®

GLOBAL STRATEGY FOR

ASTHMA MANAGEMENT AND PREVENTION
UPDATED 2008
Global Strategy for Asthma Management and Prevention
The GINA reports are available on www.ginasthma.org.
 Global Strategy for Asthma Management and Prevention 2008 (update)

GINA EXECUTIVE COMMITTEE* GINA SCIENCE COMMITTEE*

Eric D. Bateman, MD, Chair Mark FitzGerald, MD, Chair

University Cape Town Lung Institute University of British Columbia
Cape Town, South Africa Vancouver, BC, Canada
Jean Bousquet, MD, PhD Peter J. Barnes, MD
Montpellier University and INSERM National Heart and Lung Institute
Montpellier, France London, England, UK
Mark FitzGerald, MD Eric D. Bateman, MD
University of British Columbia University Cape Town Lung Institute
Vancouver, BC, Canada Cape Town, South Africa
Tari Haahtela, MD Allan Becker, MD
Helsinki University Central Hospital University of Manitoba
Helsinki, Finland Winnipeg, Manitoba, Canada
Paul O'Byrne, MD Jeffrey M. Drazen, MD
McMaster University Harvard Medical School
Ontario, Canada Boston, Massachusetts, USA

Ken Ohta, MD, PhD Peter Gibson, MD

Teikyo University School of Medicine John Hunter Hospital
Tokyo, Japan NSW, New Castle, Australia
Pierluigi Paggiaro, MD Robert F. Lemanske, Jr., M.D.
University of Pisa University of Wisconsin
Pisa, Italy School of Medicine
Madison, Wisconsin, USA
Soren Erik Pedersen, M.D.
Kolding Hospital Paul O'Byrne, MD
Kolding, Denmark McMaster University
Ontario, Canada
Manuel Soto-Quiroz, MD
Hospital Nacional de Niños Ken Ohta, MD, PhD
San José, Costa Rica Teikyo University School of Medicine
Tokyo, Japan
Wan-Cheng Tan, MD
St Paul's Hospital Soren Erik Pedersen, M.D.
Vancouver, BC, Canada Kolding Hospital
Kolding, Denmark
Gary W. Wong, MD
Chinese University of Hong Kong Emilio Pizzichini, MD
Hong Kong ROC Universidade Federal de Santa Catarina
Florianópolis, SC, Brazil
Helen K. Reddel, MD
Woolcock Institute of Medical Research
Camperdown, NSW, Australia
Sean D. Sullivan, PhD
Professor of Pharmacy, Public Health
University of Washington
Seattle, Washington, USA
Sally E. Wenzel, M.D.
University of Pittsburgh
Pittsburgh, Pennsylvania, USA
Heather J. Zar, MD
University of Cape Town
Cape Town, South Africa

*Disclosures for members of GINA Executive and Science Committees can be found at: i
http://www.ginasthma.com/Committees.asp?l1=7&l2=2
 PREFACE
Asthma is a serious global health problem. People of all In spite of these dissemination efforts, international
ages in countries throughout the world are affected by this surveys provide direct evidence for suboptimal asthma
chronic airway disorder that, when uncontrolled, can place control in many countries, despite the availability of
severe limits on daily life and is sometimes fatal. The effective therapies. It is clear that if recommendations
prevalence of asthma is increasing in most countries, contained within this report are to improve care of people
especially among children. Asthma is a significant burden, with asthma, every effort must be made to encourage
not only in terms of health care costs but also of lost health care leaders to assure availability of and access to
productivity and reduced participation in family life. medications, and develop means to implement effective
asthma management programs including the use of
During the past two decades, we have witnessed many appropriate tools to measure success.
scientific advances that have improved our understanding
of asthma and our ability to manage and control it In 2002, the GINA Report stated that “it is reasonable to
effectively. However, the diversity of national health care expect that in most patients with asthma, control of the
service systems and variations in the availability of asthma disease can, and should be achieved and maintained.”
therapies require that recommendations for asthma care To meet this challenge, in 2005, Executive Committee
be adapted to local conditions throughout the global recommended preparation of a new report not only to
community. In addition, public health officials require incorporate updated scientific information but to implement
information about the costs of asthma care, how to an approach to asthma management based on asthma
effectively manage this chronic disorder, and education control, rather than asthma severity. Recommendations to
methods to develop asthma care services and programs assess, treat and maintain asthma control are provided in
responsive to the particular needs and circumstances this document. The methods used to prepare this
within their countries. document are described in the Introduction.
In 1993, the National Heart, Lung, and Blood Institute It is a privilege for me to acknowledge the work of the
collaborated with the World Health Organization to many people who participated in this update project, as
convene a workshop that led to a Workshop Report:
well as to acknowledge the superlative work of all who
Global Strategy for Asthma Management and Prevention.
have contributed to the success of the GINA program.
This presented a comprehensive plan to manage asthma
with the goal of reducing chronic disability and premature
The GINA program has been conducted through
deaths while allowing patients with asthma to lead
unrestricted educational grants from AstraZeneca,
productive and fulfilling lives.
Boehringer Ingelheim, Chiesi Group, GlaxoSmithKline,
Meda Pharma, Merck, Sharp & Dohme, Mitsubishi Tanabe
At the same time, the Global Initiative for Asthma (GINA)
Pharma, Novartis, Nycomed, PharmAxis and Schering-
was implemented to develop a network of individuals,
Plough. The generous contributions of these companies
organizations, and public health officials to disseminate
information about the care of patients with asthma while at assured that Committee members could meet together to
the same time assuring a mechanism to incorporate the discuss issues and reach consensus in a constructive and
results of scientific investigations into asthma care. timely manner. The members of the GINA Committees
Publications based on the GINA Report were prepared are, however, solely responsible for the statements and
and have been translated into languages to promote conclusions presented in this publication.
international collaboration and dissemination of
information. To disseminate information about asthma GINA publications are available through the Internet
care, a GINA Assembly was initiated, comprised of asthma (http://www.ginasthma.org).
care experts from many countries to conduct workshops
with local doctors and national opinion leaders and to hold
seminars at national and international meetings. In
addition, GINA initiated an annual World Asthma Day (in
2001) which has gained increasing attention each year to
raise awareness about the burden of asthma, and to Eric Bateman, MD
initiate activities at the local/national level to educate Chair, GINA Executive Committee
families and health care professionals about effective University of CapeTown Lung Institute
methods to manage and control asthma. Cape Town, South Africa

ii
 GLOBAL STRATEGY FOR ASTHMA MANAGEMENT AND PREVENTION
TABLE OF CONTENTS
PREFACE .........................................................................ii INTRODUCTION ............................................................16

METHODOLOGY AND SUMMARY OF NEW CLINICAL DIAGNOSIS...................................................16

RECOMMENDATION, 2007 UPDATE.........................vi Medical History...........................................................16
Symptoms ..............................................................16
INTRODUCTION ..............................................................x Cough variant asthma ............................................16
Exercise-Induced bronchospasm ...........................17
EXECUTIVE SUMMARY: MANAGING ASTHMA IN Physical Examination .................................................17
CHILDREN 5 YEARS AND YOUNGER ......................xiv Tests for Diagnosis and Monitoring ............................17
Measurements of lung function...............................17
CHAPTER 1. DEFINITION AND OVERVIEW..................1 Spirometry ..............................................................18
Peak expiratory flow ...............................................18
KEY POINTS ....................................................................2 Measurement of airway responsiveness ................19
Non-Invasive markers of airway inflammation ........19
DEFINITION .....................................................................2 Measurements of allergic status .............................19
THE BURDEN OF ASTHMA.............................................3 DIAGNOSTIC CHALLENGES AND
Prevalence, Morbidity and Mortality .............................3
DIFFERENTIAL DIAGNOSIS.......................................20
Social and Economic Burden .......................................3
Children 5 Years and Younger ...................................20
Older Children and Adults ..........................................20
FACTORS INFLUENCING THE DEVELOPMENT AND
The Elderly .................................................................21
EXPRESSION OF ASTHMA..........................................4
Occupational Asthma .................................................21
Host Factors................................................................4
Genetic .....................................................................4 Distinguishing Asthma from COPD ............................21
Obesity .....................................................................5
Sex ...........................................................................5 CLASSIFICATION OF ASTHMA.....................................22
Environmental Factors ................................................5 Etiology ......................................................................22
Allergens ..................................................................5 Asthma Severity .........................................................22
Infections ..................................................................5 Asthma Control ..........................................................22
Occupational sensitizers...........................................5
Tobacco smoke ........................................................6 REFERENCES ...............................................................23
Outdoor/Indoor air pollution ......................................6
Diet ...........................................................................7 CHAPTER 3. ASTHMA MEDICATIONS ........................27

MECHANISMS OF ASTHMA............................................7 KEY POINTS ..................................................................28

Airway Inflammation In Asthma ....................................7
Inflammatory cells ....................................................7 INTRODUCTION ............................................................28
Inflammatory mediators ............................................7
Structural changes in the airways .............................8 ASTHMA MEDICATIONS: ADULTS ...............................28
Pathophysiology...........................................................8 Route of Administration ..............................................28
Airway hyperresponsiveness ....................................8 Controller Medications................................................29
Special Mechanisms ....................................................8 Inhaled glucocorticosteroids ...................................29
Acute exacerbations .................................................8 Leukotriene modifiers .............................................30
Nocturnal asthma .....................................................9 Long-acting inhaled ␤2-agonists .............................30
Irreversible airflow limitation .....................................9 Theophylline ...........................................................31
Difficult-to-treat asthma ............................................9 Cromones: sodium cromoglycate and
Smoking and asthma ................................................9 nedocromil sodium ........................................31
Long-acting oral ␤2-agonists...................................32
REFERENCES .................................................................9 Anti-IgE ..................................................................32
Systemic glucocorticosteroids ................................32
CHAPTER 2. DIAGNOSIS AND CLASSIFICATION .....15 Oral anti-allergic compounds ..................................32
Other controller therapies .......................................32
KEY POINTS ..................................................................16
iii
 Allergen-specific immunotherapy............................33 INTRODUCTION ............................................................54
Reliever Medications...................................................34
Rapid-acting inhaled ␤2-agonists............................34 ASTHMA PREVENTION.................................................54
Systemic glucocorticosteroids ................................34
Anticholinergics ......................................................34 PREVENTION OF ASTHMA SYMPTOMS AND
Theophylline ...........................................................35 EXACERBATIONS....................................................55
Short-acting oral ␤2-agonists..................................35 Indoor Allergens .......................................................55
Complementary and Alternative Medicine ...................35 Domestic mites .......................................................55
Furred animals .......................................................55
ASTHMA TREATMENT: CHILDREN .............................35 Cockroaches ..........................................................55
Route of Administration ..............................................35 Fungi ......................................................................56
Controller Medications................................................36 Outdoor Allergens ......................................................56
Inhaled glucocorticosteroids ...................................36 Indoor Air Pollutants ..................................................56
Leukotriene modifiers .............................................38 Outdoor Air Pollutants ................................................56
Long-acting inhaled ␤2-agonists .............................38 Occupational Exposures ............................................56
Theophylline ...........................................................39 Food and Food Additives ...........................................56
Cromones: sodium cromoglycate and nedocromil Drugs .........................................................................57
sodium .........................................................39 Influenza Vaccination .................................................57
Long-acting oral ␤2-agonists...................................39 Obesity.......................................................................57
Systemic glucocorticosteroids ................................39 Emotional Stress ........................................................57
Reliever Medications...................................................40 Other Factors That May Exacerbate Asthma .............57
Rapid-acting inhaled ␤2-agonists and short-acting
oral ␤2-agonists ..............................................40 COMPONENT 3: ASSESS, TREAT AND MONITOR
Anticholinergics ......................................................40 ASTHMA......................................................................57

REFERENCES ...............................................................40 KEY POINTS ..................................................................57

CHAPTER 4. ASTHMA MANAGEMENT AND INTRODUCTION ............................................................57

PREVENTION ................................................................49
ASSESSING ASTHMA CONTROL.................................58
INTRODUCTION ............................................................50
TREATING TO ACHIEVE CONTROL.............................58
COMPONENT 1: DEVELOP PATIENT/ Treatment Steps for Achieving Control......................58
DOCTOR PARTNERSHIP...........................................50 Step 1: As-needed reliever medication ..................58
Step 2: Reliever medication plus a single
KEY POINTS ..................................................................50 controller .........................................................60
Step 3: Reliever medication plus one or two
INTRODUCTION ............................................................50 controllers .......................................................60
Step 4: Reliever medication plus two or more
ASTHMA EDUCATION...................................................51 controllers .......................................................61
At the Initial Consultation...........................................52 Step 5: Reliever medication plus additional
Personal Asthma Action Plans ..................................52 controller options ............................................61
Follow-up and Review ...............................................52
Improving Adherence ................................................52 MONITORING TO MAINTAIN CONTROL ......................61
Self-Management in Children ....................................52 Duration and Adjustments to Treatment ......................61
Stepping Down Treatment When Asthma Is
THE EDUCATION OF OTHERS.....................................53 Controlled.................................................................62
Stepping Up Treatment In Response To Loss Of
COMPONENT 2: IDENTIFY AND REDUCE EXPOSURE Control .....................................................................62
TO RISK FACTORS ....................................................54 Difficult-to-Treat-Asthma .............................................63

KEY POINTS ..................................................................54

iv
COMPONENT 4 - MANAGE ASTHMA ECONOMIC VALUE OF INTERVENTIONS AND
EXACERBATIONS......................................................64 GUIDELINE IMPLEMENTATION IN ASTHMA...........89
Utilization and Cost of Health Care Resources.........89
KEY POINTS ..................................................................64 Determining the Economic Value of Interventions in
Asthma ...................................................................90
INTRODUCTION ............................................................64
GINA DISSEMINATION/IMPLEMENTATION
ASSESSMENT OF SEVERITY.......................................65 RESOURCES ............................................................90

MANAGEMENT–COMMUNITY SETTINGS ...................65 REFERENCES ...............................................................91

Treatment...................................................................66
Bronchodilators ......................................................66
Glucocorticosteroids ...............................................66

MANAGEMENT–ACUTE CARE SETTINGS ..................66

Assessment ................................................................66
Treatment....................................................................68
Oxygen ...................................................................68
Rapid-acting inhaled ␤2–agonists ...........................68
Epinephrine ............................................................68
Additional bronchodilators ...........................................68
Systemic glucocorticosteroids ................................68
Inhaled glucocorticosteroids ...................................69
Magnesium .............................................................69
Helium oxygen therapy ...........................................69
Leukotriene modifiers .............................................69
Sedatives ...............................................................69
Criteria for Discharge from the Emergency
Department vs. Hospitalization.................................69

COMPONENT 5. SPECIAL CONSIDERATIONS ..........70

Pregnancy.....................................................................70
Surgery .........................................................................70
Rhinitis, Sinusitis, And Nasal Polyps .............................71
Rhinitis ...................................................................71
Sinusitis ..................................................................71
Nasal polyps ...........................................................71
Occupational Asthma ....................................................71
Respiratory Infections ...................................................72
Gastroesophageal Reflux..............................................72
Aspirin-Induced Asthma ................................................72
Anaphylaxis and Asthma...............................................73

REFERENCES ...............................................................73

CHAPTER 5. IMPLEMENTATION OF ASTHMA

GUIDELINES IN HEALTH SYSTEMS .........................87

KEY POINTS ..................................................................88

INTRODUCTION ............................................................88

GUIDELINE IMPLEMENTATION STRATEGIES ............88

v
 METHODOLOGY AND SUMMARY
OF NEW RECOMMENDATIONS GLOBAL STRATEGY
FOR ASTHMA MANAGEMENT AND PREVENTION:
2008 UPDATE*
When the Global Initiative for Asthma (GINA) program was by at least 1 member of the Committee, and to reach a
initiated in 1993, a goal was to produce recommendations consensus on the changes in the report. Disagreements
for asthma management based on the best scientific were decided by vote.
information available. Its first report, NHLBI/WHO
Workshop Report: Global Strategy for Asthma Summary of Recommendations in the 2008 Update:
Management and Prevention was issued in 1995 and Between July 1, 2007 and June 30, 2008, 406 articles met
revised in 2002 and 2006. These reports, and their the search criteria; 10 additional publications were brought
companion documents, have been widely distributed and to the attention of the committee. Of the 416 articles, 40
translated into many languages. The 2006 report was papers were identified to have an impact on the GINA
based on research published through June, 2006 and can Report (updated 2007) that was posted on the website in
be found on the GINA website (www.ginasthma.org). December 2007 either by: 1) confirming, that is, adding or
replacing an existing reference, or 2) modifying, that is,
The GINA Science Committee was established in 2002 to changing the text or introducing a concept requiring a new
review published research on asthma management and recommendation to the report. The summary is reported
prevention, to evaluate the impact of this research on in three segments: A) Modifications in the text; B)
recommendations in the GINA documents related to References that provided confirmation or an update of
management and prevention, and to post yearly updates previous recommendations; and C) Changes or
on the GINA website. The first update of the 2006 report modifications to the text.
(2007 update) included the impact of publications from
July 1, 2006 through June 30, 2007. This second update Diagnosis and Management of Asthma in Children 5 Years
of the 2006 report (2008 update) includes the impact of and Younger: Throughout 2008, several pediatric experts
publications from July 1, 2007 through June 30, 2008. have been developing a report that will focus on asthma
care in children 5 years and younger. The document is ex-
Methods: The process to produce this 2008 update pected to be released in early 2009. Publications that
included a Pub Med search using search fields established appeared during the 2008 update cycle that impact on this
by the Committee: 1) asthma, All Fields, All ages, only young age group will be reviewed in preparation of the
items with abstracts, Clinical Trial, Human, sorted by new report (see section C.2.) and are not included in this
Authors; and 2) asthma AND systematic, All fields, ALL 2008 update.
ages, only items with abstracts, Human, sorted by author.
In addition, publications in peer review journals not Evidence Reviews: In preparation of GINA reports,
captured by Pub Med could be submitted to individual including this 2008 update, grading of evidence has been
members of the Committee providing an abstract and the completed using four categories as described on page xiii.
full paper were submitted in (or translated into) English. However, a new methodology called the GRADE system
has been described1 and is being widely adopted. GINA is
All members of the Committee received a summary of concerned with regard to the resource implications of this
citations and all abstracts. Each abstract was assigned to change, especially given the already rigorous method of
two Committee members, although all members were reviewing the literature and updating recommendations
offered the opportunity to provide an opinion on any that is already in place. Nonetheless, a system is being
abstract. Members evaluated the abstract or, up to her/his developed to slowly make a transition to the GRADE
judgment, the full publication, by answering specific written methodology by initially identifying key recommendations
questions from a short questionnaire, and to indicate if the that require more in-depth evaluation, and to implement
scientific data presented impacted on recommendations in the creation and evaluation of evidence tables. Attention
the GINA report. If so, the member was asked to will be paid to ensuring clarity of the recommendations
specifically identify modifications that should be made. The based on these tables. The 2009 update will begin to
entire GINA Science Committee met on a regular basis to reflect this work. (See section C.3.)
discuss each individual publication that was indicated to
have an impact on asthma management and prevention

vi
The Global Strategy for Asthma Management and Prevention (updated 2008), the updated Pocket Guides and the
complete list of references examined by the Committee are available on the GINA website www.ginasthma.org.

