2019-ATS Respiratory Book

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TAO SUNNY SUSAN TISHA

LE KHOSA PASNICK WANG
ATS Review for the
PULMONARY
BOARDS
TAO LE, MD, MHS
Associate Clinical Professor of Medicine and Pediatrics
Chief, Section of Allergy and Immunology
Department of Medicine
University of Louisville School of Medicine, Kentucky
SANDEEP KHOSA, MD
Consultant
Division of Pulmonary and Critical Care Medicine
Mayo Clinic Health System
Mankato, Minnesota
SUSAN PASNICK, MD
Clinical Instructor
Division of Pulmonary, Critical Care, Allergy and Sleep Medicine
University of California, San Francisco
TISHA WANG, MD
Assistant Clinical Professor
Associate Chief of Inpatient Services
Fellowship Program Director
Division of Pulmonary, Critical Care, and Sleep Medicine
Ronald Reagan UCLA Medical Center, Los Angeles
American Thoracic Society

New York
ATS Review for the Pulmonary Boards, First Edition
Copyright © 2015 by American Thoracic Society. All rights reserved.
Notice
Medicine is an ever-changing science. As new research and clinical experience broaden our
knowledge, changes in treatment and drug therapy are required. The authors and the publisher
of this work have checked with sources believed to be reliable in their efforts to provide
information that is complete and generally in accord with the standards accepted at the time of
publication. However, in view of the possibility of human error or changes in medical
sciences, neither the authors nor the publisher nor any other party who has been involved in
the preparation or publication of this work warrants that the information contained herein is in
every respect accurate or complete, and they disclaim all responsibility for any errors or
omissions or for the results obtained from use of the information contained in this work.
Readers are encouraged to confirm the information contained herein with other sources. For
example and in particular, readers are advised to check the product information sheet included
in the package of each drug they plan to administer to be certain that the information
contained in this work is accurate and that changes have not been made in the recommended
dose or in the contraindications for administration. This recommendation is of particular
importance in connection with new or infrequently used drugs.
DEDICATION
To our families, friends, and loved ones, who encouraged and assisted us in the task of assembling this
guide.
v
CONTENTS
Contributing Authors viii
Senior Reviewers x
Preface xii
Acknowledgements xiii
How to Contribute xiv
Chapter 1. Sleep Medicine and Neuromuscular/Skeletal Disorders 1

Sharon De Cruz, MD & Wajahat Khan, MD
Respiratory Sleep Medicine Neuromuscular Disorders and Diseases of the

Nonrespiratory Sleep Disorders Chest Wall
Chapter 2. Critical Care 47

Anthony F. Arredondo, MD, Stephanie Young Clough, MD, Nandita R. Nadig MD,
& Diana H. Yu, MD
Non-lung Critical Care Lung Critical Care
Chapter 3. Obstructive Lung Disease 131

Nidhi Aggarwal MD, Anthony F. Arredondo, MD, & Abhay Vakil, MBBS
Asthma Bronchiectasis
COPD Basic Science Primary Ciliary Dyskinesia
Comparison of Asthma and COPD Cystic Fibrosis
COPD
Chapter 4. Diffuse Parenchymal Lung Disease 221

Puneet S. Garcha, MD, Sachin Gupta, MD, & Carlos E. Kummerfeldt, MD
Interstitial Lung Disease Birt-Hogg-Dube

Sarcoidosis Lipoid Pneumonia
Pulmonary Alveolar Proteinosis Drug-Induced Lung Disease
Pulmonary Amyloidosis Occupational and Environmental Lung Disease
vi
Chapter 5. Quality, Safety, and Ethics 305

Diana H. Yu, MD
Ethical Considerations in Pulmonary and Critical Quality Improvement/Patient Care
Care Medicine Staffing Issues
Principles of Medical Ethics Physician Well-Being/Impairment
Chapter 6. Epidemiology and Statistics 313

Nazir Ahmad Lone MD MPH
Epidemiology Data Distribution and Type of Variables
Biostatistics
Chapter 7. Anatomy and Physiology of the Respiratory System 337

Muhammad Nouman Iqbal MD & Sandeep Khosa, MD
Structure and Functional Relationships of the Lung Mechanics and Lung Volumes
Lung Respiratory Control
Pulmonary Gas Exchange Acid-Base Disorders
Chapter 8. Common Respiratory Symptoms, Pulmonary Imaging,

and Procedures 355
Stephanie Young Clough, MD
Common Respiratory Symptoms Procedures
Pulmonary Imaging
Chapter 9. Lung Transplantation 395

Tessy Paul, MD
Indications and Patient Selection Complications after Transplantation

Pretransplant Evaluation Outcome of Lung Transplantation
Donor Selection and Organ Allocation
Transplant Immunosuppression
Chapter 10. Pulmonary Vascular Diseases 415

Jeffrey Albores, MD, Sachin Gupta, MD, Tessy Paul, MD, & Sandeep Sahay, MD
Pulmonary Vasculitis and Alveolar Hemorrhage Pulmonary Hypertension

Syndromes Other Pulmonary Vascular Disease
Venous Thromboembolism
Chapter 11. Infections 457

Ariffin Alam, MD, Sugeet K. Jagpal, MD, Jimmy Johannes, MD, & Naresh Nagella, MD
vii
Bronchial and Bronchiolar Infections Mycobacterium tuberculosis

Fungal Infections Pneumonia
HIV Nosocomial Pneumonia
Lung Abscess Nontuberculous Mycobacteria
Chapter 12. Lung Neoplasms 515

Sujith V Cherian MD & Fayez Kheir, MD, MSCR
Introduction Metastatic Lung Tumors

Benign Lung Neoplasms Lung Nodules
Malignant Lung Neoplasms Paraneoplastic Syndromes
Techniques for Diagnosis and Staging Pleural Neoplasms
Mediastinal Neoplasms Preoperative Assessment
Chapter 13. Pleural Disease 565

Jeffrey Albores, MD
Pleural Effusion Pleural Other

Pleural Asbestosis Pneumothorax
About the Editors 593

viii
CONTRIBUTING AUTHORS
Nidhi Aggarwal, MD Muhammad Nouman Iqbal, MD

Department of Internal Medicine, Division of Department of Medicine, Division of Pulmonary,
Pulmonary and Critical Care, Maimonides Critical Care and Sleep Medicine, MetroHealth
Medical Center, New York Medical Center, Case Western Reserve
University, Cleveland
Ariffin Alam, MD
Fellow, Clinical Instructor, University of Sugeet K. Jagpal, MD
Cincinnati College of Medicine, Department of Fellow, Pulmonary and Critical Care Medicine,
Internal Medicine, Division of Pulmonary, Critical Department of Medicine, Division of Pulmonary
Care and Sleep Medicine, Cincinnati and Critical Care Medicine, Rutgers Robert
Wood Johnson Medical School New Brunswick,
Jeffrey Albores, MD New Jersey
Pulmonary Critical Care Fellow, Department of
Medicine, Division of Pulmonary, Critical Care, Jimmy Johannes, MD
and Sleep Medicine, Ronald Reagan UCLA Pulmonary Critical Care Fellow, Department of
Medical Center, Los Angeles Medicine, Division of Pulmonary, Critical Care,
and Sleep Medicine, Ronald Reagan UCLA
Anthony F. Arredondo, MD Medical Center, Los Angeles
Pulmonary Critical Care Fellow, Department of
Medicine, Division of Pulmonary, Critical Care, Wajahat Khan, MD
and Sleep Medicine, Ronald Reagan UCLA Fellow, Sleep Medicine, Division of Sleep
Medical Center, Los Angeles Medicine, Perelman School of Medicine at the
University of Pennsylvania, Philadelphia
Sujith V. Cherian, MD
Department of Internal Medicine, Division of Fayez Kheir, MD, MSCR
Pulmonary, Critical Care and Sleep Medicine, Assistant Professor of Medicine, Department of
University of Texas Health Science Center at Medicine, Section of Pulmonary Diseases,
Houston Critical Care and Environmental Medicine,
Tulane University, New Orleans
Pulmonary and Critical Care Fellow, Department Carlos E. Kummerfeldt, MD
of Medicine, Division of Pulmonary, Critical Care Pulmonary and Critical Care Fellow, Division of
and Sleep Medicine, MetroHealth Medical Pulmonary, Critical Care, Allergy, and Sleep
Center, Case Western Reserve University, Medicine, Medical University of South Carolina,
Cleveland Charleston
Sharon De Cruz, MD Nazir Ahmad Lone MD MPH

Clinical Instructor, Department of Medicine, Pulmonary Critical Care Fellow, Department of
Division of Pulmonary, Critical Care, and Sleep Medicine, Division of Pulmonary, Critical Care
Medicine, Ronald Reagan UCLA Medical and Environmental Medicine, University of
Center, Los Angeles Missouri, Columbia
Puneet S. Garcha, MD Nandita R. Nadig MD

Associate Staff Physician, Respiratory Institute, Clinical instructor, Department of Medicine,
Cleveland Clinic Foundation Division of Pulmonary and Critical care
Medicine, Medical University of South Carolina,
Sachin Gupta, MD Charleston
Fellow, Department of Medicine, Division of
Pulmonary and Critical Care Medicine, UT
Southwestern, Dallas, Texas
ix
Naresh Nagella, MD Abhay Vakil, MBBS

Fellow, Pulmonary and Critical Care Medicine, Pulmonary Fellow, Department of Internal
Department of Medicine, Division of Pulmonary Medicine, Division of Pulmonary Medicine,
and Critical Care Medicine, Rutgers Robert Jamaica Hospital Medical Center, New York
Wood Johnson Medical School New Brunswick,
New Jersey Diana H. Yu, MD
Pulmonary and Critical Care Fellow, Department
Tessy Paul, MD of Medicine, Division of Pulmonary and Critical
Pulmonary Critical Care Fellow, Department of Care Medicine, University of California Los
Medicine, Division of Pulmonary, Critical Care, Angeles Medical Center
and Sleep Medicine, Ronald Reagan UCLA
Medical Center, Los Angeles
Sandeep Sahay, MD
Department of Internal Medicine, Division of
Pulmonary, Critical Care and Sleep Medicine,
University of Texas, Health Science Center at
Houston
x
SENIOR REVIEWERS
Diwakar D. Balachandran, MD Alan Fein, MD
Associate Professor, Department of Pulmonary Clinical Professor of Medicine, Hofstra
Medicine, Division of Internal Medicine, Northshore-LIJ School of Medicine, Hempstead,
University of Texas MD Anderson Cancer New York; Associate Program Director of
Center, Houston Pulmonary Medicine, Jamaica Hospital Medical
Center, New York
Igor Barjaktarevic, MD
Assistant Clinical Professor, Department of Dee W. Ford, MD, MSCR
Medicine, Division of Pulmonary, Critical Care, Associate Professor of Medicine, Division of
and Sleep Medicine, Ronald Reagan UCLA Pulmonary, Critical Care, Allergy, and Sleep
Medical Center, Los Angeles Medicine; Medical Director, Medical Intensive
Care Unit, Medical University of South Carolina,
Tanaya Bhowmick, MD Charleston
Assistant Professor, Department of Medicine
Division of Infectious Diseases, Rutgers Robert John T. Huggins, MD
Wood Johnson Medical School, New Brunswick, Associate Professor, Department of Medicine,
New Jersey Division of Pulmonary and Critical Care, Medical
University of South Carolina, Charleston
Charles R. Cantor, MD
Professor of Clinical Neurology, Associate Sabiha Hussain, MD
Professor of Medicine, Perelman School of Assistant Professor, Department of Medicine,
Medicine at the University of Pennsylvania; Division of Pulmonary and Critical Care
Medical Director, Penn Sleep Centers, Center Medicine, Rutgers Robert Wood Johnson
for Sleep and Circadian Neurobiology, Medical School, New Brunswick, New Jersey
Philadelphia
Thanh Huynh, MD
Marina Duran Castillo, MD Clinical Instructor, Department of Medicine,
Assistant Professor of Medicine, Case Western Division of Pulmonary, Critical Care, and Sleep
Reserve University, MetroHealth Medical Center Medicine, Ronald Reagan UCLA Medical
Cleveland Center, Los Angeles
Steven Chang, MD, PhD Corey Kershaw, MD

Associate Clinical Professor, Department of Associate Professor, Department of Internal
Medicine, Division of Pulmonary, Critical Care, Medicine, UT Southwestern Medical Center,
and Sleep Medicine, Ronald Reagan UCLA Dallas
Medical Center, Los Angeles
Yizhak Kupfer, MD
Ousama Dabbagh, MD, MS Clinical Professor of Medicine, Albert Einstein
Staff Physician, Blount Memorial Hospital, School of Medicine; Program Director, Division
Maryville, Tennessee; Adjunct Associate of Critical Care Medicine, Maimonides Medical
Professor of Clinical Medicine, Pulmonary, Center; Associate Director, Division of
Critical Care and Environmental Medicine, Pulmonary Medicine, Maimonides Medical
University of Missouri, Columbia Center, Brooklyn, New York
Ariss Derhovanessian, MD Peter Lenz, MD

Assistant Professor, Department of Medicine, Assistant Professor, Fellowship Program
Division of Pulmonary, Critical Care, and Sleep Director of Pulmonary and Critical Care
Medicine, Ronald Reagan UCLA Medical Medicine, University of Cincinnati Medical
Center, Los Angeles Center
xi
Yuji Oba, MD Donald Tashkin, MD

Associate Professor, Department of Medicine, Emeritus Professor of Medicine, Division of
Division of Pulmonary and Critical Care Pulmonary and Critical Care Medicine, David
Medicine, University of Missouri School of Geffen School of Medicine at the University of
Medicine, Columbia California, Los Angeles
Scott Oh, DO, FCCP J. Daryl Thornton, MD, MPH

Assistant Clinical Professor, Division of Associate Professor of Medicine, Case Western
Pulmonary and Critical Care Medicine David Reserve University; Director, Medical Intensive
Geffen School of Medicine at UCLA, Los Care Unit; Researcher, Center for Reducing
Angeles Health Disparities, MetroHealth Medical Center,
Cleveland
Jaime Palomino, MD
Assistant Professor, Director Pulmonary Adriano Tonelli, MD
Diseases/Critical Care Medicine Fellowship
Staff Physician, Respiratory Institute, Cleveland
Program, Tulane University, New Orleans
Clinic
Joseph Parambil, MD Edward Warren, MD
Staff Physician, Respiratory Institute, Cleveland
Associate Professor of Medicine, Director, and
Clinic
Vice Chair, Department of Internal Medicine,
Case Western Reserve University, MetroHealth
Silverio Santiago, MD Medical Center, Cleveland
Director, Division of Pulmonary, Critical Care,
and Sleep Medicine, VA Greater Los Angeles
Area Medical Center
Ziad S. Shaman, MD, RDMS

Assistant Professor, Case Western Reserve
University, Cleveland; Program Director,
Pulm/CCM Fellowship, MetroHealth Medical
Center
xii
PREFACE
With this first edition of ATS Review for the Pulmonary Boards, we attempt to provide fellows-in-training
and pulmonologists with the most high-yield and up-to-date preparation guide for the ABIM Pulmonary
Disease Certification exam. This text was written like other publications in the First Aid board review
series and is designed to fill the need for a high-quality, in-depth, conceptually driven study guide for
ABIM Pulmonary Disease Certification exam preparation. This resource is designed to be used either
alone, or in conjunction with other texts.
This book would not have been possible without the help of the many fellows-in-training, physicians, and
faculty members who contributed their feedback and suggestions. We invite you to share your thoughts
and ideas to help us improve ATS Review for the Pulmonary Boards, (see How to Contribute, p. xiv.)
Tao Le, MD, MHS

Louisville, Kentucky
Sandeep (Sunny) Khosa, MD

Mankato, Minnesota
Susan Pasnick, MD
San Francisco
Tisha Wang, MD
Los Angeles
xiii
ACKNOWLEDGMENTS
This has been a collaborative project from the start. We gratefully acknowledge the thoughtful comments
and advice of the fellows-in-training, pulmonologists, and faculty who have supported the authors in the
development of ATS Review for the Pulmonary Boards.
Thanks to the American Thoracic Society for their support and the funding necessary to undertake this
project. In particular, we would like to thank Eileen Larsson and Jennifer Siegel-Gasiewski for their
encouragement, organizational assistance, and guidance throughout this process. We thank Drs. Vikas
Bhatara and John C. Williams for their contributions to the text. We also thank Drs. Ariss Derhovanessian,
David Ross, and John Belperio for their image contributions. For outstanding editorial work, we thank
Karla Schroeder, Linda Bradford, Susan Brownstein, and Isabel Nogueira. We thank Louise Petersen for
her project editorial support. A special thanks to Thomson Digital for their excellent illustration work.
Tao Le, MD, MHS

Louisville, Kentucky
Sandeep (Sunny) Khosa, MD

Mankato, Minnesota
Susan Pasnick, MD
San Francisco
Tisha Wang, MD
Los Angeles
xiv
HOW TO CONTRIBUTE
To continue to produce a current review source for the ABIM Pulmonary Disease Certification exam, you
are invited to submit any suggestions or corrections. Please send us your suggestions for:
• Study and test-taking strategies

• New facts, mnemonics, diagrams, and illustrations
• Relevant topics that are likely to be tested in the future
For each entry incorporated into the next edition, you will receive a personal acknowledgment in the next
edition. Also let us know about material in this edition that you feel is low yield and should be deleted.
The preferred way to submit entries, suggestions, or corrections is via our email address:
education@thoracic.org
NOTE TO CONTRIBUTORS
All submissions become property of the ATS and are subject to editing and reviewing. Please verify all
data and spellings carefully. Include a reference to a standard textbook to facilitate verification of the fact.
Please follow the style, punctuation, and format of this edition if possible.
SLEEP MEDICINE AND NEUROMUSCULAR/SKELETAL DISORDERS / 1
Sleep Medicine and

1 Neuromuscular/Skeletal
Disorders
Sharon De Cruz, MD & Wajahat Khan, MD
RESPIRATORY SLEEP MEDICINE
SLEEP PHYSIOLOGY
Review of the physiologic changes that occur during sleep.
Regulation of Sleep and Wake

Sleep latency, quality and duration of sleep, and alertness are regulated by two
components (sleep homeostasis and circadian rhythm) with a third process (sleep
inertia) responsible for the transitional period of relative confusion between sleep
and wake.
SLEEP HOMEOSTASIS—Dependent on the sleep–wake cycle.

 Sleep pressure increases as the duration of wakefulness increases and declines
after sufficient sleep.
 Constant sleep throughout the sleep period is maintained because of a falling
circadian alertness opposing any decrease in homeostatic sleep drive.
CIRCADIAN SYSTEM—Biologic alerting rhythm that consists of one oscillation

every 24.2 hours (called “tau”).
 Independent of sleep–wake cycle
 Entrainment of the circadian system occurs when environmental cues called
zeitgebers; zeitgebers synchronize the circadian rhythm to the external 24- Flash Card Q1
hour period, and can be photic (light) or nonphotic (eating times).
What is the most powerful
 Constant alertness throughout the waking period occurs because of rising zeitgeber entraining the
circadian alertness opposing an increase in homeostatic sleep pressure. sleep–wake rhythm?
SLEEP INERTIA—Refers to the cognitive impairment present immediately on Flash Card Q2

awakening from sleep.
What structure in the brain
 Most pronounced in the first 15–30 minutes after wakening. acts as the master
 May be relevant in occupations involving shift work (i.e., physicians being circadian rhythm generator
awakened by a page). in mammals, and where is
it located?
2 / CHAPTER 1
Suprachiasmatic nucleus is master circadian rhythm generator in mammals

located in the anterior hypothalamus:
 Activity greatest during daytime
 Promotes wake during the day, and consolidates sleep at night
 Two circadian peaks of alertness—late morning and early evening
 Two circadian troughs of alertness—early morning and early afternoon
 Main afferent connection is the retinohypothalamic tract, which is most
sensitive to blue–blue-green wavelength light
 Ablation of the suprachiasmatic nucleus causes sleep to be randomly
distributed throughout the day and night, and it leads to a decrease in wake
period duration
Neurotransmitters in Sleep and Wake

Sleep and wake cycles are generated and regulated by central nervous system
(CNS) networks that exist in specific areas of the brain using specific
neurotransmitters (Table 1-1).
Table 1-1. Neurotransmitters Responsible for Sleep and Wake

Sleep
Neurotransmitters Clinical Associations
GABA Major CNS inhibitory neurotransmitter
Key Fact Example: Benzodiazepines, alcohol (see below)
Stimulants such as Glutamate Major CNS excitatory neurotransmitter
amphetamines and
modafinil promote Example: Alcohol is a GABA agonist and inhibits glutamate; high doses
wakefulness by increasing are sedating, but suppress REM sleep
excitatory neurotransmitters Serotonin Major CNS excitatory neurotransmitter
(norepinephrine, dopamine,
Activity increases during wake and decreases during sleep
and hypocretin).
Norepinephrine Major CNS excitatory neurotransmitter
Activity increases during wake and decreases during sleep
Dopamine Agonists promote wakefulness
Haldol is an antagonist
Example: Amphetamines (agonists)
Histamine First-generation receptor antagonists promote sleep
Example: Diphenhydramine
Acetylcholine REM sleep neurotransmitter
Hypocretin Hypocretin deficiency results in narcolepsy with cataplexy
Flash Card A1 Adenosine Decrease in adenosine activity promotes wakefulness

Example: Caffeine blocks adenosine receptors
Light
GABA, gamma-aminobutyric acid; CNS, central nervous system; REM sleep, rapid eye movement sleep
Flash Card A2
Suprachiasmatic nucleus;
anterior hypothalamus
MELATONIN—Synthesized and released by the pineal gland, it influences

circadian sleep–wake rhythms, and as such, secretion is greatest at night.
Melatonin secretion is inhibited by light exposure.
Actions of melatonin: Key Fact
 Causes phase advance circadian sleep–wake rhythm when given in early Caffeine increases
evening wakefulness by blocking
 Causes phase delay circadian sleep–wake rhythm when given in early the receptors of adenosine,
a CNS neurotransmitter.
morning
 Less effective than light exposure in shifting of circadian rhythms
Physiologic Changes During Sleep

Sleep has a significant effect on many organ systems and physiologic processes in
the body (Table 1-2).
Sleep Deprivation Flash Card Q3

Which neurotransmitter is
Sleep deprivation can affect cognition and performance. responsible for rapid eye
movement sleep
generation?
PHYSIOLOGIC EFFECTS OF SLEEP DEPRIVATION
 ↑sleepiness, sympathetic activity, cortisol and ghrelin hormones, insulin
resistance, medical errors, and motor vehicle accidents Flash Card Q4
 ↓cognition, seizure threshold, growth hormone, leptin activity, resistance to When is melatonin
infection, and response to vaccines secreted? What is its
function?
Table 1-2. Physiologic Processes During Sleep Flash Card Q5

System Physiologic Processes A 19-year-old woman
sleeps from 3 am until 11
Autonomic nervous system During NREM sleep compared to wake:
am daily. She starts
↓sympathetic activity
college in 1 month and has
↑parasympathetic activity
7 am classes. What
Respiratory system Compared to wake: circadian rhythm sleep
↓PaO2, ↓SaO2, ↑PaCO2 disorder does she have?
↓during NREM sleep When would you give her
↓VT↔RR, ↓minute ventilation melatonin?
During REM sleep:
↓↓UA dilator muscle tone Flash Card Q6
Diaphragm activity remains intact
Irregular respirations A 76-year-old man sleeps
from 7 pm until 4 am once
Cardiovascular system NREM sleep compared to wake: a day. He wants to join his
↓HR, ↓CO, ↓BP local Bingo group that
REM sleep compared to NREM sleep and wake: meets at 8 pm, and he
↑HR, ↑CO, ↑BP would like to stay up longer
at night. What circadian
Renal Decrease in urine output: rhythm sleep disorder does
↑water reabsorption, renin, ADH he have, and when would
↓GFR you give him melatonin to
treat it?
4 / CHAPTER 1
Table 1-2. Physiologic Processes During Sleep, cont.

System Physiologic Processes
Endocrine Increasing levels during sleep:
GH, prolactin, parathyroid hormone, testosterone
Decreasing levels during sleep:
Cortisol, insulin, TSH
Immune system Proinflammatory cytokines (↑sleepiness):
↑IL-1β, ↑TNFα
Anti-inflammatory cytokines (↓sleepiness):
↑IL-4, ↑IL-10
Thermoregulation Core body temperature:
Key Fact Peaks early evening (6–8 pm)
Falls at onset of sleep
Ghrelin stimulates appetite, Nadir is 2 hours prior to usual wake time (4–5 am)
and leptin inhibits appetite. Sleep occurs during falling phase of temperature rhythm, and
Ghrelin = Grow wake occurs during rising phase of temperature rhythm
Leptin = Lean ADH, antidiuretic hormone; BP, blood pressure; CO, cardiac output; GFR, glomerular filtration rate; GH, growth
hormone; HR, heart rate; IL-1β, interleukin 1β; IL-4, interleukin 4; IL-10, interleukin 10; NREM, non-rapid eye
movement; PaCO2, partial pressure of carbon dioxide in blood; PaO2, partial pressure of oxygen in blood; REM,
rapid eye movement; SaO2, saturation level of oxygen in hemoglobin; TNFα, tumor necrosis factor alpha; TSH,
thyroid-stimulating hormone; VT, tidal volume; RR, respiratory rate; UA, upper airway
POLYSOMNOGRAPHY (PSG)
Flash Card A3
Acetylcholine
Records physiologic variables during sleep using electroencephalography/-gram
(EEG), electrooculography/-gram (EOG), chin electromyography/-gram (EMG),
Flash Card A4 electrocardiography/-gram (ECG), oxygenation, snoring, respiratory effort, and
Secreted at night; leg (anterior tibialis) EMG (Figure 1-1).
promotes sleep by causing
drowsiness and lowering
body temperature (think of
melatonin as the darkness Indications for PSG
signal.)
PSG is used for:
Flash Card A5  Diagnosis of sleep-disordered breathing (SDB)
She has a delayed sleep  Testing efficacy after treatment for SDB with oral appliances or upper airway
phase disorder; should (UA) surgery
receive melatonin early in
the night to help her fall
 Positive airway pressure (PAP) titration
asleep earlier.  Diagnosis of nonrespiratory sleep disorders:
o Periodic limb movement disorders (PLMDs)
Flash Card A6 o Narcolepsy
He has advanced sleep
o Parasomnias
phase disorder, and he o Nocturnal seizures
should receive melatonin in o Rapid eye movement (REM) sleep behavior disorder
the early morning, after
being cautioned that
melatonin can cause
drowsiness
Figure 1-1. Polysomnography setup where patient lies in bed with EEG, EOG,
chin EMG, ECG, airflow, oxygenation, snoring, respiratory effort, and leg EMG
(some not pictured).
(Reproduced courtesy of the National Institutes of Health, Department of Health and Human Services.)
EEG Wave Frequencies
 Beta waves (Figure 1-2A): Alert and awake (> 13 Hz)

 Alpha waves (Figure 1-2B): Drowsy with eyes closed (8–13 Hz)
 Theta waves (Figure 1-2C): Characteristic of N1 and N2 sleep and REM sleep
(4–7 Hz)
 Delta waves (Figure 1-2D): Characteristic of N3 sleep (< 4 Hz)
Flash Card Q7
What is/are the effect(s) of
REM sleep compared to
NREM sleep on the
autonomic nervous
system?
Flash Card Q8
How are hormones ghrelin
and leptin affected by sleep
deprivation?
6 / CHAPTER 1
D
Figure 1-2. One-second sample EEG tracings showing (A) beta, (B) alpha, (C)
theta, and (D) delta waves.
(Reproduced courtesy of Hugo Gamboa, Wikimedia Commons, CC BY-SA 3.0.)
EEG WAVEFORMS—Important in the staging of sleep.

Flash Card A7  Vertex waves:
o Sharp negative waves in the theta range frequency
A transient increase in
sympathetic activity during
o Usually occurs during latter part of sleep stage 1
phasic REM sleep  K-complex (Figure 1-5):
o Sharp negative wave, followed by slower positive component
o Usually seen in sleep stage 2
Flash Card A8 o Premature ventricular contraction (PVC) waveforms of the EEG
Ghrelin increases, and  Sleep spindles (Figure 1-5):
leptin decreases o Short rhythmic waveform clusters in the 12–14 Hz frequency range
o Characteristic of sleep stage 2

 Sawtooth waves (Figure 1-7):
o Low amplitude with notched/sawtooth appearance
o Characteristic of REM sleep
Wake and Stages of Sleep
WAKE (Figure 1-3)

 > 50% of an epoch has alpha rhythm when eyes are closed
 Chin EMG tone is high
 Presence of any of the following, in the absence of alpha waves:
o Fast eye movements and eye blinks when eyes open
o Low voltage, mixed frequency pattern
Figure 1-3. PSG showing wake state. Alpha rhythm with frequency 8−13 Hz
occupies > 50% of epoch (red arrow); high chin EMG tone characteristic of wake
state (black arrow).
NREM SLEEP (Figures 1-4, 1-5, and 1-6)

 Sleep stage N1:
o Alpha activity diminished or disappeared
o Low amplitude, mixed frequency (4–7 Hz) waves that occupy > 50% of
the epoch
o Slow rolling eye movements
o Vertex waves may be present
o Chin EMG levels lower than stage wake
 Sleep stage N2:
o Low amplitude, mixed frequency waves
8 / CHAPTER 1
o Presence of K-complexes and/or sleep spindles

 Sleep stage N3:
o ≥ 20% of epoch occupied by low frequency, high amplitude delta waves
(0.5–2 Hz and > 75 µV)
Figure 1-4. PSG showing NREM sleep stage N1. Slow rolling eye movements
(red arrow); chin EMG has decreased compared to wake stage (green arrow);
alpha activity diminished or disappeared and replaced by low amplitude (black
arrow), mixed frequency waves (4–7 Hz) that occupy > 50% of epoch.
Figure 1-5. PSG showing NREM sleep stage N2. Sleep spindles diagnostic of
sleep stage N2 (black arrow); K-complex diagnostic of sleep stage N2 (red
arrow).
Figure 1-6. PSG showing NREM sleep stage N3. Low frequency, high amplitude
delta waves (0.5–2 Hz and > 75 µV) occupying ≥ 20% of epoch (arrow).
REM sleep (Figure 1-7)

 Low amplitude, mixed frequency waves
 Low chin EMG tone
 Rapid eye movements
Figure 1-7. PSG showing REM sleep. Low amplitude, mixed frequency
(sawtooth) waves (black arrow); rapid eye movements (red arrow); low chin EMG
tone (green arrow).
Flash Card Q9
What characteristic EEG
waveforms define sleep
stage N2?
10 / CHAPTER 1
Scoring
PSG data are divided into 30-second intervals or epochs, and an epoch is given a
sleep stage based on whichever stage comprises the largest percentage of that
epoch.
APNEA—Decrease in thermal sensor amplitude by ≥ 90% of baseline for ≥ 10

seconds.
 Obstructive apnea: Inspiratory effort present throughout apnea (Figure 1-10)
 Central apnea: Inspiratory effort absent throughout apnea (Figure 1-12)
 Mixed apnea: Central apnea followed by obstructive apnea (Figure 1-14)
HYPOPNEA—Decrease in nasal pressure by ≥ 30% for ≥ 10 seconds with a ≥ 4%

drop in oxygen saturation (Figure 1-8).
Figure 1-8. Ambulatory sleep study showing hypopnea. Decrease in nasal

pressure by ≥ 30% for ≥ 10 seconds with 4% oxygen desaturation (arrow).
PLM (Figure 1-9)

 ≥ 4 consecutive leg movements, for 0.5–10 seconds each
 5–90 seconds between movements
Flash Card A9
K-complex and sleep
spindles
Figure 1-9. PSG showing PLMs. PLMs as defined by ≥ 4 consecutive leg

movements, for 0.5–10 seconds each with periods of 5–90 seconds between
movements (arrow).
APNEA–HYPOPNEA INDEX (AHI)—Measure of the severity of sleep apnea.

 Number of apneas + hypopneas per hour of sleep:
o AHI 0–5, normal
o AHI 5–15, mild SDB
o AHI 15–30, moderate SDB
o AHI > 30, severe SDB
RESPIRATORY DISTURBANCE INDEX (RDI)

 Number of apneas + number of hypopneas + respiratory effort-related
arousals per hour of sleep:
o RDI 0–5, normal
o RDI 5–15, mild
o RDI 15–30, moderate
o RDI > 30, severe
Epworth Sleepiness Scale

Eight-item questionnaire that evaluates the chances of dozing off to sleep on a
scale of 0 (never) to 3 (high chance) under the following conditions:
 Sitting and reading
 Watching television
 Sitting inactive in a public place
12 / CHAPTER 1
 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 without drinking alcohol
 Stopped in a car for a few minutes in traffic
An aggregate score of ≥ 10 indicates excessive daytime sleepiness.
Multiple Sleep Latency Test (MSLT)
 Measures tendency to fall asleep in quiet settings

 Patients instructed to try to fall asleep
 Indications:
o Diagnose narcolepsy
o Evaluate unexplained hypersomnia
 Requires PSG on the night prior to test and discontinuation of any medications
that could affect sleep
 Consists of four or five 20-minute nap opportunities at 2-hour intervals with
focus on sleep latency and presence or absence of REM sleep onset periods
SHORT SLEEP-ONSET LATENCY (SOL)—Test suggestive of excessive

daytime sleepiness if there is short SOL (< 8 minutes)
 Causes of short SOL:
o Narcolepsy
o Idiopathic hypersomnia (IH)
o Sleep deprivation
o Obstructive sleep apnea
o PLMD
o Acute stimulant agent withdrawal
REM SLEEP ONSET—Test suggestive of narcolepsy if there are ≥ two sleep-

onset REM sleep periods (SOREMPs).
 Causes of SOREMPs:
o Narcolepsy
o Sleep deprivation
o OSA
o Alcohol withdrawal
o REM sleep suppressant withdrawal (e.g., antidepressants)
Maintenance of Wakefulness Test (MWT)
 Measures ability to stay awake in quiet settings

 Patients instructed to try to stay awake
 Consists of four 40-minute nap opportunities at 2-hour intervals

 Less sensitive than MSLT in detecting sleepiness and has variable predictive
accuracy for sleepiness; patients may have normal MWT and still be sleepy
 SOL interval correlates with ability to stay awake:
o SOL < 8 minutes—abnormal
o SOL > 8 minutes and < 40 minutes—intermediate
o SOL = 40 minutes (no sleep) —normal
SLEEP-DISORDERD BREATHING (SDB)
In this section, we will discuss respiratory causes of SDB including obstructive

sleep apnea, central sleep apnea (CSA), and nocturnal hypoventilation.
Obstructive Sleep Apnea (OSA)

Common and underdiagnosed, with a prevalence of 5–10%, which increases with
age.
RISK FACTORS
 Age
 Gender: Male subjects (up to age 50 years) and postmenopausal women (risk
between genders similar after menopause)
 Obesity
 Ethnicity: Greater risk in African-American, Asian, Hispanic groups
 Obstructive UA anatomy
 Medical comorbidities: Heart failure, history of cerebrovascular accident,
renal failure
SIGNS AND SYMPTOMS

 Unexplained daytime sleepiness Key Fact
 Witnessed nocturnal apneas
Absence of daytime
 Frequent nocturnal awakenings sleepiness does not rule
 Insomnia out sleep apnea, as > 50%
of patients with OSA will
 Morning headaches not have daytime
 Nocturia sleepiness.
 Difficult concentrating and mood disorders
DIAGNOSIS—History and physical exam alone often are nondiagnostic as > 50% Flash Card Q10
of patients do not have daytime sleepiness. Witnessed snoring and apneas have a What are two defining
high positive predictive value of 64%, with witnessed apneas being the best characteristics of
historic predictor. narcolepsy on PSG with
MSLT?
14 / CHAPTER 1
Key Fact  In-laboratory PSG and portable home sleep testing are the main methods of
diagnosing OSA.
Sleep apnea is uncommon
as the sole etiology for  PSG is the gold standard for the diagnosis of SDB (Figure 1-10).
significant pulmonary  Portable sleep studies are used for patients with a high pretest probability for
hypertension; when
present, other etiologies
OSA and without comorbid medical conditions such as cardiovascular disease,
should be considered. stroke, chronic obstructive pulmonary disease (COPD), and hypoventilation
syndromes.
Figure 1-10. PSG showing obstructive apneas, characterized by presence of

inspiratory effort throughout each apnea. Apnea as defined by decrease in
thermal sensor amplitude by ≥ 90% of baseline for ≥ 10 seconds (black arrow);
presence of inspiratory effort throughout the apnea as indicated by persistent
oscillations in both chest and abdomen channels (green arrow); note oxygen
desaturations following apneas (red arrow).
CONSEQUENCES
 Increases risk of:
o Myocardial infarctions
o Cerebrovascular accidents
o Pulmonary hypertension
o Hypertension
o Sudden death
 May worsen diabetes and decrease GH and testosterone secretion
 May worsen heart failure
 Increases proinflammatory immune mediators CRP, IL-6, TNFα
 Causes daytime sleepiness with resultant motor vehicle accidents
 May cause neurocognitive deficits and memory and cognitive problems, and
may increase risk of depression and mood disorders
TREATMENT—Continuous positive airway pressure (CPAP) is the mainstay of

OSA treatment (Figure 1-11).
Flash Card A10
Decreased SOL and ≥ two Patients who need treatment:
SOREMPs on MSLT
 Moderate-to-severe OSA (AHI > 15) regardless of the presence or absence of Key Fact
symptoms
Increased risk for
 Mild OSA (AHI > 5) with symptoms/comorbidities: cardiovascular disease in
o Symptoms/comorbidities are excessive daytime sleepiness, insomnia, the context of OSA is tied
more to degree of oxygen
cardiovascular disease, stroke, hypertension, depression, memory and desaturation than to AHI.
mood problems
 Patients with OSA who have other concurrent sleep-related disorders (PLMs,
insomnia, bradycardia, nocturia, etc.) should pursue CPAP therapy first, as Key Fact
these conditions often resolve with treatment of OSA. The Joint National
Committee (JNC)
guidelines now lists OSA
Treatment recommendations are listed in Table 1-3. as a secondary cause of
hypertension.
CPAP use and cardiovascular disease:
 CPAP improves left ventricular ejection fraction (LVEF) modestly in patients
with heart failure.
 CPAP reduces blood pressure and may improve mortality in patients with
SDB.
CPAP compliance:
 Defined as use > 4 hours on at least 70% of observed nights.
 CPAP compliance is generally in the range of 50–60% when measured
objectively.
 Patients commonly overestimate their subjective compliance.
 Compliance patterns are determined early.
Flash Card Q11

Which patients should not
undergo a portable home
sleep study?
Figure 1-11. PSG showing resolution of obstructive apneas from Figure 1-10,
with CPAP use. CPAP pressure (red arrow); presence of nasal flow with CPAP Flash Card Q12
use (black arrow); presence of effort (green arrow).
What is the best historic
predictor of OSA?
Flash Card Q13

What is the #1 reason for
residual daytime
sleepiness in patients who
are on CPAP therapy for
SDB?
16 / CHAPTER 1
Table 1-3. Treatment of OSA

Therapy Indications
CPAP First-line therapy
Mild, moderate, and severe OSA
Improves AHI, daytime sleepiness, quality of life
Oral device (mandibular Second-line therapy

advancement device or Snoring and mild-to-moderate OSA intolerant of CPAP
tongue retaining device)
UA surgery Alternative therapy
Intolerant of CPAP and oral devices
Uvulopalatopharyngoplasty generally is unsuccessful in resolving
OSA and is not recommended
Maxillomandibular advancement is successful in resolving OSA
Nasal EPAP (Provent) Alternative therapy

Mild OSA intolerant of CPAP and oral devices
Adjuvant therapies Avoidance of alcohol and narcotics

Key Fact Positioning belts and pillows helps patients to sleep laterally, as
OSA is generally is worse in the supine position
Nocturia associated with Weight loss and bariatric surgery improve but rarely resolve OSA
OSA improves with CPAP
use. AHI, apnea–hypopnea index; CPAP, continuous positive airway pressure; EPAP, expiratory positive airway
pressure; OSA, obstructive sleep apnea
Interventions proven to improve CPAP compliance:

 Heated humidification
 Education and early frequent contact with health care providers after CPAP
initiation
 Cognitive behavioral therapy (CBT)
 Small studies indicate that use of eszopiclone once during CPAP titration
study, and for the initial 14 nights of CPAP therapy, may be beneficial
Oral appliances for treating OSA:

 May use for snoring and mild-to-moderate OSA
 If patient has more severe disease and fails CPAP, may use oral appliance as
Flash Card A11 second-line therapy
Patients with  Testing with sleep study should be performed to assess efficacy
cardiovascular disease,  Outcomes:
stroke, COPD, and o Oral appliances as effective as CPAP for improving daytime sleepiness
hypoventilation syndromes
o Oral appliances less effective than CPAP for improving oxygenation and
Flash Card A12 AHI
Witnessed apneas— SURGERY FOR TREATING OSA
daytime sleepiness is the
most common symptom  Bariatric surgery for obese patients improves SDB but generally does not
result in resolution of the sleep apnea.
Flash Card A13
CPAP noncompliance
 Uvulopalatopharyngoplasty, the reduction or removal of portions of the soft

palate and uvula, generally is unsuccessful in resolving OSA, and it is not
recommended.
 Maxillomandibular advancement, surgery to move the upper and lower jaw
forward, has been noted to be successful in resolving OSA.
 Tracheostomy is used as a last resort for severe refractory symptomatic OSA
in patients intolerant of CPAP.
 Adenotonsillectomy is effective in children and infants.
EPAP (PROVENT) TO TREAT OSA

 Only small studies available showing some benefit in positional OSA and
mild OSA
 May be used for patients intolerant of CPAP and oral devices
 Testing with sleep study should be performed to assess efficacy
RESIDUAL SLEEPINESS
 First confirm compliance with CPAP
 Evaluate for other etiologies of excessive daytime sleepiness that may require
alternative treatment, such as narcolepsy, IH, sleep deprivation, and shift work
disorder
 Once compliance is confirmed and no other diagnoses are found, consider a
trial of modafinil, which acts as a stimulant by inhibiting dopamine and
hypocretin reuptake
Flash Card Q14
Central Sleep Apnea (CSA) Which outcome is the most

likely to improve with use
of CPAP in OSA?
Loss of ventilatory effort during sleep resulting in repetitive cessation of airflow.
Flash Card Q15
NONHYPERCAPNIC CSA—Normal or low partial pressure of carbon dioxide
A 74-year-old man with
(PaCO2) and increased ventilatory response to hypercapnia. heart failure (LVEF 20%)
and atrial fibrillation is
Cheyne–Stokes respirations (CSRs) are characterized by crescendo–decrescendo referred for frequent
nocturnal desaturations
periodic breathing (Figure 1-12). noted during a recent
 Pathophysiology: hospitalization. What type
o Increased chemoreceptor sensitivity to carbon dioxide (CO2) of SDB would you be
concerned about?
o Increased ventilatory drive
o Increased circulatory time secondary to decreased cardiac output from
heart failure
o Decreased oxygen reserve Flash Card Q16
Would a patient with CSRs
 Characteristics: be hypercapnic,
hypocapnic, or eucapnic on
o Occur predominantly in sleep stages N1 and N2 a daytime arterial blood
gas?
18 / CHAPTER 1
o Occur in about 30% of patients with heart failure, and is associated with
increased morbidity and mortality
o Cycle duration is about 40–90 seconds
o Cycle duration is directly related to blood circulation time, and is inversely
related to LVEF
o Oxygen desaturation and hypercarbia are delayed and occur during
hyperpnea; arousal therefore occurs during peak hyperpnea
o Persistent awakenings related to apneic episodes may result in sleep
fragmentation and excessive daytime sleepiness, though patients often are
asymptomatic.
 Treatment:
o There are limited data on the best therapy for CSR related to heart failure.
o First step in management is to optimize heart failure (i.e., angiotensin-
converting enzyme [ACE] inhibitors).
o Adaptive servo-ventilation (ASV) has shown promising outcomes in the
treatment of CSA, mainly CSR and complex sleep apnea; ASV adjusts
respiratory rate and tidal volume to target a set minute ventilation, and
reacts to periodic breathing by increasing inspiratory pressure during
periods of apneas or hypopneas.
o Oxygen may improve AHI and oxygen saturation in patients with CSR.
o CANPAP trial: CPAP does not improve survival in patients with heart
failure who have predominantly CSA, but CPAP does have a modest
benefit in improving LVEF.
o Auto-CPAP is not recommended for CSA.
Flash Card A14

Daytime sleepiness
Figure 1-12. Ambulatory sleep study showing Cheyne-Stokes respirations,

Flash Card A15 characterized by the classic crescendo–decrescendo periodic breathing (shown
in air flow channel). Apnea (black arrow); crescendo–decrescendo periodic
CSRs
breathing (red arrow); inspiratory effort absent throughout the apnea as shown by
lack of oscillations in the chest and abdomen leads (blue arrows).
Flash Card A16
Typically hypocapnic
Complex Sleep Apnea
 Central apneas emerge on application of CPAP treatment for OSA

 Pathophysiology not well defined
 Occurs mainly in NREM sleep and in supine position.
 Optimal treatment is not well defined:
o In most patients, there is spontaneous resolution of complex sleep apnea
with continued CPAP treatment of the obstructive apneas.
o If complex apnea occurs during in-laboratory CPAP titration, attempt
reduction of PAP as this may resolve the complex apnea.
o ASV has been used successfully for those with persistent complex sleep
apnea.
High-altitude periodic breathing:

 Occurs predominantly during NREM sleep
 Usually occurs above 2500 meters, with increased prevalence at higher
altitudes
 Mechanism is related to enhanced ventilatory response to hypoxemia
 Period length of each breath cycle is shorter than CSR
 Treatment:
o Oxygen
o Acetazolamide
Idiopathic CSA:
 Rare, and cause is unknown
 Middle aged males are most commonly affected
Sleep-onset central sleep apnea:

 Thought to be related to fluctuations in PaCO2 above and below the apneic
threshold as sleep onset occurs
 Resolves as sleep progresses and respirations stabilize
 No therapy needed
HYPERCAPNIC CSA—Elevated PaCO2 during sleep caused by decreased

ventilatory response to hypercapnia.
 Opioid-induced apnea is induced most commonly by long-acting opioids,

mainly methadone.
 Dose-dependent relationship with narcotics
 Patterns of SDB:
o Biot respirations (Figure 1-13), CSA characterized by irregular periods of
apnea (in contrast to CSR, which is characterized by regular periods of Flash Card Q17
apnea) What is the first step in the
o Obstructive apnea management of CSRs in
the setting of heart failure?
20 / CHAPTER 1
o Mixed apneas (CSA followed by OSA)

o Prolonged obstructive hypoventilation
 Optimal treatment not clear:
o Disease generally does not resolve spontaneously
o Condition may improve with reduced opioid dose
o ASV has been used, but data are lacking
Figure 1-13. Ambulatory sleep study showing Biot respirations, CSA

characterized by irregular periods of apnea. Apnea (black arrow); inspiratory
effort absent throughout apnea as shown by lack of oscillations in chest and
abdomen leads (blue arrows). Contrast this with regular periods of apnea found
in CSRs.
Mixed Apnea
CSA followed by obstructive apnea (Figure 1-14). Etiology unclear, but may
occur in patients who have CSA whereby loss of ventilatory effort and air flow
results in collapse of the UA and subsequent obstruction. Treatment consists of
management of the CSA, as discussed.
Flash Card A17

Optimize heart failure (i.e.,
ACE inhibitors)
Figure 1-14. PSG showing mixed apnea, characterized by CSA followed by

obstructive apnea. Apnea (black arrow); inspiratory effort absent during initial part
of apnea as shown by lack of oscillations in chest and abdomen leads,
characteristic of central apnea (red arrows); presence of inspiratory effort during
second part of apnea as indicated by persistent oscillations in both chest and
abdomen channels, characteristic of obstructive apnea (green arrows); note
oxygen desaturation following apnea (blue arrow).
Nocturnal Hypoventilation
 Findings in adults:
o Sleep-related oxygen desaturation
o Increase in PaCO2 during sleep to > 45 mmHg, or < 45 mmHg but
increased relative to wake time (during normal sleep, PaCO2 increases 3–5
mmHg as a result of ↓minute ventilation)
 Diagnostic studies:
o Arterial PaCO2, end tidal CO2
OBESITY HYPOVENTILATION SYNDROME (OHS)

 Pathophysiology unclear (as most obese patients are unaffected):
o Decreased chest wall compliance related to obesity
o Elevated leptin levels that are associated with hypercapnia
o Increased airway resistance related to obesity
 OSA occurs in 90% of patients with OHS.
 Pulmonary hypertension is more common in OHS than in OSA.
 Diagnosis:
o Elevated awake PaCO2 > 45 mmHg
o Body mass index (BMI) > 30 kg/m2
 Treatment:
o CPAP ± oxygen is first-line therapy
o Bilevel PAP (BPAP) may be beneficial for persistent hypoxemia
22 / CHAPTER 1
CONGENITAL CENTRAL HYPOVENTILATION

 Failure of breathing control center resulting in lack of responsiveness to O2
and CO2 that leads to hypoxemia and hypercapnia during sleep
 Onset during infancy
 Associated conditions: Autonomic dysfunction, Hirschsprung disease, neural
crest tumors
 Pathophysiology unclear but associated with mutations in the PHOX2B gene
PAP THERAPY
Treatment of choice for patients with SDB.
Characteristics (Table 1-4)
Table 1-4. PAP Therapy

PAP Pressure Indication Cautions Alternatives
CPAP One constant OSA, CSA Caution in patients Oral appliance for
pressure with heart failure as mild-to-moderate
throughout may decrease OSA
inspiration and preload UA surgery
expiration
EPAP (Provent)
CPAP Similar to CPAP OSA, CSA Similar to CPAP Similar to CPAP

(C Flex) except allows
machine transiently reduced
pressure during
expiratory phase
BPAP Two distinct Patients who Does not improve Similar to CPAP
pressures, with a need very high compliance in
higher IPAP and CPAP pressures patients with
lower EPAP and have uncomplicated OSA
difficulty expiring No difference in
Patients with efficacy in patients
hypoventilation with uncomplicated
syndromes OSA
APAP Automatically and Treatment of Not recommended Similar to CPAP

constantly adjusts uncomplicated in OSA with HF,
PAP to maintain OSA, in the hypoventilation,
UA patency setting of a home
COPD
PAP titration
ASV Pressure support Complex sleep None Oxygen

(IPAP - EPAP) apnea CPAP
increases with Cheyne Stokes
hypoventilation and Oxygen + CPAP
breathing
decreases with
hyperventilation
PAP, positive airway pressure; CPAP, continuous positive airway pressure; OSA, obstructive sleep apnea;
CSA, central sleep apnea; UA, upper airway; EPAP, expiratory positive airway pressure; BPAP, bilevel positive
airway pressure; IPAP, inspiratory positive airway pressure; APAP, autotitrating positive airway pressure; HF,
heart failure; COPD, chronic obstructive pulmonary disease; ASV, adaptive servo-ventilation.
Benefits of PAP
 May reduce mortality

 Decrease in sleepiness
 Decrease or elimination of snoring
 Reduction in AHI
 Improvement in SaO2
 Improvement in blood pressure control
 Improved LVEF in patients with heart failure
 Improvement in pulmonary artery pressures
 Decrease in proinflammatory immune mediators (i.e., CRP, IL-6, TNFα)
 Reduction in healthcare consumption
NOCTURNAL ASTHMA
Nocturnal asthma symptoms indicate poorly controlled asthma and generally

occur in the early morning hours (3–6 am).
Mechanisms
Sleep-related changes are systemic changes that occur during sleep and may
precipitate nocturnal asthma symptoms.
 Autonomic nervous system:

o Increased vagus nerve tone and cholinergic activity
o Decreased serum epinephrine levels
 Lung capacity:
o Circadian variability in airflow occurs with decreased forced expiratory
volume in 1 second (FEV1), and peak flow rates with trough pulmonary
function occur between 3–6 am
 Inflammatory agents:
o Increased inflammatory agents during early morning hours, especially
circulating eosinophils
Diagnosis and Treatment

Flash Card Q18
 Decreased peak flow, symptomatic worsening, and increased rescue inhaler
use, as in regular asthma What is the most important
determinant of sleep-
 Treatment consists of optimizing asthma medical management. related hypoxemia in
COPD?
24 / CHAPTER 1
 Concurrent sleep apnea should be treated, and PAP can improve nocturnal
asthma symptoms, in this setting.
COPD
Obstructive lung disease related to tobacco use characterized by FEV1/FVC ratio

< 70% of predicted.
Causes of Sleep Disturbance and Frequent Arousals
 Nocturnal wheezing, coughing, dyspnea

 Increased work of breathing
 Hypoxemia
NOCTURNAL HYPOXEMIA IN COPD

Mechanism:
 Hypoventilation (REM sleep > NREM sleep > awake)
 Blunted respiratory center response to hypoxemia and hypercapnia (REM
sleep > NREM sleep > awake)
 Increased UA resistance
 Decreased functional residual capacity (FRC) during sleep and in supine
position (flattened diaphragms)
 Loss of accessory respiratory muscle use during REM sleep
Causes of sleep-related hypoxemia in COPD:

 ↓wake SaO2 and ↑wake PaCO2 are major predictors of hypoxemia during sleep
 Presence of concurrent OSA
 Increased severity of obstructive lung disease
 Elevated BMI
 Increased REM sleep duration
Diagnosis:
Key Fact  Polysomnogram should be used to diagnose sleep apnea in patients with
PSG, and not ambulatory
COPD.
sleep tests, should be used  Overnight oximetry to evaluate for nocturnal hypoxemia is indicated for
for the diagnosis of SDB in COPD patients with daytime hypercapnia, daytime hypoxemia, pulmonary
patients with COPD.
hypertension, concern for right heart failure, or symptoms suggestive of
nocturnal hypoxemia (i.e., fragmented sleep).
Flash Card A18
Hypoventilation
Treatment:
 Medical management per GOLD guidelines
 Indications for nocturnal oxygen therapy in patients with signs or symptoms
of nocturnal hypoxemia, such as cognitive impairment, insomnia, and
restlessness:
o PaO2 ≤ 55 mmHg, or
o SaO2 ≤ 88%, or
o Fall of PaO2 > 10 mmHg during sleep, or
o Fall of SaO2 > 5% during sleep
OVERLAP SYNDROME
Coexistence of OSA and COPD in the same patient.
Characteristics
 Prevalence of OSA in the COPD population is similar to that in the general

population
 In COPD patients with untreated OSA, there is an increased risk of death and
severe COPD exacerbation leading to hospitalization, compared to COPD
patients without OSA; this risk is reduced with CPAP therapy
NONRESPIRATORY SLEEP DISORDERS
HYPERSOMNIAS
Many conditions can result in excessive daytime somnolence or hypersomnia.

Hypersomnia can be primary or secondary. Primary hypersomnia refers to
hypersomnia originating in the CNS. Secondary hypersomnia occurs as a result of
another medical condition or a drug. The most common primary hypersomnias are
narcolepsy and IH.
26 / CHAPTER 1
Narcolepsy
A clinical syndrome characterized by excessive daytime sleepiness, cataplexy,
Key Fact sleep paralysis, and sleep hallucinations. Although all of these symptoms may be
The hallmark of narcolepsy present, hypersomnia is the hallmark of narcolepsy, whereas cataplexy is a very
is daytime sleepiness. If a specific finding. In contrast, sleep paralysis and sleep hallucinations are
patient is not sleepy, the
diagnosis of narcolepsy is nonspecific and can occur in a variety of sleep disorders and even in normal
highly unlikely. individuals.
EPIDEMIOLOGY—Relatively uncommon disorder with prevalence in the United

States of 1:2000. Patients typically present in the second or third decade of life.
The disorder is distributed equally among male and female populations, and tends
to persist throughout an individual’s life.
ETIOLOGY—Exact etiology remains unknown. The prevailing hypotheses are

listed below.
Orexin (also known as hypocretin):

 Neurotransmitter implicated in the pathogenesis of narcolepsy
 Involved in signal transduction within the lateral hypothalamus, and orexin-
mediated nerve conduction is associated with heightened alertness and
inhibition of REM sleep
 In autopsy studies, the brains of narcoleptic patients have gliosis in the lateral
hypothalamus, with loss of hypocretin containing neurons; narcoleptic
patients have low hypocretin levels in cerebrospinal fluid.
Genetic:
 Human leukocyte antigen DQB1*0602 has been shown to confer
susceptibility in some patients, though it is nonspecific and often also present
in patients without narcolepsy.
Autoimmune:
 In China, there is an increase in the incidence of narcolepsy during the spring,
suggesting a possible association between winter month viral illnesses and an
autoimmune response
 Narcoleptic patients also have higher levels of anti-streptolysin O titers,
further raising suspicion of an immune etiology
CLINICAL FEATURES
Excessive daytime sleepiness:
 Often severe and unremitting
 Some patients may experience some degree of sleepiness throughout their
lives, despite appropriate therapy
 Sleep and daytime naps are refreshing, and help to distinguish narcolepsy
from IH, a condition in which sleep is not refreshing
Cataplexy:
 Pathognomonic of narcolepsy in any individual who complains of excessive
daytime sleepiness
 Sudden loss of muscle tone, usually triggered by strong emotions
 Typically, patients will complain of muscle weakness during laughter; the
episode is usually very brief, and the patient remains completely conscious
Sleep paralysis:
 Occurs while the patient is waking from sleep
 Although the episodes are brief in duration, they can be terrifying to the
patient
 Sleep paralysis is common and nonspecific and can occur in normal Mnemonic
individuals, especially in the setting of sleep deprivation Sleep hallucinations—GO
to sleep. POp awake.
HypnaGOgic
Sleep hallucinations usually occur at sleep onset (hypnagogic) and less HypnoPOmpic
commonly on awakening (hypnopompic), and may be visual, auditory, or tactile.
Sleep fragmentation:
 Narcolepsy can be thought of as a discontinuity in wakefulness, with features
Mnemonic
of REM sleep intruding into wakefulness
Clinical features of
 Cataplexy, sleep paralysis, and sleep hallucinations represent these disruptions narcolepsy—Some
into wake periods Patients Can Fall Hard
Sleepiness
 Similarly, wakefulness also intrudes into sleep with frequent complaints of Paralysis
sleep fragmentation and poor sleep quality Cataplexy
Fragmentation of sleep
Hallucinations
DIAGNOSIS—Diagnosing narcolepsy often can be difficult. In evaluating a

patient with suspected narcolepsy, it is important to distinguish narcolepsy with or
without cataplexy, as management differs between the two groups.
Key Fact
The key to diagnosis is a thorough history, paying close attention to sleep An MSLT is suggestive of
patterns, daytime somnolence, and associated symptoms. narcolepsy if the mean
sleep latency is < 8
minutes and if there are at
An MSLT, consisting of 4–5 20-minute naps, is recommended for the vast least two SOREMPs.
majority of patients with suspected narcolepsy. A diagnosis of narcolepsy can be
made if the mean sleep latency is < 8 minutes for the sum of naps, and if there are
≥ two naps with REM sleep periods, termed sleep-onset REM periods (or
SOREMPs). Flash Card Q19
What clinical feature is
virtually pathognomonic for
narcolepsy?
28 / CHAPTER 1
The MSLT should be preceded by an all-night PSG to rule out other sleep
disorders such as OSA (though the two disorders can coexist). Notably, up to 20%
of the general population can have an abnormal MSLT. Furthermore, patients
with severe OSA or sleep deprivation can have a shortened mean sleep latency on
MSLT.
TREATMENT—The goals of treatment are to alleviate daytime sleepiness and eliminate

cataplexy, if present.
 Nonpharmacologic treatment can be very beneficial in managing daytime
sleepiness; patients should be encouraged to have a structured sleep schedule,
with consistent bedtimes and wake times; scheduled naps should be included
in the treatment regimen of most patients with narcolepsy.
 Pharmacologic treatment (Table 1-5):
o Excessive daytime sleepiness:
 Stimulants (i.e., modafinil and armodafinil) are considered first-line
therapy for narcolepsy
 Amphetamines (i.e., methylphenidate, dextroamphetamine) are
second-line therapies
o Cataplexy:
 Serotonin selective reuptake inhibitors (SSRIs; i.e., fluoxetine,
venlafaxine, clomipramine) for mild cases
 Sodium oxybate (gamma-hydroxybutyrate, GHB) is approved to treat
both cataplexy and excessive daytime sleepiness, and is the drug of
choice for difficult-to-manage cataplexy; though GHB has gained
notoriety as the “date rape” drug, the risk for abuse in narcoleptics is
extremely low
Table 1-5. Treatment of Narcolepsy

Clinical Feature Treatment
Hypersomnolence Stimulants ( modafinil, armodafinil)
Amphetamines (methylphenidate, dextroamphetamine)
Structured sleep schedule, scheduled naps
Cataplexy SSRIs (fluoxetine, venlafaxine, clomipramine)
Sodium oxybate
Sleep fragmentation Hypnotics (zolpidem, eszopiclone, etc)
Sodium oxybate
SSRIs, serotonin selective reuptake inhibitors
Flash Card A19

Cataplexy
Idiopathic hypersomnia (IH)
IH is a condition of CNS origin that causes excessive daytime sleepiness. The

Key Fact
etiology is unknown. Patients with IH often have severe daytime sleepiness,
despite sleeping through the night. The pattern of sleepiness can help to Sleep and naps are
refreshing to patients with
distinguish IH from narcolepsy (Table 1-6). Whereas sleep is generally refreshing narcolepsy. This is in
to narcoleptics, patients with IH remain sleepy after waking up from sleep or contrast to IH, in which
naps. sleep is not refreshing.
Epidemiology—Onset of symptoms is usually in the second to fourth decades of

life. Patients may report a remote history of head trauma. Approximately 10% of
patients will experience a spontaneous remission.
Diagnosis—Making the diagnosis requires a compatible history and an MSLT

revealing a mean sleep latency of < 8 minutes and no more than one SOREMP.
Treatment—Pharmacologic treatment with either modafinil or armodafinil.
Table 1-6. Differentiating Narcolepsy from IH
Feature Narcolepsy IH
Sleepiness Intermittent throughout the day Continuous throughout the

day
Naps/sleep Refreshing Not refreshing Mnemonic
Clinical features of RLS—
Cataplexy Often present but not required No
URGE
for diagnosis
Urge to move legs
Natural course Persists for a lifetime ~10% of cases remit Rest precipitates
spontaneously symptoms
Treatment Various treatments Modafinil or armodafinil Getting up and moving
alleviates symptoms
IH, idiopathic hypersomnia Evening and nighttime
worsening of symptoms
PERIODIC LIMB MOVEMENT DISORDERS (PLMD)
Restless legs syndrome (RLS) occurs during wakefulness, typically in the evening Flash Card Q20
or at night. It is characterized by uncomfortable sensations in the legs at rest What is the treatment of
which are relieved with movement. Approximately 85% of patients who have choice for IH?
RLS also have PLMs on PSG.
Flash Card Q21
PLMs are interval, stereotypic movements of the lower extremities during sleep.
Decreased levels of which
They are very common and can occur in normal individuals or in SDB. The neurotransmitter is
patient does not feel any noxious sensations, and the PLMs usually do not affect implicated in narcolepsy?
30 / CHAPTER 1
sleep. When PLMs do cause sleep disruption, however, the condition is termed
periodic limb movement disorder (PLMD).
Key Fact
Although RLS and PLMD
are similar, they are two
different conditions. RLS is Epidemiology
a clinical diagnosis and
does not require a PSG.
However, if a PSG is
About 3–15% of the general population suffers from RLS. It typically presents in
performed, PLMs usually the first to third decades of life, but diagnosis is usually delayed until the fifth to
are found. sixth decades. Women are at higher risk.
Etiology
Key Fact RLS is felt to be related to low CNS iron stores. Iron is a cofactor for tyrosine
RLS is related to low CNS hydroxylase, the rate-limiting step in dopamine synthesis. Low CNS iron is felt
iron stores, which disrupt to disrupt CNS dopamine levels, leading to RLS. Consequently, pharmacologic
dopamine synthesis. enhancement of dopamine levels relieves the condition. Iron supplements may
Dopamine agonists relieve
RLS. also alleviate symptoms but are not as effective as dopamine agonists.
Associations include:
 Iron deficiency anemia
 End stage renal disease
 Pregnancy
 Medications: Dopamine antagonists (antipsychotics), SSRIs, TCAs
Diagnosis
Diagnosis requires an appropriate clinical history for RLS. A diagnosis of PLMD

requires a PSG demonstrating frequent leg movements resulting in sleep
disruption in a patient with sleep complaints.
Treatment
PHARMACOLOGIC—First-line medications are dopamine agonists (i.e.,

pramipexole and ropinirole). A well-known side effect of both medications is an
increase in compulsive behaviors. Patients also may complain of augmentation,
which is an occurrence of RLS symptoms earlier in the day.
Flash Card A20
Orexin (hypocretin) Second-line medications include gabapentin, opioids, and carbidopa/levodopa.
Treatment in pregnant women can be challenging due to lack of medication safety

Flash Card A21 data for the developing fetus. Mild RLS can be managed with massage and warm
Modafinil or armodafinil
compresses. More severe cases may require short courses of opioids. Folic acid
and iron supplementation may also alleviate symptoms.
SECONDARY CAUSES—Treat iron deficiency anemia (i.e., iron replacement),

renal disease, etc.
PARASOMNIAS
A parasomnia is any abnormal or complex body movement during sleep. The Key Fact
most common parasomnias include sleep terrors, sleep walking, sleep talking, and Parasomnias typically
sleep eating. They occur primarily during non-REM sleep (NREM sleep). occur during NREM sleep
and thus are more often
present during the first half
of the night.
Night Terrors
 Usually present in early childhood

 The child often will sit up screaming or mumbling.
Mnemonic
 There is a significant autonomic response, and the child may appear to be in a
Clinical features of night
panic and thrashing. terrors—SCREAMS
 These dramatic episodes are often very distressing for parents/caregivers; the
Sit up screaming
child, however, is completely unaware and amnestic to the event. Confusion/disorientation
Respond poorly to parents
 Attempts to wake the child are unsuccessful and often result in increased Elevated arousal
confusion. Amnesia to event
Mumbling
Supportive care
TREATMENT—Supportive treatment unless the episodes are very frequent and
disruptive, in which case benzodiazepines or TCAs may be beneficial.
REM Sleep Behavior Disorder (RBD)

Occurs during REM sleep, thereby distinguishing it from the other parasomnias.
In RBD, the normal muscle atonia of REM sleep is lost. Thus, the patient is
susceptible to act out dreams. This puts the patient at risk for falls and self-harm,
and the bed partner is also susceptible to injury. It occurs primarily in older men
and in contrast to the other parasomnias, the patient is awakened easily and is
rapidly alert (Table 1-7).
Approximately 40% of patients with RBD will go on to develop neuro-

degenerative disorders, the most common being Parkinson disease.
Flash Card Q22
Patients with RBD are at
high risk of developing
which condition?
32 / CHAPTER 1
Table 1-7. Distinguishing Characteristics of RBD vs. Night Terrors

Feature RBD Night Terrors
Older male patients Children
Patients
Stage REM sleep NREM sleep (N3)
Acting out dreams Screaming and panic

Clinical features Easily aroused Cannot arouse
Memory of events present Amnesia to events
Treatment Clonazepam Supportive
Sequelae Parkinson disease in 40% Benign

REM, rapid eye movement; NREM, non-rapid eye movement
DIAGNOSIS—An appropriate history of dream enactment in the right clinical

setting makes the diagnosis. PSG demonstrating abnormal movements/lack of
muscle atonia during REM sleep supports the diagnosis.
TREATMENT—The goal of nonpharmacologic treatment is to ensure safety for

both the patient and bed partner. This may include putting the mattress on the
floor, sleeping in separate beds or rooms, etc.
Pharmacologic treatment with clonazepam is preferred. Melatonin can be used

for those who cannot tolerate clonazepam. Treatment of RBD has not been shown
to decrease the risk of developing Parkinson disease.
CIRCADIAN RHYTHM DISORDERS
Although there are variations (Figure 1-15), most human beings sleep at a similar
hour at night, sleep for a similar duration, and thus wake at similar times in the
morning. Taking into account age, cultural norms, and various other factors, we
can also observe different sleeping patterns i.e., “late sleepers,” “early risers,” etc.
Circadian and metabolic hypotheses are two leading hypotheses describing the
conformity of our sleep patterns.
In the circadian hypothesis, melatonin is released by the pineal gland and sets
the circadian rhythm. Melatonin promotes sleep and its production is inhibited by
light. During the day, natural sunlight inhibits melatonin production, which results
in wakefulness. With less sunlight at night, melatonin levels rise to promote sleep.
Flash Card A22 Therefore, the sleep–wake cycle is entrained by light.
Parkinson disease
Figure 1-15. Sleep phases.
The metabolic hypothesis describes sleep as a physiologic need, serving a

restorative function. The most active parts of the brain during wakefulness have
higher levels of adenosine, a breakdown product of adenosine triphosphate (ATP).
Adenosine levels return back to baseline after sleep, presumably replenishing
ATP.
A circadian rhythm disorder occurs when an individual’s sleep–wake pattern does

not conform to accepted norms. This misalignment results in insomnia, excessive
sleepiness, or both.
For all circadian rhythm disorders, the diagnosis is generally made by history.
Sleep diaries and actigraphy also can assist with the diagnosis.
Delayed Sleep Phase Syndrome

Delayed sleep phase is a persistent, involuntary sleep pattern in which the
individual falls asleep later and wakes up later. It is very common in adolescents
and young adults. This is not a behavioral trait, but rather a true delay in the
patient’s normal circadian rhythm. When this sleep pattern causes daytime
sleepiness or impairment, it is termed delayed sleep phase syndrome.
DIAGNOSIS—Often first diagnosed in high school, when children have to wake

up earlier. Typically parents and teachers will complain that the child is falling
asleep during the day.
34 / CHAPTER 1
TREATMENT—Consists of using bright light therapy in the morning to suppress

melatonin release. Exogenous melatonin can also be used at night to help promote
sleep. Chronotherapy refers to the use of light therapy to systematically shift the
patient’s delayed sleep phase to a more acceptable time.
Advanced Sleep Phase Syndrome (ASPS)

ASPS occurs most commonly in the elderly. The patient will often complain of
waking up in the middle of the night and the inability to fall back asleep. An
appropriate history will reveal that they are also going to sleep very early in the
day. Treatment is only warranted if the sleep–wake cycle is causing distress in the
patient’s life. Treatment includes bright-light therapy at night to prevent falling
asleep until a more acceptable time.
Shift Work Sleep Disorder
Because the normal circadian rhythm is not easily reversed, many individuals who
work night shifts find it difficult to stay awake at night. Alternatively, they find it
difficult to sleep or remain asleep during the day. This is termed shift work sleep
disorder (SWSD).
TREATMENT—If switching to a daytime job is not feasible, treatment includes

bright light while at the job to suppress melatonin. Both modafinil and
armodafinil are stimulants approved for the treatment of SWSD.
During the day, the patient should wear dark sunglasses while driving home. The
bedroom should be kept dark with conditions conducive to sleep.
Jet Lag Syndrome

A temporary misalignment between the individual’s internal circadian rhythm and
external time cues. This results in insomnia, daytime sleepiness, or both.
 East travel: Difficulty falling asleep

 West travel: Difficulty maintaining sleep
TREATMENT—Short-term use of sleep aids. Light exposure during the day.

Free Running Disorder
Also known as nonentrained or non-24-hour syndrome. Typically occurs in blind

patients. As mentioned, light entrains the normal circadian rhythm.
In about 40% of blind patients, the circadian rhythm is not entrained by light. The
result is a sleep–wake cycle which is progressively delayed each night.
TREATMENT—Exogenous melatonin at night to promote sleep. Other

environmental cues such as alarm clocks or meal times also can be used to entrain
the circadian rhythm.
INSOMNIA
Inability to initiate or maintain sleep despite adequate time and opportunity to do

so. It can also be described as poor sleep quality or chronically nonrestorative
sleep. The diagnosis can only be made if the sleep limitation causes impairment or
distress to the individual’s life.
There are seven types of insomnia:

 Psychophysiologic insomnia (primary or chronic insomnia)
 Acute insomnia (adjustment or short-term insomnia)
 Inadequate sleep hygiene
 Paradoxical insomnia (also called sleep-state misperception)
 Idiopathic insomnia (also called lifelong insomnia)
 Insomnia associated with a medical condition (or psychiatric disorder,
neurologic disease, sleep disorder, medication, or drug use)
 Unspecified insomnia
Flash Card Q23

EPIDEMIOLOGY—Depending on the study population, the prevalence of
What inhibits melatonin
insomnia varies widely from about 20–70% of individuals. The prevalence production?
increases with age, and women complain of insomnia 50% more often than men.
DIAGNOSIS—Patients typically present complaining of the inability to sleep, Flash Card Q24
daytime sleepiness, or both. Good history taking will reveal limited sleep, daytime A 32-year-old woman
reports sleeping only 3
sleepiness or impairment, and the inability to sleep when time permits. The hours per night for many
history also should eliminate other medical conditions or drugs as the source of years. She reports good
insomnia. A formal sleep study generally is not required unless other sleep sleep quality, denying any
daytime impairment,
disorders are also suspected. sleepiness, or distress.
Does this patient have
insomnia?
36 / CHAPTER 1
Key Fact TREATMENT—Insomnia of short duration (i.e., acute insomnia) can be treated
effectively with sedatives/hypnotics. The gold standard treatment of insomnia of
The gold standard
treatment of insomnia of long duration, such as psychophysiologic insomnia, is CBT. Sleep hygiene should
long duration is CBT. be encouraged in both groups but is insufficient as a primary therapy for insomnia.
CBT is a systematic approach that addresses cognitive stress that exacerbates

insomnia, and the maladaptive behaviors that perpetuate further sleep
disturbances. When administered by experienced personnel, CBT is nearly
equivalent in efficacy to pharmacologic treatment in the short term and has better
sustained efficacy than pharmacologic sleep aids in the long term.
Pharmacologic treatment includes various hypnotics used for the treatment of

short-duration insomnia. These include zolpidem, temazepam, eszopiclone,
ramelteon, zaleplon, and doxepin (Table 1-8).
Table 1-8. Pharmacologic Sleep Aids

Mechanism of Duration of
Drug Indications Side effects
Action Action
Zolpidem Selective GABA 4–5 hours Sleep initiation Complex behaviors
agonist insomnia (a during sleep such
controlled release as sleep eating,
formulation is used depression,
for both sleep headaches, fatigue
initiation and
maintenance
insomnia)
Temazepam Benzodiazepine 6–8 hours Short-term (7–10 Respiratory
days) treatment of depression, fatigue,
sleep initiation dependency/abuse,
insomnia dizziness
Eszopiclone Selective GABA 6–8 hours Sleep initiation and Depression,
agonist sleep maintenance headaches,
insomnia dizziness,
unpleasant metallic
taste
Ramelteon Melatonin 4–5 hours Sleep initiation Depression,
receptor agonist insomnia headaches, fatigue
Zaleplon Selective GABA 1–2 hours Sleep initiation Depression,
agonist insomnia headaches,
Flash Card A23 dizziness, amnesia
Light Doxepin SNRI 3–5 hours Sleep maintenance Fatigue, nausea,
insomnia depression
GABA, gamma-aminobutyric acid; SNRI, serotonin–norepinephrine reuptake inhibitor
Flash Card A24
No because the patient is
not experiencing
impairment or distress as a
result of the short sleep
duration.
NEUROMUSCULAR DISORDERS AND DISEASES

OF THE CHEST WALL
NEUROMUSCULAR DISORDERS
Neuromuscular weakness of the diaphragm and accessory muscles of respiration

can impair the ability of the lungs to ventilate. Bulbar weakness can affect
muscles that aid in swallowing and clearance of secretions. Thus, neuromuscular
disorders can result in respiratory failure due to inability to ventilate the lungs or
inability to protect the airway or both (Table 1-9).
The fundamentals of respiratory management in neuromuscular disorders involve:

 Noninvasive positive pressure ventilation (NIPPV) to decrease work of
breathing
 Clinical assessment of bulbar function, cough, and clearance of secretions
 Decision making surrounding initiation of mechanical ventilation (MV) when
NIPPV is no longer working or not an option.
The diaphragm is the main muscle of respiration. Contraction moves the

diaphragm downward and results in negative pressure ventilation of the lungs.
The accessory muscles of respiration include:
 Abdominal muscles
 Intercostal muscles
 Sternocleidomastoids
 Scalene muscles
Respiratory muscle strength is assessed most often by measurement of negative

inspiratory force (NIF), which is also known as the maximum inspiratory pressure
(MIP), and the vital capacity (VC). Airway clearance by cough can be assessed
using the maximum expiratory pressure (MEP).
Principles of NIPPV
Noninvasive ventilation plays a major role in the respiratory management of most
neuromuscular disorders. Although evidence is lacking to address mode selection,
most clinicians utilize bilevel positive airway pressure (BPAP).
There are two pressures the clinician sets in BPAP:

 Inspiratory airway pressure (IPAP)
38 / CHAPTER 1
 Expiratory airway pressure (EPAP)
The EPAP splints the airway, and the IPAP helps ventilation by providing
pressure support. Typical starting pressures are:
 IPAP, 10–12 cm H2O
 EPAP, 5–6 cm H2O
Pressures can be adjusted based on the clinical situation. In many cases, overnight
PSG is used to help adjust BPAP pressures.
Minute ventilation decreases in all people during sleep due to a decrease in tidal
Key Fact volume. This physiologic decrease in ventilation can have especially deleterious
Nocturnal NIPPV is the effects in patients with neuromuscular disorders. Furthermore, the accessory
cornerstone of respiratory
management in patients
muscles of respiration are paralyzed normally during REM sleep, which
with neuromuscular compounds respiratory insufficiency at night. Therefore, nocturnal NIPPV is the
disorders. cornerstone of respiratory management in patients with neuromuscular disorders.
Table 1-9. Comparison of Neuromuscular Disorders

Disorder Distinguishing Features of Supportive Treatment
Features Weakness Respiratory
Care
GBS Neuropathic pain Ascending NIPPV or MV Plasmapheresis
Dysautonomia paralysis or IVIG
Myasthenia Ptosis is classic Often descending NIPPV or MV Pyridostigmine
gravis and worse as day during crises Immunosuppress
progresses ion
Plasmapheresis
or IVIG
Thymectomy
Lambert–Eaton Associated with Improves with NIPPV early IVIG
SCLC repetitive muscle MV late
use
ALS Cognitive Signs of upper NIPPV or MV Riluzole
impairment and and lower motor
frontotemporal neuron
dementia involvement
Botulism GI symptoms Bilateral CNS MV, often Antitoxin
involvement prolonged
ALS, amyotrophic lateral sclerosis; CNS, central nervous system; GBS, Guillain-Barré syndrome; ; IVIG;
intravenous immunoglobulin; MV, mechanical ventilation; NIPPV, noninvasive positive pressure ventilation;
SCLC, small cell lung cancer
Guillain-Barré Syndrome (GBS)

Acute inflammatory demyelinating polyneuropathy.
CHARACTERISTICS
 Classically an ascending paralysis starting in the lower extremities Key Fact
 Progressive symmetric muscle weakness
Features that distinguish
 Can involve only lower extremities, or can ascend to involve all muscles GBS from other
(including respiratory and bulbar muscles) neuromuscular disorders
include neuropathic pain,
 Often preceded by an infection, classically Campylobacter jejuni enteritis autonomic dysfunction, and
 40–50% have neuropathic pain diminished deep tendon
 10–30% will advance to ventilator-dependent respiratory failure reflexes on physical exam.
 Dysautonomia occurs in up to 70% of patients (urinary retention, blood
pressure fluctuations, diaphoresis)
DIAGNOSIS
 Clinical diagnosis:
o Symmetric muscle weakness
o Diminished deep tendon reflexes
 Confirmed with lumbar puncture (elevated protein, normal white blood cell
count) and neurophysiologic testing:
o EMG
o Nerve conduction studies (NCS)
TREATMENT/MANAGEMENT
 Respiratory failure can occur rapidly
 Initial monitoring should include frequent measurements of VC and NIF
Factors associated with impending respiratory failure requiring MV are:

 VC < 20 mL/kg
 Reduction in VC > 30%
 MIP less negative than -30 cm H2O, MEP < 40 cm H2O
 Rapid disease progression
 Bulbar dysfunction
 Bilateral facial muscle weakness
 Dysautonomia
Weaning from MV should be guided by VC, NIF, and rapid shallow breathing
index.
Plasmapheresis or intravenous immunoglobulin (IVIG) is most effective within 7

days of symptom onset, but benefits are seen even after 30 days. Treatment results
in earlier recovery from MV and more complete recovery of muscle strength. Flash Card Q25
What are the only disease-
There is no role for steroids, and they may slow recovery of muscle strength. modifying treatment
options for GBS?
40 / CHAPTER 1
Chronic Inflammatory Demyelinating Polyneuropathy

(CIDP)
When GBS progresses past 8 weeks, it is termed chronic inflammatory
demyelinating polyneuropathy. The course of CIDP can be slowly progressive or
relapsing/remitting.
As opposed to GBS, the neuromuscular weakness of CIDP responds to

glucocorticoids. Other treatments include plasmapheresis and IVIG.
Amyotrophic Lateral Sclerosis (ALS)
Progressive neurodegenerative disorder of unknown etiology. Invariably fatal due

to progressive respiratory muscle weakness.
CLINICAL FEATURES—Signs of upper and lower motor neuron involvement.

 Upper: Slowness of movement, hyperreflexia, spasticity
 Lower: Weakness, atrophy, fasciculations
Key Fact  Respiratory involvement includes bulbar, diaphragm, and accessory muscles.
Signs of upper and lower Asymmetric limb weakness is the most common presentation of ALS (80%).
motor neuron involvement  There is also cognitive involvement in a majority of patients; up to 15% have
are very characteristic of overt frontotemporal dementia.
ALS. Spasticity, atrophy,
and fasciculations will help  The course is progressive, rather than relapsing/remitting, with a median
distinguish ALS from other survival of 3–5 years.
neuromuscular disorders.
DIAGNOSIS—Mainly by history and physical; EMG and NCS can be helpful also.
TREATMENT
 Comprehensive supportive care by a multidisciplinary team is necessary
throughout the course of ALS; respiratory management is central to
supportive care
 NIPPV increases quality of life in patients with ALS; the optimal patient is
one who has more nocturnal symptoms and minimal bulbar weakness
(allowing for adequate handling of secretions); consider use in patients with:
o Nocturnal hypoxemia or orthopnea
o VC < 50% predicted
o MIP < -60 cm H2O
 NIPPV is not an alternative to MV; all patients will progress to respiratory
failure requiring MV; patients who wish to continue treatment require
tracheostomy and MV support; fewer than 10% of ALS patients choose
invasive ventilation.
Flash Card A25  Pharmacologic treatment with riluzole is the only drug treatment shown to
Plasmapheresis or IVIG increase survival.
Myasthenia Gravis
An autoimmune disorder involving the neuromuscular junction (NMJ)
characterized by ocular, bulbar, limb, and respiratory muscle weakness. The
weakness tends to worsen as the day progresses.
PATHOPHYSIOLOGY—Autoimmune process secondary to antibody-mediated T-

cell destruction of acetylcholine receptors on the postsynaptic membrane of the
NMJ.
DIAGNOSIS—Myasthenia gravis is a clinical diagnosis, but tests can be ordered

for confirmation: Key Fact
 Edrophonium test: Classically, the muscle
o A positive edrophonium test will display improved muscle strength when weakness of myasthenia
administered to patients with myasthenia gravis. gravis worsens as the day
progresses.
o Sensitivity is 80–90%, but specificity is low.
 Antibody testing: Serologic testing for autoantibodies to acetylcholine
receptor or the receptor-associated protein, muscle specific tyrosine kinase,
can be performed.
 Neurophysiologic studies: Repetitive nerve stimulation results in a decrease in
action potential.
TREATMENT—Rarely, patients may simply need symptomatic treatment. Most,

however, will need immunosuppression at some point in their course.
 Pyridostigmine provides short-term symptomatic relief.

 Glucocorticoids, azathioprine, cyclosporine, rituximab, cyclophosphamide can
be used for maintenance therapy.
 All myasthenia gravis patients with a thymoma should undergo thymectomy.
 Myasthenia crises should be treated aggressively with:
o Plasmapheresis or IVIG, or
o High-dose steroids or alternative immunosuppressive therapy, or
o Close monitoring of respiratory status with consideration for elective
intubation if VC < 20 mL/kg or if MIP is worse than -30 cm H2O
Lambert–Eaton Syndrome
A disorder of the NMJ that results in symmetric proximal muscle weakness. The
syndrome is strongly associated with small cell lung cancer and can occur at any Key Fact
point in the course of small cell lung cancer. Lambert–Eaton syndrome
is strongly associated with
In contrast to myasthenia gravis, repetitive nerve stimulation results in increased small cell lung cancer.
amplitude of action potentials. This is mirrored clinically by increasing muscle
strength with mild-to-moderate muscle activity. IVIG is the most common
42 / CHAPTER 1
therapy utilized and treatment of the underlying malignancy can also improve
symptoms of weakness.
Respiratory failure due to muscle weakness tends to occurs late in the course.
Mild respiratory muscle weakness in the earlier stages of the disease can be
managed with NIPPV.
Botulism
A potentially fatal paralytic illness, caused by a neurotoxin produced by
Clostridium botulinum.
CHARACTERISTICS
 Classically described as a symmetric, descending weakness.
 Exposure can result from ingestion of the preformed toxin or from wounds
(most commonly “black tar” injection drug users).
 Upon entry into the body via a wound or the gastrointestinal (GI) tract, the
toxin spreads hematogenously and irreversibly binds to the presynaptic
membrane of cholinergic synapses.
 Symptoms can vary in severity from mild nonspecific GI symptoms to severe
illness and death.
TREATMENT
 MV: Intubation and MV should be considered for those with worsening
bulbar symptoms, VC < 30% of predicted, or rapidly declining pulmonary
function; a long course of MV should be expected in these patients, often
several months.
 Equine serum heptavalent botulism antitoxin (Pharmacologic treatment) is
available through the CDC and should be given in severe illness.
Critical Illness Myopathy (CIM) and Critical Illness

Polyneuropathy (CIP)
CIM occurs in patients who have been in the intensive care unit (ICU) for more
than several days. Both glucocorticoids and neuromuscular blockade are risk
factors for developing CIM.
 Most common presentation of muscle weakness is flaccid quadriparesis

 May also manifest as failure to wean from MV
 The myopathy is characterized by loss of myosin in muscle fibers
 It is reversible over weeks to months
 Treatment is mostly supportive, and aimed at minimizing glucocorticoids
along with aggressive physical rehabilitation
CIP is associated with sepsis. The axonal injury to nerves is thought to be a

manifestation of the systemic inflammatory response.
 Occurs in patients who have been in the ICU for weeks.
 Characterized by limb muscle weakness, diminished deep tendon reflexes,
distal sensory loss.
 Muscle strength recovers over several months in mild-to-moderate cases.
Organophosphate Poisoning
Poisoning occurs most commonly from pesticide exposure. The classic
presentation of acute toxicity is that of cholinergic excess: salivation, lacrimation,
Mnemonic
urination, defecation, emesis, bronchospasm, and bradycardia.
Symptoms of
organophosphate
A subset of patients will develop a distinct neuromuscular weakness, sometimes poisoning—SLUDGE
termed intermediate syndrome. It is characterized by proximal muscle weakness, Salivation
respiratory insufficiency, neck flexion weakness, and decreased deep tendon Lacrimation
reflexes. Urination
Defecation
GI upset
Patients will recover spontaneously, but often require supportive MV for several Emesis
weeks.
DISEASES OF THE CHEST WALL
Pectus Excavatum
Anterior chest wall deformity consisting of a concave depression (Figure 1-16.)
Figure 1-16. Pectus excavatum.

(Reproduced from Wikimedia Commons, CC BY-SA 3.0.)
44 / CHAPTER 1
CLINICAL CHARACTERISTICS—Most commonly occurs in men. Usually

asymptomatic but may be associated with dyspnea on exertion, exercise limitation,
local chest pain, and anxiety regarding the appearance of the defect.
The deformity occasionally can limit right ventricular filling, thus limiting cardiac
output. Cardiopulmonary exercise testing may show cardiovascular limitation and
decreased aerobic capacity. Pulmonary function tests (PFTs) can be normal or
show mild restriction.
TREATMENT—Corrective surgery is available and is performed predominantly

for cosmetic reasons. Surgery may or may not improve exercise capacity. PFTs
generally remain unchanged after surgery.
Pectus Carinatum
 Protrusion of sternum from anterior chest wall (Figure 1-17).

 Less common than pectus excavatum
 Male subjects more commonly affected
 Usually discovered during growth spurt of puberty
 Associated conditions include congenital heart disease and scoliosis;
pulmonary function typically normal in the absence of concurrent scoliosis
 Growing children and teens can be treated with customized braces, whereas
adults require surgery for definitive treatment.
 As with pectus excavatum, benefits of surgery are mostly cosmetic
Figure 1-17. Pectus carinatum.

(Reproduced courtesy of Wikimedia Commons, CC BY-SA 3.0.)
Kyphoscoliosis
 Kyphosis refers to the normal anterior angulation of the thoracic spine.

 Scoliosis refers to an abnormal lateral curvature of the spine.
 Excess kyphosis or scoliosis can result in rib traction.
 Cobb angle measures the severity of hyperkyphosis or scoliosis (Figure 1-18);
the degree of spinal deformity is related to the degree of respiratory
compromise; ventilation-perfusion mismatch occurs when the scoliosis angle
is > 65 degrees.
CLINICAL CHARACTERISTICS—Begins in childhood and typically is idiopathic. Key Fact

 Both aging and progressive curvature add to decreased chest wall compliance, PFT findings in severe
kyphoscoliosis include low
which increases work of breathing. The patient compensates with low tidal TLC and VC, with
volume (VT) and increased respiratory rate to minimize work of breathing. preserved RV. This results
in an increased RV:TLC
However, this can increase dead-space ventilation, and the resultant alveolar ratio.
hypoventilation results in hypercapnia.
 PFT: Restrictive pattern with low TLC and VC but preserved RV (RV:TLC
ratio increased) and FRC usually decreased due to reduced chest wall
compliance.
 Low chest wall compliance results in lower VT and subsequent atelectasis.
The atelectasis then contributes to decreased lung compliance.
Figure 1-18. Cobb angle measurement of dextroscoliosis.

(Reproduced from Skoliose-Info-Forum.de, GNU Free Documentation License 1.2)
46 / CHAPTER 1
TREATMENT
 Supportive care in mild cases
 Treat other comorbid lung conditions.
 Surgery: Probably of limited value in adults but can be considered in select
children
 Pulmonary rehabilitation
 NIPPV, particularly at night to reduce work of breathing and prevent
hypoventilation
 Persistent hypercapnia despite NIPPV is a predictor of mortality
Obesity
The World Health Organization categorizes obesity as follows:

 Class I (moderate obesity): BMI 30–35
 Class II (severe obesity): BMI 35–40
 Class III (very severe obesity): BMI > 40
Severely obese patients tend to breathe at lower tidal volumes. Both chest wall
and lung compliance often are reduced. As weight increases, progressive airway
narrowing at low volumes can result in intrinsic positive end-expiratory pressure
and air trapping. Atelectasis occurs at the lung bases.
Mild hypoxia can be seen in the awake, upright patient. Sleep and supine
positions both independently worsen hypoxia. Obese patients tend to be eucapnic
except the subset of patients with OHS.
PFT findings in severely obese patients:

 TLC, VC, and FRC are decreased
 FEV1 and FVC are decreased with a preserved FEV1:FVC ratio
 Residual volume (RV) usually is spared (RV:total lung capacity [TLC] ratio is
elevated) except in rare severe cases
 DLCO is elevated when adjusted for alveolar volume
CRITICAL CARE / 47
2 Critical Care
Anthony F. Arredondo, MD, Stephanie Young Clough, MD, Nandita R. Nadig MD,
& Diana H. Yu, MD
NON-LUNG CRITICAL CARE
SHOCK
Shock is end-organ hypoperfusion as a result of circulatory failure. Mechanisms

of circulatory failure:
 Compromised vascular tone (distributive shock)
 Low cardiac output (CO; cardiogenic or obstructive shock)
 Low plasma volume in blood vessels (hypovolemic shock)
Diagnosis
See Table 2-1.
Table 2-1. Diagnosis of Shock
Clinical Findings Measured Parameters

Hypotension (systemic arterial hypotension) Systolic blood pressure < 90 mm Hg or
mean arterial pressure < 65−70 mm Hg
Tachycardia
Hypoperfusion Urine output < 0.5 mL/kg/h
Cold and clammy skin; cyanosis
Obtundation, disorientation, confusion
Elevated lactate level
Mechanisms
See Table 2-2.
48 / CHAPTER 2
Table 2-2. Mechanisms of Shock
Type of Shock Pathophysiology Differential

Distributive Decreased systemic vascular Severe sepsis
resistance Anaphylaxis
Spinal cord injury (neurogenic)
Cardiogenic Decreased CO due to “pump Acute myocardial infarction (right
failure” ventricular/left ventricular failure)
End-stage cardiomyopathy
Severe valvular disease
Myocarditis
Cardiac arrhythmias
Obstructive Decreased CO due to external Pulmonary embolism
forces that change ventricular size Cardiac tamponade
and function
Tension pneumothorax
Tension hydrothorax/pleural effusion
a
Abdominal compartment syndrome
Hypovolemic Decreased CO due to loss of Acute hemorrhage
plasma or blood volume that Dehydration from vomiting, diarrhea,
reduces venous return sweating, or insensible losses
CO, cardiac output.
a
Leads to decreased venous return and cardiac output.
Evaluation and Treatment

Three general principles in the evaluation and treatment of shock:
 Volume resuscitation
 Vasoactive support
 Ventilatory support when needed
Rapid recognition of the type of shock can often be achieved with a bedside
echocardiogram. However, shock is often multifactorial in a given patient.
ECHOCARDIOGRAPHIC FINDINGS
Distributive shock:
 Normal cardiac chambers and contractility
 In sepsis, ventricles often dilated to maintain stroke volume
Hypovolemic shock:
 Small cardiac chambers and normal to high contractility
Cardiogenic shock:
 Large ventricles and poor contractility with ventricular failure
 Wall motion abnormalities with ischemia
 Mechanical defects: Valvulopathy, ventricular septal defect, ventricular free
wall rupture
CRITICAL CARE / 49
Obstructive shock:
 Tamponade
o Pericardial effusion with small right and left ventricles
o Dilated inferior vena cava (IVC)
 Pulmonary embolism with right ventricular failure
VENTILATORY SUPPORT—Supplemental oxygen: Avoid hyperoxia.

Mechanical ventilation: Invasive and noninvasive
 Invasive mechanical ventilation:
o Used for severe dyspnea, hypoxemia, or acidemia
o Allows patient to rest, increasing oxygen delivery and reducing oxygen
demand
o Decreases left ventricular afterload
 Noninvasive mechanical ventilation:
o Two types: Continuous positive airway pressure (CPAP) and bilevel
positive airway pressure
o Used cautiously because failure can lead to rapid cardiopulmonary arrest
VOLUME RESUSCITATION—Objective is to improve CO by optimizing preload.

Volume responsiveness:
 Accurate assessment of volume responsiveness can help to identify patients
who will benefit from volume therapy. Even in septic shock, only ~ 50% of
patients are considered volume responsive.
 Defined as > 15% increase in CO after fluid challenge.
 Many surrogates are available for CO, including stroke volume variation,
pulse pressure variation, aortic blood flow, and IVC variation.
Dynamic assessment of volume responsiveness:

 Variation in intrathoracic pressure during respiratory cycle determines
intravascular depletion and fluid responsiveness.
 Pulse pressure variation, stroke volume variation, aortic blood flow, and IVC
variation are measurements determined by changes in intrathoracic pressure
during the respiratory cycle:
o Limitations of Pulse pressure variation, stroke volume variation, and IVC
variation: Patient must be mechanically ventilated while receiving high
tidal volumes (8–12 mL/kg) with no spontaneous respiratory effort, no
arrhythmias, and normal right ventricular function.
 Passive leg raise:
o Induced changes in stroke volume or CO with passive leg raise predict
fluid responsiveness, regardless of mechanical ventilation, underlying
arrhythmias or technique of measurement.
o CO is measured with bioreactance, pulse contour analysis, or esophageal
Doppler.
 Fluid challenge:
50 / CHAPTER 2
o Intravenous fluids (crystalloids) to infuse 300–500 mL over 20–30

minutes
o Positive test result: Increased arterial pressure, increased urine output, or
Key Fact
decreased heart rate
Pulmonary artery
catheterization can help to
diagnose and guide Static assessment of volume responsiveness:
treatment of shock, but has  Static measurements, such as central venous pressure, pulmonary capillary
not been shown to improve
survival or any other
wedge pressure, and left ventricular end-diastolic area index, are unreliable.
patient-related outcomes.
VASOACTIVE DRUGS—Vasoconstrictors are indicated if the patient remains
hypotensive despite adequate fluid resuscitation. Initiation of vasoactive therapy
during fluid resuscitation may be indicated in severe hypotension with rapid
weaning if hypovolemic shock is the primary cause (Table 2-3).
Adrenergic agonists (e.g., norepinephrine):

 First-line vasoconstrictor because of the rapid onset of action, high potency,
and short half-life
o -adrenergic agonist: Increases blood flow as a result of increased heart
rate and contractility; increases risk of myocardial ischemia.
o -adrenergic agonist: Increases vascular tone and blood pressure; can also
decrease CO and impair blood flow to hepatosplanchnic region.
Inotropic agents:
 Dobutamine is considered first-line therapy for increasing CO.
o Predominantly has -adrenergic properties.
o Blood pressure can decrease when patients are not well volume
resuscitated.
o Peripheral vasoconstriction can occur at high doses, given -agonist
properties.
 Phosphodiesterase type III inhibitors (milrinone and enoximone) decrease the
metabolism of cyclic adenosine monophosphate and combine inotropic and
vasodilating properties.
o Long half-lives (4–6 hours).
o Milrinone is known to cause hypotension via vasodilation.
CRITICAL CARE / 51
Table 2-3. Vasoconstrictors

Cardiovascular
Vasoconstrictor Receptors Effects Indication Notes
Norepinephrine Mostly - Increases First-line Arrhythmias,
(NE) adrenergic; vascular tone and vasoconstrictor bradycardia, Key Fact
modest - maintains CO for most cases of peripheral
adrenergic effects shock, regardless ischemia The VASST Study
of cause comparing norepinephrine
with norepinephrine +
Epinephrine (E) Mostly 1- and 2- Inotropic with - Alternative or Arrhythmias
vasopressin in septic shock
adrenergic effects adrenergic effects add-on therapy to Reduction in gut showed no overall
at low doses NE
Vasoconstriction blood flow difference in survival
Increasing - with -adrenergic between the treatment
Increases lactate
adrenergic effects effects groups. The
at high doses norepinephrine +
vasopressin group had
Dopamine (DA) Mostly - No protective Symptomatic More decreased norepinephrine
adrenergic effects renal effects at bradycardia arrhythmogenic requirement. Mortality
at low doses very low doses (< than NE benefit was seen in the
Not considered
3 μg/kg/min) subgroup of patients with
Mostly - an alternative May be
adrenergic effects Inotropic with 1 first-line associated with less severe septic shock
at high doses, but effects (5–10 vasoconstrictor to increased 28-day receiving both
weak μg/kg/min) NE mortality in norepinephrine+
cardiogenic shock vasopressin when the
Vasoconstriction norepinephrine dose was <
with alpha effects May be 15 μg/min.
(> 10 μg/kg/min) associated with
higher death rates
in patients with
septic shock
Phenylephrine Almost purely - Increases Rarely indicated Used in
(PE) adrenergic effects vascular tone as monotherapy neurologic
disorders, Key Fact
Can reduce CO May be used
anesthesia- In a 2012 meta-analysis,
and limit blood when other
induced shock norepinephrine was
flow to gut agents are
contraindicated Side effects: compared with dopamine
for septic shock. The
OR Reflex
results suggested an
bradycardia
When shock increased risk of death for
persists despite > dopamine compared with
2 agents norepinephrine.
Vasopressin (V) V1 receptors Direct Not indicated as VASST Study:
(vascular smooth vasoconstriction a single, NE vs. NE + V
muscle) +/- inotropic or titratable, No overall Key Fact
chronotropic vasoconstrictor mortality benefit
V2 receptors
effects Phenylephrine can reduce
(renal collecting Fixed dose: 0.03 NE + V group:
duct system) or 0.04 units/min Large decrease CO and induce reflex
in NE bradycardia.
Higher doses
requirement
associated with
cardiac and Subgroup: NE <
peripheral 15 μg/min + V
ischemia associated
mortality benefit
CO, cardiac output.
52 / CHAPTER 2
MECHANICAL SUPPORT—Intra-aortic balloon counterpulsation:

 Increases mean arterial pressure (MAP), reduces left ventricular afterload, and
Key Fact
increases coronary blood flow.
Intra-aortic balloon  Offers no survival benefit in patients with cardiogenic shock.
counterpulsation has not
shown a mortality benefit in  Difficult to use in arrhythmias and contraindicated in significant aortic
patients with cardiogenic regurgitation.
shock.
Venoarterial extracorporeal membrane oxygenation:

 Used as temporary lifesaving measure in patients with reversible cardiogenic
Key Fact shock or as a bridge to heart transplantation.
Norepinephrine is the first-
line vasoconstrictor for GOALS OF THERAPY—MAP goals:
most forms of shock.  Baseline healthy patient
o MAP goal ≥ 65–70 mm Hg.
o Purely hypovolemic patients may tolerate MAP < 65 mm Hg.
 Baseline uncontrolled hypertension
o May require higher MAP goal.
Perform volume resuscitation and vasoactive support:

 Monitoring: Mental status, skin appearance, temperature, and urine output
Perform lifesaving measures:

 Surgery, pericardial drainage, revascularization for acute myocardial
infarction, etc.
Correct hypoxemia and severe anemia:

 Target hemoglobin 7 g/dL for euvolemic patients who are not actively
bleeding
Optimize CO: After hypoxemia and anemia are corrected, CO is the main
determinant of oxygen delivery.
 The goal is to achieve adequate CO to maintain tissue perfusion.
 Mixed venous oxygen saturation (SVO2):
o Integrates oxygen supply and demand; requires pulmonary artery catheter.
o Used to interpret CO.
o Typically decreased in low-flow states (cardiogenic shock) or anemia.
o Normal to high in distributive shock (normal, 60–80%).
 Central venous oxygen saturation (SCVO2) for septic shock:
o Used as a surrogate for SVO2; measured with central venous catheter.
o Reflects O2 saturation of venous blood from upper half of the body.
o Normally, SCVO2 is slightly < SVO2.
o In the critically ill, SCVO2 is often > SVO2.
o A recent article brought into question the efficacy and mortality benefit of
early goal-directed therapy in sepsis using target SCVO2 ≥ 70% in the first 6
hours.
CRITICAL CARE / 53
Blood lactate level:

 Lactate ≥ 3 mmol/L: Targeting decrease ≥ 20% associated with reduced in- Key Fact
hospital mortality rate. SVO2 is typically decreased
 Reduced lactate clearance seen with impaired liver function. in low flow states
(cardiogenic shock) or
anemia, but is normal or
high in distributive shock.
TYPES OF SHOCK
Distributive Shock
Distributive shock is characterized by decreased systemic vascular resistance with
a high CO state.
SEPTIC SHOCK—Most common type of shock. It is sepsis with circulatory

failure despite adequate volume resuscitation.
Mnemonic
Principles of treatment: Causes of distributive
shock—SLAM D ANT
 Control of source of infection with rapid administration of intravenous (IV)
antibiotics and removal of infectious source Systemic inflammatory
response syndrome
 Respiratory support (pancreatitis, burns,
 Early goal-directed therapy: Treatment algorithm focused on resuscitation in trauma)
Liver failure
the first 6 hours: Anaphylaxis
o Volume resuscitation with goal central venous pressure 8–12 mm Hg and Myxedema coma
urine output ≥ 0.5 mL/kg/h Drugs or toxins (insect
o Vasoconstrictors started if MAP ≥ 65 not reached after fluid resuscitation bites, transfusion
o Goal SCVO2 ≥ 70% or SVO2 ≥ 65% reactions, heavy metal
poisoning)
o Blood transfusions: Goal hematocrit > 30%; controversial because packed
Adrenal insufficiency
red blood cell transfusions have potential harm in critical illness Neurogenic shock (central
o Dobutamine: Potential therapy if MAP and hematocrit are at goal and low nervous system or spinal
central/mixed venous oxygen saturation persists cord injury)
Toxic shock syndrome
 Early interventions in sepsis, not necessarily specifics of early goal-directed
therapy is a possible cause of improved outcomes
Cardiogenic Shock
Caused by cardiac pump failure characterized as decreased CO and increased
systemic vascular resistance.
TYPES—General categories of pump failure:
 Cardiomyopathies
 Arrhythmias
 Mechanical abnormalities
54 / CHAPTER 2
Cardiomyopathies:
 Post-myocardial infarction ventricular failure:
o Left ventricular failure: Most common cause of post-myocardial infarction
shock; occurs when infarction involves > 40% of left ventricular
myocardium.
o Right ventricular failure: Acute inferior myocardial infarction and
hypotension raises suspicion for right ventricular infarct, with the right
coronary artery the usual culprit. Right-sided electrocardiogram (ECG) is
obtained if suspected.
o 30–50% of inferior myocardial infarctions involve the right ventricle.
o SHOCK Trial: Emergent revascularization (percutaneous coronary
intervention or coronary artery bypass grafting) for post-myocardial
infarction cardiogenic shock improved mortality at 6 and 12 months
compared with stabilization with medical management and intra-aortic
balloon counterpulsation.
 Nonischemic cardiomyopathy (alcohol, drugs, viral)
Key Fact  Takotsubo cardiomyopathy:
Left ventricular failure is o Stress-induced cardiomyopathy or transient apical ballooning syndrome
the most common cause of o Related to extreme emotional or physical stress (~ 70% of cases)
post-myocardial infarction
shock. o Hyperdynamic cardiac base and akinetic cardiac apex on ultrasound
o Coronary angiography without stenosis to explain cardiomyopathy
Arrhythmias:
 Atrial fibrillation and flutter decrease CO by interrupting coordinated atrial
filling of the ventricles.
 Ventricular tachycardia: Ventricular fibrillation abolishes CO.
Key Fact  Bradyarrhythmias and complete heart block
Hypotension and inferior
myocardial infarction Mechanical abnormalities:
should raise suspicion for  Valvular defects:
right ventricular infarct with
associated cardiogenic o Rupture of papillary muscle or chordae tendineae
shock, especially if o Aortic insufficiency from retrograde aortic dissection into aortic valve ring
hypotension occurs after o Critical aortic stenosis
nitroglycerin or
vasodilators. Obtain right-  Ventricular septal defects or rupture:
sided ECG. ST elevation > o Post-myocardial infarction bimodal occurrence at 24 hours and 3–5 days
1 mm in lead V4R or V5R is o Pansystolic heart murmur, parasternal thrill, left-to-right intracardiac shunt
specific for right ventricular
infarct. o Treatment: Intra-aortic balloon counterpulsation, inotropes, afterload
reduction, percutaneous occluding device with definitive surgical repair
within 48 hours
CRITICAL CARE / 55
Obstructive Shock
Usually the result of extracardiac forces that lead to cardiogenic shock.
CAUSES
 Massive pulmonary embolism: Treat with thrombolytics.
 Tension pneumothorax: Treat with needle decompression and/or chest tube.
 Cardiac tamponade: Treat with pericardiocentesis.
 Severe constrictive pericarditis: Treat underlying cause; often requires
surgical intervention.
Hypovolemic Shock
 Two types: Hemorrhage and fluid losses.

 The mainstay of therapy is volume resuscitation with blood, crystalloids, or
colloids.
Multiple Organ Dysfunction Syndrome
In the critically ill patient, multiple organ dysfunction syndrome represents

progressive organ dysfunction in which homeostasis cannot be obtained without
intervention. It is the most severe entity in the spectrum of systemic inflammatory
response syndrome/sepsis.
PRIMARY AND SECONDARY CAUSES

 Primary:
o Organ dysfunction directly attributed to a specific insult
o Example: Renal failure from rhabdomyolysis
 Secondary:
o Organ dysfunction attributed to the host’s response to the insult
o Example: Acute respiratory distress syndrome (ARDS) as a result of
pancreatitis
CARDIOVASCULAR DISORDERS
Advanced Cardiac Life Support/Arrhythmias

In the intensive care setting, arrhythmias commonly occur in the setting of
metabolic disturbances, myocardial infarction, sepsis, and respiratory failure.
56 / CHAPTER 2
BRADYARRHYTHMIAS AND TACHYARRHYTHMIAS IN THE INTENSIVE

CARE UNIT (ICU)
Bradyarrhythmias:
 Sinus bradycardia: Rhythm arising from sinus node at a rate < 60 beats/min.
Treatment is indicated only for symptomatic severe cases and involves
temporary transvenous or transcutaneous cardiac pacing, isoproterenol,
dopamine, epinephrine, or atropine.
 Atrioventricular block (Figure 2-1): Disturbance of normal conduction
between the atria and ventricles.
 Bradycardia after acute myocardial infarction: Caused by disruption of
blood flow to sinus node, atrioventricular node, His-Purkinje system, or
increased vagal tone (seen in inferior myocardial infarction). Treatment
recommended in patients with hemodynamic instability, sinus pauses ≥ 3
seconds, or heart rate < 40 beats/min.
1st degree AV block
2nd degree AV block:
Mobitz type I
(Wenckebach)
Mobitz type II
3rd degree AV block

(complete)
Figure 2-1. Types of atrioventricular blocks.

(Reproduced, with permission, from USMLE-Rx.com.)
CRITICAL CARE / 57
Tachyarrhythmias: Caused by abnormal automaticity, re-entry, or triggered

automaticity.
 Regular narrow QRS complex tachyarrhythmias:
o Supraventricular tachycardia (Figure 2-2): Caused by re-entrant
mechanism.
 Treat with adenosine 6–12 mg intravenously.
 If not converted, provide rate control with  blocker or calcium
channel blocker (nondihydropyridine).
Figure 2-2. Supraventricular tachycardia.
 Irregular narrow QRS complex tachyarrhythmias:

o Atrial fibrillation and atrial flutter (Figure 2-3):
 Provide rate control with  blocker or calcium channel blocker.
 If hypotensive, consider loading with digoxin or amiodarone.
 Perform cardioversion if hemodynamically unstable.
Figure 2-3. (A) Atrial fibrillation. (B) Atrial flutter.

