis of PLMD may
precede that of RLS.10
The International Restless Legs Syndrome Study Group (IRLSSG)11 published
the following essential diagnostic criteria for RLS:
X An urge to move the legs usually but not always accompanied by or felt
to be caused by uncomfortable and unpleasant sensations in the legs.
For children, the description of these symptoms should be in the child’s own
words.
X The urge to move the legs and any accompanying unpleasant sensations
begin or worsen during periods of rest or inactivity such as lying down
or sitting.
are partially or totally relieved by movement, such as walking or stretching,
at least as long as the activity continues.
during rest or inactivity only occur or are worse in the evening or night than
during the day.
X The occurrence of the above features is not solely accounted for as symp-
toms primary to another medical or a behavioral condition.

636
In a retrospective study of children with RLS, subjects presented with sen-

sory complaints in their legs and the urge to move, occurring at rest, worse
during evenings and nights, and alleviated by movement. They often felt tired
during the day, sometimes demonstrating excessive daytime sleepiness. More
than half reported insomnia, and most had an elevated PLMI on PSG.12
Diagnosis of pediatric RLS presents some unique challenges. Because chil-
dren must describe symptoms in their own words, clinicians should take into
consideration their developmental levels and language abilities in thinking
about how they are likely to describe their sensations. Children sometimes
respond better to requests to draw how their legs feel (see Figure 35-2).13
Effects of RLS in children often manifest more in their academics and
behavior than in other domains reported by adults.10
Clinical features supporting the diagnosis of pediatric RLS include10
X Periodic limb movements of sleep > 5 per hour
X Family history of RLS among first-degree relatives
X Family history of PLMS > 5 per hour
X Family history of PLMD among first-degree relatives
Figure 35-2. Drawings by children aged 5 to 15 years with restless legs syndrome describing
their symptoms. Samples of the accompanying descriptions included the following: “I’m trying
to stretch my legs out”; “like it’s ant bites”; “these represent my tingles.”
From Picchietti DL, Arbuckle R A, Abetz L, et al. Pediatric restless legs syndrome. J Child Neurol.
2011;26(11):1365-1376. https://doi.org/10.1177/0883073811405852. © 2011 by SAGE Publications. Reprinted
by permission of SAGE Publications.

637
Sleep-related bruxism requires evidence of teeth grinding, via grinding

sounds heard during sleep, and either evidence of unexpected tooth wear for
age or symptoms such as jaw muscle pain, temporal headache in the morning,
or jaw locking on waking (see also Figure 35-3).1
Rhythmic movement disorders, too, consist of movements of specific ranges
of frequency (0.5–2 Hz) and amplitude (2× background electromyography
activity), occurring in clusters of at least 4 events.9 Such movements can
include repetitive body rocking, headbanging, or rolling at sleep onset.6
These may be described by the family or seen on the video during PSG.
Figure 35-3. A 30-second polysomnographic epoch demonstrating sleep bruxism in a 6-year-old

girl consisting of sustained (tonic) chin muscle activity.
Role of PSG
The AASM practice parameter recommends PSG in children as a standard
14
of care to clarify whether children have PLMD (this diagnosis requires an

objective correlate.) Polysomnography can also be used to evaluate children with
disorders triggered by sleep disruption such as epilepsy, frequent non-rapid eye
movement (non-REM) parasomnias, nocturnal enuresis, or PLMD if suspected,
at the level of guideline. Polysomnography can provide supportive data for diag-
nosis of RLS, as an option. Sleep-related bruxism alone, however, does not pro-
vide sufficient indication for PSG.14 Clinicians should bear in mind that PLMS
can vary significantly from night to night in children as well as in adults.15
Common Contributing Conditions

While genetic variants play an important role in RLS/PLMD, other medical
conditions place children at increased risk of these disorders as well.16 As
alluded to previously, iron deficiency and anemia figure prominently. Con-
ditions such as kidney disease and sickle cell disease logically follow as
risk factors due to the anemia involved. Spinal pathologies may also
provoke symptoms.
Epilepsy remains part of the differential diagnosis for many sleep-related move-
ment disorders, especially when markedly stereotyped movements occur and
are not consistent with classic sleep disorder presentations (the “triple flexion”

638
of PLMS). However, epilepsy, although associated with increased problems

with sleep, does not in and of itself carry a higher risk of RLS/PLMD.
Children with attention-deficit/hyperactivity disorder more frequently have
RLS/PLMD than typically developing peers; likewise with Tourette syndrome
and tic disorders.
Separation anxiety, as well as generalized anxiety disorder, carries a higher risk
for development of sleep bruxism, which should prompt additional screening
and mental health referral if appropriate.5 Children with autism and intellectual
disabilities more frequently engage in sleep-related rhythmic movement dis-
orders, but such movements are not exclusive to them. Typically developing
children with rhythmic movements may present earlier in life than children
with disabilities.17 In the absence of other symptoms, sleep-related rhythmic
movements should not prompt suspicion for autism. These children often
have attention-deficit/hyperactivity disorder.18
Sequelae
The effects of disrupted sleep on children and families in general have been
extensively documented elsewhere. Subjects with PLMI more than 5 per hour
have higher arousal indices compared with peers.4 A case control study
looking specifically at children diagnosed with RLS and a matched compari-
son group documented significantly lower quality of life in children with RLS
symptoms at least twice a week.19
Sleep bruxism not only causes wear and tear on teeth, but can also lead
to broken teeth, temporomandibular joint disorders, and headaches.5 Sleep-
related rhythmic movement disorders that are persistent and vigorous can
lead to damage to self and property, resulting in bruising, injury, and broken
furniture (eg, energetic body rocking gradually loosening screws to bed
frames). Further, these rhythmic movements can be both quite persistent
and treatment resistant.17
Management
Treatment Options
Clinicians should consider iron supplementation as treatment for RLS/PLMD
before proceeding to other medication options. The IRLSSG reviewed studies
of oral iron supplementation and intravenous iron infusion for treatment of
children with RLS. They found inadequate evidence to draw conclusions
about the safety or efficacy of either.8 Nevertheless, they reported a consensus
recommendation that oral iron treatment probably decreases symptoms of
RLS and helps sleep quality in children with RLS and PLMD.8 Limiting
factors for oral iron can include gastrointestinal effects, particularly consti-
pation, as well as aversion to the distinctive taste of the supplements. However,
increased dietary iron alone may not be sufficient to effect change.

639
The 50th percentile for serum ferritin is the most commonly used marker
of body iron stores. 50 mcg/L (50 ng/mL) is typically used as the cutoff
below which iron supplementation is recommended in children with RLS,
though some have proposed 75 mcg/L (75 ng/mL). A cohort of children
with serum ferritin less than 50 mcg/L (< 50 ng/mL) showed a significant
increase in ferritin following 8 weeks of oral iron supplementation. However,
changes in RLS scores did not meet statistical significance.20 Adherence to
supplementation naturally influenced response, defined as increase of of more
than 10 mcg/L (> 10 ng/mL). Subjects who responded reported more frequent
change in symptoms and less frequent constipation.21 While intravenous iron
infusion has been studied in children, and it appears on the IRLSSG flowchart
for iron supplementation in children with RLS (Figure 35-4), only a few
Accurate Diagnosis and Iron Assessment

Are all four core RLS features or full PLMD criteria present?
Rule out mimics, especially sore muscles and positional discomfort.
Assess symptom severity (frequency and impact).
Obtain morning fasting serum ferritin, iron, total iron binding capacity, TSAT%.
Ferritin ≥50 µg/L1 Ferritin <50 µg/L Ferritin <50 µg/L

No conditions that block Condition that blocks oral
oral iron absorption or iron absorption or makes
make response unlikely.2 response unlikely.2
No oral iron or
contraindications. Oral but not IV iron
contraindications.
Oral Iron Treatment Consider IV iron3

Start, continue, or modify Ferrous sulfate 3 mg/kg/day Iron sucrose 3–6 mg/kg
other RLS/PLMD (max 130 mg daily). (max 120 mg).
treatment as needed. Reassess iron and clinical Reassess iron and clinical
status after 12 weeks. status after 8–12 weeks.
Ferritin <50 µg/L

Ferritin <50 µg/L
Ferritin ≥50 µg/L4 But improving:
Not improving
repeat oral iron.
Therapeutic target of ferritin ≥50 mcg/L for iron therapy.

1
Serum ferritin can be falsely elevated in the presence of acute or chronic inflammation. IV iron treatment can then
be considered if transferrin saturation is <20%.
2
Such as a malabsorption syndrome, inflammatory bowel disease, heavy uterine bleeding, rheumatic diseases, etc.
3
Administer at an infusion center with pediatric experience and with care taken to avoid IV drug extravasation.
4
May need to continue oral iron to avoid return of symptoms due to decrease in iron stores with growth.
Abbreviations: IV, intravenous; PLMD, periodic limb movement disorder; RLS, restless leg syndrome; TSAT%,
percentage transferrin saturation.
Figure 35-4. Algorithm for iron treatment of pediatric restless legs syndrome/periodic limb
movement disorder.
From Allen RP, Picchietti DL, Auerbach M, et al; International Restless Legs Syndrome Study Group (IRLSSG).
Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/
Willis-Ekbom disease in adults and children: an IRLSSG task force report. Sleep Med. 2018;41:27–44
PMID: 29425576.

640
centers actually have experience with infusion for pediatric sleep disorder
indications.
Parents often ask about magnesium supplementation as an option, apparently
due to its reputation in treating leg cramps. However, systematic review of its
effects on RLS/PLMD was inconclusive.22
Medication
Medications can both treat and provoke sleep-related movement disorders. As is
common in pediatrics, there are currently no US Food & Drug Administration-
approved medications for RLS/PLMD. Dopaminergic agonists (ie, carbidopa/
levodopa, pramipexole, ropinirole, and rotigotine) remain popular among adults
for treatment of these conditions. Knowledge of side effects in children is
limited; the potential for augmentation (worsening symptoms as treatment
continues) and dopaminergic effects such as behavioral disinhibition (classi-
cally, impulsive behaviors such as gambling and compulsive sexual behaviors in
adults) tend to concern prescribers, as does the potential for nausea and vomit-
ing.16 Hypnotic supplements and medications used in pediatrics can blunt
symptoms of RLS, possibly due to hastening sleep onset. Melatonin, clonidine,
gabapentin, and pregabalin are generally well tolerated.16 Non-benzodiazepine
hypnotics such as zolpidem, zaleplon, and eszopiclone, should be used with
caution in the pediatric population due to their tendency to provoke parasomnias
and concerns about difficulty weaning off them. Clinicians typically reserve
opioids such as methadone for refractory cases, and there is little guidance for
their off-label use in pediatric RLS/PLMD. Most selective serotonin reuptake
inhibitors, except for bupropion, exacerbate RLS and PLMD.
Lifestyle
Regular physical exercise, consistent sleep schedule with age-appropriate
opportunity for adequate sleep duration, and moderation in caffeine intake
also alleviate symptoms of RLS.16
key points
} Diagnosis of RLS depends on history, not on polysomnographic data.
} Polysomnographic evidence of periodic LMs can support RLS but should not
be the sole basis for diagnosis.
} Signs and symptoms of PLMD occur during sleep; RLS symptoms occur during
wake but can interfere with sleep onset.
} Expert consensus recommends iron supplementation as first-line treatment
in pediatric RLS/PLMD. Serum ferritin levels should be maintained at 50 to
75 mcg/L (50–75 ng/mL).

641
Addressing anxiety via behavioral strategies or outpatient therapy may

lessen sleep bruxism. Some evidence supports mandibular advancement in
adolescents as treatment for sleep bruxism as well, and dental evaluation is
advisable in any case.23
References
1. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed.
American Academy of Sleep Medicine; 2014
2. DelRosso LM, Ferri R, Allen RP, et al; International Restless Legs Syndrome Study Group
(IRLSSG). Consensus diagnostic criteria for a newly defined pediatric sleep disorder: restless
sleep disorder (RSD). Sleep Med. 2020;75:335–340 PMID: 32950015
doi: 10.1016/j.sleep.2020.08.011
3. Picchietti D, Allen RP, Walters AS, Davidson JE, Myers A, Ferini-Strambi L. Restless legs
syndrome: prevalence and impact in children and adolescents—the Peds REST study. Pediatrics.
2007;120(2):253–266 PMID: 17671050 doi: 10.1542/peds.2006-2767
4. Marcus CL, Traylor J, Gallagher PR, et al. Prevalence of periodic limb movements during sleep
in normal children. Sleep. 2014;37(8):1349–1352 PMID: 25083015 doi: 10.5665/sleep.3928
5. Garmroudinezhad Rostami E, Touchette É, Huynh N, et al. High separation anxiety trajectory
in early childhood is a risk factor for sleep bruxism at age 7. Sleep. 2020;43(7):zsz317
PMID: 31894243 doi: 10.1093/sleep/zsz317
6. Gogo E, van Sluijs RM, Cheung T, et al. Objectively confirmed prevalence of sleep-related
rhythmic movement disorder in pre-school children. Sleep Med. 2019;53:16–21
PMID: 30384137 doi: 10.1016/j.sleep.2018.08.021
7. DelRosso LM, Ferri R. The prevalence of restless sleep disorder among a clinical sample of
children and adolescents referred to a sleep centre. J Sleep Res. 2019;28(6):e12870
PMID: 31087450 doi: 10.1111/jsr.12870
8. Allen RP, Picchietti DL, Auerbach M, et al; International Restless Legs Syndrome Study Group
(IRLSSG). Evidence-based and consensus clinical practice guidelines for the iron treatment of
restless legs syndrome/Willis-Ekbom disease in adults and children: an IRLSSG task force
report. Sleep Med. 2018;41:27–44 PMID: 29425576 doi: 10.1016/j.sleep.2017.11.1126
9. Berry R, Quan S, Abreu A, et al. The AASM Manual for the Scoring of Sleep and Associated
Events: Rules, Terminology, and Technical Specifications, version 2.6. American Academy
of Sleep Medicine; 2020
10. Picchietti DL, Bruni O, de Weerd A, et al; International Restless Legs Syndrome Study Group
(IRLSSG). Pediatric restless legs syndrome diagnostic criteria: an update by the International
Restless Legs Syndrome Study Group. Sleep Med. 2013;14(12):1253–1259 PMID: 24184054
doi: 10.1016/j.sleep.2013.08.778
11. Allen RP, Picchietti DL, Garcia-Borreguero D, et al; International Restless Legs Syndrome
Study Group. Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated
International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria—history,
rationale, description, and significance. Sleep Med. 2014;15(8):860–873 PMID: 25023924
doi: 10.1016/j.sleep.2014.03.025
12. de WeerdA, AricòI, SilvestriR. Presenting symptoms in pediatric restless legs syndrome
patients. J Clin Sleep Med. 2013;9(10):1077–1080 PMID: 24127152 doi: 10.5664/jcsm.3086
13. Picchietti DL, Arbuckle RA, Abetz L, et al. Pediatric restless legs syndrome: analysis of
symptom descriptions and drawings. J Child Neurol. 2011;26(11):1365–1376 PMID: 21636777
doi: 10.1177/0883073811405852
14. Aurora RN, Lamm CI, Zak RS, et al. Practice parameters for the non-respiratory indications for
polysomnography and multiple sleep latency testing for children. Sleep. 2012;35(11):1467–1473
PMID: 23115395 doi: 10.5665/sleep.2190
15. Picchietti MA, Picchietti DL, England SJ, et al. Children show individual night-to-night
variability of periodic limb movements in sleep. Sleep. 2009;32(4):530–535 PMID: 19413147
doi: 10.1093/sleep/32.4.530
16. Rulong G, Dye T, Simakajornboon N. Pharmacological management of restless legs syndrome
and periodic limb movement disorder in children. Paediatr Drugs. 2018;20(1):9–17
PMID: 28831753 doi: 10.1007/s40272-017-0262-0
17. Symons FJ, Sperry LA, Dropik PL, Bodfish JW. The early development of stereotypy and
self-injury: a review of research methods. J Intellect Disabil Res. 2005;49(Pt 2):144–158
PMID: 15634323 doi: 10.1111/j.1365-2788.2004.00632.x

642
18. Stepanova I, Nevsimalova S, Hanusova J. Rhythmic movement disorder in sleep persisting

into childhood and adulthood. Sleep. 2005;28(7):851–857 PMID: 16124665
doi: 10.1093/sleep/28.7.851
19. Sander HH, Eckeli AL, Costa Passos AD, Azevedo L, Fernandes do Prado LB, França Fernandes
RM. Prevalence and quality of life and sleep in children and adolescents with restless legs
syndrome/Willis-Ekbom disease. Sleep Med. 2017;30:204–209 PMID: 28215250
doi: 10.1016/j.sleep.2016.10.014
20. Rosen GM, Morrissette S, Larson A, Stading P, Barnes TL. Does improvement of low serum
ferritin improve symptoms of restless legs syndrome in a cohort of pediatric patients?
21. DelRosso LM, Yi T, Chan JHM, Wrede JE, Lockhart CT, Ferri R. Determinants of ferritin
response to oral iron supplementation in children with sleep movement disorders. Sleep.
2020;234 PMID: 31563958 doi: 10.1093/sleep/zsz234
22. Marshal lNS, Serinel Y, Killick R, et al. Magnesium supplementation for the treatment of restless
legs syndrome and periodic limb movement disorder: a systematic review. Sleep Med Rev.
2019;48:101218 PMID: 31678660 doi: 10.1016/j.smrv.2019.101218
23. Carra MC, Huynh NT, El-Khatib H, Remise C, Lavigne GJ. Sleep bruxism, snoring, and
headaches in adolescents: short-term effects of a mandibular advancement appliance. Sleep Med.
2013;14(7):656–661 PMID: 23643652 doi: 10.1016/j.sleep.2013.03.009

CHAPTER
36
Insomnia
Insomnia is the inability to fall asleep or to stay asleep. It is often quite

stressful to both affected children and youth and their parents. In young
children, insomnia is defined as difficulty initiating and maintaining sleep,
waking up earlier than desired, resistance going to bed on appropriate
schedule, or difficulty sleeping without parent or caregiver intervention.
A number of classification systems have been proposed for insomnia. The
International Classification of Sleep Disorders, 3rd Edition (ICSD-3) defines
insomnia as “a repeated difficulty with sleep initiation, duration, consolida-
tion, or quality that occurs despite adequate opportunity and circumstances
for sleep, and results in some form of daytime impairment.” Short-term,
chronic, and other types of insomnia are the three major categories according
to the ICSD-3.1
The most detailed classification system is the older International Classification
of Sleep Disorders, 2nd Edition (ICSD-2). The ICSD-2 classification system
categorizes 11 subtypes of insomnia.2 This chapter will focus only on those
subtypes that primarily affect children.
Major Categories of Insomnia

Short-term insomnia may last for several weeks or up to 3 months. It is usually
caused by severe trauma such as moving, death, divorce, substance use or
withdrawal, or other temporary stressors.1
Chronic insomnia is long-term insomnia that lasts more than 3 months and
can be years or even decades.1 It may be caused by medical or mental illness,
long-term stress and anxiety, sleep-onset association disorders, bedtime
refusal or fears, circadian rhythm disorders, or poor sleep hygiene.
Other Ways of Describing Insomnia

While the sleep disorder of insomnia is principally classified as either short-
term or chronic, there are other terms that may be used to describe when the
insomnia occurs during the night.
643

644
Sleep-onset insomnia, difficulty falling asleep at the beginning of the night, is

commonly caused in pediatric patients by a sleep-onset association disorder,
delayed sleep phase syndrome, or anxiety.2 In adults, stress, anxiety, “not
being able to turn one’s mind off,” going to bed too early when not sleepy,
restless legs syndrome, sleeping in an uncomfortable bed, and a suboptimal
sleep environment (eg, with noise or light) are typical underlying etiologies.2
Sleep maintenance insomnia is defined as repeated awakenings during the
night with difficulty returning to sleep. The underlying causes are similar
to those for sleep-onset insomnia, along with pain or illness.2
Terminal insomnia is awakening early in the morning and not being able
to fall back to sleep when desired. This can be caused by poor sleep quality,
an increased amount of light sleep, sleep-onset association disorder, or,
commonly, anxiety or depression.2 Older adults are most likely to experience
this pattern of insomnia due to advanced sleep phase syndrome, but young
children can be affected as well, especially if, when awakening early in the
morning, they are allowed to return to sleep in their parents’ bed.
Subtypes of Insomnia
The ICSD-2 classifies insomnia into 11 categories, as follows2:
X Adjustment insomnia (acute insomnia)
X Psychophysiological insomnia (primary insomnia)
X Paradoxical insomnia
X Insomnia due to medical condition
X Insomnia due to mental disorder
X Insomnia due to drug or substance abuse
X Insomnia not due to substance or known physiologic condition, unspecified
X Inadequate sleep hygiene
X Idiopathic insomnia
X Behavioral insomnia of childhood (BIC)
X Primary sleep disorders causing insomnia
The main subtypes affecting children are (1) adjustment insomnia,
(2) psychophysiological insomnia, (3) paradoxical insomnia, (4) insomnia
due to medical condition, (5) insomnia due to mental disorder, (6) inadequate
sleep hygiene, (7) idiopathic insomnia, and (8) behavioral insomnia
of childhood.

645
Chapter 36—Insomnia
Adjustment Insomnia
Adjustment insomnia is temporally associated with an identifiable stressor
and expected to resolve.2 Examples of common stressors affecting children
are moving, death, divorce, illness, and disruption in learning due to the
COVID-19 pandemic.
Psychophysiological Insomnia
For older children and adolescents, problems with initiating and maintaining
sleep are typically described using the term psychophysiological insomnia.2
This form of insomnia involves an excessive amount of anxiety and worry
regarding sleep and sleeplessness. The individual’s heightened anxiety about
sleeping for a less-than-adequate amount of time makes falling asleep more
challenging, which, in turn, makes sleep a more negative experience and may
lead to a vicious cycle.3
Paradoxical Insomnia
Paradoxical insomnia is most often attributed to patients with behavioral
or psychological aspects to their insomnia that have negative conditioning/
associations with their usual sleeping locations. The complaint of severe
insomnia occurs without evidence of objective sleep disturbance and without
daytime impairment to the extent that would be suggested by the amount of
sleep disturbance reported. The patient often reports little or no sleep on most
nights.2 These patients sleep better in the sleep laboratory or in a hotel than
they usually do at home.3
Insomnia Due to Medical Condition

Common examples affecting children include obstructive sleep apnea,
restless legs syndrome, eczema, asthma, allergies, gastroesophageal reflux,
fibromyalgia, and medications.2
Insomnia Due to Mental Disorder

Insomnia due to mental disorder is characterized by the onset of the mental
disorder and improves and worsens with the severity of the mental disorder.2
Anxiety, depression, and stress are common examples that can sometimes
affect even young children. Neurodevelopmental disorders such as autism
spectrum disorder or attention-deficit/hyperactivity disorder may also
play a role.
Inadequate Sleep Hygiene

Inadequate sleep hygiene for pediatric patients is characterized by irregular
sleep and wake times, stimulating activities or caffeine near bedtime, or use of
the bed for activities other than sleep.2 For adolescents, this can include the use
of electronic devices prior to sleep, doing homework or watching TV in bed,
and going to bed and waking up much later on weekends than weekdays.

646
Idiopathic Insomnia
Idiopathic insomnia is insomnia present since infancy or childhood,
which has no identifiable precipitant (insidious onset) and no period of
sustained remission.2
Behavioral Insomnia of Childhood

By 3 to 6 months after birth, a term infant’s circadian rhythms have matured
to the point where they may begin to sleep through the night.3 During the first
6 months of infancy, parents should begin to establish healthy sleep habits to
prevent later sleep problems, such as exposing newborns to light and noise
during the daytime but keeping the room dark and quiet at night, particularly
when the baby wakes at night to feed.
One of the main sleep problems arising during the developmental period of
6 months to 2 years is difficulty with self-soothing. Bedtime problems and
frequent night awakenings are highly prevalent in young children, occurring
in 20% to 30% of infants, toddlers, and preschoolers.4
The classical description of BIC includes 3 subtypes.4
Sleep-onset association disorder occurs when children become dependent
on specific associations (eg, rocking, feeding, parental presence, cuddling)
to fall asleep. For example, if the child is used to being rocked to sleep,
when they have a normal night waking on the conclusion of a sleep cycle,
they are unable to fall back to sleep until the nighttime ritual is repeated
(in this case, rocking and the presence of a parent). For older children,
sleep-onset may be associated with watching television or using phones,
tablets, or other electronics.
Limit-setting sleep disorder involves the refusal to go to bed or repeated
requests used as attempts to delay bedtime (eg, asking to use the bathroom,
one more story), and is common in young children. In these cases, parents
demonstrate difficulties in adequately enforcing bedtime limits. Parents
often have difficulties enforcing limits at other times of day as well.
Combined type involves a child having a negative association with sleep
coupled with resistance or refusal to go to bed due to a lack of limit setting
by caregivers. This can be particularly challenging for parents of children
with developmental delay and of children with autism spectrum disorder.5
A referral to a sleep laboratory for a polysomnography study is not necessary
to diagnose behavioral or psychophysiological insomnia, but may be needed
if other primary sleep disorders such as sleep-related breathing disorders,
narcolepsy, or periodic limb movement disorder are being considered. These

647
disorders may present similarly to insomnia as night awakenings or daytime

sleepiness, especially in adults.3
Health care providers should routinely ask parents and the child about sleep:
regularity and duration of sleep, sleep-onset delay, night awakenings, symp-
toms of sleep-disordered breathing, and signs of increased daytime sleepiness
or poor sleep quality. Actigraphy uses a wristwatch-like device to measure
movement, from which sleep can be inferred, allowing for assessment of
sleep-onset latency, wake after sleep onset, total sleep time, and sleep effi-
ciency. It can be useful to guide the individualized diagnosis and treatment of
insomnia. If actigraphy is unavailable, a 2-week sleep diary can provide
similar information if the family is careful in filling it out. Consumer-oriented
products are less reliable.
Management
Behavioral treatments and cognitive restructuring are the most appropriate first
line of treatment for behavioral insomnia and psychophysiological insomnia.
These interventions are based on principles of learning and behavior, includ-
ing reinforcement. Primary goals typically involve some combination of
developing positive sleep-related associations, establishing routines, and
implementing relaxation skills.5
For behavioral insomnia, these interventions frequently rely on parent
training to effect changes in the parent’s behavior, which facilitate changes
in the child’s behavior.
For the treatment of sleep-onset association disorders, the associations are
weaned slowly and gradually until the child is falling asleep and sleeping
independently. Graduated extinction involves parents ignoring bedtime crying
and tantrums for predetermined periods (5–15 minutes) before briefly checking
on the child to facilitate self-soothing.5 Limit setting with young children,
2 to 6 years of age, may involve limiting the number of times the child can
make a request, whereas limit setting for school-aged children, 6 to 11 years of
age, often revolves around how late the child can watch television, snack, do
homework, or use the internet. A consistent bedtime routine and addressing
nighttime fears can help reduce negative associations with sleep.
Interventions for the adolescent with inadequate sleep hygiene include educa-
tion, incorporating relaxation strategies into a bedtime routine, sleep restriction
(ie, limiting time in bed based on how long one actually sleeps), and using the
bed only for sleep to create more positive associations with sleeping and a
greater physiologic pressure for sleep. Avoiding light exposure when waking
at night will prevent suppression of melatonin.

648
Cognitive behavioral therapy for insomnia is a highly effective and evidence-

based approach consisting of cognitive restructuring (reshaping negative
thought patterns), stimulus control (weakening association of being awake in
bed), sleep restriction (gradually decreasing the amount of time spent in bed
awake), and sleep hygiene (incorporating a bedtime routine and good sleep
habits) therapies for psychophysiological insomnia in adolescents and adults.3
Hypnotic medications may provide rapid, short-term improvements to sleep
problems in adults, but medications typically do not have long-term positive
effects on sleep and patients often develop physiologic and psychologic
dependence and tolerance.
There are no medications approved by the US Food & Drug administration
for treatment of insomnia in children, and there are concerns about the safety
and side effects of using these medications off-label. Children may develop
physiologic and psychologic dependence and tolerance to over-the-counter
sleep aids as well.4
Expected Outcomes/Prognosis
A growing body of literature suggests that behavioral interventions for
childhood insomnia are effective. Behavioral interventions lead not only to
improvements in children’s sleep, but also to improvements in child behavior
and parental well-being. Similarly, cognitive restructuring and behavior
changes in childhood can lead to long-lasting improvements in the sleep of
adolescents and adults.
A referral to a sleep medicine specialist may be needed for any persistent
and complex cases, especially those that require pharmacotherapy or involve
concerns for underlying sleep-breathing disorders. Behavioral insomnia in
children with autism spectrum disorder, attention-deficit/hyperactivity disor-
der, and anxiety and mood disorders might warrant a referral to developmental
pediatrics or neurology.4 Referral to psychology or psychiatry may be needed
if there is underlying anxiety or depression contributing to the insomnia in a
child of any age.
Insomnia is most effectively treated on an outpatient basis with a customized
treatment plan including parent training, cognitive behavioral therapy, and
frequent follow-up.
Prevention
The best strategy for reducing sleep problems in infants and children is to
educate parents to prevent sleep issues from starting. Newborns have a physio-
logic need to wake during the night to feed.4 By 2 to 3 months, parents can
start being aware of trying not to create adverse sleep associations (eg, putting
the child to sleep when drowsy but without rocking or feeding). Sleep-onset

649
associations can be modified at any age, but it becomes more difficult and
requires more time as the child grows older. Sleep hygiene plays an important
role in virtually all sleep interventions and typically involves a combination
of creating an environment that is conducive to sleep and engaging in healthy
sleep habits in all ages. Educating adolescents, particularly on keeping regular
schedules, limiting use of electronics at night, and not sleeping in exces-
sively on weekends (more than 1 hour later than on weekdays), allows them
an opportunity to consciously make informed choices about their sleep
habits. Parents should be aware of the recommended amounts of sleep per
age.6
key points
} Medication should rarely be the first option for the treatment of insomnia. If
used, medication should always be combined with behavioral interventions
and cognitive behavioral therapy.
} Behavioral strategies that are customized to the individual family situation
have a higher chance of success than a “one model fits all” approach.
References
1. American Academy of Sleep Medicine. Chronic insomnia disorder. In: International
Classification of Sleep Disorders. 3rd ed. American Academy of Sleep Medicine; 2014:21–41
2. American Academy of Sleep Medicine. International Classification of Sleep Disorders:
Diagnostic and Coding Manual. 2nd ed. American Academy of Sleep Medicine; 2005:51–55
3. Perlis ML, Gehrman P. Types of Insomnia. Encyclopedia of Sleep. Elsevier Inc; 2013:1–4
4. Mindell JA, Kuhn B, Lewin DS, Meltzer LJ, Sadeh A; American Academy of Sleep Medicine.
Behavioral treatment of bedtime problems and night wakings in infants and young children.
Sleep. 2006;29(10):1263–1276 PMID: 17068979
5. Vriend J, Corkum P. Clinical management of behavioral insomnia of childhood. Psychol Res
Behav Manag. 2011;4:69–79 PMID: 22114537
6. Paruthi S, Brooks LJ, D’Ambrosio C, et al. Recommended amount of sleep for pediatric
populations: a consensus statement of the American Academy of Sleep Medicine. J Clin Sleep
Med. 2016;12(6):785–786 PMID: 27250809 doi: 10.5664/jcsm.5866

CHAPTER
37
Parasomnias
Introduction
Parasomnias are undesirable physical events or experiences that occur during
entry into sleep, within sleep, or during arousal from sleep. They may occur
during non-rapid eye movement (NREM) sleep, rapid eye movement (REM)
sleep, or transitions to and from sleep.1
Many parasomnias emerge and peak during the childhood years, the most
common being the arousal parasomnias: confusional arousals, sleep terrors,
nightmares, and somnambulism or sleepwalking.1 Confusional arousals occur
in 17.3% of children aged 3 to 13 years. Sleepwalking has an 18.3% lifetime
prevalence, and sleep terrors are experienced by 1% to 6.5% of children and
2.2% of adults. Rarely, these continue to adulthood, but another group of
rare parasomnias is only experienced by adults: REM behavior disorder,
sleep-related eating disorder, and sexsomnia.2
Pathophysiology
The arousal parasomnias have similar predisposing characteristics and
triggers, suggesting common pathophysiology. Parasomnias tend to be
common in families, so there may be a genetic factor. A history of sleep-
walking or sleep talking in other family members of a child experiencing
parasomnias is common. Parasomnias may be triggered by increased arousals
from sleep, including from underlying obstructive sleep apnea, restless legs
syndrome, periodic limb movement disorder, or gastroesophageal reflux.2
Other triggers can be any disruption to the person’s normal sleep pattern,
including sleep deprivation, fever and illness, travel, and sleeping in a new
or unfamiliar environment. These disorders are most common in childhood,
particularly the preschool age, and usually resolve by adolescence except
for a rare few.
651

652
Clinical Features
Non-Rapid Eye Movement Sleep Disorders of Arousal
Disorders of arousal in NREM sleep result from an incomplete arousal and
occur at the transition from deep NREM (stage N3) sleep into the lighter
stages of NREM sleep or from stage N3 into the awake state. They are most
prevalent during the first third of nocturnal sleep because N3 sleep is most
prominent early in the night.2 Since the events occur during deep N3 sleep,
the child is oblivious to surroundings, is difficult to awaken, and has no
memory of the event in the morning.
Confusional Arousals
Confusional arousals occur mainly in infants and toddlers and begin with
whimpering or moaning, then evolve to calling out or crying. The child cries
out words like “no” or “go away,” appears distressed, and remains inconsol-
able. They may appear confused, with eyes open or closed, very agitated or
even combative. Episodes may last 5 to 15 minutes before the child calms and
returns to sleep. Reassuring comments in a soothing voice may help calm the
child, but often parental presence or trying to wake the patient may prolong
the episodes.
Sleep Terrors
Sleep terrors are more intense than confusional arousals. Episodes begin
with a loud scream and an intense look of fear, mydriasis, sweating, and
tachycardia; episodes can last several minutes.2 The child is unaware of
the caregiver’s presence and will be confused and disoriented if awakened.
As with confusional arousals, attempts to console the child may prolong or
intensify the episode. Thrashing or other bodily movement is common, and
the child tends not to remember the episode in the morning. Recording events
with a video can be helpful for diagnosis. Sleep terrors usually self-resolve as
the child grows older.
Somnambulism
Mild episodes of somnambulism, in which a toddler sits up and crawls around
the bed or an older child walks to the bathroom, may initially go unnoticed.
Some patients exhibit a combination of sleep terrors and sleepwalking, though
one type usually predominates. Patients may be found walking into a parent’s
room, bathroom, or different parts of the house. They can negotiate obstacles
and seem to be awake. A video can be helpful for diagnosis. Some patients
have injured themselves by attempting to walk downstairs or climb through
windows, or by leaving the house. As with other arousal disorders, sleepwalk-
ers are unaware of the presence of other people. They are difficult to awaken
and may be confused on arousal, but no harm will result from awakening
them. The house should be made safe, with dangerous objects such as knives

653
Chapter 37—Parasomnias
locked away, and doors and windows secured. Tying a bell to the door of their
room can alert the parents, who can gently guide the child back to bed.2
Increasing total sleep time by as little as half an hour a night and maintaining
a regular sleep-wake schedule may decrease or prevent episodes. Anticipatory
awakening about 15 to 20 minutes prior to the usual time of occurrence may
modify the sleep state and prevent the event in some cases. A low dose of a
benzodiazepine (eg, clonazepam) may be used to treat persistent, severe, and
frequent episodes, but most cases do not require treatment with medication.2
Patients should be informed about the usually benign and self-limiting
nature of parasomnias. Sleep quality and daytime function generally remain
unaffected; the events do not lead to brain damage or cognitive problems.
Similar to sleep terrors, symptoms usually will resolve as children grow
older or reach puberty.2,3
Disorders of Rapid Eye Movement Sleep

Since REM sleep predominates during the final third of the night, these
disorders generally occur in the early hours of the morning. Because muscle
tone is inhibited during REM sleep, bodily movement is rare.2
Nightmares
Nightmares may be from an identifiable source such as a frightening movie
or video game, but, more commonly, they come from unspecific fears. They
tend to be more common in patients with a history of post-traumatic stress
disorder and anxiety. There is little confusion or disorientation involved;
the person is often able to recall clear details upon awakening. Management
includes reassurance/comforting, treatment of underlying anxiety disorder if
one exists, writing down the content or drawing pictures of the nightmare,
and changing the ending to a more pleasant conclusion for recurring
nightmares (imagery rehearsal).2
Rapid Eye Movement Behavior Disorder
REM behavior disorder is characterized by aggressive motor behavior as part
of dream enactment that results from a loss of muscle atonia during REM
sleep and may lead to injury.
REM behavior disorder occurs in less than 1 percent of adults (usually in men
older than 50 years) and is even less common in children. Treatments include
melatonin and benzodiazepines (such as clonazepam) and discontinuing
medications known to exacerbate RBD (including selective serotonin
reuptake inhibitors).2
Sleep Groaning/Catathrenia
Sleep groaning, or catathrenia, occurs during the exhalation phase in
REM sleep. It is different from, but may be confused with, snoring, which
occurs during inspiration.4 A video of the events can be helpful, and a

654
polysomnogram may be supportive of a diagnosis of catathrenia. It is not

typically noticed by the person producing the sound but can be disruptive
to the family. In the few published cases, most patients, whether adult or
pediatric, complained of daytime fatigue. In adult patients with catathrenia,
decreased airflow, oxygen desaturation, arousals, and hypoventilation have
been seen on polysomnograms. Nocturnal groaning/moaning, fatigue, dis-
rupted and poor family sleep, morning grogginess, and behavioral problems
were also associated with catathrenia.4 Due to the rarity of this disorder,
long-term effects and prognosis are largely unknown. There are no known
anatomical underlying causes, including otolaryngologic or vocal cord
abnormalities. Continuous positive airway pressure may be an effective
treatment even if obstructive sleep apnea is not present.5
Sleep-Related Hallucinations
Patients see, hear, feel, or smell something that does not exist during sleep.
Hallucinations that occur while falling asleep are called hypnagogic; those
upon waking from REM sleep are called hypnopompic. They have a close
association with sleep paralysis, somnambulism, and somniloquy. Narcolepsy,
anxiety, and sleep deprivation can be underlying causes.6
NREM Parasomnias
Non-rapid eye movement parasomnias occur during partial arousals in
slow-wave sleep.
Bruxism
Bruxism is an involuntary and forceful clenching, grinding, or rubbing of teeth
during NREM sleep that can be associated with anxiety and some neurodevel-
opmental disorders. A dental evaluation can be helpful, especially if there is
associated jaw pain. The patient, especially if older, can be fitted with a mouth
guard to prevent grinding down of the teeth.6
Rhythmic Movement Disorder
Rhythmic movement disorders may manifest as headbanging, body rocking,
or other movements. In some infants and toddlers, this starts at sleep onset and
when attempting to fall back to sleep. These movement disorders are thought
to be a form of self-soothing, and parents can be reassured that they generally
resolve spontaneously by the age of 3 to 4 years.7
Nocturnal Enuresis
The possibility of obstructive sleep apnea should be considered in children
presenting with nocturnal enuresis, particularly if they have one or more of
the following: habitual snoring or observed apneas, obesity, adenotonsillar
hypertrophy and/or mouth breathing, or secondary enuresis.8 This improves
with age, although about 3% of army recruits have been known to wet the

655
bed. Bell and pad devices can alert the child that enuresis is beginning.
Medications such as imipramine have also been used.8
Sleep Paralysis
In sleep paralysis, atonia that normally occurs during REM sleep intrudes
into wakefulness at sleep onset or when waking up. It may last for several
seconds to minutes and may be terrifying. Consciousness is preserved as well
as awareness of surroundings, but the person is unable to move and may feel
pressure on the chest or experience hallucinations. Sleep paralysis is often
associated with narcolepsy (see Chapter 38, Narcolepsy and Other Disorders
of Excessive Somnolence), but a form known as recurrent isolated sleep
paralysis can occur with anxiety and sleep deprivation.8
Sleep-Related Eating Disorder
Sleep-related eating disorder is characterized by recurrent episodes of
involuntary binge eating after partial awakening from sleep in the absence
of hunger or thirst. There is a partial or complete amnesia for eating episodes,
a strong association with other parasomnias, and a high frequency of arousals
from slow-wave sleep. Ingesting inedible materials is common, and sleep-
related eating disorder may result in injuries from food preparation, weight
gain, abnormal lipid levels, diabetes, and dental caries.9 Sleep-related eating
disorder is similar to somnambulism in that the patient is not really awake
and has no recollection of the episodes. It is important to distinguish from
night-eating syndrome, in which there is a period of insomnia prior to food
intake and the patient is actually awake.
Sexsomnia
Sexsomnia encompasses behaviors that occur during sleep, including sexual
intercourse, sexual assault, masturbation, sexual vocalizations, and fondling.
These events can be increased with shift work, with use of selective serotonin
reuptake inhibitors, and in patients with Parkinson disease.10 Very rarely has
a sexsomnia defense been successfully used in a case of sexual assault or
abuse. Some studies have shown improvement with clonazepam or effectively
treating underlying obstructive sleep apnea. Though sexsomnia is generally
seen in adults, there have been a few reported cases of teenagers with
this condition.
Kleine-Levin Syndrome
While both disorders are rare and intermittent, Kleine-Levin syndrome
(KLS) is also characterized by cyclic episodes of hypersomnia, hyperphagia,
hypersexuality, and cognitive or mood changes. The hypersexuality of KLS
differs from sexsomnia because the former occurs during wakefulness.11
When present, symptoms of KLS may persist for days, weeks, or even
months, during which everyday activities cease.

656
Exploding Head Syndrome

A benign disorder that is characterized by the sensation of a sudden loud noise
or explosive crashing sound that occurs during the transition from sleep onset
or awakening, occurring daily to weekly. The episodes can wake the person up
abruptly just as they are starting to fall asleep or begin to wake up.12 They can
be terrifying and accompanied by flashes of light or myoclonic jerks. Usually,
treatment is not needed, other than reassurance.
Nocturnal seizures can mimic sleep terrors. Sleep terrors can be easily
confused with nightmares. Table 37-1 breaks down the differences between
these 3 parasomnias.
Table 37-1. Differential Diagnosis of Parasomnias

Feature Sleep Terrors Nightmares Nocturnal Seizures
Age of onset Childhood Childhood Any age
Family history of Often present Nonfamilial May or may not
similar events be present
Time of occurrence First one-third of Final one-third of Sleep onset
night sleep the night
Frequency of events Can be separated by Nightly or Nightly
weeks or months separated by
weeks/months
Most common sleep Slow-wave sleep Rapid eye Stages I or II of
stage at occurrence movement (REM) non-rapid eye
sleep movement sleep
Duration of event 5–30 minutes Less than 5 minutes 0.5 to 5 minutes
Description of events Non-stereotypical Little movement Stereotypical
movements movements
Post-event symptoms None; no recollection Full alertness Postictal symptoms:
of episode generally returns headache, extreme
immediately upon grogginess, hard to
awakening arouse, as well as
incontinence of
urine or stool
Electroencephalogram No No Yes
abnormalities
Structural central No No Possibly
nervous system lesion
Derived from Boursoulian LJ, Schenck CH, Mahowald MW, Lagrange AH. Differentiating parasomnias from
nocturnal seizures. J Clin Sleep Med. 2012;8(1):108–112.

657
Indications for Polysomnography

Nocturnal polysomnography (PSG) is usually not needed in patients with
arousal parasomnias. Indications for PSG include habitual snoring, observed
apneas, daytime somnolence, behavioral problems, and mood disturbance,
suggesting sleep fragmentation from underlying obstructive sleep apnea. Leg
discomfort or involuntary jerking movements during sleep are suggestive of
restless legs syndrome or periodic limb movements during sleep.13 While
restless legs syndrome usually occurs during wakefulness (see Chapter 35,
Sleep-Related Movement Disorders), PSG may be useful to quantitate sleep
fragmentation from periodic limb movements of sleep. Atypical features that
raise concern for nocturnal seizures include daytime neurologic symptoms,
highly stereotyped behaviors, older age group, multiple occurrences on a
single night, and very frequent occurrences (eg, several nights each week).
(See Table 37-1.) In this case, the polysomnogram should include extra
electroencephalogram leads to better detect and qualify any seizures.2
key points
} Asking the parent to video record the suspected parasomnia can be helpful in
determining the diagnosis because patients may have no memory of the
episodes or have difficulty articulating what they felt.
} Often, there is a history of sleepwalking or sleep talking in other family
members of a child experiencing parasomnias.
} Medication can be helpful in severe or very frequent cases, but generally all that
is needed is reassurance and/or regulation of the patient’s sleep-wake schedule.
Most parasomnias tend to improve by puberty.
References
1. American Academy of Sleep Medicine. Parasomnias. International Classification of Sleep
Disorders. 3rd ed. American Academy of Sleep Medicine; 2014:225–278
2. Mason TBA II, Pack AI. Pediatric parasomnias. Sleep. 2007;30(2):141–151 PMID: 17326539
doi: 10.1093/sleep/30.2.141
3. Klackenberg G. Somnambulism in childhood—prevalence, course and behavioral correlations.
A prospective longitudinal study (6-16 years). Acta Paediatr Scand. 1982;71(3):495–499
PMID: 7136663 doi: 10.1111/j.1651-2227.1982.tb09458.x
4. Guilleminault C, Hagen CC, Khaja AM. Catathrenia: parasomnia or uncommon feature of sleep
disordered breathing? Sleep. 2008;31(1):132–139. doi: 10.1093/sleep/31.1.132
5. Petitto L, Com G, Jackson R, Richter G, Jambhekar S. Catathrenia and treatment with positive
airway pressure in the pediatric population. J Clin Sleep Med. 2019;15(12):1853–1857
PMID: 31855170 doi: 10.5664/jcsm.8100
6. Singh S, Kaur H, Singh S, Khawaja I. Parasomnias: a comprehensive review. Cureus.
2018;10(12):e3807 PMID: 30868021
7. Sheldon SH. Parasomnias in childhood. Pediatr Clin North Am. 2004;51(1):69–88, vi
PMID: 15008583 doi: 10.1016/S0031-3955(03)00177-9

658
8. Kotagal S. Parasomnias in childhood. Sleep Med Rev. 2009;13(2):157–168 PMID: 19064329

doi: 10.1016/j.smrv.2008.09.005
9. Allison KC, Tarves EP. Treatment of night eating syndrome. Psychiatr Clin North Am.
2011;34(4):785–796 PMID: 22098804 doi: 10.1016/j.psc.2011.08.002
10. Contreras JB, Richardson J, Kotagal S. Sexsomnia in an Adolescent. J Clin Sleep Med.
2019;15(3):505–507 PMID: 30853039 doi: 10.5664/jcsm.7686
11. Arnulf I, Zeitzer JM, File J, Farber N, Mignot E. Kleine-Levin syndrome: a systematic review
of 186 cases in the literature. Brain. 2005;128(Pt 12):2763–2776 PMID: 16230322
doi: 10.1093/brain/awh620
12. Frese A, Summ O, Evers S. Exploding head syndrome: six new cases and review of the literature.
Cephalalgia. 2014;34(10):823–827 PMID: 24907167 doi: 10.1177/0333102414536059
13. Kushida CA, Littner MR, Morgenthaler T, et al. Practice parameters for the indications for
polysomnography and related procedures: an update for 2005. Sleep. 2005;28(4):499–521
PMID: 16171294 doi: 10.1093/sleep/28.4.499

CHAPTER
38
Narcolepsy and Other Disorders
of Excessive Somnolence
Introduction
Excessive daytime somnolence (EDS) is the inability to stay awake or
adequately alert during the time of the day when the person should not be
asleep. Adequate alertness is important for good health, optimal academic
and physical performance, and avoiding accidental injuries and motor
vehicle crashes. Excessive daytime somnolence may manifest in various
ways as reported by the patient or the parent/guardian: increased tendency
to fall asleep, low energy or motivation, crankiness, moodiness, irritability,
crying, hyperactivity, inattention, memory impairment, decreased school
perfomance, behavioral problems, increased tendency for errors/accidents,
excessively long night sleep, or persistence of naps past the age they
should have been outgrown or recurrence of previously discontinued
daytime napping.1
Etiology
The most common etiologies for EDS are
X Inadequate amount of sleep relative to the person’s needs. This may
be voluntary/purposeful (eg, to have more time for homework, sports,
reading, socializing, watching TV) or because of an innate inability
to fall asleep or stay asleep (insomnia).
X Disruption of sleep. This may be due to extrinsic/environmental
factors (eg, light, noise) or intrinsic causes (eg, obstructive sleep
apnea syndrome [OSAS] or other sleep disorders).
X Inappropriate timing of sleep, as may occur with jet lag or in teens
whose internal clock is out of synch with conventional time.
659

660
Less common, but often underdiagnosed, are central disorders of hyper-

somnolence. This group of disorders encompasses clinical situations in
which the primary manifestation of EDS is not due to disrupted nocturnal
sleep (eg, from OSAS) or circadian rhythm misalignment. These include
insufficient sleep syndrome and narcolepsy (discussed in the following text),
as well as idiopathic hypersomnia, Kleine-Levin Syndrome, hypersomnia
due to a medical disorder, hypersomnia due to a medication or substance,
and hypersomnia associated with a psychiatric disorder. In as much as it
is possible, it is important to reach an accurate diagnosis of the etiology of
the EDS to be able to choose the most appropriate therapy. Many conditions
produce sleepiness and can mimic, and often coexist with, a hypersomnia of
central origin. These include OSAS, periodic limb movements, insufficient
sleep, psychiatric disorders, sedating medications, and circadian rhythm
disorders. Once properly identified, such a primary or concomitant disorder
should be treated with specific interventions, including the use of central
nervous system (CNS) stimulants, if needed.
The overall prevalence of EDS in the pediatric population is not accurately
known, with one study reporting that it was a complaint in 14% of the
children at 2 general pediatric clinics.2
Diagnostic Tests
The evaluation of a child presenting with EDS centers on a thorough
sleep history. This should include the child’s sleep habits: the typical
time the child gets into bed, falls asleep, and wakes up. From this infor-
mation, the clinician can estimate the typical amount of sleep obtained by
the patient and then compare that to what is typical for age (see Box 38-1).
Box 38-1
Recommended Amounts of Sleep for Pediatric Populations
The American Academy of Sleep Medicine Consensus Statement on Recommended
Amount of Sleep for Pediatric Populations (endorsed by the American Academy of
Pediatrics) states the following amounts of sleep should be obtained per 24 hours
on a regular basis to promote optimal health:
ū Infants aged 4 months to 12 months: 12 to 16 hours (including naps)
ū Children aged 1 to 2 years: 11 to 14 hours (including naps)
ū Children aged 3 to 5 years: 10 to 13 hours (including naps)
ū Children aged 6 to 12 years: 9 to 12 hours
ū Teenagers aged 13 to 18 years: 8 to 10 hours
Derived from Paruthi S, Brooks LJ, D’Ambrosio C, et al. Recommended amount of sleep for pediatric
populations: a Consensus Statement of the American Academy of Sleep Medicine. J Clin Sleep Med.
2016;12(6):785–786.

661
Chapter 38—Narcolepsy and Other Disorders of Excessive Somnolence
A more accurate assessment can be obtained with sleep diaries and with
actigraphy devices. Consumer sleep technologies, including wearable
devices, may allow for meaningful conversations with patients and increase
active participation in their health care, but data regarding the validity and
accuracy of such devices are currently lacking.3,4 The bedtime routine should
be evaluated for behaviors or activities, on the part of both the patient and
the parent/guardian, that may be contributing to difficulty with initiation or
maintenance of sleep. Questions regarding the sleep environment should be
targeted toward factors that would make it less conducive to sleep (ideally
the bedroom should be dark, quiet, and comfortably cool [23.8˚C (< 75˚F)]).
Inquire if there are alerting activities that are performed in bed (eg, using
electronics, reading, homework, eating) during any part of the day. Ask
about symptoms that are specific for sleep disorders (eg, snoring, difficulty
falling asleep or staying asleep, narcolepsy symptoms). If there are such
symptoms, then further investigation should be directed towards them,
such as performing an overnight polysomnogram (sleep study) or referral
to a pediatric sleep medicine specialist as clinically indicated. The medical
history should be explored for conditions and medications that may inter-
fere with sleep or directly cause excessive somnolence. Screening for
psychiatric disorders, as well as substance use, is also indicated because
many of these involve sleep disturbances. The severity of daytime sleepiness
can be quantified subjectively using tools such as the modified (pediatric)
Epworth Sleepiness Scale (Box 38-2), which can be completed by the
patient or the caregiver.
A diagnostic polysomnogram is indicated if there is clinical suspicion that
the daytime sleepiness is due to OSAS or narcolepsy. The former would
be the case if the daytime sleepiness is accompanied by habitual snoring,
observed apneas, or labored breathing during sleep. The determination
of whether an individual has isolated (benign) snoring or OSAS cannot
reliably be made clinically but should be based on a polysomnogram.1
A polysomnogram may also be indicated in the absence of these respira-
tory symptoms if the patient has a medical condition such as obesity,
craniofacial anomalies, certain genetic syndromes, or neuromuscular
disease, since these would place the patient at a particularly high risk for
having OSAS and/or obesity hypoventilation. If narcolepsy is suspected,
a multiple sleep latency test (MSLT) should be performed in the daytime
following the polysomnogram.
While restless legs syndrome is a clinical diagnosis, at times an overnight
polysomnogram is performed to obtain supportive evidence in the form
of an elevated Periodic Limb Movement Index.1,5

662
A MSLT is indicated if there is clinical suspicion for the diagnosis of

narcolepsy or idiopathic hypersomnia, or if there is a specific clinical need
to objectively measure the severity of the daytime sleepiness.1,6 Clinicians
should keep in mind that these various measures of daytime sleepiness
(history, questionnaires, MSLT) do not always correlate with each other
and must be used with appropriate clinical judgment.1
Box 38-2
The Epworth Sleepiness Scale (for ages 4 years and up).
How likely is your child to doze off or fall asleep in the following situations, in
contrast to feeling just tired?
This refers to your usual way of life in recent times. Even if your child has not
done some of these things recently, try to work out how the situation would have
affected them. Use the following scale to choose the most appropriate number
for each situation:
0 = No chance of dozing
1 = Slight chance of dozing
2 = Moderate chance of dozing
3 = High chance of dozing
Situation Chance of Dozing:

Sitting and reading (or during storytelling):
Watching TV:
Sitting inactive in a public place (eg, a movie theater):
As a passenger in a car for an hour without a break:
Lying down to rest in the afternoon:
Sitting and talking to someone:
Sitting quietly after lunch (eg, in class):
In a car, while stopped for a few minutes in traffic:
Total:
A total score of ≥ 10 is considered to be abnormal.
From Melendres MC, Lutz JM, Rubin ED, Marcus CL. Daytime sleepiness and hyperactivity in children with
suspected sleep-disordered breathing. Pediatrics. 2004;114(3):768–775.

663
Treatment
Treatment strategies should be directed at the underlying etiology. For those
who have insufficient sleep, increase the amount of sleep. This may be as
simple as increasing the time in bed (more opportunity for sleep) or may
involve treatment of underlying insomnia. (See Chapter 36, Insomnia.) Habits
or environmental factors that may be interfering with getting a good night’s
sleep should be corrected. OSAS, if present, should be treated. (See Chapter
33, Obstructive Sleep Apnea Syndrome) If the EDS seems to be caused
by a medication, then it should be stopped or switched to a nonsedating
alternative, if permitted by clinical circumstances. Psychiatric disorders
and substance use should be addressed.
Insufficient Sleep Syndrome

Insufficient sleep syndrome is the most common entity among central disor-
ders of hypersomnolence7 and is basically chronic volitional sleep restriction.
Individuals with this syndrome show excessive daytime sleepiness, fatigue,
and reduced sleep at night as a result of electing overly demanding daytime
schedules or by volitionally delaying sleep to engage in desired workplace,
recreational, or social activities.8 However, when allowing themselves suffi-
cient time to sleep, these individuals are able to initiate and maintain sleep
easily and for a normal duration.9 This is in contrast to those with chronic
insomnia disorder, who tend to have excessive wake time and reduced sleep
time despite routinely allotting sufficient time to sleep.10 Moreover, chronic
insomnia disorder is not typically associated with excessive daytime sleepi-
ness and unintentional daytime sleep episodes, which are often observed
in those with patterns of volitional sleep restriction.8 Insufficient sleep
syndrome is usually apparent on viewing a sleep diary or on actigraphy,
and a polysomnogram is rarely needed.
Narcolepsy
Narcolepsy in childhood is under-recognized and underdiagnosed, often
mistaken for behavioral or mood disorders. Narcolepsy is characterized by
excessive daytime sleepiness and symptoms of rapid eye movement (REM,
stage R) sleep dissociation, meaning that there is intrusion of REM sleep
into wakefulness. There are 2 diagnostic subtypes: narcolepsy type 1
(with cataplexy) and type 2 (without cataplexy).1
The main symptoms of narcolepsy are cataplexy, excessive daytime sleepi-
ness, hypnogogic or hypnopompic hallucinations, sleep paralysis, and sleep
disruption. The presence of cataplexy is specific and diagnostic for narcolepsy
type 1, while the other symptoms can also occur with other sleep disorders,

664
or even in normal healthy people. The body is relatively atonic during stage R
sleep, which is when dreams occur. Cataplexy is the intrusion of this aspect
of stage R sleep into wakefulness, resulting in recurrent episodes of loss of
muscle tone without loss of consciousness. These are generally sudden, brief
(< 2 minutes), and bilaterally symmetrical. The paralysis usually evolves
gradually, first affecting the face and neck and then progressing to the trunk
and limbs. Respiratory muscles are not involved, but some patients may feel
a sensation of dyspnea. Positive motor events (eg, muscle twitching or small
jerks, especially of facial muscles) are not uncommon. There is great inter-
personal variation in severity and triggers. While some patients with narco-
lepsy have multiple attacks per day, some have them less than once a month.
The degree of muscle weakness can range from very subtle (unsteady gait or
drooping of eyelids, jaw, or shoulders that may not even be noticeable to others)
to dramatic (generalized muscle atonia with collapsing to the ground). The
typical trigger is a strong positive emotion (eg, laughter, surprise), but nega-
tive emotions (eg, anger) can also induce an episode. Cataplexy is triggered
only by laughter for some patients, while others may have multiple emotional
triggers, and sometimes there is no clear relation to emotions.1,11
Excessive daytime somnolence is the most common and often the most
debilitating symptom that occurs in individuals with narcolepsy. It is also the
least specific symptom, as evidenced by the long list of potential etiologies
detailed in the previous text. Patients with narcolepsy typically experience
repeated daily episodes of unintentional lapses into sleep. Unlike patients
with other sleep disorders (eg, OSAS), patients with narcolepsy typically
wake up feeling relatively refreshed after a full night’s sleep or a brief nap
but then begin to feel sleepy again after variable times (perhaps 1–2 hours),
especially when sedentary. Be mindful that, as detailed above, sleepy
children can have seemingly paradoxical symptoms that appear more
typical of mood or behavioral disorders.1,11
The other 2 symptoms, hallucinations and sleep paralysis, are also not
specific for narcolepsy. In both of these situations, stage R sleep phenomena
(dreaming and muscle atonia) intrude into wakefulness. The hallucinations
are vivid, dreamlike experiences (visual, auditory, and/or tactile) that occur
during transition between wake and sleep. They may be frightening and
involve the perception that there is someone or something in the room. They
may occur upon falling asleep (hypnagogic hallucinations) or upon waking
(hypnopompic hallucinations). Unlike psychotic episodes, these rarely involve
complex auditory hallucinations or fixed delusions. Such hallucinations are
estimated to occur in about 20% of the general population.

665
Sleep paralysis is the temporary inability to move the body’s voluntary

muscles occurring during the transition between wake and sleep. During
these episodes, the person is awake and conscious but is unable to move at
all (including limbs or sometimes even opening the eyes). Episodes may last
for a couple of minutes, can be very frightening, and may also include a sen-
sation of dyspnea because the accessory respiratory muscles can be affected
(yet breathing will continue because the diaphragm, an involuntary muscle,
remains unaffected).1 The reported prevalence of sleep paralysis among
people with narcolepsy varies from about a quarter12,13 to about two-thirds.14,15
In comparison, the lifetime prevalence of at least one episode of sleep
paralysis is 7.6% of the general population, 28.3% of college students,
and 31.9% of psychiatric patients.16
Etiology
Narcolepsy type 1 is caused by a deficiency in CNS hypocretin (also known
as orexin), most likely caused by a selective loss of hypothalamic hypocretin-
producing neurons.11 A strong association with certain human leukocyte
antigen (HLA) subtypes (DR2/DRB1*1501, DQB1*0602) suggests the involve-
ment of an autoimmune process in the destruction of these hypocretin-releasing
brain regions.17 The specific triggering event is unknown, with varying lines
of evidence implicating various environmental factors such as trauma or
infections (including β-hemolytic streptococcus and viruses such as influenza)
and, in rare instances, also physical damage resulting from strokes, trauma,
tumors, and neurologic disease.11 The genetic and environmental factors
associated with narcolepsy type 2 are unknown.11,18
Epidemiology
Narcolepsy type 1 occurs in 0.02% to 0.18% of people in the United States.19
The prevalence of narcolepsy type 2 is more uncertain but is thought to
represent a minority (about 15% to 25%) of the total population of patients
with narcolepsy.1 Both sexes are affected, with a slight preponderance of
males.1 Typically, the age of onset is between 10 and 20 years11 (only rarely
prior to age 4 years20), but the diagnosis may not be made for decades after
symptom onset.
Diagnostic Tests
Multiple Sleep Latency Test
An overnight polysomnogram followed the next morning by an MSLT test is
indicated if there is clinical suspicion for the diagnosis of narcolepsy.1,21 The
MSLT is a validated tool used to obtain an objective measure of sleepiness
and evaluate for the emergence of REM sleep during even brief periods of
sleep. It is based on the premise that the sleepier the patient, the faster they will
fall asleep. During the MSLT, a patient in the sleep laboratory is given 5 nap

666
opportunities at 2-hour intervals starting 1.5 to 3 hours after the end of the
nocturnal polysomnogram.6 The patient is given 20 minutes to fall asleep, and
20 minutes after sleep onset to achieve REM sleep. An MSLT with a mean
sleep latency of 8 minutes or less and 2 or more sleep-onset REM periods is
needed for the diagnosis of narcolepsy.
Cerebrospinal Fluid Hypocretin-1
The diagnosis of narcolepsy type 1 can also be established if cerebrospinal
fluid (CSF) hypocretin-1 concentrations, as measured by immunoreactivity,
are either at or below 110 pg/mL or less than one-third of normal for that
specific assay. The measurement of CSF hypocretin-1 is not needed for the
diagnosis of narcolepsy type 2, but, if performed, it needs to be either greater
than 110 pg/mL or greater than one-third of normal for that specific assay.
Genetic Analysis
Genetic analysis has some limited utility in the diagnosis of narcolepsy.
Approximately 12% to 38% of the general population carries the DQB1*0602
genotype. This subset of the population includes virtually all individuals with
narcolepsy type 1; thus, a negative HLA test would make the diagnosis of
narcolepsy type 1 exceedingly unlikely. Negative HLA testing would also be
predictive of normal CSF hypocretin-1 concentrations. Human leukocyte
antigen testing is not generally helpful in the evaluation of narcolepsy type 2,
since about 45% of affected individuals are positive for the DQB1*0602
genotype.
Treatment of Narcolepsy
Narcolepsy is treated with medication as well as lifestyle/behavioral approaches.
Addressing the excessive daytime sleepiness is important because it can
negatively impact quality of life, socializing, performance at school or work,
and patient safety (in everyday situations as well as vocational activities where
drowsiness/inattention may cause injuries to self or others). The other narco-
lepsy symptoms (cataplexy, hypnagogic hallucinations, sleep paralysis, and
disrupted nocturnal sleep) are likewise treated if bothersome to the patient.
There is some inherent trial and error in the process of picking the appropriate
medication and dose for any given patient. Furthermore, due to fluctuations in
symptom severity, it is quite common to have a need to change medications
and dosing over time.
Medications
Medications for the treatment of narcolepsy have traditionally fallen into
one of 2 categories: CNS stimulants (which are used to treat the EDS) and
CNS neuromodulator agents (which are used to treat cataplexy and other
symptoms22), but there have been recent additions that can address both of
these symptom categories. Factors to contemplate when considering these
medications include efficacy, adverse effects, convenience of administration,

667
abuse potential, comorbid conditions, and coverage by individual health

insurance plans. Patients may require a combination of medications to
adequately control their symptoms.
Stimulants/Wake-Promoting Medications
Stimulants can be used to counteract EDS.22 These medications are taken
during the daytime and are used to promote wakefulness and alertness. These
include amphetamine, methamphetamine, dextroamphetamine, methylpheni-
date, and solriamfetol.23,24 The exact mechanism of action of modafinil and
armodafinil is unknown, while the others work by increasing/stimulating CNS
dopamine and norepinephrine.23,24 Modafinil and armodafinil have less abuse
potential as compared to the stimulants. Modafinil and armodafinil can lower
the efficacy of hormonal birth control, so patients should be advised to take
a higher dose and consider adding an alternate form of contraceptive
(eg, barrier method).
Other Neuromodulator Agents
Medications taken to treat the non-EDS symptoms, especially cataplexy,
include tricyclic antidepressants, selective serotonin reuptake inhibitors,
serotonin and norepinephrine reuptake inhibitors, and dopamine and
norepinephrine reuptake inhibitors.22–24 These medications are taken
during the daytime.
Oxybates
The 2 medications in the oxybate class are sodium oxybate and a newer, lower
sodium version of a mixture of calcium, magnesium, potassium, and sodium
oxybates. Both are approved by the FDA for the treatment of EDS as well as
cataplexy in patients 7 years and older. These medications are taken at night
in 2 divided doses: the first is taken at bedtime and the second is taken
2.5 to 4 hours later (during a naturally occurring awakening or via alarm).
The exact mechanism of action is unknown but seems to be via stimulation
of CNS GABAB receptors.23,24 The active ingredient of these is a form of
γ-hydroxybutyrate, which raises concerns regarding misuse; thus, in the
United States, it is only dispensed from a single centralized certified pharmacy.
Histamine Agonist
Pitolisant is currently the only medication in this class. It is a histamine-3
(H3) receptor antagonist/inverse agonist,23,24 and it is assumed that it works
by increasing CNS levels of histamine, as well as other wake-promoting
neurotransmitters (acetylcholine, dopamine, norepinephrine),24 although the
exact mechanism of action is unknown. It is currently approved by the FDA
for the treatment of both EDS and cataplexy in adults. This medication is
taken as a once-daily dose in the morning. Like modafinil and armodafinil,
pitolisant does not seem to have misuse potential and carries the same
warning regarding hormonal contraceptives.

668
Non-pharmacologic Remedies for Narcolepsy

Good sleep habits are important for everyone, and especially those with hyper-
somnia, to improve sleep quantity and quality. Patients should be encouraged
to go to sleep and wake up at the same time every day, including weekends.
Regular exercise at least 4 hours prior to bedtime can improve daytime alert-
ness and improve sleep at night. Caffeine, alcohol, and nicotine should be
avoided since these substances interfere with nocturnal sleep. There is
specific concern about use of alcohol (and other CNS depressants) in
conjunction with taking oxybates.
Two to 3 short (15–20 minutes), planned daily naps at strategic times during
the day may be refreshing, reduce sleepiness for a few hours, and prevent
unplanned lapses into sleep.23 The combination of regular bedtimes and two
15-minute regularly scheduled naps reduced unscheduled daytime sleep
episodes and sleepiness when compared to stimulant therapy alone.22 Naps
that exceed 30 minutes may be unrefreshing and result in increased drowsi-
ness. Schools are usually cooperative in scheduling later start times and a
study hall for nap purposes once the diagnosis is explained to them.
All patients with narcolepsy and other etiologies of severe EDS are at in-
creased risk of accidental injury and death related to occupational and recre-
ational activities, especially driving. They should be counseled about avoiding
or taking precautions when performing activities (eg, driving, operating
machinery) that would be dangerous if a sleep attack was to occur.
Other options to consider on an individualized basis are cognitive
behavioral therapy, support in planning school/work, peer support,
and psychological counseling.
key points
} Excessive daytime somnolence can cause a variety of symptoms and can have a
profound effect on a person’s health and quality of life.
} There are several causes of EDS, and the etiology can usually be identified with
a good clinical history, a physical examination, and sometimes testing.
} Identifying the etiology of the EDS will direct the clinician to the appropriate
treatment.

669
References
2. Archbold KH, Pituch KJ, Panahi P, Chervin RD. Symptoms of sleep disturbances among
children at two general pediatric clinics. J Pediatr. 2002;140(1):97–102 PMID: 11815771
doi: 10.1067/mpd.2002.119990
3. Khosla S, Deak MC, Gault D, et al; American Academy of Sleep Medicine Board of Directors.
Consumer sleep technology: an American Academy of Sleep Medicine position statement.
4. Patel P, Kim JY, Brooks LJ. Accuracy of a smartphone application in estimating sleep in
children. Sleep Breath. 2017;21(2):505–511
5. Aurora RN, Lamm CI, Zak RS, et al. Practice parameters for the non-respiratory indications for
polysomnography and multiple sleep latency testing for children. Sleep. 2012;35(11):1467–1473
6. Littner MR, Kushida C, Wise M, et al. Practice parameters for clinical use of the multiple sleep
latency test and the maintenance of wakefulness test. Sleep. 2005;28(1):113–121
7. Kohyama J, Anzai Y, Ono M, et al. Insufficient sleep syndrome: An unrecognized but important
clinical entity. Pediatr Int. 2018;60(4):372–375.
8. Owens J, Au R, Carskadon M, et al; Adolescent Sleep Working Group; Committee on
Adolescence. Insufficient sleep in adolescents and young adults: an update on causes and
consequences. Pediatrics. 2014;134(3):e921–e932 PMID: 25157012 doi: 10.1542/peds.2014-1696
9. Pallesen S, Saxvig IW, Molde H, Sørensen E, Wilhelmsen-Langeland A, Bjorvatn B.
Brief report: behaviorally induced insufficient sleep syndrome in older adolescents:
prevalence and correlates. J Adolesc. 2011;34(2):391–395 PMID: 20303581
doi: 10.1016/j.adolescence.2010.02.005
10. Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical guideline for the evaluation
and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4(5):487–504
PMID: 18853708 doi: 10.5664/jcsm.27286
11. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654–2662.
12. Mamelak M. Narcolepsy and depression and the neurobiology of gammahydroxybutyrate.
Prog Neurobiol. 2009;89(2):193–219
13. Overeem S, Mignot E, van Dijk JG, Lammers GJ. Narcolepsy: clinical features, new
pathophysiologic insights, and future perspectives. J Clin Neurophysiol. 2001;18(2):78–105
14. Dauvilliers Y, Billiard M, Montplaisir J. Clinical aspects and pathophysiology of narcolepsy.
Clin Neurophysiol. 2003;114(11):2000–2017
15. Stores G. The protean manifestations of childhood narcolepsy and their misinterpretation.
Dev Med Child Neurol. 2006;48(4):307–310
16. Sharpless BA, Barber JP. Lifetime prevalence rates of sleep paralysis: a systematic review.
Sleep Med Rev. 2011;15(5):311–315
17. Mahlios J, De la Herrán-Arita AK, Mignot E. The autoimmune basis of narcolepsy.
Curr Opin Neurobiol. 2013;23(5):767–773 PMID: 23725858 doi: 10.1016/j.conb.2013.04.013
18. Trotti LM. Central disorders of hypersomnolence. Continuum (Minneap Minn).
2020;26(4):890–907 PMID: 32756227 doi: 10.1212/CON.0000000000000883
19. Mignot E. Genetic and familial aspects of narcolepsy. Neurology. 1998;50(2 Suppl 1):S16–S22
PMID: 9484418 doi: 10.1212/WNL.50.2_Suppl_1.S16
20. Prasad M, Setty G, Ponnusamy A, Hussain N, Desurkar A. Cataplectic facies: clinical marker in
the diagnosis of childhood narcolepsy-report of two cases. Pediatr Neurol. 2014;50(5):515–517
PMID: 24656461 doi: 10.1016/j.pediatrneurol.2014.01.016
21. Littner MR, Kushida C, Wise M, et al; Standards of Practice Committee of the American
Academy of Sleep Medicine. Practice parameters for clinical use of the multiple sleep latency
test and the maintenance of wakefulness test. Sleep. 2005;28(1):113–121 PMID: 15700727
doi: 10.1093/sleep/28.1.113
22. Morgenthaler TI, Kapur VK, Brown T, et al. Practice parameters for the treatment of narcolepsy
and other hypersomnias of central origin. Sleep. 2007;30(12):1705–1711
23. Franceschini C, Pizza F, Antelmi E, Folli MC, Plazzi G. Narcolepsy treatment: pharmacological
and behavioral strategies in adults and children. Sleep Breath. 2020;24(2):615–627
24. Thorpy MJ, Bogan RK. Update on the pharmacologic management of narcolepsy: mechanisms
of action and clinical implications. Sleep Med. 2020;68:97–10

CHAPTER
39
Sudden Infant Death Syndrome and
Brief, Resolved, Unexplained Events
Introduction
Brief, resolved, unexplained events (BRUEs) are relatively common occur-
rences among newborns and infants. They encompass a broad range of
presentations that may be attributable to a variety of underlying medical
diagnoses with variable prognoses. Most infants and young children with
BRUEs present in urgent care settings (emergency department and hospital),
but primary care providers and pulmonologists will often be involved in
both acute evaluation and long-term management. As such, the role of
these providers is to (1) determine whether and what testing is needed
and (2) observe the infant/child long-term.
The term apparent life-threatening event (ALTE) was introduced in 1986
to replace the term near-miss SIDS since there was no good evidence that
these events were, in fact, precursors to sudden infant death syndrome (SIDS).
A National Institutes of Health Consensus Conference on Infantile Apnea
defined ALTE as an episode frightening to an observer that involved a com-
bination of apnea (central or obstructive), color change (cyanosis, pallor, or
plethora), marked change in muscle tone (usually limpness), and choking or
gagging.1 The American Academy of Pediatrics (AAP) suggested in 2016 that
the term ALTE be replaced by BRUE when certain criteria are met.2 BRUE
is the preferred term referring to an event involving infants less than 1 year
of age, when the event is characterized by the observer as sudden, brief
(lasting <1 minute, although typically 20–30 seconds), and resolved (infant
has returned to baseline state of health after the event) and “with a reassuring
history, physical examination, and vital signs at the time of clinical evalua-
tion by trained medical providers.”2 Events are typically characterized by
(1) cyanosis or pallor, (2) absent, decreased, or irregular breathing, (3) marked
change in tone (hypertonia or hypotonia), and/or (4) altered responsiveness.
BRUE should not be diagnosed unless the event is unexplained (ie, there is no
etiology determined for a qualifying event following a history and physical
671

672
examination). Infants who present with a BRUE are further categorized

as lower vs higher risk based on risk of recurrence and/or presence of a
serious underlying medical condition (Figure 39-1). These criteria have
been shown to have an excellent negative predictive value for a high-risk
BRUE of 90% but a poor positive predictive value of only 23%.3 Because
BRUE may be caused by a wide variety of unrelated underlying disease
states, the comprehensive evaluation and subsequent management of
high-risk infants can be challenging.
BRUE Diagnosis
Patient presents for initial medical assessment after a brief, resolved

event that was observed by caregiver in a child <1 year of age
Patient has additional
symptoms or abnormal
Patient is well-appearing vital signs (e.g., cough,
respiratory difficulties,
or fever)
Clinician characterizes the event as a sudden, brief, and
now resolved episode of one or more of the following:
Event
• Cyanosis or pallor criteria Not a BRUE
• Absent, decreased, or irregular breathing absent
• Marked change in tone (hyper- or hypotonia)
• Altered responsiveness
Use event Event criteria present

characteristics, Explanation for event
rather than the identified (e.g., GER,
Perform appropriate history and PE feeding difficulties, or Out of
term “ALTE,” to
airway abnormality) guideline
describe the event No explanation for event identified scope;
manage
accordingly
Diagnosis of Brief Resolved Unexplained Event is made
BRUE Risk Classification
No concerns identified from Concerns identified from history or PE

history and PE (e.g., FH of sudden cardiac death or
subtle, non-diagnostic social, feeding
or respiratory problems)
Apply risk stratification
• Age >60 days
• Born ≥32 wks gestation and corrected gestational age ≥45 wks No Higher Risk
• No CPR by trained medical provider Patient
• Event lasted <1 minute
• First event
Yes
Lower Risk Patient
Management Recommendations for Patients at Lower Risk
Should Should not

• Educate caregivers about BRUEs and engage • Obtain WBC count, blood culture, or CSF analysis or culture,
in shared decision-making to guide serum sodium, potassium, chloride, blood urea nitrogen,
evaluation, disposition, and follow-up creatinine, calcium, ammonia, blood gases, urine organic acids,
• Offer resources for CPR training to caregiver plasma amino acids or acylcarnitines, chest radiograph,
echocardiogram, EEG, studies for GER, or laboratory evaluation
for anemia
• Initiate home cardiorespiratory monitoring
• Prescribe acid suppression therapy or anti-epileptic
medications
May Need not

• Obtain pertussis testing and 12-lead ECG • Obtain viral respiratory test, urinalysis, blood glucose, serum
• Briefly monitor patients with continuous bicarbonate, serum lactic acid, or neuroimaging
pulse oximetry and serial observations • Admit the patient to the hospital solely for cardiorespiratory
monitoring
Figure 39–1. Diagnosis, risk classification, and recommended management of a brief, resolved,
unexplained event. CSF, cerebrospinal fluid; FH, family history; PE, physical examination; WBC,
white blood cell.
From Tieder JS, Bonkowski JL, Etzel RA, et al. Brief resolved unexplained events (formerly apparent life-
threatening events) and evaluation of lower-risk infants. Pediatrics. 2016;137(5):e20160590.

673
Chapter 39—Sudden Infant Death Syndrome and Brief, Resolved, Unexplained Events
Sudden infant death syndrome (SIDS) is the sudden death of an infant

younger than 1 year of age that cannot be explained even after a full inves-
tigation that includes a complete autopsy, examination of the death scene,
and review of the clinical history.4 Currently, SIDS is classified under
the umbrella term sudden unexpected infant death (SUID), which includes
SIDS, accidental suffocation in a sleeping environment, and other deaths
from unknown causes. The breakdown for SUID has been reported as 38.7%
SIDS, 24.3% suffocation, and 37% unknown.5 The rate of SIDS has declined
considerably in the United States, from 130.3 deaths per 100,000 live births
in 1990 to 35.2 deaths per 100,000 live births in 2018, primarily following
the National Institutes of Health “Back to Sleep” campaign (later renamed
the “Safe to Sleep” campaign) promoting safe infant sleep.5 Nevertheless, in
2018, there were still about 1,300 deaths due to SIDS with significant racial
and ethnic differences. American Indians, Alaska Natives, and non-Hispanic
Black Americans have a far higher rate of SUID than non-Hispanic white
Americans (Figure 39-2); it is not clear whether the origin of these disparities
lies in environmental, socioeconomic, or other factors.
Independent risk factors for SIDS include young maternal age, sleeping on a
soft surface, maternal smoking during pregnancy, preterm birth/low birth
weight, and prone sleeping position.6
200 Sudden infant death syndrome

180 Unknown cause
Deaths per 100,000 Live Births
Accidental suffocation and

160
strangulation in bed
140
120
100
80
60
40
20
0
AI/AN NHB NHW Hispanic A/PI
Race/Ethnicity
Figure 39-2. Sudden unexpected infant death by race/ethnicity, 2014–2018. AI/AN, American
Indian/Alaska Native; NHB, non-Hispanic Black; NHW, non-Hispanic white; A/PI, Asian/Pacific
Islander.
From Centers for Disease Control and Prevention. Sudden Unexpected Infant Death and Sudden Infant
Death Syndrome: Data and Statistics. https://www.cdc.gov/sids/data.htm. Updated April 28, 2021.
Accessed February 10, 2022.
Data source: Centers for Disease Control and Prevention (CDC)/National Center for Health Statistics,
National Vital Statistics System, Period Linked Birth/Infant Death Data. Rates calculated via CDC WONDER
using latest available data by subpopulation (2018).

674
Of note, a link between ALTE and SIDS has not been proven. There are not
yet good data on any relationship between BRUE and SIDS. Whereas earlier
studies suggested that infants presenting with ALTE or those with reduced
heart rate variability were at high risk of SIDS, more recent studies reveal
that SIDS cannot be predicted in an individual based on a history of apnea
or “abnormal” cardiorespiratory events. Most infants who die from SIDS
have no known predisposing causes, and few infants with ALTEs will die
from SIDS.7–10
Epidemiology
Prevalence estimates for BRUE are difficult to ascertain given the variability
in classification and heterogeneous nature of clinical presentation and ultimate
diagnoses. Available literature suggests that the incidence of ALTE in the
United States is 0.6 to 2.46 per 1,000 live births and represents 0.6% to 0.8%
of all emergency visits for children less than age 1 year.11,12 Recent literature
suggests that 20% to 40% of infants with ALTE also meet criteria for BRUE.12
The median age of infants who present with an ALTE has been reported as
6 to 8 weeks of age with equal sex distribution.12–17 Risk factors described in
infants with ALTE or BRUE are feeding difficulties, symptoms of a prior
respiratory illness, infants under 2 months of age, history of a previous epi-
sode, premature birth, low birth weight, and maternal smoking.15–18 Twelve
percent to 14% of infants presenting with an ALTE will have symptoms sig-
nificant enough to warrant hospitalization (particularly those with multiple
ALTEs within the preceding 24 hours or those aged ≤ 1 month).19 As opposed
to SIDS, which has a higher incidence in the winter months, BRUE does not
have a seasonal variation. The incidence of SIDS peaks at 1 to 4 months of
age and rapidly decreases after that.
Pathophysiology
BRUE represents a chief complaint rather than a diagnosis and is, by defini-
tion, not explained by an underlying disease process. However, dysfunction in
a diverse group of organ systems may be associated with BRUE. These include
respiratory infections, non-accidental trauma, cardiac disease, gastrointestinal
disorders (including gastroesophageal reflux and dysphagia), central nervous
system disorders, and metabolic disorders.18 Evaluation for these disorders
associated with higher-risk BRUE is discussed in the following text.

675
Clinical Features
By definition, BRUEs are events not explained by underlying pathophysiology
or disease processes, and there are no clinical features commonly associated
with or unique to ALTE or BRUE. The inclusion and exclusion criteria for
BRUE are listed in Table 39-1. Evaluation of infants with BRUE should
include a comprehensive history and thorough physical examination aimed
at identifying potential underlying causes of the event. History should ideally
be obtained from a caregiver witness or medical first responder. A complete
physical examination is necessary with a particular focus on signs of non-
accidental trauma. This information will enable the provider to categorize
infants into lower- and higher-risk groups (Table 39-2). Concerning findings
may include historical features such as loss of consciousness, need for cardio-
pulmonary resuscitation, evidence of trauma, history of similar events, family
history of unexplained infant deaths, concern for non-accidental trauma, or an
underlying known or suspected genetic syndrome or examination findings
such as lethargy or toxic appearance.
Table 39-1. Brief, Resolved, Unexplained Events (BRUEs) Definition and Inclusion/
Exclusion Criteria
BRUE Clinical
Features Inclusion Exclusion
Brief, resolved Duration < 1 min Duration ≥ 1 min
Infant returned to baseline, Abnormal vital signs and/or appearance.
normal vital signs and Not “well appearing.”
appearance. “Well
appearing.”
Unexplained No identifiable medical Event or PE consistent with a medical
condition. diagnosis (eg, GER, child abuse).
Event 1. Central cyanosis or pallor. 1. Acrocyanosis, perioral
characterization 2. Absent, decreased, or cyanosis or rubor.
by observer irregular breathing. 2. Periodic breathing of the newborn or
3. Marked change in tone breath-holding spell.
(hypotonia or hypertonia). 3. Tone changes associated with
4. Altered responsiveness. underlying medical condition (GER,
seizures).
4. Loss of consciousness.
PE, physical examination; GER, gastroesophageal reflux.

676
Table 39–2. Characteristics of Lower-Risk vs Higher-Risk Brief, Resolved, Unexplained

Events (BRUEs)
Lower-Risk BRUE Higher-Risk BRUE
Age > 60 days Age < 60 days
Gestational age ≥ 32 weeks Gestational age < 32 weeks
(≥ 45 weeks post conceptual age) (< 45 weeks post conceptual age)
First BRUE (no previous BRUE and not occurring Recurrent event or occurring in clusters
in clusters)
Duration < 1 minute Duration ≥ 1 minute
No CPR by trained medical provider CPR required by trained medical provider
No concerning historical features Concerning historical features
No concerning physical examination findings Concerning physical examination findings
CPR, cardiopulmonary resuscitation.
Adapted from Merritt JL, Quinonez RA, Bonkowski JL. A framework for evaluation of the higher-risk infant
after a brief, resolved, unexplained event. Pediatrics. 2019;144(2):e20184101.
Diagnosis
The diagnosis of BRUE is based on documentation of an event meeting cri-
teria for inclusion and exclusion of other underlying potential causes. Once a
diagnosis has been established, BRUEs are classified as lower risk or higher
risk. The basic questions are (1) Did something really happen, or did the parent
misinterpret something normal? and (2) What was the cause of the event? The
Collaborative Home Infant Monitoring Evaluation (CHIME) study showed
that even normal, healthy newborns may have central apneas for as long as
30 seconds.9 The purpose of a hospitalization is to evaluate the patient for a
treatable cause of the event; one cannot “rule out apnea.”
Management
There is no evidence to support routine hospitalization of all patients with
BRUE. The decision to hospitalize infants should be guided by the findings
during the initial assessment and categorization as lower vs higher risk.
Infants presenting with lower-risk BRUE may not require hospitalization.
Those classified as higher-risk BRUE require further evaluation and manage-
ment tailored to their history and physical examination findings. The AAP
has endorsed specific evaluation and management algorithms for lower-risk
patients; suggestions for management of high-risk patients were published as
a research paper.2,19 Although studies are limited and evidence has evolved
since the introduction of the term BRUE, a specific cause for the event may
be identified in about 50% of infants presenting with ALTE (before BRUE
was coined).17,18

677
Lower-Risk BRUE
Little intervention, other than reassurance, is typically required for
lower-risk infants (those who are asymptomatic and well appearing). The
AAP recommends against additional testing, hospital admission, or home
cardiorespiratory monitoring for these infants.2 Training of caregivers in
cardiopulmonary resuscitation and close follow-up as an outpatient is war-
ranted. Additionally, providers are encouraged to educate the family that
there is no known association between lower-risk BRUE and SIDS and
use this opportunity to reinforce safe sleep practices.20
Higher-Risk BRUE
Infants who do not meet criteria for lower-risk BRUE require additional
evaluation. Testing depends on whether there are clinical features that indi-
cate a specific diagnosis (based on history and examination). A suggested
algorithm for evaluation of higher-risk infants is shown in Figure 39-3.
Relatively common underlying disease processes that can present as BRUE
include gastroesophageal reflux, respiratory infection, seizures, and non-
accidental trauma (child abuse). Rarer causes include systemic infections,
disorders of ventilatory control, inborn errors of metabolism, cardiac
abnormalities such as prolonged Q-T intervals, and toxic ingestions
(intentional or unintentional).
Typically, higher-risk infants are monitored in the hospital for a brief period
(24 hours), enabling close observation by medical personnel. Evaluation and
testing are tailored to individual infants’ needs based on signs or symptoms
identified at presentation. Decisions regarding the need for home monitoring
should be made on a case-by-case basis after discussing with the family the
potential benefits, uncertainties, and stresses involved. Premature infants,
those with severe or recurrent episodes, and those with chronic cardiopul-
monary conditions may be candidates for home monitoring. It is important
to understand that cardiorespiratory monitors (“apnea monitors”) are not
a treatment. They simply identify that the child needs attention. Monitors
should be set at apnea and heart rate settings appropriate for age. It is import-
ant for the physician to personally review the downloaded recordings of
“events” to be able to eliminate false alarms that may be due to a low ampli-
tude signal or suboptimal lead placement. Monitoring with pulse oximetry
may be more appropriate for some infants, although these too are prone to false
alarms due to motion and cannot inform as to the cause of the desaturations.

678
Yes No Not a BRUE

Diagnosis of BRUE is made
• Manage accordingly
A BRUE Risk Classification
Concerns Apply risk criteria to history and physical examination

identified • Age ≤60 days
from No • Born <32 weeks’ gestation and corrected gestational age <45 weeks No Lower-risk
• History • Cardiopulmonary resuscitation by trained medical provider patient
• Physical • Event lasted >1 minute
examination • More than one event (at this visit or before presentation)
Yes See AAP
Yes
CPG
Higher-risk patient
B Initial Evaluation and Management Considerations for Patients at Higher Risk
Perform initial evaluation in ambulatory or emergency setting

Monitoring Diagnostic testing
• Continuous pulse oximetry monitoring • Electrocardiogram
for at least 4 hours • Rapid viral respiratory panel
Consultation • Pertussis in underimmunized and/or exposed patient in endemic
• Social worker screens for child abuse regions and outbreaksb
and social and mental health contributers • Hematocrit
and to provide parenting supporta • Blood glucose, bicarbonate or venous blood gas, lactic acid
• Feeding evaluation (feeding therapist, if If there is concern for child maltreatment
available) (e.g., bruising, torn frenulum, concerning history, etc.)
• Consultation with child abuse expert
• CT or MRI of headc
• Skeletal survey
Diagnosis that explains event

If unavailable in ED, No explanation
consider hospital admission No longer a BRUE
• Manage accordingly
C Secondary Evaluation and Management Considerations for Patients at Higher Risk
Admit to hospital
Diagnosis
• Continuous prolonged oximetry
that explains
• Observation for repeat events, better characterization of events, or social concerns
event
• Clinical swallow evaluation and feeding consultation
Evaluation based on event characteristics

If concern for silent aspiration If concern for central apnea No repeat events
due to feeding problem • CT or MRI of headc • Pulmonary consultation and no explanation
• VFSS If concern for seizures within 24 hours
If concern for GERD • Neurology consult
• Gastroenterology consultation • Prolonged electroencephalogram (~12 hours) • Discharge home
If concern for obstructive apnea If concern for arrhythmia or congenital heart • Cardiopulmonary
• Otolaryngology consultation disease resuscitation
for airway evaluation • Cardiology consult teaching
• Pulmonology consultation If concern for episodic hypoglycemia or acidosis • Provide detailed
• Comprehensive • Biochemical genetics consult information to the
polysomnography • Blood sodium, potassium, chloride, blood urea primary care
nitrogen, creatinine, calcium, ammonia clinician and
arrange close
follow-up
Figure 39–3. Evaluation and management pathway for higher-risk brief, resolved, unexplained
events. If a social worker is not available, this may be performed by other health care workers
with similar experience and skills. This assumes availability of pertussis results within a few
hours. “Rapid” magnetic resonance imaging or computed tomography is preferred to avoid
sedation risks.
From Merritt JL, Quinonez RA, Bonkowski JL. A framework for evaluation of the higher-risk infant after a
brief resolved unexplained event. Pediatrics. 2019;144(2):e20184101.

679
key points
} An ALTE/BRUE is a common, nonspecific disorder of infants that is usually
self-limited, although, rarely, it may be a symptom of a potentially serious or
life-threatening underlying disorder.
} A comprehensive history and complete physical examination are key in
differentiating lower- vs higher-risk infants and determining next steps in
management.
} No additional testing is indicated for lower-risk infants; however, higher-risk
infants may need hospitalization and additional monitoring and testing.
} Education and guidance should be provided to all caregivers. Home monitoring
is generally not indicated but may be considered in select infants.
References
1. National Institutes of Health Consensus Development Conference on Infantile Apnea and Home
Monitoring, Sept 29 to Oct 1, 1986. Pediatrics. 1987;79(2):292–299 PMID: 3808807
2. Tieder JS, Bonkowsky JL, Etzel RA, et al; SUBCOMMITTEE ON APPARENT LIFE
THREATENING EVENTS. Brief Resolved Unexplained Events (Formerly Apparent Life-
Threatening Events) and Evaluation of Lower-Risk Infants. Pediatrics. 2016;137(5):e20160590
PMID: 27244835 doi: 10.142/peds.2016-0590
3. Tieder JS, Sullivan E, Stephans A, et al; Brief Resolved Unexplained Event Research and Quality
Improvement Network. Risk factors and outcomes after a brief resolved unexplained event: center
study. Pediatrics. 2021;148(1):e2020036095 PMID: 34168059 doi: 10.1542/peds.2020-036095
4. Willinger M, James LS, Catz C. Defining the sudden infant death syndrome (SIDS): deliberations
of an expert panel convened by the National Institute of Child Health and Human Development.
Pediatr Pathol. 1991;11(5):677–684 PMID: 1745639 doi: 10.3109/15513819109065465
5. CDC/NCHS, National Vital Statistics System, Mortality Files. https://www.cdc.gov/sids/data.htm
6. Hoffman HJ, Damus K, Hillman L, Krongrad E. Risk factors for SIDS. Results of the National
Institute of Child Health and Human Development SIDS Cooperative Epidemiological Study.
Ann N Y Acad Sci. 1988;533:13–30 PMID: 3048169 doi: 10.1111/j.1749-6632.1988.tb37230.x
7. Kelly DH, Shannon DC, O’Connell K. Care of infants with near-miss sudden infant death
syndrome. Pediatrics. 1978;61(4):511–514 PMID: 662474
8. Hodgman JE, Hoppenbrouwers T, Geidel S, et al. Respiratory behavior in near-miss sudden
infant death syndrome. Pediatrics. 1982;69(6):785–792 PMID: 7079045
9. Ramanathan R, Corwin MJ, Hunt CE, et al; Collaborative Home Infant Monitoring Evaluation
(CHIME) Study Group. Cardiorespiratory events recorded on home monitors: comparison of
healthy infants with those at increased risk for SIDS. JAMA. 2001;285(17):2199–2207
PMID: 11325321 doi: 10.1001/jama.285.17.2199
10. Schechtman VL, Raetz SL, Harper RK, et al. Dynamic analysis of cardiac R-R intervals in
normal infants and in infants who subsequently succumbed to the sudden infant death syndrome.
Pediatr Res. 1992;31(6):606–612 PMID: 1635823 doi: 10.1203/00006450-199206000-00014
11. Mitchell EA, Thompson JM. Parental reported apnoea, admissions to hospital and sudden
infant death syndrome. Acta Paediatr. 2001;90(4):417–422 PMID: 11332934
doi: 10.1111/j.1651-2227.2001.tb00443.x
12. Colombo M, Katz ES, Bosco A, Melzi ML, Nosetti L. Brief resolved unexplained events:
retrospective validation of diagnostic criteria and risk stratification. Pediatr Pulmonol.
2019;54(1):61–65 PMID: 30549452 doi: 10.1002/ppul.24195
13. Ramgopal S, Noorbakhsh KA, Callaway CW, Wilson PM, Pitetti RD. Changes in the
management of children with brief resolved unexplained events (BRUEs). Pediatrics.
2019;144(4):e20190375 PMID: 31488696 doi: 10.1542/peds.2019-0375
14. Ramgopal S, Soung J, Pitetti RD. Brief resolved unexplained events: analysis of an apparent life
threatening event database. Acad Pediatr. 2019;19(8):963–968 PMID: 31401230
doi: 10.1016/j.acap.2019.08.001

680
15. Davies F, Gupta R. Apparent life threatening events in infants presenting to an emergency
department. Emerg Med J. 2002;19(1):11–16 PMID: 11777863 doi: 10.1136/emj.19.1.11
16. Esani N, Hodgman JE, Ehsani N, Hoppenbrouwers T. Apparent life-threatening events and
sudden infant death syndrome: comparison of risk factors. J Pediatr. 2008;152(3):365–370
PMID: 18280841 doi: 10.1016/j.jpeds.2007.07.054
17. Kiechl-Kohlendorfer U, Hof D, Peglow UP, Traweger-Ravanelli B, Kiechl S. Epidemiology of
apparent life threatening events. Arch Dis Child. 2005;90(3):297–300 PMID: 15723922
doi: 10.1136/adc.2004.049452
18. McGovern MC, Smith MB. Causes of apparent life threatening events in infants: a systematic
review. Arch Dis Child. 2004;89(11):1043–1048 PMID: 15499062 doi: 10.1136/adc.2003.031740
19. Merritt JL II, Quinonez RA, Bonkowsky JL, et al. A framework for evaluation of the higher-risk
infant after a brief resolved unexplained event. Pediatrics. 2019;144(2):e20184101
PMID: 31350360 doi: 10.1542/peds.2018-4101
20. American Academy of Pediatrics Task Force on Sudden Infant Death Syndrome; Moon RY,
Darnall RA, Feldman-Winter L, Goodstein MH, Hauck FR. SIDS and other sleep-related infant
deaths: updated 2016 recommendations for a safe infant sleeping
environment. Pediatrics. 2016;138(5):e20162938. 10.1542/peds.2016-2938

CHAPTER
40
Congenital Central Hypoventilation Syndrome
Iris A. Perez, MD, FAAP
Emily S. Gillett, MD, PhD, FAAP
Congenital central hypoventilation syndrome (CCHS) is a rare genetic

disorder of failure of automatic control of breathing and dysfunction of
autonomic nervous system.1–3 It is caused by a mutation in the PHOX2B
gene that plays an important role in the migration of neural crest cells and
development of the autonomic nervous system.4,5 The most serious mani-
festation is significant hypoventilation that is always present during sleep
but may also extend into wakefulness. Affected individuals commonly
present at birth. Some patients present later, although the genetic defect
is present at birth.6–8 With advances in management, patients with CCHS
can survive to adulthood.9–12
Pathogenesis
Congenital central hypoventilation syndrome is caused by a mutation in
the PHOX2B gene, located in chromosome 4p12, which encodes a highly
conserved homeodomain transcription factor that is essential in the develop-
ment of the respiratory control neurons and autonomic nervous system.1
Most CCHS cases are heterozygous for a polyalanine expansion repeat
mutation (PARM) in the PHOX2B gene (24–33 alanines) resulting in
20/24 to 20/33 genotypes (normal 20/20 PHOX2B genotype).1 The most
common genotypes in CCHS are 20/25, 20/26, and 20/27 PARM. Approxi-
mately 10% of patients with CCHS have nonpolyalanine repeat mutations
(NPARM), including missense, nonsense, frameshift and stop codon
mutations. Most of these pathogenic variants are frameshifts in exon 3.1
Less than 1% of cases have PHOX2B exon or whole gene deletion.13
681

682
Epidemiology
Congenital central hypoventilation syndrome is rare, with slightly more than
1,000 cases reported worldwide, but this is likely an underestimation.
Recent reports estimate an incidence of 1 case per 148,000 live births in
Japan14 to 1 in 200,000 live births in France.12 The male to female ratio is
generally 1:1,11,12,14,15 although more males (3:1 ratio) carry the PHOX2B 20/25
gene mutation.15
Genotype-Phenotype Relationship
The onset and severity of alveolar hypoventilation as well the need for
ventilatory support can be anticipated by a patient’s genotype. Patients who
have CCHS with shorter PARMs (20/24–20/25) typically have more subtle
symptoms and appear asymptomatic until a triggering event (ie, exposure
to respiratory illness, sedation, or anesthesia) occurs that puts them in res-
piratory compromise. They generally present later, with some surviving to
adulthood without need for around-the-clock ventilatory assistance.16,17 They
usually require assisted ventilation only during sleep. Patients with larger
PARMs (20/26 PARM–20/30 PARM) are typically symptomatic at birth and
require full-time ventilatory support.1 Generally, they are not associated with
variable penetrance or adult-onset presentations. However, an adult
with 20/27 PARM genotype and mild phenotype was reported in 2018.18
NPARM PHOX2B genotype is also generally associated with more severe
alveolar hypoventilation, with patients typically requiring full-time ventila-
tory support.1 Unlike the larger PARMs, NPARM mutations have variable
expressivity and incomplete penetrance; some patients have no symptoms,
while others need ventilatory support only during sleep.19–22 It is postulated
that frameshift variants located in the 3′ region of exon 2 and the 5′ region
of exon 3 and nonsense variants in exon 1 are associated with a milder
form of CCHS.20,21,23
Predisposition to certain autonomic nervous system dysfunctions may cor-
relate with PHOX2B gene mutations. Hirschsprung disease is most prevalent
in patients with NPARM mutations and, to a lesser degree, patients with
PARM 20/27 and higher.1,15,24 Although initial reports found life-threatening
cardiac sinus pauses 3 seconds or greater requiring cardiac pacemaker
placement in children who had CCHS with 20/26 PARM and 20/27 PARM,25
recent reports indicate presence of these arrhythmias in those with 20/25
PARM and NPARMs.19,26 Patients with NPARMs and longer PARM (20/28–
20/33) genotypes are at higher risk for tumors of neural crest origin.1 Pupillary
abnormalities may be more frequent in patients with 20/26 and 20/27 PARMs
than those with 20/25 PARM.27
Suboptimal school performance and/or neurodevelopmental impairment have
been reported in patients with CCHS, appearing as early as preschool and

683
Chapter 40—Congenital Central Hypoventilation Syndrome
school age.28,29 Bayley scores were noted to be essentially normal in children

with 20/25 PARM and lower in the other PARM groups; those with more
severe CCHS phenotype as indicated by cyanotic breath-holding spells, need
for 24 hour ventilation, prolonged sinus pauses, and seizures had more severe
neurocognitive delay.28
Clinical Presentation and Associated Features

Most patients with CCHS present in the newborn period with apnea or
hypoventilation and require assisted ventilation. When placed on ventilatory
support, extubation fails.1,11,12,14,15 Others present at a later age with unexplained
apneas, cyanosis, edema, or signs of right heart failure.16 Some patients present
in older childhood or adulthood, where a common presentation includes an
adverse reaction to general anesthesia, respiratory infections, pneumonia, or
other stressors.7,8,16,30,31 Thus, any patient with a delay in waking or achieving
adequate ventilation following general anesthesia or mild respiratory illness
should raise a suspicion of having CCHS.
Patients with CCHS lack subjective and objective responses to hypoxia or
hypercapnia,32,33 thus they do not manifest respiratory distress, increased
ventilation, retractions, nasal flaring, or a sense of dyspnea in response to
hypoxia and hypercapnia. They may report remarkable ability to hold
their breath for a prolonged period of time. As a result, hypoxia may be
detected only much later, when it has already caused central nervous
system depression with lethargy, cyanosis, or other complications. Some
patients may present with seizures due to undetected hypoxemia or
hypercapnia,16,34 while others may have unexplained polycythemia or
elevated serum bicarbonate as a presenting sign.7,18,19,35,36 Older children
and adults may present with unexplained pulmonary hypertension and cor
pulmonale resulting from unrecognized and untreated hypoxemia and
hypoventilation.36,37
The hallmark presentation of CCHS is alveolar hypoventilation, mainly
during sleep but often also during wakefulness. Hypoventilation is always
worse during sleep, particularly in non-rapid eye movement sleep where
breathing is critically dependent on metabolic control.38,39 There is a range
of ventilatory support requirement in patients with CCHS. Those with
PHOX2B 20/24, 20/25, and sometimes 20/26 PARM generally maintain
adequate ventilation while awake and require ventilatory support only during
sleep. Those with PHOX2B 20/27 PARM and higher and those with NPARM
generally have a more severe respiratory phenotype and hypoventilate during
wakefulness as well, requiring full-time ventilatory support.1 However, some
patients with these mutations have been able to maintain adequate ventilation
while breathing spontaneously while awake, and require ventilatory support
only during sleep.9,11,19 More recently, some patients have been reported to

684
require no or minimal intervention with only supplemental oxygen as part of

their supportive care.18,40
Congenital central hypoventilation syndrome is a generalized disorder of the
autonomic nervous system, and it affects more than just control of breathing.
Associated abnormalities include ophthalmologic,41,42 cardiovascular, gastro-
intestinal, endocrine, and neurodevelopmental issues; tumors of neural crest
origin; and temperature instability.1 Characteristic features are a broad, flat
face with box-like or rectangular appearance and inferior inflection of the
lateral vermillion border of the upper lip (Figure 40-1).43 Ophthalmologic
conditions may include sluggish pupils, strabismus, iris abnormalities, and
Marcus Gunn pupil.27,41,42,44,45 Patients with CCHS may present with syncope,
postural hypotension, reduced nocturnal blood pressure dipping, and reduced
heart rate variability.25,26,46–49 In patients with arrhythmias, syncope is the most
common presentation, but some may be asymptomatic.26 When CCHS is un-
diagnosed and long-standing hypoventilation is present, patients with CCHS
may present with pulmonary hypertension and cor pulmonale.
Hirschsprung disease is seen in approximately 20% of patients, particularly
in those with NPARM and PHOX2B 20/27 or higher PARM.6,15,24,41 In one
series, the pathologic segment was classic (rectosigmoid and left colic form)
in 20% and long (above the splenic flexure) in 80%.24 Thus, Hirschsprung
disease, especially with total colonic aganglionosis, should raise suspicion
of CCHS. In addition, patients with CCHS may have associated esophageal
dysmotility and swallowing dysfunction.41,50
Patients with CCHS may present with associated hypoglycemia or hyper-
glycemia and hyperinsulinism. Infants and children with CCHS presenting
with seizures or hyperhidrosis should be considered for dysregulated
glucose homeostasis.51–55
Finally, patients with CCHS may have tumors of neural crest origin (neuro-
blastoma, ganglioneuroma, and ganglioneuroblastoma). Neuroblastoma is
typically associated with NPARM, while 20/29 and 20/33 PARMs have been
associated with ganglioneuromas and ganglioneuroblastoma.1 However,
a case of an infant with CCHS with neuroblastoma and PHOX2B 20/33
PARM has been reported.56

685
Figure 40-1. Characteristic facial features in a patient with congenital central

hypoventilation syndrome.
Diagnostic Evaluation
PHOX2B gene mutation testing is required in establishing the diagnosis of
CCHS.1 PHOX2B testing methods include (1) PHOX2B targeted mutation
analysis (PHOX2B screening test; fragment length analysis), (2) PHOX2B
sequencing test, and (3) PHOX2B exon or whole gene deletion analysis.1,13,57,58
PHOX2B targeted mutation analysis identifies all PARMs and most NPARMs,
thus most pathogenic variants in CCHS. It is considered the most appropriate
test in detecting low-level mosaicism in seemingly asymptomatic and mildly

686
symptomatic individuals. The PHOX2B sequencing test identifies all PARMs

and all known NPARMs but may not detect low-level mosaicism. PHOX2B
multiplex ligation-dependent probe amplification test identifies PHOX2B
exon or whole gene deletion. When clinical suspicion is high, a combination
of all 3 tests may be required in establishing the diagnosis. While awaiting the
PHOX2B gene testing results, it is important to explore and rule out other
causes of hypoventilation. Evaluation may include magnetic resonance
imaging or computed tomography scans of the brain and brain stem to rule
out gross anatomic lesions, as well as metabolic screen and neurologic
evaluation because a variety of inborn errors of metabolism and neurologic
conditions may cause apnea and hypoventilation. A polysomnogram with
appropriately collected respiratory data, including end-tidal carbon dioxide
(CO2) is necessary to establish the presence of hypoventilation during sleep
noninvasively. It is useful to gather data during wakefulness as well. Daytime
blood gas during wakefulness will aid in establishing the presence of hypo-
ventilation. Other tests to rule out primary lung disease, ventilatory muscle
weakness, and cardiac disease, such as chest radiography, fluoroscopy of
the diaphragms, echocardiogram, and muscle biopsy, may be performed.1
Suggested evaluation of patients suspected of having a diagnosis of CCHS is
seen in Figure 40-2. The increasing availability of whole exome sequencing
with feasibility of obtaining fast results may result in earlier diagnosis.59
Infant or child with hypoxia and/or hypercapnia

and/or apnea worse during sleep than wakefulness
Suspect R/O Other Causes

CCHS • Lung disease: CXR,
polysomnogram (with PETCO2)
• Heart disease: ECG,
PHOX2B gene echocardiogram
mutation • Neurologic disease: Brain MRI
• Metabolic disease
Positive Negative
Ventilator Support ANS Evaluation • Genetic counseling

• Positive pressure/Trach • Arrhythmia • Parent PHOX2B
• NIPPV • Hirschsprung testing
• Diaphragm pacing • GI motility disorders
(at a later age) • Neural crest tumors
• Neuroophthalmology
Figure 40-2. Suggested approach in evaluation of patients suspected of having congenital

central hypoventilation syndrome.

687
Management
The fundamental goals in the treatment of CCHS are to ensure optimal oxy-
genation and ventilation at all times and anticipate occurrence of associated
autonomic nervous system conditions.1 Adequate oxygenation and ventilation
can be achieved by maintaining end-tidal CO2 less than 45 mmHg (< 5.99kPa)
and SpO2 95% or higher. Since patients with CCHS lack perception of dyspnea
and do not manifest respiratory distress, oxygen saturation monitoring with
pulse oximetry and CO2 monitoring (end tidal or transcutaneous) are essential
features in their management.
Modes of Ventilatory Support

Assisted ventilation is critical in CCHS management, because pharmacologic
respiratory stimulants have been shown to be ineffective.1 Positive-pressure
ventilators via tracheostomy, noninvasive positive-pressure ventilation (NPPV)
via face or nasal interface, negative-pressure ventilators, and diaphragm pacing
are all options for these patients.1,9,60–62 At present, the use of negative-pressure
ventilators has largely been supplanted by the preponderance of invasive and
noninvasive positive-pressure ventilators. For most patients, oxygen admin-
istration alone is inadequate because, although it relieves hypoxemia and
cyanosis, hypoventilation may persist. In those who are treated with supple-
mental oxygen alone due to minimal or no hypercapnia, close monitoring is
required with initiation of ventilatory support when hypoventilation develops
or worsens.40 There is no consensus on the choice of ventilatory support; it is
necessary for the mode of ventilation to be individualized to meet the patient’s
needs, goals of treatment, and quality of life.
Positive-Pressure Ventilation via Tracheostomy
Positive-pressure ventilation (PPV) via tracheostomy is the most common
form of ventilatory support in patients with CCHS.1,11 It is particularly effec-
tive in infants and younger children because they have longer sleep periods
and, therefore, require more hours of ventilatory support per day. The com-
ponents of their respiratory system are still immature, predisposing them to
significant respiratory instability in response to environmental stressors and
minor respiratory infections. Because patients with CCHS do not increase
their breathing frequency in response to hypercapnia and hypoxemia, the
pressure control/assist control mode or synchronized intermittent mandatory
ventilation (SIMV) with an appropriate rate is crucial to achieve ideal oxy-
genation and ventilation. Toddlers and older children who require 24-hour
ventilation can be transitioned to diaphragm pacing at daytime to allow for
mobility while continuing with PPV via tracheostomy at night.

688
Noninvasive Positive Pressure Ventilation

Patients can be ventilated by NPPV via mask (nasal or face) or nasal prongs
using bilevel positive airway pressure1,63,64 or average volume-assured pressure
support ventilation mode.60,65 Stable older children who have hypoventilation
only during sleep are ideal candidates for NPPV.1 Noninvasive positive-
pressure ventilation allows stable patients who are ventilated only during
sleep to be transitioned from PPV and be decannulated.66 For patients ven-
tilated by NPPV, only spontaneous/timed or timed modes with mandatory
backup rates guarantee breath delivery. Because patients with CCHS do not
increase their breathing frequency in response to hypercapnia or hypoxemia,
spontaneous mode or continuous positive airway pressure is inappropriate.
Long-term use of noninvasive ventilation by nasal mask can be associated
with midface hypoplasia and dental malocclusion.67 Therefore, patients
should alternate between different interfaces and must be monitored with
consideration for referral to a craniofacial team for monitoring of facial
growth as well as dental malocclusion.
Diaphragm Pacing
Diaphragm pacing (DP) can provide daytime ventilatory support for those
who are dependent on a ventilator 24 hours per day. It can be the sole
ventilatory support for those who are dependent on a ventilator only during
sleep and possibly may allow for tracheal decannulation.1,9,62 With diaphragm
pacing, the child’s own diaphragm acts as the respiratory pump. A
diaphragm pacer system involves 4 components: (1) monopolar electrodes
that are surgically implanted bilaterally on the phrenic nerves, (2) receivers
that are surgically implanted subcutaneously on the abdomen or chest
bilaterally, (3) antennae that are placed over the receivers, and (4) an external
battery-operated portable transmitter that generates electrical energy similar
to radio frequency. The electrical energy generated by the external transmit-
ter is transmitted via external antennae that are placed over the receivers.
The receivers then convert the energy to electrical currents that are then
conducted to the phrenic nerve, stimulating contraction of the diaphragm
(Figure 40-3).1,62
A normal functioning diaphragm, intact phrenic nerves, little or no lung dis-
ease, normal airway, and healthy weight are essential for successful diaphragm
pacing.1,9,10 Patients who have overweight or obesity are not ideal candidates
because the high amount of adipose tissue interferes with the antennae and
receivers of the diaphragm pacers, resulting in variability in the signal inputs
to the receiver.9 When the goals for diaphragm pacing are decannulation
and diaphragm pacing without tracheostomy, the following requirements
must also be met: (1) ventilator dependence only during sleep, (2) not requiring
daytime naps, (3) stable medical course with infrequent hospitalizations,

689
Figure 40-3. Components of diaphragm pacer system.
(4) not requiring full-time ventilatory support during respiratory illnesses, and
(5) acceptance that DP is not a secure method of ventilation and intubations
may be necessary for serious illnesses.9 A disadvantage of diaphragm pacing
without tracheostomy is the risk of obstructive sleep apnea and upper airway
obstruction, which can occur due to the diaphragm contraction without con-
comitant upper airway muscle contraction.10,68,69 However, obstructive sleep
apnea can be alleviated by decreasing the diaphragm pacer amplitude settings
to decrease the force of inspiration with each diaphragm contraction.9,10 At
present, diaphragm pacing without tracheostomy is not a viable mode of
ventilatory support in younger children.69 Because of the risk of diaphragm
fatigue, diaphragm pacing is typically used only for up to 14 to 16 hours a day.1
Therefore, during an acute illness, when additional time on assisted ventilation
is necessary, a patient must have an alternative form of ventilatory support
(NPPV or home ventilator).

690
Observation and Monitoring

Patients with CCHS require vigilant observation and monitoring at each sleep
episode. Many patients, particularly those who are young, require at least
16 hours of home nursing per day. At home, pulse oximetry and capnography
can aid in their monitoring. In this instance, the pulse oximeter is generally
set to alarm at Spo2 of 85% or less and heart rate at 50 beats per minute or
less. The goal for these alarm settings is to decrease nuisance alarms while
allowing sufficient time for caregivers to respond to potential emergencies.
The pulse oximeter will also aid in monitoring changes in respiratory status.
Apnea/bradycardia monitoring alone is not sufficient, because patients may
continue to hypoventilate without being apneic.
Long-term Management
Once the diagnosis is established, patients who have CCHS with symptoms,
or depending on their genotype, should be screened for associated autonomic
dysfunction. These tests may include (1) barium enema or rectal biopsy to
assess for Hirschsprung disease, (2) esophageal motility and swallowing
evaluation, (3) ambulatory cardiac rhythm monitoring to evaluate for sinus
pauses, (4) chest and abdominal imaging to assess for neural crest tumors,
and (5) a comprehensive ophthalmologic evaluation. These will aid in early
identification of abnormalities and allow intervention to prevent learning
delay. Patients may demonstrate developmental delay and neurocognitive
deficits as early as preschool age, indicating a need for neurocognitive
evaluation and early intervention when necessary.28,29,70
Patients with CCHS are at risk for pulmonary hypertension and cor pulmonale;
when present, these must be assumed to be caused by inadequate ventilation
until proven otherwise. Yearly overnight in-laboratory polysomnography
including capnography to assess optimal ventilator settings and echocardio-
gram should be part of anticipatory care.1 The development of pulmonary
hypertension while ventilator settings during sleep are appropriate suggests
hypoventilation during wakefulness, indicating need for ventilatory support
during wakefulness as well.
Due to the risk of life-threatening arrhythmias25,26,49 and the presence of sinus
pauses even in those who are asymptomatic, all patients would benefit from
yearly cardiac ambulatory monitoring.
All individuals with CCHS require lifelong follow-up. Potential situations
that predispose to ventilatory instability need to be anticipated. During exer-
cise, they may not increase their ventilation normally to meet their increased
oxygen consumption.71 Activities that involve breath holding, such as swim-
ming underwater, are particularly dangerous because individuals with CCHS
will not perceive the asphyxia32,33 that occurs with prolonged breath-holding.

691
Adolescent and young adult patients need to be counseled on alcohol abstinence

because of the potential adverse outcomes, including coma and death.72
Genetic Counseling for CCHS

PHOX2B gene mutation in CCHS has an autosomal pattern of inheritance
with variable penetrance.1,19,58,73,74 Although most cases occur de novo, it is
necessary to test the parents of the affected patient even if they do not report
symptoms.58 Genetic counseling is imperative for individuals diagnosed with
CCHS because there is a 50% chance of inheritance with each child. Mothers
with CCHS should undergo prenatal testing with each pregnancy. Prenatal
testing will provide optimal information about the status of the fetus and aid
the pregnant mother in making an informed decision; it also prepares the
medical and nursing team to plan for smooth delivery and neonatal care.1
key points
} Congenital central hypoventilation syndrome is a lifelong disorder without
known cure. It is caused by a mutation in the PHOX2B gene.
} PHOX2B gene mutation analysis is required to confirm the diagnosis, predict
the CCHS phenotype, and guide management.
} A high index of suspicion is critical because early identification and application
of intervention with modern techniques for home ventilation may result in
most children surviving to adolescence and adulthood with a relatively good
quality of life.
} Optimal care requires a multidisciplinary approach that is individualized for
each patient.
} Successful outcomes require adequate oxygenation and ventilation at all times
and vigilant monitoring and management of associated autonomic nervous
system dysfunction.
References
1. Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, Trang H;
ATS Congenital Central Hypoventilation Syndrome Subcommittee. An official ATS clinical
policy statement: Congenital central hypoventilation syndrome: genetic basis, diagnosis,
doi: 10.1164/rccm.200807-1069ST
2. Mellins RB, Balfour HH, Turino GM, Winters RW. Failure of automatic control of ventilation
(ondine’s curse): Report of an infant born with this syndrome and review of the literature.
Med (United States). 1970. doi: 10.1097/00005792-197011000-00003
3. American Thoracic Society. Idiopathic congenital central hypoventilation syndrome: diagnosis
doi: 10.1164/ajrccm.160.1.16010
4. Amiel J, Laudier B, Attié-Bitach T, et al. Polyalanine expansion and frameshift mutations of
the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.
Nat Genet. 2003;33(4):459–461 PMID: 12640453 doi: 10.1038/ng1130

692
5. Weese-Mayer DE, Berry-Kravis EM, Zhou L, et al. Idiopathic congenital central

hypoventilation syndrome: analysis of genes pertinent to early autonomic nervous system
embryologic development and identification of mutations in PHOX2B. Am J Med Genet A.
2003;123A(3):267–278 PMID: 14608649 doi: 10.1002/ajmg.a.20527
6. Trochet D, O’Brien LM, Gozal D, et al. PHOX2B genotype allows for prediction of tumor risk
in congenital central hypoventilation syndrome. Am J Hum Genet. 2005;76(3):421–426
PMID: 15657873 doi: 10.1086/428366
7. Magalhães J, Madureira N, Medeiros R, et al. Late-onset congenital central
hypoventilation syndrome and a rare PHOX2B gene mutation. Sleep Breath. 2015;19(1):55–60
PMID: 24792884 doi: 10.1007/s11325-014-0996-7
8. Trang H, Laudier B, Trochet D, et al. PHOX2B gene mutation in a patient with late-onset
central hypoventilation. Pediatr Pulmonol. 2004;38(4):349–351 PMID: 15334515
doi: 10.1002/ppul.20074
9. Diep B, Wang A, Kun S, et al. Diaphragm pacing without tracheostomy in congenital central
hypoventilation syndrome patients. Respiration. 2015;89(6):534–538 PMID: 25924848
doi: 10.1159/000381401
10. Wang A, Kun S, Diep B, Davidson Ward SL, Keens TG, Perez IA. Obstructive sleep apnea in
patients with congenital central hypoventilation syndrome ventilated by diaphragm pacing
without tracheostomy. J Clin Sleep Med. 2018;14(2):261–264 PMID: 29351818
doi: 10.5664/jcsm.6948
11. Vanderlaan M, Holbrook CR, Wang M, Tuell A, Gozal D. Epidemiologic survey of 196 patients
with congenital central hypoventilation syndrome. Pediatr Pulmonol. 2004;37(3):217–229
PMID: 14966815 doi: 10.1002/ppul.10438
12. Trang H, Dehan M, Beaufils F, Zaccaria I, Amiel J, Gaultier C; French CCHS Working Group.
The French Congenital Central Hypoventilation Syndrome Registry: general data, phenotype,
and genotype. Chest. 2005;127(1):72–79 PMID: 15653965 doi: 10.1378/chest.127.1.72
13. Jennings LJ, Yu M, Rand CM, et al. Variable human phenotype associated with novel
deletions of the PHOX2B gene. Pediatr Pulmonol. 2012;47(2):153–161 PMID: 21830319
doi: 10.1002/ppul.21527
14. Hasegawa H, Kawasaki K, Inoue H, Umehara M, Takase M; Japanese Society of Pediatric
Pulmonology Working Group (JSPPWG). Epidemiologic survey of patients with congenital
central hypoventilation syndrome in Japan. Pediatr Int. 2012;54(1):123–126 PMID: 21958325
doi: 10.1111/j.1442-200X.2011.03484.x
15. Shimokaze T, Sasaki A, Meguro T, et al. Genotype-phenotype relationship in Japanese patients
with congenital central hypoventilation syndrome. J Hum Genet. 2015;60(9):473–477
PMID: 26063465 doi: 10.1038/jhg.2015.65
16. Antic NA, Malow BA, Lange N, et al. PHOX2B mutation-confirmed congenital central
hypoventilation syndrome: presentation in adulthood. Am J Respir Crit Care Med.
2006;174(8):923–927 PMID: 16873766 doi: 10.1164/rccm.200605-607CR
17. Doherty LS, Kiely JL, Deegan PC, et al. Late-onset central hypoventilation syndrome:
a family genetic study. Eur Respir J. 2007;29(2):312–316 PMID: 17264323
doi: 10.1183/09031936.00001606
18. Kasi AS, Kun SS, Keens TG, Perez IA. Adult with PHOX2B mutation and late-onset congenital
central hypoventilation syndrome. J Clin Sleep Med. 2018;14(12):2079–2081 PMID: 30518452
doi: 10.5664/jcsm.7542
19. Kasi AS, Jurgensen TJ, Yen S, Kun SS, Keens TG, Perez IA. Three-generation family with
congenital central hypoventilation syndrome and novel PHOX2B gene non-polyalanine repeat
mutation. J Clin Sleep Med. 2017;13(7):925–927 PMID: 28633714 doi: 10.5664/jcsm.6670
20. Low KJ, Turnbull AR, Smith KR, et al. A case of congenital central hypoventilation syndrome in
a three-generation family with non-polyalanine repeat PHOX2B mutation. Pediatr Pulmonol.
2014;49(10):E140–E143 PMID: 24799442 doi: 10.1002/ppul.23051
21. Cain JT, Kim DI, Quast M, et al. Nonsense pathogenic variants in exon 1 of PHOX2B lead to
translational reinitiation in congenital central hypoventilation syndrome. Am J Med Genet A.
2017;173(5):1200–1207 PMID: 28371199 doi: 10.1002/ajmg.a.38162
22. Lombardo RC, Kramer E, Cnota JF, Sawnani H, Hopkin RJ. Variable phenotype in a novel
mutation in PHOX2B. Am J Med Genet A. 2017;173(6):1705–1709 PMID: 28422456
doi: 10.1002/ajmg.a.38218
23. Bygarski E, Paterson M, Lemire EG. Extreme intra-familial variability of congenital central
hypoventilation syndrome: a case series. J Med Case Reports. 2013;7:117 PMID: 23622117
doi: 10.1186/1752-1947-7-117

693
24. Broch A, Trang H, Montalva L, Berrebi D, Dauger S, Bonnard A. Congenital central

hypoventilation syndrome and Hirschsprung disease: A retrospective review of the
French National Registry Center on 33 cases. J Pediatr Surg. 2019;54(11):2325–2330
25. Gronli JO, Santucci BA, Leurgans SE, Berry-Kravis EM, Weese-Mayer DE. Congenital
central hypoventilation syndrome: PHOX2B genotype determines risk for sudden death.
26. Laifman E, Keens TG, Bar-Cohen Y, Perez IA. Life-threatening cardiac arrhythmias in
congenital central hypoventilation syndrome. Eur J Pediatr. 2020;179(5):821–825
PMID: 31950261 doi: 10.1007/s00431-019-03568-5
27. Patwari PP, Stewart TM, Rand CM, et al. Pupillometry in congenital central hypoventilation
syndrome (CCHS): quantitative evidence of autonomic nervous system dysregulation.
Pediatr Res. 2012;71(3):280–285 PMID: 22278185 doi: 10.1038/pr.2011.38
28. Charnay AJ, Antisdel-Lomaglio JE, Zelko FA, et al. Congenital central hypoventilation
syndrome: neurocognition already reduced in preschool-age children. Chest. 2016;149(3):809-815
PMID: 26378991 doi: 10.1378/chest.15-0402
29. Zelko FA, Nelson MN, Leurgans SE, Berry-Kravis EM, Weese-Mayer DE. Congenital central
hypoventilation syndrome: neurocognitive functioning in school age children. Pediatr Pulmonol.
2010;45(1):92–98 PMID: 19960523 doi: 10.1002/ppul.21170
30. Mahfouz AKM, Rashid M, Khan MS, Reddy P. Late onset congenital central hypoventilation
syndrome after exposure to general anesthesia. Can J Anaesth. 2011;58(12):1105–1109
PMID: 21989548 doi: 10.1007/s12630-011-9590-7
31. Mahmoud M, Bryan Y, Gunter J, Kreeger RN, Sadhasivam S. Anesthetic implications of
undiagnosed late onset central hypoventilation syndrome in a child: from elective tonsillectomy
to tracheostomy. Paediatr Anaesth. 2007;17(10):1001–1005 PMID: 17767640
doi: 10.1111/j.1460-9592.2007.02284.x
32. Paton JY, Swaminathan S, Sargent CW, Keens TG. Hypoxic and hypercapnic ventilatory
responses in awake children with congenital central hypoventilation syndrome. Am Rev Respir
Dis. 1989;140(2):368–372 PMID: 2764373 doi: 10.1164/ajrccm/140.2.368
33. Shea SA, Andres LP, Shannon DC, Guz A, Banzett RB. Respiratory sensations in subjects who
lack a ventilatory response to CO2. Respir Physiol. 1993;93(2):203–219 PMID: 8210759
doi: 10.1016/0034-5687(93)90006-V
34. Repetto GM, Corrales RJ, Abara SG, et al. Later-onset congenital central hypoventilation
syndrome due to a heterozygous 24-polyalanine repeat expansion mutation in the PHOX2B gene.
Acta Paediatr. 2009;98(1):192–195 PMID: 18798833 doi: 10.1111/j.1651-2227.2008.01039.x
35. Lee P, Su Y-N, Yu C-J, Yang P-C, Wu H-D. PHOX2B mutation-confirmed congenital central
hypoventilation syndrome in a Chinese family: presentation from newborn to adulthood. Chest.
2009;135(2):537–544 PMID: 19201717 doi: 10.1378/chest.08-1664
36. Antic N, McEvoy RD. Primary alveolar hypoventilation and response to the respiratory
stimulant almitrine. Intern Med J. 2002;32(12):622–624 PMID: 12512759
doi: 10.1046/j.1445-5994.2002.00284.x
37. Fine-Goulden MR, Manna S, Durward A. Cor pulmonale due to congenital central
hypoventilation syndrome presenting in adolescence. Pediatr Crit Care Med. 2009;10(4):e41–e42
doi: 10.1097/PCC.0b013e318198b219
38. Fleming PJ, Cade D, Bryan MH, Bryan AC. Congenital central hypoventilation and sleep state.
Pediatrics. 1980;66(3):425–428. Accessed March 8, 2022. https://www.ncbi.nlm.nih.gov/
pubmed/6775277 PMID: 6775277
39. Huang J, Colrain IM, Panitch HB, et al. Effect of sleep stage on breathing in children with
central hypoventilation. J Appl Physiol (1985). 2008;105(1):44–53 PMID: 18499780
doi: 10.1152/japplphysiol.01269.2007
40. Byers HM, Chen M, Gelfand AS, Ong B, Jendras M, Glass IA. Expanding the phenotype of
congenital central hypoventilation syndrome impacts management decisions. Am J Med Genet A.
2018;176(6):1398–1404 PMID: 29696799 doi: 10.1002/ajmg.a.38726
41. Croaker GD, Shi E, Simpson E, Cartmill T, Cass DT. Congenital central hypoventilation
syndrome and Hirschsprung’s disease. Arch Dis Child. 1998;78(4):316–322 PMID: 9623393
doi: 10.1136/adc.78.4.316
42. 42. Goldberg DS, Ludwig IH. Congenital central hypoventilation syndrome:
ocular findings in 37 children. J Pediatr Ophthalmol Strabismus. 1996;33(3):175–180
https://www.ncbi.nlm.nih.gov/pubmed/8771521. Accessed March 8, 2022

694
43. Todd ES, Weinberg SM, Berry-Kravis EM, et al. Facial phenotype in children and young adults
with PHOX2B-determined congenital central hypoventilation syndrome: quantitative pattern
of dysmorphology. Pediatr Res. 2006;59(1):39–45 PMID: 16327002
doi: 10.1203/01.pdr.0000191814.73340.1d
44. Mehta VJ, Ling JJ, Martinez EG, Reddy AC, Donahue SP. Congenital tonic pupils
associated with congenital central hypoventilation syndrome and Hirschsprung disease.
J Neuroophthalmol. 2016;36(4):414–416 PMID: 27340804
doi: 10.1097/WNO.0000000000000405
45. Lambert SR, Yang LLH, Stone C. Tonic pupil associated with congenital neuroblastoma,
Hirschsprung disease, and central hypoventilation syndrome. Am J Ophthalmol.
2000;130(2):238–240 PMID: 11004304 doi: 10.1016/S0002-9394(00)00480-3
46. Trang H, Boureghda S, Denjoy I, Alia M, Kabaker M. 24-hour BP in children with congenital
central hypoventilation syndrome. Chest. 2003;124(4):1393–1399 PMID: 14555571
doi: 10.1378/chest.124.4.1393
47. Trang H, Girard A, Laude D, Elghozi JL. Short-term blood pressure and heart rate variability
in congenital central hypoventilation syndrome (Ondine’s curse). Clin Sci (Lond).
2005;108(3):225–230 PMID: 15544572 doi: 10.1042/CS20040282
48. Woo MS, Woo MA, Gozal D, Jansen MT, Keens TG, Harper RM. Heart rate variability
in congenital central hypoventilation syndrome. Pediatr Res. 1992;31(3):291–296 PMID: 1561018
doi: 10.1203/00006450-199203000-00020
49. Silvestri JM, Hanna BD, Volgman AS, Jones PJ, Barnes SD, Weese-Mayer DE. Cardiac
rhythm disturbances among children with idiopathic congenital central hypoventilation
syndrome. Pediatr Pulmonol. 2000;29(5):351–358. Accessed March 8, 2022.
https://www.ncbi.nlm.nih.gov/pubmed/10790246 PMID: 10790246
doi: 10.1002/(SICI)1099-0496(200005)29:5<351::AID-PPUL3>3.0.CO;2-Z
50. Faure C, Viarme F, Cargill G, Navarro J, Gaultier C, Trang H. Abnormal esophageal motility
in children with congenital central hypoventilation syndrome. Gastroenterology.
2002;122(5):1258–1263. doi:S0016508502415405 [pii]
51. Hennewig U, Hadzik B, Vogel M, et al. Congenital central hypoventilation syndrome with
hyperinsulinism in a preterm infant. J Hum Genet. 2008;53(6):573–577 PMID: 18340402
doi: 10.1007/s10038-008-0275-1
52. Farina MI, Scarani R, Po’ C, Agosto C, Ottonello G, Benini F. Congenital central hypoventilation
syndrome and hypoglycaemia. Acta Paediatr. 2012;101(2):e92–e96
PMID: 22103583 doi: 10.1111/j.1651-2227.2011.02533.x
53. Marics G, Amiel J, Vatai B, Lódi C, Mikos B, Tóth-Heyn P. Autonomic dysfunction
of glucose homoeostasis in congenital central hypoventilation syndrome. Acta Paediatr.
2013;102(4):e178–e180 PMID: 23231723 doi: 10.1111/apa.12125
54. Gelwane G, Trang H, Carel J-C, Dauger S, Léger J. Intermittent hyperglycemia due to autonomic
nervous system dysfunction: a new feature in patients with congenital central hypoventilation
syndrome. J Pediatr. 2013;162(1):171–176.e2 PMID: 22863257 doi: 10.1016/j.jpeds.2012.06.036
55. Hopkins E, Stark J, Mosquera RA. Central Congenital Hypoventilation Syndrome associated
with hypoglycemia and seizure. Respir Med Case Rep. 2017;20:75–76 PMID: 28070480
doi: 10.1016/j.rmcr.2016.12.004
56. Armstrong AE, Weese-Mayer DE, Mian A, et al. Treatment of neuroblastoma in congenital
central hypoventilation syndrome with a PHOX2B polyalanine repeat expansion mutation:
new twist on a neurocristopathy syndrome. Pediatr Blood Cancer. 2015;62(11):2007–2010
PMID: 26011159 doi: 10.1002/pbc.25572
57. Jennings LJ, Yu M, Zhou L, Rand CM, Berry-Kravis EM, Weese-Mayer DE. Comparison of
PHOX2B testing methods in the diagnosis of congenital central hypoventilation syndrome and
mosaic carriers. Diagn Mol Pathol. 2010;19(4):224–231 PMID: 21051998
doi: 10.1097/PDM.0b013e3181eb92ff
58. Bachetti T, Parodi S, Di Duca M, Santamaria G, Ravazzolo R, Ceccherini I. Low amounts of
PHOX2B expanded alleles in asymptomatic parents suggest unsuspected recurrence risk in
congenital central hypoventilation syndrome. J Mol Med (Berl). 2011;89(5):505–513
PMID: 21336852 doi: 10.1007/s00109-010-0718-y
59. Shanthikumar S, Kevat A, Stapleton R, Lunke S, Stark Z, Vandeleur M. Use of ultra-rapid
whole-exome sequencing to diagnose congenital central hypoventilation syndrome. Pediatr
60. Khayat A, Medin D, Syed F, et al. Intelligent volume-assured pressured support (iVAPS) for the
treatment of congenital central hypoventilation syndrome. Sleep Breath. 2017;21(2):513–519
PMID: 28190166 doi: 10.1007/s11325-017-1478-5

695
61. Hartmann H, Jawad MHJN, Noyes J, Samuels MP, Southall DP. Negative extrathoracic
pressure ventilation in central hypoventilation syndrome. Arch Dis Child. 1994;70(5):418–423
PMID: 8017965 doi: 10.1136/adc.70.5.418
62. Chen ML, Tablizo MA, Kun S, Keens TG. Diaphragm pacers as a treatment for congenital
central hypoventilation syndrome. Expert Rev Med Devices. 2005;2(5):577–585
PMID: 16293069 doi: 10.1586/17434440.2.5.577
63. Kerbl R, Litscher H, Grubbauer HM, et al. Congenital central hypoventilation syndrome
(Ondine’s curse syndrome) in two siblings: delayed diagnosis and successful noninvasive
treatment. Eur J Pediatr. 1996;155(11):977–980 PMID: 8911900 doi: 10.1007/BF02282890
64. Migliori C, Cavazza A, Motta M, Bottino R, Chirico G. Early use of Nasal-BiPAP in two
infants with congenital central hypoventilation syndrome. Acta Paediatr. 2003;92(7):823–826.
Accessed March 8, 2022. https://www.ncbi.nlm.nih.gov/pubmed/12892162 PMID: 12892162
doi: 10.1111/j.1651-2227.2003.tb02540.x
65. Vagiakis E, Koutsourelakis I, Perraki E, et al. Average volume-assured pressure support
in a 16-year-old girl with congenital central hypoventilation syndrome. J Clin Sleep Med.
2010;6(6):609–612. PMID: 21206552 doi: 10.5664/jcsm.27997
66. Kam K, Bjornson C, Mitchell I. Congenital central hypoventilation syndrome; safety of early
transition to non-invasive ventilation. Pediatr Pulmonol. 2014;49(4):410–413 PMID: 23843332
doi: 10.1002/ppul.22848
67. Roberts SD, Kapadia H, Greenlee G, Chen ML. Midfacial and dental changes associated with
nasal positive airway pressure in children with obstructive sleep apnea and craniofacial
conditions. J Clin Sleep Med. 2016;12(4):469–475 PMID: 26715402 doi: 10.5664/jcsm.5668
68. Reverdin AK, Mosquera R, Colasurdo GN, Jon CK, Clements RM. Airway obstruction
in congenital central hypoventilation syndrome. BMJ Case Rep. 2014;2014:bcr2013200911. doi:
10.1136/bcr-2013-200911
69. Valika T, Chin AC, Thompson DM, et al. Airway obstruction during sleep due to
diaphragm pacing precludes decannulation in young children with CCHS. Respiration.
2019;98(3):263–267 PMID: 31288244 doi: 10.1159/000501172
70. Silvestri JM, Weese-Mayer DE, Nelson MN. Neuropsychologic abnormalities in children with
congenital central hypoventilation syndrome. J Pediatr. 1992;120(3):388–393 PMID: 1538285
doi: 10.1016/S0022-3476(05)80902-3
71. Shea SA, Andres LP, Shannon DC, Banzett RB. Ventilatory responses to exercise in humans
lacking ventilatory chemosensitivity. J Physiol. 1993;468(1):623–640. PMID: 8254528
doi: 10.1113/jphysiol.1993.sp019792
72. Chen ML, Turkel SB, Jacobson JR, Keens TG. Alcohol use in congenital central hypoventilation
syndrome. Pediatr Pulmonol. 2006;41(3):283–285 PMID: 16429433 doi: 10.1002/ppul.20366
73. Sritippayawan S, Hamutcu R, Kun SS, Ner Z, Ponce M, Keens TG. Mother-daughter
transmission of congenital central hypoventilation syndrome. Am J Respir Crit Care Med.
2002;166(3):367–369 PMID: 12153972 doi: 10.1164/rccm.2112087
74. Parodi S, Bachetti T, Lantieri F, et al. Parental origin and somatic mosaicism of PHOX2B
mutations in congenital central hypoventilation syndrome. Hum Mutat. 2008;29(1):206
PMID: 18157832 doi: 10.1002/humu.9516

PART
8
Other Pulmonary Issues
Chapter 41. Acute Aspiration and Chronic Aspiration–Related

Lung Disease........................................................................................ 699
Chapter 42. Lung Transplantation.................................................... 721

Carol Conrad, MD
Chapter 43. Asthma and Other Respiratory Disorders

Associated With Obesity.................................................................... 747
Mutasim Abu-Hasan, MD, and David Fedele, PhD, ABPP
Chapter 44. Functional Respiratory Disorders...............................763

Miles Weinberger, MD, FAAP; Manju S. Hurvitz, MD, FAAP;
and Mutasim Abu-Hasan, MD
697
48 PP 2ND ED - PO 08_697-698.indd 697 11/6/23 9:31 AM

48 PP 2ND ED - PO 08_697-698.indd 698 9/12/23 10:24 AM
CHAPTER
41
Acute Aspiration and Chronic Aspiration–Related
Lung Disease
Introduction
Aspiration of materials into the lower respiratory tract can be both a chronic
and an acute problem in children. Because the respiratory and gastrointestinal
tracts share a common site of origin, and because of the complex interplay
among breathing, chewing, and swallowing, the aspiration of both intrinsic
and extrinsic oral contents can be more prevalent in children. The clinical
picture of aspiration and aspiration-related lung disease depends on the amount
and type of material aspirated, as well as timing; therefore, a child can present
with an acutely life-threatening event, with recurrent respiratory disease, or
with subclinical disease. The 3 major types of aspiration-related lung disease
are (1) airway foreign body, (2) massive acute aspiration of chemical or liquid
contents, and (3) recurrent small-volume aspiration. In this chapter, we will
review the physiological mechanism of normal swallowing, the clinical pre-
sentation of the 4 major types of aspiration-related lung disease, evaluation
of swallowing dysfunction, and possible treatments.
Physiological Mechanism of Swallowing

Normal swallowing is a complex process dependent on normal anatomy, as
well as the normal neuromuscular function of cranial and cervical nerves.1
Swallowing consists of 4 phases: oral preparatory phase, oral transit phase
(bolus delivery), pharyngeal phase, and esophageal phase (Figure 41-1).
Swallowing involves the aerodigestive tract, which is defined as the combined
organs through which both air and food may pass: oral cavity, tongue, nose,
pharynx, vocal cords, pyriform sinus, larynx, and upper esophagus. The oral
phase is voluntary, including acceptance of the food bolus, preparation of the
food bolus by chewing or sucking, and preparing the bolus on the tongue. The
food bolus is then delivered via the tongue to the pharynx voluntarily in the
oral transit phase. There can be spillage into the hypopharynx if oral move-
ments are not coordinated. Once food bolus delivery occurs, the involuntary
pharyngeal phase begins in order to protect the airway. The pharyngeal phase
699

700
Figure 41-1. Swallowing can be separated into 4 phases: oral preparatory, oral transit, pharyngeal,
and esophageal phases. Coordination difficulties in these phases are more likely to contribute to
symptoms of dysphagia and chronic aspiration. A, Oral preparatory phase: The lips are sealed,
and the tongue assists in mastication and mixing of food into a bolus formation. The velum meets
the base of the tongue to prevent the bolus from moving posteriorly while mastication occurs.
B, Oral transit phase: The tongue elevates and makes contact with the palate to squeeze the
bolus toward the posterior oral cavity and into the pharynx while the velum starts to elevate.
C, Pharyngeal phase: The velum elevates and prevents food from entering the nasal cavity;
the vocal folds close, and the epiglottis deflects to protect the airway while the food bolus
enters the esophagus. D, Esophageal phase: The epiglottis returns to the upright position
with reopening of the vocal folds. The food bolus has passed the upper esophageal sphincter
and is in the esophagus.
Used with permission of McGraw-Hill, from Savastano ME. The role of speech/language pathologists in
dysphagia management. In: McKean SC, Ross JJ, Dressler DD, Scheurer DB, eds. Principles and Practice of
Hospital Medicine. 2nd ed. McGraw-Hill; 2017:chap 70. © 2017; permission conveyed through Copyright
Clearance Center, Inc.

701
Chapter 41—Acute Aspiration and Chronic Aspiration–Related Lung Disease
includes brief cessation of breathing, adduction of the true vocal folds along
with horizontal approximation of the arytenoid cartilages, closure of the false
vocal folds, and retroversion of the epiglottis to protect the airway. The larynx
then elevates and the intrinsic laryngeal muscles contract, diverting the food
into the pyriform sinus region. The muscles of the pharynx then propel the
food through the upper esophageal sphincter. Once the food bolus enters the
esophagus, the larynx returns to resting position and the airway reopens. The
food bolus then enters the esophagus in the esophageal phase and is pushed
downward via peristalsis. This entire intricate process can be seen as early as
10 to 14 weeks of gestation but is not generally sustained until 32 to 34 weeks
of gestation. Neurodevelopmental immaturity, difficulty with coordination of
swallowing, and abnormal anatomy of any part of the aerodigestive tract can
contribute to aspiration.
Aspiration of a Foreign Body

Approximately 80% of foreign body aspirations occur in children younger
than 3 years, with a higher incidence in boys and a peak incidence between
1 and 2 years of age.2 Food is the most aspirated material in toddlers, whereas
small nonedible objects are more common in older children (Box 41-1).
Aspiration of foreign bodies in children is usually due to children placing
items in the mouth that are unable to be chewed or swallowed. Inhalation of a
foreign body can occur if a child of any age is suddenly startled, although it is
more likely in toddlers because of the tendency of this age group toward oral
sensory behavior, poor mastication because they do not have molars to chew
adequately, and immature oropharyngeal coordination.
CASE REPORT 41-1

A 20-month-old boy had a sudden onset of choking and coughing while his
mother was on the telephone in the next room. The cough continued
throughout the next 24 hours, and he developed intermittent wheezing for
which she took him to the pediatrician. He had a prior history of wheezing
with respiratory syncytial virus at age 6 months. She was not aware of any
potential foreign bodies in his environment. At examination, he was afebrile,
with a respiratory rate of 36 breaths/min, mild suprasternal retractions, and an
oxygen saturation of 98%. Lung auscultation revealed a monophonic expira-
tory wheeze, which was transmitted equally throughout the chest. Chest
radiography showed mild bilateral hyperinflation without infiltrates. He was
referred to surgery for evaluation with rigid bronchoscopy. A tracheal foreign
body was suspected from the history and physical examination results.

702
Box 41‑1
Foreign Bodies Commonly Aspirated
by Children
Food
ū Peanuts
ū Popcorn
ū Seeds
ū Hot dogs and hot dog pieces
ū Vegetable material
ū Hard candy
ū Grapes
Nonorganic
ū Toy parts
ū Pen pieces
ū Pins
ū Crayons
ū Tacks
ū Nails
ū Screws
The most common presentation of foreign body aspiration is a history of a
choking event followed by an acute cough, although parents will often not
associate an acute coughing event with a foreign body. Many parents (≥25%)
are not aware of any aspiration or choking event; therefore, a high index of
clinical suspicion is necessary, and the lack of a witnessed event does not rule
out foreign body.3,4 There is often an asymptomatic period after the choking
spell once the foreign body becomes lodged in the lower tracheobronchial tree.
This asymptomatic period could be hours, days, or months, leading to parents
forgetting about the initial episode. A careful history should attempt to elicit
the details surrounding the beginning of the cough. Transient or persistent
cough is the primary symptom in approximately 75% of children with airway
foreign bodies. Physical findings can include asymmetrical chest expansion,
decreased breath sounds over the affected lung, or localized wheezing, or
there may be no abnormalities at examination. A tracheal foreign body is
more likely associated with monophonic wheeze on exhalation because it
reflects obstruction in a single large central airway but may sound bilateral
owing to reverberation. The presence of either monophonic or localized
wheezing that is unresponsive to bronchodilators can help distinguish an

703
asthma exacerbation from a foreign body aspiration. Finally, foreign bodies

lodged in the esophagus may push on the posterior membrane of the trachea,
leading to respiratory symptoms.
Diagnosis
A plain 2-view chest radiograph is the first diagnostic test for a foreign body
because it may quickly show radiopaque foreign bodies (Figure 41-2). An
expiratory radiograph is particularly helpful in demonstrating air trapping on
the affected side from a ball-valve effect, although tracheal or bilateral foreign
bodies will not likely cause asymmetrical findings (Figure 41-3). Atelectasis
may be a later finding. However, a normal chest radiograph does not exclude
an airway foreign body because most foreign bodies aspirated by children are
radiolucent and may not be detected. A normal radiograph is particularly com-
mon for tracheal, laryngeal, and smaller, more distal foreign bodies.3 If the
physical examination and a plain radiograph are not diagnostic, fluoroscopy,
inspiratory and expiratory radiographs, or bilateral decubitus radiographs
(particularly in the uncooperative young child) may be helpful. However,
reviews of decubitus radiographs and fluoroscopic images showed them to
be of limited predictive value for airway foreign bodies.4,5 Hence, low-dose
multidetector computed tomography (CT) is often used to investigate suspected
foreign body aspiration further. Where available, virtual bronchoscopy using
CT imaging software to recreate a virtual intraluminal evaluation of the tra-
cheobronchial tree may
be useful in identifying
a foreign body, as well
as assisting in the sur-
gical removal of foreign
bodies (Figure 41-4).
Computed tomography
imaging increases the
likelihood of positive
bronchoscopy results6,7
and is also used to detect
residual foreign bodies
after bronchoscopy.8
Figure 41-2. A plain chest radiograph can easily reveal

radiopaque objects; this example shows a nail lodged in
the trachea.

704
Figure 41-3. Inspiratory (A) and expiratory (B) chest radiographs show a right bronchus
intermedius foreign body, demonstrating the ball-valve effect with right-sided air trapping
on the expiratory radiograph. These images -are representative of a radiolucent foreign body
trapped on the right side. C, Coronal computed tomography scan shows a foreign body in the
right mainstem bronchus and air trapping in the right lower lobe. D, Image obtained during
rigid bronchoscopy shows the foreign body was a sunflower seed.
Images C and D courtesy of Christopher Oermann, MD.

705
Figure 41-4. A, Posteroanterior view chest radiograph obtained for a shoulder injury. Note the
incidental finding of a thin radiopaque metallic object near the right hilum. B and C, Computed
tomography coronal (B) and axial (C) images obtained to follow up on the chest radiograph
show a foreign body (arrow) with both a metallic bright component and a less radiopaque com-
ponent in right mainstem bronchus. D and E, Virtual bronchoscopy images with reconstructed
images of the foreign body. Note that the radiopaque metallic component is embedded in
granulation tissue. After further history was obtained, the patient recalled aspirating a thumb-
tack several years previously, which explains the radiopaque metallic component and the
radiolucent plastic component of the foreign body on the chest computed tomography images.
Courtesy of Jade Tam-Williams, MD, FAAP.

706
Management
If complete airway obstruction occurs with a witnessed choking event,
abdominal thrusts (Heimlich maneuver) are indicated for children older
than 1 year. For infants younger than 1 year, chest thrusts and back blows in
the head-down position should be used. If a foreign body is likely based on
the history, examination results, or radiographs, airway evaluation should be
performed as soon as safely possible to prevent possible dislodgement into a
more central and potentially life-threatening position in the airway. In these
situations, the airway is evaluated with the patient sedated in the operating
room via microlaryngoscopy and bronchoscopy (MLB), also colloquially
referred to as rigid bronchoscopy, to describe the type of bronchoscope. Per-
forming MLB is preferred for retrieval of foreign bodies because the larger
hollow metal bronchoscope tube allows for introduction of instruments to
secure foreign bodies. Small food-based foreign bodies may be especially
troublesome because they can lead to inflammation and obstruction of distal
airways, leading to recurrent pneumonia. These may necessitate treatment
with antibiotics and aggressive airway clearance to help with retrieval because
without reduction of local inflammation, the foreign body is difficult to remove.
Other parenchymal lung complications include pneumothorax, atelectasis, and
bronchiectasis. Small distal foreign bodies may require special instrumenta-
tion, and sometimes flexible bronchoscopy with a bronchoscope that can bend
in multiple directions can help aid diagnosis or visualization of small objects.
If the diagnosis is unlikely to be a foreign body, flexible bronchoscopy may
also be beneficial to provide another diagnosis for respiratory symptoms.
Very rarely, a lobectomy may be necessary to remove a highly embedded
foreign body.
Preemptive education for parents of infants and toddlers should be standard in
pediatric practice. This education includes advising that commonly aspirated
objects, such as peanuts or similar-sized foods, be kept out of reach; food
should be cut into small pieces; and latex-type balloons should not be
allowed in the home.
When to Refer and Admit

Any child with sudden onset of choking followed by coughing, wheezing,
or respiratory distress should be suspected of having an airway foreign body.
After initial stabilization and imaging, consultation with an otolaryngologist
or pediatric surgeon should be sought for foreign body airway evaluation via
MLB. A history of acute choking should never be ignored. A child with a
choking event but no further symptoms, such as cough, dyspnea, or fever,
who has normal physical examination or chest radiographic findings, may
not require foreign body airway evaluation but should undergo follow-up
for possible late-onset symptoms.9 If the child presents with chronic cough,

707
recurrent pneumonia, persistent chest radiographic abnormalities, or

wheezing or cough unresponsive to asthma therapy, or if the diagnosis is
in question, consultation with a pediatric pulmonologist is warranted.
Flexible bronchoscopy should be considered in these cases as well.
Acute Large-Volume Aspiration

Large-volume aspiration is typically associated with vomiting, particularly
with altered level of consciousness and diminished upper airway protective
reflexes. It may occur during trauma, seizure, or general anesthesia, or with
underlying neuromuscular disorders. Results from animal studies have
shown that volumes greater than 1 mL/kg or pH less than 2.5 are associated
with the most severe outcomes, although aspiration of particulate material
also contributes to clinically significant lung injury.10 When acute massive
aspiration is suspected, immediate intervention is paramount.
CASE REPORT 41-2

An 8-year-old boy with developmental delay developed fever and upper
airway congestion. He subsequently began vomiting and appeared to
become dyspneic. Given his history of aspiration, his mother took him to
their local hospital. His oxyhemoglobin saturation was 83% while receiving
high-flow supplemental oxygen. Inspiratory crackles were audible in both
lower lobes. While his evaluation was underway, he became increasingly
tachypneic, dyspneic, and cyanotic. He subsequently underwent intubation
and mechanical ventilation and was airlifted to a nearby children’s hospital.
His chest radiographs showed complete opacification of his right lower lobe
with streaky infiltrates and haziness in his right upper and left lower lobes.
He required intensive care with mechanical ventilation for 2 weeks and
subsequently needed supplemental oxygen for several days thereafter.
Multidisciplinary family-centered rounds with specialists in otolaryngology,
pulmonology, and palliative care included discussion about whether
tracheostomy placement would reduce morbidity from future aspiration
events and improve his quality of life.
There is no difficulty in establishing the diagnosis of acute massive aspiration
when the patient is observed to have vomited a large volume, with choking
and immediate respiratory distress. If the child has a tracheostomy tube, suc-
tioning of the tube may return some formula or stomach contents, but evidence
of vomitus may still be present in the oropharynx. In severe cases, asphyxia
may occur with loss of consciousness or respiratory arrest. Generalized
seizures may occur secondary to associated hypoxic encephalopathy.

708
Mendelson11 first described acute large-volume aspiration of gastric contents

as a complication of obstetric anesthesia, although this form of aspiration is
uncommon in the modern day because of changes in anesthesia practice.12
Clinical observation frequently reveals accessory muscle use and retractions,
inspiratory coarse crackles, and polyphonic wheezing due to aspirate obstruc-
tion. Aspiration of high-acidity gastric contents may also lead to chemical
pneumonitis due to lung injury and release of inflammatory mediators. These
findings typically include coughing, wheezing, dyspnea, tachypnea, tachycar-
dia, and possibly cyanosis. After a latent period of 1 to a few hours, fever and
crackles may develop. Initial radiographic findings typically show bilateral
multilobar infiltrates that worsen over the next 24 to 36 hours secondary to
inflammatory response (Figure 41-5). Acute respiratory distress syndrome
may develop, and bacterial infection is unusual initially, but superinfection
may develop later. Chemical pneumonitis is less likely to occur from aspiration
of tube feedings or blood because of the higher pH and lower likelihood of
bacterial contamination.12
Figure 41-5. Chest radiograph obtained a few hours after the patient vomited and
aspirated a large volume of gastric material.

709
Diagnosis
It may be difficult to differentiate between large-volume aspiration leading
to aspiration pneumonia, chemical pneumonitis, and postobstructive pneu-
monia.12 Radiographic imaging is warranted as a confirmatory first step
and for monitoring. If a child is suspected of having inhaled substances with
substantial particulate matter, bronchoscopy may be warranted. Identification
and removal of large airway particles are of diagnostic as well as therapeutic
value. If no large particles are seen in the airways, bronchoalveolar lavage
(BAL) may still reveal diagnostic foreign material, such as meat or vegetable
fibers. If lipid is aspirated, lipid-laden macrophages may be observed within
a few hours after aspiration.13
Management
Bronchoscopy may play a role in some cases of massive aspiration. There
is no value in attempting to neutralize acid aspiration because this occurs
endogenously within seconds after the event. Routine corticosteroids are not
beneficial for aspiration pneumonia or chemical pneumonitis.12 Antibiotics are
determined based on the clinical picture. Mandell and Niederman12 proposed
an algorithmic approach differentiating aspiration events between community
versus hospital acquisition, with the recommendation to use broad-spectrum
antibiotics if the patient was admitted recently, including coverage for gram-
negative bacteria, methicillin-resistant Staphylococcus aureus, and anaerobes.
However, in the immediate treatment for large-volume aspiration with mild
to moderate symptoms, antibiotics can be withheld as long as the patient can
be observed. General supportive measures, including supplemental oxygen,
bronchodilators, and possible mechanical ventilation, are mainstays of
acute treatment.
For patients at risk of vomiting and aspiration, gastric volume should be
minimized. Whenever possible, gastric acid should be suppressed. If vomit-
ing is witnessed in a patient with a poorly protected airway or artificial airway,
immediate suctioning of the airway is critical. Elevation of the head of the bed
to 30° to 45°, avoiding excess sedation (if possible), and monitoring gastric
residual volumes during enteral feedings may be helpful preventive measures.

All patients who become rapidly dyspneic from large-volume aspiration
should be admitted to a hospital. Unless the physical examination results,
oxyhemoglobin saturation, and chest radiographs are normal, all patients
suspected of having had large-volume aspiration ought to be admitted for
close observation. If a patient is able to maintain near-normal blood oxygen
levels with reasonable amounts of supplemental oxygen (fraction of inspired
oxygen < 60%), is only mildly or moderately dyspneic, is not in an altered

710
neurological state, and can be monitored by experienced staff, that patient

reasonably can be cared for in a community hospital. The patient should be
observed closely for a minimum of 48 hours because late-onset deterioration
can occur. A child whose condition deteriorates rapidly and who requires
increasing oxygen supplementation, becomes obtunded, or requires intubation
and assisted ventilation should be transferred to a center with pediatric pulmo-
nary and critical care specialists. It is very likely that, in these situations, the
patient will require prolonged and intensive treatment and will require close
follow-up in specialty clinics.
Aspiration of Hydrocarbons
Some attention must be given to the uniqueness of aspiration of hydrocarbons
because they are lipophilic, causing tissue damage and surfactant disruption
quickly. In addition, they have intrinsic properties that allow them to spread
throughout the lung easily.14 Common household hydrocarbons include kero-
sene, furniture polish, paint, paint thinner, and gasoline. Aspiration can be
accidental in children or intentional in adolescents and young adults. Once
inhaled into the alveoli, these chemicals lead to fluid leak and bleeding with
subsequent acute hypoxemic respiratory failure. Ventilation may require high
pressures and high oxygen concentration. Acute hypoxemia may also affect
neurological function. It can be difficult to assess these events because they
may or may not be witnessed and the amount aspirated may be unknown.
Treatment is generally supportive because there is no evidence that prophy-
lactic steroids or antibiotics are helpful.15 Antibiotics are reserved for superim-
posed bacterial infection. Induction of vomiting may lead to further aspiration
of hydrocarbon into the lungs. Chest radiography is indicated in any patient
suspected of having inhalation aspiration of hydrocarbons. Initial radiographic
findings may be minimal or may reflect chemical pneumonitis with multiple
patchy opacities with ill-defined margins. Radiographic findings typically
peak by 48 hours after aspiration; therefore, serial imaging in patients sus-
pected of having inhaled a hydrocarbon may be beneficial.14 Once the patient
has recovered, long-term complications may include pneumatocele or
pulmonary fibrosis.

711
CASE REPORT 41-3

A 9-month-old boy presents with a recurrent cough that is present more days
than not for the past 6 months. His newborn screening for cystic fibrosis was
normal. He spits up after most feedings, more than his older siblings did. His
cough seems to have no particular pattern, but with specific questioning, the
mother states it may be more common toward the end of and after feedings.
His physical examination results were normal except for transient inspiratory
and expiratory wheezes after a feeding. Chest radiographs showed patchy
infiltrates predominantly in the posterior right upper lobe and to a lesser
extent in the apical left upper lobe and right lower lobe with mild to moderate
hyperinflation. He has had intermittent low-grade fevers. His cough did not
improve substantially with a course of amoxicillin. He was referred for a video-
fluoroscopic swallowing study, which showed tracheal aspiration with thin
barium and mild laryngeal penetration with nectar consistency barium.
Recurrent Small-Volume Aspiration

(Gastroesophageal Reflux, Saliva)
Recurrent aspiration of small volumes of food or gastric, oral, or nasal
contents leads to acute and chronic respiratory problems. Risk factors for
chronic recurrent aspiration are listed in Box 41-2. However, chronic aspira-
tion with isolated swallowing dysfunction can occur in otherwise apparently
healthy young children.16 Oropharyngeal incoordination has been reported to
be the most common underlying problem associated with recurrent pneumo-
nia causing hospitalization.17
Box 41‑2
Risk Factors for Recurrent Aspiration
ū Vocal cord anomalies ū Dysautonomia
ū Congenital anomalies of the airways ū Poor oral hygiene
(eg, laryngomalacia, laryngeal cleft, ū Poor feeding techniques
vascular ring, and tracheoesophageal
fistula) ū Gastroesophageal reflux
ū Craniofacial anomalies (eg, Pierre- ū Swallowing immaturity
Robin sequence, choanal atresia)
ū Neurological or neuromuscular
disease

712
Small-volume aspiration, or micro-aspiration, is sometimes differentiated as
being from above, or anterograde, such as oral intake (eg, saliva or formula),
or being from below, or retrograde, such as gastroesophageal reflux (GER).
Parents may describe cough, rattling, or noisy breathing after swallowing.
A history of recurrent lower respiratory tract infections (pneumonia, bron-
chitis) may be present. Clinical clues to chronic micro-aspiration due to
GER can include apnea, recurrent cough, wheezing, and esophageal discom-
fort, although children may not be able to communicate this to their parents.
Nighttime symptoms may also be present. Aspiration of reflux causes airway
inflammation due to acidity and the presence of gastric enzymes. Aspiration
of material from the mouth can include lipids, oropharyngeal bacteria, salivary
enzymes, and upper airway secretions. Other clinical clues to small-volume
aspiration include the risk factors listed in Box 41-2. Although choking or
coughing with feedings is common with aspiration from dysphagia, silent
aspiration can also occur, especially in patients who are neurologically
impaired. Chronic aspiration can also be a coincident finding in patients
with other chronic conditions, such as cystic fibrosis, primary ciliary
dyskinesia, and asthma.
Information to ask about in the history includes timing, duration, and fre-
quency of respiratory symptoms. The patient may have a history of upper
airway, gastrointestinal, or respiratory issues. Feeding habits such as position-
ing, bottle propping, or allowing the child to sleep with a bottle are important
to assess, as well as subsequent spitting, vomiting, or arching behaviors. Other
pertinent history includes difficulty with sucking, nasopharyngeal reflux with
nasal congestion, changes in gag reflex, sialorrhea, or pooling of oropharyn-
geal secretions. The nose, oropharynx, and oral hygiene should be examined,
along with auscultation of the lower airway. In addition, one should assess for
neuromuscular weakness, dysmorphic features, and voice and cough quality.
Observation of feeding during examination can provide valuable information
and reduce the need for further workup.
Evaluation and Diagnosis

The intermittent nature of micro-aspiration and the fact that both aspiration
and GER may be seen in healthy children without respiratory symptoms make
it difficult to prove a cause-and-effect association of recurrent small-volume
aspiration and lower respiratory tract disease. Considerable clinical judgment
is required. The initial radiographic study for a child suspected of having
recurrent aspiration is plain chest radiographs. However, there are no findings
specific to aspiration, and the results may range from normal to hyperaeration
with peribronchial thickening to classically described consolidations in depen-
dent lobes or segments. Chest CT in children with chronic aspiration may

713
show persistent infiltrates or bronchiectasis in the posterior and medial lower

lobes that is not evident on radiographs.
Depending on clinical suspicion, the next steps include either a simple
barium esophagram and upper gastrointestinal series or a videofluoroscopic
swallowing study (VFSS) or fiber-optic endoscopic evaluation of swallowing
(FEES). A barium esophagram can depict gross anatomical abnormalities,
such as hiatal hernia, tracheoesophageal fistula, vascular ring, and gross
aspiration or GER; VFSS or FEES can provide an objective evaluation of
oropharyngeal dysphagia.18
The VFSS is a well-described study for evaluating swallowing and oropharyn-
geal aspiration (Figure 41-6).1,18,19 It should be performed with the assistance
of a pediatric feeding specialist, a radiologist, and a parent. The purpose of
this evaluation is to assess pharyngeal function and define motility problems
in the oral cavity, pharynx, and upper esophagus. It is usually performed
with the child seated in a normal eating position and using various consisten-
cies of barium or food soaked in barium. Although VFSS is sensitive for
oropharyngeal aspiration, it does not help evaluate lower esophageal motility
or GER. Indications for use of VFSS include intolerance of FEES, suspected
anatomical anomalies of the upper airway or esophagus, suspected swallowing
disorders, and the need for a treatment plan to improve swallowing efficiency
and decrease risk of aspiration. Contraindications include inability to be fed
orally or never having been fed orally, inability to use the correct posture
during examination for imaging, allergies to barium or iodine, and inability
to transfer to the radiology department.1
Fiber-optic endoscopic evaluation of swallowing is useful in children and is of
sensitivity similar to that of VFSS without the radiation.18,20 With this test, the
endoscopist observes multiple swallows of food of various consistencies
through a small nasopharyngoscope located above the supraglottic area. This
method allows both anatomical and functional evaluation of swallowing,
except that nothing can be viewed during pharyngeal contraction because
of airway closure, and there is no evaluation of the esophageal phase. It can
be used in children with oral aversion, although some level of cooperation,
or at least tolerance, is necessary with the nasopharyngoscope. In addition,
properly trained staff must be available to perform the procedure; therefore,
FEES is not as widely available as other diagnostic modalities. Fiber-optic
endoscopic evaluation of swallowing has increased sensitivity for detection
of laryngeal sensitivity for aspiration, but concerns have been raised regard-
ing intrusion of the fiber-optic scope negatively affecting the swallowing
process.18,21 Both FEES and VFSS can only be used to assess a brief period,
which can lead to both false-positive and false-negative results. An advantage
to both is that they can assist with providing treatment recommendations,
such as thickening of food or special positioning.