Members (2007-2008): M. FitzGerald, Chair; P. Barnes, E. Bateman, A. Becker, J. Drazen, P. Gibson, R. Lemanske,
P. Oʼ Byrne, K. Ohta, S. Pedersen, E. Pizzichini, H. Reddel, S. Sullivan, S. Wenzel, H. Zar.
A. Modifications in the text: Pg 31, left column, delete last sentence (and references)
and insert: No influence of ␤2-adrenergic receptor
Pg 3, right column, delete sentence (and references) phenotypes upon the efficacy or safety of long-acting
"There is good evidence…..may have stabilized in β 2-agonist therapy has been observed when administered
others7,8" and insert: There is good evidence that in combination with inhaled glucocorticosteroids whether by
international differences in asthma symptom prevalence the single inhaler for maintenance and relief method or at
have been reduced, particularly in the 13-14 year age a regular fixed dose in adults206. Reference 206. Bleecker
group, with decreases in prevalence in North America and ER, Postma DS, Lawrance RM, Meyers DA, Ambrose HJ,
Western Europe and increases in prevalence in regions Goldman M. Effect of ADRB2 polymorphisms on
where prevalence was previously low. Although there was response to long-acting beta2-agonist therapy: a
pharmacogenetic analysis of two randomised studies.
little change in the overall prevalence of current wheeze,
Lancet 2007 Dec 22;370(9605):2118-25.
the percentage of children reported to have had asthma
increased significantly, possibly reflecting greater Pg 32, left column, modify statement "..between ages of 11
awareness of this condition and/or changes in diagnostic and 50.." to read: "…12 years and older207…."
practice. The increases in asthma symptom prevalence in Reference 207. Bousquet J, Cabrera P, Berkman N, Buhl
Africa, Latin America and parts of Asia indicate that the R, Holgate S, Wenzel S, et al. The effect of treatment with
global burden of asthma is continuing to rise, but the omalizumab, an anti-IgE antibody, on asthma
global prevalence differences are lessening126. exacerbations and emergency medical visits in patients
Reference 126. Pearce N, Aït-Khaled N, Beasley R, with severe persistent asthma. Allergy 2005;60(3):302-8.
Mallol J, Keil U, Mitchell E, Robertson C; and the ISAAC
Phase Three Study Group. Worldwide trends in the Pg 34, left column, insert: Specific immunotherapy has
prevalence of asthma symptoms: phase III of the long-term clinical effects and the potential of preventing
International Study of Asthma and Allergies in Childhood development of asthma in children with allergic rhino
(ISAAC). Thorax 2007 Sep;62(9):758-66. Epub 2007 conjunctivitis up to 7 years after treatment termination208.
May 15. Reference 208. Jacobsen L, Niggemann B, Dreborg S,
Ferdousi HA, Halken S, Høst A, et al; (The PAT
Pg 23, left column modify current sentence to read: Some investigator group). Specific immunotherapy has long-
are suitable for self-assessment of asthma control by term preventive effect of seasonal and perennial asthma:
patients65, and some are available in …..". Reference 65. 10-year follow-up on the PAT study. Allergy 2007
Schatz M, Mosen DM, Kosinski M, Vollmer WM, Magid DJ, Aug;62(8):943-8.
O'Connor E, Zeiger RS. Validity of the Asthma Control
Test completed at home. Am J Manag Care 2007 Pg 34, right column, insert: levalbuterol HFA209.
Reference 209. Pearlman DS, Rees W, Schaefer K,
Dec;13(12):661-7.
Huang H, Andrews WT. An evaluation of levalbuterol HFA
in the prevention of exercise-induced bronchospasm.
Pg 30, right column insert: A controlled release J Asthma 2007 Nov;44(9):729-33.
formulation of zileuton allows this medication to be used
on a twice daily basis with effects equivalent to that of Pg 35, right column, insert: An integrated breathing and
standard zileuton used four times a day203. Reference relaxation technique (Papworth method) appears to
203. Nelson H, Kemp J, Berger W, Corren J, Casale T, ameliorate respiratory symptoms, dysfunctional breathing
Dube L, Walton-Bowen K, LaVallee N, Stepanians M. and adverse mood but there is no evidence of effect on
Efficacy of zileuton controlled-release tablets administered objective measures of respiratory function210. Reference
twice daily in the treatment of moderate persistent asthma: 210. Holloway EA, West RJ. Integrated breathing and
a 3-month randomized controlled study. Ann Allergy relaxation training (the Papworth method) for adults with
Asthma Immuno 2007 Aug;99(2):178-84. asthma in primary care: a randomised controlled trial.
Thorax 2007 Dec;62(12):1039-42. Epub 2007 Jun 15.
Pg 31, left column insert: A meta-analysis of all studies of
salmeterol added to inhaled glucocorticosteroids has Pg 36, left column, insert: Early intervention with inhaled
concluded that this combination does not increase the risk budesonide is associated with improved asthma control
for asthma-related deaths or intubations when compared and less additional asthma medication use211. Reference
to inhaled glucocorticosteroids alone205. Reference 205. 211. Busse WW, Pedersen S, Pauwels RA, Tan WC,
Bateman E, Nelson H, Bousquet J, Kral K, Sutton L, Chen YZ, Lamm CJ, O'Byrne PM; START Investigators
Ortega H, Yancey S. Meta-analysis: effects of adding Group. The Inhaled Steroid Treatment As Regular
salmeterol to inhaled corticosteroids on serious asthma- Therapy in Early Asthma (START) study 5-year follow-up:
related events. Ann Intern Med 2008 Jul 1;149(1):33-42. effectiveness of early intervention with budesonide in mild
persistent asthma. J Allergy Clin Immunol 2008
Epub 2008 Jun 3.
May;121(5):1167-74. Epub 2008 Apr 11.

vii
Pg 52, right column, insert: Although interactive Larsson K, Palange P, Popov T, van Cauwenberge P;
computerized asthma education programs may improve European Respiratory Society; European Academy of
patient asthma knowledge and symptoms, their effect on Allergy and Clinical Immunology; GA(2)LEN. Treatment of
objective clinical outcomes is less consistent353. exercise-induced asthma, respiratory and allergic
Reference 353. Bussey-Smith KL, Rossen RD. A disorders in sports and the relationship to doping: Part II of
systematic review of randomized control trials evaluating the report from the Joint Task Force of European
the effectiveness of interactive computerized asthma Respiratory Society (ERS) and European Academy of
patient education programs. Ann Allergy Asthma Immunol Allergy and Clinical Immunology (EAACI) in cooperation
2007 Jun;98(6):507-16. with GA(2)LEN. Allergy 2008 May;63(5):492-505.

Pg 52, Right column, delete "The written self- Pg 64, left column, insert: Exacerbations usually have a
management plan and its understanding are also progressive onset but a subset of patients (mostly adults)
reviewed" and insert: Routine follow-up visits may be an present more acutely361. Reference 361. Ramnath VR,
effective time to review the written self-management plan Clark S, Camargo CA Jr. Multicenter study of clinical
and its understanding354. Reference 354. Ring N, features of sudden-onset versus slower-onset asthma
Malcolm C, Wyke S, Macgillivray S, Dixon D, Hoskins G, exacerbations requiring hospitalization. Respir Care. 2007
Pinnock H, Sheikh A. Promoting the use of Personal Aug;52(8):1013-20.
Asthma Action Plans: a systematic review. Prim Care
Respir J 2007 Oct;16(5):271-83. Pg 88, left column, modify last line: "…medications (e.g.,
inhaled preparations), suboptimal use of medications21,
Pg 53, right column, insert: For children, symptom-based and lack of physician use of guidelines." Reference 21.
action plans are more effective than those based on peak Cazzoletti L, Marcon A, Janson C, Corsico A, Jarvis D, Pin
flows355. Reference 355: Zemek RL, Bhogal SK, I, Accordini S, Almar E, Bugiani M, Carolei A, Cerveri I,
Ducharme FM. Systematic review of randomized Duran-Tauleria E, Gislason D, Gulsvik A, Jõgi R, Marinoni
controlled trials examining written action plans in children: A, Martínez-Moratalla J, Vermeire P, de Marco R; Therapy
what is the plan? Arch Pediatr Adolesc Med 2008 and Health Economics Group of the European Community
Feb;162(2):157-63. Respiratory Health Survey. Asthma control in Europe: a
real-world evaluation based on an international population-
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account for a substantial proportion of adult asthma Dec;120(6):1360-7. Epub 2007 Nov 5.
incidence357. Reference 357. Kogevinas M, Zock JP,
Jarvis D, Kromhout H, Lillienberg L, Plana E, et al. Pg 88, right column, insert: Integrated care pathways are
Exposure to substances in the workplace and new-onset being explored as a mean to improve asthma care in
asthma: an international prospective population-based specific settings, such as patients coming to emergency
study (ECRHS-II). Lancet 2007 Jul 28;370(9584):336-41. departments22. Reference 22. Cunningham S, Logan C,
Lockerbie L, Dunn MJ, McMurray A, Prescott RJ. Effect of
Pg 57, right column, insert: A randomized clinical trial of a an integrated care pathway on acute asthma/wheeze in
self-regulation, telephone counseling intervention children attending hospital: cluster randomized trial. J
emphasizing sex and gender role factors in the Pediatr 2008 Mar;152(3):315-20. Epub 2007 Nov 26.
management of asthma indicated that a program with a
focus on asthma management problems particular to B. References that provided confirmation or update of
women can significantly assist female asthma patients358. previous recommendations:
Reference 358. Clark NM, Gong ZM, Wang SJ, Lin X,
Bria WF, Johnson TR. A randomized trial of a self- Pg 19: left column, insert: Reference 63. Shaw DE, Berry
regulation intervention for women with asthma. Chest MA, Thomas M, Green RH, Brightling CE, Wardlaw AJ,
2007 Jul;132(1):88-97. Epub 2007 May 15. Pavord ID. The use of exhaled nitric oxide to guide
asthma management: a randomized controlled trial. Am J
Pg 60, left column, insert: Information on treatment of Respir Crit Care Med. 2007 Aug 1;176(3):231-7. Epub
exercise-induced asthma in athletes can be found in a 2007 May 11.
Joint Task Force Report prepared by the European
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Clinical Immunology, and GA(2)LEN359 and the World Anti- MK, Blanc PD, Miller DP, Kamath TV, Lee JH, Sullivan
Doping Agency website (http://www.wada-ama.org). SD; for the TENOR Study Group. Asthma control,
Reference 359. Carlsen KH, Anderson SD, Bjermer L, severity, and quality of life: quantifying the effect of
Bonini S, Brusasco V, Canonica W, Cummiskey J, uncontrolled disease. J Allergy Clin Immunol. 2007
Delgado L, Del Giacco SR, Drobnic F, Haahtela T, Aug;120(2):396-402. Epub 2007 Jun 11.

viii
Pg 30: right column, insert: Reference 204. Watkins PB, Breastfeeding Intervention Trial (PROBIT) Study
Dube LM, Walton-Bowen K, Cameron CM, Kasten LE. Group. Effect of prolonged and exclusive breast
Clinical pattern of zileuton-associated liver injury: results of feeding on risk of allergy and asthma: cluster
a 12-month study in patients with chronic asthma. Drug randomised trial. BMJ 2007 Oct 20;335(7624):815.
Saf 2007;30(9):805-15. d. Ozdemir C, Yazi D, Gocmen I, Yesil O, Aydogan M,
Semic-Jusufagic A, Bahceciler NN, Barlan IB.
Pg 56: left column, insert: Reference 356. McCreanor J, Efficacy of long-term sublingual immunotherapy as an
Cullinan P, Nieuwenhuijsen MJ, Stewart-Evans J, adjunct to pharmacotherapy in house dust mite-
Malliarou E, Jarup L, Harrington R, Svartengren M, Han allergic children with asthma. Pediatr Allergy
IK, Ohman-Strickland P, Chung KF, Zhang J. Respiratory Immunol. 2007 Sep;18(6):508-15.
effects of exposure to diesel traffic in persons with asthma. e. Ducharme FM, Chalut D, Plotnick L, Savdie C,
N Engl J Med. 2007 Dec 6;357(23):2348-58. Kudirka D, Zhang X, Meng L, McGillivray D. The
Pediatric Respiratory Assessment Measure: a valid
Pg 61: right column, delete reference 104 and replace clinical score for assessing acute asthma severity from
with Reference 360: Bateman ED, Clark TJ, Frith L, toddlers to teenagers. J Pediatr 2008 Apr;152(4):476-
Bousquet J, Busse WW, Pedersen SE; Goal Investigators 80, 480.e1. Epub 2007 Oct 31.
Group. Rate of response of individual asthma control f. Schokker S, Kooi EM, de Vries TW, Brand PL, Mulder
measures varies and may overestimate asthma control: an PG, Duiverman EJ, van der Molen T. Inhaled
analysis of the goal study. J Asthma 2007 Oct;44(8):667- corticosteroids for recurrent respiratory symptoms in
73. preschool children in general practice: randomized
controlled trial. Pulm Pharmacol Ther 2008;21(1):88-
Pg 74: Substitute this for reference 24: Clark NM, 97. Epub 2007 Jan 23.
Cabana MD, Nan B, Gong ZM, Slish KK, Birk NA, Kaciroti g. Sedik HA, Barr RG, Clark S, Camargo CA Jr.
N. The clinician-patient partnership paradigm: outcomes Prospective study of sudden-onset asthma
associated with physician communication behavior. Clin exacerbations in children. Pediatr Emerg Care 2007
Pediatr (Phila). 2008 Jan;47(1):49-57. Epub 2007 Sep 27. Jul;23(7):439-44.

Pg 76: Substitute this for reference 90: Cates CJ, 3. Grading Evidence: The GINA document Global
Jefferson TO, Rowe BH. Vaccines for preventing influenza Strategy for Asthma Management and Prevention will
in people with asthma. Cochrane Database Syst Rev continue to include background information and will
2008 Apr 16;(2):CD000364. eventually include a series of specific recommendations
based on evidence tables1 (included as an appendix to the
C. Committee recommended changes: volume and/or on the GINA website.) The GINA Science
Committee will develop a system to identify
1. A new table showing current combination therapies will recommendations that are relatively controversial and
be prepared, posted on the website, and updated as new have a less robust evidence base, to assemble and
formulations become available. analyze the evidence, and to routinely update the
evidence. Three questions that have been identified to
2. In early 2009, GINA will publish a report on Diagnosis begin the work include:
and Management of Asthma in Children 5 years and
Younger. Several publications that appeared during this a. In adults with acute exacerbations of asthma, does
update cycle will be reviewed in preparation of this new intravenous magnesium sulphate compared to
document, including: placebo improve patient important outcomes?
b. In adults with asthma, does monoclonal anti-IgE,
a. Bisgaard H, Pedersen S, Anhøj J, Agertoft L, Hedlin omalazumab, compared to placebo improve patient
G, Gulsvik A, et al. Weiss ST. Determinants of lung outcomes?
function and airway hyperresponsiveness in asthmatic c. In adults with asthma, does sublingual immunotherapy
children. Respir Med 2007 Jul;101(7):1477-82. Epub compared to placebo improve patient important
2007 Mar 2. outcomes?
b. Johnston NW, Mandhane PJ, Dai J, Duncan JM,
Greene JM, Lambert K, Sears MR. Attenuation of the The analysis of the data from these questions is under
September epidemic of asthma exacerbations in review and will be available in the 2009 update.
children: a randomized, controlled trial of montelukast
added to usual therapy. Pediatric. 2007 REFERENCES
Sep;120(3):e702-12.
c. Kramer MS, Matush L, Vanilovich I, Platt R, 1. Guyatt GH, Oxman AD, Kunz R, et al. Going from
Bogdanovich N, Sevkovskaya Z, et al; Promotion of evidence to recommendations. BMJ 2008;336:1049-51.

ix
 INTRODUCTION
Asthma is a serious public health problem throughout the aim to enhance communication with asthma specialists,
world, affecting people of all ages. When uncontrolled, primary-care health professionals, other health care
asthma can place severe limits on daily life, and is workers, and patient support organizations. The Executive
sometimes fatal. Committee continues to examine barriers to implementation
of the asthma management recommendations, especially
In 1993, the Global Initiative for Asthma (GINA) was the challenges that arise in primary-care settings and in
formed. Its goals and objectives were described in a 1995 developing countries.
NHLBI/WHO Workshop Report, Global Strategy for
Asthma Management and Prevention. This Report While early diagnosis of asthma and implementation of
(revised in 2002), and its companion documents, have appropriate therapy significantly reduce the socioeconomic
been widely distributed and translated into many burdens of asthma and enhance patientsʼ quality of life,
languages. A network of individuals and organizations medications continue to be the major component of the
interested in asthma care has been created and several cost of asthma treatment. For this reason, the pricing of
country-specific asthma management programs have asthma medications continues to be a topic for urgent
been initiated. Yet much work is still required to reduce need and a growing area of research interest, as this has
morbidity and mortality from this chronic disease. important implications for the overall costs of asthma
management.
In January 2004, the GINA Executive Committee
recommended that the Global Strategy for Asthma Moreover, a large segment of the worldʼs population lives
Management and Prevention be revised to emphasize in areas with inadequate medical facilities and meager
asthma management based on clinical control, rather than financial resources. The GINA Executive Committee
classification of the patient by severity. This important recognizes that “fixed” international guidelines and “rigid”
paradigm shift for asthma care reflects the progress that scientific protocols will not work in many locations. Thus,
has been made in pharmacologic care of patients. Many the recommendations found in this Report must be
asthma patients are receiving, or have received, some adapted to fit local practices and the availability of health
asthma medications. The role of the health care care resources.
professional is to establish each patientʼs current level of
treatment and control, then adjust treatment to gain and As the GINA Committees expand their work, every effort
maintain control. This means that asthma patients should will be made to interact with patient and physician groups
experience no or minimal symptoms (including at night), at national, district, and local levels, and in multiple health
have no limitations on their activities (including physical care settings, to continuously examine new and innovative
exercise), have no (or minimal) requirement for rescue approaches that will ensure the delivery of the best asthma
medications, have near normal lung function, and care possible. GINA is a partner organization in a program
experience only very infrequent exacerbations. launched in March 2006 by the World Health Organization,
the Global Alliance Against Chronic Respiratory Diseases
FUTURE CHALLENGES (GARD). Through the work of the GINA Committees, and
in cooperation with GARD initiatives, progress toward
In spite of laudable efforts to improve asthma care over the better care for all patients with asthma should be
past decade, a majority of patients have not benefited from substantial in the next decade.
advances in asthma treatment and many lack even the
rudiments of care. A challenge for the next several years METHODOLOGY
is to work with primary health care providers and public
health officials in various countries to design, implement, A. Preparation of yearly updates: Immediately
and evaluate asthma care programs to meet local needs. following the release of an updated GINA Report in 2002,
The GINA Executive Committee recognizes that this is a the Executive Committee appointed a GINA Science
difficult task and, to aid in this work, has formed several Committee, charged with keeping the Report up-to-date
groups of global experts, including: a Dissemination Task by reviewing published research on asthma management
Group; the GINA Assembly, a network of individuals who and prevention, evaluating the impact of this research on
care for asthma patients in many different health care the management and prevention recommendations in the
settings; and regional programs (the first two being GINA GINA documents, and posting yearly updates of these
Mesoamerica and GINA Mediterranean). These efforts documents on the GINA website. The first update was

x
posted in October 2003, based on publications from as possible, while at the same time recognizing that one of
January 2000 through December 2002. A second update the values of the GINA Report has been to provide
appeared in October 2004, and a third in October 2005, background information about asthma management and
each including the impact of publications from January the scientific information on which management
through December of the previous year. recommendations are based.