58 / CHAPTER 2
 Regular wide QRS complex tachyarrhythmias:

o Supraventricular tachycardia with aberrancy and monomorphic ventricular
tachycardia (Figure 2-4):
 Manage clinically stable patient with elective synchronized
cardioversion or antiarrhythmics: Adenosine, procainamide,
amiodarone, or sotalol.
Figure 2-4. (A) Supraventricular tachycardia with aberrancy. (B)

Monomorphic ventricular tachycardia.
 Irregular wide QRS complex tachyarrhythmias.

o Polymorphic ventricular tachycardia/Torsade de pointes (Figure 2-5A and
B):
 Manage with emergent defibrillation and magnesium sulfate.
o Ventricular fibrillation (Figure 2-5C):
 Manage with emergent defibrillation.
 If persistent after defibrillation and cardiopulmonary resuscitation
(CPR), give epinephrine (1 mg IV every 3–5 minutes) with option of
vasopressin (40 units IV) as substitution for first or second dose of
epinephrine.
 No survival benefit is seen with antiarrhythmic drugs.
CRITICAL CARE / 59
Figure 2-5. (A) Polymorphic ventricular tachycardia. (B) Torsade de pointes. (C)
Ventricular fibrillation.
Hypertensive Emergency
Key Fact
Severe hypertension is defined as systolic blood pressure > 180 mm Hg and/or Common secondary
diastolic blood pressure > 120 mm Hg. Hypertensive emergency is severe causes of hypertensive
hypertension in the presence of end-organ damage. emergencies: (1) renal
crisis from collagen
vascular disease, (2)
END-ORGAN DAMAGE severe hypertension after
 Neurologic: Papilledema, hypertensive encephalopathy, intracerebral renal transplantation, (3)
pheochromocytoma, (4)
hemorrhage, subarachnoid hemorrhage cocaine, (5) rebound
 Cardiac: Acute aortic dissection, acute myocardial infarction, acute left hypertension, and (6)
ventricular failure preeclampsia/eclampsia.
 Renal: Acute kidney injury

60 / CHAPTER 2
TREATMENT
 Acute aortic dissection: Goal systolic blood pressure < 120 mm Hg. Initial
management is  blockers (esmolol, labetalol) followed by vasodilators
(nicardipine, nitroprusside).
 Acute hemorrhagic stroke: Goal systolic blood pressure < 140 mm Hg.
Reduce expansion of hematoma with nicardipine or labetalol.
 Acute ischemic stroke: Goal systolic blood pressure < 220 mm Hg with
permissive hypertension. Manage with nicardipine or labetalol.
 Hypertensive encephalopathy: Goal is initial decrease in MAP of 20–25%.
Manage with labetalol, nicardipine, or nitroprusside.
 Pre-eclampsia: Goal is diastolic blood pressure < 110 mm Hg. Manage with
magnesium, IV labetalol, nicardipine, or hydralazine. Definitive management
is delivery.
Cardiac Tamponade
Pericardial effusion may develop acutely or gradually and can be complicated by
tamponade. Cardiac tamponade is a clinical diagnosis.
 Acute cardiac tamponade can occur as a result of rupture of the heart or aorta
secondary to trauma or procedural complications.
 Subacute cardiac tamponade can occur with underlying malignancy,
infections, uremia, or pericarditis.
CLINICAL PRESENTATION
 Signs and symptoms: Dyspnea, chest pain, syncope/presyncope, hypotension,
elevated jugular venous pressure, pulsus paradoxus, pericardial rub, and
edema
 ECG: Sinus tachycardia, low QRS voltage, and electrical alternans
 Chest x-ray: Possible enlarged cardiac silhouette
 Transthoracic echocardiogram: Moderate to large pericardial effusion,
diastolic collapse of right atrium/ventricle, and dilated IVC
TREATMENT
Both pericardiocentesis and surgical drainage are effective for relief of symptoms
associated with hemodynamic compromise.
 Catheter pericardiocentesis is often preferred over surgical drainage because
of lower complication and mortality rates.
 Surgical drainage has the advantage of accessibility for pericardial biopsy.
CRITICAL CARE / 61
GASTROINTESTINAL DISORDERS
Acute Gastrointestinal Hemorrhage
UPPER GASTROINTESTINAL BLEED—Peptic ulcer disease accounts for ~ 50%

of patients with upper gastrointestinal bleed. Esophageal/gastric variceal bleeds
account for 5–10%.
Evaluation: Emphasis on stabilization and appropriate triage

Key Fact
 Urea/creatinine ratio ≥ 100 may suggest an upper gastrointestinal source. Early decompression with
 Nasogastric lavage can help to identify a potential upper gastrointestinal transjugular intrahepatic
portosystemic shunt within
source and may indicate high-risk lesions if positive. 24–48 hours in high-risk
patients results in reduction
Treatment: Hemodynamic resuscitation, risk stratification for rebleed or mortality, of treatment failure and
mortality rate in severe
pre-endoscopic medications, and endoscopy variceal bleeds
 Recent data suggest that a restrictive transfusion threshold (transfuse when

hemoglobin < 7 g/dL) in upper gastrointestinal bleed has a significantly lower
mortality rate (6% versus 9%) at 45 days compared with a liberal transfusion Key Fact
threshold (transfuse when hemoglobin < 9 g/dL ).
Indications for stress ulcer
 High-risk clinical criteria: prophylaxis in critically ill
o Age > 65 years, comorbidities, anemia, melena, fresh blood on rectal patients: mechanical
examination, hematemesis, bloody nasogastric aspirate, and transfusion ventilation > 48 hours,
coagulopathy, and two or
requirements more of the following:
 Proton pump inhibitors neutralize gastric acid, leading to stabilization of clots sepsis, ICU admission > 1
week, occult
and promotion of hemostasis. gastrointestinal bleed > 6
 Vasoactive medications, such as vasopressin, somatostatin, and their analogs days, steroid therapy.
(octreotide), decrease portal blood flow in acute variceal hemorrhage.
 Prophylactic antibiotics (e.g., quinolone or cephalosporin) in cirrhotic patients
result in reduction of infectious complications and risk of recurrent esophageal Mnemonic
variceal bleeding. Scoring system for
 Esophagogastroduodenoscopy: mortality in upper
gastrointestinal bleed:
o Specific findings are associated with subsequent risk of recurrent bleed: AIMS65
 Clean ulcer base (3–5%)
 Flat spot (7–10%) Albumin < 3.0 g/dL
INR > 1.5
 Adherent clot (25–30%) Altered Mental status
 Nonbleeding visible vessel (50%) Systolic blood pressure <
 Active arterial bleed (90%) 90 mm Hg
Age > 65 years
o High-risk endoscopic stigmata are treated with cauterization with bipolar
probes or mechanical therapy with hemostatic clips, with or without
epinephrine.
o Band ligation is preferred over sclerotherapy for esophageal varices.
62 / CHAPTER 2
 Balloon tamponade is reserved as a temporizing measure for severe

hemorrhage with hemodynamic instability.
 Transjugular intrahepatic portosystemic shunt is reserved for unsuccessful
endoscopic therapy or recurrent variceal bleed.
 Prophylactic intubation before endoscopy has not been shown to reduce the
risk of aspiration pneumonia.
LOWER GASTROINTESTINAL BLEED—The most common etiology is

diverticulosis. Bleeding from angiodysplasia or inflammatory bowel disease is
more common in young patients. Malignancy or mesenteric ischemia is more
common in older patients.
Treatment:
 Colonoscopy is diagnostic and can be therapeutic.
 Hemoclips, epinephrine injections, or bipolar coagulation are used for
bleeding vessels.
 Persistent bleeding without identifiable lesions may require further diagnostic
modalities such as radionuclide scanning (detects bleeding at rates 0.1–0.5
mL/min) or mesenteric angiography (detects bleeding at rates > 0.5 mL/min).
 Surgical intervention (colectomy) may be warranted in patients with rapid
deterioration despite resuscitation.
Acute Hepatic Failure

Severe acute injury to the liver parenchyma related to exposure to hepatotoxins
(e.g., alcohol, acetaminophen) or infectious agents (e.g., viruses) with
encephalopathy and coagulopathy (INR > 1.5) in the absence of preexisting liver
disease.
ACUTE LIVER FAILURE IN THE ICU—Given the poor prognosis, patients with
acute liver failure should be managed in an ICU at a facility with the capability
for liver transplantation.
Etiology:
 Drugs and toxins: Acetaminophen, alcohol, Amanita phalloides (mushroom
poisoning), idiosyncratic drug reactions, toxin exposure
 Infections: Hepatitis viruses (B, C, D, E), cytomegalovirus, Epstein-Barr virus
 Hypoperfusion: Ischemic hepatitis, sepsis with shock liver, veno-occlusive
disease, HELLP syndrome, hemophagocytic lymphohistiocytosis
 Genetic: Wilson disease, autoimmune hepatitis
 Infiltration: Malignant infiltration of tumor, typically metastatic
CRITICAL CARE / 63
Clinical presentation:
 Hepatic encephalopathy:
o Grade I: Mild confusion, slurred speech
o Grade II: Lethargy, moderate confusion
o Grade III: Incoherence, somnolence
o Grade IV: Coma
 Cerebral edema: Increased intracranial pressure (ICP), which can cause
hypertension, bradycardia, respiratory depression, and seizures
Diagnosis:
 Laboratory findings: Elevated aminotransferases (with elevated bilirubin and
alkaline phosphatase levels), prolonged prothrombin time (INR ≥ 1.5)
 Imaging: Abdominal ultrasound, computed tomography (CT), magnetic
resonance imaging (MRI)/magnetic resonance venography (MRV), liver
biopsy in select cases
Treatment:
 Supportive care: IV fluids, infection surveillance, and stress ulcer prophylaxis
 Treatment of underlying cause:
o N-acetylcysteine for acetaminophen toxicity and other causes of acute
liver failure
o Antiviral therapy for hepatitis B infection
o Transjugular intrahepatic portosystemic shunt placement or surgical
decompression for Budd-Chiari syndrome
 Liver transplantation:
o Decision hinges on probability of spontaneous recovery, with significant
emphasis on degree of encephalopathy. Key Fact
o King’s College Criteria are widely used for referral for liver
Hyperventilation for
transplantation: increased ICP is only
 Acetaminophen-induced liver failure: Arterial pH < 7.3, regardless of useful if there is a planned
grade of encephalopathy, or grade III/IV encephalopathy, with both intervention within 6–24
hours because it may
prothrombin time > 100 seconds and serum creatinine > 3.4 mg/dL eventually result in
 Other causes of liver failure: prothrombin time > 100 or any three of rebound elevation of ICP.
the following criteria (age < 10 or > 40 years; unfavorable etiology
[i.e., non-A or B viral hepatitis, drug reaction, or Wilson disease];
prothrombin time > 50 seconds; serum bilirubin > 18 mg/dL; > 7 days
of jaundice before encephalopathy develops)
Management of complications:
 Hepatic encephalopathy: Lactulose is controversial, with no difference in
severity of encephalopathy or overall outcome
 Cerebral edema with possible sequelae of elevated ICP, cerebral ischemia, and
brain stem herniation
64 / CHAPTER 2
o Treatment of elevated ICP: Hyperosmotic agents (e.g., mannitol),

hyperventilation (PaCO2 25–30 mm Hg) for cerebrovascular
vasoconstriction, barbiturates (pentobarbital)
Key Fact
Cerebral edema is the  Seizures: Phenytoin is recommended over benzodiazepines, given the poor
most common cause of liver clearance of sedatives.
death in acute liver failure.
 Respiratory failure: Positive end-expiratory pressure (PEEP) should be used
with caution because it can exacerbate cerebral edema.
Acute Pancreatitis
Gallstones and chronic alcohol abuse account for ~ 75% of cases of acute
pancreatitis in the U.S.
Mnemonic ACUTE PANCREATITIS IN THE ICU—Overall mortality rate in all hospitalized

Etiology of acute patients with acute pancreatitis is ~ 10% (range, 2–22%). Those with severe acute
pancreatitis—I GET pancreatitis requiring ICU care have a mortality rate of up to 30%.
SMASHED
Idiopathic Poor prognostic factors and complications:
Gallstones  Elevated C-reactive protein level
Ethanol
Trauma
 Respiratory complications of hypoxemia, atelectasis, pleural effusion,
pneumonia, or ARDS
Steroids
Mumps  Multiple organ system failure
Autoimmune (PAN)  Pancreatic pseudocysts with necrosis and abscesses
Scorpion stings
Hyperlipidemia.
 Splenic vein thrombosis with development of gastric varices
Hypercalcemia  Gastrointestinal bleed as a result of stress ulcers
ERCP
Drugs (including azathioprine
and diuretics)
Treatment:
 Aggressive fluid resuscitation and pain control
 Nutrition:
o Mild pancreatitis: Oral feeding is initiated within 24–48 hours after onset.
o Moderate to severe pancreatitis: Enteral feeding within 24–48 hours is
preferred. Parenteral nutrition is initiated if enteral feeding is not tolerated.
 Antibiotic therapy for necrotizing pancreatitis, with consideration of
interventional drainage or surgical debridement
Nutrition
Sepsis, trauma, and other causes of critical illness result in a hypercatabolic state,
with subsequent immune dysfunction, skeletal muscle atrophy, peripheral and
central weakness, and nutritional deficiencies.
CRITICAL CARE / 65
NUTRITIONAL SUPPORT IN THE ICU
Indications:
 In patients without contraindications to enteral nutrition, early enteral feeding
(within 48 hours of ICU admission) is recommended.
 In patients who are adequately nourished, early parenteral nutrition (within 1
week of ICU admission) is avoided, given increased risks of infection and
prolonged mechanical ventilation.
 In patients who are malnourished and have contraindications to enteral
nutrition, parenteral nutrition is considered. However, the timeline for
initiation of parenteral nutrition remains uncertain, given the associated risks.
Contraindications:
 Contraindications to enteral nutrition:
o Hemodynamic instability in underresuscitated patients who may be
predisposed to bowel ischemia
o Bowel obstruction, bowel ischemia, ileus, upper gastrointestinal bleed,
intractable vomiting, or diarrhea
 Contraindications to parenteral nutrition:
o Hyperosmolality, hypervolemia
o Severe hyperglycemia or electrolyte abnormalities
Potential complications: Key Fact

 Overfeeding syndrome:
Enteral feeds are often
o Excessive (particularly parenteral) nutritional support can result in held in ICU patients with a
azotemia from excess protein, hypertriglyceridemia, metabolic acidosis, large gastric residual
hyperglycemia, hepatic steatosis, and increased CO2 production. volume. However, two
recent trials showed that
 Refeeding syndrome: gastric residual volume up
o Patients with chronic malnourishment who receive excessive nutritional to 500 mL could be safely
support can have hypokalemia, hypophosphatemia, and hypomagnesemia tolerated and not
measuring gastric residual
as a result of rapid intracellular shifts, with subsequent respiratory failure, volume improved caloric
heart failure, or arrhythmias. intake without increasing
the incidence of
pneumonia.
Glucose control in the ICU: Aggressive glucose control (80–108 mg/dL)
associated with increased mortality rate compared with glucose control target ≤
180 mg/dL.
66 / CHAPTER 2
RENAL DISEASE
Acute Renal Failure

ACUTE KIDNEY INJURY IN THE ICU—Independent risk factors for hospital
mortality:
 Vasopressors
 Mechanical ventilation
 Septic shock
 Cardiogenic shock
 Hepatorenal syndrome
The need for continuous renal replacement therapy for acute kidney injury is also
associated with a high in-hospital mortality rate.
Continuous renal replacement therapy:

 Better tolerated in hemodynamically unstable patients, but does not improve
mortality or renal recovery compared with intermittent hemodialysis.
ELECTROLYTE ABNORMALITIES—See Table 2-4.

CRITICAL CARE / 67
Table 2-4. Electrolyte Derangement

Common Disease
Electrolyte Hypo/Hyper Clinical Manifestations Associations Management Notes
Potassium Hypokalemia Muscle weakness that can progress to Metabolic alkalosis, diabetic Potassium replacement
respiratory failure and colonic pseudo- ketoacidosis
obstruction
Hyperkalemia Muscle weakness, peaked-T waves, Succinylcholine, trauma, If electrocardiogram changes, treatment with
shortened QT progressing to PR/QRS rhabdomyolysis, tumor lysis, calcium
widening and asystole acute kidney injury
Sodium bicarbonate ineffective in dialysis-
dependent patients
Sodium Hyponatremia When acute, can cause cerebral Diuretics, heart failure, cirrhosis, Hypertonic saline solution for severe cases (≤
edema, altered mental status, seizures, SIADH, low solute intake 10 mEq correction over 24 h)
and death
Hypernatremia Polydipsia, muscle weakness, Dehydration, diabetes insipidus Repletion of free water deficit
confusion, coma
Calcium Hypocalcemia Prolonged QT, tetany, seizures, s/p parathyroidectomy, Calcium chloride or gluconate
hypotension, papilledema thyroidectomy, head and neck
Avoid calcium and dialyze if
surgery
hyperphosphatemia is the cause (tumor lysis,
rhabdomyolysis, acute kidney injury)
Hypercalcemia Constipation, fatigue, polyuria, Hyperparathyroidism, IV fluids + furosemide, calcitonin,
polydipsia, anorexia, nausea, mood malignancy, milk alkali syndrome bisphosphonates, hemodialysis for severe
changes cases
Phosphate Hypophosphatemia Respiratory muscle weakness Alcoholism, anorexia nervosa, IV phosphate
refeeding
Magnesium Hypomagnesemia Muscle weakness, ↓ deep tendon Hypokalemia and hypocalcemia IV magnesium
reflexes, nausea, flushing, bradycardia,
tetany, polymorphic ventricular
tachycardia with prolonged QT
Hypermagnesemia Muscle weakness, ↓deep tendon Exogenous intake, renal failure, IV calcium or hemodialysis
reflexes, flushing, bradycardia, heart treatment of eclampsia
block, and paralysis
IV, intravenous; SIADH, syndrome of inappropriate antidiuretic hormone secretion; s/p, status post
68 / CHAPTER 2
ENDOCRINE EMERGENCIES
See Table 2-5.
Table 2-5. Endocrine Emergencies

Disease Clinical Findings Risk Factors or Clues Laboratory Findings Treatment
DKA/HHS DKA: Hyperglycemia, AGMA, Precipitating event: Infection DKA: AGMA, ketonemia Treatment of underlying cause
ketonemia most common Hyperglycemia Intravenous fluids + insulin
HHS: No ketoacidosis Total body potassium deficit Hourly glucose checks to avoid drops >
Elevated lipase and amylase 100 mg/dL/h
Repletion of electrolytes (K and
phosphorus)
Thyroid Tachycardia, congestive heart Thyroid or nonthyroid surgery Suppressed thyroid- Mortality rate 10–30%
storm failure, arrhythmia, Trauma stimulating hormone Treatment of precipitating factors (i.e.,
hyperpyrexia, altered Infection Elevated T3 and free T4 infection)
mentation, liver failure, Leukocytosis, hyperglycemia Treatment of heart failure
vomiting, diarrhea Acute iodine load
Parturition Control of fever
Ophthalmopathy
Propranolol
Lid lag
Thionamide (propylthiouracil or
Tremor methimazole)
Warm/moist skin Hydrocortisone
Thyroidectomy if patient cannot take
thionamide
Myxedema Central nervous system: Thyroidectomy scar Low T4 Mortality rate 40%
coma Psychosis, confusion, History of iodine-131 therapy Thyroid-stimulating hormone Combined T4 and T3 IV
lethargy, coma, seizure Hypothyroidism level depends on etiology Hydrocortisone
Hypothermia, hypoventilation, (primary vs. secondary) Rewarming and supportive care
bradycardia, low CO Hyponatremia, hypoglycemia
Adrenal Shock, nausea, vomiting, Undiagnosed primary adrenal Hypoglycemia: Rare for acute Intravenous fluids and correction of
crisis abdominal pain, weakness, insufficiency + serious illness adrenal insufficiency electrolytes
fatigue, lethargy, fever, Bilateral adrenal infarction or Chronic adrenal insufficiency: Adrenocorticotropic hormone and
confusion, or coma hemorrhage Hyponatremia, hyperkalemia, cortisol obtained without delay in
Pituitary infarction hypercalcemia, azotemia treatment
Abrupt withdrawal of Dexamethasone in patient without prior
glucocorticoids diagnosis; otherwise hydrocortisone
Treatment of concurrent infections
DKA, diabetic ketoacidosis; HHS, hyperosmolar hyperglycemic state; AGMA, anion gap metabolic acidosis; CO, cardiac output; IV, intravenous
CRITICAL CARE / 69
HEMATOLOGY AND ONCOLOGY
One third of patients admitted to the ICU have baseline hemoglobin < 10 g/dL. Key Fact
Most patients have anemia by ICU day 3. Anemia and red blood cell transfusions Initial treatment of
are associated with worse ICU outcomes. myxedema coma requires
an IV bolus of T4 and T3.
IV hydrocortisone is also
given for potential
concurrent adrenal
Anemia and Red Blood Cell Transfusion in the ICU insufficiency.
THREE PRIMARY ETIOLOGIES

Underproduction of red blood cells:
Key Fact
 Anemia of chronic disease
 Iron deficiency Initial management of
thyroid storm includes
 Chronic kidney disease administration of
propranolol, thionamide
 Toxin-related causes (drugs, chemotherapy) (propylthiouracil or
 Myelodysplastic syndrome methimazole), and
hydrocortisone.
Intravascular red blood cell destruction:
 Microangiopathic hemolytic anemia
 Immune-related hemolysis
 Hemoglobinopathy
Extravascular red blood cell loss: Active blood loss
RED BLOOD CELL TRANSFUSION GUIDELINE—Transfusion Requirement in

Critical Care Study: Prospective randomized trial of restrictive transfusion
practice (transfuse if hemoglobin < 7 g/dL) versus liberal transfusion practice
(transfuse if hemoglobin < 10 g/dL) showed no difference in 30-day mortality rate
between the two groups.
Platelet/Plasma/Cryoprecipitate Transfusion in the ICU

PLATELET TRANSFUSION
 Indications include acute bleed and prevention of bleed before procedures in
the setting of thrombocytopenia.
 Each unit can increase platelet count by 5,000–10,000/μL, and each pheresis
unit (containing platelets from 1 unit of whole blood) can increase platelet
count by 30,000–60,000/μL.
FRESH-FROZEN PLASMA TRANSFUSION

Indications:
 Factor deficiency
 Reversal of warfarin therapy
70 / CHAPTER 2
 Thrombotic thrombocytopenic purpura

 Coagulopathy in an acute bleed
No consistent clinical evidence of benefit is seen for prophylactic or therapeutic

use.
CRYOPRECIPITATE TRANSFUSION—Indications include hypofibrinogenemia

secondary to dilution or consumptive coagulopathy.
Contains fibrinogen, fibronectin, von Willebrand factor, factor XIII, and factor
VIII.
FACTOR VII INFUSION—Increased risk of thromboembolic complications has

been shown in studies of recombinant activated factor VII for life-threatening
bleeds.
Indicated for treatment of bleeding in patients with hemophilia A or B with

inhibiting antibodies to coagulation factor VIII or IX.
Indications expanded to include management of other life-threatening bleeds:

 Severe traumatic injury
 Bleeding during surgery and transplantation
 Intracerebral hemorrhage and bleeds in the setting of anticoagulation
Transfusion-Related Acute Lung Injury (TRALI)

Clinical diagnosis that occurs when patients have acute hypoxemic respiratory
failure during or within 6 hours after blood product transfusion. It occurs with all
types of blood products, but the risk is highest with plasma-containing blood
products (i.e., fresh-frozen plasma).
DIAGNOSTIC CRITERIA—All must be present.

 Acute onset (during or within 6 hours of transfusion)
 Hypoxemia (PaO2/FiO2 < 300 or SpO2 < 90% on room air)
 Bilateral infiltrates on chest radiograph without evidence of systemic fluid
overload or pre-existing risk factors for ARDS
TRANSFUSION-ASSOCIATED CIRCULATORY OVERLOAD (TACO)—Another

cause of transfusion-related respiratory insufficiency with clinical features similar
to those of TRALI.
CRITICAL CARE / 71
TRALI versus TACO:

 TRALI is more likely to be associated with fever, hypotension, and
pulmonary infiltrates and less likely to respond to diuresis.
 TACO is more likely to be associated with volume overload.
TREATMENT—Immediate discontinuation of transfusion followed by supportive

care (respiratory/hemodynamic support; diuresis; corticosteroids not indicated)
Hemostatic Failure and Disorders

HEPARIN-INDUCED THROMBOCYTOPENIA—Clinical syndrome characterized
by thrombocytopenia and arterial-venous thrombosis resulting from an immune
response, with antibody formation to endogenous platelet factor 4 complexed to
heparin
Definition:
 Type I: Mild transient thrombocytopenia occurs within the first 2 days of
heparin exposure, with gradual normalization of platelet level. Non-immune-
mediated mechanism has a direct effect of heparin on platelets.
 Type II: Immune-mediated mechanism results in thrombosis and
thrombocytopenia.
Key Fact
Treatment: Anticoagulation is
 Immediate discontinuation of heparin followed by initiation of nonheparin recommended for 4–6
anticoagulant/direct thrombin inhibitor: weeks for patients with
heparin-induced
o Argatroban is first-line therapy. Bivalirudin is approved for percutaneous thrombocytopenia without
coronary intervention in patients at increased risk for heparin-induced thrombosis and for at least
thrombocytopenia. 3 months for patients with
thrombosis. Vitamin K
o Fondaparinux is used clinically, but data are limited. antagonists (warfarin) are
avoided because they can
exacerbate the
prothrombotic state.
THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP)-HEMOLYTIC
UREMIC SYNDROME (HUS)—TTP and HUS form a thrombotic
microangiopathy that results from abnormal activation and intravascular
aggregation of platelets accompanied by intravascular hemolysis. Key Fact
Most cases of TTP-HUS
Diagnosis: are idiopathic, but known
 Microangiopathic hemolytic anemia and thrombocytopenia associations include bloody
diarrhea caused by Shiga
 Other clinical features: Acute kidney injury, neurologic symptoms, fever toxin-producing bacteria
 Reduced ADAMTS13 (von Willebrand factor–cleaving protease) activity (e.g., Escherichia coli
0157:H7), pregnancy in
patients with congenital or
Treatment: Mortality rate before the use of plasma exchange was ~ 90%. acquired ADAMTS13
 Immediate plasma exchange until resolution of thrombocytopenia and deficiency, and drugs
hemolysis (evaluated by lactate dehydrogenase level) (chemotherapy,
immunosuppression).
72 / CHAPTER 2
 Adjunctive glucocorticoid therapy if no evidence of drug-induced etiology or

acute kidney injury in patients with persistent thrombocytopenia despite
plasma exchange
 Rituximab (anti-CD20 antibody), with or without cyclophosphamide, in
refractory or recurrent TTP-HUS
 No benefit from plasma exchange in thrombotic microangiopathy associated
with chemotherapy or stem cell transplantation
DISSEMINATED INTRAVASCULAR COAGULATION—Systemic activation of

the clotting cascade, fibrin deposition throughout the microvasculature,
fibrinolysis, and consumption of clotting factors result in systemic thrombosis and
hemorrhage.
Clinical features:
 Bleeding
 Acute kidney injury
 Hepatic dysfunction
 Pulmonary hemorrhage
 Central nervous system involvement (coma, delirium, focal neurologic deficits)
Diagnosis:
 History of sepsis, trauma, or malignancy
 Moderate to severe thrombocytopenia or microangiopathic hemolytic anemia
 Laboratory evidence of increased thrombin generation (decreased fibrinogen,
prolonged prothrombin time/activated partial thromboplastin time) and
increased fibrinolysis (elevated D-dimer; Table 2-6)
Treatment:
 Platelet and fresh-frozen plasma transfusion
 Protein C concentrate in patients with homozygous or acquired protein C
deficiency
Table 2-6. Features of Coagulopathy

Prothrombin Time,
Activated Partial
Coagulopathy Thromboplastin Time Platelets Fibrinogen D-Dimer
Thrombotic
thrombocytopenic purpura- Normal ↓ Normal Normal
hemolytic uremic syndrome
Disseminated intravascular
coagulation ↑ ↓ ↓ ↑
CRITICAL CARE / 73
Hematologic and Oncologic Emergencies

TUMOR LYSIS SYNDROME—Oncologic emergency caused by massive tumor
cell lysis with sequelae of hyperuricemia, hyperphosphatemia, hyperkalemia, and
hypocalcemia.
Clinical manifestations: Gastrointestinal symptoms (nausea, vomiting, abdominal

pain, diarrhea), lethargy, hematuria, heart failure, seizures, tetany, syncope, and
possible death
Diagnosis:
 Cairo-Bishop definition: Two or more laboratory changes within 3 days
before or 7 days after cytotoxic therapy
 Hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia
Prevention:
 Aggressive hydration, urinary alkalinization in patients with metabolic
acidosis, and hypouricemic agents (allopurinol, rasburicase)
Treatment:
 Correction of electrolyte abnormalities
 Rasburicase, loop diuretics, and IV fluids
 Emergent dialysis in patients with severe oliguria or anuria, persistent
hyperkalemia, or hyperphosphatemia-induced symptomatic hypocalcemia
ACUTE CHEST IN SICKLE CELL DISEASE—See Chapter 10.
BLAST CRISIS—Defined as one or more of the following:

 ≥ 20% peripheral blood or bone marrow blasts
 Bone marrow biopsy showing large foci or clusters of blasts
 Extramedullary blast infiltrates
Treatment:
 Urgent chemotherapy, with or without hematopoietic stem cell transplantation,
in eligible patients
 Emergent stabilization of white blood cell count with chemotherapy and
concomitant leukapheresis for symptomatic hyperleukocytosis (unclear
survival benefit, but improves neurologic and pulmonary symptoms)
74 / CHAPTER 2
INFECTION
Infections other than pneumonia and sepsis that commonly require ICU admission
include central nervous system infections, endocarditis, severe Clostridium
difficile, and severe soft tissue infections. Other common infections seen in the
intensive care setting include catheter-related infections.
Central Nervous System Infections

Infections that are of interest in the intensive care setting include meningitis,
encephalitis, and brain abscess.
Meningitis: Inflammation of the leptomeninges. Symptoms include stiff neck,

headache, and photophobia.
Encephalitis: Disturbance of cerebral function accompanied by cerebrospinal fluid

pleocytosis. Symptoms include seizures and coma.
MENINGITIS
Diagnosis:
 Lumbar puncture: White blood cell count > 1000 cells/mm3, glucose < 40
mg/dL, protein > 100 mg/dL. Contraindications include intracranial mass with
localized edema or epidural abscess. Before lumbar puncture, head CT should
be obtained in patients with a history of central nervous system disease,
immunosuppressive disorder, seizures, moderate to severe impairment of
consciousness, papilledema, or focal neurologic findings. Antibiotic therapy
should not be delayed to obtain cultures.
Etiology: Table 2-7 shows potential organisms and the associated population.
 Streptococcus pneumoniae is the most common cause of bacterial meningitis

in adults, accounting for 60–70% of cases. Neisseria meningitidis accounts for
~ 10%, Haemophilus influenzae 6%, and Listeria monocytogenes 4% (with
increasing incidence in the older population).
 Nosocomial meningitis primarily affects neurosurgical patients. Most cases
are caused by gram-negative bacilli with streptococci, Staphylococcus aureus,
and coagulase-negative staphylococcus, all accounting for ~ 10% of cases.
 Given increasing concern with bioterrorism, it is important to note that
hemorrhagic meningitis develops in 50% of patients who inhale Bacillus
anthracis spores.
CRITICAL CARE / 75
o The spores germinate and release toxins that cause hemorrhagic

mediastinitis (evident by widened mediastinum on chest x-ray).
o Typically, initial symptoms are flu-like, with rapid progression in
respiratory symptoms, hypoxia, shock, and then death.
o Antibiotic therapy is beneficial only when initiated during the initial
prodrome of flu-like symptoms and thus should be initiated when
inhalation anthrax is suspected. Recommended empirical treatment is
ciprofloxacin or doxycycline plus one or two of the following:
meropenem/imipenem, rifampin, vancomycin, penicillin/ampicillin, or
clindamycin.
Table 2-7. Potential Organisms in Meningitis
Organism Population at Risk

Streptococcus pneumonia All
Pneumococcus Head trauma
Cerebrospinal fluid leak
Hypogammaglobulinemia
Asplenia
Alcoholism
Neisseria Older children and young adults
Listeria Malignancy
Organ transplantation
Immunosuppression
Debilitation
Alcoholism
> 50 years old
Haemophilus influenzae type B Head trauma
Cerebrospinal fluid leak
Defect in humoral immunity
Gram-negative bacilli Neurosurgery
Trauma
Complication of bacteremia in patients with cancer or alcohol-
induced liver disease
Staphylococcus aureus Neurosurgery
Trauma
Associated with endocarditis or soft tissue infection
Cerebrospinal fluid shunt Flash Card Q1
Anaerobic and other Brain abscess A 47-year-old woman who
streptococci Chronic otitis worked in a textile mill with
Sinusitis wool had malaise, fever,
and myalgia 5 days ago is
Amebic Freshwater swimming now presenting with severe
Bacillus anthracis Bioterrorism hypoxia and delirium.
Chest radiography shows
~ half of patients with inhalation anthrax have hemorrhagic widened mediastinum.
meningitis (associated also with the other forms: cutaneous What type of exposure is
and gastrointestinal) suggested?
76 / CHAPTER 2
Treatment: See Table 2-8 for recommendations on empiric antibiotics for certain
clinical situations.
Table 2-8. Therapy for Bacterial Meningitis
Clinical Situation Recommended Antibiotics
Age < 50 years Ceftriaxone + vancomycin
Age > 50 years

Ceftriaxone + vancomycin + ampicillin
Immunosuppression, alcoholism, debilitation
After neurosurgery
Ceftazidime + vancomycin
Penetrating cranial trauma
Key Fact Dexamethasone: Beneficial in bacterial meningitis if given before or

In suspected bacterial simultaneously with the first antimicrobial dose. Reduces mortality and
meningitis, to be beneficial,
dexamethasone is given
neurologic sequelae. Recommended dose is 0.15 mg/kg every 6 hours for 4 days.
before or simultaneously
with the first dose of ENCEPHALITIS—Causes of encephalitis are predominantly viral.
antibiotic.
 The prognosis depends on the particular organisms, with herpes simplex and
rabies carrying the highest risk of death.
 Magnetic resonance imaging and electroencephalogram can be beneficial in
showing focal encephalitis, which could suggest herpes simplex encephalitis.
 Microorganisms at risk for producing neurologic deficits and a low risk of
death include West Nile virus, measles, and smallpox vaccination.
 Treatment is mainly supportive. Options for some forms of encephalitis are
outlined in Table 2-9.
Table 2-9. Treatment Options for Encephalitis
Organism Treatment
Rocky Mountain spotted fever Doxycycline
Neurosyphilis Penicillin G
Lyme disease Penicillin or third-generation cephalosporin
Herpes simplex Acyclovir
Varicella zoster Acyclovir
Flash Card A1
Bacillus anthracis
inhalation
CRITICAL CARE / 77
BRAIN ABSCESS—Most commonly caused by streptococci and anaerobes from

chronic infection of the paranasal sinuses, middle ear, or mastoid.
 Staphylococci and gram-negative bacilli are associated with spread from

penetrating trauma or surgery.
 Another potential etiology is hematogenous spread from S. aureus
endocarditis. Fungi or mycobacteria can be seen in immunosuppressed
patients.
Treatment: Empiric antibiotics with ceftriaxone + metronidazole and surgery.
SPINAL EPIDURAL ABSCESS—Can be secondary to bacteremia or a

complication of vertebral osteomyelitis or surgery. Most cases are caused by S.
aureus. Clinical course is back pain or nerve root pain → weakness → paralysis.
Treatment is antibiotics and surgery.
Endocarditis
Infective endocarditis is infection of the endothelial lining of the heart,
characterized by vegetation.
 It usually affects valves but also can affect mural thrombi or heart defects.
 Most cases (80%) are caused by Staphylococcus and Streptococcus species.
Enterococci and negative cultures occur 8% of the time. Fungi and HACEK
(Haemophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium
hominis, Eikenella corrodens, Kingella kingae) occur in ~ 2% of cases.
 Prosthetic valves have similar organisms, with slightly higher occurrences of
gram-negative bacilli and fungi.
DIAGNOSIS—Based on the modified Duke criteria.
Definitive infective endocarditis: 2 major OR 1 major + 3 minor OR 5 minor
Possible infective endocarditis: 1 major + 1 minor OR 3 minor
Major criteria:
 Positive blood cultures
o Typical microorganism from two separate blood cultures
o Persistently positive blood culture
o Single blood culture for Coxiella burnetii or antiphase I immunoglobulin
G antibody titer > 1:800
 Evidence of endocardial involvement
o Positive findings on echocardiogram
o New valvular regurgitation
78 / CHAPTER 2
Minor criteria:
 Predisposition (heart condition, IV drug use)
 Fever
 Vascular phenomena
o Major arterial emboli
o Septic pulmonary infarct
o Mycotic aneurysm
o Intracranial hemorrhage
o Conjunctival hemorrhage
o Janeway lesions
 Immunologic phenomena
o Glomerulonephritis
o Osler nodes
o Roth spots
o Rheumatoid factor
 Positive blood cultures that do not meet the major criteria
TREATMENT
 Intravenous antibiotics are given for 4 weeks for infection in native valves and
6 weeks for infection in prosthetic valves (counted from the first day of
negative culture results).
 If aortic or mitral valves are involved, serial electrocardiograms are obtained
to look for PR interval prolongation or other conduction abnormalities that
signal invasion of the interventricular septum.
 Main indications for valve surgery are heart failure (severe acute regurgitation
with cardiogenic shock), uncontrolled infection (abscess, enlarging vegetation,
dehiscence of prosthetic valve, persistent fever and blood cultures > 7 days),
or prevention of embolic event (vegetation > 15 mm or > 10 mm +
complication).
Catheter-Related Infections
INTRAVASCULAR CATHETERS
 Cellulitis or abscess at the site of exit of the catheter
 Infection along the tract of the tunneled catheter (tunnel infection)
 Catheter-related bacteremia (isolation of the same organism from tip and
blood)
The most common organisms that cause line infections are Staphylococcus
aureus, Staphylococcus epidermidis, and Enterococcus. Candida is more often
seen in patients who are receiving multiple antibiotics as well as parental
nutrition.
Treatment: Local infection without bacteremia usually responds to line removal.

CRITICAL CARE / 79
In bacteremia, duration of antibiotic treatment depends on complications and

organisms:
 Uncomplicated, with an organism other than S. aureus: 5–10 days after line
removal
 Uncomplicated S. aureus bacteremia: 14 days
 Complicated cases: Individually tailored
 Candidemia: Treatment for 14 days, with recommendation of ophthalmologic
examination because of the risk of endophthalmitis
Surgically implanted, long-term indwelling catheters are commonly left in place

unless complications occur.
Prevention:
 Maximal sterile barriers during insertion of central catheters
 Chlorhexidine at the insertion site for antisepsis
 Chlorhexidine-impregnated patch
 Catheters coated with antimicrobial agents
 Use of dressings at the insertion site
Other recommendations:
 Specific site (subclavian > internal jugular > femoral) and use of minimal
amount of ports
 Replacement of catheters placed during an emergency within 48 hours
 Removal of central lines when no longer necessary
 Routinely changing central intravascular catheters and using systemic
antibiotics as prophylaxis have not been shown to reduce infections.
CATHETER-RELATED URINARY TRACT INFECTION—As with intravascular

catheter infections, guidelines for prevention of catheter-related urinary tract
infections include insertion for appropriate reasons with removal as soon as
possible and use of aseptic catheter insertion techniques.
Appropriate reasons for insertion:

 Acute urinary retention
 Need for accurate measurement of output in critically ill patients
 Prolonged immobilization
 Assistance with healing of sacral or perineal wounds in incontinent patients
 Perioperatively during urologic or prolonged surgeries or with the use of
large-volume infusions or diuretics
80 / CHAPTER 2
Asymptomatic bacteriuria in patients with indwelling catheters does not require

treatment unless the patient is severely neutropenic. The most important therapy is
to remove the catheter. If bacteriuria persists 48 hours after catheter removal, a 3-
day course of an appropriate antimicrobial agent is appropriate. If bacteriuria
persists, upper urinary tract infection is assumed and warrants a 14-day course.
Candiduria treatment is based on symptoms. Asymptomatic patients should be

treated only if they are neutropenic or if they will undergo urinary tract
manipulation. A short course of fluconazole (14 days) is recommended when
treatment is necessary.
Clostridium difficile Colitis
Clinical manifestations of C. difficile colitis include fever, leukocytosis, and

watery diarrhea.
 Often temporally associated with administration of antibiotics
 Ranges from simple self-limited diarrhea to severe pseudomembranous colitis,
resulting in sepsis and toxic megacolon
 Strain NAP1/BI/027 associated with severe disease and increased production
of toxins A and B
TREATMENT—Depends on severity. There is no consensus definition for severe

C. difficile infection, but some definitions include:
 White blood cell count > 15,000 cells/μL
 Elevated serum creatinine level
 > 10 bowel movements per day
In severe disease, the recommended treatment is oral vancomycin (metronidazole

in nonsevere cases). If ileus develops, oral antibiotic passage is delayed and
addition of IV metronidazole may be beneficial. In case of profound ileus and
progression to megacolon, vancomycin enemas should be added.
Reasons for surgical invention:

 Toxic megacolon
 Perforation or impending perforation
 Necrotizing colitis
 Rapidly progressive or refractory disease with systemic inflammatory
response syndrome and multiple organ system failure
CRITICAL CARE / 81
Severe Soft Tissue Infections

Severe soft tissue infections include necrotizing cellulitis, necrotizing fasciitis,
pyomyositis, and myonecrosis (Table 2-10).
 These conditions cannot be differentiated by physical examination or
laboratory findings.
 If not recognized early, they can lead to significant mortality.
 Definitive diagnosis can be made only by surgical exploration.
 Typically, initial antibiotic treatment is a carbapenem or third-generation
cephalosporin + methicillin-resistant S. aureus coverage + clindamycin for
added toxin inhibition (against strains of streptococci and staphylococci) and
anaerobic activity.
Table 2-10. Severe Soft Tissue Infections
Disease Clinical Features

Caused by Clostridium species or nonclostridial anaerobes mixed with gram-
negative organisms
Necrotizing Skin: Thin, dark, sometimes foul-smelling wound drainage, with tissue gas
cellulitis formation
Key Fact
Mild pain and crepitus
Clindamycin is included in
Usually on extremities, perineum, and abdominal wall (involvement of male the empiric antibiotic
genitalia is called Fournier’s gangrene) treatment of severe soft
Type I: Mixed, usually gram-positive, negative aerobe, anaerobe, or Vibrio tissue infection because of
species its antitoxin effects against
Necrotizing streptococci and
fasciitis Type II: Group A streptococci staphylococci species.
Predisposing factors: Cirrhosis, diabetes, immunocompromise
Cellulitis that does not improve and spreads quickly, pain, elevated creatine
phosphokinase, and crepitus
Caused by group A Streptococcus
Necrotizing Predisposing factors: skin abrasions, blunt trauma, or heavy exercise
myositis
Severe pain and swelling and induration of affected muscle
Predisposing factors: Contaminated wounds and surgery in
immunocompromised patients
Clostridial Acute, sudden onset of painful and swollen area, severe sepsis,
myonecrosis serosanguineous drainage with sweet odor
Skin: Progression to red/yellow/green/black discoloration and bullae with
crepitus
82 / CHAPTER 2
OBSTETRIC EMERGENCIES
The rate of ICU admission for pregnant or peripartum women is low at < 2%. The
two most common indications are hypertensive disorders and postpartum
hemorrhage.
Preeclampsia and Eclampsia

Preeclampsia and eclampsia are multisystem diseases that develop during
pregnancy. Eclampsia is the convulsive end phase of preeclampsia. Although
controversial, HELLP syndrome may be a form of severe preeclampsia.
PREECLAMPSIA—Proteinuria (> 300 mg/d) and hypertension (>140/90 mm Hg)

after the 20th week of gestation are typical features.
Diagnosis: Made in two ways: Either hypertension and proteinuria or

hypertension and end-organ damage
 End-organ damage:
o Platelets < 100,000/μL
o Serum creatinine doubled or > 1.1 mg/dL
o Liver transaminase twice the normal value
o Pulmonary edema
o Cerebral or visual symptoms
Key Fact Treatment:

Single most important  Prompt delivery
predictor of hemorrhagic  Seizure prevention with magnesium sulfate
stroke in patients with  Antihypertensive therapy when diastolic blood pressure ≥ 105 mm Hg
preeclampsia is systolic
blood pressure > 160 mm o Labetalol, nicardipine, and hydralazine preferred; nitroprusside and
Hg. angiotensin-converting enzyme inhibitors contraindicated
o Goal blood pressure 140–160/90–105 mm Hg; systolic blood pressure >
160 mm Hg associated with hemorrhagic stroke
HELLP Syndrome—Constellation of hemolysis (H), elevated liver enzymes (EL),

and low platelet (LP) count. Typically presents at week 28–36, but can present as
late as 7 days postpartum.
Diagnosis:
 Microangiopathic hemolytic anemia, elevated liver enzymes, and low
platelets:
o Prevalence: < 1% of pregnancies; 10–20% in severe preeclampsia
o Elevated indirect bilirubin, low haptoglobin, platelet count < 100,000/μL
o Clinical features: Abdominal pain, nausea, vomiting, and malaise
CRITICAL CARE / 83
Management: Indications for prompt delivery:

 Disseminated intravascular coagulation
 Pulmonary edema
 Liver hemorrhage or infarction
 Renal failure
 Placental abruption
 Nonreassuring fetal status
Hemorrhage
POSTPARTUM HEMORRHAGE (PPH)
Diagnosis: Excessive bleeding that results in symptomatic anemia and/or

hypovolemia
 Primary PPH: Excessive bleeding within first 24 hours after delivery
 Secondary PPH: Excessive bleeding 24 hours to 12 weeks postpartum
Signs and symptoms: May or may not have vaginal bleeding
Risk factors:
 Retained placenta
 Placenta accreta
 Lacerations
 Instrumental delivery
Etiologies:
 Uterine atony (80% of cases)
 Trauma (uterine rupture, lacerations)
 Coagulopathy (preeclampsia, HELLP syndrome, placental abruption)
Management: Early recognition of PPH needed to prevent shock and lethal triad
of hypothermia, acidosis, and coagulopathy
General principles:
 In an observational study, an established protocol showed faster resolution of
maternal bleeding, use of fewer blood products, and reduced disseminated
intravascular coagulation.
 Standardized massive transfusion protocol is used for labor and delivery.
 Fundal massage and intrauterine tamponade are used.
 Uterotonic drugs: Oxytocin and misoprostol are given.
 Laparotomy, surgical exploration, and hysterectomy should not be delayed in
Flash Card Q2
disseminated intravascular coagulation, severe bleed, or large uterine rupture.
What is the most common
etiology of postpartum
hemorrhage?
84 / CHAPTER 2
Complication: Sheehan syndrome: Panhypopituitarism secondary to pituitary

necrosis
 Timing: Typically presents 2–12 months postpartum
 Risk factor: PPH with hypotension and multiple blood transfusions
 Panhypopituitarism: Adrenal insufficiency, hypothyroidism, and prolactin
deficiency
 Symptoms: Fatigue, lethargy, secondary amenorrhea, and hyponatremia
 Treatment: Hydrocortisone (immediately if hypotensive); thyroid and
reproductive hormone replacement
Pulmonary Edema
NONCARDIOGENIC PULMONARY EDEMA—Tocolytics are the most common

cause of noncardiogenic peripartum pulmonary edema. Other causes include
aspiration, preeclampsia, TRALI, and aggressive volume resuscitation.
Tocolytic pulmonary edema: -adrenergic tocolytic therapy for preterm labor.

Toxicity develops in up to 4% of pregnant women.
 -adrenergic agents: Terbutaline and ritodrine most commonly used

 Risk factors: Prolonged therapy > 24–48 hours; large-volume resuscitation
 Clinical features: Pulmonary edema within 24–48 hours of therapy
 Supportive care: Discontinuation of tocolytics, supplemental oxygen, diuresis
 Alternative diagnosis sought if symptoms persist 12–24 hours after stopping
therapy
CARDIOGENIC PULMONARY EDEMA—Cardiogenic pulmonary edema during

pregnancy or the postpartum period can be caused by pre-existing or new cardiac
disease.
Peripartum cardiomyopathy: New-onset cardiomyopathy (LVEF < 45%) that

develops during the last month of pregnancy or up to 5 months postpartum.
 Etiology: Unclear; likely multifactorial and related to virus, nutrition, drugs,

and/or connective tissue disease
 Echocardiogram findings: Four-chamber enlargement, global hypokinesis, and
decreased left ventricular function
 Treatment: Standard heart failure therapy (avoid angiotensin-converting
enzyme inhibitors in pregnancy)
 Prognosis: Recovery in one third of patients, residual cardiac failure in one
third, and heart transplant required in one third
Flash Card A2
Uterine atony
CRITICAL CARE / 85
ACQUIRED HEART DISEASE—Pre-existing heart disease (valvular disease,

cardiomyopathy) may be undiscovered until pregnancy. Increase in CO during
pregnancy can lead to decompensation of a previously asymptomatic condition
and pulmonary edema.
Embolic Disease In Pregnancy

Three forms of pulmonary embolic events occur in women who are pregnant or
peripartum:
 Pulmonary embolism
 Amniotic fluid embolism
 Air embolism
PULMONARY EMBOLISM—Venous thromboembolism in the form of an acute

pulmonary embolism is relatively common during pregnancy, with an occurrence
of 2–5/1,000 deliveries. Pulmonary embolisms account for ~ 9% of maternal
deaths.
Diagnosis (see Chapter 10, “Vascular Disease.”):

 V/Q scan is preferred in many centers, especially if chest x-ray findings are
normal.
 CT pulmonary angiography is typically performed if the V/Q scan is not
available or indeterminate or if chest x-ray findings are abnormal.
 CT pulmonary angiography is associated with higher radiation exposure to the
mother than V/Q scanning, but slightly lower radiation exposure to the fetus.
This is generally an accepted risk because the maternal mortality rate is high.
Treatment:
 Subcutaneous low-molecular-weight heparin is preferred, or subcutaneous or
IV unfractionated heparin may be used:
o Warfarin is teratogenic and contraindicated in pregnancy.
o Anticoagulation is discontinued 24 hours before delivery if possible for
epidural catheter placement and/or cesarean surgery.
o Patients at high risk for recurrent venous thromboembolism may
discontinue subcutaneous low-molecular-weight/unfractionated heparin
and start IV unfractionated heparin until 4–6 hours before delivery.
o Patients with poor cardiopulmonary reserve and pulmonary embolism may
benefit from an IVC filter before delivery. Another option is to deliver
while the patient is fully anticoagulated.
 Duration: For venous thromboembolism in pregnancy, therapy is continued
for the duration of pregnancy and for ≥ 6 weeks postpartum (minimum 3–6
months). Flash Card Q3
 Systemic thrombolysis is used for massive pulmonary embolism: What is the biggest risk
factor for tocolytic-
o Bleeding risk is highest peripartum, but thrombolysis is used in life- associated pulmonary
threatening massive pulmonary embolism with shock. edema?
86 / CHAPTER 2
o Surgical or mechanical clot removal is a potential alternative therapy.
AMNIOTIC FLUID EMBOLISM—Rare but catastrophic complication of

pregnancy, most commonly occurring during labor or immediately postpartum.
Clinical presentation:
 Abrupt shock with acute cardiopulmonary collapse
 Profound hypoxemia and shortness of breath
 Disseminated intravascular coagulation (common and can cause hemorrhage
after surgery)
 Pulmonary edema (common)
 Coma or seizures
Pathophysiology: Fetal cells and debris cause mechanical obstruction in the

pulmonary arteries and an immune-mediated inflammatory response.
 Early phase: Pulmonary artery obstruction leading to pulmonary hypertension
and right ventricular failure
 Later phase: Left ventricular dysfunction and cardiogenic pulmonary edema
 Immune-mediated inflammation: Activation of clotting cascade, capillary leak,
and myocardial depression
Transthoracic echocardiography:
 Severe right ventricular dilation and decreased function (within minutes of
onset of shock)
 Left ventricular dysfunction secondary to right ventricular enlargement
Key Fact Treatment:

Venous thromboembolism  Aggressive supportive care for blood pressure and hypoxemia, including
related to pregnancy is inhaled nitric oxide. Case reports show improved shock and hypoxemia with
treated with low-molecular-
weight heparin for a this treatment.
minimum of 3–6 months,  Hemorrhage control is provided with blood products and Factor VIIa.
including the duration of
the pregnancy and at least
6 weeks postpartum. AIR EMBOLISM—Venous air embolism is an uncommon complication of
pregnancy that occurs when air enters the systemic venous system.
Clinical presentation: Typically occurs in the peripartum period as a result of

cesarean delivery, uterine manipulation, or central venous catheterization. Severe
cases present as acute cardiopulmonary or neurologic decompensation.
Diagnosis: Confirmed by the finding of air in the intravascular space.
Treatment:
 Initial management: Placement in the left lateral decubitus position
Flash Card A3  Cardiac, pulmonary, or neurologic deficits: Supportive care and hyperbaric
Prolonged tocolytic therapy oxygen therapy
> 24–48 hours
CRITICAL CARE / 87
Ovarian Hyperstimulation Syndrome

Serious complication of excessive ovarian stimulation from fertility treatment.
 Ovarian enlargement because of multiple ovarian cysts and acute fluid shifts
out of the intravascular space
 Severe cases: Ascites, pleural/pericardial effusions, hypovolemic shock,
venous thromboembolism, disseminated intravascular coagulation and ARDS
Treatment: Supportive. Oophorectomy is reserved for torsion, cyst rupture, or

hemorrhage.
NEUROLOGY
Disorders of Consciousness
Delirium and confusional states are among the most common neurologic disorders
in patients in the ICU. Key Fact
Delirium is a risk factor for
DELIRIUM death in the ICU.
 Disturbance of consciousness with reduced ability to focus attention:
 Changes in cognition or development of perceptual disturbances that fluctuate
throughout the day
 Etiology: Mostly multifactorial, although risk increased by:
o Age
o Neurodegenerative disease (stroke, Parkinson’s, sensory impairment)
o Polypharmacy
o Malignancy
o Postoperative setting
o Uncontrolled pain
 Treatment: Avoidance of exacerbating factors (including sedation and
benzodiazepines) and treatment of underlying illness. Antipsychotic agents
reduce the severity and duration of episodes, although reduction in incidence
has not been observed.
Status Epilepticus
DEFINITION—No standard definition but often refers to seizures lasting longer
than 5–10 minutes without an intervening period of consciousness.
 Etiology: Noncompliance with anti-epileptic medication, drug or alcohol

withdrawal syndrome, acute brain injury or infection, metabolic derangement
88 / CHAPTER 2
 Diagnosis: Neurologic examination, electroencephalogram

 Treatment in ICU patients:
o Use midazolam infusion in place of barbiturates or propofol, which
exacerbate hemodynamic instability.
o Consider propofol in patients with increased risk of respiratory failure and
prolonged mechanical ventilation to minimize duration of sedation.
o Concomitant phenytoin or fosphenytoin is warranted if seizures persist.
o Refractory status epilepticus: Phenobarbital and pentobarbital infusions.
o Antiepileptic drugs: Topiramate, levetiracetam and valproic acid are
second-line therapies.
Ischemic and Hemorrhagic Stroke

Intracranial hemorrhage, vertebrobasilar ischemia, or bihemispheric ischemia can
result in increased ICP and respiratory failure because of diminished respiratory
drive or airway obstruction.
ELEVATED ICP—A potentially devastating complication of neurologic injury

that can result from severe traumatic brain injury, obstructive hydrocephalus,
Key Fact
stroke, and acute liver failure.
Use of glucocorticoids in
moderate to severe head
injury was associated with  Clinical manifestations: Cushing’s triad of bradycardia, respiratory depression
worsened outcomes in a and hypertension. Headaches, cranial nerve VI palsy, papilledema, and
large randomized clinical spontaneous periorbital bruising can also occur.
trial.
 ICP Monitoring: Intraventricular (gold standard) with surgically placed
catheter into the ventricular system
 Management:
o Treat the underlying cause of elevated ICP.
o Elevate head of bed.
o Hyperventilation to rapidly reduce ICP through vasoconstriction and
decreasing the volume of intracranial blood (PaCO2 goal 25–30 mm Hg)
o IV mannitol or hypertonic saline.
o Intubate with careful positioning and pretreatment with lidocaine (shown
to decrease the rise in ICP associated with intubation).
o Sedation: Propofol preferred given short half-life and ability to frequently
assess neurologic status.
Brain Death
Irreversible and complete loss of cerebral and brainstem function. In the U.S.,
brain death is equivalent to cardiopulmonary death.
CRITICAL CARE / 89
DIAGNOSIS
 Neurologic examination: Coma, absent brain-originating motor responses
(painful stimuli), absent papillary light reflex/corneal reflexes/oculovestibular
reflexes/jaw jerk/gag reflex.
 Drug intoxication or poisoning, metabolic derangements, hypothermia, and
neuromuscular paralysis because of neuropathy or medications must be ruled
out.
 Apnea test:
o Performed after all other criteria for brain death are met and cannot have
concurrent hypothermia, hypercapnia, hypotension, or hypoxia
o 8–10 minutes without observable respiratory effort – PaCO2 measured just
before reconnection to ventilator > 60 mm Hg or 20 mm Hg greater than
baseline.
o Ancillary testing: Applied only when clinical criteria cannot be applied
and includes cerebral angiography, transcranial Doppler, magnetic MRA,
CT angiography, or electrophysiologic tests.
Therapeutic Hypothermia
Therapeutic hypothermia has been recommended for unconscious survivors of

out-of-hospital cardiac arrest. A recent study found that targeting a temperature of
36°C had similar mortality and neurologic outcomes compared with a temperature
of 33°C.
DRUG AND ENVIRONMENTAL EMERGENCIES
Overdoses and Withdrawal Syndromes

Table 2-11 shows drug classes and clinical features.
90 / CHAPTER 2
Table 2-11. Toxidrome

Drugs Pupils Temp. BP HR RR Others
Cocaine, amphetamines, Agitation, hallucinations,
pseudoephedrine, ↑ ↑ ↑ ↑ ↑ paranoia
caffeine, theophylline
MAOI, SSRI, TCA, Myoclonus, hyperreflexia,
dextromethorphan diaphoresis, flushing,
↑ ↑ ↑ ↑ ↑ tremors, trismus, rigidity,
confusion, agitation
Hallucinogens Nystagmus, perceptual
(LSD, ecstasy, ↑ ↑ ↑ ↑ ↑ distortions, hallucinations,
phencyclidine) agitation
Sedatives CNS depression, confusion,
(benzodiazepines, ↓ ↓ ↓ ↓ ↓ stupor, coma, hyporeflexia
alcohol, barbiturates)
Opioids CNS depression, coma,
(morphine, methadone, hyporeflexia, pulmonary
oxycodone, ↓ ↓ ↓ ↓ ↓ edema
hydromorphone, heroin)
Cholinergic Salivation, urinary/fecal
(organophosphate, incontinence, diarrhea,
nicotine, nerve agents, ↓ ↔ ↑ ↓ ↑↓ emesis, diaphoresis,
physostigmine, lacrimation
edrophonium)
Anticholinergics Dry, flushed skin and
(antihistamines, atropine, mucous membranes; urinary
scopolamine, Jimson ↑ ↑ ↑ ↑ ↑ retention; myoclonus;
weed, TCA) hypervigilance; agitation;
delirium
BP, blood pressure; CNS, central nervous system; HR, heart rate; MAOI: monoamine oxidase inhibitor; RR,
respiratory rate; SSRI: serotonin reuptake inhibitor; TCA: tricyclic antidepressant; Temp., temperature; LSD:
lysergic acid diethylamide
Neuroleptic Malignant Syndrome/Serotonin Syndrome

A life-threatening condition presenting as altered mental status, high fevers,
Key Fact dysautonomia, and rigidity.
NMS is associated with all
classes of neuroleptic DIFFERENTIAL DIAGNOSIS
agents, including the newer
atypical antipsychotic meds  Serotonin syndrome: Similar clinical presentation as NMS but more likely to
such as risperidone and present with shivering, hyperreflexia, myoclonus, and ataxia. Rigidity and
olanzapine. hyperthermia are less severe than in NMS.
 Malignant hyperthermia: Distinguished from NMS by exposure to
halogenated inhalation anesthetic agents and succinylcholine.
TREATMENT—Supportive care along with specific medications: Dantrolene

(direct-acting skeletal muscle relaxant), Bromocriptine (dopamine agonist),
Amantadine (dopaminergic and anticholinergic effect).
CRITICAL CARE / 91
Anaphylaxis
Rapid onset of serious allergic or hypersensitivity reaction that can be life-
threatening when symptoms progress to respiratory distress (stridor, wheezing,
dyspnea, cyanosis), and cardiovascular collapse.
ACUTE MANAGEMENT
 IM epinephrine: Inject 0.3–0.5 mg intramuscularly. May repeat every 5–15
minutes
 IV epinephrine continuous infusion for refractory symptoms
 Nebulized albuterol for epinephrine refractory bronchospasm
 Diphenhydramine 20–50 mg IV with or without methylprednisolone 125 mg
IV
 Glucagon 1–5 mg IV for patients taking  blockers
Near Drowning
CLINICAL MANIFESTATIONS
 Pulmonary: Fluid aspiration that can result in hypoxemia because of
noncardiogenic pulmonary edema
 Neurologic: Cerebral edema and increased ICP.
 Cardiovascular: Arrhythmias secondary to hypothermia and hypoxemia
 Hemolysis and coagulopathy are rare complications.
In critically ill patients, the therapeutic focus is to reduce the risk of brain injury.
The role of glucocorticoids or prophylactic antibiotics is unclear.
Heat Stroke
Nonexertional heat stroke typically occurs in elderly patients with chronic Key Fact
medical conditions and impaired thermoregulation. Exertional heat stroke occurs Dantrolene,
in healthy, young patients with prolonged exposure to high ambient temperature. acetaminophen, and
aspirin are ineffective and
Managed with adequate fluid resuscitation and cooling measures. are not indicated in the
treatment of heat stroke.
COMPLICATIONS
 Pulmonary: Hypoxemia caused by noncardiogenic pulmonary edema or
bronchospasm.
 Neurologic: Seizures.
 Cardiovascular: Myocardial injury with ST-elevation, heart failure,
arrhythmias.
 Rhabdomyolysis with acute kidney injury Flash Card Q4
 Acute liver failure Concomitant use of which
antibiotic with serotonergic
 Disseminated intravascular coagulation agents can cause
serotonin syndrome?
92 / CHAPTER 2
Bioterrorism
ORGANISMS OF CONCERN
 Category A: Highest priority agents easily grown in large quantities and
difficult to destruct - anthrax and smallpox
 Category B: Second highest priority agents generally less lethal than category
A: Q fever and brucellosis
 Category C: Pathogens that can be engineered for mass dissemination:
multiple-drug-resistant tuberculosis, hantavirus.
TREATMENT OF ANTHRAX
 Bioterrorism-related cutaneous anthrax: Ciprofloxacin or doxycycline.
 Adjuvant therapy: Glucocorticoids for meningoencephalitis or extensive
edema involving head/neck; Raxibacumab (human IgG1-gamma monoclonal
antibody against protective antigen).
LUNG CRITICAL CARE
ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS)
ARDS was first described in 1967 in a case series of 12 patients. The American-
European Consensus Conference published a definition of ARDS in 1994 that
remained the standard until it was replaced in 2012 by the Berlin definition.
The Berlin criteria are superior to the American-European Consensus Conference

criteria because it improved reliability and validity of the definition by better
defining the variables. Table 2-12 outlines the important changes made in the
2012 definition.
Flash Card A4
Linezolid
CRITICAL CARE / 93
Table 2-12. Revised Definition of Acute Respiratory Distress Syndrome

American-European
Consensus Berlin Definition 2012
Conference 1994
Acute onset Addition of time frame to define acute
Developing within 1 week of known clinical insult or new/worsening
respiratory symptoms Key Fact
Bilateral infiltrates on chest Bilateral opacities not fully explained by effusions, lobar/lung With the new Berlin
radiograph collapse, or nodules definition of ARDS in 2012,
the pulmonary capillary
Pulmonary capillary wedge Removal of pulmonary capillary wedge pressure criterion
wedge pressure criterion
pressure ≤ 18 mm Hg
Respiratory failure not fully explained by cardiac failure or fluid was removed. If there is no
overload known etiologic risk factor
for ARDS, cardiac function
If no known etiologic risk factor for ARDS (Table 2-13), objective should be assessed
evaluation of cardiac function with echocardiography or cardiac objectively with
output measurement echocardiography.
PaO2/FiO2 < 300: ALI Removal of ALI term
PaO2/FiO2 < 200: ARDS Addition of PEEP to definition and severity categories:
Mild: 200 < PaO2/FiO2 ≤ 300 + PEEP/CPAP ≥ 5
Moderate: 100 < PaO2/FiO2 ≤ 200 + PEEP/CPAP ≥ 5
Severe: PaO2/FiO2 ≤ 100 + PEEP/CPAP ≥ 5
ARDS, acute respiratory distress syndrome; ALI, acute lung injury; PEEP, positive end-expiratory pressure;
CPAP, continuous positive airway pressure
Etiology
Causes of ARDS are typically classified by direct (epithelial) versus indirect

(vascular) modes of injury (Table 2-13). Regardless of the etiology, the
pathologic finding is diffuse alveolar damage. Pathology of exudative phase is
discussed in Table 2-14 and in Figure 2-6.
Table 2-13. Common Causes of Acute Respiratory Distress Syndrome
Direct Injury Indirect Injury

Pneumonia Sepsis
Aspiration Shock
Near drowning Trauma
Inhalation (smoke, toxin) Multiple blood transfusions
Pulmonary contusion Cardiopulmonary bypass
Embolism Anaphylaxis
Medications (opioids, salicylates, amiodarone, Flash Card Q5
Re-expansion injury
tocolytics, chemotherapy)
What condition is
Reperfusion injury (after lung transplant) Pancreatitis associated with the
pathologic finding of diffuse
alveolar damage with no
known cause?
94 / CHAPTER 2
Pathophysiology
See Table 2-14.
Table 2-14. The Three Pathologic Stages of Acute Respiratory Distress

Syndrome
Exudative Proliferative Fibrotic
Characterized by release of Characterized by resolution of Subset of patients
inflammatory markers, pulmonary edema, proliferation
Characterized by obliteration
resulting in injury to epithelium of type II alveolar cells,
of normal lung architecture,
and endothelium that leads to squamous metaplasia,
diffuse fibrosis, and cyst
increased permeability and interstitial infiltration by
formation
leakage of fluid into interstitial myofibroblasts, early
space and alveoli (Figure 2-6) deposition of collagen, and
obliteration of pulmonary
Diffuse alveolar damage on
capillaries
pathology
< 7–10 d 7 d–2 wk > 2 wk
Figure 2-6. Pathogenesis of acute respiratory distress syndrome and resulting

Flash Card A5 syndrome.
TNF, tumor necrosis factor; IL, interleukin.
Acute interstitial
pneumonia (Hamman-Rich
syndrome)
CRITICAL CARE / 95
Mortality
Since ARDS was first described, the mortality rate has steadily decreased, with
recent reports estimating 30- to 60-day mortality rates of 25–30%. Several studies
have considered factors that predict mortality (Table 2-15).
Table 2-15. Predictors of Mortality in Acute Respiratory Distress Syndrome

Patient-Related
Factors Disease-Related Factors Treatment-Related Factors
Older age Severe hypoxemia (PaO2/FiO2) Treatment with glucocorticoid
before onset of acute respiratory
African-American race Pulmonary vascular dysfunction
distress syndrome
(elevated transpulmonary gradient
Hispanic ethnicity
or pulmonary vascular resistance Administration of packed red blood
Female sex index) cell transfusion
Dead space (determined by Ventilation with tidal volumes ≥ 12
exhaled carbon dioxide levels) mL/kg predicted body weight
Infection
Multiple organ dysfunction
Severity of illness score
Underlying cause of acute
respiratory distress syndrome
(lower mortality rate if trauma is
etiology)
Management
Management of ARDS is focused on treatment of the inciting event. Specific

ventilator strategies, fluid management, and efforts to reduce inflammation have
been studied and are described later.
VENTILATORY STRATEGIES—Ventilator-induced lung injury results from both

mechanical and biochemical injury. Mechanical mechanisms include:
 Volutrauma: Overdistention of lung units as a result of high tidal volume
 Atelectrauma: Shear stress from repetitive opening and closing of terminal
lung units
Mechanical ventilation can also induce release of inflammatory cytokines.

Furthermore, high FiO2 causes toxicity through formation of reactive oxygen and
nitrogen species.
96 / CHAPTER 2
Patients with ARDS are especially vulnerable to ventilator-induced lung injury

because of the heterogenesis of the lung damage, resulting in regional differences
in lung compliance.
Key Fact The main strategy of mechanical ventilation is to reduce the mechanisms of
The key in mechanical ventilator-induced lung injury by preventing volutrauma and atelectrauma and
ventilator management of reducing oxygen toxicity. The principle is derived from the static inspiratory
ARDS is to prevent pressure–volume curve of the respiratory system. In ARDS, the curve is a sigmoid
volutrauma, atelectrauma,
and oxygen toxicity. shape with a lower inflection point at lower lung volumes (atelectrauma) and an
upper inflection point at higher lung volumes (volutrauma) (Figure 2-7).
As a result of the ARDS Network investigation, the current recommendations

include:
 Goal tidal volume 4–6 mL/kg predicted body weight
Key Fact  Plateau pressure < 30 cm H2O
 Adjustment of FiO2 and PEEP to achieve PaO2 of 55–80 mm Hg or SpO2 of
A low tidal volume strategy
improves outcomes in 88–95%.
ARDS. However, increases  Adjustment of respiratory rate to reach a goal pH of 7.3–7.45 with a
in respiratory rate may be
insufficient to compensate maximum of 35 breaths/min
for low tidal volumes.
Permissive hypercapnia is
allowed if there are no
contraindications.
Figure 2-7. Volume–pressure relationship of the respiratory systems showing the

lower and upper inflection points where atelectrauma and volutrauma occur.
Positive end-expiratory pressure (PEEP) is applied to prevent atelectrauma. Low
tidal volumes are used to prevent volutrauma.
CRITICAL CARE / 97
PEEP: The goal is to reduce oxygen toxicity and avoid atelectrauma and
volutrauma while preventing increases in dead space ventilation, barotrauma, and
cardiovascular consequences. The Lung Open Ventilation Study looked at
techniques to “open” collapsed alveoli through recruitment maneuvers and the use
of PEEP.
The ideal PEEP is not yet known. Three large multicenter studies have evaluated
high-PEEP versus low-PEEP strategies that showed no change in mortality rate
among all patients with ARDS. However, in patients with severe ARDS, higher
PEEP may lead to decreased mortality. The studies showed conflicting findings
on whether the high-PEEP group had a reduction in ventilator days, refractory
hypoxia, and the need for rescue therapy. Using esophageal pressures to adjust
PEEP may also lead to improved outcomes, particularly in oxygenation and
respiratory system compliance. Large clinical trials are underway.
Recruitment maneuvers have been postulated to open alveoli and keep them open
with a lower amount of PEEP by applying higher inflation pressures initially for a
certain amount of time. The technique of recruitment (degree and duration of
PEEP) has not been standardized and has not shown mortality benefit.
Volume versus pressure control: The Lung Open Ventilation Study showed that
pressure-controlled ventilation had similar patient outcomes compared with
volume-controlled ventilation.
FLUID MANAGEMENT—The ARDS Network investigators also studied fluid

management approaches by comparing a protocol-directed conservative approach
with the conventional liberal approach. The conservative treatment group had:
 More ventilator-free days
 More ICU-free days
 Similar renal function
 Similar mortality rate
 More electrolyte disorders and metabolic alkalosis (but no associated
arrhythmias)
The protocol-directed conservative approach involves assessing central venous

pressure ranges, with or without shock, and urinary output. In the absence of
shock, target goals were central venous pressure < 4 mm Hg in the conservative
group and central venous pressure 10–14 mm Hg in the liberal group.
NUTRITION—The ARDS Network investigators compared full enteral feeding

with trophic enteral feeding in the first 6 days of mechanical ventilation. The full
feeding group had more gastrointestinal complications, with vomiting, high Flash Card Q6
gastric residual volume, and constipation. No difference was found in mortality
A patient presents with
rate, length of days on the ventilator or in the ICU, or secondary infection. ARDS. You want to follow
evidence-based ventilatory
management strategies.
What are the goals?
98 / CHAPTER 2
Varying the fatty acid components of lipids has been studied because metabolites
can promote inflammation. However, the use of enteral feeds containing
eicosapentaenoic acid, gamma-linoleic acid, and antioxidants is not recommended
because the studies had methodologic errors and varying results.
CORTICOSTEROIDS—Because of the importance of inflammation in the

pathophysiology of ARDS, the use of corticosteroids has been studied. The
general guidelines provide a weak recommendation for use of corticosteroids.
However, studies have been criticized because of small sample size and crossover
between groups.
If corticosteroids are used:

 Dose should be moderate (methylprednisolone 1–2 mg/kg/d) and of longer
duration (≤ 28 days) because of earlier studies showing benefits < risks with
high doses for short duration secondary to higher infection rates.
 Do not use in patients with ARDS > 13 days. ARDS Network investigators
found increased 60- and 180-day mortality rate in this subset of patients.
Refractory Hypoxia
Despite initiation of the lung-protective ventilator strategies and application of
PEEP, some patients may continue to have severe hypoxia (refractory hypoxia).
Vasodilators, neuromuscular blockade, prone positioning, high-frequency
oscillatory ventilation, inverse-ratio ventilation, liquid ventilation, and
extracorporeal membrane oxygenation have been considered for the treatment of
ARDS with refractory hypoxia.
The principles behind the use of these modalities are outlined in Table 2-16 along
with specific considerations and recommendations. Most randomized controlled
trials of these modalities found improvements in initial oxygenation with no
change in mortality rate. These modalities can be considered for patients with
severe ARDS and refractory, life-threatening hypoxia. The exception is proning,
with recent studies showing a potential mortality benefit with initiation early in
severe ARDS. With these emerging studies, proning may no longer be considered
only as rescue therapy for refractory hypoxia at appropriate facilities.
Flash Card A6
Tidal volume 6 mL/kg
predicted body weight and
plateau pressure < 30 cm
H2O
CRITICAL CARE / 99
Table 2-16. Rescue Therapy for Refractory Hypoxia

Rescue Proposed
Therapy Mechanism Benefits Risks
Vasodilators Increased perfusion by Randomized Intravenous: Can worsen
dilation of pulmonary controlled trials: Initial shunt and oxygenation
Prostacyclin
vessels improvement in by increasing perfusion
nitric oxide
oxygenation but no to unventilated alveoli
Inhaled: Proposed
change in mortality
benefit of being delivered
and ventilator-free
only to ventilated areas,
days
which should improve
ventilation–perfusion
matching
Neuromuscular Improved oxygenation in With cisatracurium in Risk of myopathy:
blockade patients with ventilator patients with severe Use lowest effective
asynchrony ARDS: dose
Lower mortality rate Avoid corticosteroids
Possible reduction in
More ventilator-free Monitor nerve
inflammation from
days stimulation
ventilator-induced lung
Fewer instances of Periodically discontinue
injury
pneumothorax Brief duration < 48 h
No increase in
intensive care unit–
acquired paresis
Proning Improved distribution of Initial studies: Increased pressure
ventilation by reducing Improved sores
compression caused by oxygenation and
Endotracheal tube
heart and fixation of trend toward
obstruction
anterior chest by bed decreased mortality
(less compliant) in severe ARDS Dislodgement of
lines/tubes
Promotion of drainage of More recent studies:
secretions Mortality benefit in
severe ARDS when
initiated early
High-frequency Reduced volutrauma by Improvement in Complex to manage:
oscillatory delivering tidal volume < oxygenation but Frequency amplitude
ventilation 150 mL at rates > 180 possible increase in Airway pressure
breaths/min in-hospital mortality Bias gas flow
Inspiratory time
Reduced atelectrauma
Counterintuitive
by maintaining constant
targets
mean airway pressure
Barotrauma
(inspiratory bias flow and
limitation of gas outflow) Studies discontinued
because of no
improvement in mortality
100 / CHAPTER 2
Table 2-16. Rescue Therapy for Refractory Hypoxia, continued

Rescue Proposed
Therapy Mechanism Benefits Risks
Inverse ratio Airway pressure release No adequately Because of short
ventilation ventilation: Long powered randomized exhalation time, avoided
inspiratory time with brief clinical trials to in patients with:
expiratory time address outcomes Bronchospasm
Spontaneous breaths on Obstructing secretions
top of long inspiratory
phase: Better ventilation
of lung fields by
diaphragm
Liquid Use of perfluorocarbons No known benefits Randomized clinical
ventilation to improve oxygen- and trials: Trend toward:
Therapy not
carbon dioxide–carrying Increased mortality
recommended
capacity Barotrauma
Improved recruitment Hypoxia
because of lower surface Hypotension
tension of liquid
Improved ventilation–
perfusion matching by
diverting perfusion to
better ventilated areas
from weight of liquid
itself
ECMO Artificial heart and lung CESAR trial: Trend Bleeding (secondary to
toward improved need for heparin)
Venovenous connection
mortality
for respiratory failure Heparin-induced
Criticism of trial: thrombocytopenia
Venoarterial connection
Only 76% of those
for heart failure Thromboembolism
referred for ECMO
received it Vessel perforation
Comparison was with Arterial dissection
conventional centers,
which had lower rates
of low-tidal-volume
ventilation
Better outcomes in
patients with:
Reversible cause
Limited duration of
mechanical ventilation
before ECMO
No major
comorbidities
No contraindications
to anticoagulation
ARDS, acute respiratory distress syndrome; ECMO, extracorporeal membrane oxygenation
CRITICAL CARE / 101
HYPOXEMIC RESPIRATORY FAILURE

Hypoxemia is low oxygen tension in the blood. Tissue hypoxia occurs by various
mechanisms that impair oxygen delivery or use. For instance:
 Reduced oxygen content secondary to hypoxemic respiratory failure
 Reduced oxygen-carrying capacity secondary to anemia
 Impairment in oxygen delivery secondary to low cardiac output
Hypoxemic respiratory failure is a clinically significant reduction in PaO2. The

usual cutoff is PaO2 of 60 mm Hg because at this level (based on the sinusoidal
shape of the oxygen–hemoglobin dissociation curve), hemoglobin saturation
begins to fall rapidly with further decreases in PaO2.
Hypoxemia has five mechanisms (discussed later). Clinical history, alveolar–

arterial gradient, and response to administration of oxygen can help to
differentiate among them. Oxygen is typically administered to patients with
hypoxemia, so the PaO2/FiO2 ratio can help to determine the degree of shunting if
present.
Mechanisms of Hypoxemia
Hypoxia has five mechanisms:
 Decreased inspired oxygen pressure
 Alveolar hypoventilation
 Impaired diffusion
 Ventilation–perfusion mismatch
 Shunt
Table 2-17 summarizes the differences in the four common mechanisms.

Decreased inspiratory oxygen pressure is not included but can occur at higher
altitudes, reducing driving pressure across the alveolar–capillary membrane. For
more details, see Chapter 4, “Diffuse Parenchymal Lung Disease.”
102 / CHAPTER 2
Table 2-17. Summary of Mechanisms of Hypoxia

Corrects
A-a With
Mechanism gradient PCO2 Oxygen Clinical Situation
a
Alveolar Normal Increased Easily Insufficient ventilator drive
hypoventilation (opiates)
Neuromuscular disorders
Chest wall restriction
Airway obstruction
Impaired Increased Normal Yes Interstitial lung disease
diffusion
Acute respiratory distress
syndrome
Ventilation– Increased Normal Yes, units with Asthma
perfusion moderate
Chronic obstructive pulmonary
mismatch mismatch
disease
Pulmonary embolus
Pulmonary edema
Shunt Increased Normal No Intrapulmonary:
Pulmonary arteriovenous
malformation
Hepatopulmonary syndrome
Atelectasis
Pneumonia
Extrapulmonary:
Intracardiac communication
a
See Hypercapnic Respiratory Failure
Management of Hypoxic Respiratory Failure
Initial evaluation:
 Chest x-ray
 Electrocardiogram
 Arterial blood gas
It is important to obtain both PaO2 and PaCO2 to calculate the arterial–alveolar

gradient and PaO2/FiO2 to help to differentiate among the mechanisms.
Ventilation–perfusion mismatch and shunt are distinguished by response to the
addition of oxygen. The gold standard for treatment of severe hypoxemic
respiratory failure is mechanical ventilation. Noninvasive ventilation can be
considered for patients with cardiogenic pulmonary edema and exacerbation of
chronic obstructive pulmonary disease (see Noninvasive Ventilation).
Common etiologies of acute hypoxemic respiratory failure:

 Cardiac dysfunction
CRITICAL CARE / 103
 ARDS
 Pneumonia
 Pulmonary embolus
 Obstructive lung disease
 Pneumothorax
 Hemothorax
 Pulmonary contusion
ENDOTRACHEAL INTUBATION AND AIRWAY

ASSESSMENT
Indications for Intubation
Table 2-18 outlines the indications for intubation; however, this is only a guide.
The physician must consider each situation in the appropriate clinical context.
The following questions must be considered when deciding to intubate:

 What is the expected clinical course?
 What are the patient’s goals of care?
 Does the patient have a failure of airway patency or protection?
 Does the patient have a failure of oxygenation?
 Does the patient have a failure of ventilation?
Table 2-18. Indications for Intubation
Indication Examples
Airway patency or Glasgow Coma Scale score < 8
protection Inability to swallow secretions
Upper airway instability after trauma
Depressed airway reflexes
Oxygenation Clinically agitated or restless, cyanosis
PaO2/FiO2 < 200
Ventilation Hyperventilation to reduce increased intracranial pressure

Neuromuscular disorders: Forced vital capacity < 15 mL/kg body
weight, maximal inspiratory pressure < -20 cm H2O
pH < 7.25
Increasing PaCO2
Respiratory rate > 35 breaths/min
Clinical course Sepsis
Smoke inhalation injury
Need for sedation in the setting of poor airway control
Imaging and transportation of an unstable patient
Flail chest: Internal stabilization of thorax with positive end-expiratory
pressure
104 / CHAPTER 2
Assessment of the Difficult Airway
The LEMON mnemonic has been validated for evaluation of the difficult airway
Mnemonic in the emergency department. It provides information about the risk of difficult
Assessing a difficult intubation under direct laryngoscopy.
airway—LEMON
Look externally:
Abnormal facie,
abnormal anatomy,
trauma
Evaluate 3-3-2 rule (3
fingers mouth opening,
3 fingers along floor of
mandible, 2 fingers
superior to laryngeal
notch): Predicts difficult
visualization for direct
laryngoscopy
Mallampati score (Figure
2-8): Score of I or II
predicts easy
laryngoscopy, and
score of III or IV
predicts difficultly
Obstruction/obesity
Neck mobility: Ideally,
patient should be in the
sniff position for
intubation.
Figure 2-8. Mallampati scoring.

(Reproduced from Wikimedia Commons; permission granted per the GNU Free Documentation License.)
Mnemonic Predictors for difficulty in bag-mask ventilation have also been studied and are
Predictors of difficult bag- summarized by the mnemonic MOANS.
mask ventilation—MOANS
Mask seal: Abnormal If a difficult airway is anticipated, options include:
anatomy and facial hair  Use of direct laryngoscopy
Obstruction/obesity
Age > 55 years, loss of  Fiberoptic bronchoscopy
elasticity, increased  Fiberoptic rigid intubating stylet with topical anesthesia and minimal
incidence of restrictive and procedural sedation
obstructive lung disease
No teeth
Stiffness: Lung conditions If those methods are unsuccessful, intubation with a laryngeal mask, blind
that decrease lung nasotracheal intubation, or cricothyrotomy should be considered (Figure 2-9).
compliance
CRITICAL CARE / 105
Figure 2-9. Airway management.
MECHANICAL VENTILATION
Modes of Ventilation
Classification:
 What initiates the breath (trigger)?
 What controls the delivery (target volume or pressure)? Key Fact
 What terminates the breath (cycling)? In pressure-targeted
breaths, tidal volume may
vary depending on lung
See Table 2-19 for comparison of volume-targeted versus pressure-targeted compliance (and patient
breaths. assistance) and therefore
will be affected by changes
in clinical state. For
Table 2-19. Volume-Targeted Versus Pressure-Targeted Breaths example, with resolution of
pulmonary edema or
Volume-Targeted Breaths Pressure-Targeted Breaths ARDS, lung compliance
improves and results in
Set tidal volume Set inspiratory pressure larger tidal volume for the
Set inspiratory flow rate (typically 30–80 L/min) Inspiratory time: same set inspiratory
Determined by clinician on mandatory breaths pressure and time.
Higher flow rates: Shorter inspiratory time but
Determined by patient on assisted breaths
higher peak inspiratory pressure
Set pattern of delivery (square, sine, or
decelerating/ramp pattern)
Square pattern: Shorter inspiratory time, but
Flash Card Q7
higher peak inspiratory pressure A patient requires
Decelerating pattern: Longer inspiratory time intubation. He is obese and
and lower peak inspiratory pressure has a Mallampati class IV
airway. Current saturation
Airway pressures vary depending on lung and Tidal volume varies depending on compliance
is 90% on a high-flow
chest wall mechanics
mask. What is the best
next step?
106 / CHAPTER 2
Different modes can provide either mandatory or spontaneous breaths:

 Mandatory breath is an assured breath that occurs at a minimum respiratory
rate and preset volume or pressure.
 Spontaneous breath is determined by patient effort for initiation and duration
and is only pressure targeted.
Table 2-20 shows a summary of the different modes of ventilation.
Table 2-20. Modes of Mechanical Ventilation

Trigger Type of Breath
Mode Target Ventilator Patient Termination Mandatory Assisted Spontaneous
Volume-
Yes Yes Volume Yes Yes No
limited
AC
Pressure-
Yes Yes Time Yes Yes No
limited
Volume-
Yes Yes Volume Yes Yes Yes
limited
SIMV
Pressure-
Yes Yes Time Yes Yes Yes
limited
Flow,
Pressure-
PSV No Yes pressure, or No Yes No
limited
time
Pressure-
PCV Yes No Time Yes No No
limited
Time (very Yes
long throughout
Pressure-
APRV Yes Yes inspiratory, Yes Yes the
limited
short respiratory
expiratory) cycle
Pressure-
limited
PRVC with goal Yes Yes Time Yes Yes No
tidal
volume
Yes
Pressure- (inspiratory
limited Flow, pressure
VAPSV and No Yes pressure, or No varies to No
volume- time achieve
assured goal tidal
volume)
Yes
(pressure
and volume
vary
% of
Work of depending
PAV No Yes assistance set No No
breathing on
to give
pulmonary
compliance
and
resistance)
AC, assist control; SIMV, synchronized intermittent mandatory ventilation; PSV, pressure support ventilation;
Flash Card A7 PCV, pressure-controlled ventilation; APRV, airway pressure release ventilation; PRVC, pressure-regulated
volume control; VAPSV, volume-assured pressure support ventilation; PAV, proportional assist ventilation
Perform awake intubation
with fiberoptic guidance.
CRITICAL CARE / 107
ASSIST CONTROL—Additional breaths initiated by the patient above the

minimum respiratory rate trigger the ventilator to supply an additional mandatory
breath to the set volume or pressure (Figure 2-10). Potential complications include
hyperventilation and breath stacking.
Figure 2-10. Assist control mode. Example of flow and pressure versus time
graphics.
SYNCHRONIZED INTERMITTENT MANDATORY VENTILATION—Differs from

assist control in that each additional breath above the set generated by the patient
is either spontaneous or mandatory, depending on an algorithm (Figure 2-11).
Three potential types of breath:

 Mandatory
 Assisted
 Pressure-supported spontaneous
PRESSURE-SUPPORTED VENTILATION—All breaths are initiated by the

patient. Delivered volume varies from breath to breath. Duration is determined by
the patient’s inspiratory effort and terminated when inspiratory flow decreases to
a preset level, usually 25% of peak flow (Figure 2-12).
108 / CHAPTER 2
Figure 2-11. Tracings for volume-targeted synchronized intermittent mandatory

ventilation (SIMV). Note the negative deflection and smaller tidal volume for the
spontaneous breath.
Figure 2-12. Tracings for pressure support ventilation.

CRITICAL CARE / 109
PRESSURE-CONTROLLED VENTILATION—See Figure 2-13.

 Inspiratory pressure is set.
 Duration of inspiratory time is set by adjusting inspiratory time or the
inspiratory/expiratory ratio.
 Lung volumes vary, depending on lung compliance.
 Uncomfortable and requires heavy sedation because spontaneous breaths are
not being supported.
 Used in ARDS.
Figure 2-13. Tracings for pressure control ventilation. Ti, inspiratory time; I:E,
inspiratory/expiratory ratio; ARDS, acute respiratory distress syndrome.
BILEVEL VENTILATION AND AIRWAY PRESSURE RELEASE

VENTILATION—See Figure 2-14.
110 / CHAPTER 2
Key Fact
Airway pressure release
ventilation is an option for
patients with refractory
hypoxemia as a result of
ARDS. It is best used in
patients who are breathing
spontaneously and are
without bronchospasms or
copious amounts of
secretions that would put
them at high risk for auto-
PEEP.
Figure 2-14. Airway pressure release ventilation pressure-time graphic. ARDS,

acute respiratory distress syndrome; PEEP, positive end-expiratory pressure.
PRESSURE-REGULATED VOLUME CONTROL—Also referred to as Volume

Control Plus (Puritan Bennett 840), AutoFlow (Dräger), adaptive pressure control,
and adaptive support ventilation, depending on the ventilator manufacturer.
Clinician sets a goal tidal volume and inspiratory time, and with each breath the
ventilator adjusts the pressure to achieve the goal tidal volume.
VOLUME-ASSURED PRESSURE SUPPORT VENTILATION—Pressure limited

but volume guaranteed. Similar to pressure-regulated volume control, the only
difference is that the patient is breathing spontaneously and there is no set
mandatory breath.
CRITICAL CARE / 111
PROPORTIONAL-ASSIST VENTILATION—Another spontaneous mode similar

to pressure-supported ventilation. However, in this case, there is real-time
feedback so that pressure support can be adjusted based on respiratory resistance
and compliance breath to breath. No target flow, volume, or pressure is set.
NEURALLY ADJUSTED VENTILATORY ASSIST—Initiation of a breath is

determined by the electrical activity of the diaphragm, which is sensed by a
nasogastric tube with electrodes.
Monitoring Patients on Mechanical Ventilation
Monitoring airway pressure, volume, and flow can help to determine the etiology
of changes in respiratory status. Resistance can be determined by the following
equation:
Resistance = Peak inspiratory pressure − Plateau pressure/flow
The difference in peak inspiratory pressure and plateau pressures can generate a
specific differential diagnosis for the etiology of respiratory distress (Figure 2-
15).
Flash Card Q8
A patient with a severe
exacerbation of COPD is
having ineffective triggering
because of auto-PEEP.
You increase the applied
PEEP. What parameter
would you follow to
Figure 2-15. Difference in peak inspiratory pressure (PIP) and plateau to aid with determine whether
determination of the etiology of respiratory distress. PEEP, positive end- excessive PEEP is being
expiratory pressure. applied?
112 / CHAPTER 2
Static compliance = Tidal volume/Plateau – PEEP
Dynamic compliance = Tidal volume/Peak inspiratory pressure – PEEP
PATIENT–VENTILATOR ASYNCHRONY—Asynchrony with the ventilator can

occur during:
 Triggering of a breath
 Inspiratory flow
 Cycling
Triggering of a breath: Three problems can occur with triggering:

 Ineffective triggering
 Double triggering
 Auto-triggering
Ineffective triggering can occur when the patient does not create sufficient change
in airway pressure or flow to initiate a positive pressure breath (Figure 2-16).
The most common cause of ineffective triggering is auto-PEEP. With auto-PEEP,

increased intrathoracic pressure raises the pressure drop needed for the patient to
trigger a breath.
Other causes of ineffective triggering are low respiratory drive, weak inspiratory
muscles, partially blocked endotracheal tube, alkaline pH, high trigger sensitivity,
and expiratory asynchrony with delayed opening of the exhalation valve.
Flash Card A8
A rise in peak pressure. As
long as applied PEEP is
less than auto-PEEP, peak Figure 2-16. Ineffective triggering. Patient inspiratory effort does not trigger a
pressures will not change. breath (arrows).
However, once applied
PEEP is greater than auto-
PEEP, peak and plateau
pressures will increase,
placing the patient at risk
for ventilator-induced lung
injury.
CRITICAL CARE / 113
Double triggering occurs when two positive pressure breaths occur with a limited
expiratory phase between them that can result in large tidal volumes (Figure 2-
17). Double triggering occurs when ventilator inspiratory time is shorter than the
patient’s inspiratory time. Ventilator adjustments to reduce double triggering
include increasing tidal volume, inspiratory time, or sedation and switching to a
variable flow setting.
Figure 2-17. Double triggering. Two breaths with limited expiration time between
them (arrows).
Auto-triggering occurs when the ventilator is triggered without the patient

initiating a breath (Figure 2-18). This typically occurs because of circuit leaks,
fluid in the circuit, chest tube leaks, vibration from the ventilator tubing, and
cardiogenic oscillations. Exhaled tidal volumes are reduced, and respiratory rate
increases.
Figure 2-18. Auto-triggering. Note the increase in respiratory rate without

triggering by the patient (absence of negative deflection on pressure-time
graphic).
Inspiratory flow: Asynchrony occurs when the set flow rate is lower than the
patient’s desired flow rate. The pressure–time graphic shows a concave deflection
because the patient creates negative pressure to pull more flow (Figure 2-19).
114 / CHAPTER 2
Key Fact
Figure 2-19. Pressure–time graphic of normal decelerating ramp versus flow
A patient who is receiving
mechanical ventilation starvation showing the concave deflection.
because of ARDS has
increased work of Cycling: Asynchrony occurs when the duration of breath delivered by the
breathing and a concave
deflection on the pressure– ventilator does not match the duration of the patient’s desired breath. If the
time graphic. Increasing duration of breath is longer than the patient desires, an increase in airway pressure
the flow rate improves the is seen on the pressure–time graphic at the end of inspiration, with an increase in
inspiratory flow asynchrony
and relieves the work of expiratory flow on the flow–time graphic (Figure 2-20). Ventilator adjustments to
breathing. correct this cycling asynchrony include shortening inspiratory time and increasing
flow. If the duration of breath is shorter than the patient desires, because of
persistent patient effort, the airway pressure curve is pulled downward and there
is reversal of expiratory flow after breath termination (not pictured). This
persistent effort may trigger a second breath.
Table 2-21 summarizes patient-ventilator asynchrony.

Key Fact
Cycling asynchrony caused
by duration of breath
longer than the patient
desires is seen on the
flow–time graphic with
variation in expiratory flow
and is seen as pressure
spikes on the pressure–
time graphic. Increasing
the flow should improve
cycling asynchrony.
Figure 2-20. Cycling asynchrony with delayed termination. Flow–time graphic

(top) and pressure–time graphic (bottom). Variation in expiratory flow on the
flow–time graphic (green arrows). Pressure spike caused by the patient’s
expiratory effort during inspiratory time (blue arrows).
CRITICAL CARE / 115
Table 2-21. Summary of Patient–Ventilator Asynchrony
Asynchrony Etiology Graphics Adjustments

Triggering Inadequate pressure Inspiratory effort that Auto-PEEP most
change or flow does not trigger a common cause: ↑
Ineffective breath PEEP
Double Inadequate inspiratory Two subsequent ↑ tidal volume,
time breaths with limited inspiratory time,
expiratory time between sedation
them
Switch to variable flow
setting
Auto Ventilator triggering Increase in respiratory Evaluate for leak in
without patient initiation rate without patient circuit, leak in cuff, and
triggering condensation in tube
Flow Inadequate flow rate Concave deflection on ↑ flow rate
pressure–time graphic
Cycling Duration of breath is too Variation in expiratory ↓ inspiratory time

short/long flow
↑ flow
Pressure spike on
pressure–time graphic
AUTO-PEEP—When a patient cannot fully exhale between breaths, breath

stacking occurs, with resulting overinflation and auto-PEEP.
Key Fact
Overinflation → risk of alveoli rupture → compression of alveoli capillaries → ↑ Auto-PEEP is apparent on
dead space → flattened diaphragm → ↓ tidal volume and ↑ respiratory rate the flow–time graphic when
expiratory flow does not
return to baseline before
Auto-PEEP → ↓ venous return → ↓ right and left heart filling → ↑ right the next inspiratory cycle.
ventricular overload secondary to ↑ intrathoracic pressures
Uncorrected, auto-PEEP can progress to hypotension, shock, and pulseless

electrical activity. Prompt disconnection of the patient from the ventilator until
exhalation is complete results in dramatic improvement in blood pressure and
oxygenation.
Ventilator adjustments to reduce auto-PEEP include reducing respiratory rate,

reducing tidal volume, and increasing inspiratory flow rate. Bronchodilator
administration can assist exhalation in patients with bronchospasm.
If auto-PEEP is causing ineffective triggered breaths, the PEEP setting on the

ventilator can be increased to reduce the amount of pressure drop needed for the
patient to trigger a breath.
Auto-PEEP can be detected on the flow–time graphic by failure of expiratory

flow to return to baseline before the next inspiratory cycle (Figure 2-21).
116 / CHAPTER 2
Figure 2-21. Auto-PEEP. Flow–time graphic shows failure of expiratory flow to

return to baseline (arrows).
Airflow obstruction: Patients with exacerbation of COPD or status asthmaticus

have severe overflow obstruction that increases the risk of auto-PEEP and
barotrauma. Adequate sedation is needed to control tachypnea, bronchodilators
administered to reduce airflow obstruction, and reduced minute ventilation set to
provide sufficient expiratory time. Elevations of PaCO2, known as permissive
hypercapnia, are tolerated in this population unless otherwise contraindicated.
Contraindications include intracranial hypertension, pulmonary hypertension, and
cardiac arrhythmia.
PEEP has less of a role in respiratory failure from parenchymal lung disease. FiO2
is increased to treat hypoxemia unless the patient has ineffective triggering as a
consequence of auto-PEEP. In this case, increasing PEEP can help (see earlier
section on ineffective triggering).
Because flow is determined by gas density, reduction in gas density increases

flow. The use of helium has been proposed in severe airflow obstruction. Heliox
comes in 80:20, 70:30, or 60:40 mixtures of helium to oxygen.
Complications of Positive Pressure Ventilation

Table 2-22 shows complications with specific prevention and treatment options.
CRITICAL CARE / 117
Table 2-22. Complications Positive Pressure Ventilation
Complication Symptoms Prevention Treatment

Laryngeal injury: Laryngeal edema: Avoidance of large and Laryngeal edema:
Laryngeal edema Extubation failure excessive movement of Corticosteroids
Mucosal endotracheal tube
Granulomas: Granulomas: Fiberoptic
ulceration
Hoarseness 7–10 days laryngoscopy
Granulomas
after extubation
Vocal cord
paralysis Vocal cord paralysis:
Hoarseness
immediately after
extubation (unilateral) or
extubation failure
(bilateral)
Dysphagia Swallowing impairment Cause unknown Typically resolves, no
treatment necessary
Tracheal stenosis Dyspnea within 5 wk of Cuff pressure 18–25 Surgery, stenting, laser
extubation mm Hg therapy
Tracheoesophagea Recurrent aspiration Cuff pressure 18–25 Surgery

l fistula pneumonias mm Hg
Sinusitis Purulent nasal drainage No statistical difference Endoscopic-guided

and fever found between middle meatal
treatment with nasal - aspiration for culture
adrenergic agonist and (gold standard) vs.
glucocorticoid empiric antibiotics (in
practice, empiric
Ventilator- Fever, leukocytosis, Chlorhexidine mouth Antibiotics
associated purulent tracheal scrubs and keep height
pneumonia secretion, radiographic of bed equal to or
infiltrate greater than 30 degrees
Barotrauma Extra-alveolar air leaks Reduction in ventilator Chest tube Flash Card Q9
(pneumomediastinum, pressure
pneumopericardium, What are the specific
subcutaneous ventilator strategies in a
emphysema, patient with severe airflow
pneumothorax, air obstruction?
emboli)
Heart and Lung Interactions on Mechanical Ventilation Flash Card Q10

A 78-year-old woman is
Table 2-23 shows the changes to the heart and lung when positive pressure evaluated in your clinic for
exertional dyspnea that
ventilation is applied. started 1 week ago. She
was recently intubated for
10 days for ARDS and was
extubated successfully 4
weeks ago. Spirometry is
performed and shows
flattening of both the
inspiratory and expiratory
flow loops. What is the
most appropriate next step
in evaluation of this
patient’s dyspnea?
118 / CHAPTER 2
Table 2-23. Effects of Positive Pressure Ventilation on the Heart and

Lung
Key Fact
Heart Lung
Depending on the clinical
situation, it is common to ↓ venous return Distention of alveoli results in compression of
see hypotension in a alveolar blood vessels, ↑ in pulmonary vascular
patient who is given resistance, ↓ right ventricular stroke volume
positive pressure ↑ in pulmonary vascular resistance may ↓ normal intrapleural pressure gradient
ventilation because of the cause leftward shift of interventricular
effects of a decrease in septum, narrowing lumen of left ventricle,
venous return. This and worsening diastolic function
phenomenon is further ↓ left ventricular afterload Better ventilation of nondependent regions of
exacerbated with PEEP lung (poorly perfused areas), resulting in ↑
administration and alveolar dead space
hypovolemia. In ventilator modes that do not have active
contraction of diaphragm, regional closure of
alveoli at lung bases results in ↑ shunt
The reduction in venous return is partially counteracted by the decrease in left

ventricular afterload. In left-sided heart failure, the reduction in afterload from
positive pressure ventilation may improve cardiac output and impede ventilator
liberation.
Liberation from the Ventilator

PROTOCOL-BASED LIBERATION—Protocol-based liberation administered
daily by respiratory therapists can reduce the duration of ventilation with fewer
complications compared with gradual reduction in pressure support or decreasing
mandatory breaths on synchronized intermittent mandatory ventilation. These
protocols incorporate daily screenings to answer important questions outlined in
Table 2-24.
Table 2-24. Protocol-Based Liberation

Flash Card A9
Parameter Measure
Smaller tidal volume and
lower respiratory rate to Hemodynamic stability Absence of vasopressors
decrease administered
Mental status Daily sedation interruptions
minute ventilation to
reduce the risk of auto- Intermittent sedation
PEEP. If there are no Oxygenation Positive end-expiratory pressure ≤ 5
contraindications,
permissive hypercapnia is FiO2 ≤ 50%
tolerated in this subset of Lung mechanics Respiratory frequency/tidal volume < 105
patients. Ventilatory endurance Passes spontaneous breathing trial
Secretion clearance Good cough
Flash Card A10 Suction frequency < every 2 h
Airway patency Cuff leak
Fiberoptic laryngoscopy to
evaluate for tracheal
stenosis
CRITICAL CARE / 119
Sedation plays an important role in liberation from the ventilator. Studies have
shown the benefit of daily interruptions of sedation and intermittent sedation over
continuous infusion.
The rapid shallow index has been shown in some studies to delay the weaning
process. Some centers have removed this criterion from the liberation protocol.
Once certain criteria are met, patients are placed on a spontaneous breathing trial
for 30–120 minutes on either CPAP 5 cm H2O, T-tube, or automated tube
compensation (use of pressure support to overcome the resistance of breathing
through an endotracheal tube).
The percentage of cuff leak is determined by giving a breath with a tidal volume Key Fact
of 10 mL/kg of predicted body weight with the cuff inflated and then with the cuff Depending on the clinical
deflated. The optimal timing for
tracheostomy is unknown.
% cuff leak = VT exhaled (cuff inflated) – VT exhaled (cuff deflated)
VT exhaled (cuff inflated)
If cuff leak is < 25%, one study showed a reduction in postextubation stridor (6%
versus 30%) with methylprednisolone 40 mg every 6 h × 4 doses.
TRACHEOSTOMY—For long-term mechanical ventilation, tracheostomy is

considered a more stable and comfortable (with less use of sedatives) alternative
to the endotracheal tube. However, the optimal timing for tracheostomy is
unknown. A meta-analysis study found a shorter duration of mechanical
ventilation and shorter ICU length of stay with “early” tracheostomy but no
change in the rate of pneumonia or mortality. In this meta-analysis, “early” was
defined as < 7 days on mechanical ventilation and “late” was defined as 8–16
days on mechanical ventilation.
Flash Card Q11

Noninvasive Ventilation A 67-year-old man who is
being treated for
pneumonia is receiving
APPROPRIATE CANDIDATES—When determining whether a patient will be mechanical ventilation with
successful on noninvasive positive-pressure ventilation (NPPV), factors to a current setting of
consider are mental status, ability to protect the airway, and severity of the acid– pressure support of 18 cm
H2O with PEEP of 5 cm
base disorder. Table 2-25 shows which patients are not appropriate for NPPV. H2O and FiO2 40%. He is
Patients who show improvement in mental status, PCO2, pH, and respiratory rate placed on a spontaneous
within the first few hours of NPPV are likely to be more successful. breathing trial but becomes
anxious, tachycardic, and
hypertensive, with oxygen
saturation dropping to
89%. He is returned to his
baseline ventilator settings
and stabilizes. What is the
strategy to successfully
liberate him from the
ventilator?
120 / CHAPTER 2
Table 2-25. Contraindications for Noninvasive Ventilation
Overt respiratory distress Cardiopulmonary arrest
Hemodynamic instability Glasgow Coma Scale score < 10
Facial trauma or deformity Gastrointestinal bleed
NPPV has been studied in multiple populations and was found to be beneficial in
certain circumstances (Table 2-26).
Other considerations include post-lung resection and thoracoabdominal surgery.

A randomized trial of patients after lung resection also found a reduction in
intubations, ICU length of stay, and mortality rate when NPPV was used. NPPV
has also been used prophylactically to reduce atelectasis and hypoxemia in
thoracoabdominal surgery.
Table 2-26. Indications Noninvasive Positive-Pressure Ventilation

Key Fact
Good candidates for NPPV Specific Patient Population Considerations
include those with
exacerbation of COPD, Exacerbation of COPD Severity of acidosis:
cardiogenic pulmonary Initial 7.1 < pH < 7.35
edema, or Initial PCO2 < 92 mm Hg
immunocompromised state Cardiogenic pulmonary edema Absence of:
with minimal secretions, Shock
mild to moderate acidosis, Acute coronary syndrome requiring acute coronary
nonsomnolence, and revascularization
hemodynamic stability.
Fever and pulmonary infiltrates Avoidance of intubation because this population is at increased
in immunocompromised host risk for ventilator-associated pneumonia and alveolar
hemorrhage while receiving mechanical ventilation
Liberation from ventilator Beneficial in patients with COPD
Can consider if patient:

Is receiving < 15 cm H2O pressure support
Can sustain 10 minutes of unassisted breathing
Has adequate cough with minimal secretions
Has COPD
“Rescue” postextubation Considered in patients with COPD or hypercapnic respiratory
failure
Prompt reintubation if noninvasive positive-pressure ventilation

Flash Card A11 fails
COPD, chronic obstructive pulmonary disease.
Repeat spontaneous
breathing trials daily.
CRITICAL CARE / 121
HYPERCAPNIC RESPIRATORY FAILURE
Hypercapnic respiratory failure is primarily caused by problems with ventilation

Table 2-27). Hypercapnia is caused by increased production of CO2 or reduced
alveolar ventilation. Their relationship is illustrated by the following formula:
PaCO2 = K(VCO2/VA)
K = 0.863, which is a constant
VCO2 = CO2 ventilation
VA = alveolar ventilation
The most common causes of hypercapnia are disorders of alveolar ventilation.

Examples are shown in Table 2-28. Methods of monitoring for hypercapnia and
reduced alveolar ventilation are discussed later.
Table 2-27. Mechanisms of Hypercapnia

Increased CO2 Production Reduced Alveolar Ventilation
Fever, exercise See Table 2-28
Overfeeding with carbohydrates
Table 2-28. Disorders of Alveolar Ventilation

Organ System Examples
Central nervous system Overdose of narcotics and sedatives
Medullary infarct or tumor
Spinal cord injury above C3
Amyotrophic lateral sclerosis
Central sleep apnea
Congenital central hypoventilation
Tetanus
Rabies
Peripheral nervous system Guillain-Barré syndrome
Critical illness polyneuropathy and myopathy
Tick paralysis
Myasthenia gravis
Lambert-Eaton syndrome
Organ phosphorous poisoning
Disorders of airways Status asthmatics
Exacerbation of chronic obstructive pulmonary disease
Bronchiectasis flare
Disorders of alveoli Adult respiratory distress syndrome
Pulmonary edema
Pneumonia
Disorders of chest wall, Kyphoscoliosis
diaphragm, and muscles Flail chest
Diaphragmatic paralysis/paresis
Dermatomyositis, polymyositis
Severe electrolyte abnormalities (e.g., hypokalemia,
hypophosphatemia, hypomagnesemia)
122 / CHAPTER 2
Capnography
Capnography is noninvasive monitoring of partial pressure of carbon dioxide
(CO2) in exhaled breath and is expressed as CO2 concentration over time
(capnogram). End tidal CO2 (EtCO2) is the CO2 concentration at the end of each
tidal breath. The normal value is 35–45 mm Hg.
Capnogram has four phases Figure 2-22:

 Phase 1 (a) is the beginning of expiration, where the dead space is cleared
from the airways.
 Phase 2 (a–b) is the rapid rise in CO2 concentration as the CO2 from the
alveoli reaches the upper airway.
 Phase 3 (b–c) occurs when the CO2 concentration reaches a plateau. Point c,
occurring at the end of the plateau, is the maximum CO2 concentration at the
end of the tidal breath and is the EtCO2.
 Phase 4 (c–d) is the start of inspiration.
Changes in the shape of the capnography curve are diagnostic of disease
conditions, and changes in EtCO2 can be used to assess disease severity and
response to treatment. EtCO2 in patients with lung disease is only useful for
assessing trends over time, and isolated EtCO2 values may not correlate with
PaCO2. Patients with normal lung function have characteristic rectangular
capnograms, as shown in Figure 2-23 (with a narrow gradient of 0–5 mm Hg
difference between PaCO2 and EtCO2). Patients with obstructive lung disease have
impaired expiratory flow and show a more rounded ascending phase (phase 2) and
an upward slope in the alveolar plateau, as shown in Figure 2-23, denoted by the
blue arrows. Caution must be exercised in patients with ventilation–perfusion
mismatch because the EtCO2 and PaCO2 gradient widens, depending on the
severity of lung disease.
Figure 2-22. Normal capnography pattern.

CRITICAL CARE / 123
Figure 2-23. Comparison of normal capnography wave form and wave form in
chronic obstructive pulmonary disease (COPD). In COPD, a more rounded
ascending phase (phase 2) is seen as well as an upward slope in the alveolar
plateau (blue arrows).
Key Fact
During CPR, the Advanced
Cardiac Life Support
The most important clinical use of capnography is endotracheal intubation. It is a provider can use EtCO2:
reliable indicator for tube placement in the trachea. In addition, the current  To evaluate the
Advanced Cardiac Life Support guidelines recommend quantitative capnography effectiveness of CPR,
denoted by an increase in
during chest compressions to assess quality of chest compressions (EtCO2 < 10
EtCO2 (EtCO2 increases
mm Hg, indicating poor quality of CPR). Perfusion is reestablished immediately, with increased cardiac
accompanied by a dramatic increase in EtCO2. output)
 To determine resumption
of spontaneous
Hypercapnia and Neuromuscular Disorders circulation, which is
accompanied by a
dramatic increase in
Respiratory muscle weakness causing hypercapnia and leading to mechanical EtCO2 (first indicator
ventilation is a common scenario in the ICU. Common disorders include Guillain- because of increased
cardiac output)
Barré syndrome, myasthenia gravis, dermatomyositis, polymyositis, and  EtCO2 < 10 mm Hg
amyotrophic lateral sclerosis. indicates poor quality of
CPR.
No single abnormality is diagnostic of neuromuscular weakness. However,
several objective measures can be used in combination to identify abnormalities.
 Maximal inspiratory pressure reflects the strength of the diaphragm and other
inspiratory muscles. It is synonymous with negative inspiratory force and
indicates a high risk of hypercapnia.
 Maximal expiratory pressure reflects the strength of the abdominal muscles
and other expiratory muscles and indicates inadequate cough strength and risk
of retention of secretions.
 Restrictive pattern is seen on pulmonary function tests.
 Reduction is seen in supine forced vital capacity compared with upright
forced vital capacity.
 Reduction is seen in maximal voluntary ventilation.
124 / CHAPTER 2
Maximal inspiratory pressure and maximal expiratory pressure measured in an

individual patient are compared with a reference range or the lower limit of
normal and are rarely used alone. Rather, they are considered in conjunction with
other measures, such as vital capacity and forced vital capacity. The “20-30-40
rule” has been proposed and advocates the initiation of ventilatory support when
vital capacity is < 20 mL/kg, maximal inspiratory pressure is less negative than
−30 cm H2O, or MEP is < 40 cm H2O.
Serial measurements can be used as a rough guideline to predict the need for
elective intubation. However, patients who have severe respiratory distress,
marked blood gas abnormalities, high risk of aspiration, or impaired
consciousness need immediate mechanical ventilation. In most cases, clinical
findings and objective physiologic tests are used together to determine when
mechanical ventilation is indicated.
PULMONARY COMPLICATIONS OF CARDIOTHORACIC

SURGERY AND TRAUMA
Pulmonologists must be aware of common complications associated with

cardiothoracic surgery and trauma (Table 2-29). They are frequently seen by
intensivists and pulmonologists.
Table 2-29. Common Complications of Computed Tomography Surgery

and Trauma
Computed Tomography Surgery Trauma
Postoperative atelectasis, diaphragmatic Trauma and pain leading to atelectasis and

paresis diaphragmatic injury and paralysis
Postoperative pleural effusion, postcardiotomy Hemothorax, pneumothorax,
syndrome hemopneumothorax
Bronchopleural fistula because of flail chest and
Bronchopleural fistula after pneumonectomy
blunt chest trauma
Postoperative Atelectasis and Diaphragmatic Dysfunction
POSTOPERATIVE ATELECTASIS—Atelectasis is one of the most common

postoperative pulmonary complications, particularly after abdominal surgery. An
example is shown in Figure 2-24. It is caused by decreased compliance of lung
tissue, decreased regional ventilation, excessive secretions, and postoperative pain
CRITICAL CARE / 125
that interferes with deep breathing, leading to hypoxia. Proven therapies that help
with prevention include chest physiotherapy, incentive spirometry, and CPAP.
Figure 2-24. Postoperative atelectasis of the right lower lobe.

(Image reproduced from Wikimedia Commons, permission granted per the GNU Free Documentation License.)
DIAPHRAGMATIC DYSFUNCTION—The diaphragms are innervated by the

ipsilateral phrenic nerves, which derive from nerve roots C3, C4, and C5. Injury
to one of the phrenic nerves results in diaphragmatic paralysis that is usually
unilateral but can be bilateral. Patients with unilateral paralysis are usually
asymptomatic at rest, but may have symptoms on exertion.
Unilateral paralysis is usually suggested by an elevated hemidiaphragm on chest

x-ray. This can be confirmed by fluoroscopy that shows paradoxical elevation of
the paralyzed hemidiaphragm compared with rapid descent of the normal
hemidiaphragm on inspiration (sniff test). The sniff test is positive in > 90% of
patients with unilateral paralysis. Pulmonary function testing, forced vital
capacity, and maximal inspiratory pressure are usually decreased in setting of
normal maximal expiratory pressure.
Most patients with unilateral diaphragmatic paralysis are asymptomatic and

require no treatment; however, a small percentage of patients require surgical
plication, depending on the severity of symptoms. Patients with bilateral
126 / CHAPTER 2
diaphragmatic paralysis are more likely to require ventilatory support.

Diaphragmatic pacing can also be considered in patients with intact phrenic nerve
function.
Postoperative Pleural Effusion

Postoperative pleural effusion is common after abdominal and cardiothoracic
surgery. Most cases resolve spontaneously within a few days. However, atypical
characteristics of either the pleural effusion or the patient’s clinical condition
warrant further evaluation. Pleural effusion after cardiac surgery may be early (<
30 days) or late (> 30 days).
Common causes of pleural effusion after cardiac surgery are shown in Table 2-30.
Table 2-30. Etiology of Pleural Effusions After Cardiac Surgery

Early Pleural Fluid Pleural Fluid
Analysis
Late Analysis
Surgical damage of Chylous and Constrictive pericarditis Exudative or
mediastinal lymphatic exudative transudate
channels
Topical cardiac cooling Transudate or Trapped lung Transudate
leading to pleural injury exudate
Postpericardiotomy Exudative with high Heart failure Transudate

syndrome neutrophil and
eosinophil count
Pleurotomy Exudative and Unresolved Exudative with
hemorrhagic postpericardiotomy lymphocytic
syndrome predominance
Postpericardiotomy syndrome typically occurs ≥ 1 week after myocardial injury.
Characteristics:
 Fever
 Leukocytosis
 Elevated erythrocyte sedimentation rate
 Pulmonary infiltrate
 Pericardial effusion
 Pleural effusion
Physiologically, postpericardiotomy syndrome is hypothesized to be an

immunologic response to damaged cardiac tissue because of the time lag of onset,
response to steroids, and presence of antimyocardial antibodies. Pleural fluid
CRITICAL CARE / 127
analysis shows an exudative effusion with normal pH and glucose levels. The cell
count differential shows a predominance of polymorphonuclear cells during the
acute phase and mononuclear cells later in the course. Various trials have
evaluated empiric treatment with aspirin, prednisone, colchicine, and nonsteroidal
antiinflammatory drugs to prevent postpericardiotomy syndrome. However, there
is no consensus and the treatment depends on clinician preference.
Bronchopleural Fistula
Bronchopleural fistula is a patent sinus tract between the bronchus and the pleural
space that may result from a variety of causes:
 Necrotizing pneumonia/empyema
 Lung neoplasm
 Blunt and penetrating chest injury
 Complication of a procedure (lung biopsy, chest tube drainage,
thoracocentesis, pneumonectomy)
 Complication of radiation therapy
Bronchopleural fistula may occur after pneumonectomy if bronchial stump

healing does not occur and may be noted in 1–20% of cases. It is diagnosed by a
persistent air leak from a chest tube for > 24 hours and can present 7–14 days
after the procedure. In patients with no chest tube, bronchopleural fistula can
present as a steady increase in the size of the pneumothorax or as a tension
pneumothorax.
Risk factors:
 Right-sided procedure
 Large bronchial stump
 Residual tumor
 Radiation therapy
 Age > 60 years
 Prolonged postoperative mechanical ventilation
Fiber optic bronchoscopy with selective instillation of methylene blue into the
segmental bronchi, with its subsequent appearance in the chest drainage, can
confirm the location of a bronchopleural fistula.
Management options are shown in Table 2-31.

128 / CHAPTER 2
Table 2-31. Management of Bronchopleural Fistula
Management/Procedure Comments
Medical management Dependent drainage, antibiotics, nutritional supplementation

Mechanical ventilation Significant therapeutic challenge because of insufficient healing
Ventilator modes that can be used:
Single lung ventilation
High-frequency oscillation ventilation
Airway pressure release ventilation
Tube occlusion during inspiration
Low-positive end-expiratory pressure ventilation
Short inspiration times
Bronchoscopy Bronchoscopic placement of gel foam, autologous blood patch,
fibrin glue
Use of intrabronchial valves
Placement of stents
Bronchoscopic submucosal injection of absolute ethanol
Closure of small fissure with Nd:YAG laser
Surgical options Surgical closure by muscle flap to fill pleural space
Pleurodesis for management of peripheral air leaks
Surgical decortication an option in intractable cases
Flail Chest and Blunt Chest Trauma
Flail chest occurs in when three or more consecutive ribs are fractured in two or
more places, creating a floating segment in the chest wall. It occurs as a
complication of trauma and is seen in ~ 10% of patients with chest wall injury.
Flail chest is clinically diagnosed by paradoxical motion of the chest wall. The
detached segment of the chest wall is pulled into the chest cavity during
inspiration and pushed outward during expiration. This abnormal motion
increases the work of breathing and compromises respiratory function.
Conservative management with pain control and prevention of atelectasis should

be the primary goal of treatment, but intubation and ventilatory support may be
needed for internal stabilization through positive pressure. Patients who cannot be
weaned from mechanical ventilation may benefit from operative rib fracture
fixation.
Hemothorax
Hemothorax is diagnosed when pleural fluid hematocrit is > 50% of total body
hematocrit. Causes include aortic rupture, myocardial rupture, and injury to the
intercostal or mammary blood vessels postsurgery. Hemothorax is treated with
CRITICAL CARE / 129
tube thoracostomy using a large (minimum 36 French) chest tube. Immediate

bloody drainage > 1.5 L fluid is generally considered an indication for surgical
exploration.
MASSIVE HEMOPTYSIS
Massive hemoptysis is 100–1000 mL of expectorated blood in a 24-hour period.