714
Other radiographic evaluations include gastroesophageal scintigraphy

(milk scan); although offering the theoretical advantages of being more
physiological and giving a longer window of viewing than the barium eso-
phagram for detecting GER or aspiration, it is insensitive for detecting aspira-
tion. The salivagram, another radionuclide scan, has been used to assess the
aspiration of oropharyngeal contents. With this test, a small of amount of
radionuclide is administered orally to mimic the amount of saliva in the mouth,
and scanning is performed to look for tracheal or pulmonary aspiration. It may
be more sensitive than gastroesophageal scintigraphy and has approximately
the same sensitivity as VFSS.22
In patients with a tracheostomy or endotracheal tube, methylene blue used
to be administered under the tongue or mixed in with food to help diagnose
aspiration-related lung disease. Observation of stained tracheal secretions
during subsequent suctioning was an indication of aspiration into the main
airways. It is not advisable to add dye to large volumes of tube feedings
because this has the potential for toxicity and larger amounts do not increase
sensitivity for aspiration. This is a simple test that can be repeated multiple
times, but caution is advised. Although they could not establish a causal
relationship, the US Food and Drug Administration has issued an advisory
regarding methylene blue use in these scenarios, with complications reported,
including blue discoloration of the skin, urine, and feces; metabolic acidosis;
and death, especially in patients who are seriously ill or have sepsis.23
Gastroesophageal reflux may produce respiratory symptoms such as chronic
cough, with or without aspiration, through an exaggerated esophagobronchial
response through shared vagal nerve innervation.24,25 A cause-and-effect
relationship between GER and respiratory symptoms is difficult to prove,
as previously stated, because GER can exist without respiratory symptoms.
An expert panel report from the American College of Chest Physicians in
2019 recommended that for children younger than 14 years with chronic
cough (>4 weeks), a trial of GER medications should be attempted only
if the child has signs of GER.25
Examination of BAL fluid obtained with flexible bronchoscopy or tracheo-
bronchial aspirates from artificial airways can yield valuable information
regarding aspiration, including analysis for pepsin, vegetable or meat fibers,
bile, and lipid-laden macrophages. The use of biomarkers such as pepsin or
lipid-laden macrophages to diagnose aspiration-related lung disease is limited
owing to variations in study methodology and availability of testing.24 Pepsin
is a more specific biomarker of gastric pulmonary aspiration than are lipid-
laden macrophages.26 The usefulness of pepsin analysis in BAL fluid and
sputum is unclear at this time, not only because there are no clinically validated
assays but also because pepsin levels in BAL fluid did not differ between those
with chronic cough and healthy control subjects in one study.24 The finding of

715
lipid-laden macrophages is nonspecific for aspiration because it cannot

help distinguish exogenous from endogenous lipids and results from studies
evaluating the lipid-laden macrophage index have been inconsistent.24 In one
study, the lipid-laden macrophage index was higher in children with chronic
respiratory symptoms than in healthy adults but did not seem to correlate with
levels of inflammation.27 With the use of proper histological techniques, the
absence of lipid-laden macrophages highly suggests that lipid aspiration is
not occurring.28
It is critically important to consider diagnoses other than aspiration as the
cause of respiratory disease. Children with cystic fibrosis, asthma, interstitial
pneumonitis, and primary ciliary dyskinesia, among other conditions, may
present with an abnormal history or diagnostic assessment, which may
indicate aspiration, thus delaying the primary diagnosis.
Figure 41-6. An image obtained during

a videofluoroscopic swallowing study
shows tracheal aspiration of a large
volume of thin barium.
Management
Treatment should be directed at the underlying condition causing aspiration.
Other treatments will depend on the severity of respiratory problems and
whether they are caused by a swallowing dysfunction or GER. Conservative
measures to prevent aspiration during swallowing include thickening or pacing
of feedings, swallow stimulation, and change of feeding position. Thickening
foods, upright positioning, avoidance of bottle propping and smoke exposure,
and weight loss (if indicated) can be helpful in reducing GER. Medical treat-
ment with proton pump inhibitors can reduce acid reflux but has not been
shown to reduce nonacid reflux. Prokinetic agents available in the United
States are metoclopramide and erythromycin. The efficacy of either drug is
not well substantiated, and adverse effects are common with metoclopramide.
A trial of nasogastric (NG) feedings can be used while waiting for temporary
swallowing dysfunction to improve. Risks with NG tube feedings include
nasopharyngeal lesions, sinusitis, insertion trauma or misplacement, esopha-
gitis, GER due to stent placement that opens the lower esophageal sphincter,
or gastrointestinal upset. With clinically significant GER, postpyloric feed-
ings may be considered. Surgical treatment is reserved for patients with more
severe morbidities, such as recurrent pneumonias requiring hospitalization or

716
evidence of progressive lung injury. Fundoplication can be considered and

performed in conjunction with gastrostomy tube placement in children with
clinically significant GER and/or oropharyngeal dysphagia. However, a pre-
operative decision must be made whether fundoplication should be performed
at the same time as gastrostomy tube placement in children without clinically
significant GER as some patients develop symptomatic GER after gastrostomy
tube placement. Recurrent pneumonias may continue even after both fundo-
plication and gastrostomy tube placement because of continued aspiration of
oral secretions, particularly in children who are neurologically impaired.
Anticholinergic agents, such as glycopyrrolate and scopolamine, may reduce
excess salivation, but tolerance can develop, and adverse effects may occur,
such as blurred vision, dry mouth, constipation, and urinary retention.29 Exces-
sive drying of tracheal and bronchial secretions can cause mucous plugging in
the airways or life-threatening mucous plugs in tracheostomy tubes. Salivary
gland injection of botulinum toxin can reduce salivation.29 Investigators in a
single-center study reported that injection of botulinum toxin to the salivary
glands decreased or eliminated anticholinergic medications use as well as
tolerance to injections for up to 9.6 years; they also reported decreased
episodes of pneumonia and length of hospitalization stays.30 Other minimally
invasive interventions include salivary gland sclerotherapy, which is performed
by an interventional radiologist. The salivary glands are identified, and then
a sclerosing agent is injected to shrink the gland. Surgical intervention with
salivary gland removal, ductal ligation, or laryngotracheal separation may be
considered in children in whom more conservative therapy does not work.22
Tracheostomy can be considered in a patient with chronic aspiration and air-
way clearance impairment leading to chronic lung disease or respiratory in-
sufficiency. In this situation, tracheostomy is a means to improve pulmonary
hygiene, as well as to provide ventilatory assistance and oxygen delivery.
Management of chronic aspiration can be multifactorial, and treatment is
best individualized for the patient through close collaboration between the
primary physician, pulmonologist, family, and team members from surgical
subspecialties. As outlined, management can range from changing feeding
behaviors to more invasive surgical interventions. In particular, when con-
sidering tracheostomy, it is important to take into account patient and family
preferences, short- and long-term pulmonary needs, and upper airway anat-
omy, with consultation of otolaryngology subspecialists; consideration should
be given to palliative care and pediatric pulmonology consultation for
long-term care.

717

A child with recurrent pneumonia or persistent chest radiographic abnormal-
ity, dysphagia, coughing or choking with feedings, or recurrent wheezing not
responsive to routine asthma therapy should be referred to a pediatric pulmon-
ologist for further evaluation. Hospital admission would be indicated if there
is clinically significant dyspnea, hypoxemia, worsening pulmonary signs or
symptoms, equivocal history, or an acute life-threatening event. Any of these
may indicate an acute or cumulative effect of chronic aspiration. If available,
referral to a multidisciplinary aerodigestive team, generally consisting of a
pulmonologist, otolaryngologist, gastroenterologist, and speech and language
pathologist, should be considered for complex cases.
key points
} Oropharyngeal aspiration from swallowing dysfunction is the most common
cause of recurrent pneumonia in children.
} A high index of suspicion is necessary for airway foreign bodies because the
history, physical examination results, and radiographs may be normal. The
ultimate diagnosis is often made only by means of MLB. Choking episodes
should never be ignored.
} Clinical presentation for large-volume aspiration is generally associated with
respiratory distress. Supportive care and observation should be provided, with
the consideration of adding antibiotics, depending on severity of symptoms,
underlying disease processes, and recent institutionalization or instrumentation
of the airway. Routine use of corticosteroids is not indicated.
} Aspiration of hydrocarbons can cause surfactant disruption and tissue damage,
quickly leading to acute hypoxemic respiratory failure. There is no support for
routine use of oral corticosteroids or antibiotics.
} Evaluation for aspiration of foods includes physical examination during feedings,
VFSS, and FEES. Both imaging modalities have limitations and benefits, but both
allow for diagnosis of aspiration, as well as distinguishing safe consistencies of
foods. There is no test for aspiration that is both highly sensitive and specific.
Clinical judgment is always necessary to determine whether aspiration is a
likely cause of existing respiratory disease.
} Small-volume aspiration, or micro-aspiration, of both oropharyngeal secretions
and GER has been described and can be difficult to distinguish.
} Management of aspiration from feedings can include feeding therapies,
thickening of food, or changing to enteral feedings via NG tube or
gastrostomy tube.
} Management of aspiration from saliva or oropharyngeal secretions ranges from
anticholinergic medications, botulinum toxin injections to salivary glands, and
salivary gland sclerotherapy to more invasive measures such as salivary gland
ligation or laryngotracheal separation.

718
References
1. Re GL, Vernuccio F, Di Vittorio ML, et al. Swallowing evaluation with videofluoroscopy in
the paediatric population. Article in Italian. Acta Otorhinolaryngol Ital. 2019;39(5):279–288
PMID: 30933173 doi: 10.14639/0392-100X-1942
2. Salih AM, Alfaki M, Alam-Elhuda DM. Airway foreign bodies: a critical review for
a common pediatric emergency. World J Emerg Med. 2016;7(1):5–12 PMID: 27006731
doi: 10.5847/wjem.j.1920-8642.2016.01.001
3. Eren S, Balci AE, Dikici B, Doblan M, Eren MN. Foreign body aspiration in children:
experience of 1160 cases. Ann Trop Paediatr. 2003;23(1):31–37 PMID: 12648322
doi: 10.1179/000349803125002959
4. Even L, Heno N, Talmon Y, Samet E, Zonis Z, Kugelman A. Diagnostic evaluation of foreign
body aspiration in children: a prospective study. J Pediatr Surg. 2005;40(7):1122–1127
5. Assefa D, Amin N, Stringel G, Dozor AJ. Use of decubitus radiographs in the diagnosis of
foreign body aspiration in young children. Pediatr Emerg Care. 2007;23(3):154–157
PMID: 17413429 doi: 10.1097/PEC.0b013e3180328cd8
6. Gibbons AT, Casar Berazaluce AM, Hanke RE, et al. Avoiding unnecessary bronchoscopy in
children with suspected foreign body aspiration using computed tomography. J Pediatr Surg.
2020;55(1):176–181 PMID: 31706607 doi: 10.1016/j.jpedsurg.2019.09.045
7. Adaletli I, Kurugoglu S, Ulus S, et al. Utilization of low-dose multidetector CT and virtual
bronchoscopy in children with suspected foreign body aspiration. Pediatr Radiol.
2007;37(1):33–40 PMID: 17033800 doi: 10.1007/s00247-006-0331-y
8. Shin SM, Kim WS, Cheon JE, et al. CT in children with suspected residual foreign body in
airway after bronchoscopy. AJR Am J Roentgenol. 2009;192(6):1744–1751 PMID: 19457843
doi: 10.2214/AJR.07.3770
9. Cohen S, Avital A, Godfrey S, Gross M, Kerem E, Springer C. Suspected foreign
body inhalation in children: what are the indications for bronchoscopy? J Pediatr.
2009;155(2):276–280 PMID: 19446848 doi: 10.1016/j.jpeds.2009.02.040
10. Hamelberg W, Bosomworth PP. Aspiration pneumonitis: experimental studies and clinical
observations. Anesth Analg. 1964;43(6):669–677 PMID: 14230720
doi: 10.1213/00000539-196411000-00011
11. Mendelson CL. The aspiration of stomach contents into the lungs during obstetric anesthesia.
Am J Obstet Gynecol. 1946;52(2):191–205 PMID: 20993766 doi: 10.1016/S0002-9378(16)39829-5
12. Mandell LA, Niederman MS. Aspiration pneumonia. N Engl J Med. 2019;380(7):651–663
PMID: 30763196 doi: 10.1056/NEJMra1714562
13. Colombo JL, Hallberg TK, Sammut PH. Time course of lipid-laden pulmonary macrophages
with acute and recurrent milk aspiration in rabbits. Pediatr Pulmonol. 1992;12(2):95–98
PMID: 1570193 doi: 10.1002/ppul.1950120207
14. Makrygianni EA, Palamidou F, Kaditis AG. Respiratory complications following hydrocarbon
aspiration in children. Pediatr Pulmonol. 2016;51(6):560–569 PMID: 26910771
doi: 10.1002/ppul.23392
15. Das S, Behera SK, Xavier AS, Selvarajan S. Prophylactic use of steroids and antibiotics in
acute hydrocarbon poisoning in children. J Pharm Pract. 2020;33(1):90–95 PMID: 29673294
doi: 10.1177/0897190018771520
16. Lefton-Greif MA, Carroll JL, Loughlin GM. Long-term follow-up of oropharyngeal dysphagia
in children without apparent risk factors. Pediatr Pulmonol. 2006;41(11):1040–1048
PMID: 16871618 doi: 10.1002/ppul.20488
17. Owayed AF, Campbell DM, Wang EE. Underlying causes of recurrent pneumonia in children.
Arch Pediatr Adolesc Med. 2000;154(2):190–194 PMID: 10665608
doi: 10.1001/archpedi.154.2.190
18. Espitalier F, Fanous A, Aviv J, et al. International consensus (ICON) on assessment of
oropharyngeal dysphagia. Eur Ann Otorhinolaryngol Head Neck Dis. 2018;135(1S):S17–S21
PMID: 29396225 doi: 10.1016/j.anorl.2017.12.009
19. Duffy KL. Dysphagia in children. Curr Probl Pediatr Adolesc Health Care. 2018;48(3):71–73
PMID: 29571543 doi: 10.1016/j.cppeds.2018.01.003
20. Willging JP, Thompson DM. Pediatric FEESST: fiberoptic endoscopic evaluation of swallowing
with sensory testing. Curr Gastroenterol Rep. 2005;7(3):240–243 PMID: 15913485
doi: 10.1007/s11894-005-0041-x
21. Adachi K, Umezaki T, Kikuchi Y. Videoendoscopy worsens swallowing function: a
videofluoroscopic study—a randomized controlled trial. Eur Arch Otorhinolaryngol.
2017;274(10):3729–3734 PMID: 28821940 doi: 10.1007/s00405-017-4720-7

719
22. Baikie G, South MJ, Reddihough DS, et al. Agreement of aspiration tests using barium
videofluoroscopy, salivagram, and milk scan in children with cerebral palsy. Dev Med Child
Neurol. 2005;47(2):86–93 PMID: 15707231 doi: 10.1017/S0012162205000174
23. US Food and Drug Administration. FDA public health advisory: subject—reports of blue
discoloration and death in patients receiving enteral feedings tinted with the dye, FD&C Blue
No. 1. Reviewed November 15, 2017. Accessed February 10, 2022. https://www.fda.gov/industry/
medical-devices/fda-public-health-advisory-subject-reports-blue-discoloration-and-death-
patients-receiving-enteral
24. Lee AS, Lee JS, He Z, Ryu JH. Reflux-aspiration in chronic lung disease. Ann Am Thorac Soc.
2020;17(2):155–164 PMID: 31697575 doi: 10.1513/AnnalsATS.201906-427CME
25. Chang AB, Oppenheimer JJ, Kahrilas PJ, et al; CHEST Expert Cough Panel. Chronic cough and
gastroesophageal reflux in children: CHEST guideline and expert panel report. Chest.
2019;156(1):131–140 PMID: 31002783 doi: 10.1016/j.chest.2019.03.035
26. Starosta V, Kitz R, Hartl D, Marcos V, Reinhardt D, Griese M. Bronchoalveolar pepsin, bile
acids, oxidation, and inflammation in children with gastroesophageal reflux disease. Chest.
2007;132(5):1557–1564 PMID: 17925430 doi: 10.1378/chest.07-0316
27. Kazachkov MY, Muhlebach MS, Livasy CA, Noah TL. Lipid-laden macrophage index and
inflammation in bronchoalveolar lavage fluids in children. Eur Respir J. 2001;18(5):790–795
PMID: 11757629 doi: 10.1183/09031936.01.00047301
28. Colombo JL, Hallberg TK. Pulmonary aspiration and lipid-laden macrophages: in search of
gold (standards). Pediatr Pulmonol. 1999;28(2):79–82 PMID: 10423305
doi: 10.1002/(sici)1099-0496(199908)28:2%3C79::aid-ppul1%3E3.0.co;2-a
29. Little SA, Kubba H, Hussain SSM. An evidence-based approach to the child who drools saliva.
Clin Otolaryngol. 2009;34(3):236–239 PMID: 19531173 doi: 10.1111/j.1749-4486.2009.01917.x
30. Dohar JE. Sialorrhea & aspiration control—a minimally invasive strategy uncomplicated by
anticholinergic drug tolerance or tachyphylaxis. Int J Pediatr Otorhinolaryngol. 2019;116:97–101
PMID: 30554718 doi: 10.1016/j.ijporl.2018.10.035

CHAPTER
42
Lung Transplantation
Carol Conrad, MD
Introduction
The first pediatric lung transplant was performed in 1986. Lung and heart-lung
transplants were prominent in the 1980s into the early 1990s, but because of
improved surgical techniques, and in the interest of increased organ alloca-
tion, they are not as commonly performed in children as in adults. As of 2019,
a total of 2,514 pediatric lung and 733 pediatric heart-lung transplants had been
reported to the International Thoracic Organ Transplant Registry since its
inception.1 The registry reports a relatively stable number of pediatric lung
transplants between 2010 and 2018 but a decrease in pediatric heart-lung
transplants through the same period. Annually, the number of pediatric lung
transplants has ranged between 97 and 136, and there has been a concomitant
decrease in the number of centers that perform pediatric lung transplants.
Pediatric lung transplant is a very specialized surgical procedure: fewer than
5 pediatric lung transplants are performed yearly at most of these centers.1
Survival after a lung or heart-lung transplant is lower in both children and
adults than that for any other solid organ because the mechanisms that cul-
minate in chronic graft dysfunction (ie, chronic lung allograft dysfunction
[CLAD]) are not well understood. No new therapies have been introduced
that readily prevent CLAD, although survival has improved slightly in recent
years. Long-term survival for patients surviving 1 year after lung transplant
is 9.1 years. This survival outcome compares favorably with the survival out-
comes for adult recipients of lung transplants through 2009, but discrepancies
are increasing, with noted worse survival rates in adolescents for the period
from 2009 to 2017. During this period, adult lung transplant survival averaged
12.8 years, if the recipient survived to 1 year, but pediatric survival averaged
9.4 years, calculated with conditional survival to 1 year. For recipients of
heart-lung transplants, the survival is slightly worse. The average survival of
children with lung transplants varies by age group (Figure 42-1). Although the
first-year mortality is much higher for infants younger than 1 year at the time
of transplant, the mortality rate for all age groups is similar (Figure 42-2).1,2
721

722
Figure 42-1. Pediatric lung transplant survival. Kaplan-Meier survival by age group is conditional
on survival to 1 year by age group (transplants: January 1992–June 2017).
Reprinted from Hayes D Jr, Cherikh WS, Chambers DC, et al; International Society for Heart and Lung
Transplantation. The International Thoracic Organ Transplant Registry of the International Society for
Heart and Lung Transplantation: twenty-second pediatric lung and heart-lung transplantation report—
2019; focus theme: donor and recipient size match. J Heart Lung Transplant. 2019;38(10):1015–1027. © 2019,
with permission from the International Society for Heart and Lung Transplantation.
Figure 42-2. Conditional half-life survival by age group of children with a lung transplant
(transplants: January 1992–June 2017).
Reprinted from Hayes D Jr, Cherikh WS, Chambers DC, et al; International Society for Heart and Lung

723
Chapter 42—Lung Transplantation
The most life-limiting factor for recipients of lung and heart-lung transplants is
chronic graft rejection that manifests histologically as obliterative bronchiolitis
(OB) in the small airways, a restrictive disease characterized by parenchymal
fibrosis, or a combination of the two. The clinical equivalent of OB is termed
bronchiolitis obliterans syndrome (BOS). Obliterative bronchiolitis describes
luminal obliteration of the bronchioles with accumulated fibrous tissue, which
eventually leads to progressive respiratory failure once it has begun. Fibrosis
of the lung parenchyma creates restrictive mechanics and is termed restrictive
allograft syndrome (RAS). The fibrotic pathophysiology that characterizes
both BOS and RAS is considered representative of the final common pathway
of injury, occurring as a result of various forms of damage to the graft, which
includes postoperative lung injury, including ischemia-reperfusion injury,
primary graft dysfunction (PGD), immunologic phenomena such as acute
cellular rejection (ACR) episodes, antibody-mediated rejection (AMR), and
infection. The term chronic lung allograft dysfunction (CLAD) describes
dysfunction of both types (BOS and RAS) and was coined in 2015.
Types of Lung Transplant

There are 4 major types of lung transplant: unilobar, bilateral, heart-lung, and
living donor transplants. Unilobar lung transplants are uncommon in children
because of previous outcomes with high mortality.3 They are more commonly
performed in adults with nonsuppurative chronic obstructive pulmonary
disease and pulmonary fibrosis.
Bilateral lung transplant is the most common type of lung transplant per-
formed in children. The most recent surgical technique for bilateral lung trans-
plant is to transplant each lung individually via either median sternotomy or
clamshell incision. These approaches minimize bypass time, which reduces
related complications.
Pediatric heart-lung transplants performed per year have decreased to fewer
than 12 annually worldwide, and totaled only 3 in 2017.1 Because this type of
graft may use up to 3 donor organs, it is reserved for children with advanced
pulmonary vascular disease, complex congenital cardiac anomalies with
Eisenmenger syndrome, lung disease due to abnormal left ventricular function,
or cardiac anomalies with anatomy that cannot be fully corrected with bilateral
isolated lung transplant and cardiac repair.1 Patients with severe right ventricu-
lar dysfunction secondary to pulmonary hypertension but with preserved left
ventricular function can tolerate transplant with isolated bilateral lung grafts
because the right ventricle is often able to remodel and repair once the strain
of working against the pulmonary arterial pressures is removed.3,4
Living donor lobar lung transplant was developed in the early 1990s to
decrease waiting time of children who were severely ill awaiting lung

724
transplant. Waiting times were markedly reduced with the United Network for
Organ Sharing’s adoption of the new lung allocation score (LAS) in 2005, and
advances in patient care before transplant have led to a decrease in waiting list
deaths.5 The institution of the new LAS system combined with the technical
and ethical challenges associated with living lobar transplant have obviated the
living donor lobar transplant procedure in the United States.6
General Clinical Indications

Guidelines for adult transplant have been firmly established, but the issues and
the challenges regarding lung transplant for children are distinctly different
than those for adults. In 2007, the International Pediatric Lung Transplantation
Collaborative published the first set of guidelines on selection and referral
criteria for pediatric candidates for lung transplant.7 The indications vary by
age group, but generally, lung or heart-lung transplant is a treatment strategy
considered for children who have end-stage lung disease. Children should be
referred if they have progressive lung disease or life-threatening pulmonary
vascular disease that has no further options for remediation by means of
medical or surgical therapy (Table 42-1) and for whom the life expectancy is
severely limited. Complex congenital heart disease is the most common indi-
cation for infants, accounting for about 25% of transplants in this age group.
Infants with primary pulmonary hypertension and pulmonary hypertension
secondary to pulmonary vascular disease (eg, pulmonary venous obstruc-
tion, alveolar capillary dysplasia, Eisenmenger syndrome) constitute the next
largest group. Infants with surfactant protein deficiencies B and C, surfactant
deficiency (ABCA3), and pulmonary vascular malformations not manageable
with surgical correction (pulmonary venous stenosis) constitute an increasing
proportion of candidates. Interstitial pneumonitis accounts for the remainder
of indications for lung transplant in infants. In the 1- to 5-year-old age group,
primary pulmonary hypertension and interstitial pneumonitis are the pre-
dominant reasons for transplants, but for older children and adolescents, the
principal cause for referral tends to be complications of cystic fibrosis (CF),
closely followed by primary pulmonary hypertension. Box 42-1 lists the most
common reasons for referral of candidates for lung transplant.
Patients often have comorbid disorders that can complicate the procedure and
affect the outcome. Table 42-2 lists relative contraindications, but each center
uses its own criteria. Box 42-2 lists the criteria for absolute and relative con-
traindications to lung transplant. Most pediatric centers allow treatment with
mechanical ventilation for patients who develop respiratory failure after list-
ing, with certain exceptions, such as sepsis; however, this allowance poses
an increased risk factor for mortality.8

725
Table 42-1. Indications for Lung Transplant in Children (January 2002–June 2018)
Age < 1 y Age 1–5 y Age 6–10 y Age 11–17 y
Indication (%) (%) (%) (%)
Cystic fibrosis - 3.4 48.1 85.4
Idiopathic pulmonary hypertension 11.3 26.7.2 10.0 8.9
Pulmonary hypertension other than
25.8 21.6 2.9 2.1
idiopathic pulmonary hypertension
Retransplant not OB - 4.3 2.9 3.4
Retransplant OB - 3.4 2.9 2.8
Nontransplant OB - 8.6 13.3 4.8
Interstitial lung disease 8.1 5.2 2.1 3.1
Interstitial lung disease 9.7 8.6 8.7 4.1
(specific cause)
Surfactant protein B deficiency 22.8 3.4 1.2 0.2
Surfactant protein C deficiency - 0.9 - 0.2
COPD/emphysema 3.2 0.9 1.2 0.9
Bronchiectasis - - 0.8 2.0
Other 4.8 4.3 4.6 2.1
Abbreviations: COPD, chronic obstructive pulmonary disease; OB, obliterative bronchiolitis.
Adapted from Hayes D Jr, Cherikh WS, Chambers DC, et al; International Society for Heart and Lung
Box 42‑1
Characteristics Associated With the Best Outcomes
for Candidates for Lung Transplant
ū A well-defined diagnosis or projected trajectory of illness in which the child
is at risk of dying without a lung transplant despite treatment with optimal
medical therapy
ū Adequate caregivers to provide support
ū Satisfactory network of resources that ensure uninterrupted access to
transplant services and medications after transplant
ū Evidence that the patient and caregivers are motivated and that all
demonstrate the ability to adhere to the rigorous therapy, daily monitoring,
and an ongoing monitoring schedule of graft function after transplant
Derived from Conrad C, Cornfield DN. Pediatric lung transplantation: promise being realized.
Curr Opin Pediatr. 2014;26(3):334–342.

726
Table 42-2. Factors That Affect Prognosis of Lung Transplant in Children

With Cystic Fibrosis
Factor Measurement
Spirometric results FEV1, FVC
Poor exercise tolerance Decreased 6-minute walk distance
Desaturation during exercise
Decreased maximal oxygen consumption
Abnormal blood gas results Resting hypercarbia
Resting hypoxemia
V̇/Q̇ mismatch V̇/Q̇ scan
Pulmonary hypertension Cardiac catheterization, pulmonary arterial pressure
>30 mm Hg
Poor nutrition Hypoalbuminemia
Anemia
Short stature
Poor weight for height
Low body mass index
Rapid decline Rapid rate of decrease of FEV1
Frequent exacerbations
Young age
Female sex -
Increased energy expenditure Resting tachycardia
Multisystem involvement Liver disease
Diabetes mellitus
Since the early 2010s, extracorporeal support has been used to bridge
pediatric and adult patients to transplant. Venovenous extracorporeal mem-
brane oxygenation (ECMO) 9–11 and pumpless, low-resistance membrane
oxygenator devices are preferred to venoarterial ECMO because the patient
can more often participate in physical therapy while awaiting a donor. The
outcome of lung transplant after use of venoarterial ECMO as a bridge
to transplant was poor, with an overall survival rate of only 40%.12 How-
ever, expertise and experience have led to improved outcomes with use of
venovenous ECMO as a bridge, and with careful selection and emphasis
on rehabilitation, the short-term survival is similar to that of patients who
did not require venovenous ECMO before transplant.
The setting in which an optimal outcome is most assured is a center that incor-
porates experienced physical therapists, both before and after lung transplant;
centers have reported that these patients are often ambulatory less than 1
week after transplant.11–13 Some centers use central transthoracic placement of
the ECMO catheters to allow patients to move their heads freely and ambulate

727
Box 42‑2
Absolute and Relative Contraindications to Lung Transplanta
Absolute
ū Active malignancy
ū Sepsis
ū Active tuberculosis
ū Severe neuromuscular disease
ū Documented, refractory nonadherence
ū Multiple organ dysfunction
ū Immune deficiencies, including hypogammaglobulinemia
ū Hepatitis C with histologically proved liver disease
ū Infection with HIV
Relative
ū Pleurodesis
ū Renal insufficiency
ū Markedly abnormal body mass index (overweight or underweight)
ū Mechanical ventilation
ū Severe scoliosis or kyphosis
ū Poorly controlled diabetes mellitus
ū Osteoporosis
ū Chronic airway infection with multiple resistant organisms
ū Fungal infection or colonization
ū Hepatitis B surface antigen positivity
ū Long-term steroid use (eg, prednisone ≥ 10 mg daily)
ū Use of illicit drugs
a
These contraindications have been derived primarily from adults and can vary from center to center in
some respects.
From Faro A, Mallory GB, Visner GA, et al; American Society of Transplantation. American Society of
Transplantation executive summary on pediatric lung transplantation. Am J Transplant. 2007;7(2):285–292.
© 2006 The American Society of Transplantation and the American Society of Transplant Surgeons.
more easily. An important advantage to using this method is that recirculation

is prevented and minimal damage to the tricuspid valve occurs.14
Another device used more rarely to sustain survival to transplant is para-
corporeal membrane oxygenation, which has been used in some infants and
children with severe pulmonary arterial hypertension (PAH). A membrane
oxygenator is interposed between the pulmonary artery and left atrium and
acts as a pumpless oxygenator that allows for extubation and rehabilitation
and potentially affords some right ventricular rest while the patient awaits
lung transplant.15

728
Timing of Referral
There are no guidelines that determine the most appropriate time to refer a
patient for a lung or heart-lung transplant. Before 2005, all lung candidates
for transplant were prioritized according to the length of time they had been
waiting to receive organs. This system led to inappropriate and early listing
of patients who were considered too well for transplant; subsequently, a long
waiting list at all centers filled with potential candidates but created a high
waiting list mortality rate among the patients who were most severely ill. In
an effort to minimize mortality on the waiting list, and to prioritize donors
to the patients most likely to benefit from transplant, the LAS was conceived
by transplant physicians in the community of the United Network for Organ
Sharing (UNOS). The LAS was inaugurated in 2005 for patients aged 12 years
or older. A complex formula was devised to account for variables, including
the candidate’s health, diagnosis, and lung function, and assign a level of ill-
ness severity to calculate the survival benefit and target the patients who could
benefit the most. A similar formula has not been created for children younger
than 12 years because of difficulties in measuring the lung function of tod-
dlers and infants. In addition, children have fewer comorbid conditions to
be accounted for than adults have. Instead, the previous system is used,
and organs are targeted to candidates with time accumulated on the waiting
list. However, some prioritization is granted within UNOS policy that allows
for the organs from pediatric donors to be allocated first to children. Other
factors that are considered include ABO blood type (although infants can
receive ABO-incompatible organs), sensitization to human leukocyte antigens
(HLAs; major histocompatibility tissue antigens), appropriate size matching
of the lungs to the recipient’s thoracic dimensions, and distance of the donor
from the transplant center.
Selection of Candidates for Transplant

The single most important aspect of a successful lung transplant outcome is
ensuring the most appropriate candidates are selected to undergo the proce-
dure. Candidates for transplant should have generally good medical health
and well-controlled comorbid medical conditions. Generally, if the candidate
has clinically significant end-organ damage in more than 1 other solid organ,
they are rarely, if ever, considered for listing because morbidity and mortality
complicate the postoperative outcome in the short and longer terms. Accept-
able medical conditions include systemic hypertension, diabetes mellitus, and
peptic ulcer disease. Relative and absolute contraindications to lung transplant
are listed in Box 42-2.

729
Selection Guidelines for Candidates for Transplant

With Specific Diseases
Cystic Fibrosis
The criteria for referral of patients with CF are based primarily on the results
of a longitudinal study by Kerem and colleagues16 from 1992. They evaluated
predictors of mortality in a large, single-center retrospective study. They were
able to define that the patients at the greatest risk of mortality were those with
an FEV1 less than 30% predicted, a Pao2 less than 55 mm Hg, and/or a Pao2
more than 50 mm Hg. These patients had a 2-year mortality rate higher than
50%. The investigators found that the most statistically significant factor to
predict mortality was the FEV1; this factor became the foundation for the
1998 guidelines for patient referral for lung transplant, most of which have
been maintained since (Table 42-2).17
Slightly broader criteria are used to recommend referral of patients to a
transplant center than to recommend transplant. During the evaluation,
consideration is based on the following criteria: (1) the trajectory of loss
of lung function predicts less than a 2-year survival, (2) transplant is likely
to improve the patient’s quality of life, (3) no absolute contraindications to
transplant have been identified, and (4) the patient is fully informed and com-
mitted to proceeding. Most pediatric transplant centers assess quality of life
with qualitative consideration given to whether the child can participate in
usual daily activities; whether the child has exercise intolerance; the amount
of time spent in the hospital and treatment of disease exacerbations; whether
oxygen supplementation is required at rest, during exercise, or with sleep to
maintain normal oxygen saturation levels; and the patient’s functional status
as determined by means of the New York Heart Association Functional
Classification System (class I, no symptoms or limitations in ordinary physi-
cal activity; II, mild symptoms and slight limitation; III, marked limitation
due to symptoms; IV, severe limitations and symptoms even at rest).18
Physicians performing transplants attempt to balance the patient’s life
expectancy after transplant with life expectancy predicted without the
procedure when considering the most optimal time for listing, although this
aspect of care is not a science. The physician estimates the likely waiting
time for a suitable organ to become available with the known survival
statistics. In essence, early referral for transplant assessment is best because it
allows for the evaluation to proceed in an organized manner, for the patient’s
treatment plan to be considered through a thorough multidisciplinary dialogue
among team members, and for ensuring a thorough understanding of the

730
process on the part of patients and caregivers. This approach allows time
for the patient, the family, and the referring center to develop trust and a good
working relationship with the transplant center. For some children, it is the first
occasion they and their family have had to discuss openly the possibility of
their death. This situation can be quite stressful, especially for children, and
an early referral allows time for their parents and caregivers to consider the
complexities and the opportunities that transplant provides and make an
informed decision.
Microbiological Issues in Patients With Cystic Fibrosis
Most patients are colonized with organisms that have developed resistance to
many classes of antibiotics. Pretransplant colonization with multidrug-resistant
organisms does not preclude transplant and can often be successfully treated
with antibiotic therapy. In the era of routine use of inhaled antibiotics (amino-
glycosides or colistimethate) and recent development of others (eg, amikacin,
aztreonam), sputum in patients with CF is commonly colonized with species
such as Staphylococcus aureus, both methicillin resistant and methicillin sen-
sitive; Pseudomonas aeruginosa; Xanthomonas (formerly Stenotrophomonas)
maltophilia; and Achromobacter (formerly Alcaligenes) xylosoxidans. The
latter 2 organisms tend to be innately resistant to most classes of antibiotics.
In vitro detection of panresistant species may be considered a relative
contraindication because these findings often do not correspond to in vivo
responses. Microbiological review of sputum should be performed routinely,
at least at 3-month intervals during the pretransplant waiting period. If the
organism is developing increasing patterns of resistance, the length of
antibiotic use after transplant may be reconsidered.
Few data are available from pediatric transplant centers regarding the effect
of colonizing organisms present before transplant on survival and other out-
comes in pediatric transplant. Unless otherwise noted, the data that follow
are culled from studies on adult recipients of transplants.
Burkholderia cenocepacia Complex
Colonization with B cenocepacia (formerly B cepacia genomovar III) has a
marked severe and negative effect on posttransplant survival. There have been
no peri- or postoperative antibiotic interventions that prevent recolonization of
the lower airways after transplant.19–21 Results from a 2008 study using data
from patients referred for transplant in the United States suggest that the risk
of poor outcome is limited to patients colonized with nonepidemic strains of
B cenocepacia; posttransplant mortality was also increased in patients infected
with Burkholderia gladioli.22 Therefore, these organisms being cultured from
the patient’s sputum remains a strong relative, if not absolute, contraindication
to lung transplant internationally.

731
Fungus and Molds

Results from a retrospective analysis in pediatric recipients of lung transplants
demonstrated an increased risk of mortality from pulmonary fungal infections
the first year after lung transplant. Risk factors for pulmonary fungal infection
included pretransplant colonization.23 For patients whose cultures previously
had grown certain fungi, such as Aspergillus fumigatus and Scedosporium
apiospermum, secondary prophylaxis should begin in the immediate peri-
operative period because these species can become invasive infections in
patients who are immunosuppressed. Scedosporium species, in particular,
are inherently resistant to most antifungal medications but may retain
sensitivity to voriconazole.24,25
Nontuberculous Mycobacteria
There are few data with regard to mortality associated with mycobacterial
infection or colonization. Experience with adult transplant patients who have
CF is limited and mostly anecdotal or in case series. Study results indicate that
although nontuberculous mycobacteria disease causes clinically significant
morbidity in a small number of patients after transplant, it can be successfully
treated and does not influence posttransplant survival. However, the incidence
of BOS is higher in patients with nontuberculous mycobacteria.26 The isolation
of nontuberculous mycobacteria before transplant in patients with CF may
not necessarily exclude those patients from consideration for lung transplant,
but it should alert the clinician to prepare patients for the risk of recurrence
after transplant and for the possibility of the ongoing use of intravenous
antibiotics for successful control in the setting of immunosuppression. For
this reason, centers vary in their acceptance of patients colonized with
nontuberculous mycobacteria.
Surfactant Deficiencies
Infants with surfactant protein B deficiency should be referred to a pediatric
lung transplant center immediately on diagnosis because mortality is nearly
100% during the perinatal period. Surfactant protein B deficiency manifests
as unrelenting respiratory failure or progressive interstitial lung disease
with respiratory insufficiency and is unresponsive to medical interventions.
However, treatment requiring ECMO may be a contraindication to transplant,
particularly if there is other organ insufficiency, such as a comorbidity, or if
cerebral hemorrhage has occurred. The other surfactantopathies often mani-
fest with less severe symptoms and may be possible to treat with medical
therapy. Genetic testing capabilities are rapidly improving and are less ex-
pensive than in the past, but the phenotypic variation of children born with
these mutations that were previously suspected to confer lethality seems to
be widening. The severity of the defect may not be discernable solely with
gene mutation analysis to predict the long-term outcome, and watchful
waiting may be merited.27,28

732
Idiopathic Pulmonary Hypertension and

Pulmonary Arterial Hypertension
Patients with idiopathic pulmonary hypertension or PAH should be referred
to a lung transplant center if they are considered to be at New York Heart
Association functional class III or IV despite treatment with intravenous,
oral, or inhalational vasodilator therapy. Similarly, if the candidate has a
low tolerance to exercise or oxygen desaturation with a 6-minute walk test,
recurrent syncopal episodes, hemoptysis, or right-sided heart failure, referral
should be initiated. Some patients present to medical care with severe symp-
toms, and they should be referred for lung or heart-lung transplant at the
same time that they begin treatment for PAH. Major comorbidities that are
a contraindication for single-organ transplant include renal failure and liver
failure with hyperbilirubinemia. Dual-organ transplant may be necessary.
Identifiable causes of the PAH must be sought and include collagen vascular
disease, primary pulmonary disease, chronic thromboembolic disease (rare
in children), and pulmonary venous obstruction that can be treated with
surgical correction.
Eisenmenger Syndrome
Children with Eisenmenger syndrome should be referred to a transplant
center if they have profound hypoxemia despite ameliorative therapy. Con-
traindications for lung transplant in these children include the presence of
major comorbidities, left ventricular failure, irreparable congenital heart
defect (heart-lung transplant should be considered), or history of previous
thoracotomies because the consequent scarring from those surgeries can
substantially increase intraoperative mortality due to hemorrhage. Patients
with Eisenmenger syndrome should be referred when their cardiac function
is worsening or they have impaired exercise tolerance and a worsening
quality of life.
Other Pulmonary Vascular Disorders

Patients with other congenital malformations of the pulmonary vasculature
should be referred for evaluation because there are no effective medical
strategies for treatment. Infants born with total or partial anomalous pulmo-
nary venous return who undergo surgical repair but for whom the follow-up
echocardiogram demonstrates rapid recurrence of obstruction should be
referred for urgent evaluation.
Diffuse Parenchymal Lung Disease

Diffuse parenchymal lung diseases arise from heterogeneous causes and
include alveolar capillary dysplasia with misalignment of the pulmonary veins
and other idiopathic diffuse lung diseases that demonstrate unremitting pro-
gression despite optimal medical management. Contraindications for

733
transplant in patients with diffuse parenchymal lung disease include the

presence of systemic disease that might later affect the allograft. These
potential candidates should be referred early in the course of their disease
process.
Evaluation of the Donor

Box 42-3 describes the criteria used to define an ideal donor. These criteria
have been developed largely from clinical experience rather than multicenter
trials.29 Specific criteria for donors to children have not been established.
However, it is generally accepted that the ideal lung donor for children should
be a nonsmoker of the same height (particularly of chest dimensions) and
ABO-compatible blood type. The donor should have no clinically significant
history of lung disease, including asthma. Donors who have sustained pulmo-
nary trauma or infections are rarely selected. Gas exchange should be mini-
mally impaired, and ischemic time between organ harvest and implantation
should be minimal, although the optimal time frame has not been established.
Some pediatric lung transplant centers may apply more stringent criteria if
the candidate in question is reasonably stable. Organs from donors younger
than 55 years are desirable in most instances.
Depending on the need of the candidate, donors who are considered nonideal,
also referred to as extended or marginal donors, may be accepted. Data are
limited to either support or prohibit the use of lungs from a nonideal donor.
There is no evidence that organs from a marginal donor will have any effect
Box 42‑3
Features of the Ideal Donor
ū Age < 55 y
ū ABO compatibility
ū No human leukocyte antigen antibody sensitization by recipient
ū Clear chest radiographs
ū Pao2 > 300 on Fio2 = 1.0, PEEP = 5 cm H2O
ū Nonsmoker (never smoked)
ū Absence of chest trauma
ū No evidence of aspiration or sepsis
ū No prior cardiopulmonary surgery
ū Absence of organism and polymorphonuclear cells on sputum Gram stain
ū Absence of purulent secretions at bronchoscopy
Abbreviations: Fio2, fraction of inspired oxygen; PEEP, positive end-expiratory pressure.

Reproduced from Bhorade SM, Vigneswaran W, McCabe MA, Garrity ER. Liberalization of donor
criteria may expand the donor pool without adverse consequence in lung transplantation. J Heart
Lung Transplant. 2000;19(12):1199–1204. © 2000, with permission from the International Society for
Heart and Lung Transplantation.

734
on either immediate or long-term morbidity or mortality, except in egregious

cases, including if bronchopneumonia or purulent secretions of the lower
airway are detected in the donor during bronchoscopy. Lungs obtained from
donors older than 50 years who have a significant smoking history are at risk
for developing malignancy in the setting of immunosuppression.
Posttransplant Care
Postoperative Management
Immunosuppression
Successful lung transplant is achieved if acute lung allograft dysfunction
and CLAD can be prevented. Acute allograft dysfunction recorded after the
first month is most commonly associated with acute allograft rejection by the
recipient and is most commonly mediated by activation of recipient T lympho-
cytes to the allograft. Transplanted lungs still contain bronchus-associated
lymphoid tissue, which is intimately associated with the bronchi and, thus,
cannot be completely removed at the time of organ harvesting. This fact,
along with higher immunogenicity and constant exposure of the lungs to the
environment compared with what is seen with other solid organ transplants,
are possibly the main reasons for the higher rate of ACR in the transplanted
lung. Transplanted lungs are also much more easily infected because the
recipient receives high doses of immunosuppression after lung transplant. If
too aggressively implemented, strategies to prevent rejection often result in
infection. Conversely, more liberal approaches to immunosuppression to allow
for recovery from infection or Epstein-Barr virus (EBV)–associated post-
transplant lymphoproliferative disorder (PTLD) may result in acute rejection.
Induction Therapy
Recurrent trauma to the allograft, such as can be sustained with acute rejection
episodes, infections, and inhalation injury, contributes to the development of
CLAD. Chronic lung allograft dysfunction affects most recipients of lung
transplants, and its emergence is detectable in 20% of recipients within the
first 2 years after lung transplant. Most adult and pediatric transplant centers
apply induction immunotherapy at the time of transplant to decrease the risk of
acute rejection; it is presumed this will protect from both ACR and CLAD, but
evidence for these effects is lacking in the survival data.1
Maintenance Immunosuppression
On the basis of adverse effects in children and efficacy, the International
Pediatric Lung Transplant Collaborative has adopted a standard immu-
nosuppressive protocol consisting of tacrolimus, mycophenolate mofetil,
and prednisone as the cornerstone of maintenance immunosuppression.1
The most widely accepted regimens still rely on a calcineurin phosphatase
inhibitor, in combination with a cell cycle inhibitor and a corticosteroid.
The 2 main calcineurin phosphatase inhibitors currently in use are cyclo-

735
sporine and tacrolimus, with approximately 20% of patients receiving

cyclosporine and 80% receiving tacrolimus. Both work similarly, and both
have clinically significant systemic adverse effects. There is no clear benefit
of one over another in preventing OB or affecting survival. Adverse events
associated with tacrolimus treatment include hyperglycemia, alopecia, and
possibly PTLD; cyclosporine-based regimens are associated with hyper-
cholesterolemia, hypertension, hirsutism, and gingival hyperplasia. The
cosmetic effects, in particular, often lead to medication nonadherence
among the adolescent cohort.
Since 2010, the combination of tacrolimus and mycophenolate mofetil or
mycophenolic acid has been the maintenance immunosuppressive regimen
of choice, with 82% of patients receiving that combination at 1-year post-
transplant follow-up; the next most common combinations are tacrolimus
and azathioprine (7%) and single-agent therapy with tacrolimus (5%).1
Almost all pediatric lung transplant programs include steroids as part of a
triple-drug immunosuppression regimen. The steroid dose is tapered to
decrease the incidence of complications, which often include osteopenia,
fractures, and hyperglycemia.
Long-term Follow-up After Transplant
The prognosis after a successful lung transplant is guarded. Mortality due to
complications is 10% to 15% in the first year. Most complications occur in the
first 6 months after transplant.1 Early graft dysfunction occurs as a result of
ischemia-reperfusion injury and previously accounted for most deaths within
the first month after transplant. Most recipients of lung transplants have some
clinical evidence of PGD due to ischemia-reperfusion injury, and the expres-
sion is usually most prominent during the first 72 hours after the transplant.
The syndrome manifests as various levels of severity of graft dysfunction,
from mild hypoxemia to fulminant graft failure. Primary graft dysfunction
is noted histologically with neutrophil infiltration. The incidence of higher
grades of PGD is much less common because organ preservation techniques
at the time of organ harvesting have been optimized. Ischemia-reperfusion
injury that progresses to severe PGD is very likely to result in early emer-
gence of CLAD.30
Long-term Monitoring
Care for children who have received a lung transplant is complex. Monitoring
the patient and the allograft function requires the coordination of care among
several services. The transplant team components include the patient and
family; a pulmonary function laboratory that is familiar with working with
children; and ancillary services, including radiology, interventional radiology,
pharmacy, laboratory, social work, specialty nursing, and committed primary
care and pulmonary physicians. Most transplant centers monitor patients
routinely with laboratory tests, surveillance bronchoscopy for assessment of

736
rejection and infection, spirometry and comprehensive pulmonary function

tests, exercise studies, and frequent imaging. Because of the limitations of
infant pulmonary function testing and the fact that sedation is required for
many of these diagnostic procedures, follow-up of infant recipients of lung
transplants presents additional challenges. Transbronchial biopsies are the
primary means by which ACR is diagnosed; they can safely be performed
by experienced personnel.
Rejection
Children who have received lung transplants may experience 1 or more of
4 types of rejection. See Box 42-4.
Box 42‑4
Types of Lung Transplant Rejection
1 Hyperacute rejection (immediately after transplant): This is a rare event that

occurs when human leukocyte antigen sensitization to the donor antigens
is present.
2 Acute cellular rejection (most common in the first 6–12 months): This is the
most common type of rejection; it occurs with highest frequency in the
first year after transplant.
3 Humoral rejection: This is antibody-mediated rejection that occurs when
donor-specific antibody develops.
4 Chronic airway rejection: The process begins in most recipients within
the first or second year, and progression depends on host factors and on
immunologic factors related to the graft; chronic vascular rejection occurs
in the cardiac graft in heart and lung transplants and is the equivalent of
chronic airway rejection.
Hyperacute Rejection
Hyperacute rejection is rare but can cause complete rejection of the lungs
within 24 hours. It is caused by antibodies to the allograft formed by the
recipient after a sensitizing event (blood transfusion, pregnancy, connective
tissue disease, or previous transplant). The mechanism of hyperacute rejec-
tion involves the binding of preformed antibodies against major allograft
antigens, usually HLA. Hyperacute rejection manifests clinically as severe
graft dysfunction immediately postoperatively with worsening oxygenation,
a decrease in lung function, fever, pleural effusions, pulmonary edema, and
diffuse parenchymal infiltrates; it can manifest as diffuse alveolar damage.31
The incidence has decreased dramatically with increased understanding and
surveillance for HLA hypersensitivity and avoidance of donors to whom the
candidate is sensitized.32
Acute Cellular Rejection
Acute cellular rejection occurs when T lymphocytes identify foreign pro-
teins on the surface of cells in the transplanted lung and cause injury to those

737
cells. This is a normal function of the immune system and is important as

a response to control the growth of tumors and viral infections, but it is
diminished with the use of immunosuppressants.
Acute cellular rejection usually occurs in the first 6 to 12 months and is usually
detected at a mild stage because of increased surveillance with bronchoscopy
and biopsy procedures during the first 6 months after transplant. Transplant
centers differ in their surveillance protocols for transbronchial biopsy. Gener-
ally, most centers schedule these monthly for the first 3 months, at the sixth
month, and then again at 12 months. There is controversy as to when or if
transbronchial biopsies should be performed after the first year. Many centers
perform surveillance bronchoscopy annually thereafter and obtain biopsy
specimens if clinically indicated, such as when ACR or infec-tion is suspected.
Indications for bronchoscopy are to assess for the presence of infection or when
AMR is suspected when acute graft dysfunction is measured and is coincident
with an elevation of antibody levels to HLAs of the donor.
Acute rejection is graded according to how far the lymphocytes extend into
the tissue surrounding the blood vessels (Figure 42-3). Acute rejection can
occur with or without outward symptoms. If symptoms are present, they are
quite similar to those of a lung infection, and signs can include fever, cough,
dyspnea on exertion, decrease in spirometric test results (FVC and FEV1),
Figure 42-3. Lower-power hematoxylin and eosin stain shows histopathological images of
acute cellular rejection and grades of severity. Grade A1 (A) indicates minimal acute cellular
rejection, grade A2 (B) indicates mild acute cellular rejection, grade A3 (C) indicates moderate
acute cellular rejection, and grade A4 (D) indicates severe acute cellular rejection.

738
increase in the white blood cell count, and abnormal changes noted on chest
radiographs (pleural effusion or new opacifications).
Most initial low-grade episodes of acute rejection respond to treatment
with high doses of steroids, and lung function often returns to baseline once
treated. If the disease is classified as grade A2 or worse, treatment is initiated
with a pulse of intravenous corticosteroid once a day for 3 days, and follow-up
bronchoscopy and transbronchial biopsy are performed within 4 weeks after
completing treatment to confirm response. If rejection is still present at the
follow-up biopsy, and it is not grade A1 or improved, some centers may use
monoclonal antibodies or antilymphocytic antibody (rabbit anti-thymocyte
globulin), and they may alter or increase the oral immunosuppressive agents.
Most patients experience at least 1 asymptomatic episode of acute rejection in
the first year, although the risk may be lower in children younger than 1 year.
If ACR is treated early and is low-grade (A2 or better), allograft dysfunction
can be avoided. In most patients, mild acute rejection resolves after treatment.
Chronic Lung Allograft Dysfunction
Extended survival is compromised by CLAD. Chronic lung allograft dys-
function was previously termed BOS, which described obstructive graft
dysfunction due to fibrotic obliteration in the smallest airways. In 2015, a
consensus conference convened to define better the chronic rejection in lung
transplant. The acronym CLAD was originated to encompass all types of
graft dysfunction. It encompasses the several forms of CLAD defined by pul-
monary mechanics, including restrictive, obstructive, and mixed pheno-
types.33 It is thought that CLAD eventually emerges as a result of various
injuries to the graft that produce chronic active inflammation. A dysregu-
lated injury response results, and CLAD is noted. Bronchiolitis obliterans
syndrome is characterized by progressive airflow obstruction due to fibrotic
obliteration of the small airways.34 Restrictive allograft syndrome is charac-
terized by restrictive lung function mechanics. Often, study results demon-
strate elements of both. Within
5 years after transplant, fewer
than 50% of recipients are free
from BOS (Figure 42-4).
Investigators have made
substantial efforts to identify,
prevent, or treat the causes of
CLAD, yet its pathophysiologi-
cal mechanism is not well
characterized. Treatments are
generally palliative rather than
Figure 42-4. Hematoxylin and eosin stain curative.35,36
demonstrating obliterative bronchiolitis.

739
Bronchiolitis Obliterans Syndrome

The symptoms of BOS include shortness of breath and low oxygen satura-
tion levels. Patients who develop OB may have chest cold symptoms or
initially may have no symptoms at all. It is detected clinically with the use
of pulmonary function testing and/or imaging.
The most useful early indicator of OB is a decrease in lung function—
specifically, the FEV1 and the FEF 25%–75% of FVC that is not otherwise
explained. See Table 42-3 for grading criteria for BOS. The potential-BOS
stage (0-p) alerts the physician to the need for close functional monitoring and
assessment. Symptoms of more severe OB include onset of a dry or produc-
tive cough that is not related to an infection, a new onset of shortness of breath
with or without exercise, and a decrease in lung function (FEV1) that is other-
wise unexplained. A decrease in oxygen saturation measured eventually
occurs but is a late sign.
Transbronchial biopsy samples often do not indicate the histological presence
of OB because it most often initially is a sporadic process and the pieces
obtained during biopsy are very small. If present, OB appears as dense
eosinophilic intraluminal scarring, primarily involving the bronchioles.
Advanced BOS stages are associated with fibrointimal scarring that also
can be present in the pulmonary arteries and veins (Figure 42-4).
Table 42-3. Classification and Staging of Bronchiolitis Obliterans Syndrome

Stage Definition
0 FEV1 >90% of baseline and FEF 25%–75% >75% of baseline
0-p FEV1 81%–90% of baseline and/or FEF 25%–75% ≤75% of baseline
1 FEV1 66%–80% of baseline
2 FEV1 51%–65% of baseline
3 FEV1 ≤50% of baseline
Abbreviation: 0-p, potential BOS.
Reprinted from Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome 2001: an update
of the diagnostic criteria. J Heart Lung Transplant. 2002;21(3):297–310. © 2002, with permission from the
International Society for Heart and Lung Transplantation.
Restrictive Allograft Syndrome

Historically, chronic lung graft dysfunction was thought to manifest only as
BOS and lead to a decrease in the FEV1, but, in 2005, a novel subtype of graft
dysfunction was described.37 Since then, various phenotypes of CLAD with
distinct prognostic importance have been described. The entity Pakhale
and colleagues37 described is now known as RAS. Restrictive allograft
syndrome fibrosis occurs predominantly in the peripheral lung tissue rather
than in small airways, resulting in a decrease in total lung capacity, FVC, and
FEV1.

740
Phenotypes of CLAD are characterized with a combination of pulmonary

function testing and chest computed tomography. Eighty percent of patients
with CLAD have no identifiable cause for chronic graft failure, yet identifi-
able causes of graft dysfunction must be sought and fully treated. These
causes include AMR, ACR, chronic infection, aspiration, obesity, gastro-
esophageal reflux disease, and ongoing chronic inflammation. Distinct
phenotypes of CLAD have individual prognostic importance. For example,
neutrophilic reversible allograft syndrome can often be arrested with a
prolonged course of oral azithromycin and attention to airway clearance
techniques. However, RAS is rapidly progressive, difficult or impossible to
slow, and associated with a low survival rate.
Treatment Options for CLAD
There is no maintenance immunosuppression protocol known to prevent
CLAD. As stated before, using an induction regimen at the time of transplant
has not proved preventive. Once graft dysfunction is established, intervening
with more immunosuppression is ineffective to treat BOS or RAS. Bronchiol-
itis obliterans syndrome, if not associated with AMR, infection, or inflamma-
tion, may be slowed with maintaining good chest physiotherapy to prevent
postobstructive pneumonia and chronic inflammation. Many physicians resort
to substituting cyclosporine for tacrolimus, attempt a trial of azithromycin for
3 months or longer, or proceed to fundoplication of the gastroesophageal
junction if gastroesophageal reflux continues despite optimal medical treat-
ment. These steps tend to result in limited success. Photopheresis, in the
setting of recurrent ACR, or plasmapheresis in the setting of AMR, may slow
the rate of graft deterioration. If these approaches fail, retransplant is indi-
cated in selected cases.37,38 No formal guidelines for treatment of RAS exist.
Pirfenidone is a medication approved by the US Food and Drug Administra-
tion in 2014 to slow the process of idiopathic pulmonary fibrosis (IPF).
Pirfenidone has a potent effect in vivo and an antifibrotic effect in vitro. The
mechanism by which pirfenidone acts is to inhibit the synthesis of transform-
ing growth factor β and tumor necrosis factor α, which has a downstream
effect that leads to a lessening in fibroblast proliferation, less collagen
synthesis, and thus a slower decrease in lung function in animal models of
fibrosis and in patients with IPF.39 The treatment is currently experimental,
but results from case reports have confirmed some beneficial effects (ie, mild
improvement of interstitial changes and lung function) of pirfenidone.40,41
Nintedanib is a drug also developed to treat IPF by targeting cellular receptors
that have been implicated in the pathogenesis of IPF. If blocked, these receptor
and nonreceptor tyrosine kinases no longer serve to activate fibroblast growth
factor receptor, platelet-derived growth factor receptor, and vascular endothe-
lial growth factor receptor, and the intracellular signaling required for the

741
proliferation of fibroblasts is blocked.42,43 Nintedanib has not been tested in

placebo-controlled trials in patients receiving lung transplants.
Extracorporeal photopheresis (ECP) has emerged as an effective option in
arresting BOS. It has been used with success in treating cutaneous T-cell
lymphoma and graft-vs-host disease.44 Extracorporeal photopheresis induces
DNA cross-linking in T cells with the use of psoralen in the patient; then the
patient’s plasma is passed over an ultraviolet light source. This treatment
results in apoptosis of T lymphocytes, including natural killer cells. The dying
apoptotic lymphocytes are then eliminated on reinfusion by dendritic cells,
decreasing the population of activated T cells. The first successful treatment
with ECP in lung transplant occurred in 1993.44 Results from various studies
have shown that ECP modulates dendritic cells, alters cytokine profiles, and
induces specific T-cell subpopulations. Results from small studies45–47 have
validated efficacy to treat CLAD, but conclusions are limited because the
studies have been small and have not included comparison with other modes
of immunosuppression.45 Nonetheless, ECP is used in most centers as rescue
treatment for BOS.46
Posttransplant Lymphoproliferative Disorder

All patients receiving lung transplants are at risk for developing PTLD, a
form of cancer in children naïve to EBV infection before transplant but who
become exposed afterward. It can also develop in children who were previ-
ously infected with EBV. In those previously exposed, in the normal host, the
virus remains dormant in the B-lymphocyte cells. The EBV is more easily
reactivated when the child is immunosuppressed. When this happens,
lymphoid nodules form as the B cells multiply rapidly.
Posttransplant lymphoproliferative disorder occurs in about 10% to 15% of
pediatric recipients of lung transplants. It most commonly occurs in the first
2 to 3 months after transplant at the time of highest immunosuppression but
may occur many years after transplant. Most patients do not have symptoms,
and the tumor is discovered during a routine physical examination. Other
patients have flu-like symptoms associated with a primary infection, and
disease manifestations might be due to the location of the tumor (eg, diarrhea,
pharyngitis, hepatitis, cough). The prognosis depends on the amount and
location of tumor formation and the response to treatment. In a small number
of cases, PTLD is fatal. Patients who are EBV positive or who have a donor
who is EBV positive are tested frequently for EBV viremia with an EBV
DNA polymerase chain reaction test.
There are several types of treatment options for PTLD. Most often, the doses
of immunosuppressive medicines are decreased, which may cause the tumor
to shrink or even disappear. More often, chemotherapy is administered in

742
addition so that patients may recover without the risk of rejection. In some
cases, surgery is necessary to remove large, bulky tumors.
Survival
Chronic lung allograft dysfunction is the most common and clinically
significant reason for poor long-term survival among recipients of lung and
heart-lung transplants. Bronchiolitis obliterans syndrome is the most
common expression of CLAD. Children who survive 1 year after transplant
have good functionality of the allograft, although approximately 13% have
BOS and the occurrence increases over time.1 Bronchiolitis obliterans
syndrome occurs in more than 50% of recipients of lung transplants, both
adults and children, who survive 5 years after transplant. Recipients of living
donor lobar transplants more commonly die from complications of infec-
tion.48 Overall survival is equivalent regardless of the source of the transplant.
Children with lung transplants experience similar complications as do adults,
but growth and developmental issues are unique to children. For adolescents,
nonadherence is a frequent problem, leading to the lowest survival in this
age group. The 5-year survival rate after lung transplant in children is about
60% (Figure 42-2).1 Survival among children whose primary lung dysfunc-
tion was due to noninfectious lung disease (ie, other than CF) is better than
that in patients with pulmonary vascular disease or CF.48 Infants have a higher
1-year mortality, although long-term survival in infants is similar to that in
other pediatric recipients. Retransplant has much lower first-year and
long-term survival than that of primary transplants in children and adults;
thus, few patients qualify.1,38,39 Risk factors for poor survival after lung
transplant include mechanical ventilation or ECMO at time of transplant; a
diagnosis of congenital heart disease; and repeat transplant, particularly for
treatment of RAS.

743
key points
} Lung and heart-lung transplant are indicated in children who have developed
end-stage lung disease, who have no other medical or surgical treatment
options, and for whom life expectancy is less than 2 years.
} Children and adolescents are most frequently referred for transplant because
of end-stage diseases of CF and PAH.
} Lung transplant is elected as an option after careful consideration and
extensive education and does not occur emergently.
} Postoperative care is complex and requires close interaction between the
primary care clinician and the transplant team for the rest of the recipient’s life.
} Immunosuppression consists of a triple-drug regimen, including a calcineurin
phosphatase inhibitor, a T-lymphocyte antiproliferative medication, and
corticosteroid therapy. These are continued for the rest of the patient’s life.
} The maintenance medication regimen’s dosage carefully maintains a balance
between preventing rejection and preventing infection.
} The most important life-limiting complication that restricts long-term survival
of recipients of lung and heart-lung transplants after the first year is CLAD.
} Lung and heart-lung transplant extend and improve the quality of life, but
because of the occurrence of CLAD, they are not a likely means to extend life
beyond approximately 7 to 10 years.
References
1. Hayes D Jr, Cherikh WS, Chambers DC, et al; International Society for Heart and Lung
Transplantation. The International Thoracic Organ Transplant Registry of the International
Society for Heart and Lung Transplantation: twenty-second pediatric lung and heart-lung
transplantation report—2019; focus theme: donor and recipient size match. J Heart Lung
Transplant. 2019;38(10):1015–1027 PMID: 31548028 doi: 10.1016/j.healun.2019.08.003
2. Chambers DC, Cherikh WS, Harhay MO, et al; International Society for Heart and Lung
Transplantation. The International Thoracic Organ Transplant Registry of the International
Society for Heart and Lung Transplantation: thirty-sixth adult lung and heart-lung transplantation
report—2019; focus theme: donor and recipient size match.
2019;38(10):1042–1055 PMID: 31548030 doi: 10.1016/j.healun.2019.08.001
3. Benden C, Aurora P, Edwards LB, et al. The Registry of the International Society for Heart and
Lung Transplantation: fourteenth pediatric lung and heart-lung transplantation report—2011.
J Heart Lung Transplant. 2011;30(10):1123–1132 PMID: 21962019 doi: 10.1016/j.
healun.2011.08.011. Erratum in J Heart Lung Transplant. 2012;31(4):440
4. Spahr JE, West SC. Heart-lung transplantation: pediatric indications and outcomes. J Thorac Dis.
2014;6(8):1129–1137 PMID: 25132980 doi: 10.3978/j.issn.2072-1439.2014.07.05
5. Merlo CA, Weiss ES, Orens JB, et al. Impact of U.S. Lung Allocation Score on survival after lung
transplantation. J Heart Lung Transplant. 2009;28(8):769–775 PMID: 19632571
doi: 10.1016/j.healun.2009.04.024
6. Starnes VA, Woo MS, MacLaughlin EF, et al. Comparison of outcomes between living donor and
cadaveric lung transplantation in children. Ann Thorac Surg. 1999;68(6):2279–2283
PMID: 10617017 doi: 10.1016/S0003-4975(99)01155-8
7. Faro A, Mallory GB, Visner GA, et al; American Society of Transplantation. American Society of
Transplantation executive summary on pediatric lung transplantation. Am J Transplant.
2007;7(2):285–292 PMID: 17109726 doi: 10.1111/j.1600-6143.2006.01612.x
8. Yusen RD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for
Heart and Lung Transplantation: thirty-second official adult lung and heart-lung transplantation
report—2015; focus theme: early graft failure. J Heart Lung Transplant. 2015;34(10):1264–1277
PMID: 26454740 doi: 10.1016/j.healun.2015.08.014

744
9. Turner DA, Cheifetz IM, Rehder KJ, et al. Active rehabilitation and physical therapy during
extracorporeal membrane oxygenation while awaiting lung transplantation: a practical approach.
Crit Care Med. 2011;39(12):2593–2598 PMID: 21765353 doi: 10.1097/CCM.0b013e3182282bbe
10. Schmidt F, Sasse M, Boehne M, et al. Concept of “awake venovenous extracorporeal membrane
oxygenation” in pediatric patients awaiting lung transplantation. Pediatr Transplant.
2013;17(3):224–230 PMID: 23050564 doi: 10.1111/petr.12001
11. Hayes D Jr, Kukreja J, Tobias JD, Ballard HO, Hoopes CW. Ambulatory venovenous
extracorporeal respiratory support as a bridge for cystic fibrosis patients to emergent lung
transplantation. J Cyst Fibros. 2012;11(1):40–45 PMID: 22035707 doi: 10.1016/j.jcf.2011.07.009
12. Puri V, Epstein D, Raithel SC, et al. Extracorporeal membrane oxygenation in pediatric lung
transplantation. J Thorac Cardiovasc Surg. 2010;140(2):427–432 PMID: 20538306
doi: 10.1016/j.jtcvs.2010.04.012
13. de Perrot M, Granton JT, McRae K, et al. Impact of extracorporeal life support on outcome in
patients with idiopathic pulmonary arterial hypertension awaiting lung transplantation. J Heart
Lung Transplant. 2011;30(9):997–1002 PMID: 21489818 doi: 10.1016/j.healun.2011.03.002
14. Maeda K, Ryan K, Conrad CK, Yarlagadda VV. An alternative cannulation approach for
venovenous extracorporeal membrane oxygenation in children for long-term ambulatory
support. J Thorac Cardiovasc Surg. 2018;156(1):e13–e14 PMID: 29685584
doi: 10.1016/j.jtcvs.2018.03.099
15. Gazit AZ, Sweet SC, Grady RM, Huddleston CB. First experience with a paracorporeal
artificial lung in a small child with pulmonary hypertension. J Thorac Cardiovasc Surg.
2011;141(6):e48–e50 PMID: 21420104 doi: 10.1016/j.jtcvs.2011.02.005
16. Kerem E, Reisman J, Corey M, Canny GJ, Levison H. Prediction of mortality in patients
with cystic fibrosis. N Engl J Med. 1992;326(18):1187–1191 PMID: 1285737
doi: 10.1056/NEJM199204303261804
17. International guidelines for the selection of lung transplant candidates. The American Society
for Transplant Physicians (ASTP)/American Thoracic Society(ATS)/European Respiratory
Society(ERS)/International Society for Heart and Lung Transplantation(ISHLT). Am J Respir
18. Dolgin M; The Criteria Committee of the New York Heart Association. Nomenclature and
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Little, Brown; 1994
19. Aris RM, Routh JC, LiPuma JJ, Heath DG, Gilligan PH. Lung transplantation for cystic fibrosis
patients with Burkholderia cepacia complex: survival linked to genomovar type. Am J Respir
20. De Soyza A, McDowell A, Archer L, et al. Burkholderia cepacia complex genomovars
and pulmonary transplantation outcomes in patients with cystic fibrosis. Lancet.
2001;358(9295):1780–1781 PMID: 11734238 doi: 10.1016/S0140-6736(01)06808-8
21. Boussaud V, Guillemain R, Grenet D, et al. Clinical outcome following lung transplantation in
patients with cystic fibrosis colonised with Burkholderia cepacia complex: results from two
French centres. Thorax. 2008;63(8):732–737 PMID: 18408050 doi: 10.1136/thx.2007.089458
22. Alexander BD, Petzold EW, Reller LB, et al. Survival after lung transplantation of cystic fibrosis
patients infected with Burkholderia cepacia complex. Am J Transplant. 2008;8(5):1025–1030
PMID: 18318775 doi: 10.1111/j.1600-6143.2008.02186.x
23. Danziger-Isakov LA, Worley S, Arrigain S, et al. Increased mortality after pulmonary fungal
infection within the first year after pediatric lung transplantation. J Heart Lung Transplant.
2008;27(6):655–661 PMID: 18503966 doi: 10.1016/j.healun.2008.03.010
24. Denton EJ, Smibert O, Gooi J, et al. Invasive Scedosporium sternal osteomyelitis following
lung transplant: cured. Med Mycol Case Rep. 2016;12:14–16 PMID: 27595059
doi: 10.1016/j.mmcr.2016.07.001
25. Wiederhold NP. Antifungal resistance: current trends and future strategies to combat. Infect
Drug Resist. 2017;10:249–259 PMID: 28919789 doi: 10.2147/IDR.S124918
26. Shah SK, McAnally KJ, Seoane L, et al. Analysis of pulmonary non-tuberculous mycobacterial
infections after lung transplantation. Transpl Infect Dis. 2016;18(4):585–591 PMID: 27368989
doi: 10.1111/tid.12546
27. Winter J, Essmann S, Kidszun A, et al. Neonatal respiratory insufficiency caused by an
(homozygous) ABCA3-stop mutation: a systematic evaluation of therapeutic options. Klin
Padiatr. 2014;226(2):53–58 PMID: 24633979 doi: 10.1055/s-0033-1363687
28. Eldridge WB, Zhang Q, Faro A, et al. Outcomes of lung transplantation for infants and children
with genetic disorders of surfactant metabolism. J Pediatr. 2017;184:157.e2–164.e2
PMID: 28215425 doi: 10.1016/j.jpeds.2017.01.017

745
29. Orens JB, Boehler A, de Perrot M, et al; Pulmonary Council, International Society for Heart and
Lung Transplantation. A review of lung transplant donor acceptability criteria. J Heart Lung
Transplant. 2003;22(11):1183–1200 PMID: 14585380 doi: 10.1016/S1053-2498(03)00096-2
30. Shah RJ, Diamond JM. Primary graft dysfunction (PGD) following lung transplantation.
Semin Respir Crit Care Med. 2018;39(2):148–154 PMID: 29590671 doi: 10.1055/s-0037-1615797
31. Choi JK, Kearns J, Palevsky HI, et al. Hyperacute rejection of a pulmonary allograft: immediate
clinical and pathologic findings. Am J Respir Crit Care Med. 1999;160(3):1015–1018
PMID: 10471633 doi: 10.1164/ajrccm.160.3.9706115
32. Lau CL, Palmer SM, Posther KE, et al. Influence of panel-reactive antibodies on posttransplant
outcomes in lung transplant recipients. Ann Thorac Surg. 2000;69(5):1520–1524
PMID: 10881834 doi: 10.1016/S0003-4975(00)01224-8
33. Verleden GM, Raghu G, Meyer KC, Glanville AR, Corris P. A new classification system
for chronic lung allograft dysfunction. J Heart Lung Transplant. 2014;33(2):127–133
PMID: 24374027 doi: 10.1016/j.healun.2013.10.022
34. Van Herck A, Verleden SE, Sacreas A, et al. Validation of a post-transplant chronic lung allograft
dysfunction classification system. J Heart Lung Transplant. 2019;38(2):166–173 PMID: 30391199
doi: 10.1016/j.healun.2018.09.020
35. Meyer KC, Raghu G, Verleden GM, et al; ISHLT/ATS/ERS BOS Task Force Committee.
An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of
bronchiolitis obliterans syndrome. Eur Respir J. 2014;44(6):1479–1503 PMID: 25359357
doi: 10.1183/09031936.00107514
36. DerHovanessian A, Wallace WD, Lynch JP III, Belperio JA, Weigt SS. Chronic lung allograft
dysfunction: evolving concepts and therapies. Semin Respir Crit Care Med. 2018;39(2):155–171
PMID: 29579768 doi: 10.1055/s-0037-1618567
37. Pakhale SS, Hadjiliadis D, Howell DN, et al. Upper lobe fibrosis: a novel manifestation of chronic
allograft dysfunction in lung transplantation. J Heart Lung Transplant. 2005;24(9):1260–1268
PMID: 16143243 doi: 10.1016/j.healun.2004.08.026
38. Osho AA, Castleberry AW, Snyder LD, et al. Differential outcomes with early and late repeat
transplantation in the era of the lung allocation score. Ann Thorac Surg. 2014;98(6):1914–1920
39. Hall DJ, Belli EV, Gregg JA, et al. Two decades of lung retransplantation: a single-center
experience. Ann Thorac Surg. 2017;103(4):1076–1083 PMID: 28017335
doi: 10.1016/j.athoracsur.2016.09.107
40. Sivakumar P, Ntolios P, Jenkins G, Laurent G. Into the matrix: targeting fibroblasts in
pulmonary fibrosis. Curr Opin Pulm Med. 2012;18(5):462–469 PMID: 22847104
doi: 10.1097/MCP.0b013e328356800f
41. Vos R, Verleden SE, Ruttens D, et al. Pirfenidone: a potential new therapy for restrictive allograft
syndrome? Am J Transplant. 2013;13(11):3035–3040 PMID: 24102752 doi: 10.1111/ajt.12474
42. Verleden SE, Ruttens D, Vandermeulen E, et al. Restrictive chronic lung allograft dysfunction:
where are we now? J Heart Lung Transplant. 2015;34(5):625–630 PMID: 25577564
doi: 10.1016/j.healun.2014.11.007
43. Tepede A, Yogaratnam D. Nintedanib for idiopathic pulmonary fibrosis. J Pharm Pract.
2019;32(2):199–206 PMID: 29017422 doi: 10.1177/0897190017735242
44. Rook AH, Cohen JH, Lessin SR, Vowels BR. Therapeutic applications of photopheresis.
Dermatol Clin. 1993;11(2):339–347 PMID: 8477547
45. Andreu G, Achkar A, Couetil JP, et al. Extracorporeal photochemotherapy treatment for acute
lung rejection episode. J Heart Lung Transplant. 1995;14(4):793–796 PMID: 7578193
46. Benden C, Speich R, Hofbauer GF, et al. Extracorporeal photopheresis after lung transplantation:
a 10-year single-center experience. Transplantation. 2008;86(11):1625–1627 PMID: 19077900
doi: 10.1097/TP.0b013e31818bc024
47. Ratcliffe N, Dunbar NM, Adamski J, et al; American Society for Apheresis. National Institutes
of Health State of the Science Symposium in Therapeutic Apheresis: scientific opportunities in
extracorporeal photopheresis. Transfus Med Rev. 2015;29(1):62–70 PMID: 25459074
doi: 10.1016/j.tmrv.2014.09.004
48. Woo MS, MacLaughlin EF, Horn MV, Szmuszkovicz JR, Barr ML, Starnes VA.
Bronchiolitis obliterans is not the primary cause of death in pediatric living donor lobar lung
transplant recipients. J Heart Lung Transplant. 2001;20(5):491–496 PMID: 11343974
doi: 10.1016/S1053-2498(01)00234-0

CHAPTER
43
Asthma and Other Respiratory Disorders
Associated With Obesity
David Fedele, PhD, ABPP
Introduction
Asthma and obesity are both major public health problems with high preva-
lence and increasing incidence in children and adults.1–3 Both illnesses have
serious short- and long-term health consequences.4 There is an increased
interest in understanding the interaction between asthma and obesity and
in establishing a diagnostic and treatment approach specific to patients who
have both illnesses.
The association between asthma and obesity is well established by results
from several epidemiological studies.5 The incidence of asthma diagnosis
is higher in patients with obesity than in patients without obesity,6 and the
incidence of obesity in patients with asthma is higher than that in individuals
with no asthma.7 More importantly, patients with asthma and obesity have
more severe asthma than do patients without obesity.8,9 Results from interven-
tional studies have also shown that weight loss in patients with obesity and
asthma results in improvement of asthma symptoms, lung function, and
asthma-related quality of life.10,11
There are 3 possible explanations for the strong association between asthma
and obesity: (1) a common etiologic and pathophysiological pathway; (2) a
positive interaction between the 2 disease processes, by which obesity enhances
the pathophysiological characteristics of asthma and/or asthma worsens obesity;
or (3) an overlap of respiratory symptoms between asthma symptoms and other
obesity-related respiratory disorders (eg, restrictive lung disease, obesity hypo-
ventilation syndrome, obstructive sleep apnea [OSA]) that makes patients with
obesity more likely to have asthma misdiagnosed.
747

748
Atopy and Airway Inflammation in

Asthma and Obesity
Despite the strong association between asthma and obesity, there are many
more patients with asthma who do not have obesity than who have it, and,
vice versa, there are more patients with obesity who do not have asthma
than who have asthma.12 This discrepancy suggests that asthma and obesity
are separate disease entities and do not share a common cause. However,
patients with obesity and asthma have overlapping pathological and
physiological abnormalities that can potentially explain their strong
association (Table 43-1).
Atopy and allergic sensitization have been implicated as a potential common
pathway between obesity and asthma. Even though atopy is generally high
in both disease entities, investigators in epidemiological studies have failed
to demonstrate a direct link.13–15 The increased asthma prevalence among
children with obesity appears to be unrelated to atopy status in these patients.16
Airway inflammation has also been suggested as a possible link between
asthma and obesity. Increased systemic inflammation is present in patients with
obesity as indicated by increased blood levels of interleukin 6 and C-reactive
protein, which contributes to the cardiovascular complications of obesity.17
This heightened systemic inflammation in patients with obesity can potentially
contribute to airway inflammation and increased asthma symptoms and asthma
diagnosis. However, there is no evidence of direct correlation between systemic
inflammation and airway inflammation in patients with obesity and asthma.18,19
Furthermore, there is no evidence that patients with obesity have increased
Table 43-1. Differential Effects of Asthma and Obesity on the Physiological

Characteristics of the Respiratory System
Physiological Characteristic Asthma Obesity

Restrictive lung disease Absent Present
Upper airway obstruction Absent Present
Small airway obstruction Present Absent
Airway inflammation Present Absent
Airway hyperresponsiveness Present Present

749
Chapter 43—Asthma and Other Respiratory Disorders Associated With Obesity
airway inflammation compared with patients without obesity that can explain
their predisposition for asthma. For example, results from several studies
showed no increase in fractional exhaled nitric oxide (FeNO) concentration, a
biomarker of eosinophilic airway inflammation, in individuals who were obese
compared with that in those who were not.20,21
Airway inflammation might be common in patients with metabolic syndrome,
which is a specific phenotype of obesity characterized by dyslipidemia, meta-
bolic dysregulation, and tissue resistance to insulin, as well as systemic
inflammation.22,23 Patients with metabolic syndrome have a higher risk of
developing asthma compared with patients with obesity who do not have
metabolic syndrome.24 Through increased availability of biochemical
precursors to inflammatory mediators, hyperlipidemia in particular has been
proposed as the possible link between asthma and metabolic syndrome.25,26
However, study results have failed to show the presence of higher levels of
adipokines such as leptin or adiponectin in patients who have asthma.27,28
As mentioned previously, a direct link between airway inflammation and
systemic inflammation has not been established either.
In contrast to airway inflammation, which does not seem to link obesity
to asthma, there is stronger evidence that airway hyperresponsiveness is a
pathophysiological characteristic shared by asthma and obesity. Patients with
obesity have increased airway hyperresponsiveness to bronchoconstrictive
agents, as do patients with asthma.29 This airway hyperresponsiveness in
patients with obesity is more likely related to the decreased lung volumes
from increased weight on the chest and abdomen.30 These low lung volumes
can decrease the outward tethering of the small airways by the lung paren-
chymal tissue, leading to decreased airway caliber and affecting the length–
strength properties of small airway smooth muscles in a manner that leads
to increased bronchoconstriction. However, airway hyperresponsiveness
in asthma is linked to airway inflammation and is not related to low lung
volumes.31 Therefore, even though airway hyperresponsiveness is a common
pathophysiological characteristic between asthma and obesity, it appears to
originate from 2 separate pathways.
The role of the gut microbiome in the development of asthma and obesity also
suggests a possible common etiologic or pathophysiological link between the
2 illnesses.32 However, more extensive longitudinal studies and interventional
trials are needed to establish a strong link between the 2 illnesses based
on gut dysbiosis.

750
In summary, there is not yet any strong evidence for common etiologic or
pathophysiological pathways that can satisfactorily explain the high associa-
tion between the 2 disease entities. Further research is needed in this field.
Physiological Interactions Between

Asthma and Obesity
Despite the fact that asthma and obesity are separate disease entities that
originate independently, there is strong evidence for the presence of a positive
interaction between the 2 disease processes. Obesity affects physiological
characteristics of the respiratory system in a way that worsens asthma, and,
vice versa, asthma influences rapid weight gain. These interacting processes
may explain the strong association between the illnesses.
Obesity affects physiological characteristics of the respiratory system primarily
through decreasing compliance of the thoracic cage, which leads to lower lung
volumes.33 The decrease in lung volumes correlates strongly with body mass
index and is gravity dependent and more prominent in the supine position or
during exercise.34–36
This decrease in lung volumes can worsen respiratory symptoms in patients
who have obesity and asthma because of (1) increased work of breathing and
exaggerated perception of breathlessness,37 (2) worsening of gas exchange
abnormalities because of decreased ventilation,38 and (3) exaggeration of air-
way hyperresponsiveness because of the effect of low lung volumes on
decreased airway caliber.
The direct measurement of chest wall compliance in patients with obesity is
cumbersome and requires insertion of an esophageal balloon. However, lung
volume can be easily measured using spirometry and lung volume measure-
ments (plethysmography or gas dilution). A decrease in all lung volumes is
expected in patients with obesity, including decrease in vital capacity, FVC,
total lung capacity, and FEV1.39 The ratio of FEV1 and FVC (FEV1/FVC) should
be normal. However, a low FEV1/FVC ratio can occur owing to decreased
airway tethering. Functional residual capacity (FRC) is usually low. Residual
volume (RV) can be normal or low. Because of the decrease in FRC and the
normal RV, expiratory reserve volume is typically decreased in individuals
with obesity and is the most commonly found lung function abnormality.40 The
pattern of lung function abnormalities can differ between children and adults
with obesity, as well as between male and female patients.41
Unlike the restrictive physiology seen in obesity, asthma is characterized by
reversible obstructive pulmonary defects. Airway obstruction is typical in
asthma and affects airflow measures such as FEV1, FEV1/FVC ratio, and

751
FEF25%–75%.42,43 Lung volumes such as total lung capacity, FRC, and RV are
usually normal or higher than normal in patients with asthma.44,45
The deleterious effects of asthma on patients who have obesity are primarily
through decreased exercise capacity, especially in patients with severe asthma
and airway obstruction.46 Exercise-induced bronchospasm in patients who
have exercise-induced asthma can lead to exercise avoidance and a sedentary
lifestyle, which can contribute to accelerated weight gain.47 Also, the need for
repeated treatments with systemic corticosteroids or high doses of inhaled
corticosteroids can contribute to exaggerating weight gain, especially in
patients with poorly controlled asthma and frequent acute exacebations.48
Symptom Overlap Between Asthma and Other

Obesity-Related Respiratory Disorders
Obesity can be associated with respiratory disorders other than asthma as
a result of the effects of obesity on the physiological characteristics of the
respiratory system.49 These disorders can manifest with symptoms that mimic
those of asthma and can be easily misinterpreted as asthma. One example is
OSA. Patients with OSA typically present with snoring, gasping, and restless
sleeping, but they can also present with nighttime cough and shortness of
breath, which overlap with asthma symptoms.50 Both obesity and asthma
are known risk factors for OSA.51 The physiological effects of obesity on
decreasing upper airway patency during sleep are well described; however,
the mechanism for the association between asthma and OSA is less clear but
could be related to the influence of gas exchange abnormality on control of
breathing during sleep.52
Obesity hypoventilation syndrome (OHS), another obesity-related respiratory
disorder, is characterized by alveolar hypoventilation and increased carbon
dioxide level with or without OSA.53 Besides having fractured sleep and
daytime sleepiness, patients with OHS may report shortness of breath during
sleep or with exercise, similar to experiences with asthma.15 The symptoms
of obesity hypoventilation syndrome are mainly due to severe restrictive
lung disease and decreased thoracic wall compliance, not lower airway
obstruction, as is the case with asthma.54
Severe cardiovascular deconditioning is also a common morbidity in patients
with obesity because of a sedentary lifestyle and can potentially lead to
exercise-induced symptoms.55 Exercise limitation due to cardiovascular
deconditioning may contribute to higher diagnoses of asthma in patients
with obesity. However, exercise-induced symptoms in patients with asthma
are primarily due to exercise-induced bronchospasm.56

752
Obesity is also associated with increased frequency and severity of lower

respiratory tract infections (LRTIs), including pneumonia.57,58 This associa-
tion was greatly highlighted during the COVID-19 pandemic as obesity was
recognized to be a major risk factor for increased mortality and severe
LRTIs.59 In some patients, symptoms of recurrent viral LRTIs, such as cough,
mucus production, and shortness of breath, can overlap with symptoms of
recurrent asthma exacerbations.
Gastroesophageal reflux disease (GERD) is highly prevalent in patients with
asthma and in patients with obesity and can indicate an overlap between the
2 illnesses and contribute to their strong association.60 Although the relation-
ship between obesity and GERD is well established, the cause-and-effect
relationship between GERD and asthma is highly controversial.61 Despite the
overlap in symptoms between GERD and asthma, it is unlikely that GERD
contributes to the increased incidence of asthma in patients with obesity.62
However, the increased associations among the 3 comorbidities and the
overlap of their symptoms support the need for evaluation for GERD in
patients who have obesity and respiratory symptoms.
Evaluation of Patients With Asthma and Obesity

Asthma diagnosis in patients with obesity can be challenging because of
the heterogeneity of asthma manifestation and the overlap between asthma
symptoms and other obesity-related respiratory conditions. The main goal of
evaluating patients with obesity and respiratory symptoms is to determine
whether the respiratory symptoms are due to asthma or to other obesity-
related respiratory disorders. Obtaining a detailed history and performing
a physical examination in search of distinctive signs and symptoms of these
overlapping respiratory diseases can help direct further investigation and lead
to proper diagnosis (Figure 43-1). For example, a clear history of snoring,
apnea, and gasping during sleep is suggestive of OSA, even if the patient has
nighttime cough or shortness of breath as well.50,63 Also, a clear history of
shortness of breath during exercise that is not associated with wheezing and
that resolves with rest and without any need of a bronchodilator is unlikely
to be due to asthma. In this case, restrictive lung disease or cardiovascular
deconditioning should be considered.
Besides the detailed history and physical examination, diagnostic tests can
help diagnose asthma and differentiate between asthma and other obesity-
related respiratory disorders (Table 43-2). Office-based spirometry testing can
help differentiate asthma from other obesity-related disorders. Demonstration
of airway obstruction that is reversible by albuterol supports the diagnosis of
asthma, whereas the presence of a restrictive physiological pattern (ie, low
FVC) is unlikely to be due to asthma. If lung function is normal, other tests

753
Obesity with
respiratory symptoms
H & P and PFT

suggestive of asthma?
Yes No
• Evaluate asthma (ie, spirometry,

exhaled NO, methacholine challenge)
• Treat asthma
Patient responds
to treatment?
Yes No
Asthma Evaluate for other obesity-related

diagnosis respiratory comorbidities
Figure 43-1. Algorithm for evaluating patients with obesity and respiratory symptoms.
Abbreviations: H&P, history and physical examination; NO, nitric oxide; PFT, pulmonary function
test.
Table 43–2. Overlap of Respiratory Symptoms of Obesity and Asthma

Obesity-Related Respiratory Disorders Mimicking Asthma
Symptoms Cardiovascular Restrictive
and Tests OSA Deconditioning GERD Lung Disease
Asthma-like Nocturnal cough Exertional Cough Exertional
symptoms Nocturnal dyspnea dyspnea dyspnea
Wheezing
Distinctive Snoring Fatigue Heartburn Orthopnea
symptoms Witnessed apnea Postprandial
symptoms
Diagnostic Sleep study Exercise airway Swallowing Pulmonary
tests provocation studies function testing
testing Esophageal pH Cardiopulmonary
Cardiopulmonary or impedance exercise testing
exercise testing studies
Abbreviations: GERD, gastroesophageal reflux disease; OSA, obstructive sleep apnea.

754
can help with the diagnosis of obesity-related respiratory disorders.42 Elevated

levels of FeNO suggest the presence of eosinophilic airway inflammation and
support the diagnosis of atopic asthma.64 However, FeNO levels can also be
high in patients with allergic rhinitis and are not specific for asthma diagno-
sis.65 Normal levels of FeNO suggest that the symptoms are not from atopic
asthma and that other causes should be considered.
Empiric treatment with a short course of oral steroids or inhaled steroids
has been advocated as a quick and safe approach to diagnosing asthma if
symptoms are strongly suggestive (see Chapter 12, Asthma). If empiric treat-
ment fails, other obesity-related respiratory disorders should be considered.
Exercise testing may be needed to determine the cause of exercise-induced
symptoms in patients with obesity. A clinically significant decrease in FEV1
after exercise, which is associated with reproduction of symptoms and their
reversibility with bronchodilator, is considered diagnostic of exercise-induced
asthma.66 If exercise testing cannot be performed or results are inconclusive,
a negative methacholine challenge test is specifically helpful in ruling out an
asthma diagnosis.67 If asthma was excluded as the cause of exercise-induced
symptoms in patients with obesity, then cardiopulmonary exercise testing
is required to evaluate whether these symptoms are due to other obesity-
related disorders such as restrictive lung disease or cardiovascular
deconditioning, the latter being the most likely.68–70
Because of the high associations between obesity, asthma, and OSA, the
diagnosis of nighttime symptoms can be challenging. Nighttime symptoms
can be misinterpreted as asthma in patients who have OSA, and, vice versa,
asthma symptoms can be misinterpreted as OSA. Therefore, careful consid-
eration of the nighttime symptoms, review of home video recordings, and use
of validated questionnaires will help direct the physician to the most likely
diagnostic testing. Polysomnography is the gold standard test to confirm the
diagnosis of OSA.71 Polysomnography, including end-tidal CO2 measurements
and morning blood gas analysis, can help differentiate OSA from OHS as the
cause of nighttime symptoms.72
Esophageal pH and impedance studies can be helpful in establishing the
diagnosis of GERD in patients with obesity who present with postprandial
heartburn, cough, and wheezing. Alternatively, empirical therapy with
H2- blockers or proton pump inhibitors can be both diagnostic and therapeutic.
Treatment of Asthma and Obesity

Once the diagnosis of asthma is confirmed in patients with obesity, treatment
of both illnesses can be challenging due to the compounded effect of both
diseases on the physiological characteristics of the respiratory system and the
positive interaction of the 2 illnesses. Because of the chronic nature of both

755
illnesses, their treatment requires maintenance medications and sustained

changes in lifestyle. Socioeconomic disadvantage, which is associated with
both conditions, can impede effective treatment.73 Some of the socioeconomic
obstacles to effective treatment of both illnesses are related to disparity in
access to quality food, exercise facilities, and quality health care. Low self-
efficacy due to lack of health education can also affect adherence to treatment
regimens. Such challenges are more pronounced in children than in adults
because children lack autonomy.
A multidisciplinary approach to managing asthma and obesity by physicians,
dieticians, and psychologists is advisable. The primary goal of management
is to treat both illnesses simultaneously to maximize the chance of treatment
effectiveness. A comprehensive approach can help alleviate anxiety, low self-
esteem, depression, and poor adherence, which are prevalent in both diseases.
However, few treatment programs are designed to incorporate a combined
approach to treat asthma and obesity.74
Weight loss in patients with asthma and obesity results in a decrease in asthma
symptoms and asthma exacerbations and an improvement in lung function and
asthma-related quality of life.11 Several weight loss programs for children with
obesity have been developed and evaluated, most of them focusing on increas-
ing physical activity and promoting dietary changes and eating habits.75,76
The active participation of the child can be helpful in the development of self-
efficacy.77 Structured programs at home, in the health care setting, at school, or
through monitored web-based or mobile devices can help improve adherence
to dietary and physical activity recommendations.78–81 Patient motivation can
be developed through use of educational and motivational interviewing con-
ducted by trained individuals with the help of written material or interactive
software applications.82–84 The increased availability of electronic wearable
devices that monitor physical activity and other health-related parameters
also provides an opportunity for their use in weight loss programs.85
Use of medications such as metformin, sibutramine, fluoxetine, and orlistat for
weight reduction is associated with adverse effects, and these medications are
not approved for use in young children. Furthermore, the long-term effective-
ness of these medications is not known.86 Bariatric surgery, including laparo-
scopic Roux-en-Y gastric bypass, vertical sleeve gastrectomy, and gastric
banding, is associated with postoperative complications and should be reserved
for adolescents with morbid obesity in whom behavioral therapy has failed.87
Treatment of asthma in patients with obesity facilitates weight loss. Successful
control of symptoms can be achieved in most patients by using inhaled cortico-
steroids with or without long-acting β-agonists (see Chapter 12, Asthma). Use
of high-dose inhaled corticosteroids or daily oral corticosteroids should be
avoided in patients with obesity if possible. Treatment with monoclonal anti–
immunoglobulin E antibodies should be considered as an alternative therapy

756
to avoid further weight gain.88 Improvement of patients’ adherence to medica-

tions and inhaler technique can result in good control of asthma and prevent
escalation of steroid therapy. Once asthma is well controlled in patients with
obesity, weaning asthma medications should be attempted as soon as possible.
For patients with obesity and asthma, close monitoring and frequent clinic
visits are important.
Alleviation of symptoms from exercise-induced asthma promotes increased
physical activity and weight loss in patients with obesity. Most exercise-induced
symptoms can be prevented by the use of short-acting albuterol before exercise.
Inhaled corticosteroids should be considered in patients with evidence of
airway inflammation.
Treating obesity-related disorders such as OSA, OHS, and GERD is important
once the diagnosis of any of these disorders is confirmed. Treatment of OSA
may require use of continuous positive airway pressure at night. However,
evaluation and treatment of allergic rhinitis and surgical removal of enlarged
adenoids and/or tonsils, if present, may alleviate the need for continuous posi-
tive airway pressure. Obesity hypoventilation syndrome is a serious medical
condition and should be treated with noninvasive ventilation such as bilevel
positive airway pressure or invasive ventilation through a tracheostomy tube.
Finally, GERD should be treated with H2-blockers or proton pump inhibitors.
key points
} The incidence and prevalence of asthma are high in patients with obesity,
which can be partially explained by the effect of obesity on respiratory system
mechanics, including decreased chest compliance, decreased lung volumes,
and increased airway responsiveness.
} Obesity can develop in patients with asthma because of decreased physical
activity and steroid therapy.
} Symptoms of obesity-related respiratory disorders other than asthma, such as
OSA, OHS, cardiovascular deconditioning, recurrent chest infections, and GERD,
can mimic asthma symptoms in patients who are obese and potentially be
misdiagnosed as asthma.
} Reaching an accurate diagnosis of asthma versus other obesity-related
respiratory disorders in children requires a detailed history and physical
examination and may require further diagnostic testing, including spirometry,
exercise testing, polysomnography, and esophageal pH impedance.
} Treatment of obesity requires a multidisciplinary clinical and psychological
approach with a focus on behavioral changes through motivational techniques,
family involvement, and use of digital technology. Specific treatments for
obesity-related respiratory disorders should be initiated concomitantly.

757
References
1. Mazurek JM, Syamlal G. Prevalence of asthma, asthma attacks, and emergency department visits
for asthma among working adults—National Health Interview Survey, 2011–2016. MMWR Morb
Mortal Wkly Rep. 2018;67(13):377–386 PMID: 29621204 doi: 10.15585/mmwr.mm6713a1
2. Zahran HS, Bailey CM, Damon SA, Garbe PL, Breysse PN. Vital signs: asthma in children—
United States, 2001–2016. MMWR Morb Mortal Wkly Rep. 2018;67(5):149–155 PMID: 29420459
doi: 10.15585/mmwr.mm6705e1
3. Moorman JE, Rudd RA, Johnson CA, et al; Centers for Disease Control and Prevention (CDC).
National surveillance for asthma—United States, 1980-2004. MMWR Surveill Summ.
2007;56(8):1–54 PMID: 17947969
4. Park MH, Falconer C, Viner RM, Kinra S. The impact of childhood obesity on morbidity and
mortality in adulthood: a systematic review. Obes Rev. 2012;13(11):985–1000 PMID: 22731928
doi: 10.1111/j.1467-789X.2012.01015.x
5. Azizpour Y, Delpisheh A, Montazeri Z, Sayehmiri K, Darabi B. Effect of childhood BMI on
asthma: a systematic review and meta-analysis of case-control studies. BMC Pediatr.
2018;18(1):143 PMID: 29699517 doi: 10.1186/s12887-018-1093-z
6. Lang JE, Bunnell HT, Hossain MJ, et al. Being overweight or obese and the development of
asthma. Pediatrics. 2018;142(6):e20182119 PMID: 30478238 doi: 10.1542/peds.2018-2119
7. Chen Z, Salam MT, Alderete TL, et al. Effects of childhood asthma on the development of obesity
among school-aged children. Am J Respir Crit Care Med. 2017;195(9):1181–1188 PMID: 28103443
doi: 10.1164/rccm.201608-1691OC
8. Schatz M, Zeiger RS, Yang SJ, et al. Prospective study on the relationship of obesity to asthma
impairment and risk. J Allergy Clin Immunol Pract. 2015;3(4):560.e1–565.e1 PMID: 25975622
doi: 10.1016/j.jaip.2015.03.017
9. Haselkorn T, Fish JE, Chipps BE, Miller DP, Chen H, Weiss ST. Effect of weight change on
asthma-related health outcomes in patients with severe or difficult-to-treat asthma. Respir Med.
2009;103(2):274–283 PMID: 18819787 doi: 10.1016/j.rmed.2008.08.010
10. Adeniyi FB, Young T. Weight loss interventions for chronic asthma. Cochrane Database
Syst Rev. 2012;(7):CD009339 PMID: 22786526 doi: 10.1002/14651858.CD009339.pub2
11. Okoniewski W, Lu KD, Forno E. Weight loss for children and adults with obesity and asthma:
a systematic review of randomized controlled trials. Ann Am Thorac Soc. 2019;16(5):613–625
PMID: 30605347 doi: 10.1513/AnnalsATS.201810-651SR
12. Egan KB, Ettinger AS, Bracken MB. Childhood body mass index and subsequent physician-
diagnosed asthma: a systematic review and meta-analysis of prospective cohort studies. BMC
Pediatr. 2013;13:121 PMID: 23941287 doi: 10.1186/1471-2431-13-121
13. Lee EJ, Kim JH, Lee KH, Hong SC, Lee HS, Kang JW. New allergen sensitization might be
associated with increased body mass index in children. Am J Rhinol Allergy. 2016;30(4):124–127
PMID: 27456587 doi: 10.2500/ajra.2016.30.4339
14. Visness CM, London SJ, Daniels JL, et al. Association of obesity with IgE levels and allergy
symptoms in children and adolescents: results from the National Health and Nutrition
Examination Survey 2005–2006. J Allergy Clin Immunol. 2009;123(5):1163–1169, 1169.e1–4
PMID: 19230960 doi: 10.1016/j.jaci.2008.12.1126
15. Gergen PJ, Arbes SJ Jr, Calatroni A, Mitchell HE, Zeldin DC. Total IgE levels and asthma
prevalence in the US population: results from the National Health and Nutrition Examination
Survey 2005–2006. J Allergy Clin Immunol. 2009;124(3):447–453 PMID: 19647861
doi: 10.1016/j.jaci.2009.06.011
16. Visness CM, London SJ, Daniels JL, et al. Association of childhood obesity with atopic and
nonatopic asthma: results from the National Health and Nutrition Examination Survey 1999–
2006. J Asthma. 2010;47(7):822–829 PMID: 20707763 doi: 10.3109/02770903.2010.489388
17. Ellulu MS, Patimah I, Khaza’ai H, Rahmat A, Abed Y. Obesity and inflammation: the linking
mechanism and the complications. Arch Med Sci. 2017;13(4):851–863 PMID: 28721154
doi: 10.5114/aoms.2016.58928
18. Ramirez D, Patel P, Casillas A, Cotelingam J, Boggs P, Bahna SL. Assessment of high-sensitivity
C-reactive protein as a marker of airway inflammation in asthma. Ann Allergy Asthma Immunol.
2010;104(6):485–489 PMID: 20568380 doi: 10.1016/j.anai.2010.04.004
19. Shimoda T, Obase Y, Kishikawa R, Iwanaga T. Serum high-sensitivity C-reactive protein can be
an airway inflammation predictor in bronchial asthma. Allergy Asthma Proc. 2015;36(2):e23–e28
PMID: 25715235 doi: 10.2500/aap.2015.36.3816
20. Jensen ME, Gibson PG, Collins CE, Wood LG. Airway and systemic inflammation in
obese children with asthma. Eur Respir J. 2013;42(4):1012–1019 PMID: 23349447
doi: 10.1183/09031936.00124912

758
21. Singleton MD, Sanderson WT, Mannino DM. Body mass index, asthma and exhaled nitric
oxide in U.S. adults, 2007–2010. J Asthma. 2014;51(7):756–761 PMID: 24712499
doi: 10.3109/02770903.2014.912302
22. Park S, Choi NK, Kim S, Lee CH. The relationship between metabolic syndrome and asthma in
the elderly. Sci Rep. 2018;8(1):9378 PMID: 29925841 doi: 10.1038/s41598-018-26621-z
23. Brumpton BM, Camargo CA Jr, Romundstad PR, Langhammer A, Chen Y, Mai XM.
Metabolic syndrome and incidence of asthma in adults: the HUNT study. Eur Respir J.
2013;42(6):1495–1502 PMID: 23845717 doi: 10.1183/09031936.00046013
24. Forno E, Zhang P, Nouraie M, et al. The impact of bariatric surgery on asthma control differs
among obese individuals with reported prior or current asthma, with or without metabolic
syndrome. PLoS One. 2019;14(4):e0214730 PMID: 30964910 doi: 10.1371/journal.pone.0214730
25. Mizuta K, Matoba A, Shibata S, Masaki E, Emala CW Sr. Obesity-induced asthma: role of
free fatty acid receptors. Jpn Dent Sci Rev. 2019;55(1):103–107 PMID: 31516639
doi: 10.1016/j.jdsr.2019.07.002
26. Al-Shawwa B, Al-Huniti N, Titus G, Abu-Hasan M. Hypercholesterolemia is a
potential risk factor for asthma. J Asthma. 2006;43(3):231–233 PMID: 16754527
doi: 10.1080/02770900600567056
27. Jartti T, Saarikoski L, Jartti L, et al. Obesity, adipokines and asthma. Allergy. 2009;64(5):770–777
PMID: 19210351 doi: 10.1111/j.1398-9995.2008.01872.x
28. Jang AS, Kim TH, Park JS, et al. Association of serum leptin and adiponectin with obesity in
asthmatics. J Asthma. 2009;46(1):59–63 PMID: 19191139 doi: 10.1080/02770900802444203
29. Litonjua AA, Sparrow D, Celedon JC, DeMolles D, Weiss ST. Association of body mass index
with the development of methacholine airway hyperresponsiveness in men: the Normative Aging
Study. Thorax. 2002;57(7):581–585 PMID: 12096199 doi: 10.1136/thorax.57.7.581
30. Bates JH. Physiological mechanisms of airway hyperresponsiveness in obese asthma. Am J Respir
Cell Mol Biol. 2016;54(5):618–623 PMID: 26909510 doi: 10.1165/rcmb.2016-0019PS
31. Postma DS, Boezen HM. Rationale for the Dutch hypothesis: allergy and airway
hyperresponsiveness as genetic factors and their interaction with environment in the
development of asthma and COPD. Chest. 2004;126(2 suppl):96S–104S PMID: 15302769
doi: 10.1378/chest.126.2_suppl_1.96S
32. Poynter ME. Debugging obesity-related airway hyperresponsiveness by modulating the
microbiome. Am J Respir Cell Mol Biol. 2019;61(6):665–666 PMID: 31185177
doi: 10.1165/rcmb.2019-0193ED
33. Dixon AE, Peters U. The effect of obesity on lung function. Expert Rev Respir Med.
2018;12(9):755–767 PMID: 30056777 doi: 10.1080/17476348.2018.1506331
34. Sebbane M, El Kamel M, Millot A, et al. Effect of weight loss on postural changes in pulmonary
function in obese subjects: a longitudinal study. Respir Care. 2015;60(7):992–999
35. Watson RA, Pride NB. Postural changes in lung volumes and respiratory resistance in
subjects with obesity. J Appl Physiol (1985). 2005;98(2):512–517 PMID: 15475605
doi: 10.1152/japplphysiol.00430.2004
36. Steier J, Lunt A, Hart N, Polkey MI, Moxham J. Observational study of the effect of obesity on
lung volumes. Thorax. 2014;69(8):752–759 PMID: 24736287 doi: 10.1136/thoraxjnl-2014-205148
37. Sah PK, Gerald Teague W, Demuth KA, Whitlock DR, Brown SD, Fitzpatrick AM. Poor asthma
control in obese children may be overestimated because of enhanced perception of dyspnea.
J Allergy Clin Immunol Pract. 2013;1(1):39–45 PMID: 23646295 doi: 10.1016/j.jaip.2012.10.006
38. Zavorsky GS, Hoffman SL. Pulmonary gas exchange in the morbidly obese. Obes Rev.
2008;9(4):326–339 PMID: 18331421 doi: 10.1111/j.1467-789X.2008.00471.x
39. Oliveira PD, Wehrmeister FC, Gonçalves H, et al. Body composition from 18 to 22 years and
pulmonary function at 22 years—1993 Pelotas Birth Cohort. PLoS One. 2019;14(6):e0219077
PMID: 31247010 doi: 10.1371/journal.pone.0219077
40. Littleton SW, Tulaimat A. The effects of obesity on lung volumes and oxygenation. Respir Med.
2017;124:15–20 PMID: 28284316 doi: 10.1016/j.rmed.2017.01.004
41. Forno E, Han YY, Mullen J, Celedón JC. Overweight, obesity, and lung function in children
and adults—a meta-analysis. J Allergy Clin Immunol Pract. 2018;6(2):570.e10–581.e10
PMID: 28967546 doi: 10.1016/j.jaip.2017.07.010
42. Murray C, Foden P, Lowe L, Durrington H, Custovic A, Simpson A. Diagnosis of asthma in
symptomatic children based on measures of lung function: an analysis of data from a population-
based birth cohort study. Lancet Child Adolesc Health. 2017;1(2):114–123 PMID: 29034296
doi: 10.1016/S2352-4642(17)30008-1

759
43. de Jong CCM, Pedersen ESL, Mozun R, et al. Diagnosis of asthma in children: the contribution
of a detailed history and test results. Eur Respir J. 2019;54(6):1901326 PMID: 31515409
doi: 10.1183/13993003.01326-2019
44. Jain VV, Abejie B, Bashir MH, Tyner T, Vempilly J. Lung volume abnormalities and
its correlation to spirometric and demographic variables in adult asthma. J Asthma.
2013;50(6):600–605 PMID: 23521185 doi: 10.3109/02770903.2013.789058
45. Blackie SP, al-Majed S, Staples CA, Hilliam C, Paré PD. Changes in total lung capacity during
acute spontaneous asthma. Am Rev Respir Dis. 1990;142(1):79–83 PMID: 2368981
doi: 10.1164/ajrccm/142.1.79
46. Leinaar E, Alamian A, Wang L. A systematic review of the relationship between
asthma, overweight, and the effects of physical activity in youth. Ann Epidemiol.
2016;26(7):504.e6–510.e6 PMID: 27449571 doi: 10.1016/j.annepidem.2016.06.002
47. Ford ES, Heath GW, Mannino DM, Redd SC. Leisure-time physical activity patterns among US
adults with asthma. Chest. 2003;124(2):432–437 PMID: 12907526 doi: 10.1378/chest.124.2.432
48. Han J, Nguyen J, Kim Y, et al. Effect of inhaled corticosteroid use on weight (BMI) in pediatric
patients with moderate-severe asthma. J Asthma. 2019;56(3):263–269 PMID: 29672188
doi: 10.1080/02770903.2018.1455853
49. Zammit C, Liddicoat H, Moonsie I, Makker H. Obesity and respiratory diseases. Int J Gen Med.
2010;3:335–343 PMID: 21116339 doi: 10.2147/IJGM.S11926
50. 50. Wang TY, Lo YL, Liu WT, et al. Chronic cough and obstructive sleep apnoea in a
sleep laboratory-based pulmonary practice. Cough. 2013;9(1):24 PMID: 24188336
doi: 10.1186/1745-9974-9-24
51. Lal C, Kumbhare S, Strange C. Prevalence of self-reported sleep problems amongst adults with
obstructive airway disease in the NHANES cohort in the United States. Sleep Breath.
2020;24(3):985–993 PMID: 31520299 doi: 10.1007/s11325-019-01941-0
52. Gulotta G, Iannella G, Vicini C, et al. Risk factors for obstructive sleep apnea syndrome in
children: state of the art. Int J Environ Res Public Health. 2019;16(18):3235 PMID: 31487798
doi: 10.3390/ijerph16183235
53. Masa JF, Pépin JL, Borel JC, Mokhlesi B, Murphy PB, Sánchez-Quiroga MA. Obesity
hypoventilation syndrome. Eur Respir Rev. 2019;28(151):180097 PMID: 30872398
doi: 10.1183/16000617.0097-2018
54. Piper AJ, Grunstein RR. Obesity hypoventilation syndrome: mechanisms and management. Am
J Respir Crit Care Med. 2011;183(3):292–298 PMID: 21037018 doi: 10.1164/rccm.201008-1280CI
55. Shim YM, Burnette A, Lucas S, et al. Physical deconditioning as a cause of breathlessness
among obese adolescents with a diagnosis of asthma. PLoS One. 2013;8(4):e61022
56. Bernhardt V, Babb TG. Exertional dyspnoea in obesity. Eur Respir Rev. 2016;25(142):487–495
PMID: 27903669 doi: 10.1183/16000617.0081-2016
57. Maccioni L, Weber S, Elgizouli M, et al. Obesity and risk of respiratory tract infections: results
of an infection-diary based cohort study. BMC Public Health. 2018;18(1):271 PMID: 29458350
doi: 10.1186/s12889-018-5172-8
58. Kornum JB, Nørgaard M, Dethlefsen C, et al. Obesity and risk of subsequent hospitalisation
with pneumonia. Eur Respir J. 2010;36(6):1330–1336 PMID: 20351023
doi: 10.1183/09031936.00184209
59. Kwok S, Adam S, Ho JH, et al. Obesity: a critical risk factor in the COVID-19 pandemic.
Clin Obes. 2020;10(6):e12403 PMID: 32857454 doi: 10.1111/cob.12403
60. Lang JE, Hossain J, Holbrook JT, et al. Gastro-oesophageal reflux and worse asthma control in
obese children: a case of symptom misattribution? Thorax. 2016;71(3):238–246 PMID: 26834184
doi: 10.1136/thoraxjnl-2015-207662
61. Shepherd K, Orr W. Mechanism of gastroesophageal reflux in obstructive sleep apnea:
airway obstruction or obesity? J Clin Sleep Med. 2016;12(1):87–94 PMID: 26446244
doi: 10.5664/jcsm.5402
62. Dixon AE, Clerisme-Beaty EM, Sugar EA, et al. Effects of obstructive sleep apnea and
gastroesophageal reflux disease on asthma control in obesity. J Asthma. 2011;48(7):707–713
PMID: 21819338 doi: 10.3109/02770903.2011.601778
63. Sundar KM, Daly SE, Willis AM. A longitudinal study of CPAP therapy for patients with
chronic cough and obstructive sleep apnoea. Cough. 2013;9(1):19 PMID: 23845135
doi: 10.1186/1745-9974-9-19
64. Grzelewski T, Stelmach W, Stelmach R, et al. Spirometry-adjusted fraction of exhaled nitric
oxide allows asthma diagnosis in children, adolescents, and young adults. Respir Care.
2016;61(2):162–172 PMID: 26628565 doi: 10.4187/respcare.04092

760
65. Lee KJ, Cho SH, Lee SH, et al. Nasal and exhaled nitric oxide in allergic rhinitis. Clin Exp
Otorhinolaryngol. 2012;5(4):228–233 PMID: 23205229 doi: 10.3342/ceo.2012.5.4.228
PMID: 15801248 doi: 10.1016/S1081-1206(10)60989-1
67. Bhatia R, DiLullo KJ. Utility and efficiency of methacholine challenge testing in evaluating
pediatric asthma: unraveling the diagnostic conundrum. J Asthma. 2021;58(1):69–74
PMID: 31526153 doi: 10.1080/02770903.2019.1663431
68. DeLorey DS, Wyrick BL, Babb TG. Mild-to-moderate obesity: implications for respiratory
mechanics at rest and during exercise in young men. Int J Obes. 2005;29(9):1039–1047
PMID: 15917840 doi: 10.1038/sj.ijo.0803003
69. Cooper DM, Leu SY, Taylor-Lucas C, Lu K, Galassetti P, Radom-Aizik S. Cardiopulmonary
exercise testing in children and adolescents with high body mass index. Pediatr Exerc Sci.
2016;28(1):98–108 PMID: 26730653 doi: 10.1123/pes.2015-0107
70. Hansen D, Marinus N, Remans M, et al. Exercise tolerance in obese vs. lean adolescents:
a systematic review and meta-analysis. Obes Rev. 2014;15(11):894–904 PMID: 25132188
doi: 10.1111/obr.12202
71. Zhao G, Li Y, Wang X, et al. The predictive value of polysomnography combined with
quality of life for treatment decision of children with habitual snoring related to adenotonsillar
hypertrophy. Eur Arch Otorhinolaryngol. 2018;275(6):1579–1586 PMID: 29696368
doi: 10.1007/s00405-018-4984-6
72. Bingol Z, Pıhtılı A, Cagatay P, Okumus G, Kıyan E. Clinical predictors of obesity
hypoventilation syndrome in obese subjects with obstructive sleep apnea. Respir Care.
73. Min J, Xue H, Wang Y. Association between household poverty dynamics and childhood
overweight risk and health behaviours in the United States: a 8-year nationally representative
longitudinal study of 16 800 children. Pediatr Obes. 2018;13(10):590–597 PMID: 30110714
doi: 10.1111/ijpo.12292
74. Fedele DA, Janicke DM, McQuaid EL, et al. A behavioral family intervention for children with
overweight and asthma. Clin Pract Pediatr Psychol. 2018;6(3):259–269 PMID: 30416909
doi: 10.1037/cpp0000237
75. Mead E, Brown T, Rees K, et al. Diet, physical activity and behavioural interventions for the
treatment of overweight or obese children from the age of 6 to 11 years. Cochrane Database
Syst Rev. 2017;6(6):CD012651 PMID: 28639319 doi: 10.1002/14651858.CD012651
76. Al-Khudairy L, Loveman E, Colquitt JL, et al. Diet, physical activity and behavioural
interventions for the treatment of overweight or obese adolescents aged 12 to 17 years. Cochrane
Database Syst Rev. 2017;6(6):CD012691 PMID: 28639320 doi: 10.1002/14651858.CD012691
77. Loveman E, Al-Khudairy L, Johnson RE, et al. Parent-only interventions for childhood
overweight or obesity in children aged 5 to 11 years. Cochrane Database Syst Rev.
2015;2015(12):CD012008 PMID: 26690844 doi: 10.1002/14651858.CD012008
78. Antwi F, Fazylova N, Garcon MC, Lopez L, Rubiano R, Slyer JT. The effectiveness of
web-based programs on the reduction of childhood obesity in school-aged children: a systematic
review. JBI Libr Syst Rev. 2012;10(42 suppl):1–14 PMID: 27820152 doi: 10.11124/jbisrir-2012-248
79. Walter H, Sadeque-Iqbal F, Ulysse R, Castillo D, Fitzpatrick A, Singleton J. The effectiveness of
school-based family asthma educational programs on the quality of life and number of asthma
exacerbations of children aged five to 18 years diagnosed with asthma: a systematic review
protocol. JBI Database System Rev Implement Rep. 2015;13(10):69–81 PMID: 26571284
doi: 10.11124/jbisrir-2015-2335
80. Harris K, Kneale D, Lasserson TJ, McDonald VM, Grigg J, Thomas J. School-based
self-management interventions for asthma in children and adolescents: a mixed methods
systematic review. Cochrane Database Syst Rev. 2019;1(1):CD011651 PMID: 30687940
doi: 10.1002/14651858.CD011651.pub2
81. Freira S, Lemos MS, Fonseca H, et al. Anthropometric outcomes of a motivational interviewing
school-based randomized trial involving adolescents with overweight. Eur J Pediatr.
2018;177(7):1121–1130 PMID: 29766325 doi: 10.1007/s00431-018-3158-2
82. Marcano Belisario JS, Huckvale K, Greenfield G, Car J, Gunn LH. Smartphone and tablet
self management apps for asthma. Cochrane Database Syst Rev. 2013;2013(11):CD010013
PMID: 24282112 doi: 10.1002/14651858.CD010013.pub2
83. Holzmann SL, Holzapfel C. A scientific overview of smartphone applications and electronic
devices for weight management in adults. J Pers Med. 2019;9(2):31 PMID: 31181705
doi: 10.3390/jpm9020031

761
84. Fedele D, Lucero R, Janicke D, et al. Protocol for the development of a behavioral family lifestyle
intervention supported by mobile health to improve weight self-management in children with
asthma and obesity. JMIR Res Protoc. 2019;8(6):e13549 PMID: 31237240 doi: 10.2196/13549
85. McCallum C, Rooksby J, Gray CM. Evaluating the impact of physical activity apps and
wearables: interdisciplinary review. JMIR Mhealth Uhealth. 2018;6(3):e58 PMID: 29572200
doi: 10.2196/mhealth.9054
86. Mead E, Atkinson G, Richter B, et al. Drug interventions for the treatment of obesity in children
and adolescents. Cochrane Database Syst Rev. 2016;11(11):CD012436 PMID: 27899001
doi: 10.1002/14651858.CD012436
87. Inge TH, Courcoulas AP, Jenkins TM, et al; Teen-LABS Consortium. Weight loss and health
status 3 years after bariatric surgery in adolescents. N Engl J Med. 2016;374(2):113–123
PMID: 26544725 doi: 10.1056/NEJMoa1506699
88. Oliveira MJ, Vieira M, Coutinho D, et al. Severe asthma in obese patients: improvement of lung
function after treatment with omalizumab. Pulmonology. 2019;25(1):15–20 PMID: 30827349
doi: 10.1016/j.pulmoe.2018.01.005

CHAPTER
44
Functional Respiratory Disorders
Manju S. Hurvitz, MD, FAAP
Introduction
Functional respiratory disorders (FRDs) are characterized by symptoms
without medical explanation. Those likely to be encountered in children
include chronic cough, dyspnea, and dysfunctional breathing; other clinical
symptoms of FRDs include sighing, chest or throat tightness, and pain. Func-
tional respiratory disorders should not be considered diagnoses of exclusion.
They have recognizable characteristics that permit identification. Routine
investigation for all other causes of the same symptoms is usually not jus-
tified and only causes unnecessary testing and treatment. For each of the
FRDs discussed in this chapter, the unique presentation is described,
diagnostic criteria presented, and the treatment approach provided.
Habit Cough Syndrome

There are multiple causes of a chronic cough (Table 44-1). Habit cough is
an involuntary chronic cough without medical explanation. Terminology that
has been used for this disorder includes cough tic, psychogenic cough, and
somatic cough disorder. In considering these alternative terms, it is important
to understand that the symptom patients experience is obvious to an observer
as a cough, not a tic. While some patients might have a psychogenic basis,
there is little evidence to support that for most. Somatic cough disorder is
a general description, not a specific diagnosis. The term habit cough had
its origin in a 1966 publication by Boston allergist Bernard Berman, who
identified 6 children in his practice over a 5-year period who were cured
with “the art of suggestion.”15 A further advantage of the term is its
benignity in explaining the disorder to children and their parents.
763

764
Table 44-1. Etiologies of Chronic Cough Among Diagnoses of 346 Childrena

Cause Percent of 346 children
1
Protracted bacterial bronchitis 41.0
2
Asthma 15.9
Spontaneous resolutions without diagnosis 14.0
3
Bronchiectasis 9.0
4
Tracheomalacia 6.1
5
Habitual 4.3
Pertussis6 3.5
7
Aspiration 2.3
Mycoplasma 1.4
8
Pneumonia 0.9
9
Cystic fibrosis 0.3
10
Primary ciliary dyskinesia 0
11
Uvula impinging on epiglottis 0
12
Tonsils impinging on epiglottis 0
13
Achalasis 0
14
Diffuse panbronchiolitis 0
Tuberculosis 0
a
Chang AB, Robertson CF, van Asperen PP, et al. A multicenter study on chronic cough in children: burden
and etiologies based on a standardized management pathway. Chest. 2012;142(4):943–950.
The presentation is a repetitive cough, often occurring several times per

minute though with interpatient variability, classically harsh and barking,
and continuing for many hours that can include all waking hours. Habit cough
commonly follows a viral respiratory infection, a common cold. Caregivers
often describe an initial typical cough of a cold that changes after 1 to 2 weeks.
That description is present in a 1694 publication (Figure 44-1).16 It becomes
the repetitive barking cough characteristic of this disorder. The cough may
interfere with going to sleep, but a sine qua non of this disorder is the cough’s
total absence once the patient is asleep.15,17–19 Habit cough has continued to be
described in this manner since the Berman publication in 1966,15 sometimes
with different terminology but with the same presenting characteristics.15,17–22
Variations seen in one series found about 10% with a softer cough manifested
by a repetitive throat-clearing sound.18

765
Chapter 44—Functional Respiratory Disorders
Figure 44-1. Description of habit cough

in a 1694 medical book.
The median age of children with habit cough at several centers has been about
10 years with a range from 4 to 18 years.18,19 The prevalence of habit cough
at major referral centers has been an average of 9 per year at the University
of Iowa18 from 2003 to 2014 and 9 per year over 6 years at the Brompton
Hospital in London, England.19 The variable cough presentation can be seen
and heard at https://www.youtube.com/watch?v=U7p2B_Zt6AM.
The diagnosis of habit cough is based on the unique presentation of the daily
repetitive cough that is absent once asleep. None of the other causes of chronic
cough in Table 44-1 have that characteristic presentation. Other proposed
causes of chronic cough are sinusitis,23 postnasal drip (aka upper airway cough
syndrome),24,25 and gastroesophageal reflux,26,27 all of which diminish as legiti-
mate causes of chronic cough when critically examined. Although asthma
sometimes presents with cough, it rarely mimics the repetitive cough of
habit cough that is absent during sleep. Moreover, a short course of an oral
corticosteroid can readily distinguish the steroid-responsive cough of
asthma from the habit cough.28 (See also Chapter 12, Asthma.)
Various forms of suggestion therapy have been used to treat habit cough.15,18,22,29
Suggestion therapy was used most extensively over a 40-year period at the
University of Iowa Pediatric Allergy & Pulmonary Clinic.19 A guide to the
15-minute session commonly used is in Box 44-1. A demonstration of the
method is available at www.habitcough.com. The prognosis for habit cough
with suggestion therapy is good, with long-term remission in most cases.
Absence of a specific treatment plan can result in prolonged symptoms. In a
report from Mayo Clinic (Rochester, MN), 44 of 60 patients diagnosed with
habit cough required an average of 6 months beyond the diagnosis for sponta-
neous resolution, and 16 continued to be symptomatic for a mean duration of
5.9 years.30 A report from the Brompton Hospital looked at the outcome from
reassurance alone. Cough subsequently resolved in 59% of patients within
4 weeks but persisted, on average, significantly longer when the parents were
skeptical or did not accept the diagnosis.19 In contrast, the cough can be abated
after about 15 minutes of suggestion therapy, with residual symptoms fading
over the next few days or weeks.

766
CASE REPORT 44-1

D.J. is a 12-year-old boy who is brought to your office by his mother with a
complaint of cough for 3 months without systemic symptoms. A trial of inhaled
corticosteroid and a short-acting bronchodilator have not produced improve-
ment. The cough is present throughout the waking hours. It is not present once
he is asleep. It is disruptive of activities, including school; he had been sent home
multiple times. Your examination findings are normal except for a dry, harsh,
“honking” cough. The referring physician had performed chest radiography,
sinus radiography, and spirometry. Are all normal.
Comment: The presentation is diagnostic of the habit cough syndrome. While
the chest radiograph and spirometry were reasonable, though not essential,
to ensure there is no other explanation for the cough, the sinus radiograph is
not indicated since it will provide neither positive nor negative information.23,31
The indicated treatment is suggestion therapy, which was associated with a
95% success rate among 85 children seen at the University of Iowa Pediatric
Allergy & Pulmonary Clinic by 6 clinicians.18
Box 44-1
Guide for Suggestion Therapy Treatment of Habit Cough
ū Express confidence, communicated verbally and behaviorally, that the therapist
will be able to show the patient how to stop the cough.
ū Explain the cough as a vicious cycle of an initial irritant, now gone, that had set
up a pattern of coughing that caused irritation and further symptoms.
ū Encourage suppression of the cough to break the cycle. The therapist closely
observes for the initiation of the muscular movement preceding coughing and
immediately exhorts the patient to hold the cough back, emphasizing that each
second the cough is delayed makes further inhibition of cough easier.
ū An alternative behavior to coughing is offered in the form of inhaling a generat-
ed mist or sipping body-temperature water with encouragement to inhale the
mist or sip the water every time the patient begins to feel the urge to cough.
ū Repeat expressions of confidence that the patient is developing the ability to
resist the urge to cough.
ū When some ability to suppress cough is observed (usually after about
10 minutes), ask in a rhetorical manner if the patient is beginning to feel
that they can resist the urge to cough (eg, “You’re beginning to feel that
you can resist the urge to cough, aren’t you?”).
ū Discontinue the session when the patient can repeatedly answer positively
to the question, “Do you feel that you can now resist the urge to cough on
your own?” This question is only asked after the patient has gone 5 minutes
without coughing.
ū Tell the patient that what we just did can be done by the patient on their own
at home.
Reprinted from Lokshin B, Lindgren S, Weinberger M, et al. Outcome of habit cough in children treated
with a brief session of suggestion therapy. Ann Allergy. 1991;67(6):579–582. Copyright © 1991, with
permission from Elsevier.

767
Habit Throat Clearing

Habit throat clearing appears to be related to the habit cough syndrome. Of
140 children diagnosed with the habit cough syndrome over a 20-year period at
the University of Iowa, a repetitive, softer throat-clearing sound rather than the
more typical barking cough was the presenting symptom in 10% of the patients;
11% exhibited both the barking cough and the softer throat-clearing patterns of
coughing.18 Habit throat clearing has been attributed by some to gastroesopha-
geal reflex (GER). However, an association of GER and habit throat clearing
was not found in 186 patients referred for possible GER disease who underwent
consecutive ambulatory impedance studies.32 Response to suggestion therapy
was as effective in these patients as in those with the harsh barking cough.
Habit Sneezing
Habit sneezing is a much less common disorder than the habit cough syn-
drome, but there have been a substantial number of case reports. In the oldest
reported case, a 40-year-old woman had repetitive sneezing that was even-
tually stopped by suggestion.33 Two case reports in children were published
(8- and 10-year-old girls).34 Both children experienced severe repetitive
sneezing multiple times per minute that was absent once asleep. Habit
sneezing generally appears more as a cough through the nose than a true
sneeze. There is no mucus excretion; it is essentially a dry sneeze. As with
habit cough, a precipitating factor is likely to have been present (an irritant
in the case of the 40-year-old woman). In a 9-year-old girl observed by one of
this chapter’s authors, the initiating factor was a bug up her nose. Suggestion
therapy similar to that used for habit cough was rapidly effective.
Functional Causes of Dyspnea

Dyspnea is the subjective experience of uncomfortable breathing that can
vary in quality and intensity. Dyspnea can occur for many reasons (Box 44-2).
Pulmonary, cardiac, and neuromuscular disorders can cause dyspnea when they
decrease appropriate ventilation and gas exchange. Functional disorders asso-
ciated with dyspnea are those that have no physiologic basis.35 Dyspnea is also
perceived during hyperventilation attacks that involve a medically unexplained
Box 44-2
Causes of Dyspnea
Physiologic Dyspnea Functional Dyspnea
Bronchospasm from asthma Vocal cord dysfunction
Obstructive pulmonary disease Hyperventilation
Restrictive pulmonary disease Exertional dyspnea
Cardiac abnormalities Dyspnea perception
Anemia without physical correlate

768
increase in a normal function (breathing). Functional dyspnea can also occur

without any physiologic dysfunction.
Vocal cord dysfunction (VCD) has an anatomic component, but the cause of
that anatomic component is functional in that there is no organic reason for
the dysfunction. Normal functions of the vocal cords include protection of the
airway by adduction to prevent aspiration, permitting unrestricted flow of air
into the lungs by abduction, and speech. The movement of the vocal cords is
controlled by the intrinsic laryngeal muscles. All intrinsic laryngeal muscles
except the cricothyroid muscle are innervated by the recurrent laryngeal
nerves, which are branches of the vagal nerves.36 Although much of the
function of the vocal cords is reflexive and automatic, they must interact with
volitional control at higher levels of the central nervous system. The precise
interactions between cortical and subcortical control systems and reflexive
pattern generators are essential for normal laryngeal function.
Dyspnea occurs with VCD when the dysfunction results in airway obstruc-
tion at the level of the larynx. That occurs because there is failure of the
vocal cords to open and allow air to enter the lungs during inspiration.
Essentially, the complex interaction of the vagal and central nervous system
goes awry. There are 2 physiologic abnormalities of VCD: adduction of
the vocal cords during inspiration and persistent adduction during both
inspiration and expiration. Videos of both are available for viewing at
https://www.milesweinberger.com/copy-of-exercise-induced-dyspnea.
The most common abnormality is adduction of the vocal cords during inspira-
tion. The vocal cords should abduct to permit free flow of air during inspira-
tion. Adduction during inspiration is essentially a paradoxical movement of
the vocal cords, causing stridor on inspiration and dyspnea because of
Figure 44-2. Spirometry before and after exercise

of a 15-year-old girl showing a marked decrease in the
inspiratory portion of the flow-volume loop in asso-
ciation with dyspnea and an inspiratory wheeze-like
sound (technically a high-pitched stridor; see video
with audio at https://www.milesweinberger.com/
copy-of-exercise-induced-dyspnea).
From Weinberger M, Abu-Hasan M. Pseudo-asthma: when
cough, wheezing, and dyspnea are not asthma. Pediatrics.
2007;120(4):855–864.

769
increased resistance to airflow on inspiration. Spirometry shows marked

flattening of the inspiratory portion of the flow-volume loop as a result of
marked obstruction to airflow only during inspiration (Figure 44-2).37
Persistent adduction during both inspiration and expiration results in inter-
ference of airflow to and from the lungs during both phases of respiration,
causing stridorous sounds on both phases (Figure 44-3).37 Because of the
persistent decrease in airflow throughout the whole respiratory cycle, dyspnea
is much more severe and alarming when there is persistent adduction.
A report in adults indicated a third pattern where adduction occurs only on ex-
piration.38 That has not been reported in children. An American Thoracic Society
podcast discussing how dyspnea from vocal cord dysfunction can be distiguished
from other causes of dyspnea can be heard at https://www.thoracic.org/about/
ats-podcasts/evaluation-and-management-of-vocal-cord-dysfunction.php.
There are 2 distinct phenotypes of vocal cord dysfunction. Some patients have
VCD limited to being exercise-induced (EIVCD). Others have spontaneously
occurring vocal cord dysfunction (SVCD) that may or may not occur also with
exercise.39 The latter (SVCD) is more distressing to the patient since there is
not a predictable trigger for the disorder. Speech therapy by skilled speech
pathologists is reported to have been effective in enabling those with SVCD
to control the problem.40
The use of speech therapy has also been reported for EIVCD, but the prac-
ticality of that during competitive activity raises questions of its actual value.
Based on the vagal innervation of the vocal cords,39 a trial of an anticholinergic
aerosol, ipratropium metered-dose inhaler, has been used prior to planned
exercise with success in preventing EIVCD.37 Evidence that vagal stimulation
can cause abnormal function of the vocal cords provides further rationale for
Figure 44-3. Spirometry before and after the

spontaneous onset of dyspnea in a 14-year-old girl
showing marked decrease in both the inspiratory
and expiratory portion of the flow-volume loop in
association with an inspiratory wheeze-like sound
(technically a high-pitched stridor on inspiration)
and a monophonic wheeze on expiration (see video
with audio at https://www.milesweinberger.com/
copy-of-exercise-induced-dyspnea).
From Weinberger M, Abu-Hasan M. Pseudo-asthma:
when cough, wheezing, and dyspnea are not asthma.
Pediatrics. 2007;120(4):855–864.

770
this approach.41,42 While not subjected to a controlled clinical trial, multiple

patients with well-documented EIVCD have experienced effective blocking
of their paradoxical vocal cord movement.37,40
Extended follow-up in 28 patients with VCD found 26 patients asymptomatic
when contacted a median of 5 months (range of 1 week to 5 years) after
the evaluation and diagnosis.39 Two of 17 patients with EIVCD were still
using ipratropium metered dose inhaler prior to exercise for prevention. All
11 patients with SVCD were no longer having VCD symptoms when contacted.
An imitator of EIVCD is exercise-induced laryngomalacia (EIL).43 In some
cases, this may be a residuum of infantile laryngomalacia.44 Inspiratory stridor
occurs in patients with EIL only when vigorous exercise results in sufficient
air movement to invaginate the arytenoids or pull down the epiglottis over the
airway, depending on the specific anatomy.45 When exercise testing identifies
upper airway obstruction, visualization is necessary to distinguish EIVCD
from the much less common EIL.46 The treatment of EIL, if needed, is
supraglottoplasty (Figure 44-4).47,48
In summary, VCD can occur with paradoxical vocal cord adduction during
inspiration instead of the normal abduction. Some will have persistent adduc-
tion during inspiration and expiration. VCD can be limited to occurring only
Figure 44-4. A. Laryngomalacia with

obstruction by invaginated arytenoid
induced by high airflow during aerobic
exercise. B. Laryngoplasty repair.
Reprinted from Arora R, Gal TJ, Hagan LL. An unusual
case of laryngomalacia presenting as asthma
refractory to therapy. Ann Allergy Asthma Immunol.
2005;95(6):607–611. Copyright © 2005, with

771
with exercise or can occur spontaneously. While these are often distinct
phenotypes, some patients will manifest both SVCD and EIVCD. Speech
therapy can provide the patient with SVCD with the ability to stop VCD
when it occurs. Pre-exercise treatment with an anticholinergic appears to be
an effective prevention for EIVCD. A high rate of natural resolution occurs
for both forms of VCD.
Exertional Dyspnea Other Than EIVCD

Physicians may be predisposed to attribute exertional dyspnea to asthma
because it is a common cause. However, in the absence of other symptoms
of asthma, present or past, it is unlikely to be the cause of exercise-induced
dyspnea (EID). Even in the presence of a modest degree of measurable
exercise-induced bronchospasm (EIB), EID does not necessarily warrant
a diagnosis of asthma. EIB is a pathophysiological response that can be
measured using lung function testing. Exercise-induced asthma (EIA), on
the other hand, is a clinical diagnosis based on demonstration of EIB as the
cause of EID. This issue was demonstrated by Burnett et al49 who reported
an EIB prevalence of 43% in college athletes, most having no dyspnea or any
respiratory symptoms. This raised the question of the clinical relevance of
a modest degree of EIB in the absence of dyspnea on exertion or other
symptoms of asthma.50
Evaluation of exercise-induced dyspnea first warrants a trial of pre-exercise
use of a bronchodilator, such as albuterol. The complete and reliable pre-
vention of exercise-induced dyspnea supports the diagnosis of asthma. The
absence of complete and reliable prevention does not justify any other attempts
at asthma pharmacotherapy. Instead, if there is minimal or no improvement in
dyspnea from a trial of albuterol, alternative diagnoses should be considered,
and cardiopulmonary exercise testing is needed to identify other causes
of EID.46
Of 117 children and adolescents referred to the pulmonary clinic at the
University of Iowa Children’s Hospital because of EID, 100 had been pre-
viously diagnosed with asthma. They were referred because they had not
responded to usual treatment for EIA. Symptoms were reproduced during
exercise testing and the etiology identified. Although most of the patients
previously had been diagnosed with asthma, only 11 could be demonstrated
to have EIA. Other diagnoses associated with reproduced EID included vocal
cord dysfunction in 13 patients, laryngomalacia in 2 patients (1 of whom had
unilateral vocal cord paralysis), exercise-induced hyperventilation in 1 patient,
and supraventricular tachycardia in 1 patient. Restrictive abnormalities sug-
gestive of a minor degree of chest wall stiffness were seen in 15 patients.
Seventy-four of those 117 patients demonstrated only normal physiologic
exercise limitation; 48 of these 74 had normal to high cardiovascular
conditioning, and 26 had poor conditioning (Figure 44-5).51

772
11
13
EIB
VCD
Restrictive
EIL
15
EIH
EISVtach
74 Physiologic
2
1
1
Figure 44-5. The diagnoses among 117 sequential children and adolescents evaluated
for exercise-induced dyspnea. Diagnoses determined by treadmill exercise testing with
physiologic monitoring.
Abbreviations: EIB, exercise-induced bronchospasm; EIH, exercise-induced hyperventilation; EIL, exercise-
induced laryngomalacia; EISVtach, exercise-induced supraventricular tachycardia; Physiologic, normal
physiologic limitation without other abnormality; Restrictive, apparent restriction of chest wall movement;
VCD, vocal cord dysfunction.
From Weinberger M, Abu-Hasan M. Pseudo-asthma: when cough, wheezing, and dyspnea are not asthma.
Pediatrics. 2007;120(4):862; with permission. Original data from Abu-Hasan M, Tannous B, Weinberger M.
Exercise-induced dyspnea in children and adolescents: if not asthma then what? Ann Allergy Asthma Immunol.
2005;94(3):366–371.
Normal physiologic exercise limitation occurs when lactic acidosis increases

during anaerobic metabolism, resulting in an attempt to compensate for this
metabolic acidosis by increasing ventilation to create respiratory alkaloses.
However, this increased respiratory drive occurs when maximal ventilation
already has been reached. That is associated with a low pH that cannot be
compensated by a respiratory alkalosis from further increasing ventilation.
That causes progressive dyspnea, which is interpreted by even some well-
conditioned children and adolescents as pathologic rather than normal
physiologic limitation. Successful athletes in aerobic sports learn to adjust
their activity when necessary to maintain a maximal tolerated level that
may be increased with further conditioning. The treatment is counseling to
explain the physiology of exercise so that the patient understands the etiology
of their dyspnea and the necessity of pacing in addition to conditioning.
Dyspnea Without Physiologic Correlates

Although not associated with physiologic abnormality, a patient’s perception
of dyspnea may still be troublesome. The sensation of dyspnea is stronger in
patients with anxiety and has been reported in patients with anxiety disorders

773
in the absence of cardiopulmonary disease.52 These observations demonstrate

the importance of cerebral cognition in this complex symptom. Patients
with this disorder have been misdiagnosed as having asthma and treated
as such. Once recognized by a physician, treatment of the anxiety is the
appropriate measure.
Dysfunctional Breathing
Hyperventilation
Hyperventilation refers to an increase in alveolar ventilation in excess of
metabolic needs. That can result in respiratory alkalosis with a reduction in
arterial partial pressure of carbon dioxide below the normal range for age
(Paco2 < 4.66 kPa [< 35 mm Hg]) and a consequent rise in pH above 7.4. The
resulting respiratory alkalosis with its effect on calcium ionization causes
feelings of light-headedness, numbness, or tingling periorally and on the
fingers or toes. It can progress to carpopedal spasm.
While some drug overdoses, such as aspirin, can create increased ventilation,
which can also occur from metabolic disorders (eg, Kussmaul breathing during
diabetic ketoacidosis), the details of those are beyond the scope of this publica-
tion. Hyperventilation in children typically presents as a spontaneous event
related to anxiety, panic, nervousness, or stress. The term “acute hyperventi-
lation” is used to describe these brief episodes, which can occur in children
and adults. Chronic hyperventilation is a documented entity in adults but not
described in the pediatric population.53 Hyperventilation can be associated just
with anxiety or can be a part of a panic attack. There is characteristically an
abrupt onset of intense fear or discomfort that reaches a peak within minutes.
Symptoms can include palpitations, sweating, and trembling along with the
sensation of dyspnea that provokes the hyperventilation.54 Somatic complaints
can also occur.55
On examination, children and adolescents appear anxious or distressed with
usually rapid deep breathing that can involve the use of accessory muscles
of respiration. The apparent increased work of breathing and description by
the patient that they are experiencing air hunger can cause a misdiagnosis of
asthma. Lower airway sounds are unusually clear with absence of the poly-
phonic wheezes that characterize asthma. The presence of a normal pulse
oximetry, 95% or greater, is reassuring to the examiner encountering this
patient. A blood gas (capillary or venous is adequate) can confirm hyperventi-
lation if the pH is high and the Pco2 is low.
Immediate treatment of acute hyperventilation can include rebreathing into
a bag. That increases the Pco2, decreases the pH, and thereby eliminates
symptoms caused by the alkalosis. Reassuring and calming the patient can
further decrease the anxiety and fear associated with an anxiety-induced panic

774
attack. For a patient prone to have such episodes, counseling and explaining
what is being felt are essential so that future episodes are not mistaken for
acute asthma or some other illness.
Repetitive Sighing
Sighing is a normal activity, sometimes as an expression of relief. It involves
taking a deep inspiration followed by exhalation and a subsequent normal
breathing pattern. Repetitive involuntary sighing is known as the sighing
syndrome.56 As with other habit disorders, the sighing is absent once asleep.
Anxiety and stress are speculated to be associated. Although one young child
is reported to have sighing associated with asthma,57 another report that
included both adults and children suggested the potential for mistakenly
diagnosing repetitive sighing as asthma.58 When asked why they are sighing,
the common answer is just that they felt more air was needed. While the
syndrome is called sighing dyspnea in some publications, the child with
recurrent sighing generally does not express a feeling of dyspnea. The
sighing occurs most commonly when the patient is quiet, does not interfere
with activity, and does not seem to disturb the child as much as the parent.
This generally appears to be a benign condition that nonetheless disturbs the
parents who bring the child to a physician for evaluation. The child, however,
is often unconcerned and experiencing no distress. No treatment is needed
other than explaining the benignity of this minor functional deviation from
usual respiration. Since it is harmless and generally self-limited, repetitive
sighing generally warrants only benign neglect.
Dysfunctional Breathing Complicating Asthma

Dysfunctional breathing can occur in children with asthma and complicate
the clinical assessment of severity and control of the disease.59–61 However,
dysfunctional breathing seems to occur much less frequently in children
with asthma than in adults with asthma.62 A study of 203 children with
asthma, aged 5 to 18 years, used a Nijmegen Questionnaire63 and related that
to the results of an Asthma Control Questionnaire.64 Although the Nijmegen
Questionnaire is primarily used to assess hyperventilation in adults, the
results demonstrated 5% of children at a specialized asthma clinic had a high
Nijmegen score that correlated with poor asthma control. That suggests that
poor asthma control warrants investigation for dysfunctional breathing.
Breathing retraining has been used for adults with asthma and dysfunctional
breathing with benefit.65 While that has also been suggested as of value for
children with asthma,66 controlled trials have not been performed. Nonethe-
less, poor asthma control justifies observation to determine if the patient’s
symptoms or breathing pattern were disproportionate to the degree of
measured airway obstruction or gas exchange.

775
key points
} Functional respiratory disorders are symptoms without medical explanation.
} Functional respiratory disorders are not diagnoses of exclusion; they are based
on specific characteristics.
} Misdiagnosis results in overtreatment of the symptoms.
} The treatment of functional disorders is behavioral, not pharmacologic.
References
1. Kompare M, Weinberger M. Protracted bacterial bronchitis in young children: association with
airway malacia. J Pediatr. 2012;160(1):88–92 PMID: 21868031 doi: 10.1016/j.jpeds.2011.06.049
2. Weinberger M, Abu-Hasan M. Asthma in the pre-school child. In: Chernick V, Boat TF,
Wilmott RW, Bush A, eds. Kendig’s Disorders of the Respiratory Tract in Children. 8th ed.
Saunders Elsevier; 2012:686–698 doi: 10.1016/B978-1-4377-1984-0.00046-2
3. Eg KP, Mirra V, Chang AB, Santamaria F. Editorial: chronic suppurative lung disease and
bronchiectasis in children and adolescents. Front Pediatr. 2017;5:196 PMID: 28929095
doi: 10.3389/fped.2017.00196
4. Ghezzi M, Silvestri M, Sacco O, et al. Mild tracheal compression by aberrant innominate artery
and chronic dry cough in children. Pediatr Pulmonol. 2016;51(3):286–294 PMID: 26099051
doi: 10.1002/ppul.23231
5. Weinberger M. The habit cough syndrome. Pediatr Allergy Immunol Pulmonol.
2010;23(2):125–129 doi: 10.1089/ped.2010.0019
6. Barger-Kamate B, Deloria Knoll M, Kagucia EW, et al; Pneumonia Etiology Research for Child
Health (PERCH) Study Group. Pertussis-associated pneumonia in infants and children from
low- and middle-income countries participating in the PERCH study. Clin Infect Dis.
2016;63(suppl 4):S187–S196 PMID: 27838672 doi: 10.1093/cid/ciw546
7. Akelma AZ, Cizmeci MN, Kanburoglu MK, Mete E. An overlooked cause of cough in children:
foreign body aspiration. J Pediatr. 2013;163(1):292–293 PMID: 23399450
doi: 10.1016/j.jpeds.2012.12.089
8. Zar HJ, Andronikou S, Nicol MP. Advances in the diagnosis of pneumonia in children. BMJ.
2017;358:j2739 PMID: 28747379 doi: 10.1136/bmj.j2739
9. O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373(9678):1891–1904 PMID:
19403164 doi: 10.1016/S0140-6736(09)60327-5
10. Davis SD, Rosenfeld M, Lee HS, et al. Primary ciliary dyskinesia: longitudinal study of lung
disease by ultrastructure defect and genotype. Am J Respir Crit Care Med. 2019;199(2):190–198
PMID: 30067075 doi: 10.1164/rccm.201803-0548OC
11. Najada A, Weinberger M. Unusual cause of chronic cough in a four-year-old cured by
uvulectomy. Pediatr Pulmonol. 2002;34(2):144–146 PMID: 12112783 doi: 10.1002/ppul.10121
12. Gurgel RK, Brookes JT, Weinberger MM, Smith RJ. Chronic cough and tonsillar hypertrophy: a
case series. Pediatr Pulmonol. 2008;43(11):1147–1149 PMID: 18846560 doi: 10.1002/ppul.20919
13. Mehdi NF, Weinberger MM, Abu-Hasan MN. Achalasia: unusual cause of chronic cough in
children. Cough. 2008;4(1):6 PMID: 18652683 doi: 10.1186/1745-9974-4-6
14. Weinberger M, Lesser D. Diffuse panbronchiolitis: a progressive fatal lung disease that is
easily curable but only if diagnosed! Pediatr Pulmonol. 2019;54:457–462 PMID: 30609307
doi: 10.1002/ppul.24226
15. Berman BA. Habit cough in adolescent children. Ann Allergy. 1966;24(1):43–46 PMID: 5902120
16. Mercuruis F: Habitual cough, in The Spirit of Diseases. Published in 1694. Printed for Sarah
Hawkins in George-Tard, in Lambard-street
17. Lokshin B, Lindgren S, Weinberger M, Koviach J. Outcome of habit cough in children treated
with a brief session of suggestion therapy. Ann Allergy. 1991;67(6):579–582 PMID: 1750719
18. Weinberger M, Hoegger M. The cough without a cause: habit cough syndrome. J Allergy Clin
Immunol. 2016;137(3):930–931 PMID: 26483178 doi: 10.1016/j.jaci.2015.09.002
19. Wright MFA, Balfour-Lynn IM. Habit-tic cough: presentation and outcome with simple
reassurance. Pediatr Pulmonol. 2018;53(4):512–516 PMID: 29363880 doi: 10.1002/ppul.23948

776
20. Kravitz H, Gomberg RM, Burnstine RC, Hagler S, Korach A. Psychogenic cough tic in children
and adolescents. Nine case histories illustrate the need for re-evaluation of this common but
frequently unrecognized problem. Clin Pediatr (Phila). 1969;8(10):580–583 PMID: 5344422
doi: 10.1177/000992286900801009
21. Weinberg EG. ‘Honking’: psychogenic cough tic in children. S Afr Med J. 1980;57(6):198–200
PMID: 7361211
22. Cohlan SQ, Stone SM. The cough and the bedsheet. Pediatrics. 1984;74(1):11–15 PMID: 6739203
doi: 10.1542/peds.74.1.11
23. Campanella SG, Asher MI. Current controversies: sinus disease and the lower airways.
doi: 10.1002/1099-0496(200102)31:2<165::AID-PPUL1025>3.0.CO;2-O
24. Morice AH. Post-nasal drip syndrome—a symptom to be sniffed at? Pulm Pharmacol Ther.
2004;17(6):343–345 PMID: 15564073 doi: 10.1016/j.pupt.2004.09.005
25. Kemp A. Does post-nasal drip cause cough in childhood? Paediatr Respir Rev. 2006;7(1):31–35
PMID: 16473814 doi: 10.1016/j.prrv.2005.11.005
26. Chang AB, Connor FL, Petsky HL, et al. An objective study of acid reflux and cough in
children using an ambulatory pHmetry-cough logger. Arch Dis Child. 2011;96(5):468–472
PMID: 20515960 doi: 10.1136/adc.2009.177733
27. Chang AB, Lasserson TJ, Gaffney J, Connor FL, Garske LA. Gastro-oesophageal reflux
treatment for prolonged non-specific cough in children and adults. Cochrane Libr.
2011;(1):CD004823 PMID: 21249664 doi: 10.1002/14651858.CD004823.pub4
28. Doan T, Patterson R, Greenberger PA. Cough variant asthma: usefulness of a diagnostic-
therapeutic trial with prednisone. Ann Allergy. 1992;69(6):505–509 PMID: 1471782
29. Anbar RD, Hall HR. Childhood habit cough treated with self-hypnosis. J Pediatr.
2004;144(2):213–217 PMID: 14760264 doi: 10.1016/j.jpeds.2003.10.041
30. Rojas AR, Sachs MI, Yunginger JW, O’Connell EJ. Childhood involuntary cough syndrome:
a long-term follow-up study [abstract]. Ann Allergy. 1991;66:106
31. Weinberger M. Whither sinusitis? Clin Pediatr (Phila). 2018;57(9):1013–1019 PMID: 29562756
doi: 10.1177/0009922818764927
32. Abdul-Hussein M, Khalaf M, Castell D. Throat clearing, frequently reported, but is it GERD
related? J Clin Gastroenterol. 2018;52(10):869–872 PMID: 29356788
doi: 10.1097/MCG.0000000000000985
33. Shilkret HH. Psychogenic sneezing and yawning. Psychosom Med. 1949;11(2):127–128
PMID: 18131121 doi: 10.1097/00006842-194903000-00007
34. Lin TJ, Maccia CA, Turnier CG. Psychogenic intractable sneezing: case reports and a review of
treatment options. Ann Allergy Asthma Immunol. 2003;91(6):575–578 PMID: 14700443
doi: 10.1016/S1081-1206(10)61537-2
PMID: 15801248 doi: 10.1016/S1081-1206(10)60989-1
36. Nishino T. Physiological and pathophysiological implications of upper airway reflexes in
humans. Jpn J Physiol. 2000;50(1):3–14 PMID: 10866692 doi: 10.2170/jjphysiol.50.3
37. Weinberger M, Doshi D. Vocal cord dysfunction: a functional cause of respiratory distress.
Breathe (Sheff). 2017;13(1):15–21 PMID: 28289447 doi: 10.1183/20734735.019316
38. Newman KB, Mason UG III, Schmaling KB. Clinical features of vocal cord dysfunction.
Am J Respir Crit Care Med. 1995;152(4 Pt 1):1382–1386 PMID: 7551399
doi: 10.1164/ajrccm.152.4.7551399
39. Doshi DR, Weinberger MM. Long-term outcome of vocal cord dysfunction. Ann Allergy Asthma
Immunol. 2006;96(6):794–799 PMID: 16802766 doi: 10.1016/S1081-1206(10)61341-5
40. Christopher KL, Wood RP II, Eckert RC, Blager FB, Raney RA, Souhrada JF. Vocal-cord
dysfunction presenting as asthma. N Engl J Med. 1983;308(26):1566–1570
PMID: 6406891 doi: 10.1056/NEJM198306303082605
41. Zalvan C, Sulica L, Wolf S, Cohen J, Gonzalez-Yanes O, Blitzer A. Laryngopharyngeal
dysfunction from the implant vagal nerve stimulator. Laryngoscope. 2003;113(2):221–225
PMID: 12567072 doi: 10.1097/00005537-200302000-00005
42. Ardesch JJ, Sikken JR, Veltink PH, van der Aa HE, Hageman G, Buschman HPJ. Vagus nerve
stimulation for epilepsy activates the vocal folds maximally at therapeutic levels. Epilepsy Res.
2010;89(2-3):227–231 PMID: 20129758 doi: 10.1016/j.eplepsyres.2010.01.005
43. Arora R, Gal TJ, Hagan LL. An unusual case of laryngomalacia presenting as asthma refractory
to therapy. Ann Allergy Asthma Immunol. 2005;95(6):607–611 PMID: 16400903
doi: 10.1016/S1081-1206(10)61026-5

777
44. Hilland M, Røksund OD, Sandvik L, et al. Congenital laryngomalacia is related to exercise-
induced laryngeal obstruction in adolescence. Arch Dis Child. 2016;101(5):443–448
45. Smith RJ, Bauman NM, Bent JP, Kramer M, Smits WL, Ahrens RC. Exercise-induced
laryngomalacia. Ann Otol Rhinol Laryngol. 1995;104(7):537–541 PMID: 7598366
doi: 10.1177/000348949510400707
46. Bhatia R, Abu-Hasan M, Weinberger M. Exercise-induced dyspnea in children and adolescents:
differential diagnosis. Pediatr Ann. 2019;48(3):e121–e127 PMID: 30874820
doi: 10.3928/19382359-20190219-02
47. Bent JP III, Miller DA, Kim JW, Bauman NM, Wilson JS, Smith RJ. Pediatric exercise-induced
laryngomalacia. Ann Otol Rhinol Laryngol. 1996;105(3):169–175 PMID: 8615579
doi: 10.1177/000348949610500301
48. Heimdal JH, Maat R, Nordang L. Surgical intervention for exercise-induced laryngeal
obstruction. Immunol Allergy Clin North Am. 2018;38(2):317–324 PMID: 29631739
doi: 10.1016/j.iac.2018.01.005
49. Burnett DM, Burns S, Merritt S, Wick J, Sharpe M. Prevalence of exercise-induced
bronchoconstriction measured by standardized testing in healthy college athletes. Respir Care.
50. Weinberger M, Abu-Hasan M. Is exercise-induced bronchoconstriction exercise-induced
asthma? Respir Care. Invited editorial 2016;61:713
51. Weinberger M, Abu-Hasan M. Perceptions and pathophysiology of dyspnea and exercise
intolerance. Pediatr Clin North Am. 2009;56(1):33–48, ix PMID: 19135580
doi: 10.1016/j.pcl.2008.10.015
52. Zealley AK, Aitken RC. Breathlessness and anxiety. BMJ. 1970;2(5705):363 PMID: 5429467
doi: 10.1136/bmj.2.5705.363
53. Herman SP, Stickler GB, Lucas AR. Hyperventilation syndrome in children and adolescents:
long-term follow-up. Pediatrics. 1981;67(2):183–187 PMID: 7243442 doi: 10.1542/peds.67.2.183
54. Moreau D, Weissman MM. Panic disorder in children and adolescents: a review. Am J
Psychiatry. 1992;149(10):1306–1314 PMID: 1530067 doi: 10.1176/ajp.149.10.1306
55. Achiam-Montal M, Tibi L, Lipsitz JD. Panic disorder in children and adolescents with
noncardiac chest pain. Child Psychiatry Hum Dev. 2013;44(6):742–750 PMID: 23378228
doi: 10.1007/s10578-013-0367-9
56. Sody AN, Kiderman A, Biton A, Furst A. Sigh syndrome: is it a sign of trouble? J Fam Pract.
2008;57(1):E1–E5 PMID: 18171560
57. Hayes D Jr, Nance AE, Mansour HM. Sigh syndrome in pediatric asthma. Lung.
2019;197(1):111–112 PMID: 30511251 doi: 10.1007/s00408-018-0184-9
58. Perin PV, Perin RJ, Rooklin AR. When a sigh is just a sigh…and not asthma. Ann Allergy.
1993;71(5):478–480 PMID: 8250354
59. Rietveld S, Everaerd W, van Beest I. Excessive breathlessness through emotional imagery
in asthma. Behav Res Ther. 2000;38(10):1005–1014 PMID: 11004739
doi: 10.1016/S0005-7967(99)00134-5
60. Rietveld S, Prins PJ. The relationship between negative emotions and acute subjective and
objective symptoms of childhood asthma. Psychol Med. 1998;28(2):407–415 PMID: 9572097
doi: 10.1017/S0033291797006387
61. Janson C, Björnsson E, Hetta J, Boman G. Anxiety and depression in relation to respiratory
symptoms and asthma. Am J Respir Crit Care Med. 1994;149(4 Pt 1):930–934 PMID: 8143058
doi: 10.1164/ajrccm.149.4.8143058
62. de Groot EP, Duiverman EJ, Brand PLP. Dysfunctional breathing in children with asthma:
a rare but relevant comorbidity. Eur Respir J. 2013;41(5):1068–1073 PMID: 23018913
doi: 10.1183/09031936.00130212
63. van Dixhoorn J, Duivenvoorden HJ. Efficacy of Nijmegen Questionnaire in recognition of
the hyperventilation syndrome. J Psychosom Res. 1985;29(2):199–206 PMID: 4009520
doi: 10.1016/0022-3999(85)90042-X
64. Juniper EF, Gruffydd-Jones K, Ward S, Svensson K. Asthma Control Questionnaire in children:
validation, measurement properties, interpretation. Eur Respir J. 2010;36(6):1410–1416
PMID: 20530041 doi: 10.1183/09031936.00117509
65. Thomas M, McKinley RK, Freeman E, Foy C, Prodger P, Price D. Breathing retraining for
dysfunctional breathing in asthma: a randomised controlled trial. Thorax. 2003;58(2):110–115
PMID: 12554890 doi: 10.1136/thorax.58.2.110
66. Hepworth C, Sinha I, Saint GL, Hawcutt DB. Assessing the impact of breathing
retraining on asthma symptoms and dysfunctional breathing in children. Pediatr Pulmonol.
2019;54(6):706–712 PMID: 30938089 doi: 10.1002/ppul.24300

PART
9
Genetic Disorders
Chapter 45. Cystic Fibrosis................................................................ 781

Chapter 46. Cystic Fibrosis Newborn Screening and CFTR-

Related Metabolic Syndrome............................................................ 807
Danieli B. Salinas, MD, MS, and Clement L. Ren, MD, MBA
Chapter 47. Primary Ciliary Dyskinesia and Other Genetic Lung

Diseases................................................................................................. 817
Madhuri Penugonda, MD; Nico W. Vehse, MD; Thomas W. Ferkol, MD; and
779
53 PP 2ND ED - PO 09_779-780.indd 779 11/6/23 9:36 AM

53 PP 2ND ED - PO 09_779-780.indd 780 9/12/23 10:31 AM
CHAPTER
45
Cystic Fibrosis
Introduction
Cystic fibrosis (CF) was, in the past, typically described as the most common
lethal genetic disease in the white population, but the outlook for people with
a CF diagnosis has improved dramatically with advancements in treatment,
and new therapies are expected to lead to even greater changes. The US Cystic
Fibrosis Foundation (CFF) median projected survival age in 2019 (before gener-
alized availability of highly effective modulator therapies, described later, in
Management) was 48.4 years (95% CI, 45.9–51.5 years) (Figure 45-1).1 Birth
prevalence varies with racial or ethnic background; CF occurs in approximately
1 in 3,000 white Americans (constituting 93.4% of the US population with CF),
1 in 4,000 to 10,000 Hispanic Americans (9.4% of the US population with CF),
and 1 in 15,000 to 20,000 African Americans (4.7% of the US population with
CF).1 Internationally, the prevalence is quite low (but poorly ascertained)
among the people of Africa, Asia, and Oceania.2
Figure 45-1. Median predicted survival age for people with cystic fibrosis in the United States for
the period from 1989 to 2020 in 5-year increments.
From Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry: 2020 Annual Data Report. Cystic
Fibrosis Foundation; 2021:75. Accessed July 18, 2022. https://www.cff.org/sites/default/files/2021-11/
Patient-Registry-Annual-Data-Report.pdf. ©2021 Cystic Fibrosis Foundation.
781

782
Pathogenesis
Genetics
Cystic fibrosis is an autosomal recessive disease caused by an abnormal gene
on the long arm of chromosome 7. The gene product, called CF transmem-
brane conductance regulator (CFTR), localizes to the apical cell membrane
and regulates ion transport by way of a blend of Na+ absorption and Cl- secre-
tion.3 Although there have been more than 2,000 CFTR mutations identified,
about 50% of patients with CF with a Northern European background are
homozygous for the F508del mutation (involving the deletion of phenylala-
nine, which is normally the 508th amino acid in the protein), and 35% are
compound heterozygous with 1 F508del mutation.1 The mutation frequency
of CFTR varies from population to population, and the F508del is less
common in non-European populations, but no single mutation other than
F508del occurs in a frequency greater than approximately 5%.1
The CFTR mutations have been grouped into 6 classes (Figure 45-2).4 Class I
mutations include nonsense mutations (associated with a premature termina-
tion codon) and splice mutations. Most (but not all) mutations with designa-
tions ending in X, such as G542X, are nonsense mutations. Class II mutations
are protein-processing mutations, wherein a deleted or incorrect amino acid
leads to an abnormal 3-dimensional configuration and failure of the cell to
recognize and traffic the protein to the apical cell surface. This is the class
to which F508del belongs and is therefore by far the most commonly seen
mutation class. Class III mutations, such as G551D, are gating mutations;
CFTR protein localizes to its proper position on the apical cell membrane,
but the chloride channel does not open normally. Class IV mutations, such as
R117H, are conduction mutations, which allow some chloride conduction, but
not enough to allow normal function. Similarly, class V mutations, such as
A455E, allow some, but inadequate, CFTR function because of underproduc-
tion, and class VI mutations produce an unstable protein with a shortened
half-life. Some classification systems combine classes V and VI together.
Class IV, V, and VI mutations are typically associated with enough residual
CFTR activity to allow for normal pancreatic function, and patients with
pancreatic sufficiency tend to have milder pulmonary disease. However, in
any given individual, CFTR mutation is a much better predictor of pancreatic
function than of lung involvement because lung disease is also influenced by
nutritional status, sociodemographic and environmental factors, and varia-
tions in health care interventions to an extent that blurs distinct genotype–
phenotype associations.5 In addition, the presence of gene modifiers
(polymorphisms in non-CFTR genes that control the inflammatory response,
such as mannose-binding lectin, tumor necrosis factor, and alpha-1 antitryp-
sin) may also affect the severity of lung disease in patients with CF.6

783
Chapter 45—Cystic Fibrosis
Figure 45-2. Classes of CFTR mutations. Abbreviations: Cl−, chloride ion; CFTR, cystic fibrosis
transmembrane conductance regulator; mRNA, messenger RNA.
From Harutyunyan M, Huang Y, Mun KS, Yang F, Arora K, Naren AP. Personalized medicine in CF: from
modulator development to therapy for cystic fibrosis patients with rare CFTR mutations. Am J Physiol Lung
Cell Mol Physiol. 2018; 314(4): L529–L543. © 2018 The American Physiological Society.
Pathophysiology
There are several hypotheses regarding how CFTR dysfunction leads to the
phenotypic manifestation of CF, but the most well accepted is the so-called
low volume hypothesis, which holds that a combination of excessive reabsorp-
tion of sodium and deficient chloride secretion, along with passive movement
of water, results in the dehydration of airway surface materials and reduced
airway surface liquid depth.3 This situation in turn leads to a reduction in the
lubricating layer between the epithelium and mucus with compression of cilia
and inhibition of normal ciliary and cough clearance (Figure 45-3). Mucus
adherent to the underlying epithelium forms plaques with hypoxic niches
that can harbor bacteria, particularly Pseudomonas aeruginosa. Recently, an
increased appreciation has developed regarding CFTR’s role as a bicarbonate

784
Mucus layer
PCL layer
Figure 45-3. A, Mechanical clearance via mucus transport provides the primary
innate defense against inhaled bacteria. The promotion of efficient mucus transport
is facilitated by the maintenance of a well-defined periciliary liquid (PCL) layer that
exhibits an optimal height (ie, the height of extended cilia) and viscosity for effective
ciliary beating and cell surface lubrication to clear inhaled organisms. CFTR is key to
this process. B, Absence of CFTR leads to isotonic reduction in the airway surface
liquid, depleting the PCL layer and compromising ciliary function and the system
of mucociliary clearance.
channel and a driver of chloride–bicarbonate exchange, and thus a modifier of

local pH, which leads to mucin abnormalities in the airway, dysbiosis in both
the airway and gastrointestinal tract, and pH dysregulation in the gut.7 There
is also evidence of intrinsic dysregulation of the host inflammatory response.8
Results from lung lavage studies show that inflammation is present in chil-
dren as young as 4 weeks who are apparently free of infection.9
This CFTR dysfunction in the airways thus leads to susceptibility to bronchial
infection. Persistent infection leads to the elaboration of chemotactic cyto-
kines, which recruit large numbers of polymorphonuclear cells into the
airways that necrose and release DNA, leading to increased sputum viscosity;
this process is termed neutrophil extracellular trap formation.10 Bacterial
exotoxins and products of the damaged neutrophils spur further polymorpho-
nuclear cell recruitment, more inflammation, and increased tissue damage.
This vicious cycle of cellular events leads to obstruction and bronchiectasis,
persistence of infection and inflammation, and eventual respiratory failure
(Figure 45-4). Outside of the airway, abnormalities in ion transport cause
decreased water content in pancreatic and male reproductive tract secretions,
leading to ductal obstruction (pancreatic insufficiency [PI] and congenital
bilateral absence of the vas deferens [CBAVD]), decreased pH of the small
intestinal secretions, and excessive salt content of the sweat.