The process of producing the yearly updates began with a In January 2006, the Committee met again for a two-day
Pub Med search using search fields established by the session during which another in-depth evaluation of each
Committee: 1) asthma, All Fields, All ages, only items with chapter was conducted. At this meeting, members
abstracts, Clinical Trial, Human, sorted by Authors; and reviewed the literature that appeared in 2005—using the
2) asthma AND systematic, All fields, ALL ages, only items same criteria developed for the update process. The list
with abstracts, Human, sorted by Author. In addition, of 285 publications from 2005 that were considered is
peer-reviewed publications not captured by Pub Med could posted on the GINA website. At the January meeting, it
be submitted to individual members of the Committee was clear that work remaining would permit the report to
providing an abstract and the full paper were submitted in be finished during the summer of 2006 and, accordingly,
(or translated into) English. the Committee requested that as publications appeared
throughout early 2006, they be reviewed carefully for their
All members of the Committee received a summary of impact on the recommendations. At the Committeeʼs next
citations and all abstracts. Each abstract was assigned to meeting in May, 2006 publications meeting the search
two Committee members, and an opportunity to provide an criteria were considered and incorporated into the current
opinion on any single abstract was offered to all members. drafts of the chapters, where appropriate. A final meeting
Members evaluated the abstract or, up to her/his of the Committee was held be held in September 2006, at
judgment, the full publication, by answering specific written which publications that appear prior to July 31, 2006 were
questions from a short questionnaire, indicating whether considered for their impact on the document.
the scientific data presented affected recommendations in
the GINA Report. If so, the member was asked to Periodically throughout the preparation of this report,
specifically identify modifications that should be made. representatives from the GINA Science Committee have
The entire GINA Science Committee met on a regular met with members of the GINA Assembly (May and
basis to discuss each individual publication that was September, 2005 and May 2006) to discuss the overall
judged by at least one member to have an impact on theme of asthma control and issues specific to each of the
asthma management and prevention recommendations, chapters. The GINA Assembly includes representatives
and to reach a consensus on the changes in the Report. from over 50 countries and many participated in these
Disagreements were decided by vote. interim discussions. In addition, members of the Assembly
were invited to submit comments on a DRAFT document
The publications that met the search criteria for each during the summer of 2006. Their comments, along with
yearly update (between 250 and 300 articles per year) comments received from several individuals who were
mainly affected the chapters related to clinical invited to serve as reviewers, were considered by the
management. Lists of the publications considered by the Committee in September, 2006.
Science Committee each year, along with the yearly
updated reports, are posted on the GINA website, Summary of Major Changes
www.ginasthma.org.
The major goal of the revision was to present information
B. Preparation of new 2006 report: In January 2005, about asthma management in as comprehensive manner
the GINA Science Committee initiated its work on this new as possible but not in the detail that would normally be
report. During a two-day meeting, the Committee found in a textbook. Every effort has been made to select
established that the main theme of the new report should key references, although in many cases, several other
be the control of asthma. A table of contents was publications could be cited. The document is intended to
developed, themes for each chapter identified, and writing be a resource; other summary reports will be prepared,
teams formed. The Committee met in May and September including a Pocket Guide specifically for the care of infants
2005 to evaluate progress and to reach consensus on and young children with asthma.
messages to be provided in each chapter. Throughout its
work, the Committee made a commitment to develop a
document that would: reach a global audience, be based
on the most current scientific literature, and be as concise
xi
Some of the major changes that have been made in this • No (twice or less/week) need for reliever treatment
report include: • Normal or near-normal lung function results
• No exacerbations
1. Every effort has been made to produce a more
streamlined document that will be of greater use to busy 9. Emphasis is given to the concept that increased use,
clinicians, particularly primary care professionals. The especially daily use, of reliever medication is a warning of
document is referenced with the up-to-date sources so that deterioration of asthma control and indicates the need to
interested readers may find further details on various reassess treatment.
topics that are summarized in the report.
10. The roles in therapy of several medications have
2. The whole of the document now emphasizes asthma evolved since previous versions of the report:
control. There is now good evidence that the clinical • Recent data indicating a possible increased risk of
manifestations of asthma—symptoms, sleep disturbances, asthma-related death associated with the use of long-
limitations of daily activity, impairment of lung function, and acting ␤2-agonists in a small group of individuals has
use of rescue medications—can be controlled with resulted in increased emphasis on the message that
appropriate treatment. long-acting ␤2-agonists should not be used as
monotherapy in asthma, and must only be used in
3. Updated epidemiological data, particularly drawn from
combination with an appropriate dose of inhaled
the report Global Burden of Asthma, are summarized.
glucocorticosteroid.
Although from the perspective of both the patient and
• Leukotriene modifiers now have a more prominent
society the cost to control asthma seems high, the cost of
role as controller treatment in asthma, particularly in
not treating asthma correctly is even higher.
adults. Long-acting oral ␤2-agonists alone are no
longer presented as an option for add-on treatment at
4. The concept of difficult-to-treat asthma is introduced and
developed at various points throughout the report. Patients any step of therapy, unless accompanied by inhaled
with difficult-to-treat asthma are often relatively insensitive glucocorticosteroids.
to the effects of glucocorticosteroid medications, and may • Monotherapy with cromones is no longer given as an
sometimes be unable to achieve the same level of control alternative to monotherapy with a low dose of inhaled
as other asthma patients. glucocorticosteroids in adults.
• Some changes have been made to the tables of
5. Lung function testing by spirometry or peak expiratory equipotent daily doses of inhaled glucocorticosteroids
flow (PEF) continues to be recommended as an aid to for both children and adults.
diagnosis and monitoring. Measuring the variability of
airflow limitation is given increased prominence, as it is key to 12. The six-part asthma management program detailed in
both asthma diagnosis and the assessment of asthma control. previous versions of the report has been changed. The
current program includes the following five components:
6. The previous classification of asthma by severity into Component 1. Develop Patient/Doctor Partnership
Intermittent, Mild Persistent, Moderate Persistent, and Severe Component 2. Identify and Reduce Exposure to Risk
Persistent is now recommended only for research purposes. Factors
Component 3. Assess, Treat, and Monitor Asthma
7. Instead, the document now recommends a classification Component 4. Manage Asthma Exacerbations
of asthma by level of control: Controlled, Partly Controlled, Component 5. Special Considerations
or Uncontrolled. This reflects an understanding that asthma
severity involves not only the severity of the underlying 13. The inclusion of Component 1 reflects the fact that
disease but also its responsiveness to treatment, and that effective management of asthma requires the development
severity is not an unvarying feature of an individual of a partnership between the person with asthma and his
patientʼs asthma but may change over months or years. or her health care professional(s) (and parents/caregivers,
in the case of children with asthma). The partnership is
8. Throughout the report, emphasis is placed on the formed and strengthened as patients and their health care
concept that the goal of asthma treatment is to achieve professionals discuss and agree on the goals of treatment,
and maintain clinical control. Asthma control is defined as: develop a personalized, written self-management action
plan including self-monitoring, and periodically review the
• No (twice or less/week) daytime symptoms patientʼs treatment and level of asthma control. Education
• No limitations of daily activities, including exercise remains a key element of all doctor-patient interactions.
• No nocturnal symptoms or awakening because of asthma

xii
14. Component 3 presents an overall concept for asthma evidence levels2 and plans to review and consider the
management oriented around the new focus on asthma possible introduction of this approach in future reports and
control. Treatment is initiated and adjusted in a continuous extending it to evaluative and diagnostic aspects of care.
cycle (assessing asthma control, treating to achieve
control, and monitoring to maintain control) driven by the
patientʼs level of asthma control. Table A. Description of Levels of Evidence
Evidence Sources of Definition
Category Evidence
15. Treatment options are organized into five “Steps”
A Randomized controlled trials Evidence is from endpoints of
reflecting increasing intensity of treatment (dosages and/or (RCTs). Rich body of data. well designed RCTs that
number of medications) required to achieve control. At all provide a consistent pattern of
findings in the population for
Steps, a reliever medication should be provided for as- which the recommendation
needed use. At Steps 2 through 5, a variety of controller is made. Category A requires
substantial numbers of studies
medications are available. involving substantial numbers
of participants.
16. If asthma is not controlled on the current treatment Randomized controlled trials Evidence is from endpoints of
B
regimen, treatment should be stepped up until control is (RCTs). Limited body of data. intervention studies that
include only a limited number
achieved. When control is maintained, treatment can be of patients, posthoc or
stepped down in order to find the lowest step and dose of subgroup analysis of RCTs, or
meta-analysis of RCTs. In
treatment that maintains control. general, Category B pertains
when few randomized trials
exist, they are small in size,
17. Although each component contains management they were undertaken in a
advice for all age categories where these are considered population that differs from the
target population of the recom-
relevant, special challenges must be taken into account in mendation, or the results are
making recommendations for managing asthma in children somewhat inconsistent.
in the first 5 years of life. Accordingly, an Executive
C Nonrandomized trials. Evidence is from outcomes of
Summary has been prepared—and appears at the end of Observational studies. uncontrolled or nonrandomized
this introduction—that extracts sections on diagnosis and trials or from observational
management for this very young age group. studies.

D Panel consensus judgment. This category is used only in

18. It has been demonstrated in a variety of settings that cases where the provision of
patient care consistent with evidence-based asthma guide- some guidance was deemed
valuable but the clinical
lines leads to improved outcomes. However, in order to literature addressing the
effect changes in medical practice and consequent subject was insufficient to
justify placement in one of the
improvements in patient outcomes, evidence-based other categories. The Panel
guidelines must be implemented and disseminated at Consensus is based on
clinical experience or
national and local levels. Thus, a chapter has been knowledge that does not meet
added on implementation of asthma guidelines in health the above-listed criteria.
systems that details the process and economics of
guideline implementation. REFERENCES
1. Jadad AR, Moher M, Browman GP, Booker L, Sigouis C,
LEVELS OF EVIDENCE Fuentes M, et al. Systematic reviews and meta-analyses
on treatment of asthma: critical evaluation. BMJ
In this document, levels of evidence are assigned to 2000;320:537-40.
management recommendations where appropriate in 2. Guyatt G, Vist G, Falck-Ytter Y, Kunz R, Magrini N,
Chapter 4, the Five Components of Asthma Management. Schunemann H. An emerging consensus on grading
Evidence levels are indicated in boldface type enclosed in recommendations? Available from URL:
parentheses after the relevant statement—e.g., (Evidence A). http://www.evidence-basedmedicine.com.
The methodological issues concerning the use of evidence
from meta-analyses were carefully considered1.

This evidence level scheme (Table A) has been used in

previous GINA reports, and was in use throughout the
preparation of this document. The GINA Science
Committee was recently introduced to a new approach to
xiii
 EXECUTIVE SUMMARY
MANAGING ASTHMA IN CHILDREN 5 YEARS AND YOUNGER
INTRODUCTION of treatment should be to achieve and maintain control
(see Figure 4.3-2) for prolonged periods, with due regard
Since the first asthma guidelines were published more to the safety of treatment, potential for adverse effects,
than 30 years ago, there has been a trend towards produc- and the cost of treatment required to achieve this goal.
ing unified guidelines that apply to all age groups. This
has been prompted by the recognition that common
pathogenic and inflammatory mechanisms underlie all DIAGNOSIS OF ASTHMA IN CHILDREN 5 YEARS AND
asthma, evidence-based literature on the efficacy of key YOUNGER
controller and reliever medications, and an effort to unify
treatment approaches for asthma patients in different age Wheezing and diagnosis of asthma: Diagnosis of asthma
categories. This approach avoids repetition of details that in children 5 years and younger presents a particularly
are common to all patients with asthma. There is relatively difficult problem. This is because episodic wheezing and
little age-specific data on management of asthma in cough are also common in children who do not have
children, and guidelines have tended to extrapolate from asthma, particularly in those under age 3. Wheezing is
evidence gained from adolescents and adults. usually associated with a viral respiratory illness—
predominantly respiratory syncytial virus in children
This revision of the Global Strategy for Asthma younger than age 2, and other viruses in older preschool
Management and Prevention again provides a unified text children. Three categories of wheezing have been
as a source document. Each chapter contains separate described in children 5 years and younger:
sections containing details and management advice for
specific age categories where these are considered • Transient early wheezing, which is often outgrown in
relevant. These age groups include children 5 years and the first 3 years. This is often associated with
younger (sometimes called preschool age), children older prematurity and parental smoking.
than 5 years, adolescents, adults, and the elderly. Most of • Persistent early-onset wheezing (before age 3). These
the differences between these age groups relate to natural children typically have recurrent episodes of wheezing
associated with acute viral respiratory infections, no
history and comorbidities, but there are also important
evidence of atopy, and no family history of atopy.
differences in the approach to diagnosis, measures for
Their symptoms normally persist through school age
assessing severity and monitoring control, responses to
and are still present at age 12 in a large proportion of
different classes of medications, techniques for engaging
children. The cause of wheezing episodes is usually
with the patient and his/her family in establishing and
respiratory syncytial virus in children younger than age 2,
maintaining a treatment plan, and the psychosocial
while other viruses predominate in children ages 2-5.
challenges presented at different stages of life.
• Late-onset wheezing/asthma. These children have
asthma that often persists throughout childhood and
Special challenges that must be taken into account in
into adult life. They typically have an atopic
managing asthma in children in the first 5 years of life background, often with eczema, and airway pathology
include difficulties with diagnosis, the efficacy and safety of that is characteristic of asthma.
drugs and drug delivery systems, and the lack of data on
new therapies. Patients in this age group are often The following categories of symptoms are highly
managed by pediatricians who are routinely faced with a suggestive of a diagnosis of asthma: frequent episodes of
wide variety of issues related to childhood diseases. wheeze (more than once a month), activity-induced cough
Therefore, for the convenience of readers this Executive or wheeze, nocturnal cough in periods without viral
Summary extracts sections of the report that pertain to infections, absence of seasonal variation in wheeze, and
diagnosis and management of asthma in children 5 years symptoms that persist after age 3. A simple clinical index
and younger. These extracts may also be found in the based on the presence of a wheeze before the age of 3,
main text, together with detailed discussion of other and the presence of one major risk factor (parental history
relevant background data on asthma in this age group‡. of asthma or eczema) or two of three minor risk factors
(eosinophilia, wheezing without colds, and allergic rhinitis)
As emphasized throughout the report, for patients in all has been shown to predict the presence of asthma in
age groups with a confirmed diagnosis of asthma, the goal later childhood.
xiv ‡ References and evidence levels are deleted from this extracted material but are provided in the main text.
 Figure 4.3-1. Levels of Asthma Control
Characteristic Controlled Partly Controlled Uncontrolled
(All of the following) (Any measure present in any week)
Daytime symptoms None (twice or less/week) More than twice/week Three or more features
of partly controlled
Limitations of activities None Any asthma present in
Nocturnal symptoms/awakening None Any any week
Need for reliever/ None (twice or less/week) More than twice/week
rescue treatment
Lung function (PEF or FEV1)‡ Normal < 80% predicted or personal best
(if known)
Exacerbations None One or more/year* One in any week†

* Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate.
† By definition, an exacerbation in any week makes that an uncontrolled asthma week.
‡ Lung function is not a reliable test for children 5 years and younger.