Identifying the source of bleeding, minimizing contamination of nonaffected areas
of lung via positioning, and securing the airway are the most important factors.
Common causes of massive hemoptysis are listed in Table 2-32.
Table 2-32. Causes of Massive Hemoptysis
Local Causes Diffuse Causes

Pulmonary: Hematologic:
Bronchiectasis Coagulopathy
Pulmonary embolism Disseminated intravascular coagulation
Cystic fibrosis
Necrotic pneumonias
Mycetoma
Lung abscess
Tuberculosis
Lung cancer
Bronchial adenoma
Vascular: Systemic disease:
Arteriovenous malformation Goodpasture syndrome
Aortic aneurysm Granulomatosis with polyangiitis
Endocarditis causing septic emboli Systemic lupus erythematosus
Tracheal innominate artery fistula Rheumatoid arthritis
Microscopic polyangiitis
Churg-Strauss syndrome
Mixed connective tissue disease
Primary antiphospholipid syndrome
Bronchoscopy Drugs:
Pulmonary catheter placement Anticoagulants
Crack cocaine
Thrombolytic agents
Trauma: Miscellaneous:
Ruptured bronchus Lymphangioleiomyomatosis
Penetrating chest trauma Idiopathic pulmonary hemosiderosis
Foreign body
Flash Card Q12

What is the optimal
position for a patient who is
bleeding from the right
lung?
130 / CHAPTER 2
PATHOPHYSIOLOGY—Bronchial artery circulation is the first area evaluated via

angiography in massive hemoptysis. The pulmonary arteries are generally studied
only if bronchial arteriography does not identify a bleeding source because it is
responsible for < 10% of cases of massive hemoptysis.
MANAGEMENT—Management of all patients includes airway management,

correction of coagulopathy, and either nonsurgical or surgical intervention to
achieve hemostasis (Table 2-33).
Table 2-33. Management of Massive Hemoptysis and Associated Risks
Intervention Comments
Airway Bleeding side down
management Double-lumen endotracheal tube placement vs. selective main stem
intubation
Bronchoscopy Flexible bronchoscopy to evaluate source of bleeding
Rigid bronchoscopy also can be done
Application of iced saline, epinephrine 1:20,000, and thrombin
Single-lumen endotracheal tube placement under flexible bronchoscopy
Use of a bronchial blocker or balloon catheter
If lesion identified: Laser therapy, argon plasma coagulation, electrocautery,
and cryotherapy
Arteriography Bronchial arteries: First vessels studied because they are most common
source of bleeding
Complication: Paraplegia (anterior spinal artery may arise from bronchial
artery)
Bronchial wall necrosis
Surgery Unilateral, uncontrollable bleeding: Evaluation by thoracic surgeon early in
the course of presentation
Emergent surgery for massive hemoptysis: Mortality rate of ~ 20% and
surgical morbidity rate of 25–50%
Contraindications to surgery: Diffuse alveolar hemorrhage (DAH), multiple
arteriovenous malformations, multifocal bronchiectasis, poor baseline lung
function
Flash Card A12

The patient should be
placed in the right-side-
down (bleeding side down)
decubitus position.
OBSTRUCTIVE LUNG DISEASE / 131
3 Obstructive Lung Disease

Nidhi Aggarwal MD, Anthony F. Arredondo, MD, & Abhay Vakil, MBBS
ASTHMA
Asthma is characterized by airway hyperresponsiveness that leads to an

exaggerated contractile response of the airways to a variety of stimuli, resulting in
variable airflow limitation.
PATHOPHYSIOLOGY
Airway inflammation plays an important role in the pathophysiology of asthma.

In many cases, inflammation is triggered by an immune response to allergens.
Exposure to an allergen leads to sensitization. Subsequent exposure to the allergen
starts a cascade of cellular and immune response, leading to airway hyperactivity
and symptoms of asthma.
Atopy
Atopy is defined as a state of having immunoglobulin E (IgE) antibodies to

specific allergens. Total serum levels of IgE are linked to airway
hyperresponsiveness, and elevated IgE levels suggest allergic sensitization. The
correlation between atopy and asthma varies between populations. On average,
the proportion of asthma cases that are attributable to atopy is usually less than
one half. The association between wheezing and atopy is stronger in countries
with higher socioeconomic status. IgE levels correlate with asthma severity;
patients with higher IgE levels tend to have lower 1-second forced expiratory
volumes (FEV1).
Common allergen triggers in sensitized individual include:

 Dust mites
 Pollen
 Domestic pets
 Molds
 Cockroaches
132 / CHAPTER 3
Cellular Response and Inflammatory Mediators Associated

With Asthma
Asthma is mainly an inflammatory disease related to Type 2 T helper (Th2) cells.
Th2 cytokines such as IL-4, IL-5, and IL-13 play a major role in its
pathophysiology.
INITIAL SENSITIZATION—Initial exposure of antigen-presenting cells (also

known as dendritic cells) to an allergen in the airway leads to activation of T
lymphocytes (CD4+). T helper cells develop into the Th2 subtype and secrete Th2
cytokines such as IL-4 and IL-13. This cytokine release then stimulates B cells to
synthesize IgE, which causes allergic sensitization (Figure 3-1).
SUBSEQUENT EXPOSURE—Subsequent exposure to the allergen in a sensitized

individual leads to a cellular immune response and release of mediators, causing
both the early and late phases of asthma (Table 3-1).
Early phase/reaction: Antigen-specific IgE antibodies are bound to receptors on

mast cells.
 Within minutes of exposure to antigen, sensitized mast cells degranulate and
release inflammatory mediators, including histamine, tryptase, prostaglandin
D2, leukotrienes, and cytokines (Figure 3-1). These mediators cause
bronchoconstriction.
 Clinical significance: Mast cell membranes are stabilized by ß-receptor
agonists and cromones such as sodium cromoglycate.
Late phase/reaction: The late phase of the immune response is characterized by

an influx of inflammatory and immune cells, particularly eosinophils, basophils,
neutrophils, and T cells, to sites of allergen exposure.
 Eosinophils:
o The most characteristic cell of allergic asthma.
o Attracted to the bronchial walls by IL-3, IL-5, and granulocytemonocyte
colony-stimulating factor (GM-CSF) secreted by the Th2 cells.
o Release a large number of proinflammatory mediators, including
leukotrienes and basic proteins (Figure 3-1).
o Clinical significance: Corticosteroids decrease number of eosinophils in
circulation, decrease their penetration in the bronchial walls, and prevent
activation of eosinophils that have entered the bronchial walls.
 Basophils secrete IL-4 and IL-13.

 T helper cells:
o Th2 cells infiltrating the airways secrete IL-3, Il-4, IL-5, IL-13, and GM-
CSF.
o Th1 cells cause tissue inflammation and remodeling through release of
interferon  (IFN) and tumor necrosis factor (TNF).
o Th17 cells secrete IL-17 and are associated with neutrophilic inflammation
during acute exacerbation and with tissue remodeling
Table 3-1. Cellular Responses and Mediators in Asthma

Major Mediators
Phase of Asthma Major Cell Types
in Each Phase
Early phase Mast cells Histamine
PGD2
LTC4, LTD4, LTE4
Late phase Eosinophils IL-4, IL-5, IL-13
Basophils MBP
Neutrophils GM-CSF
Helper T cells
Memory T cells
GM-CSF, granulocytemonocyte colony-stimulating factor; IL, interleukins; LT, leukotrienes; MBP, major basic
protein; PG, prostaglandin.
INHIBITORY CELLS AND MEDIATORS—CD4-regulatory T cells inhibit Th2

cells by secreting IL-10 and transforming growth factor beta (TGFβ) (Figure 3-1,
Table 3-2).
Key Fact
IL-4 directs B lymphocytes
to synthesize IgE.
IL-5 regulates eosinophil
production and maturation.
Table 3-2. Inhibitory Cells and Mediators IL-13 leads to airway
eosinophilia, mucous gland
hyperplasia, airway
Inhibitory Cell Inhibitory Mediators
fibrosis, and remodeling.
IL-10
Regulatory T cells
TGFβ
IL, interleukin; TGF, transforming growth factor.
Flash Card Q1
What are the primary T
lymphocytes involved in
the pathogenesis of
asthma?
134 / CHAPTER 3
Figure 3-1. Antigen is presented to APC, leading to activation of a helper T cell.

This activation leads predominantly to Th2 response as well as to Th1 response.
Subsequent recruitment of multiple cell types and release of multiple mediators
causes the asthma response.
APC, antigen presenting cell; GM-CSF, granulocytemonocyte colony-stimulating factor; IFN, interferon; IFN ϒ,
interferon-gamma; Ig, immunoglobulin; IL, interleukin; LT, leukotriene; PG, prostaglandin; TH1, T helper 1 cells;
TH2, T helper 2 cells; Treg, regulatory T cells; Treg, regulatory T cells; TGFβ, transforming growth factor β.
Flash Card A1
Th2 CD4+ T lymphocytes
Nonimmune-Related Asthma
Not all airway hyperresponsiveness is mediated by immune responses.
Nonimmune-related asthma can be seen in reactive airway dysfunction syndrome
(RADS), a subtype of occupational asthma. In RADS, a single exposure to an
irritant renders the patient sensitive to subsequent exposures to similar compounds.
This sensitivity may last for years.
The mechanism of nonimmune airway hyperresponsiveness involves the

denudation of respiratory epithelium, direct inhibition of β-2 receptors, and the
release of substance P by injury to sensory nerves.
Airway Remodeling
Although asthma is classically thought of as a reversible disorder, many patients

with a history of moderate-to-severe allergic asthma develop airway remodeling
and irreversible lung function deficits.
Airway remodeling leads to alterations in structural cells and tissues, causing

persistent airflow obstruction (Figure 3-2).
Figure 3-2. Links between pathologic mechanisms and clinical consequences in

asthma.
(Reproduced, with permission, from Bousquet J et al. Asthma. From bronchoconstriction to Airways
inflammation and remodeling. Am J Respir Crit Care Med 2000;161:1720-1745, Fig 12.
doi:10.1164/ajrccm.161.5.9903102)
MEDIATORS AND FACTORS

 Th1 and IL-13 play an important role in airway remodeling.
 Increased production of epidermal growth factor (EGF), TGFβ, fibrogenic
growth factor (FGF), insulin-like growth factor 1 (IGF-1), vascular
endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF)
lead to cellular and structural damage.
136 / CHAPTER 3
PATHOLOGIC FEATURES—Characteristic features are listed below and shown

in Figures 3-3 and 3-4:
 Smooth muscle hyperplasia
 Subepithelial fibrosis
 Basement membrane thickening
 Increased vascular permeability
 Goblet cell hyperplasia
Figure 3-3. Clinical consequences of airway remodeling in asthma.

(Reproduced, with permission, from Bousquet J et al. Asthma. From bronchoconstriction to airways
inflammation and remodeling. Am J Respir Crit Care Med 2000;161:1720-1745, Fig 11. doi:
10.1164/ajrccm.161.5.9903102)
Figure 3-4. Airway changes in asthma remodeling.

EPIDEMIOLOGY
The age-adjusted prevalence of asthma in the United States increased from 7.3 to
8.2 percent between 2001 and 2009. Higher prevalence and death rates in blacks
than in whites have been attributed to socioeconomic factors and differences in
access to medical care. Genetic polymorphisms may also play a role.
Genetic Susceptibility
Several asthma-related genes and genetic variations have been identified using
linkage analysis in families with asthma, case-control or family-based association
studies, and animal models of asthma traits. However, as of yet, there is no
established clinical utility for these findings.
Environmental Risk Factors (See Table 3-3.)
Table 3-3. Environmental Risk Factors for Asthma

Risk Factor Comments
Perinatal factors Prematurity: increased risk with shorter gestational age
Low birth weight: increased risk independent of prematurity
Maternal diet: maternal vitamin E and zinc intake may confer
protective effect; conflicting data about vitamin D intake
Neonatal jaundice
Mode of delivery: cesarean section increases risk
Maternal smoking
Indoor and outdoor Animals (cats, dogs, rodents); insects (mites, cockroaches);
allergens fungi; plant matter (trees, grass, weeds, pollens)
Smoking and environmental
tobacco smoke
Other pollutants Occupational exposures, endotoxin exposure, indoor gas stove
smoke
Race/ethnicity and Morbidity and mortality higher in blacks than whites as well as in
socioeconomic status patients with low socioeconomic status Flash Card Q2
Obesity A 22-year-old male is seen
for evaluation of his
Early menarche asthma. He was born at a
gestational age of 42
Gender Childhood asthma more common in boys weeks by planned
cesarean section to a 19-
Incidence increases in females by puberty
year-old mother. During
Equal prevalence in both sexes by age 40 pregnancy his mother took
More common in females than males after 40 herbal pills containing
Medication use Acetaminophen vitamin K. Which of these
Antibiotic use during infancy perinatal factors is
associated with the
Postmenopausal hormone replacement therapy development of childhood
asthma?
138 / CHAPTER 3
DIAGNOSIS OF ASTHMA IN ADOLESCENTS AND ADULTS
Clinical Features
Key Fact HISTORY—Although most patients experience wheezing, coughing, and

There is no gold standard shortness of breath in varying degrees during acute episodes, there is no single
for the diagnosis of symptom that is specific for asthma. Sometimes cough is the only presenting
asthma. It is a clinical symptom. More severe episodes are accompanied by chest tightness.
diagnosis based on history,
patient characteristics,
physical findings, and the Historical features that increase the probability of an asthma diagnosis:
results of other
evaluations.
 Episodic nature of symptoms that may worsen at night, with seasonal changes
in weather, or after exposure to a trigger or allergen, and may resolve
spontaneously after removal of triggering stimulus.
 Presence of characteristic triggers, including cold air, exercise, environmental
Key Fact allergens, chemical irritants, viral and bacterial infections, or exposure to
certain medications (aspirin).
New-onset asthma,
although possible, is rare in  Symptoms usually occur within 30 minutes after exposure and resolve either
older adults. The majority with treatment or cessation of exposure.
of cases are diagnosed in
childhood, with most of the
 Personal history of environmental allergies, including presence of runny nose
remaining cases diagnosed or watery eyes with changes in seasons or exposure to allergens.
in their teens and twenties.  Family history of allergies or asthma.
 History of asthmatic symptoms as a child.
Historical features that decrease the likelihood of asthma include:

 Late age of onset (after 50 years)
 Lack of improvement following inhaled bronchodilator or oral steroid therapy
 History of smoking; these patients are more likely to have chronic obstructive
pulmonary disease (COPD) or a combination of COPD and asthma.
PHYSICAL FINDINGS—Expiratory wheezing is a characteristic feature but is not

specific for the diagnosis of asthma.
Characteristics of wheezing in asthma:

 High-pitched and widespread; most commonly present during expiration but
can also occur during inspiration.
Flash Card A2  May be absent between exacerbations.
Delivery by cesarean  Not predictive of the severity of airflow obstruction in asthma. Patients with
section. Prematurity (birth severe obstruction may not wheeze due to very poor air movement.
between 23-27 weeks
gestational age), neonatal  Should be differentiated from localized monophasic wheezing caused by
jaundice, and prenatal bronchial narrowing or a foreign body.
exposure to maternal
smoking are other risk
 Should be differentiated from other sounds such as rhonchi (low-pitched,
factors. Maternal age and usually clears with cough, present due to increased airway secretions) and
vitamin K use have not stridor (high-pitched inspiratory sound caused by upper airway narrowing).
been shown to be risk
factors.
Physical findings suggestive of severe airflow obstruction in asthma:

 Hemodynamic instability: tachypnea, tachycardia, pulsus paradoxus
 Use of accessory muscles of respiration
 Prolonged expiratory phase of respiration
However, the absence of any of these findings does not exclude the possibility of
severe airflow obstruction during an exacerbation.
Extrapulmonary physical findings that increase the probability of asthma include

clinical signs suggestive of:
 Allergic rhinitis
 Sinusitis
 Nasal polyps
 Atopic dermatitis
Extrapulmonary physical findings that decrease the probability of asthma include:

 Marked weight loss or severe wasting
 Clubbing
Evaluation
PULMONARY FUNCTION TESTING—In addition to a detailed clinical history

and physical examination, evaluation of functional airflow limitation is important
in making the diagnosis of asthma. Measurement of lung volumes is helpful to Key Fact
exclude restrictive ventilatory dysfunction. Measurement of diffusion lung Baseline spirometry should
capacity for carbon monoxide (DLCO) is helpful in differentiating asthma be obtained in all patients
(normal or supranormal DLCO) from emphysema (low DLCO). with a suspected diagnosis
of asthma.
 Spirometry can be used to determine the following:

o Presence of baseline obstructive ventilatory dysfunction (FEV1/forced
vital capacity [FVC] ratio < 0.70) or restrictive ventilatory dysfunction
(normal FEV1/FVC ratio, FVC < 80% predicted). Key Fact
o Severity of airflow limitation. Spirometry can be normal
o Differential for the etiology of airflow obstruction based on the shape of in a patient with asthma.
the flow-volume loop (Figure 3-5).
140 / CHAPTER 3
Figure 3-5. Spirometry showing obstruction on flow-volume loop.

(Reproduced, with permission, from Dr. Hinesh Upadhyay.)
 Bronchodilator response:
o If airflow obstruction is present on baseline spirometry, bronchodilator
response is assessed by administering 2–4 puffs of a short-acting
bronchodilator, then repeating the tests after 10–15 minutes.
o A positive bronchodilator response is defined as an increase in FEV1 or
FVC by 12% or more (Figure 3-6A), along with an absolute increase in
FEV1 or FVC by at least 200 mL (Figure 3-6B).
The presence of bronchodilator responsiveness in isolation is not sufficient for

making the diagnosis of asthma, because a positive response can be seen in other
conditions such as COPD, bronchiectasis, bronchiolitis, and cystic fibrosis.
However, the increase in FEV1 in patients with asthma is generally larger than in
those with other conditions.
 Causes for false-negative bronchodilator response include:

o Inadequate dose of short-acting bronchodilator
o Use of bronchodilator before starting the test, resulting in maximal
bronchodilation at baseline
o Presence of minimal airflow obstruction at the time of testing
o Concomitant presence of irreversible airway obstruction due to airway
remodeling or fibrosis
A B
Figure 3-6. (A) Positive bronchodilator response. The dotted blue line shows the
expiratory loop at baseline (the slight concavity is suggestive of obstruction); the
solid red line shows the expiratory loop 10 minutes after administration of
bronchodilators. (B) Positive bronchodilator response. The dotted blue line shows
FEV1 of 2.3 L at baseline; the solid red line shows FEV1 increasing to 3.2 L, 10
minutes after administration of bronchodilators.
 Bronchoprovocation testing:
o Used in patients with high strong clinical suspicion of asthma and normal
spirometry; or in patients with unexplained respiratory symptoms,
particularly cough or nocturnal awakening; or for individuals who require
an asthma screening test for occupational reasons. Test results should be
interpreted in the context of clinical history (Table 3-4).
Mnemonic
Table 3-4. Interpretation of Bronchoprovocation Challenge Testing Absolute contraindications
to bronchoprovocation
History Not Suggestive of testing—SMUK:
Test Result History Suggestive of Asthma
Asthma
Positive Diagnosis of asthma confirmed Up to 10% of nonatopic, nonasthmatic Severe airflow limitation
subjects (26% of all smokers) have (FEV1 < 50% predicted
reactive airways but are asymptomatic or < 1 L)
Negative Atopic patient with seasonal asthma Diagnosis of asthma ruled out Myocardial infarction or
symptoms tested “out of season” stroke in last 3 months
Uncontrolled hypertension
Patient with occupational asthma (systolic blood pressure
tested long after exposure to the > 200 mm Hg or diastolic
etiologic agent blood pressure > 100
Recent glucocorticoid use mm Hg)
Other conditions mimicking asthma Known aortic aneurysm
such as vocal cord dysfunction and
central airway obstruction
142 / CHAPTER 3
Mnemonic o Relative contraindications: moderate airflow limitation (FEV1 < 60%

predicted or < 1.5 L), inability to perform acceptable spirometry,
A false-positive
bronchoprovocation test pregnancy, breastfeeding.
can occur in patients with: o The most commonly used provocative stimulus is inhaled
ABCs methacholine.
Allergic rhinitis o Inhaled mannitol, exercise, or hyperventilation of cold, dry air can also
Bronchitis be used.
Congestive heart failure, o PC20 is defined as the concentration of drug causing a 20% drop in
COPD, cystic fibrosis
FEV1 (Figure 3-7).
o When a diagnostic threshold PC20 of ≥ 8 mg/mL is used, the test has a
very high negative predictive value; however, it lacks specificity for
the diagnosis of asthma.
Specialized provocation tests can be used for the evaluation of asthma variants
such as exercise-induced asthma (measuring lung function before and after
exercise) and occupational asthma (measuring FEV1 or PEF before and after the
work shift).
Figure 3-7. Positive methacholine bronchoprovocation testing. Blue line shows

FEV1 values obtained at baseline, after administering nebulized saline, followed
by FEV1 values obtained after administering increasing concentrations of
methacholine. The methacholine dose required to cause a 20% decrease in
FEV1 (demonstrated by solid red line) is the PC20. The test is terminated when
PC20 is reached.
(Reproduced, with permission, from Dr. Khalid Sherani.)
 Peak expiratory flow (PEF):

o Easily measured with a handheld meter and can be measured at home by
patients (Figure 3-8).
o Not used for primary diagnosis of asthma.
o Used to monitor clinical status of patients with asthma and to assess the
role of particular exposures or triggers.
o Reduced peak flow is not specific for airflow obstruction and can be seen
with other pulmonary processes.
o In asymptomatic asthma patients and in individuals without asthma, PEF
measurements vary up to 15–20% from one measurement to the next.
o PEF measurements that vary little over time do not support the diagnosis
of asthma.
o PEF measurements that repeatedly fall below 20% of the individual’s
baseline when symptoms are present and return to baseline with the
resolution of symptoms are consistent with the diagnosis of asthma.
o Improvement in PEF by more than 20%, 10–20 minutes after
administration of a short-acting bronchodilator, favors the diagnosis of
asthma.
Figure 3-8. Monitoring peak expiratory flow.

(Reproduced, with permission, from Dr. Aashir Shah and Dr. Hemant Raval.)
 Exhaled nitric oxide (eNO):

o A noninvasive biomarker of eosinophilic airway inflammation.
o Patients with asthma are known to have higher concentration of NO in
their exhaled air as compared to nonasthmatics.
o Exposure to asthma triggers, viral respiratory tract infections, elevated
sputum eosinophil count, and parameters associated with poor asthma
control have been associated with rising NO concentrations in exhaled air.
o Research is ongoing to define role of eNO in the diagnosis and treatment
of asthma.
144 / CHAPTER 3
BLOOD TESTS—There is no specific blood test to diagnose asthma. Complete

blood count can help to rule out other causes of dyspnea, such as anemia.
Key Fact Increased eosinophil count (>4% or 300–400 per mL) may support the diagnosis
Total serum IgE levels of asthma. However, asthma cannot be excluded in the absence of peripheral
should be measured in
patients with moderate-to-
blood eosinophilia. Very high eosinophil count (>15% or 800 per mL) is
severe persistent asthma suggestive of the presence of other disorders like allergic bronchopulmonary
who are being considered aspergillosis (ABPA), Churg-Strauss syndrome, parasitic infections, tropical
for omalizumab therapy or
in patients suspected of
eosinophilia, and Loeffler’s syndrome.
having ABPA.
ALLERGY TESTING—Not used to diagnose asthma, but can identify specific
triggers and allergens.
 Allergic testing includes blood tests for allergen-specific IgE and allergy skin
tests.
 Identification of specific allergens is useful for development of avoidance
treatment strategies and immunotherapy regimens.
IMAGING
 Chest radiograph is recommended to rule out other conditions that can mimic
asthma.
 Patients with uncomplicated asthma generally have unremarkable imaging
findings.
 Hyperinflation seen less commonly in patients with asthma compared to
patients with more chronic obstructive lung disease.
SPUTUM EXAMINATION—Several studies have suggested that sputum

eosinophil count can be used to predict clinical outcomes; however, more research
is needed before this is a useful clinical tool.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis for episodic shortness of breath is broad. It is important

to consider other conditions (Table 3-5), including those that can cause an
obstructive pattern on pulmonary function tests (PFTs; see Table 3-6). In addition,
a variety of comorbid conditions can exacerbate asthma symptoms (Table 3-7).
Patients should be evaluated and treated for these conditions in order to optimize
asthma control.
Table 3-5. Other Conditions in the Differential Diagnosis of Asthma

Condition Comments
CHF Dyspnea is usually exertional and not at rest
Presence of elevated JVP, S3 gallop, and peripheral edema favor CHF
Echocardiography, imaging studies, and BNP help differentiate between
CHF and asthma
Hypersensitivity History of exposure to particular allergens
pneumonitis PFTs show obstructive, restrictive, or a mixed pattern with a reduced DLCO
Imaging studies show reticular, nodular, or ground glass opacities
Parasitic lung History of travelling or residing in an area where parasites are endemic
infections Presence of peripheral blood eosinophilia and elevated serum IgE levels
Presence of IgG antibodies specific to particular parasitic antigens
Asthmatic Presence of peripheral blood eosinophilia and chronic rhinosinusitis
granulomatosis PFTs may show a reduced DLCO
Endobronchial Imaging studies may show hilar adenopathy with or without reticular or
sarcoidosis nodular opacities
BNP, B-type natriuretic peptide; CHF, congestive heart failure; DLCO, diffusion lung capacity for carbon
monoxide; Ig, immunoglobulin; JVP, jugular venous pressure; PFTs, pulmonary function testing.
Table 3-6. Conditions Producing Obstructive Pattern on Spirometry

Diagnosis Clinical Features Testing
a
COPD Significant smoking history. PFTs show irreversible or minimally
Family history of alpha-1 reversible airflow obstruction; emphysema
antitrypsin deficiency. shows reduced DLCO.
Check alpha-1 antitrypsin levels, particularly
in young nonsmokers or those with positive
family history.
Bronchiectasis Excessive, chronic sputum HRCT of the chest shows mucous plugging,
production. tram-tracking, and dilated airways.
History of recurrent infections Work up for etiology of bronchiectasis.
Constrictive History of viral illness, PFTs show progressively worsening,
bronchiolitis inhalation injury, lung irreversible airflow obstruction with reduced
transplant, rheumatoid lung DLCO.
disease, or inflammatory HRCT of the chest shows mosaic attenuation
bowel disease. with air trapping on expiratory view.
Central airway Stridor and monophonic or PFTs show characteristic flattening of flow-
obstruction localized wheezing may be volume loop (Figure 3-9A and B).
present. CT of the chest may show narrowing or
Minimal or no response to obstruction of the airways.
inhaled bronchodilator Direct visualization of the airways is usually
therapy. diagnostic.
146 / CHAPTER 3
Table 3-6. Conditions Producing Obstructive Pattern on Spirometry,

continued
Diagnosis Clinical Features Testing
Laryngeal Stridor and/or hoarseness + PFTs (performed when patient is
a
dysfunction wheezing symptomatic) show flattening of flow-
Symptoms occur in response to volume loop during inspiration (Figure
exercise or exposure to irritants 3-9C).
(perfumes) Direct laryngoscopy usually
History of intubation, trauma, or performed during exercise or after
surgery causing potential injury to exposure to methacholine shows
laryngeal nerve abnormal cord motion.
Reactive Recent history of upper respiratory None.
airways viral tract infection
syndrome Transient, usually resolves in weeks
a
Conditions can co-occur with asthma.
COPD, chronic obstructive pulmonary disease; CT, computed tomography; DLCO, diffusion lung capacity for
carbon monoxide; HRCT, high-resolution computed tomography; PFTs, pulmonary function testing.
Figure 3-9. (A) Flow-volume loop in fixed upper airway obstruction; note the
flattening during inspiration and expiration. (B) Flow-volume loop in variable
intrathoracic obstruction; note the flattening during expiration (red line) and
normal inspiration. Blue line denotes a normal flow-volume loop. (C) Flow-volume
loop in variable extrathoracic obstruction; note the flattening during inspiration
(red line) and normal expiration. Blue line denotes a normal flow-volume loop.
(Figure A reproduced, with permission, from Dr. Hinesh Upadhyay and Dr. Khalid Sehrani.)
Table 3-7. Co-morbid and Contributing Conditions

Condition Comments
Allergic rhinosinusitis Common comorbid condition and an independent risk factor for
asthma.
Patients with rhinitis symptoms and asthma should be evaluated
for nasal polyps and aspirin sensitivity.
Sinus CT is recommended in patients with severe asthma.
GERD Mimics or worsens asthma.
Patients with reflux symptoms and asthma should be given a trial
of PPI therapy.
In patients without any reflux symptoms and moderate-to-severe
asthma, consider diagnostic testing for GERD.
Obesity and deconditioning Worsens asthma severity.
Associated with increased asthma incidence in women.
OSA Increased daytime sleepiness in patients with asthma may be
associated with coexistent OSA.
Polysomnography is recommended for asthma patients with
predominantly nocturnal symptoms, increased daytime
sleepiness, and difficult-to-control asthma.
BNP, B-type natriuretic peptide; CT, computed tomography; GERD, gastroesophageal reflux disease; JVP,
jugular venous pressure; OSA, obstructive sleep apnea; PPI, proton pump inhibitor.
Other Conditions That Co-Exist with Asthma
ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (ABPA)—ABPA

is an inflammatory lung disease, primarily affecting patients with asthma or cystic
fibrosis. It is caused by a hypersensitivity reaction to chronic airway colonization
by Aspergillus species (most common) or other fungi. Clinical presentation
usually includes recurrent episodes of airway obstruction with pneumonias that
have no culture-identified source and fail to respond to standard therapy. In
addition, patients may complaint of worsening sputum production with thick, Flash Card Q3
brown mucus plugs, fever, malaise, wheezing, dyspnea, hemoptysis, and A 55-year-old patient with
extremely poor asthma control. Table 3-8 summarizes the diagnostic criteria for asthma had three episodes
ABPA. of fever with worsening
dyspnea as well as sputum
production with brownish
Treatment of ABPA: mucus plugs in the last 2
 Glucocorticoids (slowly tapered over 3–6 months) are the mainstay of therapy. months. Chest radiographs
show fleeting infiltrates and
 Recent Infectious Diseases Society of America (IDSA) guidelines recommend an HRCT shows central
combined therapy with glucocorticoids and itraconazole, with voriconazole bronchiectasis. Serum IgE
serving as a potential alternative agent. levels are elevated (1200
ng/mL) with peripheral
blood eosinophilia
(700/mL).
What is the most likely
diagnosis? Which test
should be done next?
148 / CHAPTER 3
Table 3-8. Criteria for the Diagnosis of ABPA

Condition Diagnostic Criteria
ABPA central History of asthma (mostly cases are poorly controlled)
bronchiectasis (ABPA- Immediate skin test reactivity to Aspergillus fumigatus
CB) Elevated serum total IgE (commonly > 1000 IU/mL)
Elevated serum specific IgE to A fumigatus
Serum precipitins present or elevated serum-specific IgG to A
fumigatus
Presence of central bronchiectasis on HRCT
Seropositive ABPA
(ABPA-S) Same as above, except no bronchiectasis seen on HRCT
Other findings that Elevated eosinophil count (usually > 500 mL) on peripheral blood
support the diagnosis smear
Presence of patchy, fleeting infiltrates on chest radiograph
Worsening cough with brown mucoid sputum production
Positive sputum culture for A fumigatus
Imaging studies showing bronchi filled with mucus
ABPA, allergic bronchopulmonary aspergillosis; HRCT, high-resolution computed tomography; Ig,
immunoglobulin.
EOSINOPHILIC GRANULOMATOSIS WITH POLYANGITIS (CHURG-

Mnemonic STRAUSS) (EGPA)—Vasculitis of small- and medium-sized arteries with
Medications associated
multisystem involvement, most commonly involving the lungs, and characterized
with EGPA: by the presence of allergic rhinitis, asthma, and prominent eosinophilia in
COIL peripheral blood. Some 40–60% of patients with EGPA are found to have
Cocaine
antineutrophil cytoplasmic antibodies (ANCA) in their blood. Treatment includes
Omalizumab glucocorticoid therapy with or without other immunosuppressive agents like
Inhaled glucocorticoids cyclophosphamide and azathioprine.
Leukotriene-modifying
agents
ASTHMA VARIANTS
Exercise-Induced Asthma
Many patients with asthma experience worsening symptoms with exercise.
However, a subset of patients experience only post-exercise asthma symptoms
and are asymptomatic at other times. Inhalation of large volumes of relatively
cool, dry air during vigorous exercise is thought to trigger changes in airway
physiology, resulting in exercise-induced bronchoconstriction.
Flash Card A3
Allergic bronchopulmonary
CLINICAL MANIFESTATIONS—Patients typically experience cough, chest
aspergillosis. tightness, and shortness of breath after an episode of exercise or during prolonged
A skin-prick test checking exercise. During the first 6–8 minutes of exercise, patients experience
reactivity to Aspergillus
fumigatus should be
bronchodilation. This is followed by bronchoconstriction that peaks 10–15
performed. minutes after onset of exercise. Symptoms generally resolve 60 minutes after
exercise. Bronchoconstriction is followed by a refractory period, lasting generally

< 4 hours, during which release of inhibitory prostaglandins protect against
bronchoconstriction, even if exercise is continued. Simple shortness of breath
resulting from deconditioning usually resolves within 5 minutes after stopping
exercise.
DIAGNOSIS—In patients with a clinical history suggestive of exercise-induced

asthma, the diagnosis can be confirmed by an exercise challenge test with Key Fact
spirometric measurements before and after exercise. In patients with a known The most direct way to
diagnosis of asthma who develop typical symptoms following exercise, exercise establish the diagnosis of
exercise-induced asthma is
testing is not indicated. In patients with no associated findings or symptoms via exercise challenge
suggestive of asthma, in highly trained athletes, and in adults with new-onset testing.
exercise-associated symptoms, testing should first be done to rule out other causes.
These include heart failure, coronary heart disease, central airway obstruction,
vocal cord dysfunction, laryngotracheomalacia, parenchymal lung disease, and
gastroesophageal reflux disorder.
Key Fact
TREATMENT—Therapy for exercise-induced asthma is aimed at maintaining In patients with poorly
the patient’s ability to exercise regularly (Table 3-9). controlled asthma who
experience frequent
episodes of exercise-
induced
bronchoconstriction, the
most important strategy is
Table 3-9. Management of Exercise-Induced Asthma to improve overall asthma
control.
Comments
Ensure that exercise is not avoided by patients with exercise-

Goal
induced asthma by controlling exercise-induced symptoms.
Improve cardiovascular fitness to reduce minute ventilation
requirement for a given level of exercise, thereby reducing the
stimulus for bronchoconstriction.
General Measures Improve patient education regarding the disease and
appropriate and timely use of medications.
Reduce the temperature and humidity of inspired air by using a
scarf or mask when exercising in cold, dry conditions.
Rapid-acting bronchodilators initiated about 10 minutes before
exercise.
Preventive a
Pharmacotherapy Cromoglycates (inhaled), initiated 15–20 minutes before
exercise, can be used with rapid-acting bronchodilators for
exercise in extreme conditions or for strenuous exercise.
Inhaled glucocorticoids, with or without inhaled long-acting
Control of Refractory bronchodilators, taken daily regardless of exercise.
Exercise-Induced Asthma
Antileukotriene agents, taken daily regardless of exercise.
Dietary Modifications Diet rich in omega 3 fatty acids may be helpful.
Breakthrough Symptoms Rapid-acting bronchodilators (inhaled).
a
Available only as nebulizer solution in the US.
150 / CHAPTER 3
Work-Related Asthma
Occupational exposures can cause or exacerbate asthma symptoms. Work-related
asthma is divided into several categories depending on the type and timeline of
exposures and symptoms (Table 3-10).
Table 3-10. Types of Work-Related Asthma

Type Comments
Occupational asthma (OA) Adult onset

Triggered by immunologic or nonimmunologic stimuli found only
at the workplace
Work-exacerbated asthma Presence of pre-existing or concurrent asthma
Subjective worsening at the workplace
Irritant induced asthma New-onset asthma in adulthood
Induced by exposure to an irritant, nonimmunologic stimulus at a
high level of intensity
Considered a subset of OA if exposure happens at workplace,
but physiologically different from immunologic OA
Reactive airways dysfunction Similar to irritant-induced asthma, except that an acute, single,
syndrome (RADS) high-intensity exposure to a nonimmunologic substance triggers
symptoms within minutes
Episode followed by bronchial hyperresponsiveness and ongoing
asthma-like symptoms for a prolonged period of time
Occupational nonasthmatic Adult onset
eosinophilic bronchitis Symptoms mimic asthma
Develops at workplace
Absence of bronchial hyperresponsiveness but elevated sputum
eosinophil count
Occupational Asthma (OA)

OA is one of the most common work-related pulmonary diseases in developed
Key Fact countries, with >350 reported causative agents. Exposure to an immunologic
In the development of OA, stimulus is followed by a latency period during which sensitization develops. This
the most important factor is period is followed by the development of airway inflammation, resulting in
the intensity of exposure.
clinical symptoms. The time period between stimulus exposure and the
development of symptoms is highly variable. Depending on the intensity of
ongoing exposure to the stimulus and the initiation of treatment, immunologic OA
can worsen, persist, subjectively improve, or resolve. Exposure to
nonimmunologic stimuli leads to the development of either irritant-induced
asthma or RADS, and usually does not have a latency period.
CLINICAL MANIFESTATIONS—Patients typically experience asthma-like

symptoms at work or within a few hours after completion of their shift. They
usually report subjective improvement in their symptoms during holidays or
vacation. However, the absence of such a pattern does not exclude OA. Exposure
to certain causative agents can cause rhinoconjunctivitis, allergic contact
dermatitis, or urticaria in addition to OA.
DIFFENTIAL DIAGNOSIS—See Table 3-11.
Table 3-11. Differential Diagnosis of Occupational Asthma

Condition Comments
COPD Can occur due to personal use of tobacco and/or exposure to
tobacco smoke or other pollutants at work.
PFTs show irreversible or minimally reversible airflow obstruction
and reduced DLCO.
Work-related irritable Sensory stimuli at workplace trigger hyperkinetic laryngeal
larynx syndrome symptoms.
Includes vocal cord dysfunction, sensation of fullness/tension in
throat and neck, dysphonia, and chronic cough.
Hyperventilation Accompanied by other somatic symptoms.
syndrome Symptoms can be reproduced completely or partially by voluntary
hyperventilation.
Hypersensitivity PFTs show obstructive, restrictive, or mixed pattern with reduced
pneumonitis DLCO.
Imaging studies show reticular, nodular, or ground glass opacities.
COPD, chronic obstructive pulmonary disease; DLCO, diffusion lung capacity for carbon monoxide; PFTs,
pulmonary function testing.
DIAGNOSIS—The initial approach to patients suspected of having OA is similar

to the workup of other adults suspected of having asthma. However, more focus is Key Fact
placed on occupation/exposure history, time course of symptoms, and specific In a symptomatic patient
with ongoing exposure,
testing that establishes an occupational contribution. normal spirometry, and a
negative nonspecific
History: bronchoprovocation test
excludes the possibility of
 Detailed information regarding current and previous occupations, including OA.
job description and exposure to potential causative agents, should be obtained.
 In case of an unclear cause, it is essential to obtain the list of all chemicals
used and present at the workplace. (This information can be obtained from
Material Safety Data Sheets.)
152 / CHAPTER 3
Stepwise approach to confirm OA diagnosis:

 Gather detailed occupational/exposure history as mentioned above.
 Confirm the diagnosis of asthma using an approach similar to that used for
diagnosing asthma in adolescents and adults.
 Perform testing to establish occupational relationship of the symptoms (see
Table 3-12).
 If the diagnosis is still unclear, specific bronchoprovocation testing to
sensitizing agents at the work place is indicated.
Table 3-12. Tests for Establishing Occupational Relationship

Test Comments
Serial PEFR Record 4 times a day for at least 2 weeks at work and for a similar period
measurements away from work.
Compare values to check for work-related decrease in PEFR.
Serial spirometry Perform on exposed and non-exposed days and compare the values.
Change in FEV1 is more reliable than changes in FVC.
A single pre- and post-shift measurement of FEV1 lacks sensitivity to
examine relationship between asthma and work.
Nonspecific After exposure to the causative agent, increased nonspecific bronchial
bronchoprovocation responsiveness is seen in patients with OA.
testing If normal spirometry and normal initial nonspecific bronchoprovocation
testing, repeat the test after 2 weeks away from work and again after
exposure to the workplace.
The absence of bronchial hyperresponsiveness in a symptomatic patient,
tested within 24 hours of exposure, rules out OA.
Skin and In the presence of appropriate history, symptoms, and documented
immunologic testing evidence of changes in airway physiology due to exposure, positive skin
testing supports the diagnosis of OA being caused by that specific
antigen.
Blood testing for IgE antibodies to certain sensitizers can also be done.
Markers of airway Increases in sputum eosinophil count (>1% increase) and eNO at the
inflammation end of work period are suggestive of airway inflammation and are
indirect evidence of OA.
In a symptomatic patient, the presence of elevated eosinophil count in
induced sputum (>2%) in the absence of bronchial hyperresponsiveness
is suggestive of nonasthmatic eosinophilic bronchitis.
Specific Performed only at specialized centers.
bronchoprovocation Indicated in patients with suspected but uncertain diagnosis of OA.
testing
Patients are exposed to specific occupational agents, following which
bronchial hyperresponsiveness is assessed.
False negative results are possible if the patient has become
desensitized to the specific agent or if the wrong agent is used.
eNO, exhaled nitric oxide; FEV1, 1-second forced expiratory volume; FVC, forced vital capacity; Ig,
immunoglobulin; OA, occupational asthma; PEFR, peak expiratory flow rate.
TREATMENT—The mainstay of therapy for OA is to avoid exposure to the

Key Fact
causative agent. If the agent cannot be avoided, other steps can be taken to control
symptoms (Table 3-13). The cornerstone of therapy
for OA is to avoid further
exposure to the sensitizing
agent.
Table 3-13. Management of OA
Treatment
Comments
Modalities
Exposure avoidance Continued exposure leads to progressive deterioration in lung function. Key Fact
After complete avoidance
Exposure reduction Consider in patients with mild OA who are unable or unwilling to change of exposure, OA improves
work. gradually then plateaus
Consider use of respiratory protection devices. after about 2 years.
Pharmacotherapy Same regimen as that for nonoccupational asthma.
Treat associated occupational rhinitis, if present.
Subcutaneous Consider in patients who are unable or unwilling to change work.
immunotherapy Has no role in managing OA caused by LMW allergens, corrosives, or
irritant substances.
Anti-IgE therapy In patients with poorly controlled asthma secondary to continued
occupational exposure, consider complete exposure avoidance rather
than anti-IgE therapy.
Ig, immunoglobulin; LMW, low molecular weight; OA, occupational asthma.
Reactive Airways Dysfunction Syndrome (RADS) and

Irritant-Induced Asthma (IrIA)
CLINICAL MANIFESTATIONS—RADS is usually characterized by abrupt

onset of symptoms following irritant exposure. However, in some cases,
symptoms develop as late as 7 days after exposure. Initially patients complain of a
burning sensation in the throat and nose (also called respiratory upper airway
Key Fact
distress syndrome, or RUDS) without any respiratory symptoms. This is followed
by the development of asthma-like symptoms. In most cases the symptoms are RADS and IrIA symptoms
are not reproduced by
severe enough to warrant an emergency room visit. The time course of symptoms inhalation challenge with
differs in RADS and IrIA. Due to multiple low-level exposures, patients with IrIA low levels of offending
are unable to identify a particular date or time of exposure. In addition to asthma- workplace agents, while
symptoms of immunologic
like symptoms, patients with IrIA might also present with symptoms of mucosal OA are reproduced in
irritation like nasal congestion, nasal pruritus, increased secretions, and those conditions.
rhinoconjunctivitis.
DIAGNOSIS—The approach to patients suspected of having RADS or IrIA is

similar to that of occupational asthma. However, more focus is placed on looking
for an exposure that led to the acute development of symptoms. Specific
bronchoprovocation testing is not performed for the agents known to cause RADS
and IrIA.
154 / CHAPTER 3
Criteria for establishing the diagnosis of RADS:

 No history of previous respiratory symptoms.
 Presence of a single, specific exposure leading to the onset of symptoms.
 Irritant substance present in high concentrations.
 Asthma-like symptoms begin within 24 hours of exposure and last for at least
3 months.
 Nonspecific bronchoprovocation testing positive.
 Other pulmonary diseases ruled out.
TREATMENT—Management of RADS and IrIA is similar to that of

Key Fact nonoccupational asthma and OA (Table 3-14).
After complete cessation of
exposure, RADS and IrIA
usually improve with time,
but some patients continue Table 3-14. Management of RADS and IrIA
to have symptoms for at
least 1 year and residual Condition Comments
physiologic abnormalities
like bronchial Acute RADS Evaluation and treatment is the same as that for acute asthma
hyperreactivity can last for exacerbation.
several years. No formal trials have been performed to evaluate the role of
glucocorticoid therapy in RADS.
For patients with moderate-to-severe symptoms and FEV1 < 70%
predicted, systemic steroid therapy is used.
For patients with less severe symptoms and FEV1 > 70% predicted,
inhaled steroid therapy and/or inhaled ß-agonist therapy is used.
Persistent symptoms due Management is similar to OA.
to RADS and IrIA
FEV1, forced expiratory volume in 1 second; IrIA, irritant-induced asthma; OA, occupational asthma; RADS,
reactive airways dysfunction syndrome.
Nocturnal Asthma
CLINICAL MANIFESTATIONS —Many patients with asthma experience
worsening of their symptoms at night. However, some patients present with
asthma-like symptoms only at night. This condition is thought to be due to
circadian variations in lung function that contribute to increased airway
inflammation at night, including changes in neurohormonal activation, changes in
lung volume, airway inflammation, blood volume of the pulmonary capillaries,
glucocorticoid receptor affinity, and ß2-adrenergic receptor function.
DIAGNOSIS—The evaluation and diagnostic approach is similar to that of

asthma. For patients with predominantly nocturnal symptoms, alternative
diagnoses like heart failure, GERD, and OSA should be ruled out. If patients fail
to respond to asthma therapy, peak flows should be measured at bedtime, upon
waking up, and during all nocturnal awakenings. A 15% or greater variability in
measurements favors the diagnosis of asthma.
TREATMENT—See Table 3-15.
Table 3-15. Management of Nocturnal Asthma

Condition Comments
Treatment of contributing Avoid nocturnal exposure to allergens.

factors Treat rhinitis and sinusitis, GERD, or OSA appropriately, if present.
Treatment of acute Inhaled short-acting ß agonists.
nocturnal symptoms
Refractory nocturnal Check if patient is compliant with medications, especially evening
asthma dose.
Check for exposure to inhalants or irritants at night.
Rule out alternative diagnoses.
Consider adding/changing to an alternate long-acting controller
medication.
Switch to inhaled glucocorticoid.
Consider chronotherapy (changing medication dosing time to
optimize its effect), especially for oral glucocorticoid therapy.
Re-evaluate for the presence of contributing factors, especially OSA.
GERD, gastroesophageal reflux disorder; OSA, obstructive sleep apnea.
Cough-Variant Asthma
For some patients, cough is the only presenting manifestation of asthma. Most
such patients eventually develop wheezing, dyspnea, and other asthma-like
symptoms.
Elements in clinical history that suggest cough-variant asthma:

 Seasonal nature of cough
 Occasional wheezing and dyspnea
 Personal history of environmental allergies, atopy, or childhood asthma
 Family history of allergies and/or asthma
 Worsening of cough after exposure to dust, cold, dry air, mold, fumes, and
strong fragrances
The diagnostic approach, evaluation, and management of such patients are similar
to that of patients with general asthma. However, other causes of cough, such as
medication use (ACE inhibitors), GERD, upper airway cough syndrome,
bronchiectasis, chronic bronchitis, COPD, lung cancer, acute infections, and
chronic aspiration, should be ruled out. For patients with severe disabling cough,
a 1–2 week course of oral glucocorticoids results in marked improvement.
156 / CHAPTER 3
Aspirin-Exacerbated Respiratory Disease (AERD)

AERD is clinically characterized by the presence of asthma, chronic rhinosinusitis
(CRS) with nasal polyposis, and reactions such as bronchospasm and nasal
congestion to aspirin and other COX-1–inhibiting nonsteroidal anti-inflammatory
drugs (NSAIDs). Aspirin and other COX-1–inhibiting NSAIDs are not the actual
cause of the disease. Rather, their use exacerbates and/or worsens the underlying
asthma and CRS. Complete avoidance of these agents does not lead to resolution
of the condition.
Mnemonic
Pathophysiologically, the reactions are not IgE-mediated and are labeled
Symptoms that typically
begin within 30 minutes to “pseudoallergic,” representing an abnormal biochemical response to the
3 hours following NSAID pharmacologic actions of NSAIDs. Previous NSAID use is not required to
use: ABCDEF develop sensitivity.
Asthma-like symptoms
(acute asthma CLINICAL MANIFESTATIONS—It often takes years for all three components
exacerbation) of the disorder to develop. Refractory chronic rhinosinusitis is usually the first
Bronchospasm and
laryngospasm (might be manifestation, followed by development of nasal polyps and impaired sense of
severe enough to smell. In most patients the symptoms are severe and disabling, requiring frequent
require intubation) sinus surgeries and polypectomies. Eventually patients develop asthma-like
Congestion and
conjunctival redness symptoms. The exact time period for the appearance of aspirin/NSAID sensitivity
Diffuse abdominal cramps remains unclear. However, if aspirin/NSAID sensitivity appears prior to the
(less common) development of asthma-like symptoms, it is considered an independent risk factor
Epigastric pain (less
common) and edema for the development of asthma. Even with aspirin/NSAID avoidance, progressive
(usually periorbital) worsening of AERD-related asthma and CRS is usually seen.
Facial flushing
Hives, angioedema (in about 15% of patients), and hypotension can also be seen
along with respiratory symptoms. All symptoms are dose related and usually
Key Fact
resolve slowly.
The only way to definitively
diagnose NSAID sensitivity
is via aspirin challenge
testing. However, it is DIAGNOSIS—The initial evaluation and diagnostic approach is similar to that of
rarely used clinically for asthma. However, more focus is placed on the history of NSAID sensitivity and
establishing the diagnosis
of AERD. It is mostly the type of symptoms experienced after NSAID use. If a history of NSAID
performed as a part of a sensitivity is present, attempts should be made to check if the patient has shown
protocol when aspirin reactivity to more than one COX-1–inhibiting agent. If all three characteristic
desensitization is indicated.
clinical features of AERD are present, it is easy to make the diagnosis clinically.
It might be challenging to make the diagnosis in patients who only have one or
two features. Even in such cases, challenge testing is indicated only if
desensitization therapy is planned. In patients with severe asthma who have
empirically avoided NSAID use, consider challenge testing to establish or rule out
the diagnosis of AERD.
TREATMENT—See Table 3-16.

Table 3-16. Management of AERD

Condition Comments
Treatment of asthma-like Treatment principles similar to chronic asthma management
symptoms except when considering early use of LTMAs in AERD.
Leukotriene-receptor antagonists are used initially and substituted
Key Fact
with leukotriene-synthesis inhibitors if no clinical improvement is
seen. Although other COX-1–
Treatment of CRS and NP Oral glucocorticoids: Patients with anosmia or persistent nasal inhibiting NSAIDs can be
blockage should be treated with a 15-day course of oral used safely in AERD
prednisone. patients who have been
successfully desensitized
Sinus surgery: Consider if patients fail to respond to oral steroid with aspirin, only
therapy. subsequent aspirin therapy
Topical glucocorticoids: Mainstay of therapy in patients without has been shown to slow
anosmia or persistent nasal blockage. the regrowth of nasal
polyps and improve
LTMAs: Used as an adjunct to topical steroid therapy.
asthma symptoms.
Aspirin desensitization and therapy: Consider if all the features of
AERD are present and the disease is uncontrolled despite maximal
therapy.
Antibiotics: Doxycycline may reduce the size of nasal polyps and
amount of secretions, but role in therapy is unclear.
Antihistamines: Can be used in patients on topical steroid therapy
with persistent symptoms; exact role in therapy is unclear.
Avoidance of NSAIDs Unless desensitized to aspirin, all COX-1–inhibiting NSAIDs should
be avoided.
Aspirin desensitization and
See accompanying text.
aspirin therapy
AERD, aspirin-exacerbated respiratory disease; COX, cyclooxygenase; CRS, chronic rhinosinusitis; IL,
interleukin; LTMAs, leukotriene-modifying agents; NP, nasal polyposis; NSAIDs, nonsteroidal antiinflammatory
drugs.
ASPIRIN/NSAID DESENSITIZATION AND ASPIRIN THERAPY—

Desensitization is the process of inducing tolerance to aspirin/NSAIDs in patients
who experience pseudoallergic reactions. A structured protocol is followed where
patients are administered gradually increasing doses of an NSAID, generally
aspirin, in a monitored setting. Successful desensitization to aspirin can be
achieved in nearly all AERD patients.
Indications for aspirin desensitization:

 Worsening of nasal polyposis despite maximal therapy
 Treatment of other conditions that require daily or intermittent use of NSAIDs
 Coronary artery disease and/or other vascular disorders that require the use of
aspirin for its antiplatelet effects
Contraindications to challenge testing and desensitization:

 Suboptimal/inadequate control of concurrent cardiopulmonary conditions
 Poor control of underlying asthma
158 / CHAPTER 3
Premedication:
 Leukotriene-modifying agents (LTMAs) reduce the pulmonary manifestations
after exposure to aspirin/NSAIDs but do not impact the nasal and ocular
manifestations.
 In patients with poor asthma control, systemic glucocorticoids can be used
before the test to optimize asthma control.
Symptoms should be managed appropriately as they arise during challenge (Table

3-17).
Table 3-17. Management of Symptoms During Challenge

Condition Comments
Bronchospasm Nebulized short-acting bronchodilators as needed

Nasal symptoms Topical nasal decongestants
Ocular symptoms Oral antihistamines
Laryngospasm Nebulized and/or intramuscular epinephrine
Anaphylactic reaction Systemic glucocorticoids
H1 and H2 receptor blockers
Systemic epinephrine
Airway protection, if indicated
Interpretation of test results and ongoing aspirin therapy:

 Negative challenge testing implies that patient does not have pseudoallergic
reaction to aspirin/NSAIDs; if suspicion is high, repeat testing without
premedication.
 Positive challenge testing confirms the presence of pseudoallergic reaction to
aspirin/NSAID use. Proceed with desensitization if indicated.
 A patient who can tolerate a full dose of aspirin (325 mg) is considered
Key Fact successfully desensitized.
Successfully desensitized  After desensitization, a refractory period of 2–3 days exists before patients
patients should continue again develop reactivity. Initiate daily therapy during this period.
taking 325 mg of aspirin or  Post-desensitization, patients should be started on aspirin 650 mg twice daily
equivalent dose of another
COX-1–inhibiting NSAID for at least 3 months, then decrease to 325 mg daily.
daily to maintain their  Repeat desensitization is needed in patients with > 5 days of interruption in
desensitized state.
maintenance therapy.
 Patients taking only 81 mg aspirin daily will tolerate only low doses. High
doses should not be administered to such patients. These patients also cannot
tolerate other COX-1–inhibiting NSAIDs.
 If patients fail to show any improvement, then either they do not have AERD
or they are non-responders to aspirin. In such cases, aspirin therapy should be
stopped unless there is any other indication to maintain the desensitized state.
 Despite aspirin therapy, patients can experience acute asthma exacerbations,
flares in rhinitis, and upper respiratory tract infections. Patients should be
advised to continue aspirin therapy in all these situations.
Glucocorticoid-Resistant Asthma (GRA)

In the absence of confounding factors, patients with chronic asthma who fail to
show response to high doses of glucocorticoid therapy are labeled as having GRA.
In the absence of an acute exacerbation, patients who fail to show improvement in
their FEV1 or peak expiratory flow by at least 15 % from a baseline of < 75% of
their predicted values after 1–2 weeks of daily therapy with 40 mg prednisone or
the equivalent are termed to have GRA. Such patients might demonstrate
glucocorticoid resistance in other tissues also. The optimal treatment for such
patients remains unknown. Some of the commonly used treatment strategies
include:
 Use of higher doses of systemic steroids for longer durations
 Use of non-glucocorticoid pharmacologic agents
 Use of non-pharmacologic therapies like trigger avoidance and thermoplasty
 Anti-interleukin-5 and anti-interleukin-13 have shown some benefit in such
patients
Confounding factors that need to be ruled out before making the diagnosis of
GRA include:
 Non-compliance to medications
 Continued exposure to trigger or stimulus including medications like aspirin
 Inappropriate/wrong diagnosis of asthma
 Undiagnosed or inappropriately treated concomitant conditions like COPD,
congestive heart failure, GERD, and OSA
CHRONIC MANAGEMENT OF ASTHMA
See Table 3-18.
Table 3-18. General Treatment Principles

Comments
Goals of Therapy Reduce impairment:
 Limit the number of symptomatic episodes.
 Minimize the need to use inhaled rapid-acting ß agonists to ≤ 2
days/week.
 Reduce nighttime symptoms causing awakenings to < 2/month.
 Maintain/improve quality of life.
 Optimize lung function.
Reduce risk:
 Prevent acute exacerbations requiring hospitalization or
emergency care.
 Prevent loss of lung function.
 Optimize therapy with minimal or no side effects.
160 / CHAPTER 3
Table 3-18. General Treatment Principles, continued

Comments
Patient Education Basic understanding of disease
Medication use, techniques, and mechanisms
Strategies to prevent exacerbations:
 Medication compliance (see below)
 Identification and avoidance of triggers (see below)
 Pre-medication in specific situations like exercise-induced
asthma
Strategies to identify and manage exacerbations:
 Recommend daily home monitoring of PEFR
 Introduce the concept of personal best PEFR
 Prepare a personalized plan with specific directions for daily
management, adjustment of medications, and seeking urgent
care in response to decreasing PEFR and/or worsening
symptoms
Assessment of For impairment assessment, inquire about the presence of
Patients With following in last 2–4 weeks:
Asthma During  Nighttime or early morning awakenings
Office Visits  Use of rapid-acting ß agonists to relieve symptoms
 Need for urgent or emergency room care for asthma
 Change in activity status or quality of life
 Changes in PEFR
 Side effects from medications
For risk assessment, inquire about:
 Use of oral steroids in last year
 Hospitalization for asthma in last year
 Intubation in last 5 years
 Current smoking status
 Any newly identified triggers including medications like aspirin
and/or NSAIDs
Check medication use and review the technique for using
medication device
Monitoring Compare spirometry with patient’s old values to check for
Pulmonary Function development or worsening of airflow obstruction, which, if present,
During office Visits predicts the risk for exacerbation
In the presence of a normal PEFR, spirometry has greater
sensitivity for detecting obstruction.
Optimize Treatment Treat GERD, rhinosinusitis, OSA, and COPD appropriately and
of Coexisting/ adequately if present
Contributing
Conditions
Pharmacotherapy See accompanying text
COPD, chronic obstructive pulmonary disease; GERD, gastroesophageal reflux disorder; NSAIDs, nonsteroidal
antiinflammatory drugs; OSA, obstructive sleep apnea; PEFR, peak expiratory flow rate.
Role of Medication Compliance in the Management of

Asthma
Multiple factors can contribute to nonadherence to asthma therapy, including:
 Lack of knowledge and understanding about the regular need for medication, Key Fact
even in the absence of symptoms It is important for patients
 Complexity of the regimen to understand that
medication use is required
 Inability to use the medication device to control airway
 Inability to afford the medications inflammation, even in the
absence of symptoms.
 Misconceptions and/or fear regarding the side effects of the medications
 Sociocultural and religious issues
Every possible effort should be made to identify and address the factors that
contribute to a patient’s noncompliance.
Trigger Control in the Management of Asthma

Attempts should be made to identify the agents/allergens or activities that
exacerbate asthma symptoms. Once identified, complete avoidance of the trigger
is advised (Table 3-19). If this is not possible, efforts should be made to limit the
exposure. If exposure cannot be limited, an extra dose of inhaled bronchodilator
and an antihistaminic agent can be taken prior to exposure.
162 / CHAPTER 3
Table 3-19. Commonly Identified Asthma Triggers and Steps for

Avoidance
Comments
Respiratory infections Avoidance of sick contacts
Annual vaccination for influenza
Pneumococcal vaccination for asthmatic adults
Inhalant Allergens Animal allergens (dogs, cats, rodents, birds): Advise patient not to
keep pets, especially indoors. If pets present, clean aggressively
and use HEPA filters. Aggressive pest control for rodent issues.
House-dust mites: Use of physical barriers (covers for pillows,
mattresses, etc.), minimized use of upholstery and fabric reservoirs,
use of vacuums with HEPA filters, humidity control and use of
insecticide or allergen-denaturing agents (benzyl benzoate, tannic
acid). Measures should be adopted for at least 3–6 months to see
clinical benefit.
Cockroaches: Use of air filters not helpful. Requires integrated pest
management.
Indoor fungi: Decrease humidity by increasing ventilation, and
increase temperature to reduce humidity. Visible mold can be
scrubbed off.
Outdoor plant allergens and fungi: Difficult to avoid. Stay indoors
during pollen season, and shower before going to bed to avoid
contamination of the bed.
Food Allergens Sulfite-containing food products (wine, vinegar, dry fruits,
Key Fact processed potato products) can cause asthma-like symptoms.
Identify food products and avoid exposure.
Never use inhaled long-
acting bronchodilators Occupational Allergens See section on OA.
alone in the treatment of
Irritants and Cigarette Advise smoking cessation and avoidance of secondhand smoke.
asthma. Studies suggest
Smoking See section on RADS and IrIA.
they may increase risk of
asthma-related death when Temperature and Avoid exposure to cold and dry air. Use scarves and masks.
not combined with an Weather
inhaled corticosteroid. Physical Activity See section on exercise-induced asthma.
Hormonal Fluctuations Increase medications if symptom worsening is anticipated during
menstruation. Consider trial of antileukotriene agents
Medications Avoid nonselective ß blockers (including those in topical ophthalmic
solutions) if they are found to trigger asthma.
Selective ß blockers in high doses can also trigger asthma and
should be avoided if found to do so.
For aspirin and other NSAIDs, see section on AERD.
Emotional Factors Manage underlying depression, anxiety, and psychiatric conditions.
AERD, aspirin-exacerbated respiratory disease; HEPA, high-efficiency particulate air; IrIA, irritant-induced
asthma; NSAIDs, nonsteroidal antiinflammatory drugs; OA, occupational asthma; RADS, reactive airways
dysfunction syndrome.
Classification of Asthma Severity and Treatment Options

See Table 3-20.
Table 3-20. Treatment Options for the Chronic Management of

Asthma
Comments
Short-Acting β2 First-line agents for immediate symptomatic relief of bronchospasm.
Adrenergic Agonists Increased frequency of use or decreased effectiveness can indicate
worsening asthma control.
Can cause tachycardia, tremors, palpitations, hypokalemia, lactic
acidosis.
Nonselective β1- and Used for anesthesia-induced bronchospasm.
β2-Adrenergic Agonists
Short-Acting Can be used in patients for immediate relief of symptoms who are
Anticholinergics intolerant of or do not respond to short-acting ß-agonist therapy.
Can also be coadministered with short-acting ß agonists.
Can cause adverse cardiovascular events and acute urinary
retention in patients with prostatic hypertrophy.
Inhaled Glucocorticoids Mainstay of anti-inflammatory and maintenance therapy.
Dose can be increased in a stepwise manner to achieve better
asthma control.
Rinse mouth after use to reduce risk of thrush.
Can cause skin thinning, adrenal suppression, cataracts,
osteoporosis, oral candidiasis, hoarseness of voice, easy bruising,
impaired glucose control.
Long-Acting β2 Should not be used as monotherapy due to increased risk of asthma-
Agonists related death.
Have glucocorticoid sparing effect when used in combination with
inhaled steroids.
Chronic use shown to improve pulmonary function, increase
symptom-free days, and decrease the need for rescue therapy.
Chronic use has also been associated with rare severe acute asthma
exacerbations and increased cardiac- and asthma-related mortality.
Combination Inhalers First-line controller therapy for moderate-severe persistent asthma.
(Inhaled
Glucocorticoids and
Long-Acting β2
Agonists)
Systemic Used in severe, persistent asthma uncontrolled with high-dose
Glucocorticoids inhaled steroids.
Titrate dose to the minimum required for symptom control.
Cromones Not known to have bronchodilatory effect.
Act by stabilizing airway mast cells and other inflammatory cells,
thereby preventing bronchoconstriction.
Can be used prophylactically 10–15 minutes prior to exposure to a
known trigger.
Used as a controller medication in mild persistent asthma in patients
who do not want to take inhaled steroids, or in addition to inhaled
steroids.
164 / CHAPTER 3
Table 3-20. Treatment Options for the Chronic Management of

Asthma, continued
Comments
Leukotriene Can be used as an alternative monotherapy for the treatment of mild-
Pathway Inhibitors moderate persistent asthma.
Not a first-line therapy, as efficacy is lower than inhaled steroids.
Can be added to inhaled steroid therapy in patients with moderate or
severe persistent asthma whose disease is inadequately controlled, or
used for possible steroid sparing effect.
Methylxanthines Can be used in patients with chronic asthma whose symptoms are
uncontrolled on conventional doses of inhaled steroids and in patients
who cannot take or are noncompliant with inhaled medications.
Needs drug level monitoring.
Long-Acting No FDA approval for use in asthma.
Anticholinergics Can be added to other therapies in severe, persistent asthma to
achieve control.
The classification of asthma severity and initiation of treatment in adults with the
stepwise approach are outlined in Figure 3-11 and Figure 3-12, respectively.
Figure 3-11. Classification of asthma severity and treatment initiation in adults.

FEV1, forced expiratory volume in one second; FVC, forced vital capacity.
(Reproduced courtesy of National Asthma Education and Prevention Program. Publication No. 07-405.)
Figure 3-12. Stepwise approach for asthma therapy in adults.

EIB, exercise-induced bronchospasm; ICS inhaled corticosteroid; LABA, long-acting inhaled β2 agonist, LTRA,
leukotriene receptor antagonist; SABA, inhaled short-acting β2 agonist.
(Reproduced courtesy of National Asthma Education and Prevention Program. Publication No. 07-405.)
Anti-IgE Therapy in the Management of Asthma

Omalizumab, a recombinant monoclonal antibody, binds IgE with high affinity. It
is administered subcutaneously every 2–4 weeks. Dosing is calculated by the Key Fact
patient’s body weight and the level of serum IgE. Therapy should not be started Anti-IgE therapy is not a
during an acute exacerbation and should not be self-administered. In order to first-line therapy for the
prevent local reactions, no more than 150 mg should be administered at a single majority of asthma
patients, but it can be
site. A minimum of 12 weeks of therapy is required prior to determining the considered in patients with
effectiveness of therapy. No specific laboratory tests are required to monitor the atopic asthma refractory to
standard therapy.
patients who are clinically improving on anti-IgE therapy. In patients showing
clinical response, the optimal duration of therapy has not been established.
Adverse effects include injection-site reactions, rash, and urticaria.
Criteria for use include:

 Moderate-to-severe persistent asthma.
 Inadequately controlled symptoms with inhaled steroids.
 Serum IgE level between 30–700 international units/mL; therapy requires
presence of enough free IgE to bind to ensure therapeutic effect.
166 / CHAPTER 3
 Presence of allergic sensitization demonstrated through skin testing and/or in

vitro testing for allergen-specific IgE. (Allergen should be present year-
round.)
A pretreatment eosinophil count > 300 cells/mcL may serve as a predictor of
better clinical response.
Bronchial Thermoplasty
Technique of applying heat energy to the airways during bronchoscopy using a
specialized catheter. Three separate bronchoscopies are performed over 3 weeks
under moderate sedation. The procedure is associated with a modest degree of
improvement and lacks data on long-term benefits and effects on airway
morphology. It can also result in acute exacerbation requiring hospitalization.
Performed only at specialized centers.
Criteria for consideration of bronchial thermoplasty:

 Dependence on systemic steroid therapy (intermittently or continuously)
 FEV1 ≥ 50% predicted
 No history of life-threatening exacerbations
 Understanding of the risk of asthma worsening or having an acute
exacerbation after the procedure
MANAGEMENT OF ACUTE ASTHMA EXACERBATIONS
Risk Factors for Fatal Asthma Attack

Risk factors for fatal asthma exacerbation:
Key Fact  Asthma history:
A history of severe and/or
o History of severe exacerbation requiring intubation and/or ICU monitoring.
frequent exacerbations o History of an exacerbation requiring hospitalization in the previous year.
puts patients at increased o History of ≥ 3 exacerbations requiring emergency care in the previous
risk for experiencing a fatal
exacerbation.
year.
o Decrease in peak flow to < 50% of patient’s baseline.
 Noncompliance:
o Noncompliant with medication use, including inhaled steroids.
o Noncompliant with asthma action plan and regular follow-up.
 Medication dependence:
o Requiring > 1 canister of rescue therapy per month.
o Dependent on systemic steroids.
 Patient factors/demographics:
o History of illicit drug use and/or active smoking.
o Comorbid psychological disorder.

o Poor symptom perception.
o Presence of other cardiovascular and pulmonary co-morbid conditions.
o Low socioeconomic status.
o Non-white.
o Aspirin sensitivity.
o Continued trigger exposure.
Detecting the Onset of an Exacerbation
Patients should be taught to recognize the following indications of an

exacerbation.
Symptoms:
 Progressively worsening breathlessness, wheezing, cough, and chest tightness
 Decreased exercise tolerance and fatigue
Peak expiratory flow measurement:

 Baseline peak flow should be established in every patient.
 Decrease in peak flow of > 20% from normal, or from the patient's personal
best value, serves as a marker to detect the onset of an acute exacerbation.
 Particularly useful in patients who have poor symptom perception.
 Upon detection of an acute exacerbation, patients should implement their
asthma action plan (Figure 3-10).
168 / CHAPTER 3
Figure 3-10. Asthma action plan. The patient's normal PEFR value can be used
to construct a personalized asthma action plan.
(Reproduced courtesy of The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of
Health.)
Initial Approach and Severity Assessment

On arrival to a healthcare setting, initial approach should focus on assessing
hemodynamic stability and the need for intubation. The patient should be
evaluated for the presence of alternative diagnoses that might symptomatically
present as an acute asthma exacerbation and for the presence of
concomitant/coexisting conditions that might lead to an exacerbation (e.g.,
pneumonia, congestive heart failure, pneumothorax, pulmonary embolism).
INDICATORS OF SEVERITY
Clinical findings:
 The presence of tachypnea, tachycardia (>120 bpm), use of accessory muscles of
inspiration, diaphoresis, inability to speak full phrases, inability to lie supine due
to breathlessness, and pulsus paradoxus are all suggestive of a severe
exacerbation.
 Findings can be present alone or in combination.
 These findings lack sensitivity and might be absent in patients with severe
obstruction.
Peak expiratory flow measurements:

 Best method for objective assessment of severity.
 Values < 200 L/min or < 50% of patient’s baseline are indicative of severe attack.
 Also used to monitor response to therapy and a predictive marker for the
presence of hypercapnia; a decrease in peak expiratory flow to < 25% of
patient’s baseline is an indirect marker for the presence of hypercapnia.
Arterial blood gas analysis:

 Presence of marked hypoxia (arterial partial pressure of oxygen < 60 mmHg or
oxygen saturation < 90%) is suggestive of severe exacerbation.
 Hyperventilation can lead to decreased arterial partial pressure of carbon dioxide
(PaCO2); normal or high PaCO2 is indicative of severe airway obstruction.
 Worsening hypercapnia is an indication for intubation.
Imaging studies:
 Presence of hyperinflation is a sign of severe obstruction and air trapping.
170 / CHAPTER 3
Treatment of Acute Asthma Exacerbation (See Table 3-21)
Table 3-21. Treatment of Acute Asthma Exacerbation

Comments
Goals of Therapy Rapid reversal of airflow obstruction
Maintenance of hemodynamic stability
Correction of hypercapnia and/or hypoxemia, if necessary
Supplemental Oxygen Should be used to maintain oxygen saturation ≥ 90% (> 95% in
pregnancy)
Inhaled Short-Acting Mainstay of bronchodilator therapy
β2-Agonist Therapy ≥ 3 treatments need to be given within the first hour
Nebulizer therapy is preferred over the use of metered dose inhalers
in acutely ill patients and can be administered continuously
Inhaled Can be added to inhaled β2-agonist therapy in the emergency room in
Anticholinergics the patients with severe obstruction
Can also be used in patients who have concomitant COPD or
refractory asthma
Systemic See below
Glucocorticoid
Therapy
Magnesium Sulfate Single dose of 2 g infused over 20 minutes in patients with life-
threatening exacerbation or in patients with severe exacerbations
failing to respond (peak flow < 40% baseline) after 1 hour of intensive
therapy with above-mentioned agents
Contraindicated in patients with renal failure
Methylxanthines Not indicated in the routine management of acute asthma
exacerbations
Can be used in acute exacerbations that fail to respond to
conventional therapy (no evidence)
For patients on oral therapy prior to admission, maintenance oral
therapy is continued during hospital stay
Needs drug-level monitoring
Nonstandard Anesthetic agents (intravenous ketamine, inhaled halothane) are
Therapies known to have bronchodilator properties
Reported to be used in refractory status asthmaticus
Parenteral ß agonists are used in patients suspected of having an
anaphylactic reaction leading to exacerbation, patients unable to use
inhaled bronchodilators, or in patients with acute respiratory failure
secondary to refractory exacerbation
Helium-oxygen mixtures:
 Low density of helium reduces airflow resistance
 Can be used to decrease work of breathing and improve
ventilation
 Used in patients with refractory severe exacerbations or when
significant contribution from upper airway obstruction is suspected.
 Conflicting data about efficacy limits routine use
No antibiotics to be used routinely unless concomitant bacterial
Empiric Antibiotics
pneumonia, sinusitis, or other bacterial infection is suspected
SYSTEMIC GLUCOCORTICOIDS—Essential for exacerbations refractory to

intensive bronchodilator therapy.
Indications for early administration of systemic glucocorticoid therapy during an

acute exacerbation are as follows:
 Immediate administration in a patient with peak expiratory flow rate < 40% of
patient’s baseline.
 Early administration recommended in patients with peak expiratory flow rate >
40% of patient’s baseline but < 70%.
 Lack of improvement in peak flow after several treatments with rapid-acting
bronchodilators.
 Asthma exacerbation in patients who are on current systemic steroid therapy;
such patients require steroid supplementation above their baseline dose.
Onset of action:
 Clinically evident ~6 hours after administration.
 Early administration recommended.
Optimal dose:
 Unknown for acute asthma exacerbation.
 Based on expert opinion, patients with life-threatening exacerbations should be
given initial dose of 60–80 mg methylprednisolone every 6–12 hours.
Route of administration:
 At comparable doses, the efficacy of systemic steroids administered by oral and
IV route remains the same.
 IV steroids should be used in patients who are unable to tolerate oral steroids or
who are acutely sick with impending or actual respiratory failure.
 In acutely sick patients, once patient can tolerate and absorb oral medications,
transition can be made from IV to oral route.
Duration of therapy:
 The optimal duration of systemic steroid therapy is unknown.
 Routinely, 10–14 days of systemic therapy is recommended.
 Patients can be advised to stop oral therapy earlier if marked improvement in
symptoms is noted with improvement in peak flow values (peak expiratory flow
> 70% of baseline).
 Tapering steroid therapy is not needed if the total duration of systemic therapy is
< 3 weeks.
 However, patients should be placed on inhaled glucocorticoid therapy for
maintenance.
AIRWAY MANAGEMENT IN ACUTE ASTHMA EXACERBATION—If intubation

difficulty is not anticipated, rapid-sequence intubation is preferred. Nasal
intubation is not recommended.
172 / CHAPTER 3
Indications for intubation and mechanical ventilation in acute asthma

exacerbation are as follows:
 Decrease in respiratory rate.
 Altered mental status.
 Failure to maintain respiratory effort.
 Worsening acidosis and hypercapnia.
 Hypoxia with oxygen saturation < 95% in the presence of high-flow
supplemental oxygen.
Role of noninvasive positive-pressure ventilation has not been well studied in

asthma.
Ventilation settings:
 Goal is to adequately oxygenate and ventilate the patient, minimizing the
increased airway pressures at the same time.
 Severe bronchoconstriction reduces airflow during expiration; the ventilator
settings should provide adequate time for expiration.
 Adequate time for expiration can be achieved by using high inspiratory flow
rates (80–100 L/min), low tidal volumes (6–8 mL/kg), and low respiratory rates
(10–14 breaths/min).
INDICATIONS FOR HOSPITALIZATION IN ACUTE ASTHMA EXACERBATION

 Patients who fail to show substantial improvement after 4–6 hours of aggressive
management with frequent inhaled bronchodilator and systemic glucocorticoid
treatment.
 Patients with hemodynamic instability, persistent hypoxemia, hypercarbia,
wheezing, presence of concomitant pneumonia, congestive heart failure, and
other comorbid conditions.
 Presence of potential trigger in home environment.
 Patients known to be noncompliant with medications or who are unable to care
for themselves with lack of social support.
 Presence of risk factors for fatal asthma attack.
PREGNANCY AND ASTHMA
Diagnosis of Asthma during Pregnancy

SPIROMETRY
 Diagnosis can be made by demonstration of reversible airflow obstruction on
spirometry.
 FVC, FEV1, FEV1/FVC ratio, and peak expiratory flow rates are not significantly
changed during normal pregnancy.
 Bronchoprovocation challenge testing is generally avoided.
CLINICAL FEATURES
 One third of patients show improvement in their asthma during pregnancy.
 One third of patients show worsening of their asthma during pregnancy.
 The remaining one third show no change.
 Exacerbations usually occur during the middle trimester.
 Gestational asthma is associated with perinatal mortality, pre-eclampsia, and
preterm delivery.
Treatment of Asthma during Pregnancy

GENERAL TREATMENT PRINCIPLES—The general treatment principles for
management of acute exacerbations and chronic management of asthma in pregnant
patients are the same as non-pregnant individuals. Fetal well-being should also be
monitored.
ROLE OF SPECIFIC MEDICATIONS

 Studies on the use of albuterol, metaproterenol, theophylline, and inhaled
glucocorticoids, particularly beclomethasone and budesonide, have shown lack
of adverse effects on outcomes of human pregnancy.
 Salmeterol, formoterol, ipratropium, nedocromil, zafirlukast, and montelukast
have shown reassuring data in animal studies with limited experience in human
pregnancies.
 Use of systemic steroids in pregnancy has been associated with slightly increased
risk of congenital malformations, low birth weight, pre-eclampsia, and neonatal
adrenal insufficiency.
 However, these potential risks outweigh the benefit of using systemic steroid
therapy during acute asthma exacerbations during pregnancy.
 Allergen immunotherapy for asthma should not be initiated during pregnancy but
can be continued in patients who are already on it and not prone to systemic
reactions.
COPD BASIC SCIENCE
COPD is characterized by airflow obstruction that is chronic, progressive, and for

the most part, fixed. It is generally divided into emphysema and chronic
bronchitis.
174 / CHAPTER 3
 Emphysema is defined as alveolar wall destruction with irreversible

enlargement of the air spaces distal to the terminal bronchioles and without
evidence of fibrosis.
 Chronic bronchitis is defined as a productive cough that is present for a period
of 3 months in each of 2 consecutive years in the absence of another
identifiable cause of excessive sputum production.
PATHOPHYSIOLOGY
COPD is characterized by chronic inflammation of the airways, lung tissue, and

pulmonary blood vessels. Protease-antiprotease imbalance and oxidative stress are
also involved in the pathogenesis of COPD.
Cellular Response and Inflammatory Mediators
Key Fact  Tobacco smoke and other environmental irritantsactivation of epithelial

cells and macrophagesrelease of multiple cytokines like CXC chemokine
Epithelial cellsTGFβ
small airway fibrosis ligand (CXCL) and CC chemokine ligand (CCL)recruitment of cytotoxic T
cells (TC1), Th1 cells, and neutrophilsrelease of inflammatory mediators and
proteasesdestruction of lung parenchyma and mucus production. Details are
provided in Table 3-21 and Figure 3-13.
Key Fact
o Chemokines are a group of chemoattractant cytokines secreted by cells
MacrophagesLTB4 and and can induce chemotaxis in other leukocytes.
IL-8neutrophil and T-cell
chemoattractantincrease o Two predominant chemokines involved in the immune response of COPD
d inflammation are CXC chemokines (CXC) and CC chemokines (CC).
 Epithelial cells also secrete TGFstimulation of fibroblast
productionfibrosis of small airways.
Table 3-21. Major Cellular Responses and Mediators in COPD
Cell Types Inflammatory Mediators
Epithelial cells TGFβ, CXCL

Macrophages CXCL, CXC, IL-6, IL-8, LTB4, TNFα, MMP
Neutrophils MMP, serine proteases
Th1 cells, TC cells (CD8+) Interferons
CXC, CXC chemokine; CXCL, CXC chemokine ligand; IL, interleukin; MMP, metalloproteases; TNF, tumor
necrosis factor; TGF, transforming growth factor.
Figure 3-13. Macrophages are activated by cigarette smoke and recruit

neutrophils and CD+ lymphocytes to cause elastolysis and emphysema. Similarly,
cigarette smoke activates airway epithelium to trigger airway remodeling. Both of
these processes result in airflow obstruction.
CXCR3, chemokine CXC receptor 3; CXCR2, chemokine CXC receptor 2; EGF, epidermal growth factor; IL-8,
interleukin 8; CXCL, CXC chemokine ligand; CCL, CC chemokine ligand; LTB4, leukotriene B4; MMPs, matrix
metalloproteinases; PDGF, platelet-derived growth factor; TGFβ, transforming growth factor β.
Flash Card Q4
What are the primary
lymphocytes involved in
pathogenesis of COPD?
176 / CHAPTER 3
Protease and Antiprotease Imbalance

Increased activity of proteases and decreased activity of antiproteases leads to
lung destruction.
 The primary proteases involved are serine proteases, elastases, and matrix
metalloproteases (MMP-8, MMP-9, and MMP-12).
 Main antiprotease involved is α1-antitrypsin.
Oxidative Stress
Oxidative stress due to cigarette smoke and reactive oxygen species produced by
inflammatory cells can further accentuate inflammation and protease-antiprotease
imbalance, thereby accelerating lung destruction.
PATHOLOGICAL CHANGES IN COPD
Emphysema
Neutrophil elastase and MMP released by the inflammatory cells lead to
destruction of alveolar wall and capillaries. In patients with α1-antitrypsin
deficiency, loss of α1-antitrypsin leads to unopposed breakdown of elastin by
elastase (which is released by neutrophils).
Chronic Bronchitis
 Squamous metaplasia and goblet hyperplasia  mucus hypersecretion

 Inflammation  smooth muscle hypertrophy and fibroblast proliferation 
peribronchiolar fibrosis
 Smoking  mucociliary dysfunction  mucus buildup  airflow obstruction
 air trapping
COMPARISON OF ASTHMA AND COPD
Both asthma and COPD are characterized by airway inflammation. Table 3-23
Flash Card A4 gives a broad overview of pathogenesis of both the diseases.
A: CD8+ cytotoxic T cells
Table 3-23. Overview of Asthma and COPD Pathogenesis
Feature Asthma COPD

Inciting factor Allergen or irritant Smoking or irritant
Major cell types Epithelial cells, Th2 cells Th1 and TC1 cells (CD8+)
(CD4+) Neutrophils, macrophages
Mast cells, eosinophils
Mediators IL-4, IL5, IL-13 LTB4, TNFα, IL-8
Airway and Mainly large airway Small airway fibrosis

parenchymal No parenchymal involvement Parenchymal destruction
involvement
Pathological changes Subepithelial fibrosis Peribronchial fibrosis
Smooth muscle Smooth muscle hyperplasia+
hyperplasia+++ Mucous metaplasia
Mucous metaplasia Alveolar destruction
Basement membrane
thickening
Airflow limitation
Reversible Airflow limitation Partially reversible
COPD
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines
COPD as a common, preventable, and treatable disease characterized by
persistent airflow limitation that is usually progressive. It associated with an
enhanced chronic inflammatory response in the airways and the lung to noxious
particles or gases.
178 / CHAPTER 3
MECHANISMS OF AIRFLOW LIMITATION

There are two proposed mechanisms of airflow limitation in COPD, and both
pathways are the result of the host’s modified response to chronic irritants (Table
3-22).
Small airways disease is the result of chronic inflammation leading to thickening

and narrowing of the small airways.
Before the development of emphysema and parenchymal destruction, the elastin

in the walls of the small airways is destroyed, leading to the disappearance of
small airways. The combination of narrowed and lost small airways and mucus
occlusion leads to increased peripheral airway resistance.
Parenchymal destruction is the result of chronic inflammation leading to the loss

of alveolar attachments to the small airways and decreased elastic recoil.
Destruction of the parenchyma also leads to gas exchange abnormalities.
Table 3-22. Mechanisms of Underlying Airflow Limitation
Small Airways Disease Parenchymal Destruction

Airway inflammation Loss of alveolar attachments
Narrowing of the small airways Decreased elastic recoil
Loss of elastin in airway wall
Disappearance of the small airways
Luminal plugs
Increased airway resistance
Chronic Bronchitis and Emphysema
Chronic bronchitis and emphysema are often used to describe subtypes of COPD
but should not be considered COPD unless there is associated airflow obstruction.
Figure 3-14 shows the mechanisms of underlying airflow limitation.
Chronic bronchitis is a clinical entity defined as cough or sputum production for

at least 3 months in each of 2 consecutive years. It can occur regardless of airflow
limitation, and other causes of cough must be ruled out.
Emphysema is a pathological term that describes abnormal enlargement of the

airspaces distal to the terminal bronchioles along with the destruction of airspace
walls. Emphysema represents one type of structural abnormality in COPD.
Figure 3-14. Mechanism of underlying airflow limitation. Small airways disease is

depicted as chronic obstructive bronchiolitis, and parenchymal destruction is
depicted as emphysema.
EPIDEMIOLOGY
Burden of COPD
COPD is a global disease with significant morbidity and mortality causing both a
social and economic burden. The estimated direct costs of COPD in 2010 were
$29.5 billion (largely related to COPD exacerbations), with indirect costs of $20.4
billion (lost earnings for patients and caregivers) in the US alone.
PREVALENCE OF COPD—The World Health Organization (WHO) estimated

that 64 million people had COPD worldwide in 2004, but some estimates are as Key Fact
high as 210 million. In the US, the Centers for Disease Control (CDC) reported The rate of female deaths
the prevalence of COPD as 5.1% (11.8 million) from 2007 to 2009, but the from COPD is rising and
the deaths per year have
National Health and Nutrition Examination Survey (NHANES) III, conducted exceeded that of men
between 1988 and 1994, estimated that 23.6 million US adults were afflicted with since the year 2000.
COPD. Overall, the true prevalence is difficult to determine because COPD has a
high rate of underdiagnosis. It is estimated that 60–85% of patients with mild-to-
moderate COPD are undiagnosed.
The prevalence and mortality of COPD in women is higher than in men:

 Women are 37% more likely to have COPD than men (Figure 3-15).
 Mortality in females from COPD has more than quadrupled since 1980.
 Since 2000, more women than men have died from COPD annually.
180 / CHAPTER 3
Figure 3-15. Prevalence of COPD from 1998–2009 in the U.S. was significantly
higher among women than men.
(Source: Centers for Disease Control and Prevention/ National Center for Health Statistics Health
Data Interactive, National Hospital Discharge Survey, and National Vital Statistics System.)
Prevalence of COPD is higher in older age groups:

 In the Latin American Project for the Investigation of Obstructive Lung
Disease:
o Prevalence of post-bronchodilator obstruction among people > 40 years
old was examined in five major Latin American cities.
o The highest prevalence of COPD was among those ≥ 60 years old.
 Most patients with COPD in the US are > 65 years old (Figure 3-16).
Figure 3-16. Prevalence of COPD in the US 1998–2009 by age and sex.

(Source: Centers for Disease Control and Prevention/ National Center for Health Statistics, Health Data
Interactive, National Hospital Discharge Survey, and National Vital Statistics System.)
MORBIDITY AND MORTALITY—COPD is a debilitating disease that impairs

sleep, employment, and physical and social activity.
 Associated comorbidities such as cardiovascular disease and diabetes

complicate the ability to quantify morbidity in COPD.
 Disability-adjusted life year (DALY) measures the proportion of mortality and
disability attributable to major disease and estimates that COPD will be
ranked seventh by the year 2030 (compared to 12th in 1990).
 The Global Mortality and Burden of Disease project estimates COPD
mortality will rank fourth worldwide and third in middle-income countries by
2030.
 In 2002, COPD was ranked as the fifth-leading cause of death worldwide.
 From 1999–2007, death rates declined for men but did not change
significantly for women (Figure 3-17).
Figure 3-17. Hospitalization and death rates in the U.S. for COPD, 1997–2007.
(Source: Centers for Disease Control and Prevention/ National Center for Health Statistics, Health Data
Interactive, National Hospital Discharge Survey, and National Vital Statistics System.)
182 / CHAPTER 3
RISK FACTORS FOR COPD
Smoking and Nonsmoking Risk Factors

Cigarette smoking is the single most important risk factor for the development of
COPD. However, a significant burden of disease occurs in nonsmokers. Alpha-
1antitrypsin deficiency and occupational exposures are implicated as the other
major causes of COPD. Other significant causes include outdoor air pollution,
secondhand smoke, and biomass smoke.
SMOKING— Nearly 80% of all COPD cases can be attributed to smoking. In a

retrospective cohort, smokers were more likely than never smokers to develop
COPD over a 25-year span (36% vs. 8%).
Risk of COPD and smoking:

 Cigarette smoking: 15–20% of 1 pack per day (PPD) smokers and 25% of 2
PPD smokers
 Pipe and cigars: Elevated risk, but lower than cigarette smokers
 Passive smoking: Suggestive evidence for secondhand smoke as a risk factor
NONSMOKING—Most data concerning risk factors for nonsmoking COPD were

gathered from cross-sectional epidemiologic studies that identified associations
rather than cause-and-effect relationships (Table 3-24). In the worldwide Burden
of Obstructive Lung Disease (BOLD) survey, the risk in nonsmokers was
estimated to be 3–11%.
Table 3-24. Risk of COPD Not Related to Smoking
Risk Comment
Occupational exposures Coal miners, hard-rock miners, tunnel workers, cement workers,
cotton workers (Table 3-25)
Genetic susceptibility α1-antitrypsin deficiency with > 90% caused by homozygous PiZZ
phenotype; cutis laxa (emphysema in children); metalloproteinase-
12 gene mutation
Asthma/bronchial Chronic asthma and hyperreactivity can lead to FEV1 decline and
hyperreactivity fixed obstruction in nonsmokers
Biomass smoke Indoor burning of wood, animal dung, crop residue, and coal in
poorly ventilated dwellings (primarily affects women)
Poverty Strong risk factor but unclear if related to combination of poor
nutrition, air pollution, etc.
Poor lung development Bronchopulmonary dysplasia (neonatal chronic lung disease), low
birth weight
Infections Childhood infections, tuberculosis, HIV (accelerated emphysema
in smokers)
Air pollution Outdoor pollution has been shown to be an independent risk factor
for decline in FEV1
FEV1, 1-second forced expiratory volume; HIV, human immunodeficiency virus.
Table 3-25. Occupational Irritants That Increase the Risk of COPD
Occupation Irritant
Agricultural worker Endotoxin
Coal miner Coal dust
Concrete worker Mineral dust
Construction worker Dust
Gold miner Silica
Hard rock miner Mineral dust
Rubber worker Industrial chemicals
α1-ANTITRYPSIN (AAT) DEFICIENCY—AAT is a protease inhibitor of the

proteolytic enzyme elastase and normally protects the lung from elastin
degradation. In AAT deficiency, there is an imbalance favoring degradation of
elastin leading to panacinar emphysema. Cigarette smoking increases the risk of
emphysema in AAT deficiency and accelerates lung function decline.
Phenotypes and risk for emphysema are listed in Table 3-26.
Table 3-26. α1-Antitrypsin Deficiency Phenotypes and Emphysema

Risk
Phenotype Risk for Emphysema (%)
MM (normal) No increase
MZ Causes intermediate serum level deficiency, but risk of developing

emphysema is unclear and controversial
SS No increase
SZ Mild increase (20–50%) in smokers; rarely occurs in nonsmokers
ZZ High risk (80–100%); accelerated age of onset in smokers
Null High risk (100% by age 30)

184 / CHAPTER 3
The following characteristics differentiate AAT deficiency from smoking-related

COPD:
 AAT deficiency has an earlier age of onset; mean age is 46 +/- 11 years in one
study and median age is 52 years in another
 Emphysema in a nonsmoker or minimal smoker
 First-degree relative with emphysema
 Characteristic imaging shows bullous changes predominantly at the bases
 Concurrent liver disease/cirrhosis
 Panniculitis (rare skin finding)
Treatment:
 Conventional COPD management, including smoking cessation with
nonpharmacologic and pharmacologic therapy, based on GOLD guidelines
 Intravenous α1-antitrypsin therapy (augmentation) is available for high-risk
Key Fact phenotype patients, typically PiZZ:
AAT deficiency should be
o Increases serum and bronchoalveolar lavage (BAL) fluid levels
suspected in young (<45 o Eligible patients: nonsmokers, FEV1 25–80%, plasma AAT level < 11
years), white nonsmokers
with emphysema and mol/L, other therapy optimized
imaging showing bullous o Modest effect in slowing lung function decline, but no effect in preventing
disease at the lung bases.
exacerbations
o Not recommended for emphysema unrelated to AAT deficiency or
patients with normal lung function
NATURAL HISTORY
Pulmonary Function Decline

The natural age-related decline in lung function is accelerated in COPD (Figure 3-
18). Patients with COPD often remain asymptomatic for 20–40 years prior to
diagnosis. After age 35, nonsmokers can expect to lose up to 30 mL/year in FEV1,
while smokers with COPD lose ~60 mL/year; the most loss occurs in patients
with moderate airflow obstruction. Symptoms of dyspnea and wheezing typically
occur when FEV1 is 40–59% of predicted. When a smoker stops smoking, the rate
of FEV1 loss again approximates that of a nonsmoker, but the lost lung function is
never fully regained.
Figure 3-18. Lung function decline in smokers and nonsmokers.
DIAGNOSIS
Symptoms
A diagnosis of COPD should be suspected in any patient with dyspnea, chronic
cough or sputum production, and a history of exposure to known risk factors.
Symptom onset is usually in the fifth decade of life or later and often brought to
light by respiratory infections.
ADDITIONAL CLINICAL FEATURES—Other symptoms associated with COPD

are important prognostically or may represent other disease processes (e.g.,
tuberculosis, lung cancer, congestive heart failure).
 Wheezing and chest tightness

 Fatigue
 Weight loss/muscle wasting; inflammatory mediators from the lung may play
a role
 Anorexia
 Cough attacks, which may cause rib fractures that are often asymptomatic
 Ankle swelling; may represent cor pulmonale
186 / CHAPTER 3
 Depression/anxiety; associated with an increased risk of exacerbations
Physical Exam
Abnormal physical exam findings are mostly present in severe disease.
CHEST EXAM
 Chest wall hyperinflation; limited diaphragmatic motion on auscultation
 Decreased intensity of breath and/or heart sounds
 Wheezing and prolonged expiratory time
 Pursed-lip breathing and use of accessory respiratory muscles
OTHER
Key Fact  Positional relief of dyspnea: leaning forward, arms outstretched with palms or
elbows used to bear weight
Digital clubbing is not
typical in COPD and may  Cyanosis
reflect other disease  Digital clubbing is not typical in COPD and may reflect other disease
processes such as lung processes (e.g., lung cancer)
cancer or interstitial lung
disease.  Lower extremity edema may occur with or without cor pulmonale
 Asterixis rare but can be seen with severe hypercapnia
Spirometry
DIAGNOSIS AND SPIROMETRY—In the appropriate clinical context, a

diagnosis of COPD is made with spirometry (Figure 3-19).
 Post-bronchodilator FEV1/FVC < 0.70 establishes the presence of persistent

airflow obstruction (GOLD definition).
 Degree of post-bronchodilator response to FEV1 is not required for the
Key Fact diagnosis of COPD.
After age 35, nonsmokers  Up to two thirds of COPD patients can have a significant bronchodilator
can expect to lose up to 30 response despite not having a diagnosis of asthma.
mL/year in FEV1 while  Presence of a bronchodilator response cannot definitively differentiate COPD
smokers lose close to 60
mL/year. from asthma.
 Figure 3-19 illustrates flow-volume loops of a normal lung and in obstructive
lung disease.
The lower limit of normal (LLN) for FEV1/FVC is also used to identify airflow
limitation but is not part of the GOLD criteria. Using the LLN is dependent upon
the choice of valid reference equations but can help with avoiding overdiagnosis
of COPD in the elderly. The fixed FEV1/FVC threshold can also lead to
underdiagnosis in younger patients with COPD.
Figure 3-19. Flow volume loop demonstrating obstruction.
OTHER LUNG FUNCTION FINDINGS

 Elevated total lung capacity (TLC) or functional residual capacity (FRC) >
120% predicted is consistent with hyperinflation.
 Elevated residual volume (RV) > 120% predicted is consistent with air Key Fact
trapping. When a smoker stops
smoking, the rate of FEV1
 Decreased DLCO, out of proportion to alveolar volume, is seen in emphysema. loss again approximates
 An inspiratory capacity (IC)-to-TLC ratio < 25% is an independent predictor that of a nonsmoker.
of mortality in COPD.
Radiography
CHEST X-RAY—Although not useful in the diagnosis of COPD, the chest x-ray
can be used to evaluate for other diseases that have similar symptoms (e.g.,
pulmonary fibrosis, bronchiectasis).
Classic changes on chest x-ray include hyperinflation (flattened diaphragms,

increased retrosternal space, teardrop-shaped heart) and hyperlucency of the lung
(Figure 3-20).
188 / CHAPTER 3
Figure 3-20. Chest radiograph showing hyperinflation.

(Image courtesy of Wikipedia; permission granted per the GNU Free Documentation License.)
COMPUTED TOMOGRAPHY (CT) OF THE CHEST—Not recommended for

routine diagnostic purposes, although it has much better sensitivity and specificity
than plain radiographs. If surgery is an option for resection of bullae or lung
volume reduction, a chest CT is used to identify the distribution of emphysema
(Figure 3-21).
Many patients with COPD will also meet criteria for lung cancer screening with
low-dose CT given their older age and extensive smoking histories (see Chapter
12.).
Figure 3-21. CT of the chest showing emphysema.

(Modified and reproduced, with permission, from Matsuoka S, Washko GR, Yamashiro T, et al. Pulmonary
Hypertension and Computed Tomography Measurement of Small Pulmonary Vessels in Severe Emphysema.
Am J Respir Crit Care Med 2010;181(3):218–225. Fig. 1. doi: 10.1164/rccm.200908-1189OC)
Comorbidities
Comorbidities can occur at any stage of disease and directly influence mortality
and hospitalization rates. COPD increases the risk of lung cancer, fractures,
cardiovascular disease, osteoporosis, and respiratory infections (Figure 3-22).
SYSTEMIC FEATURES—There is growing evidence that inflammatory

mediators contribute directly to the worsening of comorbidities. One proposed
mechanism describes inflammatory mediators from the lung “spilling over” into
the circulation and leading to other disease processes.
MANAGEMENT OF COMORBIDITIES—Comorbidities should be treated

independent of COPD severity. In general, the presence of COPD should not
interfere with the treatment of other diseases.
 Cardiovascular disease: The most frequent coexisting disease and the second
most common cause of death in patients with mild-to-moderate COPD.
o Cardioselective ß blockers should not be discontinued, even in severe
COPD.
 Lung cancer: The most frequent cause of death in patients with mild COPD.
 Osteoporosis, anxiety/depression, metabolic syndrome: Associated with
poor health status and prognosis.
190 / CHAPTER 3
Figure 3-22. Comorbidities of COPD.
ASSESSMENT OF DISEASE
Severity of Disease
SYMPTOMS—There are multiple validated questionnaires to assess symptoms
in COPD. GOLD recommends using the Modified British Medical Research
Council (mMRC) questionnaire (Figure 3-23) or the COPD Assessment Test
(CAT).
Figure 3-23. Modified British Medical Research Council questionnaire.
SEVERITY OF AIRFLOW OBSTRUCTION—Spirometry is used to grade the

level of airflow obstruction using FEV1, but it does not correlate well with
symptoms and quality of life assessments. The post-bronchodilator FEV1 is used
to determine GOLD classification (Table 3-27).
Table 3-27. GOLD Classification of Severity of Airflow Limitation in COPD
a
Severity FEV1/FVC FEV1 (% Predicted)
I: Mild <0.70 ≥80
II: Moderate <0.70 50–79
III: Severe <0.70 30–49
IV: Very severe <0.70 <30 or chronic respiratory

failure
a
FEV1/FVC is based on post-bronchodilator response.
FEV1, 1-second forced expiratory volume; FVC, forced vital capacity.
ASSESSING COPD EXACERBATION RISK—COPD exacerbations are

acute events characterized by the worsening of baseline respiratory symptoms
(cough, dyspnea, sputum production, etc.) requiring treatment with corticosteroids
and/or antibiotics.
192 / CHAPTER 3
Key Fact  The frequency and intensity of exacerbations are variable among individuals.
GOLD classification uses  Patients are considered high risk for exacerbations if they have more than two
three ways to identify high- exacerbations within the prior year, have been hospitalized for an
risk patients when
categorizing COPD exacerbation, or have GOLD III or IV airflow limitation.
patients: 1) FEV1 < 50%  GOLD recommends a combined COPD assessment scheme that incorporates
(GOLD III/IV), 2) >2
exacerbations within the airflow limitation, symptoms, and exacerbation risk (Figure 3-24).
previous 12 months, and 3)
one or more
hospitalizations for COPD
exacerbation.
Mnemonic
Predictor of survival in
COPD: BODE
Body mass index:

Lower BMI is a poor
prognostic marker
Obstruction (FEV1%
predicted)
Dyspnea (mMRC)
Exercise (6-minute
walk distance)
Figure 3-24. COPD assessment using symptoms, spirometric classification, and

risk of exacerbations. When assessing risk, the highest risk according to GOLD
classification or exacerbation history is used.
PREDICTING SURVIVAL—There are multiple variables associated with

mortality in COPD including FEV1, IC/TLC ratio, exercise tolerance (walk
distance), peak oxygen consumption, body weight, right heart function, and
arterial oxygen tension. The BODE method is a better predictor for survival than
any single parameter. BODE is based on a 10-point scale and predicts 4-year
mortality.
DIFFERENTIAL DIAGNOSIS OF COPD
See Table 3-28.
Table 3-28. Differential Diagnosis of COPD
Diagnosis Features
Onset in midlife.
Symptoms slowly progressive.
COPD
Strong association with tobacco smoking.
Largely irreversible airflow limitation.
Childhood onset typical but can also present in adulthood.
Symptoms may vary from day to day.
Symptoms may worsen at night/early morning.
Asthma
Allergy, rhinitis, and/or eczema may also be present.
Normalization of airflow limitation after bronchodilator is diagnostic.
Positive methacholine challenge is suggestive of asthma.
Basilar crackles on auscultation.
Congestive heart Chest radiograph shows dilated heart, pulmonary edema.
failure Pulmonary function tests show restriction, not airflow limitation.
Elevated BNP.
Large volumes of purulent sputum.
Commonly associated with bacterial infections.
Bronchiectasis
Imaging shows bronchial dilation, bronchial wall thickening.
Clubbing can be seen.
Onset in all ages.
Chest radiograph shows lung infiltrate or cavitary lesion.
Tuberculosis
Microbiologic confirmation.
Risk factors: endemic areas, incarceration.
Often associated with rheumatoid arthritis.
Inhalation of dusts, fumes, or toxins.
Chronic graft-versus-host disease of the lung seen after allogeneic
Obliterative hematopoietic stem cell transplant.
bronchiolitis
Chronic lung transplant rejection.
Expiratory HRCT shows mosaicism with hypodense areas representing
“trapped” air. Flash Card Q5
Most patients are male nonsmokers of Japanese descent. A 56-year-old female with
Almost all have chronic sinusitis. COPD describes dyspnea
Diffuse when hurrying on level
Chest radiograph and CT show diffuse small centrilobular nodular opacities
panbronchiolitis ground. Post-
and hyperinflation.
Improves with macrolide therapy. bronchodilator FEV1 is 45%
predicted with no history of
BNP, B-type natriuretic peptide; COPD, chronic obstructive pulmonary disease; CT, computed tomography; exacerbations within the
HRCT, high-resolution computed tomography. past year. What is the
GOLD combined
assessment of this patient?
194 / CHAPTER 3
COPD Versus Asthma
COPD may be difficult to distinguish from asthma, especially in the 30% of

longstanding asthma patients that have a fixed component of airflow obstruction.
A significant bronchodilator response to short-acting ß agonists (increase of FEV1
by 200 mL and 12%) can be seen in either COPD or asthma. The major
spirometric difference between COPD and asthma is that the pre- and/or post-
bronchodilator FEV1/FVC ratio remains < 0.70 or below the lower limit of normal
in COPD. Patients should be treated as having asthma if no clear distinction can
be made. Table 3-29 differentiates COPD from asthma.
OTHER FEATURES OF ASTHMA

 Eosinophilia in blood, BAL, and sputum
 Bronchial biopsy showing higher ratios of CD4+/CD8+ cells
 Higher levels of eNO
 Lower emphysema scores on CT
 Higher diffusing capacity
Table 3-29. Differentiating COPD From Asthma
Asthma COPD
Key Indicators Wheezing (especially in Progressive dyspnea or “air hunger”
children) Chronic sputum production
Risk factors: tobacco smoke, occupational
dusts and chemicals, or smoke from home
cooking and heating fuels
Other Factors Onset generally early in life Highest prevalence rates in adults ≥ 55
Intermittent symptoms years old
Environmental triggers Progressive disease with chronic symptoms
Exercise may trigger or Progressive decline in lung function

worsen symptoms Smoking history
Spirometry Bronchodilator response FEV1 Postbronchodilator FEV1/FVC < 0.70
findings ≥ 200 mL and ≥ 12% baseline
suggestive of asthma
FEV1, 1-second forced expiratory volume; FVC, forced vital capacity.
Flash Card A5
C. She is GOLD III based
on her FEV1 and scores 1
on the mMRC without a
history of exacerbations.
COPD TREATMENT
Smoking Cessation
Smoking cessation will slow FEV1 decline more than any pharmacologic therapy.
PHARMACOTHERAPIES FOR SMOKING CESSATION—First-line pharmaco-

therapy includes one of the following: combination nicotine replacement,
bupropion, or varenicline (Table 3-30). Therapy should be individualized based
on patient preferences, risk factors, and side effects.
Table 3-30. Pharmacotherapy for Smoking Cessation
Therapy Benefits Adverse Effects
NRT RCTs show NRT is superior to NRT is safe even in cardiovascular

placebo and doubles quit rates. disease
Modes of delivery: Combination NRT: long-acting Transdermal: Insomnia and vivid
transdermal, gum, (patch) + short-acting (gum, dreams if worn at night
lozenge, inhaler, lozenge, inhaler, spray) NRT is Gum: Excess nicotine release with
nasal spray most efficacious vigorous chewing (nausea, vomiting,
Duration: 2–3 months abdominal pain, constipation,
Relapse rate is the same for headaches)
those that used NRT vs. quitting Local effects: mouth irritation, ulcers,
on their own sore throat, rhinitis, bronchospasm,
sneezing
E-cigarettes Electronic system that delivers Not FDA-approved given safety

aerosolized nicotine concerns for potential toxic additives
Amount of nicotine delivered is (trace diethylene glycol,
variable depending on the nitrosamines)
individual product SE: Dry cough, irritation of
Further studies required to oropharynx
establish efficacy and safety
Bupropion (Zyban, Monotherapy doubles the Serious SE: Reduces seizure

Wellbutrin SR) likelihood of smoking cessation threshold; contraindicated in patients
compared to placebo with seizure disorder
Multicenter randomized trial FDA reported “possible association
showed improved abstinence for with suicidal events”
bupropion at 1 year (23% vs 12%) Common SE: insomnia, agitation,
Duration: 7–12 weeks dry mouth, and headache
196 / CHAPTER 3
Table 3-30. Pharmacotherapy for Smoking Cessation, continued
Varenicline Monotherapy triples the odds of Requires dose reduction in moderate

smoking cessation compared to renal insufficiency
placebo Serious SE: May increase suicide
Higher rate of abstinence at both events, cardiovascular events in
6 months and 1 year when patients with known CVD, and rates
compared to placebo of accidental injuries
Superior to Bupropion in 3 RCTs Common SE: nausea, insomnia,
Duration: 12 weeks abnormal dreams, syncope, skin
reactions
Nortriptyline Tricyclic antidepressant SE: dry mouth and sedation

Modest benefit in RCT compared
to placebo
CVD, cardiovascular disease; FDA, Food and Drug Administration; NRT, nicotine replacement
therapy; RCT, randomized control trial; SE, side effects.
COUNSELING FOR SMOKING CESSATION—Smoking cessation counseling is

effective and should be offered at each visit with a health care professional.
Behavioral therapy is not as effective as pharmacologic therapy alone.
Three types of effective counseling:

 Practical counseling
 Social support as part of treatment
 Social support arranged outside of treatment
Pharmacotherapy for COPD Maintenance

The role of pharmacotherapy is to reduce symptoms, reduce the frequency and
severity of exacerbations, and improve exercise tolerance. Mortality and the long-
term decline in pulmonary function have not been shown to definitively improve
with any pharmacologic agent. Table 3-31 lists inhaled pharmacotherapies for
COPD.
Table 3-31. Inhaled Pharmacotherapies

SABA: Transiently improves FEV1 and Resting sinus tachycardia
Albuterol symptoms Exaggerated somatic
Fenoterol tremor in older patients
Levalbuterol
Salbutamol
Terbutaline
LABA: *Significantly improves FEV1 and lung Resting sinus tachycardia
*Formoterol volumes, dyspnea, QOL, and Exaggerated somatic tremor
*Salmeterol exacerbation rates in older patients
*Indacaterol Salmeterol reduces rate of
Arformoterol hospitalizations
Tulobuterol
Indacaterol is once daily and has a
similar bronchodilator effect as
tiotropium
SAMA: Longer lasting than SABA with effects Bitter metallic taste
Ipratropium up to 8 hours Acute glaucoma (when used
Oxitropium Blocks M2 and M3 receptors via facemask)
LAMA: Tiotropium works via inhibition of the Dry mouth, constipation, and
Tiotropium M3 muscarinic receptors urinary retention (often in the
Aclidinium bromide Tiotropium reduces exacerbations and setting of concurrent BPH)
Glycopyrronium hospitalizations
Improves symptoms as well as
effectiveness of pulmonary
rehabilitation Flash Card Q6
Combination Combination SABA/SAMA improves Same as ß2 agonists and The TORCH trial revealed
bronchodilators FEV1 and symptoms better than either anticholinergics all the following findings
one alone except:
A. Salmeterol reduced
Combination LABA/LAMA exacerbations
Ex: indacaterol/glycopyrronium B. Salmeterol-fluticasone
combination reduced
ICS Improves symptoms, lung function, Oral candidiasis, hoarseness, exacerbations
QOL, and reduces exacerbations in easy bruising C. Salmeterol-fluticasone
patients with FEV1 < 60% Pneumonia combination reduced
Only approved at fixed doses with mortality
LABA D. Pneumonia was more
likely in patients taking
Combination In moderate to very severe COPD, Pneumonia and as above fluticasone
ICS/bronchodilators ICS/LABA therapy improves lung
function and reduces exacerbations
Meta-analysis has shown a mortality Flash Card Q7
benefit, but a large prospective trial
The UPLIFT trial revealed
(TORCH) did not reach statistical
that tiotropium was
significance
associated with all the
ICS/LABA + tiotropium improves lung following outcomes except:
function and QOL A. Reduction in
BPH, benign prostatic hyperplasia; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; FEV1, 1- exacerbations
second forced expiratory volume; ICS, inhaled corticosteroids; LABA, long-acting ß agonist; LAMA, long-acting B. Reduction in the rate
muscarinic antagonist; QOL, quality of life; SABA, short-acting ß agonist; SAMA, short-acting muscarinic of FEV1 decline
antagonist. C. Reduction in
hospitalizations related to
exacerbations
D. Improved quality of life
198 / CHAPTER 3
TIOTROPIUM AND CARDIOVASCULAR RISK—There is conflicting evidence

showing adverse cardiovascular effects with anticholinergic therapy.
 This association was refuted in the UPLIFT trial, which identified no
significant safety issues with the use of tiotropium in the HandiHaler dry
powder inhaler over a 4-year period.
 There were similar cardiovascular concerns attributed to the Respimat soft-
mist inhaler as compared to the HandiHaler. These concerns were refuted in a
large randomized trial (TIOSPIR), which revealed no safety issues.
Other Pharmacotherapy
METHYLXANTHINES—Theophylline is considered second-line therapy at low
doses. Proposed mechanisms of action include acting as a nonselective
phosphodiesterase inhibitor or a nonselective adenosine receptor antagonist.
 Modest bronchodilator and symptomatic effects compared to placebo.

 Recommended as possible add-on therapy in GOLD C or D.
 Combination therapy with salmeterol improves FEV1 and breathlessness
better than salmeterol alone.
 Low doses may reduce exacerbations.
 Toxicity is dose related with a small therapeutic window.
 Adverse effects: atrial and ventricular arrhythmias, seizures, headaches,
insomnia, nausea, and vomiting.
PHOSPHODIESTERASE-4 INHIBITOR—Roflumilast reduces moderate-to-

severe exacerbations in patients with chronic bronchitis, severe-to-very severe
COPD (FEV1 < 50%) and a history of exacerbations.
 Modest improvement in lung function when added to long-acting ß agonists

(LABA).
 Should always be used with a long-acting bronchodilator.
 Avoid in patients with low body mass index (BMI) and depression.
 Adverse effects: Diarrhea, nausea, reduced appetite, abdominal pain, sleep
problems, and weight loss.
VACCINES—Influenza and pneumococcal vaccines.

Flash Card A6
C; salmeterol-fluticasone Pneumococcal polysaccharide vaccine:
combination reduced
mortality  Indicated for COPD patients > 65 years old and younger patients with
comorbid conditions.
 Reduces community-acquired pneumonia in patients < 65 years old with
Flash Card A7
FEV1 < 40% predicted.
B; reduction in the rate of
FEV1 decline
Influenza vaccine recommended annually:
 Reduces death and lower respiratory tract infections.