785
Figure 45-4. Pathogenesis of cystic fibrosis. Abbreviations: CF, cystic fibrosis; CFTR; cystic
fibrosis transmembrane conductance regulator.
Clinical Features
Diagnosis
Before the universal adoption of newborn screening (NBS) in the United
States in the late 1990s, the median age at diagnosis was 6 months but the
mean age at diagnosis was 3 years because of the patients whose diagnosis
was missed until late childhood or adulthood. The most common features
leading to diagnosis in the pre-NBS era were respiratory symptoms (50%),
failure to thrive or malnutrition (34%), and steatorrhea or abnormal stools
(26%). Meconium ileus, which is present in about 20% of newborns with CF,
remains an important diagnostic marker of CF. Cystic fibrosis continues to be

786
diagnosed in adults born before NBS; the typical presentation of these patients
includes unexplained chronic bronchitis or bronchiectasis, CBAVD, and
recurrent pancreatitis.11
Cystic fibrosis is diagnosed through the recognition of clinical characteristics,
documentation of CFTR dysfunction, and a search for genetic mutations of
CFTR.12 The sweat test remains the most readily available and clinically use-
ful approach to establishing the diagnosis of CF, provided it is performed at
a laboratory that adheres to strict guidelines using pilocarpine iontophoresis
and a quantitative determination of chloride concentration.13 A sweat chloride
test result greater than 60 mmol/L (60 mEq/L) is almost always diagnostic of
CF. Patients with a sweat chloride test result in the so-called intermediate range
(30–59 for infants younger than 6 months, 40–59 years for older patients) often
have abnormalities in CFTR function and should be referred to an accredited
CF center for further evaluation. Sweat testing is feasible and reliable in patients
by 3 days of age, although it might be more difficult to obtain adequate sweat
in young infants, especially those of low birth weight.14 There are limited
causes of false-negative or false-positive sweat test results, and most of these
are clinically apparent (Box 45-1). In practice, the most common cause of in-
correct sweat test results is poor laboratory proficiency, which is unfortunately
common in laboratories not associated with CFF-accredited care centers.15
Box 45‑1
Conditions Associated With a False-Positive or
False-Negative Sweat Test Result
False positive False negative
ū Atopic dermatitis (eczema) ū Dilution of sample
ū Malnutrition ū Malnutrition
ū Congenital adrenal hyperplasia ū Peripheral edema
ū Mauriac syndrome ū Low sweat rate
ū Fucosidosis (quantity not sufficient)
ū Ectodermal dysplasia ū Hypoproteinemia
ū Klinefelter syndrome ū Dehydration
ū Nephrogenic diabetes insipidus ū CFTR mutations with preserved
sweat duct function
ū Adrenal insufficiency (eg, 3849+10kb CT, R117H-7T)
ū Hypothyroidism
ū Autonomic dysfunction
ū Environmental deprivation
ū Munchausen syndrome by proxy

787
A number of analytic methods for CFTR mutation detection are commercially

available. In general, use of a discrete panel of mutations is faster and less
costly than expanded mutation analysis, and incorporation of approximately
40 of the most frequent disease-associated mutations can help detect more
than 90% of individuals who are affected in most populations. However, the
diagnosis will be missed if the subject is affected by a mutation that is not
included on the panel in use. Full sequence analysis can help detect virtually
all CFTR mutations, but its interpretation is sometimes difficult because
it often uncovers polymorphisms and novel mutations the importance of
which is not known, so genetic testing still requires confirmatory testing
of CFTR dysfunction.12 This confirmatory testing may include sweat test-
ing, nasal transepithelial potential difference measurement, or intestinal
current measurement.16
Although most patients with CF have the classic triad of lung disease, PI, and
a high sweat chloride test result, those with class 4, 5, or 6 mutations may have
milder disease with normal pancreatic function, and a growing number of
people is recognized as having an intermediate condition that has been named
CFTR-related disorder.12 This latter group of patients presents with isolated
male infertility, recurrent pancreatitis, chronic sinusitis, or primary sclerosing
cholangitis and is then found to have evidence of mild CFTR dysfunction and/
or CFTR mutations of unclear clinical significance. Individuals with a
CFTR-related disorder (generally in 1 organ) should be assessed and
followed up by a physician specializing in CF to ensure that any additional
symptoms typical of CF that develop are detected.12,16
There is an analogous group of infants who are found through NBS to have
elevated immunoreactive trypsinogen levels with borderline or normal sweat
chloride levels and CF mutations that are not clearly disease causing. The term
CFTR-related metabolic syndrome (CRMS) has been suggested for use with
this group, allowing appropriate follow-up for complications without consider-
ing these patients as clearly having CF. These patients should be evaluated
at CF centers with expertise and experience with this clinical presentation.17
Chapter 46, Cystic Fibrosis Newborn Screening and CFTR-Related Metabolic
Syndrome, discusses this syndrome in detail.
Cystic fibrosis is a multisystem disorder that primarily affects the respiratory
tract, gastrointestinal tract, sweat glands, and reproductive tract (Box 45-2).
The appearance of CF-related symptoms occurs throughout life, with great
overlap and variability from patient to patient.

788
Box 45‑2
Cystic Fibrosis Is a Multisystem Disordera
ū Respiratory tract
• Sinusitis
• Nasal polyps (3% require surgery)
• Chronic bronchitis
º Bronchiectasis
º Atelectasis
º Pneumothorax (1%)
º Hemoptysis (massive in 2%)
º Respiratory failure
ū Gastrointestinal tract
• Pancreatic insufficiency (92%)
• Meconium ileus (21%)
• Distal intestinal obstruction syndrome (3%)
• Rectal prolapse (4%)
• Biliary obstruction, cirrhosis (6%)
ū Other
• Diabetes mellitus (21% of patients aged 14 years or older)
• Osteoporosis (12% of 18- to 24-year-olds)
ū Reproductive tract
• Congenital bilateral absence of the vas deferens
ū Sweat glands
• Increased chloride content of sweat (99.3%)
a
Prevalence, when given, is from the Cystic Fibrosis Foundation Patient Registry.1
Respiratory Tract Disease

Upper respiratory tract disease, especially chronic sinusitis, is universal
in children with CF and often a cause of considerable morbidity. Extensive
polyposis may be an additional cause of severe nasal obstruction. The patho-
genesis, as in other organ systems, is inspissation of abnormal secretions
because of CFTR dysfunction. Some children with CF require repeated sur-
gical procedures for this problem because sinus disease and polyps almost
invariably recur. Chronic nasal and sinus obstruction is associated with a
high incidence of mouth breathing, and an open-bite malocclusion can occur
as an additional morbidity.
The lungs of children with CF are healthy at birth, but airways quickly
become infected, inflamed, and obstructed in a self-perpetuating cycle
(Figure 45-4). Infection rarely spreads beyond the respiratory tract. Chronic
airway infection is typically established within the first year after birth and

789
Figure 45-5. Prevalence of respiratory microorganisms by age cohort. Abbreviations: B. cepacia

complex, Burkholderia cepacia complex; H. influenzae, Haemophilus influenzae; MRSA,
methicillin-resistant Staphylococcus aureus; P. aeruginosa, Pseudomonas aeruginosa; S. aureus,
Staphylococcus aureus; S. maltophilia, Stenotrophomonas maltophilia.
From Cystic Fibrosis Foundation. 2019 Patient Registry Annual Data Report. Cystic Fibrosis Foundation;
2020:31. Accessed July 13, 2022. https://www.cff.org/sites/default/files/2021-10/2019-Patient-Registry-
Annual-Data-Report.pdf. © 2020 Cystic Fibrosis Foundation.
can be controlled but not eradicated. Chronic bronchitis progressing to ob-

structive lung disease and bronchiectasis is the hallmark of CF lung disease.
Complications of this process include atelectasis due to plugging of segmental
and subsegmental bronchi; pneumothorax due to the development of subpleu-
ral blebs and cysts, which then rupture; and hemoptysis due to bleeding from
hypertrophied bronchial vessels. Pulmonary insufficiency is responsible for
most CF-related deaths.
The conventional view of CF microbiology has traditionally focused on a
limited suite of opportunistic bacterial pathogens, but it is now appreciated
that CF airways (and the gut, as well) typically harbor complex microbial com-
munities that bear on patients’ clinical condition and lung disease progression.18
Although these new insights may alter future clinical treatment of CF, as
of the time of this publication most clinical decisions still derive from our
understanding of aerobic culture results, which follow a fairly typical course
through the life span. Most infants initially harbor Haemophilus influenzae
and/or Staphylococcus aureus; without specific intervention, P aeruginosa
eventually becomes the predominant organism found in the airways.1 Figure
45-5 shows the frequency of different organisms by age. Organisms that play
a clinically significant role include the following:
X H influenzae: This is typically found in infancy, and less often with increas-
ing age.

790
X S aureus: This is also typically found in infancy but often persists through-
out life. Methicillin-resistant S aureus is becoming increasingly prevalent in
the population with CF as in others; data are conflicting regarding whether
its acquisition is associated with worsening lung disease.
X P aeruginosa: This becomes increasingly prevalent as patients get older.
Initially, P aeruginosa grows as a nonmucoid strain that can be cleared
by the host or eradicated with aggressive antibiotic therapy.19 Over time,
P aeruginosa colonies elaborate an alginate coat and form biofilms.20
These biofilms, once established, are difficult if not impossible to clear
with standard antibiotic therapy. There is a pronounced survival benefit for
patients who remain free of P aeruginosa infection, so close surveillance
for new acquisition of P aeruginosa is standard practice, combined with
strategies to eradicate early P aeruginosa infection (discussed later in
this chapter under Pulmonary Therapies: Infection).19
X Stenotrophomonas maltophilia: This is a relatively resistant organism that
has not been associated with acceleration of lung disease.21
X Alcaligenes xylosoxidans: This is another relatively resistant organism for
which the disease course is less clear.
X Burkholderia cepacia: This is an uncommon organism that uniquely infects
patients with CF and has worrisome implications because it is innately
multiresistant, can cause fulminant disease, and is transmissible. Infec-
tion with B cepacia can cause a rapid decrease in pulmonary function
and increased mortality in patients with CF. Occasionally, infection with
B cepacia can cause an invasive, fatal bacteremia, the so-called cepacia
syndrome. Burkholderia cenocepacia is particularly transmissible and
is associated with a striking deterioration in health, perhaps because of
its ability to elicit a more robust inflammatory response from host cells.
However, other B cepacia strains can also be transmitted from person to
person and quickly lead to deterioration, highlighting the need for effective
infection control at all CF centers.22
X Nontuberculous mycobacteria (also see Chapter 24, Nontuberculous
Mycobacteria): Mycobacterium avium complex and Mycobacterium
abscessus are the most common species found in patients with CF, and the
prevalence increases from about 10% in children to 30% in adults older
than 40 years. It is not always clear whether recovery of these organisms
from a patient’s sputum indicates true infection or only saprophytic
colonization, but patients with persistently positive sputum smears or
cultures should be monitored closely for development of worsening disease
and treated as described in recommended protocols.23
X Fungi: An intense hypersensitivity response to Aspergillus fumigatus,
known as allergic bronchopulmonary aspergillosis (ABPA), is seen in

791
1% to 15% of patients with CF, the incidence varying with geography.

Allergic bronchopulmonary aspergillosis classically manifests as wheez-
ing, pulmonary infiltrates, and central bronchiectasis, but these clues
might be obscured by the background of more typical CF lung disease.
Diagnostic criteria for ABPA include acute or subacute clinical deteriora-
tion, total serum immunoglobulin E concentration greater than 500 IU/mL
(1,200 ng/mL), immediate cutaneous reactivity to Aspergillus, and either
(a) precipitins to A fumigatus or immunoglobulin G antibody to A fumiga-
tus or (b) abnormalities on chest radiographs or computed tomography
scans that have not cleared with standard antibiotic therapy (also, see
Chapter 9, Allergic Bronchopulmonary Aspergillosis).24 There is some
speculation that A fumigatus may cause progression of lung disease in the
absence of ABPA and that other fungi such as Candida species and
Scedosporium may be pathogenic; however, this speculation remains
unproved and is an area of controversy and disagreement.25
Gastrointestinal Tract
Approximately 21% of infants with CF are born with meconium ileus, an
obstructive phenomenon secondary to inspissated material in the small and
large bowels. More than 90% of people with CF develop PI, which is usually
present at birth but may evolve during the first year after birth. Pancreatic
dysfunction is due to obstruction of intrapancreatic ducts with thickened
secretions. Typical signs of PI are steatorrhea, flatulence, abdominal bloating,
and poor weight gain. Pancreatic insufficiency leads to fat-soluble vitamin
deficiency and malnutrition. Abnormal intestinal secretions, malabsorption,
and decreased gut motility can lead to distal intestinal obstruction syndrome
and/or chronic constipation in older patients.26 Poor absorption of fat-soluble
vitamins (A, D, E, and K) can lead to acrodermatitis, anemia, neuropathy,
night blindness, osteoporosis, and bleeding disorders.
Patients with CF are at risk of developing focal biliary cirrhosis due to
obstruction of the intrahepatic bile ducts. Clinically apparent cirrhosis is
seen in about 5% of patients; it may manifest in infancy and usually is noted
by age 15 years.26
Reproductive Tract
The vas deferens is exquisitely sensitive to CFTR dysfunction. Virtually all
men with classic CF have azoospermia and are infertile due to CBAVD,
which can occur in men with only 1 CFTR mutation and no other manifesta-
tions of CF.27 Women with CF have cervical mucus abnormalities, but the
primary determinant of fertility is their overall health and nutritional status.
Results from older studies suggested that pregnancy led to worsening lung
disease in women with CF, but results from more recent studies show that
women who have adequate nutritional and pulmonary reserve can do quite
well with pregnancy, although they are more likely to develop diabetes.28

792
Other Common Manifestations

CF-Related Diabetes
As patients with CF age, the pancreas undergoes autolysis and fatty replace-
ment with loss of insulin-producing islet cells. When a sufficient proportion of
islet cells is no longer functional, the patient develops insulin insufficiency
and carbohydrate intolerance. This CF-related diabetes (CFRD) is a separate
entity encompassing characteristics of both type 1 and type 2 diabetes mellitus.
Several factors unique to CF affect glucose metabolism, including elevated
energy expenditure, acute and chronic infection, glucagon deficiency, liver
dysfunction, decreased intestinal transit time, and increased work of breathing.
Clinically apparent CFRD is increasingly common after the first decade of
life; the prevalence is more than 30% in adults.1 The onset of CFRD seems
to lead to worsening of both nutritional status and lung disease, and female
patients with diabetes have poorer survival than do male patients.29 Annual
screening with fasting blood glucose and oral glucose tolerance tests should
be performed in all patients with CF who are aged 10 years or older.30
Osteoporosis
Osteoporosis secondary to vitamin D deficiency, chronic systemic inflamma-
tion, and intermittent corticosteroid use is increasingly being recognized as a
complication of CF. Osteopenia starts in childhood but generally manifests in
adulthood. Bone resorption exceeds bone formation even in patients with CF
who are well nourished and clinically stable.31
Anxiety and Depression
Increasing attention has been paid to the high prevalence of mental health
disorders in people with CF, especially anxiety and depression. Although
a direct link to CFTR dysfunction has not been ruled out, this anxiety and
depression is most likely due to the heavy treatment burden involved in the
overall challenge of living with a lifelong chronic disease. Estimates of the
prevalence of both anxiety and depression in people with CF and caregivers
of children with CF range between 10% and 30%.32 Depression, in particular,
has been associated with decreased ability to maintain daily therapies, worse
lung function and quality of life, and decreased survival.33
Management
The dramatic improvements in life expectancy and quality of life for people
with CF over recent decades have come about largely because of an increased
appreciation of the importance of maintaining adequate nutrition and an
anticipatory and aggressive approach to controlling chronic airway infection,
combined with several new treatment modalities. The benefit of a proactive
approach to CF care has been borne out by repeated observations that improved
outcomes result from CF center practices associated with increased clinic visits

793
and clinical monitoring and more proactive use of antibiotics, nutritional

interventions, and hospitalization.34–37
Furthermore, a historic technological breakthrough has led to the development
of a new class of medications, CFTR modulator drugs (discussed later in this
section under Pulmonary Therapies: Abnormal CFTR), that appear poised to
begin a massive paradigm shift in the treatment and outcomes of CF. Before the
introduction of this medication class, all CF treatment was directed at the down-
stream effects of CFTR dysfunction. Going forward, we will be treating
patients in whom that dysfunction has been reversed, so it is not clear how
many of the previous standard treatments will be necessary. Patients will still
be dealing with the residual consequences of the disease process as it previously
manifested, such as bronchiectasis, but not the continuing disease progression
resulting from ongoing CFTR dysfunction. However, as of the time of this
writing, nearly 10% of the current population with CF have CF mutations that
will not benefit from currently available CFTR modulator drugs, and a small
percentage of those with eligible mutations are unable to tolerate those therapies
for various reasons, so the continued use and refinement of so-called down-
stream therapies will remain essential for the foreseeable future.
Nutritional Therapies
The benefits of maintaining good nutrition in regard to long-term survival
and lung health are well established,38 making nutritional support an integral
component of disease management from early infancy. Pancreatic enzyme
therapy should be prescribed for patients with PI either on clinical grounds
(steatorrhea, failure to thrive) or as documented by low human fecal elastase-1
levels.39 The dosage is titrated to minimize fat malabsorption and is standard-
ized according to the lipase activity of the enzyme preparation. The typical
dose is between 1,500 and 2,500 U of lipase per kilogram of body weight at
each meal and snack. Very high doses (> 6,000 U/kg) have been associated
with a rare complication, fibrosing colonopathy. Pancreatic enzyme prepara-
tions are not completely acid stable, and patients who appear to need rela-
tively high doses will also commonly use a proton pump inhibitor or
H2-receptor antagonist to suppress gastric acidity. The CFF guidelines
recommend fat-soluble vitamin supplementation for all patients with PI.39
Vitamin D deficiency in particular is common. Infants with CF can be safely
breastfed, and this form of feeding may confer lifelong benefits.40 Height,
weight, and body mass index should be measured at every CF clinic visit, and
patients with a decrease in these parameters should receive nutritional
counseling and other interventions. Given the strong correlation between
nutritional status and pulmonary function, attention to nutritional well-being
should be considered one of the cornerstones of good lung health in patients
with CF, and enteral supplements (administered orally or via gastrostomy tube)

794
should be strongly considered in any patient with less than optimal growth.
Patients with CF can and should be expected to maintain a body mass index
near the 50th percentile for age. However, success at achieving good weight
gain has led to an increasing prevalence of overweight and obesity, especially
in patients with pancreatic sufficiency and those on highly effective modulator
therapy, so previous blanket encouragement of a high-calorie and high-fat diet
needs to be moderated in some patients.41
Pulmonary Therapies
Airway infection and inflammation generally begin in the first year after
birth, often in the absence of any signs or symptoms. Conventional pulmonary
function testing is not sensitive to these early changes, and the average FEV1
at 5 years of age is 100% predicted. The early institution of a number of pre-
ventive and aggressive therapeutic strategies slows the progression of sympto-
matic lung disease. The effects of treatment beginning in infancy can be seen
via magnetic resonance imaging or computed tomography and measurement
of lung clearance index (multiple-breath washout), but these are primarily
used in research studies rather than in clinical practice.42 The interventions
to counter progression of lung disease can be associated with each of the
pathophysiological steps shown in Figure 45-4.
Abnormal Gene
The promise of gene therapy, which engendered substantial enthusiasm after
identification of the CFTR gene in the 1990s, has not yet been borne out, but
there continues to be active research into feasible approaches to this modality.43
Similarly, gene editing tools such as clustered regularly interspaced short palin-
dromic repeat (CRISPR)–based systems are being investigated as a possible
approach to making targeted modifications in the genome,44 but clinical trials
have not yet been initiated. However, early-phase trials of novel compounds
that deliver messenger RNA that encodes fully functional CFTR protein to
the lung epithelial cells are underway, with mixed results as of the time of
this publication.
Abnormal CFTR
As noted earlier, the advent of effective and safe CFTR modulator drugs has
been a revolutionary breakthrough in CF treatment, allowing the targeting of the
primary molecular defect in CF, CFTR dysfunction, as opposed to treating or
mitigating the secondary effects such as impaired mucus clearance and recurrent
respiratory infections. Modulators can be categorized into 3 types: CFTR
correctors, CFTR potentiators, and CFTR amplifiers. The CFTR correctors are
small molecular agents that bind to the CFTR protein produced by class 2
mutations (F508del and others) to correct abnormal folding, thus facilitating
intracellular processing to improve the probability of a stable CFTR protein
reaching the cell membrane. The CFTR potentiators are small molecular agents

795
that bind to correctly positioned CFTR protein and increase the probability of the
CFTR channel being in an open, conformational state, thereby allowing
increased ion conductance. This effect is clinically important in patients with
gating and conductance defects (class 3 and 4 mutations) but also in conjunction
with CFTR correctors by increasing ion conductance in class 2 CFTR mutations
that have reached the apical cell membrane. The CFTR amplifiers are molecular
therapies that it is hoped will increase the amount of CFTR protein made by the
cell, but at the time of this writing these are in early clinical trials.
This area is rapidly evolving, so any description of the current state of CFTR
modulator therapy will become rapidly outdated, but a brief historical
perspective regarding drug development may be of interest.
Ivacaftor: A highly effective potentiator drug, ivacaftor was the first
modulator to be developed and approved for clinical use in 2012. It was
initially studied in patients aged 12 years or older who had the G551D
gating mutation; they had a 10.4% improvement in FEV1, a 55% decrease
in the risk of pulmonary exacerbations, substantial weight gain, reduced
pulmonary symptoms, and a decrease in sweat chloride level by 48.1 mmol/L
(48.1 mEq/L).45 It has subsequently been shown to be safe and effective as
monotherapy in patients as young as 4 months, with essentially all gating and
residual function mutations (classes 3, 4, 5, 6), and (as of 2021) studies are
ongoing in infants immediately after diagnosis.
Combination corrector/potentiators: Lumacaftor/ivacaftor was the first
combination corrector/potentiator to be developed, approved in 2015 for
patients aged 12 years or older with 2 copies of the F508del mutation. This
compound was an important first step and proof of principle, but clinical
efficacy was much less than that of ivacaftor in patients with gating mutations;
pulmonary exacerbations were decreased by one-third, but FEV1 increased
by just 3% predicted, and there was no effect on pulmonary symptoms and
mixed results regarding weight gain. As of the time of this writing, it remains
the treatment option for children aged 2 to 5 years with 2 copies of the F508del
mutation or others who are responsive to the medication for whom the newer
triple therapy (discussed next) is not yet approved. Tezacaftor/ivacaftor was
approved in 2018 for patients aged 12 years and older with 2 copies of the
F508del mutation and as of 2021 is now approved for patients as young as
6 years. Its effectiveness is approximately the same as that of lumacaftor/
ivacaftor, with fewer drug interactions, but with the approval in 2021 of the
more effective triple modulator therapy for patients as young as 6 years, this
medication will likely become archaic.46
Highly effective triple combination corrector/potentiator: Elexacaftor/
tezacaftor/ivacaftor (ETI) is a triple drug combination consisting of
2 correctors and a potentiator that was approved in 2019 after showing itself

796
to be highly effective in patients aged 12 years and older with at least

1 F508del mutation or any other CFTR gene mutation shown to be responsive
on the basis of in vitro data. In this population, ETI increased FEV1 by about
14% predicted and decreased pulmonary exacerbations by 63% and sweat
chloride level by 42 mmol/L (42 mEq/L); it also decreased respiratory
symptoms and increased weight gain.47 This treatment is applicable to about
92% of the population with CF (when patients with at least 1 F508del or 1 of
about 180 mutations shown to be sensitive in vitro are included); is, as of
2021, approved for patients as young as 6 years48; and will likely dra-
matically change the face of cystic fibrosis over the next several decades.
Furthermore, additional CFTR modulators are undergoing early-phase
clinical trial testing as of the time of this writing.
There are several adverse effects of the CFTR modulator drugs, including
some that have led to discontinuation in a small percentage of patients.
Ivacaftor (and, by extension, all the combinations containing ivacaftor) has
been associated with elevated hepatic enzyme levels, and cataracts have been
reported in children. Lumacaftor/ivacaftor has been associated with chest
discomfort and dyspnea at initiation of the drug, especially in those with
advanced lung disease, and worsening of liver disease in patients with pre-
existing cirrhosis. As a CYP3A4 inducer, it increases metabolism of a host of
other drugs that are CYP3A4 substrates, whose levels need close monitoring.
These adverse effects of lumacaftor/ivacaftor are seen much less often with
tezacaftor/ivacaftor and with ETI. For all CFTR modulators, regular monitor-
ing of liver enzymes is warranted. There have also been some cognitive and
mental health adverse effects reported in patients taking ETI, which, as of the
time of this writing, have not been well characterized but anecdotally have
led to its discontinuation or dose reduction in a small group of patients.
The advent of highly effective modulator therapies has led to a questioning of
the ongoing need for the intense treatment of downstream consequences of
CFTR dysfunction that has characterized CF treatment up until now. Studies
are underway in this regard, but for the time being, most CF physicians recom-
mend continuing treatment, as outlined in the following sections, that focuses
on controlling these downstream effects.
Bronchial Obstruction
Airway Clearance Augmentation Techniques
(See also Chapter 55, Airway Clearance Techniques.) Modalities that patients
with CF use to augment clearance of tenacious airway secretions include
percussion and postural drainage, positive expiratory pressure devices,
oscillatory positive expiratory pressure devices, high-frequency chest wall
oscillation devices (eg, the Vest [Hill-rom Services, Inc, Chicago, IL), and
controlled breathing techniques such as autogenic drainage and active cycle
of breathing. The CFF-sponsored guidelines recommend twice daily use of

797
airway clearance techniques for all patients beginning in infancy.49 Because

there is no clear evidence of the superiority of one technique over the others,
convenience, ease of administration, and patient satisfaction are the primary
driving forces for choosing a mode of airway clearance. Exercise has many
beneficial effects on cardiovascular fitness and sense of well-being. Results
from a number of studies show that aerobic and anaerobic exercise improve
quality of life in patients with CF and may stabilize lung function to
some degree, but exercise should complement and not supplant airway
clearance techniques.50
Bronchodilators
About 25% of patients with CF have consistent bronchodilator responsiveness,
and most have it intermittently. The CFF consensus guideline on pulmonary
therapies for patients who have a response on pulmonary function tests recom-
mends the routine use of bronchodilators such as albuterol and salmeterol.51
Dornase alfa (Recombinant Human Deoxyribonuclease)
Neutrophils participating in the inflammatory response undergo necrosis,
releasing DNA that increases the viscoelasticity and adhesiveness of sputum
in patients with CF. Dornase alfa breaks down extracellular DNA, improv-
ing the patient’s ability to clear mucus. The dose is 2.5 mg once per day, by
inhalation. The CFF consensus guidelines recommend its use for patients
older than 5 years.51 It is often used in younger patients, but there is less
evidence of benefit in this group.
Hypertonic (7%) Saline
Acting as a hyperosmolar agent, hypertonic saline is thought to draw water
into the airways, rehydrating the periciliary layer and improving mucociliary
clearance. Twice daily administration as an aerosol has been shown to be bene-
ficial in clinical trials.52 If hypertonic saline can correct the basic hydration
defect in the airways of patients with CF, it might be most efficacious if used
early in life, before pulmonary disease becomes established. Results from
studies of hypertonic saline use in infants and in 3- to 6-year-olds suggest
that this is the case.53,54
Infection
Patients who have chronic persistent airway infection with P aeruginosa
benefit from the use of inhaled tobramycin or aztreonam every other month.55
The efficacy of inhaling other antibiotics with activity against P aeruginosa,
methicillin-resistant S aureus, and nontuberculous mycobacteria has been
suggested but still requires definitive proof. Aerosolized antibiotics achieve
high concentration in the airways, so they are potentially effective even when
the organism is resistant to levels of antibiotic that might be attainable through
systemic administration. However, aerosols do not penetrate into airways that
are obstructed, so they do not reach the most involved areas of the lung, and
evidence for effectiveness during pulmonary exacerbations is lacking.56

798
The benefit of using prophylactic antibiotics (especially systemic) long-term

in children uninfected with P aeruginosa is not clear. The CFF recommends
against prophylactic use of antistaphylococcal agents because of fears that it
increases the likelihood of acquiring P aeruginosa, but there is not universal
agreement regarding this issue.57
At its initial acquisition, P aeruginosa can often be eliminated, although
the benefit to patients so treated is not entirely clear.58 Thus, frequent surveil-
lance airway cultures are obtained, and, at initial detection, antibiotics are
prescribed to eradicate P aeruginosa (even in those without symptoms). The
most effective approach to eliminating P aeruginosa includes the use of
nebulized antibiotics, but the duration of treatment and whether there is
advantage to adding systemic antibiotics remain areas of controversy.19
Pulmonary Exacerbations and Their Treatment
Intermittent flare-ups of infection in patients with CF are associated with
increased inflammation and airway obstruction and are identified by the
development of new respiratory signs and symptoms. Increased cough,
change in sputum color or quantity, decreased appetite or weight, and
change in respiratory rate and auscultatory findings during physical examina-
tion are particularly important features (Box 45-3). These episodes are called
pulmonary exacerbations and are treated with discrete courses of systemic
antibiotic therapy chosen based on previous cultures of airway secretions. In
children, depending on the severity of the
Box 45‑3 exacerbation, it is typical for treatment with
Signs and Symptoms of a oral antibiotics to be attempted initially. If
Pulmonary Exacerbation a
this treatment does not successfully return
Symptoms the patient to baseline status, intravenous
ū Cough antibiotics are used.
ū Dyspnea There are currently no uniformly accepted
ū Chest tightness defining criteria for what constitutes a
ū Hemoptysis pulmonary exacerbation of CF.37 An aggres-
ū Increased sputum sive approach to treatment with oral antibiot-
ics—even in patients whose symptoms may
ū Anorexia
be mild or primarily viral in cause—with the
Signs
addition of intravenous antibiotics when
ū New wheezes or crackles
baseline is not promptly reattained leads to
ū Weight loss better long-term pulmonary outcomes in
Laboratory test results patients with CF.59
ū Decreased FEV1
Once a pulmonary exacerbation of CF is
ū Chest radiograph changes
identified, therapy generally includes
a
Note that the presence of even 1 of these systemic antibiotics, increased use of airway
findings should prompt treatment and clearance techniques, and improved nutrition.
attempts at return to baseline.

799
There is a surprising lack of evidence regarding best treatment.37 Combination

antibiotic therapy with 2 or more agents with different modes of action is
conventionally used to avoid emergence of resistant strains, and therapy is
generally administered for at least 10 to 14 days. Domiciliary treatment with
intravenous antibiotics is feasible but may not be as effective as hospital-based
therapy.60
Inflammation
A number of anti-inflammatory agents are beneficial in patients with CF,
but there is some controversy regarding their use.
X Systemic steroids: These can be used in selected patients in the short or
long term. They improve airway function when used long-term but are
associated with problematic adverse effects such as glucose intolerance
and cataracts.61
X Inhaled corticosteroids: These are used commonly, particularly in patients
with apparent airway reactivity, but their benefit has not been clearly
demonstrated.51
X Ibuprofen: When administered in high doses (20–30 mg/kg twice daily to a
maximum 1,600 mg per dose), ibuprofen leads to long-term benefits in lung
function, particularly in children aged between 5 and 13 years. There are
concerns regarding gastrointestinal and renal toxicity, but experience has
shown these to be unusual.62
X Azithromycin: Long-term use of macrolide antibiotics (alternate day
azithromycin 250 mg if the patient weighs < 40 kg or 500 mg if the patient
weighs ≥40 kg) is associated with slower decrease in lung function.63 It is
unclear whether macrolides work via an influence on P aeruginosa viru-
lence factors or an anti-inflammatory effect, or perhaps by affecting
microbiome diversity.64 Recent concerns have been raised regarding an
antagonistic relationship between macrolides and both aerosolized and
intravenous tobramycin; a better understanding of how this relationship
should be managed is needed.65
Tissue Damage
The end result of long-standing infection and inflammation is irreversible
bronchiectasis and eventual respiratory failure. At that point, the only remain-
ing option is bilateral lung transplant, which is generally offered when predic-
tive models (which consider current FEV1, age, sex, lung microbiological
characteristics, and rate of FEV1 decrease, among other factors) suggest that
death is likely to be imminent. The 10-year survival after lung transplant is
approximately 50%, with bronchiolitis obliterans due to chronic rejection an
ongoing problem. Use of nocturnal noninvasive ventilation can improve chest
symptoms, sleep-associated hypoventilation, and quality of life in patients
with awake hypercapnia who are awaiting transplant.66

800
The Role of the General Pediatrician

Diagnosis
As noted earlier, CF NBS has now been instituted throughout the United
States. To counsel the families of patients with positive NBS results appro-
priately, the general pediatrician must understand the local state screening
process and help facilitate it. For more detail, see Chapter 46, Cystic Fibrosis
Newborn Screening and CFTR-Related Metabolic Syndrome.
The sensitivity of the CF NBS process is not 100%, so there will always
be some patients who have CF diagnosed according to symptoms at a later
age. Thus, the pediatrician still has to consider CF in the differential diag-
nosis in children with chronic or recurrent respiratory symptoms and
gastrointestinal complaints.
Follow-up in Patients With CFTR-Related Metabolic Syndrome

Patients with CRMS are particularly important to consider in that they rely
primarily on the general pediatrician for follow-up and recognition of symp-
toms suggestive of a need for intervention. See Chapter 46, Cystic Fibrosis
Newborn Screening and CFTR-Related Metabolic Syndrome, for more
details in this regard.
Immunizations
Infants and children with CF should receive all recommended immunizations,
with special attention to influenza and pneumococcal vaccines. In addition,
the American Academy of Pediatrics Section on Pediatric Pulmonology and
Sleep Medicine agrees with the CFF recommendation67 to consider respiratory
syncytial virus prophylaxis in all infants with CF younger than 2 years.
Evaluation and Treatment of Apparently Viral Respiratory Tract Infections

As previously noted, aggressive antibiotic treatment of respiratory tract
symptoms is a key to attaining better disease outcomes. Children with CF
will get as many viral upper respiratory infections as do other children, and
these do not immediately call for antimicrobial treatment. However, viral
upper respiratory infections are frequent triggers for acute pulmonary exacer-
bations, which do require antibiotics. When these children are seen in the
general pediatric setting for what appears to be even a mild viral respiratory
tract infection, it would be advisable to contact the CF center to discuss
criteria for antimicrobial treatment, as well as the optimal choice of antibiotic
on the basis of previous airway cultures.

801
Psychosocial Issues
The emphasis on good weight gain that begins early in the course of treatment
sometimes leads to behavioral feeding problems that can cause substantial
family dysfunction. These are often easily alleviated by appropriate referral
to a psychologist with experience in this area. Psychological problems, espe-
cially anxiety and depression, are prevalent in children with CF, as well as in
their caregivers, and can affect adherence and long-term disease outcomes.32
These problems should be carefully looked for and, when found, referred for
appropriate mental health services. The teenage years for patients with CF,
as well as other chronic diseases, can be quite tumultuous, with substantial
challenges due to treatment nonadherence and participation in other
risk-taking behaviors.68
When to Refer
X Any child with an abnormal or borderline abnormal sweat test result should
be referred to a CFF-accredited care center for evaluation and treatment.
X The CF center should be consulted if a patient with CF has
ū Persistent cough or congestion (> 1 week)

ū Wheezing or new crackles at chest examination
ū Any new abnormality on chest radiographs
ū Acute dyspnea or hemoptysis
ū Any respiratory infection requiring antibiotics
ū Poor weight gain or weight loss
ū Change in stools: decrease in number, increased steatorrhea
ū Abdominal pain
When to Admit
It is generally ideal for patients with CF, when hospitalized, to be cared for by
CF center physicians. There are exceptions; if hospitalization is considered by
the primary care pediatrician, the CF center should be contacted to discuss this.

802
key points
} Cystic fibrosis is a multisystem disease that requires close attention to
pulmonary and nutritional parameters.
} Most children with CF in the United States have CF diagnosed by means of NBS.
It is important that pediatricians ensure that infants who screen positive are
promptly evaluated with a sweat test performed by a laboratory associated
with an accredited CF center.
} Patients should be followed up in centers that have experience caring for individ-
uals with CF and can offer expertise in a broad range of areas. A multidisciplinary
team including nurses, pharmacists, nutritionists, respiratory therapists, social
workers, and others is necessary to achieve the best outcomes. Good commu-
nication between the primary care pediatrician and CF care center is key to
ensuring optimal care.
} A successful treatment philosophy combines an aggressive approach with high
expectations and active participation by patients and family, with the goal of
maintaining good (ie, normal) nutrition and respiratory status.
Acknowledgments
Jonathan Ma, MD, made contributions to an early draft of this manuscript.
Brian O’Sullivan, MD, was coauthor of the original version of this chapter
in the previous edition.
References
1. Cystic Fibrosis Foundation. 2019 Patient Registry Annual Data Report. Cystic Fibrosis
Foundation; 2020. Accessed July 13, 2022. https://www.cff.org/sites/default/files/
2021-10/2019-Patient-Registry-Annual-Data-Report.pdf
2. Mirtajani SB, Farnia P, Hassanzad M, Ghanavi J, Farnia P, Velayati AA. Geographical
distribution of cystic fibrosis; The past 70 years of data analyzis. Biomed Biotechnol Res J.
2017;1(2):105–112
3. Boucher RC. Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. Annu Rev
Med. 2007;58:157–170 PMID: 17217330
4. Harutyunyan M, Huang Y, Mun KS, Yang F, Arora K, Naren AP. Personalized medicine in CF:
from modulator development to therapy for cystic fibrosis patients with rare CFTR mutations.
Am J Physiol Lung Cell Mol Physiol. 2018;314(4):L529–L543 PMID: 29351449
doi: 10.1152/ajplung.00465.2017
5. Schechter MS. Nongenetic influences on cystic fibrosis outcomes. Curr Opin Pulm Med.
2011;17(6):448–454 PMID: 21897254
6. Collaco JM, Cutting GR. Update on gene modifiers in cystic fibrosis. Curr Opin Pulm Med.
2008;14(6):559–566 PMID: 18812833
7. Borowitz D. CFTR, bicarbonate, and the pathophysiology of cystic fibrosis. Pediatr Pulmonol.
2015;50(suppl 40):S24–S30 PMID: 26335950
8. Roesch EA, Nichols DP, Chmiel JF. Inflammation in cystic fibrosis: an update. Pediatr Pulmonol.
2018;53(S3):S30–S50 PMID: 29999593
9. Ranganathan SC, Hall GL, Sly PD, Stick SM, Douglas TA; Australian Respiratory Early
Surveillance Team for Cystic Fibrosis (AREST-CF). Early lung disease in infants and preschool
children with cystic fibrosis: what have we learned and what should we do about it? Am J Respir
Crit Care Med. 2017;195(12):1567–1575 PMID: 27911585

803
10. Twaddell SH, Baines KJ, Grainge C, Gibson PG. The emerging role of neutrophil extracellular
traps in respiratory disease. Chest. 2019;156(4):774–782 PMID: 31265835
11. Nick JA, Rodman DM. Manifestations of cystic fibrosis diagnosed in adulthood. Curr Opin Pulm
Med. 2005;11(6):513–518 PMID: 16217177
12. Farrell PM, White TB, Ren CL, et al. Diagnosis of cystic fibrosis: consensus guidelines from the
Cystic Fibrosis Foundation. J Pediatr. 2017;181S:S4.e1–S15.e1 PMID: 28129811
doi: 10.1016/j.jpeds.2016.09.064
13. LeGrys VA, Yankaskas JR, Quittell LM, Marshall BC, Mogayzel PJ Jr; Cystic Fibrosis
Foundation. Diagnostic sweat testing: the Cystic Fibrosis Foundation guidelines. J Pediatr.
2007;151(1):85–89 PMID: 17586196
14. Eng W, LeGrys VA, Schechter MS, Laughon MM, Barker PM. Sweat-testing in preterm and
full-term infants less than 6 weeks of age. Pediatr Pulmonol. 2005;40(1):64–67 PMID: 15880420
15. LeGrys VA. Assessment of sweat-testing practices for the diagnosis of cystic fibrosis.
Arch Pathol Lab Med. 2001;125(11):1420–1424 PMID: 11697995
16. Sosnay PR, White TB, Farrell PM, et al. Diagnosis of cystic fibrosis in nonscreened populations.
J Pediatr. 2017;181S:S52.e2–S57.e2 PMID: 28129813 doi: 10.1016/j.jpeds.2016.09.068
17. Ren CL, Borowitz DS, Gonska T, et al. Cystic fibrosis transmembrane conductance regulator–
related metabolic syndrome and cystic fibrosis screen positive, inconclusive diagnosis. J Pediatr.
2017;181S:S45.e1–S51.e1 PMID: 28129812 doi: 10.1016/j.jpeds.2016.09.066
18. Huang YJ, LiPuma JJ. The microbiome in cystic fibrosis. Clin Chest Med. 2016;37(1):59–67
PMID: 26857768
19. Langton Hewer SC, Smyth AR. Antibiotic strategies for eradicating Pseudomonas aeruginosa in
people with cystic fibrosis. Cochrane Database Syst Rev. 2017;4(4):CD004197 PMID: 28440853
20. Campodónico VL, Gadjeva M, Paradis-Bleau C, Uluer A, Pier GB. Airway epithelial control of
Pseudomonas aeruginosa infection in cystic fibrosis. Trends Mol Med. 2008;14(3):120–133
PMID: 18262467
21. Goss CH, Mayer-Hamblett N, Aitken ML, Rubenfeld GD, Ramsey BW. Association between
Stenotrophomonas maltophilia and lung function in cystic fibrosis. Thorax. 2004;59(11):955–959
PMID: 15516471
22. Kalish LA, Waltz DA, Dovey M, et al. Impact of Burkholderia dolosa on lung function and
survival in cystic fibrosis. Am J Respir Crit Care Med. 2006;173(4):421–425 PMID: 16272450
23. Floto RA, Olivier KN, Saiman L, et al; US Cystic Fibrosis Foundation and European Cystic
Fibrosis Society. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus
recommendations for the management of non-tuberculous mycobacteria in individuals with
cystic fibrosis. Thorax. 2016;71(suppl 1):i1–i22 PMID: 26666259
24. Janahi IA, Rehman A, Al-Naimi AR. Allergic bronchopulmonary aspergillosis in patients with
cystic fibrosis. Ann Thorac Med. 2017;12(2):74–82 PMID: 28469716
25. Renner S, Nachbaur E, Jaksch P, Dehlink E. Update on respiratory fungal infections in cystic
fibrosis lung disease and after lung transplantation. J Fungi (Basel). 2020;6(4):381 PMID:
33371198
26. Wilschanski M, Durie PR. Patterns of GI disease in adulthood associated with mutations in the
CFTR gene. Gut. 2007;56(8):1153–1163 PMID: 17446304
27. Boyle MP. Nonclassic cystic fibrosis and CFTR-related diseases. Curr Opin Pulm Med.
2003;9(6):498–503 PMID: 14534402
28. Schechter MS, Quittner AL, Konstan MW, Millar SJ, Pasta DJ, McMullen A; Scientific Advisory
Group; Investigators and Coordinators of Epidemiologic Study of Cystic Fibrosis. Long-term
effects of pregnancy and motherhood on disease outcomes of women with cystic fibrosis. Ann
Am Thorac Soc. 2013;10(3):213–219 PMID: 23802817 doi: 10.1513/AnnalsATS.201211-108OC
29. Milla CE, Billings J, Moran A. Diabetes is associated with dramatically decreased survival in
female but not male subjects with cystic fibrosis. Diabetes Care. 2005;28(9):2141–2144
PMID: 16123480
30. O’Riordan SM, Robinson PD, Donaghue KC, Moran A; ISPAD Clinical Practice Consensus.
Management of cystic fibrosis-related diabetes. Pediatr Diabetes. 2008;9(4 pt 1):338–344
PMID: 18768038
31. Aris RM, Merkel PA, Bachrach LK, et al. Guide to bone health and disease in cystic fibrosis.
J Clin Endocrinol Metab. 2005;90(3):1888–1896 PMID: 15613415
32. Quittner AL, Abbott J, Georgiopoulos AM, et al; International Committee on Mental Health;
EPOS Trial Study Group. International Committee on Mental Health in Cystic Fibrosis: Cystic
Fibrosis Foundation and European Cystic Fibrosis Society consensus statements for screening
and treating depression and anxiety. Thorax. 2016;71(1):26–34 PMID: 26452630

804
33. Schechter MS, Ostrenga JS, Fink AK, Barker DH, Sawicki GS, Quittner AL. Decreased survival
in cystic fibrosis patients with a positive screen for depression. J Cyst Fibros. 2021;20(1):120–126
PMID: 32800486
34. Johnson C, Butler SM, Konstan MW, Morgan W, Wohl ME. Factors influencing outcomes in
cystic fibrosis: a center-based analysis. Chest. 2003;123(1):20–27 PMID: 12527598
35. Padman R, McColley SA, Miller DP, et al; Investigators and Coordinators of the Epidemiologic
Study of Cystic Fibrosis. Infant care patterns at Epidemiologic Study of Cystic Fibrosis sites that
achieve superior childhood lung function. Pediatrics. 2007;119(3):e531–e537 PMID: 17332172
36. Schechter MS, Michel S, Liu S, et al. Relationship of initial pancreatic enzyme replacement
therapy dose with weight gain in infants with cystic fibrosis. J Pediatr Gastroenterol Nutr.
2018;67(4):520–526 PMID: 30052568
37. Schechter MS. Reevaluating approaches to cystic fibrosis pulmonary exacerbations. Pediatr
Pulmonol. 2018;53(S3):S51–S63 PMID: 29979495
38. Konstan MW, Butler SM, Wohl ME, et al; Investigators and Coordinators of the Epidemiologic
Study of Cystic Fibrosis. Growth and nutritional indexes in early life predict pulmonary function
in cystic fibrosis. J Pediatr. 2003;142(6):624–630 PMID: 12838189
39. Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with
cystic fibrosis. J Pediatr Gastroenterol Nutr. 2002;35(3):246–259 PMID: 12352509
40. Parker EM, O’Sullivan BP, Shea JC, Regan MM, Freedman SD. Survey of breast-feeding
practices and outcomes in the cystic fibrosis population. Pediatr Pulmonol. 2004;37(4):362–367
PMID: 15022134
41. Szentpetery S, Fernandez GS, Schechter MS, Jain R, Flume PA, Fink AK. Obesity in cystic
fibrosis: prevalence, trends and associated factors data from the US cystic fibrosis foundation
patient registry. J Cyst Fibros. 2022;21(5):777–783 PMID: 35396178 doi: 10.1016/j.jcf.2022.03.010
42. Mondéjar-López P, Horsley A, Ratjen F, Bertolo S, de Vicente H, Asensio de la Cruz Ò. A
multimodal approach to detect and monitor early lung disease in cystic fibrosis. Expert Rev
Respir Med. 2021;15(6):761–772 PMID: 33843417
43. Mercier J, Ruffin M, Corvol H, Guillot L. Gene therapy: a possible alternative to CFTR
modulators? Front Pharmacol. 2021;12:648203 PMID: 33967785
44. Ensinck M, Mottais A, Detry C, Leal T, Carlon MS. On the corner of Models and Cure: gene
editing in cystic fibrosis. Front Pharmacol. 2021;12:662110 PMID: 33986686
45. Ramsey BW, Davies J, McElvaney NG, et al; VX08-770-102 Study Group. A CFTR potentiator
in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663–1672
PMID: 22047557
46. Southern KW, Murphy J, Sinha IP, Nevitt SJ. Corrector therapies (with or without potentiators)
for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del).
Cochrane Database Syst Rev. 2020;12(12):CD010966 PMID: 33331662
47. Middleton PG, Mall MA, Dřevínek P, et al; VX17-445-102 Study Group. Elexacaftor-
tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med.
2019;381(19):1809–1819 PMID: 31697873
48. Zemanick ET, Taylor-Cousar JL, Davies J, et al. A phase 3 open-label study of elexacaftor/
tezacaftor/ivacaftor in children 6 through 11 years of age with cystic fibrosis and at least one
F508del allele. Am J Respir Crit Care Med. 2021;203(12):1522–1532 PMID: 33734030
49. Flume PA, Robinson KA, O’Sullivan BP, et al; Clinical Practice Guidelines for Pulmonary
Therapies Committee. Cystic fibrosis pulmonary guidelines: airway clearance therapies.
Respir Care. 2009;54(4):522–537 PMID: 19327189
50. Bradley J, Moran F. Physical training for cystic fibrosis. Cochrane Database Syst Rev.
2008;(1):CD002768 PMID: 18254007
52. Elkins MR, Robinson M, Rose BR, et al; National Hypertonic Saline in Cystic Fibrosis
(NHSCF) Study Group. A controlled trial of long-term inhaled hypertonic saline in patients with
cystic fibrosis. N Engl J Med. 2006;354(3):229–240 PMID: 16421364
53. Stahl M, Wielpütz MO, Ricklefs I, et al. Preventive Inhalation of Hypertonic Saline in Infants
with Cystic Fibrosis (PRESIS): a randomized, double-blind, controlled study. Am J Respir Crit
Care Med. 2019;199(10):1238–1248 PMID: 30409023
54. Ratjen F, Davis SD, Stanojevic S, et al; SHIP Study Group. Inhaled hypertonic saline in
preschool children with cystic fibrosis (SHIP): a multicentre, randomised, double-blind,
placebo-controlled trial. Lancet Respir Med. 2019;7(9):802–809 PMID: 31178421

805
55. Smith S, Rowbotham NJ, Regan KH. Inhaled anti-pseudomonal antibiotics for long-term therapy
in cystic fibrosis. Cochrane Database Syst Rev. 2018;3(3):CD001021 PMID: 29607494
56. Smith S, Rowbotham NJ, Charbek E. Inhaled antibiotics for pulmonary exacerbations in cystic
fibrosis. Cochrane Database Syst Rev. 2018;10(10):CD008319 PMID: 30376155
57. Rosenfeld M, Rayner O, Smyth AR. Prophylactic anti-staphylococcal antibiotics for cystic
58. Mayer-Hamblett N, Kloster M, Rosenfeld M, et al. Impact of sustained eradication of new
Pseudomonas aeruginosa infection on long-term outcomes in cystic fibrosis. Clin Infect Dis.
2015;61(5):707–715 PMID: 25972024
59. Schechter MS, Schmidt HJ, Williams R, Norton R, Taylor D, Molzhon A. Impact of a program
ensuring consistent response to acute drops in lung function in children with cystic fibrosis.
J Cyst Fibros. 2018;17(6):769–778 PMID: 30017327
60. Schechter MS, VanDevanter DR, Pasta DJ, Short SA, Morgan WJ, Konstan MW; Scientific
Advisory Group and the Investigators and Coordinators of the Epidemiologic Study of Cystic
Fibrosis. Treatment setting and outcomes of cystic fibrosis pulmonary exacerbations. Ann Am
Thorac Soc. 2018;15(2):225–233 PMID: 29140726
61. Eigen H, Rosenstein BJ, FitzSimmons S, Schidlow DV; Cystic Fibrosis Foundation Prednisone
Trial Group. A multicenter study of alternate-day prednisone therapy in patients with cystic
fibrosis. J Pediatr. 1995;126(4):515–523 PMID: 7699528
62. Konstan MW. Ibuprofen therapy for cystic fibrosis lung disease: revisited. Curr Opin Pulm Med.
2008;14(6):567–573 PMID: 18812834
63. Nichols DP, Odem-Davis K, Cogen JD, et al. Pulmonary outcomes associated with long-term
azithromycin therapy in cystic fibrosis. Am J Respir Crit Care Med. 2020;201(4):430–437
PMID: 31661302
64. Schultz MJ. Macrolide activities beyond their antimicrobial effects: macrolides in diffuse
panbronchiolitis and cystic fibrosis. J Antimicrob Chemother. 2004;54(1):21–28 PMID: 15190022
65. Thornton C, Chin M, Somayaji R. Azithromycin and tobramycin therapy in cystic fibrosis
pulmonary exacerbations: less is more? Ann Am Thorac Soc. 2021;18(2):213–215
PMID: 33522874
66. Young AC, Wilson JW, Kotsimbos TC, Naughton MT. Randomised placebo controlled trial
of non-invasive ventilation for hypercapnia in cystic fibrosis. Thorax. 2008;63(1):72–77
PMID: 17675317
67. Borowitz D, Robinson KA, Rosenfeld M, et al; Cystic Fibrosis Foundation. Cystic Fibrosis
Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr.
2009;155(6)(suppl):S73–S93 PMID: 19914445
68. Britto MT, Garrett JM, Dugliss MA, et al. Risky behavior in teens with cystic fibrosis or sickle
cell disease: a multicenter study. Pediatrics. 1998;101(2):250–256 PMID: 9445499

CHAPTER
46
Cystic Fibrosis Newborn Screening and
CFTR-Related Metabolic Syndrome
Danieli B. Salinas, MD, MS
Cystic Fibrosis Newborn Screening

Background
Cystic fibrosis (CF) is an autosomal recessive genetic condition caused by
variants in the gene coding for the CF transmembrane conductance regulator
(CFTR).1 It affects multiple organ systems, but the 2 areas primarily affected
are the pancreas and the lungs. In the lungs, loss of CFTR function results in
abnormal mucus rheology, impaired innate immunity, and decreased muco-
ciliary clearance. These effects result in chronic endobronchial infection,
bronchiectasis, and respiratory failure. The pancreatic ducts in people with CF
are obstructed, leading to exocrine pancreatic insufficiency (see Chapter 45,
Cystic Fibrosis).
Diagnosis of CF was historically based on clinical features, and most
commonly infants presented with failure to thrive and profound malnutrition.
Establishing a CF diagnosis required performing a sweat chloride test (SCT)
in infants and children presenting with clinical features concerning for CF.2
The principle behind using the SCT as a diagnostic test for CF is based on the
fact that CFTR that is present in the sweat duct reabsorbs chloride from sweat
while it is being secreted. In the absence of CFTR, excess chloride is secreted,
which can be measured using quantitative pilocarpine iontophoresis.3
As early as the 1970s it was recognized that earlier diagnosis of CF was
associated with better clinical outcomes. The landmark Wisconsin Newborn
Screening project, a randomized clinical trial of CF newborn screening (NBS),
demonstrated that early diagnosis of CF through NBS was associated with
improved nutritional status.4 Investigators in subsequent epidemiological
studies have identified early nutrition as a critical factor in lung function in
later life, suggesting that NBS might lead to better lung function in children
with CF.5 These observations led to increasingly widespread implementation
807

808
of CF NBS in the United States and throughout the world, and CF NBS was
being offered in all 50 states by the end of 2009.
Cystic Fibrosis Newborn Screening Algorithms

Algorithms for CF NBS vary by country and by state. They are also frequently
changing, so clinicians should maintain regular contact with their local NBS
laboratory to keep current with updates to the algorithm. In the United States,
all CF NBS algorithms begin with the measurement of serum immunoreactive
trypsinogen (IRT), a pancreatic pro-enzyme that has elevated levels in almost
all newborns with CF.2,5–7 A dried blood spot assay for IRT was first developed
in 1979 for use in screening. However, an elevated IRT level is not specific
for CF. Some infants without CF, such as those under perinatal stress or of
African American descent, can have transiently elevated IRT levels.8,9 Con-
versely, IRT levels may actually be lower in infants with CF who present with
meconium ileus, although usually in those cases the clinical presentation will
have already raised the concern for CF. To improve the predictive value of
CF NBS, a second or third tier of testing is performed, the choice of which
is state specific.
In the United States, 3 different CF NBS algorithms are used. One approach
is to repeat the IRT test 2 to 4 weeks later. In infants without CF, the second
IRT test result is usually normal, whereas in infants with CF it is persistently
elevated. This approach was used in Colorado, the first state in which CF
NBS was performed in 1982, before the discovery of the CFTR gene. Another
approach is to perform CFTR gene variant analysis on the dried blood spot if
the IRT level is elevated (Figure 46-1).5 The number of the variants tested
ranges from 23 to 338, and the exact composition of the variant panel varies
from state to state. If 2 CFTR variants are identified, a diagnosis of presump-
tive CF is assigned, and the infant should be seen as soon as possible at a
qualified CF center for a confirmatory SCT and initiation of CF treatment.
If 1 variant is detected, the infant is either a CF carrier or has CF with a
rare variant not detected on the NBS panel; in this case, an SCT should be
performed to rule out CF.
In some states, gene sequencing is performed from the dried blood spot if only
1 variant is detected by the panel. If a second variant is found, a diagnosis of
presumed CF is assigned and the infant should be seen as soon as possible at
a specialized CF Center for treatment and confirmatory SCT. If no addi-
tional variants are identified on sequencing, the infant is considered a CF
carrier. In both variant panel testing and sequencing algorithms, if no
variants are found the infant is considered screen negative.
The IRT/DNA algorithm allows NBS to be performed from a single blood
spot but detects many more carriers than infants with CF. The advantage of
sequencing algorithms is a marked reduction in referrals for SCT in infants

809
Chapter 46—Cystic Fibrosis Newborn Screening and CFTR-Related Metabolic Syndrome
↑ IRT
Repeat IRT CFTR Mutation Testing
Normal Still ↑ 2 mutations 1 mutation 0 mutations
Screen Presumed CF vs. Carrier Screen

negative CF negative
Sweat Test
<30 mmol/L 30–59 mmol/L 60 mmol/L
CF unlikely CRMS/ CF
CFSPID
Figure 46-1. Cystic fibrosis newborn screening algorithms. In algorithms

using IRT/IRT/DNA, variant panel testing is done only if the second IRT is still
elevated. In algorithms using sequencing, CFTR gene sequencing is
performed in infants with 1 variant identified on variant panel analysis, and
infants with 2 variants identified are presumed to have CF, while those with
only 1 variant are classified as carriers.
Abbreviations: CF, cystic fibrosis; CFTR, CF transmembrane conductance regulator;
CRMS, CFTR-related metabolic syndrome; CFSPID, CF screen positive, inconclusive
diagnosis; IRT, immunoreactive trypsinogen.
with only 1 variant who are carriers. However, sequencing can also result in
the identification of a large number of infants with variants of unknown
significance or varying clinical consequences.
The IRT/IRT diagnostic algorithm is no longer used in the United States, as
all models include DNA analysis (ie, IRT/IRT/DNA or IRT/DNA). Adding
DNA analysis to a NBS model increases sensitivity and improves positive
predictive value, which leads to fewer false-positive results and shorter time
to diagnosis.10 With this algorithm, IRT testing is repeated 1 to 2 weeks after
the initial specimen is obtained. If the IRT level is persistently elevated, then
DNA analysis is performed. Although using an IRT/IRT/DNA algorithm can
increase the time to diagnosis, the use of this algorithm still allows for CF
diagnosis within the first month after birth.
Because IRT levels can fluctuate throughout the year, most states set a cutoff
level based on a rolling average of IRT levels (eg, ≥ 95th percentile over the
preceding 30 days). Some NBS algorithms recommend an SCT for infants

810
with very high IRT levels even if no CFTR variants are detected. The algo-
rithm for very high IRT levels can be helpful in detecting infants with rare
variants, particularly in populations with high racial and ethnic diversity,
who may be missed with a standard DNA variant panel,11 but it increases
the false-positive rate. Results from NBS will be reported as a negative
screening result, and no further testing or follow-up is required if the initial
IRT value does not meet the state-specific cutoff value. A negative screening
result substantially reduces the likelihood of CF but does not rule it out, so
SCT and/or genetic testing should be performed in any infant or child who
presents with clinical features suggestive of CF.
Initial Management of a Positive CF NBS Test Result

A positive CF NBS test result identifies infants with a high likelihood of
having CF, but it is not diagnostic for CF. Any infant with a positive CF NBS
test result should undergo an SCT to confirm the diagnosis of CF. In states
using the IRT/DNA algorithm, only about 10% of infants who have just 1
CF-causing variant from the screening panel are found to have CF (depend-
ing on the variant screening panel and ethnic background of the child); the
remaining 90% are CF carriers.5 Even in cases in which 2 CF-causing variants
have been identified, an SCT is indicated because cases of laboratory error
or misidentified newborn blood spots have been reported.7 There are 3 possible
outcomes of an SCT:
X Normal (sweat chloride level < 30 mmol/L): No further testing or follow-up
is required. However, if 2 CF-causing variants have been identified and the
SCT indicates a chloride level less than 30 mmol/L, the recommendation
of the Cystic Fibrosis Foundation (CFF) is to repeat the SCT and follow
up clinically.7
X Elevated (sweat chloride level ≥ 60 mmol/L): This infant meets diagnostic
criteria for CF and should undergo appropriate workup and receive therapy
as promptly as possible.
X Intermediate (sweat chloride level = 30–59 mmol/L): If 2 CF-causing
CFTR variants have been identified either through NBS DNA analysis
or further genetic testing, then this infant meets diagnostic criteria for
CF. If fewer than 2 CF-causing CFTR variants are present, then this infant
meets diagnostic criteria for CFTR-related metabolic syndrome (CRMS)
(see CFTR-Related Metabolic Syndrome later in this chapter).
The clinician and the parents should be informed of a positive NBS result as
soon as possible, and referral to an accredited CF center should be made for
further evaluation and SCT. Sweat chloride testing should be performed only
by using quantitative pilocarpine iontophoresis at an accredited CF care center.
The goal of CF NBS is for infants to receive diagnosis and treatment initiated

811
by 1 month of age. A delay of even 1 or 2 months can have a clinically sig-

nificant effect on nutrition, and infants with untreated CF are also at risk of
developing serious complications such as severe hyponatremic dehydration.
Data from the CFF Patient Registry show that there is wide variation in the
age at first event (SCT or clinic visit) across the United States and that many
infants are seen when they are older than 60 days.12 Improving the time to
first event is the focus of many quality improvement efforts.
In addition to diagnostic testing for CF, the CFF recommends that genetic
counseling should be offered to all parents whose infant has an abnormal
CF NBS result.6 Infants with CF diagnosed should be followed up at an
accredited CF care center, and their care should follow the guidelines
developed by the CFF.13
CF NBS Outcomes
Although CF NBS results in improved nutritional outcomes, longitudinal
studies have shown that many infants still have abnormal lung function or
evidence of structural lung damage.14 The introduction of highly effective
CFTR modulator therapy early in life may be able to affect the natural his-
tory of CF lung disease,15 but for now clinicians must be aware of the need to
monitor and treat lung disease in infants with CF diagnosed through NBS.
Although the benefits of CF NBS outweigh its disadvantages, there are some
unintended consequences of CF NBS. Both false-negative and false-positive
test results can occur. Adding DNA sequencing to NBS and broader access
to genetic testing have led to more frequent identification of CFTR variants
of unknown significance. Uncertainties in diagnosis are recognized as a
source of anxiety for parents and a risk for unnecessary medical care of
healthy children.16,17
CFTR-Related Metabolic Syndrome

Background
An unintended consequence of CF NBS is the identification of infants with a
positive CF NBS result but inconclusive diagnostic test results. In the United
States, CRMS is the term that has been used to describe the condition of these
infants.18 Although the condition is clearly not a metabolic disorder, the CRMS
label was established to ensure appropriate coding and billing for this group of
individuals in the United States. The European Cystic Fibrosis Society has
developed an analogous term, CF screen positive, inconclusive diagnosis
(CFSPID), to classify the condition of these infants.19 For the purposes of this
chapter, we will use the US terminology.
An international consensus conference on CF diagnosis in 201720 determined
that an infant has CRMS if the infant has no symptoms with a positive CF NBS

812
test result and either (a) SCT chloride level less than 30 mmol/L and 2 CFTR
variants, at least 1 of which has unclear phenotypic consequences, or (b) SCT
chloride level of 30 to 59 mmol/L and 0 or 1 CF-causing CFTR variant. It is
important to distinguish CRMS from CFTR-related disorder21,22 because
CRMS is a diagnosis that arises only from CF NBS. In contrast, individuals
with CFTR-related disorder present with symptoms with single organ condi-
tions (eg, recurrent pancreatitis) but do not fulfill diagnostic criteria for CF.
The CFF recommends that infants with CRMS be evaluated and followed up
by a clinician with expertise and experience in CF care.18 At the time of this
publication, CFF guidelines are in the process of being updated. Updated
guidelines from the European Cystic Fibrosis Society in collaboration with
international experts outline the following recommendations for short-term
and long-term follow-up of these infants23:
1. Initial assessment should include clinical evaluation, SCT, extended CFTR
analysis if the genotype is incomplete, and collection of a stool sample for
measurement of fecal elastase-1. Clinical evaluation includes respiratory,
abdominal, and nutritional assessment.
2. Offer genetic counseling and parent DNA testing if applicable.
3. Repeat the SCT at 6 months, 1 year, and 2 years. After that, it may be
repeated annually if there is a concern about disease progression or the
result at 2 years of age is intermediate.
4. Continue annual visits at least until 6 years of age.
5. Continue annual revision of CFTR variant classification.
6. Perform respiratory cultures if clinically indicated.
7. Repeat fecal elastase testing if clinically indicated.
8. Primary care physicians should receive annual reports.
9. Perform comprehensive assessment at 6 years, including a repeat SCT,
fecal elastase testing, chest radiography (or other modalities of chest
imaging), and pulmonary function tests (which may include spirometry
and lung clearance index measurement).
10. Discuss results of this comprehensive assessment with parents to decide
on future care.
11. In case the child with CRMS is discharged from care at 6 years, that child
should be referred back to the CF center for a repeat comprehensive
assessment during adolescence or the young adult years.
Prevalence of CRMS
The prevalence of CRMS is difficult to establish because not all cases are
reported to national patient registries and there is a high rate of misclassifica-
tion of infants with CRMS as having CF.24 Data from the CFF Patient Registry

813
show that approximately 1 infant receives a diagnosis of CRMS for every 5

cases of CF. Data from studies across the world have shown a prevalence of 1
CRMS case for every 2 to 10 CF cases.21 In the United States, prevalence may
vary by state depending on the NBS protocol and IRT cutoff values. States
using an IRT/DNA algorithm and lower IRT cutoff values may identify more
CRMS cases because of detection of sequenced variants of unknown signifi-
cance. States such as California and New York, which use gene sequencing as
part of screening, identify even more of such variants (eg, California’s ratio is
1.5 CRMS cases per every 1 CF case).25
CRMS Outcomes
Data on long-term outcomes in infants with CRMS are limited because CF
NBS has only recently become widespread and CRMS has only recently been
recognized as a clinical and screening outcome. However, most infants with
CRMS will have normal growth and development and will not be reclassified
as having CF.21,26,27 The rate of CRMS to CF reclassification reported so far
ranges from 6% to 48%.24,25,28–33 The discrepancy in CF reclassification rates
among studies is due to the different definitions of inconclusive and final CF
diagnosis, different interpretations of individual CFTR variants (previously
variants of unknown significance later classified as causing CF), and different
durations of follow-up.23 The decision to reclassify CRMS to CF is ultimately
a clinical decision. However, some of the clinical events that may lead to
reclassification include at least one of the following:
X The person develops signs and symptoms suggestive of CF, which may
include recurrent isolation of Pseudomonas aeruginosa from respiratory
cultures.
X The person’s CFTR variants are reclassified as causing CF.
X Extensive genotyping reveals at least 2 CF-causing variants.
X The SCT result becomes elevated (≥ 60 mmol/L) at repeat testing.
X Functional assay results (eg, nasal potential difference, intestinal current
measurement, or human nasal epithelial cell assays) for CFTR indicate
CFTR dysfunction.
The importance of the primary care clinician and their relationship with the CF
center cannot be overemphasized. As parents become reassured by their child’s
lack of symptoms in the first few years after birth, children with CRMS can
be lost to follow-up at CF centers, and the responsibility for monitoring the
development of symptoms defaults to the primary care clinician.34 In this era
of genetic uncertainty, primary care clinicians should remain aware of the
limitations in predicting risk in this population, that CFTR variant classifica-
tions are constantly changing, and that signs and symptoms may emerge that
may or may not be related to CFTR dysfunction. Therefore, primary care

814
clinicians should rely on CF center expertise and guidance for monitoring

children who have received a diagnosis of CRMS. Following are the scenarios
that could trigger an immediate re-referral to a CF center:
X One or more episodes of severe dehydration with hyponatremia
X Persistent cough (more than 4 weeks), after exclusion of other causes,
such as asthma
X Two episodes of lower respiratory tract infection in a 12 month-period or
a total of 3 episodes all together
X Poor growth, after exclusion of other causes
X Signs of malabsorption, after exclusion of other causes
X One or more episodes of pancreatitis
X One or more episodes of severe constipation, distal intestinal obstructive
syndrome, and/or small-bowel obstruction
X Findings of air trapping, peri-bronchial thickening, mucous plugging, and/or
bronchiectasis in a chest radiograph or computed tomography scan
X Male infertility due to congenital bilateral absence of the vas deferens
key points
} Early diagnosis of CF through NBS results in improved nutritional outcomes but
has not affected the progression of CF lung disease.
} Algorithms for CF NBS that are based on DNA, as applied by all states in the
United States, increase the positive predictive value of screening but lead to
detection of many more carriers than those with CF.
} Infants with a positive CF NBS result should undergo an SCT to confirm the
diagnosis of CF.
} A negative CF NBS result does not rule out CF, and an SCT should be performed
in any person presenting with clinical features concerning for CF.
} An unintended consequence of CF NBS is the detection of CRMS in infants who
have a positive CF NBS result but are asymptomatic and have inconclusive
diagnostic test results.
} The vast majority of infants with CRMS do not develop CF, but a small percent-
age of them do. Therefore, monitoring and follow-up of infants with CRMS at a
CF center is advisable. For those who are not being followed at a CF center, it is
important for the primary care clinician to be aware of the scenarios that should
trigger re-referral to these centers.

815
References
1. Paranjape SM, Mogayzel PJ Jr. Cystic fibrosis. Pediatr Rev. 2014;35(5):194–205 PMID: 24790073
doi: 10.1542/pir.35.5.194
2. Farrell PM, Rosenstein BJ, White TB, et al; Cystic Fibrosis Foundation. Guidelines for diagnosis
of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report.
J Pediatr. 2008;153(2):S4–S14 PMID: 18639722 doi: 10.1016/j.jpeds.2008.05.005
3. Gibson LE, Cooke RE. A test for concentration of electrolytes in sweat in cystic fibrosis of the
pancreas utilizing pilocarpine by iontophoresis. Pediatrics. 1959;23(3):545–549 PMID: 13633369
doi: 10.1542/peds.23.3.545
4. Farrell PM, Kosorok MR, Laxova A, et al. Nutritional benefits of neonatal screening for cystic
fibrosis: Wisconsin Cystic Fibrosis Neonatal Screening Study Group. N Engl J Med.
1997;337(14):963–969 PMID: 9395429 doi: 10.1056/NEJM199710023371403
5. Grosse SD, Boyle CA, Botkin JR, et al; CDC. Newborn screening for cystic fibrosis: evaluation of
benefits and risks and recommendations for state newborn screening programs. MMWR Recomm
Rep. 2004;53(RR-13):1–36 PMID: 15483524
6. Farrell PM, White TB, Howenstine MS; et al. Diagnosis of cystic fibrosis in screened populations.
J Pediatr. 2017;181S:S33.e2–S44.e2 PMID: 28129810
doi: 10.1016/j.jpeds.2016.09.065
7. Farrell PM, White TB, Ren CL; et al. Diagnosis of cystic fibrosis: consensus guidelines from the
Cystic Fibrosis Foundation. J Pediatr. 2017;181S:S4.e1–S15.e1
PMID: 28129811 doi: 10.1016/j.jpeds.2016.09.064
8. Kloosterboer M, Hoffman G, Rock M, et al. Clarification of laboratory and clinical variables that
influence cystic fibrosis newborn screening with initial analysis of immunoreactive trypsinogen.
9. Therrell BL Jr, Hannon WH, Hoffman G, Ojodu J, Farrell PM. Immunoreactive trypsinogen
(IRT) as a biomarker for cystic fibrosis: challenges in newborn dried blood spot screening.
Mol Gen Metab. 2012;106(1):1–6 PMID: 22425451 doi: 10.1016/j.ymgme.2012.02.013
10. Sontag MK, Lee R, Wright D, Freedenberg D, Sagel SD. Improving the sensitivity and positive
predictive value in a cystic fibrosis newborn screening program using a repeat immunoreactive
trypsinogen and genetic analysis. J Pediatr. 2016;175:150.e1–158.e1 PMID: 27131402
doi: 10.1016/j.jpeds.2016.03.046
11. Kay DM, Langfelder-Schwind E, DeCelie-Germana J, et al; New York State Cystic Fibrosis
Newborn Screening Consortium. Utility of a very high IRT/No mutation referral category in
cystic fibrosis newborn screening. Pediatr Pulmonol. 2015;50(8):771–780 PMID: 26098992
doi: 10.1002/ppul.23222
12. Martiniano SL, Elbert AA, Farrell PM, et al. Outcomes of infants born during the first 9 years
of CF newborn screening in the United States: A retrospective Cystic Fibrosis Foundation
Patient Registry cohort study. Pediatr Pulmonol. 2021;56(12):3758–3767 PMID: 34469079
doi: 10.1002/ppul.25658
2009;155(6 suppl):S73–S93 PMID: 19914445 doi: 10.1016/j.jpeds.2009.09.001
14. Ramsey KA, Rosenow T, Turkovic L, et al; AREST CF. Lung clearance index and structural
lung disease on computed tomography in early cystic fibrosis. Am J Respir Crit Care Med.
2016;193(1):60–67 PMID: 26359952 doi: 10.1164/rccm.201507-1409OC
15. Rowe SM, Clancy JP. Advances in cystic fibrosis therapies. Curr Opin Pediatr.
2006;18(6):604–613 PMID: 17099358 doi: 10.1097/MOP.0b013e3280109b90
16. Perobelli S, Zanolla L, Tamanini A, Rizzotti P, Maurice Assael B, Castellani C. Inconclusive
cystic fibrosis neonatal screening results: long-term psychosocial effects on parents. Acta
Paediatr. 2009;98(12):1927–1934 PMID: 19689478 doi: 10.1111/j.1651-2227.2009.01485.x
17. Johnson F, Southern KW, Ulph F. Psychological impact on parents of an inconclusive diagnosis
following newborn bloodspot screening for cystic fibrosis: a qualitative study. Int J Neonatal
Screen. 2019;5(2):23 PMID: 33072982 doi: 10.3390/ijns5020023
18. Borowitz D, Parad RB, Sharp JK, et al; Cystic Fibrosis Foundation. Cystic Fibrosis Foundation
practice guidelines for the management of infants with cystic fibrosis transmembrane
conductance regulator–related metabolic syndrome during the first two years of life and beyond.
J Pediatr. 2009;155(6 suppl):S106–S116 PMID: 19914443 doi: 10.1016/j.jpeds.2009.09.003
19. Mayell SJ, Munck A, Craig JV, et al; European Cystic Fibrosis Society Neonatal Screening
Working Group. A European consensus for the evaluation and management of infants with an
equivocal diagnosis following newborn screening for cystic fibrosis. J Cyst Fibros.
2009;8(1):71–78 PMID: 18957277 doi: 10.1016/j.jcf.2008.09.005

816
20. Farrell PM, White TB, Ren CL, Hempstead SE, Accurso F, Derichs N, Howenstine M, McColley
SA, Rock M, Rosenfeld M, Sermet-Gaudelus I, Southern KW, Marshall BC, Sosnay PR.
Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation. J Pediatr.
2017;181S:S4-S15.e1. doi: 10.1016/j.jpeds.2016.09.064. Erratum in: J Pediatr. 2017;184:243.
PMID: 28129811.
21. Bergougnoux A, Lopez M, Girodon E. The role of extended CFTR gene sequencing in
newborn screening for cystic fibrosis. Int J Neonatal Screen. 2020;6(1):23 PMID: 33073020
doi: 10.3390/ijns6010023
22. Bombieri C, Claustres M, De Boeck K, et al. Recommendations for the classification of diseases
as CFTR-related disorders. J Cyst Fibros. 2011;10(suppl 2):S86–S102 PMID: 21658649
doi: 10.1016/S1569-1993(11)60014-3
23. Barben J, Castellani C, Munck A, et al; European CF Society Neonatal Screening Working
Group (ECFS NSWG). Updated guidance on the management of children with cystic fibrosis
transmembrane conductance regulator–related metabolic syndrome/cystic fibrosis screen
positive, inconclusive diagnosis (CRMS/CFSPID). J Cyst Fibros. 2021;20(5):810–819
PMID: 33257262 doi: 10.1016/j.jcf.2020.11.006
24. Ren CL, Fink AK, Petren K, et al. Outcomes of infants with indeterminate diagnosis detected by
cystic fibrosis newborn screening. Pediatrics. 2015;135(6):e1386–e1392 PMID: 25963008 doi:
10.1542/peds.2014-3698
25. Kharrazi M, Yang J, Bishop T, et al; California Cystic Fibrosis Newborn Screening Consortium.
Newborn screening for cystic fibrosis in California. Pediatrics. 2015;136(6):1062–1072
PMID: 26574590 doi: 10.1542/peds.2015-0811
26. Gonska T, Keenan K, Au J, et al. Outcomes of cystic fibrosis screening-positive infants with
inconclusive diagnosis at school age. Pediatrics. 2021;148(6):e2021051740 PMID: 34814176 doi:
10.1542/peds.2021-051740
27. Ginsburg D, Wee CP, Reyes MC, Brewington JJ, Salinas DB. When CFSPID becomes CF.
J Cyst Fibros. 2022;21(1):e23–e27 PMID: 34756682 doi: 10.1016/j.jcf.2021.06.012
28. Salinas DB, Azen C, Young S, Keens TG, Kharrazi M, Parad RB. Phenotypes of California CF
newborn screen-positive children with CFTR 5T allele by TG repeat length. Genet Test Mol
Biomarkers. 2016;20(9):496–503 PMID: 27447098 doi: 10.1089/gtmb.2016.0102
29. Ooi CY, Castellani C, Keenan K, et al. Inconclusive diagnosis of cystic fibrosis after newborn
screening. Pediatrics. 2015;135(6):e1377–e1385 PMID: 25963003 doi: 10.1542/peds.2014-2081
30. Munck A, Bourmaud A, Bellon G, Picq P, Farrell PM; DPAM Study Group. Phenotype of
children with inconclusive cystic fibrosis diagnosis after newborn screening. Pediatr Pulmonol.
2020;55(4):918–928 PMID: 31916691 doi: 10.1002/ppul.24634
31. Groves T, Robinson P, Wiley V, Fitzgerald DA. Long-term outcomes of children with
intermediate sweat chloride values in infancy. J Pediatr. 2015;166(6):1469–1474.e1–3
PMID: 25812778 doi: 10.1016/j.jpeds.2015.01.052
32. Levy H, Nugent M, Schneck K, et al. Refining the continuum of CFTR-associated disorders in
the era of newborn screening. Clin Genet. 2016;89(5):539–549 PMID: 26671754
doi: 10.1111/cge.12711
33. Terlizzi V, Mergni G, Buzzetti R, Centrone C, Zavataro L, Braggion C. Cystic fibrosis screen
positive inconclusive diagnosis (CFSPID): experience in Tuscany, Italy. J Cyst Fibros.
2019;18(4):484–490 PMID: 31005549 doi: 10.1016/j.jcf.2019.04.002
34. Salinas DB, Sosnay PR, Azen C, et al. Benign and deleterious cystic fibrosis transmembrane
conductance regulator mutations identified by sequencing in positive cystic fibrosis newborn
screen children from California. PLoS One. 2016;11(5):e0155624 PMID: 27214204

CHAPTER
47
Primary Ciliary Dyskinesia and
Other Genetic Lung Diseases
Madhuri Penugonda, MD
Nico W. Vehse, MD
Thomas W. Ferkol, MD
Introduction
Several respiratory disorders in children have a genetic predisposition; how-
ever, some of these disorders may not manifest until later in life. Recognizing
the clinical presentations will aid in early diagnosis. Specific therapies can
then be offered, which can decrease the severity of the lung disease or delay
the progression. Chronicity of respiratory symptoms is a better indication of
a genetic defect than severity. An inherited component should be suspected
when chronic lung disease presents with other disease syndromes, such
as pancreatic insufficiency, heat intolerance, male sterility, situs inversus,
and emphysema at a young age. When a genetic disorder is identified or
suspected, referral to a genetic counselor should be considered to assist in
discussions of prognosis and risk to future pregnancies.
A number of congenital disorders that are not pulmonary in origin nonetheless
have significant respiratory complications; these are discussed in the latter
part of this chapter.
Primary Ciliary Dyskinesia

Introduction, Terminology, and Epidemiology
Primary ciliary dyskinesia (PCD) is a rare, inherited ciliopathy and the first
human disease linked to motile cilia dysfunction. The frequency of primary
ciliary dyskinesia has been estimated to be between 1 in 10,000 and 20,000
live births based on the prevalence of situs inversus totalis and bronchiectasis
in population surveys performed in Norway and Japan.1,2 A more recent study
examining allele frequency of disease-causing variants in genes associated
with PCD in populations worldwide estimated a minimum global prevalence
817

818
of the disease to be 1:7,500.3 Although PCD is a rare lung disease, its preva-
lence in children with repeated respiratory infections was estimated to be as
high as 5%.4
History
In 1904, the association between situs inversus and bronchiectasis was first
described.5 Thirty years later, Kartagener6 described a clinical syndrome
characterized by the triad of situs inversus totalis, chronic sinusitis, and
bronchiectasis. Afzelius and colleagues7 found that individuals with chronic
sinusitis, bronchiectasis, and situs inversus had ultrastructural defects of the
ciliary axoneme, and coined the term immotile cilia syndrome.7 Later studies of
affected individuals showed that motile cilia had uncoordinated and ineffective
beating, and the name was changed to primary ciliary dyskinesia.
Motile Cilia Biology

The upper and lower respiratory tracts are lined by a ciliated, pseudostratified
columnar epithelium that is critical for mucociliary clearance. Other epithelia
are lined by motile cilia, including the ependyma lining the ventricles in the
brain and Fallopian tubes. Spermatozoa flagellum has structure and motility
fundamentally similar to respiratory cilia.
Each ciliated respiratory epithelial cell contains roughly 200 cilia anatomically
and functionally oriented. Motile cilia are tiny (6 mcm in length), hair-like
organelles that beat rhythmically, producing a synchronized wave that moves
fluid and mucus from the conducting airways, paranasal sinuses, and eusta-
chian tubes. The central fibrillar structure, or axoneme, consists of an array
of longitudinal microtubules, organized as 9 microtubular doublets arranged
in an outer circle around a central pair, creating the characteristic “9+2” con-
figuration (Figure 47‑1).8 The outer doublets of motile cilia have distinct inner
and outer arms, consisting of several heavy, intermediate, and light chains.
Figure 47‑1. Schematic diagrams that show the microtubular structure and ultrastructural
elements of normal motile “9+2,” nonmotile primary “9+0,” and motile nodal “9+0” ciliary
axonemes.
Reprinted from Horani A, Ferkol TW. Advances in the genetics of primary ciliary dyskinesia: clinical
implications. Chest. 2018;154(3):645-652. Copyright © 2018 American College of Chest Physicians.

819
Chapter 47—Primary Ciliary Dyskinesia and Other Genetic Lung Diseases
The axonemal dyneins in the outer dynein arm are multiheaded motor proteins
that generate force through adenosine triphosphatase activity. The inner dynein
arm regulates microtubule sliding and ciliary motion through the dynein
regulatory complex.9 The dynein regulatory complex is located within the
nexin link, an elastic element that connects adjacent outer doublets and limits
microtubular sliding.10 The radial spokes connect the central apparatus and
outer doublets, and also regulate dynein activity. Normal beat frequency of
human motile cilia typically ranges between 8 and 14 beats per second but
can be altered by various environmental factors.
There are other cilia in the body. Transiently expressed during embryonic
development, nodal cilia are another class of motile cilia with a “9+0” con-
figuration (Figure 47-1) that generate leftward flow of extracellular fluid
across the nodal surface, activating a signaling cascade that establishes left-
right sidedness. In absence of flow, left-right laterality is random, leading to
situs inversus totalis and heterotaxy.11,12 Primary (sensory) cilia are non-motile
monocilia on the surface of most nondividing cells that have “9+0” micro-
tubule configuration (Figure 47-1). They are signaling organelles that sense
the extracellular environment and have been linked to a growing number of
diseases, termed ciliopathies.13
Genetics
Primary ciliary dyskinesia is a genetically heterogeneous disorder without
apparent racial or sex predilection.14 In most cases, it is an autosomal-
recessive disease, but X-linked inheritance patterns have been identified.15,16
To date, more than 50 genes have been linked to motile ciliopathies, and
approximately 70% of all patients tested have biallelic pathogenic mutations
of these genes.17 Many of these genes have been linked to specific ultrastruc-
tural defects or other ciliary abnormalities. For instance, mutations in CCNO
and MCDIAS lead to chronic respiratory symptoms due to reduction of motile
cilia on the airway epithelial surface.18,19 Pathogenic GAS2L2 variants have
been identified in patients with clinical features consistent with PCD, related
to ciliary disorientation.20
Genotype-phenotype relationships have emerged in PCD, and respiratory
disease severity and progression have been linked to specific mutated genes.
Patients with loss-of-function mutations in CCDC39 and CCDC40 have been
associated with more severe lung disease.21–23 In contrast, individuals with
mutations in RSPH1 generally have milder respiratory phenotypes compared
to other forms of PCD.24

820
Clinical Features
Primary ciliary dyskinesia leads to bronchiectasis similar to other airway
diseases, but PCD has 4 cardinal clinical features that differentiate it from
other respiratory diseases (Figure 47-2).25
Neonatal Chronic Chronic nasal Situs inversus

respiratory distress cough congestion totalis
No No No No
Yes Sensitivity: Yes Sensitivity: Yes Sensitivity: Yes Sensitivity:

81% 97% 97% 46%
Specificity: Specificity: Specificity: Specificity:
68% 17% 19% 92%
Term gestation Year-round Year-round Other laterality

defects
No No No
Sensitivity:
Yes Yes Yes Yes No
53%
Specificity:
85%
Supplemental O2 Wet Began
requirement ≥1d cough ≤6m of age
No No No
Sensitivity:
Yes Yes Yes
74%
Specificity:
60%
Meconium Began
aspiration ≤6m of age
Yes No
No Sensitivity: Yes Sensitivity:

57% 62%
Specificity: Specificity:
89% 74%
Feature 1 Feature 2 Feature 3 Feature 4
Unexplained Early onset, Early onset, Laterality defect
neonatal year-round year-round
respiratory distress wet cough nasal congestion
Figure 47‑2. Diagram showing the 4 criteria-defined clinical features most predictive of primary
ciliary dyskinesia.
Reprinted with permission of the American Thoracic Society. Copyright © 2016 American Thoracic Society.
All rights reserved. Leigh MW, Ferkol TW, Davis SD, et al. Clinical features and associated likelihood of
primary ciliary dyskinesia in children and adolescents. Ann Am Thor Soc. 2016;13(8):1305–1313. Annals of the
American Thoracic Society is an official journal of the American Thoracic Society.

821
Figure 47‑3. Anteroposterior chest radiograph

showing situs inversus totalis and atelectasis of
the morphological left upper lobe in a 1-day-
old neonate with primary ciliary dyskinesia.
Most children with PCD present with respiratory distress shortly after term
birth without clear explanation, characterized by tachypnea, persistent
hypoxemia, and upper and middle lobe atelectasis (Figure 47‑3). Affected
neonates often require supplemental oxygen or positive-pressure ventilator
support for more than 24 hours.
Infants with PCD often have daily, nonseasonal nasal congestion and rhinitis
that typically begins before 6 months of age.
Affected individuals have chronic, year-round productive (wet) cough that also
begins in early infancy. Bronchiectasis involving the morphological right
middle lobe and lingula is common. The cough can vary in severity but never
completely resolves, even following antibiotic therapy.
Left-right laterality defects occur in approximately half of patients with
PCD, usually manifested as situs inversus totalis with transposition of the
thoracic and abdominal organs (Figure 47‑3). Conversely, 25% of patients
with situs inversus totalis will have PCD. As many as 12% of patients with
PCD have heterotaxy associated with congenital heart disease, asplenia, or
polysplenia.26
These 4 criteria can be used to identify at-risk children and direct further
diagnostic testing (Figure 47-2). If 2 of these features are present, the
sensitivity and specificity for PCD are 80% and 72%, respectively. If 3 criteria
are present, they are 50% and 96%.25Another validated diagnostic predictive
tool, PICADAR, has also been created to estimate the probability of a positive
diagnosis.27
Middle ear disease is a frequent clinical manifestation in PCD, beginning in
early infancy, with varying degrees of chronic otitis media with effusion
complicated by conductive hearing loss. However, in North America,
recurrent and persistent middle ear effusions are common in otherwise healthy
infants and toddlers, often requiring tympanostomy tube placement. Thus, this
finding has not proved to be useful in identifying children with PCD.25

822
Male and female subfertility are common features in PCD, secondary to sperm
dysmotility and ciliary dysfunction in the Fallopian tubes, respectively.28
While described in the literature, neonatal hydrocephalus is a rare clinical
manifestation of classic forms of PCD.29
Patients who have sensory (primary) ciliopathies can have overlapping clinical
features with PCD, such as X-linked blindness related to mutations in the
retinitis pigmentosa GTPase regulator gene.30–32
Diagnostic Testing
While diagnostic approaches for PCD have evolved, clinicians should only
perform testing in patients who have a compatible clinical phenotype (see
Clinical Features). It is also important for clinicians to understand that there is no
single diagnostic test for PCD, and they should thoroughly evaluate suspected
patients and not rely on an individual test for diagnosis (Figure 47‑4).33
For more than 4 decades, transmission electron microscopy evaluating
the ciliary axoneme for ultrastructural defects has been the conventional
diagnostic approach, despite its limitations. Five general ultrastructural
phenotypes have been associated with PCD, including outer dynein arm
defects, inner and outer dynein arm defects, microtubular disorganization
with inner dynein arm defects, radial spokes and central apparatus defects,
and normal ultrastructure. Absent inner dynein arms alone are a rare cause of
PCD; often they are due to an acquired defect or may be an electron micro-
scopic artifact.34
Immunofluorescent staining of ciliary protein markers is a newer method
to detect ultrastructural abnormalities in PCD and, in the future, may over-
come some of the limitations of transmission electron microscopy.35
Nasal nitric oxide (nNO) measurement has been shown to be a useful screening
tool for PCD in patients 5 years and older, provided cystic fibrosis (CF) is
excluded.36 However, people who have mutations in some PCD-associated
genes can have nondiagnostic nNO values.37 It is also important to remember
that reduced nNO concentrations alone are never sufficient to make the diagno-
sis of PCD, since people with CF or primary immunodeficiencies (conditions
that have clinical features that overlap with PCD) can have reduced levels.38,39
High-speed video microscopy has been used as a diagnostic tool, primarily
in some European centers, assessing motile ciliary beat patterns and frequency
in respiratory epithelia.40 This approach has not been standardized across
centers and still needs to be validated against other diagnostics.
Ciliary beat analyses using standard bright-field microscopy can be mislead-
ing, since they can be caused by acquired ciliary defects, and should never be
used as a screen or diagnostic tool for PCD.

823
At least 2 of the 4 major clinical features for PCD:

• Unexplained neonatal respiratory distress in term infant
• Year-round daily cough beginning before 6 months of age No
• Year-round daily nasal congestion beginning before 6 months of age
• Organ laterality defect
PCD unlikely
Yes
Access to nNO testing (with chemiluminescence device and standardized protocol) at

specialty center and cooperative patient ≥5 years old, capable of performing nNO testing maneuver
Yes to both No to either

(preferred pathway when ≥5 years old
Nasal nitric oxide measurement Extended genetic testing panela
Consistently low Normal Biallellic Single No pathogenic

nNO level on nNO level pathogenic pathogenic variants in
repeated measures variants in variant in PCD-associated
PCD-associated PCD-associated genesb
gene geneb,c
Presumed diagnosis of PCD diagnosis less likely,

PCD if CF excluded consider further testing
for PCD, if strong clinical
features, or for primary Diagnosis Electron microscopy
immunodeficiency of PCD of ciliary ultrastructure
Confirm with corroborative PCD testing, Recognized ciliary Normal ciliary Inadequate sample
including extended genetic panel testing ultrastructural ultrastructure or indeterminate
(first line) and TEM of ciliary ultrastructure defectd analysis
Normal or No or single Diagnosis Possible PCD diagnosis. Unknown.

non-diagnostic pathogenic variants of PCD Consider referral to Consider repeat
ciliary in PCD-associated PCD specialty center or TEM, referral to PCD
ultrastructure genesb,c testing for primary specialty center, or
immunodeficiency testing for primary
immunodeficiency
Recommend
testing for primary
immunodeficiency
Figure 47‑4. Revised diagnostic algorithm for primary ciliary dyskinesia.

a
Genetic panels testing for mutations in >12 disease-associated PCD genes, including deletion/duplication
analysis.
b
In genes associated with autosomal recessive trait.
c
In presence of variants of unknown significance.
d
Known disease-associated TEM ultrastructural defects include outer dynein arm defects, outer dynein
arm plus inner dynein arm (IDA) defects, IDA defect with microtubular disorganization, and absent central
pair, identified using established criteria.
CF = cystic fibrosis; nNO = nasal nitric oxide; PCD = primary ciliary dyskinesia; TEM = transmission electron
microscopy.
Shapiro AJ, Davis SD, Leigh MW, Knowles MR, Lavergne V, Ferkol T. Limitations of nasal nitric oxide testing
in primary ciliary dyskinesia. Am J Respir Crit Care Med. 2020;202(3):476-477. The American Journal of
Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

824
Finally, as more primary PCD genes have been discovered, genetic testing
has become the first-line diagnostic tool in North America.33
The early clinical features of PCD distinguish it from other, more common
pediatric respiratory diseases, such as asthma.
Cystic Fibrosis
Because CF and PCD can have similar clinical phenotypes, including
chronic sinusitis and bronchiectasis, sweat chloride measurement or testing
for mutant CF transmembrane conductance regulator (CFTR) alleles is
indicated. Indeed, CF must be excluded, since these patients can also have
reduced nasal nitric oxide levels, though often not as low as patients with
PCD.38
Primary Immunodeficiencies
Because immunological defects can lead to chronic suppurative infections
involving the lungs, middle ear, and paranasal sinuses, evaluation for possible
primary immunodeficiency should be considered, including complete blood
cell counts with leukocyte differential, lymphocyte subpopulation analyses,
serum quantitative immunoglobulin and complement concentrations, neutro-
phil killing assays, and serological responses to specific immunizations.
Protracted Bacterial Bronchitis
Characterized by a persistent, isolated wet cough lasting for more than
4 weeks, protracted bacterial bronchitis is a recently described clinical
condition that has features similar to PCD in young children. However, the
cough caused by protracted bacterial bronchitis should resolve following
treatment with systemic antibiotics.
Infants and children with recurrent protracted bacterial bronchitis should
be tested for CF, immunodeficiencies, and possibly PCD.41
Management
Individuals with PCD should be regularly evaluated in a specialized center
with spirometry, surveillance respiratory cultures, chest imaging, and audio-
logical testing performed according to the PCD Foundation guidelines.42 A
list of certified centers can be found on the PCD Foundation website (see
Family and Patient Resources at the end of this chapter).
No therapies have been shown to correct ciliary dysfunction.
Because patients with PCD are dependent on cough to mobilize infected
secretions from the lower respiratory tract, airway clearance maneuvers are
key. Patients are encouraged to cough and participate in vigorous aerobic
exercises to clear secretions. Cough suppressants should be avoided.

825
Preventive counseling should include advice regarding avoidance of airborne

irritants and pollutants, such as tobacco smoke.
Individuals with PCD should receive scheduled immunizations against
pertussis, measles, influenza, Streptococcus pneumoniae, and Hemophilus
influenzae type b.
Antibiotic therapy for respiratory exacerbations or superinfections is impor-
tant for symptomatic relief and to prevent irreversible airway damage. Some
people with PCD benefit from use of azithromycin thrice weekly, which
reduces the rate of respiratory exacerbations.43 Other preventive antibiotic
therapies may be considered on a case-by-case basis. In contrast to CF, no
studies have shown that eradication of Pseudomonas aeruginosa impacts
later disease progression or clinical outcomes.
While inhaled β-adrenergic bronchodilators increase ciliary beat frequency in
normal epithelial cells, there are no data showing that they correct or reduce
cilia dysfunction in PCD.
Inhaled topical corticosteroids, other anti-inflammatory agents, and nebulized
hypertonic saline are often prescribed, but little has been published that
clearly demonstrates their efficacy in primary ciliary dyskinesia.
The inhaled mucolytic agent dornase alfa should be used with caution, since a
larger, multicenter study in non-cystic fibrosis bronchiectasis found worsening
lung function in the treatment group as compared to controls.44
Evidence concerning the benefits of tympanostomy with ventilation tube
placement is mixed. Tympanostomy placement may improve hearing but
is often complicated by otorrhea and persistent membrane perforation.45
Hearing aids should be used when necessary.
Rhinosinusitis is common in PCD, and functional endoscopic sinus surgery
and daily nasal saline irrigation may relieve severe nasosinal symptoms that
have not responded to antibiotic therapy. However, it is unclear whether this
intervention improves long-term clinical outcomes or decreases episodes of
symptomatic sinusitis.46
Historically, lobectomy was performed in patients with persistent, localized
bronchiectasis or atelectasis, usually involving the right middle lobe, but there
is no evidence demonstrating any clinical benefits.
Heart-lung and bilateral lung transplantation has been performed in patients
with end-stage lung disease, though situs inversus totalis could potentially
present technical challenges for the surgeon.

826
Prognosis
Primary ciliary dyskinesia can be compatible with a normal or near-normal
life span. However, progression of lung disease is variable and some patients
die early. Two studies indicated that early, aggressive airway therapy with
airway clearance and antibiotics can slow progression of lung disease.47,48
Other Genetic Lung Diseases

Mounier-Kuhn Syndrome
Mounier-Kuhn syndrome is a rare congenital disorder characterized by
tracheobronchomegaly. Prevalence estimates are 0.4% to 1.6% with an age
range from 18 months to 86 years based on published case reports.49
Pathogenesis
The disease is caused by a congenital deficiency (absence or atrophy) of large
airway smooth muscle and elastic fibers.50 This leads to enlargement of the
trachea and segmental bronchi, resulting in impaired mucociliary clearance
and retention of airway secretions. It has been associated with Ehlers-Danlos
syndrome, cutis laxa, and Kenny-Caffey syndrome.51 Mounier-Kuhn syn-
drome is generally diagnosed in the third to fifth decade of life and is more
common in men.49 A familial form has been described, but no specific gene
has been identified.50
Clinical Features
Patients commonly present with chronic cough, purulent sputum, dyspnea,
and recurrent pneumonia. Hemoptysis, nail clubbing, pneumothoraces,
bronchiectasis, emphysema, pulmonary fibrosis, and respiratory failure
may be present. It is unclear if tracheobronchomegaly is progressive, but
it is often misdiagnosed as asthma, tuberculosis infection, or chronic
obstructive pulmonary disease.49
Diagnosis
Pulmonary function tests may be normal or show airflow limitation with
some bronchial hyperreactivity. The trachea size will exceed the size of
the vertebral column on chest radiograph. Dynamic CT scan of the chest is
diagnostic and will show dilation of the trachea and bronchi49 (Figure 47‑5).
Management
Treatment is supportive with antibiotics, vaccinations against influenza and
pneumococcal infections, chest physiotherapy, pulmonary rehabilitation,
oxygen, and noninvasive positive-pressure ventilation (NPPV) for chronic
hypercapnic respiratory failure. Stenting of the trachea has been used but has
a high complication rate. Bronchodilators and corticosteroids may be helpful
for bronchial hyperreactivity. Surgical tracheobronchoplasty is used in select
patients and lung transplant for end-stage lung disease.52

827
Figure 47‑5. Tracheobronchomegaly in Mounier-Kuhn syndrome. A. Chest radiograph

showing large trachea. B. & C. Computerized tomography showing tracheal size.
Reprinted with permission from Simkins A, Abishek M, Cherian SV, Trujillo DO, Estrada-Y-Martin
RM. Mounier-Kuhn syndrome. BMJ Postgrad Med J. 2017;93(1104):642.
Williams-Campbell Syndrome
Williams-Campbell syndrome is a rare congenital disorder characterized by
diffuse bronchomalacia. It was initially described in 1960 as a rare form of
bronchiectasis.53 Familial cases have been reported, but no specific gene has
been identified.53
Pathogenesis
Williams-Campbell syndrome is caused by a congenital defect or absence of
cartilage in the second to seventh divisions of bronchi. This leads to airway

828
instability with airway collapse, retention of secretions, and ultimately bron-

chiectasis.53 There is no evidence that the cartilage defect occurs outside the
lungs. Trachea and central bronchi caliber are normal. It has been associated
with other congenital anomalies such as polysplenia, malrotation of the
abdominal viscera, congenital cardiac disease, and bronchial isomerism.54
Clinical Features
Patients often present early with recurrent pneumonia, chronic productive
cough, wheeze, and nail clubbing.
Diagnosis
Williams-Campbell syndrome is diagnosed by an appropriate clinical history,
radiographic evidence of expiratory airway collapse, and exclusion of other
common causes of congenital and acquired bronchiectasis. Pulmonary
function tests may suggest an obstructive or restrictive defect.53,54 A CT scan
of the chest is diagnostic and will show extensive peripheral bronchiectasis.55
A CT bronchoscopy with 3D reconstruction of the bronchial tree is a better
option and may show absences of cartilage ring impressions in the bronchial
wall.55
Management
Treatment is supportive with chest physiotherapy, airway clearance, and
antibiotics for suppurative infections and oxygen and NPPV for chronic
respiratory failure. Surgical resection of affected lobes has shown no benefit.
Lung transplant is for end-stage lung disease.
Pulmonary Lymphangioleiomyomatosis
Pulmonary lymphangioleiomyomatosis (LAM) is a rare multisystem disorder
that mainly affects postpubertal females.56 There have been rare cases in pre-
pubertal girls and in boys.56 It occurs sporadically or in patients with tuberous
sclerosis complex. Lymphangiomatosis is often confused with LAM, but
lymphangiomatosis is associated with abnormal proliferation of lymphatic
tissue and preservation of the lung parenchyma.57
Pathogenesis
The disease is characterized by proliferation of neoplastic cells resembling
smooth muscle cells within the lung, kidney, and lymphatics. Within the
lung, there is cyst formation in the parenchyma resulting in destruction and
risk of pneumothoraces. With disease progression, blood vessels can also
become affected, leading to impaired diffusion, hemosiderosis, and hemopty-
sis. Additionally, lymphatics may become involved, leading to chylothorax.
Female hormones may contribute to the disease pathogenesis. It is largely
limited to postpubertal, premenopausal females with reports of exacerbations

829
with pregnancy, menstruation, and estrogen use.58 It has also been associated
with the neurocutaneous syndrome tuberous sclerosis, suggesting a genetic
component. There are 2 forms of LAM: tuberous sclerosis complex (TSC)-
associated LAM and a sporadic type. Hamartin and tuberin proteins, which
are encoded on TSC1 gene and TSC2 gene, respectively, are absent.58,59
Patients with TSC should be screened for LAM at the age of 18 years with a
computed tomography (CT) scan of the chest.59
Clinical Features
Presenting symptoms vary and include dyspnea, chronic dry cough, wheeze,
hemoptysis, pneumothorax, cyanosis, cor pulmonale, chylous pleural effusions
and respiratory failure.
Diagnosis
Pulmonary function tests show variable patterns from normal to obstructive,
restrictive, and mixed.58 Diffusion capacity for carbon monoxide is generally
decreased. Chest radiographs may show normal lung tissue to reticulonodular
interstitial infiltrate to end-stage honeycombing. Additionally, pneumothorax
and pleural effusions may be seen on radiographs. A high-resolution CT scan
of the chest shows diffuse, thin-walled cysts, which are classic signs of LAM.
Diagnosis can often be determined based on classic CT appearance and
associated findings of LAM. If diagnosis remains uncertain, histologic
diagnosis from lung biopsy or transbronchial biopsy may be necessary and is
the gold standard.
Management
Treatment is symptomatic, primarily reversing complications such as pneumo-
thorax, ascites, and hemorrhage. General pulmonary support includes supple-
mental oxygen where appropriate, prophylactic vaccination, and pulmonary
rehabilitation. Scuba diving should be avoided, but air travel is safe for most
patients with LAM because the risk of a pneumothorax is low. Pleurodesis
for recurrent pneumothoraces and thoracic duct ligation for chylothorax may
be needed. There have been some studies using hormonal therapy with
variable results.58 In individual cases, progesterone may be tried, as some
case reports and retrospective studies have shown some reduction in the
rate of lung function decline. Currently, sirolimus, a US Food & Drug
Administration–approved mTOR inhibitor, has shown improvements in lung
function and quality of life.60 A potential prognostic biomarker in LAM may
be serum VEGF-D, which decreases with sirolimus. Lung transplant may be
an option in end-stage lung disease; however, there are some reports of
recurrence after lung transplant. Survival is about 10 years, with most children
eventually succumbing to progressive respiratory failure.58

830
Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin (AAT) deficiency is an autosomal recessive disorder,
with genetic origin from Western/Northern European regions, that was first
recognized in 1963. It is mainly a disease of adults characterized by severe
emphysema, but it can rarely show manifestations in children, who mostly
present with liver disease.61 Prevalence is 1 in 2,500 in the general North
American population.
Pathogenesis
Alpha-1 antitrypsin is a 394-amino acid glycoprotein that inhibits the activity
of certain proteolytic enzymes. It is a serine protease inhibitor encoded by
SERPINA 1 gene (also known as protease inhibitor [PI]) that is located on the
long arm of chromosome 14 and is mainly synthesized by hepatocytes. More
than 100 alleles have been identified. M alleles are most common and are
associated with normal AAT serum protein levels. ZZ, SS and SZ genotypes
have decreased AAT levels and develop pulmonary or hepatic symptoms.
MS or MZ genotypes also have decreased levels but rarely develop clinical
symptoms.61 Normal lung homeostasis and repair requires a balance between
protease inhibitors and proteolytic enzymes. Neutrophil elastase is the main
protease in the lung, where it degrades elastin, collagen, proteoglycan, and
other proteins in the alveolar wall. If left unchecked, this process can lead to
alveolar destruction. Alpha-1 antitrypsin is the main antineutrophil elastase
and prevents degradation of the lung architecture. An imbalance between
protease inhibitors and proteolytic enzymes can lead to lung damage such as
that seen in emphysema. Smoking is an independent risk factor for emphy-
sema, though in individuals who are deficient in AAT, it can hasten the
development of disease secondary to the accumulation of lung inflam-
matory cells, release of proteases from inflammatory cells, and release of
smoke-associated oxidants that inhibit antitrypsin.62 Together, these further
contribute to protease-antiprotease imbalance and, ultimately, lung damage.62
Clinical Features
Most people with AAT deficiency do not present with respiratory symp-
toms until the third or fourth decade of life, or a decade earlier in those who
smoke.62 There are a few rare cases of emphysema in children with severe
AAT deficiency.61,62 However, pulmonary function abnormalities, complaints
of wheezing, and diagnosis of asthma are not uncommon in the second decade
of life, especially if firsthand or secondhand smoking is present.62 Children
may have wheezing, chronic cough, or dyspnea on exertion. Liver disease,
such as jaundice, hepatitis, and cirrhosis, is associated with lung disease in
children. In adults, AAT deficiency usually presents as progressive dyspnea
and panacinar emphysema.

831
Physical examination findings are usually normal, though growth restriction,

digital clubbing, and signs of chronic obstructive pulmonary disease, such as
dyspnea, tachypnea, hyperexpansion, or barrel chest, may be present with
advanced lung disease.
Chest radiographs may show hyperinflation with bibasilar hyperlucency.
High-resolution chest CT is more sensitive than plain radiography and may
demonstrate emphysema and bronchiectasis.
Findings of pulmonary function testing may be normal, though as the disease
progresses, evidence of chronic obstructive pulmonary disease develops with
an obstructive pattern on spirometry, air trapping on lung volume measure-
ments, and diffusion impairment.
Diagnosis
Alpha-1 antitrypsin deficiency should be considered in cases of prolonged
neonatal jaundice, liver disease in any age group, and adults with emphysema,
bronchitis, and late-onset asthma. The differential diagnosis should include
asthma, CF, and immunodeficiencies. Serum AAT levels can be measured
and the risk of disease predicted from the relative deficiency, as 100% of
individuals with no detectable AAT develop emphysema and 60% to 85% of
those with severe deficiency develop disease.63 Alpha-1 antitrypsin is an acute
phase reactant, and levels may be falsely elevated with any acute or chronic
inflammation, such as infection, stress, or pregnancy. Currently, there is no
routinely available method for prenatal diagnosis, but protein phenotyping
and genotyping are available to confirm the diagnosis, aid in genetic counsel-
ing for families, and predict the disease course.61
Management
The clinical course of the lung disease in AAT deficiency is variable, sug-
gesting a prominent role for environmental or genetic modifiers.63 Tobacco
smoke exposure seems to be the most important risk factor. Therefore,
avoiding smoke exposure is paramount in prevention of lung disease in
patients known to be AAT deficient. Augmentation therapy, which consists
of weekly intravenous infusions of AAT, is proving to be safe and effective
at raising AAT levels, may inhibit the progression of lung disease, and should
be considered in consultation with a pulmonary specialist.64 Supportive
therapies include early antibiotics for bacterial infections, bronchodilators,
nutritional support, and oxygen as needed for hypoxemia. Patients should
receive routine vaccinations (yearly influenza and lifetime pneumococcal
vaccinations). Surgical options, such as bullectomy and, ultimately, lung
transplant, may be needed in cases of severe disease. Novel therapies under
investigation include gene transfer techniques, induced pluripotent stem cells,
chemical chaperones, hepatocyte transplantation, and autophagy inducers.

832
Pulmonary Complications of Other Congenital Disorders

Achondroplasia
Achondroplasia is the most common form of short-limbed dwarfism. It is
classified as a chondrodysplasia and is autosomal dominant. It is caused by
mutations in the fibroblast growth factor receptor- type 3 (FGFR3), which is
on chromosome 4. The average adult height is 131 cm (51.5 inches) for males
and 123 cm (48.5 inches) for females. The prevalence is 1 in 25,000 to 30,000.
Cognitive function is normal in most, but motor delays are common.
Clinical Features
The major features of achondroplasia are hypotonia, macrocephaly with fron-
tal bossing, midface retrusion, short stature with rhizomelic disproportion,
and small thoracic cavity. The large head and abnormality at the craniocervi-
cal junction contribute to significant mortality in the first year after birth.
The risk for sudden death is 2% to 5%, with the major cause of death being
spinal cord compression. Central apnea may result from vertebral artery
compression at the craniocervical junction, and obstructive apnea may
result from midface hypoplasia.65
Respiratory difficulty is commonly seen in achondroplasia due to restrictive
lung disease secondary to small chest cavity. Patients also have central and
obstructive sleep apnea. Untreated sleep apnea can cause serious develop-
mental consequences and cor pulmonale.66,67 Tracheobronchomalacia has
also been seen.
Diagnosis
Diagnosis is established by clinical and radiographic assessment plus genetic
testing.65 Diagnosis can be suspected based on fetal ultrasonography. A
polysomnogram is a necessary part of standard assessment.
Management
Caregivers must be aware of the risk of craniocervical compression, which, in
extreme form, may result in atlantoaxial dislocation. Endotracheal intubation
is difficult because of the midface hypoplasia and the necessity of avoiding
extension of the head (backward). Fiberoptic bronchoscopy assistance may
be the safest way to intubate, particularly during infancy and early childhood.
Referral to pulmonology and neurology specialists in the first year is impor-
tant to diagnose respiratory disorders as described and assess the cranio-
cervical area of the spinal column. Treatment of obstructive sleep apnea may
be tonsillectomy and adenoidectomy with hospitalization for postoperative
complications. Noninvasive positive-pressure ventilation (continuous positive
airway pressure/bilevel positive airway pressure) treatment may be needed.

833
Arthrogryposis Multiplex Congenita

The defining feature of arthrogryposis multiplex congenita (AMC) is multiple
contractures that are present at birth.
Pathogenesis
During embryogenesis, decreased fetal movement causes extra connective
tissue to develop around joints, which results in fixation of the joint, leading to
contractures and contributing to decreased chest wall movement. Decreased
fetal movement may result from multiple fetal disorders or maternal issues.
The earlier in pregnancy that the fetal movement is reduced, the more severe
the joint abnormalities. Although a genetic cause may be identified in 30%
of cases, most cases are of undetermined etiology.
Clinical Features
The deformities are present at birth, and the condition is not progressive. The
condition that causes AMC (eg, muscular dystrophy) may progress.
Classic arthrogryposis is also known as amyoplasia with symmetrical involve-
ment of limb deformity and normal intelligence. The pulmonary complications
tend to be related to the size and shape of the chest wall, which may result in a
restrictive defect. Williams et al68 reported significant pulmonary findings in
children with distal arthrogryposis type 5 (DA5). Although this report is from
Salt Lake City, UT (altitude 7,000 feet) and refers to DA5, the conclusions
apply to children at other altitudes, including sea level and other variants of
DA. These conclusions include pulmonary function tests that show severe
restrictive pulmonary defect (forced vital capacity 30% predicted; total lung
capacity 51% predicted) and reduction of maximal inspiratory and expiratory
pressures. Arterial blood gases document alveolar hypoventilation.
Restrictive chest disease is a component of DA5. This implies involvement
of the skeletal and respiratory muscles. Pulmonary evaluation of children
with distal arthrogryposis is warranted due to these findings. Additional
respiratory complications include tracheal and laryngeal clefts or stenosis.
The respiratory muscles as well as the diaphragm may be weak. Scoliosis is
common and contributes to restrictive lung disease. Early-onset respiratory
failure has a poor prognosis for long-term survival.
Management
The respiratory manifestations may be severe and require assisted ventilation.
Endotracheal intubation may be difficult because those affected tend to have
a small, immobile jaw. Also, the airway may be compromised so that a tra-
cheostomy may be necessary. Physical therapy might improve overall joint
function, and experimental surgeries, such as vertical expandable prosthetic
titanium rib, have been explored with some improvement in thoracic growth.69

834
Down Syndrome
Trisomy 21, which results in Down syndrome, is the most common chromo-
somal abnormality, affecting 1 in every 600 to 800 live births. Pulmonary
complications of Down syndrome are multiple, and pneumonia is the most
common indication for hospital admission. Despite being common, the
pulmonary features are often underappreciated.70 There are several
categories of pulmonary problems, as shown in Box 47‑1.
Sleep-Disordered Breathing
Sleep-disordered breathing (SDB) is common in Down syndrome during
infancy and occurs in older children with Down syndrome. It is reported
to be as high as 30% to 75% compared with 2% to 3% in the general popula-
tion. In infancy, the most usual cause is related to laryngotracheomalacia.
The most common cause after infancy is secondary to adenoidal and tonsillar
hypertrophy, and upper airway obstruction may result from the small size
of the midface, small nasal airways, micrognathia, increased collapsibility
of the oropharynx and nasopharynx, and enlargement of the tongue. Obesity
is often a contributing factor. The symptoms of sleep apnea include snoring,
restless sleep, difficulty awakening, and daytime sleepiness with behavioral
changes, including school problems. Evaluation of SDB, including poly-
somnography (PSG), should be considered in infancy and later because
early recognition and management will reduce the likelihood of developing
pulmonary hypertension.
Box 47‑1
Pulmonary Complications of Down Syndrome
Sleep-disordered breathing Parenchymal lung disease
Large tongue Subpleural cysts
Lax pharynx Interstitial lung disease
Adenotonsillar hypertrophy Pneumonia
Obesity Immune deficiency
Airway abnormalities Aspiration
Laryngomalacia Pulmonary Vascular Problems
Tracheomalacia Pulmonary artery hypertension
Bronchomalacia Pulmonary hemorrhage
Tracheal bronchus Pulmonary edema
Asthma

835
Sleep-disordered breathing is so common among children with Down

syndrome that the American Academy of Pediatrics recommends referral
to a specialist as early as the first year for evaluation.71 Parents are often
unaware of problems even though 97% of children with Down syndrome
who snore have SDB confirmed by PSG. Therefore, the American Academy
of Pediatrics recommends routine PSG for all patients with Down syndrome
by age 4 years.72
Airway Abnormalities
Laryngomalacia and tracheomalacia are common in those with Down syn-
drome and should be evaluated with flexible bronchoscopy. Large tonsils and
adenoids, lingual tonsils, large tongue, and lax pharyngeal tissue all contrib-
ute to the potential for upper airway obstruction. This can lead to otitis media
(50%–70% at 3–5 years of age) and alveolar hypoventilation with resulting
hypoxemia, which may lead to pulmonary hypertension. Subglottic stenosis
and tracheal stenosis are also common. Tracheal bronchus, also known as a
pig bronchus, where the right upper lobe bronchus originates from the trachea
above the carina, is not uncommon. Tracheal bronchus should be considered
if there is persistent right upper lobe infection or consolidation.
Parenchymal Lung Disease
Pathologists have long been aware of the presence of subpleural cysts in
patients with Down syndrome. The cysts are not visible on chest radiographs
but are prominently visible on CT scan. They are seen in 20% to 36% of
children with Down syndrome and are more common in children with Down
syndrome who have congenital heart disease. The presence of cysts confers
an increased risk for pneumothorax.
Children with Down syndrome studied at autopsy have shown a decrease
in the number of alveoli with increase in alveolar size. The number of alveoli
is decreased by 58% to 83% regardless of the presence of heart disease. In
addition, pulmonary hypoplasia, pulmonary lymphangiectasia, and interstitial
lung disease occur more in children with Down syndrome than in children
who do not have Down syndrome.
Pneumonia
Pneumonia is the most common cause for hospital admission among children
with trisomy 21, and, of these patients, 10% require admission to the pediatric
intensive care unit. The presence of congenital heart defect (CHD) does not
influence admission rates to the hospital, but those with CHD seem to have
more severe illness with more pediatric intensive care unit admissions and

836
longer length of stay.73 The causes of recurrent pneumonia are multiple and
include pharyngeal incoordination with aspiration as well as immune defi-
ciency. Airway abnormalities include laryngomalacia and tracheomalacia,
and tracheal bronchus may be found on CT scan or bronchoscopy.
Pulmonary Vascular Problems
Pulmonary vascular problems of children and adolescents with Down
syndrome include pulmonary hypertension, pulmonary edema, and pul-
monary hemorrhage. Congenital heart defects are common, with various
abnormalities occurring in 43% of 482 children with trisomy 21 in the review
by Weijerman et al.74 They reported atrioventricular septal defect (includes
atrioventricular canal) in 54% of cases, ventricular septal defect in 33.3%,
and patent ductus arteriosus in 5.8%. Their incidence of primary pulmonary
hypertension was 5.2%, considerably higher than that seen in the general
population. Pulmonary hypertension in children with Down syndrome has
various etiologies, including polycythemia (35%), asphyxia (12%), heman-
gioendothelioma (6%), and unknown (47%). Children with Down syndrome
who have a large left-to-right shunt typically develop pulmonary artery
hypertension (PAH). Although some die in the first few months, others do
not develop PAH despite having a large shunt.
Pulmonary artery hypertension also develops in children with Down syn-
drome who have SDB with resultant hypoxia. The problem of PAH may even
occur in Down syndrome without any obvious reason for its occurrence.
Chronic pulmonary hemorrhage is not an uncommon complication of Down
syndrome. It is a complication of children who have large left-to-right shunt,
increased pulmonary venous pressure from mitral valve dysfunction, or pul-
monary venous obstruction. Even in the absence of cardiac abnormalities, it
occurs with recurrent pneumonia or aspiration. The clinical features vary
from frank hemoptysis to a drop in hemoglobin with minimal symptoms.
Pulmonary edema is also common and is especially seen following relief of
upper airway obstruction either intraoperatively or postoperatively. Noncar-
diogenic pulmonary edema is also seen associated with acute lung injury in
children with Down syndrome with pneumonia and postoperatively following
cardiac surgery. High-altitude pulmonary edema is more common in children
with Down syndrome than in children who do not have Down syndrome.70

837
Asthma
Most studies concerning asthma in children with Down syndrome have
reported a lower incidence of asthma than in the general population. There is
an increased risk for severe respiratory syncytial virus infection, including
bronchiolitis, but the long-term risk for recurrent wheezing is decreased.
Hermansky-Pudlak Syndrome
Hermansky-Pudlak syndrome (HPS) is a rare group of autosomal recessive
disorders caused by defects in the biogenesis and function of lysosome-related
organelles, including macrophages and type II pneumocytes. The genetic
mutation has been identified, with HPS type 1 mutation being the most
common and severe.75
Clinical Features
Patients with HPS have tyrosinase-positive oculocutaneous albinism
with related ocular findings, bleeding caused by poor platelet aggregation,
pulmonary fibrosis, granulomatous enteropathic disease, and renal failure.76
Pulmonary fibrosis usually manifests in the third and fourth decades of
life, but onset of pulmonary fibrosis has been described in children as
young as 3 years old. The most common symptoms are dyspnea and
exercise intolerance.76
Diagnosis
Pulmonary function testing may demonstrate a restrictive defect with reduced
total lung capacity and impaired diffusion capacity consistent with pulmonary
fibrosis. High-resolution chest CT scans are abnormal in most patients (up to
85%), with ground-glass opacities, loss of lung volume, subpleural honey-
combing, and traction bronchiectasis75 (Figure 47-6). Diagnosis can be made
by careful ophthalmologic examination and confirming tyrosinase-positive
oculocutaneous albinism via hair bulb analysis. Although genetic testing can
help determine HPS subtype, it is expensive and not widely implemented and
some HPS patients have no identified genetic mutations, suggesting additional
HPS genes are yet to be discovered.
Management
Therapy is generally supportive with the goal being to reduce bleeding risks
and improve pulmonary quality of life. Lung transplant may be the only
option. Two antifibrotic drugs, pirfenidone and nintedanib, are being studied

838
Figure 47‑6. Radiographic findings in Hermansky-Pudlak syndrome. A. Posteroanterior chest

radiograph shows patchy areas of interstitial infiltrates (arrow). B. High-resolution computed
tomography scan shows ground-glass opacities, bronchiectasis, peribronchovascular
thickening, septal lines, and reticulation.
Reprinted from Avila NA, Brantly M, Premkumar A, Huizing M, Dwyer A, Gahl WA. Hermansky-Pudlak
syndrome: radiography and CT of the chest compared with pulmonary function tests and genetic studies.
AJR Am J Roentgenol. 2002;179(4):887–892. Copyright © 2002 American Roentgen Ray Society.

839
for HPS pulmonary fibrosis. Initial results have been disappointing. Current
clinical trials are studying better biomarkers for disease progression. Patients
generally survive to 40 or 50 years and die of complications from organ
damage.75 There is high mortality related to pulmonary complications.
Patients should be referred to a pulmonologist as soon as respiratory symp-
toms develop.
Mucopolysaccharidosis
Mucopolysaccharidoses (MPS) are a group of inherited progressive lyso-
somal storage diseases with multisystem involvement caused by an enzyme
deficiency that degrades glycosaminoglycans.77 There are 7 types, which
are inherited as autosomal recessive disorders except for MPS type II
(Hunter syndrome), which is an X-linked disorder.
Clinical Features
The spectrum and severity of disease manifestations vary between the
different MPS types. Some clinical features include coarse facial features,
respiratory and cardiac disease, hepatosplenomegaly, skeletal and joint
abnormalities, short stature, spinal cord compression, cognitive impairment,
and hearing and vision loss.78 Respiratory manifestations occur in all MPS
types. Otolaryngological manifestations present early with chronic rhinorrhea,
chronic otitis media with effusions, hearing loss, and enlarged tonsils and
adenoids. Upper airway manifestations include macroglossia, retroglossia,
pharyngeal narrowing, stridor, and laryngomalacia. Lower airway manifesta-
tions include subglottic stenosis, tracheobronchomalacia, recurrent pneumonia,
and bronchitis. Restrictive lung disease results from pectus carinatum and
kyphoscoliosis, which alter the chest wall structure, and hepatosplenomegaly
causes diaphragm excursion compromise.77 Sleep-disordered breathing is
present in 80% of MPS patients with obstructive and central sleep apnea,
hypopnea, and sleep disturbances.78 Cardiorespiratory failure and death
occur from progressive airway obstruction and respiratory insufficiency.
Diagnosis
Clinical evaluation should include urine analysis for excess levels of
glycosaminoglycans and enzyme assays. Guidelines from the International
Consensus Panel on the Management and Treatment of Mucopolysacchari-
dosis I recommend patients undergo pulmonary function testing at the time
of diagnosis and every 6 to 12 months thereafter.79 Spirometry and plethys-
mography with diffusion capacity show restrictive, obstructive, or mixed
patterns and can help assess disease progression and response to enzyme
replacement therapy. Reduced vital capacity can be a good predictor of
sleep-disordered breathing severity. Impulse oscillometry and maximum
voluntary ventilation may be an alternative test in those patients with impaired
cognition who are cooperative. A six-minute walk test can be used to assess

840
exercise tolerance. Flexible bronchoscopy may be used to assess dynamic

airway changes. Imaging studies, such as soft tissue neck radiographs for
pharyngeal narrowing, may be helpful. Routine PSG is suggested yearly
in severe forms of MPS type I and every 3 to 5 years in MPS type II.77
Management
Respiratory dysfunction poorly correlates with clinical appearance, so antici-
pation of respiratory problems and management at early stages is important
to maximize treatment outcome.78 Treatment includes vaccinations, airway
clearance, nasal decongestants, adenotonsillectomy, inhaled corticosteroids,
anticholinergic bronchodilator agents, hematopoietic stem cell transplant,
enzyme replacement therapy, spinal cord decompression surgery, and NPPV.
In severe forms, tracheostomy with assisted ventilation may be required.
Patients with MPS are at high risk for anesthetic complications, with intra-
operative and perioperative mortality as high as 20%.77 A multidisciplinary
treatment approach is needed for patients with MPS, with a referral to a
pulmonologist early for evaluation, lung function testing, and preoperative
respiratory assessments.
Pseudohypoaldosteronism
Pseudohypoaldosteronism (PHA) is a hereditary salt-wasting disorder
characterized by renal unresponsiveness or resistance to aldosterone.
Pathogenesis
Pseudohypoaldosteronism has been classified into a type I and type II.
Pseudohypoaldosteronism type I has been described to have 2 forms, with
either renal or multi-target organ disorder (MTOD).80 The severe form of PHA
type I, which involves other organs, including the lung, is inherited as an
autosomal recessive trait and causes severe salt loss secondary to a mutation
in the epithelial sodium channel.81 This defect leads to defective sodium
transport in organs such as the kidney, lung, colon, and sweat and salivary
glands. Pulmonary symptoms are common in MTOD PHA type I, where
increased airway sodium chloride concentration impairs bacterial killing and
raises the airway fluid layer, leading to airway clearance impairment.
Clinical Features
Neonatal respiratory distress syndrome at birth is possible due to failure of
lung fluid absorption in MTOD PHA type I.82
Patients with MTOD PHA type I have clinical signs and symptoms similar to
those with CF, including recurrent pneumonia secondary to impaired airway
clearance and bacterial killing.80 They may have periods of dyspnea, fever,
tachypnea, and increased work of breathing with crackles auscultated on
examination. These individuals also have severe salt-wasting episodes and are
prone to periods of dehydration. Pseudohypoaldosteronism is recognized as a

841
cause of a false-positive sweat test, where sweat sodium and chloride values
are elevated secondary to defective electrolyte transport.80 Chest radiography
can demonstrate thickened airways caused by failure to absorb liquid from
the airway surface.83 This can also appear similar to radiographic findings
in early CF, although no bronchiectasis has been reported to date.
Diagnosis
The diagnosis of PHA is clinical, with the identification of elevated urinary
sodium.
Management
Treatment is similar to CF, with aggressive management of dehydration and
electrolyte imbalance as well as early antibiotics for pulmonary infections.
Patients can develop Pseudomonas aeruginosa colonization, and this should
be considered when choosing antibiotic treatments. Supplemental oxygen may
be needed during times of active infection. Patients are treated with dietary
modification with high-sodium, low-potassium foods. Other therapies, such
as diuretics, potassium-binding resins, and alkalinizing agents, may be indi-
cated. Prognosis is guarded, with potential mortality in infancy due to the
severe metabolic/electrolyte derangements. Additionally, MTOD PHA type I
does not improve with advancing age. Treatment and monitoring are lifelong.
key points
Primary Ciliary Dyskinesia
} Primary ciliary dyskinesia has 4 cardinal clinical features: neonatal respiratory
distress in full-term infants, left-right laterality defects, persistent nonseasonal
rhinitis that begins early in life, and daily productive (wet) cough that develops
in infancy.
} Laterality defects, including situs inversus totalis and heterotaxy, occur in
roughly half of affected individuals.
} Diagnostic testing should be considered only in those patients who have a
compatible clinical phenotype.
} Diagnostic testing has evolved and includes nasal nitric oxide measurements,
high-speed videomicroscopy (outside North America), transmission electron
microscopy, and genetic testing.
} Nevertheless, there is no single test that will diagnose all cases of PCD.
} The cornerstones of therapy are daily routine airway clearance maneuvers,
aerobic exercise, scheduled immunizations, avoidance of airborne exposures,
and antibiotic therapy during respiratory exacerbations.
} Despite advances in understanding of the genetics and pathogenesis of PCD,
well-tested, disease-specific treatments are still lacking.
(continued)

842
key points (continued)

Mounier-Kuhn Syndrome
} Mounier-Kuhn syndrome is a rare congenital disease that causes
tracheobronchomegaly.
} Patients clinically present with recurrent pneumonia, bronchiectasis,
pneumothoraces, hemoptysis, emphysema, pulmonary fibrosis, and
respiratory failure.
} Treatment is supportive care with chest physiotherapy, antibiotics, and positive
end-expiratory pressure.
} Referral to a pulmonologist should be considered early when the diagnosis is
suspected to confirm and closely manage lung disease.
Williams-Campbell Syndrome
} Williams-Campbell syndrome is a rare congenital disorder that causes diffuse
bronchomalacia. Trachea and central bronchi caliber are normal.
} Patients present with recurrent pneumonias, chronic productive cough, wheeze,
and nail clubbing.
} Treatment is supportive with airway clearance and antibiotics.
Pulmonary Lymphangioleiomyomatosis
} Pulmonary lymphangioleiomyomatosis is a rare condition affecting
postpubertal females.
} Neoplastic cells proliferate in the lung, kidney, and lymphatics causing
airway narrowing, impaired diffusion, cyst formation, and chylothorax in
the respiratory system.
} Symptoms vary and may include chronic dry cough, wheeze, hemoptysis,
cyanosis, cor pulmonale, and respiratory failure.
} Treatment is supportive.
} Alpha-1 antitrypsin deficiency is an autosomal dominant inherited disorder
caused by the imbalance of protease-antiprotease enzymes in the lung.
} Clinically, patients present with symptoms later in life, with rare cases of
emphysema in children.
} Smoke exposure is an independent risk factor for emphysema in these patients.
} Treatment is supportive with avoidance of tobacco exposure, early antibiotics,
bronchodilators, oxygen as needed, and nutrition.
} Genetic counseling is advisable when the diagnosis is suspected.
} Referral to a pulmonologist should be considered when the diagnosis is
confirmed to closely monitor and manage progression of lung disease.

843
key points (continued)

Achondroplasia
} The first year after birth is important in the prevention of complications related
to craniocervical compression.
} Obstructive sleep apnea is common, and symptoms of snoring and other
sleep-disordered breathing should be evaluated by a sleep specialist.
Arthrogryposis Multiplex Congenita
} Pulmonary complications result from restrictive lung disease and airway
anomalies.
} Pulmonary management is supportive and may require assisted ventilation.
Down Syndrome
} Stay up to date on AAP policy on Health Supervision for Children With Down
Syndrome
} Airway and pulmonary complications of Down syndrome may be underappreciated.
} Sleep-disordered breathing is common in Down syndrome. Infants and children
should be evaluated by a sleep specialist.
} Pneumonia is the most common cause for admission, and 10% of patients with
pneumonia require intensive care unit admission.
Hermansky-Pudlak Syndrome
} Treatment is supportive.
Mucopolysaccharidosis
} Airway problems are the most problematic symptoms of MPS and have the most
potential for morbidity and mortality.
} Sleep-disordered breathing is present in 80% of patients with MPS.
} The airway abnormalities in severe MPS types may require tracheostomy.
Pseudohypoaldosteronism
} Clinical features are similar to CF with recurrent pneumonias, airway clearance
impairment, and Pseudomonas aeruginosa colonization, but no bronchiectasis.
} Patients may have false-positive sweat test results.
} Treatment is rehydration, early antibiotics, oxygen as needed, airway clearance,
and dietary modification.
Family and Patient Resources
} PCD Foundation. www.pcdfoundation.org
} PCD Family Support Group UK. www.pcdsupport.org.uk
} Genetic Disorders of Mucociliary Clearance Consortium.
www.rarediseasesnetwork.org/cms/gdmcc

844
References
1. Torgersen J. Situs inversus, asymmetry, and twinning. Am J Hum Genet. 1950;2(4):361–370
PMID: 14837905
2. Katsuhara K, Kawamoto S, Wakabayashi T, Belsky JL. Situs inversus totalis and Kartagener’s
syndrome in a Japanese population. Chest. 1972;61(1):56–61 PMID: 4538074
doi: 10.1378/chest.61.1.56
3. Hannah WB, Seifert BA, Truty R, Zariwala MA, Ameel K, Zhao Y, Nykamp K, Gaston B.
The global prevalence and ethnic heterogeneity of primary ciliary dyskinesia gene variants:
a genetic database analysis. Lancet Respir Med. 2022 Jan 17:S2213-2600(21)00453-7 PMID:
35051411
4. Chapelin C, Coste A, Reinert P, et al. Incidence of primary ciliary dyskinesia in children with
recurrent respiratory diseases. Ann Otol Rhinol Laryngol. 1997;106(10 Pt 1):854–858
PMID: 9342982
5. Siewert AR. Ueber einen Fall von Bronchiectasie bei einem Patienten mit Situs inversus
viscerum. Berliner Klinische Wochenschrift. 1904;41:139
6. Kartagener M. Zur pathogenese der bronkiectasien. I. Mitteilung: bronkiectasien bei situs
viscerum inversus. Beitr Klin Tuberk. 1933;82:489–501 doi: 10.1007/BF02141468
7. Afzelius BA. A human syndrome caused by immotile cilia. Science. 1976;193(4250):317–319
PMID: 1084576 doi: 10.1126/science.1084576
8. Horani A, Ferkol TW. Advances in the genetics of primary ciliary dyskinesia: clinical
implications. Chest. 2018;154(3):645–652 PMID: 29800551 doi: 10.1016/j.chest.2018.05.007
9. Roberts AJ, Kon T, Knight PJ, Sutoh K, Burgess SA. Functions and mechanics of dynein motor
proteins. Nat Rev Mol Cell Biol. 2013;14(11):713–726 PMID: 24064538 doi: 10.1038/nrm3667
10. Heuser T, Raytchev M, Krell J, Porter ME, Nicastro D. The dynein regulatory complex is the
nexin link and a major regulatory node in cilia and flagella. J Cell Biol. 2009;187(6):921–933
PMID: 20008568 doi: 10.1083/jcb.200908067
11. Nonaka S, Tanaka Y, Okada Y, et al. Randomization of left-right asymmetry due to loss of nodal
cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein.
Cell. 1998;95(6):829–837 PMID: 9865700 doi: 10.1016/S0092-8674(00)81705-5
12. Kennedy MP, Omran H, Leigh MW, et al. Congenital heart disease and other heterotaxic
defects in a large cohort of patients with primary ciliary dyskinesia. Circulation.
2007;115(22):2814–2821 PMID: 17515466 doi: 10.1161/CIRCULATIONAHA.106.649038
13. Hildebrandt F, Benzing T, Katsanis N. Ciliopathies. N Engl J Med. 2011;364(16):1533–1543
PMID: 21506742 doi: 10.1056/NEJMra1010172
14. Leigh MW, Pittman JE, Carson JL, et al. Clinical and genetic aspects of primary ciliary
dyskinesia/Kartagener syndrome. Genet Med. 2009;11(7):473–487 PMID: 19606528
doi: 10.1097/GIM.0b013e3181a53562
15. van Dorp DB, Wright AF, Carothers AD, Bleeker-Wagemakers EM. A family with RP3 type of
X-linked retinitis pigmentosa: an association with ciliary abnormalities. Hum Genet.
1992;88(3):331–334 PMID: 1733835 doi: 10.1007/BF00197269
16. Paff T, Loges NT, Aprea I, et al. Mutations in PIH1D3 cause X-linked primary ciliary dyskinesia
with outer and inner dynein arm defects. Am J Hum Genet. 2017;100(1):160–168
PMID: 28041644 doi: 10.1016/j.ajhg.2016.11.019
17. Wallmeier J, Nielsen KG, Kuehni CE, et al. Motile ciliopathies. Nat Rev Dis Primers.
2020;6(1):77 PMID: 32943623 doi: 10.1038/s41572-020-0209-6
18. Wallmeier J, Al-Mutairi DA, Chen CT, et al. Mutations in CCNO result in congenital
mucociliary clearance disorder with reduced generation of multiple motile cilia. Nat Genet.
2014;46(6):646–651 PMID: 24747639 doi: 10.1038/ng.2961
19. Boon M, Wallmeier J, Ma L, et al. MCIDAS mutations result in a mucociliary clearance disorder
with reduced generation of multiple motile cilia. Nat Commun. 2014;5(1):4418 PMID: 25048963
doi: 10.1038/ncomms5418
20. Bustamante-Marin XM, Yin WN, Sears PR, et al. Lack of GAS2L2 causes PCD by impairing
cilia orientation and mucociliary clearance. Am J Hum Genet. 2019;104(2):229–245
PMID: 30665704 doi: 10.1016/j.ajhg.2018.12.009
21. Davis SD, Ferkol TW, Rosenfeld M, et al. Clinical features of childhood primary ciliary
dyskinesia by genotype and ultrastructural phenotype. Am J Respir Crit Care Med.
2015;191(3):316–324 PMID: 25493340 doi: 10.1164/rccm.201409-1672OC
22. Pifferi M, Bush A, Mariani F, et al. Lung function longitudinal study by phenotype and
genotype in primary ciliary dyskinesia. Chest. 2020;158(1):117–120 PMID: 32059959
doi: 10.1016/j.chest.2020.02.001

845
23. Davis SD, Ferkol TW, Rosenfeld M, et al. Clinical features of childhood primary ciliary
dyskinesia by genotype and ultrastructural phenotype. Am J Respir Crit Care Med.
2018;199:190–198 PMID: 30067075 doi: 10.1164/rccm.201803-0548OC
24. Knowles MR, Ostrowski LE, Leigh MW, et al. Mutations in RSPH1 cause primary ciliary
dyskinesia with a unique clinical and ciliary phenotype. Am J Respir Crit Care Med.
2014;189(6):707–717 PMID: 24568568 doi: 10.1164/rccm.201311-2047OC
25. Leigh MW, Ferkol TW, Davis SD, et al. Clinical features and associated likelihood of primary
ciliary dyskinesia in children and adolescents. Ann Am Thorac Soc. 2016;13(8):1305–1313
PMID: 27070726 doi: 10.1513/AnnalsATS.201511-748OC
26. Shapiro AJ, Davis SD, Ferkol T, et al; Genetic Disorders of Mucociliary Clearance Consortium.
Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into
situs ambiguus and heterotaxy. Chest. 2014;146(5):1176–1186 PMID: 24577564
doi: 10.1378/chest.13-1704
27. Behan L, Dimitrov BD, Kuehni CE, et al. PICADAR: a diagnostic predictive tool for primary
ciliary dyskinesia. Eur Respir J. 2016;47(4):1103–1112 PMID: 26917608
doi: 10.1183/13993003.01551-2015
28. Vanaken GJ, Bassinet L, Boon M, et al. Infertility in an adult cohort with primary ciliary
dyskinesia: phenotype-gene association. Eur Respir J. 2017;50(5):1700314 PMID: 29122913
doi: 10.1183/13993003.00314-2017
29. Wessels MW, den Hollander NS, Willems PJ. Mild fetal cerebral ventriculomegaly as a
prenatal sonographic marker for Kartagener syndrome. Prenat Diagn. 2003;23(3):239–242
PMID: 12627427 doi: 10.1002/pd.551
30. De Brauwer PJ, Blaise P, Hermans G, Boniver V, Bartsch P, Rakic JM. Retinitis pigmentosa and
bronchiectasis: a case report on a rare association suggestive of a common underlying primary
ciliary dyskinesia (PCD). Bull Soc Belge Ophtalmol. 2010;314(314):9–14 PMID: 20480745
31. Bonneau D, Raymond F, Kremer C, Klossek JM, Kaplan J, Patte F. Usher syndrome type I
associated with bronchiectasis and immotile nasal cilia in two brothers. J Med Genet.
1993;30(3):253–254 PMID: 8474110 doi: 10.1136/jmg.30.3.253
32. Budny B, Chen W, Omran H, et al. A novel X-linked recessive mental retardation syndrome
comprising macrocephaly and ciliary dysfunction is allelic to oral-facial-digital type I syndrome.
Hum Genet. 2006;120(2):171–178 PMID: 16783569 doi: 10.1007/s00439-006-0210-5
33. Shapiro AJ, Davis SD, Polineni D, et al. Diagnosis of primary ciliary dyskinesia. An official
American Thoracic Society clinical practice guideline: Am J Respir Crit Care Med.
34. Knowles MR, Daniels LA, Davis SD, Zariwala MA, Leigh MW. Primary ciliary dyskinesia.
Recent advances in diagnostics, genetics, and characterization of clinical disease. Am J Respir
Crit Care Med. 2013;188(8):913–922 PMID: 23796196 doi: 10.1164/rccm.201301-0059CI
35. Shoemark A, Frost E, Dixon M, et al. Accuracy of immunofluorescence in the diagnosis of
primary ciliary dyskinesia. Am J Respir Crit Care Med. 2017;196(1):94–101 PMID: 28199173
doi: 10.1164/rccm.201607-1351OC
36. Leigh MW, Hazucha MJ, Chawla KK, et al. Standardizing nasal nitric oxide measurement as a
test for primary ciliary dyskinesia. Ann Am Thorac Soc. 2013;10(6):574–581 PMID: 24024753
37. Shapiro AJ, Davis SD, Leigh MW, Knowles MR, Lavergne V, Ferkol T. Limitations of
nasal nitric oxide testing in primary ciliary dyskinesia. Am J Respir Crit Care Med.
2020;202(3):476–477 PMID: 32329626 doi: 10.1164/rccm.202003-0835LE
38. Noone PG, Leigh MW, Sannuti A, et al. Primary ciliary dyskinesia: diagnostic and
phenotypic features. Am J Respir Crit Care Med. 2004;169(4):459–467 PMID: 14656747
doi: 10.1164/rccm.200303-365OC
39. Zysman-Colman ZN, Kaspy KR, Alizadehfar R. Nasal nitric oxide in primary
immunodeficiency and primary ciliary dyskinesia: helping to distinguish between clinically
similar diseases. J Clin Immunol. 2019;39(2):216–224 PMID: 30911954 doi: 10.1007/s10875-019-
00613-8
40. Lucas JS, Barbato A, Collins SA, et al. European Respiratory Society guidelines for the
diagnosis of primary ciliary dyskinesia. Eur Respir J. 2017;49(1):1601090 PMID: 27836958
doi: 10.1183/13993003.01090-2016
41. Kantar A, Chang AB, Shields MD, et al. ERS statement on protracted bacterial bronchitis in
children. Eur Respir J. 2017;50(2):1602139 PMID: 28838975 doi: 10.1183/13993003.02139-2016
42. Shapiro AJ, Zariwala MA, Ferkol T, et al; Genetic Disorders of Mucociliary Clearance
Consortium. Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD
foundation consensus recommendations based on state of the art review. Pediatr Pulmonol.
2016;51(2):115–132 PMID: 26418604 doi: 10.1002/ppul.23304

846
43. Kobbernagel HE, Buchvald FF, Haarman EG, et al. Efficacy and safety of azithromycin
maintenance therapy in primary ciliary dyskinesia (BESTCILIA): a multicentre, double-blind,
randomised, placebo-controlled phase 3 trial. Lancet Respir Med. 2020;8(5):493–505
PMID: 32380069 doi: 10.1016/S2213-2600(20)30058-8
44. O’Donnell AE, Barker AF, Ilowite JS, Fick RB. Treatment of idiopathic bronchiectasis with
aerosolized recombinant human DNase I. rhDNase Study Group. Chest. 1998;113(5):1329–1334
PMID: 9596315 doi: 10.1378/chest.113.5.1329
45. Campbell RG, Birman CS, Morgan L. Management of otitis media with effusion in children
with primary ciliary dyskinesia: a literature review. Int J Pediatr Otorhinolaryngol.
2009;73(12):1630–1638 PMID: 19796826 doi: 10.1016/j.ijporl.2009.08.024
46. Parsons DS, Greene BA. A treatment for primary ciliary dyskinesia: efficacy of functional
endoscopic sinus surgery. Laryngoscope. 1993;103(11 Pt 1):1269–1272 PMID: 8231581
doi: 10.1288/00005537-199311000-00010
47. Ellerman A, Bisgaard H. Longitudinal study of lung function in a cohort of primary ciliary
dyskinesia. Eur Respir J. 1997;10(10):2376–2379 PMID: 9387968
doi: 10.1183/09031936.97.10102376
48. Marthin JK, Petersen N, Skovgaard LT, Nielsen KG. Lung function in patients with primary
ciliary dyskinesia: a cross-sectional and 3-decade longitudinal study. Am J Respir Crit Care
Med. 2010;181(11):1262–1268 PMID: 20167855 doi: 10.1164/rccm.200811-1731OC
49. Krustins E, Kravale Z, Buls A. Mounier-Kuhn syndrome or congenital tracheobronchomegaly:
A literature review. Respir Med. 2013;107(12):1822–1828 PMID: 24070565
50. Menon B, Aggarwal B, Iqbal A. Mounier-Kuhn syndrome: report of 8 cases of
tracheobronchomegaly with associated complications. South Med J. 2008;101(1):83–87
PMID: 18176298 doi: 10.1097/SMJ.0b013e31815d4259
51. Sane AC, Effmann EL, Brown SD. Tracheobronchiomegaly. The Mounier-Kuhn syndrome
in a patient with the Kenny-Caffey syndrome. Chest. 1992;102(2):618–619 PMID: 1643956
doi: 10.1378/chest.102.2.618
52. Schmitt P, Dalar L, Jouneau S, et al; Groupe d´Endoscopie de Langue Française (GELF).
Respiratory conditions associated with tracheobronchomegaly (Mounier-Kuhn syndrome):
a study of seventeen cases. Respiration. 2016;91(4):281–287 PMID: 27022925
doi: 10.1159/000445029
53. Noriega Aldave AP, William Saliski D. The clinical manifestations, diagnosis and management
of Williams-Campbell syndrome. N Am J Med Sci. 2014;6(9):429–432 PMID: 25317385
doi: 10.4103/1947-2714.141620
54. Di Scioscio V, Zompatori M, Mistura I, et al. The role of spiral multidetector dynamic CT in the
study of Williams-Campbell syndrome. Acta Radiol. 2006;47(8):798–800 PMID: 17050358
doi: 10.1080/02841850600849084
55. George J, Jain R, Tariq SM. CT bronchoscopy in the diagnosis of Williams-Campbell syndrome.
Respirology. 2006;11(1):117–119 PMID: 16423213 doi: 10.1111/j.1440-1843.2006.00793.x
56. Johnson SR, Taveira-DaSilva AM, Moss J. Lymphangioleiomyomatosis. Clin Chest Med.
2016;37(3):389–403 PMID: 27514586 doi: 10.1016/j.ccm.2016.04.002
57. Faul JL, Berry GJ, Colby TV, et al. Thoracic lymphangiomas, lymphangiectasis,
lymphangiomatosis, and lymphatic dysplasia syndrome. Am J Respir Crit Care Med.
2000;161(3 Pt 1):1037–1046 PMID: 10712360 doi: 10.1164/ajrccm.161.3.9904056
58. Hancock E, Osborne J. Lymphangioleiomyomatosis: a review of the literature. Respir Med.
2002;96(1):1–6 PMID: 11863203 doi: 10.1053/rmed.2001.1207
59. Gupta N, Henske EP. Pulmonary manifestations in tuberous sclerosis complex. Am J Med Genet
C Semin Med Genet. 2018;178(3):326–337 PMID: 30055039 doi: 10.1002/ajmg.c.31638
60. McCormack FX, Gupta N, Finlay GR, et al. Official ATS/JRS clinical practice guidelines:
lymphangioleiomyomatosis diagnosis and management. Am J Respir Crit Care Med.
2016;194(6):748–761 PMID: 27628078 doi: 10.1164/rccm.201607-1384ST
61. Köhnlein T, Welte T. Alpha-1 antitrypsin deficiency: pathogenesis, clinical presentation,
diagnosis, and treatment. Am J Med. 2008;121(1):3–9 PMID: 18187064
doi: 10.1016/j.amjmed.2007.07.025
62. von Ehrenstein OS, von Mutius E, Maier E, et al. Lung function of school children with low
levels of alpha1-antitrypsin and tobacco smoke exposure. Eur Respir J. 2002;19(6):1099–1106
PMID: 12108863 doi: 10.1183/09031936.02.00104302
63. Coakley RJ, Taggart C, O’Neill S, McElvaney NG. Alpha1-antitrypsin deficiency:
biological answers to clinical questions. Am J Med Sci. 2001;321(1):33–41 PMID: 11202478
doi: 10.1097/00000441-200101000-00006

847
64. Hubbard RC, Sellers S, Czerski D, Stephens L, Crystal RG. Biochemical efficacy and safety of
monthly augmentation therapy for alpha 1-antitrypsin deficiency. JAMA. 1988;260(9):1259–1264
PMID: 3261353 doi: 10.1001/jama.1988.03410090091037
65. Pauli RM. Achondroplasia: a comprehensive clinical review. Orphanet J Rare Dis.
2019;14(1):1 PMID: 30606190 doi: 10.1186/s13023-018-0972-6
66. Tasker RC, Dundas I, Laverty A, Fletcher M, Lane R, Stocks J. Distinct patterns of respiratory
difficulty in young children with achondroplasia: a clinical, sleep, and lung function study.
Arch Dis Child. 1998;79(2):99–108 PMID: 9797588 doi: 10.1136/adc.79.2.99
67. Stokes DC, Wohl ME, Wise RA, Pyeritz RE, Fairclough DL. The lungs and airways in
achondroplasia. Do little people have little lungs? Chest. 1990;98(1):145–152 PMID: 2361382
doi: 10.1378/chest.98.1.145
68. Williams MS, Elliott CG, Bamshad MJ. Pulmonary disease is a component of distal
arthrogryposis type 5. Am J Med Genet A. 2007;143A(7):752–756 PMID: 17345626
doi: 10.1002/ajmg.a.31648
69. Astur N, Flynn JM, Flynn JM, et al. The efficacy of rib-based distraction with VEPTR in the
treatment of early-onset scoliosis in patients with arthrogryposis. J Pediatr Orthop.
2014;34(1):8–13 PMID: 24327164 doi: 10.1097/BPO.0b013e3182a00667
70. McDowell KM, Craven DI. Pulmonary complications of Down syndrome during childhood.
71. American Academy of Pediatrics. Committee on Genetics. American Academy of Pediatrics:
health supervision for children with Down syndrome. Pediatrics. 2001;107(2):442–449
PMID: 11158488 doi: 10.1542/peds.107.2.442
72. Bull MJ, American Academy of Pediatrics Committee on Genetics. Health supervision for
children with Down syndrome. Pediatrics. 2011;128(2):393-406
73. Hilton JM, Fitzgerald DA, Cooper DM. Respiratory morbidity of hospitalized children
with Trisomy 21. J Paediatr Child Health. 1999;35(4):383–386 PMID: 10457298
doi: 10.1046/j.1440-1754.1999.00386.x
74. Weijerman ME, van Furth AM, van der Mooren MD, et al. Prevalence of congenital heart
defects and persistent pulmonary hypertension of the neonate with Down syndrome. Eur J
Pediatr. 2010;169(10):1195–1199 PMID: 20411274 doi: 10.1007/s00431-010-1200-0
75. Vicary GW, Vergne Y, Santiago-Cornier A, Young LR, Roman J. Pulmonary fibrosis in
Hermansky-Pudlak syndrome. Ann Am Thorac Soc. 2016;13(10):1839–1846 PMID: 27529121
76. El-Chemaly S, Young LR. Hermansky-Pudlak syndrome. Clin Chest Med. 2016;37(3):505–511
PMID: 27514596 doi: 10.1016/j.ccm.2016.04.012
77. Muhlebach MS, Wooten W, Muenzer J. Respiratory manifestations in mucopolysaccharidoses.
78. Berger KI, Fagondes SC, Giugliani R, et al. Respiratory and sleep disorders in
mucopolysaccharidosis. J Inherit Metab Dis. 2013;36(2):201–210 PMID: 23151682
doi: 10.1007/s10545-012-9555-1
79. Muenzer J, Wraith JE, Clarke LA; International Consensus Panel on Management and
Treatment of Mucopolysaccharidosis I. Mucopolysaccharidosis I: management and treatment
guidelines. Pediatrics. 2009;123(1):19–29 PMID: 19117856 doi: 10.1542/peds.2008-0416
80. Hanukoglu A, Bistritzer T, Rakover Y, Mandelberg A. Pseudohypoaldosteronism with
increased sweat and saliva electrolyte values and frequent lower respiratory tract infections
mimicking cystic fibrosis. J Pediatr. 1994;125(5 Pt 1):752–755 PMID: 7965429
doi: 10.1016/S0022-3476(06)80176-9
81. Edelheit O, Hanukoglu I, Gizewska M, et al. Novel mutations in epithelial sodium channel
(ENaC) subunit genes and phenotypic expression of multisystem pseudohypoaldosteronism.
Clin Endocrinol (Oxf). 2005;62(5):547–553 PMID: 15853823 doi:
10.1111/j.1365-2265.2005.02255.x
82. Akçay A, Yavuz T, Semiz S, Bundak R, Demirdöven M. Pseudohypoaldosteronism type 1 and
respiratory distress syndrome. J Pediatr Endocrinol Metab. 2002;15(9):1557–1561
PMID: 12503866 doi: 10.1515/JPEM.2002.15.9.1557
83. Kerem E, Bistritzer T, Hanukoglu A, et al. Pulmonary epithelial sodium-channel dysfunction
and excess airway liquid in pseudohypoaldosteronism. N Engl J Med. 1999;341(3):156–162
PMID: 10403853 doi: 10.1056/NEJM199907153410304

PART
10
Lung Disease Associated
With Systemic Disorders
Chapter 48. Respiratory Considerations in Children With Cardiac

Disease................................................................................................... 851
Yehudit Pollack, MD, and Sankaran Krishnan, MD, MPH
Chapter 49. Lung Disease Associated With Endocrine

Disorders.............................................................................................. 869
Michael J. Light, MD, and Martin Draznin, MD
Chapter 50. Pulmonary Complications of Gastrointestinal

Diseases................................................................................................. 875
Edward W. Fong, MD
Chapter 51. Pulmonary Complications of Sickle Cell

Disease................................................................................................... 891
Chapter 52. Pulmonary Manifestations of Oncologic Disease

and Treatment...................................................................................... 913
Mary Bono Cataletto, MD, FAAP, and Caitlin Hurley, MD
Chapter 53. Pulmonary Complications of Immunologic

Disorders...............................................................................................929
Jay Jin, MD, PhD, and Clement L. Ren, MD, MBA
Chapter 54. Pulmonary Complications of Neuromuscular

Disorders...............................................................................................947
849
57 PP 2ND ED - PO 10_849-850.indd 849 11/6/23 9:43 AM

57 PP 2ND ED - PO 10_849-850.indd 850 9/12/23 10:43 AM
CHAPTER
48
Respiratory Considerations in Children
With Cardiac Disease
Yehudit Pollack, MD
Introduction
The heart and the lungs are intrinsically connected, functioning as a coupled
unit with a shared circulatory system. Severe lung disease and abnormalities
in the pulmonary vascular bed can cause cardiac alterations, and, conversely,
changes in blood flow and pressures in the great vessels and pulmonary
vascular bed can cause significant airway and lung changes.
Respiratory symptoms are often the initial, and sometimes the only, mani-
festation of cardiac disease, especially in a neonate or infant. Congestive
heart failure commonly presents with tachypnea, which, if left untreated,
can progress to dyspnea with intercostal and subcostal retractions. Tachypnea
is initially likely due to increased pulmonary venous pressure or volume.
Later in the clinical course, bronchial compression, due to either enlarged
pulmonary arteries or enlarged left atrium, may result in hyperinflation and
atelectasis. In some patients, the clinical picture is dominated by pulmonary
symptoms due to pulmonary edema, including chest discomfort, dyspnea,
wheezing, and cough, leading to the term cardiac asthma. Vascular anomalies
that affect the major vessels can cause symptoms of airway compression,
including stridor, wheezing, and dysphagia, which can lead to acute
respiratory presentations.1
This chapter examines the interactions between the cardiac and pulmonary
systems and, more specifically, discusses the pathophysiology and clinical
manifestations attributable to the respiratory system that are often present in
children with congenital heart diseases.
851

852
Physiology/Pathophysiology
Distribution of Pulmonary Blood Flow
Pulmonary blood flow depends on the interaction between cardiac output and
pulmonary vascular resistance. Alterations in pulmonary vascular resistance
occur due to passive and active changes to pulmonary vessel caliber. Gravity-
dependent and gravity-independent factors may alter distribution of pulmonary
blood flow. Gravity-dependent variations in pulmonary blood flow occur due
to the net differences in 3 intrapulmonary pressures: intra-alveolar pulmonary
capillary pressure, alveolar pressure, and venous pressure. Gravity-independent
determinants of passive pulmonary blood flow are affected by changes in lung
volumes causing changes in pulmonary vessel caliber.
Active changes in pulmonary vascular resistance due to changing caliber
of the resistance vessels in the pulmonary vascular bed lead to changes in
pulmonary blood flow. A variety of physiological and pharmacologic stimuli
can alter pulmonary resistance. The most important of these factors, alveolar
hypoxia, causes localized pulmonary vasoconstriction, referred to as hypoxic
pulmonary vasoconstriction. Regional alveolar hypoxia causes localized
increased vascular resistance and shunts blood toward normal lung, which
improves ventilation/perfusion (V̇ /Q̇ ) mismatch. Increased pulmonary blood
flow in children with congenital heart defects (left-to-right shunts) and in
children with arteriovenous malformations may lead to irreversible changes
in the pulmonary vascular bed and progressive pulmonary vascular disease.
Alterations in Respiratory Physiology in Congenital Heart Disease

Congenital Heart Disease With Increased Pulmonary Blood Flow
Increased pulmonary blood flow is the physiological sequela of congenital
cardiac lesions associated with left-to-right cardiac shunts. These left-to-right
shunts are most commonly seen in acyanotic defects (ventricular septal defect,
patent ductus arteriosus, atrioventricular canal defects, atrial septal defect).
However, certain cyanotic defects may have increased pulmonary blood flow
as well as right-to-left shunt (truncus arteriosus, transposition of great arteries,
total anomalous pulmonary venous return, single ventricle with unrestricted
pulmonary blood flow). The respiratory derangements seen in these patients
are secondary to a combination of excessive pulmonary blood volume and
increased pulmonary vascular pressures. Systemic arteriovenous malforma-
tions are noncardiac congenital defects that are associated with increased
pulmonary blood flow and pulmonary hypertension. Increased pulmonary
blood volume results in perfusion in excess of ventilation and a V̇ /Q̇ inequal-
ity. When alveolar ventilation is inadequate for pulmonary blood flow,
partial pressure of oxygen falls and hypoxia occurs. Increased pulmonary
blood flow increases pulmonary arteriolar, capillary, and venous pressures,
leading to increased extravascular fluid. Increased pulmonary blood volume

853
Chapter 48—Respiratory Considerations in Children With Cardiac Disease
also causes increased lung weight, which further alters pulmonary mechanics.
Increased lung weight and hypertensive pulmonary arteries lead to decreased
lung compliance. This, along with alveolar atelectasis due to cardiomegaly,
causes loss of lung volume, a reduction in lung compliance, and a decreased
tidal volume, with a compensatory increase in respiratory frequency.
During spontaneous respiration, the hypertensive pulmonary arteries in patients
with left-to-right shunts, in combination with less compliant pulmonary paren-
chyma, result in a restrictive effect on the lungs, which, in turn, requires more
respiratory effort to produce effective lung inflation. A secondary effect of this
reduction in pulmonary compliance is the need for increased airway pressure
to generate adequate lung volume in patients on mechanical ventilation.
Congenital Heart Disease With Decreased Pulmonary Blood Flow
Right-to-left shunts due to cyanotic heart disease are associated with decreased
pulmonary blood flow and have the opposite effects on respiratory mechanics
when compared with lesions with increased pulmonary blood flow. Cyanosis in
certain cyanotic defects (pulmonary atresia, critical pulmonary stenosis, tetral-
ogy of Fallot, single ventricle with pulmonary stenosis) results from a combina-
tion of obstruction to pulmonary blood flow and an intracardiac defect that
permits right-to-left shunting. Decreased pulmonary flow results in a decreased
lung weight, improved lung compliance, and alterations in V̇ /Q̇ matching.2
Physiological dead space increases due to ventilation of under-perfused lung.
The extent of the V/Q mismatch directly correlates with the level of hypoxia.3
The increase in dead space leads to compensatory mechanisms, which include
an increase in minute ventilation and a reduction in arterial carbon dioxide.
The magnitude of the increase in minute ventilation correlates inversely with
the magnitude of the reduction in partial pressure of oxygen. Thus, the acutely
hypoxic newborn with decreased pulmonary blood flow typically has effortless
tachypnea and cyanosis both due to increased physiological dead space and
stimulation of hypoxic pulmonary drive.4
In contrast, it is well known that chronic hypoxia as seen in children with
palliated or uncorrected cyanotic heart disease blunts the respiratory responses
to acute hypoxia. These findings may explain the further oxygen desaturation
seen during sleep in some of these patients.4,5 Loss of normal compensatory
responses to hypoxic stimuli may also account for the devastating effects of
pulmonary infection in these patients.
Airway Compression With Congenital Heart Disease

Vascular compression of the airway in children is usually caused either by
congenital anomalies of the great vessels (vascular rings, vascular slings) or
enlargement of otherwise normal structures, such as the aorta, pulmonary
artery, or cardiac chambers. (See Chapter 14, Congenital Lung Abnormalities.)
Both large and small airway obstruction can occur in patients with increased

854
pulmonary blood flow. Small airway obstruction results from either intrinsic
narrowing of the airways due to fluid collecting in the lumen or extrinsic obstruc-
tion from either interstitial edema or dilatation of the pulmonary vessels.2,6
The diagnosis of vascular ring is established when there is total encirclement of
the trachea and esophagus by vascular structures originating from the aortic
arch, including the arterial duct or ligament. Incomplete rings or non-circum-
ferential anomalies, termed slings, can also cause airway compression.7
The most common causes of obstructing vascular lesions include
X Double aortic arch.
X Right aortic arch with aberrant retro-esophageal left subclavian artery
arising from the descending aorta. This anomaly is due to embryonic left
arterial duct and presence of left arterial ligament after birth.
X Pulmonary artery sling, where the left pulmonary artery arises from the
right pulmonary artery and courses posteriorly and leftward between the
trachea and esophagus, compressing the distal trachea and right bronchus.
X Innominate artery compression, which is caused by more distal attachment
of the innominate artery along the aortic arch and can compress the trachea
as the artery crosses anteriorly.
Increased pulmonary blood flow combined with pulmonary arterial hyper-
tension (PAH) causes dilatation of the pulmonary arteries and the left atrium,
which predisposes to large airway compression and, consequently, air trap-
ping8 or atelectasis. The latter is most commonly observed in the left lower
lobe, followed by the left upper lobe bronchus as the left main bronchus is
entrapped and compressed between an enlarged, hypertensive left pulmonary
artery and the left atrium.
Large airway obstruction results in restriction to airflow, primarily during
expiration. When obstruction is severe, inspiration may also be compromised.
When gas trapping occurs, chest radiographs demonstrate increased lung
volumes, and studies of respiratory mechanics show abnormalities of expira-
tory flow and increased airway resistance. A rare variant of tetralogy of Fallot,
tetralogy of Fallot with absent pulmonary valve, produces airway obstruction
of both large and small airways by hugely dilated pulmonary arteries, lead-
ing to lobar collapse, bronchial obstruction with air trapping, and often
severe distress.
A combination of imaging techniques is usually required for a full assessment
of airway compression in a child with congenital heart disease.6,7 Historically,
chest radiography and barium esophagram were performed to evaluate chil-
dren suspected of having extrinsic airway compression (Figure 48‑1 and
Figure 48‑2). Multi-slice computed tomography or magnetic resonance angio-
graphy can delineate precise anatomic details of the vascular anomaly as well

855
as the relationship of the vascular structures to the airway and the airway
caliber. Bronchoscopy may also be helpful in identifying the location and
degree of airway compression.
Often the abnormalities of pulmonary function and respiratory mechanics
can be reversed with surgical correction of the vascular anomalies and other
cardiac causes of airway compression. However, long-standing extrinsic
airway compression may lead to tracheobronchomalacia, which may persist
even after correction of the cardiac defect. Therapy should be directed at
reversing the underlying cardiac lesion, because surgical interventions
aimed at the airway, such as aortopexy and airway stent placement, involve
risk and may be unsuccessful or offer only temporary relief.
Figure 48‑1. A. Anteroposterior radiograph of the chest in a child with a

double aortic arch. B. Esophagram showing compression of the upper
thoracic esophagus by the double aortic arch.
Figure 48‑2. A. Anteroposterior radiograph of the chest in child with a right aortic arch.
Note displacement of the trachea toward the left indicating a right aortic arch. B. Lateral
radiograph of the chest demonstrating narrowing and anterior displacement of the trachea
by the aberrant left subclavian artery, which passes behind it. C. Esophagram showing
posterior impression of the esophagus by the aberrant left subclavian artery.
Reprinted from Shah RK, Mora BN, Bacha E, et al. The presentation and management of vascular rings: an
otolaryngology perspective. Int J Pediatr Otorhinolaryngol. 2007;71(1):57–62. Copyright © 2007, with

856
Eisenmenger Syndrome and Pulmonary

Vascular Disease
One of the most common causes of pulmonary vascular disease is as the
result of prolonged left-to-right shunting. This usually follows a period of
large left-to-right shunt resulting in high pulmonary blood flow, but it may
rarely occur in patients who never have manifested clinical features associated
with a large left-to-right shunt, namely tachypnea, tachycardia, poor feeding,
and failure to thrive. Paradoxically, clinical signs of congestive heart failure
improve with increasing pulmonary vascular resistance. This is followed by
the appearance of cyanosis and progressively oligemic lung fields. Although
now rare due to early diagnosis and treatment of congenital heart disease,
Eisenmenger syndrome results when an unrestricted and large left-to-right
shunt leads to irreversible pulmonary vascular disease and subsequent
right-to-left shunt.9
Pulmonary vascular disease may also develop due to congenital heart
defects causing increased pulmonary venous pressure, such as congenital
mitral stenosis, cor triatriatum, and pulmonary venous stenosis. Lastly, certain
cyanotic congenital cardiac defects are associated with pulmonary hyperten-
sion and, if uncorrected, with pulmonary vascular disease. These include
transposition of great arteries, pulmonary atresia with ventricular septal
defect and unrestricted flow through aortopulmonary collaterals, and truncus
arteriosus.
Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is defined as an elevated mean
pulmonary arterial pressure of greater than 20 mm Hg, with a normal
pulmonary artery wedge pressure (PAWP <15 mm Hg) and increased pul-
monary vascular resistance (PVR >3 WU) in children older than 3 months.10–15
Pulmonary arterial hypertension may occur in the absence of congenital heart
disease and was previously classified according to the presence (secondary)
or absence (primary) of an identifiable underlying cause. Pulmonary arterial
hypertension is now classified based on underlying risk factors and associated
conditions. In 2018, the 6th World Symposium on Pulmonary Hypertension
updated the existing classification of pulmonary hypertension to include
many of the etiologies of pediatric pulmonary hypertension, as shown in
Box 48‑1.11 Persistent pulmonary hypertension of the newborn (PPHN) and
pulmonary hypertension secondary to lung disease are briefly discussed
in the following text.