Alternative causes of recurrent wheezing must be young children. Children 4 to 5 years old can be taught to
considered and excluded. These include: use a PEF meter, but to ensure accurate results parental
supervision is required.
• Chronic rhino-sinusitis
• Gastroesophageal reflux ASTHMA CONTROL
• Recurrent viral lower respiratory tract infections
• Cystic fibrosis Asthma control refers to control of the clinical
• Bronchopulmonary dysplasia manifestations of disease. A working scheme based on
• Tuberculosis current opinion that has not been validated provides the
• Congenital malformation causing narrowing of the characteristics of controlled, partly controlled and
intrathoracic airways uncontrolled asthma. Complete control of asthma is
• Foreign body aspiration commonly achieved with treatment, the aim of which
• Primary ciliary dyskinesia syndrome should be to achieve and maintain control for prolonged
• Immune deficiency periods, with due regard to the safety of treatment,
• Congenital heart disease potential for adverse effects, and the cost of treatment
required to achieve this goal.
Neonatal onset of symptoms (associated with failure to
thrive), vomiting-associated symptoms, or focal lung or ASTHMA MEDICATIONS
cardiovascular signs suggest an alternative diagnosis and (Detailed background information on asthma
indicate the need for further investigations. medications for children of all ages is included in
Chapter 3.)
Tests for diagnosis and monitoring. In children 5 years
and younger, the diagnosis of asthma has to be based Inhaled therapy is the cornerstone of asthma treatment for
largely on clinical judgment and an assessment of children of all ages. Almost all children can be taught to
symptoms and physical findings. A useful method for effectively use inhaled therapy. Different age groups require
confirming the diagnosis of asthma in this age group is a different inhalers for effective therapy, so the choice of
trial of treatment with short-acting bronchodilators and inhaler must be individualized (Chapter 3, Figure 3-3).
inhaled glucocorticosteroids. Marked clinical improvement
during the treatment and deterioration when it is stopped Controller Medications
supports a diagnosis of asthma. Diagnostic measures
recommended for older children and adults such as Inhaled glucocorticosteroids: Treatment with inhaled
measurement of airway responsiveness, and markers of glucocorticosteroids in children 5 years and younger with
airway inflammation is difficult, requiring complex asthma generally produces similar clinical effects as in
equipment41 that makes them unsuitable for routine use. older children, but dose-response relationships have
Additionally, lung function testing—usually a mainstay of been less well studied. The clinical response to inhaled
asthma diagnosis and monitoring—is often unreliable in glucocorticosteroids may depend on the inhaler chosen

xv
and the childʼ s ability to use the inhaler correctly. With use Component 1 - Develop Patient/Doctor Partnership:
of a spacer device, daily doses ≤ 400 µg of budesonide or Education should be an integral part of all interactions
equivalent result in near-maximum benefits in the majority between health care professionals and patients. Although
of patients. Use of inhaled glucocorticosteroids does not the focus of education for small children will be on the
induce remission of asthma, and symptoms return when parents and caregivers, children as young as 3 years of
treatment is stopped. age can be taught simple asthma management skills.

The clinical benefits of intermittent systemic or inhaled Component 2 - Identify and Reduce Exposure to Risk
glucocorticosteroids for children with intermittent, viral- Factors: Although pharmacologic interventions to treat
induced wheeze remain controversial. While some studies established asthma are highly effective in controlling
in older children have found small benefits, a study in symptoms and improving quality of life, measures to
young children found no effects on wheezing symptoms. prevent the development of asthma, asthma symptoms,
There is no evidence to support the use of maintenance and asthma exacerbations by avoiding or reducing
low-dose inhaled glucocorticosteroids for preventing exposure to risk factors—in particular exposure to tobacco
transient early wheezing. smoke—should be implemented wherever possible.
Leukotriene modifiers: Clinical benefits of monotherapy Children over the age of 3 years with severe asthma
with leukotriene modifiers have been shown in children
should be advised to receive an influenza vaccination
older than age 2. Leukotriene modifiers reduce viral-
every year, or at least when vaccination of the general
induced asthma exacerbations in children ages 2-5 with a
population is advised. However, routine influenza
history of intermittent asthma. No safety concerns have
vaccination of children with asthma does not appear to
been demonstrated from the use of leukotriene modifiers
protect them from asthma exacerbations or improve
in children.
asthma control.
Theophylline: A few studies in children 5 years and
younger suggest some clinical benefit of theophylline. Component 3 - Assess, Treat, and Monitor Asthma:
However, the efficacy of theophylline is less than that of The goal of asthma treatment, to achieve and maintain
low-dose inhaled glucocorticosteroids and the side effects clinical control, can be reached in a majority of patients
are more pronounced. with a pharmacologic intervention strategy developed in
partnership between the patient/family and the doctor. A
Other controller medications: The effect of long-acting treatment strategy is provided in Chapter 4, Component 3
inhaled ␤2-agonists or combination products has not yet - Figure 4.3-2.
been adequately studied in children 5 years and younger.
Studies on the use of cromones in this age group are The available literature on treatment of asthma in children
sparse and the results generally negative. Because of the 5 years and younger precludes detailed treatment
side effects of prolonged use, oral glucocorticosteroids in recommendations. The best documented treatment to
children with asthma should be restricted to the treatment control asthma in these age groups is inhaled glucocortico-
of severe acute exacerbations, whether viral-induced steroids and at Step 2, a low-dose inhaled glucocortico-
or otherwise. steroid is recommended as the initial controller treatment.
Equivalent doses of inhaled glucocorticosteroids, some of
Reliever Medications which may be given as a single daily dose, are provided in
Chapter 3 (Figure 3-4) for children 5 years and younger.
Rapid-acting inhaled ␤2-agonists are the most effective
bronchodilators available and therefore the preferred If low doses of inhaled glucocorticosteroids do not control
treatment for acute asthma in children of all ages. symptoms, an increase in glucocorticosteroid dose may be
the best option. Inhaler techniques should be carefully
ASTHMA MANAGEMENT AND PREVENTION monitored as they may be poor in this age group.

To achieve and maintain asthma control for prolonged Combination therapy, or the addition of a long-acting ␤2-
periods an asthma management and prevention strategy agonist, a leukotriene modifier, or theophylline when a
includes five interrelated components: (1) Develop patientʼs asthma is not controlled on moderate doses of
Patient/Parent/Caregiver/Doctor Partnership; (2) Identify inhaled glucocorticosteroids, has not been studied in
and Reduce Exposure to Risk Factors; (3) Assess, Treat, children 5 years and younger.
and Monitor Asthma; (4) Manage Asthma Exacerbations;
and (5) Special Considerations.

xvi
Intermittent treatment with inhaled glucocorticosteroids is ipratropium bromide to nebulized ␤2-agonist and systemic
at best only marginally effective. The best treatment of glucocorticosteroids appears to confer no extra benefit.
virally induced wheeze in children with transient early
wheezing (without asthma) is not known. None of the In view of the effectiveness and relative safety of rapid-
currently available anti-asthma drugs have shown acting ␤2-agonists, theophylline has a minimal role in the
convincing effects in these children. management of acute asthma. Its use is associated with
severe and potentially fatal side effects, particularly in
Duration of and Adjustments to Treatment those on long-term therapy with slow-release theophylline,
and its bronchodilator effect is less than that of ␤2-agonists.
Asthma like symptoms spontaneously go into remission in In one study of children with near-fatal asthma, intravenous
a substantial proportion of children 5 years and younger. theophylline provided additional benefit to patients also
Therefore, the continued need for asthma treatment in this receiving an aggressive regimen of inhaled and intravenous
age group should be assessed at least twice a year. ␤2-agonists, inhaled ipatropium bromide, and intravenous
systemic glucocorticosteroids. Intravenous magnesium
Component 4 - Manage Asthma Exacerbations: sulphate has not been studied in children 5 years and
Exacerbations of asthma (asthma attacks or acute younger.
asthma) are episodes of progressive increase in shortness
of breath, cough, wheezing, or chest tightness, or some An oral glucocorticosteroid dose of 1 mg/kg daily is
combination of these symptoms. Severe exacerbations adequate for treatment of exacerbations in children with
are potentially life threatening, and their treatment requires mild persistent asthma. A 3- to 5-day course is usually
close supervision. Patients with severe exacerbations considered appropriate. Current evidence suggests that
should be encouraged to see their physician promptly or, there is no benefit to tapering the dose of oral gluco-
depending on the organization of local health services, to corticosteroids, either in the short-term or over several
proceed to the nearest clinic or hospital that provides weeks. Some studies have found that high doses of
emergency access for patients with acute asthma. inhaled glucocorticosteroids administered frequently
during the day are effective in treating exacerbations,
Assessment: Several differences in lung anatomy and but more studies are needed before this strategy can
physiology place infants at theoretically greater risk than be recommended.
older children for respiratory failure. Despite this,
respiratory failure is rare in infancy. Close monitoring, For children admitted to an acute care facility for an
using a combination of the parameters other than PEF exacerbation, criteria for determining whether they should
(Chapter 4, Component 4: Figure 4.4-1), will permit a be discharged from the emergency department or
fairly accurate assessment. Breathlessness sufficiently admitted to the hospital are provided in Chapter 4,
severe to prevent feeding is an important symptom of Component 4.
impending respiratory failure.

Oxygen saturation, which should be measured in infants

by pulse oximetry, is normally greater than 95 percent.
Arterial or arterialized capillary blood gas measurement
should be considered in infants with oxygen saturation
less than 90 percent on high-flow oxygen whose
condition is deteriorating. Routine chest X-rays are not
recommended unless there are physical signs suggestive
of parenchymal disease.

Treatment: To achieve arterial oxygen saturation of

≥ 95%, oxygen should be administered by nasal cannulae,
by mask, or rarely by head box in some infants. Rapid-
acting inhaled ␤2-agonists should be administered at
regular intervals. Combination ␤2-agonist/anticholinergic
therapy is associated with lower hospitalization rates and
greater improvement in PEF and FEV1. However, once
children with asthma are hospitalized following intensive
emergency department treatment, the addition of nebulized
xvii
 CHAPTER

DEFINITION

AND

OVERVIEW
 Wheezing appreciated on auscultation of the chest is the
KEY POINTS: most common physical finding.
• Asthma is a chronic inflammatory disorder of the
airways in which many cells and cellular elements The main physiological feature of asthma is episodic airway
play a role. The chronic inflammation is associated obstruction characterized by expiratory airflow limitation.
with airway hyperresponsiveness that leads to The dominant pathological feature is airway inflammation,
recurrent episodes of wheezing, breathlessness, sometimes associated with airway structural changes.
chest tightness, and coughing, particularly at night
or in the early morning. These episodes are usually Asthma has significant genetic and environmental
associated with widespread, but variable, airflow components, but since its pathogenesis is not clear, much
obstruction within the lung that is often reversible of its definition is descriptive. Based on the functional
either spontaneously or with treatment. consequences of airway inflammation, an operational
description of asthma is:
• Clinical manifestations of asthma can be controlled
with appropriate treatment. When asthma is Asthma is a chronic inflammatory disorder of the airways
controlled, there should be no more than occasional in which many cells and cellular elements play a role.
flare-ups and severe exacerbations should be rare. The chronic inflammation is associated with airway
hyperresponsiveness that leads to recurrent episodes of
• Asthma is a problem worldwide, with an estimated wheezing, breathlessness, chest tightness, and coughing,
300 million affected individuals. particularly at night or in the early morning. These
episodes are usually associated with widespread, but
• Although from the perspective of both the patient and variable, airflow obstruction within the lung that is often
society the cost to control asthma seems high, the reversible either spontaneously or with treatment.
cost of not treating asthma correctly is even higher.
Because there is no clear definition of the asthma
• A number of factors that influence a personʼs risk of phenotype, researchers studying the development of this
developing asthma have been identified. These can complex disease turn to characteristics that can be
be divided into host factors (primarily genetic) and measured objectively, such as atopy (manifested as the
environmental factors. presence of positive skin-prick tests or the clinical
response to common environmental allergens), airway
• The clinical spectrum of asthma is highly variable, hyperresponsiveness (the tendency of airways to narrow
and different cellular patterns have been observed, excessively in response to triggers that have little or no
but the presence of airway inflammation remains a effect in normal individuals), and other measures of
consistent feature. allergic sensitization. Although the association between
asthma and atopy is well established, the precise links
between these two conditions have not been clearly and
comprehensively defined.
This chapter covers several topics related to asthma,
including definition, burden of disease, factors that influence There is now good evidence that the clinical manifestations
the risk of developing asthma, and mechanisms. It is not of asthma—symptoms, sleep disturbances, limitations of
intended to be a comprehensive treatment of these topics, daily activity, impairment of lung function, and use of
but rather a brief overview of the background that informs rescue medications—can be controlled with appropriate
the approach to diagnosis and management detailed in treatment. When asthma is controlled, there should be no
subsequent chapters. Further details are found in the more than occasional recurrence of symptoms and severe
reviews and other references cited at the end of the chapter. exacerbations should be rare1.

DEFINITION

Asthma is a disorder defined by its clinical, physiological,

and pathological characteristics. The predominant feature
of the clinical history is episodic shortness of breath,
particularly at night, often accompanied by cough.

2 DEFINITION AND OVERVIEW

 Social and Economic Burden
THE BURDEN OF ASTHMA
Prevalence, Morbidity, and Mortality Social and economic factors are integral to understanding
asthma and its care, whether viewed from the perspective
Asthma is a problem worldwide, with an estimated 300 of the individual sufferer, the health care professional, or
million affected individuals2,3. Despite hundreds of reports entities that pay for health care. Absence from school and
on the prevalence of asthma in widely differing days lost from work are reported as substantial social and
populations, the lack of a precise and universally accepted economic consequences of asthma in studies from the
definition of asthma makes reliable comparison of reported Asia-Pacific region, India, Latin America, the United
prevalence from different parts of the world problematic. Kingdom, and the United States9-12.
Nonetheless, based on the application of standardized
methods to measure the prevalence of asthma and The monetary costs of asthma, as estimated in a variety
wheezing illness in children3 and adults4, it appears that of health care systems including those of the United
the global prevalence of asthma ranges from 1% to 18% of States13-15 and the United Kingdom16 are substantial.
the population in different countries (Figure 1-1)2,3. There In analyses of economic burden of asthma, attention
is good evidence that international differences in asthma needs to be paid to both direct medical costs (hospital
symptom prevalence have been reduced, particularly in admissions and cost of medications) and indirect, non-
the 13-14 year age group, with decreases in prevalence in medical costs (time lost from work, premature death)17.
North America and Western Europe and increases in For example, asthma is a major cause of absence from
prevalence in regions where prevalence was previously work in many countries4-6,121, including Australia, Sweden,
low. Although there was little change in the overall the United Kingdom, and the United States16,18-20.
prevalence of current wheeze, the percentage of children Comparisons of the cost of asthma in different regions
reported to have had asthma increased significantly, possi- lead to a clear set of conclusions:
bly reflecting greater awareness of this condition and/or
changes in diagnostic practice. The increases in asthma • The costs of asthma depend on the individual patientʼs
symptom prevalence in Africa, Latin America and parts of level of control and the extent to which exacerbations
Asia indicate that the global burden of asthma is are avoided.
continuing to rise, but the global prevalence differences • Emergency treatment is more expensive than planned
are lessening126. The World Health Organization has treatment.
estimated that 15 million disability-adjusted life years
• Non-medical economic costs of asthma are substantial.
(DALYs) are lost annually due to asthma, representing 1%
of the total global disease burden2. Annual worldwide • Guideline-determined asthma care can be cost effective.
deaths from asthma have been estimated at 250,000 and • Families can suffer from the financial burden of treating
mortality does not appear to correlate well with prevalence asthma.
(Figure 1-1)2,3. There are insufficient data to determine the
likely causes of the described variations in prevalence Although from the perspective of both the patient and
within and between populations. society the cost to control asthma seems high, the cost of
not treating asthma correctly is even higher122. Proper
Figure 1-1. Asthma Prevalence and Mortality2, 3
treatment of the disease poses a challenge for individuals,
health care professionals, health care organizations, and
governments. There is every reason to believe that the
substantial global burden of asthma can be dramatically
reduced through efforts by individuals, their health care
providers, health care organizations, and local and
national governments to improve asthma control.

Detailed reference information about the burden of asthma

can be found in the report Global Burden of Asthma* .
Further studies of the social and economic burden of
asthma and the cost effectiveness of treatment are needed
in both developed and developing countries.

*(http://www.ginasthma.org/ReportItem.asp?l1=2&l2=2&intId=94).
Permission for use of this figure obtained from J. Bousquet.

DEFINITION AND OVERVIEW 3

 asthma in developed than in developing nations, in poor
FACTORS INFLUENCING THE compared to affluent populations in developed nations,
DEVELOPMENT AND EXPRESSION and in affluent compared to poor populations in developing
OF ASTHMA nations—likely reflect lifestyle differences such as
exposure to allergens, access to health care, etc.

Factors that influence the risk of asthma can be divided Much of what is known about asthma risk factors comes
into those that cause the development of asthma and from studies of young children. Risk factors for the
those that trigger asthma symptoms; some do both. development of asthma in adults, particularly de novo in
The former include host factors (which are primarily adults who did not have asthma in childhood, are less
genetic) and the latter are usually environmental factors well defined.
(Figure 1-2)21. However, the mechanisms whereby they
influence the development and expression of asthma are The lack of a clear definition for asthma presents a
complex and interactive. For example, genes likely significant problem in studying the role of different risk
interact both with other genes and with environmental factors in the development of this complex disease,
factors to determine asthma susceptibility22,23. In addition, because the characteristics that define asthma (e.g.,
developmental aspects—such as the maturation of the airway hyperresponsiveness, atopy, and allergic
immune response and the timing of infectious exposures sensitization) are themselves products of complex
during the first years of life—are emerging as important gene-environment interactions and are therefore both
factors modifying the risk of asthma in the genetically features of asthma and risk factors for the development
susceptible person. of the disease.