 Killed or inactivated virus more effective in elderly patients.
MUCOLYTICS AND ANTIOXIDANTS

 Mucolytics are not universally recommended but can be considered in those
with a chronic productive cough.
 Inhaled N-acetylcysteine or carbocysteine may reduce exacerbations in
patients not receiving inhaled corticosteroids (ICS), but the effect is very
modest.
OPIODS (MORPHINE)—Used to treat dyspnea in very severe disease.
ANTIBIOTICS—In patients with increased risk of acute exacerbations of COPD,

azithromycin was shown to reduce exacerbations and improve time to next
exacerbation and dyspnea scores when compared to placebo during a 1-year trial.
Other findings:
 No mortality benefit.
 No benefit in the rate of exacerbations requiring hospitalization.
 The treatment group exhibited increased hearing loss.
 FDA has placed a warning for azithromycin causing fatal arrhythmias (QTc
prolongation) in patients at risk for cardiovascular death.
Key Fact
ANTITUSSIVES AND VASODILATORS—Not recommended for routine use. The following inhaled
therapies reduce COPD
exacerbations: LABA,
LAMA, and LABA/ICS
Nonpharmacologic Therapies
Nonpharmacologic therapy includes pulmonary rehabilitation, oxygen therapy, Flash Card Q8

and surgical interventions (See Table 3-32). What therapy has been
shown to slow the rate of
FEV1 decline?
A. LABA
PULMONARY REHABILITATION—The goal of rehabilitation is to improve B. LAMA
C. Smoking cessation
symptoms, increase physical activity, and improve quality of life. An effective D. LAMA + LABA/ICS
treatment program typically lasts at least 6 weeks. The longer the treatment E. LAMA + LABA
program, the longer the benefits last.
Flash Card Q9
Pulmonary rehabilitation
improves all of the
following except:
A. Dyspnea,
B. Quality of life,
C. FEV1
D. 6-minute walk distance
200 / CHAPTER 3
Table 3-32. Non-pharmacologic Therapy
Therapy Benefit and Patient Population Notes
Mnemonic Oxygen Benefit: Long-term oxygen therapy Determination of oxygen therapy must
(>15 hours/day) improves survival and use resting blood gas or pulse
Benefits of pulmonary exercise tolerance oximetry confirmed twice over 3-week
rehabilitation—BREATH(e) period
EASY Patient 1: PaO2 < 55 mmHg or SaO2 <
88% +/- hypercapnia Exercise tolerance can improve even
Breathlessness reduction Patient 2: PaO2 56–59 mmHg or SaO2 in less severe hypoxemia (PaO2 ~70
Recovery after < 89% with evidence of pulmonary mmHg)
exacerbation hypertension or erythrocytosis
Exercise capacity (6-
minute walk, shuttle Noninvasive Benefit: Improves hypercapnia, and in COPD + OSA (overlap syndrome):
walk) ventilation overlap syndrome, CPAP improves one disease does not predispose to
Anxiety and depression survival and decreases the other
reduction hospitalizations < 15% of COPD patients have OSA
Training of respiratory Patient 1: severe daytime hypercapnia
muscles
Hospitalization frequency Patient 2: COPD + concurrent OSA
and days in hospital (overlap syndrome)
decreased LVRS Benefit: Improves survival, exercise, Improves elastic recoil, expiratory
and QOL in selected patients airflow, and mechanical function of
Enhanced efficacy of long-
Patient 1: Upper lobe-predominant diaphragm
acting bronchodilators
Arm function improvement emphysema and poor exercise Contraindications to LVRS: FEV1 <
and endurance training capacity (<40 W in men, <25 W in 20%, DLCO < 20%, or
of upper limbs women) after pulmonary rehabilitation diffuse/homogeneous emphysema on
Survival (possible mortality Patient 2: Upper lobe-predominant CT
benefit) emphysema and high exercise Combination of diffuse emphysema
Your quality of life capacity have no survival benefit but and high exercise capacity also has
improvement improve QOL and exercise capacity increased mortality with LVRS
BLVRS Benefit: Modest improvement in lung BLVRS may increase COPD
function, exercise tolerance, and exacerbations, pneumonia, and
symptoms hemoptysis after implantation
Patient: severe airflow limitation (FEV1 More data needed to define optimal
15–45% predicted), heterogeneous technique and ideal patient population
emphysema, and hyperinflation with
air trapping (TLC > 100% and RV >
150%)
Bullectomy Benefit: Potential improvement in Highest risk: FEV1 < 40%, PaCO2 >
dyspnea, FEV1, hypoxemia, and 45 mmHg, pulmonary hypertension
exercise tolerance Contraindications: multiple small
Patient: select patients with giant bullae, diffuse emphysema, tobacco
bullae occupying 30–50% of use
hemithorax
BLVRS, bronchoscopic lung volume reduction surgery; COPD, chronic obstructive pulmonary disease; CPAP,
continuous positive airway pressure; CT, computed tomography; DLCO, diffusion lung capacity for carbon
monoxide; FEV1, 1-second forced expiratory volume; LVRS, lung volume reduction surgery; OSA, obstructive
sleep apnea; QOL, quality of life; RV, residual volume; TLC, total lung capacity.
Flash Card A8
C; smoking cessation
Flash Card A9
C. FEV1
Palliative care and hospice:

 Prevents and relieves suffering; improves symptoms and quality of life (QOL)
Flash Card Q10
for patients and families.
 All COPD patients are eligible for palliation regardless of disease severity. A 55-year-old woman with
severe emphysema
 COPD patients are much less likely to receive hospice or palliative care than presents for consultation.
lung cancer patients. FEV1 is 38% predicted,
DLCO is 38% predicted,
 It is often difficult to predict prognosis in patients with advanced COPD. and she is on optimal
medical therapy. She has
completed pulmonary
Lung transplant: rehabilitation but still has
poor exercise capacity. CT
 Improves QOL and functional capacity, but there is no clear mortality benefit. of the chest reveals upper
 Referral for transplant: BODE Index > 5. lobe-predominant
 Transplant listing: BODE Index 7–10 plus additional criteria. emphysema. What is the
recommended treatment?
 See lung transplant chapter for detailed criteria for lung transplantation. A. Bullectomy
B. Lung transplantation
C. Hospice care
D. Lung volume reduction
surgery (LVRS)
COPD TREATMENT BASED ON SEVERITY OF DISEASE Flash Card Q11
A 55-year-old women, a
25-pack-year ex-smoker,
Nonpharmacologic Treatment presents with dyspnea
when walking on level
ground after a few minutes.
Identifying and reducing exposure to risk factors is important in the prevention Her post-bronchodilator
FEV1/FVC is 0.62. FEV1 is
and treatment of COPD (Figure 3-25). Smoking cessation is essential for all 59% predicted. She has
patient groups in the GOLD classification. Pulmonary rehabilitation is never been treated for a
recommended for GOLD B, C, and D patients. Physical activity is recommended COPD exacerbation. What
should be the initial
for all patient groups. management of her
COPD?
A. ICS + LABA
B. LAMA + LABA
C. LAMA or LABA +
pulmonary
rehabilitation
D. LAMA only
Flash Card Q12

A 67-year-old male sees
you for breathlessness
when walking at his own
pace on level ground. His
post-bronchodilator FEV1
percent predicted is 55%.
Figure 3-25. Management of stable COPD based on GOLD classification. He has been treated for a
COPD exacerbation twice
within the last year. What
GOLD classification is he
and what is the
recommended initial
therapy?
202 / CHAPTER 3
Pharmacologic Treatment
After assessing symptoms and risk, patients will fall under four GOLD
classifications that determine pharmacologic therapy. Pharmacologic therapy is
used to reduce symptoms, reduce frequency and severity of exacerbations, and
improve exercise tolerance (Table 3-33).
Table 3-33. Initial Pharmacological Management of COPD

Patient Group First-Choice Therapy Second-Choice Therapy
A SAMA prn LAMA
or or
Low risk SABA prn LABA
Fewer symptoms or
SABA + SAMA
B LAMA LAMA + LABA
or
Low risk LABA
More symptoms
C ICS + LABA LAMA + LABA
or or
High risk LAMA LAMA + PDE4 inhibitor
Fewer symptoms or
LABA + PDE4 inhibitor
D ICS + LABA ICS + LAMA
and/or or
High risk LAMA ICS + LABA + LAMA
More symptoms
ICS, inhaled corticosteroids; LABA, long-acting ß agonist; LAMA, long-acting muscarinic antagonist; PDE,
phosphodiesterase; SABA, short-acting ß agonist; SAMA, short-acting muscarinic antagonist.
BRONCHODILATORS—Inhaled bronchodilators are preferred over oral

bronchodilators. Long-acting ß2 agonists and long-acting muscarinic antagonists
are favored over short-acting formulations. If there is no improvement with either
ß2 agonists or anticholinergics alone, combined therapy may be warranted.
Flash Card A10

D; lung volume reduction CORTICOSTEROIDS—Inhaled corticosteroids are indicated as adjunct therapy to
surgery (LVRS) long-acting bronchodilators in severe and very severe COPD, especially in
patients with a history of exacerbations. There is little evidence to support either
Flash Card A11 monotherapy with ICS or long-term oral corticosteroids for COPD.
C; LAMA or LABA +
pulmonary rehabilitation
Flash Card A12

GOLD D; ICS + LABA
and/or LAMA
Surgery in the COPD Patient
Post-operative pulmonary complications are common in COPD patients. Major

post-op respiratory complications include lung infections, atelectasis, increased
airflow limitation, and respiratory failure.
NON-LUNG RESECTION SURGERY

 Increased risks of post-operative complications in COPD may vary with
disease severity, though there is no known FEV1 cut-off that would make
essential non-lung surgery completely prohibitive.
 Risk increases as surgical site approaches the diaphragm.
 Epidural and spinal anesthesia are favored and considered lower risk than
general anesthesia.
ACUTE EXACERBATIONS OF COPD
According to GOLD, an exacerbation of COPD is an acute event characterized by Key Fact

worsening of the patient’s respiratory symptoms that is beyond normal day-to-day
Inhaled corticosteroids are
variations and leads to a change in medication. associated with an
increased risk of
PRECIPITATING FACTORS—Viral or bacterial respiratory tract infections are pneumonia in COPD
patients.
the most common cause of COPD exacerbations. In about one third of
exacerbations, the etiology is not identified. Other aggravating factors include air
pollution or discontinuation of maintenance therapy. Pneumonia, pulmonary
embolism, CHF, cardiac arrhythmias, or pleural effusions can both aggravate and
resemble a COPD exacerbation and should be considered in the differential
diagnosis.
ASSESSMENT AND DIAGNOSIS—An acute COPD exacerbation is

characterized by worsening respiratory symptoms, including shortness of breath
and sputum production beyond the normal day-to-day variation.
Laboratory findings:
 Arterial blood gas (in hospital): PaO2 < 60 mmHg with or without PaCO2 > 50
mmHg on room air constitutes respiratory failure
 Complete blood count: Identifies polycythemia, anemia, or leukocytosis
 Sputum (often purulent):
o Empiric antibiotics should be initiated
o H influenzae, S pneumoniae, and M catarrhalis are the most common
bacteria implicated in acute exacerbations
o Pseudomonas becomes more common in GOLD III and IV COPD (FEV1
< 50%)
 Chemistry: Identifies electrolyte abnormalities, diabetes, and poor nutrition
204 / CHAPTER 3
Imaging: Chest radiograph used to evaluate for pneumonia and alternative

diagnoses
Pulmonary function tests: Spirometry is not indicated during an acute

exacerbation
TREATMENT—Acute COPD exacerbation treatment includes supplemental

oxygen, bronchodilators, systemic corticosteroids, and potential use of
mechanical ventilation. Careful consideration should be made for hospitalization
based on risk factors.
Management of acute exacerbation: See Table 3-34.
Table 3-34. Management of an Acute Exacerbation of COPD
Type Treatment Details

Oxygen Target saturation is 88–92%
Bronchodilators SABA inhaled (MDI or nebulized) with or without SAMA
Systemic Shortens recovery time, improves FEV1 and PaO2
corticosteroids Reduces early relapse, treatment failure, and hospital stay
Oral glucocorticoids: Rapidly absorbed and as efficacious as IV
administration
GOLD guidelines: Equivalent doses of prednisone at 30–40 mg daily, but
some clinicians use doses as high as 60–125 mg of methylprednisolone
2–4 times daily
Duration varies depending on severity of disease and initial response to
therapy but typical course is 5–14 days
Antibiotics Indication 1: Increased sputum purulence plus either increased dyspnea
or sputum production or both
Indication 2: Moderate-to-severe exacerbations and those requiring
ventilatory support (invasive or noninvasive)
Choice of antibiotic: Based on local resistant patterns; should cover likely
bacterial pathogens (H influenzae, M catarrhalis, S pneumoniae)
First-line therapy outpatient: Doxycycline or trimethoprim-
sulfamethoxazole
First-line therapy inpatient: Respiratory fluoroquinolone or third-
generation cephalosporin
Antipseudomonas coverage in patients with associated risk factors
Noninvasive Decreases mortality, hospital stay, and intubation rate
ventilation Improves dyspnea, respiratory acidosis, respiratory rate
Indications: pH < 7.35 and/or PaCO2 > 45 mmHg and/or severe dyspnea
with respiratory muscle fatigue
Early NIV after extubation facilitates weaning, prevents re-intubation, and
reduces mortality
Table 3-34. Management of an Acute Exacerbation of COPD, continued
Type Treatment Details Key Fact

Invasive ventilation Increased mortality in mechanically ventilated patients with FEV1 < 30% Viral or bacterial
predicted respiratory tract infections
are the most common
Home management Possible in select patients without respiratory acidosis or comorbidities cause of COPD
Includes nursing visits, oxygen therapy, and physical therapy exacerbations.
Patients who are hypoxemic during an exacerbation should be re-

Hospital discharge evaluated in the next 3 months with arterial blood gas or pulse oximetry;
follow-up long-term supplemental oxygen should be arranged if the patient remains Mnemonic
hypoxemic
Indications for
FEV1, 1-second forced expiratory volume; MDI, metered dose inhaler; NIV, noninvasive ventilation; SABA, hospitalization: COOL
short-acting ß agonist; SAMA, short-acting muscarinic antagonist. FISH
Comorbidities (e.g., heart

failure, new arrhythmia)
Onset of new physical
PREVENTION OF COPD EXACERBATIONS—COPD exacerbations are exam findings (e.g.,
associated with accelerated disease progression, poorer quality of life, and cyanosis, lower extremity
increased mortality after hospital discharge; thus, efforts should be made to target edema)
Older age
prevention. Lack of home support
Therapies reducing exacerbations and hospitalization: Failure to respond to

medical management
 Smoking cessation Increased and severe
 Influenza and pneumococcal vaccines symptoms (e.g., resting
dyspnea, inability to eat
 Long-acting bronchodilators with or without ICS or sleep due to
 Phosphodiesterase-4 inhibitors (reduce exacerbations only) symptoms)
Severe COPD
History of frequent
Early pulmonary rehabilitation initiated within 1 month of discharge for COPD exacerbations
exacerbation improves dyspnea, exercise capacity, and QOL and decreases
repeated exacerbations and hospital readmissions.
Key Fact
The single best predictor of
a COPD exacerbation is a
history of COPD
BRONCHIECTASIS exacerbations.
Bronchiectasis refers to abnormal and permanent dilatation of bronchi.
ETIOLOGY
The etiology of bronchiectasis is generally divided into infectious and
noninfectious causes. Causative factors are summarized in Table 3-35.
206 / CHAPTER 3
Table 3-35. Etiology of Bronchiectasis
Examples
Infections Bacterial (e.g., Staphylococcus, Pseudomonas, Mycoplasma)
Mycobacterial (Mycobacterium tuberculosis, MAC)
Viral
Immune deficiency Hypogammaglobulinemia
HIV
IgG subclass deficiency
Mucociliary clearance PCD
defects Cystic fibrosis
Young’s syndrome (bronchiectasis, sinusitis, obstructive azoospermia)
Bronchial obstruction Endobronchial tumor
Bronchial compression by lymph node
Foreign body
Broncholith
Autoimmune disease Sjögren’s disease
Rheumatoid arthritis
Inflammatory bowel disease
Relapsing polychondritis
SLE
Congenital disorders Bronchial atresia
α1-antitrypsin deficiency (e.g., in emphysema with liver disease)
Williams-Campbell syndrome (congenital deficiency of the bronchial
cartilage)
Mounier-Kuhn syndrome (congenital tracheobronchomegaly)
Tracheal-esophageal fistula
Yellow nail syndrome
Other ABPA
Post radiation
Post transplant
Traction bronchiectasis
Graft-versus-host disease
ABPA, allergic bronchopulmonary aspergillosis; HIV, human immunodeficiency virus; Ig, immunoglobulin; MAC,
Mycobacterium avium complex; PCD, primary ciliary dyskinesia; SLE, systemic lupus erythematosus.
PATHOGENESIS
The inflammatory response to foreign material and bacteria in the airway causes
tissue damage, resulting in bronchiectasis. This condition produces abnormal
mucous clearance and further bacterial colonization and inflammation (Figure 3-
266).
Airway
Neutrophil Destruction and
Inflammation Distortion
(Proteases) (Bronchiectasis)
Abnormal
Bacterial Mucus
Colonization Clearance
Figure 3-26. Vicious cycle hypothesis of bronchiectasis pathogenesis.

(Reproduced, with permission, from McShane PJ, et al. Non-Cystic Fibrosis Bronchiectasis Am J Respir Crit
Care Med. 2013;188(6):647-656. doi:10.1164/rccm.201303-0411CI)
DIAGNOSIS
The diagnosis of bronchiectasis is based on a combination of clinical signs and
symptoms, radiological features, and laboratory investigations.
Clinical Manifestations
Bronchiectasis is a chronic illness with a wide range of symptoms. Common signs

and symptoms include:
 Chronic cough with thick, foul-smelling mucus
 Hemoptysis
 Dyspnea
 Weight loss
 Recurrent lung infections
 Wheezing (asthma, ABPA)
 Clubbing
 Obstructive pattern on PFTs
ACUTE EXACERBATION OF BRONCHIECTASIS—Acute exacerbations are

identified by changes in symptoms, such as worsening dyspnea and worsening
cough associated with changes in sputum characteristics (increased volume,
thicker consistency, greater purulence, or hemoptysis) unrelated to other causes.
Patients may also have fever, chills, reduced exercise tolerance, worsening
spirometry, and radiographic changes consistent with infection.
208 / CHAPTER 3
Imaging
All patients suspected of having bronchiectasis should undergo a chest CT. High-
resolution computed tomography (HRCT) from thoracic inlet to hemidiaphragms
should be performed without contrast, taking 1-mm slices at 10-mm intervals with
the patient holding a deep breath. Three distinct radiographic patterns of
bronchiectasis have been recognized.
CYLINDRICAL/TUBULAR BRONCHIECTASIS—Characterized by mild, diffuse

dilatation of bronchi with thickened wall. Cylindrical bronchiectasis can lead to
“tram-track sign” or “signet-ring appearance”:
 Tram-track sign: Bronchi have a uniform caliber with parallel walls and lack
of bronchial tapering (Figure 3-27).
 Signet-ring appearance: In the axial plane, bronchus is markedly dilated with a
diameter at least 1–1.5 times that of the adjacent pulmonary vessel (i.e.,
bronchoarterial ratio > 1–1.5 (Figure 3-28).
Figure 3-27. CT scan with tram-track sign (red arrow).

Figure 3-28. CT scan showing signet-ring sign and other radiographic signs of
bronchiectasis. (A) Bronchus terminating in a cyst. (B) Lack of bronchial tapering
as it travels to the periphery of the lung. (C) Signet-ring sign (bronchus is larger
than the accompanying vessel). (D) Mucus plug (mucus completely filling the
airway lumen).
(Reproduced, with permission, from McShane PJ et al. Non–Cystic Fibrosis Bronchiectasis. Am J Respir Crit
Care Med 2013;188:647-656. doi:10.1164/rccm.201303-0411CI)
VARICOSE BRONCHIECTSIS—Varicose bronchiectasis is characterized by the

beaded appearance of dilated bronchi with interspersed sites of relative narrowing.
It is also referred to as “string-of-pearls” appearance (Figure 3-29).
Figure 3-29. Varicose bronchiectasis with string-of-pearls appearance (arrow).

210 / CHAPTER 3
CYSTIC/SACCULAR BRONCIECTASIS—This is the most severe form of

bronchiectasis, with cyst-like bronchi that extend to the pleural surface (Figure 3-
30). Cysts may contain air-fluid levels.
Figure 3-30. Cystic bronchiectasis.

(Reproduced, with permission, from Parr DG, et al. Prevalence and Impact of Bronchiectasis in α1-Antitrypsin
Deficiency. Am J Respir Crit Care Med. 2007;176): 1215–1221. Doi: DOI: 10.1164/rccm.200703-489OC)
LOCATION OF BRONCHIECTASIS—The radiographic appearance of

bronchiectasis can provide a clue to its etiology and guide further workup (Table
3-36).
Table 3-36. Correlation of Location of Bronchiectasis with Etiology
Disease Location Possible Etiology
Broncholithiasis
Endobronchial neoplasm
Focal bronchiectasis Foreign body
Congenital bronchial atresia
Mucus plugging
Cystic fibrosis
Upper lung Sarcoidosis
Post-tuberculosis bronchiectasis
Central lung ABPA
Atypical mycobacterial infection (e.g., MAI)

Right middle lobe and lingula Right middle lobe syndrome
Immotile cilia syndrome (primary ciliary disease)
Chronic aspiration
Usual interstitial pneumonia
Lower lung Hypogammaglobulinemia
Recurrent infections
α1-antitrypsin deficiency
ABPA, allergic bronchopulmonary aspergillosis; MAI, mycobacterium avium-intracellulare.
Other Investigations
Once a clinic history and imaging have been obtained, additional investigations
are geared towards the suspected underlying etiology (Table 3-37).
Table 3-37. Other Investigations in the Workup of Bronchiectasis

Bronchoscopy: tumor, foreign body, BAL
Focal bronchiectasis
Sputum for AFB
Sputum for AFB
CF genotyping, sweat chloride testing
Quantitative immunoglobulin testing
IgG subclass level
Diffuse bronchiectasis α1-antitrypsin level
Ciliary testing for PCD
Aspergillus precipitins and total IgE levels
Autoimmune workup
HIV testing
AFB, acid-fast bacilli; BAL, bronchoalveolar lavage; CF, cystic fibrosis; HIV, human immunodeficiency virus; Ig,
immunoglobulin; PCD, primary ciliary dyskinesia.
MANAGEMENT
Objectives of bronchiectasis treatment:

 Manage symptoms
 Treat the underlying etiology
 Limit the progression of disease
A broad overview of management of bronchiectasis can be seen in Figure 3-31.

212 / CHAPTER 3
Figure 3-31. Overview of a comprehensive approach to bronchiectasis

management. *A 2-week course is suggested.
AAT, a1-antitrypsin; ATS/IDSA, American Thoracic Society/Infectious Diseases Society of America; IgG,
immunoglobulin G; HRCT, high-resolution computed tomography; NTM, nontuberculous mycobacteria.
(Reproduced, with permission, from McShane PJ, et al. Non-Cystic Fibrosis Bronchiectasis Am J Respir Crit
Care Med. 2013;188(6):647-656. doi:10.1164/rccm.201303-0411CI)
Antibiotics
Antibiotics are the cornerstone of treatment. Patients with bronchiectasis are
generally colonized with multiple organisms. Common pathogens include
Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and
Pseudomonas aeruginosa.
Cultures should be obtained during acute exacerbations and used to guide

treatment:
 If no old cultures are available, use antipseudomonal fluoroquinolones like
ciprofloxacin.
 If cultures are available:
o H influenzae: amoxicillin clavulanate, second/third generation
cephalosporin (ceftriaxone), fluoroquinolones, doxycycline, azithromycin
o Pseudomonas sensitive to fluoroquinolones: ciprofloxacin, levofloxacin
o Pseudomonas resistant to fluoroquinolones:
 Antipseudomonal penicillins: ticarcillin/clavulanate,
piperacillin/tazobactam
 Cephalosporins: ceftazidime, cefepime
 Monobactam: aztreonam
 Carbapenems: meropenem, imipenem, doripenem
Duration of treatment: Antibiotics should be administered until the sputum is no

longer purulent or for at least 10 days. In cases of Pseudomonas infection,
treatment should continue for 14–21 days.
Additional therapies:
 Postural drainage/airway clearance: Perform twice daily.
 Bronchodilators may be useful for underlying asthma, COPD, CF, ABPA.
 Corticosteroids and antifungal medications for underlying ABPA
 Treatment of underlying diseases such as Mycobacterium avium complex
(MAC) and Mycobacterium tuberculosis (MTB).
PRIMARY CILIARY DYSKINESIA (PCD)
PCD (also known as immotile cilia syndrome) is an autosomal recessive disease

that affects the function of ciliated cells. Structural and functional impairments in
the ciliary microtubules leads to defects in the cilia lining the respiratory tract
(lower and upper, sinuses, Eustachian tube, middle ear), fallopian tubes, and also
impairs the flagella of sperm.
Clinically, PCD presents as rhinosinusitis (present in almost all patients),

bronchiectasis, and less often, male sterility. PCD is diagnosed by nasal biopsy
with electron microscopic examination of cilia. Treatment is mainly supportive
with postural drainage and antibiotics for infections.
The triad of bronchiectasis, rhinosinusitis, and situs inversus (Figure 3-32) is

known as Kartagener’s syndrome.
214 / CHAPTER 3
Figure 3-32. Chest radiograph with dextrocardia situs inversus showing the
cardiac apex facing toward the right.
(Reproduced courtesy of Nevit, Wikimedia Commons, permission granted per the GNU Free Documentation
License Version 1.2.)
CYSTIC FIBROSIS (CF)
CF is an autosomal recessive disorder that results in impaired functioning of the

chloride channels. Approximately 1000 cases are diagnosed each year in the US.
 The overall prevalence of CF in the US is 1 in 3700 births.
 Cystic fibrosis occurs most commonly among whites of Northern European
descent; an estimated 1 in 2500 whites are affected.
 Nearly half of the CF population is age 18 or older. Due to continued research
advancement in treatment, the median predicted age of survival for people
with CF is in the early 40s.
GENETIC BASIS
 Autosomal recessive disorder with variable penetrance.

 One of the most common genetic disease in the U.S.
 The CF gene, located on the long arm of chromosome 7, encodes for the CF
transmembrane regulator (CFTR) protein.
 More than 1500 gene mutations have been identified.
 The most common mutation, ΔF508 mutation (a class II mutation due to

deletion of a single phenylalanine residue at position 508), accounts for 70%
of CF cases in the US.
CFTR mutations are categorized into six classes as follows (Figure 3-33):
 Class I: Absent protein synthesis
 Class II: Abnormal processing or transport of the protein to the cell membrane
 Class III: Abnormal regulation of CFTR function, inhibiting chloride channel
activation
 Class IV: Defective chloride conductance or channel gating
 Class V: Reduced synthesis of fully active CFTR due to promoter or splicing
abnormality
 Class VI: Decreased stability of fully processed and functional CFTR
Figure 3-33. CFTR mutation classes and their functional consequences.
PATHOGENESIS
The defective CFTR results in decreased secretion of chloride and increased

reabsorption of sodium and water across epithelial cells. This leads to abnormal,
viscous secretions in the respiratory tract, pancreas, GI tract, sweat glands, and
other exocrine tissues (Figure 3-34).
216 / CHAPTER 3
Figure 3-34. Pathogenesis of cystic fibrosis.
DIAGNOSIS
All states in the U.S. perform newborn screening for CF by IRT (immunoreactive
trypsinogen) and/or DNA analysis for common CFTR mutations.
Diagnostic Criteria for CF
Newborns with screening results suggestive of CF need further testing by either

Key Fact sweat chloride or DNA analysis for CFTR gene mutations, if not performed as
part of screening. Diagnostic criteria are described in Table 3-38.
Commercially available
genotyping can diagnose
20–30 of the most common
mutations, which account Table 3-38. Diagnostic Criteria for CF
for > 90% of the most
common mutations of CF Presence of one or more characteristic phenotypic features of CF
or
Sibling with CF
or
Positive newborn-screening test (positive IRT or DNA analysis)
Plus
Laboratory evidence of an abnormality in the CFTR gene or protein (abnormal sweat
chloride or presence of CF disease-causing mutation in each copy of the CFTR gene)
Patients with physical findings suggestive of CF, a sibling with CF, or a positive
newborn-screening test should have further diagnostic testing starting with sweat
chloride testing at 2–4 weeks of life (Figure 3-35).
Figure 3-35. The CF diagnostic process for newborns with positive screening
results.
CLINICAL PRESENTATION
CF presents with both pulmonary and extrapulmonary manifestations
Pulmonary Manifestations
 Airway hyperreactivity and wheezing are common in children. Key Fact

 Bronchiectasis and obstructive lung disease are common in adults.
Infection with B
 Patients with cystic fibrosis get recurrent and chronic infections. P aeruginosa cepacia complex is
infection is most common, followed by S aureus (both methicillin-sensitive considered a
contraindication for lung
and methicillin-resistant strains; MSSA and MRSA, respectively), H transplant in many centers
influenzae, Stenotrophomonas maltophilia, and Burkholderia cepacia. because of increased
 Incidence of non-tuberculous mycobacteria (NTM) is higher in CF patients, mortality.
ranging from 7–24%.
 Noninfectious pulmonary complications include: Flash Card Q13
o Spontaneous pneumothorax (3–4%)
o Massive hemoptysis mutation in CF?
Flash Card Q14

What gene mutation is
targeted by ivacaftor?
218 / CHAPTER 3
SEVERITY OF LUNG DISEASE IN CF—Severity of lung disease is defined by

FEV1% predicted as follows:
 Normal: 90% predicted
 Mildly impaired: 70–89% predicted
 Moderately impaired: 40–69%predicted
 Severely impaired: 40% predicted
Extrapulmonary Manifestations
 Meconium ileus at birth

 Exocrine pancreatic insufficiencymalabsorption deficiency of fat-soluble
vitamins A, D, E, K (occurs in 90% of CF patients)
 Endocrine pancreatic insufficiencycystic fibrosis-related diabetes
 Thick biliary secretionsbiliary cirrhosis
 95% of male patients with CF are infertile.
 Female patients with CF have thick cervical mucus but are not infertile.
TREATMENT
Agents to Promote Airway Clearance
 Inhaled DNase I (dornase alfa):

o Decreases the viscosity of sputum by cleaving denatured DNA
released by degenerating neutrophils.
o Recommended for all patients ≥ 6 years old, especially those with
Flash Card A13
moderate-to-severe disease.
 Inhaled hypertonic saline:
ΔF508 mutation, a class II
mutation (due to deletion of
o Recommended for all patients ≥ 6 years old.
a single phenylalanine o 3% or 7% solutions are commonly used.
residue at position 508). It
is the most common
mutation in CF, affecting
70% of CF patients. Chest Physiotherapy
Airway clearance therapy is recommended for all patients with CF for clearance
Flash Card A14 of sputum, maintenance of lung function, and improved quality of life.
Ivacaftor, a recently
approved CFTR-
modulating therapy, targets
the G551D CFTR mutation
(a class III mutation), found
in only about 4% of all CF
patients.
Bronchodilators
Key Fact
Given to patients with evidence of bronchoreactivity and should be administered
Order of inhaled
prior to inhalation of hypertonic saline or DNase and chest physiotherapy. medications:
bronchodilator →
hypertonic saline →
dornase alfa → airway
Antibiotics clearance → aerosolized
antibiotic.
Antibiotics play an important role in chronic treatment and during acute

exacerbations of CF.
 Surveillance cultures are recommended every 3 months.
 CF patients with airway colonization with P aeruginosa have been shown to
have improved lung function and quality of life and reduced exacerbations
with inhaled antibiotics.
INHALED ANTIBIOTICS—In CF patients ≥ 6 years of age who are colonized

with P aeruginosa, daily inhaled antipseudomonal agents are recommended.
Inhaled aztreonam or inhaled tobramycin can be used.
INTRAVENOUS ANTIBIOTICS—Intravenous antibiotics are used for acute

exacerbations. In the absence of cultures, antibiotic coverage should include
treatment for both S aureus and Pseudomonas species.
AZITHROMYCIN—In CF patients ≥ 6 years of age with P aeruginosa persistently

present in cultures of the airways, chronic use of azithromycin is recommended.
 Inhibits neutrophil migration and elastase production.
 Long-term use of azithromycin is associated with improved lung function and
reduction in exacerbations.
 Patients should be screened for NTM before initiating azithromycin and
reassessed every 6–12 months.
Newer Treatment (CFTR-Modulating Therapy)
Ivacaftor is a drug approved for CF patients with at least one G551D CFTR
mutation. Ivacaftor is a potentiator that activates defective CFTR at the cell
surface and increases chloride transport across the cell. Only a small percentage
of CF patients have the G551D mutation, but ivacaftor is an important
breakthrough as it is the first commercially available, targeted CF therapy. Flash Card Q15
In patients with CF, chronic
infections with what
pathogens are associated
with accelerated decline in
lung functions?
220 / CHAPTER 3
Acute Exacerbations of CF
Acute pulmonary exacerbation of CF is a clinical diagnosis. Clinical features of

an exacerbation include increased cough, increased sputum production, shortness
of breath, chest pain, loss of appetite, loss of weight, and lung function decline.
 There is a strong association between the frequency of pulmonary
exacerbations and subsequent decline in pulmonary function.
 Antibiotics are the mainstay of treatment of acute exacerbations.
 Airway clearance therapies should be increased as part of the treatment of
acute exacerbations of pulmonary disease.
Key Fact ANTIBIOTICS FOR ACUTE PULMONARY EXACERBATION

Infection with Burkholderia  P aeruginosa and S aureus are the most common pathogens in CF patients.
cepacia complex is Thus, antibiotics for an exacerbation must include agents against these
considered a pathogens.
contraindication for lung
transplant in many centers  Oral antibiotics can be used for a mild exacerbation.
because of increased  Intravenous antibiotics are indicated for severe exacerbations, bacterial
mortality
resistance to orally administered antibiotics, and failure of oral antibiotic
therapy to resolve the exacerbation.
 For patient with P aeruginosa, two antipseudomonal agents are generally
used.
Flash Card A15

P aeruginosa, B cepacia,
and MRSA
DIFFUSE PARENCHYMAL LUNG DISEASE/ 221
4 Diffuse Parenchymal Lung

Disease
Puneet S. Garcha, MD, Sachin Gupta, MD, & Carlos E. Kummerfeldt, MD
INTERSTITIAL LUNG DISEASE
Definition
Diffuse parenchymal lung disease refers to a group of lung disorders affecting the
interstitium. The parenchyma of the lung includes the pulmonary alveolar and
capillary endothelium and the spaces between these structures as well as the
tissues within the septa comprising the perivascular and perilymphatic tissues.
More centrally, it includes the peribronchiolar and peribronchial tissues. Table 4-1
classifies the idiopathic interstitial pneumonias.
Table 4-1. Revised American Thoracic Society/European Respiratory

Society Classification of Idiopathic Interstitial Pneumonias
Major Idiopathic Interstitial Pneumonias
Idiopathic pulmonary fibrosis
Idiopathic nonspecific interstitial pneumonia
Respiratory bronchiolitis-interstitial lung disease
Desquamative interstitial pneumonia
Cryptogenic organizing pneumonia
Acute interstitial pneumonia
Rare Idiopathic Interstitial Pneumonias

Idiopathic lymphoid interstitial pneumonia
Idiopathic pleuroparenchymal fibroelastosis
Unclassifiable Idiopathic Interstitial Pneumonias
Table 4-2 shows the lung pathology pattern associated with the individual clinical
diagnosis of interstitial lung disease (ILD).
222 / CHAPTER 4
Table 4-2. Clinical Diagnosis and Corresponding Pathology
Clinical Diagnosis Lung Injury Pattern

Idiopathic pulmonary fibrosis Usual interstitial pneumonia
Idiopathic nonspecific interstitial pneumonia Nonspecific interstitial pneumonia
Respiratory bronchiolitis-interstitial lung
Respiratory bronchiolitis
disease
Desquamative interstitial pneumonia Desquamative interstitial pneumonia
Cryptogenic organizing pneumonia Organizing pneumonia
Acute interstitial pneumonia Diffuse alveolar damage
Diagnosis
In most idiopathic interstitial pneumonias, a stepwise approach is key to
establishing the diagnosis, as shown in Figure 4-1.
IMAGING—Chest x-ray is the initial test. High-resolution computed tomography

scan (HRCT) is now a standard diagnostic tool for all patients suspected of having
diffuse parenchymal lung disease (DPLD).
BRONCHOSCOPY—Can help to establish the diagnosis but is not essential. It

helps to exclude other etiologies, including infection, diffuse alveolar hemorrhage,
and eosinophilia and is performed before immunosuppressive therapy is started.
Transbronchial biopsy (TBBx) is not recommended as a diagnostic tool because
of the small tissue sample size.
Unique bronchoscopic features of idiopathic interstitial pneumonias are shown in

Table 4-3.
Figure 4-1. Diagnostic algorithm for interstitial lung disease.

ILD, interstitial lung disease; H&P, history and physical examination PFT, pulmonary function testing; CXR,
chest x-ray; HRCT, high-resolution computed tomography scan; BAL, bronchoalveolar lavage; TBBx,
transbronchial biopsy; SLB, surgical lung biopsy.
224 / CHAPTER 4
Table 4-3. Bronchoscopic Findings in Idiopathic Interstitial Pneumonia

Idiopathic Interstitial
Finding
Pneumonia
Idiopathic nonspecific BAL shows > 20% lymphocytosis (> 20%)
interstitial pneumonia Hypersensitivity pneumonitis and drug-induced lung disease can have
similar BAL findings
Cryptogenic organizing BAL shows a characteristic mixed pattern with increased lymphocytes
pneumonia (20–40%), neutrophils (10%), and eosinophils (5%), with some
plasma/mast cells. The CD4/CD8 ratio is decreased.
Lymphocytic interstitial Occasionally lymphocytic infiltration is seen on TBBx
pneumonia
Pulmonary Langerhans BAL showing > 5% CD1a-positive cells is virtually diagnostic
cell histiocytosis
Acute eosinophilia BAL eosinophilia (> 20–25%) is characteristic in normal peripheral
pneumonia blood eosinophilia
TBBx is not necessary for the diagnosis, but when performed, shows
marked eosinophilic infiltration in interstitium and alveoli
Chronic eosinophilic BAL shows eosinophilia
pneumonia TBBx shows eosinophilic microabscesses, low-grade vasculitis, and
interstitial fibrosis
BAL, bronchoalveolar lavage; TBBx, transbronchial biopsy
BIOPSY—Surgical lung biopsy (SLB; video-assisted thoracoscopic surgery) is

the gold standard investigation to diagnose most idiopathic interstitial pneumonias.
It is also helpful in ruling out other etiologies, establishing the pathologic pattern,
and establishing a prognosis.
IDIOPATHIC PULMONARY FIBROSIS (IPF)
Definition
IPF is a type of chronic interstitial pneumonia with a characteristic histologic
pattern of usual interstitial pneumonia (UIP). However, UIP is not pathognomic
of IPF because it can also be seen in other ILDs (connective tissue diseases,
asbestosis, drug-induced lung disease, and environmental and occupational
exposure).
Clinical Features
 IPF is the most common cause of ILD.
 It affects men in the fifth to sixth decade (male-to-female ratio 2:1).
 Dry cough and dyspnea are the presenting features.
 Cough can be disabling, especially in late-stage disease, causing profound
desaturation during a coughing spell.
 Lung auscultation shows dry bibasilar crackles, known as Velcro crackles.
 Digital clubbing can be present.
 Median survival after diagnosis is 3–5 years.
Histopathology
Key Fact
 Basilar and peripheral fibrosis (Figure 4-2)
Temporal heterogeneity is
 Microscopic subpleural and paraseptal fibrosis the cardinal feature
 Subpleural microscopic honeycombing distinguishing UIP from
other idiopathic interstitial
 Fibroblastic foci (Figure 4-3) pneumonias.
 Interspersed normal areas of lung (temporal heterogeneity)
Figure 4-2. Usual interstitial pneumonia showing low-magnification patchy

interstitial fibrosis with juxtaposition of normal areas of lung with fibrotic and
honeycombing changes.
(Image courtesy of Joseph F. Tomashefski, Jr., MD, Department of Pathology, MetroHealth Medical Center,
Case Western Reserve University, Cleveland, Ohio.)
226 / CHAPTER 4
Figure 4-3. Usual interstitial pneumonia fibroblastic foci characterized by dome-

shaped fibroblastic tissue over collagen fibrosis.
Diagnosis
IMAGING
 Chest x-ray: Bilateral basal predominant interstitial infiltrates (Figure 4-4).
 HRCT (Figure 4-5):
o Peripheral reticular opacities
o Geographic/patchy pattern of subpleural involvement
o Apicobasal gradient
o Honeycombing without associated traction bronchiectasis
Figure 4-4. Bilateral reticular opacities are more predominant in peripheral and
lower lobes.
(Image courtesy of Puneet Garcha, MD, Cleveland Clinic Foundation.)
BIOPSY—HRCT is replacing SLB as the diagnostic test of choice. However, Key Fact
video-assisted thoracoscopic surgery is the gold standard to diagnose UIP. SLB is not needed to
establish the diagnosis of
UIP if HRCT shows
PULMONARY FUNCTION TESTS characteristic findings
 Restrictive lung defect (subpleural site, basal
 Decreased diffusion lung capacity for carbon monoxide (DLCO) predominance, reticular
abnormality,
 Exercise-induced desaturation honeycombing, and
absence of features
inconsistent with UIP).
Figure 4-5. Honeycombing at the lung bases with subpleural reticulation.

(Image courtesy of Puneet Garcha, MD, Cleveland Clinic Foundation.)
228 / CHAPTER 4
Pathogenesis
The exact cause of IPF is unknown. The initial insult in IPF may occur as a
repetitive injury to alveolar epithelial cells and the subepithelial basement
membrane. Alveolar epithelial cell injury leads to an intense fibroblastic response
that results in abnormal wound healing with excessive deposition of collagen and
extracellular matrix. The familial variant of IPF occurs in fewer than 5% of cases.
Potential mechanisms of IPF:

 Cigarette smoking
 Gastroesophageal reflux disease
 Occupational and environmental exposures (metal dust, wood dust, sand,
stone, and silica)
Acute exacerbation of IPF is characterized by sudden acceleration of the

underlying fibroproliferative process. Precipitating factors include infection,
gastroesophageal reflux disease, and surgery (hyperinflation). There are no
proven therapies, and the mortality rate is high.
Treatment
No treatment stops the progression of IPF. However, there have been promising
results from pirfenidone (an antifibrotic agent) in slowing the decline of FVC in
patients with mild to moderate forms of the disease.
 Corticosteroids and immunosuppressive agents have no role in management.

 Supplemental oxygen is used for patients with resting and exertional
hypoxemia.
 Pulmonary rehabilitation is used to help improve functional status.
 Lung transplantation is recommended for patients with severe IPF. Early
referral to a transplant center is prudent. These patients should be considered
for transplant listing based on declining functional status and worsening
oxygen requirements (forced vital capacity < 60% of predicted; DLCO <
40% of predicted).
NONSPECIFIC INTERSTITIAL PNEUMONIA (NSIP)
This distinct subgroup of idiopathic interstitial pneumonias (absence of typical

findings of UIP, desquamative interstitial pneumonia, and cryptogenic organizing
pneumonia) is characterized by bronchoalveolar lavage (BAL) findings
lymphocytosis, prominent cellular infiltrate on lung biopsy, clinical improvement
with corticosteroids, and overall better long-term prognosis compared with IPF.
Clinical Features
 Most common symptoms are dyspnea on exertion and cough.
 Bibasilar crackles are noted.
 Idiopathic NSIP is common in women (nonsmokers) in the fourth or fifth
decade.
Histopathology
 NSIP is classified into cellular and fibrotic types based on histology (Table 4-
4).
 Temporal uniformity is a key feature distinguishing NSIP from UIP.
 Patients with cellular NSIP (Figure 4-6) have a higher rate of steroid
responsiveness and a better prognosis.
Figure 4-6. Cellular nonspecific interstitial pneumonia.

Table 4-4. Histopathologic Patterns of Nonspecific Interstitial Pneumonia
Cellular (Figure 4-6) Fibrotic (Figure 4-7)
Mild to moderate interstitial chronic Dense or loose interstitial fibrosis with uniform
inflammation appearance
Type II pneumocyte hyperplasia in areas of Lung architecture is frequently preserved

inflammation
Flash Card Q1
Absence of fibroblastic foci What are the known
genetic associations with
pulmonary fibrosis?
230 / CHAPTER 4
Figure 4-7. Fibrotic nonspecific interstitial pneumonia.

Diagnosis
IMAGING
 Chest x-ray: Bilateral lower lobe interstitial opacities

o Diffuse ground-glass opacities
o Reticular opacities
o Traction bronchiectasis
o Typically no honeycombing (distinguishing it from UIP, where honeycombing is
a cardinal feature)
Flash Card A1
Mutations in hTERT and
hTR are risk factors for
pulmonary fibrosis
underlying the inheritance
in 8–15% of familial cases.
In these families, IPF is
inherited as an autosomal
dominant trait with age-
dependent penetrance.
Figure 4-8. Cellular nonspecific interstitial pneumonia showing bibasilar ground-

glass opacities.
(Reproduced, with permission, from Martinez FJ. Idiopathic interstitial pneumonias: usual interstitial pneumonia
versus nonspecific interstitial pneumonia. Proc Am Thorac Soc. 2006; 3: 81-95.)
BRONCHOSCOPY—Lymphocytosis (> 20%) suggests NSIP.
PULMONARY FUNCTION TESTS

 Restrictive lung defect
 Decreased DLCO
Treatment
Immunosuppressive agents form the mainstay of therapy (Table 4-5).
Corticosteroids are usually first-line agents. Steroid-sparing cytotoxic agents are
used to avoid the significant adverse effects of corticosteroids.
Commonly used treatment regimens:

 Azathioprine and corticosteroids
 Cyclophosphamide and corticosteroids (connective tissue disease–associated
ILD with NSIP pattern)
 Mycophenolate and corticosteroids
232 / CHAPTER 4
Table 4-5. Medications Used to Treat Nonspecific Interstitial Pneumonia
Medication Adverse Effects
Corticosteroids Hyperglycemia, hypertension, insomnia
TPMT genotype and TPMT enzyme activity (phenotype) should be

Azathioprine screened in all patients with azathioprine
Gastrointestinal upset, abnormal liver function test results
Mycophenolate mofetil Gastrointestinal upset, abnormal liver function test results, leukopenia
Cyclophosphamide Bladder cancer, neutropenia
Response to therapy is monitored by improvement in symptoms (cough, dyspnea),

spirometry, gas exchange, and radiographic findings. If disease progression
occurs, change in treatment regimen and/or referral for lung transplantation
should be considered.
Prognosis
The overall prognosis for NSIP is believed to be better than that for UIP, based on
a retrospective cohort of studies.
CRYTOGENIC ORGANIZING PNEUMONIA/BRONCHIOLITIS

OBLITERANS WITH ORGANIZING PNEUMONIA
Clinical Features
 Occurs in the fourth and fifth decades.
 Affects men and women equally.
 More common in nonsmokers.
 Subacute onset of dry cough is typical.
 Dyspnea occurs.
 Patients have fever, weight loss, and malaise.
 Sparse crackles are noted on lung auscultation.
Pathogenesis
Cryptogenic organizing pneumonia is believed to follow an inciting injury that
causes lung inflammation that leads to the production of characteristic buds of
intra-alveolar granulation tissue. There seems to be an exaggerated response to the
inflammatory or injurious stimuli. There is an acute alveolar epithelial injury with
cell death and denudation of the basal laminae. The next step is organization into
myofibroblasts and fibroinflammatory buds with a loose deposition of matrix
(mainly composed of collagen and fibronectin). Progressive fibrosis with
concentric layers of myofibroblasts and connective tissues occurs, leading to the
characteristic appearance of intra-alveolar buds. The alveolar architecture is well
preserved.
Histopathology
 The classic histologic feature is the presence of intra-alveolar buds of
granulation tissue made of myofibroblasts, fibroblasts, and loose connective
tissue (Figure 4-9). Multinucleated giant cells are seen in approximately 20%
of cases.
 Foamy macrophages are conspicuous in empty alveoli.
 All lesions appear to be of similar age.
Figure 4-9. Intraluminal organizing fibrosis.

234 / CHAPTER 4
Diagnosis
IMAGING
 Chest x-ray: Multiple, migratory patchy alveolar infiltrates are usually
peripheral and bilateral in distribution. The size is variable, ranging from a
few centimeters to involving the whole lobe.
 HRCT: Density of the infiltrates can vary from ground glass to consolidation.
The consolidated areas may have an air bronchogram as well (Figure 4-10).
BRONCHOSCOPY
 BAL shows a characteristic mixed pattern with increased lymphocytes (20–
40%), neutrophils (10%), and eosinophils (5%), with some plasma/mast cells.
 The CD4/CD8 ratio is decreased.
BIOPSY—Most patients require SLB before therapy is started because of the

patchy nature of the disease, which makes TBBx less reliable.
PULMONARY FUNCTION TESTING

 Mild to moderate restrictive ventilatory defect is seen.
 DLCO can be reduced.
Figure 4-10. Computed tomography image of the chest showing a

right lower lobe opacity with air bronchogram.
(Reproduced, with permission, from Pathak V, et al. Macrolide use leads to clinical and
radiological improvement in patients with cryptogenic organizing pneumonia. Ann Am
Thorac Soc. 2014; 11: 87-91. doi: 10.1513/AnnalsATS.201308-261CR.)
Treatment
 Corticosteroids are the mainstay of treatment.
 Optimal dose and duration of treatment are not known.
 Usually, a long course of steroids is required (6–12 months). Monitor for
relapse as steroids are tapered.
 Remarkable clinical improvement occurs in 1 week, but radiologic infiltrates
take several weeks to show resolution.
 Cytotoxic agents can be used in patients who are intolerant of steroids or have
disease progression despite steroid therapy.
ACUTE INTERSTITIAL PNEUMONIA (ACUTE INTERSTITIAL

PNEUMONITIS—HAMMAN RICH SYNDROME)
Acute interstitial pneumonitis is a rapidly progressive and histologically unique

form of idiopathic interstitial pneumonia.
Clinical Features
 No sex predilection is noted.
 There is no relationship to smoking.
 Patients have acute onset of cough and dyspnea that progresses rapidly to
respiratory failure, requiring mechanical ventilation.
 Fever can be present. Up to 50% of patients have a preceding viral prodrome.
 Rapid progression to respiratory failure is key.
 Overall clinical picture is similar to adult respiratory distress syndrome, but
unlike adult respiratory distress syndrome, there is no known cause.
Histopathology
Lung biopsy shows diffuse alveolar damage. Two phases are seen: acute and
organizing. The acute (exudative) phase is characterized by edema, hyaline
membranes, and microvascular thrombi. The organizing phase shows loose
organizing fibrosis within alveolar septa and type II pneumocyte.
Diagnosis
IMAGING—Bilateral patchy alveolar opacities are seen, with regions of ground
glass along with consolidation (Figure 4-11).
236 / CHAPTER 4
Figure 4-11. Bilateral patchy symmetric ground-glass opacities with

consolidation.
(Image courtesy of Joseph Parambil, MD, Cleveland Clinic Foundation.)
BIOPSY—SLB is essential and can establish the histopathologic features of

diffuse alveolar damage.
Treatment
 There is no proven treatment.
 High doses of corticosteroids and cytotoxic agents (cyclophosphamide) are
often used.
Key Fact RESPIRATORY BRONCHIOLITIS–ASSOCIATED

Histologically, respiratory
INTERSTITIAL LUNG DISEASE
bronchiolitis–associated
interstitial lung disease is Respiratory bronchiolitis–associated interstitial lung disease is an interstitial and
indistinguishable from
respiratory bronchiolitis. bronchial process that occurs in smokers and is characterized by respiratory
Respiratory bronchiolitis– bronchiolitis on lung biopsy.
associated interstitial lung
disease is characterized by
clinical evidence of Clinical Features
interstitial lung disease
(impairment shown on
pulmonary function tests
 Affects smokers.
and x-rays) and the finding  Occurs in the fourth and fifth decades.
of respiratory bronchiolitis  No sex predilection is seen.
on lung biopsy.
 Cough and dyspnea occur.
 Crackles can be present on lung auscultation.
Histopathology
 Respiratory bronchiolitis (pigmented alveolar macrophages in and around the

respiratory bronchioles and surrounding alveoli) (Figure 4-12)
 No significant fibrosis, interstitial inflammation, or germinal centers
Figure 4-12. Pigmented alveolar macrophages filling the lumen of the respiratory
bronchiole and the surrounding airspaces.
Diagnosis
IMAGING
 Chest x-ray: Bilateral fine reticular or reticulonodular opacities
o Bronchial wall thickening
o Fine centrilobular nodules
o Bilateral, patchy ground-glass opacities in both the upper and lower lung
zones
o Possible emphysematous changes
238 / CHAPTER 4
Figure 4-13. Patchy ground-glass opacities, fine nodules, and bronchial wall
thickening.
BIOPSY—SLB is required to establish the diagnosis, but in the setting of

epidemiologic, clinical, and radiologic evidence, a clinical diagnosis can be made.
Treatment
 Smoking cessation is key.

 Steroids and other cytotoxic medications are generally ineffective.
Prognosis
Respiratory bronchiolitis-ILD has a good prognosis and mortality is rare.
DESQUAMATIVE INTERSTITIAL PNEUMONIA
Clinical Features
 Occurs predominantly in smokers.
 Nonspecific symptoms include cough and dyspnea.
 Crackles are noted on auscultation.
 Digital clubbing is seen in up to 50% of patients.
PATHOLOGY
Alveolar spaces are filled with pigment-laden macrophages called smoker’s
macrophages because they are associated with smoking and contain a light brown
pigment. This occurs in a homogenous pattern, with preserved alveolar
architecture and minimal fibrosis or honeycombing (Figure 4-14).
Figure 4-14. Uniform filling of alveolar spaces with eosinophilic macrophages.

IMAGING
 Chest x-ray: Patchy haziness or interstitial patterns with lower lung
predominance
o Peripheral ground-glass opacities involving bilateral lower lung zones
o No honeycombing
o Possible small lung cysts and emphysematous changes
240 / CHAPTER 4
Figure 4-15. High-resolution computed tomography scan of a patient with

desquamative interstitial pneumonia showing bilateral ground-glass opacities.
(Reproduced courtesy of Professor A. Pesci, University of Parma. Reproduced, with permission, from Caminati
A, Harari S. Smoking-related interstitial pneumonias and pulmonary Langerhans cell histiocytosis. Proc Am
Thorac Soc. 2006; 3: 299-306.)
BIOPSY—SLB is required to establish the diagnosis.
PULMONARY FUNCTION TESTS—Restrictive ventilatory defect with a reduced

DLCO is seen in one third of patients.
Treatment
 Smoking cessation is mandatory.
 Most patients receive corticosteroids; however, there are no data showing
their effectiveness.
 In patients with progressive disease, lung transplantation is an option.
However, desquamative interstitial pneumonia can recur in the transplanted
lung.
Prognosis
Overall prognosis is good, with > 90% of patients surviving for > 5 years.
LYMPHOCYTIC INTERSTITIAL PNEUMONIA
Clinical Features
 Can be idiopathic or secondary to lymphoproliferative disorders and immune
deficiency states, such as Sjögren syndrome (25% of cases), HIV/AIDS, and
common variable immunodeficiency (CVID).
 Most patients are women (2:1 ratio), usually in the fifth decade.
 Cough, dyspnea, fever, and weight loss occur.
 Crackles are noted on lung auscultation.
 The clinical course can vary from resolution without treatment to progressive
respiratory failure and death.
 Up to 50% of patients die within 5 years of diagnosis.
 In 5% of cases, the disease transforms to lymphoma.
Pathology
 Interstitial and bronchovascular infiltrate of small lymphocytes and plasma
cells is seen (Figure 4-16).
 Poorly formed nonnecrotizing granulomas with multinucleated giant cells are
seen in some cases.
Figure 4-16. Diffuse and dense alveolar septal infiltrate consisting of Flash Card Q2
lymphocytes, plasma cells, plasmacytoid cells, and histiocytes.
(Image courtesy of Joseph F. Tomashefski, Jr., MD, Department of Pathology, MetroHealth Medical Center, Which ILDs are most
Case Western Reserve University, Cleveland, Ohio.) commonly associated with
smoking?
242 / CHAPTER 4
Diagnosis
IMAGING
 Chest x-ray: Bilateral lower lobe reticular or reticulonodular opacities are seen.
 HRCT: Bilateral ground-glass opacities, centrilobular nodules, patchy
bronchovascular bundle thickening, interlobular septal thickening, and thin-
walled cysts are seen. Ground-glass opacities can be diffuse or may occur
predominantly in the lower lobe (Figure 4-17).
Figure 4-17. High-resolution computed tomography scan showing smooth and

nodular thickening of bronchovascular bundles, centrilobular and subpleural nodularity,
ground-glass opacification, and interlobular septal thickening.
(Reproduced, with permission, from Allen CM, et al. Imaging lung manifestations of HIV/AIDS. Ann Thorac Med.
2010; 5: 201-216. doi: 10.4103/1817-1737.69106.)
BIOPSY
 TBBx: Occasional lymphocytic infiltration seen
 SLB: Required for definitive diagnosis
PULMONARY FUNCTION TESTS—Restrictive ventilatory defect with a reduced

DLCO
Flash Card A2 Treatment

Respiratory bronchiolitis–
associated interstitial lung Oral corticosteroids are the mainstay of therapy. Response is variable.
disease, desquamative
interstitial pneumonia, and
pulmonary Langerhans cell
histiocytosis. Smoking
cessation is a critical
component of therapy.
CONNECTIVE TISSUE DISEASE–ASSOCIATED ILD
Connective tissue diseases commonly associated with ILD:

 Rheumatoid arthritis
 Systemic sclerosis/scleroderma
 Inflammatory myopathies: polymyositis/dermatomyositis
 Sjögren syndrome
 Systemic lupus erythematosus
Common serologic associations of connective tissue diseases are shown in Table

4-6.
Table 4-6. Serologic Testing
Autoantibody Type Connective Tissue Disease Association

ANA Antinuclear antibody Can be seen in multiple connective tissue
diseases (systemic lupus erythematosus,
systemic sclerosis/scleroderma, Sjögren
syndrome, polymyositis/dermatomyositis)
dsDNA Anti-dsDNA antibody Systemic lupus erythematosus
SSA Anti-Ro antibody Systemic lupus erythematosus, SS, myositis
SSB Anti-La antibody Sjögren syndrome (~15% in systemic lupus

erythematosus)
Scl-70 Anti-DNA Systemic sclerosis

topoisomerase 1
CCP Anti-CCP antibody Rheumatoid arthritis
RF Rheumatoid factor Rheumatoid arthritis
RNP Anti-U1 small nuclear Mixed connective tissue disease

RNP
Jo-1, EJ, PL7 Anti-tRNA Dermatomyositis/polymyositis/antisynthetase

syndrome
244 / CHAPTER 4
Rheumatoid Arthritis
Pulmonary disease in rheumatoid arthritis can present as ILD, obstructive airways
disease, rheumatoid lung nodules, or pleural involvement. Rheumatoid nodules
can occur in the lung and pleura (Figure 4-18). They should be distinguished from
granulomatous infection and granulomatosis with polyangiitis. Rheumatoid
arthritis-ILD is generally diagnosed in patients with long-standing rheumatoid
arthritis, but sometimes ILD is present before the diagnosis of rheumatoid arthritis.
CLINICAL FEATURES
 Cough, progressive dyspnea, pleuritic chest pain, digital clubbing, and dry
crackles (known as Velcro crackles) at the lung bases
 Pulmonary hypertension in advanced disease
 Restrictive lung defect and reduced DLCO on pulmonary function tests
PATHOLOGY—Histopathologic patterns:
 UIP (most common)
 Organizing pneumonia
 Follicular bronchiolitis
 Lymphocytic interstitial pneumonia
 Diffuse alveolar damage
Figure 4-18. Rheumatoid nodule showing characteristic cellular palisading.

DIAGNOSIS—HRCT features of rheumatoid arthritis-ILD:

 Ground-glass opacities
 Reticulation
 Bronchiectasis
 Micronodules
Four common patterns:

 UIP (honeycombing, bibasal subpleural reticular patterns)
 NSIP (lower lobe reticulation, ground-glass opacities, lack of honeycombing)
 Bronchiolitis (centrilobular nodules, bronchiectasis)
 Organizing pneumonia (peripheral airspace consolidation and ground-glass
opacities)
TREATMENT
 Corticosteroids
 Cytotoxic drugs (azathioprine, mycophenolate, cyclosporine,
cyclophosphamide)
 Biologics: tumor necrosis factor- inhibitors
 Lung transplantation
Systemic Sclerosis (Scleroderma)
CLINICAL FEATURES—Other than the common symptoms of ILD (cough and

dyspnea), systemic symptoms that suggest systemic sclerosis/scleroderma include
history of skin thickening, telangiectasias, digital nail pitting, esophageal reflux or
food regurgitation, esophageal dysmotility, and dysfunction. Sclerodactyly along
with a history of Raynaud phenomenon is suggestive of systemic
sclerosis/scleroderma.
PATHOLOGY—Most common histopathologic pattern seen is NSIP. Few

patients have the UIP pattern.
246 / CHAPTER 4
Key Fact
Pulmonary arterial
hypertension develops in >
15% of patients with
systemic sclerosis/
scleroderma. It can be an
isolated complication or
secondary to ILD. These
patients have a high
mortality rate. Elevated
levels of endothelin-1
cause enhanced
vasoconstriction, vascular
endothelial cell
proliferation, smooth
muscle hypertrophy, and
irreversible vascular Figure 4-19. Arterial remodeling of systemic sclerosis because of elevated levels
remodeling in the lungs, as
shown in Figure 4-19.
of endothelin-1.
(Image courtesy of Joseph F. Tomashefski, Jr., MD. Department of Pathology, MetroHealth Medical Center,
PULMONARY FUNCTION TESTS—Restrictive lung defect and reduced DLCO

are seen.
DIAGNOSIS
 Imaging: NSIP pattern is common on HRCT. Ground-glass opacities on initial
CT scan indicate a progressive pattern.
 Pulmonary function tests: Restrictive lung defect and reduced DLCO are seen.
TREATMENT
 Corticosteroids: Low-dose therapy is used. High-dose steroids cannot be used
because of concern about scleroderma renal crisis.
 Cytotoxic drugs: Cyclophosphamide is the most commonly used agent.
Azathioprine and mycophenolate are alternatives.
 Lung transplantation: Particular attention is paid to esophageal involvement
before lung transplant. Gastroesophageal reflux disease caused by esophageal
dysmotility can lead to allograft dysfunction.
Inflammatory Myopathy
Multiple types of inflammatory myopathy are associated with ILD, including
polymyositis, dermatomyositis, and anti-synthetase syndrome.
CLINICAL FEATURES—Proximal muscle symptoms include myalgias, muscle

weakness, and fatigue. Skin manifestations, such as Gottron’s papules (Figure 4-
20), heliotrope rash, shawl sign, and mechanic’s hands, may occur.
Figure 4-20. Gottron’s papules, scaly erythematous eruptions, or red patches

overlying the knuckles, elbows, and knees.
(Reproduced Image courtesy of EM Dugan, AM Huber, FW Miller, LG Rider, and the International Myositis
Assessment and Clinical Studies (IMACS) Group, CC BY-SA 3.0.)
PATHOLOGY
 NSIP is the most common histopathologic pattern.
 Other patterns seen are usual interstitial pneumonia (UIP), organizing
pneumonia (OP), diffuse alveolar damage (DAD).
 SLB usually is not required to establish the diagnosis.
DIAGNOSIS
 Pulmonary function testing:
o Restrictive ventilatory defect and reduced DLCO.
o Respiratory muscle insufficiency with reduction in forced vital capacity
and total lung capacity (TLC).
 Imaging: HRCT findings are similar to those for other connective tissue
disease–associated ILDs. Abnormalities usually seen are ground-glass
opacities, reticulation, and alveolar airspace opacities.
TREATMENT
 Despite lack of randomized controlled studies, corticosteroids remain the
therapy of choice.
 Azathioprine is the most commonly used cytotoxic agent.
 Cyclophosphamide is reserved for severe, life-threatening disease.
Mycophenolate, cyclosporine, methotrexate, intravenous immunoglobulin,
and rituximab are also used.
 Lung transplantation is an option for progressive or refractory disease.
248 / CHAPTER 4
Sjögren Syndrome
Sjögren syndrome can be primary or secondary. Secondary Sjögren syndrome is
associated with other connective tissue disease–associated ILDs.
CLINICAL FEATURES
 Affects middle-aged women.
 Autoantibodies to Ro (anti-SSA) and/or La (anti-SSB) are seen.
 Cough, dyspnea, wheezing, chest pain, and sicca symptoms (ocular and oral
dryness) occur.
 Crackles are noted on auscultation.
PATHOLOGY—Histopathologic patterns include NSIP, lymphocytic interstitial

pneumonia, OP, and UIP. Occasionally, primary pulmonary lymphoma and amyloidosis
are seen.
DIAGNOSIS—HRCT can show multiple abnormalities, such as large airways and small
airways disease or ILD. Thin-walled cysts suggest lymphocytic interstitial pneumonia.
Nonresolving consolidation, nodules larger than 1 cm, and lymphadenopathy can suggest
lymphoma. These patients should undergo SLB.
TREATMENT—Corticosteroids are initial therapy in most of the cases. Steroid-sparing

agents such as azathioprine also can be used.
Systemic Lupus Erythematosus

Most commonly affects young women. This immune-mediated disease causes skin rash,
oral ulceration, arthritis, kidney involvement, and hematologic abnormalities. Systemic
lupus erythematosus can cause a variety of lung manifestations (Table 4-7).
Table 4-7. Pulmonary Manifestations of Systemic Lupus Erythematosus
Manifestation Features
Acute lupus Acute onset of fever, cough, dyspnea, and hypoxia.

pneumonitis
Can progress to acute respiratory failure.
Treat with empiric antibiotics. After infection is ruled out, empiric high-dose
steroids are used.
Table 4-7. Pulmonary Manifestations of Systemic Lupus Erythematosus,

continued
Manifestation Features
Diffuse alveolar Similar presentation to acute lupus pneumonitis. Hemoptysis is not
hemorrhage universal. Acute anemia might be suggestive.
Bronchoscopy with BAL shows progressive hemorrhagic BAL fluid and

hemosiderin-laden macrophages.
Treat with empiric antibiotics. High-dose corticosteroids are used in

conjunction with cyclophosphamide. Plasmapheresis is also associated
with improved survival.
Shrinking lung Dyspnea, pleuritic chest pain, small lung volume, and diaphragmatic
syndrome elevation. Restrictive physiology without parenchymal involvement.
Steroids are first-line therapy.

Chronic interstitial Seen in older men with insidious onset of cough and dyspnea.
lung disease
Treat with corticosteroids and steroid-sparing agents (azathioprine and
MMF). Cyclophosphamide is reserved for refractory cases.
BAL, bronchoalveolar lavage; MMF, mycophenolate mofetil.
PULMONARY LANGERHANS CELL HISTIOCYTOSIS
Pulmonary Langerhans cell histiocytosis is also known as histiocytosis X, pulmonary

Langerhans granulomatosis, or pulmonary eosinophilic granuloma.
Clinical Features
 White, younger adults (third or fourth decade)
 No sex predilection
 Strong association with smoking
 Dry cough and dyspnea
 Spontaneous pneumothorax in 10–15% of patients
 Constitutional symptoms, including fever, weight loss, malaise, and anorexia
 Pulmonary hypertension in severe disease, reflecting pulmonary vascular
involvement
 Good prognosis in patients who abstain from smoking
Pathogenesis
 Believed to be induced by exposure to cigarette smoke.
 There is accumulation of Langerhans cells in lungs. Approximately 15% of
patients have involvement of extrathoracic organ systems.
250 / CHAPTER 4
Pathology
 Predominantly bronchiolocentric stellate lesions with central scarring
 Abundant Langerhans cells in the early phase of disease identified by
immunohistochemical staining for CD1a antigen and S-100 protein
 Intracellular inclusions termed Birbeck granules in Langerhans cells identified
by electron microscopy
 Extensive eosinophilic infiltration in the early phase of disease
Diagnosis
IMAGING
 Chest x-ray: Reticulonodular opacities predominantly in the upper and mid
lung zones, with sparing of costophrenic angles
 HRCT: Combination of nodules and cysts seen in the upper lung zones, with
relative sparing of lung bases (Figure 4-21)
 LUNG BIOPSY—TBBx or SLB is recommended but not required to establish

the diagnosis.
 PULMONARY FUNCTION TESTING—Variable results are seen (mixed,

obstructive, restrictive, or completely normal). DLCO is reduced in most
patients. Exercise capacity is limited, reflecting pulmonary vascular
involvement.
Figure 4-21. Diffuse thin-walled cysts and lung nodules.

Treatment
 Smoking cessation leads to stabilization of clinical and radiologic
abnormalities.
 Corticosteroids are indicated for patients with severe or progressive disease.
 Associated complications (pneumothorax, pulmonary hypertension, and
respiratory failure) must be managed.
 Lung transplantation is an option for patients with advanced disease who do
not respond to the other treatment modalities.
LYMPHANGIOLEIOMYOMATOSIS
Epidemiology
Exclusively affects premenopausal women and is characterized by hamartomatous
proliferation of atypical smooth muscles along lymphatics in the lung, thorax,
abdomen, and pelvis. Key Fact
LAM is associated with
tuberous sclerosis
Clinical Features complex, which is a
multisystem genetic
disorder caused by
 Affects women in the third and fourth decades. mutation of the TSC1 or
 Dyspnea occurs. TSC2 gene.
 Recurrent pneumothorax is common (50–80% of patients).
 Hemoptysis is noted.
 Chyloptysis occurs.
 Chylous effusion is noted.
 Most cases progress to end-stage respiratory failure.
Pathogenesis
Lymphangioleiomyomatosis is exclusively a disease of premenopausal women.
Estrogen is postulated to play a key role in its pathogenesis. Estrogen (exogenous
or endogenous) accelerates disease progression. Lymphangioleiomyomatosis cells
are of two types: myofibroblast-like spindle-shaped cells and epithelioid-like
polygonal cells. Both cells express melanoma-associated proteins HMB-45 and
CD63. Spindle-shaped cells express smooth muscle-specific proteins smooth
Flash Card Q3
muscle  actin, vimentin, and desmin.
Which cells are
pathognomic of pulmonary
Langerhans cell
histiocytosis on
bronchoalveolar lavage?
252 / CHAPTER 4
Pathology
The finding of multiple lung cysts in the absence of nodule or interstitial fibrosis
is pathognomic.
IMMUNOHISTOCHEMISTRY—Muscle-specific actin, desmin, and human

melanoma black-45.
Diagnosis
IMAGING
 Chest x-ray:
o Findings may be normal early in the disease course.
o Hyperinflated lung fields can be seen with progression of airflow
obstruction.
o Pneumothorax, cystic or reticulonodular opacities, and pleural effusions
may occur.
 HRCT:
o Multiple thin-walled cysts of varying sizes and shapes are seen. Cysts are
scattered throughout the lung zones without predilection for central or
peripheral regions. Nodules and interstitial fibrosis are not seen (Figure 4-
22).
o Abdominal CT scan can show angiomyolipomas in the kidney, spleen, or
pelvic organs or retrocrural or para-aortic lymphadenopathy.
 Ventilation-perfusion lung scan: Speckled pattern may be seen on ventilation
lung scan.
Flash Card A3
BAL showing > 5% CD1a-
positive cells is virtually
diagnostic of pulmonary Figure 4-22. Multiple cysts of varying sizes and shapes.
Langerhans cell (Image courtesy of Puneet Garcha, MD, Cleveland Clinic Foundation.)
histiocytosis.
BRONCHOSCOPY—TBBx can establish the diagnosis.
SLB—Diagnosis can be established without SLB in patients with characteristic

HRCT features or any of the following—renal angiomyolipoma, chronic chylous
ascites with abdominal lymphadenopathy, or characteristic histopathologic
findings on lymph node biopsy.
PULMONARY FUNCTION TESTING—Obstructive ventilatory pattern with air

trapping is seen in most patients. DLCO is reduced.
Treatment
 Women should be advised against pregnancy or use of exogenous estrogen.
 Corticosteroids and cytotoxic agents have no role in treatment.
 Sirolimus (mTor inhibitor) suppresses smooth muscle proliferation and DNA
synthesis of lymphangioleiomyomatosis cells. In patients with mild to
moderate disease, sirolimus decreases the decline in lung function and
improves the quality of life. Lung transplantation is an option for patients with
end-stage respiratory failure due to lymphangioleiomyomatosis.
ACUTE EOSINOPHILIA PNEUMONIA
Clinical Features
 Multiple risk factors have been identified, including drugs, infections
(parasites), heavy metals, toxin inhalation, and cigarette smoking.
 Usually affects men 20–40 years of age.
 Usually presents as acute febrile illness lasting 7–14 days. Can be confused
with community-acquired pneumonia or adult respiratory distress syndrome.
 Fever, myalgia, and pleuritic chest pain occur.
 Hypoxic respiratory failure may be seen.
 Prognosis is excellent once the diagnosis is made and therapy is instituted.
 Most patients have no long-term sequelae.
Pathogenesis
Acute cigarette smoke exposure along with other proallergic exposures may
facilitate the generation of inflammatory cytokines, leading to massive
recruitment and activation of eosinophils in lungs.
254 / CHAPTER 4
Diagnosis
IMAGING
 Chest x-ray: Bilateral alveolar opacities with small pleural effusions are seen.
 HRCT: Patchy alveolar ground-glass and/or consolidative opacities,
interlobular septal thickening, and pleural effusions are seen (Figure 4-23).
BRONCHOSCOPY (BAL, TBBx)

 BAL eosinophilia (> 20–25%) is characteristic in normal peripheral blood
eosinophilia.
 TBBx is not necessary for diagnosis, but when performed shows marked
interstitial and alveolar eosinophilic infiltration.
Figure 4-23. Chest computed tomography scan showing bilateral alveolar

opacities and pleural effusions.
(Reproduced, with permission, from Philit F, et al. Idiopathic acute eosinophilic pneumonia: a study of 22
patients. Am J Respir Crit Care Med. 2002; 166: 1235-1239. doi: 10.1164/rccm.2112056)
Treatment
Smoking cessation and high doses of corticosteroids usually result in dramatic
improvement in 24–48 hours. Total duration of therapy is usually 2–4 weeks.
CHRONIC EOSINOPHILIC PNEUMONIA
Clinical Features
 Affects middle-aged women.

 Symptoms include cough, dyspnea, fever, night sweats, malaise, and weight
loss.
 Asthma is present in 50–60% of patients.
 Immunoglobulin E levels are elevated.
 Peripheral blood eosinophilia occurs.
 Prognosis is excellent, but long-term treatment is required.
 Spontaneous resolution is rare.
Diagnosis
IMAGING
 Chest x-ray: Bilateral diffuse peripheral infiltrates are seen. This pattern has
been described as the photographic negative of pulmonary edema.
 HRCT: Peripheral infiltrates are seen in all affected lobes.
BRONCHOSCOPY (BAL, TBBx)

 BAL shows eosinophilia.
 TBBx shows eosinophilic microabscesses, low-grade vasculitis, and
interstitial fibrosis (Figure 4-24).
Treatment
Corticosteroids are given with a slow taper because relapse can occur.
256 / CHAPTER 4
Figure 4-24. Eosinophilic microabscesses.

SARCOIDOSIS
Sarcoidosis is a chronic, multisystem, noncaseating granulomatous disease of

unknown etiology. A number of diseases appear clinically and histologically
similar to sarcoidosis. Therefore, sarcoidosis is in essence a diagnosis of
exclusion. Table 4-8 describes its clinicopathologic mimics.
Table 4-8. Histopathologic Mimics of Sarcoidosis
Mimic Comment
Affects patients working with circuit boards/electronics. Similar

Berylliosis findings on x-ray. Diagnosis made with lymph transfer test on
bronchoalveolar lavage.
Interferon is used to treat hepatitis C and other conditions and
Interferon therapy
may promote granuloma formation.
Higher incidence of histologically proven pulmonary

World Trade Center responders
sarcoidosis is seen in this population.
INTRODUCTION
Table 4-9 shows the demographic features of patients with sarcoidosis.
Table 4-9. Demographic Features of Patients with Sarcoidosis
Age Sex Nationality Genetics Associations

< 40 y, peak 20–29 y F > M Highest prevalence in Heredity: 6% in Smoking appears
Sweden, Denmark, whites, 17% in African protective
In Scandinavian
and among African Americans
countries and Japan; Associated HLA
Americans
second peak No specific gene; subtypes
incidence in women > major histo-
HLA*DRB1*1101 and
50 y compatibility complex
HLA*DPB1*0101
on chromosome 6p
most studied -HLA DQB1*0201
associated with
favorable outcomes
Clinical Presentation
Table 4-10 reveals clinical patterns associated with sarcoidosis.
Table 4-10. Clinical Patterns Associated with Sarcoidosis

Clinical
Syndrome Other Key Facts Patterns
Manifestations
Pulmonary Radiographic stages: Imaging pattern may Nodular sarcoidosis
sarcoidosis mimic that seen in has highest rate of
Stage 1: Mediastinal and
other diseases spontaneous remission
hilar lymphadenopathy
Lung disease in 90% of
Stage 2: Adenopathy with
patients affected
lung disease
Stage 3: Lung disease
only
Stage 4: Fibrosis and
honeycombing
Löfgren Triad: Erythema Strong association with Resolves in 2 y in >
syndrome nodosum, hilar LAD, HLA-DQB1*0201 90% of patients
arthralgias
Seen mostly in women
Extrathoracic Skin, liver, heart, kidneys, Like pulmonary Chronic uveitis: African
manifestations central nervous system, disease, extrathoracic Americans
and bone are notable manifestations may
Lupus pernio: Puerto
sites mimic other diseases
Ricans
2–7% of patients
Erythema nodosum:
affected
Europeans
Cardiac and ocular
disease: Japanese
258 / CHAPTER 4
Clinical Findings
The clinical presentation and course are heterogeneous. Constitutional symptoms

include low-grade fever, night sweats, fatigue, and weight loss. Weight loss is
usually limited: 2–6 kg during the 10–12 weeks before presentation.
Pulmonary symptoms can include cough, wheezing, sputum production, and/or

pleurisy.
PULMONARY FUNCTION TESTS—Abnormalities are seen in only 20% of

patients with stage I disease and 40–70% of patients with stage II–IV disease
 Obstruction or restriction is seen. Occasionally, both are seen.
 Commonly a methacholine challenge test result is positive.
 Forced vital capacity and DLCO are the most predictive long-term markers of
disease.
LABORATORY TESTS
 Hypercalcemia occurs in 1–4% of cases, and hypercalciuria occurs in 15–40%.
 Angiotensin-converting enzyme levels are nonspecific for diagnosis, may be
used for disease monitoring.
o Findings may be normal in active disease.
 BAL shows lymphocytosis in > 80% of patients.
 BAL showing CD4/CD8 ratio > 3.5 has sensitivity of 53%, specificity of 94%,
positive predictive value of 76%, and negative predictive value of 85%.
IMAGING
 Chest x-ray findings other than bilateral hilar lymphadenopathy are relatively
nonspecific.
 Typical chest CT scan findings can vary. Classic findings (Figure 4-25):
o Widespread small nodules with a bronchovascular and subpleural
distribution
o Thickened interlobular septae
o Architectural distortion
o Conglomerate masses
 Radionuclide and positron emission tomography scans are used to evaluate
territory of disease.
 Echocardiogram is performed to evaluate cardiac involvement from
sarcoidosis or secondary pulmonary hypertension
Figure 4-25. Peribronchovascular disease showing small nodules (arrows) and

architectural distortion.
(Reproduced, with permission, from Müller NL, Miller RR. Computed tomography of chronic diffuse infiltrative
lung disease. Part 2. Am Rev Respir Dis. 1990; 142 [6 Pt 1]: 1440-1448.) Key Fact
Angiotensin-converting
enzyme is created by
granulomas and can be
elevated in any
Pathology granulomatous disease.
Granulomas also produce
calcitriol, which can lead to
 The diagnosis of sarcoidosis is typically made with bronchoscopy and hypercalcemia.
transbronchial biopsy. This has a diagnostic yield of 60–95%.
 Transbronchial nodal fine-needle aspiration also has high sensitivity.
 Endobronchial disease is seen in > 40% of patients with active disease. Flash Card Q4
What are normal BAL
CD4/CD8 ratios and those
PATHOLOGIC FINDINGS— See Figure 4-26.
in patients with
 In the lung, about 75% of granulomas are located near or within the sarcoidosis?
connective tissue sheath of bronchioles and subpleural or perilobular spaces
(lymphangitic distribution).
 Sarcoid granulomas either resolve or leave fibrotic changes. End-stage Flash Card Q5
sarcoidosis causes parenchymal fibrosis and honeycombing. How does the BAL
CD4/CD8 ratio differ in
HSP and sarcoidosis?
Flash Card Q6
What exposures can mimic
sarcoidosis?
260 / CHAPTER 4
Figure 4-26. Noncaseating granulomas.

(Reproduced, with permission, from Dr. Joseph F. Tomashefski, Jr., MetroHealth Medical Center, Case
Western Reserve University.)
Treatment
Spontaneous remissions occur and prognosis is based on the initial radiographic
stage:
 55–90% of patients with Stage I disease
 40–70% with Stage II disease
 10–20% with Stage III disease
 0% with Stage IV disease
The course of the disease is usually dictated within 18–24 months of onset.
Flash Card A4
Patients with worsening symptoms, worsening forced vital capacity and/or
CD4/CD8 ratio 1.5–2.0 = DLCO, or worsening lung fibrosis should receive therapy. Extrathoracic
normal
CD4/CD8 ratio >3.5 =
abnormalities also play a role in deciding whether treatment should be initiated.
suggestive of sarcoidosis Table 4-11 reveals the most commonly used therapeutic options.
Overall, respiratory failure is the most common cause of mortality. The directly
Flash Card A5 attributable mortality from sarcoidosis is < 5%.
CD4/CD8 ratio 1.5–2.0 =
normal
CD4/CD8 ratio >3.5 =
suggestive of sarcoidosis
Flash Card A6
Nearly identical clinical and
pathologic features can be
seen in berylliosis, so a
detailed exposure history is
key.
Table 4-11. Therapeutic Options
Treatment Comments
None Monitor symptoms, labs, and pulmonary function tests.
Spontaneous remission occurs in up to 40% of patients within
the first 6 mo and in 80% within the first 2 y.
Corticosteroids: prednisone/ Cornerstone of therapy; 4–6-wk initial burst with maintenance
prednisolone doses for ~6 mo.
Methotrexate/azathioprine Used in refractory disease. Methotrexate used early in those

with cardiac sarcoidosis.
Chloroquine/hydroxychloroquine Typically used for skin and central nervous system disease;
may stabilize lung function with concurrent steroid use.
Requires yearly eye exams because of toxicity.
Infliximab Used in refractory disease and extrapulmonary
manifestations. Limited evidence.
Inhaled corticosteroids Limited efficacy. Used in mild disease.
PULMONARY ALVEOLAR PROTEINOSIS
Pulmonary alveolar proteinosis is described as lipoproteinaceous material

accumulating in alveolar tissue. The disease also increases susceptibility to
opportunistic organisms.
INTRODUCTION
Estimated prevalence is 0.36–3.70 cases per 1 million people. Median age at

diagnosis is 39 years. Men are mostly affected. The disease is highly associated
with smoking tobacco.
The granulocyte-macrophage colony-stimulating factor (GM-CSF) pathway is

important in the pathogenesis of both the acquired and congenital forms of
pulmonary alveolar proteinosis. Table 4-12 shows the patterns of disease origin.
Flash Card Q7
What causes acquired
pulmonary alveolar
proteinosis?
262 / CHAPTER 4
Table 4-12. Pathogenesis of Pulmonary Alveolar Proteinosis
Type Comments
Congenital Autosomal recessive; caused by mutations on genes for surfactant B, C, or
the beta-c chain of the receptor for GM-CSF
Secondary Most common form; related to conditions that reduce pulmonary

macrophages: silica exposure, Pneumocystis jiroveci pneumonia,
malignancies, certain autoimmune diseases, immune deficiencies, and
certain drugs
Acquired Antibodies against GM-CSF
GM-CSF, granulocyte macrophage colony-stimulating factor.
Typical symptoms include cough and progressive dyspnea. Patients typically
present within 10 months of symptom onset. Some patients present with infection.
Lung examination shows crackles and occasionally cyanosis and clubbing.
LABORATORY FINDINGS—Findings strongly suggestive of pulmonary alveolar

proteinosis:
 Elevated lactate dehydrogenase level
 Possibly elevated carcinoembryonic antigen level
 Cytokeratin 19
 Mucin KL-6
 Surfactant protein-A, B, or D
 Serum or BAL showing GM-CSF antibodies

 Restrictive pattern is seen.
 Decrease in DLCO is out of proportion to restriction.
IMAGING
 Chest x-ray: Patchy and asymmetrical consolidation is seen and is more
prominent in the perihilar region bilaterally (batwing appearance).
 Chest CT scan: Patchy ground-glass opacities or consolidation, with
thickening of interlobular septae, resulting in a crazy paving pattern (Figure 4-
27).
Flash Card A7
Antibodies against GM-
CSF
Figure 4-27. Crazy paving pattern on computed tomography scan with

pulmonary alveolar proteinosis.
(Reproduced, with permission, from Müller NL, Miller RR. Computed tomography of chronic diffuse infiltrative
lung disease. Part 2. Am Rev Respir Dis. 1990; 142 [6 Pt 1]: 1440-1448.)
Pathology
The diagnosis is made via bronchoscopy with BAL. Figure 4-28A shows return of
milky effluent that shows granular, acellular, eosinophilic, proteinaceous material
with foamy macrophages. The finding of lamellar bodies (concentrically
laminated phospholipid structures) on electron microscopy is confirmatory.
Periodic acid–Schiff-positive proteinaceous alveolar deposits in the absence of a

cellular infiltrate and normal septa are characteristic (Figure 4-28B).
Flash Card Q8
What imaging pattern is
strongly suggestive of
pulmonary alveolar
proteinosis?
264 / CHAPTER 4
Figure 4-28. (A) Milky findings on bronchoscopy. (B) Periodic acid-Schiff stain in
pulmonary alveolar proteinosis.
(Figure A reproduced, with permission, from Garfied JM, Kim V. Dry cough and clubbing in a 45-year-old
woman. ATS Clinical Cases. Available at http://www.thoracic.org/clinical/ats-clinical-cases/pages/dry-cough-
and-clubbing-in-a-45-year-old-woman.php. Figure B reproduced, with permission, from Dr. Joseph F.
Tomashefski, Jr., MetroHealth Medical Center, Case Western Reserve University.)
Flash Card A8
Crazy paving pattern
Treatment
Therapies to reduce the development of proteinaceous material were historically
lacking, and management was geared toward clearance. More recently, GM-CSF
has been used (Table 4-13).
Table 4-13. Treatment Modalities for Pulmonary Alveolar Proteinosis
Modality Mode Comments

Sequential whole Up to 3 L saline mixed with Average duration of effect: ~15 months.
a
lung lavage non-anti-coagulant or heparin Average patient requires 2 lifetime lavages
(range, 1–22).
GM-CSF Subcutaneous or inhaled Helpful for acquired pulmonary alveolar
proteinosis
Proven oxygenation benefit.
Some show complete response
Lung Typically performed bilaterally Recurrence has been reported
transplantation
a
High level of evidence; standard of therapy.
GM-CSF, granulocyte macrophage colony-stimulating factor.
PROGNOSIS—No major variables predict survival; however, onset at age

younger than 5 years is associated with worse prognosis.
 Respiratory failure is the most common case of mortality.

 Infectious complications:
o Typical CAP organisms
o Mycobacteria Mnemonic
o Aspergillus—with disseminated disease, seen more often in acquired cases PAP MAN infections:
o Nocardia—with disseminated disease, seen more often in acquired cases Pulmonary
Alveolar
 Survival rate at 10 years is 68%. Proteinosis
Mycobacteria
 Spontaneous resolution may occur. Aspergillus
Nocardia
PULMONARY AMYLOIDOSIS
Pulmonary amyloid is described as a fibrillar, insoluble, proteinaceous material

that deposits within the lungs focally or diffusely.
266 / CHAPTER 4
The disease may present systemically or may be limited to the lungs.
The two most common types of amyloidosis are primary and secondary:
 Primary type is more common and is often associated with multiple myeloma.
 Secondary type is less common and is associated with chronic
inflammatory/infectious disorders.
Any organ may be affected. Pulmonary manifestations may be the first sign of
disease. Each pattern of pulmonary disease tends to occur independently, and
overlap is rare. Table 4-14 shows these patterns of disease.
Table 4-14. Spectrum of Disease with Pulmonary Amyloidosis
Location Findings
Parenchymal Cough, sputum production, dyspnea, hemoptysis
Tracheobronchial Wheezing, dyspnea, cough, hemoptysis
Upper airway Macroglossia with obstructive sleep apnea symptoms
LABORATORY TESTS—Serum protein electrophoresis or electrophoresis of

urine samples may show a monoclonal spike.

 Restriction is seen, and obstruction seen with tracheobronchial involvement.
 DLCO is reduced.
IMAGING
 Chest x-ray: Pulmonary nodules are seen with a diffuse interstitial pattern.
 Chest CT scan: Three different patterns are seen:
o Bilateral reticulonodular or nodular pattern may occur with mediastinal
adenopathy.
o Parenchymal nodules may be cavitated.
o Diffuse alveolar or tracheobronchial nodules with calcifications (Figure 4-
29).
Figure 4-29. Tracheobronchial amyloidosis.

(Reproduced, with permission, from Marchiori E, et al. [Diffuse abnormalities of the trachea: computed
tomography findings] [Article in Portuguese]. J Bras Pneumol. 2008; 34: 47-54.)
Pathology
 The diagnosis is made by sampling the affected tissue, including fine-needle

aspiration (vs. resection) of a nodule or biopsy of lung tissue.
 Bronchoscopy may show focal nodules on the major airways. Endobronchial
involvement may appear as focal stenoses with shiny, pale plaques.
 Biopsy (Figure 4-30A) shows characteristic apple-green birefringence with
Congo red staining on polarized microscopy. Nodules may also include
calcifications. Diffuse alveolar septal amyloid is shown in Figure 4-30B.
A B
Figure 4-30. Congo red staining (A). Diffuse alveolar septal amyloid (B). Flash Card Q9
(Reproduced, with permission, from Dr. Joseph F. Tomashefski, Jr., MetroHealth Medical Center,
Case Western Reserve University.) Is tracheobronchopathia
osteochondroplastica
associated with amyloid
disease?
268 / CHAPTER 4
Treatment
Treatment is centered on therapy for the underlying plasma cell dyscrasia. Focal
stenosis within the tracheobronchial tree can be treated with laser therapy.
Bevacizumab is used to treat pleural effusions in primary systemic amyloidosis.
Median survival is 16 months. Nodular-only disease has a benign course.
BIRT-HOGG-DUBE
DEFINITION—Birt-Hogg-Dube is a rare autosomal dominant disease that causes

cystic lung disease and pneumothorax.
This disease was first described as the cutaneous triad of fibrofolliculomas

(Figure 4-31), trichodiscomas, and skin tags. It also has a propensity for renal
tumors.
ETIOLOGY—It is caused by germline mutations of the BHD gene on

chromosome 17 that encodes for folliculin, a tumor suppressor.
Flash Card A9
No, tracheobronchial Figure 4-31. Fibrofolliculomas.
amyloid is its own disease (Reproduced courtesy of Thomas Habif, Dermnet.com, CC BY-SA 3.0.)
entity but can present very
similarly. Submucosal
involvement (posterior wall)
is seen only with
tracheobronchial amyloid
disease.
 Affects patients in the third or fourth decade.

 Patients present with firm, dome-shaped papules on the upper extremities,
face, and trunk.
 Renal tumors fall under the pathology of renal cell carcinoma, oncocytic
hybrid tumor, or clear cell carcinoma.
PULMONARY MANIFESTATIONS—Can occur in the absence of skin or kidney

lesions
 Pneumothorax occurs in 25% of patients.
 Symptoms can include dyspnea and cough.
 Pulmonary function tests show a restrictive pattern.
 Chest x-ray may show cystic lesions in the lung space.
 Chest CT scan shows scattered, thin-walled cysts of various sizes.
Pathology
Features include intraparenchymal air-filled spaces surrounded by normal
parenchyma or a thin wall.
Diagnosis is made by open lung biopsy. Biopsy specimens may help to exclude
lymphangioleiomyomatosis, lymphocytic interstitial pneumonia, Langerhans cell
histiocytosis, and rare forms of malignancy.
Treatment
No specific treatment exists. Usual care is provided for pneumothorax. Family
members should be genetically screened. Patients require routine screening for
renal malignancy.
Flash Card Q10

What are the causes of
noninfectious cystic lung
disease?
270 / CHAPTER 4
LIPOID PNEUMONIA
Lipoid pneumonia is divided into endogenous and exogenous forms. Early

recognition is key because this condition may mimic infectious pneumonia and
lead to incorrect management.
Exogenous lipoid pneumonia is far more commonly reported in the literature than
the endogenous form. Table 4-15 shows the differences between endogenous and
exogenous lipoid pneumonia.
Table 4-15. Pathogenesis of Lipoid Pneumonia
Type Comments
Exogenous Classically seen in chronic laxative users (mineral oil). Also associated with
old nasal sprays, aspiration, and bronchography (rarely used today).
Endogenous Related to proximal airway obstruction with resultant cholesterol-filled

macrophages distally. Rarely associated with Niemann-Pick disease.
Cough, wheezing, and dyspnea are common.
LABORATORY TESTS—Non-specific.
BAL—Lipid-laden macrophages are seen.
Flash Card A10

Lymphangioleiomyomatosis,
lymphocytic interstitial
pneumonia, Langerhans cell
histiocytosis, Birt-Hogg-
Dube, and rare forms of
malignancy
PULMONARY FUNCTION TESTING

 Restriction is noted.
 DLCO is reduced.
IMAGING
 Chest x-ray: Consolidations are seen.
 Chest CT scan: Consolidations are seen, with or without surrounding ground-
glass opacities, airspace nodules, and occasional crazy paving pattern when
associated with pulmonary alveolar proteinosis. Finding of negative
Hounsfield units is diagnostic.
Pathology
New lesions show lipid-laden macrophages in alveolar spaces. With advanced
disease, associated inflammatory cell invasion may occur. Over time, these
inflammatory cells may cause cell wall destruction and fibrosis.
Staining with Sudan black (Figure 4-32) and oil red O can show lipid-filled
vacuoles. Sometimes these are seen with hematoxylin-eosin staining (Figure 4-33).
Figure 4-32. Sudan black stain in lipoid pneumonia.

(Lekka ME, et al. The Impact of Intravenous Fat Emulsion Administration in Acute Lung Injury. Am J Respir Crit
Care Med. 2004; 169(5): 638-644.Fig 4B. doi: 10.1164/rccm.200305-620OC)
Flash Card Q11

How is infectious
pneumonia distinguished
from lipoid pneumonia on
imaging?
272 / CHAPTER 4
Figure 4-33. Hematoxylin-eosin stain showing characteristic lipoid vacuoles.

(Seif F, Hafez-Khayyata S, Hejal R. A Solitary Pulmonary Nodule Mimicking Lung Cancer. Am J Respir Crit
Care Med. 2012: 186(3): e4. Fig 1D. doi: 10.1164/rccm.201107-1182IM)
Treatment
The goal of treatment is to avoid reintroduction of exogenous substance. Focal
BAL to the site can be attempted and repeated, however little evidence exists to
its efficacy.
Prognosis
Prognosis is excellent if detected early and the exogenous source is controlled.
DRUG-INDUCED LUNG DISEASE
Introduction
Drug-induced lung disease encompasses a wide spectrum of disease.
Certain classes of medications have repeatedly been found to cause lung disease.
As a whole, drug-induced lung disease should always be included in the
Flash Card A11 differential diagnosis for pulmonary diseases. Unfortunately, the dose and length
CT scan shows fewer
of exposure do not follow a clear pattern.
Hounsfeld units compared
with typical infectious
consolidations.
In clinical practice, the Web site www.pneumotox.com is helpful for staying up to

date on the latest drug-induced lung diseases.
Table 4-16 shows the clinical presentation of drug-associated lung disease and the
associated drugs.
Table 4-16. Clinical Associations
Presentation Associated Drugs

Cough Angiotensin-converting enzyme inhibitor, rarely angiotensin
receptor blockers
Bronchospasm Beta blockers (including ophthalmic), aspirin/nonsteroidal anti-
inflammatory drugs, cetuximab
Noncardiogenic pulmonary Tocolytics, IL-2, aspirin/nonsteroidal anti-inflammatory drugs
edema
Hypersensitivity pneumonitis Methotrexate, taxanes, penicillin, sulfa drugs
Chronic fibrosis Bleomycin, Taxol, amiodarone, nitrofurantoin
Venous thromboembolism Estrogen (and estrogen receptor agonist/antagonists),

especially if positive for Factor V Leiden mutation
Lupus Hydralazine, isoniazid, penicillamine, procainamide, quinidine
Acute lung injury or pleural Imatinib, dasatinib

effusion
Pulmonary hypertension Dasatinib, methamphetamine
Table 4-17 shows drugs known to cause lung disease. Figure 4-37 shows common
lung toxicities.
Table 4-17. Specific Drug Associations
Drug Presentation Histopathology Imaging Comments

Amiodarone Older patients; Foamy Fibrosis, BOOP, Half-life: 30–60 d
higher risk when macrophages mass lesions Trial of steroids >
dose is > 400 with fibrosis, with or without 6 mo
mg/d for > 6 mo lamellated cavitation,
inclusions effusions
Nitrofurantoin Acute vs. chronic Acute: NSIP pattern, no Steroids used in
Women >> men hypersensitivity zonal severe cases
pneumonitis, OP, predominance
cellular NSIP
Chronic: NSIP
274 / CHAPTER 4
Table 4-17. Specific Drug Associations, continued
Drug Presentation Histopathology Imaging Comments

5-ASA/ Pneumonitis, Pulmonary NSIP, OP pattern Toxicity:
sulfasalazine fever, rash = eosinophilia, OP, Sulfasalazine > 5-
sulfasalazine BO ASA; eosinophilia
Methotrexate Not related to Hypersensitivity OP, NSIP, AIP Eosinophilia
intensity of pneumonitis, pattern occasionally seen;
therapy NSIP, OP rarely associated
Acute vs. with NHL
subacute vs.
chronic
presentation
Busulfan Used for CML Pneumocyte NSIP pattern Bronchoscopy
therapy and HCT dysplasia, typical rarely shows PAP
induction bronchial lining
Subacute vs. cells
chronic
presentation
Bleomycin Various times of Hypersensitivity Hypersensitivity Avoid high O2
presentation pneumonitis, pneumonitis, ALI, delivery to avoid
DAD, NSIP, UIP NSIP, UIP pulmonary toxicity
Imatinib/ Acute vs. Noncardiogenic ALI, pleural Rare PAH from
dasatinib subacute pulmonary edema effusions dasatinib
or AIP
Interferon Pneumonitis Sarcoidosis, ALI, ALI, pleural Early
potentially life- OP effusions, OP discontinuation if
threatening evidence of
pneumonitis
IVDU Acute and Foreign body Septic emboli, CAP risk
chronic sequelae granulomatosis, DAH, bullae, increased 10 x
ALI cardiogenic/non- PAH risk
cardiogenic increased
pulmonary edema
Radiation Subacute (4–12 OP, NSIP Ground-glass Distribution may
therapy wk) to chronic opacities, OP, or follow the
(6–12 mo). NSIP; often “radiation port” but
confined to a not applicable to
region SBRT, gamma
knife, 3D-CRT
Steroids in
nonfibrotic phase,
often over 12 wk
3D-CRT, 3D conformal radiation therapy; 5-ASA, mesalamine; AIP, acute interstitial pneumonitis; ALI, acute
lung injury; BO, bronchiolitis obliterans; BOOP, bronchiolitis obliterans with organizing pneumonia; CAP,
community-acquired pneumonia; CML, chronic myeloid leukemia; DAD, diffuse alveolar damage; DAH, Diffuse
alveolar hemorrhage; HCT, histocompatibility test; IVDU, intravenous drug use; NHL, non-Hodgkin’s lymphoma;
NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia; PAH, pulmonary arterial hypertension;
SBRT, stereotactic body radiation therapy; UIP, usual interstitial pneumonia
A B
Figure 4-34. Common lung toxicities. (A) Amiodarone toxicity. (B) Bleomycin
toxicity. (C) Inhaled cellulose particulate: polarized.
(Reproduced, with permission, from Dr. Joseph F. Tomashefski, Jr., MetroHealth Medical Center, Case
Western Reserve University.)
Clinical Findings
Examination findings, labs, pulmonary function test results, and imaging assist
with the diagnosis, but the findings are not diagnostic. A high index of suspicion
arises with a thorough review of medication exposure history.
Treatment
Treatment is focused on drug discontinuation. Often, this alone leads to resolution
of symptoms. Steroids are rarely efficacious.
276 / CHAPTER 4
Occupational and Environmental Lung Diseases
PNEUMOCONIOSES
These diseases are related to mineral dust exposure and are summarized in Table 4-18.
Table 4-18. Clinical Characteristics of the Most Common Pneumoconiosis
Type Occupations Presentation Radiology Pathology

Silicosis Sandblasting, tunneling, drill Chronic: 10–30 y after Simple silicosis: Mid-upper lung Early: Peribronchovascular,
operation, digging, glass exposure zone nodules (< 1 cm) (Fig. 4-35) paraseptal, and subpleural dust-
manufacturing, hard rock Accelerated: < 10 y after Progressive massive fibrosis: laden macrophages
mining, oven-brick making, exposure Silicotic nodule: Concentric
stone cutting, masonry, foundry Coalescence of lung nodules (>
Acute: Weeks to 4–5 y after 1 cm) (eggshell calcification may collagen fibers around a hyaline
work, natural gas extraction via center (Fig. 4-37)
hydraulic fracturing, sandy and exposure, usually after be seen); upward hilar retraction;
dry soil agriculture exposure to high lower lobe hyperinflation (Fig. 4- Acute: Alveolar filling with
concentrations of fine 36) proteinaceous material
respirable crystalline silica Acute: Mid-lower lung zone (phospholipids and surfactant),
ground-glass opacities with periodic acid–Schiff positive
consolidation (batwing
distribution). HCRT: Interlobular
septal thickening with ground-
glass opacities
Coal workers’ Coal mining Chronic bronchitis: Most Simple: Upper-lobe-predominant Coal macule: Focal collection of
common nodules (< 1 cm) coal dust in pigment-laden
Simple: > 20 y after exposure Progressive massive fibrosis: macrophages
Similar to silicosis, with Caplan nodule: Focal lesion
Accelerated or Complicated: < associated lower lobe with necrotic center surrounded
10 y after exposure emphysema by lymphocytes and plasma cells
Centrilobular emphysema
Table 4-18. Clinical Characteristics of the Most Common Pneumoconiosis, continued
Type Occupations Presentation Radiology Pathology

Asbestosis Pipefitters, steamfitters, 10–40-y latency period. Chest x-ray: Lower-lobe- Ferruginous bodies (asbestos
electricians, insulation workers, Pleural disease: benign predominant reticular or bodies): Large asbestos fibers
boilermakers, welders, asbestos pleural effusion, multinodular opacities (may be coated with iron from
construction workers and plaques with calcification normal) (Fig. 4-38) hemosiderin (Fig. 4-40)
shipbuilders; plastic and rubber HRCT: Subpleural lines; Asbestos fibers: Small
manufacturing workers; yarn, parenchymal and interlobular uncoated asbestos fibers of
thread, or fabric millworkers; septal fibrosis; honeycombing; different forms within
truckers and railway workers; and pleural plaques (Fig. 4-39) macrophages (Figs. 4-41 and 4-
those who work with brakelining 42)
or cement
Beryllium Aerospace, aircraft, and alloy Acute: Rare; pneumonitis, Chest x-ray: Upper-lobe- Noncaseating granulomas.
production; automotive, tracheobronchitis, predominant reticulonodular
ceramics, defense, dental and nasopharyngitis changes, hilar and mediastinal
prosthetics, electronics, nuclear, Chronic: Latency period of 3 LAD
recycling of electronics and mo–40 y (average, 10 y). HRCT:
computers; and Dyspnea, cough, fever, night Parenchymal nodules, septal
telecommunications sweats, fatigue, weight loss thickening, ground-glass,
opacities, hilar and mediastinal
LAD (Fig. 4-43)
HRCT, high-resolution computed tomography scan; LAD, lymphadenopathy; PAS, periodic acid-Schiff reagent
Flash Card Q12

Which interstitial lung
disease resembles acute
silicosis histologically and
on imaging?
278 / CHAPTER 4
Silicosis
Silicosis includes a spectrum of lung disease caused by inhalation of free
crystalline silica (silicon dioxide). It is characterized by progressive development
of parenchymal nodules and fibrosis (Figures 4-35 and 4-36) and is the most
prevalent chronic occupational lung disease worldwide.
Silicosis increases the risk of several conditions and may be complicated by:
 Mycobacterial and fungal infection, which is suspected if cavitation develops
 Lung cancer, which has been associated with bronchogenic carcinoma
 Chronic bronchitis and airflow obstruction due to airway narrowing and
distortion from nodules
 Connective tissue diseases, including scleroderma and rheumatoid arthritis,
which are the most common, and also vasculitis
Flash Card A12

Secondary pulmonary
alveolar proteinosis, which
causes alveolar filling with
proteinaceous material that
consists mostly of
phospholipids and
surfactant, staining with
periodic acid–Schiff
reagent (silicoproteinosis). Figure 4-35. Chest x-ray of a patient with silicosis showing upper-lobe-
Other exposures with predominant nodular changes with lower lobe hyperinflation.
similar findings are (Image courtesy of James Ravenel, MD, Medical University of South Carolina.)
aluminum, silica, titanium,
cement, insulation,
sawdust, paint, varnish,
chlorine, nitrogen dioxide,
and fertilizer.
Figure 4-36. Chest x-ray of a patient with progressive massive fibrosis caused by
silicosis showing coalescence of lung nodules, hilar retraction (arrow), and low
lung volumes.
(Image courtesy of James Ravenel, MD, Medical University of South Carolina.)
Flash Card Q13

Which autoimmune
disease is associated with
Caplan syndrome?
Figure 4-37. Histologic section of a silicotic nodule showing dense collagen Flash Card Q14
(black arrow) and several hyaline centers (red arrow).
(Reproduced courtesy of Yale Rosen, flikr.com, CC BY-SA 2.0) Which pneumoconiosis is
associated with
melanoptysis?
280 / CHAPTER 4
Coal Workers’ Pneumoconiosis
Also known as black lung, coal workers’ pneumoconiosis is caused by inhalation

and deposition of coal dust. Coal dust is a mixture of carbon, oxygen, nitrogen,
Key Fact crystalline silica, and trace elements, which may include boron, cadmium, nickel,
Anthracosis is the iron, antimony, lead, and zinc. It is formed by the accumulation of vegetable
accumulation of coal dust matter subjected to pressure and temperature over the ages.
within the lungs. It is often
asymptomatic and can be
seen in people living in
large urban areas where
there is significant air Asbestosis
pollution.
Asbestosis is caused by inhalation of asbestos fibers. Asbestos is a naturally
occurring hydrated silicate mineral characterized by resistance to heat and
degradation. These properties have been exploited in various industries,
Flash Card A13 particularly insulation. Asbestosis is characterized by diffuse interstitial fibrosis,
Rheumatoid arthritis. commonly in a symmetrical pattern (Figure 4-38 and 4-39). There are two types
Caplan syndrome is a of asbestos fibers: serpentine and amphiboles (Table 4-19) (Figures 4-40 through
nodular reaction that 4-42). There is a long latency period (15–40 years) from initial exposure to
occurs in individuals
exposed to coal dust who development of disease. Pleural involvement distinguishes asbestosis from
also have rheumatoid idiopathic pulmonary fibrosis. The two most commonly associated complications
arthritis or who will have are respiratory failure and malignancy (bronchogenic carcinoma is most common).
rheumatoid arthritis within
the next 5–10 years. The The most common pleural and pulmonary manifestations of asbestos exposure are
nodules can vary in summarized in Table 4-20.
diameter (0.5–5.0 cm) and
are usually multiple,
bilateral, and peripherally
located. They contain a
necrotic center surrounded
by lymphocytes and
plasma cells and a very
small amount of coal dust.
Table 4-19. Characteristics of Asbestos Fibersa
Fiber Malignancy
Shape Structure Pathology
Risk
Flash Card A14
Serpentine (chrysotile) Curly Curved Easily degraded by Low
Coal workers’ (Fig. 4-41) stranded macrophages
pneumoconiosis.
Melanoptysis is the Amphibole (crocidolite, Rod-like Straight Insoluble, virtually not High
expectoration of black amosite, anthophyllite, degradable by
sputum containing tremolite-actinolite) macrophages; more
carbonaceous particles. It (Fig. 4-42) durable
a
occurs when a Long fibers are more carcinogenic than short ones.
conglomerate of nodules
cavitates and ruptures into
the airway. Melanoptysis
has also been reported
with freebase cocaine
smoking, malignant
melanoma, and
aspergilloma caused by
Aspergillus niger, as well
as in progressive massive
fibrosis caused by silicosis.
Figure 4-38. Chest x-ray of a patient with asbestosis showing lower-lobe-

predominant reticulonodular opacities. Notice the pleural plaque on the right
diaphragm (arrow).
282 / CHAPTER 4
Figure 4-39. Computed tomography scan of a patient with asbestosis showing

lower-lobe-predominant parenchymal and interlobular septal fibrosis. Notice the
calcified pleural plaque on the right (arrow).
Figure 4-40. Asbestos (ferruginous) bodies. Notice the large size and the coating
with iron.
(Reproduced courtesy of the Ospedale San Polo, Monfalcone, Italy, Wikimedia Commons, CC BY-SA 3.0.)
Figure 4-41. Electron microscopic image of chrysotile asbestos. Notice the

curved appearance characteristic of serpentine fibers.
(Image courtesy of the U.S. Geological Survey of the U.S. Department of the Interior. Reproduced from
http://usgsprobe.cr.usgs.gov/picts2.html.)
Figure 4-42. Electron microscopic image of anthophyllite asbestos. Asbestos

fibers are rarely seen by light microscopy, are smaller than asbestos bodies, and
are not coated with iron. Notice the straight, rod-like appearance characteristic of
amphiboles.
(Image courtesy of the U.S. Geological Survey of the U.S. Department of the Interior. Reproduced, from
http://usgsprobe.cr.usgs.gov/picts2.html.)
284 / CHAPTER 4
Table 4-20. Pleural and Pulmonary Manifestations of Asbestos Exposure
Condition Latency Presentation Radiology Pathology

Benign Shortest of all, < Asymptomatic in Usually unilateral, Exudative
asbestos 1 y to > 40 y two thirds; pleurisy costophrenic effusion;
Key Fact pleural effusion and dyspnea angle blunting eosinophilic,
bloody; can
There is a multiplicative resolve
risk of lung cancer in spontaneously;
patients who are exposed low malignancy
to asbestos and smoke risk
cigarettes. The relative risk
Pleural plaques Most common; Asymptomatic; Parietal pleural Fibrosis of the
of cigarette smokers with
found in up to incidental finding thickening in the parietal pleura;
asbestos exposure is
50% of exposed on imaging mid-lower ribs no evidence of
nearly 60.
individuals; 10– and diaphragm; malignancy risk
40 y often bilateral;
calcification over
time
Pleural fibrosis > 20 y Asymptomatic; Diffuse visceral Concomitant with
incidental finding pleural thickening; asbestosis;
on imaging; usually unilateral considered direct
restriction on extension of
pulmonary parenchymal
function testing fibrosis
Visceroparietal > 20 y Asymptomatic; Pleural-based Local visceral
reactions incidental finding “mass-like” lesion and parietal
(“rounded on imaging with hilar structure pleural self-
atelectasis”) (“comet tail” sign) invagination,
(Fig. 4-43) trapping
underlying lung;
no evidence of
malignancy risk
Asbestosis 10–40 y Dyspnea; basal See Table 4-18 Asbestos bodies
crackles . and fibers; lower-
lobe-
predominant
subpleural
fibrosis; evidence
of malignancy
risk
(bronchogenic
carcinoma)
Bronchogenic 10–40 y Asymptomatic; Lung nodule or Induced
a
carcinoma weight loss, mass oncogenic
dyspnea, cough expression
leading to
abnormal tumor
cell proliferation
b
Mesothelioma ≥ 15 y Chest pain, Unilateral parietal Parietal nodules
dyspnea, cough pleural mass, leading to
nodularity, or thickening,
thickening with visceral pleural
pleural effusion; coalescence,
volume loss right and lung
> left side encasement
a
Other nonpulmonary malignancies associated with asbestos include laryngeal, pharyngeal, gastric,
colorectal, biliary, and renal cancer.
b
Tumor markers that may be elevated and measured include soluble-mesothelin related peptides
(SMRP), fibulin-3, and osteopontin.
Figure 4-43. Computed tomography scan of a sheet metal worker showing a left
pleural-based mass consistent with rounded atelectasis (red arrow). Notice the
self-invagination and trapping of lung parenchyma as well as the hilum or “comet
tail” (yellow arrow).
(Reproduced, with permission, from American Thoracic Society. Diagnosis and initial management of
nonmalignant diseases related to asbestos. Am J Respir Crit Care Med. 2004; 170: 694. doi:
10.1164/rccm.200310-1436ST.)
Beryllium Disease
Beryllium is a light metal used in many high-technology industries. Exposure
causes granulomatous lung disease (Figure 4-44). Beryllium lung disease induces
a cell-mediated or delayed hypersensitivity reaction that leads to granulomatous
inflammation. Pathologically, chronic beryllium disease and sarcoidosis are
almost indistinguishable. Documenting exposure to beryllium is an important clue
to distinguish between the two.
286 / CHAPTER 4
Figure 4-44. Computed tomography scan of a patient with berylliosis showing

hilar and mediastinal lymphadenopathy (red arrow), interlobular septal thickening
(yellow arrow), subpleural nodules, and nodularity along the bronchovascular
bundles (black arrow).
Talcosis
Talcosis results from exposure to hydrated magnesium silicate. Talc is used in the
cosmetic, ceramic, chemical, and pharmaceutical industries. Major exposures
occur after inhalation of heavy amounts of baby powder or in drug users who
inject or inhale crushed tablets.
Chest x-ray may show fibrosis, nodular lung disease, and lower lobe emphysema.
Talc granulomas, characterized by multinucleated giant cells, may occur in the
interstitium and pulmonary arteries in intravenous drug users. These granulomas
may produce pulmonary hypertension and cor pulmonale and show birefringent
talc crystals (Figure 4-45).
Key Fact
Giant odd-appearing
multinucleated cells (i.e.,
cannibalistic cells) can be
seen in patients exposed to
cobalt. This is also known
as giant cell interstitial
pneumonitis (Figure 4-49).
Figure 4-45. Low-magnification micrograph showing granulomas (arrow) in an

intravenous drug user with crystals consistent with talc. Talc crystals are
birefringent under polarizable light (bright white, not shown).
(Reproduced courtesy of Nephron, Wikimedia Commons, CC BY-SA 3.0.)
Hard Metal Lung Disease