857
Box 48-1
Classification of Pulmonary Hypertension
(Group 1) Pulmonary Arterial Hypertension (PAH)
(1.1) Idiopathic PAH
(1.2) Heritable PAH
(1.3) Drug- and toxin-induced PAH
(1.4) Pulmonary arterial hypertension associated with the following:
(1.4.1) Connective tissue disease
(1.4.2) HIV infection
(1.4.3) Portal hypertension
(1.4.4) Congenital heart disease
(1.4.5) Schistosomiasis
(1.5) Pulmonary arterial hypertension long-term responders to calcium
channel blockers
(1.6) Pulmonary arterial hypertension with overt features of venous/capillaries
involvement
(1.7) Persistent pulmonary hypertension of the newborn syndrome
(Group 2) Pulmonary Hypertension Due to Left Heart Disease
(2.1) Pulmonary hypertension due to heart failure with preserved left ventricular
ejection fraction
(2.2) Pulmonary hypertension due to heart failure with reduced left ventricular
ejection fraction
(2.3 Valvular heart disease
(2.4) Congenital/acquired cardiovascular conditions leading to post-capillary
pulmonary hypertension
(Group 3) Pulmonary Hypertension Due to Lung Diseases and/or Hypoxemia
(3.1) Obstructive lung disease
(3.2) Restrictive lung disease
(3.3) Other lung disease with mixed restrictive/obstructive pattern
(3.4) Hypoxia without lung disease
(3.5) Developmental lung disorders
(Group 4) Pulmonary Hypertension Due to Pulmonary Artery Obstructions
(4.1) Chronic thromboembolic pulmonary hypertension
(4.2) Other pulmonary artery obstructions
(Group 5) Pulmonary Hypertension With Unclear and/or Multifactorial Mechanisms
(5.1) Hematologic disorders
(5.2) Systemic and metabolic disorders
(5.3) Others
(5.4) Complex congenital heart disease
Reprinted from Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated
clinical classification of pulmonary hypertension. Eur Respir J. 2019:24;53(1):1801913. Copyright © 2019
European Respiratory Society.

858
Persistent Pulmonary Hypertension of the Newborn

Persistent pulmonary hypertension of the newborn, the most common cause
of transient PAH, is often associated with conditions such as meconium
aspiration, pneumonia, and sepsis. Persistent pulmonary hypertension of
the newborn is characterized by increased pulmonary vascular resistance,
right-to-left shunting at the atrial or the ductal level, and severe hypoxemia.
Persistent pulmonary hypertension of the newborn is typically transient and
resolves with appropriate treatment; however, it can be fatal in a small
percentage of children.
Pulmonary Hypertension Due to Lung Diseases and/or Hypoxia

The major causes of pulmonary hypertension associated with pulmonary
disease are obstructive pulmonary diseases such as bronchopulmonary
dysplasia13,14 and cystic fibrosis, restrictive pathologies including interstitial
lung disease, and obstructive sleep apnea. The pathophysiology varies, but
the common factors include chronic hypoxia with resulting vasoconstriction
and muscular arteriolar hypertrophy. The hypertrophy is initially reversible
if the underlying condition, especially the hypoxia, is remediable. Nocturnal
hypoxia due to underlying lung disease or untreated obstructive sleep apnea
may also cause pulmonary hypertension.
Clinical Features
Signs and symptoms may appear late in the clinical course of patients with
pulmonary hypertension and are often nonspecific. Infants may present with
sweating, tiring with feeding, and failure to thrive, while older patients may
experience fatigue, exertional dyspnea, and chest pain. If infants have a patent
foramen ovale, they may also present with cyanosis either at rest or with
exercise because of a concomitant right-to-left shunt. In infants and children
without the atrial level shunt to alleviate right atrial pressure and maintain
cardiac output or act as a “pop-off,” syncope can be a presenting symptom,
and, in these cases, the prognosis is worse.
Typically, the pulmonic component of the second heart sound is accentuated.
A right ventricular heave with or without chest wall distortion may be noted
as a result of right ventricular hypertrophy or dysfunction. Tricuspid regurgi-
tation is common, with a holosystolic murmur at the left lower sternal border.
Clinical signs of right heart failure, such as hepatomegaly, peripheral edema,
and cyanosis, are rare in infants but can be observed in older children and
adults. Digital clubbing may be seen in patients with persistent hypoxemia.

859
Diagnosis and Evaluation

In addition to a comprehensive history and physical examination, diagnostic
studies will need to be performed to assess for both cardiac and pulmonary
function and potential underlying etiologies. Electrocardiographic findings
may be normal early in disease or have evidence of cor pulmonale, with right
axis deviation with right ventricular hypertrophy, which may be seen later in
the disease process.10–15 Initially, chest radiograph findings may be normal
or later demonstrate cardiomegaly with increased pulmonary vascular mark-
ings. Severe pulmonary hypertension is characterized by an enlarged main
pulmonary artery segment and diminished pulmonary vascularity.10–14
Echocardiography should be used to confirm a clinical suspicion of pulmonary
hypertension and evaluate right ventricular function. An indirect estimate of
right ventricular pressure is obtained by the tricuspid regurgitation jet velocity.
The peak velocity of the tricuspid regurgitation jet is proportional to the right
ventricular to right atrial pressure difference. In addition, there are other
indirect observations suggestive of pulmonary hypertension, such as flatten-
ing or posterior bowing of the interventricular septum and right ventricular
hypertrophy and gradients across ventricular or arterial shunts. Echocardio-
graphy is useful as a noninvasive screening tool but can miss pulmonary
hypertension, even when severe, and often can underestimate pulmonary
artery pressures. Cardiac catheterization remains the gold standard in
determining the presence and severity of pulmonary hypertension.10,14
Catheterization with acute vasoreactivity testing should be performed to test
the potential reversibility of pulmonary vascular disease. Though cardiac
catheterization is regarded as the gold standard, presence of sedation, hypo-
ventilation, and hypoxia may change the pulmonary vascular resistance. Lastly,
cardiac catheterization in the presence of advanced pulmonary vascular disease
may be associated with a higher risk of morbidity and mortality and should
only be performed in centers with expertise in management of pulmonary
hypertension. Interval repeat echocardiograms and catheterizations should
be performed to monitor the clinical course and response to therapies.
Chest computed tomography, lung perfusion scan, magnetic resonance imag-
ing, cardiopulmonary exercise testing, and polysomnography may be helpful
in evaluating the underlying pathogenesis and monitoring response to therapy
of PAH. Brain natriuretic peptide or N-terminal pro b-type natriuretic peptide
are biomarkers measured at baseline and follow-up to assess cardiac disease
severity and treatment response, with elevated levels correlating with a poor
prognosis in pulmonary hypertension. The 6-minute walk distance test can be

860
used to monitor exercise tolerance in older children. This test can assess overall
distance walked, how this distance compares to predicted normal distance, and
the presence of exercise-induced oxygen desaturations. Serial walk tests can
also monitor the patient’s disease progression and response to therapy.
Vasoconstriction
Figure 48‑3. Vascular changes in pulmonary hypertension.

Reprinted from McLaughlin VV, Shah SJ, Souza R, Humbert M. Management of pulmonary arterial
hypertension. J Am Coll Cardiol. 2015;65(18):1976–1997. Copyright © 2015 American College of Cardiology
Foundation.
Evaluation of pulmonary vascular structure in lung biopsy specimens can

provide important information, especially in preoperative patients. The
Heath-Edwards Classification describes 6 grades of changes seen in patients
with pulmonary hypertension.16 These changes range from medial hypertro-
phy in grade I to formation of angiomatoid lesions and fibrinoid necrosis in
grade VI, which convert the lung to a stiff mesh-like organ (Figure 48-3).
It is believed that pulmonary vascular changes of grades Ι and II severity are
reversible, whereas more advanced changes indicate that pulmonary vascular
disease will persist or worsen following correction of the underlying lesion.
However, in practice, biopsy is rarely performed exclusively to assess the
pulmonary vasculature, in part due to the nonuniform nature of pulmonary
vascular disease and in part due to lack of widespread expertise in preparing
and interpreting pulmonary vascular changes. Lung biopsy is often useful in
the diagnosis and clinical management of underlying pulmonary pathologies
associated with pulmonary hypertension including, but not limited to,
childhood interstitial lung disease.17

861
Surgical Treatment of Pulmonary Hypertension

The recognition and management of pulmonary hypertension is important
both preoperatively and postoperatively. In most cases, early repair of the
underlying cardiac lesion will prevent development of pulmonary vascular
disease; however, in some cases, pulmonary hypertension may persist and
progress to irreversible pulmonary vascular disease despite appropriate and
timely interventions. This process seems to be accelerated at high altitudes
and in patients with Down syndrome. The timing and selection of patients
for surgical repair is of utmost importance, as intervention may be futile and
counterproductive if advanced vascular disease is present. The availability
of medical therapy increases the possibility for surgical repair of defects in
children who previously would not have been candidates for surgery.
Medical Treatment of Pulmonary Hypertension
General health care maintenance measures include recommendations for
limitation of physical activity, prevention of pregnancy, and aggressive treat-
ment of infections.12,13 Decisions regarding selection, initiation, and modifica-
tion of pulmonary hypertension–specific therapy should be made based on
disease severity, drug tolerance (and availability/cost), and consultation with
pulmonary hypertension specialists12–14 (Figure 48‑4). Supportive medical
therapies, such as diuretics and digoxin, are options for patients with right
heart failure but should be used cautiously. Oxygen can act as a pulmonary
vasodilator, and supplemental oxygen may be used in patients with daytime or
nocturnal hypoxemia. Oral anticoagulation with warfarin may be cautiously
used, particularly in patients with underlying hypercoagulability, but benefits
must be weighed against bleeding risk, such as hemoptysis.
Inhaled nitric oxide dilates the pulmonary vasculature by increasing cyclic
guanosine monophosphate (cGMP) levels, resulting in smooth muscle
relaxation. Inhaled nitric oxide can be used in the acute management of
pulmonary hypertension. Four classes of drugs are used as part of targeted
pulmonary vasodilator therapy, including (1) phosphodiesterase inhibitors,
(2) endothelin receptor antagonists, (3) prostacyclin analogues, and
(4) calcium channel blockers.

862
Determination of BPD
severity at 36 weeks PCA Severe respiratory
disease and/or signs and
symptoms of pulmonary
hypertension at any stage
No or mild BPD Moderate or severe BPD
Continued clinical
care and monitoring
Failure to improve or worsening

Perform comprehensive
respiratory course, including
echocardiogram
sustained oxygen requirement
PH absent PH: Mild–moderate PH: Severe

Echo parameters suggest Echo parameters suggest Echo parameters suggest
<1/2 SAP <1/2–2/3 SAP >2/3 SAP with severe
septal flattening
Continue BPD therapy, 1. Optimize gas exchange

Screening ECHO q4–6 mos. 2. Target saturations >92–95%
as long as O2 required 3. Extensive diagnostic evaluation
and treatment of contributing
comorbidities
Consider
empiric
Repeat echocardiogram PH-specific
drug
therapy
ECHO measures ECHO measures of PH and

of PH improve BNP or NT-proBNP
fail to improve
Cardiac catheterization
Continue BPD therapy,
to evaluate PH and
repeat ECHO q2–4 mos.
associated comorbidities
as long as O2 required
(eg, PVS, LVDD, shunts,
collateral vessel)
Figure 48‑4. Management of pulmonary hypertension in infants with bronchopulmonary

dysplasia (BPD) . Abbreviations: ECHO, echocardiogram; LVDD, left ventricular diastolic
dysfunction; O2, oxygen; SAP, systemic arterial pressure
Reprinted from Krishnan U, Feinstein JA, Adatia I, et al; Pediatric Pulmonary Hypertension Network
(PPHNet). Evaluation and management of pulmonary hypertension in children with bronchopulmonary
dysplasia. J Pediatr. 2017;188:24–34.e1. Copyright © 2017, with permission from Elsevier.

863
Phosphodiesterase Inhibitors
Phosphodiesterase type-5 inhibitors (sildenafil, tadalafil) cause vasodilation by
preventing the breakdown of cGMP.18 Tadalafil has a longer duration of action,
with dosing once daily as opposed to 3 times daily with sildenafil; however,
pediatric data are limited.
Endothelin-1 Receptor Antagonists
Endothelin-1 receptor antagonists (bosentan, ambrisentan, macitentan) lower
pulmonary vascular resistance by blocking the receptor for endothelin-1,
a potent vasoconstrictor.19
Prostacyclin Analogues
Prostacyclin analogs (epoprostenol, treprostinil, iloprost) stimulate cyclic
adenosine monophosphate, resulting in vasodilation, inhibition of platelet
aggregation, and anti-inflammatory effects.12,13 Limited by a short half-life,
they are typically administered intravenously or subcutaneously or inhaled,
with limited data on pediatric use of oral treprostinil.
Calcium Channel Blockers
Calcium channel blockers (nifedipine, diltiazem, amlodipine), which inhibit
calcium influx in vascular smooth muscle, are indicated for patients who
demonstrate vasoreactivity to inhaled nitric oxide on catheterization. These
patients form a unique subset of patients with PAH who have a significantly
better long-term prognosis and have been recently subclassified as Group 1.5
(see Box 48‑1).
Infants with pulmonary hypertension and bronchopulmonary dysplasia
should have outpatient follow-up with the multidisciplinary pulmonary
hypertension team for ongoing treatment of their chronic lung disease and
pulmonary hypertension at intervals of 3 to 4 months with use of echocardio-
graphy, biomarkers, hemodynamic studies, and sleep studies when indicated
during follow-up, depending on disease severity and clinical progress.12,13
Surgical options may be considered in severe cases unresponsive to medical
treatments. An atrial septostomy creates a right-to-left atrial shunt to improve
cardiac output while a Potts shunt, created from the descending aorta to the left
pulmonary artery, helps reduce right ventricular pressure and increase systemic
blood flow. The option of last resort is lung or heart-lung transplantation.
Prognosis
The prognosis for children with pulmonary hypertension varies depending on
the underlying etiology and associated comorbidities. Overall prognosis has
improved in the era of targeted vasodilator therapy. Despite advancements in
diagnosis and management of pediatric pulmonary hypertension, the estimated
5-year survival rate is only 75%.11–15

864
Viral Respiratory Infections in Children

With Congenital Heart Disease
Children with congenital heart disease represent a high-risk group for
viral respiratory infections. The complex risk factors include altered car-
diorespiratory status at baseline, altered pulmonary mechanics, potential
cyanosis with or without pulmonary hypertension, and V·/Q· mismatch. All
these factors exacerbate the adverse effects of respiratory disease and blunt
normal compensatory mechanisms. A review of respiratory infections in
children younger than 24 months with significant congenital heart disease
demonstrated a 10.4% incidence of hospitalization.20 Risk factors for hos-
pitalization (in order of decreasing odds ratio) include presence of 22q11
deletion syndrome, weight below the 10th percentile for age, previous res-
piratory infections, incomplete prophylaxis against respiratory syncytial virus
(RSV), recent cardiopulmonary bypass, trisomy 21, and siblings younger than
11 years. In the first report of children with congenital heart disease and RSV,
a 37% mortality was noted, with a 73% mortality in patients with pulmonary
hypertension.21 More recent studies have noted an improvement in survival,
with mortality rates of approximately 2% to 3%.22,23 Morbidity remains
high, with about 30% requiring intensive care unit admission and prolonged
mechanical ventilation. Improved outcomes have been attributed to early
repair of hemodynamically significant lesions and, more recently, use of
palivizumab for RSV immunoprophylaxis. A large, multicenter, international
clinical trial of immunoprophylaxis in infants with congenital heart disease
demonstrated a reduction in hospitalization by 45% when compared with
the placebo group.24 The investigators concluded that monthly palivizumab
prophylaxis is safe and effective in children with serious congenital heart
disease. Current American Academy of Pediatrics (AAP) guidelines25
recommend that monthly palivizumab prophylaxis is indicated for infants
12 months of age and younger with hemodynamically significant CHD, includ-
ing infants with acyanotic heart disease who are receiving medication to
control congestive heart failure and will require cardiac surgical procedures
and infants with moderate to severe PAH. The AAP does not recommend
palivizumab for children with hemodynamically insignificant CHD, those
with surgically repaired CHD who are not receiving medication for heart
failure, those with cardiomyopathy who are not taking medical therapy, or
children in their second year after birth.25 Other anti-RSV antibodies,
subunit, live-attenuated and recombinant virus, and polypeptide vaccines are
in clinical trials and have the potential for increasing protection in this
vulnerable patient population.26
The only antiviral agent approved for treatment of RSV infection is ribavi-
rin.27 It is expensive and cumbersome to deliver in a spontaneously breathing
patient and has potential health risks for caregivers; therefore, its use is

865
restricted to the highest-risk patients. Moreover, studies have documented

marginal benefit, if any, for most patients. Nevertheless, the AAP recom-
mends that ribavirin may be considered for use in highly selected situations
involving documented RSV bronchiolitis with severe disease or in those who
are at risk for severe disease (eg, immunocompromised or hemodynamically
significant cardiopulmonary disease).28 Other respiratory infections, even if
trivial, should be treated symptomatically with close follow-up and early
hospitalization if indicated in this patient population.
key points
} The cardiac and respiratory systems function as one unit, and pulmonary
manifestations occur in most patients with congenital heart disease.
} Pulmonary blood flow is dependent on both cardiac output and pulmonary
vascular resistance.
} Increased pulmonary blood flow and pulmonary hypertension are seen in many
forms of congenital heart disease with left-to-right shunts and are a cause of
impairment of lung mechanics.
} Irreversible pulmonary vascular disease may be the end result of severe
pulmonary hypertension and carries a high mortality and morbidity.
} Treatment of pulmonary hypertension requires a multidisciplinary approach.
Newer treatment strategies for pulmonary hypertension, such as prostacyclin
analogues, endothelial receptor antagonists, and phosphodiesterase inhibitors,
have shown good short-term results.
} Infections with respiratory viruses, especially RSV, can be devastating in children
with congenital heart disease; appropriate prophylaxis with palivizumab is
important in this patient population to reduce morbidity and mortality.
Acknowledgments
The authors acknowledge the work of Robert W. Morrow, MD, Nandini
Madan, MD, and Daniel V Schidlow, MD, authors of the version of this
chapter from the first edition of this book; and of Saumini Srinivasan, MD,
MS, Jean A. Ballweg, MD, Nicholas L. Friedman, DO, FAAP, and Samuel
Goldfarb, MD, who wrote on this topic in Pediatric Pulmonology, Asthma,
and Sleep Medicine: A Quick Reference Guide. Parts of this chapter are
adapted from these works.

866
References
1. Morrow WR. Aortic arch and pulmonary artery anomalies. In: Oski FA, DeAngelis C, Feigin RD,
eds. Principles and Practice of Pediatrics. 4th ed. Lippincott Company; 2006
2. Davies CJ, Cooper SG, Fletcher ME, et al. Total respiratory compliance in infants and young
children with congenital heart disease. Pediatr Pulmonol. 1990;8(3):155–161 PMID: 2349007
doi: 10.1002/ppul.1950080305
3. Fletcher R. Relationship between alveolar deadspace and arterial oxygenation in children with
congenital cardiac disease. Br J Anaesth. 1989;62(2):168–176 PMID: 2647117
doi: 10.1093/bja/62.2.168
4. Tissot C, Ivy DD, Beghetti M. Medical therapy for pediatric pulmonary arterial hypertension.
5. Hiatt PW, Mahony L, Tepper RS. Oxygen desaturation during sleep in infants and young children
with congenital heart disease. J Pediatr. 1992;121(2):226–232 PMID: 1640288
doi: 10.1016/S0022-3476(05)81193-X
6. Apostolopoulou SC. The respiratory system in pediatric chronic heart disease. Pediatr Pulmonol.
2017;52(12):1628–1635 PMID: 29076654 doi: 10.1002/ppul.23900
7. Sebening C, Jakob H, Tochtermann U, et al. Vascular tracheobronchial compression
syndromes—experience in surgical treatment and literature review. Thorac Cardiovasc Surg.
2000;48(3):164–174 PMID: 10903065 doi: 10.1055/s-2000-9633
8. Wetzel RC, Herold CJ, Zerhouni EA, Robotham JL. Intravascular volume loading reversibly
decreases airway cross-sectional area. Chest. 1993;103(3):865–870 PMID: 8449083
doi: 10.1378/chest.103.3.865
9. Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in
children. Circulation. 1999;99(9):1197–1208 PMID: 10069788 doi: 10.1161/01.CIR.99.9.1197
10. Rosenzweig EB, Abman SH, Adatia I, et al. Paediatric pulmonary arterial hypertension: updates
on definition, classification, diagnostics and management. Eur Respir J. 2019:24;53(1):1801916
11. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical
classification of pulmonary hypertension. Eur Respir J. 2019:24;53(1):1801913
12. Krishnan U, Feinstein JA, Adatia I, et al; Pediatric Pulmonary Hypertension Network (PPHNet).
Evaluation and management of pulmonary hypertension in children with bronchopulmonary
dysplasia. J Pediatr. 2017;188:24–34.e1 PMID: 28645441 doi: 10.1016/j.jpeds.2017.05.029
13. Rosenzweig EB, Krishnan U. Congenital heart disease-associated pulmonary hypertension.
14. Abman SH, Hansmann G, Archer SL, et al; American Heart Association Council on
Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Clinical Cardiology;
Council on Cardiovascular Disease in the Young; Council on Cardiovascular Radiology and
Intervention; Council on Cardiovascular Surgery and Anesthesia; and the American Thoracic
Society. Pediatric pulmonary hypertension: Guidelines From the American Heart Association
and American Thoracic Society. Circulation. 2015;132(21):2037–2099 PMID: 26534956
doi: 10.1161/CIR.0000000000000329
15. Haworth SG, Hislop AA. Treatment and survival in children with pulmonary arterial
hypertension: the UK Pulmonary Hypertension Service for Children 2001-2006. Heart.
2009;95(4):312–317 PMID: 18952635 doi: 10.1136/hrt.2008.150086
16. Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease; a description of
six grades of structural changes in the pulmonary arteries with special reference to congenital
cardiac septal defects. Circulation. 1958;18(4 Part 1):533–547 PMID: 13573570
doi: 10.1161/01.CIR.18.4.533
17. Hafezi N, Heimberger MA, Lewellen KA, Maatman T, Montgomery GS, Markel TA. Lung biopsy
in children’s interstitial and diffuse lung disease: does it alter management? Pediatr Pulmonol.
2020;55(4):1050–1060 PMID: 32040887 doi: 10.1002/ppul.24683
18. Cohen JL, Nees SN, Valencia GA, Rosenzweig EB, Krishnan US. Sildenafil use in children with
pulmonary hypertension. J Pediatr. 2019;205:29–34.e1 PMID: 30396684
doi: 10.1016/j.jpeds.2018.09.067
19. Barst RJ, Ivy D, Dingemanse J, et al. Pharmacokinetics, safety, and efficacy of bosentan in
pediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther.
2003;73(4):372–382 PMID: 12709727 doi: 10.1016/S0009-9236(03)00005-5
20. Medrano C, Garcia-Guereta L, Grueso J, et al; CIVIC Study Group from the Spanish Society of
Pediatric Cardiology and Congenital Heart Disease. Respiratory infection in congenital cardiac
disease. Hospitalizations in young children in Spain during 2004 and 2005: the CIVIC
Epidemiologic Study. Cardiol Young. 2007;17(4):360–371 PMID: 17662160
doi: 10.1017/S104795110700042X

867
21. MacDonald NE, Hall CB, Suffin SC, Alexson C, Harris PJ, Manning JA. Respiratory syncytial
viral infection in infants with congenital heart disease. N Engl J Med. 1982;307(7):397–400
PMID: 7088112 doi: 10.1056/NEJM198208123070702
22. Wang EE, Law BJ, Stephens D. Pediatric Investigators Collaborative Network on Infections in
Canada (PICNIC) prospective study of risk factors and outcomes in patients hospitalized with
respiratory syncytial viral lower respiratory tract infection. J Pediatr. 1995;126(2):212–219
PMID: 7844667 doi: 10.1016/S0022-3476(95)70547-3
23. Navas L, Wang E, de Carvalho V, Robinson J; Pediatric Investigators Collaborative Network on
Infections in Canada. Improved outcome of respiratory syncytial virus infection in a high-risk
hospitalized population of Canadian children. J Pediatr. 1992;121(3):348–354 PMID: 1517907
doi: 10.1016/S0022-3476(05)90000-0
24. Feltes TF, Cabalka AK, Meissner HC, et al; Cardiac Synagis Study Group. Palivizumab
prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with
hemodynamically significant congenital heart disease. J Pediatr. 2003;143(4):532–540
PMID: 14571236 doi: 10.1067/S0022-3476(03)00454-2
25. American Academy of Pediatrics Committee on Infectious Diseases; American Academy of
Pediatrics Bronchiolitis Guidelines Committee. Updated guidance for palivizumab prophylaxis
among infants and young children at increased risk of hospitalization for respiratory syncytial
virus infection. Pediatrics. 2014;134(2):e620–e638
26. Venkatesh MP, Weisman LE. Prevention and treatment of respiratory syncytial virus
infection in infants: an update. Expert Rev Vaccines. 2006;5(2):261–268 PMID: 16608425
doi: 10.1586/14760584.5.2.261
27. Chen CH, Lin YT, Yang YH, et al. Ribavirin for respiratory syncytial virus bronchiolitis reduced
the risk of asthma and allergen sensitization. Pediatr Allergy Immunol. 2008;19(2):166–172
PMID: 18257904 doi: 10.1111/j.1399-3038.2007.00610.x
28. American Academy of Pediatrics. Respiratory syncytial virus. In: Pickering LK, Baker CJ,
Kimberlin DW, Long SS, eds. Red Book: 2009 Report of the Committee on Infectious Diseases.
28th ed. American Academy of Pediatrics; 2009:562

CHAPTER
49
Lung Disease Associated With Endocrine Disorders
Martin Draznin, MD
The endocrine system comprises about 8 major glands; their impact on the
respiratory system is a function of the level of hormone output, be it normal,
increased, or decreased. These effects are more evident in the adult literature,
some of which may be extrapolated to the pediatric population.
Endocrine disorders may lead to pulmonary disease (Table 49-1). Thyroid
disorders may affect pulmonary function at the level of respiratory drive; para-
thyroid disorders may lead either to tetany with attendant laryngospasm or to
muscle weakness from hypercalcemia. Diabetes has considerable effect on lung
structure and function, although pituitary, adrenal, and reproductive disorders
have little effect on lung function.1
Table 49‑1. Examples of Pulmonary Effects of Endocrine Disorders
Endocrine Disorder Pulmonary Effect Clinical Significance
Hypothyroidism Diminished respiratory Usually subclinical, reversible with
drive treatment
Pleural or pericardial Usually subclinical and reversible,
effusion can be severe
Hyperthyroidism Increased respiratory Usually subclinical, reversible with
drive treatment
Thiourea drugs for Diffuse alveolar Life-threatening, prolonged
hyperthyroidism hemorrhage supportive care needed
Hypercalcemia due to Pulmonary calcinosis Can be severe, symptoms reversible,
hyperparathyroidism with respiratory failure lung changes partly reversible
Hypocalcemia Stridor due to tetany Reversible with therapy
Growth hormone Diminished lung volumes Treatable with appropriate dose of growth
deficiency and respiratory pressures hormone for appropriate duration
Acromegaly, Obstructive sleep apnea Treatable
gigantism syndrome
Diabetes Restrictive lung disease All are subclinical, may be present at
Vascular disease diagnosis, might manifest at high
altitude, in presence of chronic lung
Autonomic nerve function
disease. Possible increase in infection.
Oxidative stress
869

870
Thyroid Disorders
In hypothyroidism, the respiratory drive is reduced,2 but this may not be
evident clinically because children with hypothyroidism tend to be less active
compared to children with a thyroid that functions normally. There may be
clinical signs of subcutaneous myxedema or pleural or pericardial effusion.
In most cases, the physical signs are more evident than the clinical effects,
which tend to be minor.
Increase in thyroid hormones results in increased central respiratory drive
and responsivity to carbon dioxide with a direct relationship. There may be an
increase in respiratory rate and shortness of breath, particularly on exercise.3
The clinical effect may be minor because the finding of hyperthyroidism
typically is associated with the recommendation to limit exercise until the
thyroid hormone levels are more normal.
Alterations of pulmonary function may be temporary but will improve as
treatment improves the clinical picture. The changes may be a consequence
of myopathic weakening of respiratory muscles.
An important complication of the treatment of hyperthyroidism with the
thiouracil class of agents has been reported. It involves diffuse alveolar
hemorrhage due to antineutrophil cytoplasmic antibody-positive vasculitis.4
Parathyroid Disorders
Hypercalcemia due to primary hyperparathyroidism is uncommon in infants
and children. In one case report, a 2-month-old infant with pulmonary calci-
nosis due to hyperparathyroidism presented with respiratory distress and
failure to thrive.5 Chest radiograph and radionuclide scanning demonstrated
calcium deposits within lung tissue. The respiratory distress resolved when
calcium levels were normalized, yet the pulmonary calcinosis did not fully
resolve. Reversible respiratory muscle weakness due to the hypercalcemia
would be an expected finding; anatomical changes, though, are less likely. A
more severe case of pulmonary calcification from hyperparathyroidism was
reported in which respiratory failure ensued requiring 40 days of ventilator
support.6 The severity was such that the patient had only partial clearing
of the lung abnormalities over a 1-year period.
The respiratory disorder one would expect to be associated with hypocalcemia
would be tetany leading to increased respiratory muscle tone and stridor due
to vocal cord spasm. The lungs in children with vitamin D-dependent rickets
seem to be affected most by chest wall deformity, as reported in a series of
30 infants and children from Iran.7 In the oldest 3 children, the findings were
mild. However, in the rest, lobar or segmental atelectasis and compression
atelectasis under the costochondral junctions, where the rachitic rosary is

871
Chapter 49—Lung Disease Associated With Endocrine Disorders
seen, was described. The deformity of the chest wall and resultant restrictive
defect together with malnutrition results in diminished reserve and, in some
cases, interstitial pneumonitis.7 Treatment for chronic hypocalcemic states is
routinely monitored for induction of nephrocalcinosis; it may be prudent to
assess pulmonary changes.
Pituitary
Excess of growth hormone (somatotropin), results in acromegaly, which is
called gigantism if it occurs before puberty. Growth hormone derives from
the pituitary. Both acromegaly and gigantism are rare. In children, there
is abnormally tall stature with abnormal growth of face, hands, and feet.
After the growth plates have fused, there is not the increase in height
seen in acromegaly.
The major respiratory effect seen is obstructive sleep apnea syndrome. There
may also be shortness of breath, particularly on exertion.8
Growth hormone deficiency may result in diminished lung volume and
respiratory strength.
Cushing syndrome is a consequence of considerable exposure to exogenous or
endogenous corticosteroids. There is no adult or pediatric literature to suggest
that the myopathy associated with this results in clinically evident changes.9
Diabetes Mellitus
Children with diabetes are encouraged to be physically active. In those with
type 2 diabetes, increased activity helps reduce insulin resistance and weight,
which directly assists in the diabetes management. In children with type 1
diabetes, exercise and physical activity are encouraged to achieve fitness and
maintain cardiovascular health. There have been numerous reports of com-
promise of lung function due to diabetes. One study from the Netherlands,
done in anticipation of safety and efficacy trials for an inhaled form of insulin,
showed increased airway resistance in the treated group and no correlation
with duration of disease or age of the children.10 The concern was that the
studies had been small and that more systematic studies might be helpful,
but the conclusion is that the lung is definitely a target organ for damage
from diabetes, with both microvascular and other tissue changes being likely.
An Italian study of children with type 1 diabetes found forced vital capacity,
forced expiratory volume in the first second of inspiration, and transfer factor
for carbon monoxide to be diminished compared with age-matched controls.11
Of interest was that changes in these indices were noted at the time of diag-
nosis in the subset studied from onset and that, counter to expectations,
the duration of diabetes and level of blood glucose control or presence of

872
associated complications did not correlate with the degree of the changes.
Again, the subjects had no clinical complaints.
A more recent review summarizes changes in pulmonary physiology from the
standpoint of lung mechanics, gas exchange, autonomic function, and a newer
area of interest: the pulmonary effects of oxidative stress.12 The interesting
idea that some of the changes could occur years before diabetes is diagnosed,
as is true in adult type 2 diabetes, is important in children because the inci-
dence of type 2 diabetes in youth is increasing rapidly; children are reported
to accrue the other complications at a more rapid rate than adults. This larger
review again notes that the changes are subclinical until unmasked by inter-
current illness, high altitude, aging, or onset of primary lung disease. Obesity,
which is a nearly universal finding in type 2 diabetes when diagnosed in
children and adolescents, also affects pulmonary function. (See Chapter 43,
Asthma and Other Respiratory Disorders Associated With Obesity.)
When to Refer
The disorders of lung function that have been outlined are uncommon accom-
paniments of less-than-common conditions, with the exception of diabetes
mellitus and hypothyroidism. It would not seem cost effective to investigate
each case of dyspnea for an underlying endocrine disease. However, there are
many examples of when a combined evaluation by a pediatric endocrinologist
and pulmonologist would be valuable. Although rickets is less common in
more well-developed countries, it is important to evaluate a patient with stridor
but no fever, without an anatomical airway disorder, for tetany by clinical
examination. The changes from diabetes may not be preventable if indeed
they occur prior to diagnosis, even in type 1 diabetes, and monitoring of
lung function with the help of a pediatric pulmonologist is appropriate.
When to Admit
The need to hospitalize flows from the level of lung function and the necessity
to treat the underlying endocrine disorder on an inpatient basis. The changes
from lung calcification seen in hyperparathyroidism are the most severe, while
the changes from diabetes seem to be subclinical in children.

873
Chapter 49—Lung Disease Associated With Endocrine Disorders
key po ints
} Although not always clinically evident, endocrine disorders potentially have an
effect on lung function and physiology.
} Hyperthyroidism and hypothyroidism can lead to reduced exercise tolerance,
which normalizes with treatment.
} Pulmonary hemorrhage may be a complication of treatment of hyperthyroidism
with thiouracil agents.
} Hypocalcemia is a nonpulmonary cause of stridor in infants.
} Diabetes can cause early changes in lung structure and function; therefore, lung
function monitoring in diabetes should be studied further to assess its value
to patients.
References
1. Brüssel T, Matthay MA, Chernow B. Pulmonary manifestations of endocrine and
metabolic disorders. Clin Chest Med. 1989;10(4):645–653 PMID: 2689069
doi: 10.1016/S0272-5231(21)00658-4
2. Cakmak G, Saler T, Sağlam ZA, Yenigün M, Demir T. Spirometry in patients with clinical
and subclinical hypothyroidism. Tuberk Toraks. 2007;55(3):266–270 PMID: 17978924
3. Pino-García JM, García-Río F, Díez JJ, et al. Regulation of breathing in hyperthyroidism:
relationship to hormonal and metabolic changes. Eur Respir J. 1998;12(2):400–407
PMID: 9727792 doi: 10.1183/09031936.98.12020400
4. Thabet F, Sghiri R, Tabarki B, Ghedira I, Yacoub M, Essoussi AS. ANCA-associated diffuse
alveolar hemorrhage due to benzylthiouracil. Eur J Pediatr. 2006;165(7):435–436
PMID: 16622664 doi: 10.1007/s00431-005-0053-4
5. Topaloglu AK, Yuksel B, Tuncer R, Mungan NO, Ozer G. Primary hyperparathyroidism in an
infant with three parathyroid glands and pulmonary calcinosis. J Pediatr Endocrinol Metab.
2001;14(8):1173–1175 PMID: 11592579 doi: 10.1515/jpem-2001-0818
6. Poddar B, Bharti S, Parmar VR, Sidhu R, Chowdhary S, Rao KL. Respiratory failure due to
pulmonary calcification in primary hyperparathyroidism. Arch Dis Child. 2002;87(3):257
PMID: 12193447 doi: 10.1136/adc.87.3.257
7. Khajavi A, Amirhakimi GH. The rachitic lung. Pulmonary findings in 30 infants and children
with malnutritional rickets. Clin Pediatr (Phila). 1977;16(1):36–38 PMID: 137094
doi: 10.1177/000992287701600106
8. Merola B, Longobardi S, Sofia M, et al. Lung volumes and respiratory muscle strength in adult
patients with childhood- or adult-onset growth hormone deficiency: effect of 12 months’ growth
hormone replacement therapy. Eur J Endocrinol. 1996;135(5):553–558 PMID: 8980157
doi: 10.1530/eje.0.1350553
9. Azezli AD, Bayraktaroglu T, Ece T, Kutluturk F, Orhan Y. Static lung volumes in patients with
Cushing’s disease. Exp Clin Endocrinol Diabetes. 2008;116(1):53–57 PMID: 17973213
doi: 10.1055/s-2007-990276
10. van Gent R, Brackel HJL, de Vroede M, van der Ent CK. Lung function abnormalities in
children with type I diabetes. Respir Med. 2002;96(12):976–978 PMID: 12477210
doi: 10.1053/rmed.2002.1402
11. Cazzato S, Bernardi F, Salardi S, et al. Lung function in children with diabetes mellitus.
12. Kaparianos A, Argyropoulou E, Sampsonas F, Karkoulias K, Tsiamita M, Spiropoulos K.
Pulmonary complications in diabetes mellitus. Chron Respir Dis. 2008;5(2):101–108
PMID: 18539724 doi: 10.1177/1479972307086313

CHAPTER
50
Pulmonary Complications of
Gastrointestinal Diseases
Edward W. Fong, MD
Introduction
The interactions between the body’s organ systems can be very complex,
and what starts out as a minor problem in a seemingly unrelated organ system
may blossom into a major morbidity in another. The interaction of the gastro-
intestinal (GI) system does have a role in causing morbidity in the pulmonary
system, although the extent of this role is controversial. Aspiration syndromes,
a related topic, are discussed in Chapter 41, Acute Aspiration and Chronic
Aspiration-Related Lung Disease.
Gastroesophageal Reflux
Pathogenesis
Despite a strong association between gastroesophageal reflux (GER) and
chronic respiratory disease, the mechanism by which GER precipitates or
exacerbates respiratory illness remains incompletely understood. Gastro-
esophageal reflux is usually caused by transient lower esophageal sphincter
relaxation with retrograde movement of gastric contents into the esophagus.
Other mechanisms include low-resting lower esophageal sphincter pressure;
increased intragastric pressure; increased intra-abdominal pressure due to
coughing, which can raise the gastroesophageal pressure gradient and
increase the risk of reflux; and the presence of a hiatal hernia.
The most common respiratory manifestations of GER include wheezing and
nighttime coughing (Box 50-1). Presenting symptoms can be divided into
typical esophageal symptoms (such as heartburn and regurgitation) and
atypical/extraesophageal symptoms (which include chronic coughing,
hoarseness, wheezing, and poorly controlled asthma).1,2 Presenting symptoms
may also be age-dependent (discussed in the following sections).
875

876
Box 50‑1 Newborns and Infants

Gastroesophageal reflux is com-
Clinical Findings in
Gastroesophageal Reflux monly seen in newborns and infants
and is usually not thought to be
Frequent
pathologic (indicating an underlying
ū Cough (nocturnal)
abnormality). Regurgitation is present
ū Gagging in 50% to 70% of all newborns and
ū Emesis infants, peaks at age 4 months, and
ū Feeding resistance typically resolves by 1 year of age
ū Wheezing (physiologic GER). There is a weak
ū Recurrent bronchitis/pneumonia association with the later development
of GER disease (GERD, defined as
Infrequent
ū Apnea
GER causing troublesome symptoms
or complications).2 Newborns,
ū Brief resolved unexplained event
(previously acute life-threatening infants, and children with an absent or
event) blunted cough reflex may present with
ū Failure to thrive silent aspiration, where they aspirate
but do not have a normal reaction
ū Stridor
(coughing/choking/sputtering)
ū Abnormal head, neck, and thorax
indicating that they have done so,
positioning (Sandifer syndrome)
and have findings of increased
Rare
respiratory mucus, chronic wheezing,
ū Hoarseness
recurrent bronchitis, or recurrent
ū Hematemesis pneumonia. Others with an active
ū Anemia cough reflex may present with associ-
ū Pulmonary fibrosis ated coughing (especially with meals)
or just an isolated chronic cough. A
small group of newborns and infants may develop other symptoms including
feeding refusal, irritability, hematemesis, anemia, and failure to thrive. They
may also present with Sandifer syndrome, an abnormal hyperextension of the
neck from torticollis, but this is neither sensitive nor specific for the presence
of reflux.
Preschool-Aged Children
Preschool-aged children with GERD may present with intermittent regurgita-
tion and, less commonly, with respiratory complications. Sandifer syndrome
also has been described in children with developmental delay with more
severe GERD. Young children with GERD and swallowing difficulty may
present with only decreased food intake without other complaints.
Older Children and Adolescents
After preschool age, more classic symptoms of esophagitis develop. These
include chronic heartburn, nausea, dysphagia, odynophagia, epigastric pain,
and water brash (“angry burps”). Complications of GERD may be seen,

877
Chapter 50—Pulmonary Complications of Gastrointestinal Diseases
including esophagitis, strictures, Barrett esophagus, and hoarseness due

to reflux laryngitis.
Pulmonary Disorders Associated With GER

Apnea
Patients may experience episodes of apnea that may be categorized as central,
obstructive, or mixed (where it may start out as obstructive and progress to
central). These events may occur while awake or asleep and may be associated
with either subclinical or overt regurgitation. The pathophysiology of the event
is thought to occur with the reflux/emesis causing stimulation of the vagal
nerve (causing centrally controlled/mediated cessation of breathing), laryngo-
spasm (causing obstruction where the patient has respiratory effort but little
to no air movement), or both. Often, vigorous stimulation is required to
resolve the apnea.
Apparent Life-threatening Events
In patients 1 year or older who experience an apparent life-threatening event
(ALTE) (episodes where a combination of all or some of the following occurs:
altered muscle tone, cessation of breathing, color change, and choking/gagging
requiring vigorous stimulation to resolve), recurrent regurgitation or emesis is
common. However, investigations in patients with ALTEs have not demon-
strated a convincing relationship between GER and apnea or bradycardia. In
patients with frequent ALTE episodes in which the role of GER is uncertain,
esophageal pH or impedance monitoring with simultaneous measurement of
respiration and chest wall movement may be useful to determine if there is a
temporal association of acid or nonacid reflux with ALTE.
Brief, Resolved, Unexplained Event
In 2016, the American Academy of Pediatrics published a clinical practice
guideline3 that recommended the replacement of the term ALTE with the
term brief resolved unexplained event (BRUE) for newborns and infants
< 1 year that have experienced a sudden, brief, and now-resolved episode of
1 or more of the following: (1) cyanosis or pallor; (2) absent, decreased, or
irregular breathing; (3) marked change in tone (hypertonia or hypotonia);
or (4) altered level of responsiveness.4 The American Academy of Pediatrics
stratified these newborns and infants into 2 categories—lower- and higher-risk
BRUE—and focused on the evaluation and management of lower-risk BRUE,
defined as (1) age younger than 60 days, (2) gestational age 32 weeks or greater
and postconceptional age 45 weeks or greater, (3) no cardiopulmonary resusci-
tation required by trained medical provider, (4) BRUE duration less than
1 minute, and (5) first BRUE (no repeat events, regardless of time interval) as
well as having no concerning historical features (eg, sudden death in a relative)
and no concerning physical examination findings (eg, unexplained bruising).3
There are currently no recommendations for newborns and infants who do

878
not meet these criteria and are considered higher risk.4 One of the hallmark
differences between ALTE and BRUE is that if a newborn or infant has
choking and gagging associated with an event, which typically indicates
common diagnoses such as GER, their presence suggests the event was not a
BRUE; rather, it indicates that there is an explanation for the event: GER.
Further, the clinical practice guideline made grade C, moderate recommen-
dations for both the diagnosis and treatment of lower risk BRUE: “Clinicians
should not obtain investigations for GER (eg, upper gastrointestinal series,
pH probe, endoscopy, barium contrast study, nuclear scintigraphy, and ultraso-
nography) in infants presenting with a lower-risk BRUE; clinicians should not
prescribe acid suppression therapy for infants presenting with a lower-risk
BRUE.”3
Asthma
Symptoms of GER are common in asthma. Its prevalence is estimated to range
between 34% and 89%. Esophageal pH or impedance monitoring should be
considered in children with nocturnal asthma whose symptoms occur more
than once a week; in children with radiographic evidence of recurrent pneumo-
nia or who require either continuous oral corticosteroids, high-dose inhaled
corticosteroids, or frequent bursts of oral corticosteroids (> 2 per year); or in
children with persistent asthma unable to wean their medical management
despite the absence of GER symptoms. If esophageal or pH impedance moni-
toring demonstrates an increased frequency or duration of esophageal acid
exposure or nonacid reflux, a trial of prolonged medical therapy for GER
should be considered.
Diagnosis
Establishing the diagnosis of GER may prove challenging. For most infants
with vomiting and for older children with regurgitation and heartburn, a
history and physical examination are sufficient to reliably diagnose GER,
recognize its complications, and initiate empiric medical management.
Empiric Medical Therapy
A trial of time-limited medical therapy of 4 to 8 weeks may be useful to
determine if GER is causing specific symptoms. Empiric therapy initially
with H2 blocker and potentially progressing to proton pump inhibitor (PPI)
is widely used but has not been validated for any symptom presentation in
pediatric patients.
Upper Gastrointestinal Series
The upper gastrointestinal series study is used to evaluate for anatomical or
physiological abnormalities of the upper GI tract. These tests are neither sen-
sitive nor specific in the diagnosis of GER. Since these tests only capture a
particular time, a negative test does not necessarily mean that the patient
does not have aspiration or GER.

879
Gastroesophageal Scintigraphy
Gastroesophageal scintigraphy, also referred to as a milk scan, is a radionuclide
study that involves the ingestion of technetium-labeled food or formula followed
by scanning to detect the distribution of the isotope in the stomach, esophagus,
and lungs. This study can document aspiration and GER and assess gastric
emptying time. If the isotope is seen in the lungs, this is indicative of some
type of aspiration event (either “from above” during the swallowing phase
of the study or “from below” from a reflux episode that is then aspirated).
Unlike esophageal pH monitoring, scintigraphy can detect postprandial reflux
of both acidic and nonacidic gastric contents and measure gastric emptying
time. Radiation exposure is minimal (using technetium-99m), and the test
is noninvasive.
24-Hour Esophageal pH Probe and Impedance Monitoring
This is considered the gold-standard test for the diagnosis of GER. The test
is performed by the gastroenterologist and can be done in either the inpatient
or the outpatient setting. The probe is placed through the nasal cavity and,
using fluoroscopy, the tip is positioned at approximately 87% of the distance
from the nasal alae to the lower esophageal sphincter. Activities, meals,
position, and symptoms are recorded while the probe remains in place. Acid
reflux is defined as a decrease in pH to less than or equal to 4. The frequency,
overall time of esophageal exposure to acid, and longest reflux episode are
recorded. It should be remembered that asymptomatic episodes of acid reflux
can occur in healthy infants and children, so the interpretation of the pH probe
should be put in context with the patient’s clinical course.
Esophageal pH monitoring has the drawback of not detecting nonacidic reflux,
which can also cause lung disease. Multichannel intraluminal impedance with
pH monitoring has been increasingly used for its ability to detect anterograde
and retrograde passage of acid, nonacid, and gaseous material. Studies have
demonstrated that, in contrast to adults, infants with GER have a much greater
proportion of nonacid reflux than acid reflux, so this makes it a useful test for
assessing reflux in this population.5
Endoscopy and Biopsy
Endoscopy with biopsies allows the advantage of directly visualizing lesions
or anatomical anomalies. It can assess the presence and severity of esophagitis,
strictures, and Barrett esophagus as well as exclude other disorders such as
Crohn disease and eosinophilic or infectious esophagitis. A normal appearance
of the esophagus, however, does not exclude histopathological esophagitis
since subtle mucosal changes, such as erythema and pallor, may be observed
in the absence of esophagitis.

880
Treatment of GERD
Conservative Measures
The first line of therapy is non-medicinal. Smaller, more frequent meals as
well as dietary modifications (such as formulas composed of medium-chain
triglycerides, whey hydrolysate, or soy, or having a low osmolality) represent a
simple, first-step approach. Positioning maneuvers, such as keeping the child in
the 30- to 45-degree position for at least 30 minutes after feeding and placing
the child horizontally in the prone position, are other noninvasive interventions
available to treat GERD. Children should not sit at 90 degrees after feeding,
however, as studies have shown that GERD worsens when sitting up after
meals. This is due to increased intra-abdominal pressure generated from
bending at the waist. Milk-thickening agents do not improve acid reflux
index scores but do decrease the number of episodes of vomiting.
Medical Therapy
The second line of therapy for the treatment of GERD involves medication.
Cryoprotective agents, histamine-2 (H2) receptor blockers, PPIs, and prokinetic
agents are all used in the control of GERD.
Antacids work by neutralizing gastric acid and provide quick, short-term relief
of intermittent symptoms in older children. It has been shown that, if given in
high doses, aluminum hydroxide is as effective as cimetidine (an H2 blocker)
for the treatment of peptic esophagitis in children aged 2 to 42 months, though
its use is limited by toxicity at high levels.6 Gaviscon, an over-the-counter
antacid preparation of alginic acid, does not contain aluminum and may,
therefore, be of some benefit in infants.
H2 blockers work by inhibiting the histamine receptor of the parietal cells
that affect acid production. They have been shown to be safe and effective in
treating children with GERD and are often the first-line medical treatments for
GERD. It should be noted, though, that ranitidine was removed from the US
marketplace on April 1, 2020, by the US Food & Drug Administration (FDA)
due to it containing N-Ntirosodimethylamine (NDMA), which is a probable
human carcinogen. On April 16, 2020, the FDA alerted patients that nizatidine
oral solution had been voluntarily recalled due to the possibility that it may
contain unacceptable levels of NDMA. To date, the FDA has not found NDMA
to be contained in famotidine or cimetidine. In April 2021, Sanofi may have
inadvertently caused confusion in the marketplace with the release of its brand
Zantac-360, whose active ingredient is famotidine, whereas the brand Zantac,
whose active ingredient was ranitidine, had been previously removed from the
marketplace by the FDA.
Proton pump inhibitors are the mainstay of medical treatment of GERD. The
PPIs effectively inhibit acid production by shutting down the proton pump.
Compared to H 2 blockers, PPIs decrease acid production and have longer

881
duration of action. Because of limited experience with the use of these agents
in children, PPIs are usually used after a therapeutic failure of H2 blockers.
Adult studies have shown that PPI therapy, particularly with long-term or
high-dose administration, is associated with several potential adverse effects,
including enteric infections (eg, Clostridium difficile) and community-acquired
pneumonia.7,8 Due to this risk, an initial trial of 4 to 8 weeks should be used to
determine effectiveness of the therapy with discontinuation if there is minimal
to no change in symptoms.
Prokinetic agents act to increase lower esophageal sphincter pressures and
decrease gastric emptying time. The number of reflux episodes, however,
remain largely unchanged in patients on these agents because of transient
relaxation of the lower esophageal sphincter. Metoclopramide is the most
commonly used prokinetic agent. It functions as a cholinergic agonist and
dopamine antagonist. When used at the recommended doses, the risk for more
serious side effects, such as tardive dyskinesia, is low. The antibiotic erythro-
mycin stimulates the motilin receptor on intestinal smooth muscle cells and
decreases gastric emptying time. While its use in this manner is not approved
by the FDA, it remains useful as an off-label prokinetic agent. Baclofen has
been found to decrease transient lower esophageal sphincter relaxation and to
increase postprandial lower esophageal sphincter pressure, which may reduce
the number of reflux events.9
The surface agents sodium alginate and sucralfate both protect the esophageal
and stomach mucosa from the damaging effects of gastric acid by forming a
surface gel. There is not sufficient evidence regarding the safety and efficacy
of surface agents in the treatment of GERD in children.
Surgery
Surgery is the treatment of choice in children who fail maximal medical
therapy. Nissen fundoplication is the most common surgical procedure. Both
open and laparoscopic techniques appear to be equally effective. Success rates
vary by study but are around 75%. The most common complications include
breakdown of the fundoplication, small bowel obstruction, infection, pneumo-
nia, perforation, and esophageal stricture. Mortality varies from 0% to 4.7%.
Reoperation rates vary from 3% to 18%.10
Inflammatory Bowel Disease

Bronchopulmonary manifestations of inflammatory bowel disease (IBD)
rarely have been described in children, with only isolated cases reported in
the literature.11–14 The pulmonary involvement in IBD may include airway
inflammation involving both the pulmonary parenchyma and small and
large airways.

882
Pulmonary Parenchymal Disease

The most common lung parenchymal involvement that has been described
in IBD is bronchiolitis obliterans with organizing pneumonia and interstitial
lung disease. Pulmonary function testing in patients with airway involvement
usually reveals an obstructive respiratory pattern. Munck et al14 showed that
26 children with acute or quiescent Crohn disease all had normal chest radio-
graphs. Even though no significant differences were found between acute
and quiescent Crohn disease for pulmonary volumes and expiratory flows,
carbon monoxide diffusing capacity was significantly decreased during the
active phase of the disease when compared with values measured during
remission (15%–53% vs 19%–81% predicted). Decreased diffusing capacity
of the lungs for carbon monoxide levels may, therefore, indicate an early
interstitial disease process.15 Although pediatric reports are sparse, isolated
or diffuse lung granulomas have also been noted to be associated with IBD.
(See Chapter 26, Respiratory Disorders Associated With Systemic Inflamma-
tory Disease.) Pulmonary infiltrates in the setting of immunosuppression
present a diagnostic dilemma as it is not clear if these abnormalities are caused
by the underlying disease process or secondary to the patient’s immunosup-
pression. Krishnan et al12 reported 3 children with Crohn disease who pre-
sented with lung lesions that were unresponsive to antimicrobial therapies
but quickly responded to infliximab therapy. Although an empiric trial of
medication may help with diagnosis, a definitive diagnosis usually requires a
lung biopsy. It should also be kept in mind that patients being treated for IBD
with antitumor necrosis factor are at increased risk for pulmonary tuberculosis
and histoplasmosis as well as other serious opportunistic infections.16
Airway Inflammation
Bronchial involvement is the most common, but inflammation of the trachea
and bronchioles can also occur in IBD. Patients with bronchial involvement
due to IBD may have bronchiolitis, unexplained chronic bronchitis, or bronchi-
ectasis. The pathogenesis of the pulmonary disease associated with IBD is
not known. A common systemic mechanism affecting both the bronchial and
colonic epithelium may be responsible. It has been reported that the incidence
of respiratory changes is greater in ulcerative colitis than in Crohn disease.17
Mansi et al17 showed that bronchial hyperresponsiveness occurs in 71% of
children and adolescents with Crohn disease even in the absence of clinical,
radiologic, and functional evidence of airway disease. This indicates that
bronchial hyperresponsiveness may be the only manifestation of subclinical
airway inflammation, which, in turn, is most likely responsible for the
development of the various pulmonary manifestations in Crohn disease.18

883
Histologic similarities between the inflammatory infiltrate of the airways

and that of the colon suggest that the bronchial disease may result from a
common abnormality in immune regulation that affects both the bowel and
the bronchial tree.19
Diagnosis and Treatment

Drug-induced lung disease and superimposed bacterial infection should be
considered in patients with IBD who have lung involvement. If drug toxicity
is suspected, the offending drug should be discontinued, at least temporarily,
to help with the causality determination. However, if there is no alternative
IBD treatment, continuation of the drug, depending on the type/severity of
the lung involvement versus the severity of the IBD, should be considered.
In patients with signs of airway disease and chronic purulent sputum
production, superimposed bacterial infection must be ruled out. When drug
toxicity and bacterial infection have been ruled out, traditional therapies for
IBD, including mesalamine and other immunosuppressive agents, may be
effective depending on the type of pulmonary complications.

Alpha-1 antitrypsin (AAT) deficiency is one of the most common inherited
disorders among white individuals. Alpha-1 antitrypsin deficiency is inherited
in families in an autosomal codominant pattern, and this condition can cause
cirrhosis, usually in childhood, and chronic obstructive pulmonary disease,
which usually does not present until adulthood. Pulmonary symptoms
typically begin in the third to fourth decade of life, but children as young as 18
months can have respiratory manifestations.20–23
Diagnosis
Initially, a serum AAT level is performed if this disease is suspected. If the
level is low, then a confirmatory genetic test is obtained. Occasionally, in
patients with both the clinical manifestations and a family history of AAT
deficiency, the genetic testing is performed outright. At least 100 alleles of
AAT have been identified, all of which are categorized into 4 basic groups.24
1. Normal—There are normal levels and functioning of AAT; genotype
is MM.
2. Deficient—Plasma AAT levels are less than 35% of the average normal
level. The most common deficient allele associated with emphysema is
the Z allele, which is carried by 2% to 3% of the white population in the
United States. This genotype is MZ.

884
3. Null—No detectable AAT levels in plasma; these individuals have the

rarest and most severe form of the disease. This genotype is designated
as a null mutation.
4. Dysfunctional—Normal quantity of AAT protein, but it does not
function properly.
Population studies suggest a minimum plasma threshold of 11 µmol/L (corre-
sponding to 57 mg/dL using nephelometry) is required for proper functioning.
Below this level there is insufficient AAT to protect the lung, leading to a risk
of developing emphysema.
Symptoms include asthma, which is more severe in individuals with protease
inhibitor with MZ mutation; bronchitis; panacinar emphysema, occurring pri-
marily in the lung bases; chronic obstructive lung disease; and bronchiectasis.25
Pulmonary disease is very rare in children.
Treatment
Treatment focuses on controlling and slowing the progression of the clinical
symptoms of lung and liver disease. Weekly or monthly intravenous infusion
of purified human AAT can normalize plasma and lung AAT levels, inhibit
protease activity, and diminish airway reactivity. However, it has no effect
on intracellular aggregation of the protein in hepatocytes. Lung and liver
transplantation are end-stage measures for terminal organ dysfunction.
Pulmonary Involvement in Liver Disease

Hepatic disease may cause or be associated with pulmonary disorders with-
out a clearly understood etiology26 (Table 50-1). Acute hepatic disease asso-
ciated with lung complications can result from infections, medications, and
toxins. Chronic hepatic disease can also cause pulmonary disorders through
mechanisms resulting in cirrhosis and liver failure, which can lead to chronic
pulmonary infection. Systemic disorders, such as AAT deficiency, chronic
granulomatous disease of childhood, cystic fibrosis, hereditary hemorrhagic
telangiectasia, Langerhans cell histiocytosis, and sarcoidosis can also be
associated with hepatopulmonary syndrome.
Hepatopulmonary syndrome consists of liver disease (most commonly
cirrhosis), abnormal pulmonary vascular tone, and arterial hypoxemia. The
disease mechanisms include the imbalance of vasoactive substances caused
by the diseased liver, which leads to pulmonary vascular dilatation and

885
subsequent ventilation/perfusion mismatch, hypoxemia, and loss of hypoxic

pulmonary vasoconstriction. As the hepatic damage progresses, the alveolar-
capillary disequilibrium worsens and leads to intrapulmonary venoarterial
shunting, with limitation of oxygen diffusion and, ultimately, severe respiratory
failure. Portopulmonary anastomoses and pulmonary arterial hypertension
may also occur.27,28 Liver transplantation for hepatopulmonary syndrome in
children may be appropriate even in the absence of cirrhosis.29
Table 50-1. Pulmonary Disorders Associated With Hepatic Disorders

Hepatic Disease Pulmonary Disorder
Infections Hilar adenopathy
Pneumonia
Tracheobronchitis
Pleural effusions
Primary sclerosing cholangitis Bronchitis
Bronchiectasis
Chronic active hepatitis Pneumonia
Atelectasis
Interstitial pneumonitis
Interstitial fibrosis
Fibrosing alveolitis
Pleural effusion
Pulmonary hypertension
Pulmonary hemorrhage
Cirrhosis (alcoholic, postnecrotic, Pneumonia
cryptogenic) Pleural effusion
Pulmonary angiodysplasia
Pleural vasodilatation
Primary biliary cirrhosis Hyperreactive airway disease
Interstitial pneumonitis
Interstitial fibrosis
Fibrosing alveolitis

886
Pulmonary Involvement in Pancreatic Disease

Pulmonary disorders associated with acute and chronic pancreatitis are listed
in Box 50-2.30
Pleural Effusion
Although pleuropulmonary complications of pancreatitis have been most
commonly described in adults (most often due to alcoholism, trauma, or
cholelithiasis), pleural effusions have also been reported in children with
pancreatitis. Most pleural effusions are left-sided; however, right-sided and
bilateral effusions have also been reported.30 Pleural effusions usually occur
shortly after the onset of acute pancreatitis and are characterized by small,
serous, serosanguineous, or hemorrhagic exudates with high amylase levels.
Fluid resorption correlates with the resolution of intra-abdominal etiology.
Chronic pancreatic disease, such as a pseudocyst, abscess, or pancreatopleural
fistula, may also result in chronic pleural effusions. The etiology and patho-
genesis of the fluid have not been defined. Transdiaphragmatic lymphatic
blockade, pancreatopleural fistulae, and disruption of the pancreatic duct or
pseudocysts have been speculated.30,31 Treatment of pancreatic pleural effusion
is usually conservative but may require
Box 50‑2
thoracentesis when symptomatic.
Pulmonary Disorders Associated
With Pancreatitis Acute Respiratory Distress Syndrome
Acute respiratory distress syndrome
Acute Pancreatitis
Pleural effusion
(ARDS) is the most serious complica-
Hemidiaphragm elevation
tion of pancreatitis. The mechanism of
Atelectasis: left lower lobe
pancreatitis-induced ARDS is complex
Pneumonia: left lower lobe and has not been fully elucidated. It
Pulmonary embolism is thought to occur secondary to the
Pulmonary infarction release of active enzymes and vasoac-
Acute respiratory distress syndrome tive substances from the pancreas,
Pulmonary edema including leukotrienes and pancreatic
Cystic fibrosis transmembrane elastase. These chemical mediators
conductance regulator (CFTR) increase vascular permeability and
mutation decrease pulmonary surfactant produc-
Chronic Pancreatitis tion, which promotes the development
Pancreatopleural fistula of ARDS.31
Pancreatobronchopleural fistula
Recurrent pleural effusion
Recurrent lobar pneumonia
CFTR mutation

887
Atelectasis
Macrophages and mast cells secrete phospholipid A2 (sPLA2; lecithinase)
which hydrolyzes lecithin, the main component of the phospholipids in surfac-
tant. Secreted phospholipases A2 (sPLA2) routinely assists in the catabolism
of surfactant, which assists in maintaining the correct balance of the complex
proteolipid mixture, which is essential in maintaining alveolar opening. How-
ever, sPLA2 is also a pro-inflammatory substance. Thus, inflammation and
cell injury may result in recruiting more macrophages and mast cells to
the area, causing an imbalance in the amount of sPLA2 being secreted and,
therefore, too much catabolism of surfactant. The loss of surfactant increases
alveolar surface tension, resulting in atelectasis.
Diagnosis and Therapy

Because pancreatitis-associated acute lung injury has a wide spectrum of
presentation, the diagnosis of pancreatic pulmonary complications relies
on a thorough history, physical examination, and radiographic and
laboratory studies.
Therapy consists of supportive measures including antibiotics for pneumonia;
thoracentesis or chest tube drainage for an effusion causing respiratory distress;
chest physical therapy for atelectasis (if tolerated); anticoagulants for pulmo-
nary emboli; and lung protective ventilation strategies for patients who
require mechanical ventilation.
key points
} Because the pulmonary and GI systems are interconnected, disorders that are
primarily GI in etiology can cause serious sequelae in the pulmonary system.
} The role of GERD in asthma is controversial, but treatment of GERD may
improve a patient’s asthma control.
} Inflammatory bowel disease may directly affect the lung parenchyma or
indirectly cause serious opportunistic infections of the lung parenchyma
secondary to the immunosuppression used to treat IBD.
} Alpha-1 antitrypsin deficiency rarely causes pulmonary disease in children
but should be considered if there is a family history of early-onset
(< 45 years old) emphysema.

888
References
1. Rudolph CD, Mazur LJ, Liptak GS, et al; North American Society for Pediatric Gastroenterology
and Nutrition. Guidelines for evaluation and treatment of gastroesophageal reflux in infants and
children: recommendations of the North American Society for Pediatric Gastroenterology and
Nutrition. J Pediatr Gastroenterol Nutr. 2001;32(suppl 2):S1–S31 PMID: 11525610
doi: 10.1097/00005176-200100002-00001
2. Maqbool A, Ryan MJ. Gastroesophageal reflux disease and aerodigestive disorders.
Curr Probl Pediatr Adolesc Health Care. 2018;48(3):85–98 PMID: 29571546
doi: 10.1016/j.cppeds.2018.01.005
3. Tieder JS, Bonkowsky JL, Etzel RA, et al; Subcommittee on Apparent Life Threatening Events.
Clinical practice guideline: Brief resolved unexplained events (formerly apparent life-threatening
events) and evaluation of lower-risk infants. Pediatrics. 2016;137(5):e20160590 PMID: 27244835
doi: 10.1542/peds.2016-0590
4. Merritt JL II, Quinonez RA, Bonkowsky JL, et al. A Framework for evaluation of the higher-risk
infant after a brief resolved unexplained event. Pediatrics. 2019;144(2):e20184101
PMID: 31350360 doi: 10.1542/peds.2018-4101
5. Cucchiara S, Staiano A, Romaniello G, Capobianco S, Auricchio S. Antacids and
cimetidine treatment for gastro-oesophageal reflux and peptic oesophagitis. Arch Dis Child.
1984;59(9):842–847 PMID: 6385868 doi: 10.1136/adc.59.9.842
6. Dial S, Delaney JAC, Barkun AN, Suissa S. Use of gastric acid-suppressive agents and the risk of
community-acquired Clostridium difficile-associated disease. JAMA. 2005;294(23):2989–2995
PMID: 16414946 doi: 10.1001/jama.294.23.2989
7. Gulmez SE, Holm A, Frederiksen H, Jensen TG, Pedersen C, Hallas J. Use of proton pump
inhibitors and the risk of community-acquired pneumonia: a population-based case-control
study. Arch Intern Med. 2007;167(9):950–955 PMID: 17502537 doi: 10.1001/archinte.167.9.950
8. Lopez M, Kalfa N, Forgues D, Guibal MP, Galifer RB, Allal H. Laparoscopic redo
fundoplication in children: failure causes and feasibility. J Pediatr Surg. 2008;43(10):1885–1890
9. Warren RL, Davis SM. The role of baclofen in the treatment of gastroesophageal reflux disease.
J Pharm Technol. 2015;31(6):258–261 PMID: 34860946 doi: 10.1177/8755122515586835
10. Calder CJ, Lacy D, Raafat F, Weller PH, Booth IW. Crohn’s disease with pulmonary involvement
in a 3 year old boy. Gut. 1993;34(11):1636–1638 PMID: 8244155 doi: 10.1136/gut.34.11.1636
11. Carvalho RS, Wilson L, Cuffari C. Pulmonary manifestations in a pediatric patient with
ulcerative colitis: a case report. J Med Case Reports. 2008;2(1):59 PMID: 18298838
doi: 10.1186/1752-1947-2-59
12. Krishnan S, Banquet A, Newman L, Katta U, Patil A, Dozor AJ. Lung lesions in children with
Crohn’s disease presenting as nonresolving pneumonias and response to infliximab therapy.
13. Valletta E, Bertini M, Sette L, Braggion C, Pradal U, Zannoni M. Early bronchopulmonary
involvement in Crohn disease: a case report. BMC Gastroenterol. 2001;1(1):13 PMID: 11734067
doi: 10.1186/1471-230X-1-13
14. Munck A, Murciano D, Pariente R, Cezard JP, Navarro J. Latent pulmonary function
abnormalities in children with Crohn’s disease. Eur Respir J. 1995;8(3):377–380 PMID: 7789480
doi: 10.1183/09031936.95.08030377
15. Higenbottam T, Cochrane GM, Clark TJH, Turner D, Millis R, Seymour W. Bronchial disease in
ulcerative colitis. Thorax. 1980;35(8):581–585 PMID: 7444824 doi: 10.1136/thx.35.8.581
16. Ali T, Kaitha S, Mahmood S, Ftesi A, Stone J, Bronze MS. Clinical use of anti-TNF therapy and
increased risk of infections. Drug Healthc Patient Saf. 2013;5:79–99 PMID: 23569399 doi:
10.2147/DHPS.S28801
17. Mansi A, Cucchiara S, Greco L, et al. Bronchial hyperresponsiveness in children and adolescents
with Crohn’s disease. Am J Respir Crit Care Med. 2000;161(3 Pt 1):1051–1054 PMID: 10712362
doi: 10.1164/ajrccm.161.3.9906013
18. Camus P, Colby TV. The lung in inflammatory bowel disease. Eur Respir J. 2000;15(1):5–10
PMID: 10678613 doi: 10.1183/09031936.00.15100500
19. Perlmutter DH. Liver injury in alpha 1-antitrypsin deficiency. Clin Liver Dis.
2000;4(2):387–408, vi PMID: 11232197 doi: 10.1016/S1089-3261(05)70115-X
20. Perlmutter DH. Alpha-1-antitrypsin deficiency. Semin Liver Dis. 1998;18(3):217–225
PMID: 9773422 doi: 10.1055/s-2007-1007158
21. Needham M, Stockley RA. Alpha 1-antitrypsin deficiency. 3: clinical manifestations and natural
history. Thorax. 2004;59(5):441–445 PMID: 15115878 doi: 10.1136/thx.2003.006510

889
22. Teckman JH. Alpha1-antitrypsin deficiency in childhood. Semin Liver Dis. 2007;27(3):274–281
PMID: 17682974 doi: 10.1055/s-2007-985072
23. American Thoracic Society/European Respiratory Society. American Thoracic Society/European
Respiratory Society statement: standards for the diagnosis and management of individuals with
alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818–900 PMID: 14522813
doi: 10.1164/rccm.168.7.818
24. Wall M, Moe E, Eisenberg J, Powers M, Buist N, Buist AS. Long-term follow-up of a cohort of
children with alpha-1-antitrypsin deficiency. J Pediatr. 1990;116(2):248–251 PMID: 2299495
doi: 10.1016/S0022-3476(05)82882-3
25. Miller JW, Naimi TS, Brewer RD, Jones SE. Binge drinking and associated health risk
behaviors among high school students. Pediatrics. 2007;119(1):76–85 PMID: 17200273
doi: 10.1542/peds.2006-1517
26. Rodríguez-Roisin R, Krowka MJ, Hervé P, Fallon MB; ERS Task Force Pulmonary-Hepatic
Vascular Disorders (PHD) Scientific Committee. Pulmonary-Hepatic vascular Disorders (PHD).
27. Tumgor G, Arikan C, Yuksekkaya HA, et al. Childhood cirrhosis, hepatopulmonary
syndrome and liver transplantation. Pediatr Transplant. 2008;12(3):353–357 PMID: 18435611
doi: 10.1111/j.1399-3046.2007.00807.x
28. Gupta NA, Abramowsky C, Pillen T, et al. Pediatric hepatopulmonary syndrome is seen
with polysplenia/interrupted inferior vena cava and without cirrhosis. Liver Transpl.
2007;13(5):680–686 PMID: 17457897 doi: 10.1002/lt.21113
29. Inselman LS. Pulmonary manifestations of systemic disorders. In: Taussing LM, Landau LI,
Le Souef PN, et al. Pediatric Respiratory Medicine. 2nd ed. Elsevier; 2008:1053–1079
30. Browne GW, Pitchumoni CS. Pathophysiology of pulmonary complications of acute pancreatitis.
World J Gastroenterol. 2006;12(44):7087–7096 PMID: 17131469 doi: 10.3748/wjg.v12.i44.7087
31. Lipsett P, Cameron J. Treatment of Ascites and Fistulas. Blackwell Science Ltd; 1998

CHAPTER
51
Pulmonary Complications of Sickle Cell Disease
Introduction
Sickle cell disease (SCD) affects approximately 100,000 individuals in the
United States and is the most common inherited disorder among African
Americans.1 Because a large number of people with SCD are from vulner-
able populations (including communities of color and largely uninsured
and underinsured individuals), striking disparities exist in research and
clinical care for SCD in comparison to other inherited diseases, such as
cystic fibrosis.2 There have been advances in recent decades regarding
diagnosis, preventive management, and treatment for SCD—all of which
have led to improved survival for children3 —however, the median life
expectancy is in the fifth decade.4,5 The pulmonary complications of SCD
are numerous and have been associated with an increased risk of early
death.6–9 One autopsy study of patients with SCD with sudden death showed
that 71% of patients had significant pulmonary pathology
at the time of death.10
Acute Chest Syndrome

Acute chest syndrome (ACS) is a clinical syndrome consisting of fever,
cough, tachypnea, chest pain, wheezing, and/or hypoxemia plus a new
segmental pulmonary infiltrate on chest radiograph in individuals with
SCD (sickle cell anemia [HbSS], HbSC, HbSb-thalassemia).11 Acute chest
syndrome is a leading cause of hospitalization and early death in individuals
with SCD.5,12 There were 24,000 pediatric hospitalizations for ACS in the
United States in 2018.12
891

892
CASE REPORT 51-1

A.J. is a 7-year-old boy with sickle cell anemia (HbSS), steady-state hemoglobin
(Hb) of 85 g/L (8.5 g/dL), and 3 to 4 admissions for painful episodes per year. He
was admitted with a 2-day history of nasal congestion and cough, and a 1-day
history of head and back pain not controlled with oral pain medications. On
admission, he was febrile to 38.2°C (100.7°F), with a heart rate of 140 beats per
minute, respiratory rate of 24 breaths per minute, and an oxygen saturation
of 96% on room air. His Hb at admission was 79 g/L (7.9 g/dL). His chest radio-
graph at admission was clear. He was started on intravenous (IV) morphine
and ketorolac, IV ampicillin/sulbactam, and IV fluids, and received an incen-
tive spirometer, which he used sporadically during his first hospital day. On
his second hospital day, A.J. became increasingly tachypneic with wheezing,
intercostal retractions, and oxygen desaturation, and required 2 L/minute of
oxygen by nasal cannula to maintain an oxygen saturation above 92%. Repeat
Hb was 52 g/L (5.2 g/dL). A repeat chest radiograph showed right upper lobe
and left lower lobe opacities. Azithromycin and albuterol were added, and he
received a packed red blood cell transfusion. By hospital day 3, his Hb was
70 g/L (7.0 g/dL), his oxygen requirement had decreased to 1 L/minute, and
he was able to use the incentive spirometer more consistently. By hospital day
5, A.J. was no longer febrile, he did not require supplemental oxygen, his pain
was well controlled on oral analgesia, and he was discharged home.
Pathophysiology
The National Acute Chest Syndrome Study Group reviewed 671 episodes
of ACS in 538 adults and children.13 Community-acquired infection was the
most common identifiable cause (most commonly chlamydia, mycoplasma,
and respiratory syncytial virus), followed by fat embolism in association with
severe vaso-occlusive pain episode. Viral infections were a common etiology
in children younger than 10 years. Pulmonary infarction was presumed to be
the cause of ACS in 16% of cases in which no cause could be identified.13
Infection, atelectasis from splinting or hypoventilation, pulmonary fat
embolism, and in situ vaso-occlusion leads to ventilation-perfusion mismatch
with localized and generalized hypoxemia. Decreased oxygen content con-
tributes to polymerization of hemoglobin (Hb) and sickling of erythrocytes.
Combined with the elevated leukocyte counts seen in SCD in general14 and
in ACS specifically,13 as well as increased expression of adhesion molecules
and inflammatory mediators (such as vascular cell adhesion molecule-1,
secretory phospholipase A2, and others), there is a vicious cycle of adher-
ence of sickled red blood cells to each other, leukocytes, platelets, and the
vascular endothelium; increased transit time; more extensive polymerization
of sickled erythrocytes; and obstruction of microvascular flow.15,16 In addi-
tion to pulmonary vaso-occlusion, decreased production and increased

893
Chapter 51—Pulmonary Complications of Sickle Cell Disease
consumption of the potent pulmonary vasodilator nitric oxide leads to

increased pulmonary vasoactivity.16,17
Clinical Features
Acute chest syndrome often occurs during the first few days of a hospitali-
zation for a vaso-occlusive pain episode or after a surgical procedure, but
patients can also present with ACS in the absence of a pain episode. Episodes
can range from mild and self-limiting to severe, rapidly progressive, and
life-threatening.18–20 The main predictors of an impending severe episode
include multilobar disease, severe hypoxia, sudden rapid drop in Hb, and
thrombocytopenia.20 Severe rapidly progressive ACS is seen more commonly
in adults than in children with SCD. Children with asthma or a history of
ACS (particularly prior to 4 years of age) are at increased risk for future
ACS episodes.21
In 2 large clinical studies of ACS, fever and cough were the most common
presenting symptoms, with tachypnea, crackles, and wheeze as the most
common physical findings among younger children. Chest and rib pain
were more commonly seen in adolescents and adults.13,22 Varying degrees
of hypoxemia can be seen with ACS, although the best way to measure
oxyhemoglobin saturation has been controversial—particularly in the set-
ting of illness and severe anemia.23–25 If there is any question about the
accuracy of pulse oximetry or routine blood gas analysis in a particular
clinical situation, blood gas analysis with co-oximetry should be the method
of choice, because all forms of Hb, including the COHb produced during
hemolysis, are accounted for.26
Chest radiographic findings may include segmental, lobar, or multilobar
consolidation but may also lag behind the clinical presentation. Lower-lobe
involvement is the most common finding at all ages, though young children
are more likely to have middle- and/or upper-lobe involvement than adults.22,27
Pleural effusions—both at presentation and developing during the course
of the hospitalization—are more often seen in adolescents and adults.27
Hb concentration is typically decreased from steady-state value, and
mean white blood cell count at presentation is often greater than
20 × 109/L (20,000 cells/µL).
Acute chest syndrome can progress to respiratory failure requiring mechanical
ventilation (22% of adults vs 10% of children and adolescents in one study)
and to death (9% of adults vs < 1% of children and 2% of adolescents).13,28
Infants younger than 1 year have the highest risk of mortality from ACS in
the pediatric age group.28

894
Management
One of the main goals of overall treatment of SCD should be prevention of
ACS. Prophylactic penicillin and vaccination against Streptococcus pneumo-
niae, Hemophilus influenzae, and seasonal influenza have a role in the im-
proved survival among children with SCD because of a reduced frequency
of pulmonary infection. Incentive spirometry has been shown to reduce the
incidence of ACS among patients hospitalized with chest and back pain and
a clear chest radiograph.29,30
Both the 2014 NIH Expert Panel Report Evidence-Based Management of Sickle
Cell Disease31 and the 2015 British Thoracic Society Guidelines for the
Management of Acute Chest Syndrome in Sickle Cell Disease19 recommend a
chest radiograph and measurement of oxygen saturation for all patients with
respiratory symptoms, regardless of the presence of fever, to evaluate for
possible ACS.
Treatment of ACS is primarily supportive. The immediate goals of treatment of
an episode of ACS include prevention of alveolar collapse, maintenance of gas
exchange, and prevention of further lung injury.32 Careful pain management
is essential, with a careful balance to control chest wall pain33 and avoid the
associated rapid, shallow breathing without promoting the hypoventilation
associated with overuse of narcotic agents or IV diphenhydramine.19,34 Incen-
tive spirometry devices should be used to prevent atelectasis.35 Supplemental
oxygen should be administered to patients with oxygen saturation below 95%
(or with more than a 3% decrease from their baseline oxygen saturation as
measured by pulse oximetry [Spo2]).19,31 Epidemiologic data suggest that
broad-spectrum antibiotics, including a macrolide, should be initiated.13,19,36
Given the prevalence of airway lability among patients with SCD37 and the
frequency of wheezing associated with ACS,13 bronchodilators have become
common empiric therapy for patients with comorbid asthma or who are acutely
wheezing as part of their clinical presentation. Strict monitoring of oral and IV
fluid intake and urine output is important once ACS develops to avoid worsen-
ing pulmonary edema that develops from the increased vascular permeability
from damaged lung tissue.19 Red blood cell transfusion early in the course of
ACS serves 2 purposes: to increase oxygen carrying capacity and to reduce the
percentage of sickled erythrocytes. This can be accomplished by either simple
red blood cell transfusion19,38 (with phenotypically matched, sickle negative,
leukocyte-depleted packed red blood cells with extended crossmatching, and
only when Hb is less than 90 g/L [9 g/dL])35 or by exchange transfusion, which
does not have the associated risks of iron overload or hyperviscosity but carries
the risk for the development of catheter-associated deep venous thrombosis.39
The use of steroids to treat ACS remains controversial. Although one clinical
trial showed a beneficial effect from IV dexamethasone in children with
ACS,40 other studies have shown an increased risk of readmission and pain

895
following the use of systemic corticosteroids.41,42 The risk to benefit ratio of

systemic steroids in ACS management deserves further evaluation in the era
of more widespread use of hydroxyurea (HU).
Because recurrent vaso-occlusive and ACS episodes are associated with
progressive cardiopulmonary morbidity and mortality, preventive strategies
must be considered. Given the proportion of ACS episodes that are associated
with infection in children, pneumococcal vaccination, influenza vaccination,
and prophylactic penicillin administration are standard of care in children
with SCD.31 Hydroxyurea, which increases the concentration of fetal hemo-
globin, thus causing a decrease in the proportion of sickle hemoglobin (HbS)
and reducing erythrocyte polymerization, has been shown to reduce the
incidence of new ACS episodes in adults with frequent pain crises.43 Infants
and young children in the Pediatric Hydroxyurea Phase 3 clinical (BABY-
HUG) trial randomized to receive HU had fewer episodes of ACS in the
2-year trial compared to those randomized to receive placebo,44 and early
initiation of HU is becoming increasingly widespread for patients with
sickle cell anemia.45 Chronic transfusions have also been shown to reduce
the incidence of ACS in children46,47; hematologists should be involved in
the decision to implement chronic transfusions for patients with SCD. Given
the prevalence of viral-induced wheeze and the frequency of wheeze as a
presenting symptom of ACS in young children, a trial of preventive inhaled
corticosteroids may benefit some children—particularly in the setting of a
history of eczema or a positive family history of asthma.48,49
Asthma and Airway Disease

The pathophysiology, clinical features, and management of asthma in the
general pediatric population are discussed in detail in Chapter 12, Asthma.
This section discusses asthma as it relates specifically to SCD.
Asthma is the most common chronic disease in childhood, with African
Americans disproportionally affected.50 Because SCD is the most common
inherited genetic disorder among African Americans, a certain number of
children will be affected with both SCD and asthma. While many children
with SCD have episodic wheeze, it has not been conclusively demonstrated
that true asthma occurs at a higher frequency among children with SCD
compared to children without SCD. Several studies have reported an asso-
ciation between asthma and increased risk of acute chest syndrome,12,21 as
well as an increased risk of mortality.7 Questions still remain regarding the
extent to which asthma exists as a comorbid condition with SCD and acts
synergistically to worsen SCD outcomes, how SCD pathogenesis contributes
to an obstructive pulmonary process in children that causes clinical features
similar to asthma, and how to determine which individuals with SCD and
isolated features of asthma warrant preventive asthma therapy.

896
Pathophysiology
While the causal direction of airway disease and SCD pathogenesis has not
been conclusively determined, experimental animal models have demon-
strated exaggerated inflammatory responses to ovalbumin challenge and
house dust mite sensitization.51–53 Sickle cell mouse studies have shown that
compared to wild-type mice, SCD mice developed elevated serum levels of
immunoglobulin E and inflammatory cytokines51 and others showing elevated
bronchoalveolar lavage leukocytosis and eosinophilia in response to allergen
challenge.52 One group showed that these inflammatory responses were asso-
ciated with increased airway responsiveness to methacholine,53 while another
did not.52 In contrast to these animal data, Knight-Madden and colleagues
noted that while a Jamaican cohort of children with SCD had increased Th2
cytokines compared to age- and race-matched control children, a cohort of
children with SCD from the United Kingdom had decreased Th2 cytokines
compared to controls.54
Mechanisms for airway disease other than allergic inflammation have been
proposed. Individuals with anemia have increased cardiac output and dilation
of the pulmonary vasculature. Studies of adults and children with SCD have
demonstrated associations between increased pulmonary capillary blood
volumes and multiple indicators of lower airway obstruction.55,56 One study of
children receiving chronic transfusions showed increased pulmonary capil-
lary blood volume, increased respiratory system resistance, and decreased
forced vital capacity (FVC) and forced expiratory volume in the first second
of expiration (FEV1) posttransfusion compared to pre-transfusion,57 suggesting
that increased pulmonary capillary blood volume may result in anatomical
(rather than inflammatory) lower airway obstruction.
Clinical Features
Physician-diagnosed asthma seems to have a strong contributory effect
toward the incidence of ACS in children with SCD.49 Among 291 children
with HbSS in a prospective cohort that began in infancy, those with a comor-
bid diagnosis of asthma were younger at the time of their first episode of
ACS, had twice as many episodes of ACS, and had more frequent pain crises
than the children without asthma.58 Among 80 children with SCD in Jamaica,
asthma and atopy were more common among those with a history of recurrent
ACS (≥ 4 episodes) compared to those with 1 or fewer episodes of ACS
(53% vs 12%, P < .001).59
Determining which children with SCD have asthma is difficult. Many chil-
dren with SCD and ACS present with wheezing on physical examination.22
However, whether these children at steady state have partially reversible
airway obstruction or reproducible symptoms in response to known triggers
(in other words, meet clinical criteria for asthma) is not always clear. Children

897
with SCD may be more prone to airway obstruction and airway hyper-
responsiveness.37,60 In one study of 187 children with sickle cell anemia,
11% of children without asthma met American Thoracic Society (ATS)
criteria for lower airway obstruction.49 In the largest research cohort study
of 99 school-age children with sickle cell anemia, 55% had airway hyper-
responsiveness to methacholine.37 In one study of pulmonary function of
20 infants and toddlers (aged 3–30 months) with SCD, the majority of
children had evidence of lower airway obstruction and hyperinflation;
6 of those infants also had a history of intermittent bronchospasm.61
Management
Management of chronic, persistent asthma in children with SCD should follow
guidelines established by the National Asthma Education and Prevention
Program.62 Use of systemic steroids for asthma exacerbations in patients with
SCD is a controversial topic,63 given the observed increased risk of pain epi-
sodes following courses of systemic corticosteroids given for ACS.41,42 That
said, undertreated status asthmaticus can be life-threatening, and, therefore,
systemic corticosteroids should be used in cases of moderate-severe acute
exacerbations.62 Many clinicians employ a prolonged taper following a course
of oral steroids, but there are no data to support this recommendation. Fur-
thermore, most studies that demonstrated a risk of pain following systemic
corticosteroid administration were conducted in children with ACS, not
status asthmaticus, and before the more widespread use of HU in children.
To date, there are no published studies on the effect of improved asthma
management on sickle cell outcomes. One promising phase 2 trial showed
that administration of inhaled steroids to adults without asthma who were
experiencing respiratory symptoms was associated with reduced daily pain
and lower soluble vascular cell adhesion molecule-1 (s-VCAM-1) levels com-
pared to those who did not receive inhaled steroids, suggesting a beneficial
effect of anti-inflammatory therapy on SCD pathogenesis.64 The consequences
of asthma exacerbations, including ventilation/perfusion mismatch and local
pulmonary tissue hypoxia, on patients with sickle cell are serious. The use
of evidence-based asthma guidelines62 in the treatment of children with both
SCD and asthma is crucial. Referral to a pediatric pulmonologist should be
made for all children with SCD and signs or symptoms of asthma.
Sleep-Disordered Breathing
Pathophysiology
Children with SCD are at increased risk of nocturnal desaturation compared
with children without SCD.65–67 This observation historically has been attri-
buted to upper airway obstruction from compensatory adenotonsillar hyper-
trophy after splenic infarction or resection.68,69 This explanation is contradicted

898
by a study in which 20 of 32 research subjects had nocturnal desaturation on an

overnight oximetry study (defined as Spo2 < 92% for ≥ 5% of total sleep time);
12 of those 20 had no evidence of obstruction on a full, in-laboratory sleep
study.66 Two additional convenience clinic sample studies reported several
patients with nocturnal hypoxemia in the absence of obstructive sleep apnea
(OSA).65,70 Some authors suggest that abnormalities in gas exchange associated
with severe anemia (specifically, a rightward shift of the oxyhemoglobin dis-
sociation curve and decreased oxyhemoglobin affinity [Figure 51-1]) are a
cause of nocturnal desaturation, given the finding that nocturnal desaturation
is most commonly seen in SCD patients with low daytime Spo2.23,65,66

100
90
↑ pH
↓ DPG
80
↓ Temp
70 ↓ pH
↑ DPG
60 ↑ Temp

40
30
20
10
0
0 10 20 30 40 50 60 70 80 90 100
PO2 (mmHg)
Figure 51-1. Oxyhemoglobin dissociation curve. The rightward shift, as seen in sickle cell
disease, indicates that oxyhemoglobin saturation at a given arterial oxygen pressure is lower
in patients with sickle cell disease because of decreased oxygen affinity of HbS, increased
2,3-diphosphoglycerate in sickled erythrocytes, and hypoventilation due to pain or opioid
use, and as an adaptation to severe anemia to prevent tissue hypoxia.
From Krishnan S. Oximetry and capnography. In: Stokes DC, Dozor AJ, et al, eds. Pediatric Pulmonology,
Asthma, and Sleep Medicine: A Quick Reference Guide. American Academy of Pediatrics; 2018:63–67.

899
Clinical Features
In the largest observational cohort study of 243 unselected pediatric research
subjects with sickle cell anemia (aged 4–18 years), the prevalence of OSA
(with an obstructive apnea hypopnea index [OAHI] of ≥ 1 event per hour)
was 41%; 10% of children had an OAHI 5 or higher, consistent with moderate
OSA.71 While significant risk factors for OSA in this cohort included habitual
snoring and a resting daytime oxygen saturation of less than 96% on room air,
20% of children with moderate OSA did not have caretaker-reported habitual
snoring and only 32% had caretaker-witnessed apneas, suggesting that inquir-
ing about common OSA symptoms in the general population may be insuffi-
cient for determining which children with SCD warrant a sleep study. In the
same cohort, the presence of OSA (with an OAHI ≥ 2 events per hour) was
associated with more than twice the odds of severe nocturnal enuresis.72
Data are conflicting about the association between sleep-disordered breathing
(SDB) and SCD morbidity in children. In one study of 95 children with SCD
and no history of stroke, nocturnal desaturation (but not obstructive events)
was an independent risk factor for central nervous system events (seizure,
stroke, or transient ischemic attack),73 but these results have not been repli-
cated. In the same cohort, nocturnal desaturation was highly associated with
rates of pain (every increase of Sao2 percentage point was associated with
0.83 fewer days of pain per year, P < .001).67 In contrast, recent longitudinal
prospective data from 140 children with sickle cell anemia did not show
any association between nocturnal oxygen desaturation or higher OAHI and
increased rates of pain or ACS.74 No studies have looked at the consequences
of SDB or nocturnal desaturation in adults with SCD.
Management
All children with SCD should be screened for clinical signs and symptoms of
SDB. If a history of snoring, disturbed sleep, poor school performance, daytime
somnolence, or hyperactivity is elicited, or if daytime oxyhemoglobin satura-
tion (Spo2) is 94% or less or tonsillar enlargement is detected on physical exam-
ination, patients should be referred for nocturnal polysomnography (PSG). In
contrast to the children without SCD, in whom adenotonsillectomy is often
curative, children with SCD frequently have residual PSG abnormalities
following adenotonsillectomy.75 Positive airway pressure therapy could be
considered.76 Children with SCD and abnormal sleep studies who undergo
adenotonsillectomy should have follow-up PSG 3 to 6 months postoperatively
to assess the potential need for positive airway pressure.76,77 In addition, 3 small
case series describe improvement in OSA as well as daytime and nocturnal
hypoxemia in response to treatment with HU.78–80

900
Lung Function in Sickle Cell Disease

Overview
Our understanding of the natural history of lung function in individuals with
SCD is limited for several reasons. One reason is that while there are a small
number of studies that follow lung function among children or among adults
longitudinally, there are no large prospective studies of lung function among
individuals with SCD across the life span from childhood through adulthood.
A second reason is that lung function is interpreted differently across different
studies, with some studies using lower limit of normal criteria to determine
normal lung function vs obstructive, restrictive, or mixed ventilatory defects;
other studies classify individuals using arbitrary cutoffs (such as an FEV1/FVC
< 0.70 or 0.80) to distinguish normal vs obstruction. Despite these limitations,
a few general patterns have emerged in the literature.
Clinical Features
Children with SCD have reduced lung function compared to otherwise
healthy age- and gender-matched Black controls, but most children with SCD
have lung function in the normal range.60,81 The most common abnormality
seen in children is obstruction, occurring in about 15% to 20% of children
with SCD. A restrictive defect is less common, occurring in 7% to 9% of
children.60,81 Retrospective chart review studies of children suggested that
history of ACS may be associated with lung function abnormalities, but
the largest prospective research cohort study in children with HbSS found
that a history of ACS was not associated with lung function abnormalities
in children, and that the presence of abnormal lung function (obstruction
or restriction) did not predict future ACS or pain episodes in children.60 Data
from several studies suggest that restriction is common among adults (ranging
from 27% to 74% across studies).56,82–84 One research cohort that used ATS/
European Respiratory Society lower limit of normal criteria found that
19% of adults with SCD had obstruction.8
The longitudinal trajectory of lung function in SCD is not well understood.
One study demonstrated a 2% to 3% decline per year in total lung capacity,
FVC, and FEV1 among children with SCD85; other studies found that lung
function either does not change or declines at a much slower pace than 2%
to 3% per year.86,87 The group that demonstrated the steepest rate of decline
subsequently found that the use of HU slows the rate of lung function decline.88
In contrast to the obstructive defects often noted in children with SCD, several
studies have shown the development of a restrictive pattern on pulmonary
function tests among adults with SCD (Table 51-1), characterized by reduc-
tions in total lung capacity, FVC, and FEV1 with a normal FEV1/FVC ratio.82–84

901
Many patients also have abnormalities in the diffusion capacity for carbon
monoxide (Dlco),82,83,90 which worsen with age83 and correlate with the level
of dyspnea, independent of the degree of anemia.90 Interpretation of Dlco is
complicated in SCD for a number of reasons. Oxygen (and carbon monoxide)
carrying capacity of the blood is dependent on Hb concentration, but, in
patients with active hemolysis and increased production of carboxyhemoglo-
bin (COHb), the presence of COHb can decrease passive diffusion of carbon
monoxide into erythrocytes, leading to underestimates of Dlco. On the other
hand, the rightward shift of the oxyhemoglobin dissociation curve in SCD
(due to the decreased oxygen affinity of HbS compared to hemoglobin A; the
increased production of 2,3-diphosphoglycerate seen in severe anemia, and
carbon dioxide retention from hypoventilation) can lead to an adaptive release
of oxygen into end-organ tissues, leaving more binding sites available on the
Hb molecule and an overestimate of Dlco. Table 51-2 describes the different
findings in several studies about Dlco in SCD.
Table 51-1. Comparison of Pulmonary Function Testing Results Across Studies

of Adults With Sickle Cell Disease
Klings,83 Sylvester,82 Field,84
Study Details 2006 2006 2008 Anthi,89 2007
Without PH With PH
Number of subjects 310 33 92 15 24
Mean Age (years) 30.7 36 36 41 43
TLC (% predicted) 70 83 87 85 80
FVC (% predicted) 84 82 71 82 70
FEV1 (% predicted) 83 83 79 85 71
FEV1/FVC 0.99 0.85 0.85 0.80 0.78
Classification of Pulmonary Function Abnormalities
Obstructive (%) 1 14 36
Restrictive (%) 74 26 19
Mixed (%) 2 11
Abbreviations: FEV1, forced expiratory volume in the first second of expiration; FVC, forced vital capacity;
PH, pulmonary hypertension; TLC, total lung capacity.

902
Table 51-2. Comparison of Diffusion Capacity Testing Results Across Studies

of Adults With Sickle Cell Disease
Study N Findings Comments
91
Wall MA, 12 children w/ HbSS DLCO greater in HbSS
1979 vs 12 Black controls compared to controls
Arteta M,81 95 children Median DLCO 95% Decreased DLCO
2014 of predicted associated with
decreased TLC and
19% had DLCO < 80%
decreased Hb
of predicted
Miller GJ,92 25 adults Mean DLCO 66% for Decreased DLCO
1971 men; 71% for women attributed to reductions
in permeability across
alveolar capillary
membrane
Young RC, 66 adults vs DLCO decreased in SCD Correlated with
198893 16 Black controls (69% vs 100% in controls); degree of anemia
“lung permeability
constant” decreased
compared to controls (0.76
vs 0.99)
Klings ES, 310 adults Median DLCO adjusted DLCO inversely
200683 for Hb: 62% associated with age
Sylvester KP, 35 adults Median DLCO 75% DLCO associated with
200682 degree abnormalities
Did not decline in follow-up
on HRCT
Lunt A, study 9 years later
201456 HRCT abnormalities did
not change over time
Abbreviations: DLCO, diffusion capacity for carbon monoxide; Hb, hemoglobin; HbSS, sickle cell anemia;
TLC, total lung capacity; HRCT, high-resolution computed tomography.
Management
While there are insufficient data to support routine screening with pulmo-
nary function testing for asymptomatic individuals with SCD, pulmonary
function tests can be useful diagnostic tests for patients with respiratory
symptoms, reduced exercise capacity, and other pulmonary issues.94 Once
identified, specific management strategies for lung function abnormalities
include optimizing the care of the underlying SCD itself (ie, with HU) and
having a low threshold to formally evaluate for the other commonly seen
pulmonary conditions in this population, including asthma, SDB, and, in
adults, pulmonary hypertension.

903
Pulmonary Hypertension
Overview
Pulmonary hypertension (PH) is defined as a resting mean pulmonary arterial
pressure 20 mm Hg or greater.95 Right-heart catheterization–confirmed PH
occurs in 6% to 11% of adults with SCD and is a mortality risk factor.96,97 In
the past, an elevated tricuspid regurgitant jet velocity (TRV) by echocardiog-
raphy of 2.5 m/s or greater was considered to be indicative of pulmonary
hypertension. While we now know that an elevated TRV has a high false
positive rate for PH,98 an elevated TRV for adults, regardless of the presence
of PH or not on a cardiac catheterization, is an independent mortality risk
factor.99
In contrast to adults, an elevated TRV is not necessarily associated with
increased mortality risk in children and adolescents with SCD.100 Because
there are no published studies of right-heart catheterization in children with
SCD and there is known to be a high false positive rate of a high TRV for
true PH in adults, the significance of an elevated TRV for a child with SCD
remains unclear.
Pathophysiology
Gladwin and Vichinsky have described increased intravascular hemolysis
resulting in progressive vasculopathy from endothelial dysfunction (resulting
in priapism, stroke, and PH).15 Chronic hemolysis leads to a deficiency in
nitric oxide, causing increased vasoconstriction and increased intravascular
adhesion due to impaired downregulation of endothelial adhesion mole-
cules.101 Intravascular hemolysis also leads to platelet activation and a hyper-
coagulable state.102 Autopsy studies have shown the presence of in situ
thrombosis in patients who had PH at the time of death.10,103
Clinical Features
The threshold values traditionally associated with a positive echocardiography
screening for PH in individuals with SCD (mean pulmonary artery pressures
of ≥ 25 mm Hg or a TRV of ≥ 2.5 to 3 m/sec)9 are lower than values seen in
symptomatic patients with other forms of PH. This is because patients with
SCD are more likely to develop clinical manifestations at less elevated pul-
monary pressures due to decreased oxygen-carrying capacity from chronic
anemia as well as diffuse end-organ damage due to chronic microvessel dys-
function.104 The most common symptom of PH is exertional dyspnea, which
is also common in those with chronic anemia without PH. Individuals with
SCD and PH had a significantly shorter mean 6-minute walk test distance
compared with those without PH (320 m vs 435 m).89

904
As previously mentioned, the significance and progression of an elevated

TRV in children is not clear. In a retrospective chart review of 61 children
with screening echocardiograms, the 3 deaths that occurred were not in
children with a high TRV.100 In an observational study of 19 children with an
elevated TRV, 12 children had a normal TRV on a follow-up echocardiogram
12 to 18 months later in the absence of any intervention. Five children started
HU, and their follow-up echocardiogram was normal. In the largest study
of echocardiography findings in pediatric patients with SCD,105 11% of 290
patients had an elevated TRV (defined in that study as > 2.6 m/s). There was
no difference in pulmonary vascular resistance derived by echocardiography
between patients with SCD and age- and race-matched control subjects.
Tricuspid regurgitant jet velocity was negatively associated with Hb concen-
tration and oxygen saturation during a 6-minute walk test and was positively
associated with a history of acute chest syndrome and multiple measures of
increased pulmonary blood flow. A longitudinal study of 160 children and
adolescents with HbSS over 22 months of follow-up noted that an increased
TRV was associated with a longitudinal decline in the 6-minute walk dis-
tance and multiple markers of increased hemolysis.106 Taken together, these
findings suggest that an abnormal TRV is a marker of SCD severity. Long-
term outcomes in children with an abnormal echocardiogram warrant
further study.
Screening and Management

The optimal screening and management strategy for pulmonary hyperten-
sion in SCD is an important research priority.107 The American Society of
Hematology 2019 Guidelines for Sickle Cell Disease: Cardiopulmonary and
Kidney Disease94 recommend against routine screening echocardiography to
identify pulmonary hypertension in asymptomatic patients with SCD. Signs or
symptoms such as unexplained dyspnea, hypoxemia, chest pain, or exercise
limitation; or a history of syncope, PE, or signs of heart failure or a new
murmur should prompt a diagnostic echocardiogram or consultation with a
pulmonary hypertension specialist. A symptomatic patient with a persistently
elevated TRV should have consultation with a PH specialist for consideration
of a right-heart catheterization. The management of SCD-related PH is
complicated because of the lack of SCD-specific data on the safety and
efficacy of pharmacologic agents used for PH in other populations. The
guidelines support the use of pulmonary arterial hypertension-specific
therapies under the care of a PH specialist, but only for those patients with
right-heart catheterization–proven pulmonary arterial hypertension (not for
other subtypes of SCD-PH).94 In addition, American Thoracic Society
guidelines on the management of PH in patients with SCD recommend HU
for patients with an increased mortality risk, either because of right-heart
catheterization–proven PH or in an adult with an elevated TRV.108

905
CASE REPORT 51-2

An 18-year-old with severe sickle cell anemia has been on hydroxyurea therapy
for 6 months. He typically has 5 to 6 admissions for pain per year, recurrent
priapism, nocturnal hypoxemia, and chronic dyspnea. His steady-state Hb
averages 5 to 6 g/dL. He has had spirometry annually that has revealed long-
standing, partially reversible airway obstruction, though for the past 2 years he
has also developed a restrictive defect on plethysmography, with a recent total
lung capacity of 72% of predicted. A recent 6-minute walk test demonstrated
a resting oxygen saturation of 94% on room air, but he became hypoxic to 88%
after 2 minutes of walking. His 6-minute walk distance was 390 m (median for
healthy adult men = 580 m).109 Transthoracic echocardiogram 1 month ago did
not show an elevated TRV. After an initial period of noncompliance, he now
uses a bilevel positive airway pressure ventilation device routinely during
sleep. The frequency of painful episodes and priapism have decreased over
the past 6 months; however, he continues to report significant dyspnea when
walking across the campus of his community college. He has reluctantly agreed
to a trial of portable, supplemental oxygen when he knows he has to walk
long distances.
key points
} Pulmonary complications of SCD are a common feature of the disease and lead
to significant morbidity and mortality.
} Management of ACS includes careful pain management, supplemental oxygen,
antibiotics, bronchodilators, incentive spirometry, and red blood cell transfusion
for patients with a significant drop in Hb.
} Children with SCD should be screened for asthma and, when indicated,
managed according to guidelines established by the National Asthma
Education and Prevention Program.
} Clinicians should take a detailed history and have a low threshold to evaluate
children with SCD for SDB.
} While pulmonary function testing is not warranted as a screening test for
asymptomatic patients with SCD, it can be a useful diagnostic test for individuals
with respiratory symptoms.
} More research is needed regarding the optimal screening and management
strategy for SCD-associated PH.
} Children with signs or symptoms of persistent asthma, SDB, recurrent ACS,
or chronic dyspnea should be referred to a pediatric pulmonologist.

906
References
1. Hassell KL. Population estimates of sickle cell disease in the U.S. Am J Prev Med. 2010;38(4)
(suppl):S512–S521 PMID: 20331952 doi: 10.1016/j.amepre.2009.12.022
2. Farooq F, Mogayzel PJ, Lanzkron S, Haywood C, Strouse JJ. Comparison of US federal and
foundation funding of research for sickle cell disease and cystic fibrosis and factors associated
with research productivity. JAMA Netw Open. 2020;3(3):e201737 PMID: 32219405
doi: 10.1001/jamanetworkopen.2020.1737
3. Chaturvedi S, DeBaun MR. Evolution of sickle cell disease from a life-threatening disease of
children to a chronic disease of adults: the last 40 years. Am J Hematol. 2016;91(1):5–14
PMID: 26547630 doi: 10.1002/ajh.24235
4. Lanzkron S, Carroll CP, Haywood C Jr. Mortality rates and age at death from sickle cell disease:
U.S., 1979-2005. Public Health Rep. 2013;128(2):110–116 PMID: 23450875
doi: 10.1177/003335491312800206
5. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk
factors for early death. N Engl J Med. 1994;330(23):1639–1644 PMID: 7993409
doi: 10.1056/NEJM199406093302303
6. Fitzhugh CD, Lauder N, Jonassaint JC, et al. Cardiopulmonary complications leading to
premature deaths in adult patients with sickle cell disease. Am J Hematol. 2010;85(1):36–40
PMID: 20029950
7. Boyd JH, Macklin EA, Strunk RC, DeBaun MR. Asthma is associated with increased mortality
in individuals with sickle cell anemia. Haematologica. 2007;92(8):1115–1118 PMID: 17650441
doi: 10.3324/haematol.11213
8. Cohen RT, Madadi A, Blinder MA, DeBaun MR, Strunk RC, Field JJ. Recurrent, severe
wheezing is associated with morbidity and mortality in adults with sickle cell disease.
Am J Hematol. 2011;86(9):756–761 PMID: 21809369 doi: 10.1002/ajh.22098
9. Gladwin MT, Sachdev V, Jison ML, et al. Pulmonary hypertension as a risk factor for death in
patients with sickle cell disease. N Engl J Med. 2004;350(9):886–895 PMID: 14985486
doi: 10.1056/NEJMoa035477
10. Graham JK, Mosunjac M, Hanzlick RL, Mosunjac M. Sickle cell lung disease and sudden death:
a retrospective/prospective study of 21 autopsy cases and literature review. Am J Forensic Med
Pathol. 2007;28(2):168–172 PMID: 17525572 doi: 10.1097/01.paf.0000257397.92466.50
11. Ballas SK, Lieff S, Benjamin LJ, et al; Investigators, Comprehensive Sickle Cell Centers.
Definitions of the phenotypic manifestations of sickle cell disease. Am J Hematol.
2010;85(1):6–13 PMID: 19902523
12. Takahashi T, Okubo Y, Handa A. Acute chest syndrome among children hospitalized with
vaso-occlusive crisis: a nationwide study in the United States. Pediatr Blood Cancer.
2018;65(3):e26885 PMID: 29134776 doi: 10.1002/pbc.26885
13. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome
in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med.
2000;342(25):1855–1865 PMID: 10861320 doi: 10.1056/NEJM200006223422502
14. West MS, Wethers D, Smith J, Steinberg M. Laboratory profile of sickle cell disease: a
cross-sectional analysis. The cooperative study of sickle cell disease. J Clin Epidemiol.
1992;45(8):893–909 PMID: 1624972 doi: 10.1016/0895-4356(92)90073-V
15. Gladwin MT, Vichinsky E. Pulmonary complications of sickle cell disease. N Engl J Med.
2008;359(21):2254–2265 PMID: 19020327 doi: 10.1056/NEJMra0804411
16. Jain S, Bakshi N, Krishnamurti L. Acute chest syndrome in children with sickle cell disease.
Pediatr Allergy Immunol Pulmonol. 2017;30(4):191–201 PMID: 29279787
doi: 10.1089/ped.2017.0814
17. Stuart MJ, Setty BN. Sickle cell acute chest syndrome: pathogenesis and rationale for treatment.
Blood. 1999;94(5):1555–1560 PMID: 10477680 doi: 10.1182/blood.V94.5.1555
18. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary
of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033–1048
PMID: 25203083 doi: 10.1001/jama.2014.10517
19. Howard J, Hart N, Roberts-Harewood M, Cummins M, Awogbade M, Davis B; BCSH
Committee. Guideline on the management of acute chest syndrome in sickle cell disease.
Br J Haematol. 2015;169(4):492–505 PMID: 25824256 doi: 10.1111/bjh.13348
20. Chaturvedi S, Ghafuri DL, Glassberg J, Kassim AA, Rodeghier M, DeBaun MR. Rapidly
progressive acute chest syndrome in individuals with sickle cell anemia: a distinct acute chest
syndrome phenotype. Am J Hematol. 2016;91(12):1185–1190 PMID: 27543812
doi: 10.1002/ajh.24539

907
21. DeBaun MR, Rodeghier M, Cohen R, et al. Factors predicting future ACS episodes in children
with sickle cell anemia. Am J Hematol. 2014;89(11):E212–E217 PMID: 25088663
doi: 10.1002/ajh.23819
22. Vichinsky EP, Styles LA, Colangelo LH, Wright EC, Castro O, Nickerson B; Cooperative Study
of Sickle Cell Disease. Acute chest syndrome in sickle cell disease: clinical presentation and
course. Blood. 1997;89(5):1787–1792 PMID: 9057664 doi: 10.1182/blood.V89.5.1787
23. Caboot JB, Allen JL. Hypoxemia in sickle cell disease: significance and management.
24. Blaisdell CJ, Goodman S, Clark K, Casella JF, Loughlin GM. Pulse oximetry is a poor
predictor of hypoxemia in stable children with sickle cell disease. Arch Pediatr Adolesc Med.
25. Ortiz FO, Aldrich TK, Nagel RL, Benjamin LJ. Accuracy of pulse oximetry in sickle cell
disease. Am J Respir Crit Care Med. 1999;159(2):447–451 PMID: 9927356
doi: 10.1164/ajrccm.159.2.9806108
26. Needleman JP, Setty BN, Varlotta L, Dampier C, Allen JL. Measurement of hemoglobin
saturation by oxygen in children and adolescents with sickle cell disease. Pediatr Pulmonol.
1999;28(6):423–428 PMID: 10587417
doi: 10.1002/(SICI)1099-0496(199912)28:6<423::AID-PPUL7>3.0.CO;2-C
27. Al-Sharydah AM, Alshahrani M, Aldhaferi B, Al-Muhanna AF, Al-Thani H. Radiological
patterns in sickle cell disease patients with acute chest syndrome: are there age-related
differences? Saudi J Med Med Sci. 2019;7(2):74–79 PMID: 31080386
doi: 10.4103/sjmms.sjmms_174_17
28. Bou-Maroun LM, Meta F, Hanba CJ, Campbell AD, Yanik GA. An analysis of inpatient pediatric
sickle cell disease: Incidence, costs, and outcomes. Pediatr Blood Cancer. 2018;65(1):e26758
PMID: 28801954 doi: 10.1002/pbc.26758
29. Bellet PS, Kalinyak KA, Shukla R, Gelfand MJ, Rucknagel DL. Incentive spirometry to prevent
acute pulmonary complications in sickle cell diseases. N Engl J Med. 1995;333(11):699–703
PMID: 7637747 doi: 10.1056/NEJM199509143331104
30. Ahmad FA, Macias CG, Allen JY. The use of incentive spirometry in pediatric patients with
sickle cell disease to reduce the incidence of acute chest syndrome. J Pediatr Hematol Oncol.
2011;33(6):415–420 PMID: 21792036 doi: 10.1097/MPH.0b013e31821ed4ce
31. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary
of the 2014 eveidence-based report by expert panel members. JAMA. 2014;322(10):1033–1048
32. Johnson CS. The acute chest syndrome. Hematol Oncol Clin North Am. 2005;19(5):857–879, vi–vii
PMID: 16214648 doi: 10.1016/j.hoc.2005.08.001
33. Needleman JP, Benjamin LJ, Sykes JA, Aldrich TK. Breathing patterns during vaso-occlusive
crisis of sickle cell disease. Chest. 2002;122(1):43–46 PMID: 12114337
doi: 10.1378/chest.122.1.43
34. van Beers EJ, van Tuijn CF, Nieuwkerk PT, Friederich PW, Vranken JH, Biemond BJ. Patient-
controlled analgesia versus continuous infusion of morphine during vaso-occlusive crisis in
sickle cell disease, a randomized controlled trial. Am J Hematol. 2007;82(11):955–960
PMID: 17617790 doi: 10.1002/ajh.20944
35. Melton CW, Haynes J Jr. Sickle acute lung injury: role of prevention and early aggressive
intervention strategies on outcome. Clin Chest Med. 2006;27(3):487–502, vii PMID: 16880058
doi: 10.1016/j.ccm.2006.04.001
36. Neumayr L, Lennette E, Kelly D, et al. Mycoplasma disease and acute chest syndrome in sickle
cell disease. Pediatrics. 2003;112(1 Pt 1):87–95 PMID: 12837872 doi: 10.1542/peds.112.1.87
37. Field JJ, Stocks J, Kirkham FJ, et al. Airway hyperresponsiveness in children with sickle cell
anemia. Chest. 2011;139(3):563–568 PMID: 20724735 doi: 10.1378/chest.10-1243
38. Emre U, Miller ST, Gutierez M, Steiner P, Rao SP, Rao M. Effect of transfusion in acute
chest syndrome of sickle cell disease. J Pediatr. 1995;127(6):901–904 PMID: 8523186
doi: 10.1016/S0022-3476(95)70025-0
39. Liem RI, O’Gorman MR, Brown DL. Effect of red cell exchange transfusion on plasma levels of
inflammatory mediators in sickle cell patients with acute chest syndrome. Am J Hematol.
2004;76(1):19–25 PMID: 15114592 doi: 10.1002/ajh.20054
40. Bernini JC, Rogers ZR, Sandler ES, Reisch JS, Quinn CT, Buchanan GR. Beneficial effect of
intravenous dexamethasone in children with mild to moderately severe acute chest syndrome
complicating sickle cell disease. Blood. 1998;92(9):3082–3089 PMID: 9787142
doi: 10.1182/blood.V92.9.3082
41. Strouse JJ, Takemoto CM, Keefer JR, Kato GJ, Casella JF. Corticosteroids and increased risk of
readmission after acute chest syndrome in children with sickle cell disease. Pediatr Blood Cancer.
2008;50(5):1006–1012 PMID: 17849474 doi: 10.1002/pbc.21336

908
42. Darbari DS, Fasano RS, Minniti CP, et al. Severe vaso-occlusive episodes associated with use
of systemic corticosteroids in patients with sickle cell disease. J Natl Med Assoc.
2008;100(8):948–951 PMID: 28643632 doi: 10.1016/S0027-9684(15)31410-3
43. Steinberg MH, Barton F, Castro O, et al. Effect of hydroxyurea on mortality and morbidity
in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA.
2003;289(13):1645–1651 PMID: 12672732 doi: 10.1001/jama.289.13.1645
44. Wang WC, Ware RE, Miller ST, et al; BABY HUG investigators. Hydroxycarbamide in
very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial
(BABY HUG). Lancet. 2011;377(9778):1663–1672 PMID: 21571150
doi: 10.1016/S0140-6736(11)60355-3
45. Ware RE, McGann PT, Quinn CT. Hydroxyurea for children with sickle cell anemia: prescribe it
early and often. Pediatr Blood Cancer. 2019;66(8):e27778 PMID: 31038282
doi: 10.1002/pbc.27778
46. Hankins J, Jeng M, Harris S, Li CS, Liu T, Wang W. Chronic transfusion therapy for children
with sickle cell disease and recurrent acute chest syndrome. J Pediatr Hematol Oncol.
2005;27(3):158–161 PMID: 15750449 doi: 10.1097/01.mph.0000157789.73706.53
47. Miller ST, Wright E, Abboud M, et al; STOP Investigators. Impact of chronic transfusion on
incidence of pain and acute chest syndrome during the Stroke Prevention Trial (STOP) in
sickle-cell anemia. J Pediatr. 2001;139(6):785–789 PMID: 11743502
doi: 10.1067/mpd.2001.119593
48. Vance Utset L, Ivy Z, Willen SM, et al. Inhaled corticosteroid use to prevent severe vaso-
occlusive episode recurrence in children between 1 and 4 years of age with sickle cell disease:
a multicenter feasibility trial. Am J Hematol. 2018;93(4):E101–E103 PMID: 29322539
doi: 10.1002/ajh.25033
49. Strunk RC, Cohen RT, Cooper BP, et al. Wheezing symptoms and parental asthma are associated
with a physician diagnosis of asthma in children with sickle cell anemia. J Pediatr.
2014;164(4):821–826. e1.
50. Akinbami LJ, Moorman JE, Simon AE, Schoendorf KC. Trends in racial disparities for
asthma outcomes among children 0 to 17 years, 2001–2010. J Allergy Clin Immunol.
2014;134(3):547–553. e5.
51. Nandedkar SD, Feroah TR, Hutchins W, et al. Histopathology of experimentally induced asthma
in a murine model of sickle cell disease. Blood. 2008;112(6):2529–2538 PMID: 18579795
doi: 10.1182/blood-2008-01-132506
52. Andemariam B, Adami AJ, Singh A, et al. The sickle cell mouse lung: proinflammatory and
primed for allergic inflammation. Transl Res. 2015;166(3):254–268 PMID: 25843670
doi: 10.1016/j.trsl.2015.03.001
53. Pritchard KA Jr, Feroah TR, Nandedkar SD, et al. Effects of experimental asthma on
inflammation and lung mechanics in sickle cell mice. Am J Respir Cell Mol Biol.
2012;46(3):389–396 PMID: 22033263 doi: 10.1165/rcmb.2011-0097OC
54. Knight-Madden J, Vergani D, Patey R, Sylvester K, Hussain MJ, Forrester T. Cytokine levels and
profiles in children related to sickle cell disease and asthma status. J Interfereon Cytokin Res.
2012;32(1):1‒5
55. Wedderburn CJ, Rees D, Height S, et al. Airways obstruction and pulmonary capillary blood
volume in children with sickle cell disease. Pediatr Pulmonol. 2014;49(7):716–722
56. Lunt A, Desai SR, Wells AU, et al. Pulmonary function, CT and echocardiographic
abnormalities in sickle cell disease. Thorax. 2014;69(8):746–751 PMID: 24682519
doi: 10.1136/thoraxjnl-2013-204809
57. Lunt A, McGhee E, Robinson P, Rees D, Height S, Greenough A. Lung function, transfusion,
pulmonary capillary blood volume and sickle cell disease. Respir Physiol Neurobiol.
2016;222:6–10 PMID: 26592148 doi: 10.1016/j.resp.2015.11.006
58. Boyd JH, Macklin EA, Strunk RC, DeBaun MR. Asthma is associated with acute chest
syndrome and pain in children with sickle cell anemia. Blood. 2006;108(9):2923–2927
PMID: 16690969 doi: 10.1182/blood-2006-01-011072
59. Knight-Madden JM, Forrester TS, Lewis NA, Greenough A. Asthma in children with sickle cell
disease and its association with acute chest syndrome. Thorax. 2005;60(3):206–210
PMID: 15741436 doi: 10.1136/thx.2004.029165
60. Cohen RT, Strunk RC, Rodeghier M, et al. Pattern of lung function is not associated with prior or
future morbidity in children with sickle cell anemia. Ann Am Thorac Soc. 2016;13(8):1314–1323
61. Koumbourlis AC, Hurlet-Jensen A, Bye MR. Lung function in infants with sickle cell disease.
doi: 10.1002/(SICI)1099-0496(199710)24:4<277::AID-PPUL6>3.0.CO;2-H

909
62. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines
for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol.
2007;120(5)(suppl):S94–S138 PMID: 17983880 doi: 10.1016/j.jaci.2007.09.029
63. Ogunlesi F, Heeney MM, Koumbourlis AC. Systemic corticosteroids in acute chest syndrome:
friend or foe? Paediatr Respir Rev. 2014;15(1):24–27 PMID: 24268617
doi: 10.1016/j.prrv.2013.10.004
64. Glassberg J, Minnitti C, Cromwell C, et al. Inhaled steroids reduce pain and sVCAM levels in
individuals with sickle cell disease: A triple-blind, randomized trial. Am J Hematol.
2017;92(7):622–631 PMID: 28370266 doi: 10.1002/ajh.24742
65. Spivey JF, Uong EC, Strunk R, Boslaugh SE, DeBaun MR. Low daytime pulse oximetry reading
is associated with nocturnal desaturation and obstructive sleep apnea in children with sickle cell
anemia. Pediatr Blood Cancer. 2008;50(2):359–362 PMID: 17072857 doi: 10.1002/pbc.21054
66. Needleman JP, Franco ME, Varlotta L, et al. Mechanisms of nocturnal oxyhemoglobin
desaturation in children and adolescents with sickle cell disease. Pediatr Pulmonol.
1999;28(6):418–422 PMID: 10587416
doi: 10.1002/(SICI)1099-0496(199912)28:6<418::AID-PPUL6>3.0.CO;2-D
67. Hargrave DR, Wade A, Evans JP, Hewes DK, Kirkham FJ. Nocturnal oxygen saturation and
painful sickle cell crises in children. Blood. 2003;101(3):846–848 PMID: 12393400
doi: 10.1182/blood-2002-05-1392
68. Samuels MP, Stebbens VA, Davies SC, Picton-Jones E, Southall DP. Sleep related upper airway
obstruction and hypoxaemia in sickle cell disease. Arch Dis Child. 1992;67(7):925–929
PMID: 1308102 doi: 10.1136/adc.67.7.925
69. Maddern BR, Reed HT, Ohene-Frempong K, Beckerman RC. Obstructive sleep apnea syndrome
in sickle cell disease. Ann Otol Rhinol Laryngol. 1989;98(3):174–178 PMID: 2923395
doi: 10.1177/000348948909800302
70. Worsham CM, Martin ST, Nouraie SM, Cohen RT, Klings ES. Clinical and laboratory findings
associated with sleep disordered breathing in sickle cell disease. Am J Hematol.
2017;92(12):E649–E651 PMID: 28833466 doi: 10.1002/ajh.24892
71. Rosen CL, Debaun MR, Strunk RC, et al. Obstructive sleep apnea and sickle cell anemia.
72. Lehmann GC, Bell TR, Kirkham FJ, et al. Enuresis associated with sleep disordered breathing in
children with sickle cell anemia. J Urol. 2012;188(4)(suppl):1572–1576 PMID: 22910247
doi: 10.1016/j.juro.2012.02.021
73. Kirkham FJ, Hewes DK, Prengler M, Wade A, Lane R, Evans JP. Nocturnal hypoxaemia and
central-nervous-system events in sickle-cell disease. Lancet. 2001;357(9269):1656–1659
PMID: 11425370 doi: 10.1016/S0140-6736(00)04821-2
74. Willen SM, Rodeghier M, Rosen CL, DeBaun MR. Sleep disordered breathing does not
predict acute severe pain episodes in children with sickle cell anemia. Am J Hematol.
2018;93(4):478–485 PMID: 29266432
75. Rani S, Mahon BNA, et al. Correlates of Nocturnal Hypoxemia in Children with Sickle Cell
Disease. American Thoracic Society International Conference. Denver, CO; 2015. p A109
76. Marcus CL, Brooks LJ, Draper KA, et al; American Academy of Pediatrics. Diagnosis and
management of childhood obstructive sleep apnea syndrome. Pediatrics. 2012;130(3):e714–e755
PMID: 22926176 doi: 10.1542/peds.2012-1672
77. Aurora RN, Zak RS, Karippot A, et al; American Academy of Sleep Medicine. Practice
parameters for the respiratory indications for polysomnography in children. Sleep.
2011;34(3):379–388 PMID: 21359087 doi: 10.1093/sleep/34.3.379
78. Grady AJ, Hankins JS, Haberman B, Schoumacher R, Stocks RM. Hydroxyurea treatment effect
on children with sickle cell disease and obstructive sleep apnea. Sleep Breath. 2017;21(3):697–701
PMID: 28078488 doi: 10.1007/s11325-017-1458-9
79. Narang I, Kadmon G, Lai D, et al. Higher nocturnal and awake oxygen saturations in
children with sickle cell disease receiving hydroxyurea therapy. Ann Am Thorac Soc.
2015;12(7):1044–1049 PMID: 25970812 doi: 10.1513/AnnalsATS.201410-473OC
80. Singh SA, Koumbourlis AC, Aygun B. Resolution of chronic hypoxemia in pediatric sickle cell
patients after treatment with hydroxyurea. Pediatr Blood Cancer. 2008;50(6):1258–1260
PMID: 18293380 doi: 10.1002/pbc.21480
81. Arteta M, Campbell A, Nouraie M, et al. Abnormal pulmonary function and associated risk
factors in children and adolescents with sickle cell anemia. J Pediatr Hematol Oncol.
2014;36(3):185–189 PMID: 24309610 doi: 10.1097/MPH.0000000000000011
82. Sylvester KP, Desai SR, Wells AU, et al. Computed tomography and pulmonary function
abnormalities in sickle cell disease. Eur Respir J. 2006;28(4):832–838 PMID: 16737989
doi: 10.1183/09031936.06.00007006

910
83. Klings ES, Wyszynski DF, Nolan VG, Steinberg MH. Abnormal pulmonary function in adults
with sickle cell anemia. Am J Respir Crit Care Med. 2006;173(11):1264–1269
PMID: 16556694 doi: 10.1164/rccm.200601-125OC
84. Field JJ, Glassberg J, Gilmore A, et al. Longitudinal analysis of pulmonary function in adults
with sickle cell disease. Am J Hematol. 2008;83(7):574–576 PMID: 18383325
doi: 10.1002/ajh.21176
85. MacLean JE, Atenafu E, Kirby-Allen M, et al. Longitudinal decline in lung volume in a
population of children with sickle cell disease. Am J Respir Crit Care Med.
2008;178(10):1055–1059 PMID: 18776149 doi: 10.1164/rccm.200708-1219OC
86. Lunt A, McGhee E, Sylvester K, et al. Longitudinal assessment of lung function in children with
sickle cell disease. Pediatr Pulmonol. 2016;51(7):717–723 PMID: 26694220
doi: 10.1002/ppul.23367
87. Willen SM, Cohen R, Rodeghier M, et al. Age is a predictor of a small decrease in lung function
in children with sickle cell anemia. Am J Hematol. 2018;93(3):408–415 PMID: 29226507
doi: 10.1002/ajh.25003
88. McLaren A, Klingel M, Behera S, Odame I, Kirby-Allen M, Grasemann H. Effect of
hydroxyurea therapy on pulmonary function in children with sickle cell anemia. Am J Respir
Crit Care Med. 2017;195(5):689–691 PMID: 28248149 doi: 10.1164/rccm.201606-1119LE
89. Anthi A, Machado RF, Jison ML, et al. Hemodynamic and functional assessment of patients
with sickle cell disease and pulmonary hypertension. Am J Respir Crit Care Med.
2007;175(12):1272–1279 PMID: 17379852 doi: 10.1164/rccm.200610-1498OC
90. Delclaux C, Zerah-Lancner F, Bachir D, et al. Factors associated with dyspnea in adult patients
with sickle cell disease. Chest. 2005;128(5):3336–3344 PMID: 16304281
doi: 10.1378/chest.128.5.3336
91. Wall MA, Platt OS, Strieder DJ. Lung function in children with sickle cell anemia.
Am Rev Respir Dis. 1979;120(1):210–214 PMID: 464381
92. Miller GJ, Serjeant GR. An assessment of lung volumes and gas transfer in sickle-cell anaemia.
Thorax. 1971;26(3):309–315 PMID: 5089498 doi: 10.1136/thx.26.3.309
93. Young RC Jr, Rachal RE, Reindorf CA, et al. Lung function in sickle cell hemoglobinopathy
patients compared with healthy subjects. J Natl Med Assoc. 1988;80(5):509–514 PMID: 3418733
94. Liem RI, Lanzkron S, D Coates T, et al. American Society of Hematology 2019 guidelines for
sickle cell disease: cardiopulmonary and kidney disease. Blood Adv. 2019;3(23):3867–3897
PMID: 31794601 doi: 10.1182/bloodadvances.2019000916
95. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical
classification of pulmonary hypertension. Eur Respir J. 2019;53(1):1801913 PMID: 30545968
doi: 10.1183/13993003.01913-2018
96. Mehari A, Gladwin MT, Tian X, Machado RF, Kato GJ. Mortality in adults with sickle cell
disease and pulmonary hypertension. JAMA. 2012;307(12):1254–1256 PMID: 22453563
doi: 10.1001/jama.2012.358
97. Fonseca GH, Souza R, Salemi VM, Jardim CV, Gualandro SF. Pulmonary hypertension
diagnosed by right heart catheterisation in sickle cell disease. Eur Respir J. 2012;39(1):112–118
PMID: 21778170 doi: 10.1183/09031936.00134410
98. Parent F, Bachir D, Inamo J, et al. A hemodynamic study of pulmonary hypertension in sickle
cell disease. N Engl J Med. 2011;365(1):44–53 PMID: 21732836 doi: 10.1056/NEJMoa1005565
99. Mehari A, Alam S, Tian X, et al. Hemodynamic predictors of mortality in adults with sickle cell
disease. Am J Respir Crit Care Med. 2013;187(8):840–847 PMID: 23348978
doi: 10.1164/rccm.201207-1222OC
100. Hagar RW, Michlitsch JG, Gardner J, Vichinsky EP, Morris CR. Clinical differences between
children and adults with pulmonary hypertension and sickle cell disease. Br J Haematol.
2008;140(1):104–112 PMID: 17916102
101. Setty BN, Stuart MJ. Vascular cell adhesion molecule-1 is involved in mediating hypoxia-
induced sickle red blood cell adherence to endothelium: potential role in sickle cell disease.
Blood. 1996;88(6):2311–2320 PMID: 8822953
doi: 10.1182/blood.V88.6.2311.bloodjournal8862311
102. Villagra J, Shiva S, Hunter LA, Machado RF, Gladwin MT, Kato GJ. Platelet activation in
patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide
scavenging by cell-free hemoglobin. Blood. 2007;110(6):2166–2172 PMID: 17536019
doi: 10.1182/blood-2006-12-061697
103. Haque AK, Gokhale S, Rampy BA, Adegboyega P, Duarte A, Saldana MJ. Pulmonary
hypertension in sickle cell hemoglobinopathy: a clinicopathologic study of 20 cases.
Hum Pathol. 2002;33(10):1037–1043 PMID: 12395378 doi: 10.1053/hupa.2002.128059

911
104. Machado RF, Gladwin MT. Chronic sickle cell lung disease: new insights into the diagnosis,
pathogenesis and treatment of pulmonary hypertension. Br J Haematol. 2005;129(4):449–464
PMID: 15877728 doi: 10.1111/j.1365-2141.2005.05432.x
105. Dham N, Ensing G, Minniti C, et al. Prospective echocardiography assessment of pulmonary
hypertension and its potential etiologies in children with sickle cell disease. Am J Cardiol.
2009;104(5):713–720 PMID: 19699350 doi: 10.1016/j.amjcard.2009.04.034
106. Gordeuk VR, Minniti CP, Nouraie M, et al. Elevated tricuspid regurgitation velocity and decline
in exercise capacity over 22 months of follow up in children and adolescents with sickle cell
anemia. Haematologica. 2011;96(1):33–40 PMID: 20884713 doi: 10.3324/haematol.2010.030767
107. Ruhl AP, Sadreameli SC, Allen JL, et al. Identifying clinical and research priorities in sickle cell
lung disease. An official American Thoracic Society Workshop Report. Ann Am Thorac Soc.
2019;16(9):e17–e32 PMID: 31469310 doi: 10.1513/AnnalsATS.201906-433ST
108. Klings ES, Machado RF, Barst RJ, et al; American Thoracic Society Ad Hoc Committee on
Pulmonary Hypertension of Sickle Cell Disease. An official American Thoracic Society clinical
practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of
sickle cell disease. Am J Respir Crit Care Med. 2014;189(6):727–740 PMID: 24628312
doi: 10.1164/rccm.201401-0065ST
109. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories.
ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med.
2002;166(1):111–117 PMID: 12091180 doi: 10.1164/ajrccm.166.1.at1102

CHAPTER
52
Pulmonary Manifestations of Oncologic Disease and
Treatment
Caitlin Hurley, MD
Introduction
An estimated 16,000 cases of pediatric cancers are diagnosed in the United
States each year.1 Despite numerous advances in the diagnosis and management
of pediatric tumors, cancer remains the leading cause of death from disease in
children from infancy up to 19 years of age.1,2 Leukemia and lymphomas are
2 of the 3 most common tumors in this age group, and both can be associated
with pulmonary manifestations at presentation.
Primary lung and airway tumors are relatively rare in children but are important
to recognize because delays in diagnosis can have consequences for prognosis.
In addition to complications of the primary neoplasms, cancer therapies, in-
cluding chemotherapy and radiation, may have substantial effects on the lungs.
Lung Involvement in Hematologic Malignancy

Hematologic malignancies may cause pulmonary disease in children, including
pulmonary leukostasis in the setting of hyperleukocytosis, leukemic cell lysis
pneumonopathy, and leukemic infiltration. In addition, patients with leukemia
or lymphoma presenting with a mediastinal mass may develop superior vena
cava syndrome and airway compression.
Leukemia
Acute leukemias are the most common malignancy of childhood, accounting
for approximately 30% of pediatric cancer cases, with the majority, nearly 75%,
being acute lymphoblastic leukemia (ALL).3 Mediastinal mass with leukemic
infiltration is common at diagnosis, particularly with T-cell ALL.3 Acute mye-
loid leukemia (AML) is less common; however, it may manifest with increased
morbidity, especially with hyperleukocytosis, defined as peripheral white blood
cell count exceeding 100,000 cells/µL at presentation.4 Children with ALL,
AML, or chronic myelogenous leukemia who present with hyperleukocytosis
are at risk for leukostasis. Leukostasis is the result of increased blood viscosity
913

914
from the circulating large and stiff blast cells, as well as interactions between
the blast cells and vascular endothelial cells. Leukostasis is more common in
patients with AML at lower total white blood cell counts because of the larger
size, shape, and decreased deformability of the AML blast cell.5,6 The accumu-
lation of circulating blasts results in elevated blood viscosity, microvascular
obstructions, and, ultimately, tissue hypoxia. In the lung, this phenomenon
causes pulmonary infiltrates, hypoxia, hemorrhage, and infarction. In pulmo-
nary leukostasis, urgent cytoreduction therapy is required, and the type of
cytoreduction depends on the leukemia subtype.7,8 In addition to pulmonary
leukostasis, the release of intracellular contents of blast cells after leukemic
cell lysis causes pulmonary tissue damage and edema, which may lead to
respiratory failure, a condition known as leukemic cell pneumonopathy.
Intensive multiagent chemotherapy is successful in inducing remission in
about 70% of patients with AML.4 Children and adolescents with ALL have
an overall survival rate greater than 89% at 5 years from the time of diag-
nosis. Young adults with ALL have an overall survival rate of 61%. In infants
younger than 12 months, ALL is extremely aggressive, with high relapse
and low survival rates.9,10
Hematopoietic stem cell transplant (HSCT) is an important therapeutic option
in ALL with very high-risk features and in ALL relapse. Immunotherapy has
also changed the landscape of treatment for very high-risk or relapsed ALL.11
Lymphoma
Lymphomas are morphologically subdivided into 2 major categories—
non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL).
In adolescents and young adults between 17 and 39 years of age, NHL
accounts for approximately 8% of all cancers. Although NHL is a hetero-
geneous group of tumors, the most common subtypes include diffuse large
B-cell lymphoma and anaplastic large cell lymphoma. Young adults are a
unique subgroup of patients differing from both children and adults in
terms of clinical presentation, histological findings, and outcomes.12
Hodgkin lymphoma is a B-cell lymphoma characterized by a trimodal age
distribution curve with its highest peak in adolescence and young adulthood,
followed by 2 smaller peaks in children younger than 15 years and in adults
older than 50 years. The disease is histopathologically defined by the presence
of Hodgkin and Reed-Sternberg cells. Presenting symptoms in children
include painless lymphadenopathy; hepatosplenomegaly; and nonspecific
symptoms such as fatigue, anorexia, and weight loss. Between 17% and
40% of children with HL have a mediastinal mass at the time of presentation.
The bulky mediastinal mass may cause dysphagia, dyspnea, cough, stridor,
or superior vena cava syndrome.

915
Chapter 52—Pulmonary Manifestations of Oncologic Disease and Treatment
Mediastinal Tumors
The mediastinum is typically classified into 3 compartments on the basis of
lateral chest radiographs—anterior, middle, and posterior. The anterior compart-
ment is bordered by the sternum anteriorly and the pericardial sac posteriorly.
The posterior mediastinum extends from the posterior aspect of the pericardium
to the vertebral bodies, and the middle mediastinum includes the structures that
lie between the anterior and posterior shadows of the pericardium. The middle
mediastinum contains the trachea, main bronchi, and bronchial lymph nodes, as
well as the heart and pericardium, the ascending aorta, the lower segment of the
superior vena cava, and the bifurcation of the pulmonary artery.13 The Interna-
tional Thymic Malignancy Interest Group has also proposed new definitions
of the mediastinal compartments on the basis of computed tomography (CT)
images—prevascular, visceral, and paravertebral.14,15
Most mediastinal masses in children are malignant, and more than one-half of
these children have symptoms, typically dyspnea, cough, fever, and malaise.
However, these symptoms are often nonspecific and can resemble common
respiratory illnesses. There is a clinically significant risk of respiratory dis-
tress with acute airway compression, which can occur or worsen suddenly,
especially in young children. Patients unable to lie supine or with greater
than 50% compression of the airway during CT are at high risk of complete
obstruction with anesthesia or other procedures and may be best treated in a
pediatric center with extracorporeal membrane oxygenation support.16,17
Complications of Mediastinal Tumors

Superior vena cava syndrome occurs when the superior vena cava is com-
pressed by mediastinal tumors. In a child, superior vena cava syndrome is
most often caused by lymphomas (HL and NHL) and T-cell ALL. Clinical
signs and symptoms include edema of the face, prominent superficial chest
veins, cough, wheeze, shortness of breath, and stridor. Plethora or cyanosis
of the face, neck, and upper extremities can also occur. The diagnosis is con-
firmed by means of Doppler ultrasonography or magnetic resonance imaging.
Emergency treatment includes elevating the head of the bed, keeping the
child calm, and administering supplemental oxygen. At times, diuresis
or emergency treatment with steroids may be required.8
Anterior Mediastinum
Approximately one-half of all mediastinal masses are primary neoplasms in
the anterior mediastinum. They can be congenital, inflammatory, or neoplastic.
Thymomas are the most common primary tumor of the anterior mediastinum;
however, most occur in middle-aged and older adults and infrequently in chil-
dren and adolescents. Germ cell tumors (GCTs) of the mediastinum include
teratomas, seminomas, and nonsematomatous malignant GCTs. They are

916
believed to arise from primitive germ cells misplaced in the anterior mediasti-
num during early embryonic development. The anterosuperior portion of the
mediastinum is the most common extragonadal primary site. Teratomas are
the most common GCTs in children.18
Primary mediastinal NHL constitutes about 5% of all NHL. Age-related
differences in presentation, biological features, and outcome are seen with
NHL. Children are more likely to have high-grade tumors, including Burkitt
lymphoma, diffuse large B-cell lymphoma, lymphoblastic lymphoma, and
anaplastic large cell lymphoma. Tumor lysis syndrome and symptoms related
to compression of surrounding tissue can occur. Treatment outcomes for
children younger than 16 years with newly diagnosed NHL are better
than for those in older age groups.12,19
Posterior Mediastinum
The most common tumors in the posterior mediastinum are neurogenic in
origin and arise from the sympathetic ganglia, intercostal nerves, and para-
ganglia cells.13 The most common benign neurogenic tumor of the posterior
mediastinum in children is the ganglioneuroma, which is composed of both
ganglion cells and nerve fibers. This tumor typically manifests at an early
age and may be identified as an incidental finding or less frequently because
of symptoms secondary to nerve root or spinal cord compression. Magnetic
resonance imaging is the imaging modality of choice to define the relation-
ship of the tumor to adjacent structures, particularly the spinal cord. Surgical
resection, either complete or partial, is the treatment of choice.
Neuroblastomas are highly malignant tumors that account for more than
one-half of the neurogenic tumors of the posterior mediastinum. They arise
primarily from the adrenal medulla and less often the sympathetic nervous
system ganglia. They are most commonly seen in infants and children
younger than 3 years and have frequently metastasized by the time of diag-
nosis. Regional lymph nodes, bone, bone marrow, brain, and liver are frequent
sites of metastases, with lung rarely a site of metastasis. Clinical presentation
and prognosis are variable and depend on patient age, tumor biological
features, and tumor staging.
Ganglioneuroblastomas, composed of both mature and immature ganglion
cells, are malignant and generally symptomatic at presentation. They are
divided into 2 categories—composite ganglioneuroblastoma and diffuse
ganglioneuroblastoma. In the first category, between 65% and 70% of patients
will have metastatic disease at presentation, whereas in the latter, less than 5%
of patients will develop metastases.13

917
Solid Tumors
Thoracic Tumors
Primary pulmonary neoplasms in the pediatric age group are relatively un-
common. The true incidence and etiologic predisposing factors are unclear.
Abnormal fetal lung development has been implicated in some rare tumors.
In a systematic review of 134 publications,20 investigators analyzed congenital
pulmonary malformations (CPMs) in 76 children and 92 adults. Congenital
cystic adenomatoid malformation (CCAM) was the most frequent underlying
CPM associated with pulmonary tumors in children. The tumor most fre-
quently associated with CPM in children was pleuropulmonary blastoma
(PPB). This finding differs from findings for adults with CPM, in whom
bronchogenic cysts and CCAM are the most common underlying CPM
and adenocarcinoma and bronchoalveolar carcinoma are the most commonly
associated tumors. In
Table 52–1. Examples of Pediatric Thoracic Tumors
both children and adults,
Anatomical
Region Malignant Benign the most common pre-
senting symptom
Airway Carcinoid Infantile
hemangioma was cough.20
Mucoepidermoid
carcinoma Squamous Thoracic tumors can
papilloma manifest at any age and
Anterior Lymphoma: Hodgkin Teratoma often are identified as
mediastinum and non-Hodgkin Lymphangioma an incidental finding at
Germ cell tumors
chest imaging. Thoracic
Middle Lymphoma: Hodgkin Teratoma tumors can be malignant
mediastinum and non-Hodgkin Cardiac or benign. The diagnosis
Germ cell tumors rhabdomyoma
and surgical intervention
Rhabdomyosarcoma Bronchogenic
cyst may be delayed because
of absent or nonspecific
Posterior Neuroblastoma Ganglioneuroma
mediastinum symptoms at presentation.
Lymphoma Neurofibroma
An overview of benign
Pulmonary Primary tumors Granulomatous
and malignant pediatric
parenchyma Bronchoalveolar disease
carcinoma Inflammatory
thoracic tumors is pro-
Pleuropulmonary pseudotumor vided in Table 52–1.20–29
blastoma Hamartoma The tumors are grouped
Metastatic solid according to their
tumors anatomical locations.
Lymphoma
Chest wall Ewing sarcoma Lipoma
family Hemangioma
Rhabdomyosarcoma Osteochondroma
Osteosarcoma Neurofibroma
Lymphoma

918
Airway Tumors
Although airway tumors are rare in children, they are more likely to be
malignant than benign.21 Both tumor type and tumor location affect clinical
symptoms, which can include recurrent cough, wheezing, chest pain, atelecta-
sis, and hemoptysis. Similarities in presentation with asthma and respiratory
tract infections are frequently associated with delays in diagnosis.21–23 More
than one-half of children with airway tumors present with persistent or
recurrent pulmonary infections involving the same location, asymmetrical
findings at auscultation, or persistent cough.24
Benign Airway Tumors
Infantile hemangioma and squamous papilloma are the most frequently
occurring histological group of benign airway tumors in children.23 Sporadic
cases of inflammatory pseudotumor, leiomyoma, granular cell tumor, juvenile
xanthogranuloma, tracheal lipoblastoma, and laryngotracheal chondroma
have also been reported.23
Obstructive infantile hemangiomas typically occur at the level of the subglot-
tis, and patients present with biphasic stridor and cough as the tumor enlarges.
Cutaneous hemangiomas are seen in about one-half of infants with an airway
hemangioma, with the greatest risk of airway hemangioma in children with
cutaneous hemangioma of the head or neck.30 In a small number of cases,
there are other associated congenital anomalies. The most notable is PHACE
syndrome, which includes Posterior fossa anomalies, Hemangioma, Arterial
lesions, Cardiac abnormalities/Coarctation of the aorta, and Eye anomalies.
Patients with large segmental infantile hemangiomas of the head or neck
have a 30% risk of PHACE syndrome.31
Recurrent respiratory papillomatosis is caused by infection with human
papillomavirus. Most infections in infants occur during vaginal delivery from
infected mothers, whereas in older patients human papillomavirus is transmit-
ted sexually.32 It is seen most frequently in the larynx but has been reported in
the nasopharynx, tracheobronchial tree, and lung parenchyma. Malignant
transformation to squamous cell carcinoma is rare but has been reported.32
Malignant Airway Tumors
The most common malignant airway tumors in the pediatric age group are
carcinoids and mucoepidermoid carcinoma.21 Bronchial carcinoids account for
63% to 80% of all malignant pediatric primary lung tumors. These tumors
arise from the neuroendocrine cells within the bronchial epithelium and often
appear as polypoid projections into the airway lumen. The more common are
the typical carcinoids, which overall are less invasive, have a low malignancy
potential, and have a more favorable prognosis, with greater than 90% sur-
vival.25,28 The poorly differentiated carcinoid tumors are more aggressive,
often with local invasion at the time of patient presentation. The excessive

919
secretion of vasoactive peptides from carcinoid tumors causing wheezing,

flushing, palpitations, and diarrhea is referred to as carcinoid syndrome and is
rare in the absence of metastases. Spread to the intrathoracic lymph nodes is
the most common site of metastases.28
Lung Parenchymal Tumors

Pleuropulmonary blastomas are malignant, sarcomatous tumors arising from
the lung parenchyma, pleural surfaces, or both and are the most common pri-
mary pulmonary malignancy in children.33 Evolving from a pulmonary cyst,
PPB can be divided into 4 types on the basis of progression—type I (purely
cystic; median patient age of 8 months at presentation), type Ir (r stands for
regressing; similar to type I and occurs in older children than type I; does
not contain cancerous cells), type II (cystic and solid; median patient age of
35 months at presentation), and type III (purely solid; median patient age of
41 months at presentation). Pleuropulmonary blastoma is caused by a germ-
line mutation in DICER1; DICER1 syndrome is a rare inherited disorder that
increases the risk of tumors in multiple sites including the kidney, thyroid, and
lung. Pleuropulmonary blastoma should be included in the differential
diagnosis in children with spontaneous pneumothorax, multiple pulmonary
cystic lesions, or a family history of pulmonary cysts and PPB. Because of the
nonspecific nature of symptoms with childhood parenchymal tumors, there is
a high rate of delayed diagnosis. Treatment decisions are made on the basis of
tumor type.34 Consultation with medical genetics specialists is an important
component in the care of families of children with germline mutations.
Chest Wall Tumors

Primary chest wall tumors are also rare in the pediatric age group and are
predominantly sarcomas from the Ewing sarcoma family.35 These are aggres-
sive tumors characterized by malignant, small round cell types. Other malig-
nant tumors that can involve the chest wall include primitive neuroectodermal
tumors, rhabdomyosarcoma, neuroblastoma, malignant fibrous histiocytoma,
chondrosarcoma, osteogenic sarcoma, synovial sarcoma, chordoma, leiomyo-
sarcoma, and fibrosarcoma.36 Several benign tumors, including lipoblastoma,
mesenchymoma, chondroma, and hamartoma, can also manifest as chest wall
masses.37 Tuberculosis and actinomycosis also can manifest as chest wall
masses but only rarely.
Evaluation of chest wall masses begins with plain radiography followed by
chest CT to facilitate delineation of tumor site, size, and infiltration into con-
tiguous structures, as well as to screen for pulmonary metastases. Magnetic
resonance imaging complements the previous studies to evaluate the soft
tissue further, identify any fluid within the chest wall, and detect any exten-
sion into the spine or epidural space. Tissue biopsy is performed using either
a core needle technique or a limited open approach.36

920
Pulmonary Metastatic Lesions

Table 52-2 lists some of the pediatric tumors known to metastasize to the
lungs. Metastatic masses or nodules can be solitary or multiple and may be
found at the time of diagnosis of the malignancy, or at a recurrence of the
disease. The lung is the most common site for metastases from solid tumors.38
Computed tomography is the preferred imaging modality to identify and
follow up pulmonary nodules but lacks specificity to differentiate benign
from malignant nodules, so biopsy may still be required, particularly in
areas with high endemic fungal infection.39
Pulmonary metastases from pediatric solid tumors can be divided into 2
major categories according to the histological characteristics of the primary
tumor—those that respond well to systemic adjuvant therapy and those that
respond poorly. Box 52-1 lists tumors according to this classification.39 In
children who respond well to systemic therapy, it is the primary and first-line
treatment. Children whose malignancies respond poorly to systemic therapy
are more likely to require surgical resection.39
Table 52-2. Pediatric Tumors That Metastasize to the Lungs

Primary Site Common Rare
Skeletal system Osteosarcoma Chondrosarcoma
Ewing sarcoma
Musculoskeletal system Rhabdomyosarcoma Chondrosarcoma
Soft-tissue sarcoma Fibrosarcoma
Synovial cell sarcoma Liposarcoma
Malignant fibrous Malignant
histiocytoma neurilemmoma
Gastrointestinal tract Hepatoblastoma Leiomyosarcoma
Hepatocellular carcinoma Adenocarcinoma
Embryonal sarcoma of liver of colon
Genitourinary tract Wilms tumor Trophoblastic

Malignant rhabdoid tumor choriocarcinoma
of the kidney
Malignant germ cell tumor
Endocrine system Differentiated thyroid Adrenocortical carcinoma
carcinoma Neuroblastoma

921
Box 52‑1
Classification of Pulmonary Metastases From Solid Tumors
on the Basis of Treatment Response
Tumors responsive to adjuvant therapy
Wilms tumor
Hepatoblastoma
Ewing sarcoma
Neuroblastoma (uncommon)
Rhabdomyosarcoma
Tumors less responsive to adjuvant therapy
Nonrhabdomyosarcoma soft-tissue sarcoma
Adrenocorticoid carcinoma
Osteosarcoma
Derived from Croteau NJ, Heaton TE. Pulmonary metastasectomy in pediatric

solid tumors. Children (Basel). 2019;6(1):6.
Pulmonary Complications of Cancer Therapies

Patients with malignancies treated with chemotherapeutic drugs, radiation,or
newer biologic agents and immunotherapy are at risk for multiple infectious
and noninfectious pulmonary complications. Patients undergoing HSCT are
at particularly high risk for pulmonary complications.
Chemotherapy Pulmonary Injury

Traditional chemotherapy-related drug injury has long been recognized as
having the potential for worsening by concomitant therapies such as radiation.
Examples of classic chemotherapy drugs that induce injury include bleomy-
cin, busulfan, and nitrosureas. Bleomycin is an alkylating agent associated
with increased risk for acute respiratory distress syndrome, alveolar pro-
teinosis, and pulmonary fibrosis. Approximately 8% of patients treated with
bleomycin will develop symptomatic pulmonary injury. Cumulative doses
greater than 500 mg or 400 U/m2 and lung irradiation increase the risk for
toxicity40,41; current therapy regimens limiting doses have helped reduce the
frequency of substantial bleomycin injury. Nitrosoureas (carmustine and
lomustine) have been linked to hypersensitivity pneumonitis, alveolitis,
pulmonary veno-occlusive disease, and pulmonary fibrosis.40,41
Novel Cancer Therapy–Induced Pulmonary Injury

New innovative strategies to address recurrent and refractory pediatric
cancers may have potential pulmonary toxicities. This field is rapidly evolv-
ing, and a review of all newer agents potentially associated with pulmonary
complications is beyond the scope of this chapter. Pneumonitis is the most

922
common immune-related adverse effect associated with immune checkpoint

inhibitors, which target immune cells rather than tumor cells; it can manifest
as organizing pneumonia, nonspecific interstitial pneumonia, hypersensitivity
pneumonia, or diffuse alveolar damage. Pneumonitis can develop quickly and
can be fatal. Examples of immune checkpoint agents include ipilimumab,
pembrolizumab, and nivolumab.42–44
Targeted molecular therapies, including monoclonal antibodies and tyrosine
kinase inhibitors, are increasingly used in adult cancers and in some childhood
cancers. Pneumonitis and interstitial lung disease can be associated with these
agents and, rarely, can be fatal.45–47 For biologic agents, which include ritux-
imab, cetuximab, bevacizumab, alemtuzumab, and trastuzumab, the most
common of pulmonary adverse effects is interstitial lung disease.47
Radiation-induced Pulmonary Injury

Radiation therapy plays a major role in the curative or palliative treatment
of many intrathoracic and chest wall malignancies. With carefully targeted
modern radiation therapy, most patients remain without symptoms and with
minimal clinical manifestations of radiation-related changes. Children are
particularly sensitive to the effects of radiotherapy because of rapid lung
development, and pulmonary function abnormalities are common with
radiation in children old enough to perform pulmonary function tests.48
Radiation pneumonitis has an insidious onset and may manifest as a nonpro-
ductive cough, dyspnea on exertion, low-grade fever, pleuritic or substernal
chest pain, malaise, and weight loss. Physical examination may reveal crackles
or a pleural rub, dullness to percussion if with effusion, and skin erythema
outlining the radiation port. Tachypnea, cyanosis, and signs of pulmonary
hypertension may be seen in advanced cases. Pulmonary function testing
reveals a reduction in lung volumes, diffusing capacity, and lung compliance.
Radiographic changes are generally confined to the field of irradiation. Ini-
tially, there is a diffuse haze in the irradiated region with obscuring of vascular
outlines. Patchy consolidations appear and then coalesce to form a relatively
sharp edge that conforms to the treatment portals. These changes may clear
gradually and disappear completely but may lead to fibrous changes in the
case of severe injury.
Fibrous changes take 6 to 24 months to evolve but usually remain stable after
2 years. Chronic radiation fibrosis is indicated by findings of a well-defined
area of atelectasis with parenchymal distortion, traction, bronchiectasis,
mediastinal shift, or pleural thickening.
The diagnosis is based on history of exposure, including target, dose, and
technique, with consideration of clinical symptoms, imaging findings, timing
from completion of radiation therapy, laboratory studies, and exclusion of

923
alternate diagnoses such as infection. Treatment approaches generally include

systemic corticosteroids for patients with symptoms.49
Pulmonary Complications of Hematopoietic Stem Cell Transplant

Hematopoietic stem cell transplant has made major progress as therapy after
chemotherapy and radiation for several hematologic and nonhematologic
malignancies. Hematopoietic stem cell transplant is a general term that covers
transplant of progenitor cells from any source, such as bone marrow, periph-
eral blood, or umbilical cord, and can be either an autologous (self) or
allogeneic (nonself) stem cell source.
Infectious and noninfectious pulmonary complications after HSCT have been
well described and can lead to clinically significant morbidity and mortality
in children and adolescents both in the short term and throughout long-term
follow-up. Noninfectious complications include idiopathic pneumonia syn-
drome (IPS), diffuse alveolar damage, and chronic graft-vs-host disease
(GVHD) and bronchiolitis obliterans syndrome (BOS).
Infectious complications are common after HSCT, and the type of infection
risk varies with the underlying disease indication for HSCT, cell source, pre-
parative regimen (nonablative vs myeloablative conditioning), and time from
transplant. Infections are more common early after HSCT, especially before
engraftment; however, infections can occur later in the course, especially
in patients who have impaired immune reconstitution or develop GVHD.
Infections include bacterial, viral, and invasive fungal disease. Noninfectious
pulmonary complications can have early or late onset. Early onset is most
commonly associated with IPS, which is an acute lung injury with a median
onset at 21 days after transplant. Idiopathic pneumonia syndrome is defined
by widespread alveolar injury without lower respiratory tract infection and
the absence of pulmonary symptoms secondary to cardiogenic or renal causes.
The syndrome may include chemotherapy-induced acute interstitial pneumo-
nitis, acute respiratory distress syndrome, damaged vascular endothelium
secondary to engraftment-related respiratory distress syndrome, and diffuse
alveolar hemorrhage.50,51 Risk factors include myeloablative conditioning,
severe GVHD, acute GVHD, and an underlying diagnosis of acute leukemia
or myelodysplastic syndrome. Critical care respiratory support, including
mechanical ventilation, is often required in patients with IPS. Treatment
includes high-dose systemic corticosteroids, as well as tumor necrosis
factor α inhibition with etanercept, often with the addition of inhaled
fluticasone, montelukast, and azithromycin and supportive care.52,53
Other examples of early-onset pulmonary complications include periengraft-
ment respiratory distress syndrome, diffuse alveolar hemorrhage, cryptogenic
organizing pneumonia, secondary pulmonary alveolar proteinosis, and
drug-induced pneumonitis.