Host Factors
Figure 1-2. Factors Influencing the Development
and Expression of Asthma Genetic. Asthma has a heritable component, but it is not
simple. Current data show that multiple genes may be
HOST FACTORS involved in the pathogenesis of asthma24,25, and different
Genetic, e.g., genes may be involved in different ethnic groups. The
• Genes pre-disposing to atopy search for genes linked to the development of asthma has
• Genes pre-disposing to airway hyperresponsiveness focused on four major areas: production of allergen-
Obesity specific IgE antibodies (atopy); expression of airway
Sex hyperresponsiveness; generation of inflammatory
mediators, such as cytokines, chemokines, and growth
ENVIRONMENTAL FACTORS factors; and determination of the ratio between Th1 and
Allergens Th2 immune responses (as relevant to the hygiene
• Indoor: Domestic mites, furred animals (dogs, cats, hypothesis of asthma)26.
mice), cockroach allergen, fungi, molds, yeasts
• Outdoor: Pollens, fungi, molds, yeasts Family studies and case-control association analyses have
Infections (predominantly viral) identified a number of chromosomal regions associated
Occupational sensitizers with asthma susceptibility. For example, a tendency to
Tobacco smoke produce an elevated level of total serum IgE is co-inherited
• Passive smoking with airway hyperresponsiveness, and a gene (or genes)
• Active smoking governing airway hyperresponsiveness is located near a
Outdoor/Indoor Air Pollution major locus that regulates serum IgE levels on
Diet chromosome 5q27. However, the search for a specific
gene (or genes) involved in susceptibility to atopy or
Additionally, some characteristics have been linked to an asthma continues, as results to date have been
increased risk for asthma, but are not themselves true inconsistent24,25.
causal factors. The apparent racial and ethnic differences
in the prevalence of asthma reflect underlying genetic In addition to genes that predispose to asthma there are
variances with a significant overlay of socioeconomic and genes that are associated with the response to asthma
environmental factors. In turn, the links between asthma treatments. For example, variations in the gene encoding
and socioeconomic status—with a higher prevalence of the beta-adrenoreceptor have been linked to differences in

4 DEFINITION AND OVERVIEW

subjectsʼ responses to ␤2-agonists28. Other genes of In the case of dogs and cats, some epidemiologic studies
interest modify the responsiveness to glucocorticosteroids29 have found that early exposure to these animals may protect
and leukotriene modifiers30. These genetic markers will a child against allergic sensitization or the development of
likely become important not only as risk factors in the asthma46-48, but others suggest that such exposure may
pathogenesis of asthma but also as determinants of increase the risk of allergic sensitization47,49-51. This issue
responsiveness to treatment28,30-33. remains unresolved.

Obesity. Obesity has also been shown to be a risk factor The prevalence of asthma is reduced in children raised in
for asthma. Certain mediators such as leptins may affect a rural setting, which may be linked to the presence of
airway function and increase the likelihood of asthma endotoxin in these environments52.
development34,35.
Infections. During infancy, a number of viruses have been
Sex. Male sex is a risk factor for asthma in children. Prior associated with the inception of the asthmatic phenotype.
to the age of 14, the prevalence of asthma is nearly twice Respiratory syncytial virus (RSV) and parainfluenza virus
as great in boys as in girls36. As children get older the produce a pattern of symptoms including bronchiolitis that
difference between the sexes narrows, and by adulthood parallel many features of childhood asthma53,54. A number
the prevalence of asthma is greater in women than in men. of long-term prospective studies of children admitted to the
The reasons for this sex-related difference are not clear. hospital with documented RSV have shown that
However, lung size is smaller in males than in females at approximately 40% will continue to wheeze or have
birth37 but larger in adulthood. asthma into later childhood53. On the other hand, evidence
also indicates that certain respiratory infections early in life,
Environmental Factors including measles and sometimes even RSV, may protect
against the development of asthma55,56. The data do not
There is some overlap between environmental factors that allow specific conclusions to be drawn. Parasite infections
influence the risk of developing asthma, and factors that do not in general protect against asthma, but infection with
cause asthma symptoms—for example, occupational hookworm may reduce the risk123.
sensitizers belong in both categories. However, there are
The “hygiene hypothesis” of asthma suggests that exposure
some important causes of asthma symptoms—such as air
to infections early in life influences the development of a
pollution and some allergens—which have not been clearly
childʼ s immune system along a “nonallergic” pathway, leading
linked to the development of asthma. Risk factors that
to a reduced risk of asthma and other allergic diseases.
cause asthma symptoms are discussed in detail in
Although the hygiene hypothesis continues to be investigated,
Chapter 4.2.
this mechanism may explain observed associations between
family size, birth order, day-care attendance, and the risk of
Allergens. Although indoor and outdoor allergens are well asthma. For example, young children with older siblings and
known to cause asthma exacerbations, their specific role those who attend day care are at increased risk of infections,
in the development of asthma is still not fully resolved. but enjoy protection against the development of allergic
Birth-cohort studies have shown that sensitization to house diseases, including asthma later in life57-59.
dust mite allergens, cat dander, dog dander38,39, and
Aspergillus mold40 are independent risk factors for asthma- The interaction between atopy and viral infections appears
like symptoms in children up to 3 years of age. However, to be a complex relationship60, in which the atopic state can
the relationship between allergen exposure and influence the lower airway response to viral infections, viral
sensitization in children is not straightforward. It depends infections can then influence the development of allergic
on the allergen, the dose, the time of exposure, the childʼs sensitization, and interactions can occur when individuals
age, and probably genetics as well. are exposed simultaneously to both allergens and viruses.

For some allergens, such as those derived from house Occupational sensitizers. Over 300 substances have
dust mites and cockroaches, the prevalence of been associated with occupational asthma61-65, which is
sensitization appears to be directly correlated with defined as asthma caused by exposure to an agent
exposure38,41. However, although some data suggest that encountered in the work environment. These substances
exposure to house dust mite allergens may be a causal include highly reactive small molecules such as
factor in the development of asthma42, other studies have isocyanates, irritants that may cause an alteration in
questioned this interpretation43,44. Cockroach infestation airway responsiveness, known immunogens such as
has been shown to be an important cause of allergic platinum salts, and complex plant and animal biological
sensitization, particularly in inner-city homes45. products that stimulate the production of IgE (Figure 1-3).

DEFINITION AND OVERVIEW 5

 others to develop occupational asthma in response to the
Figure 1-3. Examples of Agents Causing Asthma in
Selected Occupations* same exposures are not well identified. Very high
exposures to inhaled irritants may cause “irritant induced
Occupation/occupational field Agent asthma” (formerly called the reactive airways dysfunctional
Animal and Plant Proteins syndrome) even in non-atopic persons. Atopy and
Bakers Flour, amylase tobacco smoking may increase the risk of occupational
Dairy farmers Storage mites sensitization, but screening individuals for atopy is of
Detergent manufacturing Bacillus subtilis enzymes limited value in preventing occupational asthma73. The
Electrical soldering Colophony (pine resin)
most important method of preventing occupational asthma
Farmers Soybean dust
is elimination or reduction of exposure to occupational
Fish food manufacturing Midges, parasites
sensitizers.
Food processing Coffee bean dust, meat tenderizer, tea, shellfish,
amylase, egg proteins, pancreatic enzymes,
papain Tobacco smoke. Tobacco smoking is associated with
Granary workers Storage mites, Aspergillus, indoor ragweed, grass
accelerated decline of lung function in people with asthma,
Health care workers Psyllium, latex
increases asthma severity, may render patients less
Laxative manufacturing Ispaghula, psyllium
responsive to treatment with inhaled74,124 and systemic75
Poultry farmers Poultry mites, droppings, feathers
Research workers, veterinarians Locusts, dander, urine proteins
glucocorticosteroids, and reduces the likelihood of asthma
Sawmill workers, carpenters Wood dust (western red cedar, oak, mahogany, being controlled76.
zebrawood, redwood, Lebanon cedar, African
maple, eastern white cedar)
Exposure to tobacco smoke both prenatally and after birth
Shipping workers Grain dust (molds, insects, grain)
is associated with measurable harmful effects including a
Silk workers Silk worm moths and larvae
Inorganic chemicals
greater risk of developing asthma-like symptoms in early
Beauticians Persulfate childhood. However, evidence of increased risk of allergic
Plating Nickel salts diseases is uncertain77, 78. Distinguishing the independent
Refinery workers Platinum salts, vanadium contributions of prenatal and postnatal maternal smoking
Organic chemicals is problematic79. However, studies of lung function
Automobile painting Ethanolamine, dissocyanates immediately after birth have shown that maternal smoking
Hospital workers Disinfectants (sulfathiazole, chloramines, during pregnancy has an influence on lung development37.
formaldehyde, glutaraldehyde), latex
Furthermore, infants of smoking mothers are 4 times more
Manufacturing Antibiotics, piperazine, methyldopa, salbutamol,
cimetidine likely to develop wheezing illnesses in the first year of life80.
Rubber processing Formaldehyde, ethylene diamine, phthalic anhydride In contrast, there is little evidence (based on meta-
Plastics industry Toluene dissocyanate, hexamethyl dissocyanate, analysis) that maternal smoking during pregnancy has an
dephenylmethyl isocyanate, phthalic anhydride,
triethylene tetramines, trimellitic anhydride, effect on allergic sensitization78. Exposure to
hexamethyl tetramine, acrylates environmental tobacco smoke (passive smoking)
*See http://www.bohrf.org.uk for a comprehensive list of known sensitizing agents
increases the risk of lower respiratory tract illnesses in
infancy81 and childhood82.
Occupational asthma arises predominantly in adults66, 67,
Outdoor/indoor air pollution. The role of outdoor air
and occupational sensitizers are estimated to cause about
pollution in causing asthma remains controversial83.
1 in 10 cases of asthma among adults of working age68.
Children raised in a polluted environment have diminished
Asthma is the most common occupational respiratory
lung function84, but the relationship of this loss of function
disorder in industrialized countries69. Occupations
to the development of asthma is not known.
associated with a high risk for occupational asthma include
farming and agricultural work, painting (including spray
Outbreaks of asthma exacerbations have been shown to
painting), cleaning work, and plastic manufacturing62.
occur in relationship to increased levels of air pollution,
and this may be related to a general increase in the level
Most occupational asthma is immunologically mediated
of pollutants or to specific allergens to which individuals
and has a latency period of months to years after the onset
are sensitized85-87. However, the role of pollutants in the
of exposure70. IgE-mediated allergic reactions and cell-
development of asthma is less well defined. Similar
mediated allergic reactions are involved71, 72.
associations have been observed in relation to indoor
pollutants, e.g., smoke and fumes from gas and biomass
Levels above which sensitization frequently occurs have
fuels used for heating and cooling, molds, and cockroach
been proposed for many occupational sensitizers.
infestations.
However, the factors that cause some people but not

6 DEFINITION AND OVERVIEW

Diet. The role of diet, particularly breast-feeding, in
Figure 1-4: Inflammatory Cells in Asthmatic Airways
relation to the development of asthma has been
extensively studied and, in general, the data reveal that Mast cells: Activated mucosal mast cells release
infants fed formulas of intact cow's milk or soy protein have bronchoconstrictor mediators (histamine, cysteinyl leukotrienes,
a higher incidence of wheezing illnesses in early childhood prostaglandin D2)93. These cells are activated by allergens
compared with those fed breast milk88. through high-affinity IgE receptors, as well as by osmotic stimuli
(accounting for exercise-induced bronchoconstriction). Increased
Some data also suggest that certain characteristics of mast cell numbers in airway smooth muscle may be linked to
airway hyperresponsiveness94.
Western diets, such as increased use of processed foods
and decreased antioxidant (in the form of fruits and vegetables), Eosinophils, present in increased numbers in the airways,
increased n-6 polyunsaturated fatty acid (found in margarine release basic proteins that may damage airway epithelial cells.
and vegetable oil), and decreased n-3 polyunsaturated They may also have a role in the release of growth factors and
airway remodeling95.
fatty acid (found in oily fish) intakes have contributed to
the recent increases in asthma and atopic disease89. T lymphocytes, present in increased numbers in the airways,
release specific cytokines, including IL-4, IL-5, IL-9, and IL-13,
that orchestrate eosinophilic inflammation and IgE production by
MECHANISMS OF ASTHMA B lymphocytes96. An increase in Th2 cell activity may be due in
part to a reduction in regulatory T cells that normally inhibit Th2
cells. There may also be an increase in inKT cells, which release
Asthma is an inflammatory disorder of the airways, which large amounts of T helper 1 (Th1) and Th2 cytokines97.
involves several inflammatory cells and multiple mediators Dendritic cells sample allergens from the airway surface and
that result in characteristic pathophysiological changes21,90. migrate to regional lymph nodes, where they interact with
In ways that are still not well understood, this pattern of regulatory T cells and ultimately stimulate production of Th2
inflammation is strongly associated with airway hyper- cells from naïve T cells98.
responsiveness and asthma symptoms. Macrophages are increased in number in the airways and may
be activated by allergens through low-affinity IgE receptors to
Airway Inflammation In Asthma release inflammatory mediators and cytokines that amplify the
inflammatory response99.
The clinical spectrum of asthma is highly variable, and Neutrophil numbers are increased in the airways and sputum of
different cellular patterns have been observed, but the patients with severe asthma and in smoking asthmatics, but the
presence of airway inflammation remains a consistent pathophysiological role of these cells is uncertain and their
feature. The airway inflammation in asthma is persistent increase may even be due to glucocorticosteroid therapy100.
even though symptoms are episodic, and the relationship
between the severity of asthma and the intensity of
inflammation is not clearly established91,92. The Figure 1-5: Airway Structural Cells Involved in the
Pathogenesis of Asthma
inflammation affects all airways including in most patients
the upper respiratory tract and nose but its physiological Airway epithelial cells sense their mechanical environment,
effects are most pronounced in medium-sized bronchi. express multiple inflammatory proteins in asthma, and release
The pattern of inflammation in the airways appears to be cytokines, chemokines, and lipid mediators. Viruses and air
similar in all clinical forms of asthma, whether allergic, pollutants interact with epithelial cells.
non-allergic, or aspirin-induced, and at all ages.
Airway smooth muscle cells express similar inflammatory
proteins to epithelial cells101.
Inflammatory cells. The characteristic pattern of
inflammation found in allergic diseases is seen in asthma, Endothelial cells of the bronchial circulation play a role in
recruiting inflammatory cells from the circulation into the airway.
with activated mast cells, increased numbers of activated
eosinophils, and increased numbers of T cell receptor Fibroblasts and myofibroblasts produce connective tissue
invariant natural killer T cells and T helper 2 lymphocytes components, such as collagens and proteoglycans, that are
(Th2), which release mediators that contribute to involved in airway remodeling.
symptoms (Figure 1-4). Structural cells of the airways Airway nerves are also involved. Cholinergic nerves may be
also produce inflammatory mediators, and contribute to the activated by reflex triggers in the airways and cause
persistence of inflammation in various ways (Figure 1-5). bronchoconstriction and mucus secretion. Sensory nerves,
which may be sensitized by inflammatory stimuli including
Inflammatory mediators. Over 100 different mediators are neurotrophins, cause reflex changes and symptoms such as
cough and chest tightness, and may release inflammatory
now recognized to be involved in asthma and mediate the
neuropeptides102.
complex inflammatory response in the airways103 (Figure 1-6).

DEFINITION AND OVERVIEW 7

 Pathophysiology
Figure 1-6: Key Mediators of Asthma

Chemokines are important in the recruitment of inflammatory Airway narrowing is the final common pathway leading to
cells into the airways and are mainly expressed in airway symptoms and physiological changes in asthma. Several
epithelial cells104. Eotaxin is relatively selective for eosinophils, factors contribute to the development of airway narrowing
whereas thymus and activation-regulated chemokines (TARC) in asthma (Figure 1-8).
and macrophage-derived chemokines (MDC) recruit Th2 cells.
Cysteinyl leukotrienes are potent bronchoconstrictors and Figure 1-8: Airway Narrowing in Asthma
proinflammatory mediators mainly derived from mast cells and eosinophils.
They are the only mediator whose inhibition has been associated
Airway smooth muscle contraction in response to multiple
with an improvement in lung function and asthma symptoms105.
bronchoconstrictor mediators and neurotransmitters is the
Cytokines orchestrate the inflammatory response in asthma and predominant mechanism of airway narrowing and is largely
determine its severity106. Key cytokines include IL-1␤ and TNF-oc, reversed by bronchodilators.
which amplify the inflammatory response, and GM-CSF, which Airway edema is due to increased microvascular leakage in
prolongs eosinophil survival in the airways. Th2-derived cytokines response to inflammatory mediators. This may be particularly
include IL-5, which is required for eosinophil differentiation and important during acute exacerbations.
survival; IL-4, which is important for Th2 cell differentiation; and
IL-13, needed for IgE formation. Airway thickening due to structural changes, often termed
“remodeling,” may be important in more severe disease and is
Histamine is released from mast cells and contributes to not fully reversible by current therapy.
bronchoconstriction and to the inflammatory response.
Mucus hypersecretion may lead to luminal occlusion (“mucus
Nitric oxide (NO), a potent vasodilator, is produced predominantly plugging”) and is a product of increased mucus secretion and
from the action of inducible nitric oxide synthase in airway epithelial inflammatory exudates.
cells107. Exhaled NO is increasingly being used to monitor the
effectiveness of asthma treatment, because of its reported
association with the presence of inflammation in asthma108. Airway hyperresponsiveness. Airway hyperresponsive-
Prostaglandin D2 is a bronchoconstrictor derived predominantly ness, the characteristic functional abnormality of asthma,
from mast cells and is involved in Th2 cell recruitment to the airways. results in airway narrowing in a patient with asthma in
response to a stimulus that would be innocuous in a
Structural changes in the airways. In addition to the normal person In turn, this airway narrowing leads to
inflammatory response, there are characteristic structural variable airflow limitation and intermittent symptoms. Airway
changes, often described as airway remodeling, in the hyperresponsiveness is linked to both inflammation and re-
airways of asthma patients (Figure 1-7). Some of these pair of the airways and is partially reversible with therapy.
changes are related to the severity of the disease and may Its mechanisms (Figure 1-9) are incompletely understood.
result in relatively irreversible narrowing of the airways109, 110.
These changes may represent repair in response to Figure 1-9: Mechanisms of Airway Hyperresponsiveness
chronic inflammation.
Excessive contraction of airway smooth muscle may result
Figure 1-7: Structural Changes in Asthmatic Airways from increased volume and/or contractility of airway smooth
muscle cells112.
Subepithelial fibrosis results from the deposition of collagen fibers
Uncoupling of airway contraction as a result of inflammatory
and proteoglycans under the basement membrane and is seen in
changes in the airway wall may lead to excessive narrowing of the
all asthmatic patients, including children, even before the onset of
airways and a loss of the maximum plateau of contraction found in
symptoms but may be influenced by treatment. Fibrosis occurs in
normal ariways when bronchoconstrictor substances are inhaled113.
other layers for the airway wall, with deposition of collagen and
proteoglycans. Thickening of the airway wall by edema and structural changes
amplifies airway narrowing due to contraction of airway smooth
Airway smooth muscle increases, due both to hypertrophy
muscle for geometric reasons114.
(increased size of individual cells) and hyperplasia (increased cell
division), and contributes to the increased thickness of the airway Sensory nerves may be sensitized by inflammation, leading to
wall111. This process may relate to disease severity and is caused exaggerated bronchoconstriction in response to sensory stimuli.
by inflammatory mediators, such as growth factors.
Blood vessels in airway walls proliferate the influence of growth Special Mechanisms
factors such as vascular endothelial growth factor (VEGF) and
may contribute to increased airway wall thickness.
Acute exacerbations. Transient worsening of asthma
Mucus hypersecretion results from increased numbers of goblet may occur as a result of exposure to risk factors for
cells in the airway epithelium and increased size of submucosal asthma symptoms, or “triggers,” such as exercise, air
glands.