Hard metal lung disease occurs after exposure to hard metals, of which the most
common is cobalt. Occupations associated with cobalt exposure include machinist,
metal toolmaker, polisher, grinder, saw sharpener, and dental driller. The
following may occur: Flash Card Q15
 Obstructive airways disease What blood or
 Acute interstitial pneumonitis bronchoalveolar lavage
 Diffuse fibrosis test is used to assist in
diagnosing chronic
beryllium disease?
288 / CHAPTER 4
Figure 4-46. Histology slide shows peribronchiolar fibrosis (arrow) and

inflammation, with giant cells in the airspace. Cobalt and tungsten are the most
common hard metals associated with giant cell interstitial pneumonia.
(Reproduced courtesy of Yale Rosen, flickr.com, CC BY-SA 2.0)
HYPERSENSITIVITY PNEUMONITIS
Also known as extrinsic allergic alveolitis, hypersensitivity pneumonitis is an

immunologic-induced syndrome (believed to be caused by a combined type III
and type IV reaction) that results in diffuse mononuclear cell inflammation of the
small airways and pulmonary parenchyma after exposure to a wide variety of
inhaled antigens (Figures 4-47 and 4-48). These antigens include organic dust
(bioaerosols, avian proteins, fungi, thermophilic bacteria) as well as low-
molecular-weight volatile and nonvolatile chemical compounds (Table 4-21). The
clinical, radiologic, and pathologic findings are similar, despite the wide range of
identified antigens.
Flash Card A15

Beryllium lymphocyte
proliferation test
Figure 4-47. Low-magnification slide (hematoxylin-eosin-stained) of a patient

with chronic hypersensitivity pneumonitis showing an interstitial mononuclear
inflammatory infiltrate with airway-centered inflammation. There are two
multinucleated giant cells on the left (arrow).
(Reproduced courtesy of Mutelysmith, Wikimedia Commons, CC BY-SA 3.0.)
Table 4-21. Examples of Etiologic Agents of Hypersensitivity Pneumonitis
Disease Antigen Exposure

Farmer’s lung Faenia rectivirgula (bacteria) Moldy hay, grain, silage
Humidifier lung; air conditioner Thermoactinomyces vulgaris Contaminated forced-air

lung; ventilation pneumonitis (bacteria) systems; water reservoirs
Bagassosis T. vulgaris (bacteria) Moldy sugar cane (bagasse)
Malt worker’s lung Aspergillus clavatus (fungi) Moldy barley
Maple bark stripper’s lung Cryptostroma corticale Moldy maple bark

(bacteria)
Cheese washer’s lung Penicillium casei (bacteria) Moldy cheese
Suberosis Thermoactinomyces viridis Moldy cork

(bacteria)
Paprika slicer’s lung Mucor stolonifer (fungi) Moldy paprika pods
Pigeon breeder’s or fancier’s Avian droppings, feathers, Parakeets, pigeons, chickens,

disease serum turkeys
290 / CHAPTER 4
Figure 4-48. High-magnification slide (trichome stain) showing granulomatous

inflammation in a patient with hypersensitivity pneumonitis.
(Reproduced courtesy of Nephron, Wikimedia Commons, CC BY-SA 3.0)
Table 4-22 shows the clinical features and classification of hypersensitivity

pneumonitis. Pulmonary function tests may show restriction, obstruction, or a
mixed pattern with reduced DLCO. Treatment often includes removal from
exposure to the offending antigen and in some cases corticosteroids. Cigarette
smoking reduces risk.
Table 4-22. Clinical Features and Classification of Hypersensitivity

Pneumonitis
Type Onset Features Radiology Pathology
Acute 4–8 h after Fever, chills, Chest x-ray findings Poorly formed,
heavy malaise, may be normal. noncaseating
exposure dyspnea, fine granulomas;
crackles (may be HCRT shows diffuse peribronchial
mistaken for or patchy ground- mononuclear cell
viral, atypical, or glass attenuation infiltration
flu-like illness)
Subacute or Gradual or Cough, dyspnea, Chest x-ray shows More well formed,
intermittent repeated fatigue, weight micronodular but loose and
exposure loss, diffuse opacities poorly arranged
crackles noncaseating
HRCT shows granulomas;
centrilobular ground- bronchiolitis with or Key Fact
glass nodules, focal without organizing
air trapping (Fig. 4- pneumonia Bronchoalveolar lavage
49) fluid from patients with
hypersensitivity
Chronic Often without a Cough, dyspnea, Chest x-ray shows a Loose and poorly
pneumonitis is
history of acute fatigue reticular pattern with arranged
characterized by an
or subacute honeycombing, noncaseating
elevated percentage of
episodes fibrosis, and volume granulomas with
lymphocytes, typically >
loss mononuclear
50%. There is proliferation
alveolitis in the +
of CD8 T-lymphocytes,
HRCT shows presence of fibrosis
resulting in inversion of the
nodules, ground- with thick alveolar
CD4/CD8 ratio.
glass opacities, and septa
honeycombing (Fig.
4-50)
Figure 4-49. Computed tomography scan of a patient with subacute

Flash Card Q16
hypersensitivity pneumonitis showing centrilobular ground-glass opacities
(arrows) in an upper-lobe-predominant distribution. What are the characteristic
(Reproduced courtesy of James Ravenel, MD, Medical University of South Carolina.) pathologic changes of
hypersensitivity
pneumonitis?
292 / CHAPTER 4
Figure 4-50. Computed tomography scan of a patient with chronic

hypersensitivity pneumonitis showing honeycombing (red arrow), ground-glass
opacities (white arrow), and nodular upper-lobe-predominant changes.
(Reproduced courtesy of James Ravenel, MD, Medical University of South Carolina.)
TOXIC GASES AND FUMES
Inhalation of gases, certain organic antigens, and fumes can result in immediate
(hyperacute) cytokine release without consequent lung injury, acute irritant lung
injury with or without alveolar damage, or subacute lung parenchymal disease.
Exposure to these gases and fumes does not result in hypersensitivity pneumonitis.
A summary of these toxic gases and fumes based on mechanism of action is
shown in Table 4-23.
Flash Card A16
Cellular bronchiolitis or
airway-centered
Table 4-23. Toxic Gases and Fumes
inflammation, an interstitial Mechanism Agent(s) Related Presentation Radiology
mononuclear cell infiltrate, exposure
and small, poorly formed
nonnecrotizing Cytokine- Metal fume fever Welding 4–8 h after No radiographic
granulomas. Conditions mediated (zinc oxide) (galvanization), intense changes
that may appear similar on reaction with no brass work inhalation; flu-
biopsy include sarcoidosis lung injury like symptoms
Organic dust Contaminated
(well-formed granulomas), (massive (fevers, chills,
toxic syndrome, grains, moldy
other granulomatous inhalation) malaise,
thermophilic hay, silage,
infections (i.e., headache,
bacteria, and flour, textile
tuberculosis, fungal myalgias),
fungal spores materials, wood
diseases), UIP, fibrosing dyspnea and
chips
NSIP, organizing cough; self-
pneumonia, and drug- limited; resolves
induced lung disease. in 12–48 h
Table 4-23. Toxic Gases and Fumes, continued

Mechanism Agent(s) Related Presentation Radiology
exposure
Acute irritant Chlorine, Industrial leaks, Mild eye, nose, Airspace
lung injury and chloramine transport leaks, and throat opacities;
diffuse alveolar swimming pool airway mucosal noncardiogenic
damage chemicals, symptoms; edema; ground-
(inorganic, low household acute dyspnea, glass opacities
water solubility) cleaning respiratory with metals
products, pulp failure;
and paper bronchiolitis
processing (with or without
obliterans) may
Nitrogen dioxide, Silo filler’s
develop 2–6 wk
ozone, acid disease
later
aerosols, (nitrogen
phosgene dioxide),
explosive
detonations
(nitrogen
oxides), welding
(ozone and
phosgene)
Metals Welding,
(cadmium, brazing, flame-
mercury, nickel cutting
carbonyl) (cadmium);
equipment
electronic
recycling
(mercury); nickel
refining
Acute irritant Fire eater’s lung Flame-blowing Acute dyspnea, Airspace
lung injury and (hydrocarbon) performances respiratory opacities;
diffuse alveolar (ingestion) failure; noncardiogenic
damage bronchiolitis edema
Paraquat Ingestion
(organic, low (with or without
water solubility) obliterans) 2–6
Popcorn Flavor industry
wk later;
worker’s lung worker
gastrointestinal
(diacetyl (inhalation)
symptoms
butanedione)
precede
pulmonary
edema with
paraquat
(oxygen may
worsen
paraquat lung
injury)
Acute irritant Smoke Firefighting, Eye, nose, and Airspace
lung injury and inhalation (fire incineration, throat irritation; opacities;
diffuse alveolar smoke, pyrolysis inhalation within dyspnea, noncardiogenic
damage (gas from plastics, a closed or respiratory edema
mixture, low aldehydes confined space failure;
Flash Card Q17
water solubility) acrolein) bronchiolitis What properties of toxic
gases and fumes
determine their pattern of
lung injury?
294 / CHAPTER 4
Table 4-23. Toxic Gases and Fumes, continued

Mechanism Agent(s) Related Presentation Radiology
exposure
Acute irritant Ammonia, Farming, Acute eye, nose, Airspace
lung injury and chlorine, sulfur refrigeration and and throat opacities;
diffuse alveolar dioxide cleaning irritation; noncardiogenic
damage (high solutions respiratory edema
water solubility) (ammonia); failure;
bleaching, bronchiolitis
disinfectant, (with or without
plastics obliterans) 2–6
(hydrogen wk later
chlorine); mining
and cement
(sulfur dioxide)
Lung Flock worker’s Textile Dyspnea Reticulonodular
parenchymal lung (nylon) manufacturing progressing to or patchy
disease interstitial lung opacities;
disease over peripheral
months to 1 y alveolar
(usually consolidation and
Ardystil (Acramin Textile printing nonspecific honeycombing
FWR/FWN) sprayers interstitial
pneumonia or
organizing
pneumonia )
WORK-RELATED ASTHMA
Work-related asthma is described as asthma that is exacerbated (work-

exacerbated asthma) or induced (occupational asthma) by inhalation exposures in
the workplace.
Occupational Asthma
Occupational asthma is de novo asthma or recurrence of previously quiescent
Flash Card A17 asthma induced by sensitization to a specific substance or chemical at work
Water solubility, duration of (sensitizer-induced asthma) or by exposure to an inhaled irritant at work (irritant-
exposure, and depth of
inhalation. For example,
induced asthma). Table 4-24 shows the characteristics that distinguish sensitizer-
more water-soluble gases induced occupational asthma from irritant-induced occupational asthma.
such as chlorine cause
more upper-airway irritation
and symptoms than less
water-soluble agents such
as nitrogen dioxide, which
cause more small airways
disease and alveolar
damage.
Table 4-24. Occupational Asthma

a
Characteristic Sensitizer-Induced Asthma Irritant-Induced Asthma
Latency period Present Absent
Onset Within months to years Within minutes or hours (< 24 h)
Causative agents Complete antigens: Fumes, gases, smoke, vapors

Inhaled proteins (high molecular
weight > 10 kd).
Incomplete antigens (haptens):

Chemicals (low molecular weight <
10 kd).
Examples of Complete antigens: Chlorine gas, aldehydes, alkaline
causative agents Animal and plant proteins, enzymes, dusts, bleaching agents, cleaning
flour, and cereals. products (ammonia), accidental
spills, smoke from fires
Incomplete antigens:
Isocyanates, anhydrides, metals,
drugs, dyes and bleaches, amines,
glues and resins, and wood dust.
Immunologic Yes No
Key Fact
response Reactive airways
dysfunction syndrome is a
Diagnosis Step 1: Confirm asthma diagnosis Step 2: Establish occupational type of irritant-induced
(spirometry and assessment for relationship occupational asthma that
airflow reversibility). Perform (serial peak flows, spirometry, occurs after exposure to
methacholine challenge test if no nonspecific bronchoprovocation high doses of a single
airflow reversibility is present after workplace exposure, skin tests, irritant.
(positive if 1-second forced immunoassay).
expiratory volume falls > 20% with ≤
4 mg/mL). Step 3: If diagnosis is still unclear,
then consider specific inhalation
challenge in a safe and controlled
fashion (considered a reference
standard, offered in a few
specialized centers).
Pathology Similar to asthma Acute: Epithelial sloughing and
hemorrhage.
Chronic: Epithelial cell regeneration;

increased basement membrane
thickness due to collagen
deposition.
Clinical Symptoms while at work; Precise timing of symptom onset is
presentation improvement on weekends or during common. Burning sensation occurs
vacations; rhinoconjunctivitis, in throat and nose.
contact dermatitis
a
The most common form of irritant-induced occupational asthma is reactive airways dysfunction
syndrome.
296 / CHAPTER 4
Work-Exacerbated Asthma
Work-exacerbated asthma is triggered by various work-related factors in those
with known preexisting or concurrent asthma.
HIGH ALTITUDE AND AIR TRAVEL
High Altitude
With high altitude, barometric pressure and partial pressure of inspired oxygen
decrease. Acclimatization is the compensatory response to high altitude and low
inspired oxygen that occurs in different organ systems to minimize the effects of
hypoxia.
The most important acclimatization changes in the body at high altitude are
Table 4-25. Physiologic Changes During Acclimatization to High Altitude
Adaptation Physiologic Change
Ventilation Hyperventilation, respiratory alkalosis
Brain Hypoxia-induced vasodilatation

Hypocapnia-induced vasoconstriction
Constant cerebral blood flow
Kidneys  bicarbonate excretion (normalization of pH); erythropoietin production
Heart ↑ blood pressure; ↑ cardiac output and heart rate (transient); ↓ SV

(bicarbonate diuresis and intravascular fluid shift)
Pulmonary vasculature Hypoxia-induced vasoconstriction (hypertension)
 hemoglobin production (increases oxygen-carrying capacity); red cell

Hematologic
mass increased in 10–14 d
Oxyhemoglobin Leftward shift due to alkalosis (improved binding at alveolar-capillary

dissociation curve membrane)
HIGH-ALTITUDE ILLNESS—Three conditions occur after rapid ascent to high

altitude where there is hypobaric hypoxia: acute mountain sickness, high-altitude
pulmonary edema, and high-altitude cerebral edema (Table 4-26). Figure 4-51
shows the altitudes at which these conditions commonly occur.
Table 4-26. Types of High-Altitude Illness
Type Mechanism Symptoms Treatment Prevention

a
Acute mountain Hypoxia- Headache, Mild: Conservative Acetazolamide,
sickness induced dizziness, Moderate-severe: dexamethasone
cerebral edema fatigue, malaise, Descent, oxygen,
anorexia, hyperbaric therapy,
nausea, acetazolamide,
b
vomiting, dexamethasone
insomnia
High-altitude Hypoxic Nonproductive Nonpharmacologic: Nifedipine,
pulmonary pulmonary cough, Oxygen, descent, tadalafil,
edema vasoconstriction progressive hyperbaric therapy sildenafil,
leading to dyspnea, pink Pharmacologic: dexamethasone,
capillary stress frothy sputum Nifedipine, salmeterol
fractures; tadalafil, or
results in sildenafil
noncardiogenic
pulmonary
edema
High-altitude More severe Headache, Descent Acetazolamide,
cerebral edema form of hypoxia- ataxia, Other: dexamethasone
induced confusion, Dexamethasone,
cerebral edema hallucinations, oxygen, hyperbaric
than acute stupor, coma therapy
mountain
sickness
a
Includes aspirin, acetaminophen, and ibuprofen for headache; promethazine and ondansetron for nausea and
vomiting; and avoidance of alcohol or other central nervous system depressants. bContraindicated in patients
with known sulfa allergies.
Air Travel
Figure 4-51 shows normal cabin pressure and usual flying altitudes for
commercial aircraft. At the usual cabin pressure, the fraction of inspired oxygen is
equivalent to 15.1% of the value at sea level.
Contraindications to air travel:

 Recent acute coronary syndrome (within 1–3 weeks) unless low or very low
risk
 Coronary artery bypass surgery within 2 weeks
Flash Card Q18
 Stroke within 2 weeks
 Severe sinusitis, large obstructing polyps, or nasal or facial surgery within 1–2 Which transcription factor
is responsible for most of
weeks the adaptive changes that
occur during
acclimatization?
298 / CHAPTER 4
 Any pneumothorax within two weeks

Key Fact  Hemoptysis
 Unstable chronic obstructive pulmonary disease, asthma, or a sea level oxygen
Factors associated with
very low risk in patients requirement > 4 L/min
with coronary artery  Single, uncomplicated diving within 12 hours, multiple dives, or a dive
syndromes include age < requiring more than one decompression stop within 2 days
65 years, ejection fraction
> 45%, first event, and no  Retinal detachment surgery with gas bubble
complications or further
planned interventions.
These patients may fly as
soon as 3 days after the
Most patients already receiving home oxygen supplementation need a higher flow
event. Low-risk patients, of oxygen at cruising altitude. Several regression equations predict whether PaO2
those with no symptoms will decrease to > 50 mm Hg while flying, but they have not been validated.
and ejection fraction >
40%, may fly as soon as
Another method of predicting in-flight PaO2 is the hypoxia inhalation test or high-
10 days after the event. altitude simulation test. A 15.1% oxygen concentration with nitrogen mixture is
given via a tight-fitting mask, and pulse oximetry is continuously recorded. An
arterial blood gas sample is obtained after 20 minutes. If oxygen saturation
remains 88% or greater and PaO2 is > 55 mm Hg, then no supplemental oxygen is
Key Fact required. If oxygen saturation is < 85% and PaO2 is < 50 mm Hg, then
Air travel should be
supplemental oxygen is recommended.
avoided until 7 days after
radiographic resolution of
pneumothorax.
Flash Card A18

Hypoxia-inducible factor-1α
stimulates vascular
endothelial growth factor,
which itself stimulates
angiogenesis and nitric
oxide synthesis. These Figure 4-51. Air travel, high-altitude, and diving-related conditions.
changes result in greater (Reproduced, with permission, from Isabel Bonenfant.)
blood flow and oxygen
delivery to tissues.
DIVING
Table 4-27 shows the most common complications of diving. Figure 4-51 shows
the complications of barotrauma, nitrogen narcosis, oxygen toxicity, and
decompression sickness.
Barotrauma
Barotrauma is the most common diving-related injury. It occurs when air-filled
cavities within the body do not equilibrate their pressure with the environment
after changes in ambient pressure. It can occur during both descent and ascent.
Decompression Sickness Key Fact

Air travel after diving
With descent, tissues become loaded with increased quantities of oxygen and should be postponed for at
nitrogen. On ascent, the tension of the gases in the tissues may exceed ambient least 12 hours in patients
who have dived once per
pressure and lead to liberation of free gas from the tissues in the form of bubbles. day. For those who have
The bubbles may cause vascular obstruction, rupture vessels, or compress the dived multiple times or
underlying tissue. This results in inflammation and clotting. have required
decompression stops,
flying should be postponed
for at least 48 hours.
Nitrogen Narcosis
Nitrogen narcosis results from the increased partial pressure of nitrogen in
nervous system tissue, occurring at depths > 100 ft (30.5 m). Alcohol, hypercarbia,
hypothermia as a result of cold water, and fatigue increase the risk of nitrogen
narcosis. Descent to depths > 300 feet (91 m) can result in loss of consciousness.
Flash Card Q19

In diving medicine, which
gas law explains the
pathophysiology of most
types of barotrauma?
Flash Card Q20

Which gas law explains the
pathophysiology behind
decompression sickness
and nitrogen narcosis?
300 / CHAPTER 4
Table 4-27. Complications of Diving Medicine
Type Mechanism Symptoms and Signs Treatment Prevention

Extra-alveolar air Barotrauma (during ascent) as Pneumomediastinum: Chest fullness, Pneumomediastinum:100% Avoid breath-holding
syndromes a result of alveolar rupture pleuritic chest pain, hoarseness, oxygen to promote reabsorption during ascent
(pneumomediastinum, Pneumomediastinum: Gas dysphagia; crepitation; Hamman’s Pneumothorax: Needle
a
pneumothorax, dissects along the perivascular sign decompression if tension; chest
arterial gas embolism) and then the bronchovascular Pneumothorax: Tension with tube insertion
sheath toward the mediastinum cardiovascular collapse; dyspnea, Arterial gas embolism:100%
Pneumothorax: Gas ruptures chest pain, tachycardia, hypotension, oxygen; hyperbaric oxygen
from the lung parenchyma into neck vein distention, tracheal therapy
the pleural space deviation, hyperresonance to
percussion, decreased breath sounds
Arterial gas embolism: Gas
bubbles into the pulmonary Arterial gas embolism: Myocardial
veins and then the systemic infarction, cerebral infarction with
circulation motor, sensory, or visual deficits
Ear and sinus Barotrauma (during descent) Ear (“squeeze”): Topical and systemic Middle ear pressure
barotrauma Ear: Eustachian tube occlusion Pain and pressure, hearing loss, decongestants, analgesics, equalization
leading to failure of the middle tympanic membrane rupture leading to antihistamines maneuvers: Yawn,
ear to equilibrate pressure vertigo, nausea, and disorientation swallow, jaw thrust,
head tilt
Sinus: Mucosal engorgement Sinus: Headache, epistaxis, sinus
and edema leading to blocked pain; pneumocephalus if occurs during
sinus ostia ascent
Flash Card A19 Flash Card A20

Boyle’s law. At a constant Henry’s law. At a constant
temperature, the volume of temperature, the amount of
a gas is inversely a gas dissolved in a liquid
proportional with the is directly proportional to
pressure to which it is the partial pressure of that
subjected. gas.
Table 4-27. Complications of Diving Medicine, continued
Type Mechanism Symptoms and Signs Treatment Prevention

Decompression Formation of gas bubbles within Malaise, fatigue, anorexia, headache Hydration, 100% oxygen, left Maintain adequate
sickness (the bends organs on ascent Type I (mild): Musculoskeletal (joint lateral decubitus positioning, mild hydration, avoid rapid
or caisson disease) pain), cutaneous (pruritus, erythema), Trendelenburg, hyperbaric oxygen ascent, avoid
and lymphatic (lymphadenopathy, therapy alcoholic beverages
edema, peau d’orange effect)
Type II (severe):Neurologic (spinal
cord paresthesias, weakness and
paralysis, memory loss, ataxia) and
pulmonary (chest pain, wheezing,
dyspnea, pharyngeal irritation, acute
right-sided heart failure)
Nitrogen narcosis Nitrogen dissolution in central Narcotic effects: Impairment of Ascent Avoid alcoholic
(rapture of the nervous system tissue intellectual performance, beverages
depths) hallucinations, confusion
a
Hamman’s sign is the auscultation of crackles or crepitation over the heart during systole.
Flash Card Q21

What condition
contraindicates hyperbaric
oxygen therapy?
302 / CHAPTER 4
HYPERBARIC MEDICINE
Hyperbaric medicine includes hyperbaric oxygen therapy and its uses to treat
different conditions. Hyperbaric oxygen therapy is inhalation of 100% oxygen
intermittently within a pressure treatment chamber where the pressure is increased
to > 1 atmosphere absolute.
Mechanisms
Hyperbaric oxygen therapy:
 Increases oxygen delivery by increasing its dissolution in plasma (Henry’s
law)
 Reduces the volume of gas bubbles (Boyle’s law)
 Replaces nitrogen within bubbles with oxygen, promoting their metabolism
within tissues
 Decreases the half-life of carboxyhemoglobin
 Promotes vasoconstriction, ameliorates ischemia-reperfusion inflammation,
facilitates angiogenesis and fibroblast proliferation, and increases neutrophil
bactericidal activity
Uses
Used to treat:
 Carbon monoxide and cyanide poisoning
 Decompression sickness and air embolism
 Acute traumatic or thermal injury
 Radiation injury
 Nonhealing ulcers, skin grafts, and wounds
 Clostridial myositis or myonecrosis
CARBON MONOXIDE, METHEMOGLOBINEMIA, THERMAL

INJURY, CYANIDE, OXYGEN, AND RADIATION TOXICITY
Table 4-28 shows the pathophysiology, clinical manifestations, and treatment of

carbon monoxide, methemoglobinemia, thermal injury, cyanide, oxygen, and
radiation toxicity.
Flash Card A21
Untreated pneumothorax
Table 4-28. Carbon Monoxide, Methemoglobinemia, Thermal Injury, Cyanide, Oxygen, and Radiation Toxicity
Condition Mechanism of Injury Signs and Symptoms Diagnosis Treatment

Carbon monoxide > 200 x greater affinity for binding Mild: Headache, malaise, Carboxyhemoglobin level > Give high-flow 100% oxygen via
exposure (odorless, iron in heme portion of nausea, dizziness 15% with exposure history nonrebreather mask
colorless, tasteless) hemoglobin than oxygen resulting Severe: Seizures, syncope, Give hyperbaric oxygen if:
in leftward shift of oxyhemoglobin coma, myocardial ischemia,  Unconscious
curve; impairs tissue oxygen arrhythmias, pulmonary edema,  Mental status changes
delivery lactic acidosis  Neurologic deficit
Delayed neuropsychiatric  End-organ ischemia
syndrome in up to 40%  CO-Hb > 25%
 CO-Hb > 20% in pregnancy
2+
Methemoglobinemia Ferrous (Fe ) state of iron in Cyanosis, chocolate brown Co-oximetry (peak Discontinue agent; give
3+
heme converted to ferric (Fe ) blood, saturation gap (difference absorbance of methylene blue if met-
that cannot bind oxygen; leftward between pulse oximetry and methemoglobin at 631 nm) hemoglobin level > 30%
shift of oxyhemoglobin curve, measured oxygen saturation in Avoid methylene blue in
impairing delivery blood gas) glucose-6-phosphate
Agents that increase formation dehydrogenase deficiency
of methemoglobinemia:
Dapsone, topical benzocaine or
lidocaine, inhaled nitric oxide,
nitroglycerin, nitroprusside,
chloroquine, metoclopramide
sulfonamides, aniline derivatives
Thermal injury Smoke inhalation with resulting Cough, stridor, wheezing, Fiberoptic laryngoscopy and Provide airway protection,
epithelial injury, airway edema, hoarseness, carbonaceous bronchoscopy supplemental oxygen
and bronchospasm sputum, blistering, and
oropharyngeal edema
Cyanide exposure Inhibits oxidative phosphorylation Headache, anxiety, confusion, Lactic acidosis, venous Give hydroxycobalamin; induce
(bitter, almond odor) by binding to ferric ion of vertigo, coma, seizures, hyperoxia (bright red venous methemoglobinemia (amyl
cytochrome oxidase a3; switch tachycardia, hypertension, blood) nitrite, sodium nitrite; avoid in
from aerobic to anaerobic arrhythmias, “cherry-red” color of concomitant carbon monoxide
metabolism, leading to acidosis lips poisoning), sodium thiosulfate
Drug most commonly
associated: Nitroprusside
304 / CHAPTER 4
Table 4-28. Carbon Monoxide, Methemoglobinemia, Thermal Injury, Cyanide, Oxygen, and Radiation Toxicity, continued
Condition Mechanism of Injury Signs and Symptoms Diagnosis Treatment

Oxygen exposure Free radical generation (superoxide Masqueraded by underlying indication No diagnostic Avoid high oxygen levels;
-
anion-O2 , hydrogen peroxide-H2O2, for oxygen testing available reduce FiO2 to lowest
-
and hydroxyl radical-OH ) with tolerable limit (≤ 0.5)
consequent cell membrane damage
and cell apoptosis or necrosis (diffuse
alveolar damage, fibrosis)
Drugs that stimulate free radical lung
injury: Bleomycin, amiodarone,
nitrofurantoin, mitomycin, and paraquat
Radiation exposure Cell breakdown leading to free radical Predisposing factors: Volume of lung Pneumonitis: Corticosteroids
generation; type II pneumocyte and tissue irradiated; dose (< 30 Gy OK; > Ground-glass (pneumonitis)
endothelial cell death with consequent 40 Gy radiographic changes; > 50 Gy opacities,
small vessel and capillary permeability, lung injury); fraction size, previous consolidation; may
hyaline membrane formation, and irradiation, concurrent chemotherapy occur outside
fibrosis (bleomycin, doxorubicin, taxanes, radiation field
gemcitabine, cyclophosphamide, Fibrosis: Volume
vincristine, mitomycin) or corticosteroids loss,
(may mask) bronchiectasis,
Pneumonitis: Within 6 mo; dyspnea, pleural thickening,
dry cough, fever, chest pain fibrosis
Fibrosis: 6 mo–2 y; asymptomatic, but
if severe then dyspnea, rarely
mediastinal fibrosis with superior vena
cava syndrome or constrictive
pericarditis
QUALITY, SAFETY AND ETHICS / 305
5 Quality, Safety, and Ethics

Diana H. Yu, MD
ETHICAL CONSIDERATIONS IN PULMONARY AND

CRITICAL CARE MEDICINE
Patients with advanced critical illness often lack decision-making capacity.

Surrogates are thus involved in making decisions to reflect patient preferences.
SURROGATE DECISION-MAKING
Three Hierarchically Ordered Standards
Standards to follow to guide surrogates to make decisions on behalf of the patient.
KNOWN-WISHES STANDARD—Patient clearly expressed a treatment preference

to a specific medical situation.
 Case example: patient completed advance directive that, in the event of

respiratory failure, he/she does not wish to receive mechanical ventilation to
prolong life
SUBSTITUTED-JUDGMENT STANDARD—Patient’s values and preferences are

known to the surrogates.
BEST-INTERESTS STANDARD—Patient’s values and preferences are not

known; surrogate makes decisions to serve patient’s best interests.
Flash Card Q1
True or false: A surrogate
can change a patient’s
advanced directive after
the patient becomes
incapable of making
medical decisions, based
on the surrogate’s own
preference.
306 / CHAPTER 5
CONCEPT OF SHARED DECISION-MAKING
Definition
Collaborative process among physicians, patients, and surrogates that serves as
the comprehensive ideal for end-of-life care and decisions. The purpose is to
focus on shared decision-making rather than the paternalistic approach of
unilateral physician decision-making.
Steps of Shared Decision-Making

INFORMATION EXCHANGE—Physician explains to the surrogate the disease
process, treatment options and prognosis. Surrogate shares patient’s values,
interests, and preferences for treatment.
DELIBERATION—Physician and surrogate together deliberate about the best

treatment option.
Key Fact
DECISION—Physician and surrogate together arrive at a shared agreement and
In the landmark case of
Karen Ann Quinlan, the
decision.
court affirmed that patients
and their surrogates have
the right to refuse any
unvantd medical reatment,
even if life-sustaining. WITHDRAWAL OF LIFE-SUSTAINING TREAMENT
Withdrawal of life-
sustaining treatment is not
legally considered killing,
but rather allowing the Ethical Principles
patient to die from the
underlying illness.
Three ethical principles help to shape the current United States consensus around
the withdrawal of life-sustaining treatment.
Key Fact  Withholding and withdrawing life support are equivalent

Many states allow for o Both philosophical and legal analyses emphasize no distinction between
physician-ordered decisions to withhold or to withdraw.
unilateral do not
resuscitate (DNR) in
 There is distinction between euthanasia and allowing death to occur.
conjunction with the local  The doctrine of “double effect” provides an ethical rationale for providing
ethics committee. relief of pain and other symptoms even when this may have the foreseen (but
Physicians are not
ethically obligated to
unintended) consequence of hastening death.
provide treatments that
they deem futile. ETHICAL CASE EXAMPLE—Administering high-dose opioids and sedatives
prior to ventilator withdrawal to make the patient comfortable may be acceptable
even if the medication hastens the unintended effect of death.
Flash Card A1
False
UNETHICAL CASE EXAMPLE—Administering high-dose opioids and sedatives Key Fact

when a patient has no clear signs of pain or distress at the request of family for a
Treatments with no
quick death. beneficial physiologic effect
are futile. Treatments with
unlikely benefit, beneficial
effect with extreme cost
and uncertain or
FUTILE AND POTENTIALLY INAPPROPRIATE TREATMENT controversial benefit are all
considered inappropriate
and inadvisable but not
futile.
Purpose and Definition
Treatments are defined as futile only when they will not accomplish their intended
goal.
FOUR CATEGORIES OF POTENTIALLY INAPPROPRIATE TREATMENT

 Treatments with no beneficial physiologic effect
 Treatments that are extremely unlikely to be beneficial
 Treatments that have a beneficial effect but are extremely costly
 Treatments that are of uncertain or controversial benefit Flash Card Q2
True or false: Withdrawal
PRACTICAL ASPECTS OF LIMITING INADVISABLE TREATMENT of and withholding life-
 Treatments that offer no physiologic benefit to the patient are futile and support measures are
ethically equivalent.
should not be offered.
 Treatments with unlikely, uncertain, or controversial benefit should be
explored with the patient/surrogate through a collaborative fair process rather Flash Card Q3
than through a unilateral decision by the physician.
True or false: If a patient is
 Treatments that have beneficial effects but are extremely costly should be paralyzed, you should
made available in a limited manner, governed by principles of distributive reverse the muscle
justice (see below). relaxant prior to starting
withdrawal of life-
sustaining treatments.
BRAIN DEATH AND WITHDRAWAL OF LIFE SUPPORT—Ethical issues
surrounding brain death have gathered national headlines recently with families
unwilling to accept brain death determined by multiple independent neurologic
examinations, including those ordered by the court. Flash Card Q4
True or false: Food and
 According to the Uniform Determination of Death Act, which has been fluids can be withheld
legally and ethically and
adopted in 45 states and recognized in the rest through judicial opinion, if the withdrawn if congruent with
patient meets neurologic criteria of brain death as defined by loss of the a patient’s goals of care.
functional activity of the brain stem and cerebral cortex, the patient is legally
deemed dead.
 Despite controversy, neither a living will nor family preferences are required
to withdraw life support in patients who meet neurologic criteria of brain Flash Card Q5
death, as they are legally dead. True or false: Advance
directives are not
portable—they are valid
only in the state where they
were written.
308 / CHAPTER 5
PRINCIPLES OF MEDICAL ETHICS
BASIC PRINCIPLES
Autonomy
Patient has the right to make an informed and uncoerced decision on medical
treatment.
INFORMED CONSENT
 Legally, adequate disclosure includes information on
o Diagnosis
o Nature and purpose of treatment
o Risk of treatment
o Treatment alternatives
LIMITATIONS OF AUTONOMY
 Decision has to be legal
o If patient requests euthanasia, the right to autonomy is denied, as
euthanasia is against the law
 Patient must have capacity to make informed decisions
o Must be able to communicate, understand relevant information, appreciate
situation and consequences, and rationally manipulate information
o Capacity may be gained or lost, requiring reevaluations as appropriate
Beneficence and Nonmaleficence

Flash Card A2
True Beneficence refers to actions that promote the well-being of others—physicians
should act in the best interest of the patient. The concept of nonmaleficence is
Flash Card A3
embodied by the phrase, “first, do no harm.” Conflicts arise when the
patient’s/surrogate’s perception of benefit differs from the physician’s view of
True; you always want to
be able to assess pain and
their own duty to beneficence and nonmaleficence.
discomfort
Flash Card A4
Justice
True
Refers to the fair distribution of limited health resources. As the physician’s
obligation is to advocate for the patient, the principle of distributive justice often
Flash Card A5 does not apply to bedside decision-making.
False
QUALITY IMPROVEMENT/PATIENT CARE
QUALITY IMPROVEMENT
Quality improvement is the scientific discipline that focuses on the structures, Key Fact
processes, and outcomes of health care delivery. Critical care medicine poses Studies suggest that
patients managed in a
unique challenges to effective health care delivery and thus is an ideal setting for closed ICU by physicians
implementing the discipline of quality improvement. with critical care training
have better outcomes than
patients managed in open
ICUs by generalists without
Understanding Quality in Health Care critical care training.
Quality health care is defined as care that is safe, timely, effective, efficient,
equitable and patient-centered. Three classic quality-of-care components—
structure, process, and outcome—serve as a useful framework for understanding
and improving the quality of health care.
COMPONENTS OF QUALITY-OF-CARE MODEL

 Structure: how we organize care
o Example: how the intensive care unit (ICU) is integrated into the hospital,
the size of the ICU, and whether the unit is open or closed
 Process: what we do or fail to do for patients and families
o Requires collaborative efforts of both clinical (data-driven) and
nonclinical processes (organizational management) Flash Card Q6
 Outcome: results we achieve True or false: Physicians
are not obligated to
continue providing
mechanical ventilatory
support after brain death.
CHECKLISTS
Flash Card Q7
Medical errors result in significant health care costs and deaths. The goal of
checklists is to reduce the frequency of errors. Error reduction correlates directly Obtaining informed
consent prior to a
with improvements in patient outcomes, patient safety, and efficacy of resource procedure is respecting
utilization. which of the four basic
principles of medical
ethics?
Flash Card Q8
What is The Belmont
Report?
310 / CHAPTER 5
Patient Outcome
EXAMPLES OF STUDIES WITH IMPROVED PATIENT OUTCOMES AND/OR

QUALITY OF CARE
 Checklist to assess eligibility criteria for mechanically ventilated patients
helped to predict successful weaning from the ventilator
 Intensive Care Delirium Screening Checklist identified patients more likely to
develop delirium
 Checklists improved effective transfer of spinal cord injury patients out of the
ICU
 Checklist for diagnosis of brain death
 Daily checklists of goals for critical care patients reduced average ICU length
of stay and ventilator days
 Checklist for central venous catheter placement and management reduced
catheter-related bloodstream infections
SLEEP DEPRIVATION, SHIFT SCHEDULES, AND

HANDOFFS
Patient Care and Outcome

The Harvard Work Hours, Health and Safety Group and others demonstrated that
Flash Card A6 interns working extended hours in traditional schedules demonstrated higher rates
of
True
 Serious medical and diagnostic errors
 Motor vehicle accidents
 Poor performance on clinical and nonclinical tasks, similar to being legally
Flash Card A7 intoxicated
 Needlestick injuries
Autonomy
In 2003, the Accreditation Council for Graduate Medical Education (ACGME)

restricted work hours to 80 hours per week for postgraduate trainees, and in 2011,
Flash Card A8 interns were restricted to shifts of ≤ 16 hours. Though studies have shown that
A statement created by the duty-hour reform reduces medical errors, a mortality benefit has not been shown,
National Commission for and there is increased concern regarding medical errors related to inadequate and
the Protection of Human frequent handoffs.
Subjects of Biomedical and
Behavioral Research that
summarizes basic ethical The most recent recommendations by the ACGME Joint Commission and the
principles and guidelines Institute of Medicine require a method to document patient handoff procedures as
for research involving
human subjects; three core well as a handoff curriculum during postgraduate training.
principles identified are
respect for persons,
beneficence, and justice.
For example, standardized, computer-assisted sign-outs have been shown to

improve continuity of care between inpatient teams.
STAFFING ISSUES
INTENSIVIST: PATIENT RATIO
Substantial indirect evidence from available literature suggests that physician:

patient ratios are a significant factor in ensuring quality care, training of future
physicians, and maintaining a stable workforce for ICUs.
Society of Critical Care Medicine Taskforce

RECOMMENDATIONS
 Appropriate staffing of ICUs with intensivists impacts the quality of patient
care, patient safety, education, and staff well-being
 Caseloads should allow for other activities such as teaching, non-ICU
duties,and administration
 Assessment of staff satisfaction, burnout, and stress should be part of the
objective data collected to assess appropriateness of ICU staffing
 Teaching institutions should objectively weigh tradeoffs between patient care
and education before expanding intensivists’ clinical duties
 In academic medical ICUs, a physician:patient ratio < 1:14 has a negative
impact on the quality of patient care, education, and workforce stability
NIGHTTIME IN-HOUSE INTENSIVISTS
A recent randomized trial in an academic medical ICU of the effects of nighttime

staffing with in-hospital intensivists compared with nighttime coverage by
daytime intensivists available for consultation over the phone revealed that
nighttime in-hospital intensivist staffing did not improve patient outcomes (length
of stay in the ICU, length of stay in the hospital, and in-hospital mortality).
This was in contrast to previous studies showing that ICUs with low-intensity or
non-intensivist daytime physician staffing benefited from in-hospital intensivists
at night.
312 / CHAPTER 5
PHYSICIAN SUPERVISION OF TRAINEES AND PHYSICIAN

EXTENDERS
The supervising attending physician is responsible and liable for the patient care
provided by physician extenders, such as nurse practitioners, physician assistants,
and resident physicians.
PHYSICIAN WELL-BEING/IMPAIRMENT
PHYSICIAN IMPAIRMENT
Physician impairment by substance abuse continues to be a significant issue for

the health care system. It has been identified as a potential source of medical
errors and liability, though little research on resident substance abuse has been
published. Physicians have legal and ethical obligations to assist and report
impaired colleagues.
Research Studies
PUBLISHED DATA
 Favorable prognoses for substance-impaired physicians with early diagnosis
and intervention
 Certain risk factors, such as family history of substance abuse, and opioid use
with concurrent diagnosis of another psychiatric disease, may predict higher
rates of relapse
 In a survey conducted among 3000 American resident physicians with a 60%
response rate, heavy substance use patterns were not observed. However,
higher rates of alcohol and benzodiazepine use were reported compared to the
general population; these were associated with impairment at later stages in
the physician’s career
 A cross-sectional mail survey of 1000 randomly selected practicing physicians
in the U.S. revealed that physicians would be more likely to report physicians
involved in substance abuse than to report those who were emotionally or
cognitively impaired
EPIDEMIOLOGY AND STATISTICS / 313
6 Epidemiology and Statistics

Nazir Ahmad Lone MD MPH
EPIDEMIOLOGY
Epidemiology is the scientific approach to the distribution and determinants of

health, disease, and injury in a population.
Aims of modern epidemiologic research:

 Plan and evaluate the strategies to prevent illness and disease
 Guide disease management
 Identify appropriate public health interventions
Clinical Epidemiology
The study of illness outcomes by observing and comparing events in a group

of individuals with shared characteristics. The shared characteristic of a group
may be a symptom, sign, illness, diagnoses, prognosis, or treatment. Clinical
epidemiology also involves the methodology for evaluating diagnostic tests
and therapeutic modalities used in clinical practice. The most common
epidemiologic terms and measures of health and disease are ratio, proportion,
and rate (Table 6-1). Key Fact
The aim of modern
Clinical epidemiology methods include: epidemiology is to
 Measures of disease occurrence: Incidence and prevalence understand the causal
pathways of disease in a
 Measures of disease outcomes: Mortality and morbidity population and to identify
 Measures of validity or performance of diagnostic and screening tests: appropriate public health
interventions.
Sensitivity, specificity, predictive values, and likelihood ratios
 Measures of disease association: Odds ratio (OR) and relative risk (RR)
314 / CHAPTER 6
Table 6-1. Common Epidemiologic Terms and Measures of Health and

Disease
Term Definition Annotation Properties Examples
Ratio Relationship a/b Always more than 0 Odds of disease =
characterized p/(1 - p)
a and b are May or may not have
by dividing two
frequencies of units p = proportion of
numbers
some event people with disease;
Numerator and
1 - p = proportion of
denominator do not
people without
have to be mutually
disease
exclusive
OR = odds of disease
in population A/odds
of disease in
population B
OR has no units
Proportion Ratio in which a/(a + b) Values between 0 Proportionate

the numerator and 1 mortality
is a subset or
Always a ratio No. affected/total
part of the
population
denominator No units
No. of deaths due to
COPD/total no. of
deaths × 100
Prevalence rate is a
proportion
Rate Proportion or a a*/(a + b) Rate is always a ratio Percent of all deaths

ratio, where due to COPD = no. of
a* = frequency Those in the
time is always COPD related deaths
of events denominator are "at
in the in calendar year/total
during a certain risk" of being in the
denominator no. of deaths in that
time period numerator
calendar year × 100
Calendar time
a + b = no. at The denominator is
period is same Incidence is a rate
risk of the expressed in person-
in both the
event during time units such as
numerator and
that time period person-hours or
denominator
person-years
COPD, chronic obstructive pulmonary disease; OR, odds ration; RR, relative risk
MEASURES OF DISEASE OCCURRENCE
Incidence and Prevalence

Prevalence is a measurement of all individuals affected by a disease at a
particular time, whereas incidence is a measurement of the number of new
individuals at risk of developing a disease during a particular period of time
(Figure 6-1).
Figure 6-1. Graphic display of dynamics of population distribution in terms of

prevalence, incidence, and mortality in a hypothetical population.
INCIDENCE RATE (IR)—Rate at which new cases occur in a calendar

Key Fact
year/total population in the same year. Incidence and IR are used
interchangeably. The denominator in IRs is usually person-time. IRs provide a direct
measure of the rate at
which new cases occur in
IR = new cases/person-years the population.
Person-years = (no. of subjects) × (years of follow-up per subject) Key Fact

IRs are calculated by
 Example: Pack-years of smoking = (no. of cigarettes or packs) × (years of dividing the total number of
smoking) events in a specified time.
PREVALENCE RATE—An estimate of the proportion of individuals in a

population who have the outcome or have experienced the event of interest.
Prevalence rate at a specific point in time is point prevalence, whereas
prevalence rate during a particular time period such as a year is a period
prevalence.
Prevalence rate = no. of individuals with disease or health condition/

no. of individuals in that population at a specified time = sick/(sick + well)
316 / CHAPTER 6
 Example: No. of elderly > 75 years of age with asthma/no. of elderly > 75
years at a specified time
PROPERTIES OF PREVALENCE
Key Fact
 Typically derived from cross-sectional surveys
Prevalence = incidence ×
duration.  Describes the burden of illness in a population
 Can be used to gather information about the impact of a disease in a
population and help in resource allocation
 Prevalence and incidence are related: Prevalence = incidence ×duration;
Key Fact
higher incidence and or longer duration of disease results in higher
Higher prevalence does prevalence (Table 6-2)
not necessarily imply an
increased risk of the health o Example: Upper respiratory tract infection has high incidence but short
event or outcome, but
rather it may indicate long
duration thus has low prevalence, whereas chronic lung disease has
duration of disease. low incidence, long duration, and high prevalence
Table 6-2. Factors Influencing Prevalence Estimate

Key Fact
Increased Prevalence Decreased Prevalence
Lower prevalence does not
necessarily imply low Longer duration of disease Shorter duration of disease
incidence, but rather it may
represent a rapidly fatal Prolonged survival without cure High CFR from disease
disease or a short duration
of illness.
Increased incidence of new cases Decreased incidence of disease
Immigration of new cases and susceptible In-migration of healthy people or out-

people or out-migration of healthy people migration of disease
Improved diagnostics and better reporting Improved cure rate of disease
CFR, case-fatality rate
MEASURES OF DISEASE OUTCOMES
Mortality and Morbidity

Two common measures of disease outcome are mortality and morbidity. All
deaths from all causes in 1 year among the entire population in that year is
called crude mortality. Mortality approximates incidence rate (IR) when case-
fatality rate (CFR) is high and or duration of the diseases is short (poor
survival).
INDICES OF MORTALITY— Annual mortality rate from all causes (per 1000
population) = d × 1000/N, where d = total number of deaths from all causes in
Key Fact
1 year and N = number of persons in the population at midyear.
Mortality rate approximates
Cause-specific mortality rate (per 1000 population) = deaths from a particular incidence rate when CFR
disease in a given year × 1000/population at midyear is high and or duration of
the diseases is short (e.g.,
 Example: Annual mortality from chronic obstructive pulmonary disease H1N1).
(COPD) (per 100 population) = no. of deaths from COPD in 1 year ×
1000/no. of persons in the population at midyear
CFR is a proportion and measure of the severity of that disease.
CFR (%) = no. of individuals dying after disease onset or diagnosis during a
specified period × 100/no. of individuals with specified disease
Years of potential life lost is a measure of premature mortality and is used to

quantify social and economic loss owing to premature death. It is estimated by
the average time a person would have lived had he or she not died
prematurely.
MORBIDITY—A measure of sickness and refers to a disease, illness, injury, or

disability in a population. The main methods for gathering morbidity data are
through surveillance systems and sample surveys.
MEASURES OF VALIDITY OR ACCURACY OF

DIAGNOSTIC AND SCREENING TESTS
A screening test identifies an occult disease among asymptomatic individuals.

A diagnostic test identifies the presence or absence of a disease. Diagnostic
tests are generally performed after a positive screening test to establish a
definitive diagnosis.
Examples:
 Low-dose computed tomography (CT) scans for detection of lung cancer
are screening tests
 Positron emission tomography (PET) CT scans to screen for metastatic
disease are also screening tests
 Mediastinoscopy or fine-needle aspiration with endobronchial ultrasound
performed after screening imaging are diagnostic tests Flash Card Q1
In a population of 1000
A gold standard test is the best available method, procedure, or measurement people in which 50 are sick
that confirms the presence or absence of disease. The performance of a new with H1NI flu illness and 25
die from H1NI in 1 year,
what is the mortality rate?
318 / CHAPTER 6
test is compared to the gold standard test to determine the sensitivity and
specificity of the new test.
Sensitivity and Specificity
SENSITIVITY—The probability that a test result will be positive when the

disease is present. It is also described as the ability of the test to identify
correctly those who have the disease, or the true positive rate. Using a
standard 2 × 2 table, the sensitivity is calculated as a/a + c (Table 6-3).
Table 6-3. Mechanics of 2 × 2

Disease Present Disease Absent
Test positive a = true positives b = false positives
Mnemonic Test negative c = false negatives d = true negatives
SnOut —A high Sensitivity a + c = all individuals with b + d = all individuals without

test has few false disease disease
negatives and effectively
rules Out a disease.
SpIn—A high Specificity

test has few false positives
SPECIFICITY—The probability that a test result will be negative when the
effectively rules In a
disease)
disease is not present. It is also described as the ability of the test to identify
correctly those who do not have the disease, or the true negative rate. Using
the 2 × 2 table, the specificity is calculated as d/b + d.
Both sensitivity and specificity are fixed characteristics of a test, but changing
the positive cutoff value for a test will yield different sensitivities and
specificities. Decreasing the cutoff value increases sensitivity (true positives)
but also creates more false positives. Increasing the cutoff decreases
sensitivity but increases specificity (true negatives) and also results in more
false negatives.
As an example, decreasing the cutoff values for d-dimer will increase

sensitivity (i.e., identify more true positives [with disease] as well as increase
the number of false positives [who do not have disease]).
Flash Card A1
Mortality rate from H1NI in
that year = 25/1000
= 0.025 or 2.5%; case rate
for H1NI disease = 25/50 =
0.5 or 50%
Predictive Values
POSITIVE PREDICTIVE VALUE (PPV)—Probability that the disease is

present when the test is positive. It is also described as the proportion of Key Fact
patients who test positive who actually have the disease. A standard 2 × 2 table uses
rows to calculate predictive
 Using the 2 × 2 table (Table 6-3), the PPV is calculated as a/a + b values, and columns for
sensitivity and specificity.
NEGATIVE PREDICTIVE VALUE (NPV)—Probability that the disease is not
present when the test is negative. It is also described as the proportion of
patients who test negative who are actually free of the disease.
Key Fact
 Using the 2 × 2 table (Table 6-3), the NPV is calculated as d/c + d
Sensitivity and specificity
and fixed characteristics of
RELATIONSHIP OF DISEASE PREVALENCE TO PREDICTIVE VALUE— the test. PPV and NPV
An increase in disease prevalence increases the PPV of a test. That is, unlike change based on the
sensitivity and specificity, PPV and NPV are not fixed characteristics of a test. prevalence of disease in a
given population.
Key points:
 High disease prevalence increases the PPV of a test
 Low disease prevalence increases the NPV of a test
 Increasing the specificity of a test increases the PPV and NPV of the test Key Fact
 Changing the sensitivity of a test (assuming no change in the specificity) Sensitivity, specificity,
PPV, and NPV as well as
does not impact the predictive values disease prevalence are
expressed as percentages.
Likelihood Ratios
Likelihood ratio is the likelihood that given test result would be expected in a
patient with the target disorder compared with likelihood that a same result
would be expected in a patient without the target disorder.
POSITIVE LIKELIHOOD RATIO (Lr+)—Ratio between the probability of a

positive test result given the presence of the disease and the probability of a
positive test result given the absence of the disease.
Lr+ = true positive rate/false positive rate = sensitivity/(1 - specificity)
NEGATIVE LIKELIHOOD RATIO (Lr-)—Ratio between the probability of a

negative test result given the presence of the disease and the probability of a
negative test result given the absence of the disease.
 Example: LR- = false negative rate/true negative rate = (1 – sensitivity)/
specificity
320 / CHAPTER 6
Other Measures of Performance of Screening and

Diagnostic Tests
RECEIVING OPERATOR CHARACTERISTICS (ROC) CURVE
 Used to estimate the discriminative power of a test
 Graphic plot of sensitivity on the y axis against (1 - specificity) on the x
axis for varying values of the threshold (Figure 6-2)
 A perfect diagnostic test has an AUC of 1.0, whereas a nondiscriminatory
test has an AUC of 0.5
VALIDITY—Ability of a test to detect which individuals have the disease and

which do not have the disease.
RELIABILITY/REPEATABILITY—Consistency of results under repeated

measurements by the same individuals under the same conditions.
NUMBER NEEDED TO SCREEN—Number of individuals needed to be

screened for a given duration to prevent or detect one outcome.
1-Specificity
Figure 6-2. Hypothetical ROC curves representing the diagnostic accuracy of
the gold standard. Line A, AUC = 1; curve B, AUC = 0.85; and a diagonal line
corresponding to random chance (line C, AUC = 0.5). As diagnostic test
accuracy improves, the ROC curve moves toward A, and the AUC
approaches 1.
Observational Bias in Screening Tests
Screening studies that report survival as an outcome are susceptible to

observational bias that undermines the validity of a screening test. Three types
of these biases occur when a disease is diagnosed by screening in the
asymptomatic period. Introduction of these biases misrepresent that early
diagnosis appears to improve survival.
 Lead-time bias
 Length-time bias
 Overdiagnosis bias
LEAD-TIME BIAS—Reflects the observed lengthening of survival time due to

earlier diagnosis by a screening test without any actual prolongation of
survival. Screening identifies disease during a latent period before it becomes
symptomatic. If survival is measured from time of diagnosis, screening will
always improve survival, even if treatment is ineffective (Figure 6-3).
Figure 6-3. Lead-time bias reflected by an increased survival time because of

early diagnosis by screening test.
(Reproduced courtesy of the National Cancer Institute.)
LENGTH-TIME BIAS—Reflects the increased likelihood of identification of

indolent tumors by intermittent screening as compared to fast-growing or
aggressive tumors that can be missed due to their rapid progression (Figure 6-
4).
Length-time bias occurs because:

 Screening identifies disease-prevalent cases
 Prevalence = incidence × duration
 Slowly growing tumors have greater duration in presymptomatic phase
and have greater prevalence; therefore, cases detected by screening will be
disproportionately those that are slow growing
322 / CHAPTER 6
Screening tends to
detect more indolent
cancers.
Figure 6-4. Length-time bias observed by intermittent screening of indolent

tumors that grow more gradually from the detectable stage to the onset of
clinical symptoms.
OVERDIAGNOSIS BIAS—Reflects the identification of disease by a

screening test that does not affect the patient’s life in the absence of screening
(Figure 6-5). Also called pseudodisease (i.e., condition that looks just like the
disease, but never would have concerned the patient).
For example, lung cancer screening may detect lung nodules that would never
cause clinical disease.
Figure 6-5. Overdiagnosis bias observed by diagnosing that is not cause of

mortality.
BIOSTATISTICS
Biostatistics refers to the application of statistical tools and methods to

address and analyze problems in health and medicine.
This section will briefly cover:

 Study designs
 Data distribution and types of variables
 Common statistical analytic tools (measures of association)
 Statistical significance
 Issues of interpretation of study results
Study Designs
Two main types of study design are used to determine whether there is an
association between an exposure and an outcome (i.e., observational studies
and experimental studies). The basic principles and classification of types of
clinical study design are shown in Figure 6-6.
In observational studies, the researchers collect information about the sample

population but do nothing to alter the exposure, whereas in experimental
studies, the researcher alters or manipulates the exposure and studies outcome.
Both observational and experimental studies can be further classified as

prospective or retrospective. In prospective studies, data are collected forward
in time after the initiation of study, whereas in retrospective studies, data are
collected from events that have already occurred from existing sources like
hospital records.
The main types of study designs and advantages and disadvantages of each are
given in Table 6-4.
324 / CHAPTER 6
Figure 6-6. The basic principles and classification of types of clinical study
design. RCT, randomized controlled trial
Table 6-4. Advantages and Disadvantages of Study Designs

Study Design Advantages Disadvantages
Case-control studies Quick and inexpensive Reliance on recall or records to
Feasible for very rare disorders or determine exposure status (recall
those with long lag between bias)
exposure and outcome Selection Bias
Fewer subjects needed than Selection of control groups often is
cross-sectional studies difficult
Usually generates OR
Cohort study Ethically safe; easier and cheaper Difficult to identify controls and
than RCT blinding is difficult
Matching is possible Randomization not present
Can establish timing and Needs large sample sizes or long
directionality of events follow-up for rare disease
Eligibility criteria and outcome Expensive to conduct
assessments can be standardized
Reduced recall error
Useful for generating RR
Cross-sectional survey Quick, cheap, simple, and Establishes association at most,
ethically safe and not causality
Population-based Recall bias susceptibility
Best for quantifying the Confounders may be unequally
prevalence of a disease or risk distributed
factor
RCT Unbiased distribution of Expensive volunteer bias
confounders Ethically problematic
Usually blinded Loss of follow-up
No bias in the assignment
process and randomization
facilitates statistical analysis
Follow-up usually is complete in
both groups
OR, odds ratio; RR, relative risk; RCT, randomized controlled trial.
CASE-CONTROL STUDY
 Retrospective
 Certain outcome or disease (cases) and controls (without the outcome or
disease) are selected; then information is collected backward to see who
has been exposed to the risk factor
 Example: Veterans with and without lung cancer are selected, then data
for prior exposure to agent orange are collected
COHORT STUDY
 Prospective
 Considered gold standard in observational epidemiology
326 / CHAPTER 6
 Group of subjects exposed to a risk factor and not exposed to the same
risk factor are followed over time; researcher does not allocate the
exposure
 Example: A group of fellows enrolled in 2010 are followed to see if there
is a reduction in central line complications by using ultrasound for line
placement; Framingham Heart Study and Nurses’ Health Study are
cohort studies
CROSS-SECTIONAL STUDY
 Exposure and outcomes are measured at the same time in a defined
population
 Example: A sample of nonsmoking veterans (population) are asked if they
were exposed to burn pits (exposure) and have been diagnosed with
obstructive lung disease (outcome)
CLINICAL TRIAL/RANDOMIZED CONTROLLED TRIAL (RCT)

 Prospective study
 An experimental design in which subjects are allocated to
treatment/intervention or control/placebo groups by a random mechanism
called randomization. Researcher does not influence who gets the
exposure or treatment.
Types of RCTs:
 Cluster randomized trial: Randomize entire groups rather than individual
subjects to treatment
o Example: A randomize hospitals and intervene with antibiotic cycling
to study outcomes of health care–associated infection
 Factorial randomized design: Randomize two or more treatments/
interventions simultaneously in all possible combinations
o Example: Effect of salmeterol + fluticasone vs. tiotropium +
salmeterol + fluticasone vs. salmeterol alone on COPD exacerbations
 Crossover design:
o Randomly allocate each patient to a sequence that includes each
treatment so that each patient can act as their own control for treatment
o Two or more treatments are given consecutively
o Can be limited by the potential for carryover of pharmacologic effect
that may alter the response to next treatment
o The washout period may be lengthy and crossover cannot be used for
treatments with permanent effects
SYSTEMATIC REVIEW—An evidence-based resource produced after

reviewing published and unpublished studies and combining the information
of all relevant studies to address a particular clinical question.
META-ANALYSIS—Type of systematic review that uses systematic methods

to combine qualitative and quantitative study data from several selected
studies. The meta-analysis has greater statistical power than any single study
due to increased sample size and greater diversity among subjects. The results
are more generalizable but can be flawed by heterogeneity of study population
and skewness of study results secondary to publication bias. Forest plots are
diagrammatic representations of meta-analyses.
In evidence-based medicine, a formal hierarchy considers the RCT and

collections of RCTs as systematic reviews or meta-analyses as the highest
form of evidence, as shown in Figure 6-7.
Key Fact
In observational studies
nothing is done to alter the
exposure, whereas
experimental studies entail
manipulation of exposure
and randomization of
subjects to treatment
groups.
Figure 6-7. Example of hierarchy of research design as per evidence-based

medicine. Review of randomized controlled trials (RCTs) includes systematic
reviews with or without meta-analysis.
(Reproduced, with permission, from Concato J. Study Design and Evidence in Patient-oriented Research.
Am J Respir Crit Care Med. 2013; 187: 1167–72. doi:10.1164/rccm.201303-0521OE)
328 / CHAPTER 6
DATA DISTRIBUTION AND TYPE OF VARIABLES
The distributions of data in a given population can be symmetric or

asymmetric (Figure 6-8).
Symmetric clustering of values around a central location is called the normal

distribution and is represented by a bell-shaped curve or the normal curve
(Figure 6-8A). Skewness on the other hand refers to asymmetry of the
distribution (Figure 6-8B–C).
The distribution with an asymmetric tail extending to the right and a central
location to the left is referred to as positively skewed or skewed to the right,
whereas a distribution with an asymmetric tail extending to the left and central
location to the right is referred to as negatively skewed or skewed to the left.
Figure 6-8. Symmetric (A) or bell-shaped distribution. Asymmetric or skewed

distribution (B, C). In positive skewness, mean is greater than median; in
negative skewness, mean is less than median.
Measures of Central Tendency
Measures of central tendency denote clustering of observation around the

center. The commonly used methods to calculate these characteristics of a
frequency distribution are mean, median, and mode.
MEAN—Sum of all observations divided by count of total number of

observations. Used for continuous variables. Easily distorted in a skewed data
set.
MEDIAN—Middle value among the ordered values above and below which
50% of the observations fall. Used for a continuous variable when the
distribution is not normal. Not affected by extreme values so it is robust. If the
number of values is odd number, the middle is the median, whereas in even
number of values, the median is the average of the middle two numbers.
MODE—Most frequent observation in the data set. Used for discrete variable.
Mode is also robust to outliers.
STANDARD DEVIATION (SD)—Measures the spread of distribution values.

Key Fact
The SD will be lower if all observed values are tightly grouped, and higher if
values are more spread out. Two-thirds of all
observations fall within 1
 If values are normally distributed, then68% of values are within 1 SD of SD of the mean, and
the mean roughly 95% of all
observations will fall within
 95% are within 2 SDs of the mean ± 2 SD in a normally
 95% are within ± 1.96 SDs of the mean distributed population.
Variable Types
Variables are measurable quantities that vary among individuals and can be
quantitative (numeric) or qualitative (categoric) in nature.
QUANTATIVE (NUMERIC) VARIABLE—Data can take on a whole range of

values.
 Continuous variable: No gaps in the values and can be infinite (e.g.,
Key Fact
weight)
 Discrete: Gaps in the values and take only finite number of values (e.g., Continuous data can be
turned into categoric data
number of beds) (e.g., blood sugar values
into normoglycemia,
QUALITATIVE (CATEGORIC) VARIABLE—Data fall into few defined prediabetes, glucose
intolerance, and diabetes).
categories.
 Ordinal: Have implicit ranking (e.g., Likert scales)
 Nominal: Descriptive and cannot be ordered (e.g., smoker and nonsmoker)
330 / CHAPTER 6
MEASURES OF ASSOCIATIONS
RR and OR
RR (Table 6-5)
 Ratio of risks
 Calculated by risk in exposed divided by risk in nonexposed, or ratio of
risk in the treated group to the risk in the control group
 Used in cohort study
RR = (a∕a + b)/(c/c + d)
INTERPRETATION OF RR
 RR = 1 means no association
 RR > 1 means positive association, meaning risk in exposed is greater than
in nonexposed
o Example: Smokers are at high risk of developing lung cancer (harm,
causation, association)
 RR < 1 means risk in exposed is less than that in nonexposed
o Example: Daily exercise protects against heart disease (protective)
OR (Table 6-5)
 Ratio of odds of disease in the exposed group to the odds of disease in
nonexposed group
 Used for both cohort and case-control studies
OR CALCULATION
 Odds of disease in exposed = a/b
 Odds of disease in not exposed = c/d
 OR of disease in exposed = a/b/c/d = ad/bc
 OR of exposure in diseased = a/c/b/d = ad/cb
INTERPRETATION OF OR
 OR = 1 means no association of exposure with disease or disease with
exposure
 OR > 1 means exposure or disease is positively related (e.g., odds of
developing lung cancer is higher in smokers or odds of smoking exposure
is higher in lung cancer patients) (harm , causation , association)
 OR < 1 means exposure or disease is negatively related 9 (e.g., odds of
developing heart disease is lower in individuals who perform daily
exercise) (protective)
OR approximates RR if:
 The cases and controls are representative of the general population
(sampled population) with regard to disease and history of the exposure
 If the disease under study is rare and incidence of the disease is low
Table 6-5. 2 ×2 Table for RR and OR

Not Incidence/ Risk Odds of
Diseased Diseased Total of Disease Disease
Exposure a b a+b a ∕(a + b) a/b (odds of
(incidence in disease in
exposed) exposed)
No. Exposed c d c+d c/(c + d) c/d (odds of
(incidence in disease in
nonexposed) nonexposed)
Odds of a/c b/d
Exposure
Other Commonly Used Statistical Methods
t-TEST—Measure of statistical difference and is used to compare the means

from two different samples in a normally distributed data.
 Two-sample unpaired t-test: Used to compare the average mean of two
independent samples
 One-sample t-test: Used to determine if there is a difference between a
known population mean and a sample mean
 Paired t-test: Used if the individuals in the group are paired
ANALYSIS OF VARIANCE (ANOVA)—Statistical test to determine if there

are significant differences between variances of multiple samples. It is similar
to the t-test for two samples. ANOVA compares the variation within each
sample to the variation between the samples.
CHI-SQUARE TEST—Statistical test of the association between two categoric

variables from two or more independent groups in the form of 2 × 2 tables. It
compares the frequency distribution from observed data to the frequency
distribution that would be expected under the null hypothesis of no
association.
 Chi-square test tells us the "goodness to fit" between observed and
expected data.
CORRELATION AND REGRESSION—Used to study relationship between

two random variables.
 Regression analysis is used to estimate the influence of one or more
independent variables and predict the value of the dependent variable;
allows good control of confounders.
 Types of regression based on the type of data include:
332 / CHAPTER 6
o Logistic regression for a discrete dependent variable

o Linear regression for a continuous dependent variable
o Poisson regression for certain types of count data
o Survival analysis for a continuous dependent variable that records the
time to an event; Kaplan–Meier is a graphic representation of this
analysis
 Correlation is a statistical measure of the association between two
variables but does not necessarily imply causation; scatter plot is the
graphic representation of correlation
PEARSON’S CORRELATION COEFFICIENT—Statistical measure of the

association between continuous numeric variables that shows how closely two
numeric variables lie in a linear association or straight line. It is denoted by r.
r can range from -1 to +1.
r = -1, perfect negative linear relationship
r = 1, perfect positive linear relationship
r = 0, no linear relationship or complete absence of relationship
STATICAL SIGNIFICANCE
Hypothesis Testing, p values, Confidence Intervals (CIs)
Steps of hypothesis testing:

 State null hypothesis and alternative hypothesis
 Pick a significance level () of the test
 Select test procedure, collect data, and calculate p value
 If p value < , reject the null hypothesis
NULL AND ALTERNATE HYPOTHESIS—Null hypothesis is a statement of

no effect or no association, whereas the alternative hypothesis is a statement
of true difference. The goal of research is to reject the null.
Key Fact p VALUES—Statistical significance is the probability that the results observed
p-Values do not indicate in a study may have been just a chance finding and is denoted by p value.
the strength or direction of Statistical significance depends on the sample size and the size of the
the association, and they
depend on sample size difference observed (effect size).
and effect size.  Arbitrarily set at 5%, or p < 0.05; or 1% , p < 0.01
 The smaller the p value the more significant the result, meaning that null
hypothesis is unlikely to be true
 p Value < 0.05 means only 5% chance of detecting a difference in effect
size if there is no actual difference in the population
CI—Range within which the true value of a parameter lies. Key Fact
 CI is constructed around a parameter that has a specified probability of
Precision of CI depends on
including the true population value of that parameter sample size and variation
 The specified probability is usually set at 95% and is called the confidence (larger sample sizes and
level; a 95% CI indicates 95% certainty that the interval contains the true less variation will have
narrower CIs, indicating
value of the expected outcome in the entire population more precision in results
 CIs can be built across many summary statistical estimates like means, and vice versa).
proportions, and ORs
 Precision of CI depends on sample size and variation (larger sample sizes
and less variation will have narrower CIs, indicating more precision in
results and vice versa)
Power and Type of Errors
The outcomes of hypothesis testing have a chance to fall into two types of
errors which depends on the power of the study.
TYPE I ERROR AND TYPE II ERROR

 Type I error ():
o Rejection of null hypothesis when the null hypothesis is true
o In diagnostic studies, it is the false positive rate
 Type II error (β):
o Accepting the null hypothesis when it is false
o In diagnostic studies, it is the false negative rate
POWER—Probability of finding a true difference when the difference really Key Fact
exists or the probability of correctly rejecting the null hypothesis when it is Power is directly
false proportional to sample
 Calculation: 1 - the probability of a type II error size. Smaller sample size
lead to type II errors.
o Example: If the probability of a type II error in a study is 5%, the
statistical power of the study is 95%
 80% to 90% power is considered good
ISSUES IN INTERPRETATION OF STUDY RESULTS
Causal Associations, Bias, and Confounding
The association of a risk factor could be direct or indirect, and may or may not
have cause–effect relationships. The observed results could be influenced by
chance, bias, and confounding.
334 / CHAPTER 6
The Bradford-Hill criteria were detailed by Sir Austin Bradford Hill in 1965
to assess evidence of causation.
 Strength: Stronger associations more likely to be causal

 Consistency: Consistent findings on replication studies by different
persons in different places with different samples strengthen the likelihood
of an effect
 Specificity: Causation is likely if a very specific population at a specific
site has disease with no other likely explanation; the more specific an
association between a factor and an effect, the bigger the probability of a
causal relationship
 Temporality: The exposure has to precede the effect
 Biologic gradient: Dose–response relationship should exist between
exposure and outcome; however, in some cases, the mere presence of the
factor can trigger the effect, and in other cases, an inverse proportion is
observed, where greater exposure leads to lower incidence
 Plausibility: A biologic mechanism consistent with knowledge between
cause and effect is helpful
 Coherence: Coherence between epidemiologic and laboratory findings
increases the likelihood of an effect
 Reversibility: Effect of removing the exposure should lower risk
 Experiment: Occasionally, it is possible to appeal to experimental
evidence
 Analogy or alternate explanations: Effect of similar factors may be
considered
BIAS—Systematic error in the design, conduct, or analysis of a study that

Key Fact results in an erroneous estimate of an association between exposure and
Bias is a measure of outcome.
systematic error.
Types of bias:
 Selection bias: Errors in participant selection or bias in assignment of
participant (e.g., nonresponse bias or exclusion bias)
 Information bias: Errors in data collection and poor categorization in
exposure or outcome status
 Recall bias: Poor recall or memory of exposure status in case-control
studies
 Interviewer bias: Results obtained differently in the diseased vs. control
groups by an unblinded interviewers
 Publication bias: Preferential publication of striking results in small
studies
CONFOUNDING—Erroneous study results because of a confounder that

threatens the internal validity. Confounder is a variable that can cause or
prevent the outcome of interest independently and is not an intermediate
variable.
Approaches to control confounding:

 During designing of a study:
o Matching: Potential confounders are assigned equally in both groups
o Restriction: Individuals with known risk factors for the outcome are
excluded from study
 During data analysis and statistical modeling:
o Stratification: Compares stratum-specific results
o Adjustment: Direct and indirect adjustment for risk factor
o Multivariate analysis: Potential confounder is added as an independent
variable during modeling
Validity and Reliability
VALIDITY—Degree to which a variable or study intervention measures what it

is supposed to measure, and is dependent on the degree of the systematic
error.
 Internal validity: Integrity of the experimental design that is dependent on
the amount of error in measurements, including exposure, disease, and Key Fact
associations between these variables; high internal validity implies a lack Internal validity is essential
of error in measurement; internal validity is essential for external validity for external validity.
 External validity: Relevance of study results to a nonstudy individual or
populations; also called generalizability
RELIABILITY—Reproducible or consistency of the results on repeated

measurement. It refers to amount of error that occurs during measurement due
to either random or chance variations.
 Intrarater reliability: Agreement between repeated results by the same
individual
 Interrater reliability: Agreement between results obtained by different
individuals
Efficacy, Effectiveness, and Number Needed to Treat

(NNT)
Flash Card Q2
EFFICACY—Measure of the benefit resulting from an intervention under ideal 241 of 487 patients treated
conditions (e.g., RCTs). with salmeterol (49.5%)
and 210 of 507 patients
treated with
EFFECTIVENESS—Measure of the benefit resulting from an intervention salmeterol/fluticasone
under usual conditions of clinical care (e.g., practical world). (41.4%) had at least one
exacerbation over the 44-
week trial. What is the NNT
INTENTION TO TREAT ANALYSIS—Method for data analysis in a to prevent one
randomized clinical trial in which individual outcomes are analyzed according exacerbation for
salmeterol/fluticasone
group?
336 / CHAPTER 6
to the assigned group, even if the study subject never received the treatment. It
provides a measure of effectiveness and not the efficacy.
NNT
 Number of patients who need to be treated in order to prevent one clinical
outcome of interest or one adverse event.
 Calculated as the inverse of the absolute risk reduction; that is, NNT =
1/ARR = 1/CER - EER, where absolute risk reduction is ARR, control
event rate is CER, and experimental event rate is EER.
Flash Card A2
The absolute risk reduction
(ARR) of 49.5%–41.4% =
8.1%. NNT with
salmeterol/fluticasone
(rather than salmeterol
alone) to prevent one
additional patient from
experiencing an
exacerbation in 44 weeks =
1/0.081 = 12.3.
ANATOMY AND PHYSIOLOGY OF THE RESPIRATORY SYSTEM / 337
7 Anatomy and Physiology of

the Respiratory System
Muhammad Nouman Iqbal MD & Sandeep Khosa, MD
STRUCTURE AND FUNCTIONAL RELATIONSHIPS

OF THE LUNG
LUNG SEGMENTS
Bronchopulmonary segments describe the anatomic, functional, and surgical units Mnemonic
of the lung (Figure 7-1). They divide the first subdivisions of the lobes on each Right lung—A PALM Seed
side into 10 segments, each with its own tertiary bronchus and pulmonary artery Makes Another Little Palm
(separated by connective tissue that contains the pulmonary veins and lymphatics). Anterior
Posterior
Apical
Lateral
Medial
Superior
Medial—basal
Anterior—basal
Lateral—basal
Posterior—basal
Mnemonic
Left lung—All Attendings
Sat In Sun And Praised
Lungs
Apicoposterior
Anterior
Superior—lingular
Inferior—lingular
Superior
Anteromedial—basal
Posterior—basal
Lateral—basal
Figure 7-1. Lobes and lung segments.

338 / CHAPTER 7
SECONDARY LOBULE
The secondary lobule of Miller is the smallest anatomic unit that is delineated by
connective tissue septa (Figure 7-2). It measures about 10–25 mm and can be
described as having three primary components, as summarized in Table 7-1.
Figure 7-2. Normal secondary lobular anatomy.
Pathologic alterations at specific sites of the secondary lobule can be visible on

thin-section computed tomography (CT); these alterations have clinical and
histopathologic correlations. Description of these patterns is discussed further in
the imaging section; in Chapter 8. ).
Table 7-1. Secondary Pulmonary Lobule
Anatomic Region Contents

Interlobular septa Pulmonary veins and lymphatics; peripheral interstitial fiber system
(better defined in the lung periphery)
Centrilobular Pulmonary artery and bronchiole
Lobular Lung acini (varies in number, 3–24)

ALVEOLAR–CAPILLARY UNIT
The alveolar–capillary unit is the site of gas exchange in the lung (Figure 7- 3). It
is composed of several important structural elements, as summarized in Table 7-2.
Subendothelial
connective tissue
Figure 7-3. The alveolar–capillary unit.
Table 7-2. Alveolar–Capillary Unit
Structural Elements Function/Key Facts
Type I pneumocytes Squamous epithelial cells

Covers 90-95% of alveolar surface area
Not capable of multiplying (mitosis)
Type II pneumocytes Cuboidal epithelial cells
Covers about 3% of alveolar surface area (but makes up for most
cells in the alveolar unit, more than type I pneumocytes)
“Defender of the alveolus”
Produce surfactant → reduces surface tension
Replicate and replace damaged type I pneumocytes under
physiologic and pathologic conditions (takes 2–5 days)
Capillary endothelium Loose junctions → leaky
Converts angiotensin I → angiotensin II
Produces adenosine, prostaglandins
Inactivates bradykinin
Clears serotonin, norepinephrine
Other cells Fibroblasts, neutrophils, eosinophils, lymphocytes, plasma cells,
basophils or mast cells
340 / CHAPTER 7
Surfactant
Formed by type II pneumocytes and functions to keep alveoli open, dry, and
clean. Without surfactant to reduce surface tension, smaller alveoli will always
have higher tension (and pressures) than larger alveoli. leading to their collapse as
described by the law of Laplace (pressure = [2 × tension]/radius). The
composition of surfactant and its properties are summarized in Table 7-3.
Key Fact Table 7-3. Components of Surfactant

Dipalmitoylphosphatidylcho
line (DPPC) is the primary Constituent Components Function
component of surfactant
that lowers the surface Lipids (90%) Main component is DPPC Hydrophilic head and hydrophobic tails →
tension. About 90% of
reduces surface tension
DPPC is recycled by type II
alveolar cells. Proteins (10%) Surface proteins: SP-A, SP-B, SP-A and SP-D (hydrophilic)—innate
SP-C, and SP-D immunity of the lung
ABCA3 (ATP-binding cassette SP-B and SP-C (hydrophobic)—reduces
family of proteins) surface tension
TTF-1 ABCA3 (transmembrane protein of lamellar
bodies)—role in transport of surfactant
TTF-1—role in surfactant regulation
ABCA3, adenosine triphosphate–binding cassette of subfamily A member 3, DPPC,
dipalmitoylphosphatidylcholine; TTF-1, thyroid transcription factor 1
Surfactant also has a significant role in the development and maintenance of lung
integrity and in pulmonary dysfunction. Several pulmonary disorders relating to
surfactant dysfunction have been identified in various age groups and are
summarized in Table 7-4.
Key Fact
Autoimmune pulmonary Table 7-4. Surfactant Dysfunction Disorders
alveolar proteinosis is
almost universally found in Age Group Mechanism Clinical Presentation
adults. Antibodies directed
against granulocyte– Neonatal/infantile Preterm delivery (rare mutations in SP-B, SP-C, Respiratory distress
macrophage colony– ABCA3, TTF-1) syndrome
stimulating factor are
present in about 90% of Children/adults Genetic mutations (rare, mutations in SP-B, SP- Pulmonary alveolar
the cases. C, ABCA3, TTF-1) proteinosis
Acquired forms—autoimmune response
(antibodies against GM-CSF found in 90% of the
cases)
ABCA3, ATP-binding cassette subfamily A member 3; GM-CSF, granulocyte–macrophage colony–stimulating
factor; SP, surface protein TTF-1 thyroid transcription factor 1
AIRWAYS AND AIRWAY RESISTANCE
Airways
The airways undergo more than 23 generations of dichotomous branching from
the trachea to the alveoli, and can be divided up into three zones.
CONDUCTING ZONE—First 16 generations. This constitutes the trachea, bronchi,

bronchioles, and terminal bronchioles. It does not participate in gas exchange and Key Fact
constitutes the anatomic dead space. The conducting zone
contains no alveoli and
TRANSITIONAL AND RESPIRATORY ZONES—Last seven generations. Made does not participate in gas
exchange. This constitutes
up of the respiratory bronchioles, alveolar ducts, and alveolar sacs. the anatomic dead space.
As the airways branch, they go through several changes to their wall structures
(summarized in Table 7-5). Due to the close relationship between structure and
function of the respiratory system, changes to the airway by disease states affect
the airway resistance.
Table 7-5. Airway Structural Properties
Property Trachea Bronchi Bronchioles Alveolus

Epithelial layer Ciliated: Ciliated: Ciliated: simple Squamous: type I
pseudostratified pseudostratified cuboidal Cuboidal: type II
columnar columnar
Smooth muscle Yes Yes Yes No
Cartilage Yes: C-shaped Yes: C-shaped No No

→ “plate-like”
Special cells Goblet cells Goblet cells Clara cells Type II

surfactant–
secreting cells
Airway Resistance
The total pulmonary resistance is determined by two factors: airway resistance

and pulmonary tissue resistance. The airway resistance itself represents
approximately 80% of the total pulmonary resistance and is the most clinically
relevant when discussing various disease states.
To simplify the flow of air through the lung, we assume the airways are rigid
tubes with columns of air with laminar flow, and use the law of Poiseuille to
describe its behavior. According to this law, small changes in the radius can have
profound effects on the resistance to air flow.
342 / CHAPTER 7
∆Pressure = air flow × resistance

Key Fact
Resistance = 8ηL/πr4
The smallest airway has
the smallest radius;
therefore, individually it has η = viscosity of fluid, L =length of tube, r = radius of tube
the highest resistance.
However, due to the lungs About a third of the total airway resistance is located in the upper airway, and the
dichotomous branching,
the smallest airways are rest in the lower airways. In the lower airways, the structures with the highest
arranged in parallel resistance to air flow are the medium-sized bronchi, rather than the small airways.
(resistances add (This is due to the parallel arrangement of the small airways, reducing their total
reciprocally) and their total
resistance is significantly airway resistance.)
reduced. As a result, the
airway structures with the Air flow can be laminar, turbulent, or mixed (transitional). Reynolds number, a
highest collective
resistance to air flow are dimensionless unit, can be used to predict whether flow will be laminar or
the medium-sized bronchi. turbulent.
Reynolds number = (ρ × Ve × D)/η
ρ = density of fluid, Ve = linear velocity of fluid, D = diameter of tube, η =

viscosity of fluid
Key Fact In general, the greater the velocity of air flow and the larger the diameter of the
Heliox has the same
airway, the higher the likelihood that air flow will be turbulent (Reynolds number
viscosity of air but has a exceeds 2000). Because of this, the air flow in the larger upper airways is usually
much lower density. This turbulent or mixed, and it is laminar in the smallest airways in normal physiologic
results in lowering the
Reynolds number, and it
state.
increases the likelihood of
laminar flow. This also will In the setting of turbulent air flow, a greater driving pressure is needed to move
increase the speed of
sound through air, and will
the same amount of air; as a result, the resistance to air flow becomes influenced
make you sound like a more by the density than viscosity of the gas. Under these circumstances, the
talking chipmunk. resistive work of breathing can be decreased with the use of heliox (80% helium,
20% oxygen). Heliox has the same viscosity of air but a much lower density, and
increases the probability of laminar flow.
PULMONARY BLOOD FLOW (PBF) AND PULMONARY

VASCULAR RESISTANCE (PVR)
Pulmonary Vessels
The lung receives blood from two vascular systems: the pulmonary circulation
and the bronchial circulation. A small portion of the bronchial circulation drains
into the pulmonary veins and is part of the natural anatomic right-to-left shunt.
Compared to the systemic circulation, the pressures within the pulmonary
circulation are very low.
PVR
The PVR cannot be directly measured, but the law of Poiseuille can be applied to
estimate its value.
R = Δpress/flow
For pulmonary circulation: PVR = (MPAP – MLAP)/PBF
MLAP = mean left arterial pressure, MPAP = mean pulmonary artery pressure,
PBF = pulmonary blood flow
MLAP is approximated using the pulmonary capillary wedge pressure (or

pulmonary artery occlusion pressure) measurement by wedging a pulmonary
artery catheter. The PBF (or cardiac output) can be measured using either the Fick
principle or thermal dilution technique.
Due to low intravascular pressures and highly compliant vessel walls,

extravascular factors, such as gravity and lung volume, are significantly
influenced by the PVR of the respiratory system. In addition, there are a number
of neural and humoral effects on the total PVR and, hence, on PBF. These are
Table 7-6. Factors Influencing Total PVR Key Fact

Positive pressure
Factors Effect ventilation can cause
profound effects on
Lung volume ↑LV → compresses alveolar vessels → ↑PVR alveolar vessels,
↓LV → compression of extraalveolar vessels → ↑PVR extraalveolar vessels, and
Gravity Hydrostatic effects lead to alveolar recruitment → other very compliant
↓PVR in gravity dependent regions intrathoracic vessels like
the vena cava. Clinically, if
Increased PBV Alveolar recruitment → ↓PVR a patient’s circulatory
system is already working
Increased interstitial pressures Compression of vessels → ↑PVR
in overdrive (i.e., sepsis,
Increased blood viscosity ↑Reynolds number → ↑PVR hypovolemia) and cannot
respond to the sudden
Positive pressure ventilation Compression and derecruitment of alveolar vessels increase in PVR from
(and extraalveolar vessels) → ↑PVR mechanical ventilation, an
Alveolar hypoxia unsafe drop in left
Locally mediated hypoxic vasoconstriction → ↑PVR
ventricular preload and
Angiotensin, endothelin, histamine, ↑PVR systemic blood pressure
norepinephrine, epinephrine, α- can result.
adrenergic agonists
Prostaglandin, prostacyclins PGE1 and PGI2 → ↓PVR
PGE2α and PGE2 → ↑PVR
Bradykinin, acetylcholine, β- ↓PVR
adrenergic agonists, nitric oxide
Autonomic nervous system Stimulation of sympathetic innervation → ↑PVR
Stimulation of parasympathetic innervation → ↓PVR
LV, lung volume, PBV, pulmonary blood volume; PG, prostaglandin; PVR, pulmonary vascular
resistance
344 / CHAPTER 7
PULMONARY GAS EXCHANGE
Gas Exchange in the Lungs

Using the Dalton law of partial pressures, we can estimate the partial pressure of
oxygen in the alveolus (PAO2) using the following equation:
PAO2 = FiO2(Pb- PH20)- PaCO2/R
FiO2 = fraction of inspired oxygen, Pb = barometric pressure, PH2O = water vapor

partial pressure, PaCO2 = partial pressure of arterial CO2, R = CO2 eliminated/O2
consumed (production of CO2/production of O2 [varies based on fuel utilized]).
A useful clinical application of the above equation is the calculation of the

alveolar– arterial oxygen difference (A–a gradient= PAO2 - PaO2). A– a gradients
of larger than normal range (5–15 mm Hg, increases with age) can be seen in
shunt-like states, ventilation/perfusion mismatches, and impairments in diffusion.
For further discussion of these topics, see hypoxic respiratory failure section in
Chapter 2.
CO2 is removed by the respiratory ventilation at the same rate it is produced. The
relationship is inversely proportional:
PaCO2 = VCO2/VA × K
PaCO2 = partial pressure of arterial CO2, VCO2 = CO2 production, VA = alveolar

ventilation, K = a constant
The VA cannot be measured directly but can be calculated if we subtract the dead
space ventilation (VD) from the minute ventilation (VE).
VA = VE - VD
As discussed earlier in this chapter, the VD in normal subjects is attributable to

anatomic dead space (conducting zone of the lung). In disease states, there may be
development of physiologic dead space (volume of gas that is ventilated but not
perfused), and this can be calculated using the Bohr equation.
VDCO2/VT = (PaCO2 - PECO2)/PaCO2
VDCO2 = physiologic dead space for CO2, PECO2 = end-tidal CO2 ~ alveolar PCO2
Gas Exchange in the Blood

O2 delivery to the tissues (DO2) is determined by the following relationships:
DO2 = CaO2 × CO
CaO2 = arterial oxygen content, CO2 = cardiac output (stroke volume × heart rate)
CaO2 (mL/dL) = (Hgb in g/dL × 1.34 × O2sat%) + (0.003 × PaO2)
It is important to note that all the increases in cardiac output, hemoglobin

concentration, O2 saturation, or partial pressure of oxygen can lead to increases in
the arterial blood oxygen content, although to varying degrees.
Ventilation and Perfusion Relationships

In a given lung unit, it is the ratio of ventilation to perfusion that ultimately
determines the effectiveness of gas exchange. In normal individuals at rest, this
ratio can vary from 0.6 to 3.0 and, in addition to the natural anatomic shunt, also
can contribute to differences in A–a gradient. In patients with lung disease, the
degree of ventilation/perfusion inequality can have profound effects on gas
exchange. Clinically, we can test for distributions of ventilation and perfusion and
we can test for their relationships using various techniques.
In greater degrees of inequality (ventilation/perfusion ratios close to 0) or in the

presence anatomic shunts, the shunt fraction equation can be applied to quantify
the proportion of cardiac output that bypasses oxygenation in the pulmonary
capillaries.
Qs/Qt = (CcO2 - CaO2)/(CcO2 - CvO2)
Qs/Qt is the shunt fraction, CcO2 is the end capillary oxygen content, CaO2 is the
arterial oxygen content, and CvO2 is the mixed venous oxygen content. CaO2 and
CvO2 are calculated from arterial and mixed venous blood gas measurements,
respectively. CcO2 is estimated from the PAO2.
To calculate areas of true anatomic shunt, 100% FiO2 should be applied to the
patient for 20 to 30 minutes to saturate the hemoglobin with oxygen in areas that
have very low ventilation/perfusion ratios and to eliminate their potential Flash Card Q1
contribution in an estimate.
A patient has a hemoglobin
(Hgb) of 6, O2 saturation of
LUNG ZONES—Ventilation/perfusion mismatches also can result from the 95%, PaO2 of 80, and a CO
effects of gravity, and as a result, this creates pressure differences between the of 3 L. Would an increase
in the Hgb to 8 or an
alveolar, arterial, and venous systems of the lung. Experimentally, this has led to increase in the PaO2 to 100
the identification of regional pressure relationships based on gravity, known as lead to a larger increase in
lung zones. the delivery of oxygen to
the tissues?
346 / CHAPTER 7
Pressure in alveoli (PA), arteries (Pa), and veins (Pv) are in

 Zone 1 = PA > Pa > Pv
 Zone 2 = Pa > PA > Pv
 Zone 3 = Pa > Pv > PA
The boundaries between the lung zones can be altered by body position and lung
volume. When dealing with pulmonary artery catheter placement, the catheter tip
is theoretically desired to be located in zone 3 to obtain accurate assessment of
left atrial pressures at end expiration.
Diffusion
The diffusion of gas through the alveolar–capillary membrane is described by the
Fick law of diffusion. The factors that limit gas transfer are based mainly on the
diffusion coefficient, alveolar capillary membrane surface area, and the partial
pressure of the gas across the membrane.
Volume of gas diffusing (mL/min) = area × diffusion coefficient × partial

pressure difference across barrier/ thickness of barrier
Diffusion coefficient is proportional to the solubility of gas in the diffusion barrier

and inversely related to its molecular weight.
 The diffusion of gases can be categorized as either

 Perfusion-limited: The partial pressure of the gas across the membrane has
sufficient time to equilibrate as it passes through pulmonary capillaries; gas
transfer is limited by perfusion, or the cardiac output (e.g., nitrous oxide)
 Diffusion-limited: The partial pressure of the gas across the membrane does
not equilibrate as it passes through the pulmonary capillaries (gas chemically
combined to hemoglobin does not contribute) and gradient is maintained; gas
transfer is limited by the alveolar–capillary barrier (e.g., carbon monoxide)
Under normal resting conditions, the diffusion of oxygen and carbon dioxide is
perfusion-limited; however, in disease states (i.e., pulmonary fibrosis, high
altitude), the transfer can become diffusion-limited.
Flash Card A1 Carbon Monoxide is unique in its properties and is used to determine the ability of
a lung to transfer gas. This is discussed further in Chapter 8.
Increase in the Hgb to 8
would result in a larger
magnitude of increased
oxygen delivery to the
tissues. This can be
determined based on the
equation listed at the op of
page 345
LUNG MECHANICS AND LUNG VOLUMES
Muscles of Respiration
The diaphragm is the primary muscle of inspiration and is innervated by phrenic

nerves emerging from C3–C5. The external intercostals, parasternal intercostals,
and scalene muscles (T1–T11 innervation) contract in collaboration with
diaphragm and increase the anteroposterior and transverse diameters of chest wall.
It is important to note that the diaphragm plays a larger role during inspiration in
the supine position than in the upright posture during normal breathing, and as a
result, early diaphragm dysfunction may present with symptoms in the supine
position. In the setting of a unilateral paralyzed hemidiaphragm, a rapid
inspiratory effort will demonstrate paradoxic movement cephalad of the paralyzed
hemidiaphragm (due to the increased negative intrapleural pressure that develops
during inspiration). This is the basis of the sniff test. Expiration is normally a
passive maneuver, and elastic recoil of the lung causes air to flow out of the lungs.
Compliance
Lung inflation is the result of a pressure gradient between the airway pressure and
the pleural pressure, and it has to overcome the elastic recoil of the lung and the
airway resistance (discussed earlier in this chapter). Instead of measuring the
elastic recoil of the lung, or elasticity, we describe its inverse, or compliance.
Compliance is defined as the ease with which the lung is expanded.
Compliance = ∆volume/∆pressure
Compliance can be used clinically during mechanical ventilation in critical illness,

and unless an esophageal balloon is used to estimate the pleural pressure, the total
compliance of the respiratory system is measured (chest wall and lung in series).
For further details, see Chapter 2, section on mechanical ventilation monitoring.
Lung Volumes
The interactions of the lung, chest wall, and muscles of respiration determine the
standard lung volumes and capacities, which are summarized in Table 7-7 and
shown in Figure 7-7. Capacities are composed of two or more volumes. The
methods of measuring lung volumes and their patterns in respiratory diseases are
discussed in Chapter 8. It is important to note that all lung volumes are affected
by height, age, race, and sex.
348 / CHAPTER 7
Table 7-7. Lung Volumes and Capacities

Volume/Capacity Definition Notes
TV Volume of gas per breath; TV can increase tremendously
determined by respiratory center during exercise
in brain; normal value ~ 500 mL in
a 70-kg adult
RV Volume of gas left in the lungs at RV is determined by strength of
the end of forced expiration; muscles of expiration and elastic
normal value ~ 1.5 L in a 70-kg recoil of lungs; diseases affecting
adult this can cause a significant
increase in RV (e.g., emphysema)
IRV Volume of gas inhaled during a IRV is determined by strength of
forceful inspiratory effort, at the inspiratory muscles
end of normal inspiration; normal
value ~ 2.5 L in a 70-kg adult
ERV Volume of gas exhaled during a Low ERV values can be seen in
forceful expiratory effort, at the obesity due to poor expiratory
end of normal expiration; normal effort
value ~ 1.5 L in a 70-kg adult
FRC Volume of gas in the lungs at end FRC is volume of gas when
of normal expiration (resting inward elastic recoil of lungs is
volume); normal value ~ 3 L in a opposite and equal to outward
70-kg adult recoil of chest wall
IC Volume of gas inspired during IC along with spirometry can be
maximal inspiratory effort, at the helpful in determining degree of
end of normal expiration (TV + obstruction
IRV); normal value ~ 3 L in a 70-
kg adult
VC Volume of gas that can be During a forced VC, the first
expelled after a maximal inhalation second of expiration (FEV1) is
(IRV + TV + ERV, or TLC - RV) most sensitive to changes in
airway resistance
TLC Volume of gas in the lungs at the TLC is determined by strength of
end of forceful inspiratory effort contraction of inspiratory muscles,
(RV + TV + IRV + ERV); normal compliance of lungs and chest
value ~ 6 L in a 70-kg adult wall
TV, tidal volume; RV, reserve volume; IRV, inspiratory reserve volume; ERV, expiratory reserve volume; FRC,
functional residual capacity; IC, inspiratory capacity; VC, vital capacity; FEV1, forced expiratory volume in 1
second; TLC, total lung capacity
Figure 7-4. Lung volumes and capacities

RESPIRATORY CONTROL
The ventilator control of respiration is complex and involves multiple sensors,

controllers, and effectors. A simplified model is illustrated in Figure 7-5. A group
of nuclei in the medullary respiratory center (beneath the floor of the fourth
ventricle) is believed to initiate breathing and is surrounded by additional nuclei
in the pons that also play a role (Table 7-8). Table 7-9 summarizes clinically
relevant receptors and reflexes that modify respiration.
Figure 7-5. Respiratory control model.

350 / CHAPTER 7
Table 7- 8. CENTRAL CONTROL—MEDULLARY RESPIRATORY CENTER

(Location)
Group Function Afferents Efferents
Nucleus
DRG (Medulla) Inspiratory CN IX, X Contralateral spinal cord
Tractus solitarius neurons → main input to phrenic
nerves
VRG (Medulla) Inspiratory Collateral Pharyngeal, laryngeal,
Nucleus ambiguus and fibers from intercostal muscles.
expiratory DRG Pre-Bötzinger complex
Retrofacial: neurons
Bötzinge is the “pacemaker” of
Pre-Bötzinger respiratory system
Para-ambigualis
Retro-ambigualis
Apneustic (Lower pons) Terminates CN X Medullary inspiratory
center inspiration neurons
PRG (Upper pons) “Fine-tune” Pulmonary Modulate medullary
Parabrachialis breathing inflation neurons
medialis pattern stretch
receptors
Kolliker-Fuse → inhibit
PRG
DRG, dorsal respiratory group; CN, cranial nerve; VRG, ventral respiratory group; PRG, pontine respiratory
group
Table 7- 9. Receptors and Reflex Mechanisms

Reflex Receptor Pathway
Hering-Breuer Slowly adapting Inflation → CN X → cessation/reduced
inflation reflex pulmonary stretch inspiration effort
receptors in airways
Hering-Breuer Stretch, irritant and J Deflation → CN X → hyperpnea
deflation reflex receptors
Paradoxic reflex of Stretch receptors Inflation → CN X → deep inspiration (sighs)
Head
Cough Irritant receptors in upper Stimulus → CN X → cough,
airway bronchoconstriction
Sneeze Irritant receptors in nasal Stimulus → trigeminal/olfactory nerves →
mucosa sneeze, bronchoconstriction
Chemoreceptor Carotid and aortic bodies Low PaO2, high PaCO2, low pH → hypercapnia
reflex → CN IX, X → DRG →hyperpnea,
bronchoconstriction, bradycardia
Baroreceptor reflex Carotid sinus and aortic High blood pressure → CN IX, X → apnea,
arch stretch receptors bronchodilation, bradycardia
Pulmonary embolism J receptors in pulmonary Vascular stimulus → CN X → tachypnea
or vascular vessels
congestion
Central chemoreceptors respond to changes in pH or PCO2, whereas the

chemoreceptors respond to changes in pH, PCO2, or PO2. In addition, the VA
response varies depending on whether the change is PCO2 or PO2. This is
illustrated in Figures 7-6 and 7-7.
There is a linear increase in VA

when CO2 rises from 38-50
mmHg
For a given PCO2, there is a
greater increase in VA for lower
PCO2 levels.
COPD, sleep, narcotics, and
anesthesia can shift the
ventilator response curve to the
right and decreases the slope.
Metabolic acidosis can shift the
ventilator response curve to the
left and increases the slope.
Key Fact
Figure 7-6. Effects of hypercapnia on VA. Both the central and
peripheral chemoreceptors
respond to changes in pH
and PCO2; however, only
the peripheral
chemoreceptors respond to
changes in the PO2. In the
setting of eucapnia, PO2
can drop to levels as low
as 40 mm Hg before VA is
Peripheral chemoreceptors (carotid
significantly affected.
>> aortic) mediate ventilator
response to hypoxia.
In setting of eucapnia, it is only until

the PO2 reaches a level below 40
mmHg is there a significantly in
increased ventilator response
In the presence of elevated PCO2

levels, ventilator response
increases at higher PCO2levels
Figure 7-7. Effect of hypoxia on VA.

352 / CHAPTER 7
ACID–BASE DISORDERS
The Kassirer–Bleich (KB) equation (modified from the Henderson–Hasselbalch

equation) describes a fixed relationship between the PaCO2, pH, and the
bicarbonate [HCO3].
pH ∝ [HCO3]/PaCO2
This equation forms the basis of blood gas interpretation. A six step approach to
acid–base problems is recommended.
STEP 1—Assess internal validity using a modified version of the above equation.
We take advantage of the linear relationship that exists between the hydrogen ion
(H+) and pH (holds true within pH ranges of 7.2 to 7.5).
H+ (nmol) = (24 × PaCO2)/[HCO3]
∆1 nmol ~ ∆0.01 pH in the opposite direction, and 40 nmol ~ pH = 7.40

(e.g., 30 nmol ~ pH = 7.50, 50 nmol ~ pH = 7.30)
If there is a discrepancy between the calculated H+ and the measured pH, the test
may be invalid. Additional errors that may occur can be due to collection methods
(venous blood, air in sample, sample > 30 minutes, and not iced) and measuring
errors (calibration, leukocyte larceny).
STEP 2—Determine the primary disorder; that is acidemia (pH < 7.40) or
alkalemia (pH > 7.40). Generally, a primary disorder can be identified based on
the direction of the CO2 alone, however it is important to note that a disturbance
can still be present even in the setting of a normal pH because of the fixed
relationship between the HCO3 and PaCO2. Table 7-10 summarizes the primary
disturbances.
Table 7-10. Primary Disturbances
Acidosis/ Primary Direction of

Alkalosis Disturbance Direction of pH PaCO2
Acidosis Respiratory pH↓ PaCO2↑
Acidosis Metabolic pH↓ PaCO2↓
Alkalosis Respiratory pH↑ PaCO2↓
Alkalosis Metabolic pH↑ PaCO2↑

STEP 3—Determine the appropriateness of compensation for the primary

disorder identified using the appropriate equation. The compensation is always in
the same direction as the primary disorder in order to normalize the pH (as per the
KB equation). If it is not in the correct direction, then there likely is an additional
acid–base disorder present. Generally, the compensation is partial rather than Key Fact
complete and does not return the pH to normal (7.40).
In the setting of a
 Metabolic acidosis ( Winter’s formula): PCO2 = [1.5 × (serum HCO3)] + 8 (± metabolic acidosis, a
useful approximation to
2) estimate the expected
 Metabolic alkalosis: ∆pCO2 = 0.6 × ∆HCO3 (±2) PCO2:: PCO2 ~ last two digits
of the pH.
 Respiratory acidosis: ↑ PCO2 by 10, ↑HCO3 by 1 (acute) or 4 (chronic)
 Respiratory alkalosis: ↓ PCO2 by 10, ↓HCO3 by 2 (acute) or 4 (chronic)
STEP 4—Determine if there is an anion gap (AG) present.
AG = Na - (HCO3 + Cl) Mnemonic

Anion gap metabolic
In the setting of a normal albumin (4 gm/dL), the normal AG range is 12 +/- 2 acidosis— MUDPILES:
mEq/L. For each 1 gm/dl decrease in albumin, the normal AG for that patient will Methanol, metformin
Uremia
be 2.5 mEq/L lower. An elevated AG can provide significant clinical clues to Diabetic/alcoholic/starvati
underlying processes. on ketoacidosis
Paraldehyde
Iron, isoniazid
STEP 5—If an AG metabolic acidosis exists, we make an assumption that for Lactic acidosis (cyanide,
each decrease in the HCO3, there will be proportional increase in the AG. If it hydrogen sulfide, CO,
does not exist, then there must be an additional acid–base disorder present. This methemoglobin)
Ethylene glycol
relationship can be calculated using the ΔΔgap. Salicylates
ΔΔgap = ΔAG/ΔHCO3 = (AG - 12*)/(24 - HCO3)

*assumes albumin= 4.0
If the ratio is between 1 and 2, a pure AG metabolic acidosis is present.
If the ratio is < 1, there is a larger decrease in the HCO3 that we account for by the
given change in the AG, indicating a concomitant nongap AG metabolic acidosis
must be present.
Flash Card Q2
A ratio > 2 indicates a smaller decrease in the HCO3 that we account for by the Identify the following acid–
given change in the AG; thus, a concomitant metabolic alkalosis must be present. base disorder(s):
A) pH = 7.56,
B) PCO2 = 22 mm Hg
Table 7-11 describes common mixed acid–base disturbances seen in clinical C) PO2 = 90 mm Hg on
practice. 35% FiO2,
D) Na= 127
K= 4.0
Cl= 80
HCO3= 20
BUN= 35
Cr= 1.5
Albumin= 4.0
354 / CHAPTER 7
Table 7-11. Selected Mixed and Complex Acid–Base Disturbances
Disorder Characteristics Selected situations
Respiratory acidosis with ↓in pH Cardiac arrest

metabolic acidosis
↓in HCO3 Intoxications
↑in PaCO2 Multi-organ failure
Respiratory alkalosis with ↑ pH Cirrhosis with diuretics

metabolic alkalosis
↑HCO3 Pregnancy with vomiting
↓PaCO2 Overventilation of COPD
Respiratory acidosis with pH in normal range COPD with diuretics,

metabolic alkalosis vomiting, NG suction
↑PaCO2
Severe hypokalemia
↑HCO3
Respiratory alkalosis with pH in normal range Sepsis

metabolic acidosis
↓PaCO2 Salicylate toxicity
↓HCO3 Renal failure with CHF or

pneumonia
Advanced liver disease
Metabolic acidosis with pH in normal range Uremia or ketoacidosis with

metabolic alkalosis vomiting, NG suction,
HCO3 normal diuretics, etc.
CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; NG, nasogastric
(Modified, with permission, from Kaufman DA. Interpretation of Arterial Blood Gases (ABGS)
American Thoracic Society. http://www.thoracic.org/clinical/critical-care/clinical-education/abgs.php. Accessed
August 20, 2014.)
Flash Card A2
A) Triple disorder is
present
B) Respiratory alkalosis
C) Metabolic acidosis
(anion gap)
D) Metabolic alkalosis
RESPIRATORY SYMPTOMS, PULMONARY IMAGING, & PROCEDURES / 355
Common Respiratory
8 Symptoms, Pulmonary
Imaging, & Procedures
COMMON RESPIRATORY SYMPTOMS
Common respiratory symptoms include dyspnea and cough. Obtaining a thorough

history and physical examination is the first step in evaluating a patient with these
complaints. If done properly, the findings generally suggest the correct diagnosis,
which can be confirmed by the appropriate diagnostic study.
DYSPNEA
The onset of dyspnea can give a clue to its cause (Table 8-1).
Table 8-1. Causes of Dyspnea Characterized by Onset
Instantaneous Acute/Subacute (Hours–Days) Chronic (Months–Years)

Pulmonary Asthma COPD
embolus COPD exacerbation Asthma
Pneumothorax Upper-airway obstruction Interstitial lung disease
Pneumonia Sarcoidosis
Pulmonary edema Bronchiectasis
Acute hypersensitivity pneumonitis Lymphangitic carcinomatosis
Lobar atelectasis Chronic thromboembolic disease
Acute interstitial pneumonia Primary pulmonary hypertension
Pulmonary hemorrhage Veno-occlusive disease
Pulmonary embolus Pleural effusion
Pulmonary vasculitis Hypoventilation:
Pleural effusion Chest wall deformity
Acute myocardial infarction Neuromuscular weakness
Arrhythmia Obesity
Valvular disease Anemia
Tamponade Thyrotoxicosis
Aortic dissection Pregnancy
Metabolic acidosis
Hyperventilation syndrome
Anxiety
Superior vena cava obstruction
Anaphylaxis
356 / CHAPTER 8
If considering the listed etiologies does not yield a diagnosis, other considerations
include carbon monoxide exposure, gastroesophageal reflux disease, and
deconditioning.
History
Additional information to obtain from the history:

 Smoking
 Occupational exposure and hobbies
 Use of home humidifier or air conditioning
 Travel
 Rheumatologic disorders/symptoms
 History of malignancy/weight loss
 Immunodeficiency
 Drug use
 New medications
Other important considerations:

 Trepopnea: Dyspnea in a lateral decubitus position suggests unilateral lung
Key Fact disease.
Platypnea is shortness of
 Platypnea: Dyspnea while upright that is relieved with lying down is
breath when upright and is associated with hepatopulmonary syndrome secondary to the increase in
commonly associated with blood by gravity to intrapulmonary vascular dilations when upright. Although
hepatopulmonary
syndrome.
commonly associated with hepatopulmonary syndrome, other causes include
intracardiac right-to-left shunt (patent foramen ovale) after pneumonectomy
or cardiac abnormality (aortic aneurysm, pericardial effusion) and skeletal
deformity as a result of increased streaming of blood from the inferior vena
cava to the left atrium caused by mechanical distortion of the interatrial
septum.
Physical Examination
A thorough physical examination is important because many etiologies of

dyspnea cause extrapulmonary manifestations.
CLUBBING—Characteristics (Figure 8-1):

 Softening and periungual erythema of the nail beds
 Increase in the normal 165° angle between the nail and cuticle
 Enlargement of the distal phalanx
 Curvature of nails
B C
Figure 8-1. Clubbing. (A) Red line showing the outline of a clubbed nail. (B) Side
view of clubbed fingers. (C) Frontal view of clubbed fingers.
(Figure A, B, and C reproduced from Wikimedia Commons, CC BY-SA 3.0.)
Table 8-2 shows conditions associated with clubbing.
Table 8-2. Conditions Associated with Clubbing
Respiratory Malignancy Cardiac Gastrointestinal Other

Interstitial lung disease: Bronchogenic Congenital Inflammatory Familial
Asbestosis lung cancer heart disease bowel disease Thalassemia
Idiopathic pulmonary Pleural tumor Subacute Advanced liver Thymoma
fibrosis bacterial disease
Collagen vascular Esophageal
tumor endocarditis Celiac disease
disease
Langerhans Lymphoma Left atrial
histiocytosis myxoma
Lipoid pneumonia Vascular
Chronic infection: disease
Bronchiectasis (Takayasu
Tuberculosis arteritis, Behçet
Lung abscess disease)
Empyema
Cystic fibrosis
358 / CHAPTER 8
When clubbing is associated with subperiosteal formation of new cancellous bone

Key Fact at the distal ends of long bones, it is called hypertrophic osteoarthropathy. This is
Hypertrophic most commonly caused by lung carcinoma. The proposed pathogenesis includes
osteoarthropathy is most circulatory bypass of the lung with localized activation of platelet–endothelial
commonly associated with
primary bronchogenic cells and subsequent release of fibroblast growth factors or tumor production and
carcinoma, involves the release of vascular endothelial growth factor.
long bones of the upper
and lower extremities, and
resolves with curative
surgery. Symptomatic Treatment
When dyspnea is not relieved by treatment of the disease, the focus is to relieve
the symptom. Considerations include:
 Reducing respiratory effort through breathing technique, nutritional repletion,
or overnight “resting” with noninvasive ventilation
 Decreasing respiratory drive with oxygen or inhaled furosemide
 Altering central perception with opiates
There is limited evidence to support their use.
Key Fact Pulmonary rehabilitation has been shown to improve symptoms in patients with
chronic obstructive pulmonary disease (COPD). Best outcomes appear to be
Pulmonary rehabilitation
improves symptoms. The
achieved with high-intensity endurance exercises. Those who have significant
greatest effect is found dyspnea and cannot tolerate high-intensity exercise can consider interval training
when high-intensity and resistance or strength training of the extremities. Neuromuscular electrical
endurance exercises are
used in patients with
stimulation can be used for severely debilitated patients, with some benefit.
COPD. Inconsistent benefits have been reported with flexibility training, inspiratory
muscle training, and anabolic hormonal supplementation as adjuncts to exercise
training.
COUGH
The most common cause of acute and subacute cough is viral infection.
Bordetella can cause persistent cough lasting 3–8 weeks. Cough from the
common cold can persist up to 8 weeks because of heightened cough reflex,
which can be treated with first-generation antihistamines and decongestants.
Newer-generation, nonsedating antihistamines are ineffective. Naproxen may also
help in this setting.
Table 8-3 shows the six most common causes of chronic cough and their
characteristics.
Table 8-3. Causes of Chronic Cough
Cause Characteristic
Associated with frequent nasal discharge, sensation of
Upper airway cough syndrome liquid dripping into back of throat, frequent throat
clearing
Nonproductive cough that occurs after meals or
Gastroesophageal reflux worsens with lying down; may be accompanied by
heartburn, a bitter taste, belching
Nocturnal cough; sputum can be thick and mucoid with
Asthma
casts
Cough productive of sputum on most days for > 3

Chronic bronchitis
consecutive months for > 2 years
Cough, with copious, foul, purulent discharge;

Bronchiectasis
intermittent blood; influenced by posture
Sputum eosinophilia; > 3% of nonsquamous cells

Nonasthmatic eosinophilic bronchitis
induced by nebulized hypertonic saline
Other potential causes:

 Bronchogenic carcinoma
 Metastatic carcinoma
 Mediastinal tumors
 Sarcoidosis
 Chronic aspiration
 Interstitial lung disease
 Left ventricular failure
Figure 8-2 shows a diagnostic algorithm for chronic cough.

360 / CHAPTER 8
Figure 8-2. Evaluation of chronic cough. ACE, angiotensin-converting enzyme;

CT, computed tomography; GERD, gastroesophageal reflux disease; HRCT
high-resolution computed tomography; PFTs, pulmonary function tests; UACS,
upper airway cough syndrome.
HEMOPTYSIS
Table 8-4 shows causes of hemoptysis. Miscellaneous causes include catamenial

hemoptysis as a result of endometriosis and cocaine use. Massive hemoptysis is
discussed separately in Chapter 2.
Figure 8-3 shows an algorithm for the evaluation of hemoptysis. It is important to

first determine the source of the bleed. When a lung source is suspected, chest x-
ray is indicated. Depending on the results and risk factors, chest computed
tomography (CT) scan or bronchoscopy is warranted.
Table 8-4. Causes of Hemoptysis

Hematologic/
Infection Neoplasm Vascular Trauma
Immunologic
Bronchitis Bronchogenic Pulmonary Foreign body Goodpasture
Tuberculosis carcinoma infarction Airway trauma syndrome
Fungal infection Bronchial Mitral stenosis Granulomatosis
adenoma Arteriovenous with polyangiitis
Pneumonia
Kaposi sarcoma malformation Idiopathic
Lung abscess hemosiderosis
Aortic aneurysm
Bronchiectasis (aortotracheal Lupus
fistula) pneumonitis
Dieulafoy disease Blood dyscrasia
(superficial, Behçet disease
subepithelial
bronchial artery
contiguous with
bronchial
mucosa)
Figure 8-3. Evaluation of hemoptysis.

BUN, blood urea nitrogen; CT, computed tomography; ENT/GI, ear, nose, and
throat/gastrointestinal.
362 / CHAPTER 8
PULMONARY IMAGING
CHEST RADIOGRAPHY
Atelectasis
Radiographic findings associated with lobar atelectasis are shown in Table 8-5
and Figure 8-4. Additional general radiographic findings:
 Displacement of hilar/mediastinal structures
 Elevation of the hemidiaphragm
 Decreased distance between ribs
 Compensatory overinflation of the remaining lobes
Table 8-5. Atelectasis and Radiographic Findings

Location of Posteroanterior/Anteroposterior
Lateral Radiograph
Atelectasis Radiograph
Right upper lobe Wedge-shaped opacity in upper right Triangular opacity
hemithorax
Major fissure displaced anteriorly
Minor fissure displaced upward
Right upper lobe collapse + central

carcinoma = reverse S sign of Golden
Left upper lobe Opacification of left perihilar area with Major fissure displaced forward
silhouetting of left heart border
Luftsichel sign: Lucency next to aortic

knob, result of compensatory
overinflation of superior segment of left
lower lobe
Lower lobe Triangular opacity in lower hemithorax Opacity over lower thoracic vertebral
bodies
Loss of posterior hemidiaphragm

Right middle lobe Opacity with silhouetting of right heart Linear or triangular opacity over
border cardiac silhouette
Major fissure displaced superiorly
Minor fissure displaced inferiorly

Figure 8-4. Right lower lobe atelectasis.