924
Late-onset, noninfectious pulmonary complications occur in up to 20% of

recipients of HSCT. They can involve the airway, lung parenchyma, pleura,
and vessels. Pulmonary function testing and chest CT are important in the
diagnosis.54 Bronchiolitis obliterans syndrome is the most frequent of the
noninfectious late-onset complications. It typically occurs within the first
2 years after HSCT, although most often after the third month. Pulmonary
function testing and high-resolution CT have replaced lung biopsy for the
diagnosis of post-HSCT BOS and rely on the National Institutes of Health
consensus criteria.54 Overall, the morbidity and mortality associated with
post-HSCT BOS remains high.
Other late-onset pulmonary complications after HSCT include interstitial
lung diseases, organizing pneumonia, and pulmonary vascular disease.
Pulmonary function testing before HSCT is important because baseline
impairments are associated with higher complications and mortality rates
after transplant; the testing should be performed serially to allow early
detection of lung dysfunction and facilitate early interventions.55
Long-term Pulmonary Outcomes

After Childhood Cancer
Outcomes data available as of January 2018 show approximately 483,000
childhood cancer survivors alive in the United States.2 A large-scale, long-
term population-based study of survivors of childhood, adolescent, and young
adult cancers showed a sevenfold increase in the risk of respiratory mortality
in survivors of childhood cancers compared with that in the general popula-
tion, and a twofold increase in the risk in respiratory mortality was seen in
survivors of adolescent and young adult cancers. In addition, an increased
number of excess respiratory deaths were found as survivors aged, although
the excess number of respiratory deaths decreased in patients treated in later
cohorts.56 In the largest cohort study of long-term survivors, the St. Jude
Lifetime Cohort Study, pulmonary function abnormalities were common
(31% with restrictive defects) and were associated with decreased physical
functioning.57 Given a slightly increasing incidence of childhood cancers and
overall improvement in survival, we can anticipate that the number of adult
survivors with pulmonary complications will continue to increase.2

925
key points
} Malignant disease is an infrequent cause of pulmonary disease in children.
} Primary tumors of the airways, mediastinum, and lung parenchyma usually
manifest with nonspecific symptoms such as cough, wheezing, dyspnea,
and chest pain.
} A variety of pediatric tumors may metastasize to the lungs and are often seen
radiographically as pulmonary nodules.
} Leukemias and lymphomas are the major systemic malignancies with
pulmonary involvement in children.
} Pediatric cancer therapies, including some chemotherapeutic agents, radiation
therapy, and bone marrow transplant, are all associated with substantial
pulmonary morbidities.
} Monitoring the pulmonary function can be useful in identifying early changes
resulting from pediatric cancer therapies.
References
1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin.
2021;71(1):7–33 PMID: 33433946 doi: 10.3322/caac.21654
2. Lewis DR, Chen HS, Feuer EJ, Cronin KA, eds. SEER Cancer Statistics Review (CSR),
1975–2018. National Cancer Institute. Updated April 15, 2021. Accessed January 5, 2023.
https://seer.cancer.gov/archive/csr/1975_2018/
3. Tran TH, Hunger SP. The genomic landscape of pediatric acute lymphoblastic leukemia and
precision medicine opportunities. Semin Cancer Biol. 2022;84:144–152 PMID: 33197607
doi: 10.1016/j.semcancer.2020.10.013
4. Elgarten CW, Aplenc R. Pediatric acute myeloid leukemia: updates on biology, risk stratification,
and therapy. Curr Opin Pediatr. 2020;32(1):57–66 PMID: 31815781
doi: 10.1097/MOP.0000000000000855
5. Lichtman MA, Rowe JM. Hyperleukocytic leukemias: rheological, clinical, and therapeutic
considerations. Blood. 1982;60(2):279–283 PMID: 7046844 doi: 10.1182/blood.V60.2.279.279
6. Bewersdorf JP, Zeidan AM. Hyperleukocytosis and leukostasis in acute myeloid leukemia: can
a better understanding of the underlying molecular pathophysiology lead to novel treatments?
Cells. 2020;9(10):2310 PMID: 33080779 doi: 10.3390/cells9102310
7. Creutzig U, Rössig C, Dworzak M, et al. Exchange transfusion and leukapheresis in pediatric
patients with AML with high risk of early death by bleeding and leukostasis. Pediatr Blood
Cancer. 2016;63(4):640–645 PMID: 26670831 doi: 10.1002/pbc.25855
8. Stephanos K, Dubbs SB. Pediatric hematologic and oncologic emergencies. Emerg Med Clin
North Am. 2021;39(3):555–571 PMID: 34215402 doi: 10.1016/j.emc.2021.04.007
9. Guest EM, Stam RW. Updates in the biology and therapy for infant acute lymphoblastic
leukemia. Curr Opin Pediatr. 2017;29(1):20–26 PMID: 27841777
doi: 10.1097/MOP.0000000000000437
10. Ibrahimova A, Pommert L, Breese EH. Acute leukemia in infants. Curr Oncol Rep.
2021;23(3):27 PMID: 33580326 doi: 10.1007/s11912-021-01021-1
11. Merli P, Algeri M, Del Bufalo F, Locatelli F. Hematopoietic stem cell transplantation in pediatric
acute lymphoblastic leukemia. Curr Hematol Malig Rep. 2019;14(2):94–105 PMID: 30806963
doi: 10.1007/s11899-019-00502-2
12. Hochberg J, Flower A, Brugieres L, Cairo MS. NHL in adolescents and young adults: a unique
population. Pediatr Blood Cancer. 2018;65(8):e27073 PMID: 29741220 doi: 10.1002/pbc.27073
13. Jaggers J, Balsara K. Mediastinal masses in children. Semin Thorac Cardiovasc Surg.
2004;16(3):201–208 PMID: 15619186 doi: 10.1053/j.semtcvs.2004.08.005

926
14. Biko DM, Lichtenberger JP III, Rapp JB, Khwaja A, Huppmann AR, Chung EM. Mediastinal
masses in children: radiologic-pathologic correlation. Radiographics. 2021;41(4):1186–1207
PMID: 34086496 doi: 10.1148/rg.2021200180
15. Carter BW. International Thymic Malignancy Interest Group model of mediastinal
compartments. Radiol Clin North Am. 2021;59(2):149–153 PMID: 33551077
doi: 10.1016/j.rcl.2020.11.007
16. Anghelescu DL, Burgoyne LL, Liu T, et al. Clinical and diagnostic imaging findings predict
anesthetic complications in children presenting with malignant mediastinal masses. Paediatr
Anaesth. 2007;17(11):1090–1098 PMID: 17897276 doi: 10.1111/j.1460-9592.2007.02279.x
17. Young S, Rettig RL, Hutchinson IV, Sutcliffe MG, Sydorak RM. Surgical approach to pediatric
mediastinal masses based on imaging characteristics. Pediatr Surg Int. 2022;38(9):1297–1302
PMID: 35794495 doi: 10.1007/s00383-022-05166-3
18. Strollo DC, Rosado de Christenson ML, Jett JR. Primary mediastinal tumors. Part 1: tumors of
the anterior mediastinum. Chest. 1997;112(2):511–522 PMID: 9266892
doi: 10.1378/chest.112.2.511
19. Sandlund JT, Martin MG. Non-Hodgkin lymphoma across the pediatric and adolescent and
young adult age spectrum. Hematology (Am Soc Hematol Educ Program). 2016;2016(1):589–597
PMID: 27913533 doi: 10.1182/asheducation-2016.1.589
20. Casagrande A, Pederiva F. Association between congenital lung malformations and lung
tumors in children and adults: a systematic review. J Thorac Oncol. 2016;11(11):1837–1845
PMID: 27423390 doi: 10.1016/j.jtho.2016.06.023
21. Pio L, Varela P, Eliott MJ, et al. Pediatric airway tumors: a report from the International Network
of Pediatric Airway Teams (INPAT). Laryngoscope. 2020;130(4):E243–E251 PMID: 31090942
doi: 10.1002/lary.28062
22. Varela P, Pio L, Torre M. Primary tracheobronchial tumors in children. Semin Pediatr Surg.
2016;25(3):150–155 PMID: 27301601 doi: 10.1053/j.sempedsurg.2016.02.013
23. Varela P, Pio L, Brandigi E, et al. Tracheal and bronchial tumors. J Thorac Dis.
2016;8(12):3781–3786 PMID: 28149577 doi: 10.21037/jtd.2016.12.67
24. Eyssartier E, Ang P, Bonnemaison E, et al. Characteristics of endobronchial primitive tumors in
children. Pediatr Pulmonol. 2014;49(6):E121–E125 PMID: 24532419 doi: 10.1002/ppul.22987
25. Fauroux B, Aynie V, Larroquet M, et al. Carcinoid and mucoepidermoid bronchial tumours in
children. Eur J Pediatr. 2005;164(12):748–752 PMID: 16133240 doi: 10.1007/s00431-005-1740-x
26. Neville HL, Hogan AR, Zhuge Y, et al. Incidence and outcomes of malignant pediatric lung
neoplasms. J Surg Res. 2009;156(2):224–230 PMID: 19631347 doi: 10.1016/j.jss.2009.03.100
27. Stachowicz-Stencel T, Orbach D, Brecht I, et al. Thymoma and thymic carcinoma in children and
adolescents: a report from the European Cooperative Study Group for Pediatric Rare Tumors
(EXPeRT). Eur J Cancer. 2015;51(16):2444–2452 PMID: 26259494
doi: 10.1016/j.ejca.2015.06.121
28. Potter SL, HaDuong J, Okcu F, Wu H, Chintagumpala M, Venkatramani R. Pediatric bronchial
carcinoid tumors: a case series and review of the literature. J Pediatr Hematol Oncol.
2019;41(1):67–70 PMID: 29432305 doi: 10.1097/MPH.0000000000001100
29. Dombrowski ND, Wolter NE, Irace AL, et al. Mucoepidermoid carcinoma of the head and neck
in children. Int J Pediatr Otorhinolaryngol. 2019;120:93–99 PMID: 30772619
doi: 10.1016/j.ijporl.2019.02.020
30. Krowchuk DP, Frieden IJ, Mancini AJ, et al; Subcommittee on the Management of Infantile
Hemangiomas. Clinical practice guideline for the management of infantile hemangiomas.
Pediatrics. 2019;143(1):e20183475 PMID: 30584062 doi: 10.1542/peds.2018-3475
31. Garzon MC, Epstein LG, Heyer GL, et al. PHACE syndrome: consensus-derived diagnosis and
care recommendations. J Pediatr. 2016;178:24.e2–33.e2 PMID: 27659028
doi: 10.1016/j.jpeds.2016.07.054
32. Fortes HR, von Ranke FM, Escuissato DL, et al. Recurrent respiratory papillomatosis: a
state-of-the-art review. Respir Med. 2017;126:116–121 PMID: 28427542
doi: 10.1016/j.rmed.2017.03.030
33. Messinger YH, Stewart DR, Priest JR, et al. Pleuropulmonary blastoma: a report on 350 central
pathology-confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary
Blastoma Registry. Cancer. 2015;121(2):276–285 PMID: 25209242 doi: 10.1002/cncr.29032
34. Zhang N, Zeng Q, Ma X, et al. Diagnosis and treatment of pleuropulmonary blastoma in
children: a single-center report of 41 cases. J Pediatr Surg. 2020;55(7):1351–1355

927
35. Seitz G, Urla C, Sparber-Sauer M, et al. Treatment and outcome of patients with thoracic tumors
of the Ewing sarcoma family: a report from the Cooperative Weichteilsarkom Studiengruppe
CWS-81, -86, -91, -96, and -2002P trials. Pediatr Blood Cancer. 2019;66(3):e27537
PMID: 30421578 doi: 10.1002/pbc.27537
36. La Quaglia MP. Chest wall tumors in childhood and adolescence. Semin Pediatr Surg.
37. Girelli L, Luksch R, Podda MG, et al. Surgical approach to primary tumors of the chest wall in
children and adolescents: 30 years of mono-institutional experience. Tumori. 2016;102(1):89–95
PMID: 26357972 doi: 10.5301/tj.5000416
38. Fuchs J, Seitz G, Handgretinger R, Schäfer J, Warmann SW. Surgical treatment of lung
metastases in patients with embryonal pediatric solid tumors: an update. Semin Pediatr Surg.
39. Croteau NJ, Heaton TE. Pulmonary metastasectomy in pediatric solid tumors. Children (Basel).
2019;6(1):6 PMID: 30626161 doi: 10.3390/children6010006
40. Leger P, Limper AH, Maldonado F. Pulmonary toxicities from conventional chemotherapy.
41. Visscher H, Otth M, Feijen EAML, Nathan PC, Kuehni CE. Cardiovascular and pulmonary
challenges after treatment of childhood cancer. Pediatr Clin North Am. 2020;67(6):1155–1170
PMID: 33131539 doi: 10.1016/j.pcl.2020.07.007
42. Zhong L, Altan M, Shannon VR, Sheshadri A. Immune-related adverse events: pneumonitis.
Adv Exp Med Biol. 2020;1244:255–269 PMID: 32301020 doi: 10.1007/978-3-030-41008-7_13
43. Altan M, Zhong L, Shannon VR, Sheshadri A. Pulmonary toxicities of immunotherapy.
Adv Exp Med Biol. 2021;1342:357–375 PMID: 34972974 doi: 10.1007/978-3-030-79308-1_14
44. Dadu R, Zobniw C, Diab A. Managing adverse events with immune checkpoint agents.
Cancer J. 2016;22(2):121–129 PMID: 27111908 doi: 10.1097/PPO.0000000000000186
45. Gharwan H, Groninger H. Kinase inhibitors and monoclonal antibodies in oncology: clinical
implications. Nat Rev Clin Oncol. 2016;13(4):209–227 PMID: 26718105
doi: 10.1038/nrclinonc.2015.213
46. Peerzada MM, Spiro TP, Daw HA. Pulmonary toxicities of tyrosine kinase inhibitors.
Clin Adv Hematol Oncol. 2011;9(11):824–836 PMID: 22252615
47. Peerzada MM, Spiro TP, Daw HA. Pulmonary toxicities of biologics: a review. Anticancer
Drugs. 2010;21(2):131–139 PMID: 20016372 doi: 10.1097/CAD.0b013e328333d662
48. Khan F, Williams AM, Weiner DJ, Constine LS. Impact of respiratory developmental stage on
sensitivity to late effects of radiation in pediatric cancer survivors. Adv Radiat Oncol.
2019;5(3):426–433 PMID: 32529137 doi: 10.1016/j.adro.2019.12.002
49. Hanania AN, Mainwaring W, Ghebre YT, Hanania NA, Ludwig M. Radiation-induced lung
injury: assessment and management. Chest. 2019;156(1):150–162 PMID: 30998908
doi: 10.1016/j.chest.2019.03.033
50. Clark JG, Hansen JA, Hertz MI, Parkman R, Jensen L, Peavy HH. NHLBI workshop summary.
Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev Respir Dis.
1993;147(6 pt 1):1601–1606 PMID: 8503576 doi: 10.1164/ajrccm/147.6_Pt_1.1601
51. Panoskaltsis-Mortari A, Griese M, Madtes DK, et al; American Thoracic Society Committee on
Idiopathic Pneumonia Syndrome. An official American Thoracic Society research statement:
noninfectious lung injury after hematopoietic stem cell transplantation: idiopathic pneumonia
syndrome. Am J Respir Crit Care Med. 2011;183(9):1262–1279 PMID: 21531955
doi: 10.1164/rccm.2007-413ST
52. Yanik GA, Ho VT, Levine JE, et al. The impact of soluble tumor necrosis factor receptor
etanercept on the treatment of idiopathic pneumonia syndrome after allogeneic hematopoietic
stem cell transplantation. Blood. 2008;112(8):3073–3081 PMID: 18664626
doi: 10.1182/blood-2008-03-143412
53. Yanik GA, Grupp SA, Pulsipher MA, et al. TNF-receptor inhibitor therapy for the treatment of
children with idiopathic pneumonia syndrome. A joint Pediatric Blood and Marrow Transplant
Consortium and Children’s Oncology Group Study (ASCT0521). Biol Blood Marrow Transplant.
2015;21(1):67–73 PMID: 25270958 doi: 10.1016/j.bbmt.2014.09.019
54. Tamburro RF, Cooke KR, Davies SM, et al. Pulmonary Complications of Pediatric
Hematopoietic Stem Cell Transplantation Workshop Participants. Pulmonary complications
of pediatric hematopoietic cell transplantation. A National Institutes of Health workshop
summary. Ann Am Thorac Soc. 2021;18(3):381–394 PMID: 33058742
doi: 10.1513/AnnalsATS.202001-006OT

928
55. Bondeelle L, Bergeron A. Managing pulmonary complications in allogeneic hematopoietic stem

cell transplantation. Expert Rev Respir Med. 2019;13(1):105–119 PMID: 30523731
doi: 10.1080/17476348.2019.1557049
56. Fidler MM, Reulen RC, Bright CJ, et al; British Childhood Cancer Survivor Study (BCCSS)
Steering Group. Respiratory mortality of childhood, adolescent and young adult cancer
survivors. Thorax. 2018;73(10):959–968 PMID: 29748251 doi: 10.1136/thoraxjnl-2017-210683
57. Green DM, Zhu L, Wang M, et al. Pulmonary function after treatment for childhood cancer.
A report from the St. Jude Lifetime Cohort Study (SJLIFE). Ann Am Thorac Soc.
2016;13(9):1575–1585 PMID: 27391297 doi: 10.1513/AnnalsATS.201601-022OC

CHAPTER
53
Pulmonary Complications of Immunologic Disorders
Jay Jin, MD, PhD
Introduction
The respiratory tract is continuously exposed to pathogens through inhalation.
To protect against infection, the lungs have a variety of defense mechanisms,
including a mucociliary barrier, the innate immune system, and the adaptive
immune system. This chapter focuses on pulmonary complications arising from
congenital and acquired defects in innate and adaptive immunity. This chapter
does not address the diagnostic workup of suspected immunologic conditions,
which should be undertaken in collaboration with an experienced immunologist.
Each component of the immune system serves a specific role in host defense. A
deficiency in any one element of the immune system renders individuals suscep-
tible to specific groups of pathogens. Table 53-1 summarizes the pattern of
infections seen in children with different immunodeficiency syndromes.
Table 53-1. Typical Pathogens Associated With Specific Congenital Immunodeficienciesa

Element of the Immune Typical Pulmonary
System Affected Example Diseases Pathogens
Neutrophils Chronic granulomatous disease Aspergillus fumigatus
Staphylococcus aureus
Nocardia sp
Burkholderia sp
B lymphocytes X-linked (Bruton) Streptococcus pneumoniae
agammaglobulinemia Hemophilus influenzae
Common variable
immunodeficiency
Specific antibody deficiency
T lymphocytes Severe: Severe combined Pneumocystis jirovecii pneumonia
immunodeficiency, AIDS Viruses, fungi
Less severe: Ataxia-telangiectasia, Bacterial pneumonia
Wiskott-Aldrich syndrome
a
This table is not intended to provide a comprehensive list of immunologic disorders.
929

930
Infectious Complications of Immunodeficiency

Complications of Neutrophil Defects
Polymorphonuclear neutrophils (PMNs) are the primary phagocytic cells of
the immune system. They play a key role in eliminating opsonized bacterial
and fungal pathogens through release of proteolytic enzymes and reactive
oxidant species. This function may be impaired through abnormalities in
cell adhesion, cell signaling, cell number, granule function or formation,
and intracellular killing.1,2
Chronic Granulomatous Disease
The most common PMN disorder is chronic granulomatous disease (CGD),
with an estimated prevalence of 1 in 200,000 in the United States.1,3 The
primary defect in CGD is a loss of nicotinamide adenine dinucleotide phos-
phate (NADPH) oxidase function. Chronic granulomatous disease exists in
X-linked and autosomal recessive forms, depending on which gene coding
for the NADPH oxidase complex is mutated; the X-linked form is more com-
mon. Loss of NADPH oxidase activity leads to a markedly reduced oxidative
burst following phagocytosis. Polymorphonuclear neutrophils from patients
with CGD can phagocytose bacteria but cannot kill them. The most common
organisms that cause pulmonary infections in CGD are Aspergillus species,
Staphylococcus aureus, Burkholderia cepacia complex, Nocardia species,
and Serratia marcescens.1
Patients with CGD present with atypical or unusually severe lymphadenitis,
skin abscesses, pneumonia, or osteomyelitis secondary to infections with
the aforementioned agents. Hepatosplenomegaly due to non-cirrhotic portal
hypertension is common as well. In addition, patients with CGD often develop
granulomas involving a number of different organs, including the bladder,
gastrointestinal tract, and lungs. Chronic granulomatous disease colitis can be
mistaken for Crohn disease. Data from a national registry of 368 patients with
CGD in the United States and 268 patients with CGD followed at the National
Institutes of Health (NIH) provide considerable insight into the pulmonary
complications of CGD.4,5 Eighty percent of the patients in the US registry and
87% in the NIH cohort have had pneumonia at least once. Aspergillus was
the most common causative organism, responsible for 41% to 55% of pneumo-
nias. In the US registry, Staphylococcus species caused 12% of pneumonias.
Burkholderia cepacia was the third most common cause of pneumonia (8%)
but the second most common cause of death (18%). Other pathogens reported
to cause pneumonia in these patients include Nocardia, mycobacteria, and
gram-negative bacteria. Pulmonary abscesses also occur frequently in
patients with CGD. Sixteen percent of patients in the registry had a lung
abscess. Of those, the most common organism isolated was Aspergillus (23%),
although Nocardia species, B cepacia, and Staphylococcus species can also
cause abscesses.4

931
Chapter 53—Pulmonary Complications of Immunologic Disorders
Aspergillus pneumonia with or without dissemination was the most common

cause of death in patients with CGD, causing 35% of deaths in the US registry.
Fungal infection was also the most common cause of mortality in the NIH
cohort, with an Aspergillus-specific mortality rate of 9%. It should be noted,
however, that the US registry was published prior to a large study showing
that antifungal prophylaxis was effective and thus leading to widespread use
of azoles for Aspergillus prophylaxis.6 Accordingly, the updated NIH cohort
showed that the overall rate of infections has decreased fourfold and the age
at death has increased by almost 15 years since 1991. These improvements in
morbidity and mortality have been attributed to effective infection prophylaxis,
including the use of azole antifungals, trimethoprim-sulfamethoxazole, and
interferon-gamma.1,6,7
In the active evaluation of respiratory infection in a patient with CGD, deter-
mination of the infecting microbe is still of great importance, as prophylaxis
regimens may affect antimicrobial sensitivity patterns. Additionally, con-
sultation with an immunologist and stem cell transplant physician may be
beneficial, as stem cell transplant is an option for selected CGD patients.
Other Neutrophil Disorders
Other PMN disorders include hyper-immunoglobulin (Ig) E syndrome
(also known as Job syndrome) and Chediak-Higashi syndrome.1 Hyper-IgE
syndrome is a rare disorder caused by heterozygous mutations in an intra-
cellular signaling protein (STAT3). Patients typically present with charac-
teristic facial features, recurrent skin infections, and extremely high serum
IgE levels (typically > 2,000 ku/L). A hallmark feature of pulmonary infection
associated with the hyper-IgE syndrome is the formation of pneumatoceles
and bronchiectasis. Although S aureus is the most common organism causing
pneumonia in those with hyper-IgE syndrome initially, after pneumatoceles
and bronchiectasis are present, these patients are predisposed to gram-negative
pulmonary infections (frequently Pseudomonas), mold infection (typically
Aspergillus), and nontuberculous mycobacteria. Alterations to STAT3 func-
tion affects maturation of Th17 cells and neutrophil chemotaxis. These defects
are thought to confer the pattern of infection susceptibility seen in this condi-
tion. These infections are the main source of morbidity and mortality for these
individuals. Chediak-Higashi syndrome is an autosomal recessive disorder
resulting from mutations in a lysosomal protein transport gene. Patients with
Chediak-Higashi syndrome have multiple abnormalities, including reduced
PMN phagocytosis and chemotaxis. In general, pulmonary complications in
these disorders are pneumonias but not pneumatoceles or bronchiectasis.

932
Complications of B Lymphocyte Disorders

B lymphocytes are the only source of Ig, or antibody.8 There are 5 different Ig
isotypes: IgM, IgG, IgA, IgD, and IgE. B cells initially express only surface
IgM and IgD but, with appropriate T-lymphocyte help, they will switch to
making other isotypes. Immunoglobulins play a key role in the opsonization
and clearance of encapsulated bacterial organisms. Thus, patients with B-cell
deficiencies are prone to infection with these organisms, primarily Strepto-
coccus pneumoniae (pneumococcus) and Hemophilus influenzae. In contrast,
because T-cell function is intact, patients tend to have normal defenses against
viruses, fungi, and mycobacteria. Because maternal IgG crosses the placental
barrier, babies with B-cell disorders receive passive protection from infec-
tion for the first 3 to 6 months after birth. After this age, patients will present
with recurrent bacterial infections of the middle ear, sinuses, and lungs.
Complications such as mastoiditis are common. Sepsis and osteomyelitis
may also be seen.8
X-linked Agammaglobulinemia
The most severe forms of B-cell disorders arise from defects in B-cell develop-
ment, leading to virtual absence of circulating B cells. Of this group, X-linked
(Bruton) agammaglobulinemia (XLA) is the most common. The molecular
defect in XLA is due to mutations in the Bruton tyrosine kinase (BTK) gene.8
Absence of BTK results in a block in B-cell maturation at the pre–B-cell
stage. Thus, patients with XLA have essentially no circulating B cells and
make no antibody to antigenic stimulation/immunization. Pulmonary infec-
tions are very common in XLA, mainly due to S pneumoniae and H influen-
zae.9 In contrast to other B-cell disorders, patients with XLA can develop
Pneumocystis jirovecii pneumonia (PCP).8 The reason for this is unclear,
although it may be related to the role of B cells as antigen-presenting cells.
Alternatively, it may be that loss of BTK function leads to subtle defects
in cellular immunity.
Common Variable Immunodeficiency
Common variable immunodeficiency (CVID) is the name given to a hetero-
geneous group of disorders characterized by varying degrees of hypogamma-
globulinemia with or without other abnormalities of T-cell function.8 The
prevalence of CVID is estimated to be 1 in 50,000 to 1 in 200,000 individu-
als.10 Patients with CVID usually have normal numbers of B cells, but the
function of these cells is impaired. Other immunologic abnormalities that
can be seen in CVID include impaired lymphocyte proliferative response to
antigens, deficiency of antigen-primed T cells, increased macrophage activa-
tion, and reduced production or expression of cytokines. Common variable
immunodeficiency can frequently occur in older children or adults following

933
a viral infection; it is sometimes referred to as acquired hypogammaglobulin-

emia. Although patients with CVID may have subtle defects in T-cell function,
they usually do not develop opportunistic infections. More commonly, patients
with CVID are prone to recurrent bacterial infections, generally of the
sinopulmonary tract. Because the condition may present in later childhood
and the diagnosis may be delayed, many of these patients have bronchiectasis
at the time of presentation.10,11 Patients with CVID can also manifest a non-
infectious, interstitial lung disease termed granulomatous-lymphocytic inter-
stitial lung disease, which is characterized by non-necrotizing granulomas
and lymphoid hyperplasia within the lung parenchyma. The development
of granulomatous-lymphocytic interstitial lung disease portends a worse
prognosis in the 10% to 15% of patients who manifest this condition.12
Immunoglobulin A Deficiency
Immunoglobulin A deficiency is the most common antibody deficiency,
with an approximate incidence of 1 in 400 to 1 in 3,000 individuals, depend-
ing on the ethnicity of the population.8 Most patients with IgA deficiency
are asymptomatic, perhaps because of compensatory protection by IgG.
Those who are symptomatic are at increased risk of gastrointestinal and
sinopulmonary infections. Symptomatic IgA deficiency is often seen in
association with IgG subclass deficiency.
Treatment Modalities
The introduction of intravenous Ig (IVIG) replacement therapy has had a
significant effect on the morbidity and mortality of B-cell immunodeficien-
cies.8,13,14 Both IVIG and the more recently introduced subcutaneous IgG
(SCIG) are prepared from pooled plasma collected from a large number of
donors. As a blood product, IVIG does carry a potential risk for pathogen
transmission. However, improved purification protocols have rendered this
risk extremely small.14 Use of IVIG/SCIG therapy significantly reduces the
incidence and severity of pneumonia and other respiratory tract infections
in patients with XLA, CVID, and other antibody deficiency syndromes.13
However, bronchiectasis can still develop in some patients in spite of IVIG/
SCIG therapy11,13 (Figure 53-1). Some patients may require concurrent
treatment or prophylaxis with antimicrobial agents, but the risks of anti-
microbial resistance and selection of resistant organisms should be
taken into consideration.

934
Figure 53-1. Chest computed tomography (CT) image from an 11-year-old girl with common
variable immunodeficiency (CVID). This child was diagnosed with CVID at 3 years of age when
she presented with chronic respiratory infections. Intravenous immunoglobulin therapy was
started at that time. In the intervening years, she did not have acute episodes of pneumonia,
but she was seen by a pulmonologist because of a 1-year history of increasing cough. A chest
CT image was obtained. Consolidation and bronchiectasis of the right middle lobe can be
seen (blue arrow).
Pulmonary Infections Associated With T Lymphocyte Disorders

T lymphocytes play important roles in coordinating the adaptive immune
system and actively eliminating foreign pathogens.15 Because of the multiple
roles that T cells play in the immune system, impairment of their function
may have profound consequences for immunity. T cells can be divided into
multiple subclasses based on their cell-surface protein expression, gene
expression, and function. Cytotoxic T lymphocytes (CTLs) usually express
CD8 and are responsible for cell-mediated immune responses. Helper T (Th)
cells usually express the cell surface receptor CD4 and are critical for B-cell
activation and optimal antibody production. Helper T cells also coordinate the
activity of CTLs. Regulatory T cells (Tregs) express CD4, CD25 (the alpha
chain of the interleukin-2 receptor), and FOXP3, a forkhead transcription
factor. Tregs are thought to play a vital role in autoimmune and allergic
disease.16 FOXP3 is critical for the development of Tregs, and loss of FOXP3

935
function results in immune dysregulation, polyendocrinopathy, enteropathy,

and X-linked syndrome.17 There are many other T-cell subsets that have
recently been defined, but their role in primary immunodeficiency is not well
defined at this time. Secondary T-cell defects associated with HIV infection
are covered later in this chapter.
Severe Combined Immunodeficiency
Severe combined immunodeficiency (SCID) is the term used to identify the
most severe forms of T-cell disorders. Severe combined immunodeficiency
can result from a diverse array of genetic mutations that affect lymphocyte
production, development, metabolism, or cell signaling.15 Regardless of the
underlying genetic defect, the immunologic consequence is near total loss
of T-cell number or function. Because B lymphocytes and T lymphocytes
develop from a single lymphoid lineage, many cases of SCID are also
associated with absent B cells. In those cases with residual circulating
B cells, the lack of T-cell help renders them nonfunctional.
The loss of T-cell function in patients with SCID leads to their being suscep-
tible to opportunistic infections, such as PCP, fungi, and viruses. Patients with
SCID tend to present early in infancy because of the severe loss of immune
function. Pulmonary infections are a common initial presenting sign in SCID,
and up to 67% of patients with SCID present with pulmonary disease at diag-
nosis.18 In patients with pulmonary complaints at presentation, 60% present
with a persistent pulmonary infiltrate and chronic cough, while the other
40% present with more acute symptoms of respiratory distress secondary
to pneumonia. Pneumocystis jirovecii pneumonia is the most common cause
of pneumonia and is associated with significant mortality (43%). Bacterial
pneumonia can also occur, with Klebsiella pneumoniae, S pneumoniae, and
S aureus being the most common pathogens isolated. Viral infections contrib-
ute to morbidity and mortality in these patients and can include parainfluenza,
cytomegalovirus (CMV), adenovirus, and respiratory syncytial virus (RSV).
In patients who are not treated with immune reconstitution (which includes
bone marrow transplant, hematopoietic stem cell transplant, or gene therapy
in selected conditions), pulmonary disease and failure to thrive are significant
causes of morbidity and mortality. Subsequent pulmonary infection occurs in
80% to 100% of patients after initial diagnosis.18
The importance of early diagnosis of children with SCID cannot be over-
emphasized. Beginning in 2008 and concluding in 2018, all states in the
United States have adopted a newborn screening (NBS) program for SCID.
The screening assay quantifies T-cell receptor excision circles by polymerase
chain reaction to estimate the number of naive T cells at birth. If below a
specific threshold (determined by each state), these children are identified
as potentially having SCID and referred to a tertiary care center for further

936
evaluation. This screening test does not identify children with a primary
B-cell maturation defect, such as XLA.19
Besides SCID, immunodeficiency can also arise from other, less severe,
defects in T-cell function. Because some degree of residual T-cell function
persists in these other conditions, the severity of disease tends to be less than
that of SCID. Often, these less severe conditions with T-cell defects are also
identified by NBS for SCID because the initial T-cell receptor excision circle
quantification will be low.20 Early identification is preferable because pulmo-
nary complications continue to be common in this group of patients. In rare
cases, NBS for SCID may be falsely negative. In these instances, quantifica-
tion of T cells may reveal the possibility of SCID at a later time. A high index
of suspicion and early referral to a tertiary care center with immunologists
and stem cell transplant physicians should be strongly considered in any
infant with unusually severe, destructive, or difficult-to-treat infections.
Other T-Cell Disorders
DiGeorge Syndrome
DiGeorge syndrome results from errors in the formation of the third and fourth
pharyngeal pouches during embryogenesis, resulting in hypoplasia or complete
absence of the thymus and parathyroid glands.15 Other midline structures may
also be affected, such as the heart and great vessels, craniofacial bones and
tissues, and upper limbs. The immunologic defect is due to thymic dysplasia
and ranges from a severe depression of T-cell function in patients with no
thymus (complete DiGeorge syndrome), to near-normal function in patients
with mild thymic hypoplasia (partial DiGeorge syndrome). In contrast to
patients with SCID or complete DiGeorge syndrome, patients with partial
DiGeorge syndrome are not commonly infected with PCP. Bacterial pneu-
monia with gram-negative organisms is more commonly seen. Severe RSV
infections have also been reported. Complete DiGeorge syndrome requires
broad antimicrobial prophylaxis (similar to SCID) while awaiting thymus
transplantation to correct the underlying immunologic defect.
Wiskott-Aldrich Syndrome
Wiskott-Aldrich syndrome (WAS) is an X-linked recessive T-cell disorder
caused by mutations in the Wiskott-Aldrich syndrome protein (WASP) gene.21
The classic clinical triad of WAS is thrombocytopenia, eczema, and recurrent
bacterial infection. Although the exact function of WASP is still undetermined,
loss of WASP function results in an inability to generate antibody to polysac-
charide antigens. Patients with WAS are, therefore, susceptible to recurrent
infections with bacteria that form polysaccharide capsules, such as S pneumo-
niae and H influenzae. Although the sites of infection tend to be the middle
ear and sinuses, pneumonia can also be seen in this group of patients. Later
in life, there is also an increased incidence of PCP.

937
Ataxia-Telangiectasia
Ataxia-telangiectasia (A-T) is a complex multisystem autosomal recessive
syndrome with abnormalities of the nervous system, endocrine system, skin,
liver, and immune system.15 Immune dysfunction in A-T is variable and affects
both T and B cells. Although A-T is classified as a T-cell immunodeficiency,
B-cell dysfunction due to loss of T-cell help is the primary immune problem.
Immunoglobulin A and IgG subclass deficiencies are commonly seen in
patients with A-T. Pulmonary infections are a common complication in A-T
and are a significant cause of mortality. Pneumonia in patients with A-T tends
to be caused by bacteria, such as S pneumoniae, S aureus, H influenzae,
Mycoplasma pneumoniae, and Pseudomonas aeruginosa. Respiratory syn-
cytial virus and CMV can also cause lower respiratory tract infection in
these patients, but fungi, mycobacteria, and PCP are rarely pathogens in this
disease.15 The underlying defect in A-T involves a defect in DNA repair, and
patients with A-T are at high risk for the development of malignancy. In some
patients with A-T, pulmonary lymphoma has led to cavitary lesions on chest
radiographs that were mistaken for pneumonia.22 It is, therefore, important to
consider the possibility of malignancy when evaluating patients with A-T and
pulmonary symptoms and to pursue an appropriate investigation.
Hyper-IgM Syndrome
Hyper-IgM (HIgM) syndrome is characterized by normal or elevated serum
IgM levels with decreased or absent levels of IgG, IgA, and IgE.15 Hyper-IgM
syndrome exists in both an X-linked and autosomal recessive form. About
55% to 65% of the patients have the X-linked form that is caused by muta-
tions in the gene for CD40 ligand (CD154), a T-cell surface molecule critical
for induction of B-cell isotype switch. Because of the absence of CD154, B
cells from patients with X-linked HIgM can only make IgM, with little or
no production of other Ig isotypes. An autosomal recessive form also exists
associated with a defect in CD40, the receptor for CD40 ligand. In addition,
there are autosomal recessive forms that are caused by mutations in at least
3 different genes involved directly in B-cell isotype switch. Bacterial pneumo-
nia is the most common pulmonary complication in HIgM syndrome, but PCP
and other opportunistic infections are seen in the X-linked form and in CD40
deficiency, indicating that CD154/CD40 interaction also plays a role in T-cell
innate immune cell interaction.
Noninfectious Pulmonary Complications

of Immunodeficiency
In addition to impaired host defense, patients with immunodeficiency can also
develop dysregulated immune responses.23 Noninfectious pulmonary diseases
that have been reported in association with immunodeficiency include intersti-
tial lung disease, organizing pneumonia, and hypersensitivity pneumonitis.

938
The presumed mechanism for these disorders is that defects that result in
an impaired ability to generate a protective adaptive immune response
may also result in excessive inflammatory responses. Common variable
immunodeficiency and A-T are the most common conditions associated with
the aforementioned disorders,8,15 although they have been reported in other
immunodeficiencies.24 Pulmonary and mediastinal adenopathy as well as
lymphoma have also been reported in patients with antibody deficiency,
cellular immune deficiencies, and DNA-repair defects. The hypothesized
causes of the malignancy in these patients are susceptibility to Epstein-Barr
virus infection, ineffective surveillance by dysfunctional natural killer cells
and CTLs, and sensitivity to ionizing radiation. Any findings of mediastinal
lymphadenopathy should be carefully evaluated for the possibility of a
lymphoproliferative process. Graft-vs-host disease can also be seen in
patients who have undergone a bone marrow transplant.25
Pulmonary Complications Associated With HIV Infection

Globally, HIV infection is the most common cause of acquired immunodefi-
ciency.26 HIV infects CD4-positive T helper (Th) cells, leading to their loss.
As HIV infection progresses, patients have a near total depletion of CD4
T cells. The loss of Th cells impairs both CTL function and B-cell function.
Infectious Complications of HIV Infection

Pneumocystis jirovecii pneumonia is one of the most common complica-
tions of HIV26,27 and may be the presenting feature in infancy. Pneumocystis
jirovecii pneumonia infections in patients infected with HIV carry a high
degree of morbidity and mortality.26 Prophylaxis against PCP is an important
part of HIV treatment and can be accomplished with either trimethoprim-
sulfamethoxazole or inhaled pentamidine.
In endemic areas of developing nations, Mycobacterium tuberculosis has
emerged as a major pulmonary complication and cause of death in patients
infected with HIV.26 Tuberculosis infections tend to be more severe and
difficult to treat in patients infected with HIV. These infections can also
be paucibacillary, making it harder to diagnose and detect antimicrobial
resistance. Non-tuberculous mycobacteria, such as Mycobacterium avium
complex (MAC), can also cause disseminated disease in adults with HIV. In
contrast, the incidence of severe pulmonary MAC disease is less in children
infected with HIV.28
Respiratory viral infections are another common complication in HIV infec-
tion. Respiratory syncytial virus, influenza A and B, and parainfluenza viruses
can all cause severe lung disease in infants infected with HIV.29 Cytomegalo-
virus can also cause pulmonary disease. However, because CMV is often shed
asymptomatically, the diagnosis of true pneumonitis should rest on evidence

939
of systemic dissemination (eg, retinitis or hepatitis) or demonstration of viral

inclusion bodies in lung biopsy specimens.
The other major group of respiratory pathogens in individuals infected
with HIV is fungi. Histoplasmosis infection is rare, but, when present, it
occurs as disseminated disease that often includes reticulonodular, miliary,
or lobar infiltrates. It can often progress to septic shock and death if untreated.
Cryptococcus and Coccidioides species can also cause pulmonary disease.
Pulmonary aspergillosis is rare and presents as invasive pulmonary disease
rather than as aspergilloma; this can be life-threatening, with poor prognosis
despite antifungal therapy.30
Although patients with HIV primarily experience opportunistic infections as
a consequence of their loss of cellular immunity, bacterial infections are also
common, especially in children.27,28,30 These occur despite normal or even ele-
vated Ig levels in patients with HIV, because the loss of CD4-positive Th cells
results in a failure to generate effective specific antibody titers. S pneumoniae
is the most common cause of bacterial pneumonia in this patient population.
Other common organisms include S aureus, group A Streptococcus,
Escherichia coli, P aeruginosa, H influenzae, and Salmonella.
Noninfectious Complications of HIV Infection

Dysregulation of the immune system is another consequence of HIV infection,
leading to an increased incidence of noninfectious disorders of the lung.26,27
In children, the most common noninfectious pulmonary complication is
lymphocytic interstitial pneumonitis (LIP). The precise pathogenesis of LIP
is unknown. It is thought to represent a dysregulated immunologic response
to Epstein-Barr virus infection. Between 30% and 40% of children who were
perinatally infected will have LIP, with an average age of 2.3 years at presen-
tation. Typically, patients with LIP present with gradual onset of cough and
dyspnea. Generalized lymphadenopathy and clubbing are associated clinical
findings. The chest radiograph demonstrates diffuse reticulonodular densities,
frequently with hilar adenopathy. Lymphocytic interstitial pneumonitis is
usually quite responsive to systemic corticosteroid therapy, which is the first
line of treatment for this condition. The condition may recur, requiring
repetitive courses of oral corticosteroids.
In addition to LIP, a nonspecific interstitial pneumonitis can also occur in
patients infected with HIV, although this is less common in children. Non-
specific interstitial pneumonitis is thought to result from localized CTL
activity against HIV-infected cells in the lung parenchyma. Therefore, it
is more commonly seen early in HIV infection, when there is still some
residual CD4-positive T-cell activity present. However, it can occur at
any stage of the disease.

940
Pulmonary Complications Related to HIV Therapy

Combined antiretroviral therapy against HIV infection was introduced in the
mid-1990s and has had a dramatic effect on the prognosis and clinical course
of HIV infection.26 One result of increased survival has been the increased
incidence of chronic lung diseases, such as bronchiectasis.31 The restoration of
immune function in patients with previously long-standing immunodeficiency
has also led to unexpected complications resulting from either exuberant
inflammatory responses or unmasking of latent opportunistic infections.32,33
As immune function is restored, there is an increased inflammatory response
against underlying latent mycobacterial infections (Mycobacterium tuberculo-
sis and MAC). Highly active antiretroviral therapy may also be associated
with reactivation of latent PCP, leading to acute respiratory failure. Noninfec-
tious complications that have been reported with combined antiretroviral
therapy include a sarcoid-like syndrome, hypersensitivity pneumonitis, and
pulmonary hypertension.33,34 Notably, newer antiretrovirals (integrase strand
inhibitors) have fewer reported hypersensitivity complications. Although most
published reports have focused on adult patients, it is likely that this same
phenomenon will be seen in children as combined antiretroviral therapy
increasingly becomes the standard of care in HIV treatment.
Pulmonary Evaluation of the Patient

With Immunodeficiency
The approach to evaluating a patient with immunodeficiency is summarized
in Box 53-1. The evaluation begins with a thorough history and physical
examination. The history should focus on symptoms of chronic infection or
bronchiectasis. The patient or patient’s parents should be questioned about the
presence of cough and sputum production. However, patients with impaired
host responses often do not feel as sick as they are, and they are often much
less symptomatic than their degree of infection would cause in a normal host.
Symptoms of wheezing may suggest an asthma or reactive airways disease
component. Elements of the physical examination of particular importance
include the patient’s height and weight, chest examination, and extremity
examination. The height and weight provide important information about
the patient’s nutritional status, which may be compromised in the setting of
chronic pulmonary disease. Auscultation of the chest is important to identify
areas of localized crackles or wheezes. The presence of digital clubbing on
extremity examination is an indication of underlying bronchiectasis or hypox-
emia. Other important aspects of the physical examination include evidence
of skin infections, absence of lymphoid tissue (eg, tonsils and lymph nodes),
and evidence of chronic or frequently recurring otitis media.

941
Radiography is an important tool in the evaluation of pulmonary disease

in patients with immunodeficiencies. Plain chest radiographs can reveal
areas of atelectasis or infiltrate. Although large areas of bronchiectasis can
be seen by plain radiographs, high-resolution computed tomography is
a more sensitive tool for the detection of early or mild bronchiectasis.35,36
Computed tomography is also helpful for delineating lesions, such as
pulmonary abscesses or lymph node pathology.
The results of pulmonary function tests in immunodeficient patients depends
on the underlying pulmonary pathology. Patients with bronchiectasis demon-
strate an obstructive pattern. (See Chapter 6, Pulmonary Function Testing.)
Patients with interstitial lung processes will have a restrictive pattern, and
the diffusion capacity may also be decreased. Pulmonary function tests can
be helpful in establishing the severity of disease and in tracking disease pro-
gression. Pulmonary function tests can also provide objective assessment of
response to medications, such as bronchodilators.
Bronchoscopy can be important for acute complications as well as for chronic
conditions. For patients who present with acute pulmonary symptoms, bron-
choscopy with bronchoalveolar lavage (BAL) can help in the diagnosis of
infections such as PCP. For patients with bronchiectasis who cannot expec-
torate sputum, BAL can provide information about the organisms colonizing
the lower respiratory tract. Transbronchial biopsy can also be performed
to identify fungal or viral infections. Bronchoscopy can also be helpful in
studying the airway anatomy, especially in patients in whom there is concern
Box 53-1
Evaluation of the Patient With Immunodeficiency
History Radiographic Imaging
Delayed umbilical cord separation Chest radiograph
History of infections High-resolution computed
Sites and etiologies of infections tomography
Physical Examination Evidence of bronchiectasis
Vital signs Presence of thymus
ū Tachypnea Pulmonary Function Testing
ū Head, eyes, ears, nose, throat Restrictive vs obstructive pattern
Presence of tonsils Diffusion defects
Chest ū Pulse oximetry or overnight
Crackles pulse oximetry
Wheezes ū Carbon dioxide levels via end-tidal
Extremities carbon dioxide or blood gas
Lymphadenopathy Bronchoscopy vs Transthoracic
Needle Aspiration/Biopsy
Clubbing

942
for compression of the bronchi by enlarged reactive lymph nodes. In most cases,
flexible fiberoptic bronchoscopy can be safely performed under moderate or
deep sedation on this group of patients. It is important to be aware that BAL
may not provide microbiological diagnosis, especially in fungal disease, but
every attempt should be made to obtain BAL samples prior to the initiation of
antimicrobial treatment. Percutaneous needle biopsy is another safe alternative
and it has much higher diagnostic yield in patients with diseases like CGD.
Treating Pulmonary Complications in Children

With Immunodeficiency
Treatment of the underlying immune defect is the best way to prevent pulmo-
nary complications, but since this may require bone marrow or hematopoietic
stem cell transplantation, temporizing measures are critical. For patients with
SCID or other T-cell disorders, bone marrow transplantation, hematopoietic
stem cell transplantation, or thymus transplantation can result in complete
correction of the immune defect depending on the specific disorder.15 Anti-
body deficiency syndromes can be treated with IVIG/SCIG replacement
therapy with or without antimicrobial prophylaxis.8,14 Combination antiretro-
viral therapy has had a dramatic effect on survival and the rates of infection in
patients with HIV.26 It is likely that as our understanding of the molecular and
cellular basis of congenital and acquired immunodeficiency increases, more
therapies aimed at correcting the underlying defect will become available.
Although specific therapy for immunodeficiencies is available, not all patients
are candidates for bone marrow transplantation, and other therapies may not
lead to complete absence of pulmonary complications. In this situation, antibi-
otic prophylaxis can be used to reduce the incidence of pulmonary infections.
The choice of antibiotic depends on the pathogens most likely to be involved
in the underlying disease process. For CGD, prophylaxis with trimethoprim-
sulfamethoxazole covers all their bacterial pathogens, whereas for T-cell
immunodeficiencies and HIV infection, PCP prophylaxis is the major concern.
Itraconazole prophylaxis for Aspergillus in CGD has been used effectively
in many centers.37
Many patients with immunodeficiency still develop bronchiectasis as a result
of either delayed diagnosis or continued infection despite treatment. This is
especially common in patients with B-cell disorders, such as XLA and CVID.
(See Chapter 17, Bronchiectasis, for treatment information.) Unfortunately,
many of the pulmonary changes that occur with immunodeficiency will
continue to progress despite improved management of respiratory infections.2,12
For patients with irreversible or progressive respiratory failure, lung trans-
plantation is an option. Lung transplantation has been performed on patients
with immunodeficiency, but there are limited data on their clinical outcomes.11,38

943
Lung transplantation is an arduous process for patients and is associated

with numerous short-term and long-term complications. Any decision to
proceed with lung transplantation must be made after a careful and thorough
consideration of the risks and potential benefits.
When to Refer
Consider referring patients with immunodeficiency to the pulmonologist
if they have persistent respiratory symptoms, recurrent severe pneumonia,
or signs of chronic lung disease (eg, baseline tachypnea, abnormal breath
sounds, or clubbing). Conversely, patients presenting with possible signs of
immunodeficiency, including pulmonary manifestations, should be referred
to a tertiary care center with immunology and stem cell transplant services.
Preliminary laboratory testing to consider would include complete blood cell
count with differential, T- and B-cell enumeration by flow cytometry, IgG,
IgA, IgM, and IgE levels, IgG titers to tetanus and pneumococcal vaccines,
and assessment of HIV status (Table 53-2). It is important to keep in mind
that these test results may appear to be “normal,” even in the setting of a true
underlying immunodeficiency condition. Any additional workup or more
specific testing should be undertaken by an immunologist. In all cases,
a multidisciplinary team approach is paramount for the appropriate
management of these complex patients.
Table 53-2. Laboratory Testing and Associated Category of Immunodeficiencya

Category of
Laboratory Test Immunodeficiency Example Conditions
Complete blood cell Innate immune Congenital neutropenia, leukocyte
count with differential deficiencies adhesion deficiency, Chediak-Higashi
syndrome
Peripheral smear
T- and B-cell quantification T-cell deficiencies Severe combined immunodeficiency,
combined immunodeficiency,
HIV serologies and
Wiskott-Aldrich syndrome, ataxia
polymerase chain
telangiectasia, DiGeorge syndrome
reaction
HIV/AIDS
B-cell deficiencies X-linked agammaglobulinemia
Quantitative Humoral immune X-linked agammaglobulinemia,
immunoglobulins and deficiencies common variable immunodeficiency,
vaccine titers specific antibody deficiency, immuno-
globulin A deficiency
Immunoglobulin E level > 2,000 kU/L
could be a sign of hyper-IgE syndrome
a
Not intended to be a comprehensive list. Additional workup should involve consultation with
an immunologist.

944
key po ints
} Pulmonary complications are common in patients with immunodeficiency,
and pulmonary infections are frequently the initial presenting sign.
} It is important to identify the microbe so that therapy can be directed
aggressively to the appropriate organism.
} Defects in different parts of the immune system result in distinctive patterns
of infection.
} Although IVIG and antibiotics can help prevent severe infections,
bronchiectasis can often still develop in patients with immunodeficiency.
} Noninfectious pulmonary diseases, such as interstitial lung disease, can
also develop.
} The primary care provider should be aware of the presenting signs of primary
immunodeficiency and evaluate patients appropriately.
} The primary care provider should maintain close follow-up of patients with
immunodeficiency and evaluate their respiratory status on a regular basis
or if signs and symptoms of lung disease develop.
References
1. Lekstrom-Himes JA, Gallin JI. Immunodeficiency diseases caused by defects in phagocytes.
N Engl J Med. 2000;343(23):1703–1714 PMID: 11106721 doi: 10.1056/NEJM200012073432307
2. Jesenak M, Banovcin P, Jesenakova B, Babusikova E. Pulmonary manifestations of primary
immunodeficiency disorders in children. Front Pediatr. 2014;2:77 PMID: 25121077
doi: 10.3389/fped.2014.00077
3. Goldblatt D, Thrasher AJ. Chronic granulomatous disease. Clin Exp Immunol. 2000;122(1):1–9
PMID: 11012609 doi: 10.1046/j.1365-2249.2000.01314.x
4. Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous disease. Report on a
national registry of 368 patients. Medicine (Baltimore). 2000;79(3):155–169 PMID: 10844935
doi: 10.1097/00005792-200005000-00003
5. Marciano BE, Spalding C, Fitzgerald A, et al. Common severe infections in chronic
granulomatous disease. Clin Infect Dis. 2015;60(8):1176–1183 PMID: 25537876
doi: 10.1093/cid/ciu1154
6. Gallin JI, Alling DW, Malech HL, et al. Itraconazole to prevent fungal infections in chronic
granulomatous disease. N Engl J Med. 2003;348(24):2416–2422 PMID: 12802027
doi: 10.1056/NEJMoa021931
7. Marciano BE, Wesley R, De Carlo ES, et al. Long-term interferon-gamma therapy for patients
with chronic granulomatous disease. Clin Infect Dis. 2004;39(5):692–699 PMID: 15356785
doi: 10.1086/422993
8. Ballow M. Primary immunodeficiency disorders: antibody deficiency. J Allergy Clin Immunol.
2002;109(4):581–591 PMID: 11941303 doi: 10.1067/mai.2002.122466
9. Lederman HM, Winkelstein JA. X-linked agammaglobulinemia: an analysis of 96 patients.
Medicine (Baltimore). 1985;64(3):145–156 PMID: 2581110
doi: 10.1097/00005792-198505000-00001
10. Thickett KM, Kumararatne DS, Banerjee AK, Dudley R, Stableforth DE. Common variable
immune deficiency: respiratory manifestations, pulmonary function and high-resolution
CT scan findings. QJM. 2002;95(10):655–662 PMID: 12324637 doi: 10.1093/qjmed/95.10.655
11. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and
immunological features of 248 patients. Clin Immunol. 1999;92(1):34–48 PMID: 10413651
doi: 10.1006/clim.1999.4725
12. Bang TJ, Richards JC, Olson AL, Groshong SD, Gelfand EW, Lynch DA. Pulmonary
manifestations of common variable immunodeficiency. J Thorac Imaging. 2018;33(6):377–383
PMID: 30067570 doi: 10.1097/RTI.0000000000000350

945
13. Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the

prevention of pneumonia in patients with common variable immunodeficiency. J Allergy Clin
Immunol. 2002;109(6):1001–1004 PMID: 12063531 doi: 10.1067/mai.2002.124999
14. Orange JS, Hossny EM, Weiler CR, et al; Primary Immunodeficiency Committee of the
American Academy of Allergy, Asthma and Immunology. Use of intravenous immunoglobulin
in human disease: a review of evidence by members of the Primary Immunodeficiency
Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin
Immunol. 2006;117(4 suppl):S525–S553 PMID: 16580469 doi: 10.1016/j.jaci.2006.01.015
15. Buckley RH. Primary cellular immunodeficiencies. J Allergy Clin Immunol.
2002;109(5):747–757 PMID: 11994695 doi: 10.1067/mai.2002.123617
16. Bacchetta R, Gambineri E, Roncarolo MG. Role of regulatory T cells and FOXP3 in human
diseases. J Allergy Clin Immunol. 2007;120(2):227–235 PMID: 17666212
doi: 10.1016/j.jaci.2007.06.023
17. Chatila TA. Role of regulatory T cells in human diseases. J Allergy Clin Immunol.
2005;116(5):949–959 PMID: 16275360 doi: 10.1016/j.jaci.2005.08.047
18. Deerojanawong J, Chang AB, Eng PA, Robertson CF, Kemp AS. Pulmonary diseases in children
with severe combined immune deficiency and DiGeorge syndrome. Pediatr Pulmonol.
1997;24(5):324–330 PMID: 9407565
doi: 10.1002/(SICI)1099-0496(199711)24:5<324::AID-PPUL4>3.0.CO;2-I
19. Puck JM. Newborn screening for severe combined immunodeficiency and T-cell lymphopenia.
Immunol Rev. 2019;287(1):241–252 PMID: 30565242 doi: 10.1111/imr.12729
20. Amatuni GS, Currier RJ, Church JA, et al. Newborn screening for severe combined
immunodeficiency and T-cell lymphopenia in California, 2010-2017. Pediatrics.
2019;143(2):e20182300 PMID: 30683812 doi: 10.1542/peds.2018-2300
21. Ochs HD, Thrasher AJ. The Wiskott-Aldrich syndrome. J Allergy Clin Immunol.
2006;117(4):725–738 PMID: 16630926 doi: 10.1016/j.jaci.2006.02.005
22. Yalçin B, Kutluk MT, Sanal O, et al. Hodgkin’s disease and ataxia telangiectasia with pulmonary
cavities. Pediatr Pulmonol. 2002;33(5):399–403 PMID: 11948987 doi: 10.1002/ppul.10057
23. Conces DJ Jr. Noninfectious lung disease in immunocompromised patients. J Thorac Imaging.
1999;14(1):9–24 PMID: 9894950 doi: 10.1097/00005382-199901000-00002
24. Levy J, Espanol-Boren T, Thomas C, et al. Clinical spectrum of X-linked hyper-IgM syndrome.
J Pediatr. 1997;131(1 Pt 1):47–54 PMID: 9255191 doi: 10.1016/S0022-3476(97)70123-9
25. Yazdani R, Abolhassani H, Asgardoon MH, et al. Infectious and noninfectious pulmonary
complications in patients with primary immunodeficiency disorders. J Investig Allergol Clin
Immunol. 2017;27(4):213–224 PMID: 28731410 doi: 10.18176/jiaci.0166
26. Moylett EH, Shearer WT. HIV: clinical manifestations. J Allergy Clin Immunol.
2002;110(1):3–16 PMID: 12110810 doi: 10.1067/mai.2002.125978
27. Bye MR. Human immunodeficiency virus infections and the respiratory system in children.
28. Pérez Mato S, Van Dyke RB. Pulmonary infections in children with HIV infection. Semin Respir
Infect. 2002;17(1):33–46 PMID: 11891517 doi: 10.1053/srin.2002.31685
29. Madhi SA, Schoub B, Simmank K, Blackburn N, Klugman KP. Increased burden of respiratory
viral associated severe lower respiratory tract infections in children infected with human
immunodeficiency virus type-1. J Pediatr. 2000;137(1):78–84 PMID: 10891826
doi: 10.1067/mpd.2000.105350
30. Mofenson LM, Yogev R, Korelitz J, et al; National Institute of Child Health and Human
Development Intravenous Immunoglobulin Clinical Trial Study Group. Characteristics of acute
pneumonia in human immunodeficiency virus-infected children and association with long term
mortality risk. Pediatr Infect Dis J. 1998;17(10):872–880 PMID: 9802627
doi: 10.1097/00006454-199810000-00005
31. Sheikh S, Madiraju K, Steiner P, Rao M. Bronchiectasis in pediatric AIDS. Chest.
1997;112(5):1202–1207 PMID: 9367458 doi: 10.1378/chest.112.5.1202
32. Wolff AJ, O’Donnell AE. Pulmonary manifestations of HIV infection in the era of highly
active antiretroviral therapy. Chest. 2001;120(6):1888–1893 PMID: 11742918
doi: 10.1378/chest.120.6.1888
33. Grubb JR, Moorman AC, Baker RK, Masur H. The changing spectrum of pulmonary disease
in patients with HIV infection on antiretroviral therapy. AIDS. 2006;20(8):1095–1107
PMID: 16691060 doi: 10.1097/01.aids.0000226949.64600.f9
34. Naccache JM, Antoine M, Wislez M, et al. Sarcoid-like pulmonary disorder in human
immunodeficiency virus-infected patients receiving antiretroviral therapy. Am J Respir Crit Care
Med. 1999;159(6):2009–2013 PMID: 10351953 doi: 10.1164/ajrccm.159.6.9807152

946
35. Kainulainen L, Varpula M, Liippo K, Svedström E, Nikoskelainen J, Ruuskanen O. Pulmonary

abnormalities in patients with primary hypogammaglobulinemia. J Allergy Clin Immunol.
1999;104(5):1031–1036 PMID: 10550749 doi: 10.1016/S0091-6749(99)70085-0
36. Barker AF. Bronchiectasis. N Engl J Med. 2002;346(18):1383–1393 PMID: 11986413
doi: 10.1056/NEJMra012519
37. Mouy R, Veber F, Blanche S, et al. Long-term itraconazole prophylaxis against Aspergillus
infections in thirty-two patients with chronic granulomatous disease. J Pediatr.
1994;125(6 Pt 1):998–1003 PMID: 7996377 doi: 10.1016/S0022-3476(05)82023-2
38. Hill AT, Thompson RA, Wallwork J, Stableforth DE. Heart lung transplantation in a patient with
end stage lung disease due to common variable immunodeficiency. Thorax. 1998;53(7):622–623
PMID: 9797766 doi: 10.1136/thx.53.7.622

CHAPTER
54
Pulmonary Complications of Neuromuscular Disorders
Introduction
Neuromuscular disorders (NMDs) may be associated with a gradual loss
of muscle function over time, and children with these disorders are at risk of
developing clinically significant respiratory morbidity from recurrent respira-
tory infections and chronic respiratory insufficiency.1–4 However, other groups
of nonprogressive NMDs, such as cerebral palsy or static encephalopathy, may
lead to the development of pulmonary complications requiring aggressive air-
way clearance, assisted ventilation, or secretion management. The approach for
the evaluation and management described in this chapter is also applicable to
such disorders. Knowledge of the expected course of the NMD is helpful in
planning the management of pulmonary complications (Table 54-1).
Loss of respiratory muscle strength that leads to ineffective cough and
decreased ventilation may result in atelectasis, decreased lung volumes, chronic
respiratory insufficiency, and respiratory failure.1 In some children, muscle
weakness may lead to oropharyngeal incompetence,5,6 gastroesophageal reflux,
feeding problems, and malnutrition (Figure 54-1).7,8 These complications may
be prevented or their onset delayed by careful serial assessment of respiratory
function, blood gas monitoring, and investigations to diagnose and treat asso-
ciated problems, such as obstructive sleep apnea (OSA),9,10 oropharyngeal
aspiration, gastroesophageal reflux, pneumonia, and asthma.11–13
947

948
Table 54-1. Natural History of Neuromuscular Disorders

(Without Disease-modifying Treatments)
Course Example of a Disorder Remark
Progressive Duchenne muscular Rate of progression may vary
dystrophy from patient to patient
Spinal muscular atrophy Severity varies according to type
Variable Congenital fiber type Some patients may show
disproportion myopathy improvement with age
Slowly progressive Post-polio syndrome —
Possibility of reversibility Guillain-Barré syndrome —
Rapidly progressive Amyotrophic lateral sclerosis Adult population
Acute flaccid myelitis Pediatric population
Chest Wall Kyphoscoliosis Inspiratory Expiratory Upper

Stiffness Muscle Muscle Airway
Weakness Weakness Weakness
Increased Restrictive Ineffective Speech

work of lung disease cough alteration
breathing
Microatelectasis Drooling Oropharyngeal

incoordination;
impaired swallow
and chew
Alveolar Aspiration
hypoventilation
Weight loss
Pneumonia
Airway Poor airway

obstruction secretions
clearance Sleep
disordered
breathing
Figure 54-1. Development of severe hypoventilation in neuromuscular disorders.

949
Chapter 54—Pulmonary Complications of Neuromuscular Disorders
CASE REPORT 54-1

A 12-year-old boy with Duchenne muscular dystrophy was referred to the pul-
monary clinic for evaluation and clearance for Achilles tendon release surgery.
The muscular dystrophy was diagnosed when the patient was 3 years old and
underwent examination for delayed motor milestones, frequent falls, and
inability to stand. The muscle weakness has been progressive, and he has used
a wheelchair for the last few weeks. The physical examination results were
remarkable for a weak cough and reduced air exchange during auscultation
of the chest, and the pulmonary function test results showed evidence of a
mild restrictive defect.
Pathophysiological Characteristics of Respiratory

Impairment in Patients With NMDs
Knowledge of normal respiratory function and control is essential to under-
stand the pathophysiological characteristics of respiratory impairment in
NMDs. Three basic components of respiratory control14 are as follows:
X Sensors, which gather afferent information: central chemoreceptors
located in the medulla, carotid, and aortic bodies and the stretch receptors
in the lungs
X Respiratory center in the brainstem, which acts as the central controller
by processing afferent impulses and sending out efferent impulses to
the periphery
X Effectors, which are the respiratory muscles responsible for ventilation
or coughing
Respiratory control occurs subconsciously. The cortex can temporarily over-
ride the automatic nature of this mechanism if voluntary control is desired.
A motor unit comprises an anterior horn cell, its peripheral nerve axon, the
neuromuscular junction, and the muscle fibers it innervates.
One way of explaining the pulmonary involvement in a patient with an NMD
is to use the paradigm of a respiratory pump (respiratory muscles and central
drive) working against pulmonary mechanics (lung and chest wall compliance,
airway characteristics, and frictional forces). Adequate ventilation requires
a balance between these 2 components; however, muscle weakness due to
an NMD tips the balance, resulting in pulmonary complications caused by
inadequate ventilation, impaired cough, and airway clearance.
Neuromuscular disorders can involve anterior horn cells, peripheral motor
nerves, and muscle fibers. Patients with NMDs often do not report dyspnea
until the diaphragm is involved.15 Diseases affecting the muscles of respiration
or their nerve supply include poliomyelitis, Guillain-Barré syndrome, myas-
thenia gravis, muscular dystrophies, and spinal muscular atrophy (SMA).

950
Young children with NMDs have high chest wall compliance normalized
to body weight.16 Therefore, the chest wall deforms during tidal breathing,
resulting in inefficient breathing17 that predisposes the child to developing
atelectasis and chest deformities. A combination of lung compliance reduced
due to generalized and widespread atelectasis (increased elastic load on the
pump) and chest wall deformity due to reduced chest wall compliance results
in increased work of breathing and chronic respiratory insufficiency. Reduced
lung stretch because of suboptimal expansion, in conjunction with chest wall
deformities, may also result in reduced lung growth.18
Tests of respiratory muscle strength, such as maximal inspiratory pressure
(MIP) and maximal expiratory pressure (MEP), can be used to assess respira-
tory pump function. Forced vital capacity (FVC) and fractional lung volumes
are the result of interplay between respiratory pump and the load and can be
used to monitor the progress of patients with NMDs.
Patients with extreme muscle weakness due to an NMD may not be able to
show the normal response to hypoventilation in the form of increased tidal
volume but may have tachypnea. Inspiratory muscle weakness leads to chest
wall stiffness and restrictive lung disease and contributes to ineffective cough
and microatelectasis. Expiratory muscle weakness results in ineffective cough,
inadequate airway clearance, aspiration, pneumonia, and alveolar hypoven-
tilation. Upper airway muscle involvement results in oropharyngeal incom-
petence, difficulties with swallowing and chewing, speech alteration, and
sleep-disordered breathing (SDB). In addition to muscle weakness due to
NMDs, musculoskeletal deformities, such as kyphoscoliosis, contribute to
restrictive lung disease. These consequences are summarized in Box 54-1.
Box 54‑1
Consequences of Compromised Respiratory Muscle Function
ū Poor clearance of lower airway secretions because of impaired cough
ū Hypoventilation during sleep
ū Recurrent infections that exacerbate muscle weakness and impair the integrity
of the lung parenchyma
ū Chest wall underdevelopment in a growing child
The consequences of NMDs depend on the stage of the disorder. Most of the
disorders are progressive, with resultant pulmonary and nutritional issues.
The major findings discovered by means of history and physical examination
are detailed in Box 54-2.

951
Box 54‑2
Pulmonary and Associated Consequences of Neuromuscular Disorders
Pulmonary
ū Weak and ineffective cough
ū Tachypnea, respiratory distress, retractions, cyanosis
ū Recurrent respiratory infections and pneumonia (secondary to aspiration)
ū Restrictive lung disease
ū Chronic respiratory insufficiency and failure
Sleep
ū Snoring, irregular breathing, apneic episodes, nocturnal awakening
ū Sleep-disordered breathing
ū Daytime somnolence, fatigue
Nutritional
ū Difficulty in chewing, swallowing
ū Oropharyngeal incompetence (nasal regurgitation), aspiration
ū Malnutrition
ū Weight loss
ū Drooling
Others
ū Speech alteration, weak voice
ū Musculoskeletal deformities, scoliosis
Evaluation and Anticipatory Guidance

In a patient with an NMD, in addition to the usual history and physical
examination, attention should be given to the strength and efficacy of cough,
speech alteration (weak, nasal), drooling, feeding difficulties (feeding with
interruptions, choking, coughing, gagging, and nasal regurgitation), weight
loss, and a history of recurrent respiratory infections. Arm muscle weakness
may interfere with the patients’ ability to feed themselves. A history sugges-
tive of SDB (snoring, apnea, awakening, daytime somnolence) will help the
physician decide which investigations, such as a sleep study, are necessary.
The physical examination should include asking the patient to cough to assess
the cough strength clinically and looking for breathing patterns, signs of
respiratory distress, tachypnea, paradoxical thoracoabdominal movements,
and cyanosis.

952
Pulmonary Function Tests

Indications for pulmonary function tests (PFTs) include the following:
X Evaluating the patient’s respiratory status at the time of diagnosis
X Monitoring the progression and course of pulmonary limitation
X Evaluating during pulmonary infections
X Evaluating before surgical procedures
X Providing an assessment of prognosis
Because PFTs require the patient’s voluntary participation, they are of limited
use in children younger than 6 years. In such patients, clinical observation for
work of breathing, respiratory rate, paradoxical thoraco-abdominal move-
ments, and cyanosis may provide useful information. Infant lung function
tests, including tidal flow-volume loop, partial flow-volume curves, raised-
volume rapid thoracic compression, and infant whole-body plethysmography,
are available in specialized centers.19–21
Forced Vital Capacity
During the FVC maneuver, the patient takes a maximum breath and,
depending on the effort, fills the lungs up to the total lung capacity and then
forcefully exhales to the maximum. The total volume of air expelled during
forced exhalation after maximal inspiration is FVC. Some physicians measure
vital capacity with the patient sitting, supine, lying on one side, or wearing a
thoracolumbar stabilizing device, which may produce more realistic informa-
tion. A greater than 25% decrease in FVC from sitting to supine may indicate
that diaphragmatic weakness is out of proportion to chest wall muscle weak-
ness.22 A supine change in lung function has been correlated with chronic
respiratory failure in patients with myotonic dystrophy.23 Seated FVC has
been proposed as the primary pulmonary outcome measure for tracking the
natural history of pulmonary progression in Duchenne muscular dystrophy
(DMD) and for assessing the effect of new therapies. Forced expiratory volume
in 1 second, MIP, MEP, cough peak flow (CPF), peak expiratory flow rate, and
sniff nasal inspiratory pressure are considered secondary end points, pending
further validation.24
Peak Expiratory Flow Rate and Cough Peak Flow
Muscle weakness due to NMDs results in reduced values for peak expiratory
flow.25 The use of CPF can minimize effort-related variation. Thus, in patients
with neuromuscular weakness, CPF is a better and more reliable measurement
of expiratory muscle strength. Cough peak flow is measured by using a peak
flow meter with a mask attached. Cough peak flow may be measured in the
primary care physician’s office, patient’s home, or pulmonologist’s office by
asking the patient to cough in it while using maximal expiratory force. This
inexpensive, simple device monitors expiratory muscle strength. The patient

953
can maintain a journal with weekly or monthly readings. Cough peak flows
correlate directly to the ability to clear secretions from the respiratory tract,26
and values lower than 160 L/min have been associated with ineffective airway
clearance.27 An expiratory CPF rate of 270 L/min has been used to identify
patients who would benefit from assisted cough techniques. A 2020 study
of CPF highlighted lower values in children,28 revealing a need to revise
the guidelines.
Assisted CPF
In assisted CPF, the patient deeply inhales successive tidal breaths without
exhaling (air stacking), then coughs while an abdominal thrust is applied. The
CPF is measured with a peak flow meter. Because the air stacking requires
patent glottis function and adequate glottis closure, the difference between
assisted and unassisted CPF can be used to measure glottic integrity, which
may be affected if there is bulbar muscle involvement or weakness.
Forced Expiratory Volume in One Second
In patients with an NMD and respiratory muscle weakness, FEV1 is reduced
in proportion to FVC. Thus, the FEV1/FVC ratio remains normal. A ratio of
FEV1/FVC less than 70% predicted suggests an obstructive process that
may coexist with the restrictive disorder.
Respiratory Muscle Strength
Maximal and minimal inspiratory pressure are measured while the patient
inhales or exhales maximally against a closed shutter; the pressure measured is
the composite of pressure generated by the inspiratory muscles and the elastic
recoil of the lung and the chest wall.29,30 The MIP and MEP are the most
sensitive indicators of decreased respiratory muscle strength. However, investi-
gators have found wide interindividual variability in the inspiratory/respiratory
muscle function in children, and they have attempted standardization.31–33
Sniff Nasal Inspiratory Pressure
In the sniff nasal inspiratory pressure test, a pressure transducer is placed in
the nostril, which is sealed using a plug while the patient sniffs maximally
through the contralateral nostril from functional residual capacity.30 The
maneuver can be performed easily in children with NMDs and used for
monitoring their progress.34
Measurement of Gas Exchange
Hypoventilation leading to hypercapnia occurs much earlier than hypoxemia.
Therefore, a low pulse oximeter reading is a late finding and suggests respira-
tory insufficiency. Pulse oximetry results and carbon dioxide levels should be
evaluated with the patient awake at least annually in conjunction with other
tests. Capnography is ideal for this purpose. If capnography is not available,
a venous blood gas or capillary gas test should be performed to assess for

954
alveolar hypoventilation. Nocturnal transcutaneous carbon dioxide measure-

ment can be used to identify patients with hypoventilation at risk for subse-
quent need of home mechanical ventilation.35
Choice of Pulmonary Function Test
Choice of PFT depends on the patient’s age and disease severity. Most children
with severe manifestations of SMA may be too weak or too young to perform
PFTs. Therefore, the most useful evaluation of respiratory muscle function may
be observation of cough ability.2 The MIP, MEP, and CPF tests can be used in
older patients and those who have relatively mild disease but are wheelchair
users to monitor their respiratory muscle function. Older patients and those
with still milder disease (those able to walk) may be able to perform PFTs
and respiratory muscle function tests.
Palliative and End-of-Life Care

Emerging therapies showing promising results in the treatment of NMDs
include dystrophin replacement therapies, anti-inflammatory agents, ataluren
for stop codon read-through, eteplirsen for exon skipping for eligible patients
with DMD,36,37 gene therapy, antisense oligonucleotides, and splicing modifiers
for SMA and other conditions.38 However, most patients with NMDs continue
to have a progressively worsening course; therefore, supportive and palliative
care to improve quality of life is critical.
Ventilatory and palliative care options should be discussed early and before
complications requiring such interventions occur. Quality-of-life judgments
should be made with the informed participation of the patient and family.1
All long-term treatment options, including invasive and noninvasive mechani-
cal ventilation, should be discussed even when the treating physician predicts
a poor quality of life with long-term ventilation.39 Such options must be pre-
sented in an open, fair, and balanced manner. End-of-life directives established
by the patient, family, and health care team must be clearly documented and
must be available in case of an emergency. Patients choosing to forgo long-
term ventilation should be provided with palliative care, which may include
management of pain and dyspnea and attending to the psychosocial and
spiritual needs of patients and their families.
Nutrition
Patients with NMDs may have feeding and swallowing problems because
of bulbar dysfunction and can develop complications such as aspiration
pneumonia. Gastrointestinal dysfunction can lead to constipation, delayed
gastric emptying, and gastroesophageal reflux.
Ideal body weight percentage and body mass index should be evaluated, and
the family should be counseled accordingly. Regular follow-up and evaluation

955
by a nutritionist are indicated. Clinical evaluation for oropharyngeal incom-

petence and confirmation with studies such as a videofluoroscopic swallowing
study should be considered. Patients should be evaluated for need of
supplemental nutrition.
Cardiac Evaluation
Cardiac involvement may be due to cardiomyopathy, such as that in patients
with DMD. Chronic respiratory insufficiency may result in pulmonary hyper-
tension or arrhythmia. Therefore, when it is clinically indicated, the patient
should be evaluated by a cardiologist who may order an electrocardiogram, an
echocardiogram, and medications, as well as regular follow-up appointments.
Sleep Evaluation
Patients with NMDs have a prevalence greater than 40% of SDB,40 a tenfold
greater occurrence than that in the general population.41 They have a much
higher incidence of OSA, gas exchange abnormalities, disrupted sleep archi-
tecture, and central apnea.4,41 Dysfunction of upper airway muscles results in
OSA, and dysfunction of diaphragm and intercostal muscles results in hypo-
ventilation. In patients with NMDs, airway resistance during sleep may be
increased because of weakness of the pharyngeal dilator muscles, which is
worse during the rapid eye movement (REM) stage when these muscles are
atonic. In patients with NMDs,42 OSA often precedes hypoventilation. Hypo-
ventilation during sleep as a result of blunting of the response to hypoxia
and hypercarbia worsens as muscle weakness progresses. Furthermore, the
presence of kyphoscoliosis can contribute to restriction of lung capacity and
impaired ventilation.43
The nature of SDB in patients with NMDs reflects the distribution of respira-
tory muscle involvement.44 When patients have severe diaphragm dysfunction,
suppression of intercostal and accessory muscles during REM sleep leads to
hypoventilation. However, if diaphragm strength is intact but the upper airway
or intercostal muscles are weak, then obstructive apneas or hypopneas are
more likely to occur. In some NMDs, such as myotonic dystrophy, primary
abnormalities in ventilatory control may also contribute to SDB, often com-
plicated by nocturnal or even diurnal hypoventilation.45 The arousal response
seen with hypoventilation is compensatory because it prevents prolonged
hypoxia or hypercarbia, but it does so at the expense of adequate sleep and
results in daytime fatigue and hypersomnolence. With time and disease pro-
gression, ventilatory chemosensitivity is reset and the arousal response is
blunted, leading to prolongation of the REM stage during which alveolar
hypoventilation occurs. Eventually respiratory drive is depressed, resulting
in severe hypoventilation and ultimate respiratory failure (Figure 54-2).45

956
Nocturnal hypoventilation is not well defined in children. In adults, sleep-

related hypoventilation, according to the International Classification of
Sleep Disorders, 3rd Edition,46 is defined as a level of arterial carbon dioxide
greater than 55 mm Hg for at least 10 minutes or an increase of at least 10 mm
Hg above the awake value to a level of at least 50 mm Hg for 10 minutes or
longer. In children, the level must be greater than 50 mm Hg for more than
25% of total sleep time.46 Sleep-related hypoxemia is defined as oxygen
desaturations to 88% or lower in adults, or 90% or lower in children, for at
least 5 minutes.46 Quality of sleep and symptoms of SDB should be reviewed
at each visit (see Chapter 33, Obstructive Sleep Apnea Syndrome). Polysom-
nography should be performed annually in patients with NMDs from the time
they are wheelchair users or when the clinical situation warrants. If polysom-
nography cannot be performed, nocturnal pulse oximetry with or without
capnography is an alternative.
RESPIRATORY FAILURE Muscle Weakness Due to NMD
Severe diurnal hypoventilation Hypercarbia and hypoxia

during REM sleep
Depression of respiratory drive

Compensatory arousal response
HCO3– retention
Fragmented sleep and
reduced sleep efficiency
Increased hypoventilation Sleep deprivation
Ventilatory chemosensitivity Daytime fatigue

is reset and arousal response Hypersomnolence
Increased periods of REM sleep is blunted
Figure 54-2. Development of sleep-disordered breathing and respiratory failure in patients

with neuromuscular disorders. Abbreviations: HCO3−, bicarbonate; NMD, neuromuscular
disorder; REM, rapid eye movement.

957
Management
Multiple approaches are available for reducing the effect of the progression
of neuromuscular weakness. The approach to investigating and treating
symptoms depends on the clinical course and is summarized in Table 54-2.
Table 54-2. Suggested Approach to Examine and Treat Patients With Progressive
Respiratory Muscle Involvement
Clinical Features Relevant Investigations Suggested Interventions
No clinical evidence of Normal FVC, normal cough Follow up regularly in the clinic
respiratory muscle peak flow (>270 L/min) (every 6 months), monitor
involvement spirometry results and cough
peak flow rate, encourage
use of incentive spirometer
Evidence of respiratory Reduced FVC (<60% predicted), Initiate lung volume
muscle involvement, cough peak flow (<270 L/min), recruitment and/or airway
weak cough, and maximal expiratory pressure clearance (cough assist
pooling of secretions < 60 cm H2O device)
Snoring, sleep-disordered Evidence of sleep-disordered Consider noninvasive
breathing, nocturnal breathing during a sleep ventilation during sleep
awakenings due to study, evidence of chronic
breathing difficulty, hypoventilation on blood gas
daytime somnolence (elevated CO2 and bicarbonate
levels) test results, hypoxia
(reduced oxyhemoglobin satu-
ration, Po2 levels on blood gas
test results), and elevated
end-tidal CO2 levels
Hypoventilation, Awake Pco2 >50 mm Hg Extend noninvasive ventilation
hypercarbia during Oxyhemoglobin saturation during daytime; may be
awake periods <92% intermittent to begin with
Persistent or worsening Awake Pco2 >50 mm Hg Use long-term ventilation: may

hypoventilation, Oxyhemoglobin saturation be noninvasive to begin with,
hypercarbia, and <92% and if there is contraindica-
hypoxia tion or failure of noninvasive
ventilation or patient or
family preference, consider
long-term tracheostomy and
ventilation
Abbreviations: CO2, carbon dioxide; FVC, forced vital capacity; H2O, water; Pco2, partial pressure of carbon
dioxide; Po2, partial pressure of oxygen.
Airway Clearance
There are 2 components of effective airway clearance: mucus mobilization
from peripheral to central airways by means of the mucociliary escalator and
mucus extraction. Cough, a primary mechanism to clear secretions from the
central airways, may be affected by respiratory muscle weakness and result in
impaired airway clearance leading to pooling of secretions, which may result
in airway obstruction and increased work of breathing and contribute to

958
chronic respiratory insufficiency. Ineffective cough may be suspected clini-

cally when there is a history of lack of secretions while coughing, recurrent
pneumonia, and reduced values for CPF. Cough peak flow may be measured
in the primary care physician’s office, patient’s home, or pulmonologist’s
office by attaching a mask to a peak flow meter and asking the patient to
cough in it (Figure 54-3).
Figure 54-3. A face mask attached to a peak flow meter for use as a cough
peak flow meter.
Courtesy of Girish D. Sharma, MD, Rush University Medical Center, Chicago.
This inexpensive, simple device monitors expiratory muscle strength, and the
patient can maintain a journal with weekly or monthly readings. Similarly,
an MEP less than 45 cm H2O has been considered an indication for assisted
cough techniques. Therefore, airway clearance (using either manual chest
physiotherapy or a mechanical device) is very important to prevent respiratory
complications, including pneumonia, atelectasis, and respiratory failure. In
the initial stages, airway clearance by means of manual chest physiotherapy
along with postural drainage may help. However, as the disease progresses,
resulting in pooling of secretions, more aggressive methods, such as the use
of a mechanical insufflation-exsufflation (MIE) device, are needed.
Use of a high-frequency chest wall oscillation (HFCWO) device alone may
not help much if the patient has weak or ineffective cough. In that case, assisted
cough for airway clearance is needed. Use of HFCWO in a patient with clini-
cally significant musculoskeletal deformities (kyphoscoliosis) may be

959
uncomfortable. However, investigators in some studies have suggested the

usefulness of HFCWO in patients with NMDs.47,48
Various techniques have been developed to overcome ineffective cough in
patients with neuromuscular weakness. Patients or caregivers should be taught
strategies to improve airway clearance and how to use those techniques early
and aggressively. Patients with clinically weak or ineffective cough and
clinical evidence of poor airway clearance should be started on a regular
airway clearance regimen. Use assisted cough techniques in patients whose
clinical history suggests difficulty in airway clearance, whose CPF is less
than 270 L/min, and/or whose MEPs are less than 60 cm H2O. An MIE
device (cough assist device) is helpful.
Manually Assisted Cough Technique

Manually assisted coughing involves inspiratory assistance followed by
augmentation of the forced expiratory effort. An increase in inspiratory
capacity can be achieved by the use of glossopharyngeal breathing (in essence,
forcing air into the lungs using one’s mouth), air stacking (taking a series of
tidal breaths without exhaling between them), positive pressure with a self-
inflating bag and mask, an intermittent positive pressure breathing device,
or a mechanical ventilator. Interfaces for inspiratory assistance include a face
mask, mouthpiece, or direct attachment of the assisting device to a tracheos-
tomy tube. Forced exhalation is augmented by pushing on the upper abdomen
or chest wall in synchrony with the subject’s own cough effort.
Mechanical Techniques
Mechanical insufflator-exsufflators (also known as cough assist devices) simu-
late a cough by providing a positive pressure breath followed by a negative
pressure exsufflation. This technique is superior to both breath stacking and
manual cough assistance.25 In patients with tracheostomies, MIE offers a
number of advantages over traditional suctioning, including clearance of
secretions from peripheral airways, avoidance of mucosal trauma from direct
tracheal suction, improved patient comfort,49 and prevention of atelectasis.
Bronchoscopy has been used in selected patients with DMD, generally in
cases of persistent atelectasis, but has not been of proved benefit, so it should
be considered only after all noninvasive airway clearance techniques have
been unsuccessful and a mucus plug is suspected.
Lung Volume Recruitment

Lung volume recruitment using a self-inflating manual ventilation bag
applied once or twice daily may have an immediate positive effect on CPF
and a long-term effect on rate of FVC decrease in patients with an NMD and
respiratory muscle weakness.24,50,51 Regular use of MIE, in addition to airway
clearance, also contributes to lung recruitment.

960
Respiratory Muscle Training

The rationale for respiratory muscle training in patients with DMD is based
on the assumption that improved muscle strength and endurance may lead to
improved preservation of lung function over time. Low-intensity inspiratory
muscle training at home may improve respiratory muscle endurance in chil-
dren with DMD, and the effectiveness of training appears to depend on the
quantity of training.52 Training with an inspiratory threshold load (70%–80%
of the maximal inspiratory mouth pressure) provides a stimulus that increases
both the pressure- and flow-generating capacities of the respiratory muscles
and therefore may provide a practical approach to inspiratory muscle training
in both children and adults with NMDs.45
Noninvasive Nocturnal Ventilation

The onset of moderately severe muscle weakness as evidenced by physical
examination results, weak or ineffective cough, pooling of secretions, and
hypoventilation or hypoxia during sleep or wakefulness differs from patient to
patient and disease to disease. For example, a patient with SMA can develop
such a weakness much earlier than a patient with DMD. Use of noninvasive
ventilation (NIV) may improve quality of life, slow the decreases in vital
capacity and maximal static inspiratory and expiratory pressures,53 and reduce
the high morbidity (SDB, including hypopnea, central and obstructive apnea,
and hypoxemia) and early mortality associated with NMDs such as DMD.1 A
combination of NIV and airway clearance using MIE may decrease the need
for intubation.54 In children, long-term home mechanical ventilation is being
increasingly used; most of these patients have NMDs and receive NIV.55,56
Nocturnal nasal intermittent positive pressure ventilation with a bilevel
positive airway pressure generator or mechanical ventilator has been used
successfully in the treatment of SDB and nocturnal hypoventilation in patients
with DMD and other NMDs.1 Family and demographic factors, especially
maternal education, may influence adherence to the positive airway pressure
therapy.57 The type of NIV interface (nasal, oronasal, nasal pillows) is chosen
based on individual needs and fitting. Improper fitting may cause air leak
resulting in inadequate ventilation; sleep disruption; skin irritation or excoria-
tion; and, more importantly, poor adherence with NIV. Discomfort, aeropha-
gia, abdominal distention, dry mouth, nasal congestion, and interference with
secretion management may occur. In children, long-term use of an orofacial
mask may lead to midfacial hypoplasia.58,59 In older patients with an NMD
requiring intermittent NIV during the day, mouthpiece ventilation is
gaining wider acceptance.60
Polysomnography should be performed to confirm the presence and extent
of SDB, hypoxia, and hypercarbia; to titrate for treatment initiation with
optimum ventilator settings; and to ensure response to treatment. In the

961
absence of polysomnography, overnight pulse oximetry with continuous

carbon dioxide monitoring can be used to monitor nighttime gas exchange.1
Daytime ventilation should be considered when measured waking Pco2
exceeds 50 mm Hg or when oxygen saturation remains less than 92% while
the patient is awake. Additional periods of assisted ventilation may be added
during acute episodes such as respiratory infection. Follow-up visits should
include monitoring for daytime hypoventilation, polysomnographic assess-
ment of nocturnal NIV adequacy, and the patient’s and/or caregiver’s feedback.
In certain situations, data downloaded from the device (eg, time the device
was used, air leak, tidal volume, pressures) is helpful to ensure adequacy of
ventilation. During the outpatient clinic visit, assessment of ventilator
parameters to ensure adequacy of ventilation (eg, expiratory tidal volume,
end-tidal carbon dioxide measurement, mask assessment to check for leak) is
helpful. Depending on the ventilation adequacy assessment results, addi-
tional hours of ventilation during the day or round-the-clock ventilation may be
needed. With an increase in the understanding of the mechanism of respiratory
insufficiency in patients with NMDs, new modes and devices for NIV and
monitoring have evolved,61–63 resulting in improved adherence and outcomes.64
However, oxygen supplementation alone should not be used to treat sleep-
related hypoventilation without ventilatory assistance because of the poten-
tial for exacerbating carbon dioxide retention and resultant acute respiratory
failure.
Tracheostomy and Invasive Ventilation

Tracheostomy should be considered when the patient cannot achieve adequate
ventilation with NIV or contraindications to NIV are present. For example,
the patient may have an aversion to NIV, lack sufficient oromotor or neck
control to use a mouthpiece interface during the daytime, or tolerate other
interfaces poorly.1
Factors such as available resources and financial burden on families and the
health care system65,66 should be considered; however, they may not be used
to deny a patient an indicated intervention such as tracheostomy or invasive
ventilation. Other important considerations include the discharge criteria
from the hospital to home and the equipment and resources needed.67 How-
ever, tracheostomies have many potential complications, including generating
more secretions; impairing swallowing and increasing the risk of aspiration;
bypassing of airway defenses, likely increasing the risk of infection; and a
higher risk of airway occlusion by a mucus plug.68 Because tracheostomies
also impair speech, communication may be restored using a relatively small
tracheostomy tube, allowing a “leak” around the airway, and a speaking valve
(Passy-Muir valve).

962
Respiratory Care for Patients With NMD Undergoing

Sedation or Anesthesia
Preoperative pulmonary evaluation69 and consultation should be performed.
Pulmonary function tests, including FVC, MIP, MEP, CPF, and oxyhemoglo-
bin saturation measurement in room air, should be performed. An FVC value
less than 50% is associated with increased risk, and when the values are less
than 30%, preoperative training for NIV should be provided. If these proce-
dures are indicated, the child should undergo extubation to NIV, such as nasal
bilevel positive airway pressure, and appropriate pain management should be
provided. Aggressive airway clearance should begin as soon as the patient
can tolerate it.69–71
Pulmonary Infections in Patients With NMDs

Ineffective cough and airway clearance due to respiratory muscle weakness
and associated dysphagia and resultant aspiration may lead to recurrent
respiratory infections in patients with NMDs (Figure 54-1). In a patient with
a clinical course suggestive of acute bacterial infection, as evidenced by fever,
purulent secretions, leukocytosis, or radiological evidence of pneumonia,
empiric use of antibiotics is warranted after relevant workup for such respira-
tory cultures. Patients or caregivers should receive a sick plan (including
increasing the frequency of airway clearance, using home oximetry, and
communicating with the pulmonary team) to decide the need for antibiotics.
Some clinics have used remote assessment via telehealth visits to assess
respiratory status and ventilator parameters and to change equipment settings.
A timely approach like this may obviate the need for a hospital visit and
admission and may also reduce the duration and severity of sickness and
associated morbidity.
Use of a 23-valent pneumococcal polysaccharide vaccine in children older
than 2 years and annual influenza vaccine is important. When a respiratory
infection is suspected, appropriate investigations, appropriate antibiotics, and
increased airway clearance are indicated.72 The COVID-19 pandemic also
highlighted the importance of looking for risk factors for severe COVID-19
infections, adjustment of disease-modifying therapies, and treatment of
pneumonia in this patient population.73,74 The COVID-19 vaccine, approved
for children aged 6 months or older as of 2022, should be used.

963
When to Refer
Pulmonologist
X Shortly after diagnosis for respiratory care evaluation and discussion of
treatment options, including identification of goals for chronic and acute
respiratory care; regular follow-up of pulmonary status should be performed
once or twice a year after the patient starts to use a wheelchair
X Before a proposed surgery for evaluation of pulmonary status and to assess
fitness for the proposed anesthesia, sedation, or surgery
X In case of acute respiratory illness
Cardiologist
The cardiologist should be consulted to diagnose and treat cardiomyopathy and
pulmonary hypertension. Cardiac evaluation should be performed for evidence
of cardiomyopathy and cardiac dysrhythmias and pulmonary hypertension.
Patients with NMDs are at high risk of developing adverse effects during the
perioperative period because of hypoxemia, anemia, and other causes of
impaired tissue oxygen delivery. Intravascular shifts can result in congestive
heart failure and impaired ventricular load.75
When to Admit
X At the time of diagnosis: Patients with late diagnosis who may have
clinically significant pulmonary compromise as evidenced by lung func-
tion, or laboratory evidence of respiratory failure or cardiac involvement,
may benefit from hospitalization.
X Inadequate or lapsed home nursing: The family or caregiver at home
cannot provide 24/7 care.
X In case of acute respiratory illness: Patients may need aggressive airway
clearance; increased respiratory support, such as NIV; management of
nutrition; hydration; and initiation of antibiotic therapy. In case of acute
respiratory decompensation due to causes such as aspiration pneumonia
in a patient already using long-term NIV, a change of ventilator and,
uncommonly, short-term endotracheal intubation may be warranted.
X For elective procedures: These include gastric feeding tube placement,
scoliosis surgery, elective tracheostomy and initiation of invasive
ventilation, and sleep studies.

964
key points
} The history in a patient with an NMD should include questions about the
strength and efficiency of coughing, activity or exercise intolerance, and
respiratory distress.
} Regular monitoring of PFT results, especially FVC, should be initiated as soon as
the child is mature enough to perform the maneuver.
} Early and proactive use of devices to facilitate lung recruitment, cough
assistance, and airway clearance is important for preservation of respiratory
function.
} Sleep-disordered breathing associated with NMDs should be suspected and
tested for if there is a history of snoring, irregular breathing, apneic episodes
during sleep, or nocturnal awakenings due to breathing difficulty (not for
change of position because of discomfort).
} A history of recurrent respiratory infections and pneumonia may suggest
chronic aspiration due to oropharyngeal incompetence. A videofluoroscopic
swallowing study may help to confirm any oropharyngeal incompetence and
associated aspiration.
} Involve the palliative care team to discuss ventilatory and palliative treatment
options before they become necessary.
References
2004;170(4):456–465 PMID: 15302625 doi: 10.1164/rccm.200307-885ST
2. Wang CH, Finkel RS, Bertini ES, et al; Participants of the International Conference on SMA
Standard of Care. Consensus statement for standard of care in spinal muscular atrophy.
J Child Neurol. 2007;22(8):1027–1049 PMID: 17761659 doi: 10.1177/0883073807305788
3. Emery AE. The muscular dystrophies. BMJ. 1998;317(7164):991–995 PMID: 9765171
doi: 10.1136/bmj.317.7164.991
4. Gozal D. Pulmonary manifestations of neuromuscular disease with special reference to
Duchenne muscular dystrophy and spinal muscular atrophy. Pediatr Pulmonol.
2000;29(2):141–150 PMID: 10639205
doi: 10.1002/(SICI)1099-0496(200002)29:2<141::AID-PPUL9>3.0.CO;2-Y
5. Willig TN, Paulus J, Lacau Saint Guily J, Béon C, Navarro J. Swallowing problems in
neuromuscular disorders. Arch Phys Med Rehabil. 1994;75(11):1175–1181 PMID: 7979925
doi: 10.1016/0003-9993(94)90001-9
6. Tomé FM, Chateau D, Helbling-Leclerc A, Fardeau M. Morphological changes in muscle fibers
in oculopharyngeal muscular dystrophy. Neuromuscul Disord. 1997;7(suppl 1):S63–S69
PMID: 9392019 doi: 10.1016/S0960-8966(97)00085-0
7. Pane M, Vasta I, Messina S, et al. Feeding problems and weight gain in Duchenne muscular
dystrophy. Eur J Paediatr Neurol. 2006;10(5–6):231–236 PMID: 17045498
doi: 10.1016/j.ejpn.2006.08.008
8. Messina S, Pane M, De Rose P, et al. Feeding problems and malnutrition in spinal muscular
atrophy type II. Neuromuscul Disord. 2008;18(5):389–393 PMID: 18420410
doi: 10.1016/j.nmd.2008.02.008
9. Aboussouan LS. Sleep-disordered breathing in neuromuscular disease. Am J Respir Crit Care
Med. 2015;191(9):979–989 PMID: 25723731 doi: 10.1164/rccm.201412-2224CI
10. Smith PE, Edwards RH, Calverley PM. Ventilation and breathing pattern during sleep in
Duchenne muscular dystrophy. Chest. 1989;96(6):1346–1351 PMID: 2582842
doi: 10.1378/chest.96.6.1346

965
11. Iannaccone ST; American Spinal Muscular Atrophy Randomized Trials (AmSMART) Group.
Outcome measures for pediatric spinal muscular atrophy. Arch Neurol. 2002;59(9):1445–1450
PMID: 12223032 doi: 10.1001/archneur.59.9.1445
12. Oskoui M, Levy G, Garland CJ, et al. The changing natural history of spinal muscular atrophy
type 1. Neurology. 2007;69(20):1931–1936 PMID: 17998484
doi: 10.1212/01.wnl.0000290830.40544.b9
13. Jeppesen J, Green A, Steffensen BF, Rahbek J. The Duchenne muscular dystrophy population in
Denmark, 1977–2001: prevalence, incidence and survival in relation to the introduction of
ventilator use. Neuromuscul Disord. 2003;13(10):804–812 PMID: 14678803
doi: 10.1016/S0960-8966(03)00162-7
14. West JB. Control of ventilation. In: Respiratory Physiology: The Essentials. 9th ed. Wolters
Kluwer Lippincott Williams & Wilkins; 2012:128–133
15. West JB. Restrictive diseases: neuromuscular disorders. Pulmonary Pathophysiology: The
Essentials. 9th ed. Wolters Kluwer Lippincott Williams & Wilkins; 2012:88
16. Papastamelos C, Panitch HB, Allen JL. Chest wall compliance in infants and children with
neuromuscular disease. Am J Respir Crit Care Med. 1996;154(4 pt 1):1045–1048
PMID: 8887605 doi: 10.1164/ajrccm.154.4.8887605
17. Lissoni A, Aliverti A, Tzeng AC, Bach JR. Kinematic analysis of patients with spinal muscular
atrophy during spontaneous breathing and mechanical ventilation. Am J Phys Med Rehabil.
1998;77(3):188–192 PMID: 9635553 doi: 10.1097/00002060-199805000-00002
18. Bach JR, Bianchi C. Prevention of pectus excavatum for children with spinal muscular atrophy
type 1. Am J Phys Med Rehabil. 2003;82(10):815–819 PMID: 14508413
doi: 10.1097/01.PHM.0000083669.22483.04
19. Stocks J, Lum S. Paediatric pulmonary function testing. Prog Respir Res. 2005;33:78–91
doi: 10.1159/000083523
20. Bates JH, Schmalisch G, Filbrun D, Stocks J. Tidal breath analysis for infant pulmonary function
testing. ERS/ATS Task Force on Standards for Infant Respiratory Function Testing. European
Respiratory Society/American Thoracic Society. Eur Respir J. 2000;16(6):1180–1192
PMID: 11292125 doi: 10.1034/j.1399-3003.2000.16f26.x
21. Beydon N, Davis SD, Lombardi E, et al; American Thoracic Society/European Respiratory
Society Working Group on Infant and Young Children Pulmonary Function Testing. An official
American Thoracic Society/European Respiratory Society statement: pulmonary function
testing in preschool children. Am J Respir Crit Care Med. 2007;175(12):1304–1345
PMID: 17545458 doi: 10.1164/rccm.200605-642ST
22. Fromageot C, Lofaso F, Annane D, et al. Supine fall in lung volumes in the assessment of
diaphragmatic weakness in neuromuscular disorders. Arch Phys Med Rehabil.
2001;82(1):123–128 PMID: 11239298 doi: 10.1053/apmr.2001.18053
23. Poussel M, Kaminsky P, Renaud P, Laroppe J, Pruna L, Chenuel B. Supine changes in lung
function correlate with chronic respiratory failure in myotonic dystrophy patients. Respir Physiol
Neurobiol. 2014;193:43–51 PMID: 24440340 doi: 10.1016/j.resp.2014.01.006
24. Sheehan DW, Birnkrant DJ, Benditt JO, et al. Respiratory management of the patient with
Duchenne muscular dystrophy. Pediatrics. 2018;142(suppl 2):S62–S71 PMID: 30275250
doi: 10.1542/peds.2018-0333H
25. Bach JR. Mechanical insufflation-exsufflation: comparison of peak expiratory flows with
manually assisted and unassisted coughing techniques. Chest. 1993;104(5):1553–1562
PMID: 8222823 doi: 10.1378/chest.104.5.1553
26. King M, Brock G, Lundell C. Clearance of mucus by simulated cough. J Appl Physiol.
1985;58(6):1776–1782 PMID: 4008399 doi: 10.1152/jappl.1985.58.6.1776
27. Bach JR, Saporito LR. Criteria for extubation and tracheostomy tube removal for patients
with ventilatory failure: a different approach to weaning. Chest. 1996;110(6):1566–1571
PMID: 8989078 doi: 10.1378/chest.110.6.1566
28. Kotwal N, Shukla PJ, Perez GF. Peak cough flow in children with neuromuscular disorders.
Lung. 2020;198(2):371–375 PMID: 32095889 doi: 10.1007/s00408-020-00340-7
29. Caruso P, Albuquerque AL, Santana PV, et al. Diagnostic methods to assess inspiratory and
expiratory muscle strength. J Bras Pneumol. 2015;41(2):110–123 PMID: 25972965
doi: 10.1590/S1806-37132015000004474
30. American Thoracic Society/European Respiratory Society. ATS/ERS statement on respiratory
muscle testing. Am J Respir Crit Care Med. 2002;166(4):518–624 PMID: 12186831
doi: 10.1164/rccm.166.4.518
31. Arnall DA, Nelson AG, Owens B, et al. Maximal respiratory pressure reference values for
Navajo children ages 6–14. Pediatr Pulmonol. 2013;48(8):804–808 PMID: 23661611
doi: 10.1002/ppul.22645

966
32. Mellies U, Stehling F, Dohna-Schwake C. Normal values for inspiratory muscle function
in children. Physiol Meas. 2014;35(10):1975–1981 PMID: 25229979
doi: 10.1088/0967-3334/35/10/1975
33. Stehling F, Alfen K, Dohna-Schwake C, Mellies U. Respiratory muscle weakness and respiratory
failure in pediatric neuromuscular disorders: the value of noninvasive determined tension-time
index. Neuropediatrics. 2016;47(6):374–379 PMID: 27552026 doi: 10.1055/s-0036-1587593
34. Nève V, Cuisset JM, Edmé JL, et al. Sniff nasal inspiratory pressure in the longitudinal
assessment of young Duchenne muscular dystrophy children. Eur Respir J. 2013;42(3):671–680
PMID: 23258781 doi: 10.1183/09031936.00127712
35. Orlikowski D, Prigent H, Quera Salva MA, et al. Prognostic value of nocturnal hypoventilation
in neuromuscular patients. Neuromuscul Disord. 2017;27(4):326–330 PMID: 28153460
doi: 10.1016/j.nmd.2016.12.006
36. Mah JK. An overview of recent therapeutics advances for Duchenne muscular dystrophy.
Methods Mol Biol. 2018;1687:3–17 PMID: 29067652 doi: 10.1007/978-1-4939-7374-3_1
37. Salmaninejad A, Jafari Abarghan Y, Bozorg Qomi S, et al. Common therapeutic advances for
Duchenne muscular dystrophy (DMD). Int J Neurosci. 2021;131(4):370–389 PMID: 32241218
doi: 10.1080/00207454.2020.1740218
38. Ramdas S, Servais L. New treatments in spinal muscular atrophy: an overview of currently
available data. Expert Opin Pharmacother. 2020;21(3):307–315 PMID: 31973611
doi: 10.1080/14656566.2019.1704732
39. Gilgoff I, Prentice W, Baydur A. Patient and family participation in the management of
respiratory failure in Duchenne’s muscular dystrophy. Chest. 1989;95(3):519–524
PMID: 2920577 doi: 10.1378/chest.95.3.519
40. Labanowski M, Schmidt-Nowara W, Guilleminault C. Sleep and neuromuscular disease:
frequency of sleep-disordered breathing in a neuromuscular disease clinic population.
Neurology. 1996;47(5):1173–1180 PMID: 8909425 doi: 10.1212/WNL.47.5.1173
41. Brunetti L, Rana S, Lospalluti ML, et al. Prevalence of obstructive sleep apnea syndrome in a
cohort of 1,207 children of southern Italy. Chest. 2001;120(6):1930–1935 PMID: 11742924
doi: 10.1378/chest.120.6.1930
42. Suresh S, Wales P, Dakin C, Harris MA, Cooper DG. Sleep-related breathing disorder in
Duchenne muscular dystrophy: disease spectrum in the paediatric population. J Paediatr Child
Health. 2005;41(9–10):500–503 PMID: 16150067 doi: 10.1111/j.1440-1754.2005.00691.x
43. Panitch HB. Respiratory issues in the management of children with neuromuscular disease.
Respir Care. 2006;51(8):885–893 PMID: 16867199
44. Piper A. Sleep abnormalities associated with neuromuscular disease: pathophysiology and
evaluation. Semin Respir Crit Care Med. 2002;23(3):211–219 PMID: 16088613
doi: 10.1055/s-2002-33029
45. Perrin C, Unterborn JN, Ambrosio CD, Hill NS. Pulmonary complications of chronic
neuromuscular diseases and their management. Muscle Nerve. 2004;29(1):5–27 PMID: 14694494
doi: 10.1002/mus.10487
47. Keating JM, Collins N, Bush A, Chatwin M. High-frequency chest-wall oscillation in a
noninvasive-ventilation-dependent patient with type 1 spinal muscular atrophy. Respir Care.
48. Lechtzin N, Wolfe LF, Frick KD. The impact of high-frequency chest wall oscillation on
healthcare use in patients with neuromuscular diseases. Ann Am Thorac Soc. 2016;13(6):904–909
49. Garstang SV, Kirshblum SC, Wood KE. Patient preference for in-exsufflation for secretion
management with spinal cord injury. J Spinal Cord Med. 2000;23(2):80–85 PMID: 10914345
doi: 10.1080/10790268.2000.11753511
50. McKim DA, Katz SL, Barrowman N, Ni A, LeBlanc C. Lung volume recruitment slows
pulmonary function decline in Duchenne muscular dystrophy. Arch Phys Med Rehabil.
2012;93(7):1117–1122 PMID: 22421625 doi: 10.1016/j.apmr.2012.02.024
51. O’Sullivan R, Carrier J, Cranney H, Hemming R. Effect of lung volume recruitment on
pulmonary function in progressive childhood-onset neuromuscular disease: a systematic review.
Arch Phys Med Rehabil. 2021;102(5):976–983 PMID: 32882219 doi: 10.1016/j.apmr.2020.07.014
52. Topin N, Matecki S, Le Bris S, et al. Dose-dependent effect of individualized respiratory muscle
training in children with Duchenne muscular dystrophy. Neuromuscul Disord.
2002;12(6):576–583 PMID: 12117483 doi: 10.1016/S0960-8966(02)00005-6

967
53. Brasil Santos D, Vaugier I, Boussaïd G, Orlikowski D, Prigent H, Lofaso F. Impact of

noninvasive ventilation on lung volumes and maximum respiratory pressures in Duchenne
muscular dystrophy. Respir Care. 2016;61(11):1530–1535 PMID: 27794082
54. Chen TH, Hsu JH, Wu JR, et al. Combined noninvasive ventilation and mechanical
in-exsufflator in the treatment of pediatric acute neuromuscular respiratory failure.
55. Amin R, Sayal P, Syed F, Chaves A, Moraes TJ, MacLusky I. Pediatric long-term home
mechanical ventilation: twenty years of follow-up from one Canadian center. Pediatr Pulmonol.
2014;49(8):816–824 PMID: 24000198 doi: 10.1002/ppul.22868
56. Pavone M, Verrillo E, Onofri A, Caggiano S, Chiarini Testa MB, Cutrera R. Characteristics and
outcomes in children on long-term mechanical ventilation: the experience of a pediatric tertiary
center in Rome. Ital J Pediatr. 2020;46(1):12 PMID: 32005269 doi: 10.1186/s13052-020-0778-8
57. DiFeo N, Meltzer LJ, Beck SE, et al. Predictors of positive airway pressure therapy adherence in
children: a prospective study. J Clin Sleep Med. 2012;8(3):279–286 PMID: 22701385
doi: 10.5664/jcsm.1914
58. Fauroux B, Lavis JF, Nicot F, et al. Facial side effects during noninvasive positive pressure
ventilation in children. Intensive Care Med. 2005;31(7):965–969 PMID: 15924228
doi: 10.1007/s00134-005-2669-2
59. Villa MP, Pagani J, Ambrosio R, Ronchetti R, Bernkopf E. Mid-face hypoplasia after long-term
nasal ventilation. Am J Respir Crit Care Med. 2002;166(8):1142–1143 PMID: 12379564
doi: 10.1164/ajrccm.166.8.257c
60. Pinto T, Chatwin M, Banfi P, Winck JC, Nicolini A. Mouthpiece ventilation and complementary
techniques in patients with neuromuscular disease: a brief clinical review and update. Chron
Respir Dis. 2017;14(2):187–193 PMID: 27932555 doi: 10.1177/1479972316674411
61. Fauroux B, Khirani S, Griffon L, Teng T, Lanzeray A, Amaddeo A. Non-invasive ventilation
in children with neuromuscular disease. Front Pediatr. 2020;8:482 PMID: 33330262
doi: 10.3389/fped.2020.00482
62. Hess DR. Noninvasive ventilation for neuromuscular disease. Clin Chest Med.
2018;39(2):437–447 PMID: 29779601 doi: 10.1016/j.ccm.2018.01.014
63. Praud JP. Long-term non-invasive ventilation in children: current use, indications, and
contraindications. Front Pediatr. 2020;8:584334 PMID: 33224908 doi: 10.3389/fped.2020.584334
64. Sunkonkit K, Al-Saleh S, Chiang J, et al. Volume-assured pressure support mode for noninvasive
ventilation: can it improve overnight adherence in children with neuromuscular disease?
Sleep Breath. 2021;25(4):1843–1850 PMID: 33469734 doi: 10.1007/s11325-021-02288-1
65. Edwards JD, Panitch HB, Constantinescu A, Miller RL, Stone PW. Survey of financial burden
of families in the U.S. with children using home mechanical ventilation. Pediatr Pulmonol.
2018;53(1):108–116 PMID: 29152895 doi: 10.1002/ppul.23917
66. Nonoyama ML, Katz SL, Amin R, et al. Healthcare utilization and costs of pediatric home
mechanical ventilation in Canada. Pediatr Pulmonol. 2020;55(9):2368–2376 PMID: 32579273
doi: 10.1002/ppul.24923
An Official American Thoracic Society clinical practice guideline: pediatric chronic home
doi: 10.1164/rccm.201602-0276ST
68. Sherman JM, Davis S, Albamonte-Petrick S, et al. Care of the child with a chronic tracheostomy.
This official statement of the American Thoracic Society was adopted by the ATS Board of
Directors, July 1999. Am J Respir Crit Care Med. 2000;161(1):297–308 PMID: 10619835
doi: 10.1164/ajrccm.161.1.ats1-00
69. Birnkrant DJ, Panitch HB, Benditt JO, et al. American College of Chest Physicians consensus
statement on the respiratory and related management of patients with Duchenne muscular
dystrophy undergoing anesthesia or sedation. Chest. 2007;132(6):1977–1986 PMID: 18079231
doi: 10.1378/chest.07-0458
70. Birnkrant DJ, Bushby K, Bann CM, et al; DMD Care Considerations Working Group. Diagnosis
and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and
orthopaedic management. Lancet Neurol. 2018;17(4):347–361 PMID: 29395990
doi: 10.1016/S1474-4422(18)30025-5
71. Birnkrant DJ, Bushby K, Bann CM, et al; DMD Care Considerations Working Group. Diagnosis
and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular,
rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol.
2018;17(3):251–267 PMID: 29395989 doi: 10.1016/S1474-4422(18)30024-3

968
72. Bushby K, Finkel R, Birnkrant DJ, et al; DMD Care Considerations Working Group. Diagnosis
and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary
care. Lancet Neurol. 2010;9(2):177–189 PMID: 19945914 doi: 10.1016/S1474-4422(09)70272-8
73. Natera-de Benito D, Aguilera-Albesa S, Costa-Comellas L, et al; Neuromuscular Working Group
of Spanish Pediatric Neurology Society. COVID-19 in children with neuromuscular disorders.
J Neurol. 2021;268(9):3081–3085 PMID: 33387010 doi: 10.1007/s00415-020-10339-y
74. Tseng YH, Chen TH. Care for patients with neuromuscular disorders in the COVID-19 pandemic
era. Front Neurol. 2021;12:607790 PMID: 33841296 doi: 10.3389/fneur.2021.607790
75. American Academy of Pediatrics Section on Cardiology and Cardiac Surgery. Cardiovascular
health supervision for individuals affected by Duchenne or Becker muscular dystrophy.

PART
11
Treating and Managing
Pulmonary Disease
Chapter 55. Airway Clearance Techniques..................................... 971

Chapter 56. Aerosol Delivery of Medication............................................. 991

Chapter 57. Bronchodilators............................................................................... 1005

John Welter, MD; H. William Kelly, PharmD; and Leslie Hendeles, PharmD
Chapter 58. Antibiotics for Pulmonary Conditions........................... 1019

Michael J. Light, MD; Nanda Ramchandar, MD, MPH, FAAP; and John S. Bradley,
MD, FAAP
Chapter 59. Nutritional Aspects of Pulmonary Conditions......... 1045

Ellen K. Bowser, MS, RDN, LDN, RN, FAND, and Mary H. Wagner, MD
Chapter 60. Oxygen Therapy............................................................................. 1061

Shyall Bhela, MD, and Sankaran Krishnan, MD, MPH
Chapter 61. Nicotine and Tobacco................................................................. 1083

Harold J. Farber, MD, MSPH, FAAP, and Marianna Martin Sockrider, MD, DrPH,
FAAP
Chapter 62. Tracheostomy..................................................................................... 1111

Chapter 63. Home Ventilation............................................................................ 1125

Howard B. Panitch, MD, and Thomas G. Keens, MD, FAAP
969
65 PP 2ND ED - PO 11_969-970.indd 969 11/6/23 9:46 AM

65 PP 2ND ED - PO 11_969-970.indd 970 9/12/23 11:15 AM
CHAPTER
55
Airway Clearance Techniques
Introduction
Normal Airway Clearance
Typically, the clearance of airway secretions relies on 2 defense mechanisms:
the mucociliary escalator and cough clearance. The mucociliary escalator
requires normally functioning cilia and a normal airway surface liquid and
mucus layer. These components of airway clearance function in the small
airways as well as the larger cartilaginous airways (Figure 55-1). Cough
clearance function is limited to the larger central airways and requires normal
inspiration, vocal cord closure, and expiration, as well as adequate rigidity of
the airway.
Cuboidal epithelial
Aqueous layer
Gel layer
(mucus)
(Sol)
cells
Airway lumen
Mucus
Water/cilia
Epithelial cells
Figure 55-1. Components of normal airway clearance.
971

972
Abnormal Airway Clearance

Children who lack any factor involved in the 2 main mechanisms, mucociliary
escalator or cough clearance, will have difficulty with normal airway clearance.
See Table 55-1 for the types of abnormalities that relate to lack of the required
components for appropriate airway clearance.
Table 55-1. Abnormalities Related to the Lack of Physical Components of Airway Clearance
Diagnostic Anatomical or
Category Functional Abnormality Pathophysiology
MUCOCILIARY ESCALATOR
Cilial dysfunction Primary ciliary dyskinesia Cilia immotile or dyskinetic
Abnormal airway Cystic fibrosis Reduced airway surface liquid; thick
surface liquid/ and viscous mucus layer; increased
mucus layer inflammatory mediators; increased
destructive compounds (elastases,
proteases)
Pseudohypoaldosteronism Increased volume of airway surface
liquid; intermittent airway obstruction
and infection as young children,
typically younger than 6 years
Asthma Abnormal and increased mucus
Airway edema
COUGH CLEARANCE
Neuromuscular Duchenne muscular Combined respiratory motor defects
disease dystrophy, spinal with abnormal inspiratory pressure
muscular atrophy, generation (limiting full inspiration)
congenital myopathies and/or expiratory pressure generation
(limiting peak cough flow rates and
shear force); bulbar dysfunction with
aspiration and/or gastroesophageal
reflux (causing chronic injury to
epithelium, further altering function)

973
Chapter 55—Airway Clearance Techniques
Table 55-1. Abnormalities Related to the Lack of Physical Components of Airway

Clearance (continued)
Diagnostic Anatomical or
Category Functional Abnormality Pathophysiology
Neuromotor disease Cerebral palsy Inability to control and/or sense
secretions in the airways or pharynx,
bulbar palsy, direct aspiration, severe
muscle imbalance causing scoliosis;
can be associated with impaired cough,
poor nasopharyngeal motor tone with
subsequent upper airway obstruction
and possible obstructive sleep apnea
Phrenic nerve injuries Profound diaphragmatic dysfunction
sometimes associated with paradoxical
motion
Traumatic or Can damage phrenic nerve and
postoperative head innervation of intercostal muscles and
and spinal cord injury accessory muscles, affecting bellows
function
Meningomyelocele Bellows dysfunction and progressive
(spina bifida) scoliosis variable depending on spinal
level affected
Neurologic Bulbar palsy and Inability to control oral secretions and/or
encephalopathy swallow, may include direct aspiration
Unstable airways Airway malacia Airways narrow/collapse with dynamic
pressure changes during inspiration
and/or expiration; phase of ventilation
affected varies: inspiratory for
obstruction above thoracic inlet or
expiratory
for obstruction below thoracic inlet
Tracheoesophageal fistula, See airway malacia; direct airway
VACTERL syndrome damage from aspiration
Bronchiectasis Progressive infection/injury causing
(bronchiolitis obliterans, cartilage destruction with collapsible
cystic fibrosis, immuno- and dilated airways similar to airway
deficiency, primary malacia.
ciliary dyskinesia,
postinfection/
tuberculosis)
Obstructed airway Tracheal stenosis Inadequate lumen for airflow and
secretion clearance
Scoliosis Airway rotational deformities
(“kinking”) and muscle imbalance
that can be progressive
Abbreviation: VACTERL, vertebral anomaly, anal atresia, cardiac defect, tracheoesophageal fistula, renal,
limb abnormalities.

974
Considerations Unique to Infants and Children

For several reasons, children are more susceptible than adults to complications
related to compromised airway clearance. The mucus of children is more
acidic and may have greater viscosity. Infants and children have an overly
compliant chest wall and relatively stiff lungs, leading to a lower functional
residual capacity. Furthermore, the airways are smaller, have less cartilage
support, and tend to collapse more easily than in adults. Finally, the bronchioles
and alveoli of children have fewer channels for collateral ventilation than those
of adults.1
Airway clearance therapy (ACT) is more difficult in infants and children
because of difficulties in obtaining cooperation. In addition, gastroesophageal
reflux is common but can be difficult to diagnose and can be aggravated par-
ticularly by a head-down drainage position.2,3 Unfortunately, data regarding
the use of ACT in children are limited. Children who require ACT often have
rare diseases; adequately powered trials are the exception rather than the
rule. Placebo-controlled studies are not possible, and the length of time needed
to judge treatment efficacy for chronic conditions can be long, making studies
costly and increasing the likelihood of nonadherence and attrition. Much
of what is known is based on case reports, small single-center studies, and
clinician experience, although increasingly meta-analyses and Cochrane
reviews are available. A meta-analysis and multiple Cochrane reviews found
low-quality evidence that chest and airway oscillatory devices and a mix of
ACTs reduce symptoms of breathlessness and cough and improve ease of
sputum expectoration compared to no treatment. The 2015 Cochrane review
includes an overview of multiple prior reviews on non–cystic fibrosis (CF)
bronchiectasis, finding airway clearance techniques may reduce sputum
production and improve quality of life. The most recent review of 2019 gives
overview of all reviews pertaining to CF and concludes that no treatment is
superior and other factors often drive selection of ACT. 4–9 Patients with CF are
the most frequently studied and account for the majority of reports in children.

Airway clearance therapy may be independently performed, relying on the
patient’s breathing skills, or may depend on other persons or machines. For
any patient, the appropriate method is one that is effective, affordable, fea-
sible, and repeatable. Importantly, a patient’s ability to choose their method
of airway clearance can also improve adherence. Box 55-1 lists the various
airway clearance techniques divided into the independent and dependent
skills categories with reference to the known physiological effects, costs,
and preferences. Parents and caregivers can teach children a vocabulary
regarding breathing that helps them learn to cooperate and participate in

975
clearing secretions. This can include simple words and phrases like breathe
in, breathe out, cough, take a big breath, blow, and hold your breath.
Box 55‑1
Independent Methods (free once trained; no equipment or assistance needed)
ū Directed cough huff maneuver
ū Active cycle of breathing techniques
ū Autogenic drainage
Dependent Methods (variable cost, free if family member helping or costly if
persons outside the home required)
ū Chest physical therapy, also known as postural drainage and percussion
and vibration
ū Manual cough assist
Handheld Device Required (minimal expense, $15–$200)
ū Manual percussor for chest physical therapy
ū Positive expiratory pressure valve (example: threshold or flow positive-pressure
valves)
ū Oscillating positive expiratory pressure devices (examples: TheraPEP, Flutter,
Aerobika)
Large Machine Required (most expensive: $400–$17,000, depending on
rent vs purchase and manufacturer vs reseller )
ū High-frequency chest wall compression (examples: The Vest, AffloVest,
SmartVest)
ū Mechanical in-exsufflator (examples: cough assist device)
ū Intrapulmonary percussive ventilator
Independent Techniques
Huff Cough Maneuver
Coughing clears normal airways quite effectively in healthy people. The
components of cough include inspiration, glottic closure, and expulsion via
forced exhalation. Coughing causes compression of the airways that moves
secretions from the smaller to the larger airways and toward the mouth.10
A cough is less effective if the airways are unstable and collapsible, and a
modification of cough (huff cough or forced expiratory maneuver) can help
decrease the compression of these airways. The huff maneuver is performed
by inhaling at various lung volumes and then exhaling with a slightly open
glottis.3 This is easily mimicked by the skill of “fogging a mirror.” The force
of exhalation is adjusted to avoid wheezing and airway collapse. Maintenance
of the open glottis avoids the excessive transmural pressures that cause airway
closure and limit secretion clearance. This skill is easy to teach and effective
for patients with collapsible airways.

976
Active Cycle of Breathing Technique

Active cycle of breathing techniques (ACBTs) combine the huff maneuver
with 2 other skills: diaphragmatic (or relaxed) breathing and thoracic expan-
sions (or deep rib breathing). Relaxed, diaphragmatic breathing occurs during
gentle inhalation using the diaphragm and allowing the abdomen to expand.3
Children often call this “belly breathing.” A child may learn this skill by
placing a favorite stuffed animal on the abdomen and watching it rise up
and down. During exhalation, the abdominal muscles are used and, with
successive breaths, large volumes are moved with improved ventilation of
the dependent lung tissue. Thoracic expansions rely more on intercostal
muscles with prominent chest expansion that improves upper lung expansion
and ventilation. The use of alternating cycles of diaphragmatic breaths with
thoracic breaths and huff maneuvers in ACBT can effectively and efficiently
mobilize and clear airways.11 This independent skill can be mastered and then
used anytime in any position, although it requires attention to be most
effective.
Autogenic Drainage
The most advanced and challenging independent skill is autogenic drainage.12
This technique is applied widely in adults and some children with CF but also
is used for adolescents and adults with bronchiectasis from any cause. The
skill is difficult to learn and typically requires a series of visits to a skilled
teacher. The patient is trained in 3 phases or levels that are serially completed:
breathing first at low-lung volumes to dislodge the mucus, then at mid-lung
volumes to collect the mucus, and then at high-lung volumes to expel the
mucus (Figure 55-2). Skilled performance of this technique is associated
Figure 55-2. The 3 phases or levels of autogenic drainage.

Reproduced with permission of the European Respiratory Society. © ERS 2023: European Respiratory Review
26 (143) 160086; DOI: 10.1183/16000617.0086-2016 Published 21 February 2017.

977
with improved oxygenation and minimization of work to expectorate.13 It

also is associated with improved oxygenation and minimization of work to
expectorate.13 Additionally, it reduces the likelihood of coughing fits that are
typically caused by forced coughing in those with unstable airways and
excessive secretions. A recent Cochrane review of autogenic drainage
compared to multiple other clearances found it not superior; studies were
inadequately powered to determine if the technique was non-inferior. Larger
studies, including quality of life outcomes, are needed.14
Dependent Techniques
Chest Physical Therapy
Chest physical therapy (CPT) may include postural drainage, percussion,
and vibration. Though multiple alternative strategies for ACT exist, this
is the first developed and still used for infants with a number of illnesses
that impair airway clearance. Parents are taught the technique and use it until
an infant’s chest circumference is large enough to fit a vest or until the child
develops language skills to permit teaching other ACTs. Classically, patients
are placed into a position to permit gravity to assist in mucus flow. The chest
wall is percussed to loosen the mucus during both inspiration and expira-
tion; intermittently, a prolonged exhalation with chest wall vibration is
applied as a final attempt to move mucus. Applying the vibrations is the
most difficult component for the respiratory therapist, physical therapist,
and families and, as a result, can be omitted. This technique is widely
practiced but has a number of drawbacks. Complications have been shown to
include desaturations, gastroesophageal reflux, aspiration, pain, fractured
ribs, and headaches.3 In addition, this technique requires assistance, leading
to poor adherence as long-term therapy when patients begin to seek inde-
pendence.11,13,15,16 Care providers performing CPT can also experience pain or
musculoskeletal abnormalities.3 This can be partially circumvented by the
use of mechanical devices. Typical postural drainage positions for children
are shown in Figure 55-3.
Augmented cough, also known as manual cough assist, is used for patients
with neuromuscular disease who cannot generate an effective cough. This
maneuver involves a Heimlich-like procedure where the caregiver uses the
heel of the hand to thrust from the abdomen toward the diaphragm in concert
with patient efforts to cough. Manual cough assist is most effective if the
child is supine.17

978
Self-Percussion—Upper Lobes
Child sits upright and reaches
across the chest to clap self on
front of chest over the muscular
area between the collarbone and
the top of the shoulder blade.
Upper Front Chest—Upper Lobes

Sitting
Child sits upright. Caregiver claps on
both sides of upper front chest over
the muscular area between the
collarbone and the top of the
shoulder blade.
Figure 55-3A and Figure 55-3B. Illustrations demonstrate typical

chest physical therapy drainage positions for children.

979
Upper Back Chest—Upper Lobes

Child sits up and leans forward on a
pillow over the back of a soft chair at a
30-degree angle. Caregiver stands or
sits behind child and claps both sides
of the upper back, taking care not to
clap on child’s backbone.
Upper Front Chest—Upper Lobes

Lying
Child lies on their back with
arms to sides. Caregiver stands
behind child’s head and
claps both sides of child’s
chest between the
collarbone and nipple.
Figure 55-3C and Figure 55-3D. Illustrations demonstrate typical chest physical therapy
drainage positions for children.

980
Right and Left Side—Front Chest

Child lies with right or left side up
and raises the arm over the head.
Caregiver claps over the lower chest
just below the nipple area on front
side of the chest. Do not clap lower
rib cage.
Lower Back Chest—Lower Lobe

Child lies on stomach. Caregiver
claps both sides at bottom of chest
just above the bottom edge of the
rib cage. Do not clap lower rib cage
or over the backbone.
Figure 55-3E and Figure 55-3F. Illustrations demonstrate typical chest physical therapy
drainage positions for children.

981
Left and Right Lower Side Back Chest—Lower Lobes

Child lies with left or right side up and rolls
toward caregiver a quarter turn so caregiver can
reach child’s back. Caregiver claps on lower side
of chest just above the bottom edge of the
rib cage.
Figure 55-3G. Illustrations demonstrate typical chest physical therapy drainage positions
for children.
Positive Expiratory Pressure

Small handheld devices are often used for generating positive expiratory
pressure (PEP),15,18 which may be constant or oscillatory. In this technique,
the patient breathes in and out 5 to 20 times through a flow resistor, which
creates a positive pressure in the airways during exhalation. After a series
of breaths, the patient performs the huff cough maneuver. Positive-pressure
devices cause motion of air via collateral channels of ventilation (alveolar
pores of Kohn and
bronchiolar-alveolar
channel of Lambert)
to equalize alveolar
filling and facilitate
mucus clearance with
the huff cough. PEP
devices can be inex-
pensive, ranging from
$10 for the valve alone
up to $150 for a valve
with visual feedback
attachments. One
example is shown in
Figure 55-4.
Figure 55-4. Example of a positive expiratory pressure valve.

© 2022 ICU Medical Inc or its Affiliates. All rights reserved.

982
Oscillating PEP Devices

High-frequency oscillations were added to PEP therapy initially with the
advent of the flutter valve device (Figure 55-5), which was then followed by a
number of alternative devices, including the Acapella valve and the Aerobika,
that have different mechanisms by which they produce the desired oscillations.
As the patient exhales actively into the devices, PEP is initially generated that
rapidly subsides and then recurs. The oscillations produced by the devices aug-
ment shear forces during exhalations along the airway walls to loosen mucus.
The flutter valve produces these oscillations with the flutter of a steel ball
inside the device that moves during use. The Acapella valve uses magnets
adjusted at a specific distance to produce vibrations. Two Acapella colors
designate devices designed for younger (blue—low flow) and older (green—
high flow) children (Figure 55-6). The Aerobika Oscillating Positive Expira-
tory Pressure device uses a proprietary pressure oscillation dynamic that
provides intermittent resistance and creates positive pressure and oscillations
simultaneously (Figure 55-7). The PEP valve and the Aerobika can pair with
b
c
Figure 55-5. Example of the flutter valve, an oscillating positive expiratory

pressure (PEP) valve. The device comprises a mouthpiece (a), a plastic cone
(b), a steel ball (c), and a perforated cover (d). During exhalation through the
device, the tracheobronchial tree undergoes internal vibrations together with
repeated variations of the exhaled airflow against the resistance (PEP) and
oscillations of the endobronchial pressure (oscillating pressure). Oscillating PEP
is most commonly performed with the flutter device or the Acapella device.

983
aerosol delivery devices to reduce treatment times and improve drug deposi-
tion. The Aerobika is dishwasher safe. Resistance is position dependent for
the flutter, but independent for the Acapella and Aerobika devices. These
oscillating PEP devices are similar in cost. All require exhalation via a
mouthpiece or mask, thus requiring adequate muscle strength to form a tight
seal around the device, since oscillations and pressure can be lost in the oral
cavity. Pressure loss can be prevented by tightening the cheek muscles or
holding them with thumb and fingers, compressing the cheeks. Cochrane
reviews comparing multiple PEP techniques, both constant and oscillatory,
find the overall study quality is low and no particular device is superior.18
Figure 55-6. Example of the Acapella device, a handheld positive

expiratory pressure (PEP) oscillation device designed using
magnets; color-coded units (green for high flow, blue for low) help
customize treatment for younger and older children.
Figure 55-7. Example of

the Aerobika, a handheld
oscillating positive expiratory
pressure device.
High-Frequency Chest Wall Compression: Vests

A number of manufacturers have devised portable machines that apply
variable high-frequency oscillations directly to the chest wall via an inflated
jacket. Collectively, these machines are called vests. The devices require
power sources and tubing to connect the generator to the jacket. The person-
ally fitted jacket is applied to the chest and inflated to avoid frictional loss of
energy at the chest wall and to effectively transmit oscillations simultaneously
over the entire chest wall. The inflation pressure can be adjusted, as can the
oscillatory frequency. Vest devices move mucus from the periphery to central
airways, but actual clearance is required through huff or cough to expectorate

984
mucus (Figure 55-8). Small studies and case series of patients with cerebral
palsy and neuromuscular disease suggest that recurrent pneumonia in these
patients can be lessened or avoided with routine use.19 Some devices are
considered portable; most are stationary. Multiple companies market this
technology; the primary care clinician may consult with local CF center
providers and adult pulmonology teams for help selecting the best product.
Some devices are self-contained battery-powered jackets with oscillating
pods that are incorporated into the jacket, making it portable for moving
during therapy without a tethering cord to a power source (Figure 55-9).
These devices are suited for older teens and young adults with US Food &
Drug Administration approval gained in 2017. Infants can be fitted for a vest
once chest circumference at the nipple is at least 16 inches or 18 inches,
depending on the specific device.
Figure 55-8. Examples of vest

device (A) and generator (B).
Figure 55-9. Examples of portable vests.

985
Cough Assist Device

The cough assist device (CAD) is used to augment weak and ineffective
cough in patients with conditions such as neuromuscular diseases and spinal
trauma. Initially called the insufflator-exsufflator, the machine was renamed
the cough assist device and has been modified and updated to become truly
portable (Figure 55-10). This device generates both positive and negative
pressure breaths and can be
used in a manual or automatic
mode. The interface between
the patient and the device can
be a mouthpiece, mask, or air-
way tube (either endotracheal
or tracheal). Weaker patients
benefit by coughing along
with the machine as able
or can remain fully passive
with glottis open. Even young
children and infants can be
assisted by using this device.
More extensive explanations
of teaching and performing
Figure 55-10. Example of a cough assist device. these cough assist skills
are referenced.17,20
Intrapulmonary Percussive Ventilator
The intrapulmonary percussive ventilator (IPV) is another large machine
that provides a mouthpiece, mask, or tube interface. In this ventilator, positive
pressure is generated with jet pulses of air with carefully controlled flow via
pistons. The inspiration to expiration ratio is fully controlled so that expiration
time always exceeds inspiration time, ensuring that mucus clearance proceeds
in the direction of the mouth. Continuous aerosol is required in conjunction
with this device because the combination of large airflows and minute volumes
is excessively drying to the airways. Epinephrine or selective bronchodilators
are made for continuous airflow use. A recent pediatric review compared
9 trials, 3 in patients with CF and 6 in patients with non-CF bronchiectasis.
Intrapulmonary percussive ventilator was not superior to other methods of
airway clearance, but in patients without CF, it showed promising results
to treat and prevent atelectasis and reduce hospital length of stay without
adverse effects.21

986
Upkeep and Cost Considerations

Devices used for airway clearance require regular cleaning. The prescribing
physician should provide detailed information to the family and the primary
care physician regarding specific upkeep and maintenance considerations for
the specific devices. All the large devices for airway clearance are significantly
more costly than handheld devices (Table 55-2). Adherence is monitored via
Bluetooth technology to generate reports transmitted to the practitioner for
review. Disposable vests have also been developed to decrease costliness and
are able to function for approximately 1 year before requiring replacement.
The standard vest, CAD, and IPV are durable machines that serve patients for
many years. Cost may be borne by insurance companies, but used devices,
without maintenance contracts, are also available via online retailers for deep
discounts. Replacement is most often stimulated by the desire for a newer,
more portable device modification rather than a machine failure. These large
airway clearance devices can be used passively or combined in the cooperative
patient with active respiration strategies as described previously.
Table 55-2. Cost Comparisons of Airway Clearance Therapy Equipment
Respiratory Therapy Training
Device (approximately 1 hour
Airway Clearance Therapy Type Cost per session)
Chest physical therapy NA 1–2 sessions
Huff NA 1 session
Active cycle of breathing technique NA 2 sessions
Autogenic drainage NA 4–6 sessions
Positive expiratory pressure valve ~ $30 1 session
Flutter valve ~ $60–$150 1 session
Acapella ~ $30 1 session
Aerobika ~ $85 1 session
Vest ~ $7,900 1 session
Monarch Vest ~ $16,425 1 session
Cough assist device ~ $3,700 2–3 sessions
Intrapulmonary percussive ventilator ~ $9,500 1 session
Abbreviation: NA, not applicable.
Selection of Airway Clearance Technique

Infants or very young children typically require assistance and dependent
methods of ACT, traditionally using CPT or large machines. Vest jackets have
been developed even for infants with a chest size of 19 inches or more. Multi-
ple options are available, and therapies may be modified to suit maturity and
lifestyle. Additionally, offering patients input and choice of techniques can

987
increase adherence. Action plans are generally supplied to the patient with a
well plan using the ACT of choice for that patient at the frequency that main-
tains health, and a sick plan for more frequent therapy to support the child
through illnesses at home. Most sick plans include treatments at a maximum
of 4 times daily. Other enhancers of airway clearance can include exercise,
playing wind instruments, and vocal training.22 Many of the techniques in this
chapter are demonstrated in online videos; a listing of some helpful video links
can be found in Table 55-3. Many respiratory therapists and some physical
therapists who teach these skills become very proficient and can assist
providers in selecting and refining skills for airway clearance.
Table 55-3. Instructional Videos of Airway Clearance Techniques
Airway Clearance
Therapy Type Video Training/Demonstration: YouTube Videos
Chest physical Chest physical therapy for infants
therapy https://www.youtube.com/watch?v=4W1PSPJReRI
Huff Huff technique: Primary Children’s Hospital
https://www.youtube.com/watch?v=8UKd-GRNUFk
Active Cycle of ACBT: Primary Children’s Hospital
Breathing https://www.youtube.com/watch?v=dJ2--HnSEEM
Technique (ACBT)
ACBT: Derriford Hospital National Health Service (NHS)
https://www.youtube.com/watch?v=XvorhwGZGm8&t=8s
Autogenic drainage Autogenic drainage technique: Derriford Hospital NHS physiotherapy
https://www.youtube.com/watch?v=_n0nuy8VWmI
Positive expiratory Positive expiratory pressure technique: NHS physiotherapy
pressure valve https://www.youtube.com/watch?v=lqKD_XxwnAM
Acapella Acapella therapy for cystic fibrosis: NHS
https://www.youtube.com/watch?v=MNtdVQe9BDQ
Aerobika Aerobika OPEP: Primary Children’s Hospital
https://www.youtube.com/watch?v=F7YFJRXecjk
Vest Vest therapy for cystic fibrosis
Multiple options for hill rom, smartvest, afflo vest
Monarch Vest Monarch therapy for cystic fibrosis
https://www.youtube.com/watch?v=v8wlaVa5Wik
Cough assist device Cough assist device: Cincinnati Children’s
https://www.youtube.com/watch?v=0hAslVzfFLs
Intrapulmonary Percussionaire
percussive https://www.youtube.com/watch?v=COlzQWaRjpM
ventilator
Abbreviation: OPEP, oscillating positive expiratory pressure.

988
Inhaled Medications and Airway Clearance Techniques

Pharmacologic therapies to aid in airway clearance have primarily been
devised for and evaluated in patients with CF. Dornase alfa (recombinant
human deoxyribonuclease [DNase]) enzymatically cleaves DNA that is found
in high concentration in the sputum of patients with CF. The DNA is present
because of the necrosis of neutrophils that have been drawn into the airway
in response to infection. DNase has a significant impact on mucus viscosity,
improves pulmonary function in patients with CF, and decreases pulmonary
exacerbations in trials lasting 6 months to 2 years. Adverse effects are mini-
mal, including voice alteration and rash.23 It is sometimes used in children
with other conditions, but there is no evidence of effectiveness outside of
CF.8 Hypertonic saline (7%) has also been shown to be of benefit in patients
with CF, presumably by osmotically augmenting airway surface liquid.24
N-acetyl cysteine (10% solution) is thought to lyse disulfide bonds in mucin
and improve the liquidity and ease of removal, but there is little supporting
evidence for efficacy when inhaled, per a 2013 review.25 Subsequent to this
review, oral administration, which may affect glutathione production, was
proven to stabilize lung function compared to placebo in a randomized
controlled trial in patients with CF.26 Bronchodilators are helpful to relieve or
prevent bronchoconstriction in patients with airway hyperreactivity but are
not universally beneficial and might be detrimental in patients with tracheo-
malacia or bronchomalacia, who depend on smooth muscle tone to maintain
airway patency.27–29
Some children have copious oral secretions and continuous drooling and
chronically aspirate. Anticholinergics are often given and may be effective
and helpful. Alternatively, the child may be treated with botox injection to
salivary or submental glands to determine if temporary cessation of output is
helpful to airway clearance. This may help about 75% of patients but is most
often effective for 6 months. If so, more permanent gland ablation can be
performed sugically.

989
key points
} A wide selection of independent and dependent techniques is available to
improve airway clearance in patients.
} Use CPT for infants and very small children.
} Teach concepts related to breathing at a young age. Children need to learn a
vocabulary for these skills. Parents can teach them cough, breathe in, breathe
out, blow, etc. Preschool-aged children can learn diaphragmatic breathing and
the huff cough.
} Most pulmonary and respiratory specialists become skilled in the application of
these techniques and can assist generalists in decision-making regarding the
selection and refinement of ACT skills.
} Weaker patients with poor cough are best managed with manual cough
assistance or the CAD.
} The Cystic Fibrosis Foundation has developed comprehensive new guidelines
on airway clearance technique (https://www.cff.org/cf-airway-clearance-
therapies-clinical-care-guidelines), which are a good reference for patients
with CF or other diseases causing bronchiectasis and productive cough.
References
1. Schechter MS. Airway clearance applications in infants and children. Respir Care.
2007;52(10):1382–1390 PMID: 17894905
2. Button BM, Heine RG, Catto-Smith AG, Phelan PD, Olinsky A. Chest physiotherapy,
gastro-oesophageal reflux, and arousal in infants with cystic fibrosis. Arch Dis Child.
2004;89(5):435–439 PMID: 15102635 doi: 10.1136/adc.2003.033100
3. McIlwaine M. Chest physical therapy, breathing techniques and exercise in children with CF.
4. Bradley JM, Moran FM, Elborn JS. Evidence for physical therapies (airway clearance and
physical training) in cystic fibrosis: an overview of five Cochrane systematic reviews.
Respir Med. 2006;100(2):191–201 PMID: 16412951 doi: 10.1016/j.rmed.2005.11.028
5. Main E, Prasad A, Schans C. Conventional chesty physiotherapy compared to other airway
clearance techniques for cystic fibrosis. Conchrane Database Syst Rev. 2005;(1):CD002011
6. Hough JL, Flenady V, Johnston L, Woodgate PG. Chest physiotherapy for reducing respiratory
morbidity in infants requiring ventilatory support. Cochrane Database Syst Rev.
2008;(3):CD006445 PMID: 18646156 doi: 10.1002/14651858.CD006445.pub2
7. Lee AL, Burge AT, Holland AE. Airway clearance techniques for bronchiectasis. Cochrane
Database Syst Rev. 2015;(11):CD008351 PMID: 26591003
8. Welsh EJ, Evans DJ, Fowler SJ, Spencer S. Interventions for bronchiectasis: an overview of
Cochrane systematic reviews [Review]. Cochrane Database Syst Rev. 2015;(7):CD010337
PMID: 26171905 doi: 10.1002/14651858.CD010337.pub2
9. Wilson LM, Morrison L, Robinson KA. Airway clearance techniques for cystic fibrosis:
an overview of Cochrane systematic reviews. 2019;1(1):CD011231 PMID 30676656
https://doi.org10.1002/14651858.CD011231.pub2
10. West JB, Luks AM. Structure and function—how the architecture of the lung serves its function.
In: West’s Respiratory Physiology: The Essentials. 10th ed. Lippincott Williams & Wilkins;
2022:1–13
11. McIlwaine M. Chest physical therapy, breathing techniques and exercise in children with CF.
12. Chevaillier J. Autogenic drainage. In: Lawson D, ed. Cystic Fibrosis: Horizons. John Wiley &
Sons, Inc; 1984:235

990
13. Giles DR, Wagener JS, Accurso FJ, Butler-Simon N. Short-term effects of postural drainage with
clapping vs autogenic drainage on oxygen saturation and sputum recovery in patients with cystic
fibrosis. Chest. 1995;108(4):952–954 PMID: 7555167 doi: 10.1378/chest.108.4.952
14. McCormack P, Burnham P, Southern KW. Autogenic drainage for airway clearance in cystic
doi: 10.1002/14651858.CD009595.pub2
15. Hardy KA, Anderson BD. Noninvasive clearance of airway secretions. Respir Care Clin N Am.
1996;2(2):323–345 PMID: 9390886
16. Passero MA, Remor B, Salomon J. Patient-reported compliance with cystic fibrosis therapy.
Clin Pediatr (Phila). 1981;20(4):264–268 PMID: 7214782 doi: 10.1177/000992288102000406
17. Bach JR. Mechanical insufflation-exsufflation. Comparison of peak expiratory flows with
manually assisted and unassisted coughing techniques. Chest. 1993;104(5):1553–1562
PMID: 8222823 doi: 10.1378/chest.104.5.1553
18. Lee AL, Burge AT, Holland AE. Positive expiratory pressure therapy versus other airway
clearance techniques for bronchiectasis. Cochrane Database Syst Rev. 2017;9(9):CD011699
PMID: 28952156 doi: 10.1002/14651858.CD011699.pub2
19. Plioplys AV, Lewis S, Kasnicka I. Pulmonary vest therapy in pediatric long-term care. J Am Med
Dir Assoc. 2002;3(5):318–321 PMID: 12807620 doi: 10.1016/S1525-8610(05)70548-X
20. Auger C, Hernando V, Galmiche H. Use of Mechanical Insufflation-Exsufflation Devices for
Airway Clearance in Subjects With Neuromuscular Disease. Respir Care. 2017;62(2):236–245
21. 21. Lauwers E, Ides K, Von Hoorenbeeck K, Verhuls S. The efficacy of Intrapulmononary
Percussive Ventilator in pediatric patients: A systematic Review. Pediatr Pulmonol
201;Nov 53(11):1463–1474.
22. Irons JY, Petocz P, Kenny DT, Chang AB. Singing as an adjunct therapy for children and adults
with cystic fibrosis. Cochrane Database Syst Rev. 2019;7:CD008036 PMID: 31425607
doi: 10.1002/14651858.CD008036.pub5
23. Yang C, Montgomery M. Dornase alfa for cystic fibrosis. Cochrane Database Syst Rev.
2018;9:CD001127 PMID: 30187450
24. Elkins MR, Robinson M, Rose BR, et al; National Hypertonic Saline in Cystic Fibrosis
(NHSCF) Study Group. A controlled trial of long-term inhaled hypertonic saline in patients
with cystic fibrosis. N Engl J Med. 2006;354(3):229–240 PMID: 16421364
doi: 10.1056/NEJMoa043900
25. Tam J, Nash EF, Ratjen F, Tullis E, Stephenson A. Nebulized and oral thiol derivatives for
pulmonary disease in cystic fibrosis. Cochrane Database Syst Rev. 2013;2013(7):CD007168
PMID: 23852992 doi: 10.1002/14651858.CD007168.pub3
26. Conrad C, Lymp J, Thompson V, et al. Long-term treatment with oral N-acetylcysteine: affects
lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized
placebo-controlled trial. J Cyst Fibros. 2015;14(2):219–227 PMID: 25228446
doi: 10.1016/j.jcf.2014.08.008
27. Panitch HB, Keklikian EN, Motley RA, Wolfson MR, Schidlow DV. Effect of altering smooth
muscle tone on maximal expiratory flows in patients with tracheomalacia. Pediatr Pulmonol.
1990;9(3):170–176 PMID: 1980538 doi: 10.1002/ppul.1950090309
28. Panitch HB, Allen JL, Alpert BE, Schidlow DV. Effects of CPAP on lung mechanics in infants
with acquired tracheobronchomalacia. Am J Respir Crit Care Med. 1994;150(5 Pt 1):1341–1346
PMID: 7952562 doi: 10.1164/ajrccm.150.5.7952562
29. 29. Alvarenga A, Campos M, Dias M, Melão L, Estevão-Costa J. BOTOX-A injection of salivary
glands for drooling. J Pediatr Surg. 2017;52(8):1283-1286 PMID 28277296

CHAPTER
56
Aerosol Delivery of Medication
Introduction
Inhaled therapy is a mainstay of treatment for a wide variety of respiratory
diseases in children. Disease management guidelines recommend inhaled
corticosteroids and bronchodilators for controlling asthma, and mucoactive
agents and antibiotics for treatment of lung disease in cystic fibrosis (CF).1,2
There is also interest in using aerosols for systemic delivery of molecules
that would otherwise be degraded in the gut or require injection.
The challenges of successful delivery of drugs to the lungs are much greater
than those of either oral or systemic drug delivery. The respiratory tract is
efficient at filtering out foreign materials. Aerosol devices and breathing
techniques must be able to bypass these defenses to deposit drugs in the
lungs. The success of aerosol delivery depends on several complex, inter-
related factors. Improper use of aerosol devices is associated with poorer
clinical outcomes,3 so it is crucial that children and their caregivers be
familiar with aerosol principles and the correct operation of different
aerosol delivery devices.
Aerosol Principles
Advantages of Aerosols
Inhaled topical therapy potentially provides a high in situ concentration and
usually requires lower doses than systemic treatment, thus maximizing the
desired effects while reducing systemic effects.4 In the case of inhaled bron-
chodilators, the onset of action is far quicker than oral therapy, providing
rapid relief of bronchospasm. The improved therapeutic index of cortico-
steroids delivered by inhaled route helps to minimize side effects of adrenal
and growth suppression. Antibiotics like tobramycin inhalation solution can
achieve 100-fold the concentration in airway secretions vs the intravenous
route for children with CF, while reducing the risk of ototoxicity and nephro-
toxicity. The gut renders protein-based drugs inactive (eg, dornase alfa for
CF), making inhalation the best modality.
991

992
Aerosol Drug Delivery

An aerosol is a suspension of solid or liquid particles in a carrier gas. There are
numerous factors that influence particle deposition, including characteristics
of the aerosol itself as well as variables pertaining to the person inhaling the
aerosol4 (Box 56‑1).
Aerosol Variables Affecting Drug Delivery
Particle size distribution of an aerosol is one of the important factors that deter-
mine the likelihood of lower airway deposition. Aerosols are characterized by
the mass median aerodynamic diameter (MMAD) (ie, the size for which half
of the mass of the drug is contained in particles that are larger, and half in
particles that are smaller), and by the geometric standard deviation (GSD).
The MMAD and GSD are measures of central tendency and distribution
around it respectively. Drug deposition occurs due to different mechanisms:
inertial impaction, gravitational sedimentation, and Brownian diffusion
(random motion at the alveolar level). Fast-traveling aerosols, those with
MMAD greater than 3 mcm, and those that have to negotiate sudden changes
in direction are deposited by iner-
Box 56‑1 tial impaction. This is the main
Factors Determining deposition mechanism in upper
Aerosol Deposition and large airways. This explains
Aerosol Factors in part why newer inhaled cortico-
Particle size steroids formulated as solutions
Velocity (MMAD closer to 1 mcm) have
Hygroscopic properties lower upper airway deposition.
Drug viscosity and surface tension Aerosols between 0.5 and 3 mcm
Suspension vs solution are mainly deposited by gravita-
Use of add-on devices tional sedimentation. This is the
Patient Factors basis for recommending the use of
Breathing pattern (eg, tidal volume, rate) a breath-holding maneuver when
Age possible.4 Finally, particles smaller
Inspiratory flow rate than 0.5 mcm are either exhaled or
Nasal vs mouth breathing deposited by Brownian diffusion.
Anatomical differences Most pharmaceutical aerosols are
Cognitive abilities polydisperse (GSD greater than
Behavior 1.2). In theory, the larger particles
Acceptance of interface deposit more centrally and the
Contrivance smaller ones deposit more
Adherence distally in the airways.

993
Chapter 56—Aerosol Delivery of Medication
Patient Variables Affecting Drug Delivery

Patient variables, including tidal volume and respiratory rate, are important
for aerosol deposition. In general, the larger the inhaled tidal volume and the
slower the respiratory rate, the higher the lung deposition. In addition, as
previously noted, a breath hold at the end of inspiration improves deposition
for pressurized metered dose inhalers (pMDIs) but not for a continuously
operating nebulizer.
Upper airway anatomy influences the degree of lung deposition. Nasal
breathing can filter half of an aerosol drug before it can reach the lower
airways.5 The upper airways of infants and young children are much smaller
than those of an adult and also filter a considerable amount of drug before it
reaches the lungs. Probably for this reason, as well as for their shorter inspira-
tory times and lower tidal volumes, infants and young children do not require
a dose adjustment based on size, since the amount reaching the lung is
proportionately smaller.
Lower airway obstruction, as found in asthma, bronchiolitis, and CF, results
in more central and patchy intrapulmonary deposition. Infants and young
children also tend to deposit aerosol more centrally since their lower airways
also have a smaller caliber. Therefore, successful aerosol delivery to the
peripheral lung in sicker and younger patients is much more challenging.
A quick review of factors determining aerosol deposition (see Box 56‑1)
highlights the challenge of delivering aerosols to infants and young children.
They are preferential nose breathers and have smaller upper and lower
airway sizes, smaller tidal volumes, and more rapid respiratory rates. They do
not have the cognitive ability to follow commands or understand specialized
inhalation maneuvers, so they are restricted to devices that only require tidal
breathing, and those with a mask as the interface between device and patient.
Nebulizers and pMDIs attached to a valved holding chamber (VHC) can
have mask attachments, but the masks must be applied close to the child’s
face with a nebulizer to prevent escape of aerosol, and they must be tight
fitting with a VHC to draw the medication out of the chamber. Unfortunately, a
high proportion of young children do not tolerate masks, even with repeated
use, and become fussy or cry during the treatment.6 The crying child exempli-
fies the challenges faced by physicians because crying involves a prolonged
exhalation, followed by a rapid inhalation. Thus, drug is wasted from the
device during the long exhalation, and the rapid inhalation increases impaction
in the upper airways, resulting in low lung deposition.7
To optimize aerosol delivery in small children, first choose the delivery device
and interface that are best tolerated. This will require some trial and error, and
the prescribed drug must be available in the desired delivery devices. Second,
distract the child during aerosol administration with toys or videos, and try to

994
make a game out of it with incentives for good performance. They should not
regard their treatments as a form of punishment, and they may not comprehend
that the medication is to make them feel better. Using the blow-by technique
with a nebulizer (holding the mask away from the face) is discouraged, based
on in vitro and deposition studies.7 Finally, there is evidence that providing
aerosols with less than 2.5 mcm to children younger than 3 years may enhance
aerosol delivery to the lungs.8
Aerosol Delivery Devices

Systems for delivery of inhaled medications include wet nebulizers, pMDIs,
soft mist inhalers, and dry powder inhalers (DPIs). Each of these systems
has unique advantages and disadvantages, but most of these technologies
are decades old and are relatively inefficient in terms of the proportion of
the nominal dose reaching the lower airways (especially in children). These
inefficiencies have been tolerated for bronchodilators and inhaled cortico-
steroids because their dose-response curves are steep at low doses and their
therapeutic indexes are high. Novel delivery technologies have been designed
to improve delivery efficiency for newer therapies that are expensive, have a
lower therapeutic index, or require precision targeting to a particular part of
the airway (eg, gene therapy in CF).9
Nebulizers
Nebulizers are aerosol devices that convert a liquid solution or suspension into
an aerosol for inhalation. The 3 main types of nebulizers are the jet nebulizer
(sometimes called small-volume nebulizer); ultrasonic nebulizer; and mesh
nebulizer. The jet nebulizer is the type most commonly prescribed by pediatri-
cians, probably because of the relatively low cost and availability. Some
advantages and disadvantages of jet nebulizers are listed in Box 56‑2.
Jet Nebulizers
Jet nebulizers deliver compressed gas (supplied by an electric compressor,
hospital air, or oxygen) through a small jet orifice, generating a negative
pressure that draws fluid from the nebulizer cup. The fluid is entrained in
the stream of gas and sheared into particles. Larger, non-respirable particles
impact against a baffle and are recirculated, whereas smaller aerosol particles
are directed to the patient. Some evaporation and cooling occur when particles
are recycled, causing an increase in drug concentration in the residual volume
that remains in the nebulizer cup after the nebulization is complete. In general,
the residual volume ranges between 0.5 and 3 mL, thus wasting a large pro-
portion of the loaded dose. Practitioners should avoid the practice of decreas-
ing loading volume as a way of decreasing patient dose because of the fixed
residual volume.10 The aerosol characteristics and delivery efficiency may
differ by severalfold among different compressor-nebulizer combinations.11

995
Box 56‑2 Electronic compressors decay over

time, resulting in longer-than-usual
Advantages and Disadvantages delivery times.
of Jet Nebulizers
Advantages There are 3 different types of jet
Easy technique (tidal breathing) nebulizers. Continuous output jet
Can use at any age nebulizers are the most common and
Can use with any disease severity least expensive type. These devices
Can be used with artificial airways waste aerosol during exhalation.
Can be used with mechanical ventilation Breath-enhanced jet nebulizers
High doses possible (eg, can be used to incorporate a one-way valve that
deliver antibiotics) entrains air into the drug reservoir
Inexpensive during inspiration. This results in
Disadvantages increased aerosol output during
Bulky, less portable than pressurized inspiration and decreased waste
metered-dose inhalers or dry-powder during exhalation. Breath-actuated
inhalers nebulizers only release aerosol
Longer treatment times during inspiration, resulting in no
Require cleaning and disinfection waste during exhalation. If a unit
Noisy (may disturb infants) dose of drug is used, the length of
Require power source treatment may be longer but deliv-
High variability between nebulizer and ered dose will be higher. Depending
compressor brands
on the drug characteristics (dose-
response curve, side-effect profile),
dose adjustments may be necessary with a breath-actuated nebulizer. Since a
certain inspiratory flow is necessary to trigger the release of aerosol from these
devices, practitioners need to make sure that young patients can indeed achieve
this inspiratory flow.
Ultrasonic Nebulizers
Ultrasonic nebulizers operate with piezoelectric crystal that vibrates at a set
frequency and transfers energy to the fluid placed in a reservoir to produce a
mist.4 Ultrasonic nebulizers are quieter and faster than jet nebulizers, though
they produce a larger particle size than jet nebulizers, which may reduce the
dose that reaches the lungs. Ultrasonic nebulizers cannot effectively deliver
suspensions like budesonide12 and could potentially denature protein drugs
like dornase alfa due to heating produced during aerosolization.
Mesh Nebulizers
Mesh nebulizers are the most recent addition to the nebulizer menu. These
devices use a piezo element to either move a perforated membrane against the
solution to “micro-pump” the fluid through the holes (Aeroneb, Aerogen, and
eFlow, PARI Pharma), or to move a vibrating horn that shoots the fluid through
a mesh to create the aerosol (MicroAir, Omron).9 Mesh nebulizers are small and
silent, have small residual volumes, and are faster than most jet nebulizers.

996
Many mesh nebulizers are designed to only deliver a specific drug by match-
ing it to the size of the apertures of the plate. The available “open” devices are
designed to give approximately the same performance efficiency as a
breath-enhanced jet nebulizer. To do this, the particle size is larger to
compensate for the lower residual volume, thus offering no advantage other
than speed. Also, the micron-sized holes in the mesh are easily clogged, so
these devices are not suitable for suspensions like budesonide. These devices
are expensive and not always covered by insurance.
Nebulizer-Patient Interface
The interface between the nebulizer and patient is very important. Although
masks and mouthpieces seem to provide similar clinical benefits,13 the use of
the latter avoids drug filtering in the nose and decreases facial deposition and
potential side effects.14 Transition to mouthpiece can usually be done at age
4 years. Mask design is an important factor in minimizing side effects. Several
studies have shown that front-loaded masks lead to less ocular deposition than
bottom-loaded masks.14
Nebulizing Multiple Drugs
The nebulization of several drugs together is discouraged because of potential
changes in their characteristics. Albuterol and ipratropium bromide are an ex-
ception, though this combination is available commercially. Also, combining
unit-dose drugs will significantly increase the delivery time (more fluid to
nebulize), so combining drugs in the nebulizer would only be advantageous
if one of them is in a concentrated form.
Nebulizer Maintenance
Routine maintenance of nebulizers is often ignored. All nebulizers need to
be cleaned after each use and disinfected according to manufacturer’s instruc-
tions. Cleaning can be done by washing with soapy water followed by rinsing
and air-drying. Disinfection can be done by several methods, including boiling
in water for 5 minutes, immersion in 70% isopropyl alcohol (5 minutes) or 3%
hydrogen peroxide (30 minutes). Rinsing with sterile or filtered water will be
necessary if either alcohol or peroxide is used. Other options include micro-
waving in water (5 minutes) or using a dishwasher (30 minutes), provided
water remains hotter than 158°F.15 Disinfection with a steam sterilizer (like
those used for baby bottles) is advisable for mesh nebulizers and can be used
for jet nebulizers as well. It is also important to change compressor filters per
manufacturer’s recommendations.

997
Pressurized Metered-Dose Inhalers

Pressurized metered-dose inhalers are popular as delivery systems because
they are small and convenient to use. However, many errors in the inhaler
technique have been reported in both patients and caregivers.16,17 Each pMDI
canister contains micronized drug suspended (fluticasone) or dissolved
(beclomethasone and ciclesonide) in a propellant (hydrofluoroalkane). A
metering valve holds a few microliters of the suspension/solution, and when
the device is actuated, the metering chamber is exposed to the atmosphere and
the reduction in chamber pressure causes the rapid boiling of the propellant,
releasing the contents at a high velocity. A delay between shaking and firing
results in a significant variance of delivered dose of suspensions.18
The newer steroid formulations have a smaller MMAD (1.1–1.2 mcm) that
minimizes upper airway deposition19 and could be potentially advantageous
for younger children compared to solutions that have a larger MMAD.8,20
Spacers and Valved Holding Chambers
Metered-dose inhalers are often used with add-on devices like spacers and
VHCs. Spacers are valveless tubes that work by allowing deceleration of
the aerosol and shrinkage of the particles. Conversely, VHCs incorporate
a one-way valve to contain the
Box 56‑3
aerosol in the chamber for a few
Advantages and Disadvantages of seconds until the valve is opened
Metered-Dose Inhalers
by the patient’s inspiratory effort
Advantages and to divert the expiratory flow
Compact, portable away from the chamber. Both
Rapid delivery spacers and VHCs reduce the high
Multidose convenience oropharyngeal deposition (and
Any age (when used with a valved local side effects) of pMDIs, but
holding chamber)
only VHCs help overcome the
Most products have dose counters
difficulty in coordinating actuation
Disadvantages with inhalation; they are, therefore,
Cleaning and priming instructions are
favored over simple spacers.
specific for each product
Requires coordination for actuation Some of the advantages and
and inhalation disadvantages of pMDIs and
High oropharyngeal dose if not used VHCs are reviewed in Box 56‑3.
with valved holding chamber/spacer
Intolerance of tight face mask
(young children)
Limited number of drugs available

998
These delivery systems are portable and noiseless, can be used for children
of any age, and can be used with artificial airways (tracheostomies, intu-
bated patients). The biggest attraction is that they are less time-consuming
than nebulizers. There are only a few types of drugs available in pMDIs,
including bronchodilators and inhaled corticosteroids (asthma medications).
Most VHCs allow insertion of the pMDI mouthpiece into a connector, thus
using its own boot (plastic holder). Some VHCs require the pMDI canister to
be removed from its own plastic boot and inserted into a universal boot for
actuation. This could potentially change the aerosol characteristics; thus, this
type is not ideal.
There are several brands and designs of VHCs, leading to a high degree of
variability in dose delivery between devices.21 Many early devices are made
from polycarbonate, which has a high electrostatic charge and can reduce the
drug output. Most newer VHCs are manufactured with a charge-dissipating
material to overcome this problem. The electrostatic charge of older devices
can be neutralized by washing the VHC in soapy water and letting it air-dry
without rinsing the inside. Although VHCs overcome the need for precise
coordination, the aerosol does not stay suspended for more than a few seconds,
so a delay in inhalation will significantly decrease drug output. Also, the delay
between shaking and actuation should be minimal. Patients requiring more
than one actuation of medication should allow a 30-second interval between
them and shake the canister right before actuating it. Patients should inhale
the drug after each actuation.
Some VHCs have whistle systems that provide feedback when high inspiratory
flows are achieved. However, these signals are largely inaccurate and vary
with the design of pMDI.
Care and Use of Inhalers
The care of hydrofluoroalkane inhalers requires frequent cleaning of the
actuator’s orifice to avoid clogging. Inhalers need to be primed with their first
use and each time they are not used for prolonged periods (varies between pro-
ducts but may be as short as 2–3 days). Unfortunately, each device has differ-
ent instructions for cleaning and priming. The prescriber should be familiar
with the specifics of each drug.
The VHCs with mask attachments allow infants and young children to use
medication via pMDI. It is important to choose a mask with a small dead space
made of flexible material that forms a good seal with the face.22,23 A good seal
is necessary for the child to open the valve of the VHC, allowing access to the
medication in the chamber. For young children who tolerate a close-fitting face
mask, the pMDI with VHC is the preferred method for delivery of inhaled
asthma medications. However, more than one-third of infants and toddlers do
not tolerate the tight-fitting mask and should use the alternate delivery system.6

999
A transition to a VHC with mouthpiece is encouraged at about 3 to 4 years of

age to avoid drug filtering by the nose and eliminating facial exposure. Young
children can use tidal breathing (3–4 breaths) with the VHC until they are old
enough to comprehend single-breath technique.24 When children reach 4 to
6 years of age, they can be taught to exhale first, seal their lips around the
mouthpiece, actuate the pMDI, and slowly inhale to full lung capacity, with
a 10-second breath hold to allow particles to settle in the airways. The same
technique applies for a pMDI without a VHC, though with corticosteroids
the use of a VHC reduces topical oropharyngeal effects.
Most pMDIs have dose counters that document the number of remaining
doses. Patients should be reminded not to use the pMDI once the counter
reaches zero. The use of pMDIs without a counter is discouraged due to
patients’ inability to easily know when the device is empty.
Recently, beclomethasone pMDI was changed from regular pMDI to a breath-
actuated one. The latter requires an inspiratory flow of at least 20 L/min to
actuate the device, making it not a viable option for either young children or
those who use VHCs. Breath-actuated devices are ideal for teens, who do not
typically like to use VHCs.
Soft Mist Inhalers

Soft mist inhalers are propellant-free inhaler devices that produce aerosol by
using the mechanical energy generated by a spring.25 The aerosol is 10-fold
slower than in a pMDI and lasts for 1.5 seconds. It is marketed to be used
without a VHC. Currently, the only drug with US Food & Drug Administration
(FDA) approval for pediatric age is tiotropium bromide. These devices also
need to be primed and should be disposed of 90 days after they are opened.
Dry Powder Inhalers

Dry powder inhalers are drug-device combinations that require breath
actuation to either release or generate and release the medication for inhalation.
The advantages and disadvantages of DPIs are listed in Box 56‑4. There are a
variety of DPI devices, including capsule-based, single-dose devices and
multidose devices with either a bulk drug reservoir or individual doses
protected by foil. Generally, the drug is milled into very small particles in the
respirable size range. However, small, micronized drug particles have strong
forces of attraction and tend to stick together. Passive systems require the
inspiratory energy generated by the patient to deagglomerate the powder into
particles that can be inhaled. As the inspiratory flow increases, the amount of
drug available in small particles also increases and offsets the losses from
impaction of the high-velocity particles in the oropharynx.4 Often, lactose is
added as a carrier to improve the separation and flow of small drug particles.
Active systems such as the newer breath-actuated devices look similar to a
pMDI and require a minimum flow to release the metered drug dose. Novel

1000
Box 56‑4 DPI formulations (antibiotics,

insulin) use light, hollow,
Advantages and Disadvantages porous particles to improve
of Dry Powder Inhalers
particle separation and deliver
Advantages
higher payloads.26 These
Compact, portable
devices have drug delivery
Rapid delivery time
that is independent of respira-
Breath-actuated
tory effort once the inspiratory
Multidose with counters
flow threshold is reached.
No need for valved holding chamber, spacer
Disadvantages Inspiratory Effort and
Need strong and consistent inspiratory effort Dry Delivery
High oropharyngeal deposition The ideal inspiratory effort is
Vulnerable to humidity different for various passive
Not suitable for young children DPI devices depending on their
Technique confusion is possible if used with internal resistance. It is a myth
other devices that require slow inhalation that low-resistance devices are
better suited for children.
Simple physics dictates that
with the same inspiratory effort, the flow rate will be higher through a low-
resistance device, and vice versa. However, higher-resistance devices have
internal channels that help the deagglomeration process, and higher resistance
may open the glottis to allow more drug to pass the larynx. Another miscon-
ception is the belief that patients who have asthma are unable to attain suffi-
cient inspiratory flow to derive clinical benefit from a higher-resistance DPI.27
Use of Dry Powder Inhalers
The main limiting factors for DPI use in young children are that they lack the
inspiratory flow necessary to power the device and that young children may
not comprehend the maneuver to operate a DPI. Young children sometimes
would rather blow into a device than inhale from it, which would moisten the
powder and make it impossible to aerosolize. For these reasons, it is reasonable
to exclude the use of DPIs until about 6 years of age, whether or not they are
approved for younger ages.
There are many types of DPIs that look and operate differently. Each pharma-
ceutical company has its own proprietary device with a unique set of instruc-
tions. This can be confusing for patients who require more than one device
for control of their asthma or other lung disease. Therefore, patients would
have to learn to inhale forcefully from their DPI controller medication and
inhale their rescue drug slowly from their pMDI. More recently, a multidose
platform of a breath-actuated DPI was approved in the United States. The
platform includes a short-acting bronchodilator, a corticosteroid, and a
corticosteroid/long-acting bronchodilator combination. Patients with CF
are often treated with inhaled antibiotics, both FDA approved and non–FDA

1001
approved. The most common of those inhaled antibiotics, tobramycin, which

was traditionally prescribed in nebulizer form, is also now available as a DPI.
Practitioners need to learn about the specifics for each device they prescribe.
Choosing the Appropriate Delivery Device

The increasing number of device choices can be confusing and intimidating to
patients and clinicians alike. There are hundreds of papers that argue the merits
of one device versus another, but a comprehensive meta-analysis of this
literature provided evidence-based guidelines in a variety of inpatient and
outpatient settings,28 concluding that each of the aerosol devices works equally
well in a variety of clinical settings in patients who can use the device appro-
priately. Clinicians have to educate themselves to properly educate their
patients in the correct techniques for use and maintenance of their devices.
The use of peak inspiratory flow meters with variable resistance can facilitate
the correct choice of the inhaler device for a given patient.29 Given the high rate
of device misuse, review of inhaler technique at each clinic visit is advised.
key points
} Some medications may require choosing a specific delivery device
(eg, nebulized budesonide and inhaled antibiotics that have been evaluated
in clinical trials).
} The choice of delivery system depends on the age, comprehension, and
capability of the child. This will often require a trial in the office to evaluate.
} The third-party payer may dictate which device is covered. Unfortunately,
this is often state-specific and changes frequently.
} Cost, time savings, and portability should be considered when choosing the
device. Decreasing the burden of care enhances adherence to the medical
regimen.
} The technique of medication delivery should be reviewed often with the
caregiver to ensure that the device is being used correctly. Clinicians need
to be familiar with the various devices to be able to teach how to use them.
} Acceptability by the child and family is of paramount importance for adherence
and clinical outcomes. Sometimes a trial with different delivery systems may
be necessary, or using 2 types of delivery systems may be appropriate
(eg, using a nebulizer at home and a pMDI with VHC at child care for
best clinical outcomes).
} An updated comprehensive guide on aerosol delivery is available from the
American Association for Respiratory Care.30 This invaluable guide has pictures
and detailed instructions for how to use and care for each device.