8 DEFINITION AND OVERVIEW

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125. Chaudhuri R, Livingston E, McMahon AD, Lafferty J, Fraser I,

Spears M, McSharry CP, Thomson NC. Effects of smoking
cessation on lung function and airway inflammation in smokers
with asthma. Am J Respir Crit Care Med 2006 Jul
15;174(2):127-33.

126. Pearce N, Aït-Khaled N, Beasley R, Mallol J, Keil U, Mitchell E,

Robertson C; and the ISAAC Phase Three Study Group.
Worldwide trends in the prevalence of asthma symptoms:
phase III of the International Study of Asthma and Allergies in
Childhood (ISAAC). Thorax 2007 Sep;62(9):758-66. Epub
2007 May 15.

DEFINITION AND OVERVIEW 13

14 DEFINITION AND OVERVIEW
 CHAPTER

DIAGNOSIS

AND

CLASSIFICATION
 KEY POINTS: CLINICAL DIAGNOSIS
• A clinical diagnosis of asthma is often prompted
by symptoms such as episodic breathlessness, Medical History
wheezing, cough, and chest tightness.
Symptoms. A clinical diagnosis of asthma is often prompted
• Measurements of lung function (spirometry or peak by symptoms such as episodic breathlessness, wheezing,
expiratory flow) provide an assessment of the severity cough, and chest tightness1. Episodic symptoms after an
of airflow limitation, its reversibility, and its variability, incidental allergen exposure, seasonal variability of
and provide confirmation of the diagnosis of asthma. symptoms and a positive family history of asthma and
atopic disease are also helpful diagnostic guides. Asthma
• Measurements of allergic status can help to identify associated with rhinitis may occur intermittently, with the
risk factors that cause asthma symptoms in patient being entirely asymptomatic between seasons or it
individual patients. may involve seasonal worsening of asthma symptoms or
a background of persistent asthma. The patterns of these
• Extra measures may be required to diagnose symptoms that strongly suggest an asthma diagnosis are
asthma in children 5 years and younger and in the variability; precipitation by non-specific irritants, such as
elderly, and occupational asthma. smoke, fumes, strong smells, or exercise; worsening at
night; and responding to appropriate asthma therapy.
• For patients with symptoms consistent with asthma, Useful questions to consider when establishing a
but normal lung function, measurement of airway diagnosis of asthma are described in Figure 2-1.
responsiveness may help establish the diagnosis.
Figure 2-1. Questions to Consider in the Diagnosis
• Asthma has been classified by severity in previous of Asthma
reports. However, asthma severity may change over • Has the patient had an attack or recurrent attacks of wheezing?
time, and depends not only on the severity of the • Does the patient have a troublesome cough at night?
underlying disease but also its responsiveness to • Does the patient wheeze or cough after exercise?
treatment. • Does the patient experience wheezing, chest tightness, or
cough after exposure to airborne allergens or pollutants?
• To aid in clinical management, a classification of • Do the patient's colds “go to the chest” or take more than 10
asthma by level of control is recommended. days to clear up?
• Are symptoms improved by appropriate asthma treatment?
• Clinical control of asthma is defined as:
In some sensitized individuals, asthma may be
- No (twice or less/week) daytime symptoms exacerbated by seasonal increases in specific
- No limitations of daily activites, inlcuding exercise aeroallergens2. Examples include Alternaria, and birch,
- No nocturnal symptoms or awakening because grass, and ragweed pollens.
of asthma
- No (twice or less/week) need for reliever treatment Cough-variant asthma. Patients with cough-variant
- Normal or near-normal lung function asthma3 have chronic cough as their principal, if not only,
- No exacerbations symptom. It is particularly common in children, and is
often more problematic at night; evaluations during the
day can be normal. For these patients, documentation of
variability in lung function or of airway hyperresponsiveness,
INTRODUCTION and possibly a search for sputum eosinophils, are
particularly important4. Cough-variant asthma must be
A correct diagnosis of asthma is essential if appropriate distinguished from so-called eosinophilic bronchitis in
drug therapy is to be given. Asthma symptoms may be which patients have cough and sputum eoinophils but
intermittent and their significance may be overlooked by normal indices of lung function when assessed by
patients and physicians, or, because they are non-specific, spirometry and airway hyperresponsiveness5.
they may result in misdiagnosis (for example of wheezy
bronchitis, COPD, or the breathlessness of old age). This Other diagnoses to be considered are cough-induced by
is particularly true among children, where misdiagnoses angiotensin-converting-enzyme (ACE) inhibitors,
include various forms of bronchitis or croup, and lead to gastroesophageal reflux, postnasal drip, chronic sinusitis,
inappropriate treatment. and vocal cord dysfunction6.

16 DIAGNOSIS AND CLASSIFICATION

Exercise-induced bronchoconstriction. Physical Tests for Diagnosis and Monitoring
activity is an important cause of asthma symptoms for
most asthma patients, and for some it is the only cause. Measurements of lung function. The diagnosis of
Exercise-induced bronchoconstriction typically develops asthma is usually based on the presence of characteristic
within 5-10 minutes after completing exercise (it rarely symptoms. However, measurements of lung function,
occurs during exercise). Patients experience typical and particularly the demonstration of reversibility of lung
asthma symptoms, or sometimes a troublesome cough, function abnormalities, greatly enhance diagnostic
which resolve spontaneously within 30-45 minutes. Some confidence. This is because patients with asthma
forms of exercise, such as running, are more potent frequently have poor recognition of their symptoms and
triggers7. Exercise-induced bronchoconstriction may occur poor perception of symptom severity, especially if their
in any climatic condition, but it is more common when the asthma is long-standing10. Assessment of symptoms such
patient is breathing dry, cold air and less common in hot, as dyspnea and wheezing by physicians may also be
humid climates8. inaccurate. Measurement of lung function provides an
assessment of the severity of airflow limitation, its
Rapid improvement of post-exertional symptoms after reversibility and its variability, and provides confirmation of
inhaled ␤2-agonist use, or their prevention by pretreatment the diagnosis of asthma. Although measurements of lung
with an inhaled ␤2-agonist before exercise, supports a function do not correlate strongly with symptoms or other
diagnosis of asthma. Some children with asthma present measures of disease control in either adults11 or children12,
only with exercise-induced symptoms. In this group, or these measures provide complementary information about
when there is doubt about the diagnosis, exercise testing different aspects of asthma control.
is helpful. An 8-minute running protocol is easily
performed in clinical practice and can establish a firm Various methods are available to assess airflow limitation,
diagnosis of asthma9. but two methods have gained widespread acceptance for
use in patients over 5 years of age. These are spirometry,
Physical Examination particularly the measurement of forced expiratory volume
in 1 second (FEV1) and forced vital capacity (FVC), and
Because asthma symptoms are variable, the physical peak expiratory flow (PEF) measurement.
examination of the respiratory system may be normal.
The most usual abnormal physical finding is wheezing on Predicted values of FEV1, FVC, and PEF based on age,
auscultation, a finding that confirms the presence of airflow sex, and height have been obtained from population
limitation. However, in some people with asthma, studies. These are being continually revised, and with the
wheezing may be absent or only detected when the exception of PEF for which the range of predicted values is
person exhales forcibly, even in the presence of significant too wide, they are useful for judging whether a given value
airflow limitation. Occasionally, in severe asthma is abnormal or not.
exacerbations, wheezing may be absent owing to severely
reduced airflow and ventilation. However, patients in this The terms reversibility and variability refer to changes in
state usually have other physical signs reflecting the symptoms accompanied by changes in airflow limitation
exacerbation and its severity, such as cyanosis, drowsiness, that occur spontaneously or in response to treatment. The
difficulty speaking, tachycardia, hyperinflated chest, use of term reversibility is generally applied to rapid improvements
accessory muscles, and intercostal recession. in FEV1 (or PEF), measured within minutes after inhalation
of a rapid-acting bronchodilator—for example after 200-400
Other clinical signs are only likely to be present if patients ug salbutamol (albuterol)13—or more sustained improvement
are examined during symptomatic periods. Features of over days or weeks after the introduction of effective
hyperinflation result from patients breathing at a higher controller treatment such as inhaled glucocorticosteroids13.
lung volume in order to increase outward retraction of the Variability refers to improvement or deterioration in
airways and maintain the patency of smaller airways symptoms and lung function occurring over time.
(which are narrowed by a combination of airway smooth Variability may be experienced over the course of one day
muscle contraction, edema, and mucus hypersecretion). (when it is called diurnal variability), from day to day, from
The combination of hyperinflation and airflow limitation in month to month, or seasonally. Obtaining a history of
an asthma exacerbation markedly increases the work variability is an essential component of the diagnosis of
of breathing. asthma. In addition, variability forms part of the
assessment of asthma control.

DIAGNOSIS AND CLASSIFICATION 17

Spirometry is the recommended method of measuring as the amplitude (the difference between the maximum
airflow limitation and reversibility to establish a diagnosis of and the minimum value for the day), expressed as a
asthma. Measurements of FEV1 and FVC are undertaken percentage of the mean daily PEF value, and averaged
during a forced expiratory maneuver using a spirometer. over 1-2 weeks19. Another method of describing PEF
Recommendations for the standardization of spirometry variability is the minimum morning pre-bronchodilator PEF
have been published13-15. The degree of reversibility in over 1 week, expressed as a percent of the recent best
FEV1 which indicates a diagnosis of asthma is generally (Min%Max) (Figure 2-2)19. This latter method has been
accepted as ≥ 12% and ≥ 200 ml from the pre-bronchodilator suggested to be the best PEF index of airway lability for
value13. However most asthma patients will not exhibit clinical practice because it requires only a once-daily
reversibility at each assessment, particularly those on reading, correlates better than any other index with airway
treatment, and the test therefore lacks sensitivity. hyperresponsiveness, and involves a simple calculation.
Repeated testing at different visits is advised.

Spirometry is reproducible, but effort-dependent. Therefore, Figure 2-2. Measuring PEF Variability*
proper instructions on how to perform the forced expiratory
Inhaled glucocorticosteroids
maneuver must be given to patients, and the highest value commenced

of three recordings taken. As ethnic differences in 800

spirometric values have been demonstrated, appropriate 700

predictive equations for FEV1 and FVC should be
600
established for each patient. The normal range of values
is wider and predicted values are less reliable in young PEF L/min
500

people (< age 20) and in the elderly (> age 70). Because
400
many lung diseases may result in reduced FEV1, a useful
assessment of airflow limitation is the ratio of FEV1 to 300

FVC. The FEV1/FVC ratio is normally greater than 0.75 to 200

0.80, and possibly greater than 0.90 in children. Any 310/700 500/710 620/720
= 44% = 70% = 86%
100
values less than these suggest airflow limitation.
0
-1 0 1 2 3 4 5 6 7 8 9 10
Peak expiratory flow measurements are made using a Weeks of Inhaled Glucocorticosteroid Treatment
peak flow meter and can be an important aid in both
*PEF chart of a 27-year-old man with long-standing, poorly controlled asthma, before
diagnosis and monitoring of asthma. Modern PEF meters and after the start of inhaled glucocorticosteroid treatment. With treatment, PEF
are relatively inexpensive, portable, plastic, and ideal for levels increased, and PEF variability decreased, as seen by the increase in Min%Max
(lowest morning PEF/highest PEF %) over 1 week.
patients to use in home settings for day-to-day objective
measurement of airflow limitation. However,
measurements of PEF are not interchangeable with other PEF monitoring is valuable in a subset of asthmatic
measurements of lung function such as FEV1 in either patients and can be helpful:
adults16 or children17. PEF can underestimate the degree
• To confirm the diagnosis of asthma. Although
of airflow limitation, particularly as airflow limitation and
spirometry is the preferred method of documenting
gas trapping worsen. Because values for PEF obtained
airflow limitation, a 60 L/min (or 20% or more of pre-
with different peak flow meters vary and the range of
bronchodilator PEF) improvement after inhalation of a
predicted values is too wide, PEF measurements should
bronchodilator20, or diurnal variation in PEF of more
preferably be compared to the patientʼs own previous best
than 20% (with twice daily readings, more than 10% 21)
measurements18 using his/her own peak flow meter. The
suggests a diagnosis of asthma.
previous best measurement is usually obtained when the
patient is asymptomatic or on full treatment and serves • To improve control of asthma, particularly in patients
as a reference value for monitoring the effects of changes with poor perception of symptoms10. Asthma
in treatment. management plans which include self-monitoring of
symptoms or PEF for treatment of exacerbations have
Careful instruction is required to reliably measure PEF been shown to improve asthma outcomes22. It is easier
because PEF measurements are effort-dependent. Most to discern the response to therapy from a PEF chart
commonly, PEF is measured first thing in the morning than from a PEF diary, provided the same chart format
before treatment is taken, when values are often close to is consistently used23.
their lowest, and last thing at night when values are usually
higher. One method of describing diurnal PEF variability is

18 DIAGNOSIS AND CLASSIFICATION

 • To identify environmental (including occupational) Non-invasive markers of airway inflammation. The
causes of asthma symptoms. This involves the patient evaluation of airway inflammation associated with asthma
monitoring PEF daily or several times each day over may be undertaken by examining spontaneously produced
periods of suspected exposure to risk factors in the home or hypertonic saline-induced sputum for eosinophilic or
or workplace, or during exercise or other activities that neutrophilic inflammation30. In addition, levels of exhaled
may cause symptoms, and during periods of non-exposure. nitric oxide (FeNO)31 and carbon monoxide (FeCO)32 have
been suggested as non-invasive markers of airway
inflammation in asthma. Levels of FeNO are elevated in
Measurement of airway responsiveness. For patients people with asthma (who are not taking inhaled gluco-
with symptoms consistent with asthma, but normal lung corticosteroids) compared to people without asthma, yet
function, measurements of airway responsiveness to these findings are not specific for asthma. Neither sputum
direct airway challenges such as inhaled methacholine and eosinophilia nor FeNO has been evaluated prospectively
histamine or indirect airway challenges such as inhaled as an aid in asthma diagnosis, but these measurements
mannitol60 or exercise challenge may help establish a are being evaluated for potential use in determining
diagnosis of asthma24. Measurements of airway optimal treatment33,34,63.
responsiveness reflect the “sensitivity” of the airways to
factors that can cause asthma symptoms, sometimes
called “triggers,” and the test results are usually expressed Measurements of allergic status. Because of the strong
as the provocative concentration (or dose) of the agonist association between asthma and allergic rhinitis, the
causing a given fall (often 20%) in FEV1 (Figure 2-3). presence of allergies, allergic diseases, and allergic rhinitis
These tests are sensitive for a diagnosis of asthma, but in particular, increases the probability of a diagnosis of
have limited specificity25. This means that a negative test asthma in patients with respiratory symptoms. Moreover,
can be useful to exclude a diagnosis of persistent asthma the presence of allergies in asthma patients (identified by
in a patient who is not taking inhaled glucocorticosteroid skin testing or measurement of specific IgE in serum) can
treatment, but a positive test does not always mean that a help to identify risk factors that cause asthma symptoms in
patient has asthma26. This is because airway individual patients. Deliberate provocation of the airways
hyperresponsiveness has been described in patients with with a suspected allergen or sensitizing agent may be
allergic rhinitis27 and in those with airflow limitation caused helpful in the occupational setting, but is not routinely
by conditions other than asthma, such as cystic fibrosis28, recommended, because it is rarely useful in establishing a
bronchiectasis, and chronic obstructive pulmonary disease diagnosis, requires considerable expertise and can result
(COPD)29. in life-threatening bronchospasm35.

Skin tests with allergens represent the primary diagnostic

Figure 2-3. Measuring Airway Responsiveness* tool in determining allergic status. They are simple and
rapid to perform, and have a low cost and high sensitivity.
However, when improperly performed, skin tests can lead
to falsely positive or negative results. Measurement of
specific IgE in serum does not surpass the reliability of
results from skin tests and is more expensive. The main
limitation of methods to assess allergic status is that a
positive test does not necessarily mean that the disease is
allergic in nature or that it is causing asthma, as some
individuals have specific IgE antibodies without any
symptoms and it may not be causally involved. The
relevant exposure and its relation to symptoms must be
confirmed by patient history. Measurement of total IgE in
serum has no value as a diagnostic test for atopy.

*Airway responsiveness to inhaled methacholine or histamine in a normal subject, and

in asthmatics with mild, moderate, and severe airway hyperresponsiveness.
Asthmatics have an increased sensitivity and an increased maximal broncho- constric-
tor response to the agonist. The response to the agonist is usually expressed as the
provocative concentration causing a 20% decline in FEV1 (PC20).