CHEST CT SCAN
Chest CT scan produces images based on the different absorption profiles of

structures in a cross-sectional plane. The additional use of intravenous contrast
helps to delineate vascular from nonvascular structures.
Chest CT scan is helpful in the evaluation of the central airways. Table 8-6
describes pathology of the tracheobronchial tree and associated CT findings.
364 / CHAPTER 8
Table 8-6. Tracheobronchial Tree Abnormalities and Computed

Tomography Scan Findings
Abnormality CT Scan Findings
Key Fact
Tracheobronchial tree Tracheal stenosis 1–2 cm narrowing of trachea at thoracic inlet
abnormalities that spare
the posterior membrane
are tracheobronchopathia > 50% decrease in cross-sectional area of lumen on
Tracheobronchomalacia
osteochondroplastica and dynamic expiratory images
relapsing polychondritis.
Marked decrease in transverse diameter of intrathoracic
Saber-sheath trachea
trachea associated with increase in sagittal diameter
Calcified nodules protruding into tracheal lumen and sparing
Tracheobronchopathia
of posterior membrane because of absence of cartilage in
osteochondroplastica
this area
Thickening of anterolateral tracheal wall with sparing of
Relapsing polychondritis
posterior membrane
With involvement of tracheobronchial tree,

Amyloidosis
concentric/nodular thickening of tracheal submucosa
Involvement of tracheobronchial tree rare, usually late in
Granulomatosis with polyangiitis course of disease, with circumferential thickening, ulceration,
and luminal narrowing
Thin wall trachea with scalloped/corrugated appearance,
Mounier-Kuhn syndrome
diameter > 3 cm, diverticulosis
CT Angiography
CT angiography has effectively replaced the use of pulmonary angiography and

ventilation–perfusion scans for the diagnosis of pulmonary embolus. Aortic
abnormalities and pulmonary venous malformations can also be identified. The
timing of bolus administration and imaging depends on the possible abnormality
being evaluated. Typically, when evaluating for a pulmonary embolus, images are
obtained 20 seconds after contrast bolus. Evaluation of an aortic dissection would
have a longer delay.
High-Resolution CT Scan
Very thin slices (1 mm versus 7–10 mm with conventional CT) are obtained. The
primary indication is identifying interstitial lung disease or bronchiectasis. Table
8-7 shows the various patterns seen on high-resolution CT scan and their
associated diagnoses. Dynamic expiratory CT (imaging after a forced vital
capacity maneuver) can detect subtle air trapping and tracheobronchomalacia.
Table 8-7. Patterns on High-Resolution Computed Tomography Scan
Pattern Description Examples Image

Linear Thickening of interlobular septa Pulmonary edema
Lymphangitic spread
Sarcoidosis
Reticular Mess or net-like appearance Usual interstitial pneumonia
Asbestosis
Collagen vascular disorder
Drug toxicity
Nodular Multiple round opacities < 1 cm Perilymphatic sarcoidosis, lymphangitic spread

in diameter
Centrilobular
May be:
Perilymphatic Hypersensitivity pneumonitis, infection
Centrilobular
Random Random metastasis, military tuberculosis
366 / CHAPTER 8
Table 8-7. Patterns on High-Resolution Computed Tomography Scan, continued
Pattern Description Examples Image

Ground-glass Haziness Pneumocystis jiroveci pneumonia, hemorrhage,
opacity bronchioloalveolar carcinoma, lipoid pneumonia,
Preserved bronchovascular pulmonary edema, hypersensitivity pneumonitis,
markings sarcoidosis
Represents partial filling of air Typically represents active disease (also can
spaces reflect fibrosis below resolution of high-resolution
computed tomography scan)
“Crazy paving” (ground-glass opacity +

interlobular septal thickening), alveolar
proteinosis
Consolidation Attenuation with complete Chronic eosinophilic pneumonia
obscuring of bronchovascular
markings Cryptogenic organizing pneumonia
Complete filling of air spaces
Cystic Thin-walled, well-defined air Lymphangioleiomyomatosis

lesions < 1 cm in diameter
Langerhans cell histiocytosis
Lymphocystic interstitial pneumonia
Birt-Hogg-Dubé syndrome (associated with skin

tags and renal tumors)
a
Tree-in-bud opacities are a form of centrilobular nodules and represent dilated and impacted distal terminal bronchioles. Their presence indicates endobronchial spread of infection.
(Figures on row 1 and 6vreproduced, with permission, from Dr. Stephanie Clough, MetroHealth Medical Center; figure on row 2 reproduced, with permission, from Travis WD, et al. An
Official American Thoracic Society/European Respiratory Society Statement: Update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias. Am J
Respir Crit Care Med. 2013; 188: 733-748; figure on row 3 reproduced, with permission, from Dr. Daniel Monroy Chaves, MetroHealth Medical Center. Figures on rows 4-5 rows
reproduced from Wikimedia Commons, CC BY-SA 3.0.)
NUCLEAR MEDICINE TECHNIQUES
Positron Emission Tomography (PET) Scan

PET scans are classically obtained to differentiate between benign and malignant Key Fact
lesions. These scans also can provide information on staging and prognosis and The cutoff of a standard
can help to differentiate between recurrence and posttreatment fibrosis. PET scans uptake value of 2.5 is used
use 2-[fluorine-18]fluror-2-deoxy-D-glucose (FDG), a D-glucose analog labeled to distinguish between
benign and malignant
with a positron emitter (fluorine-18). Typically, lung cancers with show uptake of lesions.
FDG > 2.5.
Infectious and inflammatory processes (tuberculosis, histoplasmosis, and

rheumatoid nodules) can give false-positive results. False-negative results can Key Fact
occur with carcinoid, adenocarcinoma in situ (formerly bronchioloalveolar Carcinoid, adenocarcinoma
carcinoma), and small (< 10 mm) nodules. FDG-PET scan has sensitivity of ~ in situ, and nodules < 10
90% and specificity of 80%, yielding an overall diagnostic accuracy for nodules mm can cause false-
negative findings on PET
of ~ 91%. scan.
Ventilation–Perfusion Scan
Ventilation–perfusion scans are typically used in conjunction with the clinical

probability of pulmonary embolus to aid in the diagnosis (see Figure 8-5) and
Chapter 10). However, ventilation–perfusion scans can also quantify the
magnitude of a right-to-left shunt in patients with pulmonary arteriovenous
malformations.
VENTILATION IMAGES—Performed with radiolabeled gas or aerosol (xenon-

133 or technetium-99m). Three types of images are obtained:
 Breath hold: Radiolabeled gas/aerosol is administered, the patient takes a deep
inspiratory breath and holds, and an image is taken.
 Equilibrium: Patient takes normal tidal breaths for 4 minutes, and images are
taken.
 Washout: Patient breathes room air while radiolabeled gas is exhausted and an
image is taken.
o Retained activity in washout images indicates air trapping.
PERFUSION IMAGES—Obtained after intravenous injection of radiolabeled

particles (technetium-99m-labeled macroaggregated albumin). The number of Flash Card Q1
particles embolized is proportional to pulmonary arterial blood flow. For diseases that have a
cystic pattern, which ones
are predominant in the
upper lobe, predominant in
the lower lobe, and
diffuse?
368 / CHAPTER 8
Figure 8-5. Ventilation–perfusion scan. (A) After the patient inhaled xenon-133
gas, images were obtained in the posterior projection with uniform ventilation to
the lungs. (B) After intravenous injection of technetium-99m-labeled
macroaggregated albumin, showing decreased activity in the apical segment of
the right upper lobe, the anterior segment of the right upper lobe, the superior
segment of the right lower lobe, the posterior basal segment of the right lower
lobe, the anteromedial basal segment of the left lower lobe, and the lateral basal
segment of the left lower lobe.
ULTRASONOGRAPHY
Ultrasound is nonaudible sound energy that creates waves that undergo

attenuation, scatter, refraction, or reflection as they travel through tissue. The
reflected waves form the basis of ultrasound images. Fluid appears anechoic
(black) or hypoechoic (darker). Soft tissue appears gray (isoechoic). Air appears
white (hyperechoic). Bone creates an acoustic shadow that is an anechoic area
behind the bony structure.
Randomized trials have found that real-time ultrasound guidance of needle

placement of venous cannulation reduces time and risk (Figure 8-6). Ultrasound
guidance is also associated with reduced risk of pneumothorax during
thoracentesis. See Chapter 13 for an ultrasound image of pleural effusion.
Flash Card A1
Upper lobe: Langerhans cell
histiocytosis
Lower lobe: Lymphocystic
interstitial pneumonia and
Birt-Hogg-Dubé syndrome
Diffuse:
Lymphangioleiomyomatosis
Figure 8-6. Ultrasound image of the left internal jugular vein (red arrow) and left
carotid artery (white arrow) for ultrasound guidance of needle placement for
venous cannulation.
(Reproduced, with permission, from Sandeep Khosa, MD, MetroHealth Medical Center.)
The use of lung ultrasonography in the evaluation of acute respiratory distress is

an emerging field. Definitions and examples are shown in Table 8-8.
370 / CHAPTER 8
Table 8-8. Ultrasound Vocabulary/Image Examples
Ultrasound Vocabulary Definition/Image

Lung sliding To-and-fro motion of lung pleura with respiration
Seashore sign Lung sliding displayed in M mode (motion mode)
Reflected energy is shown as areas of brightness traced from

left to right on screen with time on x-axis
Stratosphere sign Absence of lung sliding seen in M mode

Table 8-8. Ultrasound Vocabulary/Image Examples, continued
Ultrasound Vocabulary Definition/Image

A lines Echoes of pleural line indicate air–soft tissue interface
Pleural line
A lines
B lines Comet tail artifacts that spread all the way to edge of screen
without fading represent interstitial thickening
Pleural
line
B lines
Lung point Point where it is possible to see lung sliding and no lung sliding
plus A lines in same view
Flash Card Q2
Hepatization Lung visualized with similar tissue pattern to liver
A patient undergoes a
difficult central line
(Figures on rows 3-5 reproduced, with permission, from Dr. Ziad Shaman, MetroHealth Medical Center. Figure placement. Ultrasound is
on row 6 reproduced, with permission, from Dr. Stephanie Clough, MetroHealth Medical Center.) used to evaluate the lungs
after the procedure. Lung
sliding is absent, with an A-
line-predominant pattern.
Table 8-9 shows common etiologies and their associated ultrasound findings. What is the likely
explanation for the
ultrasound finding?
372 / CHAPTER 8
Table 8-9. Ultrasound Findings in Specific Conditions
Condition Ultrasound Findings

Normal Lung sliding
A lines
Seashore sign
Pleural effusion Anechoic (black) collection bordered by diaphragm, chest wall, and
atelectatic lung (Figure 8-7)
Interstitial syndrome Numerous B lines
Pneumothorax No lung sliding

No B lines
Lung point
Consolidation Hepatization of lung
Pleural effusion
Lung
Diaphragm
Figure 8-7. Ultrasound image showing pleural effusion.

(Reproduced, with permission, from Dr. Ziad Shaman, MetroHealth Medical Center.)
Flash Card A2
Pneumothorax
PROCEDURES
PULMONARY FUNCTION TESTS (PFTs)
Clinical indications for PFTs:

 Further evaluate specific respiratory symptoms, signs, or radiographic
abnormalities
 Aid in the diagnosis of respiratory disease
 Monitor respiratory disease and response to therapy
 Determine prognosis
 Evaluate for effects of occupational, environmental, or drug exposure
 Evaluate risk before lung resection
 Objectively assess impairment
Reference Values
Important considerations for reference values:

 Lung function values plateau at ~ age 20–35 years. Key Fact
 1-second forced expiratory volume (FEV1) decreases approximately 30 mL/y. Acceptable spirometry
 Vital capacity decreases with age, whereas residual volume increases. results are extrapolated
volume < 5% or FVC of
 African-Americans, Asians, and East Indians have lower values than white 0.15 L, plateau on volume–
persons of similar age, height, and sex (if no reference range for these specific time curve, exhalation time
populations, use correction factor of 0.88). > 6 seconds, and no
artifacts.
 Accurate height and weight are needed (in kyphoscoliosis, arm span
estimation of height).
Spirometry
ACCEPTABILITY—Determined by:
 Good start: Sharp takeoff without hesitation, with extrapolated volume < 5%
or forced vital capacity (FVC) 0.15 L Key Fact
 End of test criteria met: Exhalation to residual volume, plateau on volume– Repeatability criteria are
time curve, exhalation time > 6 seconds met if the two largest
 Absence of artifact: No cough, glottis closure, air leak, or obstructed values of FEV1 and FVC
are within 0.15 L of each
mouthpiece other.
REPEATABILITY—Determined once acceptability criteria are met, three

acceptable spirograms with both FVC and FEV1 showing the two largest values
within 0.15 L of each other.
374 / CHAPTER 8
MAXIUMUM VOLUNTARY VENTILATION (MVV)—Full volume of air a patient

can breathe over a specified period, usually 12–15 seconds (MVV= FEV1 x 40
approximately). It is expressed as liters per minute at body temperature, ambient
pressure saturated with water vapor. It is not included in the diagnosis or
monitoring of disease; however, it can be useful in certain clinical situations. A
disproportional decrease in MVV compared with FEV1 is seen in neuromuscular
disorders and upper-airway obstruction. It is also used to estimate breathing
reserve in cardiopulmonary exercise testing; however, its utility in mild to
moderate COPD is limited.
MEAN EXPIRATORY FLOW 25–75% of FVC—Not specific but can suggest

small airway disease.
BRONCHODILATOR RESPONSE—Defined by the American Thoracic

Society/European Respiratory Society task force as an increase in FEV1 or FVC
by 12% and at least 200 mL. To test for bronchodilator response, the patient
should avoid using a short-acting bronchodilator at least 4 hours and a long-acting
bronchodilator at least 12 hours before testing.
Lung Volume
Lung volume is measured by nitrogen washout, body plethysmography, and
inhaled inert gas dilution. The definitions of the different lung volumes are
explained in Chapter 7. Table 8-10 compares body plethysmography and gas
dilution techniques.
Table 8-10. Lung Volume Determination
Technique Procedure Concept Limitations

Body Patient pants against Boyle’s law Gold standard
plethysmography closed shutter in sealed V1 × P1 = V2 × P2
box Expensive, complex,
Change is space-consuming
Adequate if 3 FRC pressure that is
values agree within 5% measured and Exceeding 1 pant/sec
used to determine results in overestimation
lung volumes of FRC
Table 8-10. Lung Volume Determination, continued
Technique Procedure Concept Limitations

Gas dilution Patient inhales known Measuring Only measures exhaled
techniques concentration and exhaled gas volume, so air
volume of gas concentration can trapping causes
allow calculation underestimation of lung
Nitrogen washout Washout accomplished
of lung volume volume
when nitrogen
concentration < 1.5% for
≥ 3 consecutive breaths
Helium rebreathing Mixture of 10% helium and
25–30% oxygen inhaled
Equilibrium reached when <

0.02% change in
concentration occurs for ≥
30 sec
FRC, functional residual capacity.
Diffusing Capacity
Diffusing capacity is measured by the rate of carbon monoxide transfer, and

values are reported in milliliters per minute per millimeter of mercury. Factors
that influence the diffusion of gas across the alveolar–capillary barrier can be
explained by Fick’s law for diffusion:
Volume of gas diffusing = A × D × (P1 − P2)/T

A = surface area of barrier
D = diffusion coefficient of particular gas
T = thickness of barrier
P1 − P2 = partial pressure difference of gas across barrier
The most common method to measure diffusion lung capacity for carbon
monoxide (DLCO) is the single-breath technique. Others include the steady-state,
intrabreath, and rebreathing techniques.
Method:
 Gas inhaled is a mixture of nitrogen, 0.3% CO, helium, and 19–21% oxygen.
 Patient exhales down to the residual volume (exhaled volume is at least 85%
of largest vital capacity), and the valve opens.
 Patient rapidly inhales gas to total lung capacity (< 4 seconds).
 Patient holds for 10 seconds (± 2 seconds).
 Patient exhales rapidly (< 4 seconds), and gas is collected.
Factors that affect DLCO are shown in Table 8-11.

376 / CHAPTER 8
Table 8-11. Conditions that Affect Diffusion Lung Capacity For Carbon
Monoxide
Conditions that ↑ DLCO Conditions that ↓ DLCO
Key Fact Evening (↓ by 1–2%/h throughout day)
Morning
Conditions that increase
pulmonary capillary blood Premenses (unknown; not related to variation Smoking (related to carboxyhemoglobin)
volume (polycythemia, left- in hemoglobin levels)
to-right shunt, asthma,
Müller’s maneuver, Exercise (secondary to recruitment of After exercise (↓ below pre-exercise levels)
exercise, supine position, capillaries) Postulated to be related to redistribution of
and obesity) increase pulmonary capillary blood volume to peripheral
DLCO. Those that muscles
decrease pulmonary
capillary blood volume Supine position (secondary to increase in Standing
(anemia, pulmonary pulmonary capillary blood volume)
vascular disease, Valsalva Müller’s maneuver (after forced expiration, Valsalva maneuver
maneuver) decrease inspiration is made against closed mouth and
DLCO. nose)
Pulmonary hemorrhage Lung resection
Bronchodilator administration (↑ to 6%) Interstitial lung disease
Left-to-right shunt Pulmonary vascular disease
Polycythemia Emphysema
Asthma
Obesity
DLCO, diffusion lung capacity for carbon monoxide.
ADJUSTING DLCO—Hemoglobin,supplemental oxygen, altitude, and

carboxyhemoglobin can substantially affect the measurement of DLCO. Table 8-
12 shows the adjustment equations.
Table 8-12. Adjusting Diffusion Lung Capacity for Carbon Monoxide
Condition Equation
Adjusting for hemoglobin Male = DLCO (predicted) × [1.7 Hgb/(10.22 + Hgb)]

Female = DLCO (predicted) × [1.7 Hgb/(9.38 + Hgb)]
Supplemental oxygen Assuming sea level of PAO2 of 100 mm Hg
DLCO (predicted)/[1.0 + 0.0035(PAO2 − 100)]
Altitude Assuming sea level of PAO2 of 150 mm Hg
DLCO (predicted)/[1.0 + 0.00311(PAO2 − 150)]
Carboxyhemoglobin DLCO (predicted) × (102% − COHgb%)
DLCO, diffusion lung capacity for carbon monoxide.

DLCO can also be corrected for lung volume. However, the clinical utility is
questionable because the relationship between DLCO and lung volume is not
linear.
Respiratory Muscle Pressure

Respiratory muscle strength can be measured by obtaining maximal inspiratory
pressure (MIP) and maximal expiratory pressure (MEP). MIP is obtained by
exhaling to residual volume and breathing in as fast as possible for 2 seconds. For
MEP, the patient inhales to total lung capacity and exhales as fast as possible.
These maneuvers are repeated at least three times with < 10 cm H2O variability.
There are no definitive reference ranges, but there is a decrease with age and ~
one-third decrease in women compared with men. MIP < one third of normal
predicts hypercarbic respiratory failure. MEP < 60 cm H2O predicts a weak cough
and difficultly clearing secretions.
These measurements have a poor positive predicted value. A better alternative in

detecting inspiratory muscle weakness is a decrease in FVC from upright to
supine, which typically declines by 5–10% in normal subjects. A decrease of >
30% is associated with severe diaphragmatic weakness.
Airway Challenge
Testing for airway hyper-responsiveness can be done by direct (methacholine or
histamine) or indirect (exercise, eucapnic voluntary hyperventilation, cold, or
mannitol) methods.
Methacholine is the most common method and is accomplished by the tidal

breathing method (preferred) or the dosimeter method (sensitivity questioned). It
is expressed as the provocation concentration that causes a 20% drop in FEV1.
Table 8-13 shows the American Thoracic Society guidelines for interpretation of
methacholine test results.
Table 8-13. Interpretation of Methacholine Test Results
Normal > 16 mg/mL
Borderline 4–16 mg/mL
Mild airway hyper-responsiveness 1–4 mg/mL
Moderate to severe airway hyper-

< 1 mg/mL
responsiveness
378 / CHAPTER 8
False-positive findings can be caused by allergic rhinitis, COPD, smoking, cystic

fibrosis, bronchiectasis, bronchiolitis, and recent respiratory tract infection.
False-negative findings are far less common. Most physicians believe that a
negative test result effectively rules out asthma in a patient presenting with
asthma-like symptoms in the last 2 weeks.
Factors to consider:
 If patient is taking intensive anti-inflammatory medications before testing, this
can suppress airway responsiveness.
 If symptoms are related to aeroallergens, the season of exposure may have
passed.
 Occasionally, occupational asthma caused by a single antigen may respond
only when challenged with that specific agent.
Absolute contraindications to testing:

 Severe airflow limitation (FEV1 < 50% predicted or < 1.0 L)
 Myocardial infarction or stroke in the last 3 months
 Uncontrolled hypertension (systolic blood pressure > 200 mm Hg or diastolic
blood pressure > 100 mm Hg)
 Known aortic aneurysm
Relative contraindications:
 Moderate airflow limitation (FEV1 < 60% predicted or < 1.5 L)
 Inability to perform acceptable spirometry
 Pregnancy
 Nursing
 Current use of cholinesterase inhibitor medication for myasthenia gravis
Medications withheld before methacholine test:

 Short-acting β2-agonist: 8 hours
 Short-acting anticholinergic: 24 hours
 Long-acting β2-agonist: 48 hours
 Long-acting anticholinergic: 7 days
 Short-acting theophylline: 24 hours
 Sustained-release theophylline: 48 hours
Exercise Challenge Testing

MODES OF EXERCISE—Motor-driven treadmill with adjustable speed and
grade versus electromagnetically braked cycle ergometer
INHALATE—Dry air < 25°C with a nose clip in place

PROTOCOL—Work rate, speed, and grade for the different modes are
determined to target a particular ventilation or heart rate for at least 4 minutes
(usually 6–8 minutes total exercise). The primary outcome is FEV1, and values Key Fact
are obtained at postexercise intervals of 5, 10, 15, 20, and 30 minutes. On an exercise challenge
test, a decrease in FEV1 of
INTERPRETATION—Decrease in FEV1 of 10–15% is abnormal. Positive results 10–15% is considered
abnormal if it occurs during
have been seen in abnormal posterior motion of the arytenoid region or vocal cord postexercise intervals of 5,
dysfunction. Therefore, it is important to examine the flow–volume curve. 10, 15, 20, or 30 minutes.
Interpreting PFT Results

Table 8-14 shows the interpretation of PFT test results.
Table 8-14. Pulmonary Function Test Results for Different Disorders

Upper Airway
Result Obstructive Restrictive Mixed
Obstruction
Spirometry FEV1/VC ≤ LLN FEV1/VC ≥ LLN FEV1/VC ≤ LLN FEV1/PEF > 8 in
or and fixed or variable
intrathoracic
FEV1/VC ≥ LLN VC ≤ LLN
and VC ≤ LLN MIF50/MEF50 ~ 1
for fixed, < 1
variable
extrathoracic, > 1
intrathoracic
Lung volume TLC ≥ LLN TLC < LLN TLC ≤ LLN Normal
Flow–volume Scooping of Shortened and Scooping of Fixed: Flattening

loop expiratory limb shifted to right expiratory limb; of both inspiratory
shifted to right and expiratory
limbs
Variable
extrathoracic:
Flattening of
inspiratory limb
Variable
intrathoracic:
Flattening of
expiratory limb
See Figure 8-8
DLCO Normal in asthma Normal in chest Variable Normal

or COPD wall and
Decreased in neuromuscular
emphysema disorders Flash Card Q3
Decreased in A patient is receiving a
interstitial lung long-acting anticholinergic
disease and a methacholine test is
FEV1, 1-second forced expiratory volume; VC, vital capacity; LLN, lower limit of normal; PEF, peak expiratory ordered for further
flow; MIF50, maximum inspiratory flow; at 50% of forced vital capacity; MEF50, maximum expiratory flow at evaluation. How long
50% of forced vital capacity; TLC, total lung capacity; DLCO, diffusion lung capacity for carbon monoxide; should the medication be
COPD, chronic obstructive pulmonary disease. withheld before testing?
380 / CHAPTER 8
A B C
Figure 8-8. Flow-volume loops of upper airway obstructions. (A) Fixed; (B)
variable extrathoracic; and (C) variable intrathoracic.
(Reproduced, with permission, from Pellegrino R, et al. Interpretative strategies for lung function tests. Eur
Respir J. 2005; 26: 948-968. doi: 10.1183/09031936.05.00035205.)
Key Fact Other abnormalities on PFTs and their associated diagnoses:

 Isolated reduction in DLCO: Pulmonary vascular disease or early interstitial
An isolated reduction in
DLCO can suggest lung disease
pulmonary vascular  Reduction in functional residual capacity (FRC) and expiratory reserve
disease or early interstitial volume (ERV): Likely related to obesity
lung disease.
The severity of the abnormality is determined by the degree of reduction in FEV1

and is shown in Table 8-15.
To identify worsening lung function, reduction should be > 15%/y in FEV1,

according to the American Thoracic Society/European Respiratory Society
recommendations.
Table 8-15. Severity of Abnormality Determined by 1-Second Forced

Expiratory Volume According to the American Thoracic Society/European
Respiratory Society Task Force Guidelines
Severity 1-Second Forced Expiratory Volume % Predicted
Mild > 70
Moderate 60–69
Moderately severe 50–59
Severe 35–49
Very severe < 35
Flash Card A3
Up to 7 days
PFT Results in Pregnancy
Table 8-16 shows changes in PFT results during pregnancy. The major change is
the decrease in ERV and residual volume as a result of the enlarging uterus and
diaphragmatic elevation. Key Fact
In pregnancy, ERV,
Table 8-16. Changes in Pulmonary Function Test Results During residual volume, and FRC
are reduced, whereas total
Pregnancy lung capacity is essentially
unchanged. Increases in
Variable Change
minute ventilation occur
Expiratory reserve volume ↓ by 8–40% almost exclusively as a
result of increases in tidal
Residual volume ↓ by 7–22% volume caused by a direct
Functional residual capacity ↓ by 10–25% progesterone-mediated
increase in central
Total lung capacity Mild ↓ respiratory drive and
Inspiratory capacity ↑ enhancement of
hypercapnic ventilatory
Vital capacity No change drive. Tachypnea is an
↑ by 30–50% (likely secondary to progesterone-mediated unusual finding and
Tidal volume
↑ in central respiratory drive) warrants investigation.
Respiratory rate No change or mild ↑
Minute ventilation ↑ by 20–50%
1-second forced expiratory volume No change
Diffusion capacity ↑ initially in first trimester, then ↓
CARDIOPULMONARY EXERCISE TESTING
Indications
Commonly, cardiopulmonary exercise testing is the final evaluation of
unexplained dyspnea when the methods described earlier do not yield an etiology.
It is helpful in identifying a cardiovascular or respiratory cause for limitation of
activity.
Other indications:
 Objective assessment of symptoms
 Evaluation of severity of impairment
 Early detection of disease, assessment of response to therapy Flash Card Q4
 Assessment of disability
A 26-year-old woman is
 Preoperative risk and transplantation assessment evaluated for dyspnea on
 Prognosis in certain diseases exertion. PFTs show FEV1
84%, total lung capacity
96%, ERV 50%, FRC 76%,
and DLCO 119%. These
findings are most
consistent with what
diagnosis?
382 / CHAPTER 8
Protocol
Maximal symptom-limited incremental protocols are usually performed.

Endurance exercise protocols continued at a constant work rate can be used to
determine response to therapy. A stationary cycle ergometer is more commonly
used and offers better direct measurement of work rate, has less potential for
artifact, and is typically better tolerated. However, the motorized treadmill yields
higher values for peak oxygen consumption (VO2) and is more appropriate for fit
normal subjects. Table 8-17 shows common absolute and relative
contraindications and indications for terminating cardiopulmonary exercise
testing.
Table 8-17. Contraindications and Reasons for Termination of

Cardiopulmonary Exercise Testing
Absolute Relative
Reasons for Termination
Contraindications Contraindications
Within 3–5 days of myocardial Left main coronary stenosis Chest pain and
infarction electrocardiogram changes
suggestive of ischemia
Unstable angina Moderate stenotic valvular ↓ in systolic pressure > 20 mm
heart disease Hg
Uncontrolled arrhythmias Severe untreated arterial > 250 mm Hg systolic or >

causing symptoms or hypertension 120 mm Hg diastolic
hypotension
Syncope High-degree atrioventricular Saturation < 80% associated
block with symptoms and signs of
severe hypoxemia
Symptomatic severe aortic Hypertrophic cardiomyopathy Sudden pallor
stenosis
Uncontrolled heart failure Significant pulmonary Dizziness

hypertension
Acute pulmonary embolism or Advanced or complicated

infarct pregnancy
Thrombosis of lower
extremities
Uncontrolled asthma
Pulmonary edema
Resting room air saturation ≤

85%
Flash Card A4
Obesity can cause a
reduction in ERV and FRC
and an increase in DLCO.
Cardiovascular and Pulmonary Systems in Exercise
Exercise in a healthy individual is limited by the cardiovascular system.
CARDIAC OUTPUT—Initially increases during exercise through increased stroke

volume and heart rate. As work rate is increased, cardiac output increases almost
exclusively through increases in heart rate.
BLOOD PRESSURE—Systolic blood pressure typically rises with exercise.

Diastolic blood pressure typically remains unchanged or increases slightly.
VENTILATION—Increases in exercise by both tidal volume and respiratory rate.

In low-level exercise, it is increased primarily by tidal volume at the expense of
inspiratory reserve volume. At ~ 70–80% of peak exercise, increases in
ventilation are predominately caused by increases in respiratory rate.
Measurement
VO2—Oxygen uptake is related to oxygen demand and transport. It increases

linearly as work rate increases. VO2max (maximal oxygen consumption) occurs
when VO2 plateaus despite further increases in work rate. This plateau often is not
observed. Instead the maximal value of VO2 achieved is reported as VO2peak.
Normalization for body mass is typically done by VO2/kg, but this may produce
low values in obese patients.
ANAEROBIC THRESHOLD (AT)—Estimated at the onset of metabolic acidosis

from increases in lactic acid during exercise. It is usually 50–60% of VO2max in
healthy individuals and higher in fit individuals. Normal value is 40–80%. It can
be measured invasively by arterial lactate (gold standard) or noninvasively by the
V-slope method and the ventilator equivalents method. The V-slope method is the
most popular and measures the change in slope of the amount of carbon dioxide
exhaled from the body per unit of time (VCO2) versus the (VO2) (Figure 8-9). The
respiratory exchange ratio (VCO2/VO2) should also be ~ 1 at AT.
HEART RATE RESERVE (HRR)—Difference between age-predicted maximal

heart rate (220 − age; may underestimate in the elderly) and maximum heart rate
achieved during exercise. Normally, at maximal exercise there is little or no HRR.
The slope of heart rate versus VO2 is linear. In heart disease, the line shifts to the
left with an increase in slope (Figure 8-10). In trained individuals, the line shifts
to the right. In lung disease, the predicted maximal heart rate is not achieved.
384 / CHAPTER 8
Figure 8-9. Determination of anaerobic threshold with the V-slope method.

STPD, standard temperature and pressure; VCO2, carbon dioxide output; VO2,
oxygen uptake.
(Reproduced, with permission, from the ATS/ACCP Statement on Cardiopulmonary Exercise Testing. Am J
Respir Crit Care Med. 2003; 167: 211-277. doi: 10.1164/rccm.167.2.211.
http://www.atsjournals.org/doi/pdf/10.1164/rccm.167.2.211)
A B
Figure 8-10. Cardiovascular response during exercise in cardiomyopathy versus

chronic obstructive pulmonary disease. The dashed line represents a normal
healthy individual. (A) cardiomyopathy. The slope is shifted to the left, with an
increase in slope. (B) Chronic obstructive pulmonary disease. The maximal heart
rate is not achieved. HR, heart rate; Max Pred., maximum predicted ; VO2, oxygen
uptake.
Respir Crit Care Med. 2003; 167: 211-277. doi: 10.1164/rccm.167.2.211.
http://www.atsjournals.org/doi/pdf/10.1164/rccm.167.2.211)
OXYGEN PULSE—Ratio of VO2 to heart rate and is normally > 80% predicted. It
is an indirect measure of stroke volume.
VENTILATORY RESERVE (VR)—Relationship between ventilatory demand and

ventilatory capacity. Ventilatory demand is the peak minute ventilation achieved
during exercise (VEmax). Ventilatory capacity is typically measured by MVV,
although this maneuver has limitations with reproducibility, the breathing strategy
during MVV is different than during exercise, and it does not take into account
the bronchodilation of exercise. Alternatively, it can be estimated by FEV1 × 37–
40. However, this calculation may not be appropriate for patients with
neuromuscular disorders or respiratory weakness. Ventilatory demand is
increased and ventilatory capacity is decreased in patients with respiratory disease
that results in reduced VR (Figure 8-11).
Reduced VR can be expressed as either:

 High VEmax/MVV
o Normal: 70%
 Low MVV − VEmax Key Fact
o Normal: 15–50%
Oscillatory breathing
 Cyclical fluctuations in minute ventilation (VE) are seen in patients with response during exercise
congestive heart failure and are related to exercise-associated can be seen in patients
with congestive heart
hemodynamic impairment in patients with congestive heart failure. failure and is predictive of a
poor outcome.
A B
Figure 8-11. Respiratory response during exercise in a healthy person versus a

patient with lung disease. (A) In a healthy person, peak VE (minute ventilation)
approaches 70% of maximal value. (B) In a patient with chronic obstructive
pulmonary disease, peak VE exceeds predicted maximal value. VO2, oxygen
uptake; VCO2, carbon dioxide output; MVV, maximum voluntary ventilation.
Respir Crit Care Med. 2003; 167: 211-277. doi: 10.1164/rccm.167.2.211.)
386 / CHAPTER 8
VENTILATORY EQUIVALENT—For O2, ventilatory equivalent is the ratio of VE

to VO2. For CO2, it is the ratio of VE to VCO2. Normally, VE/VO2 increases at AT
and VE/VCO2 has a delayed increase (Figure 8-12). In hyperventilation, the two
increase simultaneously. VE/VCO2 is normally < 32–34 at AT.
Figure 8-12. Ventilatory equivalents in a healthy subject. Note the increase at

anaerobic threshold of ventilatory equivalent of oxygen (VE/VO2), before an
increase in ventilatory equivalent of carbon dioxide (VE/VCO2).
Respir Crit Care Med. 2003; 167: 211-277. doi: 10.1164/rccm.167.2.211.)
END-TIDAL PARTIAL PRESSURE OF OXYGEN (PETO2) AND END-TIDAL

PARTIAL PRESSURE OF CARBON DIOXIDE (PETCO2)—PETO2 first increases
and PETCO2 first remains constant during the isocapnic buffering time. If VE/VCO2
is high and PETCO2 does not decrease, dead space ventilation is suggested.
Table 8-18 shows normal values and typical response patterns in different
diseases.
Table 8-18. Cardiopulmonary Exercise Response Patterns

Normal Poor
HD COPD ILD PVD Obesity Deconditioned
Values Effort
VO2max/ ≥ 85% ↓ ↓ ↓ ↓ ↓ ↓ ↓
peak (VO2/kg)
Anaerobic > 40% ↓ Normal/ Normal/ ↓ Normal Normal/ Normal

threshold Vo2max ↓/ ↓ ↓ or
absent absent
Heart rate < 15 Normal ↑ ↑ Normal Normal Normal ↑
reserve
Oxygen > 80% ↓ Normal/ Normal/ ↓ Normal ↓ ↓

pulse ↓ ↓
VE/MVV < 85% Normal/ ↑ Normal/ Normal Normal/ Normal ↓

↓ ↑ ↑
VE/VCO2 < 34 Normal/ ↑ ↑ ↑ Normal Normal Normal

↑
VD/VT < 0.30 ↑ ↑ ↑ ↑ Normal Normal Normal
PaO2 > 80 mm Normal Variable ↓ ↓ Normal Normal Normal

Hg
PAO2 − < 35 mm Normal Variable ↑ ↑ Normal Normal Normal

PaO2 Hg
COPD, chronic obstructive pulmonary disease; HD, heart disease; ILD, interstitial lung disease; PVD,
pulmonary vascular disease;VO2max, maximal oxygen consumption; VE/MVV, ventilatory reserve; VE/VCO2,
ventilatory equivalent for carbon dioxide; VD/VT, ratio of physiologic dead space to tidal volume; PAO2, alveolar
oxygen pressure.
Interpretation
Figure 8-13 shows the basic strategy for interpretation of cardiopulmonary
exercise test results. Typical responses for different diseases are further explained
later.
CARDIOVASCULAR DISEASE—Reduced VO2max and AT. Because O2 pulse is

an indirect measure of stroke volume, it is reduced. Cardiac output is maintained
exclusively by increases in heart rate. Thus, there typically is no HRR. However, Flash Card Q5
this is variable, depending on the severity of heart disease. With increasing
A 70-year-old man who is
severity, HRR is abnormal because of chronotropic dysfunction. VD/VT and undergoing
VE/VCO2 are increased because of reductions in pulmonary perfusion secondary to cardiopulmonary exercise
the reduction in cardiac output. Reduced VR may indicate a respiratory limitation. testing for further
evaluation of dyspnea on
exertion has a reduced O2
pulse and an oscillatory
pattern of changes on
ventilation. What is the
most likely diagnosis?
388 / CHAPTER 8
Figure 8-13. Basic strategy for interpretation of cardiopulmonary exercise testing. Abnl., abnormal;
AT, anaerobic threshold; CAD, coronary artery disease; COPD, chronic obstructive pulmonary
disease; ECG, electrocardiogram; HRR, heart rate reserve; HR, heart rate; Hyperven.,
hyperventilation; ILD, interstitial lung disease; PETCO2, end-tidal partial pressure of carbon dioxide;
norm, normal; PFTs, pulmonary function tests; Sao2, arterial oxygen saturation; VE, minute
ventilation; VO2, oxygen uptake; VR, ventilatory reserve.
(Reproduced, with permission, from the ATS/ACCP Statement on Cardiopulmonary Exercise Testing. Am J Respir Crit Care Med. 2003;
167: 211-277. doi: 10.1164/rccm.167.2.211.)
Key Fact DECONDITIONING—Typically shows low VO2, low or normal AT, reduced O2
The typical pattern of pulse, and no HRR. It is difficult to distinguish from early or mild cardiovascular
cardiovascular disease is
reduced O2 pulse, variable
disease. Although rare, mitochondrial myopathy produces a similar pattern and is
HRR depending on included in the differential diagnosis.
severity, increase in VD/VT
and VE/VCO2, and normal
VR.
COPD—Produces a spectrum of patterns, depending on severity. Moderate to
severe disease has distinguishing reduced VR with significant HRR, signifying an
unstressed cardiovascular system. O2 pulse can be reduced secondary to
hypoxemia, deconditioning, or dynamic hyperinflation. Because of increased
dead space ventilation, VD/VT and VE/VCO2 are increased. Decreases in PaO2 and
abnormal widening of PAO2–PaO2 (alveolar-arterial difference for oxygen
Flash Card A5 pressure) are seen in more severe disease.
Congestive heart failure
INTERSTITIAL LUNG DISEASE—Produces a similar pattern to COPD, given the

ventilatory limitation. AT is typically normal unless there is pulmonary Key Fact
circulatory involvement. Arterial desaturation and abnormal widening of PAO2–
The typical pattern of lung
PaO2 are seen. disease is reduced VR with
significant HRR.
Reproducibility
If serial cardiopulmonary exercise testing (CPET) is obtained to determine the

response to therapy, generally there should be change > 12–20% of the variables
(e.g., V02max, HRR, VR, etc.) to be considered clinically significant.
Key Fact
BRONCHOSCOPY
There is no firm guideline
for the timing of
bronchoscopy after
Indications myocardial infarction.
However, the British
Thoracic Society
Indications include evaluation of the nodule or mass (lung cancer recommends waiting 6
diagnosis/staging), mediastinal/hilar lymphadenopathy, hemoptysis, suspected weeks after myocardial
infarction, if possible.
airway obstruction, persistent atelectasis/infiltrate, recent history of lung
transplantation (rejection or inspection of airway anastomosis), chest trauma, and
inhalation injury.
Contraindications to bronchoscopy are shown in Table 8-19.
Table 8-19. Contraindications to Bronchoscopy
Absolute Relative
Uncorrectable hypoxemia Severe hypercarbia
Lack of patient cooperation Uncontrolled asthma
Unstable angina Uncorrectable coagulopathy Flash Card Q6

A 78-year-old man who is
Uncontrolled arrhythmias Unstable cervical spine
undergoing
cardiopulmonary exercise
testing for evaluation of
dyspnea has increased
ventilator equivalents,
increased VE/MVV ratio,
and significant oxygen
desaturation. Baseline
spirometry results show no
obstructive ventilatory
impairment. What is the
most likely diagnosis?
390 / CHAPTER 8
Diagnostic Bronchoscopy Techniques
BRONCHOALVEOLAR LAVAGE—Used to further evaluate lung abnormalities

that suggest infectious, immunologic, or malignant etiology. If disease is diffuse,
bronchoalveolar lavage is obtained from the right middle lobe. Otherwise, it is
obtained from the area of abnormality. It can be sent for cell count, microbiology,
cytology, flow cytometry, polymerase chain reaction, DNA probes, and tissue
markers. Serial cell counts can be diagnostic for alveolar hemorrhage.
Bronchoalveolar lavage can be diagnostic in the following situations:

 Opportunistic infection
 Pulmonary alveolar proteinosis
o Milky or opaque appearance
o Alveolar macrophages filled with periodic acid-Schiff–positive material
o Lamellar bodies
 Alveolar hemorrhage
 Malignant infiltrate
 Eosinophilic lung disease
o > 25% eosinophils
 Chronic beryllium disease
o Beryllium proliferative test (lymphocytes stimulated with soluble
beryllium salts)
 Langerhans cell histocytosis
o > 4% CD1+ Langerhans cells
 Ventilator-associated pneumonia
o Quantitative cultures showing ≥ 104 colony-forming units/mL
BRONCHIAL BRUSHES—Available for cytology and microbiology. A protected

specimen brush can be sent for quantitative culture for the diagnosis of ventilator-
associated pneumonia (≥ 103 colony-forming units/mL).
ENDOBRONCHIAL BIOPSY—Used to obtain sampling from a visualized lesion.

Three biopsy specimens from a suspicious lesion is usually diagnostic in > 97%
of cases. Tumors may show false-negative results because of peripheral necrosis.
Wang needle sampling deeper in the tissue may be beneficial.
TRANSBRONCHIAL BIOPSY (TBBx)—Most helpful in evaluation of diffuse

parenchymal lung disease. Typically, 6–10 specimens are obtained under
fluoroscopic guidance. TBBx is diagnostic in lymphangitis carcinomatosis,
sarcoidosis, rejection after lung transplantation, hypersensitivity pneumonitis, and
mycobacterial and invasive fungal infection.
Flash Card A6
Interstitial lung disease
Complications include pneumothorax and hemorrhage. Pulmonary hypertension

increases the risk of hemorrhage. TBBx is safe in patients receiving aspirin, but
clopidogrel bisulfate (Plavix) should be withheld 5–7 days before the test.
TRANSBRONCHIAL NEEDLE ASPIRATION—Typically used for staging

cancer, evaluating mediastinal or hilar lymphadenopathy, and increasing the yield
of peripheral nodules.
ENDOBRONCHIAL ULTRASOUND—Can help to improve the yield of sampling

peripheral nodules and guiding transbronchial needle aspiration. See Chapter 13
on specific nodes that can be sampled and the diagnostic yield of the different
modalities. There are two types of endobronchial ultrasound: radial and convex
probe. Table 8-20 shows a comparison of the two modalities.
Can also help to determine the likelihood of malignancy.
ELECTROMAGNETIC NAVIGATION—Creates an electromagnetic fluid around

the chest and superimposes this field on previously acquired CT images. A
microsensor is used to determine positioning within the endobronchial tree. It can
then guide placement for peripheral lung lesions or mediastinal lymph nodes.
AUTOFLUORESCENCE—Can be used to detect early cancers in the airways

(carcinoma in situ and squamous cell carcinoma) by causing a red-brown
appearance in the airway. Normal mucosa appears green.
Table 8-20. Radial Versus Convex Probe Endobronchial Ultrasound
Modality Type of Images Ideal Applications

Used to determine airway
tumor invasion
360° image of airway wall and Distance and direction of

Radial
surrounding structure nodule or mass
Useful to guide transbronchial

biopsy of peripheral nodules
Images parallel to
Convex probe Real-time sampling
bronchoscope
Flash Card Q7
When performing TBBx,
how long should Plavix be
withheld?
392 / CHAPTER 8
Therapeutic Bronchoscopy Techniques (Table 8-21)
Table 8-21. Therapeutic Bronchoscopy Technique

Contra-
Method Mechanism Indications Complications
indications
Electrocautery Alternating high- Debulking of Pacemaker Airway perforation
frequency current to intraluminal tumor Defibrillators Airway fire with high
generate heat to Snare used in FiO2
cut, vaporize, or High oxygen
pedunculated requirement
coagulate tissue lesions
Knife useful before
dilation for tracheal
stenosis
Argon plasma Argon gas used to Hemorrhage Pacemaker Depth of
coagulation achieve tissue Excess granulation penetration 2–3 mm
coagulation and tissue (< risk of perforation
hemostasis than laser)
Papillomatosis
Postinfectious
airway stenosis
Cryotherapy Freezing of tissue Sloughing in 24–48 None Postprocedural
with either liquid h so repeat fever
nitrogen, nitrous bronchoscopy
oxide, or carbon needed
dioxide Ideal for foreign
bodies with high
water content
(grapes,
vegetables)
Laser Nd:YAG for rapid Central airway High oxygen Depth 10 mm;
destruction/vaporiz obstruction for requirement highest risk of
ation of tissue exophytic lesion perforation
Tracheal stenosis Airway fire
Ocular/skin damage
Photo- 3 steps: Malignant airway Tracheal–carinal Skin
dynamic Intravenous involvement lesions photosensitivity
therapy photosensitizing Postpneumonec- (avoid sunlight 4–6
agent, laser light tomy weeks)
exposure for Local airway edema
activation (after 48 Porphyria
h), “clean up” Stricture
bronchoscopy Hemorrhage
Fistula formation
Flash Card A7
Plavix should be withheld
5–7 days before TBBx. It is
safe to perform TBBx in a
patient taking aspirin.
Table 8-21. Therapeutic Bronchoscopy Technique, continued

Contra-
Method Mechanism Indications Complications
indications
Brachytherapy Implantation of Malignant airway Known fistula Intolerance of
radioactive source obstruction (intrinsic involving airway catheter
adjacent to airway or extrinsic) Tumors invading Radiation bronchitis
lesion major arteries or Airway perforation
mediastinal
structures Massive
hemorrhage (if
lesion in upper
lobes)
Stenting General anesthesia T-tube in Metal-covered Stent migration
and rigid conjunction with stents only for Bacterial
bronchoscopy for tracheostomy for malignant colonization of stent
placement high tracheal compression
stenosis Stent fractures
Extrinsic airway Granulation tissue
compression
Tracheobronchomal
acia
Tracheoesophageal
fistula
Bronchial Thermal energy Asthma None None
thermoplasty applied for airway
(still under ablation
research)
FiO2, fraction of inspired oxygen
394 / CHAPTER 8
LUNG TRANSPLANTATION / 395
9 Lung Transplantation
Tessy Paul, MD
INDICATIONS AND PATIENT SELECTION
Lung transplantation has become a viable therapeutic option for end-stage lung
disease (ESLD) in the last 25 years. Indications for lung transplantation (Figure 9-
1) include obstructive disease (i.e., chronic obstructive pulmonary disease
[COPD], cystic fibrosis [CF], alpha-1 antitrypsin deficiency, bronchiectasis),
restrictive disease (i.e., idiopathic pulmonary fibrosis [IPF] and other interstitial
lung diseases), and less commonly, pulmonary vascular disease (pulmonary
arterial hypertension [PAH]) and congenital diseases. Table 9-1 shows disease-
specific guidelines for lung transplantation in common lung diseases.
Figure 9-1. Indications for adult lung transplantation.

COPD, chronic obstructive pulmonary disease; CF, cystic fibrosis; IPAH, idiopathic pulmonary
arterial hypertension; IPF, idiopathic pulmonary fibrosis; LAM, lipoarabinomannan; OB, obliterative
bronchiolitis.
396 / CHAPTER 9
Table 9-1. Disease-Specific Indications

Disease Indication
COPD and A1AT BODE Index score of at least 7–10 (BODE Index derived from body
mass index, degree of airflow obstruction, dyspnea, and exercise
capacity measured by 6MWT)
or at least one of the following:
 Hospitalization for exacerbation with acute PaCO2 > 50 mm Hg
 Pulmonary hypertension and/or cor pulmonale despite oxygen
therapy
 FEV1 < 20% AND either DLCO < 20% or homogenous distribution
of emphysema
Cystic fibrosis FEV1 < 30% or rapid decline, especially in young women
Exacerbation requiring ICU stay
Increased frequency of exacerbations requiring antibiotics
Refractory or recurrent pneumothorax
Recurrent hemoptysis not controlled with embolization
Oxygen-dependent respiratory failure or PaO2 < 55 mm Hg on room
air
Hypercapnia with PaCO2 > 50 mm Hg
Pulmonary hypertension
Idiopathic pulmonary UIP pattern on CT scan or biopsy with any of the following:
fibrosis  6MWT desaturation (SpO2 < 89%)
 Long-term oxygen therapy
 > 10% decline in FVC over 6 months
 DLCO < 39%
 Honeycombing on high-resolution computed tomography scan
(fibrosis score > 2)
Pulmonary arterial Functional class III or IV despite maximal medical therapy (IV
hypertension (including epoprostenol or equivalent)
congenital heart disease Cardiac index < 2 L/min/m
2
and Eisenmenger
syndrome) Mean RAP > 15 mm Hg
Low (< 350 m) or declining 6MWT
A1AT, alpha-1 antitrypsin deficiency; 6MWT, 6-minute walk test; COPD, chronic obstructive pulmonary disease;
CT, computer tomography; DLCO, diffusion lung capacity for carbon monoxide; FVC, forced vital capacity; IV,
intravenous; FEV1,1-second forced expiratory volume; PaCO2, partial pressure of carbon dioxide; PaO2, partial
pressure of oxygen, arterial; RAP, right atrial pressure; SpO2, oxygen saturation; UIP, usual interstitial
pneumonia.
Recipient Selection and Contraindications

In general, patients considered for lung transplantation should have:
 ESLD that is either untreatable or is not responding to available therapy.
 No other significant medical diseases.
 Limited life expectancy.
 Psychosocial stability.
Table 9-2 shows absolute and relative contraindications to lung transplantation.

Table 9-2. Contraindications to Lung Transplantation

Relative Absolute
Age > 65 years Untreatable advanced dysfunction of another
organ (e.g., cirrhosis, end-stage renal disease,
congestive heart failure)
Critical or unstable clinical condition (e.g., Untreatable chronic extrapulmonary infection
shock) (e.g., active hepatitis B, hepatitis C)
Severely limited functional status or poor Malignancy in the last 2 years (except non-
rehabilitation potential melanoma skin cancer)
Chronic colonization with highly resistant or Tobacco or other substance abuse within 6
virulent organisms (e.g., Burkholderia months
cenocepacia, Mycobacterium abscessus, pan-
resistant Pseudomonas aeruginosa
2
Obesity (body mass index > 30 kg/m ) or poor Significant chest wall or spinal deformity, such
nutritional status as kyphoscoliosis
Severe or symptomatic osteoporosis Absence of reliable social support system
Mechanical ventilation History of noncompliance or untreatable
Extrapulmonary comorbidities without psychiatric illness associated with inability to
significant end-organ damage (e.g., diabetes comply with treatment
mellitus, hypertension, peptic ulcer disease,
GERD)
GERD, gastroesophageal reflux disease.
Choice of Surgical Procedure

BILATERAL LUNG TRANSPLANT (BLT)
 Now performed more often than single-lung transplant (SLT) across all major Key Fact
indications. Suppurative lung diseases,
 Recipients have improved survival across all major indications, although this such as CF and
advantage is considerably attenuated after adjustment for confounders, bronchiectasis always
require BLT rather than
particularly in the setting of advanced age and the diagnosis of IPF. SLT.
 Also provides improved physiologic function.
 Mandatory for patients with suppurative lung diseases, such as CF and
bronchiectasis.
 Preferred in patients with PAH because postoperative insults to the lung may
be poorly tolerated after SLT. Complications such as pneumonia may result in
severe hypoxemia and V/Q mismatch because of pre-existing severely
elevated pulmonary vascular resistance in the native lung.
Flash Card Q1
SINGLE-LUNG TRANSPLANT (SLT)
 Can be performed for nonsuppurative obstructive and restrictive lung diseases. Colonization with what
organism is a relative
 Advantages: contraindication to lung
o Reduced operative time and complexity. transplantation in patients
o Reduced ischemic time. with CF?
o Potentially reduced risk of surgical morbidity in some patients.

o Potentially shorter waiting list time.
 Extends the limited supply of critical donor organs. Flash Card Q2
What are the major
benefits of SLT vs. BLT?
398 / CHAPTER 9
HEART-LUNG TRANSPLANT (HLT)

 Rarely performed.
 Most frequent indications are Eisenmenger syndrome with a surgically
uncorrectable cardiac anomaly or severe ESLD with concurrent severe heart
disease.
PRETRANSPLANT EVALUATION
Patients with ESLD should be referred early to transplant centers. Once they are
deemed potential candidates, they undergo multiple studies for additional
assessment for candidacy.
Laboratory Values
 Renal and liver function tests.

 Infectious serologies (e.g., HIV, viral hepatitis, cytomegalovirus [CMV],
Epstein-Barr virus [EBV]).
 Human leukocyte antigen (HLA) typing and screening for pre-existing HLA
antibodies.
 Sputum cultures in patients with suppurative lung disease to assist with the
postoperative antimicrobial regimen.
Imaging and Other Studies
 Pulmonary function tests: spirometry, lung volume, diffusion capacity.

 Exercise performance with 6MWT.
 Cardiac evaluation: EKG, echocardiogram, cardiac stress test, and coronary
angiography for high-risk patients (e.g., age > 40 years, risk factors for
Flash Card A1 coronary artery disease).
Burkholderia cenocepacia  Chest computed tomography (CT) scan to evaluate for nodules not seen on
chest x-ray and to evaluate for bronchiectasis if BLT is considered.
 Formal evaluation for GERD and gastroparesis in some high-risk patients (pH
Flash Card A2
probe, manometry, gastric emptying).
SLT: shorter
ischemia/operative time,
possibly shorter waiting list
time, and more efficient
use of limited organ supply.
BLT: improved long-term
outcome and life
expectancy.
DONOR SELECTION AND ORGAN ALLOCATION
Most organs are obtained from brain-dead donors; living donor transplantation is
rarely performed. Living donor transplantation is primarily done in patients with
CF. In this case, two blood group–compatible living donors each provide a lower
lobe to the patient.
Donor Selection
Donor selection criteria:
 Age < 55–70 years.
 No significant lung disease or pulmonary infection; no purulent secretions on
bronchoscopy.
 Limited smoking history.
 Clear lung fields on chest x-ray; minimal or no evidence of aspiration.
 Adequate gas exchange: PaO2/FiO2 >300 mmHg on 5cm H2O PEEP.
 No active infection, including HIV or hepatitis.
 No history of malignancy.
 Minimal or no chest trauma.
Organ Allocation
Revisions were made to the donor allocation system in 2005. They system is now
based on a benefit- and need-based lung allocation score (LAS).
 The LAS is calculated using the transplant benefit measure, which is derived
from the difference between the predicted posttransplant survival measure
(expected days lived during the first posttransplant year) and waiting list
urgency measure (expected days lived during an additional year on the
waiting list).
 Each patient receives a normalized score of 0–100. Higher scores represent
greater urgency and greater potential for transplant benefit.
 Factors considered in the LAS calculation include diagnosis, age, functional
status, use of assisted ventilation, height and weight, presence of diabetes, use
of supplemental oxygen, percentage of predicted forced vital capacity (FVC),
6MWT distance, serum creatinine, pulmonary artery pressure, pulmonary
capillary wedge pressure, and arterial or venous Pco2.
 Since the implementation of the LAS system, waiting list mortality and
waiting times have improved. However, overall 1-year survival after lung
transplant has not significantly changed.
400 / CHAPTER 9
TRANSPLANT IMMUNOSUPPRESSION
Patients are managed with induction immunosuppression immediately

postoperatively and typically receive a three-drug maintenance
immunosuppressive regimen posttransplant to combat rejection (Table 9-3).
Table 9-3. Transplant Immunosuppression

Agent Mechanism of Action Adverse Effects
Induction
Polyclonal antibody against T Leukopenia, thrombocytopenia,
ATG/ALG and B cells serum sickness, infusion reactions
(cytokine release syndrome,
anaphylaxis)
Antagonize IL-2–induced T cell Relatively well tolerated with rare
IL-2 receptor antagonists proliferation infusion reactions
(basiliximab/daclizumab)
Maintenance
Decreases T-cell activation Nephrotoxic, neurotoxic, TMA,
Cyclosporine and proliferation via inhibition HLD, HTN, hypomagnesemia,
of calcineurin-dependent hyperkalemia, gastrointestinal
induction of IL-2 expression disturbance, gingival hyperplasia,
hypertrichosis
Decreases T-cell activation Nephrotoxic, neurotoxic, TMA,
Tacrolimus and proliferation via inhibition HLD, HTN, hypomagnesemia,
of calcineurin-dependent hyperkalemia, gastrointestinal
induction of IL-2 expression disturbance, hyperglycemia
Antagonizes purine Pancytopenia, hepatotoxicity,
Azathioprine metabolism and DNA pancreatitis
synthesis
Inhibits the de novo pathway Pancytopenia, diarrhea, abdominal
Mycophenolate mofetil of purine synthesis pain, nausea
Decreases inflammation Hyperglycemia, weight gain,
Prednisone through multiple mechanisms hyperlipidemia, osteoporosis,
myopathy, insomnia, cataracts
Decreases cell cycle Pancytopenia, anastomotic
Sirolimus progression via inhibition of dehiscence and poor wound
mTOR-dependent cyclin D1 healing, interstitial pneumonitis,
synthesis HLD, arthralgia, LE edema, acne,
stomatitis
ATG, antithymocyte globulin; ALG, antilymphocyte globulin; DNA, deoxyribonucleic acid; HLD, hyperlipidemia;
IL-2, Interleukin-2; HTN, hypertension; LE, lower extremity; mTOR, mammalian target of rapamycin; TMA,
thrombotic microangiopathy
INDUCTION—Benefit of induction immunosuppression (antithymocyte globulin

[ATG]/antilymphocyte globulin [ALG], interleukin-2 [IL-2] receptor antagonists,
alemtuzumab) and the choice of agent remain controversial. Approximately half
of all recipients receive no induction therapy.
MAINTENANCE—Initial maintenance regimen most commonly includes a Key Fact

combination of a calcineurin inhibitor (tacrolimus or cyclosporine), an
Most transplant recipients
antimetabolite (azathioprine or mycophenolate mofetil), and corticosteroids eventually have at least
(prednisone). some degree of chronic
kidney disease attributed to
the chronic nephrotoxic
ALTERNATE REGIMENS—Mammalian target of rapamycin (mTOR) effects of calcineurin
inhibitor–based regimens (sirolimus/everolimus) are used in < 10% of recipients inhibitor therapy.
by 1 year, but are avoided in the early postoperative period because of concerns
about delayed wound healing and anastomotic dehiscence.
COMPLICATIONS AFTER TRANSPLANTATION
EARLY PERIOPERATIVE COMPLICATIONS
Primary Graft Dysfunction (PGD)

PGD, or ischemia-reperfusion injury, develops in the first 72 hours after
transplantation and is the leading cause of early death after lung transplantation. Flash Card Q3
PGD shares many features with non–transplant-associated acute lung injury. Which immunosuppressive
agent is most likely to
cause poor wound healing
FINDINGS—Characterized by new diffuse radiographic opacities and hypoxemia and anastomotic
along with decreased lung compliance and increased pulmonary vascular dehiscence?
resistance (Figure 9-2 and Table 9-4). The pathologic hallmark of PGD is diffuse
alveolar damage. Other postoperative complications, such as rejection, infection,
and volume overload, must be ruled out. Flash Card Q4
Which immunosuppressive
agents are known to cause
thrombotic microangiopathy
(TMA)?
Table 9-4. Primary Graft Dysfunction
Radiographic Evidence of
Grade PaO2/FiO2 Flash Card Q5
Pulmonary Edema
0 > 300 Absent Which immunosuppressive
agent can cause
1 > 300 Present
pancreatitis and cholestatic
2 200–300 Present hepatitis?
3 < 200 Present

Pao2, partial pressure of oxygen, arterial; FiO2, fraction of inspired oxygen. Flash Card Q6
If the patient shown in
Figure 9-2 has 60% FiO2
with a PaO2 of 90 on
posttransplant day 2, does
this patient have PGD?
402 / CHAPTER 9
Figure 9-2. Primary graft dysfunction.

(Courtesy of Dr. Ariss Derhovanessian, David Geffen School of Medicine at UCLA.)
RISK FACTORS
 Donor: age, female sex, African American race, and smoking history
 Recipient: PAH and possibly use of cardiopulmonary bypass
TREATMENT—The mainstay of treatment is supportive care and diuresis. Other

therapies, such as protective ventilator strategies, inhaled nitric oxide (iNO) and
extracorporeal membrane oxygenation (ECMO) have been utilized, and
retransplantation has been performed in refractory cases.
Flash Card A3
Sirolimus
Airway/Anastomotic Complications
Flash Card A4
Figure 9-3 shows a normal-appearing transplant anastomosis site. Early airway
Tacrolimus and cyclosporine complications that occur in the first 4–8 weeks and can lead to anastomotic
(calcineurin inhibitors).
Neurotoxicity is also common strictures and bronchomalacia include:
with both agents.
 Partial or complete anastomotic dehiscence.
 Fungal anastomotic infection: Aspergillus (Figure 9-4) and Candida.
Flash Card A5
 Bacterial anastomotic infection: Staphylococcus and Pseudomonas.
Azathioprine
Flash Card A6
Yes, PGD grade 3
Figure 9-3. Bronchoscopic view of normal transplant anastomosis.

(Courtesy of Dr. David J. Ross, David Geffen School of Medicine at UCLA)
A B
Figure 9-4. (A) and (B) Aspergillus infection of an anastomosis site (arrows); (C)
bronchoscopic view of Aspergillus infection of an anastomosis site.
(Courtesy of Dr. John A. Belperio, David Geffen School of Medicine at UCLA)
404 / CHAPTER 9
PRESENTATION—Usually dyspnea on exertion, cough, wheezing, and

worsening obstruction on pulmonary function tests. Bronchial strictures or
stenoses (Figure 9-5) are seen on imaging and bronchoscopy. Patients may also
have mediastinal emphysema or air adjacent to the anastomosis site on CT scan.
Figure 9-5. Bronchoscopic view of stenosis of the anastomosis site.

(Courtesy of Dr. David J. Ross, David Geffen School of Medicine at UCLA)
TREATMENT—Includes balloon dilatation, stent placement, laser therapy, and

surgery along with appropriate antimicrobial treatment for infectious causes.
REJECTION
Transplant rejection is categorized into hyperacute, acute, chronic, and antibody-

mediated types based on the timing of the insult and histopathologic findings
(Table 9-5).
Acute Rejection (AR)
Despite advances in transplant immunosuppression, more than one third of lung

transplant recipients require treatment for AR. AR is the most well-established
risk factor for chronic rejection.
TIMING—AR typically occurs in the first 3 months after lung transplant and is
rarely seen later than the first year after transplantation.
PRESENTATION AND FINDINGS—Patients may present with cough, shortness

of breath, malaise, and fever. However, many episodes are diagnosed in
asymptomatic patients undergoing surveillance biopsy.
Physiologic findings include hypoxia and decline in lung function, as seen in

FEV1, FEF25–75%, and VC. Because clinical signs and symptoms are nonspecific,
the diagnosis is made histologically with bronchoscopy and transbronchial biopsy.
Pathologically, AR is graded as A0–A4 for perivascular inflammation (Figure 9-

6, arrow) and as B0–BX for airway involvement (lymphocytic bronchiolitis).
TREATMENT
 Pulse steroids with methylprednisolone 10–15 mg/kg/day intravenously × 3
days followed by increased maintenance prednisone to 0.5–1.0 mg/kg/day
with taper over several weeks.
 Augmentation/alteration of maintenance immunosuppression in appropriate
cases.
Resolution of symptoms occurs in days, and histologic resolution should occur in

3–4 weeks.
Table 9-5. Transplant Rejection

Grading/
Category of Rejection Findings
Severity
Acute cellular rejection Grade 0 Normal lung
A grade Grade 1 Small amount of mononuclear perivascular infiltrates
Grade 2 More frequent mononuclear perivascular infiltrates ±
eosinophils
Grade 3 Dense mononuclear perivascular infiltrates with
extension into the interstitium ± endothelialitis,
eosinophils, and neutrophils
Grade 4 Diffuse perivascular, interstitial, and air space
mononuclear infiltrates with lung injury and
endothelialitis ± neutrophils
Acute cellular rejection Grade 0 No airway inflammation
B grade Grade 1R Scattered mononuclear submucosal and
peribronchiolar infiltrates
Grade 2R Extensive mononuclear submucosal and
peribronchiolar infiltrates with epithelial infiltrates and
damage
Grade X Ungradable, no bronchiolar tissue available
Chronic airway rejection 0–absent Normal airways
1–present Obliterative bronchiolitis with dense, eosinophilic
hyaline fibrosis
Chronic vascular rejection Accelerated vascular sclerosis of the graft with
fibrointimal thickening of pulmonary arteries and veins
406 / CHAPTER 9
Figure 9-6. Lung transplant rejection with perivascular lymphocytic infiltrate

(arrow).
(Reproduced courtesy of Nephron, Wikimedia Common, CC BY-SA 3.0.)
Chronic Rejection/Bronchiolitis Obliterans Syndrome

(BOS)
Chronic allograft rejection is the leading cause of long-term mortality after lung
transplantation. It is classically characterized by the histopathologic finding of
obliterative bronchiolitis (OB) and its clinical correlate, BOS, which is defined by
a progressive, irreversible obstructive ventilatory defect caused by obliteration
and fibrosis of terminal respiratory bronchioles.
Key Fact
The most important risk POSSIBLE CAUSES/RISK FACTORS—Acute rejection, lymphocytic
factor for chronic rejection bronchiolitis, CMV and other infections, Aspergillus colonization, GERD, PGD,
is acute rejection.
medication noncompliance, HLA mismatch, donor antigen-specific reactivity,
older donor age, and organizing pneumonia.
PRESENTATION—Nonspecific symptoms of cough and progressive dyspnea on

exertion with onset that is insidious or abrupt, but is typically more gradual than
the onset of AR. Otherwise unexplained progressive airflow obstruction is the
physiologic hallmark.
IMAGING—High-resolution CT with hyperinflation, air trapping, cylindrical

bronchial dilation, or bronchiectasis.
DIAGNOSIS—Unlike in AR, transbronchial biopsy has low sensitivity for

diagnosing OB and is used primarily to exclude other diagnoses.
STAGING—The International Society for Heart and Lung Transplantation

(ISHLT) devised a BOS staging system based on FEV1 with or without pathologic
documentation (Table 9-6).
Table 9-6. Staging of Bronchiolitis Obliterans Syndrome

Stage Pulmonary Function Test Result
0 FEV1 > 90% baseline and FEF25–75% > 75%
0-p (potential bronchiolitis obliterans FEV1 81–90% baseline and/or FEF25–75% ≤ 75%
syndrome) baseline
1 FEV1 66–80% baseline
2 FEV1 51–65% baseline
3 FEV1 ≤ 50% baseline
FEV1, forced expiratory volume in 1 second; FEF25–75%, average forced expiratory flow during the mid (25 - 75%)
portion of the FVC
.
TREATMENT
 No established treatment regimen exists for BOS, and conventional
immunosuppressive strategies have been largely unsuccessful.
 Strategies include alteration of maintenance immunosuppression, high-dose
glucocorticoids, cytolytic therapy, and extracorporeal photophoresis, possibly
slowing progression of BOS in some cases.
 Azithromycin has shown promise in small clinical trials for treatment and
prevention of BOS.
 Aggressive therapy for GERD, including fundoplication, may be considered
in patients with confirmed severe refractory GERD.
 Retransplantation is considered for some patients, although overall survival is
further reduced compared with first-time transplants.
Antibody Mediated Rejection (AMR)
AMR is suggested by graft dysfunction with new or increasing antibodies to

donor HLA or other graft epitopes and histologic findings of acute lung injury
with complement deposition and neutrophilic capillaritis. However, these findings
are nonspecific. AMR is less well defined in lung transplantation than in other
solid organ transplants, and no widely accepted diagnostic criteria exist. Flash Card Q7
Treatment options include combinations of high-dose glucocorticoids, intravenous What is the leading cause
of posttransplant mortality
immunoglobulin, plasmapheresis, anti-CD20 monoclonal antibodies (rituximab), after the first year?
and bortezomib.
Hyperacute rejection is a rare form of AMR that occurs within 24 hours of Flash Card Q8
transplant because of pre-existing donor-specific alloantibodies. True or False. BOS can be
diagnosed with
transbronchial biopsies.
408 / CHAPTER 9
INFECTION
Infection rates are higher in patients with lung transplant compared with other
solid organ recipients because of the higher levels of immunosuppression required
and the constant exposure of the lung to the environment. Therefore, infection is a
leading cause of morbidity and mortality and many also be a risk factor for
subsequent chronic rejection. Transplant patients should be given standard
vaccinations, but live vaccines should be avoided.
Bacterial Infections
 Up to one fourth of patients have bacterial pneumonia in the first month after
transplantation.
 Common organisms include Pseudomonas aeruginosa and Staphylococcus
species.
 Although patients are at risk for opportunistic infection throughout their
course, the greatest risk is within the first 6 months.
 At most centers, patients are treated with broad-spectrum empiric antibiotics
at the time of transplantation, targeting both donor- and recipient-derived
pathogens. The course and choice of agents are tailored to specific culture
findings.
Viral Infections
 Viral infections are less common with the use of postoperative prophylactic
antiviral agents (ganciclovir or acyclovir).
Key Fact  The most common viral infection in the first 6 months is CMV. The highest
CMV is the most common
risk is in seronegative recipients with seropositive donors (D+/R−). Patients
viral infection after lung may be asymptomatic or may present with pneumonitis or, less commonly,
transplantation. gastroenteritis, hepatitis, and colitis. Diagnosis of CMV pneumonia can be
made with bronchoscopy with transbronchial biopsy and bronchoalveolar
lavage with CMV polymerase chain reaction (PCR) or findings of pathologic
Flash Card A7 hallmark intranuclear inclusions (“owl’s eye,” as seen in Figure 9-7). Oral
Bronchiolitis obliterans valganciclovir and IV ganciclovir are effective in the treatment and
syndrome prophylaxis of CMV, though resistance has rarely been reported.
 Other less commonly seen viral infections include herpes simplex virus,
Flash Card A8
respiratory syncytial virus, influenza, parainfluenza, human metapneumovirus,
and adenovirus.
False. Unlike AR,
transbronchial biopsy has
low sensitivity for
diagnosing BOS and is
used primarily to exclude
other diagnoses.
Figure 9-7. Active cytomegalovirus infection in the lung (arrow).

(Reproduced from the CDC Public Health Image Library; content provider, Dr. Edwin P. Ewing, Jr.)
Fungal Infections
 Between 15% and 35% of patients have fungal infections posttransplant.

 Mortality rate may be as high as 80%, particularly for drug-resistant and
invasive molds.
 Routine prophylaxis with azoles or aerosolized amphotericin is now used by
most centers, although evidence is limited.
ASPERGILLUS—Aspergillus species (A. flavus, A. fumigatus, A. niger, A.

terreus) can colonize the allograft or cause pneumonia; invade blood vessels,
causing infarction and hemoptysis; or result in pseudomembranous
tracheobronchitis.
 Diagnosis of invasive aspergillosis requires identification of the organism in
the tissue or recovery of the organism in the sputum or bronchoalveolar Key Fact
lavage in the appropriate clinical setting.
Use of azoles, such as
 Organisms appear as septated hyphae with branching at acute angles (Figure voriconazole, can
9-8). significantly increase
 Voriconazole is the drug of choice. Other azoles (posaconazole and cyclosporine and
tacrolimus levels.
itraconazole, but not fluconazole), echinocandins, and amphotericin may also
be effective.
 Concurrent reduction in immunosuppression is advisable when feasible.
CANDIDA SPECIES—Can cause wound infection, line sepsis, mucocutaneous

disease, and less often, pulmonary involvement. Echinocandins are the treatment Flash Card Q9
of choice, and fluconazole, although active against Candida albicans, is less What is the most important
effective against non-albicans species, such as C. glabrata and C. krusei. risk factor for CMV
infection in posttransplant
patients?
410 / CHAPTER 9
Figure 9-8. Pulmonary aspergillosis.

(Reproduced from the CDC Public Health Image Library and Armed Forces Institute of Pathology [AFIP];
content provider Dr. Hardin.)
PNEUMOCYSTIS CARINII PNEUMONIA— Incidence is now < 1% because of

standard prophylaxis with trimethoprim-sulfamethoxazole.
OTHER—Rare fungal infections include Scedosporium and Fusarium species,

mucormycosis, and the endemic mycoses (Cryptococcus, Histoplasma,
Coccidioides, and Blastomyces), with treatment depending on the specific
pathogen.
Given their frequent use after lung transplantation, it is important to note the
strong interactions between azoles and other transplant medications. In particular,
therapy with azoles significantly increases levels of cyclosporine and tacrolimus,
uniformly requiring dose reductions for these agents.
Mycobacterial Infections
 Rarely seen in patients with lung transplant.

 Mycobacterium abscessus infection is associated with poor outcomes.
Flash Card A9
Donor seropositivity and
recipient seronegativity for
CMV
POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER

(PTLD)
 PTLD is more common in lung transplant recipients compared with other

solid organ transplants because of the greater levels of immunosuppression
required.
 Most are lymphomas, and the vast majority (76–95%) are associated with
EBV and are of B-cell origin. Recipient seronegative EBV status pretransplant
significantly increases the risk as acquisition of EBV from the donor leads to
persistent viral replication and transformation of B lymphocytes in
immunosuppression.
 Estimated incidence is 2–8%.
 Often presents with constitutional symptoms and an infectious
mononucleosis-like illness. May be nodal, extranodal, localized, or widely
disseminated. Among lung transplant recipients, 69–89% of cases involve the
thorax. Imaging shows nodules, infiltrates, or thoracic lymphadenopathy.
 Peak incidence is within the first year after transplantation
 First-line treatment is reduction of immunosuppression. Other modalities
include rituximab and consideration for antiviral therapy, chemotherapy,
radiation, adaptive immunotherapy, and surgical intervention.
OTHER MALIGNANT COMPLICATIONS
 According to ISHLT registry reports, malignancy develops in 3.5% of 1-year

lung transplant survivors and 14.1% of 5-year survivors.
 Skin cancer is most common in patients 5 years posttransplant.
 SLT recipients are also at risk for lung carcinoma in the native lung given
their older age, underlying COPD/interstitial lung disease, and frequent
smoking history.
 General age- and sex-appropriate cancer screening should be performed with a
low threshold to further investigate suspicious findings or lesions.
 In general, treatment involves reduction in immunosuppression in addition to
the specific cancer-related therapy.
MISCELLANEOUS POSTTRANSPLANT COMPLICATIONS
 Pleural: effusions, hemothorax, persistent air leak, empyema, and rarely

chylothorax. Flash Card Q10
 Recurrence of primary disease has been reported in those with Langerhans What is the first-line
cell histiocytosis, pulmonary alveolar proteinosis, desquamative interstitial therapy for PTLD?
412 / CHAPTER 9
pneumonitis, lymphangioleiomyomatosis, sarcoidosis, idiopathic

hemosiderosis, giant cell interstitial pneumonitis, and diffuse panbronchiolitis.
 GERD and gastroparesis.
 Osteoporosis.
 Thromboembolic disease.
 Some degree of chronic kidney disease in > 50% of patients at 5 years.
 Dyslipidemia, diabetes mellitus, and hypertension.
OUTCOME OF LUNG TRANSPLANTATION
Key Fact
Survival after lung transplantation is lower than in other solid organ transplant
recipients. The 5-year survival rate is ~53% and is highest in patients with CF and
The average 5-year
survival rate after lung
lowest in those with IPF, likely because of the confounding effects of age and
transplant is about 50%. accompanying comorbidities.
Table 9-7 shows posttransplant survival over time, and Figure 9-9 shows survival
based on diagnosis according to ISHLT registry data.
Table 9-7. Survival After Lung Transplant

Time 3 months 1 year 3 years 5 years 10 years
Survival 88% 79% 64% 53% 30%
Flash Card A10

Reduction in
immunosuppression
Figure 9-9. Lung transplant survival by diagnosis.

COPD, chronic obstructive pulmonary disease; CF, cystic fibrosis; IPAH, idiopathic pulmonary arterial
hypertension; IPF, idiopathic pulmonary fibrosis.
QUALITY OF LIFE AND PHYSIOLOGIC OUTCOME

 Patients report improvement in quality of life posttransplant, with > 80%
reporting no limitations in activity at 1 year.
 The degree of improvement in lung function is gradual and plateaus 3–6
months after transplant.
 Peak posttransplant spirometric index is variable and depends on both the type
of transplant and the native lung disease.
 Lung volumes are typically superior after BLT, often yielding normal lung
function. These patients also have equal division of ventilation and perfusion.
 After SLT, most ventilation and perfusion is directed toward the transplanted
lung, leading to essentially normal gas exchange in most patients.
 Patients with PAH who undergo transplantation have marked improvement in
gas exchange, near-normal hemodynamics, and almost complete recovery of
right ventricular function. This obviates the need for HLT in most patients
with PAH.
MORTALITY
 Early (< 30 day): most often as a result of PGD.
 30 days to 1 year: most often because of infectious complications.
 Late (> 1 year): most often because of chronic rejection or BOS.
414 / CHAPTER 9
PULMONARY VASCULAR DISEASE / 415
10 Pulmonary Vascular Diseases

Jeffrey Albores, MD, Sachin Gupta, MD, Tessy Paul, MD & Sandeep Sahay, MD
PULMONARY VASCULITIS AND ALVEOLAR

HEMORRHAGE SYNDROMES
Vasculitis is the inflammation of blood vessel walls. The Chapel Hill Consensus
Conference in 2012 defined the current classification of vasculitic syndromes as
Idiopathic or primary vasculitis syndromes are a group of immune-mediated

diseases of unknown etiology. Secondary vasculitis syndromes are typically
secondary to connective tissue disease (e.g., systemic lupus erythematous [SLE]),
infection, or drug use (therapeutic or illicit).
Vasculitides can be classified based on the vessel size:

 Small-vessel vasculitis:
o Immune complex-associated vasculitis
o Antineutrophilic cytoplasmic antibodies (ANCA)-associated vasculitis
 Medium-vessel vasculitis
 Large-vessel vasculitis
Immune complex small-vessel vasculitis is characterized by immune complex

deposits, which are either immunoglobulin G (IgG) or complement and are
readily detected in the affected tissues. Small-vessel vasculitides are of utmost
importance to the pulmonologist as they tend to involve the small
intraparenchymal pulmonary arteries, arterioles, capillaries, and venules. These
conditions will be discussed in detail later. Medium arteries and bronchial veins
may also be affected.
416 / CHAPTER 10
Table 10-1. Classification of Vasculitis

Small-vessel ANCA-associated vasculitis (pauci-immune):
vasculitis GPA (formerly Wegener’s granulomatosis)
MPA
EGPA (formerly Churg-Strauss syndrome)
Immune complex-associated vasculitis:
Primary Cryoglobulinemic vasculitis
Vasculitis Hypocomplementemic urticarial vasculitis (anti-C1q
vasculitis)
Syndromes
Anti-GBM disease
IgA vasculitis(Henoch-Schönlein)
Medium-vessel Polyarteritis nodosa
vasculitis Kawasaki disease
Large-vessel Takayasu arteritis
vasculitis Giant cell (temporal) arteritis
Lupus vasculitis
Rheumatoid vasculitis
Sarcoid vasculitis
Secondary Vasculitis
Drug-associated ANCA-associated vasculitis
Syndromes Cancer-associated vasculitis
Vasculitis related to hepatitis C and hepatitis B
Syphilis-associated aortitis
ANCA, antineutrophilic cytoplasmic antibodies; EGPA, eosinophilic granulomatosis with polyangiitis; GBM,
glomerular basement membrane; GPA, granulomatosis with polyangiitis; Ig, immunoglobulin; MPA, microscopic
polyangiitis
SMALL-VESSEL VASCULITIS
Mnemonic
The most common causes
of pulmonary vasculitides
ANCA-Associated Vasculitis (AAV)
are the AAV diseases:
GME ANCA associated vasculitides are characterized by systemic necrotizing small-
vessel vasculitis. This group of diseases includes granulomatosis with polyangiitis
Granulomatosis with
polyangiitis (GPA, (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with
formerly Wegener’s polyangiitis (EGPA). Frequent occurrence of ANCA is pathognomonic, but not
granulomatosis) required for diagnosis. More than half of patients with these vasculitides have
Microscopic polyangiitis
(MPA) ANCA positivity as well as predominant pulmonary symptoms.
Eosinophilic
granulomatosis with EPIDEMIOLOGY—AAV can affect patients of any age and gender. GPA is seen
polyangiitis (EGPA,
formerly Churg-Strauss more commonly in whites. EGPA does not show any predilection to any race or
syndrome) ethnicity (Table 10-2).
Table 10-2: Comparison of AAV Clinical Features

GPA MPA EGPA
Epidemiology
Age at diagnosis Any age Any age (higher 30–40 years
incidence > 50 years)
Gender (M:F) 1:1 1:1 1:1
Race >90% whites, Southern European, No predilection
Northern European Mediterranean
descent descent
Clinical Features
Upper airway 90–95% No 50–60%
involvement
Pulmonary parenchymal 54–85% 20% 30%
disease
Skin involvement 33–46% 62% 50–60%
Alveolar hemorrhage 5–15% 10–50% < 3%
Glomerulonephritis 51–80% 60–90% 10–25%
Eye involvement 35–52% < 5% < 5%
CNS involvement 20–50% 60–70% 70–80%
GI involvement < 5% 30% 30–50%
Cardiac involvement 8–16% 10–15% 10–15%
Asthma No No Yes
Type of Inflammation
Granulomatous Yes No Yes
Inflammatory cell type Neutrophilic Neutrophilic Eosinophilic
inflammation inflammation inflammation
Histopathology
Lung Capillaritis ± Capillaritis Necrotizing
granulomatosis eosinophilic
granulomatosis
(allergic granuloma)
Kidney Segmental necrosis, Segmental necrosis, Necrotizing crescentic
crescent crescent glomerulonephritis
Immunofluorescence
Lung Negative Negative -
Kidney Pauci-immune Pauci-immune Pauci-immune
Serology
ANCA positivity 90% 70% 50%
a a
Type of ANCA cANCA (80–90%) pANCA (70–80%) pANCA (70–75%)
(antiproteinase) (myeloperoxidase) (myeloperoxidase)
a
20% of patients with GPA or MPA can have alternate ANCA antibodies. ~10% can be ANCA negative.
ANCA, antineutrophilic cytoplasmic antibodies; cANCA, cytoplasmic antineutrophil cytoplasmic antibodies;
CNS, central nervous system; EGPA, eosinophilic granulomatosis with polyangiitis; GI, gastrointestinal; GPA,
granulomatosis with polyangiitis; Ig, immunoglobulin; MPA, microscopic polyangiitis; pANCA, perinuclear
antineutrophilic cytoplasmic antibodies.
CLINICAL FEATURES—There is a significant overlap in the clinical presentation

of the AAV diseases. Table 10-2 highlights the clinical features of the AAVs.
 GPA: Ear, nose, and throat (ENT) symptoms are usually noticed in > 85% of
patients with GPA. Cavitary nodules or masses characterize pulmonary
involvement in GPA.
 EGPA: Triad of asthma (allergic disease), eosinophilia (blood and tissue;
Figure 10-1), and vasculitis (tissue necrosis). Leukotriene inhibitors are
418 / CHAPTER 10
known to unmask EGPA. In EGPA, ANCA follows the vasculitis activity.
Figure 10-1. Micrograph showing an eosinophilic tissue infiltration with

necrotizing vasculitis consistent with EGPA (formerly Churg-Strauss syndrome).
Hematoxylin and eosin (H&E) stain.
(Reproduced courtesy of Nephron, Wikipedia Commons, permission granted per the GNU Free Documentation
License, Version 1.2.)
ANCA TESTING—Cytoplasmic antineutrophil cytoplasmic antibody (cANCA)

pattern is characterized by the diffuse cytoplasmic staining (Figure10-2). In cases
with cANCA, antibodies are directed against antiproteinase (PR-3); rarely,
antibodies against myeloperoxidase (MPO) can also be seen.
Figure 10-2. Immunofluorescence pattern produced by binding of ANCA from a

patient with GPA (formerly Wegener's granulomatosis) to ethanol-fixed
neutrophils.
Perinuclear antineutrophil cytoplasmic antibody (pANCA, Figure 10-3) is

characterized by perinuclear staining. The responsible antibody is usually directed
against MPO, but rarely is also directed against PR-3.
Figure 10-3. Immunofluorescence pattern produced by binding of serum from a

patient with MPA to ethanol-fixed neutrophils.
420 / CHAPTER 10
MANAGEMENT OF AAV—Therapeutic approach for this group of conditions is

based on similar principles, as the intent is to induce and maintain remission.
Treatment should be individualized based on the extent and the severity of the
disease (Table 10-3).
Definition of severe disease: Life-threatening or irreversible loss of an organ; for

example, glomerulonephritis, alveolar hemorrhage, eye involvement (except
simple episcleritis), and central nervous system (CNS) involvement.
Limited disease: All others who do not have severe disease.
Table 10-3. Treatment of AAV
GPA MPA EGPA

Standard Therapy GCS + MTX GCS+MTX GCS ±MTX/AZA
(Limited Disease)
Standard Therapy GCS + CYC or GCS+RTX GCS + CYC or RTX
(Severe Disease) GCS + RTX or anti-IL-5
Remission MTX or AZA MTX or AZA MTX or

Maintenance AZA (after CYC)
(Limited)
Remission Following CYC: MTX RTX MTX or
Maintenance or AZA AZA or leflunomide
(Severe) Following RTX: (after CYC)
unclear
Refractory Disease GCS + RTX/CYC or GCS + RTX or RTX GCS + CYC or RTX
plasma exchange alone or plasma Plasma exchange
exchange
AZA, azathioprine; CYC, cyclophosphamide; GCS, glucocorticoids; MTX, methotrexate; RTX, rituximab
PROGNOSIS
 GPA or MPA: Untreated patients have mortality rate of 90% in 2 years. Major
cause of death is renal or respiratory failure, and less commonly, heart failure.
 EGPA: The 5-year survival rate is 70–90%. Most deaths are due to heart
failure or myocardial infarctions.
A five-factor score (FFS) system has been developed to quantify prognosis in

EGPA. Each factor is assigned one point:
 Age > 65 years
 Cardiac insufficiency
 Renal insufficiency (creatinine > 1.7 mg/dL)
 Gastrointestinal (GI) involvement
 Absence of ENT manifestations
A score ≥ 1 has been associated with mortality ranging between 25–45% at 5

years. The worst prognosis is seen in older patients (> age 65) with cardiac and GI
involvement.
OTHER PULMONARY VASCULITIDES
This group consists of large- and medium-vessel vasculitic conditions that affect
the lungs. Table 10-4 highlights their clinical features.
Table 10-4. Clinical Features of Other Pulmonary Vasculitides

Clinical Features/
Vasculitic Pulmonary Diagnosis/
Condition Epidemiology Symptoms Treatment
Giant cell 25/100,000 per year Malaise, myalgias, Elevated ESR (typically
arteritis Scandinavian countries fever, headaches 100 mm/hour or more),
Age > 50 years Pulmonary features elevated CRP
seen in 25% of patients. Treatment: steroids
Cough, sore throat,
hoarseness
Lung nodules,
interstitial infiltrates,
bronchocentric
granulomas
Takayasu 1–3/1 million per year Claudication, V/Q scan and MR
arteritis Women < 40 years mesenteric ischemia, angiography
More common in Asian and renal artery Treatment: steroids,
women stenosis. methotrexate,
Pulmonary artery leflunomide
involvement, stenoses,
pulmonary hypertension
reported as high as 50%
of patients.
PAN 2–33/1 million per year Associated with Renal arteriography,
Male predominance hepatitis B or C tissue diagnosis; biopsy
th
infection. Skin, nerves, shows necrotizing
Usually in 6 decade GI, and kidney arteritis of medium-sized
commonly involved. arteries.
Rarely involves Treatment: steroids,
bronchial arteries. methotrexate, CYC in
Alveolar hemorrhage in severe cases
PAN indicates presence
of other disease, as it
never causes capillaritis.
422 / CHAPTER 10
Table 10-4. Clinical Features of Other Pulmonary Vasculitides, continued

Clinical Features/
Vasculitic Pulmonary Diagnosis/
Condition Epidemiology Symptoms Treatment
IgA-associated Affects children and Fever, purpura, large Pathology shows
vasculitis young adults (mean age joint arthralgias, characteristic IgA
(Henoch- 17 years) abdominal colic, deposits in skin and
Schönlein) nephritis. kidney.
Glomerulonephritis is
Alveolar hemorrhage is predominantly
extremely rare. proliferative and
necrotizing type.
Treatment: steroids,
NSAIDs
Anti-GBM < 1/1 million per year Hemoptysis and Anti-GBM antibodies,
disease Patients < 30 years hematuria. Lungs are renal biopsy. Severity of
(male predominance) affected in 50% of renal disease at
present with patients with anti-GBM diagnosis determines
Goodpasture’s antibodies, causing the prognosis.
syndrome (DAH) clinical presentation of Treatment: steroids,
DAH. plasma exchange, CYC
Patients > 50 years
(female predominance) Renal involvement is or RTX
usually have isolated seen almost in all cases,
renal disease. and isolated lung
involvement is rare.
Cryoglobulinemic ~50% of patients have Peripheral nerve and Diagnosis by tissue
vasculitis associated hepatitis C renal involvement are biopsy showing
infection common. cryoglobulin deposition
Alveolar hemorrhage is in small vessels,
seen in 3% but carries a predominantly
mortality of ~80%. capillaries, venules, and
arterioles.
Treatment: RTX
CRP, C-reactive protein; CYC, cyclophosphamide; DAH, diffuse alveolar hemorrhage; ESR, erythrocyte
sedimentation rate; GBM, glomerular basement membrane; GI, gastrointestinal; Ig, immunoglobulin; MR,
magnetic resonance; NSAID, nonsteroidal antiinflammatory drug; PAN, polyarteritis nodosa; RTX, rituximab;
V/Q, ventilation-perfusion
DIFFUSE ALVEOLAR HEMORRHAGE SYNDROMES (DAH)
DAH is characterized by diffuse hemorrhage into the alveolar spaces. Hemoptysis

may be absent in up to 30% of patients. Progressive dyspnea and hypoxemia leads
to respiratory failure. Chest radiograph typically shows diffuse alveolar infiltrates
bilaterally. Reduced and/or declining hemoglobin (iron-deficiency) is also seen.
Coagulopathy and thrombocytopenia can predispose to alveolar hemorrhage.
Etiology of DAH is multifactorial. The most common etiologies are listed in

Table 10-5.
Table 10-5. Etiology of DAH

DAH associated with pulmonary capillaritis
AAVs (GPA, MPA, EGPA)
Connective tissue disorders (SLE, RA, mixed connective tissue disorders, Behçet disease,
polymyositis, IgA-associated vasculitis
DAH with or without capillaritis

Goodpasture’s syndrome
SLE
Antiphospholipid syndrome
Drug-induced DAH
DAH without pulmonary capillaritis

Malignancies
Lymphangioleiomyomatosis
Pulmonary veno-occlusive disease
Pulmonary capillary hemangiomatosis
Mitral stenosis
Inhalation toxins (crack cocaine, trimetallic anhydride)
Severe coagulopathy (thrombocytopenia, iatrogenic)
Idiopathic pulmonary hemosiderosis
Drugs (anticoagulation, abciximab, all transretinoic acid, sirolimus)
AAV, ANCA-associated vasculitides; DAH, diffuse alveolar hemorrhage; EGPA, eosinophilic granulomatosis
with polyangiitis; GPA, granulomatosis with polyangiitis; Ig, immunoglobulin; MPA, microscopic polyangiitis; RA,
rheumatoid arthritis; SLE, systemic lupus erythematous.
DIAGNOSIS
 Determine severity and rate of progression.
 Look for other organ involvement.
 Check complete blood count (CBC) and serial hemoglobin (Hgb)
determinations; serum creatinine (> 2.5 mg/dL) and blood urea nitrogen
(BUN); urinalysis and urine microscopy. Ruling out coagulopathy is essential.
 Look for specific etiology of the DAH. Autoimmune causes of DAH are listed
in Table 10-5. Other causes include bone marrow transplantation, acquired
immune deficiency syndrome (AIDS), and idiopathic rapidly progressive
glomerulonephritis.
DAH ASSOCIATED WITH BONE MARROW TRANSPLANTATION

 Usually seen within first 30 days.
 Risk is higher with autologous than with allogeneic transplant.
 Risk factors: intensive conditioning, age > 40 years.
 Hemoptysis is often absent—don’t be misled.
 Treatment: High-dose steroids, but evidence is not convincing.
ROLE OF BRONCHOSCOPY—DAH from any cause is best confirmed by

bronchoalveolar lavage (BAL). The serial lavage aliquots will be gradually more
hemorrhagic, confirming the alveolar origin of the blood. Hemosiderin-laden
Flash Card Q1
macrophages (demonstrated by Prussian blue staining) are also characteristically
found in BAL fluid from patients with DAH, and in the absence of active Is DAH more commonly
found in autologous or
hemorrhage, > 20% of hemosiderin-laden macrophages in the BAL fluid is allogenic BMT?
424 / CHAPTER 10
indicative of alveolar hemorrhage. Transbronchial lung biopsy is too small to

allow diagnosis and relatively contraindicated in patients on mechanical
ventilators. Patients are often too critically ill to tolerate video-assisted
thoracoscopic surgery (VATS) or open-lung biopsy (Figure 10-4).
DAH is seen in the variety of autoimmune conditions (Table 10-5). Serological

markers, immunofluorescence pattern and the histopathologic findings seen in
these conditions is show in Table 10-6.
Table 10-6. Specific Serological Markers and the Pathology of

Autoimmune DAH
Lung Pathology Immunofluorescence Serology
Capillaritis ± Negative cANCA (more
GPA
granulomatosis common)
MPA Capillaritis Negative pANCA or cANCA
SLE Capillaritis Granular ANA
Idiopathic ± Capillaritis Negative Negative
Pulmonary
Hemosiderosis
Goodpasture’s ± Capillaritis Linear ABMA (± pANCA)
Syndrome
ABMA, anti-basement membrane antibody; ANA, antinuclear antibody; cANCA, cytoplasmic antineutrophil
cytoplasmic antibodies; DAH, diffuse alveolar hemorrhage; GPA, granulomatosis with polyangiitis; MPA,
microscopic polyangiitis; pANCA, perinuclear antineutrophilic cytoplasmic antibodies; SLE, systemic lupus
erythematous.
Figure 10-4. Lung biopsy specimen showing hemosiderin-laden macrophages

Flash Card A1 and blood filling the alveolar spaces. H&E stain.
(Image courtesy of Nephron, Wikimedia commons, CC BY-SA 3.0)
Autologous BMT
TREATMENT—Corticosteroids. High-dose pulse dose steroids (500 mg–2g/day

in divided doses) for 5 days followed by gradual tapering and maintenance
therapy. Cyclophosphamide (CYC) with steroids and plasma exchange have also
been tried in refractory cases.
DAH with Antiphospholipid Syndrome (APS)

CLINICAL FEATURES—Presents with rapidly progressing respiratory failure and
is associated with high mortality. Subclinical to massive hemoptysis may be
absent in 50% of patients. Tissue necrosis from microthrombosis and capillaritis
are the mechanisms of alveolar hemorrhage.
TREATMENT—Steroids are helpful. Early plasma exchange along with

immunosuppressive therapy should be considered.
Idiopathic Pulmonary Hemosiderosis (IPH)
EPIDEMIOLOGY—Primarily reported in the pediatric population. Exact

incidence and prevalence are unknown. There is no definite gender predilection.
CLINICAL FEATURES—Diagnosis of exclusion. It is a disease limited to the

lungs. Recurrent hemoptysis and ground-glass infiltrates seen. Iron-deficiency
anemia is a hallmark of the disease. Bland-lung histopathology with fibrosis seen
in chronic recurrent cases. Predominantly seen in children; 20% of patients are
adults (age 20–40 years).
TREATMENT—Immunosuppression, plasma exchange, gluten-free diet.
VENOUS THROMBOEMBOLISM (VTE)
VTE constitutes the spectrum of disease related to deep venous thrombosis (DVT)
and pulmonary embolism (PE). About 79% of patients who present with PE also
will have concomitant DVT; on the other hand, only ~50% of patients presenting
with DVT will have PE. VTE pathogenesis, diagnosis, and therapy are discussed
in this chapter.
Flash Card Q2
What is Lane-Hamilton
syndrome?
426 / CHAPTER 10
Pathogenesis
Thrombosis is related to one or more of the three factors in Virchow’s triad:
1) Disturbed blood flow
2) Endothelial cell injury
3) Hypercoagulability
Table 10-7 discusses the etiologies for hypercoagulability.
Table 10-7. Etiologies for the Hypercoagulable State
Thrombophilia Etiology
Factor V Leiden mutation, protein C or S deficiency, antithrombin III

Inherited
deficiency, prothrombin gene mutation
Malignancy, surgery, pregnancy, CVA, hormone replacement, tamoxifen,
Acquired antiphospholipid syndrome, IBD, nephrotic syndrome, myeloproliferative
disorders
CVA, cerebrovascular accident; IBD, inflammatory bowel disease.
DEEP VENOUS THROMBOSIS (DVT)
Diagnosis begins with clinical suspicion. Affected proximal veins include the
popliteal, femoral, and iliac; distal veins are those of the calf muscles. Nearly 90%
of acute PEs originate from proximal DVTs; these clots more often are related to
chronic disease. Workup is therefore geared towards detection of proximal DVT.
For DVT, the clinical signs and symptoms have poor sensitivity and specificity.
Therefore, prior to initiating testing it is important to stratify patients with a
clinical prediction algorithm. The Wells’ prediction rule is presented in Table 10-
8.
Flash Card A2
Association of gluten-
sensitive sprue (celiac
sprue) with idiopathic
pulmonary hemosiderosis.
Only 18 cases are
described in the literature.
All IPH patients should be
screened for sprue with
serologies (antigliadin and
antiendomysial antibodies).
Gluten-free diet seems key
to therapy and prevention
of relapses.
Table 10-8. Wells’ Prediction Rule for Diagnosing DVT
Clinical Characteristic Score

Active cancer (patient receiving treatment for cancer within the previous 6
+1
months or currently receiving palliative treatment)
Paralysis, paresis, or recent plaster immobilization of the lower extremities +1
Recently bedridden for 3 days or more, or major surgery within the previous
+1
4 weeks
Entire leg swollen +1
Calf swelling—circumference ≥ 3 cm larger than that on the asymptomatic
+1
side when measured 10 cm below tibial tuberosity
Pitting edema confined to symptomatic leg +1
Collateral superficial veins (nonvaricose) +1
Alternative diagnosis is at least as likely -2
Clinical Probability of PE Sum
Low <1
Intermediate 1–2
High >2
Diagnosis
After assigning the patient to low-, moderate-, or high-risk pretest probability, it is

appropriate to initiate testing based on risk.
D-Dimer—Use first if Wells’ score ≤ 2.

 High sensitivity (88%), poor specificity (40–60%)
 High negative predictive value: 96%
 If negative, DVT has been ruled out.
 If positive, proceed to testing.
Imaging—Refer to Table 10-9 if Wells’ score ≥ 2.
Table 10-9. Imaging Studies for Diagnosing DVT
Test Sensitivity/Specificity Comments
Noninvasive
Impedance plethysmography 91%/96% Rarely used, cumbersome.
Misses iliac veins; may
Compression ultrasonography 100%/99% repeat.
Clinical gold standard.
Invasive
Used when above studies fail,
Contrast venography Reference test
or concern for iliac thrombus.
428 / CHAPTER 10
PULMONARY EMBOLISM (PE)
With treatment, 3-month mortality for PE patients is 8–15%. The formation of

chronic thromboemboli is a consequence of inadequate therapy; however, the
development of pulmonary hypertension is rare, affecting only 3% of those with
acute thromboemboli. Chronic thromboembolic pulmonary hypertension is
discussed later in this chapter.
The evaluation of possible PE begins in a similar fashion to DVT. Like DVT, the
clinical signs and symptoms have poor sensitivity and specificity. Therefore,
before initiating testing, it is important to stratify patients for disease probability
with a clinical prediction algorithm. Both the Wells’ score and Geneva score have
been demonstrated to be efficacious. The Wells’ score is most often cited (and
tested) and hence presented in Table 10-10.
Table 10-10. Wells’ Prediction Rule for Diagnosing PE
Clinical Characteristic Score

Previous PE or DVT +1.5
HR > 100 bpm +1.5
Recent surgery or immobilization in last 30 days +1.5
Alternative diagnosis less likely than PE +3
Clinical signs of DVT +3
Hemoptysis +1
Cancer (treated within the last 6 months) +1
Clinical Probability of PE Sum

Low 0–1
Intermediate 2–6
High ≥7
DVT, deep venous thrombosis; HR, heart rate; PE, pulmonary embolism.
Diagnosis
After assigning the patient to low-, intermediate-, or high-risk pretest probability,

it is appropriate to initiate testing based on risk. The management algorithm is
found in Figure 10-5. Features of diagnostic testing are described in Table 10-11.
Figure 10-5. Diagnosis of PE.
Table 10-11. Testing Methods for PE

Sensitivity/
Test Comments
Specificity
Noninvasive
D-dimer 96%/40% Useful if negative in low/intermediate pretest probability
only.
V/Q scan 77%/98% Affected by lung pathology; preferred in cases of renal
failure and contrast allergy.
Spiral CTA 83%/96% Evaluate clot burden, cardiac changes. High NPV.
Extremity 29%/97% Useful when signs/symptoms suggestive of DVT; if + then

ultrasound no further workup necessary.
Invasive
Pulmonary Reference test Morbidity 5%, mortality 2%. Rarely performed.
angiography
CTA, computed tomography angiography; DVT, deep venous thrombosis; NPV, negative predictive value; V/Q,
ventilation-perfusion.
430 / CHAPTER 10
VTE IN PREGNANCY
PE is associated with a high risk of postpartum morbidity and mortality and is the
cause of 20% of maternal mortality in the U.S. (Table 10-12). The management
algorithm is shown in Figure 10-6.
Table 10-12. VTE in Pregnancy
Incidence Timing Causes Diagnosis Comments

10.6 per PE most Increased protein See D-dimer
100,000 frequently C resistance; algorithm in sensitivity/specificity:
postpartum (up to increased venous Figure 10-6. 73%/15%; therefore,
6 weeks); DVT stasis from IVC not used in pregnancy.
most frequently compression and
Left leg DVT more
antepartum. vessel injury
common than right leg
during delivery.
because of
compression of left iliac
vein by right iliac artery
when gravid.
DVT, deep venous thrombosis; IVC, inferior vena cava; PE, pulmonary embolism; VTE, venous
thromboembolism.
Figure 10-6. Management algorithm for PE in pregnancy.

CTPA, computed-tomographic pulmonary angiography; CUS, compression ultrasound; CXR, chest radiography;
PE, pulmonary embolism; V/Q, ventilation–perfusion.
(Reproduced, with permission, from Leung AN, Bull TM , Jaeschke R, et al. An Official American Thoracic
Society/Society of Thoracic Radiology Clinical Practice Guideline: Evaluation of Suspected Pulmonary
Embolism In Pregnancy. Am J Respir Crit Care Med. 2011; 184(10): 1200-1208. Fig. 1.DOI:
10.1164/rccm.201108-1575ST.)
Treatment
Standard pharmacological therapy reduces morbidity and mortality from VTE.

Complications of VTE include recurrence of disease, fatal PE, extension of
thrombus, post-thrombotic syndrome, and chronic thromboembolic pulmonary
hypertension. Table 10-13 details the features of therapies, while Figure 10-7
demonstrates schematically their mechanisms of action. More details on therapies
are found in the American College of Chest Physicians (ACCP) guidelines.
Table 10-13. Therapies for VTE

Reversal
Treatment Mechanism Monitoring Comments
Agent
Heparin Binds AT III and PTT levels Protamine Can cause Type II HIT
factor Xa when Ab to PF4 form;
treat with argatroban.
Enoxaparin Binds factor Xa Factor Xa Protamine Recommended agent in
>>> AT III levels malignancy and
pregnancy; monitor
levels. Do not use if CrCl
< 30 or weight > 150 kg.
Warfarin Blocks vitamin K INR Vitamin K, Category X; OK during
epoxide: Slow FFP, lactation; multiple drug
decrease in prothrombin interactions.
factors II, VII, IX, complex
X, and thrombin
Argatroban Direct thrombin PTT None Primarily used for HIT.
inhibitor
Dabigatran Oral factor IIa None None FDA approved,
inhibitor noninferior to warfarin;
lower overall bleeding but
increased major bleeding.
Rivaroxaban Oral factor Xa None None FDA approved; equivalent
inhibitor bleeding risk; long-term Key Fact
studies forthcoming.
Protamine should be given
Thrombolytic Increased None None None proven superior; only when resuscitation
therapy: plasminogen tPA preferred given techniques and treatment
streptokinase, increases shortest infusion time. No of anaphylactic and
urokinase, tPA plasmin, which mortality benefit. anaphylactoid shock are
breaks down Indicated for massive PE. readily available. Reduce
fibrin. the rate of administration in
IVC filter Placed when a Retrievable No short-term or long- cases of bradycardia,
contraindication or permanent term demonstrable dyspnea, and hypotension.
exists to mortality benefit. Administration that is too
anticoagulation or Increased risk of DVT. rapid may cause severe
if poor hypotension.
cardiopulmonary
reserve after PE.
Compression Reduces Pharmacologic therapy
stockings symptoms of for post-thrombotic
post-thrombotic syndrome not
syndrome. recommended (rutosides,
hidrosmin).
Ab, antibodies; AT, antithrombin; CrCl, creatinine clearance; DVT, deep venous thrombosis; FFP, fresh frozen
plasma; HIT, heparin-induced thrombocytopenia; IVC, inferior vena cava; PE, pulmonary embolism; PF, platelet
factor; PTT, partial thromboplastin time; tPA, tissue plasminogen activator; VTE, venous thromboembolism.
432 / CHAPTER 10
Mnemonic
RivaroXaban and
ApiXaban are factor Xa
inhibitors
StreptoKinase and
uroKinase are systemic
agents
AltePlase is a targeted
agent (specific ‘plase’)
Figure 10-7. Coagulation cascade with select VTE therapies.
(Reproduced, with permission, from Gallego P, Roldan V, Lip GYH. Conventional and New Oral Anticoagulants
in the Treatment of Chest Disease and Its Complications. Am J Respir Crit Care Med. 2013;188(4):413-21. doi:
10.1164/rccm.201301-0141PP)
MASSIVE AND SUBMASSIVE PE
Massive PE is defined by the presence of hypotension and shock, not by the size
of the embolism. Submassive PE is less clearly defined in the literature and may
be related to increased risk of complications. Management of submassive PE is no
different than that for standard PE; however, there may be instances where
thrombolytic therapy is considered. Table 10-14 shows mortality rates from PE.
Table 10-14. In-Hospital Mortality Based on Degree of Hemodynamic

Compromise
Finding Mortality
RV dysfunction, no hypotension 8.1%
Hypotension 15.2%
Cardiogenic shock 24.5%
Cardiopulmonary resuscitation 64.8%

RV, right ventricular.
Electrocardiogram (ECG) changes, including S1Q3T3 and T-wave inversions in

V1-4, as well as elevated brain natriuretic peptide (BNP) and troponin serve as
markers for prognosis in PE (Table 10-15).
Table 10-15. Clinical Markers in PE
Test Comments
6x increased mortality when BNP > 100,

BNP
16x increased mortality when NT-proBNP > 600
Increased risk of short-term mortality (OR 5.24, 95% CI 3.28–8.38) or death

Troponin
due to PE (OR 9.44, 95% CI 4.14–21.49)
RV dysfunction Incongruent findings on mortality effect in 2 meta-analyses
Correlated with both increased all-cause mortality (adjusted HR 2.05, 95%

Concomitant DVT CI 1.24–3.38) and increased PE-specific mortality (adjusted HR 4.25, 95%
CI 1.61-–1.25)
BNP, brain natriuretic peptide; CI, confidence interval; DVT, deep venous thrombosis; HR, hazards ratio; NT, N-
terminal; OR, odds ratio; PE, pulmonary embolism; RV, right ventricular.
Figure 10-8 details the management algorithm in the setting of massive PE.
Thrombolytic therapy carries a significant risk for massive bleeding. Therefore,
its use must be weighed carefully against the risk of complications. Table 10-16
discusses the indications and contraindications for thrombolytic therapy in detail.
434 / CHAPTER 10
Figure 10-8. Management algorithm for massive PE.