1002
References
1. National Heart, Lung, and Blood Institute, National Asthma Education and Prevention
Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma.
US Department of Health and Human Services, National Institutes of Health; 2007.
https://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm. Accessed March 28, 2022
doi: 10.1164/rccm.200705-664OC
3. Román-Rodríguez M, Metting E, Gacía-Pardo M, Kocks J, van der Molen T. Wrong inhalation
technique is associated to poor asthma clinical outcomes. Is there room for improvement?
Curr Opin Pulm Med. 2019;25(1):18–26 PMID: 30461535 doi: 10.1097/MCP.0000000000000540
4. Laube BL, Janssens HM, de Jongh FH, et al; European Respiratory Society; International
Society for Aerosols in Medicine. What the pulmonary specialist should know about the new
inhalation therapies. Eur Respir J. 2011;37(6):1308–1331 PMID: 21310878
doi: 10.1183/09031936.00166410
5. Chua HL, Collis GG, Newbury AM, et al. The influence of age on aerosol deposition in children
with cystic fibrosis. Eur Respir J. 1994;7(12):2185–2191 PMID: 7713202
doi: 10.1183/09031936.94.07122185
6. Marguet C, Couderc L, Le Roux P, Jeannot E, Lefay V, Mallet E. Inhalation treatment: errors
in application and difficulties in acceptance of the devices are frequent in wheezy infants and
young children. Pediatr Allergy Immunol. 2001;12(4):224–230 PMID: 11555320
doi: 10.1034/j.1399-3038.2001.012004224.x
7. Erzinger S, Schueepp KG, Brooks-Wildhaber J, Devadason SG, Wildhaber JH. Facemasks and
aerosol delivery in vivo. J Aerosol Med. 2007;20(s1)(suppl 1):S78–S83 PMID: 17411409
doi: 10.1089/jam.2007.0572
8. Schueepp KG, Devadason SG, Roller C, et al. Aerosol delivery of nebulised budesonide in young
children with asthma. Respir Med. 2009;103(11):1738–1745 PMID: 19540100
doi: 10.1016/j.rmed.2009.04.029
9. Kesser KC, Geller DE. New aerosol delivery devices for cystic fibrosis. Respir Care.
2009;54(6):754–767 PMID: 19467162 doi: 10.4187/002013209790983250
10. Kradjan WA, Lakshminarayan S. Efficiency of air compressor-driven nebulizers. Chest.
1985;87(4):512–516 PMID: 3979140 doi: 10.1378/chest.87.4.512
11. Berg EB, Picard RJ. In vitro delivery of budesonide from 30 jet nebulizer/compressor
combinations using infant and child breathing patterns. Respir Care. 2009;54(12):1671–1678
PMID: 19961633
12. Berlinski A, Waldrep JC. Effect of aerosol delivery system and formulation on nebulized
budesonide output. J Aerosol Med. 1997;10(4):307–318 doi: 10.1089/jam.1997.10.307
13. Mellon M, Leflein J, Walton-Bowen K, Cruz-Rivera M, Fitzpatrick S, Smith JA. Comparable
efficacy of administration with face mask or mouthpiece of nebulized budesonide inhalation
suspension for infants and young children with persistent asthma. Am J Respir Crit Care Med.
14. Harris KW, Smaldone GC. Facial and ocular deposition of nebulized budesonide: effects of face
mask design. Chest. 2008;133(2):482–488 PMID: 18071018 doi: 10.1378/chest.07-1827
15. Saiman L, Siegel JD, LiPuma JJ, et al; Cystic Fibrous Foundation; Society for Healthcare
Epidemiology of America. Infection prevention and control guideline for cystic fibrosis: 2013
update. Infect Control Hosp Epidemiol. 2014;35(S1)(suppl 1):S1–S67 PMID: 25025126
doi: 10.1086/676882
16. Scarfone RJ, Capraro GA, Zorc JJ, Zhao H. Demonstrated use of metered-dose inhalers and peak
flow meters by children and adolescents with acute asthma exacerbations. Arch Pediatr Adolesc
Med. 2002;156(4):378–383 PMID: 11929373 doi: 10.1001/archpedi.156.4.378
17. Self TH, Arnold LB, Czosnowski LM, Swanson JM, Swanson H. Inadequate skill of
healthcare professionals in using asthma inhalation devices. J Asthma. 2007;44(8):593–598
PMID: 17943567 doi: 10.1080/02770900701554334
18. Berlinski A, von Hollen D, Pritchard JN, Hatley RH. Delay between shaking and actuation
of a hydrofluoroalkane fluticasone pressurized metered-dose inhaler. Respir Care.
19. Roller CM, Zhang G, Troedson RG, Leach CL, Le Souëf PN, Devadason SG. Spacer inhalation
technique and deposition of extrafine aerosol in asthmatic children. Eur Respir J.
2007;29(2):299–306 PMID: 17005581 doi: 10.1183/09031936.00051106

1003
20. Janssens HM, De Jongste JC, Hop WC, Tiddens HA. Extra-fine particles improve lung delivery
of inhaled steroids in infants: a study in an upper airway model. Chest. 2003;123(6):2083–2088
PMID: 12796192 doi: 10.1378/chest.123.6.2083
21. Asmus MJ, Liang J, Coowanitwong I, Hochhaus G. In vitro performance characteristics of
valved holding chamber and spacer devices with a fluticasone metered-dose inhaler.
Pharmacotherapy. 2004;24(2):159–166 PMID: 14998215 doi: 10.1592/phco.24.2.159.33147
22. Shah S, Berlinski A, Rubin B. Force-dependent static dead space of face masks used with
holding chambers. Respir Care. 2006;51(2):140–144 PMID: 16441958
23. Chavez A, McCracken A, Berlinski A. Effect of face mask dead volume, respiratory rate,
and tidal volume on inhaled albuterol delivery. Pediatr Pulmonol. 2010;45(3):224–229
PMID: 20146371 doi: 10.1002/ppul.21156
24. Berlinski A, von Hollen D, Hatley RHM, Hardaker LEA, Nikander K. Drug delivery in
asthmatic children following coordinated and uncoordinated inhalation maneuvers:
a randomized crossover trial. J Aerosol Med Pulm Drug Deliv. 2017;30(3):182–189
PMID: 27977309 doi: 10.1089/jamp.2016.1337
25. Iwanaga T, Tohda Y, Nakamura S, Suga Y. The Respimat® soft mist inhaler: implications
of drug delivery characteristics for patients. Clin Drug Investig. 2019;39(11):1021–1030
PMID: 31377981 doi: 10.1007/s40261-019-00835-z
26. Geller DE, Konstan MW, Smith J, Noonberg SB, Conrad C. Novel tobramycin inhalation powder
in cystic fibrosis subjects: pharmacokinetics and safety. Pediatr Pulmonol. 2007;42(4):307–313
PMID: 17352404 doi: 10.1002/ppul.20594
27. Borgström L. On the use of dry powder inhalers in situations perceived as constrained.
J Aerosol Med. 2001;14(3):281–287 PMID: 11693839 doi: 10.1089/089426801316970231
28. Dolovich MB, Ahrens RC, Hess DR, et al; American College of Chest Physicians; American
College of Asthma, Allergy, and Immunology. Device selection and outcomes of aerosol
therapy: evidence-based guidelines: American College of Chest Physicians/American College
of Asthma, Allergy, and Immunology. Chest. 2005;127(1):335–371 PMID: 15654001
doi: 10.1378/chest.127.1.335
29. Sanders MJ. Guiding inspiratory flow: development of the In-Check DIAL G16, a tool for
improving inhaler technique. Pulm Med. 2017;2017:1495867 PMID: 29348936
doi: 10.1155/2017/1495867
30. Gardenshire DS, Burnett D, Strickland S, Myers TR. A Guide to Aerosol Delivery Devices
for Respiratory Therapists. 4th ed. American Association for Respiratory Care; 2017.
https://www.aarc.org/wp-content/uploads/2018/03/aersol-guides-for-rts.pdf.
Accessed March 28, 2022

CHAPTER
57
Bronchodilators
John Welter, MD
H. William Kelly, PharmD
Introduction
Bronchodilators are used in a number of obstructive respiratory diseases of
childhood for the relief of airway smooth muscle contraction (ie, broncho-
spasm). Although bronchodilators are approved by the US Food & Drug
Administration (FDA) only for the treatment of asthma and chronic obstruc-
tive pulmonary disease (COPD), they are commonly prescribed for children
with cystic fibrosis (CF), bronchiolitis, and bronchopulmonary dysplasia
(BPD), despite lack of consistent evidence of efficacy for these conditions.
Neonates are born with fully functional airway smooth muscle whose mass
relative to airway size is fully developed by 25 weeks’ gestation.1 Neonatal
bronchial tissue responds to both β2-agonists and cholinergic stimulation
similarly to adult bronchial tissue because neonatal β-adrenergic receptors
are similar in density to the airway smooth muscle in adults.2,3 Thus, differ-
ences in response to the various bronchodilators between infants, children,
and adults will more likely be due to issues involving mechanisms of airway
obstruction, dosing, responsive capacity of the lung, and drug delivery
than to pharmacologic responsiveness of the smooth muscle.
Bronchodilator Mechanisms
Three categories of bronchodilators are used clinically. These include
β2-agonists, methylxanthines, and anticholinergic drugs.
β2-Agonists
The β2-agonists are the most effective bronchodilators used in clinical
practice. The β2-adrenergic receptor is a G protein–coupled transmembrane
receptor that exists in a conformational equilibrium between the activated and
inactivated states. Agonist binding shifts the equilibrium to the activated
state, leading to increased intracellular production of cyclic adenosine
1005

1006
monophosphate and a corresponding, proportional decrease in smooth

muscle tone. Continued stimulation by an agonist will result in desensitization
that occurs within 1 to 2 weeks of regular administration, levels off, and does
not then worsen over time.4 It is a receptor phenomenon; therefore, cross-
tolerance to all of the β2-agonists occurs. Concomitant use of corticosteroids
can attenuate the β2 tolerance.
Synthetic β2-agonists differ in their potency and selectivity for β2-adrenergic
receptors. Naturally occurring epinephrine equally stimulates α-adrenergic
receptors (smooth muscle constriction), β1-adrenergic receptors (cardiac
tissue contraction and conductance), and β2-adrenergic receptors, whereas
early synthetic agents such as isoproterenol are selective β-agonists, equally
potent for the β1-adrenergic and β2-adrenergic receptors.4 The currently
available short-acting β2-agonists (SABAs)—albuterol and terbutaline—
are equally β2 selective, whereas the inhaled long-acting β2-agonists (LABAs)
are slightly more β2 selective.4 The LABAs have a duration of action of 12 to
24 hours compared with the 2- to 4-hour duration of SABAs, due to LABAs’
increased lipophilicity, allowing them to be retained in the lung tissue for
prolonged periods.4,5 Retention in the lung also improves their therapeutic
index (bronchodilation to systemic effect ratio) over the SABAs.6 Although
all LABAs have a similar duration, the onset of effect for formoterol is
similar to that of a SABA.
The synthetic β2-agonists exist as racemic mixtures of equal amounts of
2 enantiomers (mirror image chemicals) with the exception of levalbuterol
and arformoterol, which contain only the most active enantiomers,
(R)-albuterol and (R,R)-formoterol, respectively. The inactive isomers
do not significantly compete for the receptor.6
Anticholinergics
The anticholinergics competitively block acetylcholine at the muscarinic
receptors in the airways.7 Unlike the β2-adrenergic receptors, the distribution
of muscarinic receptors in the lung diminishes as the airways become more
peripheral, as does the cholinergic innervation.7 Atropine is a tertiary ammo-
nium compound that is readily absorbed across membranes, including the
central nervous system, so it is of limited clinical utility as an anticholinergic
due to adverse effects.7 The quaternary ammonium compounds, such as ipra-
tropium bromide and tiotropium, are very poorly absorbed across membranes,
causing minimal to no systemic effects when applied topically. Umeclindium,
aclidinium, and tiotropium have a longer duration of action (24 hours) due
to greater lipophilic nature than ipratropium bromide (duration 6 hours).5
Unlike with β2-agonists, bronchodilation tolerance does not appear to
occur in response to anticholinergics.5

1007
Chapter 57—Bronchodilators
Methylxanthines
Theophylline is the only methylxanthine that has been used clinically as a
bronchodilator. It has modest bronchodilator effects at optimal serum concen-
trations. In addition, it has modest anti-inflammatory, immunomodulatory,
and bronchoprotective effects, which contribute to its efficacy as a controller
medication for persistent asthma. It increases intracellular concentrations of
cyclic adenosine monophosphate in airway smooth muscle and inflammatory
cells by nonspecific phosphodiesterase inhibition.
Theophylline is used infrequently for asthma because of its risk of adverse
effects. It may be considered, however, when patients are unable to tolerate
first-line therapies. The benefits and risks from theophylline are closely
correlated with serum concentrations. The maximum potential benefit with
the least risk of adverse effects is achieved at peak concentrations of 55.50 to
83.25 mcmol (10 to 15 mcg/mL). Because of variable rates of metabolism,
concentrations can vary greatly among children receiving the same dose;
therefore serum concentrations must be measured to adjust dosage.8
Pathophysiology and Clinical Features

of Airway Obstruction
Airway obstruction in children with asthma is produced by bronchospasm,
airway edema, desquamation of airway epithelium, and mucus plugging. The
rapid response to bronchodilators seen in most patients with acute severe
asthma exacerbations suggests that much of the obstruction is caused by
bronchospasm. The excessive bronchospasm triggered by external stimuli,
such as irritants, exercise, chemicals, and allergens, is termed bronchial
hyperresponsiveness (BHR) and is a cardinal feature of asthma.9 While
asthma is primarily an inflammatory disease, it is clear that bronchodilators
play an important role in treating and preventing ongoing symptoms and
reducing the severity of exacerbations.
Bronchospasm plays a less prominent role in the airway obstruction of air-
way diseases other than asthma; thus, bronchodilators are less likely to be
effective. The airway obstruction of children with CF is caused by chronic
bacterial infection leading to airway inflammation and mucus with increased
viscosity that is difficult to clear from the airways.10 Bronchopulmonary
dysplasia has a component of neutrophilic inflammation as well but is primar-
ily caused by a maturational failure of airway development combined with
damage from either the high oxygen or barotrauma secondary to mechanical
ventilation.11 Airway edema, increased airway resistance, and BHR are
features of BPD.11 The bronchospasm seems to be primarily induced via
cholinergic mechanisms similar to that seen in COPD of adults, where the

1008
inflammatory process is also primarily due to neutrophils and not eosino-

phils.12 Acute severe bronchiolitis, generally secondary to respiratory syncytial
virus and other viruses, induces airway obstruction via inflammation, edema,
and mucus plugging.13 Wheezing, hyperinflation, dyspnea, retractions, and
cough are all signs of airway obstruction, regardless of mechanism; therefore,
the differential diagnosis is broad and includes a number of conditions that are
not responsive to bronchodilators.9 Nonetheless, given the difficulty of estab-
lishing a clear diagnosis, many clinicians will give a trial of bronchodilators to
assess response.
Clinical Pharmacology and Disease Management

Asthma is the only disease for which β2-agonists, anticholinergics, and
theophylline are approved for children by the FDA.9 Furthermore, the use of
any bronchodilators in children younger than 2 years and the use of metered-
dose inhalers (MDIs) in children younger than 4 years is off-label. These
therapies have not been evaluated adequately for FDA approval despite
extensive clinical experience and use.14,15 The dosages in Table 57-1 are based
on clinical trials or clinical use that was not controlled. Tiotropium is approved
for use in children 6 years and older with asthma; the remainder of the anticho-
linergic bronchodilators are approved only for COPD in adults.16
Acute Bronchospasm
The β2-agonists are the most effective bronchodilators for reversing broncho-
spasm in asthma.9 As functional antagonists, they can reverse bronchospasm
secondary to any mediator or neurogenic mechanism.12 Aerosolized SABAs
are the drugs of choice for both the relief of symptoms associated with mild
bronchospasm and the initial treatment of severe asthma exacerbations
together with systemic corticosteroids to treat the inflammatory component.
(See Table 57-1 for dosing.)9 In settings of increased inflammation in the out-
patient management of bronchospasm, such as viral-induced exacerbations and
nocturnal asthma, the usual dose of SABAs can be insufficient to reverse the
bronchospasm and the doses may be repeated 3 times at 20-minute intervals
depending on the severity of symptoms.17 The short-acting anticholinergic
ipratropium bromide provides additive efficacy with SABAs in severe acute
exacerbations, but only improves lung function another 10% to 20% (reversing
the cholinergic component) over frequent administration of high-dose SABAs.9
However, the addition of frequent dosing of inhaled ipratropium bromide to
SABAs has resulted in a significant reduction in hospitalizations of children
presenting to the emergency department (ED) with severe obstruction.18 It
has not been shown to be beneficial in any other clinical scenario in childhood,
either at home or in the hospital. Theophylline and intravenous aminophylline
have not demonstrated additive benefit to optimal aerosolized β2-agonists
in the ED.19

Table 57-1. Bronchodilator Medication Dosing Charta
Years of Age
Medication <5 5–11 ≥ 12
Inhaled SABAs
Albuterol MDI Home: 2–6 puffs with VHC + face Exercise: 2–6 puffs with VHC 5 minutes Exercise: 2–6 puffs 5 minutes prior to
mask every 4–6 hours as needed prior to exercise. exercise.

90 mcg/puff,
for symptoms. May give 2 doses Home: 2–6 puffs with VHC every 4 hours Home: 2–6 puffs every 4 hours as
200 puffs/canister
20 minutes apart as needed for as needed for symptoms. May give 2 doses needed for symptoms. May give 2 doses
(Use VHC; add mask for initiation of treatment of acute 20 minutes apart as needed for initiation 20 minutes apart as needed for initiation
children < 4 years of age) exacerbation. of treatment of acute exacerbation. of treatment of acute exacerbation.
OR ED: 4–8 puffs with VHC + face mask ED: 4–8 puffs with VHC every 20 minutes ED: 4–8 puffs with VHC every 20 minutes
Albuterol dry powder every 20 minutes for 3 doses, then for 3 doses, then every 1–4 hours as for 3 doses, then every 1–4 hours
inhaler every 1–4 hours as needed. needed. as needed.
FDA approved for children Hosp: 4–8 puffs with VHC + face Hosp: 4–8 puffs with VHC every Hosp: 4–8 puffs with VHC every
4 years and older mask every 1–4 hours as needed. 1–4 hours as needed. 1–4 hours as needed.
Albuterol nebulizer Home: 1.25–2.5 mg up to every Home: 1.25–2.5 mg every 4 hours as Home: 2.5–5 mg every 4 hours as needed
solutions 20 minutes by face mask for up to needed for symptoms. May give up to for symptoms. May give up to every
2 doses, then every 4 hours as needed. every 20 minutes for up to 2 doses for 20 minutes for up to 2 doses for initiation
0.63 mg/3 mL
initiation of treatment of acute exacerba- of treatment of acute exacerbation.
ED: 0.15 mg/kg (minimum 2.5 mg)
1.25 mg/3 mL tion.
every 20 minutes for 3 doses then ED: 2.5–5.0 mg every 20 minutes for
2.5 mg/3 mL 0.15–0.3 mg/kg up to 10 mg every ED: 0.15 mg/kg (minimum 2.5 mg) every 3 doses, then 2.5–10 mg every 1–4 hours
5.0 mg/mL 1–4 hours as needed or 0.5 mg/kg/h 20 minutes for 3 doses, then 0.15–0.3 mg/ as needed or 10–15 mg/h by continuous
(0.5% diluted with 2–3 mL by continuous nebulization. kg up to 10 mg every 1–4 hours as needed nebulization.
of normal saline) or 0.5 mg/kg/h by continuous nebuliza- Hosp: 2.5–10 mg every 1–4 hours as
Hosp: 0.15–0.3 mg/kg up to 10 mg every
tion. needed or 10–15 mg/h by continuous
1–4 hours as needed or 0.5 mg/kg/h
by continuous nebulization. Hosp: 0.15–0.3 mg/kg up to 10 mg every nebulization.
1–4 hours as needed or 0.5 mg/kg/h
1009
by continuous nebulization.
(continued)
11/6/23 9:56 AM
Table 57-1. Bronchodilator Medication Dosing Charta (continued)
1010
Years of Age
Inhaled SABAs (continued)
b
Levalbuterol MDI
45 mcg/puff,
200 puffs/canister See albuterol MDI doses above. See albuterol MDI doses above. See albuterol MDI doses above.
Levalbuterol nebulizer Home: 0.63–1.25 mg up to every Home: 0.63–1.25 mg every 4 hours as Home: 1.25–2.5 mg every 4 hours as need-

solutions 20 minutes by face mask for up to needed for symptoms. May give up to ed for symptoms. May give up
3 doses, then every 2–4 hours every 20 minutes for up to 3 doses for to every 20 minutes for up to 3 doses
0.31 mg/3 mL
as needed. initiation of treatment of acute exacerba- for initiation of treatment of acute exacer-
0.63 mg/3 mL tion. bation.
ED: 0.075 mg/kg (minimum 1.25 mg)
1.25 mg/3 mL every 20 minutes for 3 doses, then ED: 0.075 mg/kg (minimum 1.25 mg) ED: 1.25–2.5 mg every 20 minutes for
0.075–0.15 mg/kg up to 5 mg every every 20 minutes for 3 doses, then 3 doses, then 1.25–5 mg every 1–4 hours
1–4 hours as needed or 0.25 mg/kg/h 0.075–0.15 mg/kg up to 5 mg every as needed or 5–7.5 mg/h by continuous
by continuous nebulization. 1–4 hours as needed or 0.25 mg/kg/h nebulization.
by continuous nebulization. Hosp: 1.25–5 mg every 1–4 hours as
Hosp: 0.075–0.15 mg/kg up to 5 mg
every 1–4 hours as needed or 0.25 mg/ Hosp: 0.075–0.15 mg/kg up to 5 mg every needed or 5–7.5 mg/h by continuous
kg/h by continuous nebulization. 1–4 hours as needed or 0.25 mg/kg/h nebulization.
by continuous nebulization.
Injectable epinephrine ED: 0.01 mg/kg up to 0.3–0.5 mg sq ED: 0.01 mg/kg up to 0.3–0.5 mg sq every ED: 0.3–0.5 mg sq every 20 minutes
every 20 minutes for 3 doses sq. 20 minutes for 3 doses sq. for 3 doses.
1:1,000 (1 mg/mL)
Injectable terbutaline ED: 0.01 mg/kg up to 0.25 mg sq every ED: 0.01 mg/kg up to 0.25 mg sq every ED: 0.25 mg sq every 20 minutes
20 minutes for 3 doses sq, then every 20 minutes for 3 doses sq, then every for 3 doses.
(1 mg/mL)
2–6 hours as needed. 2–6 hours as needed.
11/7/23 10:21 AM
Years of Age
Anticholinergics
Ipratropium bromide MDI ED: 4 puffs with VHC + face mask every ED: 4 puffs with VHC every 20 minutes ED: 8 puffs every 20 minutes as needed
20 minutes times 3 doses, then every times 3 doses, then every 1 hour up to up to 3 hours.
17 mcg/puff,
1 hour up to 3 hours 3 hours.

200 puffs/canister
Ipratropium nebulizer ED: 0.25–0.5 mg every 20 minutes, then ED: 0.25–0.5 mg every 20 minutes, then as ED: 0.5 mg every 20 minutes, then
solution as needed. (May mix with albuterol needed. (May mix with albuterol nebulizer as needed. (May mix with albuterol
0.25 mg/mL (0.025%) nebulizer solution.) solution.) nebulizer solution.)
Ipratropium/albuterol ED: 1.5 mL every 20 minutes for 3 doses, ED: 1.5–3 mL every 20 minutes for 3 doses, ED: 3 mL every 20 minutes for 3 doses,
nebulizer solution then as needed. then as needed. then as needed.
0.5 mg/2.5 mg per 3 mL
Abbreviations: ED, emergency department; Hosp, hospitalized patient; IV, intravenously; MDI, metered-dose inhaler; SABA, short-acting β2 -agonist; sq, subcutaneously; VHC, valved
holding chamber.
a
All doses for asthma unless otherwise indicated.
b
At equimolar doses, levalbuterol is neither more effective nor does it have fewer systemic effects than racemic albuterol.
Derived from National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program. Full Report of the Expert Panel: Guidelines for the Diagnosis and Management of Asthma
(EPR-3). US Department of Health and Human Services, National Institutes of Health; 2007. https://www.nhlbi.nih.gov/guidelines/asthma
1011
11/6/23 9:57 AM
1012
Intravenous magnesium sulfate has been used for adults and children with
severe asthma that is unresponsive to the usual doses of SABAs in the ED.20
Magnesium sulfate is a moderately potent smooth muscle relaxant, and some
studies, but not all, have demonstrated improved bronchodilation and reduced
hospitalizations in children when it is added to usual SABA therapy in the
ED.9,20 There are no studies comparing magnesium sulfate with other treat-
ment strategies in patients with severe, unresponsive asthma, including the
addition of frequent doses of ipratropium bromide or providing continuous
nebulization of SABA, both of which improve lung function and reduce the
risk of hospitalization.9 Thus, the National Heart, Lung, and Blood Institute’s
National Asthma Education and Prevention Program’s Expert Panel Report 3
(EPR-3) Guidelines for the Diagnosis and Management of Asthma states that
magnesium sulfate can be considered but falls short of recommending its use.9
During hospitalization, the dosage of SABAs is based on the severity of
the asthma and the patient’s response to therapy.9 As the patient improves,
lowering the dose and spreading out the dosing interval may proceed quickly.
Once the child is hospitalized, the addition of ipratropium bromide to SABAs
has not been shown to improve outcomes and is not recommended in the
EPR-3.9
Administration of aerosolized SABAs is more effective and produces fewer
adverse effects than oral or parenteral administration, making inhalation the
preferred route of SABA administration.9 Aerosolized SABAs can be adminis-
tered by either jet nebulization or MDI with equivalent results. A nebulizer
or valved holding chamber fitted with appropriately sized face masks may be
used for delivery to infants and children younger than 5 years.9 (See Chapter
56, Aerosol Delivery of Medication.) In addition to requiring higher doses in
severe asthma exacerbations, the duration of significant bronchodilation is
decreased so more frequent administration (every 20 minutes initially) and
even continuous nebulization can improve outcomes over administration on
an hourly basis in patients with more severe asthma.21
Administering high doses of SABAs can lead to β2-agonist‒mediated
systemic side effects, including tachycardia, hypokalemia, hyperglycemia,
and prolonged QTc interval, so these should be monitored.9 Although QTc
interval is prolonged by all β2-agonists, reports of significant cardiac arrhyth-
mias, such as torsades de pointes, are exceedingly rare.5.6 Metabolic acidosis
is a common finding in those who are quite ill with asthma and who are on
β2-agonist therapy. Due to vascular dilatation, SABAs can also slightly worsen
the ventilation/perfusion mismatching seen in severe exacerbations, so low-
flow oxygen should always be administered during severe exacerbations and
transcutaneous partial pressure of oxygen should be monitored.9 Tachycardia
from hypoxemia and stimulation of irritant receptors is common in severe

1013
asthma exacerbations and is not a contraindication for high doses of SABAs.

Indeed, the heart rate often decreases in patients receiving high-dose
aerosolized SABAs as the airway obstruction improves.9
There is no advantage among any of the β2-selective SABAs (albuterol, leval-
buterol, or terbutaline) when given in equipotent doses.6,9 They all produce
a similar degree of bronchodilation and amount of β2-adrenergic–mediated
side effects. Isoproterenol and epinephrine have the potential to produce sig-
nificantly greater cardiac toxicity. The use of intravenous isoproterenol in
children with severe asthma has resulted in myocardial ischemia and is an
outdated practice.9
Asthma
The SABAs are indicated for as-needed treatment of symptoms associated
with bronchospasm (cough, wheezing, and dyspnea) in the outpatient manage-
ment of asthma.9 They constitute the primary treatment of intermittent asthma
and the primary prevention of exercise-induced bronchospasm (EIB).9 They
are not indicated for regular maintenance administration. Patients who require
as-needed SABA therapy for more than 2 days per week, not counting preven-
tion of EIB, generally should not be considered well-controlled and should
either be placed on regular anti-inflammatory controller therapy or have their
regular controller therapy increased if their compliance is adequate.17 The use
of 2 or more SABA canisters per month has been associated with a significant
increase in the risk of severe asthma exacerbations, including death, and the
use of 1 or more canisters every 1 to 2 months indicates poor asthma control
and an increased risk of needing ED care.9
The inhaled β2-agonists are the most effective preventive therapy for EIB.9
The SABAs have a duration of protection of 2 to 4 hours, whereas the LABAs
protect for up to 12 hours after a single dose. However, the duration of protec-
tion against EIB from LABAs when taken regularly decreases to 4 to 6 hours
due to tolerance.6,12 Despite the tolerance from regular administration of a
β2-agonist, most patients are fully protected against EIB in the 1 to 2 hours
following SABA administration.6 Leukotriene receptor antagonists are only
partially effective for prevention of EIB, and they are ineffective in up to
40% to 50% of children.22
Because of their lack of clinically significant anti-inflammatory effects,
LABAs are currently only indicated as adjunct therapy in patients incom-
pletely controlled on low to medium doses of inhaled corticosteroids.9 They
improve base-line lung function and decrease symptoms and as-needed
SABA use when added to inhaled corticosteroid therapy. Early studies in
which monotherapy with a LABA was added to the usual therapy in children
showed an increased risk of serious asthma exacerbations (hospitalization for

1014
asthma).9,23 This same finding did not occur in studies of combination LABA
and inhaled corticosteroids.24,25 Currently, LABAs are not FDA approved
for use in children younger than 4 years. However, enough evidence has
accumulated that the 2020 National Heart, Lung, and Blood Institute
asthma guidelines recommend combination therapy in infants and toddlers
not responding to medium-dose inhaled corticosteroids.17
The LABA formoterol is less lipophilic than salmeterol, which allows for a
more rapid onset of bronchodilation similar to the SABAs albuterol and ter-
butaline.4,12 Some studies have reported improved outcomes compared with
SABAs as measured by fewer exacerbations requiring oral corticosteroids or
ED visits.6 In addition, combination inhalers containing both a corticosteroid
and formoterol now are recommended by the EPR-3 as a maintenance plus
relief medication because clinical trials in children and adults have demon-
strated fewer exacerbations with lower overall corticosteroid dosing compared
with standard dosing of combination or higher-dose inhaled corticosteroids
plus SABAs as reliever.17,25 The FDA-approved labeling for combination
budesonide/formoterol states the drug is only for maintenance therapy and
states it should not be used for treatment of acute bronchospasm.
Sustained-release theophylline is still considered an alternative, not preferred,
maintenance and adjunctive therapy to the inhaled corticosteroids in children
5 to 11 years of age but not in children 0 to 4 years of age.9 It is not recom-
mended by the EPR-3 in 0- to 4-year-olds because of a lack of clinical trial
data on efficacy and the potential for serious adverse effects in young children
and infants.26 When using theophylline in 5- to 11-year-old children, serum
drug concentration monitoring is required to prevent serious toxicity.
The short-acting anticholinergics do not have an FDA-approved indication
in children with asthma and have not been shown to improve outcomes in
clinical trials.27 Some have advocated that ipratropium bromide could be used
as a reliever in patients unable to tolerate SABAs. It has been used success-
fully as a reliever in clinical trials involving patients with mild asthma but has
a slower onset of action and is not as effective as SABAs.9 The long-acting
anticholinergic tiotropium has been shown to improve lung function in
children and adolescents and is FDA approved for maintenance therapy of
asthma in children 6 years and older.16

1015
Bronchiolitis
The use of bronchodilators in the treatment of acute viral bronchiolitis has been
controversial for years. Systematic reviews of SABA use indicate a modest
short-term improvement in clinical scores but no improvement in hospitaliza-
tion rates or duration of hospitalization.28 However, some of the studies may
have included infants with recurrent wheezing and family histories of asthma.
Some experts have advocated aerosolized epinephrine for its α-agonist effect
producing pulmonary vascular constriction, thus decreasing airway edema.29
Studies show no benefit of epinephrine in hospitalized infants but show a
slightly greater benefit compared with albuterol in outpatient treatment.28
However, the studies comparing epinephrine as either a single isomer or
racemic mixture often used doses of epinephrine that were higher than that of
albuterol in terms of β2-adrenergic potency, so it is unclear whether the slight
difference was due to an α-agonist effect or just greater β2-agonist dose. A
large study giving equivalent β2-agonist doses found no difference between
epinephrine and albuterol.30 Due to potential adverse effects and lack of
significant clinical benefit, the current recommendation from the American
Academy of Pediatrics is that SABAs not be used in acute bronchiolitis.31
Aerosolized bronchodilators, both SABAs and ipratropium bromide, reduce
airway resistance and improve dynamic compliance in infants with BPD.11 Use
of bronchodilators does not prevent the development or change the natural his-
tory of BPD and is, therefore, indicated for symptomatic control of increased
airway resistance. Continuous treatment without evidence of symptomatic
improvement is not indicated. Albuterol and ipratropium last 4 to 6 hours and,
in some patients, produce an additive effect when used together.11
Cystic Fibrosis
Some patients with CF have a component of BHR, and recurrent wheezing
or dyspnea that responds to a SABA is an indication for the short-term use
of bronchodilators.32 Albuterol is often given before hypertonic sodium
chloride, chest physiotherapy, and inhaled tobramycin 32 to prevent reflex
bronchospasm, but it has not been assessed in controlled trials. The LABAs
also improve lung function in the short term but have produced inconsistent
long-term effects. Thus, current guidelines recommend neither for nor against
chronic use of β2-agonist in people with CF.32 Currently, Anticholinergics
have not demonstrated beneficial responses in people with CF and are not
routinely indicated.33

1016
key points
} The SABAs are the most effective bronchodilators for all clinical situations
involving bronchoconstriction.
} Although desensitization occurs with regular β2-agonist use, it is not
progressive and is easily overcome with 1 or 2 extra doses of a SABA.
} The LABAs and long-acting muscarinic antagonists should only be used as
adjunctive therapy to inhaled corticosteroids.
} Short-acting anticholinergics are second-line agents that should only be used
in specific indications (acute severe asthma in the ED, and BPD).
} Numerous pulmonary diseases other than asthma (ie, CF, BPD, bronchiolitis)
are associated with wheezing that may or may not be secondary to broncho-
spasm. Bronchodilators should only be used if there is a documented
positive response.
References
1. Sward-Comunelli SL, Mabry SM, Truog WE, Thibeault DW. Airway muscle in preterm infants:
changes during development. J Pediatr. 1997;130(4):570–576 PMID: 9108855
doi: 10.1016/S0022-3476(97)70241-5
2. Sparrow MP, Weichselbaum M, McCray PB Jr. Development of the innervation and airway
smooth muscle in human fetal lung. Am J Respir Cell Mol Biol. 1999;20(4):550–560
PMID: 10100986 doi: 10.1165/ajrcmb.20.4.3385
3. McCray PB Jr. Spontaneous contractility of human fetal airway smooth muscle. Am J Respir Cell
Mol Biol. 1993;8(5):573–580 PMID: 8481238 doi: 10.1165/ajrcmb/8.5.573
4. Anderson GP. Interactions between corticosteroids and β-adrenergic agonists in
asthma disease induction, progression, and exacerbation. Am J Respir Crit Care Med.
2000;161(3 Pt 2)(suppl 2):S188–S196 PMID: 10712373
doi: 10.1164/ajrccm.161.supplement_2.a1q4-9
5. Williams DM, Rubin BK. Clinical pharmacology of bronchodilator medications. Respir Care.
6. Kelly HW. What is new with the β2-agonists: issues in the management of asthma.
Ann Pharmacother. 2005;39(5):931–938 PMID: 15811904 doi: 10.1345/aph.1E611
7. Barnes PJ. Distribution of receptor targets in the lung. Proc Am Thorac Soc. 2004;1(4):345–351
PMID: 16113456 doi: 10.1513/pats.200409-045MS
8. Hendeles L, Weinberger M. Theophylline use in asthma. UpToDate. Updated September 16,
2021. Accessed May 6, 2022. https://www.uptodate.com/contents/theophylline-use-in-asthma
9. National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program.
Full Report of the Expert Panel: Guidelines for the Diagnosis and Management of Asthma
(EPR-3). US Department of Health and Human Services, National Institutes of Health; 2007.
https://www.nhlbi.nih.gov/guidelines/asthma
10. Elborn JS. Cystic fibrosis. Lancet. 2016;388(10059):2519–2531 PMID: 27140670
doi: 10.1016/S0140-6736(16)00576-6
11. Pantalitschka T, Poets CF. Inhaled drugs for the prevention and treatment of bronchopulmonary
dysplasia. Pediatr Pulmonol. 2006;41(8):703–708 PMID: 16779858 doi: 10.1002/ppul.20467
12. Anderson GP. Current issues with β2-adrenoceptor agonists: pharmacology and molecular and
cellular mechanisms. Clin Rev Allergy Immunol. 2006;31(2-3):119–130 PMID: 17085788
doi: 10.1385/CRIAI:31:2:119
13. Griffiths B, Ducharme FM. Combined inhaled anticholinergics and short-acting beta2-agonists
for initial treatment of acute asthma in children. Cochrane Database Syst Rev.
2013;(8):CD000060.
14. Chavasse R, Seddon P, Bara A, McKean M. Short acting beta agonists for recurrent wheeze in
children under 2 years of age. Cochrane Libr. 2002;2002(3):CD002873 PMID: 12137663
doi: 10.1002/14651858.CD002873

1017
15. Bentur L, Canny GJ, Shields MD, et al. Controlled trial of nebulized albuterol in children younger
than 2 years of age with acute asthma. Pediatrics. 1992;89(1):133–137 PMID: 1727998
doi: 10.1542/peds.89.1.133
16. Murphy KR, Chipps BE. Tiotropium in children and adolescents with asthma. Ann Allergy
Asthma Immunol. 2020;124(3):267–276.e3 PMID: 31805357 doi: 10.1016/j.anai.2019.11.030
17. Cloutier MM, Baptist AP, Blake KV, et al; Expert Panel Working Group of the National Heart,
Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education
and Prevention Program Coordinating Committee (NAEPPCC). 2020 Focused Updates to the
Asthma Management Guidelines: A Report from the National Asthma Education and Prevention
Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol.
2020;146(6):1217–1270 PMID: 33280709 doi: 10.1016/j.jaci.2020.10.003
18. Mitra A, Bassler D, Goodman K, Lasserson TJ, Ducharme FM. Intravenous aminophylline for
acute severe asthma in children over two years receiving inhaled bronchodilators. Cochrane Libr.
2005;(2):CD001276 PMID: 15846615 doi: 10.1002/14651858.CD001276.pub2
19. Su Z, Li R, Gai Z. Intravenous and nebulized magnesium sulfate for treating acute asthma in
children: a systematic review and meta-analysis. Pediatr Emerg Care. 2018;34(6):390–395
PMID: 29851914 doi: 10.1097/PEC.0000000000000909
20. Camargo CA Jr, Spooner CH, Rowe BH. Continuous versus intermittent beta-agonists in the
treatment of acute asthma. Cochrane Database Syst Rev. 2003;(4):CD001115 PMID: 14583926
21. Raissy HH, Harkins M, Kelly F, Kelly HW. Pretreatment with albuterol versus montelukast for
exercise-induced bronchospasm in children. Pharmacotherapy. 2008;28(3):287–294
PMID: 18294107 doi: 10.1592/phco.28.3.287
22. Janjua S, Schmidt S, Ferrer M, Cates CJ. Inhaled steroids with and without regular formoterol for
asthma: serious adverse events. Cochrane Database Syst Rev. 2019;9(9):CD006924.
23. Sorkness CA, Lemanske RF Jr, Mauger DT, et al; Childhood Asthma Research and Education
Network of the National Heart, Lung, and Blood Institute. Long-term comparison of 3 controller
regimens for mild-moderate persistent childhood asthma: the Pediatric Asthma Controller Trial.
24. Bisgaard H, Le Roux P, Bjåmer D, Dymek A, Vermeulen JH, Hultquist C. Budesonide/formoterol
maintenance plus reliever therapy: a new strategy in pediatric asthma. Chest.
2006;130(6):1733–1743 PMID: 17166990 doi: 10.1378/chest.130.6.1733
25. Seddon P, Bara A, Ducharme FM, Lasserson TJ. Oral xanthines as maintenance treatment
for asthma in children. Cochrane Libr. 2006;(1):CD002885 PMID: 16437447
doi: 10.1002/14651858.CD002885.pub2
26. McDonald NJ, Bara AI, McKean MC. Anticholinergic therapy for chronic asthma in children
over two years of age. Cochrane Libr. 2003;2014(3):CD003535 PMID: 12917970
doi: 10.1002/14651858.CD003535
27. Gadomski AM, Bhasale AL. Bronchodilators for bronchiolitis. Cochrane Database Syst Rev.
2006;(3):CD001266 PMID: 16855963
28. Hartling L, Wiebe N, Russell K, Patel H, Klassen TP. Epinephrine for bronchiolitis. Cochrane
29. Ralston S, Hartenberger C, Anaya T, Qualls C, Kelly HW. Randomized, placebo-controlled trial
of albuterol and epinephrine at equipotent beta-2 agonist doses in acute bronchiolitis. Pediatr
30. Ralston SL, Lieberthal AS, Meissner HC, et al; American Academy of Pediatrics. Clinical
practice guideline: the diagnosis, management, and prevention of bronchiolitis. Pediatrics.
2014;134(5):e1474–e1502 PMID: 25349312 doi: 10.1542/peds.2014-2742
31. Nikolaizik WH, Trociewicz K, Ratjen F. Bronchial reactions to the inhalation of high-dose
tobramycin in cystic fibrosis. Eur Respir J. 2002;20(1):122–126 PMID: 12166559
doi: 10.1183/09031936.02.00264002
32. Ratjen F, Koker P, Geller DE, et al; Tiotropium Cystic Fibrosis Study Group. Tiotropium
Respimat in cystic fibrosis: Phase 3 and Pooled phase 2/3 randomized trials. J Cyst Fibros.
2015;14(5):608–614 PMID: 25819269 doi: 10.1016/j.jcf.2015.03.004

CHAPTER
58
Antibiotics for Pulmonary Conditions
John S. Bradley, MD, FAAP
Introduction
There are many considerations for the choice of antibiotic, as there are with
any prescription. The product label (package insert) provides the indications
that have been approved by the US Food & Drug Administration (FDA). The
FDA-approved indication means that adequate and controlled clinical trials
have been conducted and reviewed by the FDA. Accepted medical practice
often includes drug use that is not reflected in approved drug labeling. Lack
of approval for an indication does not necessarily mean lack of effectiveness
but indicates that appropriate regulatory studies have not been performed
and submitted to the FDA for approval for that indication. The decision to
prescribe a drug is based on the best interest of the patient, taking into account
reasonable medical evidence. The physician who prescribes the drug must
weigh the benefits and risks of using the drug, regardless of whether the drug
has received approval from the FDA for the specific indication and age of the
patient. Consultation with infectious diseases and pulmonology specialists is
often indicated for severe cases.
The major focus of this chapter is on the ambulatory patient. Parenteral
antibiotics are included because, increasingly, children with illnesses or
diseases requiring these antibiotics are managed outside the hospital setting.
1019

1020
Choice of Antibiotic and Dosage

Multiple factors guide the choice of antibiotic and are included in Box 58-1.
Dosages listed in this chapter are for the typical patient and should be con-
sidered as guidance and individualized for the patient who is being treated
(Table 58-1). The dosages are for patients who are adequately hydrated and
have normal renal and hepatic function. The duration of treatment should
be individualized. The dosages are based on the literature, common practice,
and experience.
Updates for treatment of SARS-CoV-2 are at www.aap.org/Nelsons.
Box 58‑1
Considerations for the
Choice of Antibiotic
ū Condition to be treated
ū Specific illness suspected or proven
ū Proven efficacy in clinical trials
ū Degree of potency for a particular
pathogen
ū Age of the child
ū Immune status of the child
ū Weight of the child
ū Tolerance
ū Degree of hydration
ū Renal function
ū Liver function
ū Cost
ū Transportation
ū Access to antibiotics and follow-up
care

Table 58-1. Antibiotic Choices
UPPER AIRWAY INFECTIONS
Clinical Diagnosis Therapy (evidence grade) Comments
Epiglottitis Ceftriaxone 50 mg/kg/day IV, IM q24h for 7–10 days Emergency: provide airway.
(supraglottitis) H influenzae type b For suspected S aureus infection (causes only 5% of epiglottitis),
in an unimmunized child; rarely consider adding clindamycin to ceftriaxone or using ceftaro-

pneumococcus, S aureus line single-drug therapy.
Tracheitis, bacterial Clindamycin 40 mg/kg/day IV div q8h or vancomycin For suspected susceptible S aureus, oxacillin/nafcillin or
S aureus, including CA-MRSA; 40 mg/kg/day IV div q8h AND ceftriaxone 50 mg/kg/day cefazolin.
group A streptococcus; q24h OR ceftaroline single-drug therapy: 2 mo–<2 y, May represent bacterial superinfection of viral
pneumococcus; H influenzae 24 mg/kg/day IV div q8h; ≥2 y, 36 mg/kg/day IV div q8h laryngotracheobronchitis , including influenza.
type b, rarely Pseudomonas (max single dose 400 mg); >33 kg, either 400 mg/dose IV
q8h or 600 mg/dose IV q12h
LOWER RESPIRATORY TRACT INFECTIONS
Abscess, lung
• Primary (a complication of Empiric therapy with ceftriaxone 50–75 mg/kg/day q24h For presumed Mycoplasma, add a fluoroquinolone (levofloxacin)
severe, necrotizing community- AND clindamycin 40 mg/kg/day div q8h or vancomycin or macrolide.
acquired pneumonia caused by 45 mg/kg/day IV div q8h for ≥14–21 days (AIII) OR (for Bronchoscopy may be necessary if abscess fails to drain; surgical
pneumococcus; Staphylococcus MRSA) ceftaroline single-drug therapy: 2–<6 mo, 30 mg/ excision is rarely necessary for pneumococcus but may be
aureus, particularly CA-MRSA; kg/day IV div q8h (each dose given over 2 h); ≥6 mo, important for CA-MRSA and MSSA.
group A streptococcus, rarely 45 mg/kg/day IV div q8h (each dose given over 2 h) (max
Mycoplasma pneumoniae) single dose 600 mg) (BII) Focus antibiotic coverage based on culture results.
For MSSA: oxacillin/nafcillin or cefazolin.
(continued)
1021
Chapter 58—Antibiotics for Pulmonary Conditions
11/7/23 10:31 AM
Table 58-1. Antibiotic Choices (continued)
1022

Abscess, lung (continued)
• Secondary to aspiration (ie, foul Clindamycin 40 mg/kg/day IV div q8h or meropenem Alternatives: ceftriaxone AND metronidazole OR imipenem IV
smelling; polymicrobial 60 mg/kg/day IV div q8h for ≥10 days (AIII) OR pip/tazo IV (BIII)
infection with oral aerobes and Oral step-down therapy with clindamycin or amox/clav (BIII)
anaerobes)
Allergic bronchopulmonary Prednisone 0.5 mg/kg qd for 1–2 wk and then taper (BII) for Not all allergic pulmonary disease is associated with true fungal

aspergillosis mild, acute stage illness AND (for more severe disease) infection. Larger steroid dosages to control inflammation may
voriconazole 18 mg/kg/day PO div q12h load followed by lead to tissue invasion by Aspergillus.
16 mg/kg/day div q12h (AIII) OR itraconazole 10 mg/kg/ Corticosteroids are the cornerstone of therapy for exacerbations,
day PO div q12h (BII). Voriconazole and itraconazole and itraconazole and voriconazole have a demonstrable
require trough concentration monitoring. corticosteroid-sparing effect.
Aspiration pneumonia Clindamycin 40 mg/kg/day IV div q8h; ADD ceftriaxone Alternatives: ceftriaxone AND metronidazole OR imipenem IV
(polymicrobial infection with 50–75 mg/kg/day q24h for additional Haemophilus OR pip/tazo IV (BIII)
oral aerobes and an aerobes) activity OR, as a single agent, meropenem 60 mg/kg/day
Oral step-down therapy with clindamycin or amox/clav (BIII)
IV div q8h; for ≥10 days (BIII).
Atypical pneumonia (See Mycoplasma pneumoniae and Legionnaires disease later in this table under Pneumonias of other established etiologies.)
Bronchitis (bronchiolitis), acute For bronchitis/bronchiolitis in children, no antibiotic With PCR multiplex diagnosis now widely available, a nonbacte-
needed for most cases, as disease is usually viral rial diagnosis will allow clinicians to avoid use of antibiotics,
but viral/bacterial coinfection can still occur.
11/7/23 10:31 AM
Community-acquired pneumonia (See Community-acquired pneumonia: empiric therapy later in this table.)
Cystic fibrosis: Seek advice from experts in acute and chronic management. Larger than standard dosages of beta-lactam antibiotics have been required in the
past to achieve the same blood concentrations as those in children without CF, but in the current era of maximal pulmonary and nutritional support of CF, it
seems that most antibiotics eliminated by the kidney can be administered at typical doses to achieve adequate blood concentrations. However, we do not know

whether the concentrations of antibiotics achieved at the deep sites of infection in the CF lung are adequate, particularly with advanced CF disease. The Cystic
Fibrosis Foundation posts guidelines (www.cff.org/Care/Clinical-Care-Guidelines/Respiratory-Clinical-Care-Guidelines/Pulmonary-Exacerbations-Clini-
cal-Care-Guidelines; reviewed July 2021; accessed September 21, 2022). Dosages of beta-lactams should achieve their pharmacokinetic/pharmacodynamic goals
to increase the chance of response.
• Acute exacerbation (Pseudomo- Cefepime 150–200 mg/kg/day div q8h or meropenem Monitor concentrations of aminoglycosides, vancomycin.
nas aeruginosa primarily; also 120 mg/kg/day div q6h AND tobramycin 6–10 mg/kg/day Insufficient evidence to recommend routine use of inhaled
Burkholderia cepacia, Stenotro- IM, IV div q6–8h for treatment of acute exacerbation (AII); antibiotics for acute exacerbations.
phomonas maltophilia, S aureus many alternatives: imipenem IV, ceftazidime IV, or
[including CA-MRSA], ciprofloxacin 30 mg/kg/day PO, IV div tid Cultures with susceptibility will help select antibiotics, as
nontuberculous mycobacteria) multidrug resistance is common, but synergy testing is not
May require vancomycin 60–80 mg/kg/day IV div q8h for well standardized.
MRSA, OR ceftaroline 45 mg/kg/day IV div q8h (each dose
given over 2 h) (max single dose 600 mg) (BIII) Combination therapy may provide synergistic killing and delay
the emergence of resistance (BIII). Attempt at early eradication
Duration of therapy not well-defined: 10–14 days (BIII) of new-onset Pseudomonas may decrease progression of
disease.
Failure to respond to antibacterials should prompt evaluation for
appropriate drug doses and for invasive/allergic fungal disease
as well as maximization of pulmonary hygiene.
(continued)
1023
11/7/23 10:31 AM
1024

Cystic fibrosis (continued)
• Chronic inflammation in CF: Inhaled tobramycin 300 mg bid, cycling 28 days on therapy, Alternative inhaled antibiotics: colistin (BIII).
impact of inhaled antibiotics 28 days off therapy, is effective adjunctive therapy Two newer powder preparations of inhaled tobramycin are
and azithromycin to minimize between exacerbations, with new data suggesting a available.
long-term damage to lung benefit of alternating inhaled tobramycin with inhaled
aztreonam (AI). Azithromycin does not decrease the benefit of improved
pulmonary function with inhaled tobramycin in those with

Azithromycin adjunctive chronic therapy, greatest benefit Pseudomonas airway colonization.
for those colonized with Pseudomonas (AII).
Pertussis Azithromycin: for those ≥6 mo, 10 mg/kg/day for day 1, Azithromycin and clarithromycin are better tolerated than
then 5 mg/kg/day for days 2–5; for those <6 mo, 10 mg/ erythromycin; azithromycin is preferred in young infants to
kg/day for 5 days; OR clarithromycin 15 mg/kg/day div bid reduce pyloric stenosis risk.
for 7 days; or erythromycin (estolate preferable) 40 mg/ Provide prophylaxis to family members.
kg/day PO div qid for 7–10 days (AII)
Unfortunately, no adjunctive therapy has been shown to be
Alternative: TMP/SMX 8 mg/kg/day of TMP div bid for beneficial in decreasing the cough.
14 days (BIII)
Community-acquired pneumonia: empiric therapy for bronchopneumonia, lobar consolidation, or complicated pneumonia with pleural fluid/
empyema
• Mild to moderate “chest cold”– No antibiotic therapy unless epidemiologic, clinical, or Broad-spectrum antibiotics may increase risk of subsequent
like illness (overwhelmingly laboratory reasons to suspect bacterial coinfection, or infection with antibiotic-resistant pathogens.
viral, especially in preschool Mycoplasma
children)
11/7/23 10:31 AM
empyema (continued)
• Moderate to severe illness Empiric therapy Tracheal aspirate or BAL for Gram stain/culture for severe
(pneumococcus; group A infection in intubated children.

For most regions now with high PCV13 vaccine use or low
streptococcus; S aureus, pneumococcal resistance to penicillin: ampicillin For CA-MRSA: if vancomycin is being used rather than ceftaro-
including CA-MRSA; M 150–200 mg/kg/day div q6h. line, check vancomycin serum concentrations and renal
pneumoniae; for those with function, particularly at the higher dosage needed to achieve
aspiration and underlying For regions with low rates of PCV13 use or high pneumo-
an AUC:MIC of 400.
comorbidities, Haemophilus coccal resistance to penicillin: ceftriaxone 50–75 mg/kg/
influenzae, nontypeable; and day q24h (AI). Alternatives to azithromycin for atypical pneumonia include
for unimmunized children, H erythromycin IV, PO, or clarithromycin PO, or doxycycline IV,
For suspected CA-MRSA: ceftaroline: 2–<6 mo, 30 mg/kg/
influenzae type b) PO for children >7 y, or levofloxacin IV, PO.
day IV div q8h (each dose given over 2 h); ≥6 mo, 45 mg/
kg/day IV div q8h (each dose given over 2 h) (max single Benefits of combination empiric therapy with a beta-lactam and
dose 600 mg) (BII), OR vancomycin 40–60 mg/kg/day a macrolide conflict and may apply only to certain populations.
(AIII). Duration of therapy is still not well-defined in prospective,
For suspected Mycoplasma/atypical pneumonia agents, controlled trials in pediatric community-acquired pneumonia.
particularly in school-aged children, ADD azithromycin Retrospective data with diagnosis based only on clinical
10 mg/kg IV, PO on day 1, then 5 mg/kg qd for days 2–5 of examination and radiograph suggested that 10 days may be
treatment (AII). unnecessary for all children (5 days may be sufficient). Empiric
oral outpatient therapy for less severe illness: high-dosage
amoxicillin 80–100 mg/kg/day PO div tid (NOT bid, which is
used for otitis) (BIII).
(continued)
1025
11/7/23 10:31 AM
1026

empyema (continued)
• Pleural fluid/empyema (same Empiric therapy: ceftriaxone 50–75 mg/kg/day q24h AND Initial therapy based on Gram stain of empyema fluid; typically,
pathogens as for community- vancomycin 40–60 mg/kg/day IV div q8h (BIII) OR clinical improvement is slow, with persisting but decreasing
associated bronchopneumonia) ceftaroline single-drug therapy: 2–<6 mo, 30 mg/kg/day “spiking” fever for 2–3 wk.
(Based on extent of fluid and IV div q8h; ≥6 mo, 45 mg/kg/day IV div q8h (each dose Concerns about the effectiveness of vancomycin monotherapy

symptoms, may benefit from given over 2 h) (max single dose 600 mg) (BII) in influenza-associated MRSA pneumonia. Combination
chest tube drainage with therapy with agents added to vancomycin, or monotherapy
fibrinolysis; rarely from with other agents like ceftaroline, may provide a better option.
video-assisted thoracoscopic
surgery.)
• Interstitial pneumonia If Chlamydia trachomatis suspected, azithromycin 10 mg/kg Most often respiratory viral pathogens, CMV, or chlamydial; role
syndrome of early infancy on day 1, followed by 5 mg/kg/day qd days 2–5 OR of Ureaplasma uncertain
erythromycin 40 mg/kg/day PO div qid for 14 days (BII)
Pneumonia: definitive therapy for pathogens of community-acquired pneumonia
• Pneumococcus (may occur Empiric therapy Change to PO after improvement (decreased fever, no oxygen
with non-PCV13 serotypes) For regions with high PCV13 vaccine use or low pneumo- needed); treat until patient clinically asymptomatic and chest
coccal resistance to penicillin: ampicillin 150–200 mg/kg/ radiograph significantly improved (7–21 days) (BIII).
day div q6h No reported failures of ceftriaxone for pen-R pneumococcus; no
For regions with low rates of PCV13 use or high pneumo- need to add empiric vancomycin for this reason (CIII).
coccal resistance to penicillin: ceftriaxone 50–75 mg/kg/ Oral therapy for pneumococcus may also be successful with
day q24h (AI) amox/clav, cefdinir, cefixime, cefpodoxime, or cefuroxime,
Empiric oral outpatient therapy for less severe illness: particularly for fully pen-S strains.
high-dosage amoxicillin 80–100 mg/kg/day PO div tid Levofloxacin is an alternative, particularly for those with severe
(NOT bid, which is used for otitis) allergy to beta-lactam antibiotics (BI), but, due to theoretical
cartilage toxicity concerns for humans, should not be first-line
therapy.
11/7/23 10:31 AM
Pneumonia: definitive therapy for pathogens of community-acquired pneumonia
• Pneumococcal, pen-S Penicillin G 250,000–400,000 U/kg/day IV div q4–6h for After improvement, change to amoxicillin 50–75 mg/kg/day PO
10 days (BII) OR ampicillin 150–200 mg/kg/day IV div q6h div tid OR penicillin V 50–75 mg/kg/day div qid.
• Pneumococcal, pen-R Ceftriaxone 75 mg/kg/day q24h for 10–14 days (BIII) Addition of vancomycin has not been required for treatment of
pen-R strains.

Ceftaroline is more active against pneumococcus than
ceftriaxone, but with no current ceftriaxone resistance,
ceftaroline is not required.
For oral convalescent therapy, high-dosage amoxicillin (100–150
mg/kg/day PO div tid), clindamycin (30 mg/kg/day PO div tid),
linezolid (30 mg/kg/day PO div tid), or levofloxacin PO.
• Staphylococcus aureus For MSSA: oxacillin/nafcillin 150 mg/kg/day IV div q6h or Check vancomycin serum concentrations and renal function,
(including CA-MRSA) is a rare cefazolin 100 mg/kg/day IV div q8h (AII) particularly at the higher dosage designed to attain an
(1%) cause of pediatric For suspected CA-MRSA: ceftaroline: 2–<6 mo, 30 mg/kg/ AUC:MIC of 400, or serum trough concentrations of 15 mcg/mL
community-acquired day IV div q8h (each dose given over 2 h); ≥6 mo, 45 mg/ for invasive CA-MRSA disease.
pneumonia. kg/day IV div q8h (each dose given over 2 h) (max single For life-threatening disease, optimal therapy for CA-MRSA has
dose 600 mg) (BII), OR vancomycin 40–60 mg/kg/day not been studied and remains poorly defined: consider adding
(AIII); may need addition of rifampin, clindamycin, or gentamicin and/or rifampin for combination therapy (CIII).
gentamicin (AIII) Linezolid 30 mg/kg/day IV, PO div q8h is another option, more
effective in adults than vancomycin for MRSA nosocomial
pneumonia (follow platelet and WBC counts weekly).
For influenza-associated MRSA pneumonia, vancomycin
monotherapy was inferior to combination therapies.
Do NOT use daptomycin for pneumonia.
Oral convalescent therapy for MSSA: cephalexin PO; for
CA-MRSA: clindamycin or linezolid PO.
Total course for ≥21 days (AIII).
1027
(continued)
11/7/23 10:31 AM
1028

Pneumonia: definitive therapy for pathogens of community-acquired pneumonia (continued)
• Group A streptococcus Penicillin G 250,000 U/kg/day IV div q4–6h for 10 days (BII) Change to amoxicillin 75 mg/kg/day PO div tid or penicillin V
50–75 mg/kg/day div qid to tid after clinical improvement

(BIII).
Pneumonia: immunosuppressed, neutropenic host
• Immunosuppressed, Cefepime 150 mg/kg/day IV div q8h (AII), OR meropenem Biopsy/BAL for histology/cultures or serum/BAL for cell-free

neutropenic host (P aerugino- 60 mg/kg/day div q8h (AII) (BIII), OR pip/tazo 240–300 next-generation sequencing testing helps determine need for
sa, other community-associated mg/kg/day div q6h; AND if S aureus (including MRSA) is antifungal, antiviral, antimycobacterial treatment. Antifungal
or nosocomial gram-negative suspected clinically, ADD vancomycin 40–60 mg/kg/day therapy usually started if no response to antibiotics in 48–72 h
bacilli, S aureus, fungi, AFB, IV div q8h (AIII) OR ceftaroline: 2–<6 mo, 30 mg/kg/day IV (AmB, voriconazole, or caspofungin/micafungin).
Pneumocystis, viral [adenovirus, div q8h; ≥6 mo, 45 mg/kg/day IV div q8h (max single dose For septic patients, the addition of tobramycin will increase
CMV, EBV, influenza, RSV, 600 mg) (BIII). coverage for most gram-negative pathogens.
others])
For those with mucositis, anaerobic coverage may be needed, as
provided by carbapenems and pip/tazo (or with the addition
of clindamycin or metronidazole to other agents).
Consider use of 2 active agents for definitive therapy for
Pseudomonas for neutropenic hosts to assist clearing the
pathogen and potentially decrease risk of resistance, but there
is no evidence to support better outcomes (BIII).
11/7/23 10:31 AM
Pneumonia: nosocomial (health care–associated/ventilator-associated)
• Nosocomial (health care– Commonly used regimens Empiric therapy should be institution specific, based on your
associated/ventilator- hospital’s nosocomial pathogens and susceptibilities.
Meropenem 60 mg/kg/day div q8h, OR pip/tazo 240–
associated) (P aeruginosa, Pathogens that cause nosocomial pneumonia often have
300 mg/kg/day div q6–8h, OR cefepime 150 mg/kg/day

gram-negative enteric bacilli multidrug resistance. Cultures are critical. Empiric therapy also
div q8h; ± gentamicin 6.0–7.5 mg/kg/day div q8h (AIII);
[Enterobacter, Klebsiella, Serratia, based on child’s prior colonization/infection. Do not treat
ADD vancomycin or ceftaroline for suspected CA-MRSA
Escherichia coli], Acinetobacter, colonization, though.
(AIII).
Stenotrophomonas, and For MDR gram-negative bacilli, available IV therapy options
gram-positive organisms include ceftazidime/avibactam (now FDA approved for
including CA-MRSA and children), tol/taz, meropenem/vaborbactam, cefiderocol,
Enterococcus) plazomicin, or colistin.
Aerosol delivery of antibiotics may be required for MDR
pathogens, but little high-quality controlled data are available
for children.
Pneumonias of other established etiologies
• Chlamydophila pneumoniae, Azithromycin 10 mg/kg on day 1, followed by 5 mg/kg/day Doxycycline (patients >7 y). Levofloxacin should also be
Chlamydophila psittaci, or qd days 2–5 or erythromycin 40 mg/kg/day PO div qid; for effective.
Chlamydia trachomatis 14 days
• CMV (immunocompromised Ganciclovir IV 10 mg/kg/day IV div q12h for 2 wk (BIII); if Bone marrow transplant recipients with CMV pneumonia whose
host) needed, continue at 5 mg/kg/day q24h to complete ganciclovir therapy alone fails may benefit from therapy with
4–6 wk total (BIII). IV CMV hyperimmunoglobulin and ganciclovir given together
(BII).
Oral valganciclovir may be used for convalescent therapy (BIII).
Foscarnet for ganciclovir-resistant isolates.
1029
(continued)
11/7/23 10:31 AM
1030

Pneumonias of other established etiologies (continued)
• E coli Ceftriaxone 50–75 mg/kg/day q24h (AII) For cephalosporin-R strains (ESBL producers), use meropenem,
imipenem, or ertapenem (AIII). Use high-dose ampicillin if

susceptible.
• Enterobacter spp Cefepime 100 mg/kg/day div q12h or meropenem 60 mg/ Addition of aminoglycoside to third-generation cephalosporins
kg/day div q8h; OR ceftriaxone 50–75 mg/kg/day q24h (ceftriaxone, ceftazidime) may retard the emergence of

AND gentamicin 6.0–7.5 mg/kg/day IM, IV div q8h (AIII) ampC-mediated constitutive high-level resistance, but concern
exists for inadequate aminoglycoside concentration in
airways; not an issue for ampC-stable beta-lactams (cefepime,
meropenem, imipenem, or pip/tazo).
• Francisella tularensis Gentamicin 6.0–7.5 mg/kg/day IM, IV div q8h for ≥10 days Other alternative for oral therapy for mild disease: doxycycline
for more severe disease (AIII); for less severe disease, PO for 14–21 days (but watch for relapse). See www.cdc.gov/
ciprofloxacin or levofloxacin (AIII) tularemia/clinicians/index.html (reviewed July 5, 2022;
accessed September 21, 2022).
• Fungi For suspected endemic fungi or mucormycosis in an For immunocompetent hosts, triazoles (fluconazole, itracon-
immunocompromised host, treat empirically with a lipid azole, voriconazole, posaconazole, and isavuconazole) are
Community-associated
AmB and not voriconazole; biopsy needed to guide better tolerated than AmB and equally effective for many
pathogens, which vary by
therapy. Posaconazole and isavuconazole have in vitro community-associated pathogens.
region (eg, Coccidioides,
activity and clinical efficacy data against some Rhizopus Check voriconazole trough concentrations; need to be at least
Histoplasma)
spp. >2 mcg/mL.
Aspergillus; mucormycosis; other
For suspected invasive aspergillosis, treat with voricon- For Coccidioides infection refractory to fluconazole therapy,
mold infections in immuno-
azole (AI) (load 18 mg/kg/day div q12h on day 1, then consider increasing the dose, switching to other azoles, or
compromised hosts
continue 16 mg/kg/day div q12h). switching to AmB.
11/7/23 10:31 AM
– Influenza virus. Empiric therapy, or documented influenza A or B Check for antiviral susceptibility each season at www.cdc.gov/
flu/professionals/antivirals/index.htm (reviewed by the CDC
– Recent seasonal influenza A Oseltamivir (AII):
September 8, 2022; accessed September 21, 2022).
and B strains continue to be <12 mo:

resistant to adamantanes. For children 12–23 mo, the unit dose of oseltamivir of 30 mg/
Full-term infants 0–8 mo: 3 mg/kg/dose bid dose may provide inadequate drug exposure. 3.5 mg/kg/dose
9–11 mo: 3.5 mg/kg/dose bid PO bid has been studied for pharmacokinetics, but sample
sizes were limited.
≥12 mo:
Limited data for oseltamivir in preterm neonates:
≤15 kg: 30 mg PO bid
<38 wk of PMA (gestational plus chronologic age): 1.0 mg/kg/
>15–23 kg: 45 mg PO bid dose PO bid
>23–40 kg: 60 mg PO bid 38–40 wk of PMA: 1.5 mg/kg/dose PO bid
>40 kg: 75 mg PO bid The adamantanes (amantadine and rimantadine) had activity
Zanamivir inhaled (AII): for those ≥7 y, 10 mg (two 5-mg against influenza A before the late 1990s, but all circulating A
inhalations) bid strains of influenza have been resistant for many years.
Influenza B is intrinsically resistant to adamantanes.
Peramivir (BII):
6 mo–12 y: single IV dose of 12 mg/kg, up to 600 mg max
13–17 y: single IV dose of 600 mg
Baloxavir (BI):
≥5 y:
<20 kg: single dose PO of 2 mg/kg
20–79 kg: single dose PO of 40 mg
≥80 kg: single dose PO of 80 mg
1031
(continued)
11/7/23 10:31 AM
1032

• Klebsiella pneumoniae Ceftriaxone 50–75 mg/kg/day IV, IM q24h (AIII); for For K pneumoniae that contain ESBLs, other carbapenems, pip/
ceftriaxone-resistant strains (ESBL strains), use meropen- tazo, and fluoroquinolones are other options. Data in adults
em 60 mg/kg/day IV div q8h (AIII) or other carbapenem. suggest that outcomes with pip/tazo are inferior to those with
carbapenems. For KPC-producing strains that are resistant to
meropenem, alternatives include ceftazidime/avibactam (FDA

approved for adults and children), fluoroquinolones, or colistin
(BIII).
• Legionnaires disease (Legionella Azithromycin 10 mg/kg IV, PO q24h for 5 days (AIII) Alternatives: clarithromycin, erythromycin, ciprofloxacin,
pneumophila) levofloxacin, doxycycline
• Mycobacteria, nontuberculous In a normal host with pneumonia that requires therapy, Highly variable susceptibilities of different nontuberculous
(Mycobacterium avium complex 3 drugs are now recommended: azithromycin PO (or mycobacterial spp. Culture and susceptibility data are
most common) clarithromycin PO) AND ethambutol, AND rifampin, given important for success.
3 times/wk to prevent macrolide/azalide resistance. Check if immunocompromised: HIV or interferon-γ receptor
Duration of treatment is not well-defined; consider 12 mo, deficiency.
or 6–12 wk if susceptible.
Consider consulting an ID physician.
For more extensive cavitary or advanced/severe
bronchectatic disease, ADD amikacin or streptomycin
(AIII).
• Mycobacterium tuberculosis (See
Tuberculosis later in this table.)
11/7/23 10:31 AM
• M pneumoniae Azithromycin 10 mg/kg on day 1, followed by 5 mg/kg/day Mycoplasma often causes self-limited infection and does not
qd days 2–5, OR clarithromycin 15 mg/kg/day div bid for routinely require treatment (AIII). Little prospective, well-
7–14 days, OR erythromycin 40 mg/kg/day PO div qid for controlled data exist for treatment of documented

14 days mycoplasma pneumonia, specifically in children.
Doxycycline (patients >7 y) or levofloxacin.
Macrolide-resistant strains have recently developed worldwide
but may respond to doxycycline or levofloxacin.
Studies have been difficult without better diagnostic tech-
niques, but respiratory tract PCR testing is now available to
assist in early identification of possible infections.
• Pneumocystis jiroveci (formerly Severe disease: preferred regimen is TMP/SMX, 15–20 mg/ Alternatives for TMP/SMX intolerant, or clinical failure: pentami-
carinii); disease in immunosup- kg/day of TMP IV div q8h for 3 wk (AI). dine 3–4 mg IV qd, infused over 60–90 min (AII); TMP AND
pressed children and those with Mild to moderate disease: may start with IV therapy, then dapsone; OR primaquine AND clindamycin; OR atovaquone.
HIV after acute pneumonitis is resolving, TMP/SMX 20 mg/kg/ Prophylaxis: TMP/SMX as 5 mg/kg/day of TMP PO, div in 2 doses,
day of TMP PO div qid for 21 days (AII). q12h, daily or 3 times/wk on consecutive days (AI); OR TMP/
SMX 5 mg/kg/day of TMP PO as a single dose, qd, given
Use steroid adjunctive treatment for more severe disease
3 times/wk on consecutive days (AI); once-weekly regimens
(AII).
have also been successful; OR dapsone 2 mg/kg (max 100 mg)
PO qd, or 4 mg/kg (max 200 mg) once weekly; OR atovaquone:
30 mg/kg/day for infants 1–3 mo, 45 mg/kg/day for infants
4–24 mo, and 30 mg/kg/day for children >24 mo.
(continued)
1033
11/7/23 10:31 AM
1034

• P aeruginosa Cefepime 150 mg/kg/day IV div q8h ± tobramycin 6.0– Ciprofloxacin IV, or colistin IV for MDR strains of Pseudomonas.
7.5 mg/kg/day IM, IV div q8h (AII). Alternatives:

meropenem 60 mg/kg/day div q8h, OR pip/tazo 240–
300 mg/kg/day div q6–8h (AII) ± tobramycin (BIII).
• RSV infection (bronchiolitis, For immunocompromised hosts, the only FDA-approved Treat only for severe disease, immunocompromised, severe

pneumonia) treatment is ribavirin aerosol: 6-g vial (20 mg/mL in sterile underlying cardiopulmonary disease, as aerosol ribavirin
water), by SPAG-2, over 18–20 h daily for 3–5 days, provides only a small benefit. Airway reactivity with inhalation
although questions remain regarding efficacy. precludes routine use. We have not personally used inhaled
ribavirin for the past several years.
Palivizumab (Synagis) is not effective for treatment of an active
RSV infection but cost-effective for prevention of hospitaliza-
tion in high-risk patients.
RSV antivirals and more potent monoclonal antibodies are
currently under investigation.
11/7/23 10:31 AM
Tuberculosis
• Primary pulmonary disease INH 10–15 mg/kg/day (max 300 mg) PO qd for 6 mo AND Obtain baseline LFTs. Consider monthly LFTs for at least 3 mo or
rifampin 15–20 mg/kg/day (max 600 mg) PO qd for 6 mo as needed for symptoms. It is common to have mildly elevated
AND PZA 30–40 mg/kg/day (max 2 g) PO qd for first 2 mo liver transaminase concentrations (2–3 times normal) that do
of therapy only (AII). Twice-weekly treatment, particularly not further increase during the entire treatment interval.

with DOT, is acceptable. Children with obesity may have mild elevation when therapy
is started.
If risk factors present for multidrug resistance, ADD
ethambutol 20 mg/kg/day PO qd OR streptomycin 30 mg/ New recommendations on short-course (4-mo) daily therapy for
kg/day IV, IM div q12h initially. children with non-severe TB may soon be made for the United
States, following new World Health Organization guidelines
(www.who.int/publications/i/item/9789240046764; accessed
September 21, 2022).
Contact TB specialist for therapy for drug-resistant TB. Fluoro-
quinolones may play a role in treating MDR strains.
Bedaquiline, in a new drug class for TB therapy, is approved for
adults and children >5 y with MDR TB when used in combina-
tion therapy. Delamanid is not FDA approved as of July 2022.
DOT preferred; after 2 wk of daily therapy, can change to
twice-weekly dosing double dosage of INH (max 900 mg), PZA
(max 2 g), and ethambutol (max 2.5 g); rifampin remains same
dosage (15–20 mg/kg/day, max 600 mg) (AII).
LP ± CT of head for children ≤2 y to rule out occult, concurrent
CNS infection; consider testing for HIV infection (AIII).
Mycobacterium bovis infection from unpasteurized dairy
products is also called “tuberculosis” but rarely causes
pulmonary disease; all strains of M bovis are PZA resistant.
Treat 9–12 mo with INH and rifampin.
1035
(continued)
11/7/23 10:31 AM
1036

Tuberculosis (continued)
• Latent TB infection (skin test Many options now Obtain baseline LFTs. Consider monthly LFTs or as needed for
conversion; more recently just symptoms. Stop INH/rifapentine if AST or ALT ≥5 times the
INH/rifapentine:
called “TB infection” in contrast ULN even in the absence of symptoms or ≥3 times the ULN in
to “TB disease” for symptomatic For children 2–11 y: once-weekly DOT for 12 wk: INH 25 mg/ the presence of symptoms.
TB infection) kg/dose (max 900 mg), AND rifapentine:
For children <2 y: INH and rifapentine may be used, but there

10.0–14.0 kg: 300 mg are less data on safety and efficacy.
14.1–25.0 kg: 450 mg For exposure to known INH-resistant but rifampin-susceptible
25.1–32.0 kg: 600 mg strains, use rifampin 6 mo (AIII).
32.1–49.9 kg: 750 mg

≥50.0 kg: 900 mg (max)
For children 2–11 y: INH 25 mg/kg, rounded up to nearest
50 or 100 mg (max 900 mg), AND rifapentine (See above.)
Rifampin alone (all ages): 15–20 mg/kg/dose daily (max
600 mg) for 4 mo
INH/rifampin (all ages): INH 10–15 mg/kg/day (max 300 mg)/
rifampin 15–20 mg/kg/day (max 600 mg) daily for 3 mo
INH 10–15 mg/kg/day (max 300 mg) PO daily for 6–9 mo (12
mo for immunocompromised patients) (AIII); treatment
with INH at 20–30 mg/kg twice weekly for 9 mo also effec-
tive (AIII)
11/7/23 10:31 AM
Tuberculosis (continued)
• Exposed child <4 y, or Prophylaxis for possible infection for 2–3 mo after last expo- Alternative regimens
immunocompromised patient sure with rifampin 15–20 mg/kg/dose PO qd OR INH INH 10–15 mg/kg PO qd AND rifampin 15–20 mg/kg/dose qd
(high risk for dissemination) 10–15 mg/kg PO qd; for at least 2–3 mo (AIII), with (max 600 mg) for up to 3 mo.

repeated skin test or interferon-γ release assay test (AIII).
Also called “window prophylaxis.” If PPD or interferon-γ release assay test remains negative at 2–
3 mo and child appears well, consider stopping empiric
therapy. PPD may not be reliable in immunocompromised
patients. Not much data to assess reliability of interferon-γ
release assays in very young infants or immunocompromised
hosts, but not likely to be much better than the PPD skin test.
AFB, acid-fast bacilli; ALT, alanine transaminase; AmB, amphotericin B; amox/clav, amoxicillin/clavulanate; ampC, amphotericin C; AST, aspartate transaminase;
AUC:MIC, area under the curve (the mathematically calculated area below the serum concentration-versus-time curve) to minimum inhibitory concentration; BAL,
bronchoalveolar lavage; bid, twice daily; CA-MRSA, community-associated methicillin-resistant Staphylococcus aureus; CF, cystic fibrosis; CMV, cytomegalovirus;
CNS, central nervous system; CT, computed tomography; div, divided; DOT, directly observed therapy; EBV, Epstein-Barr virus; ESBL, extended-spectrum
beta-lactamase; FDA, US Food and Drug Administration; ID, infectious disease; IM, intramuscular; INH, isoniazid; IV, intravenous; KPC, Klebsiella pneumoniae
carbapenemase; LFT, liver function test; LP, lumbar puncture; max, maximum; MDR, multidrug resistant; MRSA, methicillin-resistant S aureus; MSSA,
methicillin-susceptible S aureus; PCR, polymerase chain reaction; PCV13, Prevnar 13-valent pneumococcal conjugate vaccine; pen-R, penicillin-resistant; pen-S,
penicillin-susceptible; pip/tazo, piperacillin/tazobactam; PMA, postmenstrual age; PO, orally; PPD, purified protein derivative; PZA, pyrazinamide; q, every; qd,
once daily; qid, 4 times daily; RSV, respiratory syncytial virus; SPAG-2, small particle aerosol generator-2; spp, species; TB, tuberculosis; tid, 3 times daily; TMP/SMX,
trimethoprim/sulfamethoxazole; tol/taz, ceftolozane/tazobactam; ULN, upper limit of normal; WBC, white blood cell.
Adapted from Bradley JS, Nelson JD, eds. 2023 Nelson’s Pediatric Antimicrobial Therapy 2022. 29th ed. American Academy of Pediatrics; 2023.
(continued)
1037
11/7/23 10:31 AM
1038
Classes of Antibiotics
Oral Cephalosporins
The oral cephalosporins (Box 58-2) have an advantage over oral penicillins of
somewhat greater spectrum of activity. The serum half-lives of cefpodoxime,
ceftibuten, and cefixime are greater than 2 hours, which allows for twice-
daily dosing. There is varying activity against
Box 58‑2
Haemophilus influenzae and Streptococcus
Oral pneumoniae.
Cephalosporins
First-generation cephalosporins (Box 58-3)
ū Cephalexin
are used mainly for treatment of gram-positive
ū Cefadroxil
infections. Cefazolin is well tolerated on intramus-
ū Cefaclor cular or intravenous injection.
ū Cefprozil
Second-generation cephalosporins (Box 58-3)
ū Cefuroxime
provide increased activity against many gram-
ū Cefixime negative organisms. Cefoxitin has additional
ū Cefdinir activity against up to 80% of strains of Bacteroides
ū Cefpodoxime fragilis. In empiric therapy for mild to moderate
ū Cefditoren (≥12 years) infections at low risk of being caused by B fragilis,
ū Ceftibuten cefoxitin can be considered for use in place of the
more active agents such as metronidazole or
Box 58‑3 carbapenems. Cefotetan has a spectrum similar to
cefoxitin with a longer half-life, so it can be given
Parenteral every 12 hours. Cefuroxime is given as a single
Cephalosporins
injection in many countries for pneumonia that is
First Generation
caused by gram-positive cocci or H influenzae
ū Cefazolin
type b, or H influenzae nonencapsulated strains in
Second Generation children with underlying lung diseases.
ū Cefamandole
Third-generation cephalosporins (Box 58-3)
ū Cefuroxime
have enhanced potency against gram-negative
ū Cephamycins
bacilli but lack activity against inducible amphoter-
• Cefoxitin
icin C (AmpC) β-lactamases and extended-
• Cefotetan
spectrum β-lactamases. They are inactive against
Third Generation enterococci and Listeria and have variable activity
ū Ceftriaxone against Pseudomonas and Bacteroides. Ceftazi-
ū Ceftazidime dime has the unique property of activity against
Fourth Generation Pseudomonas aeruginosa and is widely used in
ū Cefepime patients with cystic fibrosis (CF).
Fifth Generation The fourth-generation cephalosporin cefepime has
ū Ceftaroline antipseudomonal activity as well as activity

1039
against gram-positive organisms and inducible AmpC β-lactamase–produc-

ing gram-negative bacilli, such as Enterobacter and Serratia.
The fifth-generation cephalosporin ceftaroline is the first of the β-lactam
antibiotics to demonstrate activity against methicillin-resistant Staphylococcus
aureus (MRSA). In addition, it provides activity against the gram-negative
enteric bacilli similar to the third-generation cephalosporins, lacking activity
against inducible AmpC β-lactamase‒producing pathogens, extended-spectrum
β-lactamase‒producing pathogens, and Pseudomonas aeruginosa.
Penicillinase-Resistant Penicillins
The penicillinase-resistant penicillins (Box 58-4) were specifically formulated
to address stability against the β-lactamase produced by S aureus. These
compounds are not stable to the β-lactamases produced by gram-negative
bacteria. They are active against methicillin-sensitive S aureus (MSSA) but not
MRSA. Nafcillin is excreted primarily by the liver rather than the kidneys,
compared with the others in this group, which
Box 58‑4 may explain the relative lack of nephrotoxicity
Penicillinase-Resistant when this penicillin is compared with methicil-
Penicillins lin, which is no longer available in the United
ū Dicloxacillin States.
ū Nafcillin The oral antibiotics cloxacillin, dicloxacillin,
ū Oxacillin and oxacillin are equivalent in activity but
virtually unpalatable.
Antipseudomonal β-lactams
Piperacillin/tazobactam (Zosyn) and ceftazidime/avibactam (Avycaz) (both
FDA approved for children), and, still under investigation in children,
ceftolozane/tazobactam (Zerbaxa), imipenem/relebactam (Recarbrio), and
meropenem/vaborbactam (Vabomere), represent combinations of a β-lactam
and a β-lactamase inhibitor. The antibiotic binds effectively to the target site
in the bacteria, resulting in death of the organism, whereas the second
β-lactamase inhibitor binds irreversibly
Box 58‑5 to and neutralizes the β-lactamase
Antipseudomonal β-lactams enzyme the organism produced to
ū Piperacillin and tazobactam degrade the original antibiotic. The
ū Aztreonam antipseudomonal intracellular binding
activity of the combination is no different
ū Ceftazidime
than the original; in addition, there is
ū Cefepime
increased protection by these β-lactamase
ū Meropenem inhibitors for other β-lactamase–positive
ū Imipenem bacteria, including S aureus (MSSA
ū Ertapenem strains only) and B fragilis.

1040
Pseudomonas has an intrinsic capacity to develop resistance to β-lactam

antibiotics by many mechanisms (β-lactamases, efflux pumps, cell wall
changes to decrease drug entry into the bacteria). Particularly for ceftazidime,
β-lactamase induction may lead to resistance with single-drug therapy, so
combination with an aminoglycoside (or other active antibiotic) is advisable.
Cefepime, meropenem, and imipenem are less likely to develop resistance
from β-lactamases and can be used as single therapy. However, in patients
who are immunocompromised, have CF, or have life-threatening infections,
these antibiotics should be used in combination with an aminoglycoside or
other active antibiotic.
Aminopenicillins
Ampicillin, an aminopenicillin (Box 58-6), is more likely than the other
aminopenicillins to cause diarrhea and to cause overgrowth of Candida.
Amoxicillin is well absorbed, good tasting, and associated with very few side
effects. Amoxicillin and clavulanic acid (Augmentin) is available in the
United States in oral form and for parenteral use in many other countries; it
has activity against many β-lactamase–producing bacteria, including H
influenzae and S aureus (MSSA strains only).
Carbapenems
Carbapenems (Box 58-7) have a broader spectrum of activity than any
other β-lactams currently available. They are active against streptococci and
S aureus (MSSA strains only), Pseudomonas, most coliform bacilli (including
ceftriaxone-resistant strains), and anaerobes, including B fragilis. Ertapenem
does not have activity against Pseudomonas.
Macrolides
Erythromycin is the prototype macrolide antibiotic, and the 3 shown in Box
58-8 are the only commercial macrolide antibiotics available in the United
States. Azithromycin is more accurately called an azalide but is structurally
very similar to macrolides. Azithromycin and clarithromycin have activity
against certain nontuberculous mycobacteria but should not be used as
monotherapy because of the potential to develop resistance. The macrolides
are usually active against the “atypical pneumonia” pathogens (Mycoplasma,
Legionella, Chlamydia, Chlamydophila).
Box 58‑6 Box 58‑7 Box 58‑8

Aminopenicillins Carbapenems Macrolides
ū Amoxicillin ū Meropenem ū Erythromycin
ū Amoxicillin and clavulanate ū Imipenem ū Azithromycin
ū Ampicillin ū Ertapenem ū Clarithromycin
ū Ampicillin and sulbactam

1041
Aminoglycosides
Amikacin, gentamicin, and tobramycin (Box 58-9) are widely used for
systemic therapy of aerobic gram-negative infections and for synergy in
the treatment of certain gram-negative and gram-positive infections. It is
advisable to monitor levels because of potential toxicity to the kidneys and
the eighth cranial nerve. The desired peak concentrations of amikacin are
20 to 35 mcg/mL, and the optimal trough concentration should be less than
10 mcg/mL; for gentamicin and tobramycin, peak concentrations should be
5 to 10 mcg/mL and trough concentrations less than 2 mcg/mL. Children
with CF usually require significantly higher dosages of these medications.
Aminoglycosides demonstrate concentration-dependent killing of organisms,
and the peak serum concentrations when given once daily are greater than
those achieved with dosing 3 times daily with less associated toxicity. Once-
daily dosing of tobramycin is increasingly being
Box 58‑9 prescribed, with doses of 5 to 7.5 mg/kg and, in
Aminoglycosides patients with CF, doses of 9 to 10 mg/kg. When using
ū Amikacin high doses given less frequently, peak levels are
often not measured and typically are 20 to 30 mcg/
ū Gentamicin
mL, but it is important that the trough level is less
ū Tobramycin
than 1.0 mcg/mL to avoid renal toxicity and ototoxic-
ū Streptomycina ity. There are sufficient prospectively collected
ū Kanamycina comparative data for the Cystic Fibrosis Foundation
a
Not commonly used. to recommend once-daily treatment, compared with
8-hourly dosing in children with CF.1
Fluoroquinolones
Ciprofloxacin usually has very good gram-negative activity against enteric
bacteria (Escherichia coli, Klebsiella, Enterobacter, Salmonella, and
Shigella, as well as coverage against P aeruginosa) but has minimal coverage
for gram-positive organisms, so if S aureus or pneumococcus is suspected,
additional coverage should be added. The newer quinolones, such as levoflox-
acin, have improved coverage against these organ-
Box 58‑10 isms but should not be considered optimal therapy
Fluoroquinolones for staphylococcal infections.
ū Ciprofloxacin There are theoretical concerns regarding toxicity
ū Levofloxacin of fluoroquinolones to cartilaginous weight-bearing
ū Moxifloxacin joints, so the fluoroquinolones (Box 58-10) should
be used cautiously in children.

1042
Antifungal Agents
Amphotericin B
Amphotericin B is a polyene antifungal antibiotic that has been available since
1958 for the treatment of invasive fungal infections. It remains the most
broad-spectrum antifungal available for clinical use, with a mechanism of
action against the fungal cell membrane in which pores are created, compro-
mising the integrity of the membrane and creating a fungicidal effect. The
toxicity of the conventional formulation, amphotericin B deoxycholate, can
be substantial from the standpoints of systemic reactions (eg, fever, rigors) and
renal toxicity. Premedication with acetaminophen, diphenhydramine, and
meperidine is often required to prevent systemic reactions during infusion.
Renal dysfunction develops primarily as decreased glomerular filtration with a
rising serum creatinine concentration, but substantial tubular nephropathy
is associated with potassium and magnesium wasting, requiring supplemen-
tal potassium for many neonates and children, regardless of clinical symptoms
associated with infusion. Newer lipid preparations decrease toxicity with no
apparent decrease in clinical efficacy and should be used because they are
far better tolerated than amphotericin B deoxycholate.
Azoles
The azoles were first approved in 1981. All the azoles work by inhibition
of ergosterol synthesis (fungal cytochrome P450 sterol 14-demethylation)
that is required for fungal cell membrane integrity. In general, the azoles are
fungistatic in vivo, in contrast to polyenes like amphotericin and echinocan-
dins, which are fungicidal.
Primarily active against Candida species, ketoconazole is available for
systemic treatment in an oral formulation. Fluconazole is active against a
broader range of fungi than ketoconazole and includes clinically relevant
activity against Cryptococcus, Coccidioides, and Histoplasma. Fluconazole
remains one of the most active and safest systemic antifungal agents for the
treatment of most Candida infections, although some resistance is present in
many non-albicans Candida species as well as in Candida albicans in chil-
dren repeatedly exposed to fluconazole. Fluconazole is available in parenteral
and oral formulations, and toxicity is unusual and primarily hepatic.
Itraconazole is active against an even broader range of fungi and molds, in-
cluding Aspergillus. However, pediatric clinical data are limited. Voriconazole
was approved for adults in 2002 and is FDA approved for children 2 years
and older. It is the treatment of choice for Aspergillus infections. Voriconazole
is active against Candida species, including some that are fluconazole resis-
tant, but fluconazole is preferred if the Candida is susceptible. Voriconazole
produces some unique transient visual field abnormalities in about 10% of
adults and children. There are an increasing number of reports, seen in as high

1043
as 20% of patients, of a photosensitive sunburn-like erythema that is not aided

by sunscreen (only sun avoidance). In some rare long-term (mean of 3 years of
therapy) cases, this voriconazole phototoxicity has developed into cutaneous
squamous cell carcinoma. Discontinuing voriconazole is recommended in
patients experiencing chronic phototoxicity. Hepatotoxicity is uncommon,
occurring in 2% to 5% of patients. Voriconazole is cytochrome P450 metabo-
lized, interacts with any similarly metabolized drugs, and may produce
profound changes in serum concentrations of many concurrently administered
drugs.
Posaconazole is the most recently FDA-approved triazole for children. It has
activity against Candida and Aspergillus but, importantly, it has substantial
activity against Rhizopus species and Mucor species, as well as Coccidioi-
des, Histoplasma, and Blastomyces, with a more clinically acceptable drug-
drug interaction profile when compared with voriconazole.
Echinocandins
The echinocandin class of antifungals was approved in 2001. Echinocandins
inhibit cell wall formation by inhibiting glucan synthesis. They are fungicidal
against yeasts like Candida, and fungistatic against molds like Aspergillus.
Caspofungin was the first to be approved. Active in vitro against most Candida
and Aspergillus species, published data suggest that the echinocandins produce
equivalent outcomes in the therapy of invasive Candida infections compared
with amphotericin but with fewer side effects. Caspofungin has received FDA
approval for children aged 3 months to 17 years for the following:
X Empiric therapy of presumed fungal infections in febrile neutropenic
children
X Treatment of candidemia (including esophagitis, peritonitis, and empyema)
X Salvage treatment of invasive Aspergillus
Micafungin was recently FDA approved for pediatric patients 4 months and
older for the treatment and prophylaxis of a wide range of Candida infections.
Anidulafungin is a similar echinocandin agent, approved for adults but not
officially approved for pediatric patients. The echinocandins are highly
protein bound (>95%), but, unlike some of the triazole antifungals, they are
not metabolized by the P450 system.
Adverse Reactions to Antibiotics

Adverse drug reactions to antibiotics should be considered whenever there is
a symptom that is associated with the side-effect profile of the drug or when
unexpected symptoms and signs arise. The most common of these is a rash,
often with itching, but more severe reactions can occur, including anaphy-
laxis. These reactions may require discontinuation of the drug or further
supportive treatment.

1044
Drug Interactions
Infectious diseases consultants and pharmacists should be consulted when-
ever there is a potential for drug interaction. There are also sources on the
internet that provide extensive information concerning drug interactions.
Acknowledgment
This chapter is adapted with permission from Bradley JS, Nelson JD, eds.
2023 Nelson’s Pediatric Antimicrobial Therapy. 29th ed. American Academy
of Pediatrics; 2023. © 2023 John S. Bradley, MD, and John D. Nelson, MD.
Reference
1. Flume PA, Mogayzel PJ Jr, Robinson KA, Goss CH, Rosenblatt RL, Kuhn RJ, Marshall BC,
Clinical Practice Guidelines for Pulmonary Therapies Committee. Cystic fibrosis pulmonary
guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med. 2009;180(9):802-
808. doi: 10.1164/rccm.200812-1845PP

CHAPTER
59
Nutritional Aspects of Pulmonary Conditions
Ellen K. Bowser, MS, RDN, LDN, RN, FAND
Mary H. Wagner, MD
Pulmonary disorders such as cystic fibrosis (CF), bronchopulmonary dyspla-

sia (BPD), and asthma may compromise a child’s growth and acquisition of
specific nutrients, and nutritional deficiencies may adversely affect the overall
course of these conditions. On the other hand, overnutrition plays a role in the
development or severity of pulmonary disorders, such as obstructive sleep
apnea (OSA) or Prader-Willi syndrome. Thus, understanding nutritional
issues is important in the care of children with pulmonary disorders.
General Nutritional Evaluation

Nutritional assessment of children with pulmonary conditions can be
accomplished using the ABCDEF method (Table 59-1). Anthropometric
data determine the child’s growth and body composition in comparison
to their peers. Biochemical indices assist the pediatrician in determining
hematologic, protein, and vitamin and mineral status. Clinical examination
helps in the determination of nutritional status, while dietary, elimination,
and feeding information assist in the formulation of a diagnosis. Dietary
intake data provide an accurate depiction of daily intake and meal patterns.
Elimination patterns help identify bowel and bladder issues. Feeding history
illuminates oral motor skills acquisition and timing of meals and snacks.
Anthropometric Evaluation
Anthropometric data include growth plotted on standard growth charts, as well
as head circumference (up to 3 years of age) and skinfold measurements. The
Centers for Disease Control and Prevention recommendations are to use the
World Health Organization international growth charts for children younger
than 24 months and the Centers for Disease Control and Prevention growth
charts for individuals 2 to 19 years of age.3 Genetics play a major role in each
child’s growth potential. Evaluation of the parents’ height (midparental height
calculation) provides an estimate of the child’s potential for height. Well-
nourished children with CF and asthma are able to meet their genetic potential
for growth. Children with BPD who were born preterm are often shorter and
1045

1046
weigh less than their peers.4 Body mass index (BMI, [weight in kg]/[height in
m2]) is an overall assessment of the child’s weight for their height. Children's BMI
values change as they grow. Body mass index percentiles provide a better assess-
ment of the child’s weight for height compared to peers. Normal or healthy BMI
percentiles for children are between the 5th and 85th percentiles. Optimal nutri-
tion for children with CF is a BMI greater than the 50th percentile for age.
Table 59-1. ABCDEF Nutritional Assessment in Children With Pulmonary Conditions:
Components of Interest for Specific Conditions
Assessment All Children CF Asthma/OSA BPD
Anthropometric Weight percentile Midparental Neck size (OSA) Correction for
dataa height prematurity
Height percentile
(up to 2 years
Weight/height of corrected
percentile age)1,2
(< 3 years)
BMI percentile
(> 3 years)
Head
circumference
(< 3 years)
Biochemical Prealbumin Serum vitamin A, 25-Hydroxy
indices 25-hydroxy vitamin D
Hemoglobin
vitamin D,
Hematocrit —
vitamin E, PT/INR
(a marker for
vitamin K status)
Clinical Appearance Increased Acanthosis, Increased
examination cough, frequent striae work of
Skin turgor
respiratory breathing,
Wasting or infections pulse oximetry
excess weight
Dietary 24-hour dietary 3-day diet 3-day diet Formula
information recall record record preparation
Portion sizes, Solid foods
consumption of
sugary beverages
Elimination Bladder, bowel Detailed
patterns habits stooling history,
constipation or
Emesis — —
distal intestinal
obstruction
syndrome?
Feeding Location and Enzyme dosing Skipping meals Oral motor
history timing of meals or overeating feedings/
and snacks skills
Abbreviations: BPD, bronchopulmonary dysplasia; BMI, body mass index; CF, cystic fibrosis; INR, international
normalized ratio; OSA, obstructive sleep apnea; PT, prothrombin time.
a
See information on growth charts under Anthropometric Evaluation in main text.

1047
Chapter 59—Nutritional Aspects of Pulmonary Conditions
Growth for infants who are born preterm should be corrected for their
gestational age.1 Health care providers usually correct for weight and length
for up to 2 years on standard growth charts.2
Biochemical Evaluation
Biochemical indices most commonly used for nutritional assessment include
prealbumin, hemoglobin and hematocrit, and vitamin levels. Prealbumin is a
serum protein synthesized by the liver that is an indicator of protein status.
Prealbumin reflects protein status of the preceding 2 to 3 days. Prealbumin
can be decreased in various circumstances, including liver disease and
acute illness.5
Hemoglobin and hematocrit are indicators of anemia. Anemia in children with
lung conditions can be caused by poor dietary intake of iron, folate, vitamin
B12, or vitamin E. Malabsorption can also contribute to anemia in children
with CF. Anemia of chronic disease also may be found in children with CF.
Serum fat-soluble vitamin levels are routinely measured in children with CF.
Serum 25-hydroxy vitamin D levels have been found to be decreased in
children with obesity, asthma, and OSA.6,7
Clinical Evaluation
Clinical examination of the child with a pulmonary condition includes
evaluation of overall appearance, skin turgor, and evidence of wasting or
excess weight. Acanthosis or striae may be found in children with obesity.
In children undergoing evaluation for OSA, neck circumference should be
measured because those with a higher neck circumference have an increased
risk of OSA.8
Dietary Evaluation
Dietary information is essential in assessing the nutritional status of a child
with a pulmonary condition. A 24-hour dietary recall is useful in obtaining a
general indicator of a child’s caloric and protein intake. However, this is often
inaccurate and may not reflect usual intake. A 3-day diet record is the most
accurate means to assess intake, but this may be difficult and should be done
in consultation with a registered dietitian. Specific instructions need to be
given to the caregivers and child on estimating portion size and providing
details, such as product brands and restaurant names. It is also important
to evaluate portion sizes and timing of meals and snacks. The amount of
beverages containing added sugar (sodas, sports drinks, etc) should also be
evaluated because the consumption of these is associated with overweight
and obesity in children.9

1048
Elimination Evaluation
Elimination patterns include bladder and bowel habits as well as emesis. In
addition to determining current patterns, it is important to assess if there are
any recent changes. The number and consistency of stools should be estab-
lished. In children with CF, pancreatic insufficiency (PI) is associated with
steatorrhea with malodorous, greasy stools. Distal intestinal obstruction
syndrome should be considered in a child with CF with abdominal pain,
cramping, nausea/vomiting, and lack of bowel movements.10
Feeding Evaluation
Feeding history should include location and timing of meals and snacks.
Length of meals and oral motor and feeding skills are also important to assess.
Children with BPD often have a delay in normal oral motor skill development
due to their prematurity, delay in oral feedings, and/or length of time on a
ventilator. The calorie intake should be assessed and, as recall is often poor, a
prospective 3-day dietary record of intake is useful. Meal skipping (usually
breakfast) and compensatory overeating should be evaluated. Infants and
children with a history of choking or coughing with feedings should receive a
swallowing evaluation.
Nutritional Management of Respiratory Conditions

Associated With Undernutrition
Cystic Fibrosis
Nutrition plays a key role in the management of persons with CF. Adequate
nutrition is important in maintaining health, fighting infection, and avoiding
deficiencies that may accompany the disorder. Assessment of nutritional
parameters is an important part of routine care of persons with CF. (See
Chapter 45, Cystic Fibrosis.) A decline in growth may herald worsening
pulmonary status, onset of CF-related diabetes, or CF-related liver disease.
The Cystic Fibrosis Foundation (CFF) recommends that children with CF
maintain normal weight and height for age, as normal growth has been
associated with better lung function and survival.11 The CFF suggests that
children (those > 2 years, including adolescents) should achieve energy intake
at levels of 110% to 200% above the usual requirements in healthy children
to achieve age-appropriate weight gain.10 This may require a combination
of approaches, including calorie boosting, nutritional supplements, and
behavioral interventions.
Nutritional intervention begins when a diagnosis of CF is established. Approx-
imately 85% to 90% of persons with CF will have exocrine PI. This most often
presents at birth or shortly thereafter, but, in some children, it develops after
the first year.12 The diagnosis of PI may be confirmed by finding a low level of

1049
fecal elastase.12 Persons with PI have malabsorption of fat, protein, and other
nutrients, including the fat-soluble vitamins (A, D, E, and K).
Anthropometric measurements, including height, weight, and weight for
length or BMI, should be obtained at each clinic visit. A goal of maintain-
ing BMI at the 50th percentile or greater is suggested because this level of
growth is associated with a forced expiratory volume in 1 second near 80%
of predicted.10 All persons with CF should have additional monitoring of their
nutritional status by yearly laboratory evaluation, including complete blood
cell count, differential, liver function tests, clotting studies, and vitamin
levels (A, E, and D 25-hydroxy vitamin D).13
Enzyme Replacement Therapy
Patients with PI should be given pancreatic enzyme replacement therapy
with all meals and snacks, including human milk and predigested formulas.
The microsphere tablet preparations are enteric-coated to avoid degrada-
tion in the acidic gastric environment, so the enzymes are released in the
proximal small intestine to optimize nutrient absorption. Some patients may
benefit from the addition of a histamine type-2 receptor blocker or proton
pump inhibitor because gastric acid passing into the duodenum, unbuffered
by pancreatic bicarbonate secretion, may decrease the effectiveness of
pancreatic enzymes.13
Enzymes should be taken before every meal or snack unless the snack is
exclusively carbohydrate, such as fruit or fruit juice. Patients usually take half
of the typical meal dose before a snack. The dose of enzymes for a meal may
need to be distributed throughout the meal for patients who take an extended
period to eat or who are snacking throughout the day. The family and patient
need to learn how to adjust the enzyme dose depending on the size, content,
and duration of the meal. All caregivers, including in child care and school
environments, need to be educated about the need for enzymes with all snacks
and meals.
Enzyme doses should be in the range of 1,500 to 2,500 units of lipase per
kilogram of body weight per meal, with an upper limit of 10,000 units of lipase
per kilogram per day.10 These dose ranges are formulated to avoid risk of
fibrosing colonopathy. Patients with persistent malabsorption need further
evaluation for other conditions, such as small bowel bacterial overgrowth,
celiac disease, or lactase deficiency.
Infants With Cystic Fibrosis
Infants with CF may be identified by either newborn screening or clinical
history. For most infants, the major form of nutrition in the first year after birth
should be human milk. Formulas with a caloric density greater than 20 kcal/oz
or human milk are often necessary to maintain the desirable level of weight
gain. The caloric density of formula or human milk can be augmented by

1050
concentrating the formula or adding fat or carbohydrate. Solid foods can be

added at age 4 to 6 months per recommendations of the American Academy
of Pediatrics.14 However, the primary source of caloric intake should remain
formula or human milk, especially if adequate growth is an issue. Infant
cereal should be mixed with formula or human milk rather than juice or
water. Whole milk can be used after 1 year of age for children who are
growing well.12
For patients with PI, enzymes can be administered in a small amount of
formula or baby food. Infants should receive vitamin supplementation,
including vitamins A, D, E, and K. The adequacy of dietary iron and fluoride
should be evaluated and supplements should be added if necessary. Those
infants with suboptimal growth may need supplementation of their caloric
intake by addition of carbohydrate or fat.12
Due to the extra sodium and chloride losses in sweat, infants with CF should
be supplemented with 1/8 teaspoon of salt daily for infants up to age 6 months
and 1/4 teaspoon of salt daily for infants older than 6 months.12,13 This can be
given in 1 or 2 doses mixed with formula or expressed human milk or given
in the applesauce and enzyme mixture for infants who are breastfed. The
CFF developed guidelines for the care of the infant with CF, which are
available at www.cff.org.
Toddlers and Preschool-Aged Children With CF
Families with toddlers and preschool children with CF may experience
more mealtime difficulties (ie, more feeding resistance, longer mealtimes)
than families who do not have children with CF.15 This can lead to mealtime
battles and dysfunctional eating behaviors. Clinical or behavioral psychology
services can be useful to enhance positive feeding behaviors and consistent
weight gain.15
The CFF developed clinical practice guidelines for the preschool child with
CF, available at www.cff.org.
School-Aged Children With CF
Children with CF who are of school age may experience decreased growth16
because of the number of activities that limit time for meals and snacks.
Disease progression may also affect growth velocity. Diets high in protein
and fat should be encouraged, and vitamin supplementation should continue.
Behavioral interventions may be required if mealtime problems are identified.
Children with PI should understand the need for enzyme supplementation.
A plan should be developed so that enzymes can be taken at school or
childcare. School staff education is necessary so that enzymes are given
immediately prior to eating. Educational materials are available for caregivers,
teachers, and coaches who work with children with CF.17

1051
Adolescents With CF
Calorie and nutrient requirements increase in adolescents for several reasons,
including pubertal growth spurt, increased activity, and disease progression
in some children. Girls are at greater risk of underweight primarily because
of gender-specific social norms and expectations regarding weight.18 Some
patients may develop CF-related diabetes as the incidence and prevalence of
this condition increases after age 10 years.19 Decreased growth or delayed
sexual maturation may occur in those with severe disease.13 Additional issues
that may be encountered with adolescents with CF include loss of parental
control over medication administration and intentional weight loss. The ado-
lescent should understand the link between good nutrition, good lung health,
and avoiding hospitalization. Adolescents experiencing weight loss should
be questioned about their perspective on their body image and if any weight
loss is intentional. Adolescents with CF can develop eating disorders with
potentially severe consequences.20 Adolescents should be involved with
their own treatment plan to improve adherence and results.
Nutritional Supplements and Calorie Boosters
Children and adolescents with chronic pulmonary conditions may benefit
from strategies to increase the caloric density of their usual diet. This can
be accomplished using milkshakes or calorie boosters with their daily foods
(Box 59-1). Other children and adolescents with suboptimal growth may bene-
fit from the use of commercial formulas. These preparations can be useful and
convenient but entail additional expense and may be difficult for the families
to obtain. Dietary intake should be monitored so that these preparations are
used to supplement rather than replace meals. They can be delivered orally
or enterally if a feeding tube is present. Nutritional supplement of the child’s
choice is best. Most will benefit from a rotation of different supplements
because they may tire of the same one if used repeatedly. Patients and fami-
lies should be questioned about what over-the-counter supplements they may
be using to avoid excess intake of specific nutrients. Herbal or other over-the-
counter supplements are not regulated by the Food & Drug Administration and
may contain harmful ingredients.13
Cystic Fibrosis Transmembrane Conductance Regulator Modulation
Therapy and Growth
New medications designed to correct the cystic fibrosis transmembrane con-
ductance regulator mutation defect have shown improvements in lung function
and growth. (See Chapter 45, Cystic Fibrosis). A 2022 systematic review
found some improvements in weight gain and growth in children with CF
depending on cystic fibrosis transmembrane conductance regulator mutation
class and specific modulator(s) examined.21

1052
Box 59-1
Tips to Help a Child Gain Weight
Feeding Suggestions
Stick to a regular meal schedule (for example, 3 meals and 3 snacks each day).
Offer solid foods first and then liquids.
Limit juice to 4 oz per day.
Praise positive behavior and ignore negative behavior.
Do not force a child to eat; this can be counterproductive.
Avoid the TV and other distractions during mealtimes.
Limit meals and snacks to 20 to 30 minutes.
Calorie Boosters
Adding extra calories to a child’s diet may help them gain weight. There are many
ways to add extra calories to common foods. Following are some examples:
Sour cream: Put on baked potatoes, add to burritos and tacos, stir into cream soups.
Cheese dip: Eat with pretzels, apples, or celery. Melt over broccoli or cauliflower.
Nut butters: Spread on breads, crackers, apples, bananas, and celery.
Cream cheese: Spread on bagels; use flavored cream cheese as a dip for fruits.
Vegetable oil: Drizzle over noodles and vegetables. Use to make scrambled eggs
or as a dipping oil for breads and rolls.
Salad dressings: Use as dip for vegetables or as a sandwich spread.
Recipes
Power milk: 1 cup whole milk, 2 tbsp heavy whipping cream, 2 tbsp chocolate or
strawberry syrup.
Nachos: 15 tortilla chips, 1/4 cup cheese, 2 tbsp sour cream, 2 tbsp black olives,
2 tbsp guacamole or avocado dip.
Chocolate peanut butter shake: 1/2 cup heavy whipping cream, 3 tbsp creamy
peanut butter, 3 tbsp chocolate syrup, 1½ cups chocolate ice cream. Mix in blender
and top with crushed sandwich cookies.
Apple pie a la mode shake: 1 cup apple pie filling, 1/2 cup whole milk, 1 cup vanilla
ice cream, dash of cinnamon. Mix in blender and top with caramel and crushed
graham crackers.
French toast sandwich: Spread 2 tbsp of peanut butter and 1 tbsp of jelly between
2 slices of French toast.
No bake chocolate cookies: Mix 1/4 cup softened margarine, 1/4 cup peanut butter,
1/2 cup instant sweet cocoa mix, 1 cup oatmeal. Form into 1-inch balls and chill in
refrigerator for 10 minutes.
Cooked carrots: 2 tbsp apricot preserves and brown sugar, or 2 tbsp honey added to
buttered, cooked carrots.
Chocolate pudding: Use 1 can (12–14 oz) sweetened condensed milk instead of
regular milk when making pudding and sprinkle white chocolate chips on top.

1053
Tube Feedings
Children who are unable to consume adequate calories during their daily
intake may benefit from tube feedings. This approach should be considered
in those who are unable to attain growth/weight maintenance goals.22 Feedings
can be administered via tubes placed nasally (nasogastric [NG]) or percutane-
ously (gastrostomy tubes). Some children who are unable to consume adequate
calories will appreciate the option of being able to supplement their intake
with NG feedings delivered during sleep; however, NG tubes are generally
considered for a short-term (< 3 months) basis due to the risks of tube displace-
ment and aspiration. Longer-duration feedings will require a more permanent
gastrostomy tube placement in those children who are unable to attain weight
goals by exclusively oral intake. Pancreatic enzymes are usually given prior
to the start of the feeding and again in the morning. Some children require
additional enzyme administration during the midpoint of the feeding period.
Patient response to these feedings should be carefully monitored, including
weight gain, symptoms of malabsorption, and daytime appetite. Other strategies
include using predigested formulas with and without enzymes. These formulas
incur additional expense and have not been shown to be better absorbed, but
they may be preferred in those who have had small intestine resection.23 Tube
feedings may need to end 2 hours prior to the usual wake-up time for the child
to feel hungry for breakfast. The CFF has developed guidelines for the use of
enteral feedings in children with CF, which are available at www.cff.org.
Vitamins
Persons with CF are at risk for deficiencies of fat-soluble vitamins, including
A, D, E, and K. The CFF has specific recommendations for supplementation
of fat-soluble vitamins.13 These preparations are available in a variety of forms
(soft gels, chewable tablets, and drops). Vitamin levels should be monitored at
least annually with supplementation if adequate levels cannot be achieved
despite intake of recommended formulations.13
All patients should receive the dietary reference intake suggested for calcium
based on age. Calcium supplementation may be required for those on oral cor-
ticosteroids or those with decreased dietary calcium intake or decreased bone
density. Suboptimal serum levels of vitamin D (< 74.88 nmol/L [< 30 ng/mL]
of 25-hydroxy vitamin D) are seen commonly in children with CF. This is
thought to be a combination of inadequate intake, decreased storage, and
decreased synthesis.24 There is a higher incidence of osteopenia and
osteoporosis in children with CF than in those without CF.24
Salt
Children with CF experience increased losses of sodium and chloride through
their sweat. Salt requirements in older children and adolescents can be met with
liberal use of high-salt foods or adding table salt to meals. They may require

1054
additional salt supplementation at times of increased salt losses, such as with

fever, hot weather exposure, vigorous physical activity, or diarrheal
illnesses.13
Infants with BPD are often of extremely low or very low birth weight due
to their prematurity. Weight gain in the neonatal intensive care unit (NICU)
early in the disease process may be poor, and these infants tend to remain
small for their gestational age. Upon discharge from the NICU, they may
continue to experience growth faltering. Adequate nutrition to allow normal
growth and development is key to the resolution of BPD.4 Growth of new lung
tissue can occur in humans up to 8 years of age; therefore, it is important to
continue to encourage good nutrition.
Numerous factors need to be considered when evaluating and managing the
nutritional needs of children with BPD. These include increased metabolic rate,
increased work of breathing, need for catch-up growth, volume intolerance,
feeding issues, frequent respiratory infections, and fluid restrictions.
The effects of increased metabolic rate and increased work of breathing may
increase energy expenditure by 25% for infants with BPD.25 Human milk is
considered the optimal form of nutrition for all infants. Exclusive breastfeed-
ing until age 4 months, and partial breastfeeding thereafter, is associated
with significant reduction of respiratory and gastrointestinal morbidity rates
in infants up to 1 year of age. For infants with BPD, the increase in caloric
expenditure along with the need for catch-up growth often mandate the use of
human milk fortifiers or the addition of concentrated formula to human milk.
Human milk can be enhanced to reach a caloric density of 24 to 30 kcal/oz. If
human milk is not available, special infant formulas designed for the preterm
or low birth weight infant can be used. These formulas have higher caloric and
nutrient density. Nutrient-enriched formulas are also available for the preterm
neonate after discharge from the NICU.4 When using high–caloric density
formulas, caution should be taken due to the dilution of protein, vitamins, and
minerals in the formula. These infants may also need additional free water. A
registered dietitian/nutritionist familiar with the nutritional care of the child
with BPD should be consulted if an increased caloric density formula is
required. Infants with BPD are often fluid restricted and given diuretics to
improve lung function and prevent pulmonary edema.26
Volume intolerance can be caused by hyperinflation of the lungs and com-
pression of the diaphragm and stomach. This can lead to limited intake of
the nutrient-enriched formula. Gastroesophageal reflux can make feeding
the infant with BPD more challenging. Evaluation for gastroesophageal reflux

1055
may be appropriate, as medical or even surgical treatment may be necessary

to ensure adequate oral intake and prevent aspiration.
Feeding issues for the infant or toddler with BPD may include uncoordinated
suck, swallow, and breathing; oral motor difficulties; and adverse feeding
behaviors. If these issues are suspected, a feeding evaluation should be con-
sidered by a speech-language or occupational therapist. Ongoing therapy for
oral motor difficulties may be required to allow the child with BPD to achieve
adequate oral intake for growth.
Feeding Challenges
Most children with pulmonary conditions such as CF or asthma will have
normal oral motor skill development. However, children with a history of
prematurity are at increased risk for delayed development of oral motor skills.
Children who were born preterm are at increased risk for impairments in
swallowing and feeding disruptions.27
Chronic lung disease may be associated with uncoordinated suck, swallow,
and breathing patterns, which increase the risk of aspiration. Infants who
were mechanically ventilated for an extended period may develop oral motor
defensiveness. Those who remain on supplemental oxygen may experience
fatigue with feeding and tolerate only small volumes of formula. Infants and
children with neuromuscular, genetic, and craniofacial disorders may also
experience feeding difficulties. Infants and older children with feeding
difficulties should receive treatment from a speech-language pathologist
or occupational therapist.
Children with tracheostomies can feed orally once it is ascertained that the
child is not aspirating. Children who receive exclusive tube feedings should
receive oral motor stimulation during feedings to help associate the sensa-
tions of fullness with oral involvement. Failure to cough or clear the throat in
response to aspiration is common in children with complex medical conditions.
Parental feeding behaviors and the feeding environment are also vital for
appropriate feeding skills. A calm, non-stimulating setting (TV and other
distractions turned off) is important. Scheduled meals and snacks, parental
role modeling, and the use of positive reinforcement should be encouraged.
Gastrostomy tube feedings are often used when a child with a pulmonary
disorder is unable to maintain adequate oral intake over time. These feedings
may be either bolus or continuous. Gastrostomy tube feedings may be used to
supplement inadequate oral intake or as a substitute for oral intake in children
who may be at significant risk for aspiration. Oral motor stimulation should
be encouraged if the child is receiving exclusive tube feedings.

1056
Nutritional Aspects of Respiratory Conditions

Associated With Obesity
The overall prevalence of pediatric obesity in the US population was 19.3%
in 2017 to 2018.28 The prevalence has been increasing in all age groups over
recent years.29 Obesity is associated with a variety of pulmonary disorders
including OSA, asthma, and restrictive lung disease. (See Chapter 43,
Asthma and Other Respiratory Disorders Associated With Obesity.)
Children with obesity may have restricted chest wall movement and a
restrictive pattern on their pulmonary function tests; if obesity is severe,
they may have obesity hypoventilation syndrome with impaired response
to carbon dioxide.
The Endocrine Society clinical practice guidelines for the prevention and
treatment of pediatric obesity, published in 2017,30 recommend that treatment
for overweight and obesity include appropriate lifestyle changes, including
diet, physical activity, and behavioral counseling for the patient and the family.
This panel recommended physical activity, including moderate-to-vigorous
exercise for 60 minutes per day, and restriction of sedentary activities,
including TV viewing, video gaming, and use of computers. Lifestyle
modification that included family involvement was emphasized. Many of these
recommendations are mirrored by the Academy of Nutrition and Dietetics,
suggesting multi-component programs, including diet, physical activity,
nutritional counseling, and parent participation, for the intervention to be
successful.31
Asthma
An association between overweight and asthma has been reported in the
literature, but a cause-and-effect relationship has not been clear.32 One group
concluded that school-aged children with BMI at the 85th percentile or greater
had a 50% higher risk of developing asthma than their normal-weight peers.
They also found neonates with a birth weight of 3.8 kg or higher had a 20%
higher risk of future asthma than their peers.32 A recent systematic review
found improvement in quality of life and, in some cases, asthma control
in children with overweight and asthma who participated in weight
loss programs.33
Children and adolescents with asthma are often discouraged from drinking
milk or other calcium-rich dairy products due to the ongoing belief by some
individuals that milk or dairy consumption increases mucus production.

1057
Although this theory has been disproved, the “milk-mucus connection” myth
remains widespread.34 Parents of children with asthma often report avoiding
dairy in their children’s diets.34 This is an important topic to discuss with
families, as some children who receive inhaled corticosteroids have been
found to have decreased bone density and growth velocity.35 Children with
asthma should be encouraged to consume adequate amounts of calcium and
vitamin D for bone growth and mineralization. Pediatricians should inquire
about calcium and vitamin D intakes when working with children with
asthma. Parents who remain hesitant to give their children dairy products
should be encouraged to give their children calcium and vitamin D supple-
ments to meet the Institute of Medicine Food and Nutrition Board’s dietary
reference intake levels.36
Several dietary interventions have been proposed for reducing the incidence
or severity of asthma, including supplementation with fish oils, antioxidants,
vitamins C and E, and beta-carotene, and reduction in dietary sodium.
However, recent analyses do not support these interventions.37
Obstructive Sleep Apnea

Obstructive sleep apnea is estimated to occur in 2% to 3% of the general
pediatric population.38 Obesity is a risk factor for the development of OSA.39
However, young children may present with failure to thrive. Many children
will have no growth issues. Weight loss has been shown to result in an
improvement in sleep-related breathing disorders40; thus, assessment of
nutritional status is important in children with OSA. Nutritional intervention
is an important component of the multifaceted management plan for children
with OSA.
Prader-Willi Syndrome
Prader-Willi syndrome has an estimated prevalence of 1 in 10,000 to 1 in
25,000 live births.41 Initial nutritional symptoms include poor suck, hypotonia,
and poor growth. Patients with Prader-Willi syndrome evolve to a pattern of
food-seeking behavior and insatiable appetite with subsequent development of
obesity.42 Pulmonary manifestations can include restrictive lung disease and
sleep-related breathing disorders, including OSA, central apnea, and exces-
sive daytime sleepiness.43 Dietary management is very important to deal
with the different nutritional phases these patients experience and should be
under the direction of a registered dietitian experienced in the care of these
patients. Strategies for dietary management include environmental manage-
ment of food intake, a calorically controlled diet, and constant supervision.

1058
key points
} One method to evaluate nutritional status in children with pulmonary
conditions is the ABCDEF method (Table 59-1).
} Nutritional status is linked to lung function and survival in CF.
} Children with CF and PI should receive pancreatic enzymes before all snacks
and meals.
} All children with CF should be supplemented with additional vitamins, with a
focus on the fat-soluble vitamins.
} The stepwise approach to increase caloric intake in children with CF includes
calorie boosters added to meals/snacks, oral nutritional supplements, and
tube feedings.
} The CFF is an excellent resource for age-specific dietary recommendations.
} Children with BPD with inadequate weight gain should be evaluated by a
pediatric registered dietitian/nutritionist.
} Obesity in children is increasing, and successful weight management programs
incorporate the family and lifestyle changes, including physical activity and
moderation in caloric intake.
} Weight loss can improve asthma symptoms and quality of life in children with
asthma and obesity.
} Weight management is important in the treatment of children with OSA
and obesity.
References
1. Engle WA; American Academy of Pediatrics Committee on Fetus and Newborn. Age terminology
during the perinatal period. Pediatrics. 2004;114(5):1362–1364. doi: 10.1542/peds.2004-1915
2. American Academy of Pediatrics. Corrected age for preemies. HealthyChildren.org.
https://www.healthychildren.org/English/ages-stages/baby/preemie/Pages/Corrected-Age-
For-Preemies.aspx. Accessed April 26, 2022
3. Grummer-Strawn LM, Reinold C, Krebs NF; Centers for Disease Control and Prevention.
Use of World Health Organization and CDC growth charts for children aged 0–59 months in
the United States. MMWR Recomm Rep. 2010;599(RR-9):1‒15. https://www.cdc.gov/mmwr/
preview/mmwrhtml/rr5909a1.htm. Accessed March 9, 2022
4. Lista G, Meneghin F, Bresesti I, Cavigioli F. Nutritional problems of children with
bronchopulmonary dysplasia after hospital discharge. Pediatr Med Chir. 2017;39(4):183
PMID: 29502385 doi: 10.4081/pmc.2017.183
5. Spiekerman AM. Nutritional assessment (protein nutriture). Anal Chem. 1995;67(12):429R–436R
PMID: 8686865 doi: 10.1021/ac00108a026
6. Marino R, Misra M. Extra-skeletal effects of vitamin D. Nutrients. 2019;11(7):1460
PMID: 31252594 doi: 10.3390/nu11071460
7. Kheirandish-Gozal L, Peris E, Gozal D. Vitamin D levels and obstructive sleep apnoea in
children. Sleep Med. 2014;15(4):459–463 PMID: 24684979 doi: 10.1016/j.sleep.2013.12.009
8. Katz S, Murto K, Barrowman N, et al. Neck circumference percentile: A screening tool for
pediatric obstructive sleep apnea. Pediatr Pulmonol. 2015;50(2):196–201 PMID: 24574055
doi: 10.1002/ppul.23003
9. Welsh JA, Wang Y, Figueroa J, Brumme C. Sugar intake by type (added vs. naturally occurring)
and physical form (liquid vs. solid) and its varying association with children’s body weight,
NHANES 2009-2014. Pediatr Obes. 2018;13(4):213–221 PMID: 29318755 doi: 10.1111/ijpo.12264

1059
10. Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H; Clinical Practice Guidelines
on Growth and Nutrition Subcommittee; Ad Hoc Working Group. Evidence-based practice
recommendations for nutrition-related management of children and adults with cystic
fibrosis and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc.
2008;108(5):832–839 PMID: 18442507 doi: 10.1016/j.jada.2008.02.020
11. Yen EH, Quinton H, Borowitz D. Better nutritional status in early childhood is associated with
improved clinical outcomes and survival in patients with cystic fibrosis. J Pediatr.
2013;162(3):530–535.e1 PMID: 23062247 doi: 10.1016/j.jpeds.2012.08.040
2009;155(6)(suppl):S73–S93 PMID: 19914445 doi: 10.1016/j.jpeds.2009.09.001
13. Schindler T, Michel S, Wilson AW. Nutrition Management of Cystic Fibrosis in the 21st Century.
Nutr Clin Pract. 2015;30(4):488–500 PMID: 26113561 doi: 10.1177/0884533615591604
14. Kleinman RE, Greer FR, eds. Pediatric Nutrition. 8th ed. American Academy of Pediatrics; 2019
15. Lahiri T, Hempstead SE, Brady C, et al. Clinical practice guidelines from the Cystic Fibrosis
Foundation for preschoolers with cystic fibrosis. Pediatrics. 2016;137(4):e21051784
PMID: 27009033 doi: 10.1542/peds.2015-1784
16. Kelly A, Schall J, Stallings VA, Zemel BS. Trabecular and cortical bone deficits are present in
children and adolescents with cystic fibrosis. Bone. 2016;90:7–14 PMID: 27143111
doi: 10.1016/j.bone.2016.04.030
17. Teachers Guide to Cystic Fibrosis. https://www.cff.org/Life-With-CF/Daily-Life/CF-and-School/
For-Teachers/A-Teacher-s-Guide-to-CF/. Accessed March 9, 2022
18. Tierney S. Body image and cystic fibrosis: a critical review. Body Image. 2012;9(1):12–19
PMID: 21963674 doi: 10.1016/j.bodyim.2011.09.001
19. Moran A, Brunzell C, Cohen RC, et al; CFRD Guidelines Committee. Clinical care guidelines for
cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a
clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine
Society. Diabetes Care. 2010;33(12):2697–2708 PMID: 21115772 doi: 10.2337/dc10-1768
20. Linkson L, Macedo P, Perrin FMR, Elson CM. Anorexia nervosa in cystic fibrosis. Paediatr
Respir Rev. 2018;26:24–26. doi: 10.1016/jprrv.2017.03.002
21. Academy of Nutrition and Dietetics Evidence Analysis Library. “CFTR Modulation Therapy.”
Accessed April 27, 2022: https://www.andeal.org/topic.cfm?menu=5876&cat=5884
22. Schwarzenberg SJ, Hempstead SE, McDonald CM, et al. Enteral tube feeding for individuals
with cystic fibrosis: Cystic Fibrosis Foundation evidence-informed guidelines. J Cyst Fibros.
2016;15(6):724–735 PMID: 27599607 doi: 10.1016/j.jcf.2016.08.004
23. Erskine JM, Lingard CD, Sontag MK, Accurso FJ. Enteral nutrition for patients with
cystic fibrosis: comparison of a semi-elemental and nonelemental formula. J Pediatr.
1998;132(2):265–269 PMID: 9506639 doi: 10.1016/S0022-3476(98)70443-3
24. Tangpricha V, Kelly A, Stephenson A, et al; Cystic Fibrosis Foundation Vitamin D Evidence-
Based Review Committee. An update on the screening, diagnosis, management, and treatment of
vitamin D deficiency in individuals with cystic fibrosis: evidence-based recommendations from
the Cystic Fibrosis Foundation. J Clin Endocrinol Metab. 2012;97(4):1082–1093 PMID: 22399505
doi: 10.1210/jc.2011-3050
25. Denne SC. Energy expenditure in infants with pulmonary insufficiency: is there evidence for
increased energy needs? J Nutr. 2001;131(3):935S–937S PMID: 11238789
doi: 10.1093/jn/131.3.935S
26. Bell EF, Acarregui MJ. Restricted versus liberal water intake for preventing morbidity and
mortality in preterm infants. Cochrane Database Syst Rev. 2014;2014(12):CD000503.
PMID: 25473815 doi: 10.1002/14651858.CD000503.pub3. Epub 2014 Dec 4.
27. Crapnell TL, Rogers CE, Neil JJ, Inder TE, Woodward LJ, Pineda RG. Factors associated
with feeding difficulties in the very preterm infant. Acta Paediatr. 2013;102(12):e539–e545
PMID: 23952198 doi: 10.1111/apa.12393
28. Fryar CD, Carroll MD, Afful J. Prevalence of overweight, obesity, and severe obesity among
children and adolescents aged 2-19 years: United States, 1963-1965 through 2017-2018.
Health E-Stats. National Center for Health Statistics. December 2020
29. Prevalence of Childhood Obesity in the United States. Centers for Disease Control and
Prevention. https://www.cdc.gov/obesity/data/childhood.html. Accessed March 9, 2022
30. Styne DM, Arslanian SA, Connor EL, et al. Pediatric obesity-assessment, treatment, and
prevention: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab.
2017;102(3):709–757 PMID: 28359099 doi: 10.1210/jc.2016-2573

1060
31. Henry BW, Ziegler J, Parrott JS, Handu D. Pediatric weight management evidence-based practice
guidelines: components and contexts of interventions. J Acad Nutr Diet. 2018;118(7):1301–1311.
e23. PMID: 29233517. doi: 10.1016/j.jand.2017.08.007
32. Azizpour Y, Delpisheh A, Montazeri Z, Sayehmiri K, Darabi B. Effect of childhood BMI on
asthma: a systematic review and meta-analysis of case-control studies. BMC Pediatr.
2018;18:(1)143AU
33. Okoniewski W, Lu KD, Forno E. Weight loss for children and adults with obesity and asthma.
A systematic review of randomized controlled trials. Ann Am Thorac Soc. 2019;16(5):613–625
PMID: 30605347 doi: 10.1513/AnnalsATS.201810-651SR
34. Thiara G, Goldman RD. Milk consumption and mucus production in children with asthma.
Can Fam Physician. 2012;58(2):165–166 PMID: 22337739
35. Sutter SA, Stein EM. The skeletal effects of inhaled glucocorticoids. Curr Osteoporos Rep.
2016;14(3):106–113 PMID: 27091558 doi: 10.1007/s11914-016-0308-1
36. Ross AC, Taylor CL, Yaktine AL, et al, eds. Dietary Reference Intakes for Calcium and
Vitamin D. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for
Vitamin D and Calcium; Washington (DC). National Academies Press; 2011
37. Lis-Święty A, Milewska-Wróbel D, Janicka I. Dietary strategies for primary prevention of atopic
diseases - what do we know? Dev Period Med. 2016;20(1):68–74 PMID: 27416628
38. Rosen CL, Larkin EK, Kirchner HL, et al. Prevalence and risk factors for sleep-disordered
breathing in 8- to 11-year-old children: association with race and prematurity. J Pediatr.
2003;142(4):383–389 PMID: 12712055 doi: 10.1067/mpd.2003.28
39. Keefe KR, Patel PN, Levi JR. The shifting relationship between weight and pediatric obstructive
sleep apnea: A historical review. Laryngoscope. 2018;2019;129(10): 2414‒2419 PMID: 30474230
doi: 10.1002/lary.27606
40. Andersen IG, Holm JC, Homøe P. Impact of weight-loss management on children and
adolescents with obesity and obstructive sleep apnea. Int J Pediatr Otorhinolaryngol.
2019;123:57–62 PMID: 31075707 doi: 10.1016/j.ijporl.2019.04.031
41. Prader-Willi Syndrome. https://ghr.nlm.nih.gov/condition/prader-willi-syndrome#resources.
42. Abel F, Tan HL, Negro V, et al. Hypoventilation disproportionate to OSAS severity in children
with Prader-Willi syndrome. Arch Dis Child. 2019;104(2):166–171 PMID: 30007944
43. Muscogiuri G, Formoso G, Pugliese G, Ruggeri RM, Scarano E, Colao A; RESTARE.
Prader-Willi syndrome: an uptodate on endocrine and metabolic complications. Rev Endocr
Metab Disord. 2019;20(2):239–250 PMID: 31065942 doi: 10.1007/s11154-019-09502-2

CHAPTER
60
Oxygen Therapy
Shyall Bhela, MD
Introduction
Oxygen is a gas that is essential for human life and cellular metabolism. Con-
ditions that are associated with diminished partial pressure of oxygen (Po2)
in the blood result in a decreased oxygen content, which, if not corrected,
can lead to organ damage and eventually death. Oxygen is administered as
a medical therapy in these situations.
Definitions
X Hypoxemia: Decreased partial pressure of oxygen in the blood
X Hypoxia: Decreased oxygen content in the tissues
X Normobaric oxygen therapy: Administration of oxygen under atmo-
spheric pressure (760 mm Hg at sea level)
X Hyperbaric oxygen: Delivery of oxygen under pressures that exceed the
atmospheric pressure
X High-flow oxygen: Delivery of oxygen at significantly higher flow rates
using specialized cannula as compared to traditional flow rates used for
oxygen therapy
Determinants of Oxygen Delivery to Tissues

Oxygen-carrying capacity is the sum of the amount of oxygen dissolved in
blood plus oxygen bound to hemoglobin (which provides ~98% of the oxygen
delivered to tissue). The oxygen dissociation curve (Figure 60-1) describes the
relationship between the Po2 and the oxygen saturation as measured by pulse
oximetry (Spo2 , often referred to as ‘percentage of hemoglobin saturated
with oxygen’).
The relationship between Po2 and Spo2 is not linear but rather S-shaped. The
curve flattens out at higher Po2 levels, indicating that, at these levels, there is
little incremental increase in Spo2 for a given increase in Po2. For example,
1061

1062
when the hemoglobin is 90% saturated, the arterial partial pressure of oxygen
(Pao2) is 60 mm Hg. Above this value, further increases in the Pao2 result in
only a small increase in the Spo2. Below 60 mm Hg, however, a small change
in Pao2 level results in a large change in the Spo2. Certain conditions, such
as elevated partial pressure of carbon dioxide (Pco2), increased temperature,
and acidosis, decrease hemoglobin’s affinity for oxygen, which results in an
increase in the unloading of oxygen at the tissue level with a shifting of the
curve rightward. In contrast, lower Pco2, decreased temperature, and alkalosis
increase hemoglobin’s affinity for oxygen and facilitate oxygen uptake by red
blood cells, thus shifting the curve leftward.1

100
90
↑ pH
↓ DPG
80
↓ Temp
70 ↓ pH
↑ DPG
60 ↑ Temp

40
30
20
10
0
0 10 20 30 40 50 60 70 80 90 100
PO2 (mmHg)
Figure 60-1. The oxygen dissociation curve. DPG = diphosphoglycerate, Po2 = partial pressure of
oxygen, Spo2 = oxygen saturation as measured by pulse oximetry (percentage of hemoglobin
saturated with oxygen).
From Krishnan S. Oximetry and capnography. In: Stokes DC, Dozor AJ, eds. Pediatric Pulmonology, Asthma,
and Sleep Medicine: A Quick Reference Guide. American Academy of Pediatrics; 2018: 63–67.

1063
Chapter 60—Oxygen Therapy
The Alveolar Gas Equation and the Alveolar-Arterial Gradient

The alveolar gas equation is used to calculate the alveolar partial pressure of
oxygen (Pao2), which is required to calculate the alveolar-arterial oxygen
gradient (A-a gradient).
Pao2 = Pio2 − Paco2 (where Pio2 is the partial pressure of inspired air).
Pio2 (in room air) = Fio2 × (Pb − 47 mm Hg), where Pb is barometric pressure
(760 mm Hg at sea level), 47 mm Hg is the partial pressure of water vapor or
humidified air as it reaches the alveoli, and Fio2 (fraction of inspired oxygen)
is 0.21 at sea level. At sea level, Pio2 is 150 mm Hg.
Assuming a Paco2 of 40 mm Hg, the Pao2 would be 110 mm Hg. With an
arterial O2 (Pao2) of 100 mm Hg, therefore, the normal A-a gradient is
approximately 10 mm Hg.
Conditions that affect the ventilation-perfusion relationships in the lung or
those that affect the alveolar-capillary membrane will be associated with an
abnormal (increased) A-a gradient.
Causes of Hypoxia and Hypoxemia

The causes of hypoxia and hypoxemia can be broadly grouped into 6 categories:
1. Ventilation-perfusion (V̇ /Q̇ ) mismatch: Resulting from differential ventila-
tion and perfusion of the lungs, observed in conditions that impair either of
these functions.
2. Hypoventilation:
a. Central/neurogenic conditions (eg, central hypoventilation syndromes,
encephalopathies, opioid/sedative overdose).
b. Neuromuscular conditions (eg, spinal muscular atrophy, muscular
dystrophies, myopathies, myasthenia gravis).
3. Diffusion defect: Diseases and conditions that affect the alveolar-capillary
barrier (eg, interstitial lung disease).
4. Shunting: Occurs when blood returns to the systemic circulation after
passing through areas not being ventilated. Can be classified as physiologic
(eg, the Thebesian vessels of the heart) or pathologic (eg, congenital cyanotic
heart defects or pulmonary arteriovenous malformations).
5. Alteration in oxygen-carrying capacity: Diseases and conditions that disrupt
the structure or function of the hemoglobin molecule, thereby altering the
oxygen-carrying capacity (eg, carboxyhemoglobinemia, methemoglobinemia,
and cyanide toxicity).
6. Decreased inspiratory concentration of oxygenation as seen at high altitudes.

1064
Ventilation-Perfusion Mismatch
This term refers to an imbalance between ventilation (V·) (gas flow into
the lungs) and blood flow (Q· ) through the lung. Blood flow and ventilation
vary according to region of the lung and the patient’s position. In healthy
individuals, pulmonary blood vessels are regulated such that if a particular
gas exchange unit is not receiving adequate ventilation, the vascular supply
to that unit will correspondingly decrease. This compensation, however,
may not be seen in disease conditions such as pneumonia, bronchiolitis,
atelectasis, pulmonary edema, asthma, and acute lung injury/acute respira-
tory distress syndrome. In these conditions, blood flow continues into areas
of the lung that are under-ventilated, leading to less oxygen uptake and
resultant hypoxemia.
Hypoventilation
Hypoventilation (insufficient ventilation) is a result of either a decreased
central respiratory drive to breathe or weak respiratory neuromuscular appa-
ratus. Apart from the disease states listed in the previous paragraph, sedation
or anesthesia as well as certain drugs may present with hypoxemia due to
hypoventilation. A hallmark of hypoxemia due to hypoventilation is a normal
A-a gradient.2
Supplemental oxygen should be administered with caution when hypoxemia
is due to hypoventilation. The application of supplemental oxygen may correct
the Spo2 but may place the patient at greater risk because of blunting of the
hypoxic drive. Patients who have hypoventilation may require ventilatory
support rather than supplemental oxygen alone.
Diffusion Defect
A diffusion defect usually occurs when there is a thickening or disruption of
the normal surface area available for gas exchange in the lung. In otherwise
healthy individuals, the space across which oxygen passes from the alveolus
to the blood is less than 1 micron thick. At baseline, the red blood cells have
more than a sufficient amount of time to traverse the pulmonary capillary and
receive oxygen from the alveolus. In the healthy individual, this arrangement
accommodates states of increased demand, such as exercise, during which the
cardiac output increases up to fivefold and the capillary transit time decreases.
In children with defects in diffusion, there may be insufficient time for the
blood to be fully oxygenated (especially when the system is stressed), resulting
in hypoxemia. Diffusion defects are rare in children, occurring in conditions
such as interstitial lung diseases and pulmonary hemosiderosis.

1065
Shunts
Cardiac and intrapulmonary shunts cause blood to bypass functional alveoli
and result in hypoxemia. This hypoxemia cannot be completely corrected by
administering oxygen. Oxygen saturation in patients with intracardiac right-
to-left shunts does not improve even when 100% oxygen is administered.
Alteration in Oxygen-Carrying Capacity

Dyshemoglobinemias are a collection of diseases and conditions where
the structure and/or function of the hemoglobin molecule has been altered,
affecting the oxygen-carrying capacity and resulting in tissue hypoxia.3
Dyshemoglobinemias include carboxyhemoglobinemia, methemoglobinemia,
and cyanide toxicity.
Carboxyhemoglobinemia results from carbon monoxide (CO) exposure in
which the CO binds to hemoglobin with a higher affinity than oxygen, result-
ing in a left shift of the oxygen disassociation curve and causing tissue hypoxia.
Sources of CO poisoning include smoke inhalation, idling cars in closed
garages, gas grills, kerosene heaters, and camp stoves in enclosed spaces.3
Methemoglobinemia results when iron species in the hemoglobin is con-
verted from a ferrous (2+) to ferric (3+) state, which leads to an inability
of the hemoglobin to bind oxygen. Methemoglobinemia may be congenital
or acquired. Congenital methemoglobinemia is secondary to mutations of
the cytochrome-B3-reductase enzyme and can either be type 1 (normal life
expectancy) or type 2 (decreased life expectancy). Acquired methemoglobin-
emia occurs after exposures to agents that oxidize the iron species on the
hemoglobin. Common exposures include well water that may be contami-
nated with nitrites from fertilizer runoff, topical anesthetics (lidocaine and
benzocaine), and foods rich in nitrites.3
Cyanide toxicity occurs due to inhibition of cytochrome C oxidase that
interferes with oxidative phosphorylation, halting cellular respiration. Cya-
nide exposures most commonly occur secondary to structural fires; other
etiologies include industrial accidents and, occasionally, medical exposure
to sodium nitroprusside.
Changes in Oxygenation at High Altitude

Hypoxemia also can result from inspiration of a lower partial pressure of
ambient oxygen (ie, Fio2), which can occur at high altitude or during air travel.
Certain individuals who are normoxic at sea level (whether on room air or
supplemental oxygen) may require an increased amount of oxygen during air
travel or at altitude. The body’s normal compensatory response in the presence
of a decreased Fio2is to increase the ventilatory drive. A child with neuromus-
cular weakness with decreased chest wall compliance may not be able to

1066
sufficiently produce the required sustained respiratory muscle force to

compensate for the hypoxemia.
High-Altitude Simulation Test
This test is advisable for persons with known risk of hypoxemia prior to
taking a flight in commercial jets. This involves the patient breathing air with
a known, decreased Fio2 (usually 0.15, which simulates 8,000 feet), calibrated
to approximate a pressurized aircraft cabin. These settings are because com-
mercial aircraft cabins are pressurized to simulate conditions at 8,000 feet,
irrespective of the flight altitude. Though a person would be breathing room
air, the Po2 at this altitude would approximate breathing 15% Fio2 at sea level.
This test is performed with the patient breathing via a mask, with continual
monitoring of Spo2 , respiratory rate, and heart rate. The body’s normal
response is to increase minute ventilation to maintain adequate oxygenation.
Once it is established that the patient is unfit for air travel on room air, the
testing session may be used to calibrate the flow needed by the patient.4
The cutoff value for initiating supplemental oxygen during air travel
remains controversial.5
Use of Oxygen While Flying
Current Federal Aviation Administration rules do not permit travelers to
carry their own oxygen tanks or liquid oxygen aboard commercial aircraft
because they are defined as hazardous materials. Instead, patients may use a
Department of Transportation-approved battery-powered portable oxygen
concentrator. A prescription is necessary.
Portable oxygen concentrators are available for rent from most durable medical
equipment suppliers; however, they must be approved by the airline, with a
48-hour advance notice, along with completed approval forms. Different
portable oxygen concentrators are available, including conserving devices,
which are flow triggered and deliver oxygen only in response to a patient’s
inhalation. These are sufficient for older children and adults; however, the
infant or young child with neuromuscular weakness may not be able to
actively trigger this delivery. Therefore, for these children, it is best to
procure a portable concentrator with continuous flow.
Travelers are expected to bring enough 12-cell batteries for 1½ times the
anticipated duration of the flight. Specific battery approval forms must be
completed as per airline policy.
The clinician should be aware that commercial aircraft are typically pressur-
ized up to an altitude of 8,000 feet only, beyond which there may be a drop
in oxygen saturations.

1067
Clinical Features of Hypoxemia

Signs on Physical Examination
Acutely, hypoxemia will manifest with signs of respiratory distress, such as
tachypnea, tachycardia, and evidence of efforts to increase ventilation, includ-
ing the use of accessory muscles of respiration (such as supraclavicular, supra-
sternal, intercostal, and subcostal retractions) as well as thoraco-abdominal
asynchrony and nasal flaring. Cyanosis of the mucus membranes is seen late
and constitutes a medical emergency. If the patient has been chronically
hypoxemic, digital clubbing may be seen late in the course of the disease.
Evaluation of Hypoxemia
Pulse Oximetry
First described in the 1940s, pulse oximetry is now considered the “fifth vital
sign” and has evolved to be the method of choice to monitor the oxygenation
status of a patient.6
Pulse oximetry measures oxygen saturation (ie, Spo2) by relying on the
differential absorption spectra of deoxyhemoglobin (red light, 660 nm)
and oxyhemoglobin (infrared light, 940 nm) (Figure 60-2).
The comparative ratio of light absorbance at these 2 wavelengths is calcu-
lated and calibrated against direct measurements of arterial oxygen saturation
Red Infrared
(660 nm) (940 nm)
10
Extinction Coefficient
0.1
.01
600 700 800 900 1000
Wavelength, nm
Methemoglobin Carboxyhemoglobin
Reduced hemoglobin Oxyhemoglobin
Figure 60-2. The oxygen dissociation curve. DPG = diphosphoglycerate, Po2 = partial pressure of
oxygen, Spo2 = oxygen saturation as measured by pulse oximetry (percentage of hemoglobin
saturated with oxygen).
Adapted from Krishnan S. Oximetry and capnography. In: Stokes DC, Dozor AJ, eds. Pediatric Pulmonology,
Asthma, and Sleep Medicine: A Quick Reference Guide. American Academy of Pediatrics; 2018: 63–67.

1068
(SaO2) by blood gas measurements. This establishes the Spo2. Pulse oximeters
typically consist of 2 light-emitting diodes (LEDs), one emitting at the red
spectrum and the other at the infrared spectrum. At the other end of the diodes,
a detector measures non-absorbed energy. A microprocessor subtracts absorp-
tion by constant sources like bone and tissue and displays the final signal
electronically as a waveform. The waveform reflects the pulsatile nature of
blood flow and thus is a marker of pulse or heart rate. Spo2 is calculated by
converting the absorption ratios using dedicated calibration algorithms stored
in the microprocessor of the device. These algorithms are derived from blood
gas measurements in healthy volunteers breathing standard oxygen concen-
trations. They are not useful below Spo2 of 75% because it is unethical to
expose volunteers to oxygen concentrations to test the algorithm in these
conditions. In most pulse oximeters, displayed Spo2 represents the mean of the
measurements obtained during the previous 3 to 6 seconds. Typical measur-
ing sites include the finger, toe, pinna, and lobe of the ear. Newer technology
uses a patented signal extraction technique to smooth out motion artifacts.
Pulse oximeters equipped with this technology tend to reflect Spo2 more
accurately in infants and young children.
Blood Gas Measurements
Arterial blood gas provides direct measurement of Pao2 and Paco2, as well
as pH. Venous blood gas is less useful because the values obtained may be
variable and inconsistent and may not adequately represent oxygenation
status. Capillary blood gas may be more reliable than venous blood gas, due
to proximity to the arterial circulation, and relatively easier to obtain than
arterial blood gas, especially in young infants. Mixed venous saturation,
obtained directly from a central line or during cardiac catheterization, can
provide a measure of oxygen extraction at the tissue level. Because of the
potential for error in blood gas measurement, proper collection of the speci-
men is paramount. The sample should be of sufficient quantity and collected
directly into a heparinized syringe that is quickly placed on ice. Increased
quantity of heparin may adversely affect the pH measurement, when not using
prefilled syringes. Care must also be taken not to introduce air into the syringe;
an air bubble may falsely elevate the Pao2 or depress the Paco2.
Co-oximetry
Co-oximetry is useful in determining the cause of a discrepancy between
percent saturation and Po2, as may be seen in CO poisoning or methemoglo-
binemia.1,2 Co-oximetry uses technology that is similar to pulse oximetry
but evaluates absorbance using multiple wavelengths; thus, the co-oximeter
determines not only the percent saturation of hemoglobin by oxygen (oxyhe-
moglobin), but also carboxyhemoglobin and methemoglobin. An individual
with CO poisoning will often present with bright red or cherry red mucous

1069
membranes; the blood similarly is bright red. The pulse oximeter will display
a normal Spo2 in the face of a low Pao2. In contrast, those with methemoglo-
binemia will appear cyanotic, and the blood specimen will appear chocolate
brown; Pao2 can be normal, but the Spo2 is low. Anemic patients will often
not appear cyanotic despite a low Pao2, whereas patients with polycythemia
will appear cyanotic at more mild levels of desaturation. Pulse oximetry
results are not completely accurate in patients with hemoglobinopathies.1,2
Use of Home Oxygen Therapy

In general, the clinical goals of home oxygen therapy include maintaining
saturations within an appropriate range based on the underlying medical
condition (usually > 92%; possibly higher in children with pulmonary hyper-
tension and lower for children with congenital heart disease), limiting poten-
tial complications of hypoxemia, improving symptoms associated with
hypoxemia, and promoting sustained adequate growth.7–9 Optimal somatic
growth is crucial for children with lung disease because there is a finite
window, usually up to 6 to 8 years of age, in which to grow new alveoli.
The most important consequences of chronic hypoxemia are due to reflex
increases in pulmonary vascular resistance leading to acute pulmonary
hypertension and, ultimately, chronic pulmonary hypertension and cor
pulmonale, increased right-to-left shunting through a patent foramen ovale,
and poor growth.9,10
Specific Clinical Conditions

Bronchopulmonary dysplasia (BPD) is defined by the need for supplemental
oxygen at 36 weeks’ postmenstrual age in the preterm neonate. Some studies
suggest that the incidence of supplemental oxygen dependence in infants with
BPD is decreasing,11 but this may reflect changed practices and new defini-
tions of BPD.12 In general, prescribing supplemental oxygen in the infant with
BPD results in a quicker discharge, improvement in growth, and reduced
episodes of desaturation. In addition, prevention of hypoxemia reduces the
risk of development of pulmonary hypertension.
Optimal target oxyhemoglobin saturations in BPD continue to be debated.
Saturation targets of 90% to 92% are well tolerated in the nursery setting
and are associated with similar rates of infant growth and development over
time. To promote adequate growth and help prevent pulmonary hypertension,
American Thoracic Society guidelines recommend that in-home oxygen
saturation levels be 95% to 99% for children no longer at risk for oxygen-
induced retinopathy. These saturations should be maintained while the
child is awake and asleep.8,9

1070
Home oxygen is often prescribed for infants with other lung diseases and
malformations, such as congenital diaphragmatic hernia.13 These infants may
experience a component of BPD as well because of exposure to high pressures
and oxygen concentration while receiving mechanical ventilation.
Cyanotic Congenital Heart Disease
Children with cyanotic congenital heart disease usually do not require
supplemental oxygen. An exception is the child with cyanotic congenital heart
disease and pulmonary hypertension. Supplemental oxygen therapy is used
as supportive therapy, to alleviate symptoms, and to promote good growth.
Pulmonary Hypertension
Pulmonary hypertension may develop secondary to persistent hypoxemia in
the context of lung disease, may be idiopathic in nature, or may develop in
those with long-standing congenital heart disease. In individuals with lung
disease, hypoxemia leads to smooth muscle contraction in pulmonary arteries
with possible endothelial remodeling. Hypoxic crises may be episodic, and the
severity of hypoxemia often worsens with stressors such as illness or exercise.
The conditions that cause interstitial lung disease in childhood are hetero-
geneous, with a variable age of onset and prognosis, and are quite different
from the conditions causing interstitial lung disease in adults. Primary child-
hood interstitial lung diseases are broadly classified as diffuse developmental
disorders like alveolar capillary dysplasias, lung growth abnormalities like
pulmonary hypoplasia, surfactant protein deficiency syndromes, and specific
conditions of uncertain etiology like neuroendocrine cell hyperplasia of
infancy.14 Interstitial lung disease may also be secondary to infectious etiolo-
gies, malignancies, rheumatologic disorders, and posttransplant syndromes,
including bronchiolitis obliterans.
Children with these conditions often require long-term oxygen supplemen-
tation throughout infancy, and sometimes through childhood. The goals
are similar to oxygen supplementation in infants with BPD: good growth,
decreasing the risk of pulmonary hypertension, and alleviating the dyspnea
and increased respiratory work associated with hypoxemia.9
Use of Oxygen in the Setting of Obstructive Sleep Apnea
Supplemental oxygen is generally not indicated in obstructive sleep apnea,
in which hypoxemia, when it occurs, is due to episodic periods of airway
obstruction leading to intermittent hypoxia.
Supplemental oxygen may depress the respiratory drive, especially in
those children who have hypoventilation as a component of their disease.
Positive-pressure ventilation, such as continuous positive airway pressure
(CPAP) or bilevel positive airway pressure (BiPAP), is more physiologically

1071
appropriate in these patients. However, some children may not tolerate the
interface necessary for delivery of positive pressure. In those cases, it is
necessary to weigh the risks of worsened hypoventilation with the benefits
of normalizing oxygenation, such as augmented growth and decreased like-
lihood of developing pulmonary hypertension. Careful titration of optimal
supplemental oxygen and monitoring for induced hypoventilation by
polysomnogram is necessary.9,14
Discharge From Hospital With Supplemental Oxygen

Before discharge home with supplemental oxygen, the child must maintain
stable oxygen levels within the targeted saturation goal. The child’s family
must be familiar and comfortable with the care plan and have suitable
resources in place (eg, for reliable access to electrical sources). Family
members should receive training in the care of a child receiving supplemen-
tal oxygen, and they must feel secure in providing this care.7–9,15 Table 60-1,
excerpted from the American Thoracic Society statement on care of children
with chronic lung disease of infancy, describes the considerations and
planning for the child discharged on home oxygen (see rows on assessment,
nutrition, oxygen, emergency management, anticipatory guidance, and travel).
Table 60-1. Topics for Discharge Teaching

Topic Teaching Component
Chronic lung disease of infancy Disease process, sequelae, management
Assessment Vital signs (temperature, pulse, respirations)
Evaluation of color
Breathing pattern
Lung auscultation
Fluid balance, skin turgor
Neurologic status
Changes in appetite, behavior
Use of cardiorespiratory monitor (if needed)
Well-child care Bathing, diapering, skin care
Immunizations
Development and stimulation
Car, home safety
Nutrition Feeding schedule, importance of weight gain
Formula preparation
Methods of feeding
Techniques to maximize oral feeding
Nasogastric/gastrostomy tube feedings
Use of enteral feeding pumps
Antireflux measures
(continued)

1072
Table 60-1. Topics for Discharge Teaching (continued)

Medications Name, purpose
Dosage, route, frequency
Method of administration
Side effects
Omitting or repeating a dose
Storage, safety
Indications for as-needed medications
Oxygen Purpose, flow rate
Method of administration
Reading the flow meter
Maintenance and cleaning of equipment
Weaning procedure
Oximetry technique and interpretation
Safety considerations
Pulmonary treatments Purpose, frequency of treatments
Methods to clear secretions, bulb syringe, suction
Nebulizer technique
Chest physical therapy
Infection control Minimize exposure, day care issues
Handwashing technique
Care providers to receive influenza vaccine
Tracheostomy care Suctioning technique
Humidification
Changing the tracheostomy tube
Skin care
Techniques to facilitate speech
Care, cleaning of the tracheostomy tube
Safety considerations, emergency management
Mechanical ventilation Principles of operation
Settings
Operation, maintenance, cleaning of equipment
Troubleshooting equipment
Schedule for ventilation, weaning
Response to alarms
Safety considerations, emergency management
Emergency management Who and when to call for symptoms
Procedure for emergency assistance
Cardiopulmonary resuscitation technique
Telephone numbers posted near phone

1073
Table 60-1. Topics for Discharge Teaching (continued)

Anticipatory guidance Emotional and social needs of family
Sibling rivalry
Rehospitalization
Alternatives to home care
Travel Transport bag with emergency supplies
Portable suction machine
Air travel with oxygen
Reprinted with permission of the American Thoracic Society. Copyright © 2003 American Thoracic Society. All
rights reserved. Allen J, Zwerdling R, Ehrenkranz R, et al. Statement on the care of the child with chronic lung
disease of infancy and childhood. Am J Respir Crit Care Med. 2003;168:356–396. The American Journal of
Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.
Monitoring
A pulse oximeter or cardiorespiratory monitor should be used to monitor the
child on oxygen at home. Monitoring patterns should be based on the
patient’s needs, including during awake and/or sleeping states, as well as with
feeding and activity. A pulse oximeter provides immediate heart rate and
oxygen saturation data, but its use can be fraught with difficulty in the home, as
movement artifacts can lead to inaccurate readings and false alarms. The
American Thoracic Society recommends home monitoring for infants with
BPD as well as other chronic lung diseases since these children may develop
apnea or bradycardia should the flow of oxygen become disrupted and hypox-
emia ensue.8,9 Parameters for heart rate, respiratory rate, apnea delay, or
saturation for the monitoring equipment should be determined based on the
needs of the child, in conjunction with the pulmonary specialist. Caregivers
should be proficient in the use of this equipment and should be aware that most
alarms are false alarms, resulting from poor lead placement, shallow respira-
tions, or, in the case of pulse oximetry, movement artifact.
Successful discharge planning requires a team approach. Often, this begins
with a multidisciplinary meeting, including the durable medical equipment
company, a social worker, the child’s physician, nursing, the discharge care
management team, and the family. The child’s family (and the child, if
developmentally appropriate) should be educated regarding use and mainte-
nance of all equipment.
The family should be comfortable assessing the causes of equipment alarms.
In addition, caregivers should be able to recognize the signs and symptoms of
hypoxia and any worsening of the child’s baseline pulmonary status and have
a written care plan to follow for such problems. Education should be ongoing
until the caregivers feel comfortable with their child’s needs and can demon-
strate competency in managing both the child’s disease and the accompany-
ing technology.

1074
Special attention should be paid to precautions and safety measures. There

should be no smoke exposure in the home. The electrical system should
be functional, safe, and able to provide the power necessary to maintain
equipment. This assessment should be performed by personnel from the
medical equipment company prior to discharge.
Equipment for Oxygen Therapy

Delivery interface and oxygen source must be considered in light of patient
size, disease process, and patient and family preference when selecting equip-
ment for an individual patient, in both the inpatient and ambulatory settings.16–18
Box 60-1 provides a list of equipment that is typically necessary for home
oxygen delivery.
Delivery Interfaces
Fraction of inspired oxygen is determined by individual patient characteristics,
such as size, tidal volume, and breathing pattern (slow or fast, deep or shal-
low), and by characteristics of the delivery device (flow, oxygen concentra-
tion, amount of room air entrained).
Table 60-2 describes the different delivery devices, accompanying maximal
flow rates, and achievable Fio2.
Low-Flow Devices
Nasal prongs or cannulae sit directly in the anterior nares. They are available
in several sizes that are appropriate for infants, children, and adults. Typically,
infants can tolerate flows up to 2 L/min, whereas an older child or adult can
tolerate higher flows, up to 4 L/min. The prongs must be held in place in infants
and young children, typically by using an adhesive to affix tubing to the
cheeks. For short-term administration, tape is often sufficient, but for long-term
home use, it is often irritating to infant skin. There are tapes made espe-
cially for sensitive skin and several different types of gentle adhesives that are
Box 60‑1
Typical Equipment for Delivery of Supplemental Oxygen at Home
ū For portable use: concentrator, small ū Appropriately sized cannulae/
liquid portable unit, or lightweight mask/tubing
compressed gas cylinder ū Adhesive to keep cannula in place
ū For home: concentrator, liquid (tape, “tender grips”)
oxygen reservoir, or large ū Stroller with necessary structure to
compressed gas tank transport concentrator or cylinders
ū Low-flow meter ū Pulse oximeter with extra probes
ū Humidification system, if needed

1075
Table 60-2. Oxygen Delivery Devices, Maximal Flow Rates, and Maximal Fraction of
Inspired Oxygen Achievable.
Maximal Maximal Fio2 Entrainment
Device flow rate achievable Flow of room air
Nasal cannula 1–2 L/m Variable Variable Yes
Simple face mask 6–10 L/m 30%–60% Variable Yes
Partial rebreather mask 10–12 L/m 50%–60% Variable Yes
Non-rebreather mask 10–12 L/m Up to 95% Relatively fixed No
Oxyhood 10–15 L/m 80%–90% Relatively fixed No
Oxygen tent 10–15 L/m 30%–50% Variable Yes
Venturi mask Variable Variable, predictable Fixed Yes
From Krishnan S. Oxygen therapy. In: Stokes DC, Dozor AJ, eds. Pediatric Pulmonology, Asthma, and Sleep
Medicine: A Quick Reference Guide. American Academy of Pediatrics; 2018:805–811.
applied to the skin that may remain in place for several days. Parents should be
cautioned to be especially careful during sleep because prongs may dislodge
from the nares and infants may become entangled in long cords.
High-Flow and Reservoir Devices
There are several mask interfaces that may be used to deliver oxygen therapy,
mostly in the inpatient setting but now being increasingly used as a home
oxygen delivery system for patients who require additional support but are
unable to tolerate CPAP or BiPAP. Standard masks have apertures on either
side to allow for exhalation and room air entrainment. Venturi masks allow
for oxygen to be administered at a set concentration, at high flows. The high
flows create a shearing effect, entraining a specific proportion of room air;
because the flow often exceeds an individual’s peak inspiratory flow, the Fio2
is more predictable. A non-rebreather mask administers 100% oxygen using
2 one-way valves to prevent mixing of delivered supplemental oxygen with
both expired gas and entrained room air. This mask achieves the highest
Fio2 in a non-intubated patient.
Delivery Methods
Oxygen may be stored and delivered in several ways: compressed gas, in
tanks of several sizes; liquid oxygen, contained in a large central reservoir to
distribute to smaller tanks for portability; and concentrating devices (which
extract oxygen from the air). Each of these systems has its own advantages
and disadvantages and a patient’s prescription may include more than one
modality, accounting for cost, convenience, and portability.19,20 Table 60-3
describes various available delivery methods for home use.