DIAGNOSIS AND CLASSIFICATION 19

 glucocorticosteroids has not been shown to affect the
DIAGNOSTIC CHALLENGES AND development of asthma40.
DIFFERENTIAL DIAGNOSIS
Alternative causes of recurrent wheezing must be
The differential diagnosis in patients with suspected considered and excluded. These include:
asthma differs among different age groups: infants,
children, young adults, and the elderly. • Chronic rhino-sinusitis
• Gastroesophageal reflux
Children 5 years and Younger • Recurrent viral lower respiratory tract infections
• Cystic fibrosis
The diagnosis of asthma in early childhood is challenging • Bronchopulmonary dysplasia
and has to be based largely on clinical judgment and an • Tuberculosis
assessment of symptoms and physical findings. Since
• Congenital malformation causing narrowing of the
the use of the label “asthma” for wheezing in children has
intrathoracic airways
important clinical consequences, it must be distinguished
from other causes persistent and recurrent wheeze. • Foreign body aspiration
• Primary ciliary dyskinesia syndrome
Episodic wheezing and cough is very common even in • Immune deficiency
children who do not have asthma and particularly in those • Congenital heart disease
under age 336. Three categories of wheezing have been
described in children 5 years and younger: Neonatal onset of symptoms (associated with failure to
thrive), vomiting-associated symptoms, or focal lung or
• Transient early wheezing, which is often outgrown in cardiovascular signs suggest an alternative diagnosis and
the first 3 years. This is often associated with indicate the need for further investigations.
prematurity and parental smoking.
A useful method for confirming the diagnosis of asthma in
• Persistent early-onset wheezing (before age 3). These children 5 years and younger is a trial of treatment with
children typically have recurrent episodes of wheezing short-acting bronchodilators and inhaled glucocorticosteroids.
associated with acute viral respiratory infections, have Marked clinical improvement during the treatment and
no evidence of atopy37 and, unlike children in the next deterioration when treatment is stopped supports a
category of late onset wheezing/asthma, have no family diagnosis of asthma. Use of spirometry and other
history of atopy. The symptoms normally persist measures recommended for older children and adults
through school age and are still present at age 12 in a such as airway responsiveness and markers of airway
large proportion of children. The cause of the episode inflammation is difficult and several require complex
is usually the respiratory syncytial virus in children equipment41 making them unsuitable for routine use.
younger than age 2, while other viruses predominate in However, children 4 to 5 years old can be taught to use a
older preschool children. PEF meter, but to ensure reliability parental supervision is
• Late-onset wheezing/asthma. These children have required42.
asthma which often persists throughout childhood and
into adult life38, 39. They typically have an atopic Older Children and Adults
background, often with eczema, and airway pathology
is characteristic of asthma. A careful history and physical examination, together with
the demonstration of reversible and variable airflow
The following categories of symptoms are highly obstruction (preferably by spirometry), will in most
suggestive of a diagnosis of asthma: frequent episodes of instances confirm the diagnosis. The following categories
wheeze (more than once a month), activity-induced cough of alternative diagnoses need to be considered:
or wheeze, nocturnal cough in periods without viral
infections, absence of seasonal variation in wheeze, and • Hyperventilation syndrome and panic attacks
symptoms that persist after age 3. A simple clinical index • Upper airway obstruction and inhaled foreign bodies43
based on the presence of a wheeze before the age of 3, • Vocal cord dysfunction44
and the presence of one major risk factor (parental history • Other forms of obstructive lung disease, particularly COPD
of asthma or eczema) or two of three minor risk factors • Non-obstructive forms of lung disease (e.g., diffuse
(eosinophilia, wheezing without colds, and allergic rhinitis) parenchymal lung disease)
has been shown to predict the presence of asthma in later • Non-respiratory causes of symptoms (e.g., left
childhood38. However, treating children at risk with inhaled
ventricular failure)

20 DIAGNOSIS AND CLASSIFICATION

Because asthma is a common disease, it can be found in Since the management of occupational asthma frequently
association with any of the above diagnoses, which requires the patient to change his or her job, the diagnosis
complicates the diagnosis as well as the assessment of carries considerable socioeconomic implications and it is
severity and control. This is particularly true when asthma important to confirm the diagnosis objectively. This may
is associated with hyperventilation, vocal cord dysfunction, be achieved by specific bronchial provocation testing46,
or COPD. Careful assessment and treatment of both the although there are few centers with the necessary facilities
asthma and the comorbidity is often necessary to establish for specific inhalation testing. Another method is to
the contribution of each to a patientʼs symptoms. monitor PEF at least 4 times a day for a period of 2 weeks
when the patient is working and for a similar period away
The Elderly from work47-50. The increasing recognition that occupational
asthma can persist, or continue to deteriorate, even in the
Undiagnosed asthma is a frequent cause of treatable absence of continued exposure to the offending agent51,
respiratory symptoms in the elderly, and the frequent emphasizes the need for an early diagnosis so that
presence of comorbid diseases complicates the diagnosis. appropriate strict avoidance of further exposure and
Wheezing, breathlessness, and cough caused by left pharmacologic intervention may be applied. Recent
ventricular failure is sometimes labeled “cardiac asthma,” publications provide an evidence-based approach to the
a misleading term, the use of which is discouraged. The identification of occupational asthma and compare specific
presence of increased symptoms with exercise and at inhalation challenge testing with alternative tests for
night may add to the diagnostic confusion because these confirming the responsible agents52,61.
symptoms are consistent with either asthma or left
ventricular failure. Use of beta-blockers, even topically Distinguishing Asthma from COPD
(for glaucoma) is common in this age group. A careful
history and physical examination, combined with an ECG Both asthma and COPD are major chronic obstructive
and chest X-ray, usually clarifies the picture. In the elderly, airways diseases that involve underlying airway
distinguishing asthma from COPD is particularly difficult, inflammation. COPD is characterized by airflow limitation
and may require a trial of treatment with bronchodilators that is not fully reversible, is usually progressive, and is
and/or oral/inhaled glucocorticosteroids. associated with an abnormal inflammatory response of the
lungs to noxious particles or gases. Individuals with
Asthma treatment and assessment and attainment of asthma who are exposed to noxious agents (particularly
control in the elderly are complicated by several factors: cigarette smoking) may develop fixed airflow limitation and
poor perception of symptoms, acceptance of dyspnea as a mixture of “asthma-like” inflammation and “COPD-like”
being “normal” in old age, and reduced expectations of inflammation. Thus, even though asthma can usually be
mobility and activity. distinguished from COPD, in some individuals who develop
chronic respiratory symptoms and fixed airflow limitation,
Occupational Asthma it may be difficult to differentiate the two diseases. A
symptom-based questionnaire for differentiating COPD
Asthma acquired in the workplace is a diagnosis that is and asthma for use by primary health care professionals
frequently missed. Because of its insidious onset, is available53,54.
occupational asthma is often misdiagnosed as chronic
bronchitis or COPD and is therefore either not treated at all
or treated inappropriately. The development of new
symptoms of rhinitis, cough, and/or wheeze particularly in
non-smokers should raise suspicion. Detection of asthma
of occupational origin requires a systematic inquiry about
work history and exposures. The diagnosis requires a
defined history of occupational exposure to known or
suspected sensitizing agents; an absence of asthma
symptoms before beginning employment; or a definite
worsening of asthma after employment. A relationship
between symptoms and the workplace (improvement in
symptoms away from work and worsening of symptoms on
returning to work) can be helpful in establishing a link
between suspected sensitizing agents and asthma45.

DIAGNOSIS AND CLASSIFICATION 21

CLASSIFICATION OF ASTHMA Figure 2-4. Classification of Asthma Severity by
Clinical Features Before Treatment*

Etiology Intermittent
Symptoms less than once a week
Many attempts have been made to classify asthma Brief exacerbations
Nocturnal symptoms not more than twice a month
according to etiology, particularly with regard to
• FEV1 or PEF ≥ 80% predicted
environmental sensitizing agents. However, such a • PEF or FEV1 variability < 20%
classification is limited by the existence of patients in
Mild Persistent
whom no environmental cause can be identified. Despite
this, an effort to identify an environmental cause for Symptoms more than once a week but less than once a day
Exacerbations may affect activity and sleep
asthma (for example, occupational asthma) should be part
Nocturnal symptoms more than twice a month
of the initial assessment to enable the use of avoidance • FEV1 or PEF ≥ 80% predicted
strategies in asthma management. Describing patients as • PEF or FEV1 variability < 20 – 30%
having allergic asthma is usually of little benefit, since
Moderate Persistent
single specific causative agents are seldom identified.
Symptoms daily
Exacerbations may affect activity and sleep
Asthma Severity Nocturnal symptoms more than once a week
Daily use of inhaled short-acting ␤2-agonist
Previous GINA documents subdivided asthma by severity • FEV1 or PEF 60-80% predicted
based on the level of symptoms, airflow limitation, and • PEF or FEV1 variability > 30%
lung function variability into four categories: Intermittent,
Severe Persistent
Mild Persistent, Moderate Persistent, or Severe Persistent
Symptoms daily
(Figure 2-4). Classification of asthma by severity is useful
Frequent exacerbations
when decisions are being made about management at the Frequent nocturnal asthma symptoms
initial assessment of a patient. It is important to recognize, Limitation of physical activities
however, that asthma severity involves both the severity of • FEV1 or PEF ≤ 60% predicted
the underlying disease and its responsiveness to • PEF or FEV1 variability > 30%
treatment. Thus, asthma can present with severe *The worst feature determines the severity classification.
symptoms and airflow obstruction and be classified as
Severe Persistent on initial presentation, but respond fully Asthma Control
to treatment and then be classified as Moderate Persistent
asthma. In addition, severity is not an unvarying feature of Asthma control may be defined in a variety of ways. In
an individual patientʼs asthma, but may change over general, the term control may indicate disease prevention,
months or years. or even cure. However, in asthma, where neither of these
are realistic options at present, it refers to control of the
Because of these considerations, the classification of manifestations of disease. Ideally this should apply not
asthma severity provided in Figure 2-4 which is based on only to clinical manifestations, but to laboratory markers
expert opinion rather than evidence is no longer of inflammation and pathophysiological features of the
recommended as the basis for ongoing treatment disease as well. There is evidence that reducing
decisions, but it may retain its value as a cross-sectional inflammation with controller therapy achieves clinical
means of characterizing a group of patients with asthma control, but because of the cost and/or general
who are not on inhaled glucocorticosteroid treatment, as in unavailability of tests such as endobronchial biopsy and
selecting patients for inclusion in an asthma study. Its measurement of sputum eosinophils and exhaled nitric
main limitation is its poor value in predicting what oxide30-34, it is recommended that treatment be aimed at
treatment will be required and what a patientʼs response to controlling the clinical features of disease, including lung
that treatment might be. For this purpose, a periodic function abnormalities. Figure 2-5 provides the
assessment of asthma control is more relevant and characteristics of controlled, partly controlled and
useful64. uncontrolled asthma. This is a working scheme based
on current opinion and has not been validated.

22 DIAGNOSIS AND CLASSIFICATION

 Figure 2-5. Levels of Asthma Control
Characteristic Controlled Partly Controlled Uncontrolled
(All of the following) (Any measure present in any week)
Daytime symptoms None (twice or less/week) More than twice/week Three or more features
of partly controlled
Limitations of activities None Any asthma present in
Nocturnal symptoms/awakening None Any any week
Need for reliever/ None (twice or less/week) More than twice/week
rescue treatment
Lung function (PEF or FEV1)‡ Normal < 80% predicted or personal best
(if known)
Exacerbations None One or more/year* One in any week†

* Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate.
† By definition, an exacerbation in any week makes that an uncontrolled asthma week.
‡ Lung function is not a reliable test for children 5 years and younger.

Complete control of asthma is commonly achieved with REFERENCES

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DIAGNOSIS AND CLASSIFICATION 25

26 DIAGNOSIS AND CLASSIFICATION
 CHAPTER

ASTHMA

TREATMENTS
 KEY POINTS:
ASTHMA MEDICATIONS: ADULTS
• Medications to treat asthma can be classified as
controllers or relievers. Controllers are medications Route of Administration
taken daily on a long-term basis to keep asthma
under clinical control chiefly through their anti- Asthma treatment for adults can be administered in
inflammatory effects. Relievers are medications different ways—inhaled, orally or parenterally (by
used on an as-needed basis that act quickly to subcutaneous, intramuscular, or intravenous injection).
reverse bronchoconstriction and relieve its symptoms. The major advantage of inhaled therapy is that drugs are
delivered directly into the airways, producing higher local
• Asthma treatment can be administered in different concentrations with significantly less risk of systemic
ways—inhaled, orally, or by injection. The major side effects.
advantage of inhaled therapy is that drugs are
delivered directly into the airways, producing higher Inhaled medications for asthma are available as pressurized
local concentrations with significantly less risk of metered-dose inhalers (MDIs), breath-actuated MDIs, dry
systemic side effects. powder inhalers (DPIs), soft mist inhalers, and nebulized
or “wet” aerosols* . Inhaler devices differ in their efficiency
• Inhaled glucocorticosteroids are the most effective of drug delivery to the lower respiratory tract, depending
controller medications currently available. on the form of the device, formulation of medication,
particle size, velocity of the aerosol cloud or plume (where
• Rapid-acting inhaled ␤2-agonists are the applicable), and ease with which the device can be used
medications of choice for relief of by the majority of patients. Individual patient preference,
bronchoconstriction and for the pretreatment of convenience, and ease of use may influence not only the
exercise-induced bronchoconstriction, in both adults efficiency of drug delivery but also patient adherence to
and children of all ages. treatment and long-term control.

• Increased use, especially daily use, of reliever Pressurized MDIs (pMDIs) require training and skill to
medication is a warning of deterioration of asthma coordinate activation of the inhaler and inhalation.
control and indicates the need to reassess Medications in these devices can be dispensed as a
treatment. suspension in chlorofluorocarbons (CFCs) or as a solution
in hydrofluoroalkanes (HFAs). For a pMDI containing
CFCs, the use of a spacer (holding chamber) improves
INTRODUCTION drug delivery, increases lung deposition, and may reduce
local and systemic side effects1. However, CFC inhaler
devices are being phased out due to the impact of CFCs
The goal of asthma treatment is to achieve and maintain upon the atmospheric ozone layer, and are being replaced
clinical control. Medications to treat asthma can be by HFA devices. For pMDIs containing bronchodilators,
classified as controllers or relievers. Controllers are the switch from CFC to HFA inhalers does not result in a
medications taken daily on a long-term basis to keep change in efficacy at the same nominal dose2. However,
asthma under clinical control chiefly through their anti- for some glucocorticosteroids, the HFA formulations
inflammatory effects. They include inhaled and systemic provide an aerosol of smaller particle size that results in
glucocorticosteroids, leukotriene modifiers, long-acting less oral deposition (with associated reduction in oral side
inhaled ␤2-agonists in combination with inhaled effects), and correspondingly greater lung deposition.
glucocorticosteroids, sustained-release theophylline, This may result in greater systemic efficacy at equivalent
cromones, anti-IgE, and other systemic steroid-sparing ex-actuator doses, but also greater systemic exposure
therapies. Inhaled glucocorticosteroids are the most and risk of side effects3-5. Clinicians are advised to consult
effective controller medications currently available. the package inserts of each product to confirm the
Relievers are medications used on an as-needed basis recommended dose equivalent to currently used drugs.
that act quickly to reverse bronchoconstriction and relieve Some of these comparisons are provided in Figure 3-1.
its symptoms. They include rapid-acting inhaled ␤2-
agonists, inhaled anticholinergics, short-acting
theophylline, and short-acting oral ␤2-agonists.

*Information on various inhaler devices available can be found on the GINA Website
28 ASTHMA TREATMENTS (http://www.ginasthma.org).
Pressurized MDIs may be used by patients with asthma clinical control follows within weeks to months in a
of any severity, including during exacerbations. Breath- proportion of patients14,15.
actuated aerosols may be helpful for patients who have Inhaled glucocorticosteroids differ in potency and
difficulty using the “press and breathe” pressurized MDI6. bioavailability, but because of relatively flat dose-response
Soft mist inhalers appear to require less coordination. relationships in asthma relatively few studies have been
Dry powder inhalers are generally easier to use, but they able to confirm the clinical relevance of these differences191.
require a minimal inspiratory flow rate and may prove Figure 3-1 lists approximately equipotent doses of different
difficult for some patients. DPIs differ with respect to the inhaled glucocorticosteroids based upon the available
fraction of ex-actuator dose delivered to the lung. For efficacy literature, but the categorization into dosage
some drugs, the dose may need to be adjusted when categories does not imply that clear dose-response
switching from an MDI to a DPI7. Nebulized aerosols are relationships have been demonstrated for each drug.
rarely indicated for the treatment of chronic asthma in adults8.
The efficacy of some products varies when administered
CONTROLLER MEDICATIONS via different inhaler devices16. Most of the benefit from
inhaled glucocorticosteroids is achieved in adults at
relatively low doses, equivalent to 400 ug of budesonide
Inhaled glucocorticosteroids* per day17. Increasing to higher doses provides little further
benefit in terms of asthma control but increases the risk of
Role in therapy - Inhaled glucocorticosteroids are currently side effects17,18. However, there is marked individual
the most effective anti-inflammatory medications for the variability of responsiveness to inhaled glucocorticosteroids
treatment of persistent asthma. Studies have demonstrated and because of this and the recognized poor adherence to
their efficacy in reducing asthma symptoms9, improving treatment with inhaled glucocorticosteroids, many patients
quality of life9, improving lung function9, decreasing airway will require higher doses to achieve full therapeutic benefit.
hyperresponsiveness10, controlling airway inflammation11, As tobacco smoking reduces the responsiveness to
reducing frequency and severity of exacerbations12, and inhaled glucocorticosteroids, higher doses may be
reducing asthma mortality13. However, they do not cure required in patients who smoke.
asthma, and when they are discontinued deterioration of

Figure 3-1. Estimated Equipotent Daily Doses of Inhaled Glucocorticosteroids for Adults †
Drug ␮g)
Low Daily Dose (␮ ␮g)
Medium Daily Dose (␮ ␮g)‡
High Daily Dose (␮
Beclomethasone dipropionate 200 - 500 >500 - 1000 >1000 - 2000
Budesonide* 200 - 400 >400 - 800 >800 - 1600
Ciclesonide* 80 - 160 >160 - 320 >320 - 1280
Flunisolide 500 - 1000 >1000 - 2000 >2000
Fluticasone 100 - 250 >250 - 500 >500 - 1000
Mometasone furoate* 200 - 400 >400 - 800 >800 - 1200
Triamcinolone acetonide 400 - 1000 >1000 - 2000 >2000
† Comparisons based upon efficacy data.
‡ Patients considered for high daily doses except for short periods should be referred to a specialist for assessment to consider alternative combinations of
controllers. Maximum recommended doses are arbitrary but with prolonged use are associated with increased risk of systemic side effects.
* Approved for once-daily dosing in mild patients.