BNP, brain natriuretic peptide; IVC, inferior vena cava; IVF, intravenous fluid; LMWH, low-molecular-weight
heparin; PE, pulmonary embolism; SK, streptokinase; tPA, tissue plasminogen activator; UFH, unfractionated
heparin; UK, urokinase.
Table 10-16. Therapy for Massive VTE

Potential Relative Absolute
Indications Indications for Contraindications Contraindications to
for Therapy Therapy to Therapy Therapy
Severe Persistent hypotension Severe uncontrolled Previous hemorrhagic
hypoxemia HTN (BP > 180/110) stroke at any time; other
stroke or cerebrovascular
events within 1 year
Large perfusion Shock Hx of prior Known intracranial
defect on V/Q CVA/intracranial neoplasm
scan disease not covered in
absolute
contraindications
Extensive Massive proximal LE Current use of Active internal bleeding
embolic burden thrombus associated anticoagulants; known
on CT with severe swelling or bleeding diathesis
limb ischemia
RV dysfunction Recent trauma (within Suspected aortic
2–4 weeks); prolonged dissection
CPR (> 10 minutes) or
major surgery within 3
weeks
Free-floating RA Noncompressible
or ventricular vascular punctures
thrombus
PFO Recent (2–4 weeks)
internal bleeding
CPR Pregnancy, PUD
For streptokinase: prior

exposure (especially
within 5 days–2 years)
or prior allergic reaction
BP, blood pressure; CPR, cardiopulmonary resuscitation; CT, computed tomography; CVA, cerebrovascular
accident; DVT, deep venous thrombosis; HTN, hypertension; Hx, history; LE, lower extremity; PFO, patent
foramen ovale; PUD, peptic ulcer disease; RA, right atrial; RV, right ventricular; V/Q, ventilation-perfusion; VTE,
venous thromboembolism.
Length of Treatment
The length of optimal therapy for PE has been studied extensively. The ACCP
Antithrombotic Guidelines published in 2012 discuss this issue and are
436 / CHAPTER 10
Table 10-17. Length of Treatment for VTE
Event Duration of Therapy Comments

First VTE Provoked: 3 months Consider risk/benefit for extended
Unprovoked: at least 3 months therapy
LMWH indicated over VKA if patient
has active malignancy
Consider D-dimer testing within 4
weeks of discontinuation of therapy
Recurrent VTE Low bleeding risk: extended (> 1 year) Consider IVC filter placement if
High bleeding risk: 3 months recurrent despite anticoagulation
IVC, inferior vena cava; LMWH, low-molecular-weight heparin; VKA, vitamin K antagonists; VTE, venous
thromboembolism.
VTE PREVENTION
VTE prevention is focused entirely on the risk/benefit ratio, factoring potential

benefit over harm. Table 10-18 is also based on the ACCP 2012 Antithrombotic
Guidelines and summarizes how VTE prevention should be implemented.
Table 10-18. VTE Prevention

Key Fact Risk Population Management
For patients undergoing High (> 40% VTE) Orthopedic surgery, major (LMWH, fondaparinux,
major orthopedic surgery, trauma, spinal cord injury rivaroxaban, VKA) +
extend thromboprophylaxis mechanical; mechanical only if
in the outpatient period for increased bleeding risk
up to 35 days (rather than Moderate (10–40% VTE) General medical/surgical LMWH > UFH; mechanical if
10–14 days). patients on bedrest, antepartum increased bleeding risk
with high-risk women
Low (< 10% VTE) Ambulatory patients; includes Early ambulation only
high-risk patients (e.g., active
malignancy) during travel
LMWH, low-molecular-weight heparin; UFH, unfractionated heparin; VKA, vitamin K antagonists; VTE, venous
thromboembolism.
PULMONARY HYPERTENSION
Pulmonary hypertension is a group of conditions characterized by elevated

pressures in the pulmonary vasculature, which can ultimately lead to right heart
dysfunction and failure.
The Fifth World Symposium on Pulmonary Hypertension (Nice, 2013)

categorized pulmonary hypertension into five groups (Table 10-19).
Group 1 includes patients with pulmonary arterial hypertension (PAH). PAH is

defined as a mean pulmonary arterial pressure (mPAP) ≥ 25 mm Hg at rest
associated with a pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg and
pulmonary vascular resistance (PVR) > 3 Wood units. Group I can be further
subdivided into idiopathic PAH (IPAH) or PAH associated with other medical
conditions such as connective tissue disease, human immunodeficiency virus
(HIV), congenital left-to-right shunts, or liver disease/portal hypertension
(portopulmonary hypertension). The term “pulmonary arterial hypertension” is
reserved for diseases of the pulmonary artery (classically idiopathic PAH). In
contrast, an elevated cardiac output or elevated filling pressures can cause an
increase in PAP without an increase in PVR.
Flash Card Q3
How is pulmonary vascular
resistance calculated in
Wood units?
Flash Card Q4
cause of pulmonary
hypertension?
Flash Card Q5
What are common
drugs/toxins implicated in
pulmonary hypertension?
438 / CHAPTER 10
Table 10-19. Updated Fifth World Symposium on Pulmonary Hypertension

Classification
Group 1. PAH
1.1 Idiopathic PAH
1.2 Heritable PAH
1.2.1 BMPR2
1.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK3
1.2.3 Unknown
1.3 Drug- and toxin-induced
1.4 Associated with:
1.4.1 Connective tissue disease
1.4.2 HIV infection
1.4.3 Portal hypertension
1.4.4 Congenital heart diseases
1.4.5 Schistosomiasis
1’ Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis
1” PPHN
Group 2. Pulmonary hypertension due to left heart disease
2.1 Left ventricular systolic dysfunction
2.2 Left ventricular diastolic dysfunction
2.3 Valvular disease
2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital
cardiomyopathies
Group 3. Pulmonary hypertension due to lung diseases and/or hypoxia
3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease
3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern
3.4 Sleep-disordered breathing
3.5 Alveolar hypoventilation disorders
3.6 Chronic exposure to high altitude
3.7 Developmental lung diseases
Group 4. CTEPH
Flash Card A3 Group 5. Pulmonary hypertension with unclear multifactorial mechanisms
5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders,
(mPAP – PCWP) ÷ cardiac
output (L/min) = PVR in
splenectomy
Wood units 5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis,
lymphangioleiomyomatosis
5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental
Flash Card A4 PH
ALK-1, activin receptor-like kinase-1; BMPR-2, bone morphogenetic protein receptor-2; CAV1, caveolin 1;
Left-sided systolic or CTEPH, chronic thromboembolic pulmonary hypertension; ENG, endoglin; HIV, human immunodeficiency virus;
diastolic heart disease KCNK3, potassium channel K3; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; PPHN,
(WHO Group 2), although persistent pulmonary hypertension of the newborn; SMAD9, Mothers Against Decapentaplegic 9.
this represents pulmonary
venous hypertension rather
than pulmonary arterial
hypertension.
Flash Card A5
Aminorex, fenfluramine,
dexfenfluramine,
amphetamines,
methamphetamines
PULMONARY ARTERIAL HYPERTENSION (PAH)
PAH is a disease with significant morbidity and mortality; its pathogenesis is

complex and still poorly understood.
Epidemiology
Based on French registry data, the prevalence of PAH is approximately 15 cases

per 1 million adults. The Registry to Evaluate Early and Long-Term PAH Disease
Management (REVEAL) is a multicenter, observational, US-based, prospective
registry initiated in 2006, which found that the mean age of patients with group 1
PAH was 50 years, with 79% female patients and 73% white patients.
Approximately half (47%) of the patients had idiopathic PAH, 3% had heritable
PAH, and the remaining 50% had associated PAH, mostly related to connective
tissue disease. Heritable PAH patients were less likely to show vasoreactivity
during right heart catheterization. Key Fact
BMPR2 mutations are
detected in ~70% of
Pathophysiology heritable PAH cases and
11–40% of IPAH patients
(regardless of family
The pathogenesis of PAH includes both genetic and environmental factors that history).
alter vascular structure and function in genetically prone individuals (Figure 10-
9).
Figure 10-9. Risk factors that trigger PAH in genetically predisposed individuals.
Flash Card Q6
What are the most
common mutations seen in
heritable PAH?
440 / CHAPTER 10
The vascular changes involve the pulmonary arteriole and are characterized by
vasoconstriction, vascular remodeling with intimal and medial proliferation,
varying degrees of inflammation, the formation of plexiform lesions, and
thrombosis (Figure 10-10). These changes lead to progressive obstruction of flow,
increased pulmonary vascular resistance, and eventually, right heart failure and
death.
Three pathways are implicated in PAH:

 Prostacyclin (prostaglandin I2)
 Nitric oxide (NO)-cyclic guanosine monophosphate-phosphodiesterase 5
(cGMP)
 Endothelin-1
An imbalance between the vasoconstrictive (proliferative) endothelin system and

the vasodilatory (antiproliferative/anti-thrombotic) NO and prostaglandin I2
systems is a key factor in the pathogenesis (Figure 10-11). Platelets play an
important role as procoagulants by increasing the release of serotonin, vascular
endothelial growth factor, and platelet-derived growth factor. Reduced levels of
tissue plasminogen activator may also contribute to the procoagulant state.
Figure 10-10. Photomicrograph showing the plexiform lesion in a patient with

pulmonary hypertension.
(Reproduced courtesy of Dr. Bulent Celasun, CC BY-SA 2.0)
Flash Card A6
Bone morphogenetic
protein mutation type 2
(BMPR2) and activin
receptor-like kinase (ALK-
1)
Figure 10-11. Flow diagram depicting the mechanisms involved in the

pathogenesis of PAH.
SYMPTOMS—Dyspnea on exertion, fatigue, and syncope are common
symptoms. Patients may also present with chest pain. Hemoptysis is rare but may
occur as a consequence of pulmonary vascular rupture. Key Fact
As part of the evaluation of
Disease-specific symptoms are seen in certain patients; for example, Raynaud’s PAH, look for signs and
phenomenon is a frequent finding in PAH associated with scleroderma. symptoms of connective
tissue disease and
stigmata of liver disease.
PHYSICAL EXAMINATION
 Loud P2 component of S2, often with a split S2 that is accentuated with
inspiration. A pansystolic left lower sternal border murmur that is louder
during inspiration reflects tricuspid regurgitation.
Flash Card Q7
 Jugular venous distension with elevated “a” wave. This finding can be
Which of the following
followed serially to assess volume status. Prominent “v” wave is commonly cellular mechanisms is
seen with significant tricuspid regurgitation. involved in the
 Right ventricular (RV) heave development of PAH?
A. Increased prostacyclin
 RV S3 can indicate elevated right ventricular end-diastolic filling pressure and synthase
RV failure. RV S4 can indicate stiffened RV and RV hypertrophy. B. Increased NO
synthase
C. Increased endothelin
levels
442 / CHAPTER 10
In patients with florid right ventricular failure, hepatomegaly, ascites, and

extremity edema (even anasarca) can also be seen.
ECG FINDINGS—Right atrial or right ventricular hypertrophy, right-axis

deviation, and/or right bundle branch block (RBBB).
IMAGING—Chest radiograph can show an enlarged cardiac silhouette, enlarged R

heart border consistent with RV hypertrophy, and enlarged pulmonary arteries in
severe cases (Figure 10-12).
CLASSIFICATION—Functional capacity, characterized by the WHO functional

classification, is strongly predictive of mortality and helps to guide pharmacologic
therapy (Table 10-20).
Figure 10-12. Chest radiograph of a patient with pulmonary hypertension

showing enlarged pulmonary arteries and an enlarged cardiac silhouette.
(Reproduced, with permission, from Drs. Sandeep Sahay and Adriano Tonelli.)
Flash Card A7
C. Increased endothelin
levels
Table 10-20. WHO Classification of PAH Functional Class

Patients with PAH but without resulting limitation of physical activity. Ordinary
Class I physical activity does not cause undue dyspnea or fatigue, chest pain, or near
syncope.
Patients with PAH resulting in slight limitation of physical activity. These patients
Class II are comfortable at rest, but ordinary physical activity causes undue dyspnea or
fatigue, chest pain, or near syncope.
Patients with PAH resulting in marked limitation of physical activity. These patients
Class III are comfortable at rest, but less than ordinary physical activity causes undue
dyspnea or fatigue, chest pain, or near syncope.
Patients with PAH resulting in inability to perform any physical activity without
symptoms. These patients manifest signs of right heart failure. Dyspnea and/or
Class IV
fatigue may be present at rest, and discomfort is increased by any physical
activity.
PAH, pulmonary arterial hypertension; WHO, World Health Organization.
Diagnosis
Patients with risk factors, clinical symptoms, and exam findings suspicious for
PAH should be screened. PAH should also be considered in patients with
unexplained reduction in diffusing capacity.
ECHOCARDIOGRAM FINDINGS—Transthoracic echocardiogram (TTE) is used

initially to estimate RV systolic pressure (a surrogate for pulmonary artery
systolic pressure) through the tricuspid regurgitant velocity. It can also determine
RV size and function to assess for RV failure. Echo-derived inferior vena cava
(IVC) size and respiratory variation can estimate central venous pressure and
volume status. Other findings can further characterize RV function: RV akinesis
of midventricular free wall but normal apical contraction (McConnell’s sign), D-
shaped left ventricle, and paradoxical interventricular septal motion (movement of
septum away from LV free wall during systole). TTE with agitated saline contrast
or “bubble study” can be added to look for intracardiac shunts. Importantly, TTE
can assess for evidence of left heart and valvular disease as a cause for pulmonary
hypertension (WHO Group 2 PH).
IMAGING AND LABORATORY TESTS—Pulmonary function testing

(spirometry, diffusing capacity, arterial blood gas) and a computed tomography
(CT) scan of the chest can be performed to exclude underlying respiratory disease
and/or hypoxemia. When suggested by history, an overnight polysomnogram can
be performed to assess for sleep-disordered breathing. Flash Card Q8
How is a positive
vasoreactivity test defined
Blood tests for underlying liver disease or congestive hepatopathy, HIV, and during RHC?
autoimmune disease should be performed in most patients with unexplained PAH,
and a ventilation-perfusion (V/Q) scan or chest CT angiography should be
performed to evaluate for chronic thromboembolic pulmonary hypertension Flash Card Q9
(CTEPH). How does one establish a
definitive diagnosis of
PAH?
444 / CHAPTER 10
Measurement of serum BNP can also be useful in disease monitoring and

management.
RIGHT HEART CATHETERIZATION (RHC)—Because TTE can be nonspecific

and less sensitive in patients with pulmonary disease, RHC is the gold standard
for diagnosis. It is performed to assess hemodynamics (PA pressures, pulmonary
capillary wedge pressure, and cardiac output), help exclude WHO Group 2 PH,
and diagnose other forms of PH. It is indicated in patients with suspected PAH
being considered for PAH-specific therapy. It can be used to assess response to
continuous prostanoid therapy or inhaled NO therapy in the setting of critically ill
decompensated RV failure due to PAH.
VASOREACTIVITY TESTING—Evaluates the response to selective pulmonary

vasodilators (e.g., inhaled NO, intravenous adenosine, or epoprostenol). A
positive response to therapy with vasodilators is defined as a fall in mean PAP of
> 10 mm Hg to reach a mean PAP of < 40 mm Hg with an increased or
unchanged cardiac output.
True responders are uncommon in IPAH, comprising of ~10–12% of all IPAH

patients. The usefulness of acute vasoreactivity tests and long-term treatment with
calcium channel blockers in patients with other PAH types, such as heritable
PAH, connective tissue disease, and HIV patients is less clear than in IPAH.
MEASUREMENT OF EXERCISE CAPACITY—Formal assessment of exercise

capacity is an integral part of the evaluation. A 6-minute walk test (6MWT) is
usually performed to determine the degree of exercise limitation, as it has been
proven to be reproducible and to correlate well with other measures of functional
status.
Flash Card A8 Treatment

A positive response to
therapy with vasodilators is There is no cure for PAH and most treatment recommendations are based on
defined as a fall in mean clinical data from IPAH and PAH related to connective tissue disease and use of
PAP of > 10 mm Hg to
reach a mean PAP of < 40 anorexigens.
mm Hg with an increased
or unchanged cardiac PHARMACOLOGICAL TREATMENT
output.
 Diuretics are effective in relieving dyspnea and edema and may reduce right
ventricular overload in the presence of tricuspid regurgitation.
Flash Card A9  Anticoagulation therapy with warfarin is commonly used in IPAH and
With RHC showing a
anorexigen-induced PAH to prevent local thrombosis, but there is insufficient
mPAP ≥ 25 mm Hg with evidence to recommend it routinely.
pulmonary capillary wedge
pressure ≤ 15 mm Hg and
pulmonary vascular
resistance > 3 Wood units
5
(240 dynes/sec/cm ).
 Digoxin can lead to modest increases in cardiac output and a reduction in

circulating norepinephrine levels in patients with IPAH.
 Oxygen supplementation when indicated.
PAH-SPECIFIC THERAPY—Initiation and intensification of treatment depends

on WHO functional class (Figure 10-12 and Table 10-21).
Key Fact
Patients with IPAH who
respond to acute
vasodilator testing should
be treated initially with
calcium channel blocker
therapy.
Flash Card Q10

Which group of drugs is
Figure 10-12. PAH-specific drug treatment algorithm. associated with
*ERA’s are typically not used for patients in WHO Class IV. hepatotoxicity?
Flash Card Q11

Which group of drugs is
contraindicated with the
use of nitrates?
Flash Card Q12

Which group of drugs
causes teratogenicity?
446 / CHAPTER 10
Table 10-21 describes the major pharmacologic agents used in the treatment of
PAH.
Table 10-21. Dosage Forms and Side Effects of the PAH-Specific

Therapies
Method of
Key Fact Drug Class Generic Administration Adverse Effects
Prostanoids Epoprostenol Continuous IV Flushing, headache, nausea/
Riociguat, a soluble infusion vomiting, thrombocytopenia,
guanylate cyclase hypotension, jaw pain
stimulator, was recently
approved for the treatment Iloprost Aerosol (inhalation) Flushing, cough, headache, nausea,
of PAH after the PATENT- flu-like illness
1 trial showed Treprostinil Continuous IV or Site pain and erythema in SC
improvement in exercise SC administration, headache, nausea,
capacity/6MWD in patients diarrhea
with Group 1 PAH.
Treprostinil Inhaled Cough, headache, throat irritation,
nausea, flushing, syncope
ERAs Bosentan Oral Hepatotoxicity (stop if bilirubin 2X
ULN, AST/ALT > 3X ULN), peripheral
edema, nasopharyngitis, teratogenic
Ambrisentan Oral AST/ALT elevation (stop treatment if
> 8X ULN) peripheral edema,
headache, nasal congestion,
flushing, teratogenic
Macitentan Oral URI, peripheral edema,
nasopharyngitis, headache, anemia,
AST/ALT elevation, teratogenic
PDE-5 inhibitors Sildenafil Oral Headache, dyspepsia, flushing,
epistaxis, optic neuritis (rare),
potentiates hypotensive effects of
nitrates and alpha blockers
Tadalafil Oral Headache, flushing, respiratory
infections, extremity pain
Avoid if renal and hepatic impairment
Soluble Riociguat Oral Headache, dyspepsia, nausea,
guanylate peripheral edema
cyclase
stimulator
Calcium channel Amlodipine, Oral Peripheral edema, hypotension,
Flash Card A10 blockers nifedipine bradycardia
Endothelin receptor ALT, alanine aminotransferase; AST, aspartate aminotransferase; ERA, endothelin receptor antagonist; IV,
intravenous; PAH, pulmonary arterial hypertension; PDE, phosphodiesterase; SC, subcutaneous; ULN, upper
antagonists (ERAs) limit of normal; URI, upper respiratory infection.
Flash Card A11

Phosphodiestrase-5 (PDE-
5) inhibitors
Flash Card A12

Endothelin receptor
antagonists (ERAs)
Prognosis
The median duration of survival of patients diagnosed with PAH between 1980–
85 was 2.8 years. Since that time, survival has improved and patients without
evidence of right ventricular failure may survive > 10 years. Responders to
calcium channel blockers have the best prognosis with a 95% 5-year survival rate.
Patients with WHO functional classes III–IV treated with epoprostenol have a 5-
year survival rate that is twice that of matched control subjects. Patients with
evidence of right heart failure have a much lower survival rate. IPAH patients fare
better than patients with PAH associated with scleroderma. Overall, patients with
PAH associated with congenital heart disease have the best prognosis.
CHRONIC THROMBOEMBOLIC PULMONARY

HYPERTENSION (CTEPH)
CTEPH is a separate disease entity that causes pulmonary hypertension. It is

classified as WHO Group 4.
Epidemiology
Exact incidence is unknown but ranges from 0.5–3.8% of patients after an episode
of acute PE and 10% in patients with recurrent PE. It is unclear why only some
patients develop CTEPH after an episode of PE.
Pathophysiology
CTEPH is characterized by the obstruction of pulmonary arteries by organizing
thrombi, small vessel arteriopathy, and the development of high pulmonary
vascular resistance (PVR). Microscopic similarities between CTEPH and other
forms of PAH have been demonstrated clearly and with reproducibility on lung
biopsy. Pulmonary hypertensive lesions and plexogenic lesions are seen in
proximal open vessels exposed to high pressures and in vessels distal to Flash Card Q13
obstructed vessels, suggesting that release of cytokines and other endothelin-
Which of these categories
derived factors occurs in response to pulmonary hypertension and may contribute of PAH has the best
to its progression. The progressive nature of pulmonary hypertension in CTEPH prognosis?
patients is related to these resistance changes in small vessels and not necessarily A. PAH associated with
congenital heart
to recurrent pulmonary emboli. disease
B. PAH associated with
scleroderma
C. PAH associated with
HIV
D. PAH associated with
liver disease
448 / CHAPTER 10
Clinical Features
Risk factors for CTEPH:

 PE (recurrent or unprovoked), large perfusion defect
 Pulmonary artery systolic pressure > 50mm Hg at time of initial PE
 Persistently elevated right ventricular systolic pressure (RVSP) 6 months after
PE
 Chronic medical conditions (cancer, thyroid disease, splenectomy), or
thrombotic factors (lupus anticoagulant, antiphospholipid antibodies,
increased factor VIII)
 Genetic factors (ABO blood groups, human leukocyte antigen [HLA]
polymorphisms)
 History of splenectomy
Patients with CTEPH have similar clinical presentations to those patients with
PAH. Unexplained dyspnea on exertion, dizziness, syncope, and exertional chest
pain are all common complaints. Examination findings are similar to other PAH
patients: increased jugular venous pressure, loud split S2 with an increased P2
component, RV heave, RV S4 gallop, and tricuspid regurgitation murmur.
Diagnosis
Diagnostic algorithm is similar to PAH. All patients suspected to have CTEPH
need right heart catheterization to confirm the presence of pulmonary
hypertension. RHC criteria to diagnose PH are the same as previously discussed
for PAH.
A V/Q scan is considered the gold standard to diagnose chronic thromboembolic

disease as the cause of PH. Several areas or a single area of segmental or
subsegmental V/Q mismatch is suggestive of CTEPH. A V/Q scan is more
sensitive in diagnosing CTEPH than a CT pulmonary angiography.
Management
CTEPH is the only cause of PH where surgery (pulmonary endarterectomy) can
be curative. However, surgery is often difficult, only available at selected centers,
and indicated only in carefully selected patients.
Flash Card A13

A. PAH associated with
congenital heart disease.
Patients who cannot undergo surgery should be considered for medical

management. Recently, the FDA approved the use of riociguat in patients with
CTEPH after a recent trial showed improvement in the hemodynamics and
6MWD in patients with CTEPH in WHO functional classes II and III. All patients
with CTEPH should be anticoagulated. Evidence regarding the use of other PAH-
specific drugs in CTEPH is limited, but experts recommend their use in patients
who cannot be considered for surgery.
Prognosis
Prognosis is dependent on the type of management received. Successful surgical
candidates have excellent prognosis. Experienced centers have a low 30-day
mortality rate of ~4–7%. In patients who have inoperable disease or persistent
disease (CTEPH persisting after surgery), medical management improves exercise
capacity, functional class, hemodynamics, and symptoms.
PULMONARY VENO-OCCLUSIVE DISEASE (PVOD)
PVOD is a rare cause of pulmonary hypertension. Although it is classified as a

subgroup of PAH (WHO Group 1), PVOD involves obstructive vascular
remodeling affecting postcapillary pulmonary venules and small veins instead of
precapillary arterioles and arteries. Because it is difficult to distinguish from
precapillary PAH, its exact incidence is unknown, and many patients are
misclassified as IPAH or other precapillary PAH. Compared to IPAH, however,
PVOD is associated with a significantly worse prognosis.
Epidemiology
PVOD accounts for ~10% of PAH cases. The estimated annual incidence of
PVOD is 0.1–0.2 cases per million worldwide, with a male to female ratio of 1:1
(compared to a female predominance in IPAH). PVOD has been reported in a
wide age range, from infants to > 60 years, but it is more commonly seen in
children and young adults.
Pathology
In PVOD, fibrotic remodeling of the intima of preseptal pulmonary venules and Flash Card Q14
interlobular septal veins causes flow obstruction, often with intraluminal
What gene plays a role in
thrombosis. This is associated with ectasia and proliferation of alveolar the pathogenesis of
capillaries, which become tortuous. These changes can be confused with PVOD?
450 / CHAPTER 10
pulmonary capillary hemangiomatosis. Despite predominance of postcapillary

disease, pulmonary arterioles are also involved in 50% of cases of PVOD,
resulting in similar remodeling as IPAH. Unlike IPAH, PVOD characteristically
lacks arteriolar plexiform lesions. Chronic passive congestion can result in occult
pulmonary hemorrhage, with hemosiderin loading of macrophages and type II
pneumocytes. The disease can affect the lungs diffusely or in a patchy
distribution.
Etiology
The etiology of PVOD remains unclear. The rarity of this disease makes to
difficult to identify causes. Nevertheless, associations have been described, many
of which are shared with etiologic associations of PAH in general. These include
bone morphogenetic protein receptor type II (BMPR-2) mutation in familial
cases, connective tissue diseases, sarcoidosis, pulmonary Langerhans cell
histiocytosis, HIV infection, anorexigen exposure, bleomycin and other
chemotherapy agents exposure, tobacco smoking, and hematopoietic stem cell
transplant.
Clinical Features
Clinical presentation is very similar to that of heart failure and PAH. Most
patients present with exertional dyspnea and fatigue. In late stages, they may
present with syncope, edema, orthopnea, or hemoptysis, along with RV failure.
Diagnosis
PVOD requires a diagnosis of PAH. Beyond this, it is very difficult to distinguish
precapillary PAH from PVOD. Findings favoring PVOD over precapillary PAH
include the following:
 Chest imaging consistent with pulmonary edema, despite low PCWP
 BAL consistent with alveolar hemorrhage
 Development of pulmonary edema with initiation of PAH-specific therapy
The above findings are insensitive to diagnose PVOD. The definitive diagnosis of
PVOD requires open lung biopsy, though this procedure may have a high risk for
many patients.
IMAGING—Chest imaging, particularly with high-resolution CT, can reveal

findings consistent with pulmonary edema, including septal thickening,
centrilobular ground glass opacities, and lymph node enlargement. These findings
Flash Card A14 are usually more frequently apparent after pulmonary vasodilator therapy.
BMPR-2 Nevertheless, normal imaging in PAH should not rule out PVOD.
The V/Q scan is usually normal but occasionally patchy areas of hypoperfusion
are seen, which may lead to misclassification of these patients as having CTEPH.
RHC—Diagnosis of PVOD first requires that PAH be diagnosed based on RHC.

RHC hemodynamics are not useful to differentiate PVOD from other types of
PAH.
Vasoreactivity testing in patients with PVOD can result in acute pulmonary

edema, but more commonly it does not. As such, acute vasoreactivity testing does
not reliably predict whether a patient with PVOD will develop pulmonary edema
with pulmonary vasodilator treatment. Further, positive vasoreactivity testing in
patients with PVOD does not predict durable response to calcium channel
blockers.
Treatment
CONVENTIONAL TREATMENT—Same in PVOD as in other types of PAH.

Key Fact
PAH-SPECIFIC TREATMENT—Benefits of PAH-specific therapy for PVOD are
unclear due to limited data, and evidence supporting its use is based on reported Because of the significant
risk of pulmonary edema,
cases of mild improvement or stabilization of disease. Nevertheless, PAH-specific initiation of PAH-specific
therapy with prostacyclins, PDE-5 inhibitors, and ERAs are still used in PVOD. therapy in patients with
Calcium channel blockers appear to yield limited durable response, even with a PVOD needs to be
carefully monitored, likely
positive vasoreactivity test. Importantly, pulmonary edema is common with all in an intensive care unit
PAH-specific therapies, usually occurring in the first 72 hours of therapy. (ICU) setting, with a slow
titration and aggressive
use of diuretics.
Lung transplantation should be considered early when PVOD is suspected. Post-
transplant survival is similar to that of IPAH.
Prognosis
Prognosis of PVOD is significantly worse than that of IPAH. The 1-year mortality
has been reported to be as high as 72%. Time from onset of symptoms to death is
found to average 24 months for PVOD, as compared to 58 months for IPAH.
Most patients with PVOD die within 2 years of diagnosis.
452 / CHAPTER 10
OTHER PULMONARY VASCULAR DISEASE
PULMONARY COMPLICATIONS OF SICKLE CELL DISEASE
Sickle cell disease (SCD) is an autosomal recessive inherited genetic disorder that
produces a myriad of pulmonary complications. Acute chest syndrome and
pulmonary hypertension are the leading causes of mortality in this disease.
 Vasoocclusion is the main cause of tissue injury in sickle cell disease (Figure
10-13).
 Hemoglobin SS polymerizes on deoxygenation, assumes a rigid configuration,
and adheres to the microvasculature, which impairs blood flow and leads to
recurrent hemolysis and vasoocclusive episodes.
Figure 10-13. Vicious cycle of vasoocclusive crisis and acute chest syndrome.
(Modified, with permission, from Miller AC, Gladwin MT. Pulmonary Complications of Sickle Cell Disease. Am J
Respir Crit Care Med. 2012;185(11): 1154-1165. Fig. 1.doi:10.1164/rccm.201111-2082CI.)
Acute Chest Syndrome

PRESENTATION—An acute lung injury syndrome presenting as chest pain,
fever, tachypnea, and cough during a painful crisis.
DIAGNOSIS
 New pulmonary infiltrate on chest radiograph consistent with consolidation
involving at least one complete lung segment.
 Pathogenesis multifactorial:
o Pneumonia or systemic infection Key Fact
o Fat embolism Acute chest syndrome is
o Direct pulmonary infarction from hemoglobin-S (HbS)-containing the leading cause of death
erythrocytes in patients with sickle cell
disease.
o Often idiopathic
 Most common pathogens identified: Chlamydia pneumoniae, Mycoplasma
pneumoniae, respiratory viruses
TREATMENT—Largely supportive:
 Analgesics
 Hydration
 Supplemental oxygen to prevent sickling
 Blood transfusion (increases Hb oxygen saturation)
 Incentive spirometry
 Empiric antibiotics for pneumonia
 Inhaled β-agonists for associated bronchospasm
 Exchange transfusion in severe or rapidly progressive illness
Fat Emboli Syndrome
 Severe vasoocclusion involving multiple bones results in infarction and

necrosis of the marrow compartment. Marrow contents and fat disseminate
into the bloodstream, causing diffuse vascular injury and organ dysfunction.
 Fat emboli can cause acute chest syndrome, neurologic dysfunction, renal
failure, acute respiratory distress syndrome (ARDS), thrombocytopenia, and
petechiae.
 Identification of oil-red-O–positive lipid accumulations within alveolar
macrophages on BAL is diagnostic of fat emboli to the lung and has been
associated with systemic fat emboli syndrome.
TREATMENT—Mostly supportive; exchange transfusion if severe.

Flash Card Q15
pathogen identified in
patients with acute chest
syndrome?
454 / CHAPTER 10
Pulmonary Hypertension
 Lysed red blood cells release arginase and free hemoglobin, leading to NO
dysregulation and vasoconstriction, endothelial dysfunction, and pulmonary
hypertension.
 Most patients with pulmonary hypertension from sickle cell disease have mild
disease based on hemodynamic data, but the associated mortality rate is
extremely high.
TREATMENT
 Large clinical studies are lacking to guide specific therapy of pulmonary
hypertension in sickle cell disease; one trial suggests that sildenafil leads to an
overall increase in pain crises.
 Current recommendations focus on primary prevention and control of the
hematological disease (hydroxyurea, transfusions).
Chronic Lung Disease
Key Fact  Develops from recurrent acute chest syndrome.

The most important
 Progressive hypoxemia, pulmonary fibrosis, and restrictive lung disease.
predictor of chronic  High-resolution CTs usually reveal scattered areas of lung scarring.
restrictive lung disease in
sickle cell disease is the
number of prior episodes of
acute chest syndrome.
HEPATOPULMONARY SYNDROME (HPS)
Definition and Cause
 Pulmonary vascular complication of liver disease causing abnormal gas

exchange.
 Thought to be caused by derangement in vasoactive substances (e.g., NO) in
the lung, which lead to pulmonary capillary dilation and arteriovenous
malformations that cause intrapulmonary shunting (Figure 10-14).
 Seen in up to one third of patients evaluated for liver transplant though often
clinically insignificant.
Flash Card A15

Chlamydia pneumoniae
A B
Figure 10-14. (A) Normal oxygenation and (B) hypoxia with HPS.
Signs and Symptoms
 Hypoxia, orthodeoxia: Hypoxia is worse in the upright position compared to

supine position because of increased shunting and V/Q mismatch in the
upright position, as the vascular abnormalities tend to be worse in the lung
bases.
 Dyspnea, platypnea: Dyspnea is worse in the upright position and relieved
when supine.
 Other: clubbing, cyanosis, spider angiomas; rarely embolic neurologic
complications such as hemorrhage, cerebral abscess, and stroke
Flash Card Q16

Diagnostic Criteria What molecule is felt to be
primarily responsible for
the intrapulmonary
 Evidence of liver disease vascular dilations seen in
 Alveolar-arterial (A-a) oxygen gradient ≥15 mm Hg OR PaO2 < 80 mm Hg on HPS?
room air
 Evidence of intrapulmonary vascular dilation (IPVD) by:
o Contrast transthoracic echo with microbubbles in left atrium 3–6 cycles Flash Card Q17
after administration of agitated saline—preferred method. What is the most
o Radionuclide (technetium-labeled macroaggregated albumin) lung scan commonly used method for
with abnormal uptake in brain and kidneys; enables calculation of a shunt confirming IPVD in HPS
patients?
fraction.
 Exclude other causes of hypoxia: chest imaging, pulmonary function testing Flash Card Q18
What intervention has been
shown to improve
oxygenation and survival in
HPS patients?
456 / CHAPTER 10
Treatment and Prognosis
 There is no definitive medical therapy for HPS. Agents such as pentoxifylline

and garlic are thought to alter the deranged vasodilator pathways and have
been utilized in some patients with modest improvements in PaO2.
 Supplemental O2 can partially correct hypoxemia.
 Rarely, those with large arteriovenous malformations may be amenable to
angiographic embolization.
 Pre-liver transplant patients with HPS have worsened quality of life,
functional status and survival compared to those without HPS.
 Liver transplantation (LT):
o Only treatment known to improve survival
o Generally improves or resolves gas exchange abnormalities within 6–12
months after LT
o HPS patients with severe hypoxemia (PaO2 < 60) are eligible to receive
additional Model for End-Stage Liver Disease (MELD) exception points
to decrease their waiting time prior to LT.
Flash Card A16

Nitric oxide
Flash Card A17

Contrast enhanced
transthoracic echo
Flash Card A18

Liver transplantation
INFECTIONS / 457
11 Infections
Ariffin Alam, MD, Sugeet K. Jagpal, MD, Jimmy Johannes, MD, & Naresh
Nagella, MD
BRONCHIAL AND BRONCHIOLAR INFECTIONS
ACUTE BRONCHITIS
Self-limited, infectious process in the large and midsized airways not associated
with pneumonia on chest x-ray (CXR).
Microbiology
Generally an inflammatory process, mostly of viral etiology, but 10% of cases are
bacterial, most commonly Mycoplasma pneumoniae, Chlamydophila pneumoniae,
and Bordetella pertussis.
Winter outbreaks are associated with influenza A and B viruses. Other viral
etiologies include parainfluenza virus, coronavirus, rhinovirus, respiratory
syncytial virus (RSV), and human metapneumovirus.
The pathogenesis is related to the direct cytopathic effects of the pathogen and the
immune response of the host (pro-inflammatory cytokine release).
Clinical Features
Nasal congestion, rhinitis, sore throat, malaise, and low-grade fevers are typical Key Fact
initial symptoms, usually occurring in the winter. Shortly thereafter, a dry or
Consider B. pertussis in
productive cough becomes the dominant complaint. It usually lasts < 3 weeks. patients presenting with
Illness severity is affected by factors such as underlying medical conditions, cough of > 4 weeks, even
immune status, age, and smoking. those who have been
vaccinated.
458 / CHAPTER 11
Diagnosis
Rapid antigen detection can be helpful for RSV in infants and influenza in all age
groups (low sensitivity 40–60%). Reverse-transcription polymerase chain reaction
(PCR) assay may be needed to identify other viral pathogens.
B. pertussis can be detected by PCR or serology. Cultures of the posterior

nasopharynx can make the diagnosis but are relatively insensitive.
C. pneumoniae can be detected by PCR or serology.
M. pneumoniae can be detected by pathogen-specific immunoglobulin (Ig) M in

serum or by PCR.
Generally, these agents do not need to be identified except in outbreaks when

antibiotics may help prevent further spread.
Treatment
The goal of treatment is to largely control symptoms: cough, wheezing, and
bronchospasm. The Infectious Diseases Society of America (IDSA) does not
recommend routine use of antibiotics for uncomplicated cases in normal persons.
In the absence of pneumonia, patients with bronchitis due to M. pneumoniae or C.
pneumoniae may not benefit from antibiotics.
Treatment of B. pertussis infection with macrolides or tetracyclines is beneficial if

these drugs are given within the first week; treatment can be offered later in the
course if the goal is to limit transmission.
Influenza should be treated early in its course with neuraminidase inhibitors, such
as oseltamivir, to reduce duration of illness. Oseltamivir also can be used for
prophylaxis in select patients.
BRONCHIOLITIS
Characterized by infection resulting in inflammation of the bronchioles. It is the

most common acute lower respiratory tract illness in children > 2 years of age.
The etiology is usually viral, with RSV being the major pathogen. Other
pathogens include human metapneumovirus, parainfluenza virus, influenza virus,
and rhinovirus.
INFECTIONS / 459
The virus replicates in the upper respiratory tract and spreads to the lower tract.
Inflammation of the bronchial and bronchiolar epithelium results in necrosis and
sloughing of the lumen, with subsequent obstruction of the small airways.
Clinical Features/Diagnosis
Upper respiratory tract signs such as fever, cough, and rhinorrhea are common. A
prominent cough, tachypnea/increased work of breathing, wheezing, lethargy, and
poor feeding signal lower respiratory tract involvement. Acute onset of upper
respiratory tract signs followed by lower tract signs in a child < 2 years of age is
diagnostic. Bronchiolitis has a seasonal pattern depending on the geography and
climate. Complications include apnea, aspiration, and recurrent wheezing.
Laboratory evaluation to determine infectious etiology is unnecessary, as it does
not change management.
Treatment
Supportive measures include adequate hydration and antipyretics to reduce fever.

Bronchodilators, corticosteroids, intravenous (IV) antibiotics, and anticholinergic
medications have inconsistent efficacy and are not recommended routinely.
INFECTIOUS COMPLICATIONS OF BRONCHIECTASIS
Mucus-filled airways foster growth of organisms such as H. influenzae and P.

aeruginosa. When compared to other bacteria, presence of P. aeruginosa has been
shown to correlate with increased disease severity, more frequent exacerbations,
worse lung function and decreased quality of life. Other organisms such as
Streptococcus and Staphylococcus are less common. Nontuberculous
Mycobacterium/mycobacteria (NTM) also are common in this patient population.
These bacteria form biofilms that make their eradication difficult for the
following reasons:
 Biofilms have zones of anoxia, acidity or nutrient depletion; these can cause
bacteria to enter a dormant phase and become resistant to antibiotics.
 Antibiotics do not penetrate biofilms well.
 Antibiotics may become inactivated or diluted by the contents of biofilms.
 Antibiotic-specific efflux pumps in biofilms can make the antibiotics
ineffective.
 Bacteria within biofilms are protected from phagocytosis and host antibodies.
460 / CHAPTER 11
Refer to Chapter 3 for further information regarding the pathogenesis and

management of bronchiectasis.
FUNGAL INFECTIONS
With increasing numbers of immunocompromised patients, the incidence of

fungal infections has dramatically increased over recent years. Based on
pathogenicity, fungal infections can be grouped into opportunistic and endemic
mycoses (Table 11-1).
Opportunistic mycoses typically cause infections in immunocompromised

patients, whereas endemic mycoses affect both healthy hosts and
immunocompromised patients. Adequate cell-mediated immunity generally is
required for successful clearance of infection by the endemic mycoses.
Fungal pathogens include molds and yeasts. Molds primarily cause pulmonary
disease and occasionally involve other organs. In contrast, yeasts typically cause
bloodstream infections and sepsis. Fungal infections are associated with
significant morbidity and mortality, and recognizing risk factors for fungal
disease is crucial for timely management.
Table 11-1. Classification of Pulmonary Fungal Diseases
Opportunistic Mycoses Endemic Mycoses
Aspergillosis Histoplasmosis
Candidiasis Coccidioidomycosis
Cryptococcosis Blastomycosis
Mucormycosis Paracoccidioidomycosis
Fusarium species Sporothrix schenckii
Scedosporium species
INFECTIONS / 461
DETECTION METHODS
Routine complete blood counts may reveal neutropenia or leukopenia reflecting

an immunocompromised state, though leukocytosis or neutrophilia also can be
seen. Peripheral eosinophilia has been described with fungal disease, especially
coccidioidomycosis.
Direct microscopic examination of sputum studies can reveals fungal elements,

whereas cultures can confirm the suspected organism. As oropharyngeal
contamination can result in false-positive results, bronchoscopy with
bronchoalveolar lavage (BAL) and transbronchial biopsies often are required for a
more definitive diagnosis.
Nonculture-based methods are increasingly being utilized to detect fungal

infections. The serum Fungitell® assay detects 1,3-β-D-glucan, which is a
component of many fungal cell walls. Although nonspecific, this test can be
positive in invasive fungal disease prior to overt clinical manifestations. Multiple
serologic studies detecting specific fungal antigens or antibodies are routinely
used and will be discussed below.
ANTIFUNGAL AGENTS
Table 11-2 describes commonly used antifungal agents.
Table 11-2. Antifungal Agents
Agent Mechanism of Action Notes

Flucytosine Converted to 5-fluorouracil in target Used for pathogenic yeasts
cells and inhibits DNA replication (Cryptococcus) as mostly
through premature chain adjunctive treatment
termination
Polyene antifungal Bind to ergosterol, the main sterol Broad-spectrum use given its
agents: in fungal membranes, and cause relative affinity for any fungal cell
Amphotericin B leakage of cell contents from membrane
disturbed cell membrane
Nephrotoxicity common but lipid
formulations cause less systemic
toxicity
462 / CHAPTER 11
Table 11-2. Antifungal Agents, continued
Agent Mechanism of Action Notes

Antifungal azoles: Inhibit the cytochrome P450– Voriconazole interacts with statins,
Older: dependent enzyme lanosterol 14α- many immunosuppressants,
Itraconazole demethylase in the ergosterol antiseizure medications, warfarin,
Fluconazole biosynthetic pathway; this causes and digoxin; requires dose
Newer: eventual cell membrane adjustments and close monitoring
Voriconazole dysfunction
Posaconazole Posaconazole has emerged as an
effective agent for antifungal
prophylaxis in at-risk patients and
has class-unique activity against
mucormycoses
Echinocandins: Target fungal cell glucan synthesis Extremely active against Candida
Caspofungin by inhibiting the enzyme 1,3-ϐ-D- species; no activity against
Micafungin glucan synthase, leading to endemic mycoses, Fusarium,
Anidulafungin impaired integrity of the fungal cell Scedosporium
wall
IV formulations only
DNA, deoxyribonucleic acid; IV, intravenous
Key Fact
A false-positive
galactomannan enzyme
immunoassay can occur
OPPORTUNISTIC MYCOSES
from treatment with
piperacillin–tazobactam or
amoxicillin–clavulanate.
Aspergillus
Aspergillus is ubiquitous in the environment and virtually unavoidable. More than
Key Fact 250 species of Aspergillus have been identified, but A. fumigatus causes > 50% of
infections. Other species commonly associated with invasive disease include A.
COPD and critically ill
patients in the ICU have
flavus, A. niger, and A. terreus.
been identified recently as
at-risk groups for invasive Aspergillus species cause a wide spectrum of disease ranging from allergic
pulmonary aspergillosis
despite not having
bronchopulmonary aspergillosis (ABPA) to invasive disease (Figures 11-1, 11-2).
traditional risk factors of The severity of disease often correlates with the degree of immunosuppression.
overt immunocompromise The incidence of aspergillosis has been increasing in recent years paralleling a
such as prolonged
neutropenia or high-dose
rise in the use of immunosuppression for stem cell and solid organ transplants as
steroids. well as other disorders. ABPA is discussed in Chapter 3.
Aspergillus is a mold with septate hyphae that branch at a V-shaped (45-degree)

angle (Figure 11-3). The galactomannan enzyme immunoassay (EIA) tests for a
component of the Aspergillus cell wall. Sensitivity is reported to be 44–90%,
Key Fact varying depending on the number of samples obtained, severity of infection,
A negative culture from a underlying immune status, and prior antifungal treatment. It is most reliable in
sputum or BAL sample patients with hematologic malignancies and also can be tested in BAL fluid.
does not rule out invasive
aspergillosis.
INFECTIONS / 463
Mnemonic
Aspergillus terreus is
terribly resistant to
amphotericin.
Figure 11-1. Host factors and degree of immunosuppression are associated with
severity of disease.
ABPA, allergic bronchopulmonary aspergillosis.
Flash Card Q1
What is the characteristic
branching angle when
Aspergillus is viewed on
histopathologic (potassium
hydroxide, India ink)
stains?
Figure 11-2. Chest radiograph shows an aspergilloma (fungus ball) in the upper Flash Card Q2
lobe of the right lung.
(Reproduced from the CDC Public Health Image Library [PHIL]; content provider, M. Renz, ID #3955.) Which antifungal agents
have activity against
Aspergillus?
464 / CHAPTER 11
Figure 11-3. Aspergillus with its characteristic 45-degree branching.

(Reproduced from the CDC Public Health Image Library [PHIL] and Armed Forces Institute of Pathology [AFIP];
content provider Dr. Hardin.)
Candidiasis
CHARACTERISTICS—Candida species cause a wide spectrum of infections
including mucocutaneous infection, invasive disease affecting any organ, and
bloodstream infections. Notably, Candida found in the upper and lower
respiratory tracts is rarely pathogenic and likely a colonizer that does not require
treatment. C. albicans is the predominant species, but C. glabrata and C. krusei
are emerging pathogens. Candidemia is a rising nosocomial pathogen, particularly
in the intensive care unit (ICU). This section focuses on candidemia.
PATHOGENESIS—Disseminates via gastrointestinal (GI) translocation or

manipulation of colonized spaces (GI/genitourinary surgery). Risk factors for
candidemia include central venous catheters, total parenteral nutrition, renal
replacement therapy, prior colonization, neutropenia/immunosuppression, and
Flash Card A1 exposure to antibiotics.
45-degree branching with
septations; do not confuse PRESENTATION—Candidemia presents as sepsis. Dissemination also can affect
with mucormycosis, which the eye (endophthalmitis), central nervous system (CNS) (meningitis), skin,
is characterized by 90-
degree branching without cardiovascular system (endocarditis), and spleen and liver (hepatosplenic
septations candidiasis).
Flash Card A2 DIAGNOSIS

 Blood cultures are not consistently positive
Voriconazole, itraconazole,
amphotericin B, and the  Skin manifestations may provide a clinical clue
echinocandins–fluconazole  Histopathology may be required and reveals yeast with pseudohyphae
is inactive against
Aspergillus species formation
INFECTIONS / 465
TREATMENT—Prompt removal of all central venous catheters; antifungal

treatment depends on disease severity; for isolated candidemia, antifungal therapy Key Fact
is continued until 2 weeks after the last negative blood culture. Fluconazole is All patients with
appropriate for infections caused by C. albicans or parapsilosis and for stable candidemia require early
dilated retinal examination
patients without recent azole treatment. Fluconazole has good CNS, eye, and to rule out Candida
urinary penetration. endophthalmitis.
Echinocandins do not have
good eye penetration.
 Echinocandins are recommended for critically ill and neutropenic patients;
this should be continued if non-C. albicans infection is confirmed
 Voriconazole can be used if concomitant coverage for molds is needed
 Liposomal amphotericin B is noninferior to the above options, but its use is
limited by side effects; it is primarily used for
o CNS candidiasis (along with fluconazole)
o Candida endophthalmitis
o Candida endocarditis (along with echinocandins)
PROGNOSIS—Attributable mortality from candidemia varies from 15–47%.
Cryptococcus neoformans
Key Fact
CHARACTERISTICS—Cryptococcus neoformans is budding encapsulated yeast
All immunocompromised
ubiquitously found in the soil, particularly in pigeon excrement. It affects mostly patients with pulmonary
human immunovirus (HIV) and other immunocompromised patients. cryptococcal infection
require work-up for
disseminated disease with
PRESENTATION—Meningoencephalitis is the most commonly diagnosed form serum and CSF
of cryptococcal infection. Pulmonary manifestations range from colonization cryptococcal antigen and
with blood and CSF
(especially in chronic lung disease) to asymptomatic infection to severe cultures.
pneumonia and respiratory failure. Treatment of HIV can induce an immune
reconstitution syndrome (IRIS).
Key Fact
DIAGNOSIS—Meningoencephalitis is diagnosed with serum and cerebrospinal
fluid (CSF) cryptococcal antigen and examination of the CSF with India ink. Cryptococcus gattii more
often infects
Pulmonary disease is diagnosed with chest imaging and isolation of organism in immunocompetent hosts
culture, typically in BAL or lung biopsy specimens. Although serum cryptococcal and is found in the
antigen is sensitive and specific in disseminated disease, it has limited sensitivity Northwest United States.
in pulmonary disease (25–56%). Staining of BAL fluid with India ink can reveal a
characteristic halo appearance (Figure 11-4).
Flash Card Q3
Which antifungal is
preferred for treatment of
invasive candidiasis in
pregnant women?
466 / CHAPTER 11
Figure 11-4. Cryptococcus neoformans in India ink. Note the halo from the
polysaccharide capsule.
(Reproduced from the CDC Public Health Image Library [PHIL]; ID #14391.)
TREATMENT
 Mild or moderate pulmonary disease or asymptomatic immunocompromised
patients:
o Fluconazole for prolonged course (6–12 months)
 Severe pulmonary disease and/or those with CNS disease:
o Induction: Amphotericin B and flucytosine (2–4 weeks)
o Consolidation: Fluconazole 400–800 mg daily (8 weeks)
o Maintenance: Fluconazole 200 mg daily (6–12 months)
Mucormycosis
CHARACTERISTICS—Mucormycosis is caused by organisms that exist

ubiquitously in the environment. Species Rhizopus, Mucor, and Rhizomucor,
commonly called zygomyces, are responsible for > 70% of mucormycosis cases.
Mucormycosis is the second leading cause of fungal pneumonia after Aspergillus,
and it typically causes sinopulmonary infections in immunocompromised patients.
PATHOGENESIS—Inhalation of conidia (spores) into the respiratory tract leads

to growth of the hyphal form and invasive infection in the immunocompromised
Flash Card A3
host. The disease progresses with extensive angioinvasion with vessel thrombosis,
Systemic amphotericin B; tissue necrosis, and crossing of tissue planes.
echinocandins and most
azoles are category C;
flucytosine and
voriconazole are
contraindicated because of
fetal abnormalities in
animal studies
INFECTIONS / 467
Risk factors:
 Immunocompromised state
 Antifungal treatment/prophylaxis for Aspergillus (i.e., previous voriconazole
use)
 Hyperglycemia/poorly controlled diabetes
 Iron overload states
PRESENTATION—Mucormycosis has a high propensity to develop into sinusitis

with necrotic lesions in the nasopharynx and endocranial soft tissues. Pulmonary
manifestations are indistinguishable from Aspergillus and are otherwise
nonspecific with fever, cough, dyspnea, and pleuritic chest pain.
Aggressive angioinvasiveness and ability to cross tissue planes result in rapid

dissemination and distal organ involvement:
 Involvement of bronchi, diaphragm, chest wall, pleura, and contralateral lung
o Necrosis of surrounding parenchyma due to invasion of blood vessels
leads to cavitation and hemoptysis, which can be fatal
 Death usually is from disseminated disease before respiratory failure
 Atypical presentations:
o Chronic infection with constitutional symptoms
o Multiple mycotic pulmonary artery aneurysms/pseudoaneurysms
o Bronchial obstruction (usually in diabetic patients)
DIAGNOSIS
 Chest computed tomography (CT):
o Multiple nodules (> 10) favor mucormycosis over invasive pulmonary
aspergillosis (IPA)
o Pleural effusions weakly favor mucormycosis over IPA
o Halo and air-crescent signs are less common in mucormycosis than IPA
 Air-crescent sign in perihilar areas can portend risk of pulmonary
artery erosion and massive hemoptysis
 Tissue swabs, sputum, or BAL fluid often nondiagnostic and blood cultures
rarely positive
 Tissue samples often required for histologic evidence of Mucor species (broad
nonseptate hyphae branching at right angles) and evidence of tissue invasion
(Figure 11-5)
TREATMENT
 Reversal of underlying predisposing factors if possible
 Surgical debridement of affected tissue
 Antifungal therapy—No guidelines; limited data:
o Amphotericin B
o Posaconazole—Provides long-term oral treatment option and possibility
for suppressive therapy during continued immunosuppression
468 / CHAPTER 11
Figure 11-5. Mucor pusillus in a heart valve. Notice the 90-degree hyphal
branching.
(Reproduced from the CDC Public Health Image Library [PHIL]; content provider, L. Ajello, ID #3955.)
PROGNOSIS—Mortality ranges from 50–70% but up to 95% with extrathoracic

dissemination.
Uncommon and Emerging Opportunistic Fungal Infections

of the Lung
The septate filamentous fungi Fusarium and Scedosporium species can cause
invasive fungal pneumonia in immunosuppressed patients and have clinical
presentations similar to IPA, often with a poor prognosis.
FUSARIUM SPECIES
 Presentation: Highly angioinvasive with hemorrhagic infarction of tissue,
disseminated disease, and fungemia; skin involvement suggests disseminated
disease
 Pathogenesis: Fusarium species enter the immunocompromised host via the
lungs, paranasal sinuses, skin breaks, and intravascular catheters
 Treatment: Susceptibility to antifungals varies by species; response rates to
various antifungal agents limited
 Prognosis: Mortality ~ 66% in patients with hematologic malignancy who
have disseminated disease 70% of the time
INFECTIONS / 469
SCEDOSPORIUM SPECIES
 Presentation: Typically presents as invasive pulmonary disease; at
presentation, ~ 50% of transplant recipients have disseminated disease with
skin, CNS, and bloodstream involvement.
 Immunocompetent hosts with the following risk factors can also develop
pulmonary disease:
o Diabetes
o Heavy exposure during trauma
o Near-drowning incidents associated with aspiration pneumonia or lung
abscesses
 Treatment and prognosis: Infections due to Scedosporium species are
difficult to treat and frequently are fatal; voriconazole has shown variable
results, and surgery and reversal of immunosuppression may be the only
effective therapeutic options.
ENDEMIC MYCOSES
Histoplasmosis and blastomycosis have some geographic overlap and are seen in
the Midwest or the south-central United States. Coccidioidomycosis is seen
mostly in the southwestern U.S.
In a subset of patients taking a tumor necrosis factor-α (TNFα) inhibitor who

develop an endemic mycosis, discontinuation of the TNFα blocker can lead to a
paradoxic worsening of pulmonary symptoms and radiographic findings
consistent with an immune reconstitution inflammatory syndrome.
Histoplasmosis
CHARACTERISTICS—Histoplasma capsulatum is a dimorphic fungus, existing
as a mold in the environment and a yeast in the host. It is endemic in the Midwest
and south-central U.S., in the Ohio and Mississippi River valleys. High
concentrations are found in caves with bat guano, in chicken coops, decaying
trees, and riverbanks.
PATHOGENESIS—Inoculation occurs with inhalation of airborne spores. At

body temperature, the yeast form grows before spreading locally and then into
hilar and mediastinal lymph nodes. Immunocompromised hosts are at higher risk
for severe and disseminated disease.
470 / CHAPTER 11
DIAGNOSIS—Positive culture from sputum, BAL, or tissue biopsy confirms the

diagnosis; there is no colonization. Blood cultures can confirm disseminated
disease and histopathology reveals caseating granulomas and narrow-based
budding yeast.
Urine and serum Histoplasma antigen combined have a sensitivity of > 90% for
Key Fact acute pulmonary histoplasmosis. The specificity of the urine Histoplasma antigen
Urine and serum is nearly 100%. Complement fixation antibodies for Histoplasma remain positive
Histoplasma antigen for years after an acute infection and high titers correlate with severity of disease.
studies each has a
sensitivity of ~60%, but
combined they have a Imaging can show focal (Figure 11-6), diffuse, or multinodular findings which in
sensitivity of >90%. general are larger and better defined compared to miliary tuberculosis (TB)
(Figure 11-7). Mediastinal lymphadenopathy and calcified granulomas are
commonly seen.
Key Fact PRESENTATION/TREATMENT—Disease is typically asymptomatic. In
Given its clinical and symptomatic cases, the disease can manifest as acute, subacute, and chronic
radiographic similarities to
sarcoidosis, histoplasmosis
pulmonary histoplasmosis, as well as disseminated histoplasmosis. The severity
must be excluded prior to of disease depends on the inoculum and host immune status. Treatment varies by
diagnosing sarcoidosis and disease severity.
starting
immunosuppressive
treatment.
Figure 11-6. Chest radiograph showing a pulmonary nodule in the left lower lung
field (arrow) from histoplasmosis, characteristic of a coin lesion.
(Reproduced from the CDC Public Health Image Library [PHIL] and Massachusetts General Hospital Case
Records; ID #463.)
INFECTIONS / 471
ACUTE AND SUBACUTE PULMONARY HISTOPLASMOSIS—Acute (< 1

month of symptoms) and subacute (> 1 month of symptoms) cases present with
nonspecific constitutional symptoms (fevers, chills, malaise, myalgias), with
cough and pleuritis. Extrapulmonary manifestations include pericarditis, erythema
nodosum, and polyarthritis. Mild cases resolve while severe cases can progress to
acute respiratory distress syndrome (ARDS).
Other pulmonary complications are:

 Mediastinal granulomas: Cause compression-related symptoms; usually
improves slowly
 Broncholithiasis: Calcified lymph nodes erode into airway causing obstructive
pneumonia, expectoration of stones, and possibly hemoptysis
 Fibrosing mediastinitis: Caused by Histoplasma antigen release and associated
with these conditions:
o Pulmonary hypertension
o Superior vena cava syndrome
o Airway constriction
o Splenic and liver calcifications, which help identify histoplasmosis as the
etiology of the mediastinitis
o Pericarditis, with sterile pericardial effusions
Treatment of acute and subacute pulmonary histoplasmosis:

 Mild-to-moderate acute pulmonary histoplasmosis—if symptoms last > 4
weeks, treat with itraconazole
 Moderately severe or severe acute pulmonary histoplasmosis (diffuse
infiltrates and hypoxemia):
o Amphotericin B for 1–2 weeks, followed by itraconazole
o Methylprednisolone at 0.5–1 mg/kg daily for 1–2 weeks
 No antifungal therapy recommended for mild mediastinal lymphadenitis, mild
mediastinal granulomas, or mediastinal fibrosis
CHRONIC PULMONARY (CAVITARY) HISTOPLASMOSIS—Seen in patients

with symptom duration of > 3 months and structurally abnormal lungs, resulting
in destruction of proximal normal lung parenchyma with upper lobe predilection
and cavitary pulmonary infiltrates. Sputum cultures are most consistently positive
in this form of histoplasmosis. It is treated with itraconazole for ≥ 12 months and
continued until no further radiographic improvement is seen.
PROGRESSIVE DISSEMINATED HISTOPLASMOSIS—Occurs in the setting of

impaired T cell immunity with granuloma formation. Bone marrow and tissue
biopsies reveal macrophages full of yeast and can even show necrosis without
granuloma formation. Treatment is liposomal amphotericin B for 1–2 weeks
followed by prolonged itraconazole. Steroids are recommended for severe cases. Flash Card Q4
What extrathoracic findings
suggest histoplasmosis as
the cause of a patient’s
fibrosing mediastinitis?
472 / CHAPTER 11
Figure 11-7. Chest radiograph shows diffuse pulmonary infiltration due to acute
pulmonary histoplasmosis.
(Reproduced from the CDC Public Health Image Library [PHIL]; ID #3954.)
Coccidioidomycosis
CHARACTERISTICS—Typically occurs in the southwestern United States.
Coccidioides immitis is most common but Coccidioides posadasii is also virulent.
Key Fact Usually infects construction, agricultural, or field workers with symptoms
Patients of Korean, appearing 1–4 weeks after exposure (valley fever). Coccidioides is listed as a
Filipino, Japanese, select agent for bioterrorism purposes.
Hispanic, and African-
American descent are at
increased risk of PRESENTATION—Primary pulmonary infection can present in a variety of forms.
developing disseminated  Localized pneumonia usually heals spontaneously but can rupture into the
coccidioidomycosis, even
in the absence of pleural space
immunosuppression.  Diffuse pneumonia occurs after a large exposure and can rarely cause
respiratory failure
 Chronic fibrocavitary pneumonia is characterized by pulmonary cavitation
and interstitial fibrosis; more common among diabetics and patients with
underlying lung disease Disseminated disease occurs in < 1% of cases but is
common in immunosuppressed patients, including those with diabetes
mellitus (DM); imaging typically shows diffuse reticulonodular or miliary
infiltrates; the CNS, bone, joints, and skin are common extrapulmonary sites
Flash Card A4 of infection
Splenic and hepatic
calcifications DIAGNOSIS—Affected by the level of exposure, immune status of the patient,
and type of infection.
INFECTIONS / 473
 Peripheral eosinophilia is common

 Serologic tests are positive in 90% of clinically recognized cases, but can be
negative in mild illness, immunocompromised states, or early in the course of
disease; antibody titers decline to undetectable levels with resolution of Mnemonic
disease with or without treatment:
o Cocci IgG and IgM EIA—screening studies True Positive to ID the cocci
Can Follow the titer
o Cocci tube precipitin—specific test that confirms cocci infection
o Cocci immunodiffusion—specific test that confirms cocci infection Cocci Tube Precipitin
o Cocci complement fixation—quantifies IgG; the titer predicts active Cocci ImmunoDiffusion ID
Cocci Complement Fixation
infection and extent of disease with higher titers predicting dissemination
 Cultures of skin or bone lesions are positive in 95% of disseminated cases
 Histopathology revealing the presence of giant spherules with endospores is
definitive (Figure 11-8)
TREATMENT—Mandatory for all infections in the immunocompromised host and
for diffuse pneumonia and disseminated disease in the normal host. Otherwise
treatment of pulmonary infection is reserved for those with enlarging cavities,
hemoptysis, or prolonged symptoms (> 3 months).
 Limited pulmonary disease: Fluconazole or itraconazole
 Diffuse pulmonary disease: Amphotericin B until clinical improvement
followed by fluconazole or itraconazole for > 1 year
 Meningitis: Lifelong itraconazole or fluconazole plus intrathecal amphotericin
B in severe cases
Figure 11-8. Histopathology of coccidioidomycosis of lung. Mature spherule with

endospores of Coccidioides immitis and intense infiltrate of neutrophils.
(Reproduced from the Centers for Disease Control and Prevention Public Health Image Library [PHIL]; content
provider CDC/ Dr. Lucille K. Georg.)
474 / CHAPTER 11
Blastomycosis
CHARACTERISTICS—Blastomycosis is the least common of the endemic
mycoses. It is acquired by inhaling soil colonized with Blastomyces dermatitidis,
typically in the central and southeastern U.S. and in the Mississippi and Ohio
River valleys, similar to Histoplasmosis. Like Histoplasma, Blastomyces is a
dimorphic fungus existing as a yeast form in the host.
PRESENTATION—Symptoms can mimic acute bacterial pneumonia with fever

and cough or be more indolent with weight loss and night sweats. Asymptomatic
disease is common and fibrocavitary disease is rare. Immunocompromised
patients can develop ARDS and CNS symptoms and disseminated disease can
involve the skin, bone, genitourinary, and central nervous systems. Skin lesions
are usually pustules, papules, or subcutaneous nodules seen on the face and
extremities.
DIAGNOSIS—Antigen detection is positive in the urine and/or serum in ~ 90% of

patients with disseminated or pulmonary blastomycosis.
Key Fact  Antigen titers decline with treatment and increase in relapse, guiding
treatment decisions
Blastomyces dermatitidis
are broad-based budding  Cultures are definitive but slow growing and poorly sensitive
yeast.  Wet preparation shows characteristic round broad-based, budding yeast of
blastomycosis (Figure 11-9)
 Imaging can show lobar or diffuse infiltrates
Figure 11-9. Grocott methenamine silver-stained biopsy of a section from a

human leg lesion shows broad-based budding characteristic of Blastomyces
dermatitidis.
(Reproduced courtesy of J Scott, Wikimedia Commons, CC0 1.0.)
INFECTIONS / 475
TREATMENT—Indicated for symptomatic patients with pulmonary disease and

for all patients with disseminated disease.
 Itraconazole is first-line therapy for most cases
 Life-threatening severe blastomycosis, ARDS, or meningeal infection requires
amphotericin B until clinically improved, followed by long-term itraconazole.
Paracoccidioidomycosis
CHARACTERISTICS—Caused by Paracoccidioides brasiliensis and seen in

South America, Central America, and southern Mexico, with U.S. cases reported
in patients who previously lived in these endemic areas.
PRESENTATION—Respiratory symptoms often are nonspecific and indolent.

Skin and mucocutaneous involvement, especially in the oropharynx, is seen with
possible dissemination to the lymph nodes, liver, spleen, and bone marrow.
DIAGNOSIS—By culture or direct visualization of fungal elements, typically in a

pilot-wheel appearance (Figure 11-10). Chest imaging is nonspecific, but bat-
wing distribution of infiltrates (reticular, nodular, or alveolar) are highly
characteristic of paracoccidioidomycosis.
TREATMENT—Very sensitive to antifungals and treatment of choice is

itraconazole with sulfonamides, azoles, and amphotericin B as alternatives.
Figure 11-10. Histopathology of paracoccidioidomycosis. Budding cells of

Paracoccidioides brasiliensis in methenamine silver stain. Flash Card Q5
provider Dr. Lucille K. Georg; ID #527.) Which fungal infection has
the classic presentation of
a rose gardener injuring his
finger with a thorn?
476 / CHAPTER 11
Sporothrix schenckii
S. schenckii is seen in decaying vegetation and soil. It usually is cutaneously
inoculated and has the classic presentation of the rose gardener who injures his
finger with a thorn.
The lymphocutaneous form is much more common, but pulmonary and

disseminated disease can occur with inhalation of S. schenckii spores. Pulmonary
disease manifests as chronic cavitary fibronodular disease, classically in middle-
aged men with risk factors (e.g., alcoholism, chronic obstructive pulmonary
disease [COPD]). Outcomes can be poor and often related to delayed diagnosis.
DIAGNOSIS—Culture is the gold standard for diagnosis with histopathology

showing a mixed granulomatous and pyogenic inflammatory process.
TREATMENT
 Mild disease: Itraconazole for 12 months
 Severe disease: Amphotericin B with transition to prolonged itraconazole and
consideration of surgery for localized pulmonary disease
HIV
Epidemiology
HIV-related diseases have caused the deaths of more than 35 million people since
the disease was first recognized in 1981. Heterosexual contact is the predominant
mode of transmission worldwide, whereas injection drug users, men who have sex
with men, and sex workers are at greatest risk in the developed world.
Immunologic Abnormalities
The degree of immune dysfunction is the primary determinant of the risk of

developing specific pulmonary disorders in patients with HIV. When the immune
system is not significantly impacted, the pulmonary disorders that occur are
similar to those found in the general population. When immune dysfunction is
severe, opportunistic infections can occur.
HIV infection leads to the following immunologic abnormalities and alterations in

Flash Card A5 host defenses that increase the risk of pulmonary complications such as:
Sporothrix schenckii
INFECTIONS / 477
 Massive depletion of CD4+ T lymphocytes of the effector memory type from

mucosal associated lymphoid tissue
o Progressive decline of naïve and memory T cell pools
 B cell dysfunction
 Problems with mucociliary clearance and pathogen recognition by alveolar
macrophages
Spectrum of Pulmonary Manifestations

The CD4+ lymphocyte count is an excellent indicator of an HIV-infected person’s
risk of developing a specific infection or neoplasm (Table 11-3).
INFECTIOUS
Bacterial: Despite antiretroviral therapy, bacterial pneumonia is still a significant
cause of morbidity and mortality in HIV-infected individuals:
 Streptococcus pneumoniae and H. influenzae are the most frequent causes of
bacterial pneumonia in HIV-infected persons
 P. aeruginosa and Staphylococcus aureus are the most common causes of
bacterial pneumonia in hospitalized patients; these patients tend to have lower
CD4+ counts
 Treatment is the same as that for non-HIV-infected hosts
 It is important to vaccinate these patients for S. pneumoniae
Table 11-3. CD4+ Count and HIV-Associated Pulmonary Disease
CD4+ Count Infection or Neoplasm
Any Bacterial pneumonia, TB, non-Hodgkin lymphoma
< 200 cells/µL Bacterial pneumonia with bacteremia, disseminated TB, Pneumocystis TB,
Cryptococcus neoformans
< 100 cells/µL Bacterial pathogens such as Staphylococcus, Pseudomonas, pulmonary
manifestations of Kaposi sarcoma, toxoplasmosis Flash Card Q6
50–100 cells/µL Endemic fungi, CMV, MAC, nonendemic fungi
Name three risk factors for
CMV, cytomegalovirus; MAC, Mycobacterium avium complex; TB, tuberculosis Pneumocystis pneumonia
(PCP) among HIV-infected
patients.
Flash Card Q7
Name two alternatives to
TMP-SMX for PCP
prophylaxis.
478 / CHAPTER 11
Mycobacterial: Mycobacterium tuberculosis is the most prevalent opportunistic

infection in HIV-infected hosts worldwide. It is not clear whether HIV patients
are more susceptible to TB than non-HIV hosts; however, once an individual
becomes infected, the risk of progression from latent to active disease is much
higher.
 HIV-infected persons should be tested for latent TB with either a tuberculin
skin test or interferon-y (INFy) assay when HIV is first diagnosed and
annually thereafter if they are at risk of continued exposure.
 HIV-infected patients with TB who begin therapy for both infections
simultaneously are at increased risk of IRIS and are also at increased risk of
drug interactions.
Fungal: Pneumocystis jirovecii (also known as pneumocystis) pneumonia (PCP)

is the most common acquired immunodeficiency syndrome (AIDS)-defining
opportunistic infection, and is a common cause of HIV-associated pneumonia
(Figure 11-11).
 Treatment of choice for mild, moderate, or severe PCP remains trimethoprim
(TMP)–sulfamethoxazole (SMX) for 21 days; in moderate to severe PCP
(defined by a PaO2 < 70 or an alveolar–arterial gradient > 35), adjunctive
steroids have been shown to have a benefit in reducing mortality and
respiratory failure
 HIV-infected adults with CD4+ < 200 or a history of oropharyngeal
candidiasis should receive PCP prophylaxis, usually one double-strength
TMP-SMX tablet three times a week
Flash Card A6
CD4+ < 200,
oropharyngeal candidiasis,
and a history of PCP
Flash Card A7
CD4+ < 200, Dapsone 100 Figure 11-11. Pneumocystis cysts as seen on BL, stained with toluidine
mg daily, or aerosolized blue.
pentamidine 300 mg once (Reproduced from the Centers for Disease Control and Prevention Public Health Image Library [PHIL].)
per month
INFECTIONS / 479
Other fungal diseases seen in HIV-infected hosts include Cryptococcus

neoformans, Histoplasma capsulatum, and Coccidioides immitis. Invasive
aspergillosis is a life-threatening disease seen in the severely immunosuppressed. Key Fact
Most cases of CMV
VIRAL—Cytomegalovirus (CMV) is an important agent of pulmonary disease in pneumonia occur in
HIV patients, although the most common sites of CMV infection are the retina patients with CD4+ < 50.
and GI tract.
The diagnosis of CMV pneumonitis cannot be made on BAL alone, as

cytopathogenic changes need to be seen; CMV organisms can be shed from
respiratory secretions without being diagnostic of pulmonary disease. Key Fact
The prophylaxis of choice
PARASITES—In general, helminth infections are uncommon in HIV patients. Of for T. gondii is TMP-SMX,
the unicellular and multicellular parasites, T. gondii is the most frequent cause of the same drug as for PCP.
disease in HIV patients. It usually manifests as encephalitis, and pulmonary
symptoms are nonspecific and hard to distinguish from other pathogens.
HIV patients should be tested for T. gondii antibodies, and those who are negative
for disease should be instructed to avoid raw, uncooked meat and cat feces
Noninfectious
HIV-infected patients appear to be at increased risk for a number of noninfectious

pulmonary diseases, including COPD, lung cancer, and pulmonary arterial
hypertension.
MALIGNANCY—HIV-infected patients are at increased risk for Kaposi sarcoma

and non-Hodgkin lymphoma, both of which can involve the thorax as isolated
pulmonary disease. Non-small cell lung cancer also has a greater incidence in
HIV-infected population, although it is difficult to pinpoint HIV as the cause.
 Kaposi sarcoma is the most common HIV-associated malignancy, although

rates have declined with antiretroviral therapy; diagnosis can be established
via bronchoscopy revealing characteristic endobronchial, flat or slightly
raised. red or violaceous lesions (Figure 11-12). Flash Card Q8
 HIV-associated non-Hodgkin lymphoma tends to be of B cell origin; bilateral, Nonsmokers with signs of
exudative lymphocytic pleural effusions are common; chemotherapy for non- emphysema at an early
age should be evaluated
Hodgkin lymphoma often is complicated by opportunistic infections, for what systemic
particularly PCP, so PCP prophylaxis is indicated. diseases?
Flash Card Q9
What are two treatment
options for excessive
inflammation in immune
reconstitution syndrome?
480 / CHAPTER 11
Figure 11-12. Endobronchial Kaposi sarcoma.

(Reprinted, with permission, from Nagata N, Shimbo T, Yazaki H, Asayama N, Akiyama J, Katsuji T, et al.
Predictive clinical factors in the diagnosis of gastrointestinal Kaposi's sarcoma and its endoscopic severity.
PLOS one 2012; 7(11): e46967. doi:10.1371/journal.pone.0046967. CC BY 2.0)
OBSTRUCTIVE LUNG DISEASE—Obstructive lung disease occurs frequently in

the HIV-infected population, but the role of HIV in the pathogenesis of
obstruction is unclear.
INTERSTITIAL PNEUMONITIDIES
 HIV-associated lymphocytic interstitial pneumonia is striking for its early age
of incidence (children >> adults); diagnosis is confirmed by histology from
transbronchial biopsy.
 Nonspecific interstitial pneumonitis has been reported in HIV; its clinical
features are indistinguishable from PCP, although it can occur at higher CD4
counts.
OTHER
 IRIS: Paradoxic worsening of clinical status temporally related to recovery of
the immune system following a period of immunosuppression, or after the
initiation of antiretroviral therapy.
o Infections (mycobacterial, fungal, and viral) are often exacerbated by
IRIS.
 Pulmonary hypertension:
Flash Card A8 o Rare complication of HIV infection and treatment modalities remain
α1-antitrypsin deficiency, experimental
HIV, connective tissue o Unclear whether antiretroviral therapy improves pulmonary arterial
diseases hypertension
Flash Card A9
Nonsteroidal
antiinflammatory drugs
(NSAIDs) and steroids
INFECTIONS / 481
PREVENTION AND SCREENING OF HIV AND

OPPORTUNISTIC INFECTIONS
Evidence-based guidelines from 2013 for the management of HIV and associated
opportunistic infections are summarized here.
 HIV-infected patients should be tested for TB with either a skin test or INFy
INFy release assay); those who test positive should be treated for latent TB
after active TB has been excluded via a CXR.
 All HIV-infected patients who are Toxoplasma seronegative should be
counseled on how to avoid new infection.
 Routine testing for MAC and cryptococcal infections is not recommended but
can be considered in select patients with CD4 counts < 50.
 Influenza vaccine should be administered annually.
 Pneumococcal vaccine, either heptavalent or tridecavalent, should be
administered to all HIV-infected persons.
LUNG ABSCESS
Lung abscesses develop after an infection causes necrotic lung tissue to cavitate
(Tables 11-4 and 11-5). Necrotizing pneumonia refers to the formation of multiple Mnemonic
small abscesses. Risk factors include seizures, alcoholism, esophageal
Noninfectious causes of
abnormalities, periodontal disease, and dysphagia. Abscesses commonly are cavitary lung lesions:
caused by aspiration of oral anaerobes—pneumonitis is followed by necrosis in CAVITY
1–2 weeks. The differential diagnosis includes noninfectious causes of cavitary
Cancer
lung lesions. Autoimmune (Wegener’s,
rheumatoid)
Vascular (bland or septic
emboli)
Pathophysiology Infection
Trauma (pneumatocele)
Youth (pulmonary
Small zones of necrosis in consolidated regions of pneumonia form single or sequestration,
multiple abscesses that erode into bronchi, ultimately resulting in fibrosis (Figure bronchogenic cyst,
11-13). congenital pulmonary
airway malformation)
482 / CHAPTER 11
Table 11-4. Bacterial Infections That Cause Pulmonary Cavitation
Organism Radiographic Features Clinical Presentation/ Diagnosis Management
Actinomyces (Figs. 11-14, 11-15): Mass lesion, segmental Cervicofacial osteomyelitis or abscess in PCN is drug of choice but can use
Gram + anaerobe consolidation, adenopathy, an alcoholic or person with poor dental tetracycline, erythromycin,
Forms sulfur granules bronchiectasis, ± pleural thickening hygiene (but otherwise clindamycin, imipenem
Part of normal oral flora or effusions/empyema immunocompetent) with recent dental
6 weeks of IV therapy followed by 6–
GI/vaginal tract procedure; pulmonary manifestations
Suspect if you see air 12 months of oral therapy
(cough, fever, hemoptysis, chest pain)
bronchograms in the mass lesion
are rare, indolent, and occur through
and if it invades or erodes
aspiration or direct extension of disease
through chest wall.
from head, neck, or abdominal cavity
Part of normal flora so sputum/
bronchoscopic studies unhelpful unless
sulfur granules present; may need
transbronchial or open lung biopsy to
confirm
Nocardia (Fig. 11-16): Usually cavitary, bilateral multifocal Immunocompromised patient with TMP-SMX is drug of choice: can use
Gram + aerobe pneumonia, masses, nodules, underlying lung disease and subacute minocycline, third-generation
Weakly acid fast effusions/ empyema pulmonary symptoms (most common cephalosporins, linezolid
Found in soil presentation), hematogenous
6–12 months
Can be inhaled, ingested, or metastasis (brain, skin, bone, muscle)
inoculated directly from trauma
Bronchoscopy for diagnosis
Cultures take weeks to grow
GI, gastrointestinal; PCN, penicillin; IV, intravenous; TMP-SMX, trimethoprim–sulfamethoxazole
INFECTIONS / 483
Figure 11-13. Lung abscess. Suppuration with central liquefaction surrounded by

a thin fibrous capsule.
(Reproduced courtesy of Yale Rosen, flikr.com. CC BY-SA 2.0)
Classification
 Acute (less than 4–6 weeks old) vs. chronic

 Primary (infectious etiology in a healthy host) vs. secondary (due to a
preexisting condition such as bronchiectasis, spread from an extrapulmonary
site, immunocompromised state)
A B
Figure 11-14. (A)Patient with actinomycosis on the right side of the face. (B)
Fite–Faraco stain with sulfur granule in the middle of the image. These granules
represent colonies that macroscopically demonstrate a gross yellow color when
unstained.
(Reproduced from the Centers for Disease Control and Prevention Public Health Image Library [PHIL]. Image A
content provider, Dr. Thomas F. Sellers/Emory University; image B content provider, Dr. Lucille Georg.)
484 / CHAPTER 11
Figure 11-15. Gram stain shows thin, gram-positive, filamentous Actinomyces at

the periphery of sulphur granules (arrow).
(Reproduced courtesy of Yale Rosen, flickr.com, CC BY-SA 2.0)
Microbiology
 Predominantly anaerobes or a mixture of both anaerobes and aerobes

 Most common anaerobes:
o Peptostreptococcus
o Bacteroides
o Fusobacterium
Mnemonic
NOCARDIA
Nodules seen on imaging

Organ spread
Cavitary lesions
SulfonAmide antibiotic to
treat
Respiratory symptoms
Dirt exposure
Immunocompromised
Acid fast (weak)
Figure 11-16. Nocardia.

provider, Dr. Hardin; ID# 15056.)
INFECTIONS / 485
Table 11-5 Parasitic Infections That Cause Pulmonary Cavitation

Organism Radiographic Clinical Management
Features Presentation/
Diagnosis
Echinococcus: Spherical, round or Can occur in any Treat with
Cestode tapeworm oval cysts with patient. Often macrolides, rifampin,
found in the smooth borders asymptomatic. Can vancomycin, FQ,
Mediterranean region, surrounded by have chronic cough, AG, or imipenem
Middle East, South normal lung; liver hemoptysis, fever,
America, Australia; cysts more common chest pain
infection occurs via than lung.
Blood cultures are high
ingestion of feces of
yield
wolves, dogs, foxes
that are hosts
Paragonimiasis: Cavities and cyst- Hemoptysis, chest pain, Treat both
Found in Japan, like lesions with fever, eosinophilia in symptomatic and
Korea, Philippines, linear or patchy any patient asymptomatic
parts of China; infiltrates, pleural patients with
Diagnosis via
infection via ingestion effusion, fibrosis, antihelminths
microscopy (eggs in
of freshwater crabs, calcification
sputum, BAL, stool), or
raw boar meat
serology (serum or
CSF)
AG, aminoglycoside; BAL, bronchoalveolar lavage; CSF, cerebrospinal fluid; FQ, fluoroquinolone
 Other bacteria:
o Tuberculous mycobacteria and NTM (see below)
 Fungi (see Fungal Infections section):
o Aspergillus species, Cryptococcus neoformans, Blastomyces dermatitidis,
Sporothrix schenckii, Histoplasma, Coccidioides
Diagnosis
 Indolent symptoms of fevers, cough with putrid sputum, constitutional

symptoms for > 2 weeks, and digital clubbing
 Imaging shows infiltrate with cavity, often with air–fluid level; CT helps
differentiate empyema from lung abscess (Figures 11-17 and 11-18)
 Bronchoscopy is helpful in excluding TB and malignancy; diagnostic yield for
infectious organism is variable
 Complications
o Empyema
o Pleural fibrosis
o Trapped lung
o Respiratory failure
o Bronchopleural fistula
o Pleurocutaneous fistula
486 / CHAPTER 11
Key Fact
CXR shows infiltrates
within a cavity, typically in
the parts of the lung that
are dependent in the
recumbent position
(superior segment of the
lower lobe or posterior
segment of the upper
lobes).
Figure 11-17. Abscess in right lung; cavitary lesion with an air–fluid level and
surrounding consolidation.
(Reproduced courtesy of Yale Rosen, flickr.com, CC BY-SA 2.0.)
Figure 11-18. CT scan of chest shows bilateral pneumonia with abscesses and
pleural effusions.
(Reproduced courtesy of Christaras A, Wikimedia Commons, GFDL1.2)
INFECTIONS / 487
Treatment
 Before era of antibiotics, 1/3 died, 1/3 recovered, 1/3 developed complications
such as empyema or bronchiectasis. Key Fact
 Appropriate therapy results in clinical improvement in 3–4 days; fevers more The mortality for lung
abscess ranges between
than 7–10 days may indicate need for further diagnostic tests; recalcitrant 5–20%. Larger size is a
cases (e.g., large cavities, resistant organisms such as P. aeruginosa, worse prognostic marker.
obstructing neoplasm—massive hemorrhage) may require lobectomy or
pneumonectomy.
 Empirically cover anaerobes until etiology identified: Key Fact
o Clindamycin or β-lactam with β-lactamase inhibitor Routine bronchoscopy to
aspirate lung abscesses is
not recommended due to
lack of evidence of benefit
and potential risk of
massive fatal aspiration of
Mycobacterium tuberculosis abscess contents. If it is
performed, requires
experienced operator.
History
Key Fact
TB can be caused by any of the mycobacterial pathogens in the Mycobacterium Aztreonam, TMP-SMX,
aminoglycosides, and
tuberculosis complex, the most common of which is Mycobacterium tuberculosis. ciprofloxacin do not cover
The World Health Organization has estimated that nearly one third of all the anaerobes.
people in the world are infected with TB. A resurgence of the disease was noted
in the U.S. in the late 1980s and early 1990s because of the epidemic of HIV and
the deterioration of public health systems.
Epidemiology
A total of 9945 cases of TB were reported in the U.S. in 2012; the majority (>
60%) of the newly diagnosed cases of TB in U.S. were among foreign-born
persons. Annual rates of TB are especially high in immigrants from sub-Saharan
Africa and Southeast Asia.
Major challenges to successful control of TB include:

 TB among new immigrants to the U.S.
 Delays in detection and reporting of cases
 Deficiencies in protecting contacts of persons with infectious TB
 Presence of a large reservoir of persons with latent TB
 Difficulty maintaining clinical and public health expertise in an era of
declining incidence of TB Flash Card Q10
What is the most effective
mechanism for generating
droplet nuclei?
488 / CHAPTER 11
Transmission
Transmission of TB occurs when airborne droplets of secretions (droplet nuclei)

containing infectious organisms are expelled into the environment. Transmission
rates depend on characteristics of the source case, the exposed person, and the
surrounding environment.
SOURCE CASE—Patients with active TB are more likely to transmit the disease
if they have:
 A high concentration of acid-fast bacilli in their sputum
 Cavitary disease on chest radiograph
 Frequent and strong cough
EXPOSED PERSON—Only 30–40% of persons with close exposure to a patient

with active pulmonary TB become infected. Innate immunity may protect certain
persons from infection.
Latent TB may confer protection against subsequent reinfection.
ENVIRONMENT—Under standard indoor temperature and humidity conditions, ~

Key Fact
70% of TB organisms survive 3 hours, ~ 50% survive 6 hours, and ~ 30% survive
TB is acquired by 9 hours.
inhalation of one or more
tubercle bacilli contained in
an airborne particle small Only effective filtration or ultraviolet light can remove TB organisms from the
enough (1–5 µm) to reach environment.
an alveolus.
Crowding and intimacy of contact increase likelihood of transmission of TB.
Pathogenesis
IMMUNOLOGIC RESPONSE TO EXPOSURE—Active TB can develop as a
result of early progression from infection to disease or after late progression of
latent infection (Figure 11-19). The course of infection likely depends on the
immune response of the host.
The principal immune response associated with protection against TB is cell-

Flash Card A10
mediated immunity involving T lymphocytes and macrophages.
Coughing—a forced
expiratory maneuver that
involves the sudden It is unclear to what extent clinical pulmonary TB can be attributed to new
acceleration of air and infection by recently inhaled exogenous organisms (i.e., from the environment) as
disruption of a liquid opposed to a reactivation of viable bacilli that have been maintained for many
surface and therefore
aerosolizing of particles; years in a dormant or growth-restricted state within the body.
sneezing, yelling, singing, Current TB control efforts are based on the idea that TB in low-incidence areas is
and loud talking are also the result of endogenous reactivation.
ways to transmit droplet
nuclei
INFECTIONS / 489
Figure 11-19. Events after exposure to smear-positive patient. LTBI, latent

tuberculous infection.
(Reproduced, with permission, from Ahmad S. New approaches in the diagnosis and treatment of latent
tuberculosis infection. Respir Res. 2010; 11(1), 169. doi:10.1186/1465-9921-11-169. CC BY 2.0)
490 / CHAPTER 11
Risk Factors
The risk of developing active TB after exposure is related to the host response to
infection and the dose of bacilli inoculated in the lungs. Other factors that increase
the risk of developing active TB include:
Key Fact  Time since exposure: The risk is highest during first year after infection.
In persons with both HIV  HIV infection: Impaired cellular immunity renders patients with HIV
and latent TB infection, susceptible to TB infection, although they may be less infectious to others,
antiretroviral therapy and because they are less likely to have cavitary lesions.
prophylactic therapy with
isoniazid substantially  Therapies that interfere with cell-mediated immunity, such as TNFα blocking
decrease the risk of drugs (Figure 11-20).
developing active TB.
 Silicosis: Risk thought to be mediated by the detrimental effect of silica on
alveolar macrophages.
 Hemodialysis
 Diabetes
 Age: The incidence in children is many times greater than in adults; however,
there appears to be a second peak in incidence after age 65, perhaps due to
natural decline in host defenses.
Figure 11-20. Effect of anti-TNF agents on TB. Binding of TNFα inhibits

development and maintenance
TB granulomas. M tb, Mycobacterium tuberculosis. (Reproduced, with permission, from Lalvani A, Millington KA.
Screening for tuberculosis infection prior to initiation of anti-TNF therapy. Autoimmun Rev.2008; December
8(2):147–152. doi: 10.1016/j.autrev.2008.07.011.)
INFECTIONS / 491
Prevention
In high prevalence countries, vaccination with Mycobacterium bovis bacillus Key Fact
Calmette–Guérin (BCG) is routine, although the efficacy has been difficult to
BCG should not be given
document. Vaccination likely protects infants and young children from meningeal to immunocompromised
and military TB. persons, including those
with symptomatic HIV
infection and pregnant
women.
Diagnosis
More than 70% of new cases of TB involve only the lungs, and diagnosis is
centered often on pulmonary symptoms and imaging.
History
 Cough is the most common symptom; early in the course, it is nonproductive,

but as tissue necrosis occurs, sputum is produced.
 Hemoptysis can occur from extensive parenchymal involvement or from
bronchiectasis as a result of residual disease.
 Systemic features include fever, malaise, and weight loss.
Laboratory Findings
 Hyponatremia can occur because of production of antidiuretic hormone–like

substance within affected lung tissue; leukocytosis and anemia also can occur.
Imaging
Radiographic findings of active TB vary, but often demonstrate variable-sized

nodules and tree-in-bud opacities (Figure 11-21).
Key Fact
 Primary TB, occurring as a result of recent infection, usually is seen in the
In patients with HIV
middle and lower lung zones with ipsilateral hilar adenopathy. infection, a normal chest
 TB that develops many years after the original infection (endogenous radiograph occurs in as
reactivation) usually involves the upper lobes of one or both lungs; cavitation many as 11% of patients
with positive sputum
is common.
cultures.
 Healing of TB lesions results in development of fibrotic scar, shrinkage of
lung parenchyma, and, often, calcification.
 Erosion of a parenchymal focus of TB into a blood or lymph vessel may result
in dissemination of the organism and a miliary pattern on the chest film.
492 / CHAPTER 11
Figure 11-21. Chest x-ray and CT findings of drug-sensitive TB demonstrate

common findings of variable-sized nodules (A,B) and tree-in-bud signs (C,D).
(Reproduced with permission, from Cha J, Lee HY, Lee KS, Koh WJ, Kwon OJ, Yi CA, et al. Radiological
findings of extensively drug-resistant pulmonary tuberculosis in non-AIDS adults: comparisons with findings of
multidrug-resistant and drug-sensitive tuberculosis. Korean J Radiol. 2009; 10(3): 207–216. doi:
10.3348/kjr.2009.10.3.207. Published online April 22,2009.)
Tuberculin Skin Test
 Standard intermediate tuberculin test consists of the intracutaneous injection

of 0.1 mL of material, which contains 0.0001 mg of purified protein derivative.
 The reaction size is determined by measuring the diameter of any induration
with a ruler 48–72 hours after administration; erythema should not be
measured (Figure 11-22).
 Testing does not distinguish between active and latent TB infection.
INFECTIONS / 493
Induration Positive in
≥ 15 Everyone
≥ 10 Recent immigrants, high-risk
populations (health care
professionals), IV drug users,
comorbid medical conditions,
exposure to index case
≥5 Immunosuppressed (including
HIV), close contact with active TB,
high clinical suspicion
Figure 11-22. A ruler is used to measure induration. Erythema should not be

measured.
(Figure reproduced from Wikimedia Commons.)
INFγ Release Assays
INF-γ release assays can be used in place of tuberculin skin tests. Like skin
testing, the INFγ release assay cannot distinguish between active and latent
infection.
 INFγ release assays have some advantages over skin testing: Only one visit,
more specific in the presence of BCG vaccination, less reader variability, and
no recall of waned immunity.
 Disadvantages: Must be processed within 12 hours of collection; infection
with some NTMs can cause false-positive results (Mycobacterium szulgai,
Mycobacterium kansasii, Mycobacterium marinum).
Bacteriologic Evaluation
A definitive diagnosis of TB is established only by isolation of bacilli in culture or

identification of specific nucleic acid sequences from sputum samples, preferably
from the first sputum of the day. If sputum cannot be isolated, the next diagnostic
step is bronchoscopy with lavage (Table 11-7).
Differential Diagnosis of NTM
 Can present as cavitary disease

 NTM is ubiquitous in the environment; up to 40 species have been
documented to cause pulmonary symptoms.
Flash Card Q11
 See NTM section at end of this chapter for additional details
Who should get a
screening tuberculin skin
test or INFy assay?
494 / CHAPTER 11
Table 11-7. Diagnostic Testing for Tuberculosis
Type of Test Value of Test

Acid-fast staining Finding AFB is very specific for mycobacteria, but it provides no
information about species
Mycobacterial culture Necessary for drug susceptibility testing, which requires isolation of
mycobacteria in culture; takes many weeks for final results
Drug-susceptibility testing Varying techniques; molecular methods are much quicker than other
techniques
Genetic polymorphisms Useful for studying epidemiology and transmission dynamics
AFB, acid-fast bacillus
TREATMENT
Standard Therapy for Active TB
The recommended basic treatment regimen for previously untreated patients with
pulmonary TB consists of an initial phase of rifampin, isoniazid, pyrazinamide,
and ethambutol (also known as RIPE therapy) given for 2 months, followed by a
4-month continuation phase of isoniazid and rifampin.
Routine measurements of hepatic function, renal function, and platelets are not
necessary unless patients have baseline abnormalities or are at increased risk for
hepatotoxicity. However, patients should be monitored clinically throughout
treatment.
Sputum cultures should be checked monthly until two consecutive negative

sputum cultures are obtained.
Figure 11-23 demonstrates treatment algorithms for culture-positive and culture-

negative TB.
After 3 months of therapy, more than 90% of patients taking isoniazid and
rifampin have negative sputum cultures. If sputum cultures are still positive after
4 months of therapy, a new regimen should be started based on drug susceptibility
testing.
Flash Card A11
Contacts of infectious
cases, children younger
than 17 years, pregnant
women, recent immigrants,
and health care workers
should get a skin test or
INFγ assay
INFECTIONS / 495
B.
Figure 11-23. Treatment algorithms for culture-positive (A) and culture-negative (B) TB. CXR, chest x-
ray; AFB, acid-fast bacillus; EMB, ethambutol; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin; RPT,
rifapentine; Sx, symptoms.
(Reproduced courtesy of the Centers for Disease Control and Prevention. Thoracic Society, CDC, and Infectious Diseases Society of America.
Treatment of tuberculosis. MMWR Morb Mortal Wkly Rep. 2003; 52(11): 6-7.)
496 / CHAPTER 11
Special Cases
HIV—Concerns include drug interactions with antiretrovirals, and the possibility

of IRIS. The general recommendation is that antiretrovirals should be started in
patients with newly diagnosed TB and a CD4 count < 200. For those with higher
CD4 counts, the benefits of antiretrovirals are unclear.
Pregnancy—The risks of active, untreated TB are higher for pregnant women

than the risks of treatment. No modification of treatment regimen is needed for
pregnant or lactating mothers.
Latent TB
Testing and treatment for latent infection is indicated for patients recently
Key Fact exposed to TB and patients with clinical conditions that increase the risk of
Rifampin can stain urine, progressing from latent infection to active TB. The treatment regimen that is most
saliva, tears, and soft commonly used is isoniazid and/or rifampin daily for 9 months. Another option
contact lenses orange.
for latent TB is rifapentine plus isoniazid for 3 months. Evidence suggests that
this regimen is as effective as 9 months of isoniazid alone and has a higher rate of
treatment completion.
EXTRAPULMONARY TB
Key Fact Although most commonly seen in the lungs, TB can infect all major organ
systems. Extrapulmonary TB is seen in up to 50% of HIV patients with TB.
Because of the frequency
of extrapulmonary TB in Immunosuppression and young age are also risk factors for extrapulmonary TB.
HIV-infected patients,
diagnostic specimens from
any suspected site of
disease should be cultured Disseminated TB
for mycobacteria.
 Patients have multiple 1–2mm yellowish nodules that are granulomas on

histologic examination – miliary. Figure 11-24 demonstrates miliary TB seen
in abdominopelvic organs mimicking ovarian malignancy.
INFECTIONS / 497
Figure 11-24. (A) Miliary TB noted on abdominopelvic organs during surgery for
suspected ovarian malignancy. (B) Chronic granulomatous inflammation noted
on histopathology.
(Reproduced, with permission, from Yassaee F, Farzaneh F. Familial tuberculosis mimicking advanced ovarian
cancer. Infect Dis Obstet Gynecol. 2009; 2009: 736018. doi: 10.1155/2009/736018.)
Flash Card Q12

What is the value of
checking a pleural fluid
adenosine deaminase?
498 / CHAPTER 11
Lymphatic TB
 Presents as painless swelling of one or more lymph nodes.

 Diagnosis is established by lymph node biopsy.
 Rate of response to drug therapy is much slower than that of pulmonary TB.
 Corticosteroid treatment has been used to shrink intrathoracic nodes and
relieve bronchial obstruction.
Pleural TB
 The pleural space is considered an extrapulmonary site for TB.

 Can be asymptomatic or presents with fever and pleuritic pain; TB empyema
requires chest tube drainage.
 Diagnosis is made by analysis of pleural fluid and pleural biopsy.
 See Chapter 13 for a more in-depth discussion of TB pleuritis.
CNS TB
 In TB meningitis, characteristic lumbar puncture results include increased

opening pressure, and lymphocytic predominance and elevated protein levels
in the CSF.
 Acid-fast bacillus staining and culture is often negative, and the diagnosis
generally is made by evidence of disease in another site along with
characteristic CSF findings.
 There is reasonable evidence for the use of dexamethasone in TB meningitis
and cerebral edema in both children and adults.
Spinal TB
 TB can spread to bones and joints; when it spreads to the spine, it is known as
Pott disease; Figure 11-25 demonstrates severe kyphoscoliosis due to
childhood TB affecting the spine.
Flash Card A12
Adenosine deaminase has
been shown to have high
sensitivity (except in HIV
patients) but variable
specificity in diagnosing TB
pleural effusion
INFECTIONS / 499
A B C
Figure 11-25. Childhood TB leading to spinal deformity, which will continue to

cause problems as the child grows. (A, B) Increasing curvature as evidenced by
X-ray findings despite an attempt at surgical correction. (C) Clinical photograph
of the same child (note the surgical scar and significant kyphosis).
(Reproduced, with permission, from Jain AK, Dhammi IK, Jain S, Mishra P. Kyphosis in spinal tuberculosis—
prevention and correction. Indian J Orthop. 2010; 44(2): 127–36. doi: 10.4103/0019-5413.61893. CC BY 2.0)
PNEUMONIA
COMMUNITY ACQUIRED PNEUMONIA (CAP)
There are about five cases of CAP per 1000 persons per year in the U.S.. The
incidence increases with age. Annual all-cause mortality in CAP patients is up to
28%.
Microbiology
In 50% of cases, the etiologic organism responsible for CAP cannot be identified.
In the remaining cases, a variety of causative organisms have been identified
(Tables 11-8−10). The patient’s clinical history can provide clues to the
underlying etiology (Table 11-11).
500 / CHAPTER 11
Table 11-8. Organisms Associated with Community Acquired Pneumonia
Outpatient Inpatient (Non-ICU) Inpatient (ICU)

Streptococcus Above organisms plus Streptococcus pneumoniae
pneumoniae Legionella species Staphylococcus aureus
Mycoplasma Aspiration Legionella species
pneumoniae
Gram-negative bacilli
Haemophilus influenzae
H. influenza
Chlamydophila
pneumoniae
Respiratory viruses
ICU, intensive care unit
Bacterial
Table 11-9. Typical Bacterial Causes of CAP
Organism Details
S. pneumoniae Most common cause (30–60%) of CAP
Common etiology in post-influenza pneumonia
Severe infections seen in those with functional or anatomic asplenia
Vaccination reduces the risk of invasive pneumococcal disease
H. influenzae At risk patients: Those with underlying lung disease (COPD, cystic
Key Fact fibrosis)
Vaccination has decreased the incidence of disease but not for the
Necrotizing/cavitary
nontypeable strains
infiltrates or empyema
S. aureus Accounts for 2–5% of CAP
should raise suspicion for
Staphylococcus aureus. More frequent after influenza
CA-MRSA in the U.S. has been associated with severe necrotizing
pneumonia that has a mortality rate between 29–60%; this may be
mediated by the Panton–Valentine leukocidin gene
Gram-negative bacilli Generally uncommon, but may require ICU admission for CAP
(excluding H. influenzae)
Common organisms: Klebsiella, Pseudomonas, Enterobacter species,
E. coli, Serratia species, Proteus species, Acinetobacter species
Risk factors: Probable aspiration and underlying lung disease
CAP, community acquired pneumonia; COPD, chronic obstructive pulmonary disease; CA-MRSA, community
acquired methicillin-resistant Staphylococcus aureus; ICU, intensive care unit
INFECTIONS / 501
Table 11-10. Atypical Organisms
Organism Details
Mycoplasma pneumoniae Most common of the atypicals
Usually affects healthy individuals in their 20s–30s. Key Fact
Person-to-person transmission via respiratory droplets. Atypicals are responsible
for 10–20% of cases of
Prodrome of upper respiratory tract infection followed by community acquired
nonproductive cough and extrapulmonary symptoms such as low- pneumonia and may even
grade fever, diarrhea, myalgia, arthralgia, and rash. Severe cases cause a coinfection with
can result in thrombocytopenia, myocarditis, hemolytic anemia (due other typical organisms.
to cold agglutinins), and transaminitis.
Gram stain is usually negative. Diagnosis can be made by culture,
PCR, serology with IgM and IgG.
CXR usually shows unilateral segmental infiltrate but can have
patchy or bilateral interstitial infiltrates
Legionella species Exposure to aerosols of contaminated water (cooling towers,
showers, grocery store mist machines, whirlpool spas, water
distribution systems)
Cannot be detected by Gram stain
Can be associated with high fever, rapid progression on
radiographic studies, ICU care, transaminitis, renal failure,
GI/neurologic abnormalities
Chlamydophila pneumoniae Minimally symptomatic but recovery may be slow (cough/malaise
(formerly Chlamydia can last weeks to months)
pneumoniae) Associated with COPD or asthma exacerbations
PCR, polymerase chain reaction; Ig, immunoglobulin; CXR, chest x-ray; ICU, intensive care unit; GI,
gastrointestinal; COPD, chronic obstructive pulmonary disease
Table 11-11. Organisms Associated With Various Conditions Key Fact

Diagnostic yield of PCR >
Condition Commonly Encountered Pathogen(s) culture/antigen detection
assays but may
Alcoholism Streptococcus pneumoniae, oral anaerobes, Klebsiella overestimate viruses being
pneumoniae, Acinetobacter species, Mycobacterium tuberculosis a cause of community
acquired pneumonia since
COPD and/or smoking Haemophilus influenzae, Pseudomonas aeruginosa, Legionella they can be present in the
species, Streptococcus pneumoniae, Moraxella catarrhalis, nasopharynx in healthy
Chlamydophila pneumoniae people.
Aspiration Gram-negative enteric pathogens, oral anaerobes
Lung abscess CA-MRSA, oral anaerobes, endemic fungi, Mycobacterium

tuberculosis, atypical mycobacteria
HIV infection (early) S. pneumoniae, H. influenzae, Mycobacterium tuberculosis
HIV infection (late) The pathogens listed for early infection plus Pneumocystis
jirovecii, Cryptococcus, Histoplasma, Aspergillus, atypical
mycobacteria Flash Card Q13
Recently on a cruise ship Legionella species What causative organism
is responsible for
pneumonia associated with
bat droppings? Birds?
Rabbits? Farm animals?
502 / CHAPTER 11
Table 11-11. Organisms Associated With Various Conditions, continued
Condition Commonly Encountered Pathogen(s)
Southwestern U.S. Coccidioides species, hantavirus
Southeast and East Asia Burkholderia pseudomallei, avian influenza, SARS
Influenza active in community Influenza, S. pneumoniae, Staphylococcus aureus, H.

influenzae
Unrelenting cough for weeks Bordetella pertussis
Structural lung disease (e.g., Pseudomonas aeruginosa, Burkholderia cepacia,

bronchiectasis) Staphylococcus aureus
Endobronchial obstruction Anaerobes, S. pneumoniae, H. influenzae, Staphylococcus
aureus
In context of bioterrorism Bacillus anthracis (anthrax), Yersinia pestis (plague),
Francisella tularensis (tularemia)
COPD, chronic obstructive pulmonary disease; CA-MRSA, community acquired methicillin-resistant
Staphylococcus aureus; SARS, severe acute respiratory syndrome
Key Fact
Agents such as Legionella
species, mycobacterial TB, Viral
mycobacterial pneumonia,
C. pneumoniae or C.
psittaci are rarely ever  Influenza, RSVs:
colonizers and represent o The most common viral pathogens, but can be difficult to differentiate
true disease. On the other
hand, some organisms are from bacterial pneumonia.
virtually never pathogenic:  Parainfluenza, adenovirus, RSV
Candida species,
coagulase-negative
o Can cause fatal/severe pneumonia in patients who are
Staphylococcus aureus, immunocompromised, including stem cell and solid organ transplant
enterococci, gram-positive recipients.
rods (except Nocardia), H.
parainfluenzae.  Coronaviruses:
o Responsible for severe acute respiratory syndrome (SARS) (travel to
China, Hong Kong, Singapore; no cases reported since 2004) and Middle
East Respiratory Syndrome (MERS) (recent travel to Arabian peninsula or
neighboring countries).
 Hantavirus:
Flash Card A13 o Can cause a severe respiratory illness. Associated with travel to
southwestern U.S., causes an ARDS-like picture.
Bat droppings:
Histoplasma capsulatum  Varicella pneumonia:
Birds: Chlamydophila o Most frequent complication of varicella infection in healthy adults;
psittaci (if poultry, think fatality rate 10–30%.
avian influenza)
Rabbits: Francisella
tularensis;
Farm animals: Coxiella
burnetii (Q fever).
INFECTIONS / 503
Diagnosis
CLINICAL FEATURES—Cough with or without sputum, dyspnea, fever or

Key Fact
hypothermia, chest pain, chills. Extrapulmonary symptoms: headache, myalgia,
and GI symptoms. Elderly patients may
present with confusion,
failure to thrive, weakness,
PHYSICAL EXAM—Tachypnea, rales, egophony, increased fremitus, and or delirium and frequently
dullness to percussion. do not have fever.
Pneumonia within 48 hours of admission to hospital is considered CAP.
IMAGING—CXR showing air space consolidation with air bronchograms strongly Key Fact
suggests bacterial pneumonia. Interstitial infiltrates are not seen with usual Follow-up imaging after
bacterial pneumonias. Studies suggest that early CXRs lack sensitivity. In patients treatment may not show
whose presentation is suggestive of pneumonia, it may be reasonable to start resolution for up to 12
weeks in certain patients.
treatment and repeat imaging in 24–48 hours.
LABORATORY TESTS
 Leukocytosis with a left shift; white blood cell count can be depressed in
severe shock or normal in the elderly. Leukopenia portends a poor prognosis.
 Sputum cultures optional for outpatients with CAP since they do very well
with empiric treatment. Key Fact
Sputum gram stains
 Per IDSA/ATS 2007 guidelines, investigation for specific pathogens should represent lower respiratory
be done when such pathogens are suspected based on clinical and tract secretions when
epidemiologic clues, and the results of such an investigation would change PMNs > 25 and epithelial
cells < 10/lpf.
management (Table 11-12 for indications for extensive diagnostic testing).
 Routine serologic testing for Legionella, Streptococcus pneumoniae, and C.
pneumoniae is not recommended.
 Blood cultures are positive in < 10% of patients but are recommended in those
ill enough to be hospitalized. Most common isolate is S. pneumoniae.
 Procalcitonin (precursor of calcitonin) is elevated in bacterial infections but
decreased in viral infections; a low level (< 0.1 µg) favors a decision to avoid
or stop antibiotics; use as an adjunct to clinical judgment.
 Bronchoscopy (BAL, brushing, washing, protected specimen brushing)
usually not done unless the pneumonia is severe, or refractory to antibiotic
therapy.
504 / CHAPTER 11
Table 11-12. Clinical Indications for More Extensive Diagnostic Testing
Indication Laboratory Test(s)

ICU admission Blood culture, sputum culture, Legionella UAT,
a
pneumococcal UAT, other
Failure of outpatient antibiotic therapy Sputum culture, Legionella UAT, pneumococcal
UAT
b
Cavitary infiltrates Blood culture, sputum culture, other
Leukopenia Blood culture, pneumococcal UAT
Active alcohol abuse Blood culture, sputum culture, Legionella UAT,

pneumococcal UAT,
Chronic severe liver disease Blood culture, pneumococcal UAT
Severe obstructive/ structural lung disease Sputum culture
Asplenia (anatomic or functional) Blood culture, pneumococcal UAT
Recent travel (within past 2 weeks) Legionella UAT, other (Table 11-11)
c
Positive Legionella UAT result Sputum culture
Positive pneumococcal UAT result Blood culture, sputum culture
Pleural effusion Blood culture, sputum culture, Legionella UAT,
pneumococcal UAT, thoracentesis, and pleural
fluid cultures
ICU, intensive care unit; UAT, urinary antigen test.
a
Endotracheal aspirate if intubated, possibly bronchoscopy or nonbronchoscopic BAL
b
Fungal and TB cultures.
c
Special medium for Legionella
Severity
Many classification systems exist, two of which are shown in Table 11-13.
Objective scores should not be used as the sole determinant for hospitalization.
Reasons to admit low risk patients: complications of pneumonia, exacerbation of
underlying diseases, inability to take oral medications.
IDSA/ATS guidelines recommend direct admission to ICU when 3 minor criteria

or 1 major criterion for severe CAP are met (Table 11-14).
INFECTIONS / 505
Table 11-13. Classification of Severity in Community Acquired Pneumonia
System Scoring Interpretation

Pneumonia Points given based on age, medical Points tallied to determine class;
a
severity index conditions (cancer, heart failure, 30-day mortality in classes I–III
cerebrovascular disease, renal disease, (0.1–0.9%) and IV and V (9.3%
liver disease), physical exam findings and 27%, respectively)
(altered mental status, tachycardia,
tachypnea, hypotension, hypo- or
hyperthermia) and
laboratory/radiographic findings.
CURB-65 Confusion, urea > 7, RR > 30, SBP < 90 30-day mortality rate: 0.7% for 0
b
severity score mm Hg or DBP < 60 mm Hg, age > 65 factors, 2.1% for 1 factor, 9.2% for
2 factors, 14.5% for 3 factors, 40%
for 4 factors, and 57% for 5 factors
DBP, diastolic blood pressure; RR, respiratory rate; SBP, systolic blood pressure.
a
On the basis of mortality rates, classes I and II should be treated as out-patients, class III should have a short
observational stay, classes IV and V should be admitted; highly sensitive, well-validated, widely endorsed but
cumbersome to use.
b
Patients with 0–1 factors can be out-patients, those with 2 factors usually warrant hospitalization, and those
with 3–5 factors should be assessed for admission to the intensive care unit. Not as extensively studied as the
pneumonia severity index, but easier to use; unclear which is superior.
Table 11-14. Criteria for Severe CAP
Minor Criteriaa Major Criteria

b
Tachypnea ≥ 30 breaths/min Invasive mechanical ventilation
Multilobar infiltrates Septic shock with the need for vasopressors
Confusion/disorientation
Uremia (BUN level, ≥ 20 mg/dL)
c 3
Leukopenia (WBC count, < 4000 cells/mm )
Thrombocytopenia (platelet count, < 100,000
3
cells/mm )
Hypothermia (core temperature, < 36°C)
Hypotension requiring aggressive fluid
resuscitation
BUN, blood urea nitrogen; CAP, community acquired pneumonia; WBC, white blood cell.
a
Other criteria to consider include hypoglycemia (in nondiabetic patients). Acute alcoholism/alcoholic
withdrawal, hyponatremia, unexplained metabolic acidosis or elevated lactate level, cirrhosis, and asplenia.
b
A need for noninvasive ventilation can substitute for a respiratory rate > 30 breaths/min or a PAO 2:FiO2 ratio <
250
c
As a result of infection alone
506 / CHAPTER 11
Treatment
The appropriate treatment regimen depends on the severity of the disease and the
suspicion for particular pathogens (Table 11-15).
Table 11-15. Treatment of Community Acquired Pneumonia
Scenario Antibiotics Comments

Outpatient Macrolide (azithromycin, May need to reserve FQ to prevent
clarithromycin) or doxycycline FQ-resistant strains. If at risk for
Mycobacterium tuberculosis, avoid FQ
Alternative: Anti-PNM FQ
until it has been ruled out. FQ use in
If risk factors for drug resistance: FQ
out-patients is discouraged unless
or anti-PNM BL (high-dose amoxicillin,
patients have risk factors for drug
amoxicillin–clavulanate, cefpodoxime)
resistance or are in a community
+ macrolide
known to have macrolide-resistant
pneumococcus
Duration: Minimum of 5 days
Inpatient, FQ (IV or oral) alone or If PCN allergy, use FQ or substitute
non-ICU Anti-PNM BL (cefotaxime, ceftriaxone, aztreonam for the β -lactam
ampicillin–sulbactam) + macrolide
Doxycycline can be used instead of a
If concern for CA-MRSA, add macrolide
vancomycin or linezolid
Duration: 5–7 days for typical
If structural lung disease, cover PSD organisms, 10–14 days for atypical
except Legionella (21 days); convert to
oral from IV therapy when patient
improving clinically.
Inpatient, IV BL (piperacillin–tazobactam, When covering PSD, use combination
ICU imipenem, meropenem, cefepime) + treatment to prevent inappropriate
Key Fact either an FQ (IV or oral) or a macrolide initial therapy; adjust therapy once
susceptibilities are known.
Both macrolides and If concern for CA-MRSA, add
fluoroquinolones can cause vancomycin or linezolid Duration: As above but longer if
prolonged QTc. Use extrapulmonary infection (meningitis,
If suspecting PSD or resistant
doxycycline instead (unless endocarditis), initial therapy inactive
pathogens:
patient is pregnant). against pathogen identified later, if
BL above plus anti-PSD FQ or
infected by PSD, Staphylococcus
BL + AG + azithromycin or
aureus, Legionella, unusual/less
BL + AG + anti-PNM FQ
common pathogens, or if evidence of
necrotizing pneumonia, empyema, or
lung abscess
AG, aminoglycoside; BL, β-lactam; CA-MRSA, community acquired methicillin-resistant Staphylococcus aureus;
FQ, fluoroquinolone; IV, intravenous; PNM, pneumococcal; PSD, pseudomonal or Pseudomonas; anti-
pneumococcal FQ, levofloxacin, moxifloxacin, and gemifloxacin; anti-pseudomonal FQ, ciprofloxacin (400 mg IV
every 8 hours or 750 mg by mouth daily) or levofloxacin (750 mg IV by mouth daily)
INFECTIONS / 507
Risk factors for drug resistant pathogens:

 Age > 65
 Alcoholism
 Significant medical comorbidities (COPD, liver/kidney diseases, cancer, DM,
chronic heart disease, immunosuppression)
 Recent (3–6 months) history of β-lactam, macrolide, or FQ use
ASPIRATION PNEUMONIA—Per IDSA/ATS guidelines, anaerobic coverage is

indicated in those with a history of loss of consciousness from alcohol/drug
overdose or after seizures in people with gingival disease or esophageal motility
disorders.
 β-lactam/β-lactamase inhibitor
 Penicillin plus metronidazole (50% failure rate with monotherapy)
 Clindamycin
Key Fact
REFRACTORY PNEUMONIA—Some clinical improvement generally is seen 20% of nonresolving
within 48–72 hours of initiating antibiotic therapy; if no improvement within 72 pneumonia cases are due
to noninfectious causes
hours, the patient is considered to be a nonresponder (6–15% of hospitalized (neoplasm, vasculitis,
patients). The median defervescence time is 3 days. Other symptoms may take up Bronchiolitis obliterans
to a month to resolve, especially when age > 50 years, severe pneumonia, and organizing pneumonia/
cryptogenic organizing
comorbid conditions present. Antibiotic changes prior to 72 hours should be pneumonia, eosinophilic
considered in only patients who are deteriorating or have new culture pneumonias, drug-induced
data/epidemiologic history. lung disease, and
pulmonary edema/
embolism). In such cases,
CAUSES OF TREATMENT FAILURE bronchoscopy with biopsy
 Inadequate or delayed host response. is useful, especially in
young, nonsmokers with
 Ineffective antibiotic coverage (TB, fungi, Nocardia, Actinomyces, resistant diffuse parenchymal
pathogens). involvement.
 Complications of initial infection: Consider chest CT and thoracentesis to
evaluate for effusions, abscess, airway obstruction, and empyema.
Prevention
PNEUMOCOCCAL VACCINE—PPSV23 is a capsular polysaccharide from 23

serotypes responsible for 90% of invasive pneumococcal infections; shown to
prevent invasive pneumococcal disease.
 Cost-effective in those > 65 years of age in preventing bacteremia
 Who should be vaccinated
o All immunocompetent patients age > 65
o Age < 65 and with any of the following: COPD, CHF, DM, alcoholism, Flash Card Q14
cirrhosis, CSF leaks, asplenia, those living in long-term care facilities What is an appropriate
antibiotic regimen for a
patient with a prolonged
QT and risk factors for drug
resistance?
508 / CHAPTER 11
o Efficacy in immunosuppressed unknown but still recommended in: HIV,

leukemia/lymphoma, multiple myeloma, organ transplantation, chronic
steroid use
o Can be given simultaneously with other vaccines but at a separate site
o Revaccinate once if over age 65 and received the initial vaccine > 5 years
prior
PCV13is a pneumococcal protein conjugate polysaccharide vaccine; 39–55% of

cases in 2009 were caused by PCV13 serotypes.
 Stimulates good antibody response, mucosal immunity, herd protection and
immunologic memory in children and adults
 Vaccination in children has shown to decrease invasive disease in both adult
and children
 Not yet recommended for use in healthy adults due to lack of efficacy
however some data seem to suggest benefit in immunocompromised patients
 The following patients should receive sequential vaccination with both
PCV13 and PPSV23
o With congenital or acquired immunodeficiency
o With HIV
o With chronic renal failure
o With nephrotic syndrome
o With leukemia/lymphoma, multiple myeloma, generalized malignancy
o Solid organ transplant recipients
o Those who use immunosuppressants
INFLUENZA VACCINE—Influenza infection can result in secondary bacterial

pneumonia, commonly by S pneumoniae.
Who should be vaccinated

 Recommended for everyone > 6 months of age
 Particularly important in high-risk groups
o Persons with increased risk of complications
 Age > 65
 Residents of nursing homes or long-term care facilities
 Those with chronic diseases such as DM, chronic kidney disease,
immunosuppression, hemoglobinopathy
o Persons 50–64 years of age
o Those who can transmit influenza to those at high risk
 Health care workers
 Employees of home health care, nursing homes, long-term care or
Flash Card A14 assisted-living facilities
Monotherapy with a  Household members of patients at high risk
macrolide is NOT
recommended due to
concern for macrolide-
resistant S. pneumoniae.
Doxycycline plus β-lactam
is a good choice.
INFECTIONS / 509
NOSOCOMIAL PNEUMONIA
Hospital-acquired pneumonia (HAP): Occurs > 48 hours after admission and not
present at the time of admission.
Ventilator-associated pneumonia (VAP): HAP that occurs > 48–72 hours after
endotracheal intubation.
Health care–associated pneumonia (HCAP):

 Nonhospitalized patients exposed to a health care setting (home IV therapy,
wound care, IV chemotherapy in the past 30 days
 Resident of nursing home or long-term care facility
 Recent hospitalization for 2 or more days in the last 90 days
 Hemodialysis clinic in the past 30 days
Primary route of infection is through microaspiration of colonized organisms of

the oropharyngeal or GI tract.
Microbiology
Common pathogens are aerobic gram-negative bacilli (E. coli, Klebsiella,
Enterobacter, Pseudomonas aeruginosa [PSDA], Acinetobacter) and gram-
positive cocci (Staphylococcus, Streptococcus). Key Fact
Staphylococcus
Etiology also dependent on risk factors for multidrug-resistance: epidermidis, enterococci,
 Recent antibiotics within last 90 days most gram-positive bacilli
 Current hospitalization of 5 days or more (except Actinomyces and
Nocardia) are not
 High frequency of antibiotic resistance in the community or hospital unit pathogenic.
 Immunosuppression
 Risk factors for HCAP (see above), although some studies report that it may
be an overgeneralization to consider all HCAP patients to be at risk for MDR
pathogens
Diagnosis
New/progressive infiltrate on imaging plus two of the following: fever, purulent
sputum, leukocytosis/leukopenia, or increased oxygen requirements.
Differential diagnoses include aspiration pneumonitis, pulmonary infarction,

ARDS, pulmonary hemorrhage/contusion, infiltrative tumor, radiation
pneumonitis, pulmonary drug toxicity and cryptogenic organizing pneumonia.
510 / CHAPTER 11
Obtain blood cultures, and thoracentesis, if possible.
Obtain lower respiratory tract samples via tracheobronchial aspiration through

endotracheal tube or bronchoscopically via BAL or protected specimen brush
(PSB).
Quantitative culture is significant if the value exceeds 1,000,000 colony forming

units (CFU)/mL for tracheobronchial aspiration, 10,000 CFU/mL for BAL, or
1000 CFU/mL for samples obtained by PSB. Consider lower thresholds if risk of
missing a VAP exceeds risk of unnecessary treatment.
Treatment
Initial treatment regimen should be selected based on the risk of drug-resistant
Key Fact pathogens (Table 11-16). It can then be tailored when susceptibility data becomes
Daptomycin does not available. If Staphylococcus aureus or gram-negative bacilli (grow easily in
achieve high culture) are not isolated from good quality sputum specimen, stop coverage for
concentrations in the lung.
these organisms.
Key Fact Duration: Generally 7 days, but up to 15 days if pseudomonas is cultured and up
Ceftaroline is approved by
to 21 days if MRSA is cultured. Duration can be extended based on clinical
FDA for community course and extent of infection.
acquired pneumonia but
not if caused by MRSA; not
to be used for hospital- Table 11-16. Treatment of Nosocomial Pneumonia
acquired
pneumonia/ventilator- Scenario Antibiotics Notes
associated
pneumonia/HCAP. No known Ceftriaxone 2 g IV daily; or ampicillin– If concern for resistant GNB based on
MDR risk sulbactam 3 g IV q6h; or levofloxacin 750 institutional data, can start piperacillin–
factors mg IV daily; or moxifloxacin 400 mg IV tazobactam, cefepime, or anti-PSD
daily;. or ertapenem 1 g IV daily carbapenem as monotherapy
Key Fact Known MDR Cefepime (2 g q8h) or ceftazidime (2 g No conclusive evidence to support
Tigecycline has activity risk factors q8h), or combination therapy for gram-negative
against MRSA but is Imipenem, meropenem, or doripenem, or pathogens such as PSD but commonly
associated with an Piperacillin–tazobactam done since MDR pathogens that may be
increased risk of death, resistant to one antibiotic may be
AND
therefore do not use unless susceptible to the other
other agents are not Anti-PSD FQ, or Anti-PSD FQ is preferred if Legionella is
suitable. AG, or likely
Colistin
AG can be stopped in 5–7 days in those
AND if suspecting MRSA: who respond
Linezolid (600 mg q12h IV or oral), or Colistin may be appropriate if highly
Vancomycin (15–20 mg/kg IV q8-12h resistant PSD species, Acinetobacter
with target trough 15–20 mg/L) species, Enterobacteriaceae family are
suspected or established
AG, aminoglycoside (gentamicin, tobramycin, amikacin); anti-PSD FQ, anti-pseudomonal fluoroquinolone,
ciprofloxacin (400 mg IV every 8 h or 750 mg PO BID) or levofloxacin (750 mg IV PO daily)FQ, fluoroquinolone;
IV, intravenous(ly); GNB, gram-negative bacilli; MDR, multidrug resistance; PSD, pseudomonal or
Pseudomonas.
INFECTIONS / 511
Prevention
Hydrogen blockers/proton pump inhibitors are associated with increased risk of
HAP. The IDSA recommends avoiding them in patients who are not at high risk
for developing stress ulcer or stress gastritis.
The following interventions may reduce the incidence of VAP but have not been
shown to change patient outcomes.
 Digestive tract decontamination with oral antiseptics such as chlorhexidine
 Positioning patients in a semirecumbent position with the head of the bed at ≥
30 degrees
 Silver-coated endotracheal tubes
NTM
Epidemiology
More than 140 NTM have been identified, at least 40 of which are associated with
human lung infection. It is difficult to determine the epidemiology of NTM, as
reporting is not mandatory, but it appears that the incidence and prevalence are
increasing.
Transmission
NTM is ubiquitous in the environment and can be found in natural and drinking
water, biofilms, soil, and aerosols. Human-to-human transmission has never been
documented. Risk factors for disease include impaired host immunity, impaired
lung immunity, and host demographics.
Clinical Presentation Flash Card Q15

What antibiotic can be
NTM pulmonary disease can present in diverse ways including used to treat nosocomial
 TB-like cavitary disease pneumonia in a patient with
a penicillin and/or a
 Bronchiectasis cephalosporin allergy?
 Hypersensitivity-like lung disease
 Esophageal dysmotility
Flash Card Q16
NTM in AIDS most commonly causes disseminated disease that presents with
nonspecific symptoms such as fever, night sweats, diarrhea, abdominal pain, and Describe Lady Windermere
syndrome.
512 / CHAPTER 11
lymphadenopathy. In such patients, Mycobacterium avium complex (MAC) is the

most frequent isolate.
Diagnosis
Clinical, radiographic, and microbiologic criteria must be met to make a diagnosis

of NTM infection. Clinical criteria include pulmonary symptoms and exclusion of
other diagnoses, and radiographic criteria include nodular or cavitary opacities on
chest radiograph or bronchiectasis with small nodules on chest CT. The
microbiologic criteria are summarized in Table 11-17.
Table 11-17. Microbiologic Criteria for Diagnosis of NTM Lung Disease

At least 3 sputum results available 2 positive culture results regardless of the results of AFB
smear
Single available bronchial wash or 1 positive culture regardless of the results of the AFB
lavage smear
Tissue biopsy Compatible histopathology and a positive biopsy culture ;

compatible histopathology and a positive sputum or
bronchial wash culture for NTM
AFB, acid-fast bacillus; NTM, nontuberculous Mycobacterium/mycobacteria
DIFFERENTIAL DIAGNOSIS—Clinical manifestations of NTM infection include

lymphadenitis, and disseminated, skin, soft tissue, and bone diseases. The most
important differential is TB lymphadenitis.
Flash Card A15

Aztreonam; if the patient SLOWLY GROWING Mycobacterium
had a severe allergic
reaction to ceftazidime in
the past, then cross-
reactivity is variable, and NTM species generally are categorized as slowly growing or rapidly growing
aztreonam should not be organisms. Slowly growing NTM that cause human disease include MAC,
given until the patient is
evaluated by an allergy Mycobacterium kansasii, and Mycobacterium xenopi.
specialist
Flash Card A16

Thin, postmenopausal
women with NTM disease;
often associated with right
middle lobe and lingular
bronchiectasis
INFECTIONS / 513
MAC
There are three manifestations of pulmonary disease due to MAC—

nodular/bronchiectatic disease, cavitary disease, and advanced or previously
treated disease.
Recommended duration of treatment is 12 months after documented sputum

culture negativity; treatment involves a macrolide, ethambutol, and rifamycins.
Preventive therapy for MAC is recommended for all HIV patients with CD4+ <
50; azithromycin 1200 mg weekly is the preferred agent.
Mycobacterium kansasii
Tap water is the major reservoir, and there is no recommended prophylaxis for
disseminated disease.
Recommended regimen for treating pulmonary M. kansasii disease is three agents

for 12 months of negative sputum cultures: rifampin (600 mg/day), isoniazid (300
mg/day), and ethambutol (15 mg/kg/day).
Mycobacterium xenopi
 Survives in hot water systems and natural hot water reservoirs

 Rarely isolated in the U.S., but often isolated in Canada, United Kingdom, and
Europe
 Overall mortality is high
 A number of accepted treatment regimens include clarithromycin, rifampin,
and ethambutol isoniazid for 12 months
RAPIDLY GROWING Mycobacterium
Mycobacterium abscessus Key Fact

Mycobacterium abscessus
Fulminant, rapidly progressive form of the disease has been seen in patients with infection in patients with
cystic fibrosis who have
gastroesophageal disorders and cystic fibrosis. undergone lung
transplantation has been
 Typically resistant to most of the medications used to treat TB, and therapy associated with severe and
sometimes fatal disease.
usually consists of IV agents such as imipenem or cefoxitin plus amikacin
514 / CHAPTER 11
Therapy should be continued for at least 2–4 months, although cure with medical
therapy alone may be difficult to achieve
PREVENTION OF NTM DISEASE
NTM is ubiquitous in the environment, so complete avoidance is difficult.