1076
Table 60-3. Delivery Methods for Home Oxygen Use

Features Concentrator Compressed gas Liquid
Availability Common Common Limited
Reliability Good with regular Good but gauges may Generally good, but
service become inaccurate connector may freeze
Cost Low, but cost of Moderate High
electricity borne by
patient
Power: wall Required Not required Not required
current
Stationary 35–50 lb Portable 2–4 lb H cylinder 200 lb, Reservoir 120 lb, 6 lb with
weight (Deliver continuous or E cylinder 22 lb with no conserver, portable
pulsed oxygen) cart, M6 cylinder 3.4 lb with conserver
4.5 lb
Use time at Continuous. Variable on 2.5 days for “H,” 5 hours 8.9 days, 4 hours, and
2 L/min−1 portable devices, for “E ,” and 12 hours 10 hours
based on battery life/ for “M6” type
charging.
Derived from Jacobs SS, Krishnan JA, Lederer DJ, et al. Home oxygen therapy for adults with chronic lung
disease. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med.
2020;202(10):e121–e141.
Monitoring and Weaning

A pulse oximeter is a useful tool for families to use to become familiar with a
child’s normal baseline Spo2, heart rate, and oxygen saturation. Often, tachy-
cardia may be the first sign of distress. Tracking the child’s normal values,
especially resting heart and respiratory rates, in conjunction with oxygen
saturation, provides trends that may be used to begin the weaning process.
In conjunction with the child’s medical equipment company, downloads of
pulse oximeter data over a night of sleep can provide oxygen saturation and
heart rate. The quality of data is variable, however, and must be interpreted
with caution. In special situations, polysomnography, in a laboratory familiar
with pediatric patients, may provide a more accurate record of overnight oxy-
genation and a full picture of the child’s respiratory status with sleep, includ-
ing variation in heart and respiratory rates, end-tidal carbon dioxide levels,
and differences with sleep stages.
There is significant variability in practice, monitoring, and assessment during
the weaning process.8,9,19 Oxygen needs during wakefulness are often less
than during sleep. As a first step in the weaning process, a trial of weaning
supplemental oxygen may be performed with the child awake in a moni-
tored setting, such as during a prolonged visit to a physician’s office. When
gradually decreasing oxygen flow rates, it is practical to wean by halving
because conventional home oxygen delivery devices easily allow for this (1 L/
min to 0.5 L/min then 0.25 L/min, and so forth) before room air challenges.8,9
Weaning flow rate should be done gradually over the course of weeks while

1077
HYPOXEMIA
Very
Threshold No preterm; No Retinal Yes
ROP early immature vascualization
eyes without complete?
ROP
Pre-threshold Yes
SpO2 Target SpO2 Target O2 Supplementation

95%–99% 90%–94% SpO2 95%–99%
Wean O2 as tolerated
Ill, poor feeding,

FTT, desaturation No Yes
with activity or Is patient well
sleep, cor and thriving?
pulmonale, etc.
Wean daytime O2
Equipment
functioning? No No SpO2
Fix equipment,
Adherence educate adequate?
adequate?
Yes
No Yes
Well Assess nighttime
sleeping SpO2
Complicating
condition? Yes
Treat condition
GER, cor No
SpO2 adequate
pulmonale,
asleep?
RAD?
Yes
No
Wean Oxygen
Candidate for
ventilator
support?
No Yes
No Yes
Well
Continue current
program or consider
transplant, terminal care
Initiate ventilator Wean ventilator
support support
No Yes
Well
Figure 60-3. The bottom portion of this decision tree shows an approach to weaning supple-
mental oxygen in the child with chronic lung disease. GER, gastroesophageal reflux; RAD,
reactive airway disease; Spo2, oxygen saturation as measured by pulse oximetry.
All rights reserved. Allen J, Zwerdling R, Ehrenkranz R, et al. Statement on the care of the child with chronic
lung disease of infancy and childhood. Am J Respir Crit Care Med. 2003;168:356–396. The American Journal
of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

1078
frequently monitoring for adverse effects. Regular (weekly to monthly) visits

with the physician are needed to assess the child’s progress.8,9 Once the child
has been weaned to room air while awake and has tolerated this well for a
period at home by demonstrating continued good growth and acceptable
oxygen saturations, then oxygen weaning during sleep can be attempted.
Oxygen levels while awake do not accurately reflect oxygen levels during
sleep. Nighttime weaning may require a review of downloadable readings
from overnight pulse oximeter monitoring or a formal polysomnography.8,9
Failure to progress successfully with weaning, in conditions such as BPD,
should prompt a diagnostic workup for confounding conditions, including
aspiration of gastric or oral contents, gastroesophageal reflux, airway malfor-
mations, sleep-disordered breathing, pulmonary hypertension, and congenital
heart disease. Figure 60-3 suggests an approach to weaning oxygen in
children with chronic lung disease.
Adverse Effects of Oxygen Therapy

Oxygen therapy should be treated as any drug therapy, with the physician and
the patient/caregiver aware of risks associated with it. Some adverse effects
reported include
X Retinopathy of prematurity in infants born preterm.
X Carbon dioxide narcosis. Oxygen administration only corrects hypoxemia
and not ventilatory failure with elevated carbon dioxide. It is particularly
important in those who have hypoventilation from neuromuscular weak-
ness where injudicious oxygen therapy can mask impending respiratory
failure or arrest.
X Possible increase of pulmonary blood flow, which can be deleterious in
patients with certain cardiac pathologies.
X Oxygen therapy is associated with free radical production and subsequent
damage to lung tissue, even with relatively short durations of oxygen therapy.
X Persistent oxygen therapy, especially at high inspired concentrations, can
lead to pulmonary fibrosis.
High-Flow Oxygen Therapy

High-flow oxygen therapy (HFOT), delivered via a variety of devices, is a
relatively new noninvasive ventilation therapy. Current literature suggests that
HFOT is a relatively safe, well-tolerated, and feasible method for delivering
oxygen to children, with few adverse events reported. High flow is usually

1079
defined as flow rate 4 L/min or higher but ranging from 4 to 20 L/m, with some
studies reporting flows as high as 70 L/m. High-flow oxygen therapy may
reduce the need for less-tolerated and more invasive respiratory supports, such
as CPAP or BiPAP and mechanical ventilation. Among children, HFOT has
been most frequently used for infants and young children who were hospital-
ized with bronchiolitis. There are reports of HFOT use in congenital heart
disease, obstructive sleep apnea, and pulmonary edema. Even though there is
no conclusive evidence for the safety, effectiveness, or relative cost analysis
of HFOT, use in clinical practice continues to increase.21–23
The mechanisms of action of HFOT are incompletely understood as the flow
rates delivered are greater than the normal minute ventilation of patients.21–23
Possible effects of HFOT include
X Nasopharyngeal dead space washout.
X Reduction of inspiratory resistance and work of breathing.
X Providing positive end-expiratory pressure to the lungs.
X Improvement of airway conductance and pulmonary compliance by providing
adequate heating and humidification, thereby reducing the effects of dry air.
Pressures Generated by HFOT

The amount of pressure generated by HFOT is variable depending on the
flow rate, the diameter of the nasal cannula compared to the nares, the weight
and size of the patient, and whether or not the mouth is closed. Recent
studies have suggested limited pressure delivery as measured in the pharynx
and esophagus, ranging from 2 to 4 cm H2O in both children and adults.
Patient Comfort With HFOT

Studies in children outside the neonatal period and adults report HFOT to
be more comfortable and associated with less dyspnea and mouth dryness
compared to oxygen delivered via face mask. Improved patient tolerance
may be one of the reasons for the increasing use of HFOT despite lack of
conclusive evidence for clinical effectiveness.
Adverse Effects and Safety of HFOT

Most studies report no adverse events. There are anecdotal reports of pneumo-
thorax in younger infants with flows exceeding 10 L/m, abdominal distention,
and nasal bleeding. Unlike CPAP, there is no regulatory pressure-relief valve;
pressure effects may be seen if there is minimal or no leak.

1080
When to Refer
X Documented persistent hypoxemia or frequent episodes of subnormal
oxyhemoglobin saturation
X Most children requiring chronic supplemental oxygen
X Intermittent desaturations during a polysomnogram
X Poor growth despite adequate caloric intake
When to Admit
X Documented persistent significant increase in supplemental oxygen
requirement despite additional airway clearance methods (see Chapter 55,
Airway Clearance Techniques) and other measures to treat the underlying
disease process.
X Significant signs and symptoms of respiratory distress, such as accessory
muscle use and tachypnea.
X For children receiving supplemental oxygen at home, the threshold for
hospitalization may be individualized. In certain circumstances, particu-
larly if the patient has only a mild illness or there is significant nursing
support in the home, then pulmonary care, including increased oxygen
administration and airway clearance, may escalate safely without hospital-
ization. In these cases, there must be close communication between the
child’s home care provider and pulmonary specialist or pediatrician. If
there is any concern about the patient’s stability, then it is best to err on the
side of caution and hospitalize the patient for closer evaluation.
Resources for Physicians

X Pulse oximetry (American Thoracic Society).
www.thoracic.org/patients/patient-resources/resources/pulse-oximetry.pdf
X Using the Pulse Oximeter (World Health Organization).
www.who.int/patientsafety/safesurgery/pulse_oximetry/
who_ps_pulse_oxymetry_tutorial2_advanced_en.pdf
Parts of this chapter are adapted from Krishnan S. Oxygen therapy. In:
Stokes DC, Dozor AJ, eds. Pediatric Pulmonology, Asthma, and Sleep
Medicine: A Quick Reference Guide. American Academy of Pediatrics;
2018:805–811.
Grateful acknowledgment is given to Patricia M. Quigley, MD, and Elizabeth
K. Fiorino, MD, for their work on the original version of this chapter.

1081
key points
} The number of children with complex respiratory care provided in the home
setting is increasing, so the general pediatrician must be familiar with equip-
ment such as supplemental oxygen and home monitoring requirements.
}
· ·
Etiologies of hypoxemia include V /Q mismatch, hypoventilation, diffusion
defects, shunts, alterations in oxygen-carrying capacity, and high-altitude
ascent. Ventilation-perfusion mismatch is the most common etiology.
} Administering supplemental oxygen without investigating the cause may mask
hypoventilation; the alveolar gas equation helps differentiate hypoventilation
from other causes of hypoxemia.
} A patient’s required Fio2 is determined by their size, tidal volume, underlying
lung disease, and mode of supplemental oxygen delivery.
} Oxygen therapy, while generally safe, is not without potential complications
and should only be prescribed when all risks and benefits are considered, with
adequate supervision and monitoring.
} High-flow oxygen therapy is a relatively new approach, predominantly used in
hospitals, but recently finding its place in the home of selected patients.
} Family education is vital.
} Close collaboration between the primary care provider, medical equipment
company, nursing agency, pulmonary specialist, and family is essential for the
success of home supplemental oxygen therapy.
References
1. West JB. Respiratory Physiology: The Essentials. Lippincott, Williams and Wilkins; 2005
2. Nichols DG, Rogers MC. Rogers’ Textbook of Pediatric Intensive Care. Lippincott Williams
& Wilkins; 2008
3. Farmer BM, Nelson LS. Dyshemoglobinemias. In: Tintinalli JE, Stapczynski J, Ma O, Yealy
DM, Meckler GD, Cline DM, eds. Tintinalli’s Emergency Medicine Manual. 9th ed. American
College of Emergency Physicians. McGraw Hill Publishing. 2022
4. Dine CJ, Kreider ME. Hypoxia altitude simulation test. Chest. 2008;133(4):1002–1005
PMID: 18398121 doi: 10.1378/chest.07-1354
5. Martin AC, Verheggen M, Stick SM, et al. Definition of cutoff values for the hypoxia test used
for preflight testing in young children with neonatal chronic lung disease. Chest.
2008;133(4):914–919 PMID: 17890460 doi: 10.1378/chest.07-1198
6. Mower WR, Sachs C, Nicklin EL, Baraff LJ. Pulse oximetry as a fifth pediatric vital sign.
Pediatrics. 1997;99(5):681–686 PMID: 9113944 doi: 10.1542/peds.99.5.681
7. Moyer-Mileur LJ, Nielson DW, Pfeffer KD, Witte MK, Chapman DL. Eliminating sleep-
associated hypoxemia improves growth in infants with bronchopulmonary dysplasia. Pediatrics.
1996;98(4 Pt 1):779–783 PMID: 8885961
8. Allen J, Zwerdling R, Ehrenkranz R, et al; American Thoracic Society. Statement on the care of
the child with chronic lung disease of infancy and childhood. Am J Respir Crit Care Med.
2003;168(3):356–396 PMID: 12888611 doi: 10.1164/rccm.168.3.356

1082
9. Hayes D Jr, Wilson KC, Krivchenia K, et al. Home Oxygen Therapy for Children. An official
American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med.
10. Poets CF. When do infants need additional inspired oxygen? A review of the current
literature. Pediatr Pulmonol. 1998;26(6):424–428 PMID: 9888217
doi: 10.1002/(SICI)1099-0496(199812)26:6<424::AID-PPUL7>3.0.CO;2-G
11. Geary C, Caskey M, Fonseca R, Malloy M. Decreased incidence of bronchopulmonary dysplasia
after early management changes, including surfactant and nasal continuous positive airway
pressure treatment at delivery, lowered oxygen saturation goals, and early amino acid
administration: a historical cohort study. Pediatrics. 2008;121(1):89–96 PMID: 18166561
doi: 10.1542/peds.2007-0225
12. Davis PG, Thorpe K, Roberts R, Schmidt B, Doyle LW, Kirpalani H; Trial Indomethacin
Prophylaxis in Preterms Investigators. Evaluating “old” definitions for the “new”
bronchopulmonary dysplasia. J Pediatr. 2002;140(5):555–560 PMID: 12032521
doi: 10.1067/mpd.2002.123291
13. Lally KP, Engle W; American Academy of Pediatrics Section on Surgery; American Academy
of Pediatrics Committee on Fetus and Newborn. Postdischarge follow-up of infants with
congenital diaphragmatic hernia. Pediatrics. 2008;121(3):627–632 PMID: 18310215
doi: 10.1542/peds.2007-3282
14. Kurland G, Deterding RR, Hagood JS, et al; American Thoracic Society Committee on
Childhood Interstitial Lung Disease (chILD) and the chILD Research Network. An official
American Thoracic Society clinical practice guideline: classification, evaluation, and
management of childhood interstitial lung disease in infancy. Am J Respir Crit Care Med.
2013;188(3):376–394 PMID: 23905526 doi: 10.1164/rccm.201305-0923ST
15. Marcus CL, Carroll JL, Bamford O, Pyzik P, Loughlin GM. Supplemental oxygen during
sleep in children with sleep-disordered breathing. Am J Respir Crit Care Med.
16. Gracey K, Talbot D, Lankford R, Dodge P. The changing face of bronchopulmonary dysplasia:
Part 2. Discharging an infant home on oxygen. Adv Neonatal Care. 2003;3(2):88–98
PMID: 12881950 doi: 10.1053/adnc.2003.50018
17. Myers TR; American Association for Respiratory Care (AARC). AARC Clinical Practice
Guideline: selection of an oxygen delivery device for neonatal and pediatric patients—2002
revision & update. Respir Care. 2002;47(6):707–716 PMID: 12078654
18. Kacmarek RM. Delivery systems for long-term oxygen therapy. Respir Care. 2000;45(1):84–92
PMID: 10771784
19. McCoy RW. Options for home oxygen therapy equipment: storage and metering of oxygen in the
home. Respir Care. 2013;58(1):65–85 PMID: 23271820 doi: 10.4187/respcare.01932
20. Solis A, Harrison G, Shaw BN. Assessing oxygen requirement after discharge in chronic lung
disease: a survey of current practice. Eur J Pediatr. 2002;161(8):428–430 PMID: 12172825
doi: 10.1007/s00431-002-0991-z
21. Milési C, Boubal M, Jacquot A, et al. High-flow nasal cannula: recommendations for
daily practice in pediatrics. Ann Intensive Care. 2014;4(1):29 PMID: 25593745
doi: 10.1186/s13613-014-0029-5
22. Mikalsen IB, Davis P, Øymar K. High flow nasal cannula in children: a literature review. Scand
J Trauma Resusc Emerg Med. 2016;24(1):93 PMID: 27405336 doi: 10.1186/s13049-016-0278-4
23. Mayfield S, Jauncey-Cooke J, Hough JL, Schibler A, Gibbons K, Bogossian F. High-flow nasal
cannula therapy for respiratory support in children. Cochrane Database Syst Rev.
2014;3(3):CD009850 PMID: 24604698 doi: 10.1002/14651858.CD009850.pub2

CHAPTER
61
Nicotine and Tobacco
Harold J. Farber, MD, MSPH, FAAP
Marianna Martin Sockrider, MD, DrPH, FAAP
Introduction
Tobacco dependence is one of the most important preventable causes of
premature death and disability. It is a severe chronic illness with serious
consequences for smokers and individuals close to them. The 2006 US
Surgeon General Report found, “Massive and conclusive scientific evidence
documents adverse effects of involuntary smoking on children and adults,
including cancer and cardiovascular diseases in adults, and adverse respira-
tory effects in both children and adults.”1 Involuntary smoking is the tobacco
smoke exposure of nonusers. Tobacco smoke is a complex mixture of more
than 4,000 substances, including respiratory irritants, toxins, and carcinogens.
The greatest contribution to the tobacco smoke exposure of children is from
their parents and caregivers.2 Addressing tobacco dependence in parents and
other caregivers is important for achieving and maintaining their children’s
respiratory health.
There is currently an epidemic of electronic nicotine delivery systems (ENDS)
use among middle and high school students, with rates of current electronic
cigarette use skyrocketing from 1.5% in 2011 to 27.5% in 2019 among high
school students in the United States.3,4 With the COVID-19 pandemic and
increase of age for sale of tobacco products to 21 years in 2020, current elec-
tronic cigarette use in high school students dipped to 19.6% in 2020 and 11.3%
in 2021; however, with the end of the pandemic lockdown, e-cigarette use
among high school students has started to rise again, with a rate of current
e-cigarette use among high school students reported as 14.1% in 2022.5,7 Use
of 2 or more different tobacco products is common among youth (11.3% in
2018).3 Survey data may underestimate true usage rates both because young
people may use different terms for the tobacco product than those used in
the surveys and because they may consider a positive response not socially
acceptable. As ENDS use becomes more popular, involuntary exposure to
ENDS emissions by nonusers is a growing concern. It is not uncommon for
high school students to report the fruity odor of ENDS emissions in their
school bathrooms.
1083

1084
Parents and caregivers who are tobacco dependent are an important source
of involuntary smoke and ENDS emission exposure, as well as important role
models for their children. It is important for pediatricians and pediatric pul-
monologists to address both prevention and treatment of tobacco and nicotine
dependence in their patients, parents, and caregivers. Pediatric patients should
be screened for tobacco product use and exposure. Anticipatory guidance to
prevent tobacco and nicotine product use initiation should start as soon as a
child is able to understand the concepts. Tobacco and nicotine dependence
most commonly start before the completion of adolescence.
Tobacco Products
Cigarettes
A cigarette is a tube-shaped roll of tobacco wrapped in thin paper. The most
commonly used tobacco product worldwide, cigarettes are commonly taxed at
a higher rate than other tobacco products. In the United States, most flavoring
of cigarettes is prohibited, with the significant exception of menthol. Menthol
decreases the natural harshness of tobacco smoke. Menthol cigarette smokers
are less likely to stop smoking compared to non-menthol cigarette smokers.8
Adolescents who initiate tobacco use with menthol cigarettes are more likely
to go on to become regular smokers.9
Innovations in cigarette design have increased their addictiveness and toxicity.
The tobacco industry has repeatedly misled the public about purported harm
reduction of innovative tobacco products. Flue-curing of the tobacco allowed
the smoke to be inhaled more deeply into the lungs. Filters reduced the large
particles but allowed the small particles that would penetrate deeply into the
lungs to pass. Addition of ammonia increased the amount of nicotine in the
free-base form, increasing its addictiveness. The Kent Micronite filter in
the 1950s, reported to have “proof of greatest health protection,” contained
asbestos.10,11 “Low tar,” “natural,” and “organic” cigarettes are no less deadly.12,13
Electronic Nicotine Delivery Systems

Electronic nicotine delivery systems are referred to by many terms, including
electronic cigarettes, e-cigarettes, vape pens, vapes, vaporizers, e-hookah,
and mechanical mods, as well as brand names such as JUUL and Puff Bar.
Some of these devices are marketed for use with substances of abuse other
than nicotine (eg, “favorite herb,” a euphemism for marijuana). Many popular
electronic cigarette products are optimized for stealth use—to enable the user
to discretely use the product in places (such as schools and airplanes) where
its use is prohibited. Stealth ENDS devices have been designed to resemble a
USB drive, writing pen, key fob, cell phone, candy container, hoodie zipper,
and even an asthma inhaler.14,15 ENDS are available in a wide variety of

1085
Chapter 61—Nicotine and Tobacco
youth-appealing flavors. Fruit-, candy-, mint-, and menthol-flavored ENDS

products are popular among adolescents.5
ENDS produce an aerosol for inhalation from a solution that typically con-
tains nicotine, propylene glycol, vegetable glycerin, and flavoring chemicals.
Propylene glycol and vegetable glycerin adversely impact cell viability in
cell culture assays in a dose-dependent manner.16 Many commonly used
flavoring agents have irritant and/or cytotoxic effects.17 Volatile organic
compounds, metallic nanoparticles (including nickel, tin, cadmium, and
lead), and tobacco-related carcinogens, including nitrosamines and poly-
cyclic aromatic hydrocarbons, have been identified in ENDS emissions.
Heating the liquid to create the aerosol generates additional toxicants
and carcinogens, including formaldehyde, acetaldehyde, and acrolein.18
The Centers for Disease Control and Prevention (CDC) reported a large series
of patients with severe lung injury and death from ENDS use (referred to as
electronic cigarette, or vaping, product use-associated lung injury [EVALI]),
with 2,807 cases of severe lung injury requiring hospitalization and 68 deaths
reported as of February 18, 2020. Although most of the cases reported “vaping”
of tetrahydrocannabinol (THC) containing products alone or in combination
with nicotine (with lung injury suspected to be from vitamin E acetate con-
taminating those products), 14% of the cases report exclusive use of nicotine-
containing products.19,20 There have been multiple published case reports and
case series of severe injuries from ENDS, including reports of burns and facial
and eye injuries from product explosions,21–23 acute nicotine acute poisoning
(from ingestion or dermal exposure),24 eosinophilic pneumonia,25,26 diffuse
alveolar hemorrhage,27 hypersensitivity pneumonitis,28 organizing pneumonia,29
lipoid pneumonia,30,31 and severe asthma.32 Population health studies have found
ENDS use to be associated with increased risk of cough, phlegm, bronchitis,
asthma, and emphysema.33,34 ENDS use is associated with increased risk for
myocardial infarction,35,36 with biologic plausibility supported by laboratory
studies that have found evidence of endothelial damage, DNA damage, and
oxidative stress from electronic cigarette aerosols, as well as increased athero-
sclerotic plaque in mice exposed to ENDS emission.37–39 Laboratory mice that
are chronically exposed to nicotine-containing electronic cigarette aerosols
develop changes in lung structure and function typical of emphysema.40
ENDS aerosols dampen innate immune responses and impair mucociliary
clearance.41 Murine models show ENDS emission exposure to be associated
with decreased defenses against bacterial and viral pathogens as well as
increased risk for lung cancer.42,43 Most smokers who use ENDS remain dual
users of ENDS and combustible tobacco products. This exposes the user to
both the toxins in combustible tobacco and additional toxins unique to ENDS.
Evidence from population health studies suggests higher rates of incident
respiratory disease, worse general health scores, and increased stroke risk in

1086
dual users compared to those using combustible cigarettes only.44–46 A 2019

European Respiratory Society task force report concluded that there is “no
evidence that electronic cigarettes are safer than tobacco in the long term.”47
Compared to nonusers, ENDS use among adolescent and young adult
nonsmokers is associated with greater rates of progression to combustible
tobacco smoking48 and progression from intermittent to regular combustible
tobacco use.49 Among adult smokers, electronic cigarette use is associated
with decreased rates of stopping combustible tobacco use.50,51 Among former
smokers, electronic cigarette use is associated with a greater rate of relapse
to combustible cigarette smoking.52 The World Health Organization (WHO)
advises, “Unlike the tried and tested nicotine and non-nicotine pharmaco-
therapies that are known to help people quit tobacco use, WHO does not
endorse electronic cigarettes as cessation aids.”53
The JUUL product has been aggressively promoted to young people. This
ENDS product is designed to look like a USB drive for a computer. A high
school student was quoted about JUUL in a 2018 news article as saying, “The
vapor cloud is so small and dissipates so quickly that teachers are usually none
the wiser.”54 JUUL’s advertising imagery in its first 6 months on the market
was patently youth oriented, including aggressive use of social media and
“influencers.” After JUUL claimed to have stopped social media promotion,
JUUL hashtags on Instagram surged.55,56 JUUL uses a nicotine salt (nicotine
benzoate) that does not have the aversive properties of free-base nicotine and
very rapidly goes to the brain after inhalation.57 The JUUL product uses a high
concentration of nicotine (59 mg/mL—higher than most other ENDS products
when it was introduced). Although all nicotine products are highly addictive,
the pro-ducts using nicotine salts in high concentration, such as JUUL, appear
to be particularly addictive.58 Since JUUL was introduced to the market in
2015, it surged to a 76% market share by December 2018 and became very
popular among youth.59,60 Reacting to the popularity of JUUL among youth, the
US Food & Drug Administration (FDA) Center for Tobacco Products took
action in January 2020 to ban flavors other than tobacco and menthol in
cartridge-based ENDS devices (such as JUUL); subsequent to that action,
JUUL market share dropped. Other ENDS products have stepped in to fill the
void. Discreet disposable ENDS devices using nicotine salts, high nicotine
concentrations, youth-appealing flavors, and youth-targeted online marketing
(such as Puff Bar) have become popular, overtaking JUUL in relative search
volume on Google by February 2020.61,62 The 2021 National Youth Tobacco
Survey reports that Puff Bar has become the most commonly used ENDS
product among middle and high school students.6 The adverse environmental
impact of disposable ENDS products is of increasing concern.
ENDS are considered “tobacco products” for regulatory purposes in the
United States. Several cities and states have banned sale of flavored ENDS

1087
products as a public health measure.63 The FDA Center for Tobacco Products
is mandated to conduct premarket reviews on tobacco products introduced to
the market after February 2007 and reject products if their introduction is not
appropriate for the protection of the public health.64 The FDA has begun pre-
market reviews and has authorized for marketing a high-nicotine electronic
cigarette product (Vuse Solo), although it has limited available flavors. Vuse
is the second-most popular electronic cigarette brand among middle and high
school students.6 The American Academy of Pediatrics (AAP) has expressed
significant concern that children will access these products, and the FDA’s
decision is a departure from policies in other countries that prohibit high-
nicotine electronic cigarette products. The AAP is also concerned that
the FDA is considering authorizing menthol flavors, which are popular
among youth.65
Heat-Not-Burn Tobacco
The IQOS brand of heat-not-burn tobacco product, marketed by Philip Morris
International, was authorized by the FDA for marketing in the United States
in 2019.66 This product heats a tobacco-filled stick sufficiently to generate an
aerosol but not to combust. The smoke released by IQOS contains elements
from pyrolysis and thermogenic degradation that are the same harmful con-
stituents of conventional tobacco cigarette smoke.67 There is no evidence to
demonstrate that heated tobacco products are less harmful than conventional
tobacco products. There is substantial concern that these products appeal to
young people. Analyses of 2019 National Youth Tobacco Survey data found
3% of US high school students reported having used heated tobacco prod-
ucts.68 Despite promises to the FDA not to market to young people, Philip
Morris International has been found to be doing so on social media.69,70
Hookah
A hookah (water pipe, also called narghile, argileh, shisha, hubble-bubble,
and goza) is used to smoke tobacco that is moist, shredded, mixed with
sweeteners such as honey or molasses, and often fruit or candy flavored.
Charcoal is used to heat the tobacco to generate the smoke, with the smoke
from the tobacco and charcoal combining to produce high levels of toxins,
carcinogens, and carbon monoxide.
Hookah smoking has many of the same health risks as cigarette smoking.
Inhaling the smoke through water lowers the temperature of the smoke but
does not reduce the concentration of toxins and carcinogens. Because of the
way a hookah is used, with prolonged sessions and inhaling deeply, a typical
hookah session involves inhaling much more smoke and tobacco-related
toxins than a typical smoker would inhale from a cigarette.71 Flavors,
misperception of safety, and social aspects of use increase the appeal
of the hookah for young people.

1088
Cigars and Little Cigars

What differentiates a cigar from a cigarette is that a cigar is wrapped in
tobacco leaf and a cigarette is wrapped in paper. In the United States, cigars
are not subject to the same level of taxes and restrictions on flavorings as cig-
arettes. Inexpensive fruit- and candy-flavored cigars, which appeal to young
people, are commonly marketed in the United States and are available in
many supermarkets, gas stations, and convenience stores.
Other Tobacco Products

Chewing tobacco is loose leaves, plugs, or twists of tobacco that are placed
between the cheek and gum. Snuff is finely ground tobacco. Moist snuff is
placed between gum and lower lip or cheek. Dry snuff can be sniffed. Snus is
similar to snuff but is usually not fermented. Youth-appealing fruit and candy
flavors are common. A former US Tobacco (now a subsidiary of Altria) sales
representative was quoted as saying, “Cherry Skoal is for somebody who
likes the taste of candy, if you know what I’m saying.”72
Bidis (or beedis), popular in South Asia, are tobacco (often with added flavors)
wrapped in a tendu leaf and tied with a string at one end. Kreteks are ciga-
rettes made with tobacco, cloves, and other flavors. Cloves contain eugenol,
whose local anesthetic effect allows deeper inhalation of the smoke.
Tobacco and Nicotine Initiation

Risk Factors for Initiation
Marketing
Marketing that is accessible and appeals to youth increases rates of tobacco
and ENDS initiation. Conversely, anti-tobacco media campaigns are effec-
tive in reducing tobacco product initiation. The 2014 US Surgeon General
Report concluded, “The evidence is sufficient to conclude that advertising
and promotional activities by the tobacco companies cause the onset and
continuation of smoking among adolescents and young adults” and “The
evidence is sufficient to conclude that mass media campaigns, comprehen-
sive community programs, and comprehensive statewide tobacco control
programs prevent initiation of tobacco use and reduce the prevalence of
tobacco use among youth and adults.”12 Tobacco marketing disproportionately
targets communities of color; a meta-analysis of 7 studies found 2.6 times
more smoking-related billboards in predominantly Black communities
compared to predominantly white communities.73
Exposure to point-of-sale marketing, such as in convenience stores, markets,
and gas stations, is associated with increased rates of smoking initiation
among youth.74,75 Therefore, marketing of tobacco products should be pro-
hibited in proximity to schools, playgrounds, sports facilities, and other areas
accessible to children.

1089
Cost matters when it comes to tobacco use. Low-priced products facilitate

tobacco use initiation. Increasing excise taxes on tobacco products reduces
both tobacco use and tobacco product initiation.76
Flavors
Most youth who are current tobacco smokers started smoking with a flavored
product.77 Perceptions of “fun” and having “great flavorings” and “fun tricks”
increase the appeal for electronic cigarettes among youth.78
Social Influences
Adolescents whose family and friends smoke are more likely to initiate
smoking and progress to regular smoking.79 Similarly, report of observation
of ENDS use at school is associated with increased risk for initiation of ENDS
use.80 Adolescents who perceive strong parental disapproval of smoking are
less likely to become smokers. Teens who attend religious activities and
those who feel it is important to contribute to their community are less
likely to smoke.81–83
Lesbian, gay, bisexual, transgender, and questioning youth, as well as Native
American youth, have significantly higher rates of smoking.84,85 Lower levels
of educational attainment and lower family income are associated with greater
rates of cigarette smoking.12,84,86 ENDS use impacts adolescents of all socio-
economic strata. Adolescents who begin using ENDS, as well as those who
progress to use of combustible tobacco, often do not have the socioeconomic
and psychosocial risk factors (rebelliousness, lack of parental support, willing-
ness to smoke) as those who begin tobacco product use with combustible
tobacco products.87,88
Emotional/Mental Health
Mental health disorders are a risk factor for smoking initiation and current
smoking among adolescents.89,90 Teens with mental health problems are more
likely to become tobacco and/or ENDS users.91,92 Psychiatric comorbidities
and other substance use are common among adolescents who are dependent
on tobacco.
Preventing Initiation of Nicotine and Tobacco Use

Nicotine and tobacco dependence does not occur if use is not initiated.
Opportunities for intervention to prevent nicotine and tobacco use initiation
are present for both individual clinicians and public policy decision makers
and advocates.
Clinician Interventions
Counseling from a health care provider reduces the risk of smoking initiation.93
Messages should be clear, personally relevant, and age appropriate. The AAP
recommends that anticipatory guidance should start as early as children are
developmentally ready, generally around 5 years of age.94 Ask children and
adolescents to identify their own reasons for being tobacco free and to make a

1090
commitment to be tobacco free. The clinician can help the young person to
expand on those reasons. Messages that may resonate include the effects of
tobacco and nicotine product use on appearance, breath, and sports perfor-
mance; how much money they would have to spend; and how the tobacco
industry deceives them. Encourage the child to value good health. Correct
misperceptions about how fast tobacco dependence develops and the severity of
tobacco addiction. With ENDS use rapidly rising in popularity among adoles-
cents, messages should also include a focus on ENDS. Teens may incorrectly
believe that ENDS are safe or that nicotine is not highly addictive.95 Help them
develop skills to resist peer pressure to use tobacco and nicotine products.
Counsel parents on signs that their child may be using ENDS (Table 61-1).
Table 61-1. Signs of Vaping (Electronic Nicotine Delivery Systems Use) That a Parent
Should Look For
Sign Guidance for Parents
Equipment You may find devices that look like flash (USB) drives, e-liquid bottles,
pods/cartridges (that contain the liquid used in electronic nicotine
delivery systems [ENDS] devices) or product packaging.
Online purchases/ Look for purchases made online and charged to your credit card, and
packages in the mail unexpected packages that arrive in the mail.
Scent The scent of flavors, such as bubble gum, chocolate cake, fruit, candy,
mint, or menthol, might be from a vaping product.
Increased thirst/ Some of the chemicals used in ENDS dry out the mouth and nose. This
nosebleeds/interest may lead to drinking more liquids, having nosebleeds, and/or a
in stronger flavors desire for stronger flavors (when the mouth is dry, flavor perception
is reduced).
Vaping slang You may see vaping slang in text messages such as “atty” for an
atomizer, “VG” for vegetable glycerin found in the liquids used in
ENDS device or “sauce” referring to the liquids used in ENDS
devices. Getting “nicked” refers to the euphoria experienced with
high doses of nicotine and feeling “nic sick” refers to heart
palpitations, nausea/vomiting or light-headedness associated with
the overuse of nicotine vapes.
Social media and Kids often brag about their vaping exploits on social media. Look for
online references pictures or references on their social media accounts. Take note of
popular vaping terms in their online searches.
Appearance and Vaping nicotine may lead to anxiety, irritability, difficulty concentrating,
behavior changes and loss of appetite.
Physical symptoms Physical side effects of vaping may include trouble breathing,
headaches, cough, dizziness, sore throat, and/or chest pain.
Adapted from Partnership to End Addiction (2018). Vaping: What Families Need to Know to Help Protect Children,
Teens and Young Adults. See original at: https://drugfree.org/wp-content/uploads/2018/11/What-You-Need-to-
Know-and-How-to-Talk-to-Your-Kids-About-Vaping-Guide-Partnership-for-Drug-Free-Kids.pdf.

1091
Public Policy Interventions

Pediatric health care providers also have important responsibilities to advocate
for public policies to eliminate children’s tobacco smoke and ENDS emission
exposure and to protect youth from becoming tobacco dependent. The AAP
recommends the following evidence-based public policies be implemented96:
X Prohibit all tobacco product advertising and promotion in forms that are
accessible to children and youth.
X Ban point-of-sale tobacco product advertising and product placement that
can be viewed by children, including in proximity to schools, playgrounds,
sports facilities, and other areas where children congregate.
X Restrict depictions of tobacco products in movies and other media that can
be viewed by youth. Tobacco control programs should change the image of
tobacco by telling the truth about tobacco and ENDS.
X Increase the price of all tobacco products to reduce youth tobacco-use
initiation.
X Increase the minimum age for sale of tobacco products to 21 years.
Enforce regulations on age for sale of tobacco. While the age for sale of
tobacco was increased to 21 years in the United States. on December 20,
2019, most other countries still have 18 years as the legal age for sale.
Age-for-sale regulations are not consistently enforced.
X Prohibit use of all flavoring agents, including menthol in all tobacco and
ENDS products.
X Ensure adequate funding of tobacco control programs.
X Comprehensive smoking bans should be enacted and include any tobacco
product that produces an emission. Prohibit smoking in workplaces, res-
taurants, bars, and other public venues. Prohibit smoking in or near schools,
parks, playgrounds, sports facilities, entertainment venues, and other areas
where young persons congregate. Prohibit smoking in multiunit housing.
Make tobacco-dependence treatment resources available to people who
are dependent on tobacco products.
Tobacco and Nicotine Dependence

Development of Nicotine Dependence
Nicotine dependence most commonly starts in the pediatric years; close to
90% of adult smokers started smoking before the age of 18 years.12 The rapidly
developing adolescent brain is particularly susceptible to nicotine; nicotinic
acetylcholine receptors regulate critical facets of brain maturation during

1092
adolescence.97 Symptoms of nicotine dependence can develop rapidly after

smoking initiation and are present even among low-level and intermittent
smokers. Progression from intermittent use to daily use is driven by progres-
sion in number and severity of nicotine dependence symptoms and shortening
of latency to withdrawal.98,99 Inhaled nicotine moves quickly via the arterial
circulation from the lungs to the brain, where it binds to nicotinic cholinergic
receptors, which release a variety of neurotransmitters, including dopamine.
The dopamine is released in the mesolimbic area, the corpus striatum, and
the frontal cortex. The stimulation of dopamine release is critical for the plea-
surable experience and reinforcing effects of nicotine use. Neuroadaptation
(tolerance) develops, leading to the craving and withdrawal symptoms
associated with tobacco dependence.100
DiFranza et al describe severity of compulsion to smoke as wanting, craving,
and needing. Wanting is a mild desire to smoke that is short-lived and easily
ignored. Craving is a stronger urge to smoke that is more persistent and
difficult to ignore. Needing is an intense and urgent desire to smoke that
is unpleasant and unremitting.101
Nicotine withdrawal is not just craving or compulsion to use tobacco products.
Withdrawal symptoms include anxiety, depression, irritability, frustration,
anger, insomnia, anhedonia, difficulty concentrating, increased appetite,
constipation, nausea, and tremors.102 Nicotine withdrawal can lead to mood
disturbances of similar intensity to those seen in psychiatric outpatients.103
Assessment of Nicotine Dependence

Tobacco dependence in adults can be assessed with the Fagerström Test for
Nicotine Dependence. Adolescent-specific instruments include the Modified
Fagerström Tolerance Questionnaire and the Hooked on Nicotine Check-
list.104–106 As non-cigarette tobacco products become increasingly popular,
cigarette-based assessments of nicotine dependence become problematic. A
modification to the Fagerström Test for Nicotine Dependence for electronic
cigarettes has been proposed.107
Treatment of Tobacco and Nicotine Dependence

Treatment of tobacco and nicotine dependence involves suppression of nicotine
withdrawal symptoms with medications and learning skills to manage or cope
with nicotine withdrawal symptoms. The most effective methods for tobacco-
dependence treatment for adults include both counseling and pharmacotherapy.
Patients with more severe addiction or less ability to cope with withdrawal

1093
symptoms (such as patients with psychiatric comorbidities) often need more

intensive pharmacotherapy to better control the withdrawal symptoms.
Non-pharmacologic Approaches to Tobacco Dependence
Commonly recommended counseling approaches are described in Box 61-1.
Counseling approaches start with helping the patient or parent to appreciate
the importance of stopping tobacco use and then building confidence in their
ability to stop. To build confidence in ability to stop tobacco use, help the
patient identify nicotine withdrawal symptoms, develop skills to cope with
nicotine withdrawal symptoms, develop strategies to anticipate and manage
difficult periods (such as times or situations at risk for smoking), and organize
needed social supports. Counseling approaches include counseling about the
ability of pharmacotherapy to control withdrawal or reduce it to a manageable
level. If the patient or parent has had prior experience in stopping smoking,
build on that as a success that provided important insight and experience.
Telephone “quit lines” (such as 1-800-QUIT-NOW) and online support
(see smokefree.gov and quitSTART app) can help adults and teenagers
with strategies, motivational messages, and support. (See Box 61-2.)
Box 61‑1
Tobacco-Dependence Counseling Approaches
Counseling to Facilitate Smoking Not Ready to Stop Smoking: 5 Rs
Cessation: 6 As Relevance of smoking cessation.
Anticipate risk of tobacco use. Risks of tobacco use.
Ask about tobacco use and exposure Rewards of smoking cessation.
history. Roadblocks to smoking cessation.
Advise about the harm of active Repetition at every office visit
smoking and secondhand exposure. follow-up.
Assess readiness to change, and
severity of, nicotine dependence. Facilitate Behavior Change: ASK NOW
Assist in developing a tobacco- Assess the health behavior.
dependence treatment plan. Determine the Stage of change.
Arrange follow-up. Keep in mind Key facts.
Jointly Negotiate an action plan.
Observe outcome in follow-up.
Work toward the next stage.

1094
Box 61‑2
Telephone and Online Tobacco-Dependence Resources
1-800-QUIT-NOW: Connects caller to their state quitline for free telephone
counseling.
Smokefree.gov: Hosts the National Cancer Institute’s tobacco prevention and
cessation resources with support, tools, and advice for stopping smoking.
Teen.Smokefree.gov: Hosts the National Cancer Institute’s tobacco prevention and
cessation resources for teenagers, including the following:
SmokefreeTXT: A mobile text messaging program from the National Cancer
Institute that provides tips, advice, and encouragement for stopping smoking
quitSTART: A smartphone-based app from the National Cancer Institute made
for teens that provides tailored tips, inspiration, and challenges to help
smokers become smoke free.
1-877-44U-QUIT: Telephone smoking cessation support from National Cancer
Institute counselors. Support is available in English and Spanish.
A Smoking Prevention Interactive Experience (https://aspire.mdanderson.org/
aspirestudent): An internet-based program from MD Anderson Cancer Center that
delivers an individually tailored interactive smoking prevention and cessation
curriculum that can be used by individuals or in the school setting.
Smoke Out: Tobacco Pirates: A smartphone- or tablet-based game designed in
consultation with the American College of Chest Physicians Tobacco Dependence
Treatment Toolkit Committee to help people to learn about tobacco addiction and
its treatment, and become more conscious of their tobacco use as they defeat the
tobacco bosses to rule the seven seas. It is free for download from Google Play
and the Apple App Store.
Partnership to End Addiction: How to Talk to Your Child About Vaping:
A motivational interviewing–based guide to assist parents in counseling
their adolescent child about ENDS (https://drugfree.org/article/how-to-talk-with-
your-kids-about-vaping/).
The American Academy of Pediatrics has collected resources for Behavioral
Tobacco and ENDS Cessation Supports for Youth and Young Adults at
https://www.aap.org/en/patient-care/tobacco-control-and-prevention/
youth-tobacco-cessation/behavioral-cessation-supports-for-youth/
Pharmacotherapy of Tobacco and Nicotine Dependence

The FDA-approved medications for the treatment of tobacco dependence in
adults 18 years and older include the prescription medications varenicline,
bupropion, nicotine nasal spray, nicotine oral inhaler, and over-the-counter
medications (nicotine patch, nicotine gum, and nicotine lozenge). Varenicline
is the most effective single medication for tobacco dependence treatment.108
Combination of varenicline with nicotine replacement therapy is more effec-
tive than either alone.109 The combination of nicotine patch plus nicotine gum
has greater efficacy than either treatment alone.110 Sustained smoking

1095
cessation is improved by extended courses (more than 12 weeks) of pharmaco-

therapy, with supporting evidence best for varenicline.111
Varenicline, bupropion, and nicotine patch are long-acting medications.
Nicotine gum, nicotine lozenge, nicotine oral inhaler, and nicotine nasal
spray are shorter-acting medications. As such, they can be combined with
the longer-acting medications to use “as needed” for withdrawal symptoms.
They are not as rapid acting as a cigarette. Nicotine from a cigarette achieves
peak levels in the brain in as little as 8 seconds and can saturate close to 90%
of the nicotine receptors. The nicotine is absorbed through oral mucosae for
the nicotine gum, lozenge, and oral inhaler, and thus takes about 30 minutes
to reach peak levels. The nicotine nasal spray has a more rapid time to peak
(about 8 minutes) but is still not as rapid as a cigarette. It is likely that the
slower onset of action is what makes these products effective for treating
tobacco dependence.
Which medications to choose will depend on the severity of the patient’s
nicotine dependence, ability or motivation to cope with withdrawal symp-
toms, and medication that the patient is willing to accept. Parents may not have
adequate health insurance or may have limited ability to pay for medications,
in which case over-the-counter nicotine replacement therapy (nicotine patch,
nicotine gum, and/or nicotine lozenge) can be recommended. If an individual
is ready to reduce but not stop tobacco product use within the next month, use
of nicotine patch and/or varenicline can help the person reduce smoking and
get ready to stop.112,113 Electronic cigarettes should never be recommended
because of substantial safety and efficacy concerns.
Nausea is common with varenicline and usually improves or resolves with
continued use. Bupropion can lower seizure threshold; having a seizure dis-
order is considered a relative contraindication. Vivid dreams or nightmares
are common with use of the nicotine patch and can be managed by removing
the patch before going to sleep. Swallowed nicotine from the gum or lozenge
can cause nausea or hiccups; this can be managed by chewing the gum a
little to release the bitter-tasting nicotine, then parking it between the cheek
and gums and chewing a little again when the taste goes away. The nicotine
lozenge can be simply parked between the cheek and gums rather than being
sucked on like a candy; this allows the nicotine to be absorbed through the
oral mucosae and not swallowed. Varenicline, bupropion, and nicotine patch
do not increase risk for suicide, suicidal ideation, or other psychiatric comor-
bidities over placebo.108 Inadequately controlled nicotine withdrawal can
lead to psychiatric symptoms.103
On follow-up, the health care provider should assess both tobacco product
use and control of nicotine-withdrawal symptoms. If the patient is not using
tobacco products and withdrawal is well controlled, medications for tobacco-

1096
dependence treatment can be stepped down. If withdrawal is not well con-

trolled or the patient is using tobacco products, consider whether medications
need to be stepped up. Use of pharmacotherapy may need to extend beyond
the time frames recommended on package inserts.
Tobacco-Dependence Treatment in Adolescents
Tobacco-dependence treatment in adolescents can be challenging. Counsel-
ing strategies include reaching an agreement on the importance of stopping
tobacco and nicotine use and building confidence in the adolescent’s ability
to stop. For the adolescent to invest in making a behavior change, belief in
the importance of the change and having confidence in being able to accom-
plish it are key building blocks. Helping the adolescent explore the pros and
cons can help them consider change by highlighting discrepancies between
their values and their current behavior. To build confidence, review lessons
learned from previous attempts to stop smoking, anticipate challenges, and
plan coping strategies. Teens may need assistance in developing refusal
skills and managing peer pressure.114 Provide concrete and readily accessible
support and resources such as stop smoking support offered by telephone,
text message, smartphone app, or the internet (see Box 61-2) and/or referral
to local community or school-based resources (if available). Multi-session,
school-based group interventions, including Project EX and Not On Tobacco,
help adolescents to stop smoking. Cessation rates in these programs are greater
for those with mild nicotine dependence compared with those with more
severe nicotine dependence.115–117
In contrast to research in adults with tobacco dependence, the literature on
pharmacotherapy of tobacco dependence in adolescents is limited. Achieving
adherence to therapy is challenging, and relapse after cessation of medication
is common. Poorly controlled nicotine withdrawal has been associated with
lapses of smoking in adolescents on tobacco-dependence treatment.118 A cli-
nical trial among adolescents with moderate to severe tobacco dependence
who were motivated to stop smoking found that use of nicotine patches com-
bined with cognitive behavioral therapy improved smoking cessation rates at
3 months after the 12-week intervention concluded (20.6% vs 5%, P = .06).119
A study of bupropion 150 mg twice a day given for 6 weeks demonstrated
benefit only during the active treatment period (29% vs 16% abstinence at
6 weeks, P = .02); there was not a sustained benefit compared to the control
group after bupropion was discontinued.120 A 12-week clinical trial of vareni-
cline vs placebo in adolescents aged 14 to 21 years with tobacco dependence
was limited by large loss to follow-up (55% of varenicline group, 39% of
placebo group lost to follow-up). The study found increased cotinine-confirmed
tobacco abstinence with varenicline during the trial; however, there was no

1097
between-group difference by the end of treatment. Importantly, there were no

medication-related serious adverse events in either the varenicline or placebo
group; the rates of non-severe adverse events were not significantly different.121
Acknowledging the low quality of the evidence in adolescents, the AAP
recommends that tobacco-dependence pharmacotherapy can be considered
as an option for adolescents with moderate to severe tobacco dependence
who want to stop tobacco products.94 There is no biological or cognitive
rationale to have age 18 years as the minimum for offering pharmacotherapy
of tobacco dependence. Treatment should be appropriate to the adolescent’s
level of tobacco dependence, readiness to change, and treatments they are
ready to accept.94 Counseling should address the behavioral, social, and
motivational factors that contribute to continued tobacco product use
in adolescents. Keep in mind that other substance use may complicate
tobacco-dependence treatment.
For teens who are not ready to stop tobacco use, focus on the “5 Rs”:
Relevance, Risks, Rewards, Roadblocks, Repetition (see Box 61-1).110
Give messages that are age appropriate and personally relevant.
Impact of Exposure on the Non-user

Involuntary Tobacco Smoke and ENDS Emission Exposure
The harms of tobacco smoke and ENDS are not restricted to the user. Involun-
tary exposure to tobacco smoke and ENDS emissions includes secondhand
exposure (from breathing in the smoke and aerosols generated by the device
and/or exhaled by the user) and thirdhand exposure (from the toxins and
carcinogens absorbed into walls, furniture, carpeting, etc, and exposing the
nonuser by either dermal absorption, ingestion, or off-gassing and inhalation).
Although research on the harms of involuntary exposure to ENDS emissions
is limited, we do know that exposure to ENDS product emissions leads to
increased levels of nicotine, tobacco-related carcinogens, and exposure to
respiratory irritant chemicals in the nonuser.122,123
Children living in rented homes are more than twice as likely to be exposed
to tobacco smoke compared to children who live in homes that are owned.124
Smoking in multiunit housing is an important source of involuntary tobacco
smoke exposure among nonsmokers.125 In July 2018, the US Department
of Housing and Urban Development (HUD) implemented a rule prohibiting
the use of tobacco in, and within 25 feet of, HUD housing. To ensure equity,
as part of implementation of smoke-free multiunit housing policies, it is
important to have tobacco dependence treatment resources available
to the residents.

1098
The National Health and Nutrition Examination Survey (NHANES) data show
that non-Hispanic Black children are 1.85 times more likely to have evidence
of tobacco smoke exposure than non-Hispanic white children.124 A survey of
children in a Medicaid managed care program serving a diverse low-income
population in southeast Texas found that children who self-identified as white
were more likely to have a smoker in the home compared to other ethnic
groups.126 These findings, which may appear contradictory on the surface,
suggest that the National Health and Nutrition Examination Survey finding of
increased tobacco smoke exposure in children of color reflects economic
disparities rather than a racial/ethnic characteristic.
Tobacco Use by Parents

Because a parent’s tobacco product use impacts their child’s health, it is
appropriate for the child’s health care provider to assess, counsel, and either
recommend or prescribe tobacco dependence treatment for the parents. Most
parents who are tobacco dependent would accept treatment or referral from
their child’s health care provider.127 With appropriate assessment, counseling,
and documentation, it is appropriate for pediatric health care providers to
prescribe medication for parents to treat their tobacco dependence.94
Prenatal Effects of Maternal Active and Involuntary

Nicotine and Tobacco Exposure
Tobacco and nicotine harms children from conception forward. Nicotine,
carbon monoxide, and other tobacco-related toxins readily cross the placenta.
Given the developmental processes in progress, fetuses as well as young chil-
dren are at greater risk than adults. Maternal smoking as well as involuntary
tobacco smoke exposure increases risk for premature birth and decreases birth
weight, with dose-response effects demonstrated. Maternal smoking, oral
tobacco use, and tobacco smoke exposure increase risk of stillbirth. Maternal
smoking is associated with increased risk of placental complications,
including placental abruption and placenta previa.128–132
Maternal smoking increases a child’s risk of wheezing illnesses, including
bronchiolitis and asthma. In utero exposure impacts lung development, with
laboratory animal models demonstrating causation by impact of nicotine on
alpha-7 nicotinic receptors on lung development.133
Maternal smoking is associated with increased risk of orofacial clefts and
has possible associations with congenital heart defects, particularly septal
and right-sided obstructive defects.1 Association between in utero smoking
and decreased fetal head circumference as well as later development of

1099
attention deficit disorder and decreased academic performance have

been demonstrated.134–136
Sudden Infant Death Syndrome
Risk of sudden infant death syndrome is increased by both active and second-
hand maternal smoking during pregnancy, with reduced arousal responses
and reduced recovery from hypoxic challenge as likely mechanisms to
account for this risk.137,138 Smoking during pregnancy causes an estimated
1,015 infant deaths per year in the United States.12
Respiratory Infections
Infants and children with parents who smoke have an increased risk of lower
respiratory tract illness, including bronchiolitis, bronchitis, and pneumonia.1
Respiratory Symptoms
Respiratory symptoms, including cough, phlegm, and wheeze, are more
common in the children of smokers. The greatest impact is at younger ages
and if both parents smoke.1
Asthma and Other Lung Diseases
Tobacco smoke exposure is associated with increased asthma prevalence and
severity, worse asthma control, increased bronchial hyperresponsiveness,
increased risk of requiring emergency department care, and decreased
corticosteroid responsiveness.139,140 Tobacco smoke exposure accelerates
decline in lung function in children with chronic pulmonary problems
such as cystic fibrosis.141
Otitis Media
Tobacco smoke exposure increases risk of otitis media1 and decreases
resolution of chronic otitis media with effusion.142
Dental Caries
Parental smoking history and elevated cotinine levels (a biomarker of
tobacco smoke exposure) are associated with increased rates of caries in
deciduous teeth.143,144
Cancer Risk
Tobacco smoke exposure increases risk of childhood cancers. House dust
samples in homes of smokers can contain carcinogens at levels high enough
to increase the risk of cancer.145 Toddlers commonly explore by placing
objects in the mouth, increasing their level of exposure. Tobacco-specific
carcinogens have been detected in the blood of children who have a tobacco
smoker in the home.146 Increased cancer risk in children whose parents

1100
Box 61‑3
Screening for Secondhand Smoke and Electronic Nicotine Delivery Systems
Emission Exposure in Pediatric Practice
Questions to Ask
1. Does anyone who lives with (name of child) smoke or vape?
If yes: Does (person) smoke or vape inside of the home or car?
2. Does anyone who provides care for (name of child) smoke or vape?
3. Does (name of child) visit places where people smoke or vape?
4. Does anyone in the home use other tobacco products such as hookah,
IQOS (heat not burn), or dip (chewing tobacco)?
smoke has been demonstrated, with findings documenting increased risk

for lymphoma, acute lymphocytic leukemia, and brain cancer.147,148
Cardiovascular Risk
Tobacco smoke exposure causes coronary heart disease and strokes in adults.1,12
Tobacco smoke exposure has been shown to lead to preclinical findings of
atherosclerosis in adolescents.149
Reducing Tobacco Smoke and ENDS Emission Exposure

Pediatric clinicians should routinely ask about a child’s tobacco smoke and
ENDS emission exposure (Box 61-3). Ask if a smoker or ENDS user lives
in the child’s home, cares for the child, or is visited on a regular basis.
The best way to eliminate a child’s tobacco smoke and ENDS emission expo-
sure is for those individuals close to the child to be nonsmokers and non–
ENDS users. If the source of tobacco smoke or ENDS emission exposure
cannot be eliminated, advise the parents to keep the home and car strictly
smoke and ENDS free. Smoking should be kept well away from doors,
windows, and any area where children are playing. Use of a high-efficiency
particulate air (HEPA) filter in the home may provide some benefit if sources
of smoke exposure cannot be eliminated.150 Advise the family to stay away
from places where people smoke or use ENDS, if possible. Advocate for
smoke-free and ENDS-free communities.

1101
key points
} Tobacco dependence is one of the most important preventable causes of
premature death and disability.
} Tobacco dependence is a pediatric disease. The vast majority of tobacco and
nicotine dependence starts in adolescence.
} Electronic nicotine delivery systems (electronic cigarettes, others) have
substantial adverse health effects and are addicting a new generation to
nicotine and tobacco.
} Pediatric health care providers should take an active role in addressing tobacco
smoke exposure and smoking prevention through clinical practice and
advocacy efforts.
} The incidence of tobacco and nicotine dependence among youth is increased
by tobacco industry marketing efforts; availability of flavored products,
including mint and menthol; parent and peer influences and role models;
and the presence of psychiatric comorbidities.
} Ask about tobacco and nicotine product use and exposure. Anticipatory
guidance to prevent tobacco and nicotine product use initiation should start
as soon as a child is able to understand the concepts.
} Pediatric health care providers should assist both patients and parents in
stopping tobacco product use, including prescribing or recommending
pharmacotherapy for tobacco dependence.
} Pediatric health care providers need to be advocates for legislation and
community action to reduce the incidence of tobacco dependence and reduce
the risk for involuntary tobacco smoke exposure, both locally and worldwide.
Related American Academy of Pediatrics Policy

Farber HJ, Groner J, Walley S, et al; Section on Tobacco Control. Protecting
children from tobacco, nicotine, and tobacco smoke. Pediatrics.
2015;136(5):e1439–e1467 PMID: 26504135 doi: 10.1542/peds.2015-3110
Farber HJ, Nelson KE, Groner JA, Walley SC; Section on Tobacco Control.
Public policy to protect children from tobacco, nicotine, and tobacco smoke.
Pediatrics. 2015;136(5):998–1007 PMID: 26504133
doi: 10.1542/peds.2015-3110
Farber HJ, Walley SC, Groner JA, Nelson KE; Section on Tobacco Control.
Clinical practice policy to protect children from tobacco, nicotine, and
tobacco smoke. Pediatrics. 2015;136(5):1008–1017 PMID: 26504137
doi: 10.1542/peds.2015-3108
Jenssen BP, Walley SC, Boykan R, et al; Section on Nicotine and Tobacco
Prevention and Treatment; Committee on Substance Use and Prevention.
Protecting children and adolescents from tobacco and nicotine. Pediatrics.
2023;151(5):e2023061804 PMID: 37066685 doi: 10.1542/peds.2023-061804

1102
Jenssen BP, Walley SC, Groner JA, et al; Section on Tobacco Control.
E-cigarettes and similar devices. Pediatrics. 2019;143(2):e20183652
PMID: 30835247 doi: 10.1542/peds.2018-3652
Moon RY, Carlin RF, Hand I; Task Force on Sudden Infant Death Syndrome,
Committee on Fetus and Newborn. Sleep-related infant deaths: updated 2022
recommendations for reducing infant deaths in the sleep environment. Pediat-
rics. 2022;150(1):e2022057990 PMID: 35726558 doi: 10.1542/peds.2022-
057990
Siqueira LM, Ryan SA, Gonzalez PK, Patrick SW, Quigley J, Walker LR;
Committee on Substance Use and Prevention. Nicotine and tobacco as
substances of abuse in children and adolescents. Pediatrics.
2017;139(1):e20163436 PMID: 27994114 doi: 10.1542/peds.2016-3436
Other Resources
American Academy of Pediatrics Julius B. Richmond Center of Excellence.
https://www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/
Richmond-Center/Pages/default.aspx. The AAP Richmond Center is dedicated
to the elimination of children’s exposure to tobacco and secondhand smoke.
The AAP Richmond Center provides the education, training, and tools needed
to effectively intervene to protect children from the harmful effects of tobacco
and secondhand smoke.
American College of Chest Physicians Tobacco Dependence Treatment
Toolkit. https://foundation.chestnet.org/wp-content/uploads/2021/06/
Tobacco_Dependence_Treatment_Toolkit_CHEST_Foundation.pdf. The
toolkit provides practical strategies for helping patients stop tobacco product
use, including use of pharmacotherapy, to suppress the withdrawal and
overcome the reinforcing effects of nicotine, as well as strategies for coping
with the nicotine withdrawal symptoms.
References
1. US Department of Health and Human Services. The Health Consequences of Involuntary
Exposure to Tobacco Smoke: A Report of the Surgeon General. US Department of Health and
Human Services, Centers for Disease Control and Prevention, Coordinating Center for Health
Promotion, National Center for Chronic Disease Prevention and Health Promotion, Office on
Smoking and Health; 2006
2. Farber HJ, Knowles SB, Brown NL, et al. Secondhand tobacco smoke in children with asthma:
sources of and parental perceptions about exposure in children and parental readiness to change.
Chest. 2008;133(6):1367–1374 PMID: 18339788 doi: 10.1378/chest.07-2369
3. Gentzke AS, Creamer M, Cullen KA, et al. Vital signs: tobacco product use among middle
and high school students - United States, 2011-2018. MMWR Morb Mortal Wkly Rep.
2019;68(6):157–164 PMID: 30763302 doi: 10.15585/mmwr.mm6806e1
4. Wang TW, Gentzke AS, Creamer MR, et al. Tobacco product Use and associated factors among
middle and high school students - United States, 2019. MMWR Surveill Summ. 2019;68(12):1–22
PMID: 31805035 doi: 10.15585/mmwr.ss6812a1
5. Wang TW, Neff LJ, Park-Lee E, Ren C, Cullen KA, King BA. E-cigarette use among middle
and high school students - United States, 2020. MMWR Morb Mortal Wkly Rep.
2020;69(37):1310–1312 PMID: 32941408 doi: 10.15585/mmwr.mm6937e1

1103
6. Park-Lee E, Ren C, Sawdey MD, et al. Notes from the field: e-cigarette use among middle
and high school students - National Youth Tobacco Survey, United States, 2021. MMWR Morb
Mortal Wkly Rep. 2021;70(39):1387–1389 PMID: 34591834 doi: 10.15585/mmwr.mm7039a4
7. Park-Lee E, Ren C, Cooper M, Cornelius M, Jamal A, Cullen KA. Tobacco product use among
middle and high school students - United States, 2022. MMWR Morb Mortal Wkly Rep.
2022;71(45):1429 -1435 PMID: 36355596 doi: 10.15585/mmwr.mm7145a1
8. Mills SD, Hao Y, Ribisl KM, Wiesen CA, Hassmiller Lich K. The relationship between menthol
cigarette use, smoking cessation, and relapse: findings from waves 1 to 4 of the Population
Assessment of Tobacco and Health Study. Nicotine Tob Res. 2021;23(6):966–975
PMID: 33063826 doi: 10.1093/ntr/ntaa212
9. Nonnemaker J, Hersey J, Homsi G, Busey A, Allen J, Vallone D. Initiation with menthol
cigarettes and youth smoking uptake. Addiction. 2013;108(1):171–178 PMID: 22862154
doi: 10.1111/j.1360-0443.2012.04045.x
10. Longo WE, Rigler MW, Slade J. Crocidolite asbestos fibers in smoke from original Kent
cigarettes. Cancer Res. 1995;55(11):2232–2235 PMID: 7757969
11. 10. P. Lorillard Co. KENT Magazine Advertisement. The Saturday Evening Post. May 30, 1953.
https://csts.ua.edu/micronite/. Accessed March 9, 2022
12. U.S. Department of Health and Human Services. The Health Consequences of Smoking—
50 Years of Progress. A Report of the Surgeon General. U.S. Department of Health and Human
Services, Centers for Disease Control and Prevention, National Center for Chronic Disease
Prevention and Health Promotion, Office on Smoking and Health; 2014
13. Proctor RN. Golden Holocaust: Origins of the Cigarette Catastrophe and the Case for Abolition.
University of California Press; 2011
14. Yingst JM, Lester C, Veldheer S, Allen SI, Du P, Foulds J. E-cigarette users commonly stealth
vape in places where e-cigarette use is prohibited. Tob Control. 2019;28(5):493–497
PMID: 30097510 doi: 10.1136/tobaccocontrol-2018-054432
15. Ramamurthi D, Chau C, Jackler RK. JUUL and other stealth vaporisers: hiding the habit from
parents and teachers. Tob Control. 2018; tobaccocontrol-2018-054455.
16. Sassano MF, Davis ES, Keating JE, et al. Evaluation of e-liquid toxicity using an open-source
high-throughput screening assay. PLoS Biol. 2018;16(3):e2003904 PMID: 29584716
doi: 10.1371/journal.pbio.2003904
17. Fowles J, DiBartolomeis M. Toxicological Concerns from Inhaled Food Flavorings Found in
Electronic (E-) Cigarette Aerosols: A Report from the Environmental Health Investigations
Branch. Exposure Assessment Section, Environmental Health Investigations Branch, California
Department of Public Health. January 2017. https://www.cdph.ca.gov/Programs/CCDPHP
/DCDIC/CTCB/CDPH%20Document%20Library/Policy/FlavoredTobaccoAndMenthol
/Eliquid%20Flavoring%20Paper_Final%2008_06_18.pdf. Accessed May 2, 2022
18. Kosmider L, Sobczak A, Fik M, et al. Carbonyl compounds in electronic cigarette vapors:
effects of nicotine solvent and battery output voltage. Nicotine Tob Res. 2014;16(10):1319–1326
PMID: 24832759 doi: 10.1093/ntr/ntu078
19. Clinical Guidance for Health Care Providers Evaluating Patients with Lung Injury Linked to Use
of E-cigarette, or Vaping, Products. CDC Newsroom October 11, 2019. https://www.cdc.gov
/media/releases/2019/p1011-guidance-health-lung-injury.html. Accessed March 9, 2022
20. CDC, States Update Number of Cases of Hospitalized E-cigarette, or Vaping, Product Use
Associated Lung Injury (EVALI). CDC Newsroom. Centers for Disease Control and Prevention.
December 5, 2019. https://www.cdc.gov/media/releases/2019/s1206-e-cigarette-vaping-product-
hospitalized-update.html. Accessed March 9, 2022
21. Rossheim ME, Livingston MD, Soule EK, Zeraye HA, Thombs DL. Electronic cigarette
explosion and burn injuries, US Emergency Departments 2015-2017. Tob Control.
2019;28(4):472–474 PMID: 30219795 doi: 10.1136/tobaccocontrol-2018-054518
22. Katz MG, Russell KW. Injury from e-cigarette explosion. N Engl J Med. 2019;380(25):2460
PMID: 31216401 doi: 10.1056/NEJMicm1813769
23. Khairudin MN, Mohd Zahidin AZ, Bastion ML. Front to back ocular injury from a
vaping-related explosion. BMJ Case Rep. 2016;2016:bcr2016214964 PMID: 27048399
doi: 10.1136/bcr-2016-214964
24. Chang JT, Wang B, Chang CM, Ambrose BK. National estimates of poisoning events related to
liquid nicotine in young children treated in US hospital emergency departments, 2013-2017.
Inj Epidemiol. 2019;6(1):10 PMID: 31245259 doi: 10.1186/s40621-019-0188-9
25. Arter ZL, Wiggins A, Hudspath C, Kisling A, Hostler DC, Hostler JM. Acute eosinophilic
pneumonia following electronic cigarette use. Respir Med Case Rep. 2019;27:100825
PMID: 30963023 doi: 10.1016/j.rmcr.2019.100825

1104
26. Thota D, Latham E. Case report of electronic cigarettes possibly associated with eosinophilic
pneumonitis in a previously healthy active-duty sailor. J Emerg Med. 2014;47(1):15–17
PMID: 24462024 doi: 10.1016/j.jemermed.2013.09.034
27. Agustin M, Yamamoto M, Cabrera F, Eusebio R. Diffuse Alveolar Hemorrhage Induced by
Vaping. Case Rep Pulmonol. 2018:9724530. eCollection 2018
PMID: 29773665 doi: 10.1542/peds.2016-3927
29. Khan MS, Khateeb F, Akhtar J, et al. Organizing pneumonia related to electronic cigarette use:
A case report and review of literature. Clin Respir J. 2018;12(3):1295–1299 PMID: 29392888
doi: 10.1111/crj.12775
30. Viswam D, Trotter S, Burge PS, Walters GI. Respiratory failure caused by lipoid pneumonia
from vaping e-cigarettes. BMJ Case Rep. 2018;2018:bcr2018224350 PMID: 29982176
doi: 10.1136/bcr-2018-224350
31. Itoh M, Aoshiba K, Herai Y, Nakamura H, Takemura T. Lung injury associated with electronic
cigarettes inhalation diagnosed by transbronchial lung biopsy. Respirol Case Rep.
2017;6(1):e00282 PMID: 29321926 doi: 10.1002/rcr2.282
32. Bradford LE, Rebuli ME, Ring BJ, Jaspers I, Clement KE, Loughlin CE. Danger in the vapor?
ECMO for adolescents with status asthmaticus after vaping. J Asthma. 2020;57(11): 1168‒1172.
Epub 2019 PMID: 31352844
33. McConnell R, Barrington-Trimis JL, Wang K, et al. Electronic cigarette use and respiratory
symptoms in adolescents. Am J Respir Crit Care Med. 2017;195(8):1043–1049 PMID: 27806211
doi: 10.1164/rccm.201604-0804OC
34. Xie W, Kathuria H, Galiatsatos P, et al. Association of electronic cigarette use with incident
respiratory conditions among US adults from 2013 to 2018. JAMA Netw Open.
2020;3(11):e2020816 PMID: 33180127 doi: 10.1001/jamanetworkopen.2020.20816
35. Bhatta DN, Glantz SA. Electronic cigarette use and myocardial infarction among adults in the
US Population Assessment of Tobacco and Health. J Am Heart Assoc. 2019;8(12):e012317
PMID: 31165662 doi: 10.1161/JAHA.119.012317
36. Alzahrani T, Pena I, Temesgen N, Glantz SA. Association between electronic cigarette use
and myocardial infarction. Am J Prev Med. 2018;55(4):455–461 PMID: 30166079
doi: 10.1016/j.amepre.2018.05.004
37. Lee WH, Ong SG, Zhou Y, et al. Modeling cardiovascular risks of e-cigarettes with
human-induced pluripotent stem cell-derived endothelial cells. J Am Coll Cardiol.
2019;73(21):2722–2737 PMID: 31146818 doi: 10.1016/j.jacc.2019.03.476
38. Anderson C, Majeste A, Hanus J, Wang S. E-cigarette aerosol exposure induces reactive
oxygen species, DNA damage, and cell death in vascular endothelial cells. Toxicol Sci.
2016;154(2):332–340 PMID: 27613717 doi: 10.1093/toxsci/kfw166
39. Espinoza-Derout J, Hasan KM, Shao XM, et al. Chronic intermittent electronic cigarette
exposure induces cardiac dysfunction and atherosclerosis in apolipoprotein-E knockout mice.
Am J Physiol Heart Circ Physiol. 2019;317(2):H445–H459 PMID: 31172811
doi: 10.1152/ajpheart.00738.2018
40. Garcia-Arcos I, Geraghty P, Baumlin N, et al. Chronic electronic cigarette exposure in mice
induces features of COPD in a nicotine-dependent manner. Thorax. 2016;71(12):1119–1129
PMID: 27558745 doi: 10.1136/thoraxjnl-2015-208039
41. Kaur G, Muthumalage T, Rahman I. Mechanisms of toxicity and biomarkers of flavoring and
flavor enhancing chemicals in emerging tobacco and non-tobacco products. Toxicol Lett.
2018;288:143–155 PMID: 29481849 doi: 10.1016/j.toxlet.2018.02.025
42. Sussan TE, Gajghate S, Thimmulappa RK, et al. Exposure to electronic cigarettes impairs
pulmonary anti-bacterial and anti-viral defenses in a mouse model. PLoS One.
43. Tang MS, Wu XR, Lee HW, et al. Electronic-cigarette smoke induces lung adenocarcinoma and
bladder urothelial hyperplasia in mice. Proc Natl Acad Sci USA. 2019;116(43):21727–21731
PMID: 31591243 doi: 10.1073/pnas.1911321116
44. Bhatta DN, Glantz SA. Association of e-cigarette use with respiratory disease among adults:
a longitudinal analysis. Am J Prev Med. 2020;58(2):182–190 PMID: 31859175
doi: 10.1016/j.amepre.2019.07.028
45. Wang JB, Olgin JE, Nah G, et al. Cigarette and e-cigarette dual use and risk of cardiopulmonary
symptoms in the Health eHeart Study. PLoS One. 2018;13(7):e0198681 PMID: 30044773
46. Parekh T, Pemmasani S, Desai R. Risk of stroke with e-cigarette and combustible cigarette
use in young adults. Am J Prev Med. 2020;58(3):446–452 PMID: 31924460
doi: 10.1016/j.amepre.2019.10.008

1105
47. Bals R, Boyd J, Esposito S, et al. Electronic cigarettes: a task force report from the
European Respiratory Society. Eur Respir J. 2019;53(2):1801151 PMID: 30464018
doi: 10.1183/13993003.01151-2018
48. Soneji S, Barrington-Trimis JL, Wills TA, et al. Association between initial use of e-cigarettes
and subsequent cigarette smoking among adolescents and young adults: a systematic review
and meta-analysis. JAMA Pediatr. 2017;171(8):788–797 PMID: 28654986
doi: 10.1001/jamapediatrics.2017.1488
49. Chaffee BW, Watkins SL, Glantz SA. Electronic cigarette use and progression from
experimentation to established smoking. Pediatrics. 2018;141(4):e20173594 PMID: 29507167
doi: 10.1542/peds.2017-3594
50. Kulik MC, Lisha NE, Glantz SA. E-cigarettes associated with depressed smoking cessation: a
cross-sectional study of 28 European Union countries. Am J Prev Med. 2018;54(4):603–609
PMID: 29449132 doi: 10.1016/j.amepre.2017.12.017
51. Kalkhoran S, Glantz SA. E-cigarettes and smoking cessation in real-world and clinical settings:
a systematic review and meta-analysis. Lancet Respir Med. 2016;4(2):116–128 PMID: 26776875
doi: 10.1016/S2213-2600(15)00521-4
52. Gomajee R, El-Khoury F, Goldberg M, et al. Association between electronic cigarette use and
smoking reduction in France. JAMA Intern Med. 2019;179(9):1193–1200; Epub ahead of print
PMID: 31305860 doi: 10.1001/jamainternmed.2019.1483
53. World Health Organization. WHO Report on the Global Tobacco Epidemic, 2019: Offer help to
quit tobacco use. Geneva: World Health Organization; 2019. https://apps.who.int/iris/bitstream
/handle/10665/326043/9789241516204-eng.pdf?ua=1 (Accessed August 3, 2019)
54. Ibarra AB. Juul e-cigarettes and teens: ‘Health problem of the decade’? CNN Healthline.
March 15, 2018. https://edition.cnn.com/2018/03/15/health/juul-e-cigarette-partner/index.html.
55. Jackler RK, Chau C, Getachew BD, et al. JUUL Advertising Over its First Three Years on the
Market. Stanford University Research into the Impact of Tobacco Advertising White Paper.
https://tobacco-img.stanford.edu/wp-content/uploads/2021/07/21231836
/JUUL_Marketing_Stanford.pdf. Accessed April 27, 2022
56. Jackler RK, Ramamurthi D, Louis-Ferdinand N. Rapid Growth of JUUL Hashtags After the
Company Ceased Social Media Promotion. Stanford University Research Into the Impact of
Tobacco Advertising White Paper. https://tobacco-img.stanford.edu/wp-content
/uploads/2021/07/21231755/HashtagJUUL_Project_2.5.2021F.pdf. Accessed April 27, 2022
57. Behind the Explosive Growth of Juul: Social Influences and Flavors Drive Rising Teen Use of the
Top E-Cigarette. Truth Initiative, December 2018. https://truthinitiative.org/sites/default/files
/media/files/2019/03/Behind-the-explosive-growth-of-JUUL.pdf Accessed March 9, 2022
58. Boykan R, Goniewicz ML, Messina CR. Evidence of nicotine dependence in adolescents who
use Juul and similar pod devices. Int J Environ Res Public Health. 2019;16(12):2135
PMID: 31212888 doi: 10.3390/ijerph16122135
59. Craver R. Juul ends 2018 with 76 percent market share. Winston Salem Journal Jan 8, 2019.
https://www.journalnow.com/business/juul-ends-with-percent-market-share
/article_6f50f427-19ec-50be-8b0c-d3df18d08759.html. Accessed August 11, 2019
60. Hammond D, Wackowski OA, Reid JL, O’Connor RJ. Use of Juul e-cigarettes among youth in
the United States. Nicotine Tob Res. 2020;22(5):827-832;
61. Dai H, Hao J. Online popularity of JUUL and Puff Bars in the USA: 2019–2020. Tob Control.
2022;33(1):7-10AU
62. Glantz S. Puff Bar continues to thumb its nose at FDA. UCSF Center for Tobacco Control
Research and Education Online Blog. 2020. Available at: https://tobacco.ucsf.edu
/puff-bar-continues-thumb-its-nose-fda. Accessed March 9, 2022
63. Ducharme J. As the number of vaping-related deaths climbs, these states have implemented
e-cigarette bans. TIME. September 25, 2019. https://time.com/5685936/state-vaping-bans/.
64. Farber HJ, Neptune E, Ewart G. U.S. Food and Drug Administration regulation of tobacco
products. Time for a course correction. Ann Am Thorac Soc. 2019;16(1):44–48 PMID: 30407839
doi: 10.1513/AnnalsATS.201809-597PS
65. Savio Beers L. AAP Statement on FDA Authorization of First E-Cigarette Product. New
Release; October 13, 2021. https://www.aap.org/en/news-room/news-releases/aap/2021
/aap-statement-on-fda-authorization-of-first-e-cigarette-product/. Accessed March 9, 2022
66. FDA permits sale of IQOS Tobacco Heating System through premarket tobacco product
application pathway. FDA News Release. US Food and Dry Administration; April 30, 2019
https://www.fda.gov/news-events/press-announcements/fda-permits-sale-iqos-tobacco-heating-
system-through-premarket-tobacco-product-application-pathway. Accessed March 9, 2022

1106
67. Auer R, Concha-Lozano N, Jacot-Sadowski I, Cornuz J, Berthet A. Heat-not-burn tobacco

cigarettes: smoke by any other name. JAMA Intern Med. 2017;177(7):1050–1052 PMID: 28531246
doi: 10.1001/jamainternmed.2017.1419
68. Lee J, Thompson LA, Salloum RG. Heated tobacco product use among US adolescents in 2019:
The new tobacco risk. Tob Prev Cessat. 2021;7:01
69. McKelvey K, Popova L, Kim M, et al. Heated tobacco products likely appeal to adolescents
and young adults. Tob Control. 2018;27(suppl 1):s41–s47 PMID: 30352843
doi: 10.1136/tobaccocontrol-2018-054596
70. Myers ML. Philip Morris Caught Red-Handed Marketing IQOS to Young People
on Social Media. Press Release: Campaign for Tobacco Free Kids; May 10, 2019
https://www.tobaccofreekids.org/press-releases/2019_05_10_pmi_iqos_socialmedia_marketing.
71. Primack BA, Carroll MV, Weiss PM, et al. Systematic review and meta-analysis of inhaled
toxicants from waterpipe and cigarette smoking. Public Health Rep. 2016;131(1):76–85
PMID: 26843673 doi: 10.1177/003335491613100114
72. Freedman A. Juiced up: How a tobacco giant doctors snuff brands to boost their ”kick.”
Wall Street Journal. October 26, 1994 [quoting former US Tobacco sales representative].
73. Primack BA, Bost JE, Land SR, Fine MJ. Volume of tobacco advertising in African American
markets: systematic review and meta-analysis. Public Health Rep. 2007;122(5):607–615
PMID: 17877308 doi: 10.1177/003335490712200508
74. Henriksen L, Schleicher NC, Feighery EC, Fortmann SP. A longitudinal study of exposure
to retail cigarette advertising and smoking initiation. Pediatrics. 2010;126(2):232–238
PMID: 20643725 doi: 10.1542/peds.2009-3021
75. Slater SJ, Chaloupka FJ, Wakefield M, Johnston LD, O’Malley PM. The impact of retail cigarette
marketing practices on youth smoking uptake. Arch Pediatr Adolesc Med. 2007;161(5):440–445
PMID: 17485618 doi: 10.1001/archpedi.161.5.440
76. Task Force on Community Preventive Services. Recommendations regarding interventions to
reduce tobacco use and exposure to environmental tobacco smoke. Am J Prev Med. 2001;20(2)
(suppl):10–15 PMID: 11173214
77. Villanti AC, Johnson AL, Ambrose BK, et al. Flavored tobacco product use in youth and adults:
findings from the first wave of the PATH study (2013-2014). Am J Prev Med. 2017;53(2):139–151
PMID: 28318902 doi: 10.1016/j.amepre.2017.01.026
78. Hilton S, Weishaar H, Sweeting H, Trevisan F, Katikireddi SV. E-cigarettes, a safer alternative
for teenagers? A UK focus group study of teenagers’ views. BMJ Open. 2016;6(11):e013271
PMID: 27852721 doi: 10.1136/bmjopen-2016-013271
79. Gritz ER, Prokhorov AV, Hudmon KS, et al. Cigarette smoking in a multiethnic population of
youth: methods and baseline findings. Prev Med. 1998;27(3):365–384 PMID: 9612827
doi: 10.1006/pmed.1998.0300
80. Dai H. Youth observation of e-cigarette use in or around school, 2019. Am J Prev Med.
2021;60(2):241–249 PMID: 33353794 doi: 10.1016/j.amepre.2020.07.022
81. Kaufman NJ, Castrucci BC, Mowery PD, Gerlach KK, Emont S, Orleans CT. Predictors of
change on the smoking uptake continuum among adolescents. Arch Pediatr Adolesc Med.
82. Sargent JD, Dalton M. Does parental disapproval of smoking prevent adolescents from
becoming established smokers? Pediatrics. 2001;108(6):1256–1262 PMID: 11731645
doi: 10.1542/peds.108.6.1256
83. DiNapoli PP. Early initiation of tobacco use in adolescent girls: key sociostructural influences.
Appl Nurs Res. 2009;22(2):126–132 PMID: 19427575 doi: 10.1016/j.apnr.2007.07.001
84. Corliss HL, Wadler BM, Jun HJ, et al. Sexual-orientation disparities in cigarette smoking in a
longitudinal cohort study of adolescents. Nicotine Tob Res. 2013;15(1):213–222 PMID: 22581940
doi: 10.1093/ntr/nts114
85. Centers for Disease Control and Prevention (CDC). Racial/ethnic differences among youths in
cigarette smoking and susceptibility to start smoking—United States, 2002-2004. MMWR Morb
Mortal Wkly Rep. 2006;55(47):1275–1277 PMID: 17136022
86. Corona R, Turf E, Corneille MA, Belgrave FZ, Nasim A. Risk and protective factors for tobacco
use among 8th- and 10th-grade African American students in Virginia. Prev Chronic Dis.
2009;6(2):A45 PMID: 19288988
87. Wills TA, Sargent JD, Gibbons FX, Pagano I, Schweitzer R. E-cigarette use is differentially
related to smoking onset among lower risk adolescents. Tob Control. 2016;26(5):534–539
PMID: 27543564 doi: 10.1136/tobaccocontrol-2016-053116

1107
88. Wills TA, Knight R, Williams RJ, Pagano I, Sargent JD. Risk factors for exclusive e-cigarette
use and dual e-cigarette use and tobacco use in adolescents. Pediatrics. 2015;135(1):e43–e51
PMID: 25511118 doi: 10.1542/peds.2014-0760
89. Hockenberry JM, Timmons EJ, Vander Weg MW. Adolescent mental health as a risk factor for
adolescent smoking onset. Adolesc Health Med Ther. 2011;2:27–35 PMID: 24600273
doi: 10.2147/AHMT.S11573
90. Upadhyaya HP, Deas D, Brady KT, Kruesi M. Cigarette smoking and psychiatric comorbidity in
children and adolescents. J Am Acad Child Adolesc Psychiatry. 2002;41(11):1294–1305
PMID: 12410071 doi: 10.1097/00004583-200211000-00010
91. Bush T, Richardson L, Katon W, et al. Anxiety and depressive disorders are associated with
smoking in adolescents with asthma. J Adolesc Health. 2007;40(5):425–432 PMID: 17448400
doi: 10.1016/j.jadohealth.2006.11.145
92. Becker TD, Arnold MK, Ro V, Martin L, Rice TR. Systematic review of electronic cigarette use
(vaping) and mental health comorbidity among adolescents and young adults. Nicotine Tob Res.
2021;23(3):415–425 PMID: 32905589 doi: 10.1093/ntr/ntaa171
93. US Preventive Services Task Force; Owens DK, Davidson KW, Krist AH, et al. Primary care
interventions for prevention and cessation of tobacco use in children and adolescents: US
Preventive Services Task Force recommendation statement. JAMA. 2020;323(16):1590–1598
PMID: 32343336 doi: 10.1001/jama.2020.4679
94. Farber HJ, Walley SC, Groner JA, Nelson KE; Section on Tobacco Control. Clinical practice
policy to protect children from tobacco, nicotine, and tobacco smoke. Pediatrics.
2015;136(5):1008–1017 PMID: 26504137 doi: 10.1542/peds.2015-3110
95. Anand V, McGinty KL, O’Brien K, Guenthner G, Hahn E, Martin CA. E-cigarette use and
beliefs among urban public high school students in North Carolina. J Adolesc Health.
2015;57(1):46–51 PMID: 26095408 doi: 10.1016/j.jadohealth.2015.03.018
96. Farber HJ, Nelson KE, Groner JA, Walley SC; Section on Tobacco Control. Public policy to
protect children from tobacco, nicotine, and tobacco smoke. Pediatrics. 2015;136(5):998–1007
PMID: 26504133 doi: 10.1542/peds.2015-3110
97. Yuan M, Cross SJ, Loughlin SE, Leslie FM. Nicotine and the adolescent brain. J Physiol.
2015;593(16):3397–3412 PMID: 26018031 doi: 10.1113/JP270492
98. Caraballo RS, Novak SP, Asman K. Linking quantity and frequency profiles of cigarette
smoking to the presence of nicotine dependence symptoms among adolescent smokers:
findings from the 2004 National Youth Tobacco Survey. Nicotine Tob Res. 2009;11(1):49–57
PMID: 19246441 doi: 10.1093/ntr/ntn008
99. DiFranza JRA. A 2015 update on the natural history and diagnosis of nicotine addiction.
Curr Pediatr Rev. 2015;11(1):43–55 PMID: 25938380 doi: 10.2174/1573396311666150501002703
100. Benowitz NL. Nicotine addiction. N Engl J Med. 2010;362(24):2295–2303 PMID: 20554984
doi: 10.1056/NEJMra0809890
101. DiFranza JR, Ursprung WW, Carson A. New insights into the compulsion to use tobacco
from an adolescent case-series. J Adolesc. 2010;33(1):209–214 PMID: 19406464
doi: 10.1016/j.adolescence.2009.03.009
102. McLaughlin I, Dani JA, De Biasi M. Nicotine withdrawal. Curr Top Behav Neurosci.
2015;24:99–123 PMID: 25638335 doi: 10.1007/978-3-319-13482-6_4
103. Hughes JR. Clinical significance of tobacco withdrawal. Nicotine Tob Res. 2006;8(2):153–156
PMID: 16766409 doi: 10.1080/14622200500494856
104. Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. The Fagerström Test for
Nicotine Dependence: a revision of the Fagerström Tolerance Questionnaire. Addiction.
1991;86(9):1119–1127 PMID: 1932883 doi: 10.1111/j.1360-0443.1991.tb01879.x
105. Prokhorov AV, De Moor C, Pallonen UE, Hudmon KS, Koehly L, Hu S. Validation of the
modified Fagerström tolerance questionnaire with salivary cotinine among adolescents.
Addict Behav. 2000;25(3):429–433 PMID: 10890296 doi: 10.1016/S0306-4603(98)00132-4
106. Wheeler KC, Fletcher KE, Wellman RJ, Difranza JR. Screening adolescents for nicotine
dependence: the Hooked On Nicotine Checklist. J Adolesc Health. 2004;35(3):225–230
PMID: 15313504 doi: 10.1016/S1054-139X(03)00531-7
107. Foulds J, Veldheer S, Yingst J, et al. Development of a questionnaire for assessing dependence on
electronic cigarettes among a large sample of ex-smoking e-cigarette users. Nicotine Tob Res.
2015;17(2):186–192 PMID: 25332459 doi: 10.1093/ntr/ntu204
108. Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline,
bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a
double-blind, randomised, placebo-controlled clinical trial. Lancet. 2016;387(10037):2507–2520
PMID: 27116918 doi: 10.1016/S0140-6736(16)30272-0

1108
109. Chang PH, Chiang CH, Ho WC, Wu PZ, Tsai JS, Guo FR. Combination therapy of varenicline
with nicotine replacement therapy is better than varenicline alone: a systematic review and
meta-analysis of randomized controlled trials. BMC Public Health. 2015;15(1):689
PMID: 26198192 doi: 10.1186/s12889-015-2055-0
110. Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update.
Clinical Practice Guideline. U.S. Department of Health and Human Services. Public Health
Service; 2008
111. Livingstone-Banks J, Norris E, Hartmann-Boyce J, West R, Jarvis M, Hajek P. Relapse
prevention interventions for smoking cessation. Cochrane Database Syst Rev. 2019;2:CD003999
PMID: 30758045
112. Rose JE, Behm FM, Westman EC, Kukovich P. Precessation treatment with nicotine skin patch
facilitates smoking cessation. Nicotine Tob Res. 2006;8(1):89–101 PMID: 16497603
doi: 10.1080/14622200500431866
113. Ebbert JO, Hughes JR, West RJ, et al. Effect of varenicline on smoking cessation through
smoking reduction: a randomized clinical trial. JAMA. 2015;313(7):687–694 PMID: 25688780
doi: 10.1001/jama.2015.280
114. Naar-King S, Suarez M. Motivational Interviewing with Adolescents and Young Adults. The
Guilford Press; 2011
115. Sussman S, Dent CW, Lichtman KL. Project EX: outcomes of a teen smoking cessation program.
Addict Behav. 2001;26(3):425–438 PMID: 11436934 doi: 10.1016/S0306-4603(00)00135-0
116. Grimshaw GM, Stanton A. Tobacco cessation interventions for young people. Cochrane
117. Horn K, Fernandes A, Dino G, Massey CJ, Kalsekar I. Adolescent nicotine dependence and
smoking cessation outcomes. Addict Behav. 2003;28(4):769–776 PMID: 12726789
doi: 10.1016/S0306-4603(02)00229-0
118. Bagot KS, Heishman SJ, Moolchan ET. Tobacco craving predicts lapse to smoking among
adolescent smokers in cessation treatment. Nicotine Tob Res. 2007;9(6):647–652
PMID: 17558821 doi: 10.1080/14622200701365178
119. Moolchan ET, Robinson ML, Ernst M, et al. Safety and efficacy of the nicotine patch and
gum for the treatment of adolescent tobacco addiction. Pediatrics. 2005;115(4):e407–e414
PMID: 15805342 doi: 10.1542/peds.2004-1894
120. Muramoto ML, Leischow SJ, Sherrill D, Matthews E, Strayer LJ. Randomized, double-blind,
placebo-controlled trial of 2 dosages of sustained-release bupropion for adolescent smoking
cessation. Arch Pediatr Adolesc Med. 2007;161(11):1068–1074 PMID: 17984409
doi: 10.1001/archpedi.161.11.1068
121. Gray KM, Baker NL, McClure EA, et al. Efficacy and safety of varenicline for adolescent
smoking cessation: a randomized clinical trial. JAMA Pediatr. 2019;173(12):1146–1153
PMID: 31609433 doi: 10.1001/jamapediatrics.2019.3553
122. Visser WF, Klerx WN, Cremers HW, Ramlal R, Schwillens PL, Talhout R. The Health Risks of
Electronic Cigarette Use to Bystanders. Int J Environ Res Public Health. 2019;16(9):1525.111
123. Schober W, Szendrei K, Matzen W, et al. Use of electronic cigarettes (e-cigarettes) impairs
indoor air quality and increases FeNO levels of e-cigarette consumers. Int J Hyg Environ Health.
2014;217(6):628–637 PMID: 24373737 doi: 10.1016/j.ijheh.2013.11.003
124. Merianos AL, Jandarov RA, Choi K, Mahabee-Gittens EM. Tobacco smoke exposure disparities
persist in U.S. children: NHANES 1999-2014. Prev Med. 2019;123:138–142 PMID: 30902698
doi: 10.1016/j.ypmed.2019.03.028
125. Wilson KM, Klein JD, Blumkin AK, Gottlieb M, Winickoff JP. Tobacco-smoke exposure in
children who live in multiunit housing. Pediatrics. 2011;127(1):85–92 PMID: 21149434
doi: 10.1542/peds.2010-2046
126. Farber HJ, Batsell RR, Silveira EA, Calhoun RT, Giardino AP. The impact of tobacco smoke
exposure on childhood asthma in a medicaid managed care plan. Chest. 2016;149(3):721–728
PMID: 26512943 doi: 10.1378/chest.15-1378
127. Winickoff JP, Tanski SE, McMillen RC, Klein JD, Rigotti NA, Weitzman M. Child health care
clinicians’ use of medications to help parents quit smoking: a national parent survey. Pediatrics.
2005;115(4):1013–1017 PMID: 15805379 doi: 10.1542/peds.2004-1372
128. Jaddoe VW, Troe EJ, Hofman A, et al. Active and passive maternal smoking during pregnancy
and the risks of low birthweight and preterm birth: the Generation R Study. Paediatr Perinat
Epidemiol. 2008;22(2):162–171 PMID: 18298691 doi: 10.1111/j.1365-3016.2007.00916.x
129. Salihu HM, Sharma PP, Getahun D, et al. Prenatal tobacco use and risk of stillbirth:
a case-control and bidirectional case-crossover study. Nicotine Tob Res. 2008;10(1):159–166
PMID: 18188756 doi: 10.1080/14622200701705431

1109
130. Baba S, Wikström AK, Stephansson O, Cnattingius S. Influence of snuff and smoking habits in
early pregnancy on risks for stillbirth and early neonatal mortality. Nicotine Tob Res.
2014;16(1):78–83 PMID: 23943841 doi: 10.1093/ntr/ntt117
131. Leonardi-Bee J, Britton J, Venn A. Secondhand smoke and adverse fetal outcomes in
nonsmoking pregnant women: a meta-analysis. Pediatrics. 2011;127(4):734–741 PMID: 21382949
doi: 10.1542/peds.2010-3041
132. Aliyu MH, Lynch O, Wilson RE, et al. Association between tobacco use in pregnancy and
placenta-associated syndromes: a population-based study. Arch Gynecol Obstet.
2011;283(4):729–734 PMID: 20354707 doi: 10.1007/s00404-010-1447-8
133. Wongtrakool C, Wang N, Hyde DM, Roman J, Spindel ER. Prenatal nicotine exposure alters
lung function and airway geometry through α7 nicotinic receptors. Am J Respir Cell Mol Biol.
2012;46(5):695–702 PMID: 22246862 doi: 10.1165/rcmb.2011-0028OC
134. Lambe M, Hultman C, Torrång A, Maccabe J, Cnattingius S. Maternal smoking during
pregnancy and school performance at age 15. Epidemiology. 2006;17(5):524–530
PMID: 16878043 doi: 10.1097/01.ede.0000231561.49208.be
135. Abraham M, Alramadhan S, Iniguez C, et al. A systematic review of maternal smoking during
pregnancy and fetal measurements with meta-analysis. PLoS One. 2017;12(2):e0170946
136. Roza SJ, Verburg BO, Jaddoe VW, et al. Effects of maternal smoking in pregnancy on
prenatal brain development. The Generation R Study. Eur J Neurosci. 2007;25(3):611–617
PMID: 17298594 doi: 10.1111/j.1460-9568.2007.05393.x
137. Sawnani H, Jackson T, Murphy T, Beckerman R, Simakajornboon N. The effect of maternal
smoking on respiratory and arousal patterns in preterm infants during sleep. Am J Respir Crit
Care Med. 2004;169(6):733–738 PMID: 14684558 doi: 10.1164/rccm.200305-692OC
138. Schneider J, Mitchell I, Singhal N, Kirk V, Hasan SU. Prenatal cigarette smoke exposure
attenuates recovery from hypoxemic challenge in preterm infants. Am J Respir Crit Care Med.
2008;178(5):520–526 PMID: 18565950 doi: 10.1164/rccm.200803-432OC
139. Lazarus SC, Chinchilli VM, Rollings NJ, et al; National Heart Lung and Blood Institute’s
Asthma Clinical Research Network. Smoking affects response to inhaled corticosteroids or
leukotriene receptor antagonists in asthma. Am J Respir Crit Care Med. 2007;175(8):783–790
PMID: 17204725 doi: 10.1164/rccm.200511-1746OC
140. Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W, Thomson NC. Cigarette
smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir
141. Ong T, Schechter M, Yang J, et al; EPIC Study Group. Socioeconomic status, smoke exposure,
and health outcomes in young children with cystic fibrosis. Pediatrics. 2017;139(2):e20162730
PMID: 28093464 doi: 10.1542/peds.2016-2730
142. Maw R, Bawden R. Spontaneous resolution of severe chronic glue ear in children and the effect
of adenoidectomy, tonsillectomy, and insertion of ventilation tubes (grommets). BMJ.
1993;306(6880):756–760 PMID: 8490338 doi: 10.1136/bmj.306.6880.756
143. Aligne CA, Moss ME, Auinger P, Weitzman M. Association of pediatric dental caries with
passive smoking. JAMA. 2003;289(10):1258–1264 PMID: 12633187
doi: 10.1001/jama.289.10.1258
144. Goto Y, Wada K, Konishi K, et al. Association between exposure to household smoking and
dental caries in preschool children: a cross-sectional study. Environ Health Prev Med.
2019;24(1):9 PMID: 30684963 doi: 10.1186/s12199-019-0764-1
145. Ramírez N, Özel MZ, Lewis AC, Marcé RM, Borrull F, Hamilton JF. Exposure to nitrosamines
in thirdhand tobacco smoke increases cancer risk in non-smokers. Environ Int. 2014;71:139–147
146. Thomas JL, Guo H, Carmella SG, et al. Metabolites of a tobacco-specific lung carcinogen in
children exposed to secondhand or thirdhand tobacco smoke in their homes. Cancer Epidemiol
Biomarkers Prev. 2011;20(6):1213–1221 PMID: 21467230 doi: 10.1158/1055-9965.EPI-10-1027
147. Milne E, Greenop KR, Scott RJ, et al. Parental prenatal smoking and risk of childhood acute
lymphoblastic leukemia. Am J Epidemiol. 2012;175(1):43–53 PMID: 22143821
doi: 10.1093/aje/kwr275
148. Rumrich IK, Viluksela M, Vähäkangas K, Gissler M, Surcel HM, Hänninen O. Maternal
smoking and the risk of cancer in early life - a meta-analysis. PLoS One. 2016;11(11):e0165040
149. Kallio K, Jokinen E, Saarinen M, et al. Arterial intima-media thickness, endothelial function,
and apolipoproteins in adolescents frequently exposed to tobacco smoke. Circ Cardiovasc Qual
Outcomes. 2010;3(2):196–203 PMID: 20197510 doi: 10.1161/CIRCOUTCOMES.109.857771
150. Butz AM, Matsui EC, Breysse P, et al. A randomized trial of air cleaners and a health coach to
improve indoor air quality for inner-city children with asthma and secondhand smoke exposure.
Arch Pediatr Adolesc Med. 2011;165(8):741–748 PM

CHAPTER
62
Tracheostomy
Introduction
As the incidence of long-term pediatric tracheostomy has risen, general
pediatricians increasingly care for children with tracheostomies in the
outpatient setting. Pediatric patients who require tracheostomy are a diverse
group of patients with complex needs. Optimal care for the child with a long-
term tracheostomy requires a collaborative medical home, with several
interdisciplinary team members. In addition to the primary care physician,
the team includes an otolaryngologist or surgeon to place the tracheostomy,
coordinate equipment and supplies, and provide ongoing tracheostomy care;
a pulmonologist to monitor the patient’s respiratory status; a speech therapist
to assist with speech and/or swallowing; home nursing care; often, a complex
care physician; and family members well trained in tracheostomy care. The
general pediatrician should understand indications for tracheostomy place-
ment, changes in normal physiology following tracheostomy, the patient’s
respiratory equipment, home care procedures, common complications of
tracheostomy, and indications for decannulation.
Indications for Tracheostomy

The most common indications for tracheostomy have shifted substantially
since the 1970s.1 Widespread vaccination against Haemophilus influenzae and
Corynebacterium diphtheriae as well as advances in endotracheal intubation
have markedly decreased the need for tracheostomy for acute inflammatory
airway compromise. In addition, medical improvements have led to increased
survival of preterm neonates and those with complex congenital cardiopulmo-
nary anomalies. Consequently, the general need for pediatric tracheostomy
has shifted primarily to those patients with prolonged mechanical ventilation
and anatomic airway abnormalities.1-4 Of pediatric tracheostomies, 40%
to 70% are now performed on children younger than 1 year,5-7 and more
than half of children may have their tracheostomy in place for more than
24 months.2 Indications for tracheostomy may be organized into 2 main
categories delineated in Box 62-1.
1111

1112
Box 62‑1 In several recent series, the

most common tracheostomy
Indications for Tracheostomy indication was prolonged
Prolonged Ventilatory Support mechanical ventilation due to
Chronic respiratory failure an underlying chronic medical
Bronchopulmonary dysplasia condition.2 Tracheostomy is
Congenital heart disease often indicated for more com-
fortable long-term ventilation or
Pulmonary hypoplasia
prolonged weaning from respira-
Neuromuscular diseases or impairment
tory support. The recommended
Central respiratory dysfunction timing of tracheostomy for those
Upper Airway Obstruction children who require prolonged
Foreign body mechanical ventilation may
Craniofacial disorders, such as be age and patient dependent.
macroglossia/micrognathia Preterm neonates may tolerate
Laryngeal or pharyngeal cysts/neoplasms intubation with appropriately
Epiglottitis sized, uncuffed endotracheal
tubes for several weeks with
Bilateral true vocal cord paralysis
minimal inflammation and/or
Laryngeal, subglottic, or tracheal stenosis stenosis. However, because the
or agenesis
laryngeal cartilage is firmer
Tracheobronchomalacia
in older infants and children,
Facial or laryngotracheal trauma intubation for only a few weeks
Laryngeal injury after smoke inhalation or in this patient population may
caustic ingestion result in more significant laryn-
geal inflammation and scarring.
Thus, it is critical to ensure appropriate endotracheal tube sizing and cuff
leaks in infants and children. Additionally, tracheostomy may be necessary
for children with congenital or acquired anatomical abnormalities leading to
critical upper airway obstruction that is not amenable to correction, such as
micrognathia or subglottic stenosis. Finally, children with neuromuscular
conditions leading to weak cough, aspiration, and difficulty clearing
secretions may benefit from tracheostomy for improved control of
secretions and pulmonary hygiene.

1113
Chapter 62—Tracheostomy
CASE REPORT 62-1

A 12-week-old former 26-week preterm infant has been intubated and
hospitalized in the neonatal intensive care unit since birth. Extubation has
failed 3 times, with early development of post-extubation stridor, retractions,
and, ultimately, respiratory distress. The neonatal intensive care team con-
sulted pediatric otolaryngology to evaluate her upper airway. She underwent
microdirect laryngoscopy and bronchoscopy and was found to have anterior
laryngeal stenosis extending into the subglottis due to granulation tissue
and scarring (Figures 62-1 and 62-2). This was treated serially 3 times over
several weeks with endoscopic laryngeal steroid injection, incision, and balloon
dilation. After failure to provide an adequate laryngeal opening and
an additional failed attempt at extubation, the infant ultimately underwent
tracheostomy.
Figure 62-1. Normal

pediatric larynx with
patent glottis.
Figure 62-2. The larynx of the patient in the case

report: Anterior glottic stenosis (arrow) after
prolonged intubation.

1114
Surgical Technique
Pediatric tracheostomy is usually performed under general anesthesia in the
operating room. Preoperative airway evaluation, including direct microlaryn-
goscopy and bronchoscopy, may be beneficial to explore potentially treatable
pathology. Prior to tracheal incision, non-absorbable retention sutures are
placed through the tracheal cartilage rings on each side of midline. These
sutures provide traction on the trachea in the event of accidental decannulation
during the initial healing phase. For tracheal incision, the preferred technique
is a midline vertical tracheal incision (Figure 62-3).8,9 With any technique,
there is a risk of bleeding, pneumothorax, pneumomediastinum, subcutaneous
emphysema, acute loss of airway, false passage, granuloma, and tracheal
stenosis. Early complication rates range from 7% to 11%.10
Figure 62-3. Standard pediatric
tracheostomy with a vertical tracheal
incision and retention sutures on either
side of the tracheostomy opening.
From Rutter MJ, Hart CK. Trachea.
In: Potsic WP, Cotton RT, Handler SD, Zur KB.
Surgical Pediatric Otolaryngology. 2nd ed.
Thieme;2016:360–370.
Tube Selection and Considerations

Tracheostomy tubes are available in neonatal, pediatric, and adult sizes, which
vary by length and curvature. Cuffed and uncuffed pediatric tracheostomy
tubes are shown in Figure 62-4. Tubes are made out of silicone, polyvinyl
chloride, or, uncommonly, metal. Most plastic materials cause nominal local
tissue reaction. Many recently manufactured nonmetal tracheostomy tubes are
compatible with magnetic resonance imaging, but this should be confirmed for
each specific tracheostomy tube. Ideally, tubes are made of a flexible material
that conforms to the tissues of the trachea and neck, without causing discom-
fort, pressure, or injury. Choice of tube type and size depends on the initial
indication for tracheostomy, keeping in mind the patient’s pulmonary function,
tracheal size and shape, upper airway resistance, and allowance for air leak
to achieve vocalization. The diameter of the tracheostomy tube can often
be estimated by determining the appropriate-sized endotracheal tube for the
child. The tube size should be large enough to allow appropriate gas exchange
without causing pressure injury on the tracheal mucosa. In general, uncuffed
tubes are preferred for children to allow for vocalization and prevent tracheal
injury. However, cuffed tubes are often necessary for patients who require
mechanical ventilation with high pressures, or who are at risk for aspiration.

1115 1115
Pediatric Pulmology Chapter 62—Tracheostomy
Figure 62-4. Cuffed

tracheostomy tube (top),
uncuffed tracheostomy
tube (bottom).
Cuff pressures are kept below 20 cm H2O to prevent necrosis and injury to
airway epithelium. Customized tubes can be constructed if standard tubes do
not correspond well to the child’s anatomy, such as in cases of cervicofacial
abnormalities, tracheal stenosis, or tracheomalacia.2,11
Altered Physiology After Tracheostomy

Once tracheostomy is performed, there are multiple consequences on normal
tracheal function and physiology. Airway clearance may become impaired
because scar tissue can develop in the anterior trachea at the tracheostomy
site, and normal ciliary function will be disrupted in that location, leading to
mucus stasis. In addition, cough clearance is less effective because the com-
pressive phase of glottic closure before forced expiration is bypassed with
the tracheostomy in place.12 As a result, the patient is at increased risk for
recurrent tracheitis and pneumonia. A normal sense of smell requires airflow

1116
through the nose, and, if upper airway obstruction is significant, airflow will
be directed through the tracheostomy tube, thereby decreasing subjective
sense of smell. Similarly, speech requires adequate airflow past the vocal
cords, which depends on the degree of upper airway obstruction and tolerance
of a speaking valve or tracheostomy tube capping. To achieve speech without
augmentative communication devices, the tracheostomy tube must not exceed
two-thirds of the tracheal lumen.11 Development of normal speech requires
early speaking valve assessment and speech therapy. The humidification of
inspired air is another important function of the nasopharynx that is bypassed
with a tracheostomy. The lack of humidity can lead to desiccation of secre-
tions, damage to mucus glands, mucus plugging, and impaired ciliary function
unless external humidification is provided.13 This, in turn, can cause increased
infection risk and reduction of lung function. Finally, swallowing function
can be affected by the presence of the tracheostomy tube because it limits
superior excursion of the larynx with deglutition, may inhibit the normal
laryngeal reflex that prevents aspiration, and may contribute to mass effect
on the esophagus posteriorly.2,14 Dysphagia and oral aversion are extremely
common in neonates and infants with tracheostomy.15
Tracheostomy Care at Home

Caregiver education is an important step in successful transition from hospital
to home care and ideally begins prior to tracheostomy placement. The benefits
and risks of tracheostomy, as well as its associated care, should be discussed
in detail with the caregivers before the surgery. As soon as the tracheostomy
is placed, bedside hands-on teaching is initiated. Training initially begins
with the relevant anatomic structures and the functions of the upper airway in
warming, humidifying, and clearing secretions.2 Education should take place
in the hospital under the supervision of the nurses and physicians. Instruction
should include decision-making as well as technical skills. It should encom-
pass stoma care and evaluation, tracheostomy tube and tie changes, suctioning
techniques, cardiopulmonary resuscitation (CPR) training, recognizing signs
and symptoms of respiratory distress, and troubleshooting any problems. This
teaching should be individualized to the child and family, taking into account
the cultural and language needs. Audiovisual aids and mannequins may be
used in addition to written materials. Many institutions require training of at
least 2 adult caregivers who will provide consistent care to the child. They
must demonstrate proficiency in both skills and decision-making prior to
discharge. Some institutions require that caregivers provide all care for their
child, using only home equipment, for 24 hours prior to discharge. All children
with tracheostomy should receive skilled home nursing care during a transi-
tional adjustment time after discharge. Unfortunately, a national shortage of

1117
home nursing care availability may create significant challenges in receiving

this care. The following resources may be helpful for caregivers.
X Aaron’s Tracheostomy Page (independent nonprofit).
www.tracheostomy.com
X Use of a Tracheostomy With a Child (American Thoracic Society).
www.thoracic.org/patients/patient-resources/resources/
tracheostomy-in-child.pdf
X Pediatric Tracheostomy App (Review) (iMedicalApps). www.imedicalapps.
com/2013/02/pediatric-tracheostomy-app-kids-parents-trach
Tracheostomy Supplies for Home

Every child with a tracheostomy should have adequate supplies at home
(Box 62-2). These include spare tracheostomy tubes (including one size
smaller for emergencies), cleaning supplies, tracheostomy ties, suctioning
equipment and catheters, humidification equipment, and monitoring equip-
ment. To obtain the appropriate type and sufficient number of home supplies,
advocacy to the insurance company by the provider is often required. Before
a child is discharged, it is essential to make sure all the supplies are available
from the durable medical equipment company. All home care equipment and
supplies should be tested and used in the hospital prior to discharge.
Box 62-2
Tracheostomy Home Care Supplies
ū Extra tracheostomy ū Scissors ū Cotton swabs and
tube, same size ū External humidification gauze
ū Extra tracheostomy (nebulizer, compressor ū Oxygen with tubing
tube, ½ size smaller or heat and moisture (if ordered)
ū Suction machine and exchanger) ū Breathing monitor,
tubing ū Tracheostomy ties such as pulse oximeter
ū Suction catheters ū Sterile water (if ordered)
ū Resuscitation bag with ū Normal saline for

tracheostomy adapter suctioning
and face mask
Changing the Tube

Tracheostomy tubes should be changed on a regular basis to prevent infection,
decrease granuloma formation, and reduce the risk of tube occlusion by thick
or dried secretions.2,11 The frequency of tube changes varies by the child’s
age, amount of secretions, and type of tube. Recommended tube-changing
schedules may vary from daily to monthly; in many cases, weekly changes

1118
are sufficient. Caregivers should comprehend that more frequent tube changes
may be required when the child is sick or has increased secretions.
Cleaning the Tube

Most tracheostomy tubes may be cleaned and reused, as detailed in the
manufacturer’s instructions. Because tracheostomy tubes may develop cracks
or become stiff over time, all tubes should be inspected for damage prior to
insertion. Used tracheostomy tubes are generally cleaned using a mild liquid
detergent and water. After rinsing thoroughly, the tube should be allowed to
air-dry completely and then stored in a plastic bag.
Suction and Irrigation

Suctioning is a vital component in the management of a child with a chronic
tracheostomy because occlusion of the tube by secretions or mucus plugs
can be life-threatening. If possible, the child should be encouraged to cough
and clear accumulated mucus. When suctioning is performed, the catheter
should be inserted just past the end of the tracheostomy tube.2 Attention to
clean technique is important.16 After each aspiration, the catheter should be
flushed with saline solution until secretions are cleared from the lumen. The
catheter should then be wiped with alcohol, allowed to air-dry, and stored
in a clean, dry area.
Changing the Ties

Tracheostomy ties should be replaced during tracheostomy tube changes or
when wet or soiled. Soft Velcro material helps to minimize irritation of the
skin. The ties should be tight enough to minimize movement of the tube but
still allow a finger to be inserted underneath the tie. If tracheostomy ties are
too tight, skin breakdown can occur.
Skin Care
Usually, there is minimal skin care in pediatric patients with tracheostomy.2
However, irritation of the stoma, area under the tube or flanges, and area
under the ties may develop. These sites may be cleaned with cotton swabs
and hydrogen peroxide. Occasionally, antibiotic ointment, antifungal powder,
or specialized dressings may be necessary. If granulation tissue develops, it
may be treated with topical steroid drops or silver nitrate.
Humidification
Ensuring adequate humidification is important as the tracheostomy bypasses
the upper airway and the inspired air may have significantly lower humidity
than normal. External humidification can be delivered with a humidifier,
nebulizer, or heat and moisture exchanger (aka artificial nose). The latter is a
passive humidification device that collects moisture from the patient’s exhaled

1119
gas and delivers it during inspiration; it may be particularly useful when the
child is mobile.2,11
Speech
Special consideration and counseling regarding communication and language
development should begin prior to tracheostomy placement. Some patients
may be able to vocalize around their tracheostomy tube without an additional
device in place. However, speech can be facilitated with the use of a speaking
valve in suitable candidates. To use the speaking valve, the patient must be
awake, interactive, and medically stable. The child should have a cuffless tube
or be able to tolerate deflation of the tracheostomy tube cuff, and must not
have excessive thick secretions or high tracheal pressures. Initial trials with
a speaking device are performed in the hospital or clinic setting with close
monitoring for discomfort or desaturations. If tolerated, the clinician may pro-
vide instruction on increasing speaking valve trials to be continued at home
with monitoring. Other children may benefit from use of augmentative and
alternative communication devices. A speech-language pathologist plays
an integral role in speech development and should be consulted as soon as
possible to assist with the care of every child with a tracheostomy.11,17
Monitoring
A well-trained, attentive, and properly equipped caregiver should be able to
provide excellent monitoring. For young children or those unable to provide
self-care of the tracheostomy, an awake caregiver should be available for
monitoring for airway obstruction, which means many children require 8
to 12 hours of overnight nursing. Pulse oximeters are frequently used and are
considered the best airway monitoring devices.2 Home apnea monitors are of
limited utility because they do not diagnose airway obstruction. For high-risk
or medically complex patients with a tracheostomy (ie, those patients who are
tracheostomy dependent secondary to a critically narrow airway), 24-hour
nursing may be necessary. Provider advocacy is often necessary to obtain
appropriate nursing coverage.
Routine Evaluation
Regular follow-up with a primary care physician, otolaryngologist, pulmo-
nologist, and potentially complex care physician is indicated for children
with tracheostomy. During the follow-up visit, the child should be assessed
for related complications and the ongoing need for the tracheostomy. Routine
evaluation with flexible tracheoscopy via the indwelling tracheostomy tube is
usually performed every 6 to 12 months and can easily be done in clinic. Full
upper airway evaluation, including direct laryngoscopy and bronchoscopy,
is often performed every 12 to 18 months for surveillance and must be com-
pleted under general anesthesia. The purpose of this evaluation is to assess for

1120
underlying airway pathology, detect and treat complications, assess tube size
and position, and determine the readiness for decannulation. The tube length
and width may need to be changed as the child grows or ventilatory require-
ments change. Decannulation should be considered if the original condition
or need for the tracheostomy is no longer present and the patient is able to
maintain a safe and adequate airway.
Complications
Between 10% and 51% of children will develop late complications following
tracheostomy,10 and each child should be regularly evaluated to minimize mor-
bidity. Complications are more common in younger children and those with
long-term tracheostomies.11 Tracheal injury and lesions, such as granulomas,
fistulas, and erosions, can develop as a result of rubbing of the tracheostomy
tube or suction catheter against the tracheal wall. The suprastomal region
is particularly vulnerable to collapse, malacia, and granuloma formation.
Routine direct laryngoscopy and bronchoscopy can identify granulomas,
which can then be excised.2 Infection, particularly tracheitis, can develop as a
result of direct communication with the external environment and inhibition
of the normal defense mechanisms of mucociliary transport, cough, and upper
airway filtration. Most patients with tracheostomies become colonized with
bacteria such as Pseudomonas aeruginosa. Erythema and drainage at the
stoma site are usually managed with more frequent tube changes, dressings,
and topical antibiotics. Clinical signs of tracheitis or pneumonia, including
increased cough and change in quality or color of secretions, accompanied
by leukocytes and organisms identified by Gram stain, indicate acute infec-
tion. Cultures aspirated from the tracheostomy tube should guide antibiotic
therapy.18 Catastrophic bleeding as a result of erosion of the tracheostomy tube
into a major vessel is rare, but any recurrent or significant bleeding should be
promptly evaluated by the pulmonologist or otolaryngologist.11 Lastly, obstruc-
tion or displacement of the tube can lead to life-threatening airway obstruction
and even death; therefore, the family and caregivers should be comfortable
with suctioning, replacing the tube, providing positive-pressure resuscitation
through the tube or upper airway with a mask, and performing CPR should
such an event take place.19
Decannulation
Decannulation should only be performed once the initial indication for
tracheostomy placement has resolved and the patient has demonstrated the
ability to maintain a patent airway and adequate respiratory physiology
independent of the tracheostomy tube and mechanical ventilation for a mini-
mum of several weeks. Decannulation is ultimately achieved in 35% to 75%

1121
of patients.4 The average time to decannulation ranges from 4 to 21 months

and varies based on original indication.6,20,21 Those patients undergoing trache-
ostomy for facial or laryngotracheal trauma have significantly shorter times to
decannulation than patients with cardiopulmonary or neurologic indications.2,4
The patient should first undergo direct laryngoscopy and bronchoscopy to
evaluate the airway for feasibility of decannulation, including the presence or
absence of laryngeal or subglottic stenosis, granulomas, suprastomal collapse,
and/or tracheomalacia. The tube may be progressively downsized, although
this approach is limited in small children due to the proportionately larger
increase in airway resistance and mucus plugging of the smaller tube. Capping
trials may be employed in the office of the otolaryngologist or pulmonologist.
If tolerated, the specialist may provide instruction on short capping trials to be
initiated at home with monitoring to determine how well the patient tolerates
occlusion of the tube for extended periods. Finally, polysomnography can
be performed to assess the adequacy of gas exchange with a capped trache-
ostomy tube prior to decannulation. Decannulation should be attempted in
the inpatient setting, with initial high acuity monitoring. The patient should
be monitored in the hospital for 24 to 48 hours following decannulation to
observe for any obstructive symptoms.2,11,22
CASE REPORT 62-2

A 2-year-old boy sustained significant head trauma in a motor vehicle
collision. Due to an inability to wean from ventilatory support, he underwent
tracheostomy. He was transitioned to rehabilitation care and made significant
improvements in his functional status, recovering the ability to speak, eat, and
walk. He was successfully weaned to room air and underwent evaluation for
decannulation by pediatric otolaryngology at the age of 4 years. Direct laryn-
goscopy revealed a normal larynx; however, there was suprastomal granulation
tissue (Figure 62-5), which was excised. In addition, airway evaluation was
notable for enlarged adenoids and tonsils. Capping trials were initiated, and he
tolerated these well during the daytime. Overnight polysomnography demon-
strated increased snoring, obstructive apnea/hypopnea, and desaturations
when the tracheostomy tube was capped. He then underwent adenotonsillec-
tomy, and his snoring resolved. Repeat capped polysomnography revealed
resolution of obstructive apnea/hypopnea. He was able to tolerate overnight
capping and was successfully decannulated.

1122
Figure 62-5. Suprastomal granulation tissue proximal to tracheostomy tube obstructing a

portion of airway lumen. A. Suprastomal granulation tissue due to tracheostomy tube.
B. Example of trachea without suprastomal granulation tissue
key po ints
} Caring for a child with a chronic tracheostomy requires a collaborative
multidisciplinary team.
} Indications for tracheostomy placement include conditions requiring prolonged
mechanical ventilation (ie, cardiopulmonary disease, neurologic impairment)
and critical upper airway obstruction.
} Tracheostomy tubes are made in neonatal, pediatric, and adult sizes and are
most commonly made of silicone or polyvinyl chloride.
} Uncuffed tubes are generally preferred to allow for vocalization and prevent
tracheal injury, but cuffed tubes can be used for patients who are on ventilators
or at risk for aspiration.
} Changes in airway clearance, sense of smell, speech, humidification, and
swallowing function can be expected following tracheostomy.
} Parents and other caregivers should receive detailed counseling prior to
tracheostomy placement, including the significant caregiver and home nursing
responsibilities. Caregivers must be trained in suctioning, positive-pressure
resuscitation, stoma and skin care, tracheostomy tube and tie changes,
cleaning tubes, troubleshooting, and CPR prior to discharge from the hospital.
} Patients with tracheostomy should undergo routine airway evaluations to
evaluate airway anatomy, evaluate for complications, assess size and fit, and
determine readiness for decannulation.
} Long-term complications of tracheostomy include granulomas, fistulae,
erosions, infection, bleeding, and life-threatening obstruction of the tube.
} Decannulation can be considered in patients once the initial indication for
tracheostomy placement has resolved.
} Evaluation for decannulation includes direct laryngoscopy, bronchoscopy,
capping trials, downsizing of the tube, and/or polysomnogram.

1123
Acknowledgment
The author wishes to acknowledge Renée C. Benson, MD, and Manisha
Newaskar, MBBS, for their work on the previous version of this chapter.
References
1. Chang J, Sidell DR. Tracheostomy in infants in the neonatal intensive care unit. Neoreviews.
2020;21(5):e323–e334 PMID: 32358145 doi: 10.1542/neo.21-5-e323
2. Wetmore RF. Tracheotomy. In: Bluestone CD, Simons JP, Healy GB, eds. Pediatric
Otolaryngology. 4th ed. Saunders; 2014:1565–1580
3. Gergin O, Adil EA, Kawai K, Watters K, Moritz E, Rahbar R. Indications of pediatric
tracheostomy over the last 30 years: has anything changed? Int J Pediatr Otorhinolaryngol.
2016;87:144–147 PMID: 27368463 doi: 10.1016/j.ijporl.2016.06.018
4. Funamura JL, Durbin-Johnson B, Tollefson TT, Harrison J, Senders CW. Pediatric
tracheotomy: indications and decannulation outcomes. Laryngoscope. 2014;124(8):1952–1958
PMID: 24430892 doi: 10.1002/lary.24596
5. Lewis CW, Carron JD, Perkins JA, Sie KC, Feudtner C. Tracheotomy in pediatric patients:
a national perspective. Arch Otolaryngol Head Neck Surg. 2003;129(5):523–529
PMID: 12759264 doi: 10.1001/archotol.129.5.523
6. Shinkwin CA, Gibbin KP. Tracheostomy in children. J R Soc Med. 1996;89(4):188–192
PMID: 8676314 doi: 10.1177/014107689608900404
7. Corbett HJ, Mann KS, Mitra I, Jesudason EC, Losty PD, Clarke RW. Tracheostomy—a 10-year
experience from a UK pediatric surgical center. J Pediatr Surg. 2007;42(7):1251–1254
8. Rutter MJ, Hart CK. Tracheotomy. In: Potsic WP, Cotton RT, Handler SD, Zur KB, eds.
Surgical Pediatric Otolaryngology. 2nd ed. Thieme; 2016:360–370
9. Yoon PJ. The infant tracheostomy. Operative Techniques in Otolaryngology—Head Neck Surg.
A2005;16(3):183–186 doi: 10.1016/j.otot.2005.05.010
10. Roberts J, Powell J, Begbie J, et al. Pediatric tracheostomy: a large single-center experience.
Laryngoscope. 2020;130(5):E375–E380 PMID: 31251404 doi: 10.1002/lary.28160
11. Sherman JM, Davis S, Albamonte-Petrick S, et al. American Thoracic Society statement: care
of the child with a chronic tracheostomy. Am J Respir Crit Care Med. 2000;161(1):297–308
PMID: 10619835 doi: 10.1164/ajrccm.161.1.ats1-00
12. McCool FD. Global physiology and pathophysiology of cough: ACCP evidence-based
clinical practice guidelines. Chest. 2006;129(1)(suppl):48S–53S PMID: 16428691
doi: 10.1378/chest.129.1_suppl.48S
13. Van Oostdam JC, Walker DC, Knudson K, Dirks P, Dahlby RW, Hogg JC. Effect of breathing
dry air on structure and function of airways. J Appl Physiol. 1986;61(1):312–317 PMID: 3733618
doi: 10.1152/jappl.1986.61.1.312
14. Abraham SS, Wolf EL. Swallowing physiology of toddlers with long-term tracheostomies:
a preliminary study. Dysphagia. 2000;15(4):206–212 PMID: 11014883
doi: 10.1007/s004550000029
15. Norman V, Louw B, Kritzinger A. Incidence and description of dysphagia in infants and
toddlers with tracheostomies: a retrospective review. Int J Pediatr Otorhinolaryngol.
2007;71(7):1087–1092 PMID: 17482279 doi: 10.1016/j.ijporl.2007.03.018
16. Fitton C, Myers C. Home care of the child with a tracheostomy. In: Myer C, Cotton R, Shott S,
eds. The Pediatric Airway: An Interdisciplinary Approach. JB Lippincott; 1995
17. Hess DR. Facilitating speech in the patient with a tracheostomy. Respir Care.
2005;50(4):519–525 PMID: 15807915
18. Rusakow LS, Guarín M, Wegner CB, Rice TB, Mischler EH. Suspected respiratory tract
infection in the tracheostomized child: the pediatric pulmonologist’s approach. Chest.
1998;113(6):1549–1554 PMID: 9631792 doi: 10.1378/chest.113.6.1549
19. Toder DS, McBride JT. Home care of children dependent on respiratory technology. Pediatr Rev.
1997;18(8):273–280 PMID: 9255994 doi: 10.1542/pir.18.8.273
20. Zenk J, Fyrmpas G, Zimmermann T, Koch M, Constantinidis J, Iro H. Tracheostomy in young
patients: indications and long-term outcome. Eur Arch Otorhinolaryngol. 2009;266(5):705–711
PMID: 18766359 doi: 10.1007/s00405-008-0796-4

1124
21. Leung R, Berkowitz RG. Decannulation and outcome following pediatric tracheostomy. Ann
Otol Rhinol Laryngol. 2005;114(10):743–748 PMID: 16285263 doi: 10.1177/000348940511401002
22. Clark K. Tracheotomy. In: Hilman BC, ed. Pediatric Respiratory Disease: Diagnosis and
Treatment. WB Saunders; 1993

CHAPTER
63
Home Ventilation
Howard B. Panitch, MD
CASE REPORT 63-1

A neonate was born at 24 weeks’ gestation weighing 20.36 oz (570 g). He
developed respiratory distress and underwent endotracheal intubation and
mechanical ventilation. Following stabilization, repeated efforts to wean
ventilatory support resulted in episodes of respiratory distress and weight
loss. At 5 months of age, he underwent elective tracheostomy placement
to facilitate long-term mechanical ventilation. Following an interdisciplinary
team meeting with the child’s family where options for his ongoing care were
discussed, the family expressed a desire to bring him home while he was still
being supported by mechanical ventilation. Over the ensuing 8 weeks, his
parents learned all aspects of their child’s medical care, including how to
suction and change his tracheostomy tube, how to assess his respiratory
status, and how to ventilate him manually in the event of a ventilator failure.
The necessary equipment and skilled nursing services were arranged, and the
child was successfully discharged from the hospital at 8 months of age. With
assisted ventilation and ongoing interdisciplinary and nutritional support, he
demonstrated both somatic and developmental catch-up, and his respiratory
status improved. He completely weaned off mechanical ventilation by age
17 months and had his trachea decannulated by age 20 months.
History and Epidemiology of

Pediatric Home Mechanical Ventilation
Chronic respiratory failure (CRF) can be defined as the need for mechanical
ventilatory support for at least 4 hours per day for a month or longer.1 The
concept of supporting patients with CRF at home arose during the polio
epidemics of the late 1940s and early 1950s, both because of the numbers
of patients versus the number of available acute care beds and the desire of
families to have their loved ones home.
1125

1126
The medical indications for chronic ventilatory support have shifted over
time. In the 1970s and 1980s, the group of children with CRF comprised
infants with chronic respiratory disease, children with anoxic encephalopathy,
and infants surviving formerly fatal congenital anomalies.2 Infants chronically
dependent on ventilatory support were identified as having a new form of
disability, and were considered “a creature of our new technology.”3 Over
the last 3 decades, the population most likely to require chronic ventilatory
support at home has shifted again, from survivors of neonatal disease to
children with underlying neuromuscular or central nervous system diseases.4,5
As the types of patients receiving mechanical ventilation at home have changed
over the years, the number of children receiving such care has continued to
increase. In 1987 there were an estimated 600 to 2,000 children dependent
on ventilatory support in the United States.6 In Massachusetts, a 2005 survey
of children supported by mechanical ventilation outside of an acute care hos-
pital showed an almost threefold increase in number when compared with
numbers derived from a similar survey conducted 15 years earlier. A similar
shift was seen in the reasons for mechanical ventilation from children born
prematurely with chronic lung disease to those with neuromuscular and central
nervous system conditions.4 Data extrapolated from the Pennsylvania Ventila-
tor Assisted Children’s Home Program provided estimates of approximately
8,000 children receiving some type of home mechanical ventilation in the
United States in 2012.7
Goals of Home Mechanical Ventilation

No matter what the diagnosis is, growing up in an acute care hospital is
considered detrimental to a child’s overall health and development. Children
who receive their respiratory support in hospitals for prolonged periods are at
risk for nosocomial infection, in part because resistant bacteria are selected for
in hospital environments and also because other children with communicable
diseases from the community are admitted into the hospital and increase the
risk of exposure. Growth and development are enhanced when hospitaliza-
tion can be shortened, in part because therapies and play activities can occur
according to the child’s schedule at home rather than fit into regimented days
with caregivers who are responsible for the care of several other children as
well. In addition to the drawbacks for the child, caring for children in acute
care hospitals is expensive, and excellent quality care can typically be
accomplished for less in the home environment.1,8
The goals of home mechanical ventilation are listed in Box 63-1. In the hos-
pital, assisted ventilation represents an impediment to advancing to the next
step of rehabilitation and eventual discharge; thus, the focus is on withdrawing
support even at the expense of increasing the patient’s own breathing effort.

1127
Chapter 63—Home Ventilation
Since the patient requiring home ventilation is no longer taking up the

limited resources of a hospital, weaning can proceed as the natural outcome
of growth, development, and rehabilitation. For some children, as the under-
Box 63‑1 lying disease improves
and growth and devel-
Goals of Home Mechanical Ventilation opmental milestones
ū Extend life and enhance its quality are achieved, mechani-
ū Reduce morbidity and risk of nosocomial infection cal ventilatory support
ū Improve physiological function becomes less needed
ū Achieve normal growth and development and finally unnecessary.
whenever possible This philosophy is the
ū Optimize habilitative potential key to understanding
many of the factors
ū Reintegrate with home and community
that are considered in
ū Reduce health care costs
the weaning process
Derived from O’Donohue WJ Jr, Giovannoni RM, Goldberg AI, et al. of children with CRF,
Long-term mechanical ventilation. Guidelines for management in as discussed in the
the home and at alternate community sites. Report of the Ad Hoc
Committee, Respiratory Care Section, American College of Chest
following sections.
Physicians. Chest. 1986;90:1S–37S.
Causes of Chronic Respiratory Failure

Ventilatory muscle power and central respiratory drive need to be adequate to
overcome the respiratory load to achieve adequate ventilation (Figure 63-1).
Ventilatory
Central
Respiratory Muscle
Drive
Load Power
The
Respiratory
Balance
Respiratory Adequate
Failure Ventilation
Figure 63–1. The respiratory balance: Ventilatory muscle power and central respiratory drive
must be sufficient to overcome the respiratory load to achieve adequate ventilation. Respiratory
failure results when ventilatory muscle power and/or central drive are decreased, and/or the
respiratory load is increased.

1128
Respiratory failure occurs when ventilatory muscle power and/or central

respiratory drive are sufficiently decreased, and/or the respiratory load
is sufficiently increased, to the point that a child cannot achieve adequate
ventilation. Conditions
Box 63‑2 that cause respiratory
Conditions for Which Home Mechanical failure in children can be
Ventilation Might Be Considered broadly considered within
Thoracic/Intrathoracic the context of disorders
ū Obstructive lung disease of the respiratory pump
• Chronic lung disease of infancy (the chest wall, ventral
(bronchopulmonary dysplasia) abdominal wall, and
• Tracheomalacia muscles of respiration),
• Cystic fibrosis respiratory control center
ū Restrictive lung disease abnormalities, lung paren-
• Neuromuscular diseases chymal abnormalities, and
• Chest wall disorders airway anomalies. One way
• Spinal cord injury to categorize these condi-
• Lung hypoplasia tions is shown in Box 63-2.
• Recurrent aspiration syndromes In general, a patient’s suit-
Extrathoracic ability for home mechanical
ū Craniofacial malformations ventilation has less to do
ū Obstructive sleep apnea with the underlying diag-
Central Control nosis than with the degree
ū Congenital central hypoventilation syndrome of medical stability and the
ū Brain/brain stem injury extent of support available
ū Central nervous system tumors for home care.
Clinical Features of Chronic Respiratory Failure

Often, CRF follows an acute illness from which the child does not recover com-
pletely. In such situations, it is not possible to reduce ventilatory support because
respiratory distress or signs of respiratory insufficiency quickly ensue. In other
situations, the effects of respiratory failure are more insidious. Because nobody
breathes as well during sleep as they do when awake, children with progres-
sive neuromuscular diseases, for example, develop sleep-disordered breathing
before inadequate ventilation while awake. They may report frequent awaken-
ings and morning headaches when nocturnal hypoventilation is present.9 As
respiratory muscle weakness progresses, daytime fatigue, poor school function-
ing, and weight loss will ensue. Older children and adolescents with respiratory
muscle weakness who chronically breathe at low tidal volumes eventually
develop reduced chest wall compliance as ligaments and tendons stiffen and
ankylosis of the costovertebral joints develops,10 adding to the load against
which respiratory muscles have to work.

1129
Respiratory load can also increase because of airway obstruction from

uncontrolled bronchospasm or during acute viral illnesses, with atelectasis
or pneumonia, or when mechanical ventilator support is weaned too aggres-
sively. When the respiratory load increases, the work of the respiratory pump
must also increase to avoid failure. This work of increasing respiratory pump
expenditure to attain near-normal gas exchange often comes at the expense of
growth,11 energy for play, or acquisition of developmental milestones. Inade-
quate ventilatory support can also be associated with hypoxemia, and even
intermittent hypoxemia can lead to pulmonary hypertension, cor pulmonale,
right heart failure, and neurodevelopmental damage.
Mechanical ventilation can be used to provide occasional breaths that are
larger than tidal volume (sigh breaths) to maintain chest wall flexibility and
reverse areas of microatelectasis that occur after prolonged low tidal volume
breathing. By shifting inspiratory work from the muscles of ventilation to the
mechanical ventilator, calories can be conserved and redistributed for somatic
growth and other physical (developmental) activities. Ventilatory support
improves sleep quality in patients who have sleep-related hypoventilation,9
and restoration of normal gas exchange can often help reverse pulmonary
hypertension and cor pulmonale.
Patient Selection for Home Ventilation

There are several criteria that must be fulfilled to consider a child eligible for
home ventilation, independent of the cause of CRF. These include medical,
social, and economic factors. If a child with a life-threatening condition or
irreversible, progressive respiratory failure does not meet the usual criteria
but would be better managed in the home environment, a shared decision-
making approach with the family should be used and assessment must
be individualized.
Medical Stability
The child must fulfill both physiological and clinical requirements for safe
care outside of the intensive care unit (ICU) (Box 63-3). Physiological criteria
refer to the child’s airway and gas exchange capabilities. The child’s airway
must be stable, whether it is the natural airway or an artificial one. A stable
airway means that, under usual circumstances, (1) there is a patent passage
from atmosphere to alveoli, (2) any artificial airway will remain in place
despite movement of the child, and (3) tube repositioning, if it occurs, does
not require routine radiographic confirmation. Children with parenchymal
lung disease should be able to maintain a Pao2 above 60 mm Hg in a fraction
of inspired oxygen (Fio2) less than 0.40 while on ventilatory support. This
is not only a practical consideration (it is technically difficult to maintain
a supply of home oxygen when demands are greater than 0.50) but also

1130
Box 63‑3
Determinants of Medical Stability for Ventilator-Dependent
Children Outside of the Intensive Care Unit
Physiological Criteria
ū Stable airway
ū Parenchymal lung disease
• Pao2 > 60 mm Hg in Fio2 < 0.40 on ventilatory support
• Paco2 < 50 mm Hg on ventilatory support
ū Chest wall/neuromuscular disease
• Pao2 > 60 mm Hg in room air on ventilatory support
• Paco2 < 45 mm Hg on ventilatory support
ū No need for frequent ventilator changes to maintain
adequate gas exchange
Clinical Criteria
ū Positive trend on growth curve
ū Stamina for periods of play or therapies
ū No frequent fevers or infections
ū Resolution of any outstanding medical issues requiring
evaluation
Abbreviations: Fio2, fraction of inspired oxygen; Paco2, partial pressure of arterial

carbon dioxide; Pao2, partial pressure of arterial oxygen.
somewhat of a pragmatic one: it suggests that the child has some degree of
reserve so that in the event of a mild illness, the child’s condition is unlikely
to deteriorate precipitously and the child might be able to be cared for through
the acute illness at home. The child’s Paco2 should be less than 50 mm Hg on
the current level of ventilatory support. In the case of children with respira-
tory failure from causes other than parenchymal lung disease, the Pao2 and
Paco2 should both be normal on ventilatory support without the need for
supplemental oxygen. Frequent changes in ventilator settings should not be
required to maintain adequate gas exchange.
Clinical criteria that must be satisfied include a positive trend on the growth
curve for infants and young children or weight maintenance for older chil-
dren, stamina for periods of play or participation in therapy sessions, freedom
from infection or frequent fevers, and resolution of any outstanding diagnostic
considerations. Other medical conditions should be controlled similarly, such
that frequent alterations to the medical plan are not required to maintain the
child’s stability. Once a decision has been made to send a child home on
mechanical ventilatory support, there must be a predefined period, which
can range from 1 to 4 weeks before the planned discharge, where no changes
are made to any aspect of the medical regimen.12 In this way, the treating
team gains understanding of how the patient is tolerating the current level of

1131
support. Furthermore, the care team is better able to smooth the transition
to home, which often is a tumultuous time, and unexpected medical issues
resulting from a change in support are avoided.
CASE REPORT 63-2

A neonate with a congenital diaphragmatic hernia and severe pulmonary
hypoplasia received support with extracorporeal membrane oxygenation
therapy for 19 days and underwent patch repair of her defect at 9 days of age.
She developed persistent pulmonary hypertension that was managed with
chlorothiazide and sildenafil. A tracheostomy was placed to facilitate chronic
mechanical ventilation at 3 months of age. Her parents discussed home care
issues with the care team and learned all aspects of their daughter’s medical
care. At the same time, a home equipment company and nursing agency were
identified. The home was assessed for adequacy of supporting the child, and
the care team and insurance case managers agreed on the amount of nursing
care and types of durable and disposable equipment that would be covered
by the insurance company. Episodically, however, the infant experienced
severe spells of respiratory distress, with oxyhemoglobin desaturation, diapho-
resis, and poor air entry on chest auscultation. Treatment of the spells typically
required sedation rescues, a temporary increase in positive end-expiratory
pressure, and increased Fio2. The planned discharge was suspended. Evalua-
tion disclosed severe gastroesophageal reflux despite the use of acid blockers
and motility agents. The infant underwent fundoplication and placement of
a gastrostomy tube at 4 months of age. Following recovery from her surgery,
she experienced a 2-week period without spells. Over the same time, no
changes were made to any of her medications or ventilator settings. At
5 months of age, she was considered to be safe for home care and was
successfully discharged home using continuous mechanical ventilation
and medications for the treatment of her pulmonary hypertension.
Caregiver Training
Early in the process of identifying a child as a candidate for home ventilation,
the family must agree to the concept and be willing and able to learn all
aspects of the child’s medical care. A brief checklist of the issues that need to
be addressed before a child can be safely discharged using assisted ventilation
is presented in Box 63-4. There should be at least 2 adults available to learn
the care, although additional family members should be encouraged to learn
as well, to provide support to the primary caregivers. This will require family
caregivers to understand the ventilator or bilevel pressure generator and its
circuit, issues related to the patient/machine interface (eg, tracheostomy care
or skin care for noninvasive ventilation), a general respiratory assessment
and what to do in emergency situations, and all aspects of the child’s medical
regimen. Special attention should be paid to educating families on how to

1132
Pediatric Pulmology
Box 63‑4
Checklist of Items Required for Safe Home Ventilation Discharge
Caregiver training (2 people)
ū Ventilator and monitors
ū Tracheostomy or noninvasive interface
ū Airway clearance equipment
ū General respiratory assessment
ū Medications
ū Cardiopulmonary resuscitation
ū Responses to potential emergency situations in the home
Identification of home care providers
ū Primary care provider
ū Skilled nursing agency
ū Durable medical equipment company with 24-hour emergency availability
ū Local ambulance service/emergency care facility
Written agreement with insurance company of what and how much will be covered
ū Durable and disposable equipment
ū Hours of skilled nursing
ū Therapies
Home assessment and any necessary modifications
ū Adequate space for equipment and personnel
ū Electrical, water, heat
ū Generator if frequent power outages are expected
ū Telephone
ū Ramps or elevators
Notification to community services
ū Electrical company to provide priority services in the event of interruption
of service and medical discount utility rate
ū Local ambulance service/emergency department
ū Telephone company to provide priority services in the event of interruption
of service
ū School
Prescriptions filled
All necessary equipment and supplies delivered to home before discharge
Child adequately supported on home equipment in the hospital 1 to 7 days
handle emergency situations in the home. Family members and in-home

nurses often lack knowledge in this area.13 A curriculum focused on response
to in-home emergencies should be given to all caregivers.14 The family also
should have some understanding of the child’s underlying condition that has
caused the CRF. The primary caregivers do not necessarily need to be the

1133
child’s biological parents; in single-parent homes, a grandparent, close friend,

or neighbor can be the backup caregiver. Given the plethora of information
and skills that family members must acquire, the family can expect the pro-
cess to take 6 to 8 weeks between the time that they commit to taking the
child home and being prepared to do so.
Preparing the Home
The home environment must be adequate to support a child who requires
ventilatory support. There must be sufficient space for the equipment and
additional personnel who will be caring for the child, as well as adequate heat,
electricity, and water supply. A working telephone is critical, as the telephone
becomes the lifeline between the family and the child’s medical caregivers. A
child who is confined to a wheelchair will require alterations to the home for
access and egress. If the child lives in a remote area, or in an area where power
outages are frequent, it is prudent for the family to have a backup generator.
When the child lives a distance from the discharging tertiary care center, com-
munity resources such as the local hospital’s emergency department and local
ambulance service must be identified, so that the child can be stabilized and
transported in the event of an acute illness.
Skilled Nursing Care
Care of a child with CRF at home is stressful for parents, and parental stress
has been shown to increase with duration of time at home.15 Skilled nursing
care is often prescribed to help parents cope with the extraordinary demands
of caring for the child. Any child who would experience life-threatening
respiratory embarrassment if the ventilator interface were to become inadver-
tently disconnected or obstructed, and who would be unable to physically
correct the problem, should receive a minimum of 8 hours of skilled nursing
care. In this way, parents can be assured that a trained adult is available to
assess and intervene on their child’s behalf while they sleep. The nurse pro-
vides care as directed by a written medical plan and provides ongoing assess-
ments and documentation of the child’s medical status as well as the family’s
level of functioning. The nurse can also teach and reinforce procedures and
assessment skills that were introduced to the family during the initial hos-
pitalization of the child. The home care nurse must be knowledgeable and
proficient in all aspects of high-technology home care, including function of
home ventilators, assessment of respiratory and cardiac status, care of long-
term tracheostomies or nasal interfaces, use of airway clearance techniques
and devices, and appropriate responses to emergency situations.
Depending on the medical needs of the child, up to 24 hours per day of nursing
care may be necessary for the safety and well-being of the child.16 Nursing care
represents the most expensive aspect of home mechanical ventilation.1 Never-
theless, there are no uniform criteria to determine the quantity or duration of
nursing care that children who require ventilatory support should receive.

1134
The period following the initial discharge of the child is perhaps the most
tenuous with regard to achieving a successful transition from hospital to
home care. For this reason, many advocate that families receive around-the-
clock nursing care for 1 to 2 weeks until the child’s home regimen is well-
established, after which the number of nursing hours provided can be reduced
based on the child’s status and level of the family’s functioning.16 The number
of nursing hours funded by third-party payers may require temporary increases
during periods of acute illness of the child or family caregivers. In addition,
the well-being of caregivers demands a rational approach to providing funded
periods of respite care for families.17 The need for respite care services, to
allow families some time off from the highly stressful duties of caring for a
child supported by mechanical ventilation, has been repeatedly identified both
by parents and experts in the field as essential and a mechanism to help avoid
a care crisis or family breakdown.16,18,19 Presently, however, respite care is not
routinely funded by insurers; therefore, families or home ventilation programs
have to find alternate sources of funding for these services.
Sometimes, nursing agencies cannot provide in-home nursing due to illness of
the nurse, nursing shortages, etc. Therefore, the family must be fully trained to
provide all aspects of the child’s care when in-home nursing is not available.20
Economic and Payment Issues

Home mechanical ventilation is purported to be cost saving when compared
with caring for children in ICUs.1 Nevertheless, it is still expensive and beyond
the financial capabilities of most families. Thus, funding for durable medical
equipment (DME), nursing services, disposable supplies, medications, and
specialized formulas all must be established and guaranteed. This is typically
accomplished through third-party payers, state Medicaid programs, or model
waiver programs. Since the establishment of the Katie Beckett Waiver in
1982, children who require ventilatory assistance are eligible for Supplemental
Security Income (SSI) independent of their parents’ income to help offset costs
related to their care. The items and services that these programs will cover
must be established before the child is discharged from the hospital to avoid
unexpected catastrophic financial burdens for the family. Some expenses that
are bundled into a hospital stay will become out-of-pocket costs for families,
such as medications or formula. The home electric, water, and telephone bills
are also likely to increase. However, medical discount utility rates are often
available for electricity and telephone. Each family must consider this in their
decision to bring the child home. Families must also try to anticipate the effect
of lost income related to the child’s unexpected illnesses and if there is no nurse
available. By discussing these issues early in the discharge process, the family
can often make contingency plans, seek additional funding from other commu-
nity resources, or devise alternate strategies to make up any shortfalls.21

1135
Organizational Issues
Successful discharge from the hospital of a child who receives ventilatory
support requires the efforts and input of a multidisciplinary team that includes
appropriate medical subspecialists; case managers; nurse coordinators; social
workers; nutritionists; respiratory, speech, physical, and occupational therapists
from the discharging institution; a case manager from the insurance company;
and the primary care physician and home nursing and DME company person-
nel in the community.19,20 While no single care model is used universally to
support patients following hospital discharge, home ventilation programs
should provide family- and patient-centered care in a medical home model.20
Local customs and practices often dictate roles of various providers, but
comanagement between professional caregivers in the community, the pri-
mary care provider, appropriate subspecialists determined by the child’s
medical needs, and members of the hospital-based home ventilation
program is the approach most likely to provide such care successfully.20
The complexity of care of children supported by mechanical ventilation
will be exacerbated by social inequities. Financial stresses and lack of family
resources can make such care disruptive or even untenable. Limitations in
transportation can result in missed visits and compromised care. While tertiary
care centers usually have translation services, language barriers can still exist
between families and community caregivers, including home nurses. Care-
givers, in accordance with ideals of the medical home, must ensure equal
access to care that is culturally competent and that addresses social
determinants of health.
Any child who receives skilled nursing care at home must also have a set of
written medical orders. These encompass everything from the recommended
ventilator settings and routine medication regimen to frequency of vital signs,
the types of monitoring to be used, the amount of skilled nursing the child
should receive, the type and frequency of airway clearance to provide, and
the nutritional plan. Actions to take in case of a change in the child’s medical
status, such as the range of supplemental oxygen permissible, frequency of
extra bronchodilator aerosol treatments to be given, or other changes in sup-
port, are documented as well. The initial plan is written by the discharging
team before the child first leaves the hospital, but it must be reviewed periodi-
cally. This review can be the responsibility of the primary care physician or
the subspecialist (usually a pulmonologist or critical care medicine physician)
who monitors the child’s ventilator care.
The role and responsibilities of the primary care physician will vary depend-
ing on the level of comfort of the physician regarding the care of a child who
requires mechanical ventilation, prior training, proximity of the patient to
the tertiary care center, regional customs of care delivery, and established

1136
relationships with the family.22 In general, the primary care physician is the
person responsible for general pediatric care, but, as noted previously, this
professional may also want to be responsible for care plan review and even
ventilator management. In some programs, a multidisciplinary team of
pulmonologists, advanced practice nurses, social worker, nutritionist, and
therapists provide ongoing care through telephone contact and scheduled
outpatient visits, and work in concert with the primary care physician to
ensure continued success of the child and family at home. Patients are seen for
routine visits at intervals from 1 to 6 months, depending on their underlying
disease, expected trajectory regarding weaning, and degree of illness. In
many programs in the United States, when children require rehospitaliza-
tion, they return to the discharging institution. In contrast, in other systems
like that of the United Kingdom, when a child is discharged home with
ventilatory support, the care of the child is also transferred from the tertiary
care center to a community health care team.23
Modes of Mechanical Ventilation

Most types of mechanical ventilation provided at home involve the application
of positive pressure to the airway, although negative pressure and positive-
pressure body ventilators are occasionally used. Whether a child receives
positive pressure noninvasively or invasively depends on several factors, as
listed in Box 63-5. In general, if a child cannot control secretions, requires
support for more than 16 hours per day, has facial features that make a stan-
dard nasal interface difficult to use, or is not (or the child’s caregivers are not)
committed to a noninvasive approach, then tracheostomy placement should
be considered to facilitate assisted ventilation. At times, supporting a young
child with noninvasive ventilation can increase the complexity of care for
families who must also manage airway clearance and provide physical and
other therapies. In these situations, placement of a tracheostomy can actually
simplify care, even though the caregivers must learn additional skills related
to tracheostomy management. Thus, the decision to manage a child with
invasive or noninvasive ventilation is a highly individualized one.
The mode of ventilation, whether pressure or volume controlled, is also a
choice that is individualized. There are no data that generally support one style
over the other, and newer portable mechanical ventilators designed for home
Box 63‑5
Factors to Consider for Noninvasive Versus
Tracheostomy Positive-Pressure Ventilation
ū Level of consciousness ū Adequacy of available interfaces
ū Ability to control oral secretions ū Willingness of patient and family
ū Duration of daily support ū Caregiver skills and aptitude

1137
use can provide either method of support. Occasionally, one style is preferred
over the other. For example, volume control ventilation in patients with neuro-
muscular weakness provides an option for breath stacking and lung volume
recruitment that cannot be accomplished in a pressure control mode. In con-
trast, when leak around a tracheostomy is large, ventilation in a volume control
mode will be unreliable and can lead to significant episodes of hypoventilation.24
In this situation, pressure-controlled ventilation can help overcome the leak and
avoid the need for a cuffed tracheostomy tube. An uncuffed tracheostomy tube
that is small relative to the diameter of the airway is preferred when possible,
because the leak around the tube permits speech. Use of a small tracheostomy
tube also decreases the risk of tracheomalacia; use of a large tube, which can
compress the tracheal mucosa and compromise blood flow, can result in
tracheomalacia or tracheal stenosis.
Equipment and Monitoring

There is no single home mechanical ventilator that is the most appropriate
for all situations. Current models provide continuous flow and are capable of
giving pressure support during spontaneous efforts. They differ from each
other in size and weight, circuit configurations they support, trigger and cycle
sensitivities, and special algorithms used for monitoring patient-ventilator
interactions. The model of ventilator or bilevel pressure generator should be
chosen based on its ability to deliver the mode of support prescribed, adequate
trigger and cycle sensitivity, and portability (for those who require support
for most of the day).25 Accompanying equipment for the ventilator will vary,
depending on whether the child receives support via tracheostomy or noninva-
sively.2 Children who cannot be independent of mechanical ventilation for at
least 4 hours of the day, or who live more than 1 to 2 hours from their DME
company or health care facility, should have a second complete ventilator and
circuit in the event that the primary unit fails,26 although this is uncommon.27
While all portable ventilators have alarms to detect obstruction, accidental
disconnection, or decannulation, these are not adequate to be used as the
sole means of monitoring patients. This is especially true for children with
tracheostomy tubes that have inside diameters smaller than 4.5 mm, where
high tube resistance can mask an inadvertent tracheal decannulation.28 A moni-
tor on the patient, which alarms separately from ventilator alarms, is required.
Such monitoring is typically needed at minimum when the child is asleep or
not in direct line of sight of an awake and vigilant caregiver. There is, however,
no consensus regarding the type and extent of monitoring to be used beyond
that supplied by the ventilator. Pulse oximetry can be used both as a routine
monitoring device and as an aid in adjusting ventilator settings during acute
illnesses, or as a monitoring device during weaning of the patient if appro-
priate. Cardiorespiratory monitors are advocated by some2 but considered

1138
redundant by others.29 Continuous capnometry is not indicated for patients

at home, but intermittent determinations of end-tidal carbon dioxide can be
useful to assess adequacy of ventilation, especially during weaning trials or
during acute illnesses. At present, transcutaneous carbon dioxide determina-
tions are not routinely performed in the home, but advances in monitor
technology may make such measurements more commonplace, especially
in individuals supported by noninvasive ventilation.
Long-term Outcomes of Home Mechanical Ventilation

Outcomes of children who depend on ventilatory support can be gauged in
terms of survival, ability to wean from support, quality of life of the child,
and quality of life of the caregivers. In general, survival is considered quite
good. Factors to consider regarding survival include the natural history of the
underlying disease (ie, is the child’s underlying condition expected to improve
over time, remain static, or worsen) and whether the child is supported
noninvasively or via tracheostomy.
Recent reports of outcomes of children supported at home by mechanical
ventilation represent single-center experiences. In general, all reflect that
home mechanical ventilation extends life. The cumulative survival at 5 and
10 years among 228 children who receive chronic mechanical ventilation via
tracheostomy was 80% (95% CI, 75%–85%) and 63% (95% CI, 51%–73%),
respectively.30 In a center that followed 379 children ventilated both invasively
(17%) and noninvasively (83%), 324 children (86.5%) survived over 20 years
of follow-up, while 106 (28%) transitioned to adult care. Similarly, another
center that used only noninvasive ventilation in 449 children younger than 18
years of age over an 18-year period reported survival in 340 (76%), with 181
(40%) transitioning to adult care.31 Chronic mechanical ventilation does not
reverse the respiratory failure associated with a progressive parenchymal
disease like cystic fibrosis,32 but it does contribute to a longer survival of
patients with neuromuscular disease after the onset of respiratory failure.33
The presence of a tracheostomy adds a small but significant survival risk
because of the possibility of inadvertent decannulation, tube obstruction,
and, less commonly, serious bleeding from erosion of the tube into a major
vessel. Furthermore, life-threatening tracheostomy-related accidents are
more likely to occur in the home than in the hospital. In one review, life-
threatening airway accidents in children who receive chronic mechanical
ventilation by tracheostomy occurred among hospitalized children at a rate
of 0.9/10,000 patient days, whereas the rate at home was almost 3 times greater,
or 2.3/10,000 patient days.34 Among the 47 deaths reported in a group of
children invasively mechanically ventilated at home, 19% were related to a
tracheostomy complication.30

1139
Other outcomes frequently measured in children who receive mechanical

ventilatory support outside of the ICU are reduction of mechanical ventila-
tor support to fewer than 12 hours per day and complete liberation from
mechanical ventilation.35 The likelihood that a child with CRF will wean
from mechanical ventilation is greatly influenced by the underlying cause of
respiratory failure. Children with chronic lung disease after prematurity or
a central airway problem like tracheomalacia are less likely to require long-
term mechanical ventilation compared with children who have underlying
neurologic or neuromuscular conditions.30,35 In the home setting, 18% to
59% of children with CRF can be liberated from mechanical ventilation,
most of whom are infants with a history of chronic lung disease or a
central airway disorder.30,36
In general, patients supported by home mechanical ventilation view it posi-
tively. Its use is associated with improved physiological function and sleep
quality, and fewer rehospitalizations.9,33,37 Home ventilation of 23 males with
Duchenne muscular dystrophy not only resulted in 1- and 5-year survival rates
of 85% and 73%, respectively, but nocturnal ventilatory support also normal-
ized daytime unassisted oxygen and carbon dioxide values.33 Among 15 chil-
dren with neuromuscular diseases who received noninvasive mechanical
ventilation at home, there was an 85% reduction in the number of hospital days
after initiation of mechanical ventilation compared with the pre-ventilation
period.9 In another retrospective series, patients experienced an average of
only 0.7 rehospitalizations per year over the 20-year observation period.38
Adjustment to Mechanical Ventilation at Home

Home ventilation is psychologically acceptable to the children who use it.39
Interviews with 38 children requiring ventilatory support showed that 79%
were satisfied with their quality of life.40 Most (77%) were also considered
to be well-adjusted. Adolescents were, in general, less content with their daily
activities than were younger children, but greater satisfaction trended with
greater activity levels. Notably, quality of life did not correlate with whether
the child had required ventilatory support from birth or acquired respiratory
failure later in life, with duration of ventilation at home, or with the child’s
disease being static or progressive.
Although children who require ventilatory support have expressed concern
about their health and being a burden to their families,18 their outlook toward
mechanical ventilation in general is a positive one, and mechanical ventilation
is considered a minor aspect of their lives.39,41 Furthermore, access to informa-
tion and communication technologies enhance their lives.39 One group noted
that 83% of their subjects left home each day to attend school, and many
reported traveling for vacations.38 Others note, however, that some children
who require mechanical ventilation feel isolated and stigmatized.41 Some

1140
children also express a concern that they are burdens to their families.18
Perhaps paramount in the discussion is that health care providers routinely
underestimate the quality of life of patients who require ventilatory support
and so might not consider chronic mechanical ventilation as a reasonable
choice for some patients.42
While children who use ventilatory support generally express satisfaction
with their general condition, the feelings of their family caregivers are more
complicated. Parents (or other family caregivers) commonly express that
having their child at home is both good and desirable, but they also speak
about the stresses of caring for their child. Parents frequently voice a fear of
having the child die at home.18 Several studies cite a lack of privacy associated
with home nursing care, as well as a concern for the quality of professional
care provided as sources of family stress.43,44 Financial concerns result not only
from increased expenses (utility bills, special formulas, medications), but also
from the loss of income that occurs when one spouse must remain home to
care for the child.21 Parents often feel isolated, since it is difficult or impossible
to find a babysitter who is trained to care for a child who requires ventilatory
support, and some public facilities restrict access to people with tracheostomies
or mechanical ventilators.18,43 Parents also experience frequent sleep disruption
to answer alarms or to provide care when nighttime nursing is not available.45
The degree of sleep disruption as well as ventilation via tracheostomy as
compared with noninvasive ventilation both contribute to worse parental
quality of life and family functioning.15 The stresses related to caring for a
child who is supported by mechanical ventilation increase over time.8 Despite
these hardships, parents would choose to do so again if given the choice.46
In general, both medical professionals and family members have a sense that
having the child at home improves both growth and developmental outcomes.
When to Admit
The general goal of chronic mechanical ventilation is to support the child’s
growth and development. These, therefore, must be monitored routinely by
either the primary care provider or the team that manages the child’s ventila-
tor care. Adjustments to routine care, including a change in ventilator
settings, can be achieved without the need for hospitalization. If ventilator
support is being gradually weaned, weekly status updates with the caregivers
should be arranged by phone. Acute illnesses often can be cared for without
the need for emergency department or hospital visits. Tracheal samples and
even appropriate blood work can be obtained at home and sent for analysis
with advanced planning. Antibiotic therapy can be instituted, and bronchodila-
tor administration can be started or increased based on reports and observa-
tions of home nurses or family caregivers. Ventilatory support can also be
adjusted based on reports of physical examination, pulse oximetry, and
capnography evaluations. It is imperative that families always have ready

1141
access to a medical provider who can help them navigate where, how, and
which interventions should occur. Since the late 2010s, telemedicine has also
been used to assist in the assessment of patients, and the visual evaluation can
add to the information that parents or skilled caregivers transmit to the
provider. Use of remote ventilator downloads can also provide insight into
patient-ventilator interactions and assist with acute interventions.
Hospitalization for acute illnesses or deterioration in the patient’s status is
warranted any time anyone on the family/health care team feels uncomfortable
with the child’s situation. That means if the parent or home nurse is uneasy
about keeping the child home under current conditions, or if members of the
health care team do not feel that they have an adequate understanding of the
child’s status, hospitalization or a visit to the emergency department should be
recommended. Practical limitations of care delivery also will dictate hospital-
ization. This could include a need for supplemental oxygen beyond what
is deliverable in the home environment (eg, Fio2 > 0.50), or exhaustion of
caregivers, especially if skilled nursing care is not available. Return to the
hospital must never be seen as a hurdle for families, because this undermines
the relationship with the health care team. Rarely, children will be hospital-
ized electively for a comprehensive evaluation. Hospitalization, however,
is disruptive for the patient and the family and increases the child’s risk of
nosocomial infection; thus, this should occur only when the necessary tests
cannot be performed on an outpatient basis.
key points
} The indications for chronic home mechanical ventilation, and the number of
children so supported, continue to grow.
} Successful discharge of a child who needs ventilatory support requires careful
planning and intense training of family caregivers.
} Maintaining a child who is on home mechanical ventilator support requires a
patient- and family-focused care team that includes hospital-based multidisci-
plinary team of health care professionals, the primary care provider, community
health care professionals, and family working together with defined roles and a
written, shared care plan.
} Outcomes of children requiring ventilatory support generally are good and are
determined primarily by the prognosis of the underlying disease.
} While the practice of caring for a child with CRF at home on mechanical ventila-
tory support has become more commonplace, such care must be considered an
extraordinary commitment on the part of the health care team, and especially
on the part of the family who agrees to undertake this care.
} The remarkable efforts and needs of families and patients must be recognized
and supported by health care and societal systems so that they may achieve
optimal growth, development, and wellness.

1142
References
1. Downes JJ, Parra MM. Costs and reimbursement issues in long-term mechanical ventilation
of patients at home. In: Hill NS, ed. Long-Term Mechanical Ventilation. Marcel Dekker, Inc;
2001:353–374
2. Schreiner MS, Donar ME, Kettrick RG. Pediatric home mechanical ventilation. Pediatr Clin
North Am. 1987;34(1):47–60 PMID: 3468475 doi: 10.1016/S0031-3955(16)36180-6
3. Koop CE. The Surgeon General’s Workshop on Children with Handicaps and Their Families.
Keynote address. Clin Pediatr (Phila). 1983;22(8):567–571 PMID: 6222861
doi: 10.1177/000992288302200809
4. Graham RJ, Fleegler EW, Robinson WM. Chronic ventilator need in the community: a 2005
pediatric census of Massachusetts. Pediatrics. 2007;119(6):e1280–e1287 PMID: 17485451
doi: 10.1542/peds.2006-2471
5. Rose L, McKim DA, Katz SL, et al; CANuVENT Group. Home mechanical ventilation in
Canada: a national survey. Respir Care. 2015;60(5):695–704 PMID: 25587173
6. US Congress, Office of Technology Assessment. Technology-dependent children:
hospital v. home care—a technical memorandum. Washington, DC: US Government Printing
Office; May 1987. Report No: OTA-TM-H-38
7. Boroughs DS, Dougherty J. In-home care of the child on chronic mechanical ventilation.
In: Sterni LM, Carroll JL, eds. Caring for the Ventilator Dependent Child. Springer Science
and Business Media; 2016:165–183 doi: 10.1007/978-1-4939-3749-3_9
8. Quint RD, Chesterman E, Crain LS, Winkleby M, Boyce WT. Home care for ventilator-
dependent children. Psychosocial impact on the family. Am J Dis Child. 1990;144(11):1238–1241
PMID: 2239864 doi: 10.1001/archpedi.1990.02150350070028
9. Katz S, Selvadurai H, Keilty K, Mitchell M, MacLusky I. Outcome of non-invasive positive
pressure ventilation in paediatric neuromuscular disease. Arch Dis Child. 2004;89(2):121–124
PMID: 14736624 doi: 10.1136/adc.2002.018655
10. Estenne M, De Troyer A. The effects of tetraplegia on chest wall statics. Am Rev Respir Dis.
1986;134(1):121–124 PMID: 2942066
11. Loui A, Tsalikaki E, Maier K, Walch E, Kamarianakis Y, Obladen M. Growth in high risk
infants <1500 g birthweight during the first 5 weeks. Early Hum Dev. 2008;84(10):645–650
PMID: 18539413 doi: 10.1016/j.earlhumdev.2008.04.005
12. Kun SS, Edwards JD, Ward SL, Keens TG. Hospital readmissions for newly discharged pediatric
home mechanical ventilation patients. Pediatr Pulmonol. 2012;47(4):409–414 PMID: 21901855
doi: 10.1002/ppul.21536
13. Kun SS, Davidson Ward SL, Hulse LM, Keens TG. How much do primary care givers know
about tracheostomy and home ventilator emergency care? Pediatr Pulmonol. 2010;45(3):270–274
PMID: 20146395 doi: 10.1002/ppul.21169
14. Kun SS, Beas VN, Keens TG, Ward SS, Gold JI. Examining pediatric emergency home
ventilation practices in home health nurses: opportunities for improved care. Pediatr Pulmonol.
2015;50(7):691–697 PMID: 24706404 doi: 10.1002/ppul.23040
15. Israelsson-Skogsberg Å, Persson C, Markström A, Hedén L. Children with home mechanical
ventilation-Parents’ health-related quality of life, family functioning and sleep. Acta Paediatr.
2020;109(9):1807–1814 PMID: 31955457 doi: 10.1111/apa.15177
16. Panitch HB, Downes JJ, Kennedy JS, et al. Guidelines for home care of children with
chronic respiratory insufficiency. Pediatr Pulmonol. 1996;21(1):52–56 PMID: 8776267
doi: 10.1002/(SICI)1099-0496(199601)21:1<52::AID-PPUL9>3.0.CO;2-S
17. Parra MM. Nursing and respite care services for ventilator-assisted children. Caring.
2003;22(5):6–9 PMID: 12802851
18. Carnevale FA, Alexander E, Davis M, Rennick J, Troini R. Daily living with distress and
enrichment: the moral experience of families with ventilator-assisted children at home.
19. Sobotka SA, Gaur DS, Goodman DM, Agrawal RK, Berry JG, Graham RJ. Pediatric patients
with home mechanical ventilation: the health services landscape. Pediatr Pulmonol.
2019;54(1):40–46 PMID: 30461228 doi: 10.1002/ppul.24196
An official American Thoracic Society Clinical Practice Guideline: pediatric chronic home
doi: 10.1164/rccm.201602-0276ST

1143
21. Edwards JD, Panitch HB, Constantinescu A, Miller RL, Stone PW. Survey of financial burden
of families in the U.S. with children using home mechanical ventilation. Pediatr Pulmonol.
2018;53(1):108–116 PMID: 29152895 doi: 10.1002/ppul.23917
22. Goldberg AI, Monahan CA. Home health care for children assisted by mechanical
ventilation: the physician’s perspective. J Pediatr. 1989;114(3):378–383 PMID: 2921682
doi: 10.1016/S0022-3476(89)80554-2
23. Jardine E, Wallis C; UK Working Party on Paediatric Long Term Ventilation. Core guidelines
for the discharge home of the child on long-term assisted ventilation in the United Kingdom.
Thorax. 1998;53(9):762–767 PMID: 10319058 doi: 10.1136/thx.53.9.762
24. Gilgoff IS, Peng RC, Keens TG. Hypoventilation and apnea in children during mechanically
assisted ventilation. Chest. 1992;101(6):1500–1506 PMID: 1600764 doi: 10.1378/chest.101.6.1500
25. Fierro JL, Panitch HB. Transitioning from an ICU ventilator to a portable home ventilator.
Semin Fetal Neonatal Med. 2019;24(5):101041 PMID: 31662273 doi: 10.1016/j.siny.2019.101041
26. Make BJ, Hill NS, Goldberg AI, et al. Mechanical ventilation beyond the intensive care unit.
Report of a consensus conference of the American College of Chest Physicians. Chest.
1998;113(5)(suppl):289S–344S PMID: 9599593 doi: 10.1378/chest.113.5_Supplement.289S
27. Srinivasan S, Doty SM, White TR, et al. Frequency, causes, and outcome of home ventilator
failure. Chest. 1998;114(5):1363–1367 PMID: 9824015 doi: 10.1378/chest.114.5.1363
28. Kun SS, Nakamura CT, Ripka JF, Davidson Ward SL, Keens TG. Home ventilator low-pressure
alarms fail to detect accidental decannulation with pediatric tracheostomy tubes. Chest.
2001;119(2):562–564 PMID: 11171738 doi: 10.1378/chest.119.2.562
29. Kacmarek RM. Home mechanical ventilatory assistance for infants. Respir Care.
1994;39(5):550–561 PMID: 10146012
30. Edwards JD, Kun SS, Keens TG. Outcomes and causes of death in children on home mechanical
ventilation via tracheostomy: an institutional and literature review. J Pediatr. 2010;157(6):955–
959.e2 PMID: 20713294 doi: 10.1016/j.jpeds.2010.06.012
31. Chatwin M, Tan HL, Bush A, Rosenthal M, Simonds AK. Long term non-invasive ventilation in
children: impact on survival and transition to adult care. PLoS One. 2015;10(5):e0125839
32. Young AC, Wilson JW, Kotsimbos TC, Naughton MT. Randomised placebo controlled trial
of non-invasive ventilation for hypercapnia in cystic fibrosis. Thorax. 2008;63(1):72–77
PMID: 17675317 doi: 10.1136/thx.2007.082602
33. Simonds AK, Muntoni F, Heather S, Fielding S. Impact of nasal ventilation on survival in
hypercapnic Duchenne muscular dystrophy. Thorax. 1998;53(11):949–952 PMID: 10193393
doi: 10.1136/thx.53.11.949
34. Downes JJ, Pilmer SL. Chronic respiratory failure—controversies in management. Crit Care
Med. 1993;21(9)(suppl):S363–S364 PMID: 7689944 doi: 10.1097/00003246-199309001-00039
35. Kharasch VS, Haley SM, Dumas HM, Ludlow LH, O’Brien JE. Oxygen and ventilator weaning
during inpatient pediatric pulmonary rehabilitation. Pediatr Pulmonol. 2003;35(4):280–287
PMID: 12629625 doi: 10.1002/ppul.10253
36. Cristea AI, Carroll AE, Davis SD, Swigonski NL, Ackerman VL. Outcomes of children with
severe bronchopulmonary dysplasia who were ventilator dependent at home. Pediatrics.
2013;132(3):e727–e734 PMID: 23918888 doi: 10.1542/peds.2012-2990
37. Khan Y, Heckmatt JZ, Dubowitz V. Sleep studies and supportive ventilatory treatment in
patients with congenital muscle disorders. Arch Dis Child. 1996;74(3):195–200 PMID: 8787421
doi: 10.1136/adc.74.3.195
38. Gilgoff RL, Gilgoff IS. Long-term follow-up of home mechanical ventilation in young children
with spinal cord injury and neuromuscular conditions. J Pediatr. 2003;142(5):476–480
PMID: 12756376 doi: 10.1067/mpd.2003.47
39. Israelsson-Skogsberg Å, Hedén L, Lindahl B, Laakso K. ‘I’m almost never sick’: everyday life
experiences of children and young people with home mechanical ventilation. J Child Health
Care. 2018;22(1):6–18 PMID: 29298495 doi: 10.1177/1367493517749328
40. Lumeng JC, Warschausky SA, Nelson VS, Augenstein K; Julie C. Lumeng, Seth A. Warschausk.
The quality of life of ventilator-assisted children. Pediatr Rehabil. 2001;4(1):21–27
PMID: 11330847 doi: 10.1080/13638490151068438
41. Noyes J. Health and quality of life of ventilator-dependent children. J Adv Nurs.
2006;56(4):392–403 PMID: 17042819 doi: 10.1111/j.1365-2648.2006.04014.x
42. Gibson B. Long-term ventilation for patients with Duchenne muscular dystrophy: physicians’
beliefs and practices. Chest. 2001;119(3):940–946 PMID: 11243978 doi: 10.1378/chest.119.3.940

1144
43. Aday LA, Wegener DH. Home care for ventilator-assisted children: implications for the children,
their families, and health policy. Child Health Care. 1988;17(2):112–120 PMID: 10290557
doi: 10.1207/s15326888chc1702_9
44. Hazlett DE. A study of pediatric home ventilator management: medical, psychosocial, and
financial aspects. J Pediatr Nurs. 1989;4(4):284–294 PMID: 2760802
45. Meltzer LJ, Mindell JA. Impact of a child’s chronic illness on maternal sleep and daytime
functioning. Arch Intern Med. 2006;166(16):1749–1755 PMID: 16983054
doi: 10.1001/archinte.166.16.1749
46. Allen NL, Simone JA, Wingenbach GF. Families with a ventilator-assisted child: transitional
issues. J Perinatol. 1994;14(1):48–55 PMID: 8169678

INDEX
A Acute chest syndrome (ACS), 891–892

AAP. See American Academy of Pediatrics clinical features of, 893
(AAP) management of, 894–895
AASM Manual for the Scoring of Sleep and pathophysiology of, 892–893
Associated Events, The, 634 Acute eosinophilic pneumonia (AEP). See
ABCA3 protein, 514–515 Eosinophilic pneumonia
ABCDEF method, 1045, 1046 Acute idiopathic pulmonary hemorrhage
Abdomen (AIPH) of infancy, 574–575
congenital diaphragmatic hernia (CDH) of, Acute large-volume aspiration, 707–710
267–271, 303 Acute laryngotracheobronchitis. See Croup
elimination evaluation and, 1048 Acute lung allograft dysfunction, 734
examination of, 73, 285 Acute lymphoblastic leukemia (ALL),
gastroschisis and omphalocele of, 304 913–914
Abnormal airway clearance, 972–973 Acute mountain sickness (AMS), 41–42
ABO blood type, 728 management of, 44–45
ABPA. See Allergic bronchopulmonary Acute myeloid leukemia (AML), 913–914
aspergillosis (ABPA) Acute respiratory distress syndrome (ARDS),
Abscess. See Lung abscess 19
Absence of main pulmonary artery, 125 clinical manifestations of, 886
Acanthosis, 1047 reduced lung compliance in, 33
Acapella valve, 982–983 Adenocarcinoma of colon, 920
cost of, 986 Adenosine triphosphate (ATP), 39
instructional videos on, 987 Adenotonsillectomy, 610–611
ACBT. See Active cycle of breathing Adenovirus, 353, 360
techniques (ACBTs) disease processes associated with
Acclimatization, 41 bronchiectasis, 330
Acetazolamide, 44–45 Adjunctive therapy for allergic
Achondroplasia, 832 bronchopulmonary
pulmonary disorders resulting from, 56 aspergillosis (ABPA), 178
Acid-base status, 20–22 Adjustment insomnia, 645
carbonic acid and, 20 Adolescents
lung regulation of, 20 cystic fibrosis (CF) nutritional therapies for,
nomogram of abnormalities in, 21–22 1051
primary disorders and compensation in, gastroesophageal reflux (GER) in, 876–877
20–21 nonviral pneumonia in, 371
Acinus, 4 pneumonia in, 370
Acoustic pharyngometry, 627 sleep needs of, 581–582
ACR. See Acute cellular rejection (ACR) tobacco-dependence treatment in, 1096–
ACS. See Acute chest syndrome (ACS) 1097
Active cycle of breathing techniques (ACBTs), Adrenal insufficiency, 786
976 Adrenocortical carcinoma, 920, 921
cost of, 986 Adverse drug reactions to antibiotics, 1043
instructional videos on, 987 Aerobic capacity, 40
Acute bronchospasm, 1008–1013 Aerobika device, 982–983
Acute cellular rejection (ACR), 156, 723, cost of, 986
736–738 instructional videos on, 987
1145
75 PP 2ND ED - INDEX_1145-1192.indd 1145 11/8/23 9:50 AM

1146
Index
Aerosol medications Airway clearance therapy (ACT), 974

advantages of, 991 Airway compression, 121–122
delivery devices with congenital heart disease (CHD),
choosing the appropriate, 1001 853–855
dry powder inhalers, 999–1001 Airway inflammation
inspiratory effort and dry delivery, 1000 in asthma and obesity, 748–750
nebulizers, 994–996 in inflammatory bowel disease (IBD),
pressurized metered dose inhalers 882–883
(pMDIs), 993, 997–999 Airway injury, 330
soft mist inhalers, 999 Airway management and examination, 152
delivery of, 992–994 Airway obstruction
patient variables affecting, 993–994 in asthma and obesity, 750–751
variables affecting, 992 congenital heart disease (CHD) and, 854
AGBM. See Anti-glomerular basement cystic fibrosis (CF) and, 796–797
membrane (AGBM) disease dyspnea and, 768
AGNB. See Anaerobic gram-negative bacilli pathophysiology and clinical features of,
(AGNB) 1007–1008
AIPH. See Acute idiopathic pulmonary pseudohypoaldosteronism (PHA) and, 840
hemorrhage (AIPH) of infancy Airway reactivity, 89–93
Air travel, oxygen use during, 1066 Airway remodeling, 119
Airway abnormalities Airway resistance, 34
in Down syndrome, 835 Airway tumors, 918–919
in neuromuscular disorders (NMDs), 950 Albuterol, 216, 1006, 1009
in sickle cell disease (SCD), 895–897 Alcaligenes xylosoxidans
Airway cartilage deficiency, 331 cystic fibrosis (CF) and, 790
Airway clearance Alemtuzumab, 922
abnormal, 972–973 Algorithms, cystic fibrosis newborn screening,
active cycle of breathing techniques 808–810
(ACBTs), 976 ALL. See Acute lymphoblastic leukemia (ALL)
after tracheostomy, 1115–1116 Allergic bronchopulmonary aspergillosis
autogenic drainage, 976–977 (ABPA), 115, 116, 117,
considerations unique to infants and 165–166
children, 974 antibiotics for, 1022
dependent techniques clinical presentation of, 169
chest physical therapy (CPT), 475, 476, culture for, 171
977–981 cystic fibrosis (CF) and, 790–791
cough assist device (CAD), 985 diagnostic criteria for, 172–176
high-frequency chest wall compression, disease processes associated with
983–984 bronchiectasis, 330
intrapulmonary percussive ventilator epidemiology of, 168–169
(IPV), 985 etiology of, 166–167
oscillating PEP devices, 982–983 evaluation of, 170–172
positive expiratory pressure (PEP), 981 prognosis for, 179
huff cough maneuver, 975 pulmonary function testing for, 172
independent techniques radiologic studies of, 171–172
active cycle of breathing techniques risk factors for, 168
(ACBTs), 976 serologic testing for, 171
autogenic drainage, 976–977 skin testing for, 170–171
huff cough maneuver, 975 therapy for, 176–179
inhaled medications and, 988 Allergic rhinitis, 56, 65–66, 74, 93, 756
for neuromuscular disorders (NMDs), asthma differentiated from, 343
957–959 ciliary biopsy and, 156
normal, 971 eosinophilic granulomatosis and, 494
selection of technique for, 986–987 FeNO levels in, 754
upkeep and cost considerations for, 986 late-onset allergic asthma following, 211

1147
Index
as risk factor for pneumonia, 402 Anterior nasal stenosis, 243

treatment of, 225 Anthropometric evaluation, 1045–1047
Allergic sensitization in asthma and obesity, Antibiotics, 1019
748–750 adverse reactions to, 1043
Alliance for Radiation Safety in Pediatric for allergic bronchopulmonary aspergillosis,
Imaging, 101 1022
Alpha-1 antitrypsin (AAT) deficiency for aspiration pneumonia, 1022
clinical features of, 830–831, 884 for atypical pneumonia, 1022
diagnosis of, 831, 883–884 for bronchitis, 1022
disease processes associated with classes of
bronchiectasis, 331 aminoglycosides, 1041
management of, 831, 844 aminopenicillins, 1040
pathogenesis of, 830 antifungal agents, 1042–1043
Alveolar-arterial (A-a) gradient, 30, 1063 antipseudomonal β-lactams, 1039–1040
Alveolar gas equation, 1063 carbapenems, 1040
Alveolar hypoventilation, 950 fluoroquinolones, 1041
Alveolar ventilation, 17–20 macrolides, 1040
Alveoli, 5 oral cephalosporins, 1038–1039
gas exchange in, 15–16 penicillinase-resistant penicillins,
American Academy of Pediatrics (AAP), 58 1039
on brief, resolved, unexplained events for community-acquired pneumonia, 1023,
(BRUEs), 671 1024–1026
on bronchiolitis, 345–346 considerations for choice of, 1020
on electronic nicotine delivery systems for cystic fibrosis (CF), 1023–1024
(ENDS), 1087 drug interactions with, 1044
on obstructive sleep apnea syndrome for epiglottitis, 1021
(OSAS), 603 for fungi, 1030
on skin testing for tuberculosis (TB), 419 for group A Streptococcus, 1028
American Thoracic Society, 418 for interstitial pneumonia syndrome of early
Amikacin, 1041 infancy, 1026
drug-resistant TB and, 412, 434 for lung abscess, 1021–1022
for mycobacteria, 460, 461, 462 for pertussis, 1024
toxicities and monitoring, 463 for pneumococcal diseases, 1026–1027
Xpert Ultra treatment and, 426 for pneumonias, 1026–1034
Aminoglycosides, 1041 for Staphylococcus aureus, 1027
Aminopenicillins, 1040 toxicities and monitoring, 463
AML. See Acute myeloid leukemia (AML) for tracheitis, 1021
Amoxicillin, 1026, 1040 for tuberculosis, 1035–1037
Amphotericin B, 1030, 1042–1043 Anticholinergics
Amphotericin C, 1038 for airway clearance, 988
Ampicillin, 1025, 1040 mechanism of, 1006
AMS. See Acute mountain sickness (AMS) Antifungal agents, 1042–1043
Anaerobic gram-negative bacilli (AGNB), Anti-glomerular basement membrane (AGBM)
376–377 disease, 495–496
Anaerobic organisms, 376–377 Antipseudomonal β-lactams, 1039–1040
Anemia Anxiety
in gastroesophageal reflux (GER), 876 cystic fibrosis (CF) and, 792
indicators of, 1047 hyperventilation due to, 773
Anesthesia, 19 sighing syndrome due to, 774
neuromuscular disorders (NMDs) and, 962 Apert syndrome, 245
for tracheostomy, 1114 Apnea
Angiography, 108 in gastroesophageal reflux (GER), 876
Anidulafungin, 1043 gastroesophageal reflux (GER) and, 877
Anterior mediastinal masses, 136–137, in micro-aspiration, 712
915–916 Apnea-Hypopnea Index (AHI), 617–618

1148
Index
Apparent life-threatening event (ALTE), 671, 674 Assisted CPF, 953

gastroesophageal reflux (GER) and, 877 Asthma, 207–208
ARDS. See Acute respiratory distress syndrome alpha-1 antitrypsin (AAT) deficiency and,
(ARDS) 830
Area of apposition, 279–281 assessing severity of, 214
Arnold-Chiari malformations, 67 bronchiolitis versus, 343
Arousal parasomnias, 651, 652–653 bronchodilators for, 1008
Arterial blood gas, 96 chest radiography for, 118–119
Arterial Pco2 clinical characterization of phenotypic
alveolar-arterial (A-a) gradient and, 30–31 patterns of, 209–212
arterial blood gas analysis, 30–31 diagnosis of, 208–209
hypoventilation and, 23–24 difficulty treating, 224–225
noninvasive monitoring of, 28–30 disease processes associated with
oxygenation and, 22–23 bronchiectasis, 331
oxygen transport and, 26–27 disparities in treatment and outcomes for,
regulation of, 20 230–231
ventilation relationship to, 18–20 diving and, 49
Arthrogryposis multiplex congenita (AMC), 833 Down syndrome and, 837
Aspergillus dysfunctional breathing complicating, 774
allergic bronchopulmonary aspergillosis emergency department and hospitalization
(ABPA), 115, 116, 117, for, 225
165–166 environmental considerations with,
clinical presentation of, 169 223–224
culture for, 171 exacerbations of, 213
cystic fibrosis (CF) and, 790–791 exercise-induced, 224
diagnostic criteria for, 172–176 feeding challenges with, 1055
epidemiology of, 168–169 gastroesophageal reflux (GER) and, 878
etiology of, 166–167 habit cough and, 765
evaluation of, 170–172 insomnia due to, 645
prognosis for, 179 intermittent, 210–211
pulmonary function testing for, 172 intervention action plan for, 228
radiologic studies of, 171–172 intervention medications for, 214–219
risk factors for, 168 less common phenotypes of, 211–212
serologic testing for, 171 maintenance medications for, 219–223
skin testing for, 170–171 monitoring the clinical course of, 226–228
therapy for, 176–179 natural history of, 228–230
antibiotics for, 1030 obesity and
chronic granulomatous disease (CGD) and, atopy and airway inflammation in,
930 748–750
echinocandins for, 1043 evaluation of patients with, 752–754
itraconazole for, 1042 nutritional aspect of, 1056–1057
for patient with immunodeficiency, 942 physiological interactions between,
pneumonia due to, 931 750–751
posaconazole for, 1043 reasons for association between, 747
Aspiration, 128–129 symptom overlap between, 751–752
acute large-volume, 707–710 treatment of, 754–756
antibiotics for pneumonia caused by, 1022 peak expiratory flow rate (PEFR) and, 78–79
foreign body, 701–707 persistent, 211
of hydrocarbons, 710–711 prenatal nicotine and tobacco exposure and,
physiological mechanism of swallowing 1099
and, 699–701 pulmonary disorders resulting from, 56
recurrent small-volume, 711–717 recurrent pneumonia and, 402
Aspirin, 565 seasonal allergic, 211
hyperventilation due to, 773 short-acting β2-agonists (SABAs) for,
overdose of, 773 1013–1014
Reye syndrome and, 360

1149
Index
sickle cell disease (SCD) and, 895–897 Avycaz, 1039

clinical features of, 896–897 Azathioprine
pathophysiology of, 896 for posttransplant lymphoproliferative
treating comorbidities of, 225–226 disorder (PTLD), 735
treatment of, 214–226 Azithromycin, 1024, 1025, 1026, 1029, 1032,
when to refer for, 96 1033, 1040
work of breathing in, 34 for cystic fibrosis (CF), 799
Ataxia-telangiectasia (A-T), 937 for mycobacteria, 461
Atelectasis, 112, 119, 887 for primary ciliary dyskinesia (PCD), 825
bronchoscopy for, 151 toxicities and monitoring, 463
chest physical therapy (CPT) for, 475, 476 Azoles, 1042–1043
clinical features of, 473 Aztreonam, 1024, 1039
cystic fibrosis (CF) and, 789 for cystic fibrosis (CF), 797
diagnosis of, 473–475
epidemiology of, 469–470 B
etiology of, 469–473 Bacille Calmette-Guérin vaccine, 424
intrapulmonary percussive ventilation for, Bacterial croup. See Bacterial tracheitis
477 Bacterial pneumonia, 371–380
management of, 475–477 anaerobic organisms, 376–377
nonobstructive, 473 atypical, 377–379
obstructive, 469–472 disease processes associated with
recombinant human DNase for, 477 bronchiectasis, 330
when to admit for, 477 gram-negative bacteria, 374–376
when to refer for, 477 gram-positive bacteria, 372–374
Atmosphere and atmospheric pressure, 15, other causes of, 380
23–24 Bacterial tracheitis
Atopy and allergic sensitization in asthma and causative organisms of, 321
obesity, 748–750 clinical presentation of, 321–322
Atypical mycobacteria, 330 complications of, 324
Atypical pneumonia, 377–379 diagnosis of, 323
antibiotics for, 1022 epidemiology of, 320–321
macrolides for, 1040 management of, 323
Augmentation therapy, alpha-1 antitrypsin tracheostomy and, 323
(AAT) deficiency, 831 Bacteroides fragilis
Augmented cough, 977 antipseudomonal β-lactams for, 1039
Auscultation, 65, 72–73 carbapenems for, 1040
of patient with airway tumors, 918 cephalosporins for, 1038
of patient with asthma, 226, 256 BAL. See Bronchoalveolar lavage (BAL)
of patient with bronchiectasis, 335 Balloon dilation of airway, 158
of patient with bronchiolitis, 342 Baloxavir, 1031
of patient with gastroesophageal reflux Bariatric surgery, 755
(GER), 712 Barotrauma, 48–49
of patient with hemoptysis, 565 Beckwith-Wiedemann syndrome, 246
of patient with immunodeficiency, 940 Bedaquiline, 462
of patient with pneumonia, 366, 402 Behavioral insomnia of childhood, 646
of patient with pneumothorax, 553, 559 Benign airway tumors, 918
of patient with scoliosis, 284 β2-agonists, 1005–1006
Autism spectrum disorder, 648 Bevacizumab, 922
Autogenic drainage, 976–977 Bicarbonate, 20–21
cost of, 986 Bidis, 1088
instructional videos on, 987 Bilevel positive airway pressure (BiPAP),
Autoimmune disorders, pulmonary disorders 1070–1071, 1075
resulting from, 56 Biochemical evaluation, 1047
Autoimmune pulmonary hemorrhage, Biologic agents, pulmonary injury due to, 922
572–574 Biomotion sensors for monitoring obstructive
Autonomic dysfunction, 786 sleep apnea (OSA), 630

1150
Index
Biopsy Brief, resolved, unexplained events (BRUEs),

ciliary, 156 671–674
for gastroesophageal reflux (GER), 879 clinical presentation of, 675–676
for interstitial lung disease (ILD), 513–514 diagnosis of, 676
for pulmonary arterial hypertension (PAH), epidemiology of, 674
860 in gastroesophageal reflux (GER), 876
transbronchial, 156 gastroesophageal reflux (GER) and,
Blastomyces, posaconazole for, 1043 877–878
Bleomycin, 921 higher-risk, 677–678
Blood lower-risk, 677
distribution of pulmonary blood flow, 852 management of, 676–678
hemoglobin in, 23, 28 pathophysiology of, 674
pH of, 20, 21 Bronchia atresia, 122
Blood gas measurement Bronchial carcinoids, 918–919
atelectasis and, 477 Bronchial challenge testing, 93
in evaluation of hypoxemia, 1068 Bronchial hyperresponsiveness (BHR), 1007
Blood sampling Bronchial obstruction in cystic fibrosis (CF),
for arterial blood gas measurement, 31 796–797
for potential smoke exposure, 96 Bronchiectasis, 115, 121
Blood supply to lungs, 6 clinical manifestations of, 329–335
Blood transfusion, hyperacute reaction to, 736 evaluation of, 335–336
B lymphocyte disorders, 929 management of, 336–337
common variable immunodeficiency pathophysiology of, 335
(CVID), 932–934 prognosis for, 337–338
immunoglobulin A deficiency, 933 pulmonary hemorrhage and, 569–570
treatment modalities, 933 Bronchioles, 4
X-linked agammaglobulinemia, 932 Bronchiolitis, 119–120
BMI. See Body mass index (BMI) antibiotics for, 1022
Bochdalek hernia, 11, 267 asthma and, 208
Body mass index (BMI), 1046 bronchodilators for, 1015
asthma and, 1056 clinical presentation of, 342
cystic fibrosis (CF) and, 1049 differential diagnosis of, 343
Bony thorax, 5 discharge from hospital after, 348
Bordetella pertussis, 367 epidemiology of, 341
BOS. See Bronchiolitis obliterans syndrome hospitalization for, 346–348
(BOS) laboratory and radiological findings in, 345
Botox injection for airway clearance, 988 management of, 345–346
BPD. See Bronchopulmonary dysplasia (BPD) natural history, 344–345
Brasfield Scoring System, 135 pathophysiology of, 344
Breathing, 31–34. See also Lungs prophylaxis for, 346
airway resistance in, 34 Bronchiolitis obliterans syndrome (BOS), 723
area of apposition, 279–281 after lung transplant, 739
assessment of lung mechanics in, 34 Bronchoalveolar lavage (BAL), 153–156
dysfunctional abnormal cell differentials, 154–155
complicating asthma, 774 for acute large-volume aspiration, 709
hyperventilation, 773–774 for interstitial lung disease (ILD), 513
repetitive sighing, 774 microbiology and, 155–156
elastic properties of the lung and chest wall normal cell types and, 153–154
in, 33 for recurrent small-volume aspiration,
inspiration versus exhalation, 279 714–715
muscles of, 31–32 for systemic inflammatory diseases, 482
sleep-disordered Bronchodilators
in Down syndrome, 834–835 for acute bronchospasm, 1008–1013
in sickle cell disease (SCD), 897–899 for airway clearance, 988
thoracoabdominal mechanics in, 281–282 for alpha-1 antitrypsin (AAT) deficiency,
work of, 34 831

1151
Index
for asthma, 1013–1014 diagnostic procedures, 153–156

for bronchiolitis, 1015 extrathoracic airway and, 148–150
for bronchopulmonary dysplasia, 1015 for foreign body, 143, 157
clinical pharmacology and disease for hemoptysis and pulmonary hemorrhage,
management using, 1008 144
for cystic fibrosis (CF), 797, 1015 indications for flexible, 144–147
dosing chart for, 1009–1011 intrathoracic airway and, 150–151
inhaled, 991 pathophysiological and clinical features in,
inhaled β-adrenergic, 825 148–151
mechanisms of, 1005–1007 for pulmonary hemorrhage, 568
anticholinergics, 1006 special studies, 156
methylxanthines, 1007 therapeutic, 156–159
β2-agonists, 1005–1006 Bronchospasm, 1007–1008
pathophysiology and clinical features of acute, 1008–1013
airway obstruction and, exercise-induced, 94, 224, 771
1007–1008 BRUEs. See Brief, resolved, unexplained
for primary ciliary dyskinesia (PCD), 825 events (BRUEs)
short-acting β2-agonists (SABAs), 1008, Bruxism, 637, 638, 654
1012–1015 Bupropion, 1095
testing of, 89–92 Burkholderia cenocepacia, 730
Bronchogenic cysts, 124, 262–264 chronic granulomatous disease (CGD) and,
Bronchomalacia, 256–257 930
Bronchopleural fistulas, 393–395 cystic fibrosis (CF) and, 790
Bronchopulmonary dysplasia (BPD) Burkholderia cepacia, 375
anthropometric evaluation in, 1045–1046 Busulfan, 921
blood gas measurements in, 21
bronchodilators for, 1015 C
chronic mechanical ventilation for, 529–531 CAD. See Cough assist device (CAD)
clinical features of, 526 Calcium channel blockers, 863
comorbidities with, 526–527 Calcium supplementation, 1053
definition of, 522–523 asthma and, 1056–1057
epidemiology of, 521–522 Calorie boosters, 1051, 1052
feeding evaluation in, 1048 Canalicular period, lung development, 4
future of, 535 Cancer. See Oncogenic disease
history of, 521 Candida albicans, 318
invasive mechanical ventilation for, 529 ampicillin for, 1040
longitudinal care for patients with, 533–535 azoles for, 1042
medications for, 531–533 echinocandins for, 1043
noninvasive respiratory support for, posaconazole for, 1043
528–529 voriconazole for, 1042
nutritional therapies for, 1045, 1054–1055 Capacitor-based systems for obstructive sleep
oxygen therapy for, 1069–1070 apnea (OSA), 630
pathophysiology of, 523–526 Capnography, 29
prenatal, perinatal, and preventive for neuromuscular disorders (NMDs),
management of, 527–528 953–954
pulmonary arterial hypertension (PAH) and, Capreomycin
858 drug-resistant TB and, 412, 434
respiratory management with, 527–531 Xpert Ultra treatment and, 426
specific ventilation strategies for patients Carbapenems, 1032, 1040
with severe type 2, 529 Carbon dioxide
Bronchoscopy, 141–142 excretion with exercise, 39
choosing between flexible and rigid, exercise physiology and, 39
142–144 noninvasive monitoring of, 28–30
complications of, 159 production of, 16
for congenital heart disease (CHD), 855 transport of, 20
contraindications for, 148 ventilation and changes in, 18

1152
Index
Carbonic anhydrase, 20 on electronic nicotine delivery systems

Carbon monoxide (CO) (ENDS), 1085
carboxyhemoglobinemia and, 1065 Cephalexin, 1038
diffusing capacity of, 87–89, 184 Cephalosporins, oral, 1038–1039
toxicity levels of, 52 Cephamycins, 1038
Carboxyhemoglobin (COHb), 52 Cerebrospinal fluid hypocretin-1, 666
Carboxyhemoglobinemia, 1065 Cetuximab, 922
Carcinoid syndrome, 919 CF. See Cystic fibrosis (CF)
Cardiac abnormalities CF transmembrane conductance regulator
neuromuscular disorders (NMDs) and, 955 (CFTR), 782
prenatal nicotine and tobacco exposure and, CFTR modulator drugs, 793, 794–796
1100 CFTR-related metabolic syndrome, 800,
pulmonary hemorrhage due to, 571–572 811–814
Cardiac catheterization and pulmonary arterial outcomes of, 813–814
hypertension (PAH), 859 prevalence of, 812–813
Cardiac output, 39–40 Chediak-Higashi syndrome, 931
exercise and, 39–40 Chemotherapy
Cardiopulmonary exercise testing (CPET), for posttransplant lymphoproliferative
94–95 disorder (PTLD), 741–742
Cardiorespiratory monitoring, home, 1073 pulmonary injury due to, 921
Caseation, tuberculosis (TB), 414 Chest pain, 62–63
Caspofungin, 1043 pleural effusion, 545
Catathrenia, 653–654 in pulmonary hypertension in sickle cell
Cavitation, 114 disease (SCD), 904
CCHS. See Congenital central hypoventilation Chest physical therapy (CPT), 475, 476
syndrome (CCHS) cost of, 986
CDC. See Centers for Disease Control and instructional videos on, 987
Prevention (CDC) Chest radiography, 103
CDH. See Congenital diaphragmatic hernia for acute chest syndrome (ACS), 893
(CDH) acute large-volume aspiration, 708
Cefaclor, 1038 for allergic bronchopulmonary aspergillosis
Cefadroxil, 1038 (ABPA), 171
Cefamandole, 1038 for alpha-1 antitrypsin (AAT) deficiency,
Cefazolin, 1027, 1038 831
Cefdinir, 1038 for aspiration, 128
Cefditoren, 1038 for asthma, 118–119
Cefepime, 1023, 1028, 1029, 1030, 1034, 1038, for atelectasis, 473–474
1039, 1040 for bronchiectasis, 333
Cefixime, 1038 for bronchiolitis, 345
Cefotetan, 1038 for congenital heart disease (CHD), 854–855
Cefoxitin, 1038 for COVID-19, 356–357
for mycobacteria, 461, 462 fluoroscopy, 111
toxicities and monitoring, 463 for Hermansky-Pudlak syndrome (HPS),
Cefpodoxime, 1038 837–838
Ceftaroline, 1021, 1023, 1025, 1026, 1027– for interstitial lung disease (ILD), 510–512
1028, 1029, 1038, 1039 landmarks and structures in, 110
Ceftazidime, 1023, 1038, 1039, 1040 for lung abscess, 392–393
Ceftazidime/avibactam, 1039 for necrotizing pneumonia, 394–395
Ceftibuten, 1038 for nonviral pneumonia, 366–367
Ceftolozane/tazobactam, 1039 for obstructive sleep apnea (OSA), 627
Ceftriaxone, 1021–1022, 1026, 1027, 1030, other specific findings in, 112–115
1032, 1038 for pleural effusion, 129–130, 541–542,
Cefuroxime, 1038 546–547
Centers for Disease Control and Prevention for pneumatocele, 396
(CDC), 58, 362, 383, 384, for pneumococcal pneumonia, 373
411, 418 for pneumomediastinum, 559–560

1153
Index
for pneumonia, 126–127 Chronic granulomatous disease (CGD),

for pseudohypoaldosteronism (PHA), 841 930–931
for pulmonary hemorrhage, 566 Chronic insomnia, 643
reading, 109–115 Chronic lung allograft dysfunction (CLAD),
for recurrent pneumonia, 401–402 723, 738–740
report on, 109 phenotypes of, 740
silhouette sign in, 110–111 treatment options for, 740–741
for systemic inflammatory diseases, 482 Chronic mountain sickness (CMS), 44
Chest wall Chronic myelogenous leukemia, 913–914
assessing function of, 284–288 Chronic respiratory failure (CRF)
compliance of, 282 causes of, 1127–1128
asthma and obesity and, 750–751 clinical features of, 1128–1129
endocrine disorders and, 870–871 goals of home mechanical ventilation for,
neuromuscular disorders (NMDs) and, 1126–1127
950 home mechanical ventilation for, 1125–
congenital diaphragmatic hernia (CDH) of, 1126. See Home mechanical
303 ventilation
elastic properties of, 33 patient selection for home ventilation for,
functional consequences of developmental 1129–1134
and structural changes in, Chronic tuberculosis (TB), 418
282–283 Churg-Strauss syndrome. See Eosinophilic
gastroschisis and omphalocele of, 304 granulomatosis with
lung function testing and, 285–287 polyangiitis (EGPA)
mechanics of breathing and, 279–282 Chylous pleural effusion, 544, 549
muscular abnormalities of, 303–304 Ciclesonide, 221–222
pathophysiology of, 282–283 Cigarettes, 1084
pectus excavatum and carinatum of, 288–292 Cigars, 1088
physical examination of, 284–285 Ciliary beat analysis, 822
quantitative assessment of motion of, 285 Ciliary biopsy, 156
respiratory muscle strength and, 287–288 Ciprofloxacin, 1023, 1030, 1041
scoliosis and, 19, 284, 285–286, 292–297 Circadian rhythm, 592–596
structural abnormalities of, 288–303 Cirrhosis and cystic fibrosis (CF), 791
structural changes resulting from growth and CLAD, 734
development of, 282 Clarithromycin, 1032, 1033, 1040
thoracic insufficiency syndrome, 298–303 toxicities and monitoring, 463
trauma and deformity of, 19 Clavulanic acid, 1040
tumors of, 919 CLE. See Congenital lobar emphysema (CLE)
Chewing and neuromuscular disorders Cleft lip nasal deformity, 245
(NMDs), 950 pulmonary disorders resulting from, 56
Chewing tobacco, 1088 Clindamycin, 1021–1022, 1027
Child abuse, pulmonary hemorrhage due to, 571 Clinical presentation
Chlamydia trachomatis, 367, 371, 377–379 achondroplasia, 832
antibiotics for, 1029 acute chest syndrome (ACS), 893
Chlamydophila pneumoniae, 379 acute large-volume aspiration, 707–708
antibiotics for, 1029 acute respiratory distress syndrome, 886
Chlamydophila psittaci, 379 airway obstruction, 1007–1008
antibiotics for, 1029 allergic bronchopulmonary aspergillosis
Choanal atresia, 244 (ABPA), 169
Chondrosarcoma, 920 alpha-1 antitrypsin (AAT) deficiency, 830–
Chromosomal defects and pulmonary 831, 884
disorders, 56 anti-glomerular basement membrane
Chronic cough, 763–764 (AGBM) disease, 495–496
asthma and, 208 arthrogryposis multiplex congenita (AMC),
Chronic eosinophilic pneumonia (CEP). See 833
Eosinophilic pneumonia atelectasis, 473

1154
Index
Clinical presentation (continued) sickle cell disease (SCD) with asthma,

bacterial tracheitis, 321–322 896–897
brief, resolved, unexplained events sleep-disordered breathing in sickle cell
(BRUEs), 675–676 disease (SCD), 899
bronchiectasis, 329–335 systemic lupus erythematosus (SLE), 487
bronchiolitis, 342 thoracic insufficiency syndrome, 298–299
bronchopulmonary dysplasia (BPD), 526 tuberculosis (TB), 415–418
chronic respiratory failure (CRF), 1128– Williams-Campbell syndrome, 828
1129 Clofazimine, 461, 462
congenital central hypoventilation syndrome toxicities and monitoring, 463
(CCHS), 683–685 Cloves, 1088
COVID-19, 355 Clubbing, 68
croup, 312 Clustered regularly interspaced short
eosinophilic granulomatosis with palindromic repeat (CRISPR)-
polyangiitis (EGPA), 494 based systems
eosinophilic pneumonia, 198–199 cystic fibrosis (CF) and, 794
epiglottitis, 318 CMV. See Cytomegalovirus (CMV)
foreign body aspiration, 702–703 CO. See Carbon monoxide (CO)
gastroesophageal reflux (GER), 875–877 Coccidioides, 383
granulomatosis with polyangiitis (GPA), 491 azoles for, 1042–1043
Hermansky-Pudlak syndrome (HPS), 837 as complication of HIV, 939
juvenile dermatomyositis (JDM), 488 COHb. See Carboxyhemoglobin (COHb)
juvenile idiopathic arthritis (JIA), 485 Collaborative Home Infant Monitoring
juvenile systemic sclerosis (JSS), 488 Evaluation (CHIME) study,
lung abscess, 392 676
microscopic polyangiitis (MPA), 493 Collapsed intrathoracic airway, 150
mixed connective tissue disease (MCTD) Colonic interposition, 260
and Sjögren syndrome, 490 Combination corrector/potentiators, 795
Mounier-Kuhn syndrome, 826 Combined type sleep disorder, 646
mucopolysaccharidosis (MPS), 839 Common cold and asthma, 213
narcolepsy, 663–665 Common variable immunodeficiency (CVID),
necrotizing pneumonia, 394–395 932–934, 942
neuromuscular disorders (NMDs), 950 Community-acquired pneumonia (CAP)
nontuberculous mycobacteria, 455–456 antibiotics for, 1023, 1024–1026
nonviral pneumonia, 366 lung abscess and, 391–393
nutrition evaluation, 1047 necrotizing pneumonia and bronchopleural
obstructive sleep apnea syndrome (OSAS), fistulas, 393–395
604–605 parapneumonic effusion and, 387–391
parapneumonic effusion, 388 pneumatocele, 395–397
parasomnias, 652–656 Complete blood cell count (CBC)
pectus excavatum and carinatum, 288–289 for bronchiolitis, 345
pleural effusion, 544–546, 886 for nonviral pneumonia, 367
pneumatocele, 396 for pulmonary hemorrhage, 565–566, 569
pneumomediastinum, 559 Complicated pneumonia, 365
pneumothorax, 555 Complications of pneumonia, 129–132
primary ciliary dyskinesia (PCD), 820–822 lung abscess, 391–393
pseudohypoaldosteronism (PHA), 840–841 necrotizing pneumonia and bronchopleural
pulmonary arterial hypertension (PAH), 858 fistulas, 393–395
pulmonary hypertension in sickle cell parapneumonic effusion, 387–391
disease (SCD), 903–904 pneumatocele, 395–397
pulmonary lymphangioleiomyomatosis when to admit for, 397
(LAM), 829 when to refer for, 397
recurrent small-volume aspiration, 712 Computed tomography (CT), 115–116
sarcoidosis, 498–499 for allergic bronchopulmonary aspergillosis
scoliosis, 292–295 (ABPA), 172

1155
Index
for asthma, 119 pseudohypoaldosteronism (PHA),

for atelectasis, 475 840–841
for bronchiectasis, 121, 333–334 Congenital heart disease (CHD), 851
for congenital heart disease (CHD), 854–855 airway compression with, 853–855
for COVID-19, 357 alterations in respiratory physiology in,
for cystic fibrosis (CF), 134–135 852–853
for Hermansky-Pudlak syndrome (HPS), with decreased pulmonary blood flow, 853
837–838 distribution of pulmonary blood flow and,
for lung abscess, 131, 392–393 852
for necrotizing pneumonia, 131–132, 394 Down syndrome and, 835–836
for nonviral pneumonia, 367 with increased pulmonary blood flow,
for pleural effusion, 129, 547 852–853
for pneumomediastinum, 560 oxygen therapy for, 1070
for pneumonia, 126 physiology/pathophysiology of, 852–853
for pulmonary arterial hypertension (PAH), viral respiratory infections and, 864–865
859 Congenital hypothyroidism, 66
for systemic lupus erythematosus (SLE), Congenital lobar emphysema (CLE), 123,
133–134 266–267
Confusional arousals, 652 Congenital lobar hyperinflation, 123
Confusional parasomnias, 651 Congenital pulmonary airway malformation
Congenital adrenal hyperplasia, 786 (CPAM), 123, 264–266
Congenital anomalies, 121–126 Congenital pulmonary malformations (CPMs),
of the lungs. See Lung anomalies 917
of the upper airway. See Upper airway Congenital subglottic stenosis, 248–249
abnormalities Connective tissue disease, 330
Congenital bronchopulmonary foregut hyperacute rejection in, 736
malformation, 271 Consolidation, 112
Congenital central hypoventilation syndrome Constitutional symptoms in in review of
(CCHS), 18 systems, 60
clinical presentation and associated features Continuous positive airway pressure (CPAP),
in, 683–685 347, 528, 1070–1071, 1075
diagnostic evaluation of, 685–686 Co-oximetry, 1068–1069
diaphragm pacing (DP) for, 688–689 Coronavirus, 353, 354
epidemiology of, 682 Corticosteroids
genetic counseling for, 691 for allergic bronchopulmonary aspergillosis
genotype-phenotype relationship in, 682–683 (ABPA), 176–178
long-term management of, 690–691 for asthma, 217–223, 754
management of, 687–691 for croup, 315
modes of ventilatory support for, 687–689 for eosinophilic pneumonia, 202
noninvasive positive-pressure ventilation habit cough and, 765
(NPPV) for, 688 for hypersensitivity pneumonitis (HP),
observation and monitoring of, 690 190–192
pathogenesis of, 681 for inflammation in cystic fibrosis (CF), 799
Congenital constricted chest wall syndrome, 288 Corynebacterium diphtheriae, 1111
Congenital cystic adenomatoid malformations, Cough, 61–62
123, 264, 917 abnormal airway clearance and, 972
Congenital diaphragmatic hernia (CDH), alpha-1 antitrypsin (AAT) deficiency and,
267–271, 303 830
Congenital disorders, pulmonary complications in asthma, 208
of augmented, 977
achondroplasia, 832 in cardiac disease, 851
arthrogryposis multiplex congenita (AMC), chronic, 763–764
833 dependent techniques
Down syndrome, 66, 245–246, 834–837 chest physical therapy (CPT), 977–981
mucopolysaccharidosis (MPS), 839–840 cough assist device (CAD), 985

1156
Index
Cough (continued) CPT. See Chest physical therapy (CPT)

high-frequency chest wall compression, Crackles, 72–73
983–984 in acute chest syndrome (ACS), 893
intrapulmonary percussive ventilator in bronchiolitis, 342
(IPV), 985 in hypersensitivity pneumonia, 184
oscillating PEP devices, 982–983 in pulmonary hemorrhage, 563
positive expiratory pressure (PEP), 981 Craniofacial abnormalities, 245–246
in foreign body aspiration, 706–707 obstructive sleep apnea syndrome (OSAS)
in gastroesophageal reflux (GER), 875, 876 and, 606
in granulomatosis with polyangiitis (GPA), Crohn disease, 500, 882
491 Croup
habit cough syndrome, 763–766 assessment of severity of, 313
independent airway clearance techniques bacterial tracheitis
active cycle of breathing techniques causative organisms of, 321
(ACBTs), 976 clinical presentation of, 321–322
autogenic drainage, 976–977 complications of, 324
huff cough maneuver, 975 diagnosis of, 323
manually assisted, 959, 977 epidemiology of, 320–321
neuromuscular disorders (NMDs) and, 950, management of, 323
952–953, 957–958 tracheostomy and, 323
airway clearance and, 957–959 causes of, 311
cough assist devices, 959 clinical features of, 312
manually assisted cough and, 959 differential diagnosis of, 312–313
normal airway clearance and, 971 epidemiology of, 312
pleural effusion, 546 investigations of, 313–314
primary ciliary dyskinesia (PCD) and, 824 management of, 314–316
recurrent pathophysiology of, 312
in micro-aspiration, 712 when to admit for, 317
in pneumonia, 405 when to refer for, 316
Cough assist device (CAD), 985 Crouzon syndrome, 66, 245
cost of, 986 Cryptococcus gatii, 380
instructional videos on, 987 azoles for, 1042
Cough tic, 763 as complication of HIV, 939
COVID-19, 354–358 Cushing syndrome, 871
chest imaging for, 356–357 Cutaneous hemangiomas, 918
classification of severity of, 355 Cutis laxa, 257
clinical features of, 355 Cyanide toxicity, 52–53, 1065
long, 357 Cyanosis, 63–64
management of, 358 Cyanotic congenital heart disease, oxygen
neuromuscular disorders (NMDs) and, 962 therapy for, 1070
obesity and, 752 Cyclosporine
pediatric inflammatory multisystem for posttransplant lymphoproliferative
syndrome and multisystem disorder (PTLD), 735
inflammatory syndrome in Cycloserine, 434
children, 357–358 Cystic fibrosis (CF), 57–58
persistence of pulmonary symptoms of, allergic bronchopulmonary aspergillosis
357–358 (ABPA) and, 168–169,
symptoms of, 355 172–175
vaccine against, 227 aminoglycosides use with, 1041
CPAM. See Congenital pulmonary airway antibiotics for, 1023–1024
malformation (CPAM) anxiety and depression with, 792
CPAP. See Continuous positive airway pressure biochemical evaluation of serum fat-soluble
(CPAP) vitamin levels in, 1047
CPET. See Cardiopulmonary exercise testing bronchiectasis and, 329, 336–337
(CPET) bronchodilators for, 797, 1015

1157
Index
CFTR-related metabolic syndrome and, 800, pulmonary exacerbations, 798–799

811–814 tissue damage, 799
chronic sinusitis in, 65–66 recurrent pneumonia and, 406, 408
clinical features of, 785–792 reduced lung compliance in, 33
cyanosis in, 64 reproductive tract and, 791
diabetes related to, 792 role of general pediatrician in, 800–801
diagnosis of, 800 spirometry and, 79
differentiated from primary ciliary viral respiratory tract infections with, 800
dyskinesia (PCD), 824 wheezing and stridor with, 62
elimination evaluation in, 1048 when to admit for, 774
feeding challenges with, 1055 when to refer for, 774
gastrointestinal tract and, 791 Cysts, 114–115
genetics of, 782–783 bronchogenic, 124, 262–264
imaging of, 134–135 parenchymal lung disease, 835
immunizations and, 800 pneumatocele, 395–397
impaired mucociliary clearance in, 330 saccular, 248
incidence of, 781 thyroglossal duct, 247
lung transplant for patients with, 729–731 tongue, 246
management of, 792–793 Cytomegalovirus (CMV), 361
newborn screening for antibiotics for, 1029
algorithms for, 808–810 as complication of HIV, 938–939
background on, 807–811 Cytotoxic T lymphocytes (CTLs), 934
CFTR-related metabolic syndrome and,
811–814 D
initial management of positive results Daytime napping, 594
of, 810–811 Dead space, 17–19
outcomes with, 811 ventilation and changes in, 18
nutritional therapies for, 793–794, 1048– Decannulation after tracheostomy, 1120–1122
1049 Decompression sickness, 47–48
for adolescents, 1051 Dehydration, 786
enzyme replacement therapy, 1049 Dental caries, 1099
for infants, 1049–1050 Dependence, nicotine and tobacco
salt, 1053–1054 assessment of, 1092
for school-aged children, 1050 development of, 1092
supplements and calorie boosters, 1051, treatment of, 1093–1094
1052 Dependent airway clearance techniques
for toddlers and preschoolers, 1050 chest physical therapy (CPT), 475, 476,
transmembrane conductance regulator 977–981
modulation therapy, 1051 cough assist device (CAD), 985
tube feedings, 1053 high-frequency chest wall compression,
vitamins, 1053 983–984
osteoporosis and, 792 intrapulmonary percussive ventilator (IPV),
pathogenesis of, 782–785 985
pathophysiology of, 783–785 oscillating PEP devices, 982–983
psychosocial issues with, 801 positive expiratory pressure (PEP), 981
pulmonary arterial hypertension (PAH) and, Depression
858 cystic fibrosis (CF) and, 792
pulmonary disorders resulting from, 56 Dexamethasone, 44–45
pulmonary hemorrhage in, 564, 569–570 Diabetes mellitus
pulmonary therapies for, 794–799 cystic fibrosis (CF)-related, 792
abnormal CFTR, 793, 794–796 pulmonary complications of, 871–872
abnormal gene, 794 pulmonary disorders resulting from, 56
bronchial obstruction, 796–797 Diagnosis and evaluation
infection, 797–799 achondroplasia, 832
inflammation, 799 acute large-volume aspiration, 709

1158
Index
Diagnosis and evaluation (continued) pancreatic disease, 887

allergic bronchopulmonary aspergillosis parapneumonic effusion, 388–391
(ABPA), 172–176 parasomnias, 656
alpha-1 antitrypsin (AAT) deficiency, 831, pectus excavatum and carinatum, 289–290
883–884 pleural effusion, 546–547
anti-glomerular basement membrane pneumomediastinum, 559–560
(AGBM) disease, 496 pneumothorax, 555–556
asthma, 208–209 primary ciliary dyskinesia (PCD), 406–407,
atelectasis, 473–475 822–824
bacterial tracheitis, 323 pseudohypoaldosteronism (PHA), 841
brief, resolved, unexplained events pulmonary arterial hypertension (PAH),
(BRUEs), 676 859–860
bronchiolitis, 343 pulmonary hemorrhage, 565
bronchoscopy, 153–156 pulmonary hypertension in sickle cell
congenital central hypoventilation syndrome disease (SCD), 904
(CCHS), 685–686 pulmonary lymphangioleiomyomatosis
croup, 312–313 (LAM), 829
cystic fibrosis (CF), 800 recurrent pneumonia, 405–407
eosinophilic granulomatosis with recurrent small-volume aspiration, 712–715
polyangiitis (EGPA), 494–495 sarcoidosis, 499
eosinophilic pneumonia, 200 sleep-related movement disorders, 634–638
epiglottitis, 318–319 systemic inflammatory diseases, 482–483
excessive daytime somnolence (EDS), systemic lupus erythematosus (SLE), 487
660–662 thoracentesis in, 549
foreign body aspiration, 703–705 tuberculosis (TB), 418–427
gastroesophageal reflux (GER), 878–879 Williams-Campbell syndrome, 828
granulomatosis with polyangiitis (GPA), Diaphragm, 11–12
491–492 area of apposition, 279–281
Hermansky-Pudlak syndrome (HPS), 837 congenital diaphragmatic hernia (CDH),
hypoxemia, 1067–1069 267–271, 303
inflammatory bowel disease (IBD), 883 physical examination of, 284–285
insomnia, 646–647 as primary muscle of inspiration, 31
interstitial lung disease (ILD), 509–514 Diaphragm pacing (DP) for congenital central
juvenile dermatomyositis (JDM), 488–489 hypoventilation syndrome
juvenile idiopathic arthritis (JIA), 485 (CCHS), 688–689
juvenile systemic sclerosis (JSS), 488 Dicloxacillin, 1039
microscopic polyangiitis (MPA), 493 Dietary evaluation, 1047
mixed connective tissue disease (MCTD) Differentiated thyroid carcinoma, 920
and Sjögren syndrome, 490 Diffuse lung disease (DLD), 505
Mounier-Kuhn syndrome, 826, 827 Diffuse parenchymal lung disease, 732–733
mucopolysaccharidosis (MPS), 839–840 Diffusing capacity of the lung for carbon
narcolepsy, 665–666 monoxide (Dlco), 87–89
neuromuscular disorders (NMDs), 950–956 exercise and, 39
nontuberculous mycobacteria, 457–459 hypersensitivity pneumonitis (HP) and, 184
nonviral pneumonia, 369, 370–371 Diffusion defects, 24–25
nutritional as cause of hypoxia and hypoxemia, 1063,
ABCDEF method of, 1045, 1046 1064
anthropometric, 1045–1047 DiGeorge syndrome, 936
biochemical indices in, 1047 Discharge teaching on oxygen
clinical evaluation in, 1047 supplementation, 1071–1074
dietary evaluation in, 1047 Dominant posterior rhythm, 588
elimination evaluation in, 1048 Dornase alfa, 156–157
feeding evaluation in, 1048 for airway clearance, 988
obstructive sleep apnea (OSA), 618, for cystic fibrosis (CF), 797
619–622 for primary ciliary dyskinesia (PCD), 825
obstructive sleep apnea syndrome (OSAS), Down syndrome, 66, 245–246
607–610 airway abnormalities and, 835

1159
Index
asthma and, 837 Eczema

parenchymal lung disease and, 835 asthma and, 343, 895
pneumonia and, 835–836 due to food allergy, 74
pulmonary disorders resulting from, 56 insomnia due to, 645
pulmonary vascular problems and, 836 in pediatric pulmonary history, 59
sleep-disordered breathing with, 834–835 pneumonia and, 402
Dreaming, 596–597 in review of systems, 60
Drowning, 49–50 sweat test and, 786
Drug-induced sleep endoscopy (DISE), 609 Wiskott-Aldrich syndrome (WAS) and, 936
Drug interactions with antibiotics, 1044 EDS. See Excessive daytime somnolence
Dry powder inhalers, 999–1001 (EDS)
Duchenne muscular dystrophy (DMD), EGPA. See Eosinophilic granulomatosis with
606–607 polyangiitis (EGPA)
pulmonary disorders resulting from, 56 Ehlers-Danlos syndrome, 257, 289
Duration of present illness, 55 Eisenmenger syndrome, 572, 856
Dwarfism, 832 lung transplant and, 732
Dysfunctional breathing Elastic properties of lung and chest wall, 33
complicating asthma, 774 Electroencephalography (EEG) patterns of
hyperventilation, 773–774 sleep, 583–584
repetitive sighing, 774 Electromagnetic navigational bronchoscopy,
Dyshemoglobinemias, 1065 159
Dysmorphic lung syndrome, 125 Electronic cigarette, or vaping, product
Dysphagia use-associated lung injury
after tracheostomy, 1116 (EVALI), 1085
with aspiration, 330 Electronic nicotine delivery systems (ENDS),
Dyspnea, 63, 69 1083–1087
alpha-1 antitrypsin (AAT) deficiency and, 830 involuntary exposure to, 1097–1098
in cardiac disease, 851 reducing exposure to, 1100
exercise-induced (EID), 771–772 Electrosurgery, 158
exercise-induced vocal cord dysfunction Elexacaftor/tezacaftor/ivacaftor (ETI), 795–796
(EIVCD) and, 769–772 Elimination evaluation, 1048
functional causes of, 767–771 Embolus, pulmonary, 19
in granulomatosis with polyangiitis (GPA), carbon dioxide exhalation with, 30
491 drowning, 49–50
neuromuscular disorders (NMDs) and, 949 Embryology of lungs, 3–5
pleural effusion, 545 arthrogryposis multiplex congenita (AMC)
pseudohypoaldosteronism (PHA) and, 840 and, 833
in pulmonary hypertension in sickle cell Embryonal sarcoma of liver, 920
disease (SCD), 904 Embryonic phase, lung development, 3
sighing, 774 Emesis in gastroesophageal reflux (GER), 876
vocal cord dysfunction (VCD) and, 768–771 Emotional/mental health and tobacco use, 1089
without physiologic correlates, 772–773 Empiric medical therapy for gastroesophageal
reflux (GER), 878
E Encephalocele, 244–245
Eagle-Barrett syndrome, 304 Endobronchial stents, 157–158
Ears in review of systems, 60 Endobronchial tumor, 331
Echinocandins, 1043 Endobronchial ultrasonography, 158
Echocardiography Endocrine disorders
for interstitial lung disease (ILD), 509 pulmonary complications of, 869
for pulmonary arterial hypertension (PAH), parathyroid, 870–871
859 pituitary, 871
for pulmonary hypertension in sickle cell thyroid, 870
disease (SCD), 904 tumors that metastasize to the lungs from,
Ectodermal dysplasia, 786 920
End-of-life care for neuromuscular disorders
(NMDs), 954

1160
Index
Endoscopic intubation, 157 Epiglottitis

Endoscopy for gastroesophageal reflux (GER), antibiotics for, 1021
879 causative organisms of, 318
Endothelin-1 receptor antagonists, 863 clinical presentation of, 318
ENDS. See Electronic nicotine delivery diagnosis of, 318–319
systems (ENDS) epidemiology of, 317
End-tidal carbon dioxide monitoring, 29 management of, 319
Enterobacter when to admit for, 320
antibiotics for, 1030, 1041 when to refer for, 320
cephalosporins for, 1039 Epilepsy, 637–638
fluoroquinolones for, 1041 Epinephrine, 156, 1006
Enteropathy, 935 for croup, 315–316
Environmental deprivation, 786 dosing chart for, 1010
Environmental exposure Epstein-Barr virus (EBV), 734
asthma and, 223–224 as complication of HIV, 939
primary ciliary dyskinesia (PCD) and, 825 Epworth Sleepiness Scale, 662
recurrent pneumonia and, 402 Equipment
Environmental history, 55–56, 59 Acapella valve, 982–983
Environmental tobacco smoke (ETS), 55, cost of, 986
61–62 instructional videos on, 987
prenatal effects of exposure to, 1098–1100 Aerobika device, 982–983
reducing exposure to, 1100 cost of, 986
Enzyme replacement therapy, 1049 instructional videos on, 987
Eosinophilic granulomatosis with polyangiitis aerosol medications
(EGPA), 494–495 choosing the appropriate, 1001
Eosinophilic pneumonia, 117–118, 197–198 dry powder inhalers, 999–1001
clinical presentation of, 198–199 inspiratory effort and dry delivery, 1000
diagnostic testing for, 200 nebulizers, 994–996
pathophysiology of, 201 pressurized metered dose inhalers
treatment of, 202 (pMDIs), 993, 997–999
Epidemiology and etiology soft mist inhalers, 999
allergic bronchopulmonary aspergillosis airway clearance
(ABPA), 168–169 cough assist device (CAD), 985
atelectasis, 469–473 intrapulmonary percussive ventilator
bacterial tracheitis, 320–321 (IPV), 985
brief, resolved, unexplained events oscillating PEP devices, 982–983
(BRUEs), 674 positive expiratory pressure (PEP), 981
bronchiolitis, 341 home mechanical ventilation, 1137–1138
bronchopulmonary dysplasia (BPD), mechanical insufflation-exsufflation (MIE)
521–522 device, 958–959
congenital central hypoventilation syndrome oxygen therapy, 1074–1075
(CCHS), 682 positive expiratory pressure (PEP), 981
croup, 312 cost of, 986
epiglottitis, 317 instructional videos on, 987
excessive daytime somnolence (EDS), oscillating devices, 982–983
659–660 vest devices, 983–984
hemorrhage, pulmonary, 564–565 cost of, 986
home mechanical ventilation, 1125–1126 instructional videos on, 987
hypersensitivity pneumonitis (HP), 185–187 Ertapenem, 1039, 1040
narcolepsy, 665 Erythromycin, 1024, 1026, 1029, 1033, 1040
obstructive sleep apnea syndrome (OSAS), Escherichia coli
603 antibiotics for, 1030, 1041
primary ciliary dyskinesia (PCD), 817–818 as complication of HIV, 939
sleep-related movement disorders, 633–634 fluoroquinolones for, 1041
Esophageal atresia, 257–261

1161
Index
Esophageal reflux, 330 Extrinsic compression, 331

Esophagus, 10–11 Exudative pleural effusion, 543
Ethambutol, 1032, 1035 Eyes in review of systems, 60
for mycobacteria, 461
toxicities and monitoring, 463 F
in treatment of TB, 433 Failure to thrive in gastroesophageal reflux
Ethionamide (GER), 876
drug-resistant TB and, 434 False ribs, 5
Xpert Ultra and, 426 Familial pulmonary fibrosis, 56
ETS. See Environmental tobacco smoke Family history, 56, 59
(ETS) Fatigue
Eupnea, 69 in hypersensitivity pneumonia, 184
Evaluation. See Diagnosis and evaluation in review of systems, 60
Evidence-Based Management of Sickle Cell Fat-soluble vitamins, 1047
Disease, 894 Feeding evaluation, 1048
Ewing sarcoma, 919, 920, 921 Feeding resistance in gastroesophageal reflux
Excessive daytime somnolence (EDS) (GER), 876
diagnostic tests for, 660–662 FEES. See Fiber-optic endoscopic evaluation
etiology of, 659–660 of swallowing (FEES)
insufficient sleep syndrome, 663 FEV. See Forced expiratory volume (FEV)
narcolepsy, 663–668 Fever in review of systems, 60
treatment for, 663 Fiber-optic endoscopic evaluation of
Exercise challenge testing, 94 swallowing (FEES), 713
Exercise-induced asthma, 224 Fibromyalgia, insomnia due to, 645
obesity and, 751, 756 Fibrosarcoma, 920
Exercise-induced bronchospasm (EIB), 94, Fibrosing colonopathy, 793
224, 771 Financial support, 59
Exercise-induced dyspnea (EID), 771–772 Flail chest, 288
Exercise-induced vocal cord dysfunction Flavors, tobacco product, 1089
(EIVCD), 769–770 Fleischner Society, 112
exertional dyspnea other than, 771–772 Flexible bronchoscopy
Exercise physiology, 39–40 airway management and examination, 152
cardiac responses, 39–40 choosing between rigid and, 142–144
maximal oxygen uptake and, 40 complications of, 159
pulmonary hypertension in sickle cell extrathoracic airway and, 149
disease (SCD) and, 904 indications for, 144–147
Exhalation, 279 for mucopolysaccharidosis (MPS), 840
Exhaled nitric oxide (FeNO), 227 for systemic inflammatory diseases, 482
Expiration Flexible bronchoscopy for evaluating
dyspnea and, 769 in ABPA, 169
muscles of, 32 Flow-volume loops, 81–83
neuromuscular disorders (NMDs) and, 950 Fluconazole, 1042
Exploding head syndrome, 656 Fluoroquinolones, 1041
Extracorporeal membrane oxygenation Xpert Ultra treatment and, 426
(ECMO), 726–727 Fluoroscopy, 111
after lung transplant, 742 Fluoxetine
Extracorporeal photopheresis (ECP), 741 for asthma and obesity, 755
Extralobar sequestrations, 271–272 Flutter valve, 982–983, 986
Extrapulmonary tuberculosis (TB), 418, 456 Forced expiratory volume (FEV), 79–81,
diagnosis of, 459 285–287
Extrathoracic airway, 148–150 with asthma and obesity, 750–751
Extremities, examination of, 68 lung function in sickle cell disease (SCD),
Extrinsic allergic alveolitis, 117, 183. See also 900
Hypersensitivity pneumonitis lung volumes, 86–87
(HP) neuromuscular disorders (NMDs) and, 953

1162
Index
Forced vital capacity (FVC), 79–81, 285–287 asthma and, 878

with asthma and obesity, 750–751 brief, resolved, unexplained events (BRUEs)
lung function in sickle cell disease (SCD), and, 877–878
900 bronchopulmonary dysplasia (BPD) and,
lung volumes, 86–87 1054–1055
neuromuscular disorders (NMDs) and, 950, clinical manifestations of, 875–877
952 diagnosis of, 878–879
Foreign body aspiration habit throat clearing and, 767
bronchoscopy for, 143, 157 insomnia due to, 645
clinical presentation of, 702–703 in newborns and infants, 876
common objects in, 701–702 in older children and adolescents, 876–877
diagnosis of, 703–705 pathogenesis of, 875
management of, 706 in preschool-aged children, 876
retained foreign body and, 331 pulmonary disorders associated with,
when to refer and admit for, 706–707 877–878
Formula feeding, 1049–1050 pulmonary disorders resulting from, 56
Francisella tularensis, antibiotics for, 1030 Gastroesophageal reflux disease (GERD),
FRC. See Functional residual capacity (FRC) 154–155, 247
Free diving, 46 habit cough and, 765
Front chest lying, 980 obesity and, 752, 754
Fucosidosis, 786 recurrent pneumonia and, 405
Functional residual capacity (FRC), 279, recurrent small-volume aspiration, 711–717
282–283 treatment of, 880–881
Functional respiratory disorders (FRDs) Gastroesophageal scintigraphy, 879
dyspnea, 63, 69 Gastrointestinal diseases, pulmonary
exercise-induced (EID), 771–772 complications of, 875
exercise-induced vocal cord alpha-1 antitrypsin (AAT) deficiency,
dysfunction (EIVCD) and, 883–884
769–772 gastroesophageal reflux (GER), 875–881
functional causes of, 767–771 inflammatory bowel disease (IBD), 881–883
pleural effusion, 545 liver disease, 884–885
vocal cord dysfunction (VCD) and, pancreatic disease, 886–887
768–771 Gastrointestinal tract
without physiologic correlates, 772–773 in cystic fibrosis (CF), 791
habit cough syndrome, 763–766 tumors that metastasize to the lungs from,
habit sneezing, 767 920
habit throat clearing, 767 Gastroschisis, 304
Fungal infections Gastrostomy tubes, 1053
antibiotics for, 1030, 1042–1043 feeding challenges with, 1055
as complication of HIV, 939 Gaviscon, 880
cystic fibrosis (CF) and, 731, 790–791 Genetic disorders
pneumonia due to, 380–383 alpha-1 antitrypsin (AAT) deficiency,
Fungal pneumonia, 380–383 830–831
FVC. See Forced vital capacity (FVC) congenital central hypoventilation syndrome
(CCHS), 681–691
G cystic fibrosis (CF), 57–58
Gagging in gastroesophageal reflux (GER), 876 allergic bronchopulmonary aspergillosis
Ganciclovir, 1029 (ABPA) and, 168–169,
Gas exchange, 15–16 172–175
dead space volume in, 17 anxiety and depression with, 792
neuromuscular disorders (NMDs) and, bronchiectasis and, 329, 336–337
953–954 CFTR-related metabolic syndrome and,
Gastroesophageal reflux (GER) 800, 811–814
apnea and, 877 chronic sinusitis in, 65–66
apparent life-threatening events (ALTEs) clinical features of, 785–792
and, 877 cyanosis in, 64

1163
Index
diabetes related to, 792 clinical features of, 820–822

diagnosis of, 800 diagnosis of, 406–407, 822–824
differentiated from primary ciliary differential, 824
dyskinesia (PCD), 824 genetics of, 819
gastrointestinal tract and, 791 history of studies on, 818
genetics of, 782–783 introduction, terminology, and
imaging of, 134–135 epidemiology of, 817–818
immunizations and, 800 management of, 824–825
incidence of, 781 motile cilia biology and, 818–819
lung transplant for patients with, prognosis for, 826
729–731 pulmonary complications of other, 832–841
management of, 792–793 pulmonary disorders and, 56
newborn screening for pulmonary lymphangioleiomyomatosis
algorithms for, 808–810 (LAM), 828–829
background on, 807–811 and testing for interstitial lung disease
CFTR-related metabolic syndrome (ILD), 509–510
and, 811–814 Williams-Campbell syndrome, 827–828
initial management of positive Genitourinary tract tumors, 920
results of, 810–811 Gentamicin, 1029, 1030, 1041
outcomes with, 811 Geometric standard deviation (GSD), 992
nutritional therapies for, 793–794 GERD. See Gastroesophageal reflux disease
osteoporosis and, 792 (GERD)
pathogenesis of, 782–785 Germ cell tumors, 137
pathophysiology of, 783–785 Ghon complexes, 413–414
psychosocial issues with, 801 Glandular period, lung development, 4
pulmonary hemorrhage in, 564, Gliomas, 244–245
569–570 Global Initiative for Asthma (GINA), 207
pulmonary therapies for, 794–799 Global Strategy for Asthma Management, 207
abnormal CFTR, 793, 794–796 Glycogen storage diseases, 66
abnormal gene, 794 GPA. See Granulomatosis with polyangiitis
bronchial obstruction, 796–797 (GPA)
infection, 797–799 Gram-negative bacteria, 114, 374–376
inflammation, 799 aminoglycosides for, 1041
pulmonary exacerbations, 798–799 Gram-positive bacteria, 372–374
tissue damage, 799 aminoglycosides for, 1041
recurrent pneumonia and, 406, 408 Gram stain and culture, 368
reduced lung compliance in, 33 Granulomatosis with polyangiitis (GPA),
reproductive tract and, 791 490–493
role of general pediatrician in, 800–801 Granulomatous lung disease
spirometry and, 79 inflammatory bowel disease, 500
viral respiratory tract infections with, Langerhans cell histiocytosis (LCH),
800 499–500
wheezing and stridor with, 62 sarcoidosis, 497–499
when to admit for, 774 Granulomatous-lymphocytic interstitial lung
when to refer for, 774 disease, 933
Down syndrome, 66, 245–246, 834–837 Gray hepatization, 369
Hermansky-Pudlak syndrome (HPS), Ground-glass attenuation, 116
837–839 Ground-glass opacities, 113, 134
Mounier-Kuhn syndrome, 257, 826–827 Group A Streptococcus, 114, 371, 373–374
narcolepsy and, 666 antibiotics for, 1028
obstructive sleep apnea syndrome (OSAS) as complication of HIV, 939
in, 606–607, 610 Growth hormone deficiency, 871
primary ciliary dyskinesia (PCD), 66, 156, Guillain-Barré syndrome, 949
404–405, 822–824

1164
Index
H cystic fibrosis and bronchiectasis and,

569–570
Habit cough syndrome, 763–766
due to cardiac abnormalities, 571–572
Habit sneezing, 767
due to child abuse, 571
Habit throat clearing, 767
due to infection, 568–569
HACE. See High-altitude cerebral edema
due to tracheostomy, 570–571
(HACE)
etiology of, 564–565
Haemophilus influenzae, 317, 320, 321, 336,
general evaluation of child with hemoptysis
371, 375
and, 565
acute chest syndrome (ACS) and, 894
general management of, 568
aminopenicillins for, 1040
idiopathic, 574–575
ataxia-telangiectasia (A-T) and, 937
imaging and laboratory evaluation of,
cefuroxime for, 1038
565–568
as complication of HIV, 939
Hemorrhagic pleural effusion, 543–544
cystic fibrosis (CF) and, 789
Hemosiderosis, 574–575
tracheostomy and, 1111
Henoch-Schönlein purpura, 497
Wiskott-Aldrich syndrome (WAS) and, 936
Hepatic disease, 884–885
Haller index, 289
Hepatoblastoma, 920, 921
Hallucinations in narcolepsy, 664
Hepatocellular carcinoma, 920
Head in review of systems, 60
Hepatopulmonary syndrome, 884–885
Health disparities and socioeconomic factors
Hermansky-Pudlak syndrome (HPS)
in asthma and obesity, 755
clinical features of, 837
in sleep patterns, 596
in tobacco use, 1089
High-altitude cerebral edema (HACE), 43
Heart, 8, 10–11
management of, 44–45
response to exercise, 39–40
High-altitude illness, 40–45
Heart disease, pulmonary disorders resulting
acclimatization in, 41
from, 56
acute mountain sickness (AMS), 41–42
Heart-lung transplant, 728
chronic mountain sickness (CMS), 44
for primary ciliary dyskinesia (PCD), 825
high-altitude cerebral edema (HACE), 43
Heat-not-burn tobacco, 1087
high-altitude pulmonary edema (HAPE),
Heliox, 316
43–44
Helper T cells, 934
hypoxemia, 1065–1066
Hemangiomas of the tongue, 246
Hematemesis in gastroesophageal reflux
High-altitude pulmonary edema (HAPE),
(GER), 876
43–44
Hematocrit, 1047
Hematopoietic stem cell transplant (HSCT), 914
High-altitude simulation test, 1066
pulmonary complications of, 923–924
High-flow nasal cannula, 347, 1075
Hemidiaphragm, 11
High-flow oxygen therapy (HFOT), 1061,
Hemoglobin
1078–1079
in acute chest syndrome (ACS), 892, 893
High-frequency chest wall compression,
affinity for oxygen, 28, 1061–1062
983–984
biochemical evaluation of, 1047
High-frequency chest wall oscillation
light absorption spectra of, 29
(HFCWO), 958–959
oxygen saturation of, 26
Highly effective triple combination corrector/
Hemophilia, 56
potentiator, 795–796
Hemoptysis, 144
High-resolution CT (HRCT) scan, 115, 134,
causes of, 568–576
333–334, 336
cystic fibrosis (CF) and, 789
for interstitial lung disease (ILD), 510–512
general evaluation of child with, 565
for systemic inflammatory diseases, 482
hypersensitivity pneumonitis (HP) and, 184
High-speed video microscopy of primary
malignancy and, 575
ciliary dyskinesia (PCD), 822
Hemorrhage, pulmonary, 144, 563
Hilum, 11
autoimmune, 572–574
Histamine-2 (H2) receptor blockers for GERD,
causes of hemoptysis and, 568–576
880

1165
Index
Histamine agonists for narcolepsy, 667 Hospitalization

Histoplasma, azoles for, 1042–1043 for acute large-volume aspiration, 709–710
History, pulmonary for asthma, 225
asthma and obesity, 752–754 for atelectasis, 477
common symptoms in, 61–64 for bronchiolitis, 346–348
family history and, 56, 59 for complications of pneumonia, 397
history of present illness and, 55–56, 59 for croup, 317
medical history and, 56–57, 59 for cystic fibrosis (CF), 774
review of systems and, 60 discharge from, with supplemental oxygen,
social history, 58–59 1071–1074
surgical history, 57–58, 59 for epiglottitis, 320
History of present illness, 55–56, 59 for foreign body aspiration, 706–707
HIV infection, 935 home mechanical ventilation and, 1140–
disease processes associated with 1141
bronchiectasis, 330 for interstitial lung disease (ILD), 518
infectious complications of, 938–939 for lung function disorders, 872
noninfectious complications of, 939 for neuromuscular disorders (NMDs), 963
pulmonary complications related to therapy for nonviral pneumonia, 384–385
for, 940 for recurrent small-volume aspiration, 717
HL. See Hodgkin lymphoma (HL) supplemental oxygen and, 1080
Hoarseness for tuberculosis (TB), 447
in gastroesophageal reflux (GER), 876 for viral pneumonia, 362–363
in granulomatosis with polyangiitis (GPA), HP. See Hypersensitivity pneumonitis (HP)
491 HPIV. See Human parainfluenza virus (HPIV)
Hodgkin lymphoma (HL), 136, 914 HRCT. See High-resolution CT (HRCT) scan
pleural effusion with, 544 HSAT. See Home sleep apnea test (HSAT)
Home care HSCT. See Hematopoietic stem cell transplant
oxygen therapy, 1069 (HSCT)
for bronchopulmonary dysplasia (BPD), Huff cough maneuver, 975
1070 cost of, 986
delivery methods, 1075–1076 instructional videos on, 987
monitoring of, 1073–1074, 1076–1078 Human metapneumovirus, 353, 360–361
tracheostomy, 1116–1119 Human milk, 1049–1050
Home mechanical ventilation Human papillomavirus, 918
adjustment to, 1139–1140 Human parainfluenza virus (HPIV), 353, 360
caregiver training for, 1131–1133 Human rhinovirus/enterovirus, 353
causes of chronic respiratory failure (CRF) Humified air, 316, 323
and, 1127–1128 Hydrocarbon aspiration, 710–711
clinical features of chronic respiratory Hydrogen cyanide toxicity, 52–53
failure (CRF) and, 1128–1129 Hydropneumothorax, 129
economic and payment issues with, 1134 Hydroxyurea, 895
equipment and monitoring in, 1137–1138 Hyperacute rejection, 736
goals of, 1126–1127 Hyperbaric oxygen, 1061
history and epidemiology of, 1125–1126 Hypercalcemia, 870
long-term outcomes of, 1138–1139 Hyper-IgM (HIgM) syndrome, 937
medical stability and, 1129–1131 Hyper-immunoglobulin (Ig) E syndrome, 931
modes of, 1136–1137 Hyperinflation, 118
organizational issues with, 1135–1136 Hyperpnea, 69
patient selection for, 1129–1134 Hypersensitivity pneumonitis (HP), 117,
preparing the home for, 1133 183–184
skilled nursing care for, 1133–1134 clinical manifestations of, 184–185
when to admit with, 1140–1141 differential diagnosis and evaluation of,
Home sleep apnea test (HSAT), 609–610 188–190
Honeycomb lung, 114–115 epidemiology and etiology of, 185–187
Hookah, 1087–1088 treatment and prognosis of, 190–192

1166
Index
Hypersomnia, 660 Imaging, pulmonary

Hypertonic saline angiography, 108
for airway clearance, 988 chest radiography, 103, 110–115, 118–119
for cystic fibrosis (CF), 797 computed tomography (CT), 115–116, 119,
Hyperventilation, 773–774 121, 126
Hypnagogic hypersynchrony, 588–589 for cystic fibrosis (CF), 134–135
Hypocalcemia, 870 for interstitial lung disease (ILD), 134
Hypoinflation, 118 magnetic resonance imaging (MRI), 105–
Hypoplasia, pulmonary, 122, 261–262 106, 122
Hypoplastic chest wall, 288 modalities in, 102–109
Hypopnea, 69 multidetector CT (MDCT) scanning, 104–
Hypoproteinemia, 786 105, 122
Hypothyroidism, 786 for nonviral pneumonia, 366–367
Hypoventilation, 23–24 for obstructive sleep apnea syndrome
as cause of hypoxia and hypoxemia, 1063, (OSAS), 609
1064 for pneumonia, 126–132
neuromuscular disorders (NMDs) and, for pulmonary hemorrhage, 565–568
953–954, 956 for pulmonary nontuberculous mycobacteria,
Hypoxemia, 23–26 133
in acute chest syndrome (ACS), 893 radiation exposure in children and, 101–102
asthma and, 220 for specific conditions, 117–138
causes of, 1063–1066 for systemic lupus erythematosus (SLE),
clinical features of, 1067–1069 133–134
defined, 1061 for tuberculosis, 133
diffusion defects and, 24–25 ultrasonography, 107
at high altitude, 1065–1066 ventilation/perfusion scanning, 109
hypoventilation and, 23–24 Imipenem, 1023, 1039, 1040
low venous Po2 and, 26 for mycobacteria, 461, 462
neuromuscular disorders (NMDs) and, toxicities and monitoring, 463
953–954, 956 Imipenem/relebactam, 1039
in pulmonary hypertension in sickle cell Immunizations
disease (SCD), 904 acute chest syndrome (ACS) and, 894
shunt and, 25–26 alpha-1 antitrypsin (AAT) deficiency and,
V̇ /Q̇ mismatch and, 26 831
Hypoxia asthma and, 227
causes of, 1063–1066 Bacille Calmette-Guérin, 424
congenital heart disease (CHD) and, 852 COVID-19, 227
defined, 1061 cystic fibrosis (CF) and, 800
high altitude and, 40–41 history taking on, 58
pulmonary arterial hypertension (PAH) and, influenza, 227
858 neuromuscular disorders (NMDs) and, 962
Hypoxic pulmonary vasoconstriction, 852 PCV7, 384
primary ciliary dyskinesia (PCD) and, 825
I tuberculosis (TB), 443–446
IBD. See Inflammatory bowel disease (IBD) varicella-zoster virus, 227
Ibuprofen, 45 Immunodeficiency, 330
for cystic fibrosis (CF), 799 B lymphocyte disorders, 929, 932–934
Idiopathic insomnia, 646 infectious complications of
Idiopathic pulmonary hemorrhage, 574–575 immunodeficiency and,
Idiopathic pulmonary hypertension and lung 930–937
transplant, 732 neutrophil defects and, 929, 930–931
ILD. See Interstitial lung disease (ILD) noninfectious pulmonary complications of,
Image Gently campaign, 101 937–938
Image sequence analysis of obstructive sleep pulmonary complications associated with
apnea (OSA), 630 HIV infection, 938–940

1167
Index
pulmonary evaluation of patient with, disease processes associated with

940–942 bronchiectasis, 330
recurrent pneumonia and, 402 pulmonary parenchymal disease, 882
T lymphocyte disorders, 929, 934–937 Influenza A and B, 353
treating pulmonary complications in acute chest syndrome (ACS) and, 894
children with, 942–943 antibiotics for, 1031
typical pathogens involved in, 929 as complication of HIV, 938
when to refer for, 943 viral pneumonia, 359–360
Immunofluorescent staining in primary ciliary Influenza vaccine, 227
dyskinesia (PCD), 822 INH. See Isoniazid (INH)
Immunoglobulin A deficiency, 933 Inhalation injury, 50–53
Immunosuppression therapy, 734 disease processes associated with
Immunotherapy, 222–223 bronchiectasis, 330
Independent airway clearance techniques Inhaled therapy. See Aerosol medications
active cycle of breathing techniques Insomnia
(ACBTs), 976 adjustment, 645
autogenic drainage, 976–977 behavioral, of childhood, 646
huff cough maneuver, 975 chronic, 643
Induction therapy, 734 diagnosis of, 646–647
Infants due to medical condition, 645
behavioral insomnia of childhood in, 646 due to mental disorder, 645
confusional arousals in, 652 expected outcomes/prognosis for, 648
food aspiration by, 706 idiopathic, 646
heart-lung transplant in, 728 inadequate sleep hygiene and, 645
intermittent asthma in, 210 major categories of, 643
normal respiratory rate in, 69 management of, 647–648
otitis media in, 821 other ways of describing, 643–644
pneumonia in, 370 paradoxical, 645
positive-pressure ventilation (PPV) in, 687 prevention of, 648–649
rhythmic movement disorder in, 654 psychophysiological, 645
sickle cell disease (SCD) in, 897 short-term, 643
sleep needs of, 593–594 sleep maintenance, 644
sleep-related movement disorders in, 634 sleep-onset, 644
tuberculosis in, 133 subtypes of, 644
use of inhalers in, 998 terminal, 644
Infection Inspection, 65
congenital heart disease (CHD) and, of cardiovascular system, 73
864–865 chest wall, 70
in cystic fibrosis (CF), 797–799 of patient with bronchiectasis, 336
differentiated from primary ciliary of patient with eupnea and dyspnea, 69
dyskinesia (PCD), 824 of patient with trauma, 319
HIV, 935 of tonsillar size, 66, 620
pulmonary complications associated Inspiration, 279
with, 938–940 decreased concentration of oxygenation
neuromuscular disorders (NMDs) and, 962 in, as cause of hypoxia and
Infectious Diseases Society of America, 418 hypoxemia, 1063
Infiltrate, 112 dyspnea and, 770
Inflammation muscles of, 31
in asthma and obesity, 748–750 neuromuscular disorders (NMDs) and, 950
in cystic fibrosis (CF), 799 Inspiratory effort and dry delivery of aerosol
in inflammatory bowel disease (IBD), medications, 1000
882–883 Insufficient sleep syndrome, 663
Inflammatory bowel disease (IBD), 500, 881 Intercostal muscles, 11–12
airway inflammation in, 882–883 Intermittent asthma, 210–211
diagnosis and treatment of, 883 International Classification of Sleep Disorders,
607, 617–618, 633, 643, 956

1168
Index
International Harmonization Project, 137 K

International Pediatric Lung Transplant
Kanamycin, 1041
Collaborative, 734
drug-resistant TB and, 412, 434
Interstitial lung disease (ILD), 112–113, 134,
Xpert Ultra treatment and, 426
505–508
Kawasaki disease, 497
bronchoalveolar lavage (BAL) for, 513
K-complexes, 589, 591
evaluation of, 509–514
Ketoconazole, 1042
lung biopsy for, 513–514
Kidneys and bicarbonate concentration, 20
Klebsiella pneumoniae, 318, 375
oxygen therapy for, 1070
antibiotics for, 1032, 1041
pathophysiology of, 509
fluoroquinolones for, 1041
physiological testing for, 512–513
Kleine-Levin syndrome (KLS), 655, 660
prognosis for, 517–518
Klinefelter syndrome, 786
pulmonary disorders resulting from, 56
KLS. See Kleine-Levin syndrome (KLS)
pulmonary injury and, 922
Kreteks, 1088
specific diseases in infancy, 514–516
Kyphoscoliosis, 950
when to admit for, 518
when to refer for, 518 L
Interstitial pneumonia syndrome of early
infancy, antibiotics for, 1026 LABA. See Long-acting β2-agonist (LABA)
Interstitium, 112–113 Laboratory evaluation
Intervention medications for asthma, 214–219 bronchiolitis, 345
Intrapulmonary percussive ventilation (IPV), nonviral pneumonia, 367
477, 985 pleural effusion, 546
cost of, 986 pulmonary hemorrhage, 565–568
instructional videos on, 987 Langerhans cell histiocytosis (LCH), 499–500,
Intrathoracic airway, 150–151 884
Intravenous immunoglobulin (IVIG) Laryngeal anomalies, 247–250
replacement therapy, 933, 942 Laryngoceles, 248
Invasive mechanical ventilation for Laryngomalacia, 247, 255
bronchopulmonary dysplasia Laser bronchoscopy, 158
(BPD), 529 Latent tuberculosis (TB), 417
Ionizing radiation, 101–102 LCH. See Langerhans cell histiocytosis (LCH)
Ipratropium, 219 Legionella pneumophila, 376
Ipratropium bromide, 1011 antibiotics for, 1032
IPV. See Intrapulmonary percussive ventilation Leiomyosarcoma, 920
(IPV) Less invasive surfactant administration (LISA),
IQOS products, 1087 528–529
Isavuconazole, 1030 Leukemia, 913–914
Isoniazid (INH), 433, 461 Leukemic cell pneumonopathy, 914
toxicities and monitoring, 463 Levalbuterol, 1010
Itraconazole, 1022, 1042 Levofloxacin, 1030, 1041
for allergic bronchopulmonary aspergillosis drug-resistant TB and, 434
(ABPA), 177–178 LGBTQ youth, tobacco use by, 1089
Ivacaftor, 795 Limit-setting sleep disorder, 646
Line probe assays, 426
J Linezolid, 434
for mycobacteria, 461, 462
JDM. See Juvenile dermatomyositis (JDM)
toxicities and monitoring, 463
Jet nebulizers, 994–995
Liposarcoma, 920
JIA. See Juvenile idiopathic arthritis (JIA)
LISA. See Less invasive surfactant
JSS. See Juvenile systemic sclerosis (JSS)
administration (LISA)
JUUL product, 1086–1087
Listeria, 1038
Juvenile dermatomyositis (JDM), 488–489
Little cigars, 1088
Juvenile idiopathic arthritis (JIA), 485–486
Liver disease, 884–885
Juvenile systemic sclerosis (JSS), 489–490
prealbumin in, 1047

1169
Index
Lobectomy for primary ciliary dyskinesia Lung abscess, 130–131, 391–392

(PCD), 825 antibiotics for, 1021–1022
Lobes, lung, 8–10 clinical presentation of, 392
Long-acting muscarinic receptor antagonist management of, 393
medications, 223 prognosis for, 393
Long-acting β2-agonist (LABA), 222–223, Lung anomalies
1006 bronchogenic cysts, 124, 262–264
for asthma and obesity, 755 congenital diaphragmatic hernia, 267–271
Long COVID-19, 357 congenital lobar emphysema (CLE),
Lower airway infections, 406, 408 266–267
antibiotics for, 1021–1037 congenital pulmonary airway malformation
bronchiectasis, 329–338 (CPAM), 264–266
bronchiolitis, 341–348 laryngomalacia, 247, 255
complications of pneumonia, 387–397 lung growth and development and, 253–255
nontuberculous mycobacteria, 453–464 prenatal nicotine and tobacco exposure and,
nonviral pneumonia, 365–385 1099
obesity and, 752 pulmonary agenesis or hypoplasia, 122,
pulmonary hemorrhage due to, 568–569 261–262
recurrent pneumonia, 401–408 pulmonary sequestration, 124, 271–272
tuberculosis (TB), 133 tracheobronchial abnormalities, 255–257
Bacille Calmette-Guérin vaccine and, tracheoesophageal fistula (TEF), 257–261
424 vascular rings, 272–275
chronic disease, 418 Lung function in sickle cell disease (SCD)
clinical presentation of, 415–418 clinical features of, 900–902
control of, 442–443 management of, 902
development of new antibiotics and overview of, 900
recycling older antibiotics for, Lung function testing, 285–287
435–441 Lung parenchymal tumors, 919
diagnosis of, 418–427 Lungs. See also Breathing
directly observed therapy for, 442 airway resistance in, 34
dissemination of, 414 blood supply of, 6
drug-resistant, 412–413 bony thorax and, 5
extrapulmonary disease, 418 elastic properties of, 33
improving immunologic diagnosis of, embryology of, 3–5
426–427 gross anatomy of, 8–10
incidence of, 411–412 growth and development of, 253–255, 282
latent, 417 inhalation injury to, 50–53
primary infection with, 413 intercostal muscles and diaphragm, 11–12
primary pulmonary disease, 415–416 lymphatics of, 6–7
prognosis for, 442 malformations of, 122–126
reactivation disease, 417 mediastinum and, 8, 10–11
screening tests for, 418–419 nerve supply of, 7
sequencing-based techniques for physical examination of, 70–73
detecting, 425–426 Lung transplant, 156, 721–723
skin testing for, 419–424 for cystic fibrosis (CF) tissue damage, 799
sputum analysis for, 424–425 diffuse parenchymal lung disease and,
treatment of, 429–435 732–733
treatment of, with no evidence of active Eisenmenger syndrome and, 732
disease, 427–428 evaluation of donor for, 733–734
vaccine development for, 443–446 general indications for, 724–727
when to admit for, 447 for Hermansky-Pudlak syndrome (HPS),
when to refer for, 447 837
viral pneumonia, 353–363 for hypersensitivity pneumonitis (HP), 191
Low venous Po2, 26 idiopathic pulmonary hypertension
Lumacaftor/ivacaftor, 796 and pulmonary arterial
hypertension and, 732

1170
Index
Lung transplant (continued) Malignant germ cell tumor, 920

immunosuppression after, 734 Malignant neurilemmoma, 920
induction therapy after, 734 Malignant rhabdoid tumor of the kidney, 920
long-term follow-up after, 735 Malnutrition, 786
long-term monitoring after, 735–736 Management and treatment. See also
maintenance immunosuppression after, Medications; Surgical
734–735 interventions
for patients with cystic fibrosis (CF), achondroplasia, 832
729–731 acute chest syndrome (ACS), 894–895
for patients with immunodeficiency, acute large-volume aspiration, 709
942–943 alpha-1 antitrypsin (AAT) deficiency, 831,
posttransplant care, 734–742 884
posttransplant lymphoproliferative disorder anti-glomerular basement membrane
(PTLD) after, 734, 735, (AGBM) disease, 496
741–742 arthrogryposis multiplex congenita (AMC),
for primary ciliary dyskinesia (PCD), 825 833
for pulmonary lymphangioleiomyomatosis asthma, 214–226
(LAM), 829 atelectasis, 475–477
pulmonary vascular disorders and, 732 bacterial tracheitis, 323
rejection of, 736–741 brief, resolved, unexplained events
acute cellular, 156, 723, 736–738 (BRUEs), 676–678
chronic lung allograft dysfunction, 723, bronchiectasis, 336–337
738–741 bronchiolitis, 345–346
hyperacute, 736 bronchopulmonary dysplasia (BPD),
selection of candidates for, 728–734 527–533
surfactant deficiencies and, 731 congenital central hypoventilation syndrome
survival after, 721–723, 742 (CCHS), 687–691
timing of referral for, 728 COVID-19, 358
types of, 723–724 croup, 314–316
Lung volumes, 86–87 cystic fibrosis (CF), 792–793
in asthma and obesity, 751 differentiated from primary ciliary
neuromuscular disorders (NMDs) and, 950 dyskinesia (PCD), 824–825
recruitment, 959 eosinophilic granulomatosis with
Lymphangiomas of the tongue, 246 polyangiitis (EGPA), 495
Lymphatics, pulmonary, 6–7 eosinophilic pneumonia, 202
Lymphocytic interstitial pneumonitis (LIP), epiglottitis, 319
939 excessive daytime somnolence (EDS), 663
Lymphomas, 136–137, 914 foreign body aspiration, 706
Hodgkin, 136, 544, 914 granulomatosis with polyangiitis (GPA),
non-Hodgkin, 136, 914 492–493
pleural effusion with, 544 Hermansky-Pudlak syndrome (HPS), 837,
839
M HIV, pulmonary complications related to,
Macroglossia, 246 940
Macrolides, 1032, 1040 hypersensitivity pneumonitis (HP), 190–192
for mycobacteria, 460 inflammatory bowel disease (IBD), 883
Magnesium sulfate, 1012 insomnia, 647–648
Magnetic resonance imaging (MRI), 105–106, interstitial lung disease (ILD), 516–517
122 juvenile dermatomyositis (JDM), 489
for atelectasis, 474–475 juvenile idiopathic arthritis (JIA), 485–486
for pleural effusion, 547 juvenile systemic sclerosis (JSS), 488–489
Maintenance medications for asthma, 219–223 lung abscess, 393
Malabsorption, 1047 microscopic polyangiitis (MPA), 493
Malignancy. See Oncogenic disease mixed connective tissue disease (MCTD)
Malignant airway tumors, 918–919 and Sjögren syndrome, 490
Malignant fibrous histiocytoma, 920 Mounier-Kuhn syndrome, 826

1171
Index
mucopolysaccharidosis (MPS), 840 neuromuscular disorders (NMDs)

narcolepsy, 666–668 and, 953–954, 956
necrotizing pneumonia, 395 in pulmonary hypertension in sickle
neuromuscular disorders (NMDs), 957–962 cell disease (SCD), 904
nicotine and tobacco dependence, 1093– shunt and, 25–26
1097 V̇ /Q̇ mismatch and, 26
nontuberculous mycobacteria, 460–464 hypoxia and
nutritional support causes of, 1063–1066
alpha-1 antitrypsin (AAT) deficiency, congenital heart disease (CHD)
831 and, 852
for asthma, 1056–1057 defined, 1061
bronchopulmonary dysplasia (BPD), high altitude and, 40–41
1045, 1054–1055 pulmonary arterial hypertension
challenges in, 1055 (PAH) and, 858
cystic fibrosis (CF), 793–794, 1048– for interstitial lung disease (ILD), 1070
1054 monitoring and weaning, 1076–1078
gastroesophageal reflux disease obstructive sleep apnea (OSA) and,
(GERD), 880 1070–1071
neuromuscular disorders (NMDs), for pneumothorax, 557
954–955 for pulmonary hypertension, 1070
for obstructive sleep apnea (OSA), resources for physicians, 1080
1057 when to admit for, 1080
for Prader-Willi syndrome, 1057 when to refer for, 1080
obstructive sleep apnea syndrome (OSAS), while flying, 1066
610–612 pancreatic disease, 887
oxygen therapy parapneumonic effusion, 391
adverse effects of, 1078 of patient with immunodeficiency, 942–943
alveolar gas equation and alveolar- pectus excavatum and carinatum, 290–292
arterial gradient and, 1063 pleural effusion, 548
for bronchopulmonary dysplasia (BPD), pneumatocele, 396
1069–1070 pneumomediastinum, 560
for congenital central hypoventilation pneumothorax, 556–558
syndrome (CCHS), 687–689 pseudohypoaldosteronism (PHA), 841
for croup, 316 pulmonary arterial hypertension (PAH),
for cyanotic congenital heart disease, 861–863
1070 pulmonary hemorrhage, 568
definitions in, 1061 pulmonary hypertension in sickle cell
delivery methods, 1075–1076 disease (SCD), 904
determinants of oxygen delivery to pulmonary lymphangioleiomyomatosis
tissues and, 1061–1063 (LAM), 829
discharge from hospital with, 1071– recurrent pneumonia, 407–408
1074 recurrent small-volume aspiration, 715–716
equipment for, 1074–1075 sarcoidosis, 499
high-flow (HFOT), 1061, 1078–1079 scoliosis, 295–297
home therapy, 1069, 1073–1074 sickle cell disease (SCD) with asthma, 897
hypoxemia and, 23–26 sleep-disordered breathing in sickle cell
in acute chest syndrome (ACS), 893 disease (SCD), 899
asthma and, 220 sleep-related movement disorders, 638–640
causes of, 1063–1066 systemic lupus erythematosus (SLE), 488
clinical features of, 1067–1069 thoracic insufficiency syndrome, 299–303
defined, 1061 Williams-Campbell syndrome, 828
diffusion defects and, 24–25 Manually assisted coughing, 959, 977
at high altitude, 1065–1066 Marfan syndrome, 289
hypoventilation and, 23–24 disease processes associated with
low venous Po2 and, 26 bronchiectasis, 331
pulmonary disorders resulting from, 56

1172
Index
Marketing, tobacco, 1088–1089 inhaled, 991

Mass median aerodynamic diameter (MMAD), inhaled β-adrenergic, 825
992 mechanisms of, 1005–1007
Mauriac syndrome, 786 pathophysiology and clinical features
Maximal expiratory pressure (MEP), 950, 953 of airway obstruction and,
Maximal inspiratory pressure (MIP), 950, 953 1007–1008
Maximal oxygen uptake, 40 for primary ciliary dyskinesia (PCD),
MCTD. See Mixed connective tissue disease 825
(MCTD) short-acting β2-agonists (SABAs),
MDI. See Metered dose inhaler (MDI) 1008, 1012–1015
Measles, 330, 361 testing of, 89–92
Mechanical insufflation-exsufflation (MIE) carbapenems, 1040
device, 958–959 for community-acquired pneumonia, 1023,
Meconium ileus and cystic fibrosis (CF), 791 1024–1026
Mediastinal masses considerations for choice of, 1020
anterior, 136–137 for cystic fibrosis (CF), 1023–1024
location and types of, 136 drug interactions with, 1044
middle, 137 for epiglottitis, 1021
posterior, 137–138 fluoroquinolones, 1041
pulmonary manifestations of, 915–916 for fungi, 1030
Mediastinum, 8, 10–11 for group A Streptococcus, 1028
Medical history, 56–57, 59 for interstitial pneumonia syndrome of early
Medication allergy history, 58 infancy, 1026
Medications. See also Management and for lung abscess, 1021–1022
treatment macrolides, 1040
adverse reactions to, 1043 oral cephalosporins, 1038–1039
aerosol penicillinase-resistant penicillins, 1039
advantages of, 991 for pertussis, 1024
delivery devices, 993–1001 for pneumococcal diseases, 1026–1027
delivery of, 992–994 for pneumonias, 1026–1034
for allergic bronchopulmonary aspergillosis, for Staphylococcus aureus, 1027
1022 for tobacco and nicotine dependence,
aminoglycosides, 1041 1094–1096
aminopenicillins, 1040 for tracheitis, 1021
antibiotics, 1019 for tuberculosis, 1035–1037
anticholinergics Membranous croup. See Bacterial tracheitis
for airway clearance, 988 Meropenem, 1021–1023, 1029, 1030, 1032,
mechanism of, 1006 1034, 1039, 1040
antifungal agents, 1042–1043 Meropenem/vaborbactam, 1039
antipseudomonal β-lactams, 1039–1040 Mesh nebulizers, 995–996
for aspiration pneumonia, 1022 Metabolic acidosis, 20–21
for atypical pneumonia, 1022 Metabolic alkalosis, 20–21
for bronchitis, 1022 Metabolic syndrome, CFTR-related, 800,
bronchodilators 811–814
for acute bronchospasm, 1008–1013 Metered dose inhaler (MDI), 213, 214–216,
for airway clearance, 988 221
for alpha-1 antitrypsin (AAT) for asthma, 1008
deficiency, 831 pressurized metered dose inhalers (pMDIs),
for asthma, 1013–1014 993, 997–999
for bronchiolitis, 1015 Metformin
for bronchopulmonary dysplasia, 1015 for asthma and obesity, 755
clinical pharmacology and disease Methemoglobinemia, 1065
management using, 1008 Methicillin-resistant Staphylococcus aureus
for cystic fibrosis (CF), 797, 1015 aminopenicillins for, 1040
dosing chart for, 1009–1011 antibiotics for, 1037

1173
Index
antipseudomonal β-lactams for, 1039 Motile cilia biology, 818–819

aspiration events and, 709 Mounier-Kuhn syndrome, 257
bacterial pneumonia and, 371, 380 clinical features of, 826
carbapenems for, 1040 diagnosis of, 826, 827
cephalosporins for, 1039 management of, 826
cystic fibrosis (CF) and, 730, 790, 797 pathogenesis of, 826
necrotizing pneumonia and, 393 Moxifloxacin, 1041
penicillinase-resistant penicillins for, 1039 toxicities and monitoring, 463
Staphylococcal pneumonia and, 374 MPA. See Microscopic polyangiitis (MPA)
Methylxanthines, 1007 MRI. See Magnetic resonance imaging (MRI)
Micafungin, 1043 MSLT. See Multiple sleep latency test (MSLT)
Micro-aspiration, 712 Mucopolysaccharidosis (MPS), 839–840
Microbiology pulmonary disorders resulting from, 56
bronchoalveolar lavage and, 155–156 Mucor, posaconazole for, 1043
cystic fibrosis (CF), 789–790 Mucus mobilization, 957–959
nonviral pneumonia, 368–369 Multidetector CT (MDCT) scanning, 104–105,
in patients with cystic fibrosis (CF), 122
730–731 for aspiration, 129
Micronodules, 113–114 Multiple sleep latency test (MSLT), 665–666
Microscopic polyangiitis (MPA), 493 Multisystem inflammatory syndrome in
Middle mediastinal masses, 137 children (MIS-C), 357–358
MIS-C. See Multisystem inflammatory Munchausen syndrome by proxy, 786
syndrome in children (MIS-C) Muscles, respiratory
Mixed connective tissue disease (MCTD), 490 for breathing, 31–32
Monarch vest, 986, 987 neuromuscular disorders (NMDs) and, 950,
Monitoring 953
carbon dioxide, 28–30 respiratory muscle training, 960
clinical course of asthma, 226–228 strength of, 287–288
Collaborative Home Infant Monitoring Muscular dystrophies, 949
Evaluation (CHIME) study, Musculoskeletal system, tumors that
676 metastasize to the lungs from,
congenital central hypoventilation syndrome 920
(CCHS), 690 Myasthenia gravis, 949
end-tidal carbon dioxide, 29 Mycobacterium abscessus, 455
home cardiorespiratory, 1073 cystic fibrosis (CF) and, 790
home mechanical ventilation, 1137–1138 Mycobacterium avium, 455, 456
long-term, after lung transplant, 735–736 antibiotics for, 1032
noninvasive arterial Pco2, 28–30 cystic fibrosis (CF) and, 790
obstructive sleep apnea (OSA) Mycobacterium kansasii, 455
biomotion sensors for, 630 Mycobacterium marinum, 456
capacitor-based systems for, 630 Mycobacterium tuberculosis, 59, 114, 330,
monitoring classifications in, 622–627 336, 392, 411. See also
radar, 629 Nontuberculous mycobacteria;
sheets and mats for, 630 Tuberculosis (TB)
type 1 monitoring, 622, 624 antibiotics for, 1032
type 2 monitoring, 624–625 as complication of HIV, 938
type 3 portable monitoring, 624–626 sequencing-based techniques for detecting,
type 4 portable monitoring, 624–627 425–426
oxygen therapy, 1076–1078 Mycobacterium ulcerans, 456
home care, 1073–1074, 1076–1078 Mycophenolate mofetil
Monoclonal anti–immunoglobulin E antibodies for posttransplant lymphoproliferative
for asthma and obesity, 755–756 disorder (PTLD), 735
pulmonary injury and, 922 Mycophenolic acid
Montelukast, 222 for posttransplant lymphoproliferative
Moraxella catarrhalis, 318, 336 disorder (PTLD), 735

1174
Index
Mycoplasma pneumoniae Neisseria, 318

antibiotics for, 1033 Neonatal respiratory distress syndrome, 33
ataxia-telangiectasia (A-T) and, 937 Nephrogenic diabetes insipidus, 786
bacterial pneumonia and, 367, 371, 377–378 Nerve supply of lungs, 7
disease processes associated with Neuroblastoma, 920, 921
bronchiectasis, 330 Neurofibromatosis 1, 56
Neurological examination, 73–74
N Neuromodulators for narcolepsy, 667
N-acetyl cysteine, 988 Neuromuscular disorders (NMDs), 288, 947
NAEPP. See National Asthma Education and clinical manifestations of, 950
Prevention Program (NAEPP) evaluation and anticipatory guidance for,
Nafcillin, 1039 950–951
Napping, daytime, 594 cardiac, 955–956
Narcolepsy. See also Excessive daytime nutrition, 954–955
somnolence (EDS) palliative and end-of-life care, 954
cerebrospinal fluid hypocretin-1 in, 666 pulmonary function tests (PFTs) in,
clinical manifestations of, 663–665 952–954
diagnosis of, 665–666 sleep, 955–956
epidemiology of, 665 management of, 957–962
etiology of, 665 airway clearance, 957–959
genetic analysis of, 666 lung volume recruitment, 959
medications for, 666–667 manually assisted cough technique, 959
multiple sleep latency test (MSLT) for, mechanical techniques, 959
665–666 noninvasive nocturnal ventilation,
non-pharmacologic remedies for, 668 960–961
treatment of, 666–668 pulmonary infections with, 962
Narrowed intrathoracic airway, 150–151 respiratory muscle training, 960
Nasal anomalies, 243–245 tracheostomy and invasive ventilation,
Nasal dermoid, 244–245 961
Nasal flaring, 34 while undergoing sedation or
Nasal nitric oxide (nNO) measurement of anesthesia, 962
primary ciliary dyskinesia natural history and development of, 948
(PCD), 822 pathophysiological characteristics of
Nasal polyps, 66 respiratory impairment in,
Nasal prongs, 1074–1075 949–950
Nasogastric (NG) tubes, 1053 when to admit for, 963
Nasolacrimal duct cyst, 244 when to refer for, 963
National Asthma Education and Prevention Neuromuscular scoliosis, 288
Program (NAEPP), 207 Neutrophil defects, 929, 930–931
Native American, tobacco use by, 1089 Neutrophil extracellular trap formation, 784
Near-miss SIDS, 671 Newborn screening (NBS) programs
Nebulizers, 994–996 cystic fibrosis (CF)
jet, 994–995 algorithms for, 808–810
maintenance of, 996 background on, 807–811
mesh, 995–996 CFTR-related metabolic syndrome and,
multiple drug, 996 811–814
patient interface, 996 initial management of positive results
ultrasonic, 995 of, 810–811
Neck circumference, 1047 outcomes with, 811
Necrotizing pneumonia, 131–132, 393–394 severe combined immunodeficiency (SCID),
clinical presentation of, 394–395 935–936
disease processes associated with NHL. See Non-Hodgkin lymphoma (NHL)
bronchiectasis, 330 Nicotinamide adenine dinucleotide phosphate
management of, 395 (NADPH), 930
prognosis for, 395 Nicotine and tobacco, 1083–1084
Needle aspiration for pneumothorax, 557 clinician interventions in use of, 1090–1091

1175
Index
dependence on, 1092–1097 pleural effusion, 129–130, 541–550

electronic nicotine delivery systems pneumomediastinum, 558–560
(ENDS), 1083–1084 pneumothorax, 119, 184, 553–560
involuntary exposure to, 1097–1098 pulmonary hemorrhage, 144, 563–576
environmental tobacco smoke (ETS), 55, respiratory disorders associated with
61–62 systemic inflammatory
flavors of, 1089 diseases, 481–500
impact of exposure on non-users of, 1097– Noninvasive monitoring of oxygen, 28–30
1100 Noninvasive nocturnal ventilation, 960–961
initiation Noninvasive positive-pressure ventilation
preventing, 1089–1091 (NPPV)
risk factors for, 1088–1089 for achondroplasia, 832
marketing of, 1088–1089 for congenital central hypoventilation
parental use of, 1098 syndrome (CCHS), 688
prenatal effects of maternal exposure to, for Mounier-Kuhn syndrome, 827
1098–1100 Nonobstructive atelectasis, 473
products containing Non-rapid eye movement (NREM) sleep, 581
bidis, 1088 development of EEG biomarkers of mature,
chewing tobacco, 1088 587–592
cigarettes, 1084 disorders of arousal in, 652–653
cigars and little cigars, 1088 in infants 0 to 2 months of age, 584–587
cloves, 1088 shift from REM to NREM sleep onsets and,
electronic, 1084–1087 595
heat-not-burn tobacco, 1087 slow-wave activity of, 589, 591–592
hookah, 1087–1088 ultradian distribution of NREM-REM sleep
kreteks, 1088 cycles and, 594–595
public policy interventions in use of, 1091 Non-rebreather masks, 1075
reducing exposure to, 1100 Nonrhabdomyosarcoma soft-tissue sarcoma,
social influences and use of, 1089 921
Nicotine patch therapy, 1094–1095 Nontuberculous mycobacteria, 453–454
Nifedipine, 45 antibiotics for, 1032
Nightmares, 653 clinical features of, 455–456
Night sweats, 60 cystic fibrosis (CF) and, 790
Nintedanib diagnosis of, 457–459
for CLAD, 740–741 extrapulmonary disease, 418, 456, 459
for Hermansky-Pudlak syndrome (HPS), management of, 460–464
837 pathophysiology of, 454–455
Nirmatrelvir, 358 in patients with cystic fibrosis (CF), 731
Nissen fundoplication, 881 pulmonary disease, 455, 457–459
Nitric oxide Nonviral pneumonia, 365
acute chest syndrome (ACS) and, 893 from 5 years of age to adolescence, 371
for pulmonary arterial hypertension (PAH), bacterial, 371–380
861 common clinical presentations of, 366
Nitrogen narcosis, 47 evaluation of suspected, 366–369
Nitrosureas, 921 fungal, 380–383
N-Ntirosodimethylamine (NDMA), 880 in infants to school-aged children, 371
Nocardia, 930 laboratory evaluation of, 367
Nocturnal enuresis, 654–655 microbiology of, 368–369
Non-Hodgkin lymphoma (NHL), 136, 914 pathology of, 369–370
Noninfectious pulmonary disorders prevention of, 383–384
atelectasis, 112, 119, 151, 469–478 when to admit for, 384–385
bronchopulmonary dysplasia, 521–535 when to refer for, 384
as complication of HIV, 939 Normobaric oxygen therapy, 1061
of immunodeficiency, 937–938 Nose in review of systems, 60
interstitial lung disease (ILD), 112–113, 134, Nosocomial pneumonia, 1029
505–518

1176
Index
NREM. See Non-rapid eye movement (NREM) audio and video recording of, 629
sleep biomotion sensors for monitoring, 630
Nuss procedure, 290–291 capacitor-based systems for monitoring, 630
Nutritional evaluation clinical evaluation of, 1047
ABCDEF method of, 1045, 1046 comorbidities in, 618
anthropometric, 1045–1047 diagnosis of, 618, 619–622
biochemical indices in, 1047 image sequence analysis of, 630
clinical evaluation in, 1047 in-laboratory polysomnography of, 620–622
dietary evaluation in, 1047 monitoring classifications in, 622–627
elimination evaluation in, 1048 neuromuscular disorders (NMDs) and, 955
feeding evaluation in, 1048 nutritional aspects of, 1057
Nutritional support obesity and, 751, 754
alpha-1 antitrypsin (AAT) deficiency, 831 other monitoring options for, 627–630
for asthma, 1056–1057 oxygen supplementation and, 1070–1071
bronchopulmonary dysplasia (BPD), 1045, peripheral arterial tonometry for, 627–628
1054–1055 proteomics studies for, 629
challenges in, 1055 pulmonary arterial hypertension (PAH) and,
cystic fibrosis (CF), 793–794, 1048–1054 858
gastroesophageal reflux disease (GERD), 880 pulmonary function tests for, 628
neuromuscular disorders (NMDs), 954–955 radar monitoring of, 629
for obstructive sleep apnea (OSA), 1057 radiologic studies of, 627
for Prader-Willi syndrome, 1057 sheets and mats for monitoring, 630
snoring evaluations for, 627
O thermal video cameras for detecting, 629
Obesity tidal volume decrease in, 18–19
asthma and type 1 monitoring, 622, 624
atopy and airway inflammation in, type 2 monitoring, 624–625
748–750 type 3 portable monitoring, 624–626
evaluation of patients with, 752–754 type 4 portable monitoring, 624–627
physiological interactions between, Obstructive sleep apnea syndrome (OSAS)
750–751 adenotonsillectomy for, 610–611
reasons for association between, 747 clinical presentation of, 604–605
symptom overlap between, 751–752 diagnosis of, 607–610
treatment of, 754–756 drug-induced sleep endoscopy and, 609
clinical evaluation of, 1047 endocrine disorders and, 871
disorders associated with, 751–752 epidemiology of, 603
exercise limitation with, 751, 756 genetic conditions and, 606–607, 610
gastroesophageal reflux disease (GERD) home sleep apnea tests (HSATs) and,
and, 752, 754 609–610
lower respiratory tract infections (LRTIs) in infants and young children, 605–606
and, 752 laboratory and home sleep testing for,
nutritional aspects of respiratory conditions 617–631
associated with, 1056 management and treatment of, 610–612
asthma, 1056–1057 medications and oral appliance for, 612
obesity hypoventilation syndrome (OHS) pathophysiology of, 603–604
and, 751 polysomnography and, 607–609, 620–622
obstructive sleep apnea (OSA) and, 751, 754 positive airway pressure (PAP) therapy for,
Obesity hypoventilation syndrome (OHS), 751 611–612
Obliterative bronchiolitis (OB), 723 sequelae of untreated, 612
Obstruction, airway, 575–576 upper airway imaging and, 609
Obstructive atelectasis, 469–472 Omadacycline, 462
Obstructive bronchitis, 207 Omphalocele, 304
Obstructive infantile hemangiomas, 918 Oncogenic disease
Obstructive sleep apnea (OSA), 18–19, 246, airway tumors, 918–919
617–619 chest wall tumors, 919
acoustic pharyngometry for, 627 endobronchial, 331

1177
Index
hemoptysis and, 575 decreased inspiratory concentration of,

leukemias, 913–914 as cause of hypoxia and
lung parenchymal tumors, 919 hypoxemia, 1063
lymphomas, 914 factors that alter affinity of hemoglobin for
mediastinal masses, 136–138 oxygen in, 28
mediastinal tumors, 915–916 mechanism of hypoxemia in, 23–26
pleural effusion and, 544 noninvasive monitoring of, 28–30
prenatal nicotine and tobacco exposure and, oxygen transport and, 26–27
1099 Oxygen-carrying capacity, 1061
prevalence of pediatric, 913 alteration in, 1065
pulmonary complications of therapies for, as cause of hypoxia and hypoxemia, 1063
921–924 Oxygen consumption, 16
pulmonary metastatic lesions, 920–921 Oxygen content, 26
solid tumors, 917–919 Oxygen saturation, 26
that metastasize to the lungs, 920 in bronchopulmonary dysplasia (BPD), 1069
thoracic, 917 home therapy and, 1069
tobacco smoke exposure and, 1099 Oxygen tension, 26
Oncologic disease, pulmonary manifestations Oxygen therapy
of. See also Malignancy adverse effects of, 1078
airway tumors, 918–919 alveolar gas equation and alveolar-arterial
chest wall tumors, 919 gradient and, 1063
as complications of cancer therapies, for bronchopulmonary dysplasia (BPD),
921–924 1069–1070
chemotherapy pulmonary injury, 921 for congenital central hypoventilation
hematopoietic stem cell transplant, syndrome (CCHS), 687–689
923–924 for croup, 316
novel cancer therapy-induced for cyanotic congenital heart disease, 1070
pulmonary injury, 921–922 definitions in, 1061
leukemia, 913–914 delivery methods, 1075–1076
long-term, 924 determinants of oxygen delivery to tissues
lung parenchymal tumors, 919 and, 1061–1063
lymphomas, 914 discharge from hospital with, 1071–1074
mediastinal tumors, 915–916 equipment for, 1074–1075
pulmonary metastatic lesions, 920–921 delivery interfaces, 1074
solid tumors, 917–919 high-flow and reservoir devices, 1075
Onset of present illness, 55 low-flow devices, 1074–1075
Opacity, 113 high-flow (HFOT), 1061, 1078–1079
Oral cephalosporins, 1038–1039 home therapy, 1069
Oral contraceptives, 565 monitoring of, 1073–1074
Orlistat hypoxemia and, 23–26
for asthma and obesity, 755 in acute chest syndrome (ACS), 893
OSA. See Obstructive sleep apnea (OSA) asthma and, 220
OSAS. See Obstructive sleep apnea syndrome causes of, 1063–1066
(OSAS) clinical features of, 1067–1069
Oscillating PEP devices, 982–983 defined, 1061
Oseltamivir, 360, 361–362, 1031 diffusion defects and, 24–25
Osteogenesis imperfecta, 289 at high altitude, 1065–1066
Osteoporosis and cystic fibrosis (CF), 792 hypoventilation and, 23–24
Osteosarcoma, 920, 921 low venous Po2 and, 26
Otitis media, 1099 neuromuscular disorders (NMDs) and,
Oxacillin, 1027, 1039 953–954, 956
Oxybates for narcolepsy, 667 in pulmonary hypertension in sickle cell
Oxygenation, 22–31 disease (SCD), 904
assessment of ventilation and, 28–31 shunt and, 25–26
changes at high altitude, 1065–1066 V̇ /Q̇ mismatch and, 26

1178
Index
Oxygen therapy (continued) disorders of rapid eye movement sleep,

hypoxia and 653–654
causes of, 1063–1066 indications for polysomnography in, 657
congenital heart disease (CHD) and, 852 non-rapid eye movement, during partial
defined, 1061 arousals, 654–656
high altitude and, 40–41 non-rapid eye movement sleep disorders on
pulmonary arterial hypertension (PAH) arousal, 652–653
and, 858 pathophysiology of, 651
for interstitial lung disease (ILD), 1070 types of, 651
monitoring and weaning, 1076–1078 Parathyroid disorders, 870–871
obstructive sleep apnea (OSA) and, 1070– Parenchymal lung disease, 835
1071 Partial pressure of gases, 15–16
for pneumothorax, 557 Pasteurella multocida, 318
for pulmonary hypertension, 1070 Pathophysiology
resources for physicians, 1080 acute chest syndrome (ACS), 892–893
when to admit for, 1080 airway obstruction, 1007–1008
when to refer for, 1080 alpha-1 antitrypsin (AAT) deficiency, 830
while flying, 1066 arthrogryposis multiplex congenita (AMC),
Oxygen toxicity, 47 833
Oxygen transport, 26–27 brief, resolved, unexplained events
Oxyhemoglobin, 29 (BRUEs), 674
bronchiectasis, 335
P bronchiolitis, 344
PAH. See Pulmonary arterial hypertension bronchopulmonary dysplasia (BPD),
(PAH) 523–526
Pain, chest, 62–63, 344–345 chest wall abnormalities, 282–283
acute chest syndrome (ACS), 893 congenital central hypoventilation syndrome
in cardiac disease, 851 (CCHS), 681
in micro-aspiration, 712 congenital heart disease (CHD), 852–853
pleural effusion, 545 croup, 312
Pain in review of systems, 60 cystic fibrosis (CF), 783–785
Palivizumab, 346 eosinophilic pneumonia, 201
for prevention of pneumonia, 383 gastroesophageal reflux (GER), 875
for RSV immunoprophylaxis, 864 interstitial lung disease (ILD), 509
Palliative care for neuromuscular disorders Mounier-Kuhn syndrome, 826
(NMDs), 954 nontuberculous mycobacteria, 454–455
Palpation, 65, 72 nonviral pneumonia, 369–370
for chest pain, 62 obstructive sleep apnea syndrome (OSAS),
of chest wall, 70 603–604
for sinusitis, 66 parasomnias, 651
Pancreatic disease, 886–887 pneumomediastinum, 559
elimination evaluation in, 1048 pneumothorax, 554–555
Pancreatic enzyme therapy, 793 pseudohypoaldosteronism (PHA), 840
Panic attack, hyperventilation due to, 773 pulmonary hypertension in sickle cell
Paradoxical insomnia, 645 disease (SCD), 903
Parainfluenza, as complication of HIV, 938 pulmonary lymphangioleiomyomatosis
Paralysis, vocal cord, 249–250 (LAM), 828–829
Paramyxoviridae, 360, 361 recurrent pneumonia, 402–405
Parapneumonic effusion, 387–388 sickle cell disease (SCD) with asthma and,
clinical presentation of, 388 896
diagnosis of, 388–391 sleep-disordered breathing in sickle cell
management of, 391 disease (SCD), 897–898
Parasomnias sleep-related movement disorders, 634
clinical features of, 652–656 Williams-Campbell syndrome, 827–
diagnosis of, 656 828

1179
Index
PCD. See Primary ciliary dyskinesia (PCD) Pertussis

PCR. See Polymerase chain reaction (PCR) antibiotics for, 1024
PCV7 vaccine, 384 disease processes associated with
Peak expiratory flow rate (PEFR), 78–79 bronchiectasis, 330
neuromuscular disorders (NMDs) and, PGD. See Primary graft dysfunction
952–953 (PGD)
Peak flow meter, 958 PH. See Pulmonary hypertension (PH)
Pectus carinatum, 70–71 pH, blood, 20, 21
Pectus deformity, 288 PHACE syndrome, 918
Pectus excavatum and carinatum, 70–71, 288 Phosphodiesterase type-5 inhibitors, 863
clinical features of, 288–289 Photopheresis for CLAD, 740
diagnostic evaluation of, 289–290 Physical examination
medical management of, 290 abdomen, 73, 285
Pectus severity index, 289 for alpha-1 antitrypsin (AAT) deficiency,
Pediatric inflammatory multisystem syndrome 831
(PIMS), 357–358 bronchoscopy for, 152
Pediatric pulmonary history, 59 chest wall, 284
PEFR. See Peak expiratory flow rate (PEFR) diaphragm, 284–285
Penicillinase-resistant penicillins, 1039 eupnea and dyspnea, 69
Penicillin G, 1027–1028 extremities, 68
Peramivir, 1031 hypoxemia, 1067
Percussion, 65, 72 lungs and thorax, 70–73
as airway clearance measure, 460 neurological, 73–74
in chest physical therapy, 476–477, 977 for neuromuscular disorders (NMDs),
of patient with atelectasis, 473 950–956
in patient with cough, 546 of patient with immunodeficiency, 940–
in patient with cystic fibrosis (CF), 796 942
of patient with parapneumonic effusion, 388 for pleural effusion, 546
of patient with pneumococcal pneumonia, skin, 74
372 spine, 284
of patient with pneumonia, 366 upper airway, 65–67
in patient with pneumothorax, 555 Physiology, pulmonary
in patient with radiation pneumonitis, assessment of oxygenation and ventilation,
922 28–31
self-, 978 effect of pregnancy on, 53
Pericardium, 10–11 exercise physiology, 39–40
Periodic limb movement disorder (PLMD), gas exchange, 15–16
633, 634 high-altitude illness, 40–45
common contributing conditions in, inhalation injury, 50–53
637–638 mechanics of breathing, 31–34
diagnosis of, 635–636 oxygenation, 22–31
management of, 638–640 oxygen consumption and carbon dioxide
role of polysomnography in diagnosing, 637 production, 16
sequelae of, 638 underwater medicine, 46–49
Periodic limb movements of sleep (PLMS), ventilation, 17–22, 28–31
633–634 Pierre Robin sequence, 66, 245
clinical features, 634 Pigeon breeder’s lung, 183
diagnosis of, 634–636 PIMS. See Pediatric inflammatory multisystem
management of, 638–640 syndrome (PIMS)
role of polysomnography in diagnosing, 637 Piperacillin/tazobactam, 1028–1029, 1039
Peripheral arterial tonometry, 627–628 Pirfenidone
Peripheral edema, 786 for CLAD, 740
Persistence of present illness, 55 for Hermansky-Pudlak syndrome (HPS),
Persistent asthma, 211 837
Persistent pulmonary hypertension of the Pituitary disorders, 871
newborn, 858 Plasma, 24

1180
Index
Plethysmography eosinophilic. See Eosinophilic pneumonia

for mucopolysaccharidosis (MPS), 839 fungal, 380–383
Pleural effusion, 129–130, 541–542 in gastroesophageal reflux (GER), 876
associated with malignancies, 544 necrotizing, 131–132, 393–395
chest pain with, 545 disease processes associated with
chylous, 544, 549 bronchiectasis, 330
clinical presentation of, 544–546, 886 neuromuscular disorders (NMDs) and, 950
cough with, 546 nonviral, 365–385
diagnosis of, 546–547 recurrent, 401–408
diagnostic thoracentesis and, 549 due to pseudohypoaldosteronism
dyspnea with, 545 (PHA), 840
exudative, 543 round, 126–127
fluid characteristics in, 542–543 viral, 353–363
hemorrhagic, 543–544 Pneumonitis, 921–922
laboratory studies in, 546 radiation, 922
magnetic resonance imaging of, 547 Pneumothorax, 119
management of, 548 causes of, 553–554
physical findings in, 546 clinical features of, 555
prognosis and when to refer for, 549 cystic fibrosis (CF) and, 789
transudative, 543 diagnostic tests for, 555–556
Pleurodesis for pneumothorax, 558 hypersensitivity pneumonitis (HP) and, 184
pulmonary lymphangioleiomyomatosis management of, 556–558
(LAM) and, 829 needle aspiration for, 557
Pleuroperitoneal canals, 268 observation with or without use of
PLMD. See Periodic limb movement disorder supplemental oxygen for, 557
(PLMD) pathophysiology of, 554–555
PLMS. See Periodic limb movements of sleep pleurodesis for, 558
(PLMS) prognosis for, 558
Pneumatocele, 114 surgical intervention for, 558
clinical presentation of, 396 thoracostomy tube for, 557–558
management of, 396 Poliomyelitis, 949
prognosis for, 397 Polyarteritis nodosa, 497
Pneumococcal disease, 372–374 Polyendocrinopathy, 935
antibiotics for, 1026–1027 Polymerase chain reaction (PCR), 368,
Pneumocystis jirovecii, 155 425–426
antibiotics for, 1033 Polymorphonuclear neutrophils (PMNs),
as complication of HIV, 938 930–931
Pneumomediastinum, 558–560 Polysomnography, 607–609
Pneumonia, 126 for excessive daytime somnolence (EDS),
after tracheostomy, 1120 660–662
antibiotics for, 1026–1034 in-laboratory, 620–622
Aspergillus, 931 for mucopolysaccharidosis (MPS), 840
asthma and, 208 for neuromuscular disorders (NMDs), 956
atypical, 377–379 for parasomnias, 657
antibiotics for, 1022, 1040 sleep-related movement disorders and, 637
bacterial, 371–380 Posaconazole, 1030, 1043
anaerobic organisms, 376–377 Positive airway pressure (PAP) therapy for
atypical, 377–379 obstructive sleep apnea
disease processes associated with syndrome (OSAS), 611–612
bronchiectasis, 330 Positive expiratory pressure (PEP), 981
gram-negative bacteria, 374–376 cost of, 986
gram-positive bacteria, 372–374 instructional videos on, 987
other causes of, 380 oscillating devices, 982–983
complicated, 365, 391 Positive-pressure ventilation (PPV)
complications of, 129–132, 387–397 for congenital central
Down syndrome and, 835–836 hypoventilation syndrome
(CCHS), 687

1181
Index
Positron emission tomography (PET) scan, 137 pulmonary physical examination in, 66
Posterior mediastinal masses, 137–138, 916 sleep needs of, 581–582
Posterolateral diaphragmatic hernia, 11 spirometry in, 79
Postnasal drip and habit cough, 765 tobacco smoke exposure in, 348
Postnatal period, lung development, 5 use of inhalers in, 999
Postprimary pulmonary TB, 133 Pressurized metered dose inhalers (pMDIs),
Posttransplant care 993, 997–999
immunosuppression, 734 Preterm neonates, surfactant decrease in, 33
induction therapy, 734 Prevotella, 376–377
long-term follow-up, 735 Primary ciliary dyskinesia (PCD), 66, 156,
long-term monitoring in, 735–736 404–405, 822–824
maintenance immunosuppression, 734–735 clinical features of, 820–822
Posttransplant lymphoproliferative disorder diagnosis of, 406–407, 822–824
(PTLD), 734, 735, 741–742 differential, 824
survival from, 742 genetics of, 819
Potter syndrome, 262 history of studies on, 818
Prader-Willi syndrome (PWS), 1057 impaired mucociliary clearance in, 330
Prealbumin, 1047 introduction, terminology, and epidemiology
Prednisone, 1022 of, 817–818
Pregnancy management of, 824–825
alpha-1 antitrypsin deficiency in, 831 motile cilia biology and, 818–819
arthrogryposis multiplex congenita (AMC) prognosis for, 826
in, 833 pulmonary disorders resulting from, 56
CFTR mutation in, 791 Primary graft dysfunction (PGD), 723
effect on pulmonary function, 53 Primary immunodeficiencies, 824
genetic counseling for congenital central Primary pulmonary TB, 133
hypoventilation syndrome Prognosis
(CCHS) in, 691 allergic bronchopulmonary aspergillosis
hyperacute rejection in, 736 (ABPA), 179
maternal smoking during, 673 bronchiectasis, 337–338
premature rupture of membranes in, 262 hypersensitivity pneumonitis (HP), 190–192
pulmonary history and, 57 insomnia, 648
tobacco smoke exposure during, 345 interstitial lung disease (ILD), 517–518
Premature rupture of membranes, 262 lung abscess, 393
Prenatal nicotine and tobacco exposure, necrotizing pneumonia, 395
1098–1100 pleural effusion, 549
Preoperative pulmonary evaluation, 962 pneumatocele, 397
Preschool-aged children pneumothorax, 558
bacterial tracheitis in, 321 primary ciliary dyskinesia (PCD), 826
behavioral insomnia of childhood in, 625, pulmonary arterial hypertension (PAH), 863
646 tuberculosis (TB), 442
chest radiography landmarks and structures Progressive congenital scoliosis and spinal
in, 110 disorders, 288
congenital central hypoventilation syndrome Prokinetic agents, 880–881
(CCHS) in, 682–683, 690 Prophylaxis
cystic fibrosis (CF) in, 1050 acute chest syndrome (ACS), 894
dreaming by, 597 bronchiolitis, 346
episodic asthma in, 228 for patients with immunodeficiency, 942
frequency of common colds in, 213 pneumonia, 383–384
gastroesophageal reflux disease (GERD) respiratory syncytial virus (RSV), 864
in, 876 Prostacyclin analogues, 863
intermittent asthma in, 210 Proteomics studies, 629
nontuberculous mycobacteria infection in, Proton pump inhibitors (PPI) for
456 gastroesophageal reflux
obstructive sleep apnea (OSA) in, 617, 625 (GER), 878, 880–881
parasomnias in, 651

1182
Index
Protracted bacterial bronchitis, 824 alpha-1 antitrypsin (AAT) deficiency and,

Prune belly syndrome, 304 830
Pseudoglandular period, 4 arterial blood gas, 96
Pseudohypoaldosteronism (PHA), 840–841 assessing airway reactivity, 89–93
Pseudo-Meigs syndrome, 544 cardiopulmonary exercise testing, 94–95
Pseudomembranous croup. See Bacterial exercise challenge testing, 94
tracheitis indications for, 77
Pseudomonas aeruginosa, 169, 318, 336, lung volumes, 86–87
374–375 for neuromuscular disorders (NMDs),
antibiotics for, 1034 952–954
antipseudomonal β-lactams for, 1040 for obstructive sleep apnea (OSA), 628
ataxia-telangiectasia (A-T) and, 937 for patient with immunodeficiency, 940–942
carbapenems for, 1040 peak expiratory flow rate (PEFR), 78–79
cephalosporins for, 1038 pulse oximetry, 95–96
as complication of HIV, 939 reference values, 84–85
cystic fibrosis (CF) and, 783, 789–790, spirometry, 79–83, 96
797–798 for systemic inflammatory diseases, 482
fluoroquinolones for, 1041 when to refer after, 96
pseudohypoaldosteronism (PHA) and, 841 Pulmonary hypertension (PH)
tracheostomy and, 1120 in Down syndrome, 836
Psychogenic cough, 763 oxygen therapy for, 1070
Psychophysiological insomnia, 645 in sickle cell disease (SCD), 903–905
Psychosocial issues Pulmonary injury
anxiety chemotherapy, 921
cystic fibrosis (CF) and, 792 novel cancer therapy-induced, 921–922
hyperventilation due to, 773 radiation-induced, 922–923
sighing syndrome due to, 774 Pulmonary lymphangioleiomyomatosis (LAM)
with cystic fibrosis (CF), 801 clinical features of, 829
nicotine and tobacco use, 1089 diagnosis of, 829
palliative and end-of-life care, 954 management of, 829
Public policy and tobacco use, 1091 pathogenesis of, 828–829
Pulmonary agenesis, 122, 261–262 Pulmonary metastatic lesions, 920–921
Pulmonary arterial hypertension (PAH), 727 Pulmonary nontuberculous mycobacteria, 133,
classification of, 856–857 455
clinical features of, 858 diagnosis of, 457–459
congenital heart disease (CHD) and, 854 Pulmonary parenchymal disease, 882
diagnosis and evaluation of, 859–860 Pulmonary pleura, 10
due to lung diseases and/or hypoxia, 858 Pulmonary sequestration, 124, 271–272
lung transplant and, 732 Pulmonary vascular disease
medical treatment of, 861–863 Down syndrome and, 836
persistent pulmonary hypertension of the Eisenmenger syndrome and, 572, 732, 856
newborn, 858 Pulse oximetry, 28–30, 95–96, 345
prognosis for, 863 arterial pulsations detected by, 29
surgical treatment of, 861 atelectasis and, 477
Pulmonary arteriovenous malformation, in evaluation of hypoxemia, 1067–1068
125–126 for oxygen therapy monitoring at home,
Pulmonary edema 1073, 1076–1078
in cardiac disease, 851 PWS. See Prader-Willi syndrome (PWS)
Down syndrome and, 836 Pyrazinamide, 433
reduced lung compliance in, 33 Pyriform aperture stenosis, 243
Pulmonary fibrosis in gastroesophageal reflux
(GER), 876 Q
Pulmonary function tests (PFTs) Q̇ s/Q̇ t, 25
for allergic bronchopulmonary aspergillosis
(ABPA), 172

1183
Index
R Respiratory distress syndrome (RDS), 514–

515, 521
Rabbit anti-thymocyte globulin, 738
pseudohypoaldosteronism (PHA) and, 840
Rachitic rosary, 870–871
Respiratory inductive plethysmography, 285
RAD. See Reactive airway disease (RAD)
Respiratory muscle strength, 287–288
Radar monitoring of obstructive sleep apnea
Respiratory quotient, 16
(OSA), 629
Respiratory rate, 69
Radiation exposure in children, 101–102
ventilation and changes in, 18
Radiation-induced pulmonary injury, 922–923
Respiratory syncytial virus (RSV), 344, 345,
Radiography, chest. See Chest radiography
346, 353, 359, 360–361
Rales, 72–73
antibiotics for, 1034
Ranitidine, 880
as complication of HIV, 938
Rapid eye movement (REM) behavior disorder,
congenital heart disease (CHD) and,
653
864–865
Rapid eye movement (REM) sleep, 581
Restless legs syndrome (RLS), 634
development of EEG biomarkers of mature,
common contributing conditions in,
587–592
637–638
disorders of, 653–654
in infants 0 to 2 months of age, 584–587
insomnia due to, 645
neuromuscular disorders (NMDs) and, 955
shift from REM to NREM sleep onsets and,
role of polysomnography in diagnosing, 637
595
sequelae of, 638
ultradian distribution of NREM-REM sleep
Restrictive allograft syndrome (RAS), 723,
cycles and, 594–595
739–740
RAS. See Restrictive allograft syndrome (RAS)
Retained foreign body, 331
Ravitch procedure, 290
Retractions, 34
RDS. See Respiratory distress syndrome (RDS)
Rett syndrome, 56
Reactivation of tuberculosis (TB), 417
Review of systems, 60
Reactive airway disease (RAD), 207
Rhabdomyosarcoma, 920, 921
Recarbrio, 1039
Rheumatic diseases, 483–484
Recombinant human DNase, 477
juvenile dermatomyositis (JDM), 488–489
Recurrence of present illness, 55
juvenile idiopathic arthritis (JIA), 485–486
Recurrent bronchiolitis, 207
juvenile systemic sclerosis (JSS), 489–490
Recurrent pneumonia, 401–402
mixed connective tissue disease (MCTD)
evaluation of child with, 405–407
and Sjögren syndrome, 490
pathophysiology of, 402–405
systemic lupus erythematosus (SLE), 133–
treatment of, 407–408
134, 486–488
Recurrent small-volume aspiration, 711–717
Rhinosinusitis and primary ciliary dyskinesia
Red hepatization, 369
(PCD), 825
Reference values, pulmonary function test,
Rhizopus, posaconazole for, 1043
84–85
Rhonchi, 73
Rejection, lung transplant, 736–741
Rhythmic movement disorders, 637, 654
acute cellular, 156, 723, 736–738
Ribavirin, 1034
chronic lung allograft dysfunction, 723,
Rib cage deformity, 288
738–741
Ribs, 5
hyperacute, 736
false, 5
REM. See Rapid eye movement (REM) sleep
fusion, 288
Remdesivir, 358
true, 5
Repetitive sighing, 774
Rickets, 870
Reproductive tract in cystic fibrosis (CF), 791
Rifampin, 1027, 1032, 1035, 1036, 1037
Rescue medications for asthma, 214–219
for mycobacteria, 461
Reservoir devices, 1075
toxicities and monitoring, 463
Resistance, airway, 34
in treatment of TB, 433
Respiratory acidosis, 20–21
Rigid bronchoscopy
Respiratory alkalosis, 20–21
choosing between flexible and, 142–144
for foreign body, 143

1184
Index
Ritonavir, 358 Shallow water blackout, 46

Rituximab, 922 Sheets and mats for monitoring obstructive
RLS. See Restless legs syndrome (RLS) sleep apnea (OSA), 630
Round pneumonia, 126–127 Shigella, fluoroquinolones for, 1041
Roux-en-Y gastric bypass, 755 Short-acting β2-agonists (SABAs), 1008,
RSV. See Respiratory syncytial virus (RSV) 1012–1015
Short-term insomnia, 643
S Shunts, 25–26
Saccular cysts, 248 as cause of hypoxia and hypoxemia, 1063,
Saccular period, lung development, 4–5 1064
Salmonella, 1041 Sibutramine
as complication of HIV, 939 for asthma and obesity, 755
fluoroquinolones for, 1041 Sickle cell disease (SCD), 28, 377, 887
Salt intake and cystic fibrosis (CF), 1053–1054 acute chest syndrome (ACS) in, 891–895
Sandifer syndrome, 876 asthma and airway disease in, 895–897
Sarcoidosis, 497–499 management of, 897
SARS-CoV-2. See COVID-19 lung function in, 900–902
Sawtooth waves, 588 prevalence of, 891
Scalene muscle, 31, 34 pulmonary disorders resulting from, 56
School-aged children pulmonary hypertension in, 903–905
asthma exacerbation in, 213 sleep-disordered breathing with, 897–899
cystic fibrosis (CF) in, 1050 Sighing syndrome, 774
gastroesophageal reflux disease (GERD) in, Silent aspiration, 74
876–877 Silhouette sign, 110–111
hypersensitivity pneumonitis in, 185 Single maintenance and reliever therapy
insomnia in, 647 (SMART), 218
nonviral pneumonia in, 373 Sinusitis, 65–66
obstructive sleep apnea syndrome (OSAS) habit cough and, 765
in, 603 primary ciliary dyskinesia (PCD) and, 825
sickle cell anemia in, 897 Sirolimus
sleep needs of, 593–594 for pulmonary lymphangioleiomyomatosis
Scimitar syndrome, 125 (LAM), 829
Scoliosis, 19, 284, 288 Sistrunk procedure, 247
clinical features of, 292–295 Sjögren syndrome, 490
medical management of, 295 Skeletal system, tumors that metastasize to the
surgical management of, 295–297 lungs from, 920
total lung capacity with, 285–286 Skin examination, 74
Scuba diving, 46–47 in review of systems, 60
complications of, 47–49 Skin testing
pulmonary lymphangioleiomyomatosis allergic bronchopulmonary aspergillosis
(LAM) and, 829 (ABPA), 170–171
Seasonal allergic asthma, 211 tuberculosis (TB), 419–424
Seasonal coronavirus, 353 SLE. See Systemic lupus erythematosus (SLE)
Self-percussion, 978 Sleep
Separation anxiety, 638 congenital central hypoventilation syndrome
Serologic testing for allergic (CCHS) and, 681–691
bronchopulmonary daytime napping, 594
aspergillosis (ABPA), 171 decrease in total time in, 595–596
Serratia, cephalosporins for, 1039 development and maturation of, 581–597
Serum IgE and allergic bronchopulmonary development of
aspergillosis (ABPA), 171 changes in architecture of, 592
Severe combined immunodeficiency (SCID), circadian rhythm and sleep/wake
935–936, 942 patterns in babies and young
Sexsomnia, 655 children, 592–596

1185
Index
EEG biomarkers of mature NREM and diagnosis of, 634–638

REM, 587–592 epidemiology of, 633–634
as distinctive behavior state, 582–584 lifestyle and, 640
in-laboratory polysomnography of, 607–609, management of, 638–640
620–622 medication for, 640
insomnia and, 643–649 pathophysiology of, 634
K-complexes in, 589, 591 role of polysomnography in diagnosing, 637
laboratory and home testing of, 617–631 sequelae of, 638
movement disorders related to, 633–640 Sleep spindles, 588–590
narcolepsy and other disorders of excessive Sleep terrors, 651, 652
somnolence, 659–668 Sleepwalking, 651, 652–653
neuromuscular disorders (NMDs) and, Slow-wave activity of non-rapid eye movement
955–956 3 sleep, 589, 591–592
non-rapid eye movement (NREM), 581 decrease in, 595
obstructive sleep apnea (OSA) in, 18–19, NREM parasomnias during, 654–656
246, 617–631 SMART. See Single maintenance and reliever
obstructive sleep apnea syndrome (OSAS) therapy (SMART)
in, 603–613 Smoke inhalation, 50–52
ontogeny of dreaming in, 596–597 alpha-1 antitrypsin (AAT) deficiency and, 831
parasomnias and, 651–657 primary ciliary dyskinesia (PCD) and, 825
rapid eye movement (REM), 581 Smoking. See Nicotine and tobacco
recommendations for, 581–582 Sneezing, habit, 767
shift from REM to NREM sleep onsets in, Sniff nasal inspiratory pressure, 953
595 Snoring
sleep spindles in, 588–590 defined, 241
slow-wave activity of non-rapid eye evaluation of, 627
movement in, 589, 591–592, in obstructive sleep apnea (OSA), 617–619
595 in obstructive sleep apnea syndrome
socioeconomic differences in infant and (OSAS), 604, 606–607, 612
child patterns of, 596 Social history, 58–59
sudden infant death syndrome and brief, Social influences on nicotine and tobacco use,
resolved, unexplained events 1089
and, 671–679 Sodium alginate, 881
ultradian distribution of NREM-REM sleep Soft mist inhalers, 999
cycles in, 594–595 Soft-tissue sarcoma, 920
vertex waves in, 589–591 Solid tumors, 917–919
and wake patterns in infants 0 to 2 months Somatic cough disorder, 763
of age, 584–587 Somnambulism, 652–653
Sleep-disordered breathing (SDB) Spacers, metered-dose inhaler, 997–998
in Down syndrome, 834–835 Spasmodic croup, 62
neuromuscular disorders (NMDs) and, 950 SPECS-R3, 242
in sickle cell disease (SCD), 897–899 Spinal deformity, 288
Sleep groaning, 653–654 Spinal muscular atrophy (SMA), 949
Sleep hygiene, inadequate, 645 pulmonary disorders resulting from, 56
narcolepsy and, 668 Spine, 5, 284
Sleep maintenance insomnia, 644 scoliosis of, 19, 284, 285–286, 292–295
Sleep-onset association disorder, 646 Spirometry, 79–83
Sleep-onset insomnia, 644 for mucopolysaccharidosis (MPS), 839
Sleep paralysis, 655, 665 Sputum analysis for tuberculosis (TB),
Sleep-related bruxism, 637, 638, 654 424–425
Sleep-related eating disorder, 655 Stachybotrys chartarum, 575
Sleep-related hallucinations, 654 Staphylococcus aureus, 74, 114, 318, 336, 371,
Sleep-related movement disorders 374
common contributing conditions in, acute large-volume aspiration and, 709
637–638 aminopenicillins for, 1040

1186
Index
Staphylococcus aureus (continued) Supplements, nutritional, 1051, 1052

antibiotics for, 1027 Supraglottitis. See Epiglottitis
antipseudomonal β-lactams for, 1039 Surfactant
ataxia-telangiectasia (A-T) and, 937 deficiencies and lung transplant, 731
cephalosporins for, 1039 development of, 5
chronic granulomatous disease (CGD) and, increased lung compliance due to, 33
930 Surgical history, 57–58
as complication of HIV, 939 bariatric surgery, 755
complications of pneumonia and, 393, 395 Surgical interventions. See also Management
cystic fibrosis (CF) and, 789–790 and treatment
fluoroquinolones for, 1041 for alpha-1 antitrypsin (AAT) deficiency, 831
penicillinase-resistant penicillins for, 1039 for gastroesophageal reflux disease (GERD),
Steatorrhea, 1048 881
Stem cell transplantation. See Hematopoietic lung transplant, 156, 721–723
stem cell transplant (HSCT) for cystic fibrosis (CF), 799
Stenotrophomonas maltophilia diffuse parenchymal lung disease and,
cystic fibrosis (CF) and, 790 732–733
Stent placement, 157–158 Eisenmenger syndrome and, 732
Sternocleidomastoid muscle, 31, 34 evaluation of donor for, 733–734
Sternum, 5 general indications for, 724–727
Stertor, 241 for hypersensitivity pneumonitis (HP),
Stickler syndrome, 66 191
Stimulants for narcolepsy, 667 idiopathic pulmonary hypertension
Streptococcus pneumoniae, 318, 336, 369, 371, and pulmonary arterial
372, 380 hypertension and, 732
acute chest syndrome (ACS) and, 894 immunosuppression after, 734
ataxia-telangiectasia (A-T) and, 937 induction therapy after, 734
carbapenems for, 1040 long-term follow-up after, 735
as complication of HIV, 939 long-term monitoring after, 735–736
complications of pneumonia and, 393 maintenance immunosuppression after,
Wiskott-Aldrich syndrome (WAS) and, 936 734–735
Streptococcus pyogenes, 371 for patients with cystic fibrosis (CF),
Streptomycin, 1041 729–731
drug-resistant TB and, 434 for patients with immunodeficiency,
for mycobacteria, 461 942–943
Striae, 1047 posttransplant care, 734–742
Stridor, 62, 67, 241 posttransplant lymphoproliferative
congenital subglottic stenosis and, 248 disorder (PTLD) after, 734,
defined, 241 735, 741–742
flexible bronchoscopy for evaluating, 144 pulmonary vascular disorders and, 732
in gastroesophageal reflux (GER), 876 rejection of, 156, 723, 736–741
in granulomatosis with polyangiitis (GPA), selection of candidates for, 728–734
491 surfactant deficiencies and, 731
vocal cord paralysis and, 249 survival after, 721–723, 742
Stroke volume, 40 timing of referral for, 728
Subcutaneous immunoglobulin G (SCIG) types of, 723–724
replacement therapy, 933, 942 for Mounier-Kuhn syndrome, 827
Sucralfate, 881 obstructive sleep apnea syndrome (OSAS),
Sudden infant death syndrome (SIDS), 610–611
671–674 pneumothorax, 558
prenatal nicotine and tobacco exposure and, for primary ciliary dyskinesia (PCD), 825
1099 for pulmonary arterial hypertension (PAH),
Sudden unexpected infant death (SUID), 673 861
Suggestion therapy for pulmonary lymphangioleiomyomatosis
for habit cough, 765, 766 (LAM), 829
for habit throat clearing, 767 scoliosis, 295–297

1187
Index
thoracic insufficiency syndrome, 299–303 TBM. See Tracheobronchomalacia (TBM)

tracheostomy, 323 Teeth grinding, 637
altered physiology after, 11115–11116 TEF. See Tracheoesophageal fistula (TEF)
complications of, 1120 Terbutaline, 1006
for congenital central hypoventilation dosing chart for, 1010
syndrome (CCHS), 687 Terminal insomnia, 644
decannulation and, 1120–1122 Theophylline, 1007
feeding challenges with, 1055 Therapeutic bronchoscopy, 156–159
home care after, 1116–1119 Therapeutic lavage, 157
changing the ties, 1118 Thermal cameras for detecting obstructive
changing the tube, 1117–1118 sleep apnea (OSA), 629
cleaning the tube, 1118 Thoracentesis for pleural effusion, 548–549
humidification, 1118–1119 Thoracic cavity
monitoring, 1119 gross anatomy of lungs, 8–10
skin care, 1118 mediastinum, 8, 10–11
speech and, 1119 physical examination of, 70–73
suction and irrigation, 1118 Thoracic insufficiency syndrome (TIS), 288
supplies for, 1117 clinical features of, 298–299
indications for, 1111–1113 medical management of, 299
for neuromuscular disorders (NMDs), surgical management of, 299–303
961 Thoracic squeeze, 46
pulmonary hemorrhage and, 570–571 Thoracic tumors, 917
routine evaluation after, 1119–1120 Thoracic vertebrae, 5
surgical technique for, 1114 Thoracoabdominal mechanics, 281–282
tube selection and considerations in, Thoracostomy tube for pneumothorax,
1114–1115 557–558
Swallowing Throat clearing, habit, 767
after tracheostomy, 1116 Throat in review of systems, 60
neuromuscular disorders (NMDs) and, 950 Thymus, 10–11
physiological mechanism of, 699–701 mediastinal masses of, 136
studies of, 713 Thyroglossal duct cysts, 247
Sweat test, 786 Thyroid disorders, 870
Symptoms, pulmonary system, 61–64 Tic disorders, 638
Synovial cell sarcoma, 920 Tidal volume, 17, 18–19
Systemic inflammatory diseases, 481–483 causes of decrease in, 18–19
granulomatous lung disease, 497–500 work of breathing and, 34
rheumatic diseases, 483–490 Tigecycline
vasculitic diseases, 490–497 for mycobacteria, 462
Systemic lupus erythematosus (SLE), 133–134, toxicities and monitoring, 463
486–488 Tiotropium, 222
pulmonary hemorrhage in, 564–565 TIS. See Thoracic insufficiency syndrome
(TIS)
T Tissue damage in cystic fibrosis (CF), 799
Tachycardia T lymphocyte disorders, 929, 934–937
in hypoxemia, 28 ataxia-telangiectasia (A-T), 937
Tachypnea, 34, 69 DiGeorge syndrome, 936
in acute chest syndrome (ACS), 893 hyper-IgM (HIgM) syndrome, 937
in decreased lung and chest wall severe combined immunodeficiency (SCID),
compliance, 34 935–936
in hypoxemia, 28 Wiskott-Aldrich syndrome, 936
in pseudohypoaldosteronism (PHA), 840 Tobacco. See Nicotine and tobacco
Tacrolimus Tobramycin, 1023–1024, 1034, 1041
for posttransplant lymphoproliferative for cystic fibrosis (CF), 797
disorder (PTLD), 735 inhaled, 991
TB. See Tuberculosis (TB)

1188
Index
Toddlers routine evaluation after, 1119–1120

aspiration of food by, 701, 706 surgical technique for, 1114
behavioral insomnia of childhood in, 646 tube selection and considerations in,
confusional arousals in, 652 1114–1115
heart-lung transplant in, 728 Transbronchial biopsy, 156
intermittent asthma in, 210 Transcutaneous Pco2, 30
normal respiratory rate in, 69 Transmembrane conductance regulator
otitis media in, 821 modulation therapy, 1051
pneumonia in, 370 Transmission electron microscopy of primary
positive-pressure ventilation (PPV) in, 687 ciliary dyskinesia (PCD), 822
rhythmic movement disorder in, 654 Transudative pleural effusion, 543
sickle cell disease (SCD) in, 897 Trastuzumab, 922
sleep needs of, 593–594 Trauma
sleep-related movement disorders in, 634 and deformity of chest wall, 19
tobacco smoke exposure in, 1099 inspection for, 319
tuberculosis in, 133 Treacher Collins syndrome, 66
use of inhalers in, 998–999 Treatment. See Management and treatment
viral croup in, 321 Tree-in-bud pattern, 116
Tongue anomalies, 246–247 Tricuspid regurgitant jet velocity (TRV),
Total ventilation, 17–18 903–904
Tourette syndrome, 638 Triggers of present illness, 55
Tracé discontinu, 583 Trimethoprim-sulfamethoxazole, 942, 1033
Trachea, 10 Trisomy 21 and obstructive sleep apnea
Tracheal bronchus, 255 syndrome (OSAS), 606
Tracheitis Trophoblastic choriocarcinoma, 920
after tracheostomy, 1120 True ribs, 5
antibiotics for, 1021 Tube feedings, 1053
Tracheobronchial abnormalities, 255–257 challenges with, 1055
Tracheobronchomalacia (TBM), 255 Tuberculosis (TB), 133
bronchopulmonary dysplasia (BPD) and, 526 antibiotics for, 1035–1037
Tracheobronchomegaly, 257, 331 Bacille Calmette-Guérin vaccine and, 424
Tracheobronchoplasty for Mounier-Kuhn chronic disease, 418
syndrome, 826 clinical presentation of, 415–418
Tracheoesophageal fistula (TEF), 257–261 control of, 442–443
Tracheomalacia, 256–257 development of new antibiotics and
Tracheomegaly, 255 recycling older antibiotics for,
Tracheostomy, 323 435–441
altered physiology after, 1115–1116 diagnosis of, 418–427
complications of, 1120 directly observed therapy for, 442
for congenital central hypoventilation dissemination of, 414
syndrome (CCHS), 687 drug-resistant, 412–413
decannulation and, 1120–1122 extrapulmonary disease, 418
feeding challenges with, 1055 improving immunologic diagnosis of,
home care after, 1116–1119 426–427
changing the ties, 1118 incidence of, 411–412
changing the tube, 1117–1118 latent, 417
cleaning the tube, 1118 primary infection with, 413
humidification, 1118–1119 primary pulmonary disease, 415–416
monitoring, 1119 prognosis for, 442
skin care, 1118 reactivation disease, 417
speech and, 1119 screening tests for, 418–419
suction and irrigation, 1118 sequencing-based techniques for detecting,
supplies for, 1117 425–426
indications for, 1111–1113 skin testing for, 419–424
for neuromuscular disorders (NMDs), 961 sputum analysis for, 424–425
pulmonary hemorrhage and, 570–571 treatment of, 429–435

1189
Index
treatment of, with no evidence of active Upper great vessels, 10

disease, 427–428 Upper respiratory infections
vaccine development for, 443–446 antibiotics for, 1021
when to admit for, 447 bacterial tracheitis, 320–324
when to refer for, 447 croup, 311–317
Turbulent flow, 34, 241–242, 316 cystic fibrosis (CF) and, 800
23-valent pneumococcal polysaccharide epiglottitis, 317–320, 1021
vaccine, 962 recurrent pneumonia and, 402
24-hour dietary recall, 1047 tracheitis, 1021
24-hour esophageal pH probe and Ureaplasma, 525
impedance monitoring for Urticaria, 60
gastroesophageal reflux
(GER), 879 V
Tympanostomy and primary ciliary dyskinesia Vabomere, 1039
(PCD), 825 Vaccines. See Immunizations
Valved holding chambers (VHCs), 997–999
U Vancomycin, 1021, 1023, 1026, 1027–1028,
Ulcerative colitis, 500, 882 1029
Ultradian distribution of NREM-REM sleep for bacterial tracheitis, 323
cycles, 594–595 for staphylococcal pneumonia, 374
Ultrasonic nebulizers, 995 Varenicline, 1094–1095
Ultrasonography, 107 Varicella-zoster virus, 361
for atelectasis, 474 disease processes associated with
for COVID-19, 356 bronchiectasis, 330
endobronchial, 158 vaccine against, 227
for nonviral pneumonia, 367 Vascular anomalies, 121–122, 272–275
for pleural effusion, 129–130, 547 lung transplant and, 732
for systemic inflammatory diseases, 482 Vascular rings, 272–275
Undernutrition Vasculitic diseases
bronchopulmonary dysplasia (BPD) and, anti-glomerular basement membrane
534 (AGBM) disease, 495–496
respiratory conditions associated with, eosinophilic granulomatosis with
1048–1054 polyangiitis (EGPA), 494–495
Underwater medicine, 46–49 granulomatosis with polyangiitis (GPA),
drowning, 49–50 490–493
scuba diving, 46–47 Henoch-Schönlein purpura, 497
shallow water blackout, 46 Kawasaki disease, 497
thoracic squeeze, 46 microscopic polyangiitis (MPA), 493
United Network for Organ Sharing (UNOS), polyarteritis nodosa, 497
724, 728 VATS. See Video-assisted thoracoscopic
UNOS. See United Network for Organ Sharing surgery (VATS)
(UNOS) Ventilation, 17–22
Upper airway abnormalities, 241–242 acid-base status and, 20–22
assessment of, 242 alveolar and dead space, 17–18
craniofacial abnormalities, 245–246 assessment of oxygenation and, 28–31
laryngeal, 247–250 hyper-, 773–774
nasal, 243–245 intrapulmonary percussive ventilation (IPV),
obstructive sleep apnea syndrome (OSAS) 477, 985
and, 606, 609 mechanical
tongue lesions, 246–247 after lung transplant, 742
Upper airway examination, 65–67 neuromuscular disorders (NMDs) and,
Upper airway obstruction, work of breathing 949–950
with, 34 noninvasive nocturnal ventilation,
Upper gastrointestinal series for 960–961
gastroesophageal reflux tracheostomy and invasive ventilation,
(GER), 878 961

1190
Index
Ventilation (continued) W
in palliative and end-of-life care, 954
Walking pneumonia, 377
relationship to arterial Pco2, 18–20
Warfarin, 565
total, 17–18
Weight loss
Ventilation/perfusion (V̇ /Q̇ ) mismatch, 26
for asthma and obesity, 755
asthma and, 219
in hypersensitivity pneumonia, 184
as cause of hypoxia and hypoxemia, 1063,
for neuromuscular disorders (NMDs),
1064
954–955
congenital heart disease (CHD) and, 852
in review of systems, 60
Ventilation/perfusion scanning, 109
Wheezing, 73, 241
Venturi masks, 1075
in acute chest syndrome (ACS), 893
VEPTR. See Vertical expandable prosthetic
in allergic bronchopulmonary aspergillosis,
titanium rib (VEPTR)
791
Vertex sharp waves, 589–591
in alpha-1 antitrypsin (AAT) deficiency, 830
Vertical expandable prosthetic titanium rib
in asthma, 207, 208, 210, 214, 256
(VEPTR), 299–303
in bronchiectasis, 329
Vest, high-frequency chest-wall compression,
in bronchiolitis, 342, 343
983–984
in cardiac disease, 851
cost of, 986
conditions causing focal, 343
instructional videos on, 987
in congenital lung anomalies, 266–267, 270
VFSS. See Videofluoroscopic swallowing study
defined, 241
(VFSS)
due to foreign body aspiration, 208–209
VHC. See Valved holding chambers (VHCs)
due to respiratory infections, 62
Video-assisted thoracoscopic surgery (VATS),
flexible bronchoscopy for evaluating,
557
144–145
Videofluoroscopic swallowing study (VFSS),
in foreign body aspiration, 701–702,
713
706–707
Viral pneumonia, 353
in gastroesophageal reflux (GER), 875, 876
adenovirus, 360
in granulomatosis with polyangiitis (GPA),
atypical, 377–379
491
coronavirus and, 353, 354
in high-altitude pulmonary edema (HAPE),
COVID-19, 354–358
44
cytomegalovirus, 361
in hypersensitivity pneumonia, 184
human metapneumovirus, 353, 360–361
in micro-aspiration, 712
human parainfluenza virus (HPIV), 353, 360
during or after exercise, 95
influenza virus, 359–360
in pneumonia, 366
measles virus, 361
pulmonary function tests (PFTs) and, 77, 93
prevention of, 362
in pulmonary hemorrhage, 563
respiratory syncytial virus (RSV), 359
recurrent, with other causes, 343
supportive care for, 361–362
in respiratory syncytial virus (RSV), 359
varicella-zoster virus, 361
in thoracic squeeze, 46
when to admit for, 362–363
Wheezy bronchitis, 207
when to refer for, 362
Williams-Campbell syndrome, 827–828
Virtual bronchoscopy (VB), 104–105
clinical features of, 828
Vitamins, cystic fibrosis (CF) and, 1053
diagnosis of, 828
Vocal cord dysfunction (VCD), 768–771
management of, 828
exercise-induced, 769–772
pathogenesis of, 827–828
Vocal cord paralysis, 249–250
Wilms tumor, 920, 921
Voice, 66–67
Wiskott-Aldrich syndrome (WAS), 936
Voriconazole, 1022, 1030, 1042–1043
Work of breathing, 34

1191
Index
World Health Organization (WHO) Y

clinical criteria for diagnosis of pneumonia,
Yellow nail syndrome, 331
366
Young syndrome, 331
on electronic nicotine delivery systems
(ENDS), 1086 Z
growth charts, 1045
on pulse oximetry, 1080 Zanamivir, 362, 1031
on tuberculosis, 412 Zantac, 880
Zerbaxa, 1039
X Zosyn, 1039
XLA. See X-linked (Bruton)
agammaglobulinemia (XLA)
X-linked (Bruton) agammaglobulinemia
(XLA), 932
X-linked syndrome, 935


2023 Pediatric Pulmonology 2ed - AAP

Uploaded by

Copyright:

Available Formats

2023 Pediatric Pulmonology 2ed - AAP

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

2023 Pediatric Pulmonology 2ed - AAP

Uploaded by

Copyright:

Available Formats

Am Po

00 FM PP 2ND ED.indd 1 11/7/23 8:03 AM

00 FM PP 2ND ED.indd 2 11/7/23 8:03 AM

Committees, Councils, and Sections

00 FM PP 2ND ED.indd 3 11/7/23 8:03 AM

Rajeev Bhatia, MD, FAAP

Lauren Elizabeth (L.E.) Faricy, MD, FAAP

Theresa Guilbert, MD, FAAP

Brooke Gustafson, MD, FAAP

Binal Kancherla, MD, FAAP

Rebekah Nevel, MD, FAAP

Christopher Oermann, MD, FAAP

Andrew Sokolow, MD, FAAP

Kristin Van Hook, MD, MPH, FAAP

00 FM PP 2ND ED.indd 5 11/7/23 8:03 AM

00 FM PP 2ND ED.indd 7 11/7/23 8:03 AM

Richard M. Kravitz, MD, FAAP

00 FM PP 2ND ED.indd 8 11/7/23 8:03 AM

00 FM PP 2ND ED.indd 9 11/7/23 8:03 AM

John S. Bradley, MD, FAAP

00 FM PP 2ND ED.indd 10 11/7/23 8:03 AM

Laurie C. Eldredge, MD, PhD

00 FM PP 2ND ED.indd 11 11/7/23 8:03 AM

00 FM PP 2ND ED.indd 12 11/7/23 8:03 AM

00 FM PP 2ND ED.indd 13 11/7/23 8:03 AM

00 FM PP 2ND ED.indd 14 11/7/23 8:03 AM

Susanna A. McColley, MD, FAAP

00 FM PP 2ND ED.indd 15 11/7/23 8:03 AM

Iris A. Perez, MD, FAAP

00 FM PP 2ND ED.indd 16 11/7/23 8:03 AM

Bruce K. Rubin, MEngr, MD, MBA, FRCPC, FAAP

00 FM PP 2ND ED.indd 17 11/7/23 8:03 AM

Marianna Martin Sockrider, MD, DrPH, FAAP

00 FM PP 2ND ED.indd 18 11/7/23 8:03 AM

00 FM PP 2ND ED.indd 19 11/7/23 8:03 AM

00 FM PP 2ND ED.indd 20 11/7/23 8:03 AM

00 FM PP 2ND ED.indd 21 11/7/23 8:03 AM

Part 2. Allergic Conditions.................................................................... 163

00 FM PP 2ND ED.indd 23 11/7/23 8:03 AM

Part 3. Anatomical Disorders................................................................................. 239

Part 4. Upper Airway Infections........................................................................... 309

Part 5. Lower Airway Infections............................................................................327

00 FM PP 2ND ED.indd 24 11/7/23 8:03 AM

Part 6. Noninfectious Pulmonary Disorders................................................ 467

Part 7. Pediatric Sleep Medicine.......................................................................... 579

00 FM PP 2ND ED.indd 25 11/7/23 8:03 AM

Chapter 39. Sudden Infant Death Syndrome and Brief, Resolved,

Part 8. Other Pulmonary Issues........................................................................... 697

Part 9. Genetic Disorders......................................................................................... 779

Part 10. Lung Disease Associated With Systemic Disorders.............. 849

00 FM PP 2ND ED.indd 26 11/7/23 8:03 AM

Chapter 51. Pulmonary Complications of Sickle Cell Disease................................ 891

Part 11. Treating and Managing Pulmonary Disease...............................969

00 FM PP 2ND ED.indd 27 11/7/23 8:03 AM

00 FM PP 2ND ED.indd 29 11/7/23 8:03 AM

Chapter 1. Anatomy of the Lung........................................................... 3

Chapter 2. Pulmonary Physiology........................................................15

Chapter 3. Applied Pulmonary Physiology........................................39

Chapter 4. Taking the Pulmonary History......................................... 55

Chapter 5. The Pulmonary Physical Examination............................65