Transmission of NTM disease in the health care setting has most frequently been
linked to tap water exposure. Therefore, it is recommended that tap water not be
used in various nosocomial settings. Potent disinfectants have been unsuccessful
in eradicating these organisms.
Prophylaxis should be given to adults with AIDS with CD4 counts < 50;
azithromycin and clarithromycin have proven efficacy.
LUNG NEOPLASMS / 515
12 Lung Neoplasms
Sujith V Cherian MD & Fayez Kheir, MD, MSCR
INTRODUCTION
Lung neoplasms can be classified as benign or malignant. Lung cancer remains

the most common cause of cancer-related death in the United States among both
men and women. Benign lung tumors are < 5% of all resected lung neoplasms.
Most benign lung tumors present as asymptomatic solitary pulmonary nodules,
incidentally discovered radiographically. About 50% of benign lung neoplasms
are hamartomas.
BENIGN LUNG NEOPLASMS
Benign lung tumors are broadly divided into epithelial and nonepithelial tumors.
EPITHELIAL NEOPLASMS
Types include:
 Papilloma
 Micronodular pneumocyte hyperplasia
Papillomas
SQUAMOUS PAPILLOMA—Most often associated with cigarette smoking and

human papilloma virus. Most occur in central large airways.
RECURRENT RESPIRATORY PAPILLOMATOSIS—Also known as juvenile

laryngotracheal papillomatosis.
516 / CHAPTER 12
 Associated with human papilloma virus types 11 and 6.

 Surgical excision and laser ablation are the mainstays of treatment.
 Lung involvement occurs in 3% of patients and generally has an aggressive
course, with no effective medical therapy.
 Squamous cell carcinoma is the most feared complication and may appear as
cavitating nodules or masses (Figures 12-1 and 12-2).
Figure 12-1. Image showing tracheal papillomatosis.

(Reproduced, with permission, from Martin RT, Miller AN. Squamous cell carcinoma arising in recurrent
respiratory papillomatosis. A83. Great Cases: Clinical, Radiologic and Pathologic Correlations by Master
Physicians, 2011; 83: 6466, Fig. 2. DOI: 10.1164/ajrccm-conference.2011.183.1_MeetingAbstracts.A646610.)
Figure 12-2. (A)Chest computed tomography scan showing presence of cavitary

infiltrates in the right lung field, and (B,C) positron emission tomography (PET)
scans showing increased fluorodeoxyglucose (FDG) avidity that was diagnosed
as squamous cell carcinoma.
(Reproduced, with permission, from Martin RT, Miller AN. Squamous cell carcinoma arising in recurrent
respiratory papillomatosis. A83. Great Cases: Clinical, Radiologic and Pathologic Correlations by Master
Physicians, 2011; 83: 6466. DOI: 10.1164/ajrccm-conference.2011.183.1_MeetingAbstracts.A646610.)
Micronodular Pneumocyte Hyperplasia

 Characterized by numerous small, well-demarcated parenchymal nodules.
 Classically associated with tuberous sclerosis and/or
lymphangioleiomyomatosis.
 Histopathology shows hyperplastic type II pneumocytes.
 Findings are not progressive, so no treatment is indicated.
NONEPITHELIAL NEOPLASMS
Types include:
 Hamartomas
 Solitary fibrous tumors
Hamartomas
 Most common benign lung neoplasm in adults
 More common in men
 Generally discovered incidentally in the sixth or seventh decade
 Parenchymal or endobronchial (10%) nodules with characteristic popcorn
calcification (Figure 12-3). Figure 12-4 and 5 demonstrate solitary pulmonary
nodules.
 Typically mature hyaline cartilage with fat, fibromyxoid tissue, and/or smooth
muscle cells
Flash Card Q1
A 23-year-old man
presents with cavitary lung
nodules and a vocal polyp.
Figure 12-3. Lung hamartoma with popcorn calcification. He has a history of
(Reproduced, with permission, from Khan, et al. The calcified lung nodule: What does it mean? Ann Thorac
Med. 2010; 5: 67-79.) hoarseness as a child.
What is the diagnosis?
518 / CHAPTER 12
Figure 12-4. Chest x-ray showing a solitary pulmonary nodule (black box) in the
left upper lobe.
(Reproduced from Wikimedia Commons under the Creative Commons Attribution-Share Alike 3.0 Unported
license.)
Flash Card A1
Figure 12-5. Chest CT scan showing a solitary pulmonary nodule (arrow).
Recurrent respiratory (Reproduced from Wikimedia Commons under the Creative Commons Attribution-Share Alike 3.0 Unported
papillomatosis with lung license.)
involvement, most likely
squamous cell cancer
Solitary Fibrous Tumors

Key Fact
 These rare, spindle cell tumors are also referred to as localized fibrous
mesotheliomas. Hamartomas are the most
common benign
 Generally arise from the visceral (most common) or parietal pleura. neoplasms in adults and
 Mean age at diagnosis is the sixth decade. are generally solitary
nodules. Computed
 Men and women are affected equally. tomography scans show a
characteristic combination
of calcifications and/or fat.
MALIGNANT LUNG NEOPLASMS
Lung cancer is the third most common cancer in the United States (excluding
non-melanoma skin cancers). Although breast and prostate cancer are more
frequently diagnosed, lung cancer is the most common cause of cancer-related
death in both genders.
Predominant types include:

 Non-small cell lung cancer (NSCLC)
 Small cell lung cancer (SCLC)
 Primary pulmonary lymphoma
NON-SMALL CELL LUNG CANCER
NSCLC is the most common form of lung cancer and is divided into the following
types:
 Squamous cell carcinoma
 Adenocarcinoma
 Large cell carcinoma
 Carcinoid tumors
Squamous Cell Carcinoma

Squamous cell carcinoma is a malignant epithelial tumor with keratinization
and/or intercellular bridges on histopathology (Figure 12-6). Keratinization is
most often in the form of squamous pearls.
520 / CHAPTER 12
Figure 12-6. Histopathologic specimen of squamous cell carcinoma of the lung

with intercellular bridges (arrow).
 Strongly associated with cigarette smoking (Figure 12-7).

 Occurs predominantly in men.
 Two thirds of cases occur centrally, with involvement of the main stem, lobar,
or segmental bronchi.
 Compared with other histologic subtypes, it is more commonly associated
with cavitation, Pancoast syndrome, and hypercalcemia.
 Immunohistochemistry: Usually stains positive for p63, cytokeratin 5/6.
Figure 12-7. Incidence of types of lung cancer in smokers and nonsmokers.

Adenocarcinoma
Adenocarcinoma is the most frequently diagnosed histologic type of lung cancer.

It is the most common subtype in women and nonsmokers. Most tumors occur in
the periphery. Positive immunohistochemical stains include thyroid transcription
factor-1, napsin A, and cytokeratin 7.
Common subtypes:
 Acinar: Cuboidal/columnar cells that form acini and tubules (Figure 12-8)
 Papillary: Malignant cells are arranged on the surface of fibrovascular cores.
 Bronchioalveolar carcinoma, now known as adenocarcinoma in situ:
Characterized by slow lepidic growth
 Solid with mucin production
 Mixed subtype
Figure 12-8. Histopathologic specimen of lung adenocarcinoma showing an

acinar pattern.
522 / CHAPTER 12
BRONCHIOLOALVEOLAR CARCINOMA (BAC)—BAC grows in a uniform

manner along alveolar walls without evidence of stromal, vascular, or pleural
invasion (Figure 12-9). These very slow-growing neoplasms have a 100% 5-year
survival rate if the lesion is < 2 cm at the time of resection. They can present
radiographically as ground-glass opacities, with or without a solid component, or
as diffuse disease (Figure 12-10). Diffuse disease is associated with worse
survival.
Figure 12-9. Hematoxylin-eosin-stained lung biopsy specimen showing

extensive mucin production.
(Figure reproduced from Wikimedia Commons under the Creative Commons Attribution-Share Alike 3.0
Unported license.)
Figure 12-10. Chest CT scan showing ground-glass opacity, which was shown
on biopsy to be bronchioalveolar carcinoma.
(Reproduced courtesy of Wikimedia Commons under the Creative Commons Attribution-Share Alike 3.0
Unported license.)
Large Cell Carcinoma

Undifferentiated malignant epithelial tumors that lack features of small cell
carcinoma and glandular or squamous differentiation. They are characterized by
large nuclei, prominent nucleoli, and a moderate amount of cytoplasm.
Carcinoid Tumors
Pulmonary carcinoid tumors represent about 1–5% of all lung malignancies. They
are mainly of two types, typical and atypical:
 Typical carcinoid: < 2 mitoses per 10 high-power fields and absence of
necrosis (Figure 12-11)
 Atypical carcinoid: > 2 mitoses per 10 high-power fields or presence of
necrosis
CLINICAL FEATURES
 Usually occur in those who have never smoked.
 About 70% of carcinoids develop in the proximal airways and may be
associated with chronic cough, hemoptysis, and bronchial obstruction.
 Peripheral carcinoids are generally asymptomatic.
 Fewer than 2% of cases are associated with carcinoid syndrome.
 Low to moderate activity is seen on PET scan.
Figure 12-11. Histopathologic specimen of lung carcinoid with cells arranged in a

trabecular pattern.
((Reproduced courtesy of Yale Rosen, flikr.com, CC BY-SA 2.0.)
524 / CHAPTER 12
TREATMENT—Treatment of carcinoid tumors is different from that of other

types of NSCLC:
 Typical carcinoid: Limited resection with segmentectomy and regional lymph
node dissection
 Atypical carcinoid: Lobectomy and mediastinal lymph node dissection
 Metastasis: No known benefit to chemotherapy or radiation therapy. Local
treatment of metastases may lead to prolonged remission.
Staging of NSCLC
Perhaps the most critical role of the pulmonologist in the management of lung
cancer is the diagnostic and staging evaluation of lung cancer. The lung cancer
staging system is relatively complex, but accurate staging helps the clinician to
estimate prognosis, define the extent of tumor, select treatment options, and report
outcomes (Table 12-1).
Five-year survival rates based on the current staging system:

 Stage IA: 73%
 Stage IB: 58%
 Stage IIA: 46%
 Stage IIB: 36%
 Stage IIIA: 24%
 Stage IIIB: 9%
 Stage IV: 13%
Table 12 -1. American Joint Committee on Cancer Staging System for Lung
Cancer
Stage Tumor Lymph Node Metastases
IA T1a or T1b N0 M0
IB T2a N0 M0
IIA T1a or T1b or T2a N1 M0
T2b N0 M0
IIB T2b N1 M0
T3 N0 M0
IIIA Any T between T1a and T2b N2 M0
T3 N1 or N2 M0
T4 N0 or N1 M0
IIIB T4 N2 M0
Any T between T1a N3 M0
and T4
IV Any T Any N M1a or b
Table 12 -1. American Joint Committee on Cancer Staging System for

Lung Cancer, continued
TNM Definitions
T TX Positive malignant cell, but primary tumor not visualized by imaging or
bronchoscopy
T0 No evidence of primary tumor
Tis Carcinoma in situ

T1 Tumor ≤ 3 cm, surrounded by lung or visceral pleura, without bronchoscopic
evidence of invasion more proximal than the lobar bronchus
T1a- ≤ 2 cm
T1b- > 2 cm, but < 3 cm
T2 Tumor with any of the following features of size or extent:
• > 3 cm in greatest dimension, but > 7 cm
• Involves main bronchus, ≥ 2 cm distal to the carina
• Invades the visceral pleura
• Associated with atelectasis or obstructive pneumonitis that extends to the hilar
region but does not involve the entire lung
T2a- > 3 cm, but < 5 cm

T2b- > 5 cm, but < 7 cm
T3 Tumor of any size that directly invades any of the following: chest wall (including
superior sulcus tumors), diaphragm, mediastinal pleura, parietal pericardium; or
tumor in the main bronchus < 2 cm distal to the carina, but without involvement of
the carina; or associated atelectasis or obstructive pneumonitis of the entire lung,
or separate tumor nodules in the same lobe
T4 Tumor of any size that invades any of the following: mediastinum, heart, great
vessels, trachea, esophagus, vertebral body, or carina; or with separate tumor
nodule(s) in a different ipsilateral lobe of the lung
N NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and

intrapulmonary nodes involved by direct extension of the primary tumor
N2 Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or
contralateral scalene, or supraclavicular lymph node(s)
M MX Presence of distant metastasis cannot be assessed
M0 No distant metastasis
M1 a Contralateral lung nodules, pleural or pericardial nodules, or malignant pleural or
pericardial effusion
M1 b Distant metastasis
526 / CHAPTER 12
Staging of NSCLC
Overall 5-year survival rate is a dismal 14%. Survival curves vary by stage at
diagnosis, with early-stage disease associated with much better survival. In
general, early-stage disease is surgically managed, locally advanced disease is
managed with chemotherapy and radiation therapy, and advanced disease is
managed with chemotherapy and supportive care.
PROGNOSTIC FACTORS
 Strongest predictors of survival:
o Good performance status (Karnofsky scale)
o Lesser extent of disease
o Younger age
o Absence of weight loss
 Other predictors of better survival:
o Smoking cessation
o Standard uptake value of the primary tumor on positron emission
tomography (PET) scan
 Histologic subtype not considered a predictor of survival.
TREATMENT BY STAGE OF DISEASE

Stage I and II:
 Surgery is first-line treatment. There is no role for chemotherapy or
postoperative radiation therapy in stage IA disease. Adjuvant chemotherapy
may be useful in selected cases of stage IB disease, especially if the tumor is >
4 cm.
 Stage II disease is treated with surgery followed by adjuvant chemotherapy.
Lobectomy is preferred. Sublobar resection is reserved for tumors < 3 cm and
patients with severely compromised pulmonary function, advanced age, or
extensive comorbidity.
 Radiation therapy is reserved for patients who are poor surgical candidates
and those with positive surgical resection margins.
Stage IIIA:
 Most cases are unresectable. Chemotherapy and/or radiation therapy may be
used. Some tumors are only definitively staged as IIIA during resection. In
these cases, surgery proceeds and is generally followed by adjuvant
chemotherapy.
Stage IIIB:
 Combined chemotherapy and radiation therapy is used.
Stage IV:
 Chemotherapy
 Radiation therapy for palliation only
Post-therapy surveillance:
 Follow-up in clinic with chest computed tomography (CT) scans every 4–6
months for the first 2 years and annually thereafter.
CHEMOTHERAPY REGIMENS—Somatic genomic alterations known as driver

mutations occur in cancer cells that encode for proteins critical to cell growth and
survival. Targeted therapy involves agents that target these specific molecular
pathways.
If driver mutation is present:

 Epidermal growth factor receptor mutation: Treatment with a single-agent
epidermal growth factor receptor tyrosine kinase inhibitor (erlotinib, getinib,
afatinib) can be used for initial management. These agents improve
progression-free survival compared with traditional chemotherapy. This
mutation is most common in female patients of East Asian decent with
adenocarcinoma and no history of smoking.
 ALK mutation: Crizotinib is first-line therapy in ALK-positive cases.
SPECIAL CONSIDERATIONS
 Superior sulcus tumor with Pancoast syndrome: Pancoast syndrome is a
constellation of symptoms and signs that include shoulder and arm pain along
the distribution of the C8, T1, and T2; Horner’s syndrome; and weakness and
atrophy of the hand. It is seen in one third of patients with superior sulcus
tumors. Because of its location, transthoracic need aspiration is diagnostic in >
90% of cases. If the disease is localized, this is one exception where the
treatment starts with neoadjuvant chemotherapy and radiation therapy
followed by resection.
 Superior vena cava syndrome: Superior vena cava syndrome is usually the
result of direct obstruction of the superior vena cava by malignancies.
Bronchogenic carcinoma is the most common cause. It is not a medical
emergency, and a diagnosis should be obtained before treatment is provided.
Bronchoscopy or mediastinoscopy can be safely performed.
Treatment:
 Secondary to SCC: Chemotherapy
 Secondary to NSCLC: Concurrent chemotherapy and radiation therapy
SMALL CELL LUNG CANCER
SCLC is characterized by proliferation of small cells with scant cytoplasm, ill-

defined borders, salt and pepper chromatin, frequent nuclear molding, and a high
528 / CHAPTER 12
mitotic count (Figure 12-12). Staining is usually positive for thyroid transcription
factor-1,CD 56, synaptophysin, and chromogranin.
Up to 98% of patients with SCLC have a history of smoking. The natural history
of SCLC is early metastasis and death. Unlike NSCLC, SCLC is always
considered a systemic disease at diagnosis. Liver, bone, bone marrow, and the
central nervous system are the most commonly affected extrapulmonary organs.
SCLC shows an excellent response to chemotherapy, but almost always recurs.

Median survival for disease confined to the chest is 4–6 months without treatment.
For metastatic disease, median survival is 5–9 weeks without treatment.
Figure 12-12. Histopathologic specimen of small cell carcinoma of the lung.

(Reproduced courtesy of Wikimedia Commons under the Creative Commons Attribution-Share Alike 3.0
Unported license.)
Staging of SCLC
Although TNM staging can be used in SCLC, many clinicians prefer a simpler
two-stage system. This staging system was originally proposed by the Veterans
Administration Lung Study Group and has been found to have prognostic utility:
 Limited stage (25–30% of patients): Disease confined to a single radiation
portal or localized to one hemithorax
 Extensive stage (70–75% of patients): Any disease outside of the hemithorax
Chemotherapy
LIMITED DISEASE—Response rate of 70–80% to chemotherapy and thoracic
radiation therapy, with a complete clinical response rate of 50–60%. Concurrent
radiation therapy begins with the first or second cycle of chemotherapy. No
benefit has been shown beyond 4–6 cycles of chemotherapy.
EXTENSIVE DISEASE—Response rate of 60–80% to chemotherapy, with only

20% of patients achieving complete clinical remission. Standard approach is
chemotherapy for 4–6 cycles, followed by assessment for progression. Radiation
therapy is strictly palliative and can be used for symptomatic control of primary
and metastatic lesions.
Prophylactic whole brain radiation is recommended for all patients with a good
performance status who have attained remission after induction chemotherapy and
radiation therapy.
PRIMARY PULMONARY LYMPHOMA
Primary pulmonary lymphoma is lymphoma affecting one or both lungs, without

evidence of extrapulmonary involvement or bone marrow disease at the time of
diagnosis and during the subsequent 3 months.
Most frequent subtypes:
 Mucosa-associated lymphoid tissue–type lymphoma
 Lymphomatoid granulomatosis
Mucosa-Associated Lymphoid Tissue–Type Lymphoma
 Accounts for 70–90% of primary pulmonary lymphomas.

 Characterized by diffuse infiltration of small monomorphic lymphoid cells
with a typical lymphangitic growth pattern. These cells spread along the
bronchovascular bundles and interlobular septa and form solid nodules that fill
the alveolar spaces (Figure 12-13A).
 Occurs mainly in patients > 45 years of age, with a slight male preponderance,
although it can occur in younger patients, especially those with underlying
immunosuppression.
 Most common imaging pattern is pneumonia-like alveolar consolidation with
air bronchograms. Sometimes appears as nodular opacities or an “infiltrative”
pattern (Figure 12-13B).
 Disease is typically indolent and prognosis is excellent, with 5-year survival
rates > 80%.
530 / CHAPTER 12
 Management:
o Watchful waiting for asymptomatic patients
o Surgical excision for localized disease
o Rituximab-based chemotherapy for multifocal or disseminated disease
B
Fig 12-13. (A) Histopathologic specimen of the biopsy specimen of the infiltrate
showing total replacement of lung parenchyma with lymphocytes (low-power
view). (B) Chest x-ray of a patient with persistent right lower lobe infiltrate that
was found to be primary pulmonary lymphoma on biopsy.
(Image A mage reproduced, with permission, from Dr. Shakuntala H. Mauzo, University of Texas Health
Science Center at Houston.)
Lymphomatoid Granulomatosis
 Malignant B cell angiocentric and angiodestructive lymphoproliferative

disorder occurs mainly in 40–50-year-old men. The lung is the most frequent
location, although the brain, skin, and central nervous system may be involved.
 Forms multiple and confluent nodules composed of atypical, angiocentric, and
polymorphous lymphoid infiltration involving the vascular walls from the
subendothelium to the adventitial zones, with focal lumen obliteration.
 Contains mainly CD4 T lymphocytes with scattered atypical B cells infected
by Epstein-Barr virus.
 Prognosis is grim, with 5-year survival rate of 30–40%.
 Most common treatment is chemotherapy with high-dose steroids and
cyclophosphamide.
TECHNIQUES FOR DIAGNOSIS AND STAGING
A combination of radiographic and invasive techniques is used to diagnose and

stage lung cancer. The primary lesion is often identified with computed
tomography (CT) and positron emission tomography (PET scans). Extrathoracic
scanning can detect metastatic disease at common sites, including the adrenal
glands, liver, brain, and skeletal system. Appropriate imaging allows
identification of targets for tissue sampling.
RADIOGRAPHIC TECHNIQUES
CT Scan
All patients with lung cancer should have CT scan imaging through the adrenals,
with contrast, if possible, to help to distinguish vascular structures from lymph
nodes.
Flash Card Q2
PET Scan
A 36-year-old patient with
unresolving right middle
More accurate than CT scanning for staging of mediastinum in patients with lung lobe pneumonia of 2
cancer. Sensitivity of 74% and specificity of 85% for identifying mediastinal months’ duration presents
metastases. Negative findings on PET scan can obviate the need for invasive for evaluation. Chest CT
scan shows a right middle
lymph node sampling. However, if mediastinal nodes are positive on PET scan, lobe alveolar infiltrate with
invasive sampling is required, given the high false-positive rate. air bronchograms. What is
the next step?
532 / CHAPTER 12
Magnetic Resonance Imaging (MRI) Scan

Mainly useful for evaluating superior sulcus tumors, especially for possible
invasion of the brachial plexus, and for evaluating vertebral invasion.
INVASIVE DIAGNOSTIC AND STAGING TECHNIQUES
Fiberoptic Bronchoscopy
A combination of brushing, endobronchial biopsy, and washing provides a
diagnosis in 88% of cases of centrally located lesions. In submucosal and
peribronchial lesions, transbronchial needle aspiration has a higher yield (71%)
than endobronchial biopsy (55%). Transbronchial needle aspiration can be used to
sample lymph nodes that appear to be involved based on CT or PET scan.
Transthoracic Needle Aspiration

Useful for parenchymal lesions that are not accessible by bronchoscopy.
Sensitivity and specificity are 90% and 97%, respectively. The main drawback is
the risk of pneumothorax, which is 22–45%. Risk is increased with emphysema,
smaller lesion size, and greater depth from pleural surface to edge of lesion.
Endobronchial Ultrasound
Endobronchial ultrasound with transbronchial needle aspiration is indicated for
assessment of mediastinal and hilar lymph nodes and diagnosis of lung and
mediastinal tumors. It is used to access nodes at the following levels (Figure 12-
14):
 Highest mediastinal: Station 1
 Upper paratracheal: Stations 2R, 2L
 Lower paratracheal: Stations 4R, 4L
 Subcarinal: Station 7
Flash Card A2  Hilar: Station 10
 Interlobar: Station 11
CT-guided lung biopsy.
The biopsy showed
complete replacement of In a patient with a lung mass and lymphadenopathy in the lymph node stations,
lung architecture by endobronchial ultrasound with transbronchial needle aspiration is indicated.
monomorphic small
lymphoid cells with positive
immunohistochemistry for
mucosa-associated
lymphoid tissue–type
lymphoma.
Figure 12-14. Schematic representation of lymph node stations.
Endoscopic Ultrasound
Used to sample the posterior mediastinum through the esophageal wall.
Sensitivity is 84% and specificity is 99.5%. Can be used to reach lymph nodes
that are not accessible by other techniques (e.g., mediastinoscopy), including the
paraesophageal and para-aortic lymph nodes.
534 / CHAPTER 12
Mediastinoscopy
Gold standard for staging the mediastinum in patients with known or suspected
lung cancer. It is often done before thoracotomy and is mainly used to sample
nodes of the paratracheal (station 4) and anterior subcarinal (station 7) regions.
Mediastinoscopy and video-assisted thoracoscopic surgery are the only methods
that can access station 5 nodes.
Sensitivity of 78% and specificity of 100% have been reported in nodes that
appear to be involved on imaging studies. However, the procedure requires
general anesthesia, with a morbidity rate of 2% and a mortality rate of 0.08%.
MEDIASTINAL NEOPLASMS
OVERVIEW
Definition
The mediastinum is defined by the pleural cavities laterally, the thoracic inlet
superiorly, and the diaphragm inferiorly (Figure 12-15). Anatomically, it is
divided into anterior, middle, and posterior compartments (Figure 12-16).
Thoracic inlet
Pleural cavity
Diaphragm
Figure 12-15. Lateral chest radiograph showing the boundaries of the

mediastinum.
(Reproduced, with permission, from Dr. Fayez Kheir.)
536 / CHAPTER 12
Anterior
mediastinum
Middle
mediastinum
Posterior
mediastinum
Figure 12-16. Lateral chest radiograph showing the compartments of the

mediastinum.
(Reproduced, with permission, from Dr. Fayez Kheir.)
Epidemiology
In adults, more than two thirds of mediastinal tumors are benign. Masses in the
anterior compartment are more likely to be malignant. Patients with symptoms are
more likely to have a malignant neoplasm.
Most common mediastinal masses:

 Thymoma: 15–20%
 Neurogenic neoplasms: 12–21%
 Metastatic disease: 40%
 Lymphoma: 10%
Differential Diagnosis
The differential diagnosis of a mediastinal mass is driven by the anatomic
location. Other important factors include patient age, symptoms, and the
radiologic characteristics of the mass.
Imaging
CT scan is the most important tool in the evaluation of mediastinal masses.

Specific attenuation of air, fat, water, and calcium as well as the anatomic
relationships of tumors to adjacent structures can be seen on CT scan. MRI scan
adds little information to CT scan but is important in evaluating neurogenic
tumors.
ANTERIOR MEDIASTINUM
The anterior mediastinum is located in the retrosternal space, anterior to the heart
and great vessels. It contains the thymus, fat, and lymph nodes and can give rise
to a variety of neoplasms (Table 12-2).
Table 12-2. Anterior Mediastinal Masses

Mnemonic
Neoplasm Mass Imaging Features
Interior mediastinal
Thymoma Soft tissue attenuation Patients generally ≥ 40 years old masses— four Ts:
Mild to moderate contrast Associated with myasthenia gravis, Thymoma
enhancement hypogammaglobulinemia, and pure Teratoma
Round, well-circumscribed lesion red cell aplasia Intrathoracic Thyroid
Terrible lymphoma
Usually homogenous
Lymphoma Mediastinal lymphadenopathy Usually found in young adults
Homogeneous lobulated soft tissue Involves mediastinum as part of
mass widespread disease
Hodgkin > non-Hodgkin
Teratoma Well-circumscribed unilocular or Usually asymptomatic
multilocular cystic lesion containing
fluid, soft tissue, and fat
Seminoma Large lobulated homogeneous well- Usually symptomatic
defined mass -fetoprotein normal
Nonseminoma Large, irregular, heterogeneous Usually symptomatic

mass with areas of central necrosis, -fetoprotein increased
hemorrhage, or cyst formation
Thyroid goiter Encapsulated, lobulated, Often discovered incidentally during a
heterogeneous mass physical examination
538 / CHAPTER 12
Thymoma
Most common primary neoplasm of the anterior mediastinum (Figure 12-17).
 Epidemiology: Usually occurs in patients > 40 years of age.
 Presentation: About one third of patients have pressure-induced symptoms.
 Diagnosis: Achieved by CT-guided or surgical biopsy.
o Imaging:
 Chest x-ray shows well-defined lobulated masses in the anterosuperior
mediastinum.
 Chest CT scan usually shows homogeneous solid tumors with soft
tissue attenuation and well-demarcated borders. Up to one third may
have necrotic, hemorrhagic, or cystic components. Calcification may
be found in the capsule or throughout the mass.
 Parathymic syndromes, such as myasthenia gravis, hypogammaglobulinemia,
and pure red cell aplasia, may develop.
 About 30%–50% of patients with a thymoma have myasthenia gravis, and 10–
15% of patients with myasthenia gravis have a thymoma.
 Thymectomy can attenuate symptoms of myasthenia, but the benefit is often
delayed for months after surgery.
Figure 12-17. Chest CT scan showing a large necrotic mass in the left anterior
mediastinum marked (red line). Pathology showed thymoma.
(Reproduced, with permission, from Kurukumbi M, et al. Rare association of thymoma, myasthenia gravis and
sarcoidosis : a case report. J Med Case Reports. 2008;2:245. doi:10.1186/1752-1947-2-245.)
 Treatment is based on the Masaoka-Koga staging system, which describes the

degree of spread of the tumor beyond the capsule.
o About two thirds of patients have encapsulated disease, which is treated
with surgical resection. Five-year survival rate is >75%.
o About one third of patients have invasive disease, which is treated with
surgical resection and adjuvant chemotherapy and radiation therapy. Five-
year survival rate is about 50%.
o Metastatic disease is uncommon and is treated primarily with
chemotherapy.
 Prognosis: Other characteristics associated with poor prognosis include:

o Large tumor (> 10 cm)
o Tracheal or vascular compression
o Age < 30 years
o Epithelial or mixed histologic features
o Hematologic paraneoplastic syndrome
Lymphoma
Mediastinal lymphoma usually occurs as part of widespread disease. Hodgkin
lymphoma (Figure 12-18) accounts for 50–70% of mediastinal lymphomas,
whereas non-Hodgkin lymphoma represents 15–25%.
Figure 12-18. Chest CT scan showing a soft tissue mass in the anterior right
Flash Card Q3
mediastinum with enlarged nodes. Pathology showed Hodgkin lymphoma.
(Reproduced, with permission, from USMLE-Rx.com.) What neoplastic
syndromes are associated
with thymoma?
540 / CHAPTER 12
 Diagnosis:
o Imaging: Lymphoma appears as a lobulated, homogeneous soft tissue
anterior mediastinal mass with mild to moderate contrast enhancement,
mediastinal lymphadenopathy, and no vascular involvement. Cystic and
necrotic changes may be identified.
o Diagnosis is usually made by core needle or surgical biopsy.
 Treatment: Hodgkin lymphoma is treated with radiation with or without
chemotherapy. Non-Hodgkin lymphoma is treated with radiation plus
chemotherapy.
 Prognosis: Overall survival is better for Hodgkin than for non-Hodgkin
lymphoma.
Germ Cell Tumors

Germ cell tumors typically occur in young adults. The mediastinum is the most
common extragonadal site. Types include teratomas, seminomas, and
nonseminomas (embryonal) tumors.
TERATOMAS—Most common type.

 Epidemiology: Typically seen in children and young adults.
Key Fact  Presentation: Mature teratomas are usually asymptomatic and represent 60–
Mediastinal teratomas tend
70% of mediastinal germ cell tumors.
to be cystic.  Usually benign unless they contain fetal or neuroendocrine tissue. These are
considered immature and are associated with a poor prognosis.
 Chest x-ray: Benign teratomas are well-circumscribed, round, or lobular
masses that may contain fat, cystic changes, or calcification.
 Diagnosis: CT scan usually shows a well-defined uni- or multilocular cystic
lesion containing fluid, soft tissue, and fat attenuation.
 Treatment: Complete surgical resection is performed.
SEMINOMAS—Usually occur in men 20–40 years old.

 Presentation: Associated with chest pain, fever, cough, weakness, and weight
loss.
 Diagnosis:
o -Fetoprotein: Usually normal, but β-human chorionic gonadotropin is
elevated in 10–35% of patients.
o Chest x-ray: Large, lobulated, homogeneous, well-defined mass.
 Treatment: Radiation and chemotherapy because most patients have
metastatic disease.
 Prognosis: Overall 5-year survival rate is around 80–90%.
Flash Card A3
Pure red cell aplasia,
myasthenia gravis, and
hypogammaglobulinemia
NONSEMINOMAS—Heterogeneous group of masses, including embryonal cell

carcinomas, endodermal thymus tumors, choriocarcinomas, yolk sac tumors, and
mixed germ cell tumors.
 Presentation: Usually occur in young men. Patients are often symptomatic.

 Diagnosis:
o β-Human chorionic gonadotropin: Elevated in 30% of cases, and -
fetoprotein is elevated in 80% of cases.
o Chest x-ray: Large, irregular, heterogeneous masses with areas of central
necrosis, hemorrhage, or cyst formation.
o Often invasive and metastatic.
 Treatment: Usually includes cisplatin-based combination chemotherapy, with
possible resection of residual tumor.
 Prognosis: Poorer prognosis than seminomas, with a 5-year overall survival
rate of 40–50%.
Thyroid Goiter
Usually euthyroid and found incidentally on physical examination.
Chest x-ray: Mediastinal goiters are encapsulated, lobulated heterogeneous

masses with tracheal narrowing or deviation.
MIDDLE MEDIASTINUM
Located between the anterior and posterior mediastinum. It contains the heart,
pericardium, ascending and transverse aorta, brachiocephalic veins, trachea,
bronchi, and lymph nodes (Table 12-3).
Table 12-3. Middle Mediastinal Masses
Cyst Imaging Features

Bronchogenic Well-circumscribed mass with a Usually asymptomatic
cyst homogenous density with water
attenuation
Located paratracheally or in the
subcarinal area
Pericardial cyst Most commonly located at the right Usually asymptomatic
cardiophrenic angle
Unilocular, nonenhancing mass with
water attenuation
542 / CHAPTER 12
Bronchogenic Cyst
Approximately 7–15% of mediastinal cysts

 Formed by abnormal branching of the tracheobronchial tree during embryonic
development.
 Histology: Lined by respiratory epithelium and cartilaginous plates.
 Presentation: 40% of patients have symptoms (e.g., cough, dyspnea, or chest
pain).
 Diagnosis:
o Chest x-ray: Well-circumscribed mass with a homogenous density and
water attenuation (Figure 12-19).
o Usually located paratracheally or in the subcarinal area.
o Accomplished by CT-guided or bronchoscopic needle aspiration.
 Treatment: Usually removed surgically or drained by needle aspiration if
symptomatic.
Figure 12-19. Computed tomography scan of the chest showing a soft tissue
mass (arrow) paratracheally with fluid density compatible with a bronchogenic
cyst.
(Reproduced, with permission, from Dr. Khalid Alokla.)
Pericardial Cysts
Asymptomatic cysts usually located at the right cardiophrenic angle followed by
the left cardiophrenic angle. CT scan shows unilocular, nonenhancing cysts with
water attenuation.
OTHER—Other causes of middle mediastinal masses:

 Lymphoma
 Metastatic carcinoma
 Nonmalignant lymphadenopathy, such as sarcoidosis
POSTERIOR MEDIASTINUM
Extends from the posterior border of the heart and trachea to the posterior aspect
of the vertebral bodies. It includes the descending thoracic aorta, esophagus,
azygous vein, autonomic ganglia and nerves, thoracic lymph nodes, and fat (Table
12-4).
Table 12-4. Posterior Mediastinal Masses
Imaging Features Manifestations

Neurogenic Magnetic resonance imaging is more Schwannoma is the most common
tumors sensitive than computed tomography type
scan in delineating intraspinal
extension
Extramedullary Single or multiple posterior masses Associated with myeloproliferative
hematopoiesis adjacent to the vertebrae, ribs, or diseases or hemolytic anemia
both
Neurogenic Tumors
Most common cause of posterior mediastinal tumors.
 Derived from neural crest tissue; 70–80% are benign.

 Presentation: Nearly half of patients are asymptomatic. However, compressive
or neurologic symptoms may occur.
o Neurogenic tumors may arise from the peripheral, autonomic, or
paraganglionic nervous systems. The former are the most common and
include schwannomas.
o Malignant nerve sheath tumors are painful, heterogeneous masses. Local
invasion is treated with complete surgical resection if feasible.
Extramedullary Hematopoiesis
Hematopoiesis occurring outside of the bone marrow.
 Cause: Bone marrow replacement (myeloproliferative disorders) or hemolytic
anemia (hemoglobinopathies, chronic anemia)
 Presentation: Usually asymptomatic
 Diagnosis: Chest x-ray: One or more posterior masses adjacent to the
vertebrae, ribs, or both (Figure 12-20)
544 / CHAPTER 12
Figure 12-20. Chest computed tomography scan showing multiple posterior

masses (arrows) in a patient with thalassemia compatible with extramedullary
hematopoiesis.
(Reproduced from http://radiopaedia.org/articles/extramedullary-haematopoiesis under the Creative Commons
Attribution-Noncommercial-Share Alike 3.0 Unported licence.)
Other
Other causes of posterior mediastinal masses:
 Diaphragmatic hernia
 Meningocele
 Paravertebral abscess
METASTATIC LUNG TUMORS
The lung is a common site for metastasis of malignant tumors from other organs.
Most of these tumors are asymptomatic because most people have a large degree
of reserve pulmonary function.
 Nodules caused by metastases from a solid organ primary tumor vary in size
and location. They have a proclivity for the lung bases and tend to be
subpleural.
 Metastatic lesions are usually round, with sharply demarcated borders.

 Metastases that tend to hemorrhage (e.g., choriocarcinoma, renal cell
carcinoma, melanoma, thyroid carcinoma, Kaposi sarcoma) may have
indistinct, fuzzy borders and occasionally show a halo of ground-glass
opacity.
 Cavitation occurs in < 5% of malignant lesions and is preferentially seen in
squamous cell carcinoma.
 The most common malignancies that present as multiple pulmonary nodules
include primary neoplasms of the testes, ovaries, and kidneys as well as
melanoma and sarcoma.
 Other cancers, such as breast, colorectal, prostate, and thyroid tumors, present
with metastatic lung masses after discovery and initial treatment of the
primary cancer.
DIAGNOSIS
The diagnosis of metastases is usually made in the setting of a known cancer

presenting with multiple pulmonary nodules with smooth borders in the
dependent lobes. When a single nodule is the only evidence of metastasis,
recognizing it as a metastasis may be difficult.
TREATMENT
The tissue of origin largely dictates treatment of lung metastasis. Curable cancers,
such as germ cell tumors, neuroblastoma, lymphoma, and osteosarcoma with lung
metastasis, should be treated aggressively, mainly with chemotherapy.
The goal of curative resection of pulmonary metastases is identification and

removal of all foci of malignancy, with preservation of a maximal amount of
normal lung tissue. The following are the generally accepted criteria for
pulmonary metastasectomy.
Absolute criteria:
 Patient is a good candidate for surgery.
 Primary tumor is controlled.
 No extrapulmonary metastases exist.
 Pulmonary metastases are completely resectable.
Relative criteria:
546 / CHAPTER 12
 Pulmonary metastases are symptomatic.

 Tissue is needed for diagnostic reasons.
FACTORS INDICATING POOR PROGNOSIS
 Inability to resect all lesions

 Large number of metastases (> 6)
 Involvement of lymph nodes
 Short disease-free interval after primary tumor treatment
LUNG NODULES
SOLITARY PULMONARY NODULES (SPNs)
SPNs are radiographic opacities ≤ 3 cm in diameter surrounded by lung

parenchyma in at least two thirds of the margin (Figure 12-21). Prevalence is 20–
51% in high-risk patients. Most are benign, but 1.1–12% are malignant.
Figure 12-21. Chest computed tomography scan showing a solitary pulmonary

nodule (arrow).
(Reproduced courtesy of Wikipedia under the Creative Commons Attribution-Share Alike 3.0 Unported license.)
Differential Diagnosis
Broad for pulmonary nodules (Table 12-5)
Table 12-5. Differential Diagnosis of Solitary Pulmonary Nodules

Infectious Lymphatic Mnemonic
Granuloma Intrapleural or subpulmonary lymph node Differential diagnosis of
Abscess Congenital solitary pulmonary
Round pneumonia nodules—CASH PLEASe:
Bronchogenic cyst
Fungal infection
Lung sequestration Cancer
Septic embolus
Inflammatory Abscess
Neoplastic Solitary metastasis
Rheumatoid lung
Hamartoma Hamartoma
Sarcoidosis
Metastatic lesion
Granulomatosis with polyangiitis Pseudotumor
Carcinoid tumor
Organizing pneumonia Lymphoma
Carcinoma
Lymphoma Miscellaneous Echinococcus
Amyloidosis Actinomyces
Vascular Sequestration
Atelectasis
Arteriovenous malformation
Scar
Hematoma
Mucous impaction
Pulmonary aneurysm
Pulmonary infarct
Etiology
It is important to determine the etiology. Early surgical resection of malignant

SPNs confers a high cure rate. Avoiding surgery for benign SPNs prevents
morbidity.
Radiologic Characteristics
CT images are important for characterizing SPNs. Thin sections with contiguous
1-mm images through nodules are preferred. Both lung and mediastinal windows
should be obtained. Comparison with previous chest x-rays and CT scans is key.
GROWTH RATE
 Volumetric doubling of malignant SPNs occurs in 20–400 days and
corresponds to a 26% increase in nodule diameter.
 SPNs that double in volume in > 400 days are typically benign, except for
slow-growing lung cancers.
 SPNs that double in volume in < 20 days are often caused by an acute
inflammatory process.
 In general, a solid SPN with stable volume for 2 years can be considered
benign.
SIZE—Likelihood of malignancy increases with nodule diameter.

548 / CHAPTER 12
Radiographic follow-up is often determined by nodule size (Table 12-6).
Table 12-6. Radiographic Follow-up in Solitary Pulmonary Nodule ≤ 8 mm

Cancer Risk
Size Low High
≤ 4 mm No surveillance Chest CT scan at 12 mo
No further follow-up if no change
4–6 mm Chest CT scan at 12 mo Chest CT scan at 6–12 mo
No further follow-up if no change Chest CT scan at 18–24 mo if no change
> 6–8 mm Chest CT at 6–12 mo Chest CT scan at 3–6 mo
CT chest at 18–24 mo if no change Chest CT scan at 9–12 month if no
change
Chest CT scan at 24 mo if no change
CT, computed tomography
MORPHOLOGY
 Defined by edge characteristics, such as smooth, lobulated, irregular, halo or
spiculated.
Key Fact  Smooth edges: Usually benign, but 20–30% of malignant nodules have
Hamartomas: smooth borders.
 Benign but can grow
slowly
 Irregular, lobulated, and spiculated edges often indicate uneven growth and
 Fat visible on CT scan in are usually but not exclusively found in malignant tumors.
about 60%  SPNs surrounded by a halo of ground-glass opacities can indicate adjacent
 Most often found in men hemorrhage or lepidic spread.
> 50 years of age
 Popcorn calcification
seen in about 25% LOCATION—Malignant SPNs are more common in the upper lobes compared
with other lobes.
FAT—CT finding of fat attenuation usually signifies a benign hamartoma or

lipoid lesion.
CALCIFICATION—Benign patterns of calcification on chest CT scan:

 Central: Bull’s eye
 Diffuse solid: Granulomatous disease
 Laminated: Rings
 Popcorn-like: Chondroid matrix, such as hamartoma
No pattern of calcification is specific for malignancy. Punctuate and eccentric

calcifications are often but not exclusively seen in lung cancer.
CAVITATION—Secondary to necrosis. Can be seen in malignant and benign

SPNs.
GROUND-GLASS NODULES—Focal nodular areas of increased lung attenuation

without obscuring of the lung parenchyma (Figure 12-22)
 Classified into pure ground-glass and partly solid types.
 More solid components are associated with a higher likelihood of malignancy.

 Have a slower growth rate and low metabolic activity, with a doubling time of
> 2 years and low or no activity on PET scan.
Figure 12-22. Chest computed tomography scan showing ground-glass nodule

(arrow).
(Reproduced, with permission, from Ost DE, Gould MK. Decision making in patients with pulmonary nodules.
Am J Respir Crit Care Med. 2012: 185: 363-372. doi:10.1164/rccm.201104-0679CI)
PET-CT Imaging
 Indicated for nodules > 8–10 mm in diameter. Lower sensitivity for smaller
SPNs.
 High metabolic activity (standard uptake value > 2.5) suggests possible
malignancy.
 Sensitivity of 96% and specificity of 79% in differentiating benign from
malignant lesions in nodules larger than 8–10 mm.
 SPNs with intermediate pretest probability of malignancy should be evaluated.
 Tumors with low metabolic rate, ground-glass nodules, and SPNs < 8–10 mm
have higher false-negative rates. Infectious and inflammatory conditions yield
higher false-positive rates.
 Whole-body image can detect extrapulmonary tumors and help in lung cancer
staging.
Management
Flash Card Q4
Figure 12-23 summarizes an algorithm for management of SPNs. What is appropriate
management when a
solitary, pure ground-glass
nodule > 5 mm is found on
chest CT scan?
550 / CHAPTER 12
Figure 12-23. Approach to solid pulmonary nodules.

SPN, solitary pulmonary nodule; CT, computed tomography; GGN, ground-glass nodule; PET, positron
emission tomography.
Flash Card A4
Initial follow-up at 3 months
and then annual
surveillance for at least 3
years.
Invasive Diagnostic Evaluation
CT-GUIDED BIOPSY
 Sensitivity is 90%; specificity is 100%.
 Nondiagnostic results are much more common in benign than malignant
SPNs.
 Pneumothorax rate is 20–25%, with 4–7% requiring chest tube.
CONVENTIONAL BRONCHOSCOPY
 Safe, well-tolerated procedure.
 Forceps biopsy improves tissue yield.
 Higher accuracy for central versus peripheral lesions.
 Higher diagnostic yield if CT scan shows a bronchus leading to the lesion.
RADIAL ENDOBRONCHIAL ULTRASOUND AND ELECTROMAGNETIC

NAVIGATION
 Increase diagnostic yield of peripheral lesions.
 Can be considered with air bronchus sign and pathway to the lesion.
Treatment
SURGERY—Video-assisted thoracic surgery, thoracotomy, or sometimes a

combination is indicated to establish a diagnosis when the probability of cancer is
high (> 60%). Surgery may also serve as definitive treatment.
RADIATION THERAPY—Patients who are nonsurgical candidates with malignant

SPNs may undergo stereotactic radiation therapy.
PARANEOPLASTIC SYNDROMES
Epidemiology
Paraneoplastic syndromes are clinical syndromes caused by underlying malignant

disease. Systemic manifestations of paraneoplastic syndromes are mediated
by humoral factors excreted by tumor cells or by responses to tumor antigen. Flash Card Q5
Which type of lung cancer
 Associated with many types of lung cancer (Table 12-7). is most frequently
 Can be the first manifestation of disease or disease recurrence associated with
paraneoplastic
syndromes?
552 / CHAPTER 12
 About 10% of patients with lung cancer present with a paraneoplastic

syndrome.
 Curative cancer treatment not precluded.
 May resolve with treatment of underlying disease.
Table 12-7. Lung Cancer and Common Paraneoplastic Syndromes

Adenocarcinoma
Hypertrophic pulmonary osteoarthropathy
Small cell lung cancer
Syndrome of inappropriate antidiuretic hormone secretion
Cushing syndrome
Carcinoid syndrome
Neurogenic syndromes
Squamous cell lung cancer
Hypercalcemia
HYPERCALCEMIA
Elevated calcium in blood is caused by tumor secretion of parathyroid hormone-

related protein, increased active metabolite of vitamin D (calcitriol), and localized
osteolytic hypercalcemia.
 Occurs in 10–25% of patients with lung cancer.

 Most commonly associated with squamous cell lung cancer.
 Median survival in patients with lung cancer after diagnosis of hypercalcemia
is about 1 month.
Presentation
Clinical symptoms of hypercalcemia depend on calcium level and acuity of onset:
 For patients with mild or moderate hypercalcemia, symptoms include polyuria,
polydipsia, nausea, confusion, vomiting, abdominal pain, and myalgia.
 With severe hypercalcemia (serum calcium level > 14.0 mg/dL), symptoms
include mental status changes, coma, bradycardia, arrhythmias, and
hypotension.
 Hypercalcemia can also cause severe dehydration and acute renal failure.
Flash Card A5
Small cell lung cancer
Diagnosis
Diagnostic evaluation includes assessment of intact parathyroid hormone,
parathyroid hormone-related protein, 25-hydroxyvitamin D, 1,25-
dihydroxyvitamin D, calcium, albumin, magnesium, and phosphorus.
Treatment
Fluid resuscitation and bisphosphonate therapy
SYNDROME OF INAPPROPRIATE ANTIDIURETIC

HORMONE SECRETION
Most commonly associated with small cell lung cancer (SCLC).
 ADH is produced by the tumor in an unregulated manner, leading to water

retention by reabsorption in renal tubules.
 Manifested as euvolemic hypo-osmolar hyponatremia.
Presentation
Clinical signs and symptoms depend on degree of hyponatremia and acuity of
hypo-osmolality. They range from general weakness, headache, and nausea to
altered mental status, coma, and seizure.
Diagnosis
Lab findings:
 Urine sodium level > 40 mEq/L
 Urine osmolality > 500 mOsm/kg
 Serum osmolality < 275 mOsm/kg
 Serum uric acid concentration < 4 mg/dL
Treatment
Management of inappropriate antidiuretic hormone secretion–induced
hyponatremia:
 Free water restriction for asymptomatic mild hyponatremia
 Administration of hypertonic 3% saline in life-threatening disease
554 / CHAPTER 12
 Cautious use of vasopressin receptor antagonists to avoid overcorrection

 Treatment of the underlying tumor for permanent resolution
CUSHING SYNDROME
Caused by ectopic secretion of adrenocorticotropic hormone. Most commonly

associated with SCLC and bronchial carcinoid tumors.
Presentation
Clinical manifestations:
 Weight gain
 Moon facies
 Acne
 Purple striae
 Proximal muscle weakness
 Peripheral edema
 Skin hyperpigmentation
Diagnosis
Diagnostic laboratory tests:
 High plasma adrenocorticotropic hormone
 Nonsuppressed morning cortisol level after high-dose dexamethasone
suppression test
 Elevated 24-hour urine free cortisol level
Treatment
Treat underlying disease. Patients with SCLC and Cushing syndrome have a
worse response to chemotherapy, shorter survival, and a higher rate of surgical
complications.
HYPERCOAGULABLE DISORDERS
Venous thromboembolism occurs within 2 years of diagnosis in 3% of patients

with lung cancer.
 Tumor cells directly activate clotting via tissue factor and cancer procoagulant.
 Low-molecular-weight heparin is the preferred treatment.
HYPERTROPHIC PULMONARY OSTEOARTHROPATHY

Characterized by digital clubbing (Figure 12-24), painful symmetrical arthropathy Key Fact
(involving the wrists, elbows, ankles, and knees), and periosteal new bone Hypertrophic pulmonary
formation in the distal long bones of the limbs. osteoarthropathy resolves
completely with treatment
of the primary cancer.
 Most commonly associated with adenocarcinoma of the lung.
 Histologic features include vascular hyperplasia, edema, and excessive
fibroblast and osteoblast proliferation.
 Overexpression of vascular endothelial growth factor may play a role in
pathogenesis.
 Treatment of the primary malignancy results in resolution.
Flash Card Q6
paraneoplastic syndromes
is appropriately matched
with the corresponding
antibodies?
Lambert–Eaton
myasthenia syndrome—
Figure 12-24. Digital clubbing is characterized by enlargement of the terminal Anti-Yo antibodies
segments of the fingers. Cerebellar
(Reproduced courtesy of Desherinka, Wikimedia Commons, under the Creative Commons Attribution-Share degeneration—Voltage-
Alike 3.0 Unported license.) gated channel antibodies
Limbic encephalitis—Anti-
Hu antibodies
556 / CHAPTER 12
NEUROGENIC SYNDROMES
Paraneoplastic syndromes causing nervous system dysfunction occur almost

exclusively in SCLC. They are caused by neuronal autoantibodies resulting in T-
cell mediated damage to the central nervous system.
Anti-Hu Syndrome
 Most common paraneoplastic neurologic syndrome associated with lung

cancer.
 The presence of anti-Hu antibodies has specificity of 99% and sensitivity of
82% for diagnosing a neurogenic paraneoplastic syndrome, but these
antibodies are not themselves pathogenic.
 Symptoms include brain stem encephalitis, opsoclonus-myoclonus, cerebellar
degeneration, myelopathy, and peripheral nerve palsy.
 Response to therapy for SCLC helps, but does not cure the disease.
Anti-Yo Syndrome
 Caused by anti-Yo antibodies directed against Purkinje cells in the cerebellum.

 Antibodies have both a diagnostic and a pathogenic role.
 Manifests clinically as cerebellar degeneration.
 Intravenous immunoglobulins may stabilize clinical symptoms if administered
early after onset of symptoms.
 Treatment of underlying cancer does not cure the disease.
Lambert–Eaton Myasthenia Syndrome
 Autoantibodies are directed against voltage-gated calcium channel type P/Q.

 Affects the presynaptic neuromuscular junction.
 Manifested clinically as proximal muscle weakness progressing
craniocaudally.
 Antibodies have both a diagnostic and a pathogenic role.
 Immunosuppressive therapy improves muscle strength.
 Treatment of the underlying tumor usually leads to resolution of symptoms.
Flash Card A6
Limbic encephalitis—Anti-
Hu antibodies
PLEURAL NEOPLASMS
The pleura is composed of a single layer of mesothelial cells overlying a matrix of

collagen, elastic fibers, blood vessels, and lymphatics. Primary pleural tumors are
rare, but can arise from either the parietal or visceral pleura and can be malignant
or benign. Malignant mesothelioma is the most common pleural tumor overall.
DIAGNOSIS
Once a pleural abnormality has been identified, diagnostic work-up includes:

 A detailed clinical history, including environmental and occupational
exposures.
 A comprehensive physical examination: Pleural neoplasms often result from
Key Fact
metastatic disease, so evaluation for primary tumors is important.
The diagnosis of pleural
 Appropriate imaging and tissue sampling: Thoracentesis can aid in diagnosis neoplasm is established
if there is an associated effusion. Video-assisted thoracoscopic surgery has a with proper history,
high diagnostic yield. imaging, tissue specimens,
and histopathology with
 Appropriate histologic and immunohistochemical analyses differentiate immunohistochemical
malignant from reactive mesothelial cells and mesothelioma from other staining.
metastatic disease, including adenocarcinoma.
 Table 12-8 lists the common differential diagnoses for pleural tumors.
Table 12-8. Common Differential Diagnoses for Pleural Tumors

Metastatic disease
Pleural plaques
Diffuse pleural thickening
Loculated pleural effusion
Loculated empyema
Loculated hemothorax
Rounded atelectasis
Extramedullary hematopoiesis
558 / CHAPTER 12
MALIGNANT PLEURAL MESOTHELIOMA (MPM)
MPM is an aggressive tumor arising from mesothelial cells. It typically originates

in the parietal pleura before spreading into the visceral pleura (Figure 12-25). It
can also arise from the pericardium, peritoneum, or tunica vaginalis.
Figure 12-25. Computed tomography scan of the chest in a patient with left-
sided mesothelioma showing an extensive pleural mass with contraction of the
left hemithorax.
(Reproduced from http://radiopaedia.org/cases/mesothelioma-1, under the Creative Commons Attribution-Share
Alike 3.0 Unported license.)
Epidemiology
The incidence of MPM is increasing worldwide. There are 2000–3000 new cases
per year in the United States, with a male-to-female ratio of 5:1. The median
survival time after diagnosis is 9–17 months. The 5-year survival rate is < 5%.
MPM is more frequent with advanced age because of the long latency period
between exposure and onset of symptoms.
Etiology
Asbestos exposure is documented in about 85% of patients with MPM. There is
no synergistic effect between asbestos and cigarette smoke.
 Other potential etiologies include simian monkey virus 40, radiation, chemical
carcinogens, erionite (a mineral found in volcanic ash), and chronic pleural
disease.
 MPM is not believed to arise from pleural plaques, although both are
associated with asbestos exposure.
Diagnosis
Diagnosis of MPM requires strong clinical suspicion along with appropriate
information on the exposure history and knowledge of the latency period from
exposure to diagnosis.
SYMPTOMS—Nonspecific. Include shortness of breath, cough, and nonpleuritic

chest pain.
IMAGING
 Chest x-ray: Large unilateral pleural effusion obscuring an underlying pleural
mass or thickening.
 Chest CT scan: Better defines the extent of pleural disease.
 MRI scan: Sometimes delineates soft tissue planes.
 PET scan: Detects occult metastatic disease in approximately 10% of patients.
BIOPSY—Video-assisted thoracoscopic surgery is recommended to obtain tissue

for diagnosis or immunohistochemistry.
 MPM must be differentiated from metastatic adenocarcinoma (Table 12-9).
 No serum biomarkers are useful for diagnostic or screening purposes.
Flash Card Q7
Table 12-9. Immunohistochemical Markers statements about MPM is
Carcinoembryonic false?
Vimentin Calretinin Periodic Acid–Schiff Antigen A. There is a synergistic
effect between asbestos
Mesothelioma + + - - exposure and smoking.
B. Serum biomarkers are
not useful as a
Adenocarcinoma - - + + screening tool.
C. There is a long latency
period between
exposure to asbestos
and development of
symptoms.
D. Treatment is rarely
curative.
560 / CHAPTER 12
Treatment
Despite advancement in treating MPM, prognosis remains very poor. Referral to a
specialized center is strongly advised.
Key Fact  For symptomatic effusions, optimal palliative therapy is drainage of fluid with
subsequent pleurodesis.
Treatment of MPM is rarely
curative. However,  For bulky intrapleural disease, pleurectomy may provide palliative relief of
multimodal treatment symptoms.
regimens combining
surgery, radiation therapy,
 Treatment is rarely curative and involves a multimodal approach:
and chemotherapy may o Extrapleural pneumonectomy versus pleurectomy/decortications
offer a significant increase  Standard management of surgically resectable patients has yet to be
in survival for subgroups of
patients with
established.
mesothelioma.  Surgical intervention might benefit patients with early-stage disease,
good performance status, epithelioid histology, and no mediastinal
lymph node involvement.
o Radiation therapy
o Adjuvant chemotherapy with pemetrexed and cisplatin
Prognosis
Favorable prognostic signs:
 Good performance status
 Age < 60 years
 Platelet count < 400,000
 Epithelioid histology
 < 5% weight loss
 Tumor confined to ipsilateral pleura
SOLITARY FIBROUS TUMORS
Solitary fibrous tumors are rare spindle cell mesenchymal tumors originating from
the pleura (80% visceral and 20% parietal). They account for about 5% of all
pleural tumors. Most solitary fibrous tumors (about 80%) are benign.
Flash Card A7 Presentation

The correct answer is A. Most patients are asymptomatic, but may have cough, chest pain, and dyspnea on
There is no synergy
between asbestos presentation.
exposure and smoking in
MPM.
Imaging
Tumors appear as a pleural-based soft tissue masses, with well-defined margins
and no associated rib destruction or chest wall abnormality.
Treatment
Treatment for both malignant and benign tumors is complete resection. Long-term
follow-up with imaging is needed because of high recurrence rates.
PREOPERATIVE ASSESSMENT
Although surgery is the best curative option for patients with early-stage NSCLC,
careful preoperative assessment of individual risk factors is needed to avoid short-
and long-term operative complications. Preoperative evaluation allows patients to
be counseled appropriately regarding treatment options and risks.
The American College of Chest Physicians has published guidelines for patients
with lung cancer that are being considered for possible curative lung resection.
Evaluation by a multidisciplinary team consisting of a thoracic surgeon, medical
oncologist, radiation oncologist, and pulmonologist is recommended. Smoking
cessation is strongly advised because it is associated with short-term perioperative
and long-term survival benefits.
 Smokers and former smokers with lung cancer are at increased risk for
cardiovascular disease. Thus, a preoperative cardiovascular risk assessment is
needed to stratify the risk of major postoperative cardiac complications.
 The thoracic revised cardiac risk index (Table 12-10) is a validated tool for
assessing cardiovascular risk factors for patients undergoing lung resection.
 Patients with a score > 1.5, any cardiac condition requiring medication, a
newly suspected cardiac condition, or limited exercise tolerance (inability to Flash Card Q8
climb two flights of stairs) should be referred for cardiac consultation. Which of the following
parameters places the
 Patients at low risk for cardiovascular disease may proceed for further patient at high risk for
evaluation for possible lung resection (Figure 12-26). surgical complications?
A. 77 years old
Refer to Table 12-11 for calculation of predictive postoperative forced expiratory B. Chronic obstructive
volume in 1 second (FEV1) and diffusion capacity for carbon monoxide (DLCO). pulmonary disease
with hypercapnia
C. Able to climb three
Refer to Table 12-12 for definition of risk for lung resection. flight of stairs
D. VO2 max 30% of
predicted
562 / CHAPTER 12
Table 12-10. Thoracic Revised Cardiac Risk Index
Creatinine > 2 mg/dL = 1 point
Pneumonectomy = 1.5 points
Previous cerebrovascular accident or transient ischemic attack = 1.5 points
Previous ischemic heart disease = 1.5 points
Figure 12-26. Algorithm for evaluation of lung resection. (Refer to Table 12-11
for calculation of ppo [FEV1 and DLCO]).
FEV1, forced expiratory volume in 1 second; DLCO, diffusing capacity for carbon monoxide; VO2 max, maximal
oxygen uptake.
Flash Card A8
D. VO2 max < 35% of
predicted places the
patient at very high risk for
surgery.
Table 12-11. Calculation of Predicted Postoperative Forced Expiratory

Volume in 1 Second and Diffusing Capacity for Carbon Monoxide
Pneumonectomy Lobectomy
PPO FEV1 = preoperative FEV1 x (1 - fraction PPO FEV1 = preoperative FEV 1 x (1 - y/z)
of total perfusion for the resected lung)
PPO DLCO = preoperative DLCO x (1 - y/z)
PPO DLCO = preoperative DLCO x (1 - Key Fact
fraction of total perfusion for the resected lung) y = number of functional or unobstructed lung VO2 max < 10 mL/kg/min
segments to be removed or 35% of predicted
Quantitative radionuclide perfusion scan indicates a high risk of
performed to measure the fraction of total z = total number of functional segments mortality and long-term
perfusion for the resected lung disability.
Anatomic method used where total number of
segments for both lungs is 19 (10 in the right
lung and 9 in the left lung)
PPO, predicted postoperative; FEV1, forced expiratory volume in 1 second; DLCO, diffusing
capacity for carbon monoxide.
Key Fact
If % PPO FEV1 and % PPO
 Six months after lobectomy: DLCO values are both >
60%, the patient is
o 1-second forced expiratory volume (FEV1) ~10% < preoperative FEV1 considered at low risk for
o Exercise capacity as measured by maximal oxygen uptake (VO2 max) 0– surgical complications and
no further tests are
13% < preoperative VO2 max indicated.
 Six months after pneumonectomy:

o FEV1 34–41% < preoperative FEV1
o VO2 max 20–28% < preoperative VO2 max
Table 12-12. Definition of Risk for Lung Resection

Low risk Expected risk of mortality > 1%
Major anatomic resection can be safely performed
Moderate risk Morbidity and mortality rates may vary according to split lung function,
exercise tolerance, and extent of resection
Risks and benefits of surgery should be thoroughly discussed with patient
High risk Risk of mortality after standard major anatomic resection may be > 10%
Considerable risk of severe cardiopulmonary morbidity and residual
functional loss expected
Patients should be counseled about alternative surgical (minor resection
or minimally invasive surgery) or nonsurgical options
564 / CHAPTER 12
PLEURAL DISEASE / 565
13 Pleural Disease
Jeffrey Albores, MD
PLEURAL EFFUSION
A pleural effusion is excess fluid that accumulates between the parietal and
visceral pleura.
THORACENTESIS
Key Fact
One of the first steps to be considered in the management of a patient with a new
pleural effusion. It is a procedure to remove fluid from the pleural space for The normal pleural space
is filled with approximately
diagnostic and/or therapeutic purposes (Figure 13-1). 7–14 mL of low-protein
pleural fluid in a normal
adult man and
approximately 0.15 mL/kg
of fluid is produced hourly
by the parietal pleura.
Figure 13-1. Thoracentesis.

(Reproduced courtesy of the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S.
Department of Health & Human Services.)
566 / CHAPTER 13
Supporting Tools
ULTRASOUND—Assists with site selection and increases the safety of pleural
Key Fact procedures.
British Thoracic Society
guidelines strongly PLEURAL MANOMETRY—Measurement of pleural pressures that reflects
recommend ultrasound pleural space elastance.
guidance for all pleural
procedures used to remove
pleural fluid.  Pleural elastance is the change in pleural pressure relative to the volume of
pleural fluid (PF) removed (∆P/∆V).
 Manometry may have clinical applications for the diagnosis of trapped and
entrapped lung. Serial manometry during a large volume thoracentesis may
also be able to predict the development of re-expansion pulmonary edema.
However, there are no guidelines at this time recommending the routine use of
manometry.
Fluid Removal
AMOUNT OF FLUID TO REMOVE—Fluid removal is stopped at the onset of
chest discomfort or when 1000–1500 mL of PF is aspirated.
Key Fact
RE-EXPANSION PULMONARY EDEMA
The symptom most
associated with significant  Noncardiogenic pulmonary edema that occurs after rapid re-expansion of
drops in pleural pressure is atelectatic lung following drainage of a moderate-to-large pleural effusion or
chest discomfort. pneumothorax (Figure 13-2).
 The condition is usually self-limited and treatment is mainly supportive.
Figure 13-2. Re-expansion pulmonary edema following thoracentesis of a large

left pleural effusion.
(Dias OM, Teixeira LR, Vargas FS. Reexpansion pulmonary edema after therapeutic thoracentesis.
Clinics [serial on the Internet]. 2010; 65(12): 1388. Fig 1. doi.org/10.1590/S1807-59322010001200026. CC-
BY-NC 3.0)
PLEURAL FLUID ANALYSIS

A transudative pleural effusion develops when low-protein fluid leaks across an
intact capillary barrier because of increased hydrostatic pressure or decreased
osmotic pressure.
An exudative pleural effusion develops when fluid leaks across an altered

capillary barrier with increased permeability, thus allowing transfer of protein and
liquid. It typically represents an inflammatory process of the lung or pleura.
Light’s Criteria
Light’s criteria characterize PF as a transudate or an exudate that permits
significant narrowing of the differential diagnosis (Table 13-1).
Table 13-1. Light’s Criteria
Pleural Fluid Light’s Criteria for Exudative Effusions
PF:serum total protein ratio > 0.5
PF LDH > 2/3 upper limit of normal
PF:serum LDH ratio > 0.6
LDH, lactate dehydrogenase; PF, pleural fluid
Pleural Fluid Values

pH—Good correlation between pH and glucose values.
Pitfalls for pH values: Flash Card Q1

 Air in the syringe increases pH. When should you consider
 Time increases pH. terminating fluid removal
during thoracentesis?
 Lidocaine decreases pH.
Table 13-2 lists exudative pleural effusions with low pH. Flash Card Q2
Which organism is
associated with a
complicated
parapneumonic pleural
effusion that has an
elevated pH?
568 / CHAPTER 13
Table 13-2. Exudative Pleural Effusions with Low pH (< 7.3)
Disease Clinical Pearls
Parapneumonic effusion Clinical diagnosis of pneumonia

Consider chest-tube drainage for PF pH < 7.2
A pH < 7.0 is a poor prognostic indicator
Malignant effusion ~1/3 of patients with malignant pleural effusion have pH < 7.3
Malignant effusions with pH < 7.3 compared to those with pH >
7.3 are associated with greater tumor burden, higher probability of
positive PF cytology, and shorter survival
Tuberculous effusion PF pH < 7.3 in ~20% of cases
A low pH is more characteristic of chronic tuberculous empyema
than of tuberculous pleural effusion
RA effusion Typically with pH < 7.3 in contrast to the effusions seen with SLE
Hemothorax Grossly bloody with PF hematocrit > 50% of the peripheral blood
hematocrit
Esophageal rupture Severe retching or vomiting followed by chest pain and fever
Usually, left pneumothorax early and left pleural effusion later
Low pH and elevated amylase in effusion
Paragonimiasis Cough, fever, hemoptysis, chronic asymptomatic pleural effusion
Associated with eosinophilia
PF, pleural fluid; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus
GLUCOSE—Low glucose effusions (< 60 mg/dL) are found in the same

diagnoses involving exudative pleural effusions with low pH.
PROTEIN, LACTATE DEHYDROGENASE (LDH), AND ALBUMIN

 PF protein and LDH help separate transudative from exudative effusions.
 Elevated PF LDH may be a marker of pleural inflammation when measured
serially.
 PF albumin (or protein) gradient is useful in diagnosing false exudates in a
Flash Card A1 congestive heart failure (CHF) patient who has undergone diuresis:
When a patient complains o Albumin gradient = serum albumin - PF albumin.
of chest discomfort or o Albumin gradient > 1.2g/dL is consistent with a transudate.
when 1.5L has been o Albumin gradient ≤ 1.2g/dL is consistent with an exudate.
removed
o Protein gradient > 3.1 g/dL is consistent with a transudate.
Flash Card A2
Proteus. In general, all
other complicated
parapneumonic effusions
will have a low pH.
AMYLASE, CHOLESTEROL, AND TRIGLYCERIDES—See sections on

chylothorax, pseudochylothorax, and elevated amylase effusions.
CELL COUNT & DIFFERENTIAL Key Fact

 In patients with an exudative pleural effusion, the cell count and differential The most common causes
provide diagnostic clues. of lymphocytic effusions
 Lymphocytic effusions: are tuberculous pleuritis,
malignancy, and post-
o Tuberculous pleuritis, post-coronary artery bypass grafting (CABG), CABG.
rheumatoid arthritis (RA) pleural effusion, yellow nail syndrome,
chylothorax (typically > 80% of total nucleated cells)
o Malignant effusions (typically 50–70% of nucleated cells) Key Fact
 Eosinophilic effusions > 10% of nucleated cells: Eosinophils in an effusion
are nonspecific and usually
o Most common: Trauma (pneumothorax, hemothorax, surgery), reflect blood (hemothorax)
malignancy or air (pneumothorax).
o Others: Benign asbestos pleural effusion (BAPE), parasitic disease, fungal
infection, drug-induced
INCIDENCE OF PLEURAL EFFUSION
Approximately 1.5 million pleural effusions are diagnosed in the U.S. each year
(Figure 13-3).
Flash Card Q3
Which pleural effusion
most commonly presents
with dyspnea out of
proportion to pleural
effusion size?
Flash Card Q4
A patient with CHF being
diuresed has an exudative
pleural effusion. What is
the best way to evaluate
whether this is a false
Figure 13-3. Annual incidence of pleural effusion in the U.S. exudate in the setting of
diuresis?
570 / CHAPTER 13
TRANSUDATIVE PLEURAL EFFUSIONS
Congestive Heart Failure (CHF)
 Due to increased pulmonary capillary pressure

 Diagnosis:
o Chest x-ray with bilateral pleural effusions, typically with cardiomegaly
Key Fact and pulmonary vascular congestion:
CHF is the most common  Bilateral effusions ~70%
cause of a transudative
pleural effusion and of
 Unilateral effusion ~30%, more often seen on the right
pleural effusions in o PF: Transudate with 15–20% presenting as false borderline exudates, often
general. in the setting of diuresis
 Treatment:
o Optimization of underlying CHF
o Consider therapeutic thoracentesis if effusion does not respond to optimal
diuretic therapy
o Indwelling pleural catheters (IPCs) or chest-tube pleurodesis may rarely
be considered, but only in refractory cases for symptom palliation.
Hepatic Hydrothorax
 Ascites in the chest via diaphragmatic defects driven by pressure gradient
from abdomen to pleural space
 Presents with signs and symptoms of cirrhosis and ascites
 Chest x-ray:
o Unilateral right-sided effusion ~80%
o Unilateral left-sided effusion ~15%
o Bilateral effusions rare
 In rare cases, a hydrothorax can exist without ascites due to negative pleural
pressures
 Can be superinfected (spontaneous bacterial pleuritis) but often remains
transudative
 Treatment:
o Key to management is optimization of underlying ascites
o Transjugular intrahepatic portosystemic shunt (TIPS) or liver transplant
may be considered in severe refractory cases.
o Chest-tube drainage is contraindicated and leads to renal failure, protein
Flash Card A3 loss, and cardiovascular collapse.
Pleural effusion secondary
to CHF SPONTANEOUS BACTERIAL PLEURITIS
 Diagnosis: Positive PF culture plus neutrophil count > 250 cells/mm3 or > 500
Flash Card A4 cells/mm3 with negative PF cultures, in the absence of pneumonia
Check PF albumin (or
protein) gradient
 Treatment: Treat with antibiotics alone; chest-tube drainage is seldom

required.
Nephrotic Syndrome
 Decreased oncotic pressure and increased hydrostatic pressure from salt
retention and hypervolemia
 Diagnosis:
o Chest x-ray typically with bilateral pleural effusions
o Albumin < 2.0 g/dL in nephrotic syndrome with effusions
 Pulmonary emboli may occur in ~20% of patients with nephrotic syndrome
due to acquired protein S deficiency.
 Treatment: Targeted at the underlying protein-losing nephropathy with Key Fact
avoidance of serial thoracenteses to minimize additional protein loss. PF glucose is elevated and
is midway between
dialysate and serum values
in the setting of an effusion
Peritoneal Dialysis (PD) secondary to PD.
 Movement of fluid through diaphragmatic defects, similar to hepatic

hydrothorax
 Most occur within 30 days of initiation of PD, but may occur after > 1 year
 Diagnosis: Chest x-ray with right-sided effusion ~90% of the time
 Treatment: Stop PD for 2–6 weeks; 50% of patients are able to resume PD
without recurrence
 Consider pleurodesis or video-assisted thoracoscopic surgery (VATS) to
correct diaphragmatic defects and pleurodesis.
Trapped and Entrapped Lung

 Trapped and entrapped lung represent a disease continuum
 Pleural manometry (Figure 13-4):
o Trapped lung: Abnormally high pleural elastance
o Entrapped lung: Initial normal elastance that becomes abnormally high as
more fluid is removed
Flash Card Q5
ENTRAPPED LUNG—Active inflammation or malignant pleural disease leading What is the treatment of
to visceral pleural restriction that prevents normal lung expansion. choice for spontaneous
bacterial pleuritis?
 May resolve with treatment of the active pleural process.
Flash Card Q6
A patient with nephrotic
syndrome presents with an
exudative pleural effusion.
What diagnosis should you
suspect?
572 / CHAPTER 13
Figure 13-4. Pleural elastance curves for normal, entrapped, and trapped lungs
Clinical features:
 Typically PF related to the active pleural process is exudative
 Endobronchial lesions leading to obstruction and prevention of lung
expansion should be excluded by bronchoscopy if clinically suspected.
Treatment:
 Thoracentesis rarely provides significant symptomatic relief unless there is a
significant superimposed process such as a malignant effusion.
 Consider an IPC for patients with malignant effusions who improve
symptomatically after a thoracentesis.
TRAPPED LUNG
 Remote pleural inflammatory process
 Irreducible pleural space (Figure 13-5):
o Fibrous visceral pleural thickening prevents lung re-expansion, leading to
a trapped lung
o Space between visceral and parietal pleura fills with fluid due to an
imbalance of hydrostatic pressures.
Flash Card A5
Antibiotics (e.g., Clinical features include chronic undiagnosed effusion:
cefotaxime), similar to
treatment of spontaneous  Can be asymptomatic and diagnosis is often delayed
bacterial peritonitis  Thoracentesis leads to a pneumothorax ex-vacuo due to a lung that does not
re-expand, even with chest-tube drainage of the pleural space.
Flash Card A6
 PF typically transudative or borderline exudative
Pulmonary embolus
Causes:
 CABG/cardiac surgery
 Post-cardiac injury syndrome (PCIS)
 Empyema
 Uremic pleuritis
 Hemothorax
 Rheumatoid pleuritis
 Tuberculous pleuritis
Treatment:
 Avoid unnecessary thoracic surgery or repeated thoracenteses.
 Consideration for surgery (decortication) only if dyspnea clearly is due to
trapped lung
Key Fact
A CT scan after
thoracentesis showing
incomplete lung re-
expansion with a thickened
visceral pleura suggests
either a trapped or an
entrapped lung. Chest-tube
placement in this scenario
is unlikely to lead to lung
re-expansion.
Figure 13-5. Chest computed tomography (CT) demonstrates large right-sided

hydropneumothorax with underlying visceral and parietal pleural thickening and
fibrosis (trapped lung).
(Reproduced from Kim YS, Susanto I, Lazar C, et al. Pneumothorax Ex-vacuo or “trapped lung” in the setting of
hepatic hydrothorax. BMC Pulm Med. 2012, 12:78. Fig 2. doi:10.1186/1471-2466-12-78. CC-BY-NC 3.0.)
574 / CHAPTER 13
Others (Rare)
URINOTHORAX—Presence of urine in the pleural space.
 Due to an obstructive uropathy
Key Fact
 Pleural creatinine: Serum creatinine ratio > 1
Urinothorax is the only
cause of a low pH
 Treatment involves relieving the obstruction
transudative pleural
effusion. DUROPLEURAL FISTULA/SUBARACHNOID PLEURAL FISTULA—
Cerebrospinal fluid (CSF) leak from the subarachnoid space to the pleural space.
 Positive pressure of the subarachnoid space drives fluid to lower pressure
pleural space
 Mostly due to blunt or penetrating trauma or thoracic spinal surgery
 Clear-looking pleural fluid with protein < 1 g/dL
 Detection of pleural fluid beta-2 transferrin level is a specific and sensitive
marker to identify CSF leak
 No strong consensus for treatment
HYPOALBUMINEMIA—Decreased oncotic pressure of the blood with increased

rate of PF formation, but unclear how frequently hypoalbuminemia truly causes
pleural effusions (likely only in severe hypoalbuminemia).
EXUDATIVE PLEURAL EFFUSION
Parapneumonic Effusion and Empyema

Key Fact PARAPNEUMONIC EFFUSION—Any pleural effusion associated with bacterial
Parapneumonic effusion is pneumonia, lung abscess, or bronchiectasis.
the most common cause of
exudative pleural effusion EMPYEMA—An infected pleural space with either pus or thick purulent
in the U.S.
appearing pleural fluid upon drainage.
Table 13-3 compares parapneumonic effusion and empyema.

Table 13-3. Stages of Parapneumonic Effusion and Empyema

Simple Complicated
Parapneumonic Parapneumonic
Effusion Effusion Empyema
Stage Exudative Fibrinopurulent Organizing
Appearance Clear or slightly turbid Usually cloudy Pus
pH > 7.20 < 7.20 Usually not measured
Glucose > 60 mg/dL < 60 mg/dL Usually not measured
LDH < 1000 U/L > 1000 U/L Usually not measured
Gram Stain/ Negative May be positive May be positive

Key Fact
Culture
MIST-1 study = intrapleural
Imaging Small-to-moderate Effusion occupies > half Loculated effusion
tPA vs. placebo in
effusion (> 10 mm of the hemithorax
Thickened pleural treatment of empyema with
thickness but < half the
Loculated effusion membrane no benefits noted.
size of the hemithorax)
Thickened pleural
Free-flowing effusion
membrane
LDH, lactate dehydrogenase
MICROBIOLOGY—Community-acquired and hospital-acquired pleural infections Key Fact

exhibit different microbiologic patterns.
MIST-2 study = intrapleural
 Community-acquired → predominantly Streptococcus (50%), anaerobes tPA + DNase superior to
(20%), and Staphylococcus (10%) either agent alone in
 Hospital-acquired → predominantly methicillin-resistant Staphylococcus treatment of empyema in
terms of improved fluid
aureus (MRSA) (25%) and gram-negative anaerobes (20%) drainage, reduced
 Higher mortality rate with hospital-acquired parapneumonic effusion or frequency of surgical
referral, and reduced
empyema duration of hospital stay.
TREATMENT
 Empiric antibiotics tailored by microbiology, community- vs. hospital-
acquired
 Therapeutic thoracentesis
 Chest tube, with current trend toward smaller-bore tubes (10–14 French
catheter) for complicated parapneumonic effusions and empyemas
 Consider intrapleural tissue plasminogen activator (tPA) + deoxyribonuclease
(DNase) (Multicenter Intrapleural Sepsis Trial [MIST]-2)
 Surgical consultation if persistent sepsis and/or residual pleural collection
despite drainage and antibiotics
Flash Card Q7
What are the indications for
chest-tube drainage of a
parapneumonic effusion?
576 / CHAPTER 13
Pleural Effusion Due to Malignancy
Figure 13-6 shows the origin of metastatic malignant pleural effusions.

Key Fact
Malignant pleural effusions  Dyspnea is the most common symptom
are the second leading
cause of exudative  Most common cause of a massive effusion and a bloody effusion
effusions next to  Diagnosed by demonstrating malignant cells via PF cytology or pleural biopsy
parapneumonic effusions.
TREATMENT (Figure 13-7)

Key Fact  Observation, if asymptomatic
A new unilateral left-sided  Therapeutic thoracenteses
pleural effusion in the  Chemical pleurodesis with talc using a small-bore chest tube
absence of active infectious
symptoms should be  Chronic IPC
considered a malignant  VATS with mechanical pleurodesis (pleural abrasion) and/or chemical
pleural effusion until proven
otherwise.
pleurodesis (talc poudrage)
 Parietal pleurectomy + decortication
 Pleuroperitoneal shunt (rarely performed)
Key Fact
Talc is the most effective
agent for chest-tube
pleurodesis.
Figure 13-6. Origin of metastatic malignant pleural effusions.
Flash Card A7
Frankly purulent or
turbid/cloudy PF, pH < 7.2,
positive Gram stain or
culture
Figure 13-7. Management of malignant pleural effusion based on British

Thoracic Society 2010 Guidelines.
Pleural Effusion Due to Malignant Mesothelioma Key Fact

Therapeutic Intervention in
CLINICAL FEATURES Malignant Effusion (TIME)-
 Pathophysiology related to asbestos exposure Key
2 Study Fact
= IPC vs. chest-
 Chest x-ray: moderate-to-large unilateral pleural effusion or unilateral pleural tube pleurodesis in
Talc is the most
management effective
of malignant
thickening agent for chest-tube
pleural effusion → no
pleurodesis.
difference in dyspnea at 6
weeks but shorter length of
initial hospitalization and
less dyspnea at 6 months
in IPC group.
578 / CHAPTER 13
PLEURAL FLUID
 PF markers: Exact role of PF and serum markers remain undetermined
o Soluble mesothelin–related peptide, osteopontin, megakaryocyte
potentiating factor
 Cytology yield is generally poor
 Immunohistochemistry with calretinin and cytokeratin favors mesothelioma
over adenocarcinoma
 Tissue sampling needed (gold standard)
TREATMENT—Refer to specialized center.

 Best therapeutic approach remains undefined
 Surgery, radiation, chemotherapy, and combination therapies are reported
 For the palliative management of the recurrent pleural effusion, options
include thoracenteses, IPC, pleurodesis, or VATS pleurectomy.
Pulmonary Embolism
 20–50% of patients with pulmonary embolism have an associated pleural

effusion
 Related to increased pulmonary capillary permeability
 Effusions usually small and almost always exudative
 Management is treatment of the underlying pulmonary embolism
Key Fact Pleural Effusion Secondary to Cardiovascular Surgery or

Presence of a bloody
Injury
pleural effusion is not a
contraindication to the Table 13-4 compares pleural effusions secondary to post-coronary artery bypass
usual management of
pulmonary embolism
graft (CABG) and post-cardiac injury syndrome (PCIS).
(anticoagulation and/or
thrombolytics when
indicated). Table 13-4. Post-CABG vs. PCIS
a
Characteristics Post-CABG PCIS
Clinical Dyspnea Fever, pleuritic chest pain,

Key Fact pericardial rub
Dressler syndrome is a b
secondary form of Pathogenesis Early : due to surgical trauma Myocardial or pericardial injury
c
pericarditis that occurs Late : Unknown
after myocardial or
pericardial injury and Imaging Mostly small unilateral left-sided Small effusion, unilateral or bilateral
consists of the triad of pleural effusions, ~10% with large Parenchymal infiltrate
fever, pleuritis, and effusions
pericarditis. Appearance
b
Early : bloody Bloody or serosanguineous
c
Late : clear yellow
Table 13-4. Post-CABG vs. PCIS, continued

a
Characteristics Post-CABG PCIS
b
Cell count differential Early : Neutrophilic or PMNs or mononuclear cells
eosinophilic
c
Late : Lymphocytic
pH and glucose Normal Normal
Antimyocardial antibody Absent High titer
Treatment Serial thoracentesis NSAIDs or corticosteroids
Colchicine effective in prevention
CABG, coronary artery bypass grafting; NSAIDs, nonsteroidal anti-inflammatory drugs; PCIS, post-cardiac
injury syndrome; PMNs, polymorphonuclear neutrophils
a
PCIS can occur after myocardial infarction, after cardiac surgery, or after trauma
b
Early post-CABG < 30 days
c
Late post-CABG > 30 days
Key Fact
Pleural fluid from patients
with TB rarely contains
>5% mesothelial cells and
Tuberculous Pleuritis would strongly argue
against tuberculous
pleuritis if present.
CLINICAL FEATURES
 Due to primary disease (rupture of a parenchymal subpleural caseous focus
into the pleural space) or reactivation tuberculosis (TB)
 Primary disease mostly in younger patients, whereas reactivation occurs in
older patients
 Mostly present with dry cough, pleuritic chest pain, and fever Key Fact
PLEURAL FLUID PF cultures positive in <
40% of patients with
 PF characteristics: Exudative, low glucose, lymphocytic predominant (though tuberculous pleuritis.
neutrophil predominant ~10% of the time), mesothelial cells < 5%
 Neutrophilic predominant tuberculous pleural effusion: Shorter duration of
symptoms and higher adenosine deaminase (ADA) and LDH compared to
lymphocytic predominant effusion Key Fact
 Unilateral, usually small-to-moderate effusion Two main diseases other
than tuberculous pleuritis
 Pleural fluid markers: ADA, interferon gamma release assay, polymerase that are associated with a
chain reaction, nucleic acid amplification high PF ADA are empyema
 Demonstration of an elevated PF ADA level is useful in establishing the and rheumatoid pleuritis.
diagnosis of tuberculous pleuritis; both sensitivity and specificity ~90%
 Pleural fluid acid-fast bacilli (AFB) smears usually negative unless HIV
positive, tuberculous empyema, or neutrophilic predominant
 HIV test should be obtained in all patients with tuberculous pleuritis
 Diagnostic yield approaches 90-100% with pleural biopsy, either closed or via
thoracoscopy
TREATMENT—Same as for pulmonary TB, with thoracentesis as needed for

symptoms.
580 / CHAPTER 13
Rheumatoid Arthritis (RA) and Systemic Lupus

Erythematosus (SLE)
Table 13-5 compares rheumatoid pleural effusion and SLE pleuritis.
Table 13-5. Rheumatoid Pleural Effusion and SLE Pleuritis
Characteristic RA SLE
Clinical Classically in older male patients with Predominantly female in any age
RA and subcutaneous nodules group with SLE
Arthritis precedes pleural effusion Pleuritic chest pain, pleural rub,
fever, cough, dyspnea
PF Low glucose (< 40 mg/dL) Glucose > 60 mg/dL
Low pH (< 7.20) pH > 7.35
High LDH (> 700 IU/L or 2X upper LDH < 500 IU/L or < 2X upper
normal limit) normal limit
High rheumatoid factor titer (> 1:320) Elevated PF ANA (but neither
sensitive nor specific for diagnosis)
Key Fact Chest radiograph Unilateral, small-to-moderate pleural Predominantly small effusions
The most striking effusion occupying < 50% of the ~50% bilateral effusions
characteristics of the hemithorax
rheumatoid pleural effusion ~25% bilateral effusions
are its low glucose and low
pH, helping distinguish it Treatment Treatment of underlying RA; NSAIDs, steroids
from lupus pleuritis. otherwise non-specific
ANA, antinuclear antibodies; LDH, lactate dehydrogenase; NSAIDs, nonsteroidal anti-inflammatory drugs; PF,
pleural fluid; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus
Hemothorax
Hemothorax is defined as a bloody effusion with a PF hematocrit of at least 50%
of the peripheral blood hematocrit.
TRAUMATIC HEMOTHORAX—Arises predominantly from penetrating or blunt

trauma, or can be iatrogenic (i.e., after thoracentesis).
SPONTANEOUS HEMOTHORAX—Relatively uncommon.
TREATMENT—Both are managed with large-bore chest-tube drainage with

surgical intervention for severe cases.
Chylothorax and Pseudochylothorax (Cholesterol Effusion)

Table 13-6 differentiates chylothorax from pseudochylothorax (cholesterol
effusion).
Table 13-6. Chylothorax vs. Pseudochylothorax

Cholesterol Effusion/
Characteristic Chylothorax
Pseudochylothorax
Pathogenesis Lymph fluid accumulates in pleural PF contains a high concentration of
space due to disruption or cholesterol
obstruction of the thoracic duct
PF appearance Milky or opalescent Milky or opalescent
PF values Triglyceride > 110 mg/dL Cholesterol > 220 mg/dL
Chylomicron-positive even if No chylomicrons
triglyceride < 110 mg/dL
Cholesterol < 220 mg/dL
Diagnosis Look for underlying cause: Most common etiologies are chronic
traumatic (iatrogenic) vs. tuberculous effusion and chronic
nontraumatic (rule out malignancy) rheumatoid pleural effusion
Treatment Address underlying cause Observation
Trial of dietary measures in
nontraumatic, nonmalignant
chylothoraces (high-protein, low-fat
diet supplemented with medium-
chain triglycerides)
PF, pleural fluid
Elevated Amylase Effusions

Key Fact
 Acute pancreatitis Effusions secondary to
pancreatitis are typically
 Chronic pancreatitis left-sided.
 Esophageal rupture
 Malignancy
Miscellaneous
BAPE—See Pleural Asbestosis section below.
YELLOW NAIL SYNDROME—Triad of yellow and thickened nails, lymphedema,

and pleural effusion. Treatment is primarily supportive.
582 / CHAPTER 13
DRUG-INDUCED—Drugs convincingly incriminated in the development of

pleural disease include nitrofurantoin, dantrolene, ergot alkaloids, amiodarone,
interleukin-2, procarbazine, methotrexate, and clozapine.
OVARIAN HYPERSTIMULATION SYNDROME (OHS)—Pleural effusions may

occur as part of OHS, which is the result of the use of human chorionic
gonadotropin hormone for fertility purposes. Treatment is primarily supportive.
MEIGS SYNDROME—Characterized by the presence of ascites and pleural

effusions in patients with benign solid ovarian tumors. Ascites and pleural
effusions resolve on removal of the ovarian tumor.
ENDOMETRIOSIS—Severe endometriosis can be complicated by massive ascites

and pleural effusion.
PLEURAL ASBESTOSIS
BENIGN ASBESTOS PLEURAL EFFUSION (BAPE)
 Latency from asbestos exposure to BAPE typically is 15–20 years

 Involves visceral and parietal pleura
Key Fact
 Presentation: Often asymptomatic but can present with pleuritic chest pain,
BAPE is typically the first
manifestation of asbestos- fever, dyspnea
related disease that occurs  Variable clinical course:
after exposure.
o Resolution (rare)
o Blunted costophrenic angle (most common)
o Rounded atelectasis
o Diffuse pleural thickening
Key Fact
 PF: Unilateral, exudative, 1/3 eosinophilic, > 1/2 bloody
BAPE has no clear
prognostic implications for  Diagnosis: Exposure history, exclusion of other causes
the development of pleural
plaques or malignancy.  Must exclude malignancy and may require VATS for pleural biopsy
ASBESTOS-INDUCED PLEURAL PLAQUES
 Latency: > 20 years

 High prevalence (>25%) in occupationally exposed workers (e.g., shipyard
workers)
 Discrete collagenous material along parietal pleura of the middle-lower ribs
and diaphragm
 Plaques serve as a marker of asbestos exposure
 Incidental finding on routine chest radiograph or chest CT (Figure 13-8) with
minimal clinical consequence; pulmonary function tests often normal
 Calcify over time, typically > 30 years
Key Fact
Pleural plaques serve as a
marker of asbestos
exposure
Figure 13-8. Chest CT demonstrating circumscribed and calcified, bilateral

pleural plaques.
(Reproduced from Miles SE, Sandrini A, Johnson AR, et al. Yates DH. Clinical consequences of asbestos-
related diffuse pleural thickening: A review. J Occup Med Toxicol.2008, 3:20. Fig..4 doi: 10.1186/1745-6673-3-
20. CC BY 2.0)
584 / CHAPTER 13
ROUNDED ATELECTASIS
 Distinctive comet-tail sign pointing toward the hilum on chest CT scan

(Figure 13-9)
 Pleural-based mass that can appear similar to bronchogenic carcinoma
o Distinguished by asbestos exposure history, stability of the lesion in a 2-
to 3-year period, and comet-tail sign
 With progression, pleural fibrosis can trap underlying lung
Figure 13-9. CT scan of the chest demonstrates rounded atelectasis with comet-
tail sign (thick arrows).
(Reproduced from Anevlavis S, Bouros D. Images in Pneumonology. PNEUMON 2013, 26(3):276. Fig 4. CC
BY 2.0)
PLEURAL OTHER
PLEURAL IMAGING
Chest Radiography
 First radiographic test for patients with suspected pleural effusion. Different
views are able to visualize varying amounts of fluid:
o Lateral decubitus film, 5–10 mL fluid
o Lateral film shows blunting of costophrenic sulcus, 25–50 mL fluid
o Upright posteroanterior film, > 200 mL fluid
Ultrasonography
Figure 13-10 demonstrates ultrasonography of pleural effusion with landmarks.
Detection of pneumothorax:
 Normal lung:
o Lung sliding on two-dimensional (2-D) mode
o M-mode demonstrates the seashore sign —motionless portion above the
pleural line creating horizontal waves and sliding below it creates granular
sand pattern (Figure 13-11A)
 Pneumothorax:
o Absence of lung sliding on 2-D mode
o M-mode demonstrates the stratosphere sign—parallel horizontal lines
above and below the pleural line resembling a barcode (Figure 13-11B)
Figure 13-10. Ultrasound image of pleural effusion (red arrows) and lung (yellow
arrow).
(Reproduced from Bostantzoglou C, Moschos C, Introduction to transthoracic ultrasound for the pulmonologist. Flash Card Q8
PNEUMON 2013, 26(3):223-228. Fig 4. CC BY 2.0)
What are the signs of a
pneumothorax on
ultrasound?
586 / CHAPTER 13
Figure 13-11. Ultrasonography with M-mode of (A) normal lung and (B)
pneumothorax.
(Image courtesy of Dr. Jeffrey Albores, UCLA Division of Pulmonary and Critical Care Medicine)
Chest Computed Tomography (CT)
 Angle—parenchymal vs. pleural:

o Acute angle suggests parenchymal lesion
o Obtuse angle suggests pleural process
 Parietal pleural enhancement in empyema or complicated parapneumonic
effusion (visualized with intravenous contrast)
 Split-pleura sign of thickened parietal and visceral pleura separated by PF is
valuable in differentiating diagnosis of pleural rather than parenchymal
disease
 Lung abscess vs. empyema with air-fluid level
 Figure 13-12 demonstrates characteristic features of lung abscess and
empyema.
Flash Card A8
Absence of lung sliding on
2-D mode and presence of
stratosphere or barcode
sign on M-mode
Figure 13-12. Chest radiograph and chest CT demonstrate lung abscess and
pleural empyema: top chest CT shows large lung abscess in right upper lobe with
relatively thick wall; notice acute angle that abscess makes with posterior chest
wall; bottom chest CT shows pleural empyema with enhancement of both
visceral and parietal pleura, sign of pleural inflammation that occurs with
empyema (split-pleura sign); notice obtuse angle that effusion makes with
posterior chest wall.
(Image reproduced from Huang HC, Chen HC, Fang HY, et al. Lung abscess predicts the surgical outcome in
patients with pleural empyema. J Cardiothorac Surg. 2010 Oct 20;5:88. doi: 10.1186/1749-8090-5-88. Fig. 2.
CC BY 2.0)
Magnetic Resonance Imaging and Positron Emission

Tomography
Limited value for both in pleural disease.
INVASIVE PLEURAL TESTS
Pleural Biopsy
In a large number of patients, blind pleural biopsies do not provide a definitive
diagnosis for pleural pathology.
588 / CHAPTER 13
Thoracoscopy
 Invasive diagnostic test of choice
 Indications: Diagnosis of recurrent or refractory exudative pleural effusions,
pleural-based tumors, and pleural thickening
 Advantages: Ease of procedure, high diagnostic accuracy, low cost, and
excellent safety record
 Low complication rates, but can include chest wall pain, subcutaneous
emphysema, local wound infection, empyema
 Only absolute contraindication is lack of pleural space due to severe and dense
pleural adhesions
PNEUMOTHORAX
Pneumothorax is air within the pleural space.
PNEUMOTHORAX CLASSIFICATION
See Figure 13-13 for pneumothorax classification.
Figure 13-13. Pneumothorax classification.

SPONTANEOUS PNEUMOTHORAX
Spontaneous pneumothorax occurs without preceding trauma or an obvious

underlying precipitating cause or event.
Classification of Spontaneous Pneumothorax

Diagnosis requires suspicion and confirmation with imaging such as chest
radiograph and ultrasonography (emerging role).
PRIMARY SPONTANEOUS PNEUMOTHORAX (PSP)—Occurs in patients

without clinically obvious lung disease.
 Risk factors include smoking and ectomorphic body type (tall and thin)
 Male > female
SECONDARY SPONTANEOUS PNEUMOTHORAX (SSP)—Occurs in patients

with underlying lung disease.
 Chronic obstructive pulmonary disease most common underlying lung disease
but also can see in AIDS or HIV, particularly associated with Pneumocystis
pneumonia
 Dyspnea more dramatic in SSP compared to PSP due to underlying lung
disease
 Mortality greater in SSP compared to PSP
Recurrence Rates in Spontaneous Pneumothorax
Recurrence rates in spontaneous pneumothorax will impact treatment selection.
 ~30% in PSP and ~40% in SSP

 Most recurrences for both PSP and SSP occur in the first 6 months
Management of Spontaneous Pneumothorax
 Treatment options in initial spontaneous pneumothorax include observation or

small-bore chest-tube (< 10 French) placement.
 Supplemental oxygen increases the pleural air reabsorption rate. Flash Card Q9
 Management strategy is based more on the patient’s clinical status than the
When should recurrence
size of the pneumothorax. prevention be offered for
spontaneous
pneumothorax?
590 / CHAPTER 13
 Regarding recurrence prevention, the American College of Chest Physicians

(ACCP) guidelines propose offering prevention at the time of the second
occurrence of a PSP and at the first occurrence of an SSP.
o When considering recurrence prevention, surgical options are more
effective than chemical pleurodesis.
 British Thoracic Society (BTS) guidelines define a large pneumothorax as one
with a > 2-cm distance from the visceral to the parietal pleural surface at the
level of the hilum (Figure 13-14).
Key Fact
Surgical options are more
effective than chemical
pleurodesis in
pneumothorax recurrence
prevention.
Figure 13-14. Measuring the size of a pneumothorax. A=apex to cupola distance

per ACCP guidelines. B=interpleural distance at level of the hilum per BTS
guidelines.
TRAUMATIC PNEUMOTHORAX
Traumatic pneumothorax results from direct or indirect trauma to the chest,

including diagnostic or therapeutic procedures.
Flash Card A9 Iatrogenic Pneumothorax

At the time of the second
occurrence of a PSP or the Iatrogenic pneumothorax is a traumatic pneumothorax that occurs due to medical
first occurrence of a SSP interventions (Figure 13-15).
Figure 13-15. Common causes of iatrogenic pneumothorax.
TREATMENT
 Observation may be reasonable in an asymptomatic and stable patient
 Small-bore chest-tube placement if symptoms or if expanding/sizeable
pneumothorax; also consider in patients with underlying emphysema who
develop a pneumothorax after transthoracic needle aspiration
 Consider bronchopleural fistula in the setting of positive-pressure ventilation
Noniatrogenic Traumatic Pneumothorax
Occurs with trauma such as penetrating or blunt injuries.
TENSION PNEUMOTHORAX
A medical emergency (Figure 13-16).

592 / CHAPTER 13
DIAGNOSIS
 Clinical diagnosis suspected in patients with rapid clinical deterioration, on
mechanical ventilation, or who have undergone a procedure known to cause a
pneumothorax
 Physical findings are those of any large pneumothorax; additional findings
include enlargement of the involved hemithorax relative to the contralateral
hemithorax with widened costal interspaces, and contralateral tracheal
deviation
 Valuable time should not be wasted on radiologic studies, as the clinical
situation and physical findings are often sufficient to establish the diagnosis.
TREATMENT—When diagnosis is suspected, perform urgent needle

Key Fact decompression or chest-tube placement.
Tension pneumothorax is a
medical emergency and
urgent needle
decompression, or chest
tube placement, should not
be delayed when the
diagnosis is suspected.
Figure 13-16. Tension pneumothorax with marked leftward deviation of the

trachea, heart, and mediastinum
(Reproduced from Pourmand A, Shokoohi H. Tension Pneumothorax, Pneumoperitoneum, and Cervical
Emphysema following a Diagnostic Colonoscopy. Case Reports in Emergency Medicine, vol. 2013, Article ID
583287, 2013. doi:10.1155/2013/583287. CC BY 3.0)
593
ABOUT THE EDITORS
Tao Le, MD, MHS

Dr. Le developed a passion for medical education as a medical student. He currently edits more than 15
titles in the First Aid series. In addition, he is the founder of the USMLE-Rx online video and test bank
series as well as a cofounder of the Underground Clinical Vignettes series. As a medical student, he was
editor-in-chief of the University of California, San Francisco (UCSF) Synapse, a university newspaper with
a weekly circulation of 9000. Dr. Le earned his medical degree from UCSF in 1996 and completed his
residency training in internal medicine at Yale University and fellowship training at Johns Hopkins
University. At Yale, he was a regular guest lecturer on the USMLE review courses and an adviser to the
Yale University School of Medicine curriculum committee. Dr. Le subsequently went on to cofound
Medsn, a medical education technology venture, and served as its chief medical officer. He currently has
an interest in medical education and education research at the University of Louisville.
Sandeep Khosa, MD
Dr. Khosa has a love for pulmonary physiology and medical education, receiving numerous teaching
awards throughout his training. He is a graduate of Saba University School of Medicine, Netherlands, and
completed his Internal Medicine Residency and Chief Residency at Case Western Reserve University
(MetroHealth) program. He went on to complete his Fellowship in Pulmonary and Critical Care Medicine
at MetroHealth, and currently serves as a Consultant for Pulmonology and Intensive Care at the Mayo
Clinic Health System in Mankato, Minnesota. Dr. Khosa has a special interest in Critical Care
Ultrasonography and has served as faculty lecturer and instructor for courses at the American College of
Chest Physicians, Case Western Reserve University (MetroHealth), and Cleveland Clinic. In addition, Dr
Khosa has served as a contributing editor to online resources for quality improvement designed for
healthcare professionals.
Susan Pasnick, MD
Dr. Pasnick earned her medical degree at Northwestern University’s Feinberg School of Medicine and
completed her residency training in internal medicine at Brigham and Women’s Hospital in Boston. She
recently completed her fellowship in pulmonary and critical care medicine at UCSF. She has a strong
commitment to medical education and devoted the research portion of her fellowship to educational
scholarship. She is also an alumna of the Harvard Macy Institute Program for Postgraduate Trainees.
Particular interests include procedural teaching and the use of novel technologies to streamline and
customize content delivery. Dr. Pasnick co-directs the critical care ultrasound course at UCSF and
continues her work in postgraduate medical education through the American Thoracic Society.
Tisha Wang, MD
Dr. Wang has a longstanding interest in medical education and board review, and contributed to the
Underground Clinical Vignettes series while going to medical school in Texas. She earned her medical
degree at UTMB Galveston in 2002, and completed her residency training in internal medicine and
fellowship training in pulmonary and critical care at UCLA. Dr. Wang is board certified in internal
medicine, pulmonary, critical care, and sleep medicine, and has taken a number of leadership roles since
joining the UCLA faculty in 2008 as a clinician educator. In 2011, she became program director of a
growing pulmonary and critical care fellowship program and was instrumental in the creation of a
successful clinician educator track within the training program. In addition, she is director of the liver
transplant intensive care unit at UCLA and as of 2014, Dr. Wang was appointed as the Associate Chief of
594
Inpatient Services for the UCLA Division of Pulmonary, Critical Care, and Sleep Medicine. She regularly
publishes review articles, case reports/series, and book chapters and is actively involved in medical
education through the American Thoracic Society.

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›› Concise topic summaries

ideal for quick review

TAO SUNNY SUSAN TISHA

American Thoracic Society

Copyright © 2015 by American Thoracic Society. All rights reserved.

How to Contribute xiv

Chapter 1. Sleep Medicine and Neuromuscular/Skeletal Disorders 1

Respiratory Sleep Medicine Neuromuscular Disorders and Diseases of the

Chapter 2. Critical Care 47

Non-lung Critical Care Lung Critical Care

Chapter 3. Obstructive Lung Disease 131

Chapter 4. Diffuse Parenchymal Lung Disease 221

Interstitial Lung Disease Birt-Hogg-Dube

Chapter 5. Quality, Safety, and Ethics 305

Chapter 6. Epidemiology and Statistics 313

Chapter 7. Anatomy and Physiology of the Respiratory System 337

Chapter 8. Common Respiratory Symptoms, Pulmonary Imaging,

Chapter 9. Lung Transplantation 395

Indications and Patient Selection Complications after Transplantation

Chapter 10. Pulmonary Vascular Diseases 415

Pulmonary Vasculitis and Alveolar Hemorrhage Pulmonary Hypertension

Chapter 11. Infections 457

Bronchial and Bronchiolar Infections Mycobacterium tuberculosis

Chapter 12. Lung Neoplasms 515

Introduction Metastatic Lung Tumors

Chapter 13. Pleural Disease 565

Pleural Effusion Pleural Other

About the Editors 593

Nidhi Aggarwal, MD Muhammad Nouman Iqbal, MD

Sharon De Cruz, MD Nazir Ahmad Lone MD MPH

Puneet S. Garcha, MD Nandita R. Nadig MD

Naresh Nagella, MD Abhay Vakil, MBBS

Steven Chang, MD, PhD Corey Kershaw, MD

Ariss Derhovanessian, MD Peter Lenz, MD

Yuji Oba, MD Donald Tashkin, MD

Scott Oh, DO, FCCP J. Daryl Thornton, MD, MPH

Ziad S. Shaman, MD, RDMS

Tao Le, MD, MHS

Sandeep (Sunny) Khosa, MD

Tao Le, MD, MHS

Sandeep (Sunny) Khosa, MD

• Study and test-taking strategies

Sleep Medicine and

RESPIRATORY SLEEP MEDICINE

Review of the physiologic changes that occur during sleep.

Regulation of Sleep and Wake

SLEEP HOMEOSTASIS—Dependent on the sleep–wake cycle.

CIRCADIAN SYSTEM—Biologic alerting rhythm that consists of one oscillation

SLEEP INERTIA—Refers to the cognitive impairment present immediately on Flash Card Q2

Suprachiasmatic nucleus is master circadian rhythm generator in mammals

Neurotransmitters in Sleep and Wake

Table 1-1. Neurotransmitters Responsible for Sleep and Wake

Flash Card A1 Adenosine Decrease in adenosine activity promotes wakefulness

MELATONIN—Synthesized and released by the pineal gland, it influences

Physiologic Changes During Sleep

Sleep Deprivation Flash Card Q3