Notes
• The most important determinant of appropriate dosing is the clinicianʼs judgment of the patientʼs r esponse to therapy. The clinician must monitor the patientʼs
response in terms of clinical control and adjust the dose accordingly. Once control of asthma is achieved, the dose of medication should be carefully titrated to
the minimum dose required to maintain control, thus reducing the potential for adverse effects.
• Designation of low, medium, and high doses is provided from manufacturersʼ re commendations where possible. Clear demonstration of dose-response
relationships is seldom provided or available. The principle is therefore to establish the minimum effective controlling dose in each patient, as higher doses
may not be more effective and are likely to be associated with greater potential for adverse effects.
• As CFC preparations are taken from the market, medication inserts for HFA preparations should be carefully reviewed by the clinician for the equivalent
correct dosage.

*In this section recommendations for doses of inhaled glucocorticosteroids are given as “␮/day budesonide or
equivalent,” because a majority of the clinical literature on these medications uses this standard. ASTHMA TREATMENTS 29
To reach clinical control, add-on therapy with another Leukotriene modifiers.
class of controller is preferred over increasing the dose
of inhaled glucocorticosteroids. There is, however, a Role in therapy - Leukotriene modifiers include cysteinyl-
clear relationship between the dose of inhaled gluco- leukotriene 1 (CysLT1) receptor antagonists (montelukast,
corticosteroids and the prevention of severe acute pranlukast, and zafirlukast) and a 5-lipoxygenase inhibitor
exacerbations of asthma12. Therefore, some patients with (zileuton). Clinical studies have demonstrated that
severe asthma may benefit from long-term treatment with leukotriene modifiers have a small and variable broncho-
higher doses of inhaled glucocorticosteroids. dilator effect, reduce symptoms including cough34, improve
lung function, and reduce airway inflammation and asthma
Side effects: Local adverse effects from inhaled exacerbations35-37. They may be used as an alternative
glucocorticosteroids include oropharyngeal candidiasis, treatment for adult patients with mild persistent asthma38-40,
dysphonia, and occasionally coughing from upper airway and some patients with aspirin-sensitive asthma respond
irritation. For pressurized MDIs the prevalence of these well to leukotriene modifiers41. However, when used alone
effects may be reduced by using certain spacer devices1. as controller, the effect of leukotriene modifiers are
Mouth washing (rinsing with water, gargling, and spitting generally less than that of low doses of inhaled
out) after inhalation may reduce oral candidiasis. The use glucocorticosteroids, and, in patients already on inhaled
of prodrugs that are activated in the lungs but not in the glucocorticosteroids, leukotriene modifiers cannot
pharynx (e.g., ciclesonide)19, and new formulations and substitute for this treatment without risking the loss of
devices that reduce oropharyngeal deposition, may asthma control42,43. Leukotriene modifiers used as add-on
minimize such effects without the need for a spacer or therapy may reduce the dose of inhaled glucocorticosteroids
mouth washing. required by patients with moderate to severe asthma44, and
may improve asthma control in patients whose asthma is
Inhaled glucocorticosteroids are absorbed from the lung, not controlled with low or high doses of inhaled
accounting for some degree of systemic bioavailability. glucocorticosteroids43,45-47. With the exception of one
The risk of systemic adverse effects from an inhaled study that demonstrated equivalence in preventing
glucocorticosteroid depends upon its dose and potency, exacerbations48, several studies have demonstrated that
the delivery system, systemic bioavailability, first-pass leukotriene modifiers are less effective than long-acting
metabolism (conversion to inactive metabolites) in the inhaled ␤2-agonists as add-on therapy49-51,192. A controlled
liver, and half-life of the fraction of systemically absorbed release formulation of zileuton allows this medication to be
drug (from the lung and possibly gut)20. Therefore, the used on a twice daily basis with effects equivalent to that
systemic effects differ among the various inhaled of standard zileuton used four times a day203.
glucocorticosteroids. Several comparative studies have
demonstrated that ciclesonide, budesonide, and fluticasone Side effects - Leukotriene modifiers are well tolerated,
propionate at equipotent doses have less systemic effect20- and few if any class-related effects have so far been
23
. Current evidence suggests that in adults, systemic recognized. Zileuton has been associated with liver
effects of inhaled glucocorticosteroids are not a problem at toxicity204, and monitoring of liver tests is recommended
doses of 400 ␮g or less budesonide or equivalent daily. during treatment with this medication. The apparent
association of leukotriene modifiers with Churg-Strauss
The systemic side effects of long-term treatment with high syndrome is probably largely the result of reductions in the
doses of inhaled glucocorticosteroids include easy doses of systemic and/or inhaled glucocorticosteroids
bruising24, adrenal suppression1,20, and decreased bone unmasking the underlying disease, but a causal association
mineral density25,26. Inhaled glucocorticosteroids have in some patients cannot be entirely excluded52-54.
also been associated with cataracts27 and glaucoma in
cross-sectional studies28,29, but there is no evidence of Long-acting inhaled ␤2-agonists.
posterior-subcapsular cataracts in prospective studies30-32.
One difficulty in establishing the clinical significance of Role in therapy - Long-acting inhaled ␤2-agonists,
such adverse effects lies in dissociating the effect of high- including formoterol and salmeterol, should not be used
dose inhaled glucocorticosteroids from the effect of as monotherapy in asthma as these medications do not
courses of oral glucocorticosteroids taken by patients with appear to influence the airway inflammation in asthma.
severe asthma. There is no evidence that use of inhaled They are most effective when combined with inhaled
glucocorticosteroids increases the risk of pulmonary glucocorticosteroids55,56,193, and this combination therapy is
infections, including tuberculosis, and inhaled gluco- the preferred treatment when a medium dose of inhaled
corticosteroids are not contraindicated in patients with glucocorticosteroid alone fails to achieve control of
active tuberculosis33.

30 ASTHMA TREATMENTS
asthma. Addition of long-acting inhaled ␤2-agonists to a does not increase the risk for asthma-related deaths or
daily regimen of inhaled glucocorticosteroids improves intubations when compared to inhaled glucocorticosteroids
symptom scores, decreases nocturnal asthma, improves alone205. No influence of ␤2-adrenergic receptor
lung function, decreases the use of rapid-acting inhaled phenotypes upon the efficacy or safety of long-acting
␤2-agonists57-59, reduces the number of exacerbations12,57-62, ␤2-agonist therapy has been observed when administered
and achieves clinical control of asthma in more patients, in combination with inhaled glucocorticosteroids whether
more rapidly, and at a lower dose of inhaled glucocortico- by the single inhaler for maintenance and relief method or
steroids than inhaled glucocorticosteroids given alone63. at a regular fixed dose in adults206.

This greater efficacy of combination treatment has led to Theophylline.

the development of fixed combination inhalers that deliver
both glucocorticosteroid and long-acting ␤2-agonist Role in therapy - Theophylline is a bronchodilator and,
simultaneously (fluticasone propionate plus salmeterol, when given in a lower dose, has modest anti-inflammatory
budesonide plus formoterol). Controlled studies have properties77-79. It is available in sustained-release
shown that delivering this therapy in a combination inhaler formulations that are suitable for once- or twice-daily
is as effective as giving each drug separately64, 65. Fixed dosing. Data on the relative efficacy of theophylline as a
combination inhalers are more convenient for patients, may long-term controller is lacking. However, available
increase compliance66, and ensure that the long-acting ␤2- evidence suggests that sustained-release theophylline has
agonist is always accompanied by a glucocorticosteroid. little effect as a first-line controller80. It may provide benefit
In addition, combination inhalers containing formoterol and as add-on therapy in patients who do not achieve control
budesonide may be used for both rescue and maintenance. on inhaled glucocorticosteroids alone81-83. Additionally in
Both components of budesonide-formoterol given as such patients the withdrawal of sustained-release
needed contribute to enhanced protection from severe theophylline has been associated with deterioration of
exacerbations in patients receiving combination therapy for control84. As add-on therapy, theophylline is less effective
maintenance67,194 and provide improvements in asthma than long-acting inhaled ␤2-agonists85,86.
control at relatively low doses of treatment67-70.
Side effects - Side effects of theophylline, particularly at
Long-acting ␤2-agonists may also be used to prevent higher doses (10 mg/kg body weight/day or more), are
exercise-induced bronchospasm, and for this purpose significant and reduce their usefulness. Side effects can
may provide longer protection than rapid-acting inhaled be reduced by careful dose selection and monitoring, and
␤2-agonists71. Salmeterol and formoterol provide a similar generally decrease or disappear with continued use.
duration of bronchodilation and protection against Adverse effects include gastrointestinal symptoms, loose
bronchoconstrictors, but there are pharmacological differences stools, cardiac arrhythmias, seizures, and even death.
between them. Formoterol has a more rapid onset of action Nausea and vomiting are the most common early events.
than salmeterol72, 73, which may make formoterol suitable Monitoring is advised when a high dose is started, if the
for symptom relief as well as symptom prevention68. patient develops an adverse effect on the usual dose,
when expected therapeutic aims are not achieved, and
Side effects - Therapy with long-acting inhaled ␤2-agonists when conditions known to alter theophylline metabolism
causes fewer systemic adverse effects—such as exist. For example, febrile illness, pregnancy, and
cardiovascular stimulation, skeletal muscle tremor, and anti-tuberculosis medications87 reduce blood levels of
hypokalemia—than oral therapy. The regular use of rapid- theophylline, while liver disease, congestive heart failure,
acting ␤2-agonists in both short and long acting forms may and certain drugs including cimetidine, some quinolones,
lead to relative refractoriness to ␤2-agonists74. Data and some macrolides increase the risk of toxicity. Lower
indicating a possible increased risk of asthma-related doses of theophylline, which have been demonstrated to
death associated with the use of salmeterol in a small provide the full anti-inflammatory benefit of this drug82, are
group of individuals75 led to advisories from the US Food associated with less frequent side effects, and plasma
and Drug Administration (FDA)‡ and Health Canada § that theophylline levels in patients on low-dose therapy need
long-acting ␤2-agonists are not a substitute for inhaled or not be measured unless overdose is suspected.
oral glucocorticosteroids, and should only be used in
combination with an appropriate dose of inhaled
glucocorticosteroid as determined by a physician. A meta-
analysis of all studies of salmeterol added to inhaled
glucocorticosteroids has concluded that this combination

‡ http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2003/serevent_hpc-cps_e.html
§ www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2003/serevent_hpc-cps_e.html ASTHMA TREATMENTS 31
Cromones: sodium cromoglycate and nedocromil Systemic glucocorticosteroids.
sodium.
Role in therapy - Long-term oral glucocorticosteroid
Role in therapy – The role of sodium cromoglycate and therapy (that is, for periods longer than two weeks as a
nedocromil sodium in long-term treatment of asthma in glucocorticosteroid “burst”) may be required for severely
adults is limited. Efficacy has been reported in patients uncontrolled asthma, but its use is limited by the risk of
with mild persistent asthma and exercise-induced significant adverse effects. The therapeutic index
bronchospasm. Their anti-inflammatory effect is weak (effect/side effect) of long-term inhaled glucocortico-
and they are less effective than a low dose of inhaled steroids is always more favorable than long-term systemic
glucocorticosteroid88. glucocorticosteroids in asthma95,96. If oral glucocortico-
steroids have to be administered on a long-term basis,
Side effects - Side effects are uncommon and include attention must be paid to measures that minimize the
coughing upon inhalation and sore throat. Some patients systemic side effects. Oral preparations are preferred over
find the taste of nedocromil sodium unpleasant. parenteral (intramuscular or intravenous) for long-term
therapy because of their lower mineralocorticoid effect,
Long-acting oral ␤2-agonists. relatively short half-life, and lesser effects on striated
muscle, as well as the greater flexibility of dosing that permits
Role in therapy - Long acting oral ␤2-agonists include titration to the lowest acceptable dose that maintains control.
slow release formulations of salbutamol, terbutaline, and
bambuterol, a prodrug that is converted to terbutaline in Side effects - The systemic side effects of long-term oral
the body. They are used only on rare occasions when or parenteral glucocorticosteroid treatment include
additional bronchodilation is needed. osteoporosis, arterial hypertension, diabetes, hypothalamic-
pituitary-adrenal axis suppression, obesity, cataracts,
Side effects - The side effect profile of long acting oral glaucoma, skin thinning leading to cutaneous striae and
␤2-agonists is higher than that of inhaled ␤2-agonists, and easy bruising, and muscle weakness. Patients with asthma
includes cardiovascular stimulation (tachycardia), anxiety, who are on long-term systemic glucocorticosteroids in any
and skeletal muscle tremor. Adverse cardiovascular
form should receive preventive treatment for osteoporosis
reactions may also occur with the combination of oral
(Figure 3-2)97-99. Although it is rare, withdrawal of oral
␤2-agonists and theophylline. Regular use of long-acting
glucocorticosteroids can elicit adrenal failure or unmask
oral ␤2-agonists as monotherapy is likely to be harmful
underlying disease, such as Churg-Strauss Syndrome54,100.
and these medications must always be given in
Caution and close medical supervision are recommended
combination with inhaled glucocorticosteroids.
when considering the use of systemic glucocorticosteroids
in patients with asthma who also have tuberculosis,
Anti-IgE.
parasitic infections, osteoporosis, glaucoma, diabetes,
severe depression, or peptic ulcers. Fatal herpes virus
Role in therapy - Anti-IgE (omalizumab) is a treatment
infections have been reported among patients who are
option limited to patients with elevated serum levels of IgE.
Its current indication is for patients with severe allergic exposed to these viruses while taking systemic
asthma89 who are uncontrolled on inhaled glucocortico- glucocorticosteroids, even short bursts.
steroids, although the dose of concurrent treatment has
varied in different studies. Improved asthma control is Oral anti-allergic compounds.
reflected by fewer symptoms, less need for reliever
medications, and fewer exacerbations90,91. Further Role in therapy - Several oral anti-allergic compounds
investigations will likely provide additional clarification of have been introduced in some countries for the treatment
the role of anti-IgE in other clinical settings. of mild to moderate allergic asthma. These include
tranilast, repirinast, tazanolast, pemirolast, ozagrel,
Side effects: As indicated by several studies involving celatrodast, amlexanox, and ibudilast. In general, their
asthma patients ages 12 years and older207, who were anti-asthma effect appears to be limited101, but studies on
already receiving treatment with glucocorticosteroids the relative efficacy of these compounds are needed
(inhaled and/or oral) and long-acting ␤2-agonists89, anti- before recommendations can be made about their role in
IgE appears to be safe as add-on therapy92-94. the long-term treatment of asthma.

Side effects - Sedation is a potential side effect of some of

these medications.

32 ASTHMA TREATMENTS
 Figure 3-2. Glucocorticosteroids and Osteoporosis

Asthma patients on high-dose inhaled glucocorticosteroids or oral glucocorticosteroids at any dose are considered at risk of developing
osteoporosis and fractures, but it is not certain whether this risk exists for patients on lower doses of inhaled glucocorticosteroids1. Physicians
should consider monitoring patients who are at risk. The following summarizes monitoring and management but more detailed guidelines for
the management of steroid-induced osteoporosis are available2,3.
Screening - Chest X-rays should be reviewed for the presence of vertebral fractures. Wedging, compressions, and cod-fishing of vertebral
bodies are synonymous with fractures, and indicate those who are at the highest risk for future fractures. In men, this may be a better predictor
of fracture risk than bone mineral density (BMD). BMD measurements by dual energy X-ray absorptiomety (DXA scan) should be undertaken in:
• Any patient with asthma who has been taking oral glucocorticosteroids for over 6 months duration at a mean daily dose of 7.5 mg
prednisone/prednisolone or above.
• Post-menopausal women taking over 5 mg prednisone/prednisolone daily for more than 3 months.
• Any patient with asthma and a history of vertebral or other fractures that may be related to osteoporosis.
Bone density measurements should also be offered to:
• Post-menopausal women taking > 2 mg inhaled BDP or equivalent daily
• Any patient who is receiving frequent short courses of high-dose oral glucocorticosteroids
Osteoporosis is present if the bone density in lumbar spine or femoral neck shows :
• T-score below -2.5 (2.5 standard deviations below the mean value of young normal subjects of the same sex in patients 19-69 years).
• Z-score below -1 (1 standard deviation below the predicted value for age and sex).
Follow-up scanning - Repeat scanning should be done:
• In 2 years in those whose initial scan was not osteoporotic but in whom treatment (as above) with oral glucocorticosteroids continues.
• In 1 year for those with osteoporosis on the first scan who are started on osteoporosis treatment.
Management
• General measures include avoidance of smoking, regular exercise, use of the lowest dose of oral glucocorticosteroid possible, and a good
dietary intake of calcium.
• For women with osteoporosis up to 10 years post-menopausal offer bisphosphonates or hormone therapy4,5,6 (Evidence A).
• For men, pre-menopausal women, and women more than 10 years since menopause consider treatment with a bisphosphonate7 (Evidence A).
References
1. Goldstein MF, Fallon JJ, Jr., Harning R. Chronic glucocorticoid therapy-induced osteoporosis in patients with obstructive lung disease. Chest 1999; 116:1733-1749.
2. Eastell R, Reid DM, Compston J, Cooper C, Fogelman I, Francis RM et al. A UK Consensus Group on management of glucocorticoid-induced osteoporosis:
an update. J Intern Med 1998; 244:271-292.
3. Sambrook PN, Diamond T, Ferris L, Fiatarone-Singh M, Flicker L, MacLennan A et al. Corticosteroid induced osteoporosis. Guidelines for treatment. Aust Fam
Physician 2001; 30:793-796.
4. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML et al. Risks and benefits of estrogen plus progestin in healthy
postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-33.
5. Cauley JA, Robbins J, Chen Z, Cummings SR, Jackson RD, LaCroix AZ, LeBoff M, Lewis CE, McGowan J, Neuner J, Pettinger M, Stefanick ML, Wactawski-
Wende J, Watts NB. "Effects of Estrogen Plus Progestin on Risk of Fracture and Bone Mineral Density." JAMA 2003;290(13):1729-1738.
6. Brown JP, Josse RG. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ. 2002;167:S1-34.
7. Homik J, Cranney A, Shea B, Tugwell P, Wells G, Adachi R et al. Bisphosphonates for steroid induced osteoporosis. Cochrane Database Syst Rev 2000;CD001347.

Other controller therapies. some patients. The macrolide, troleandromycin, has a

small steroid-sparing effect when used with systemic
Role in therapy - Various therapeutic regimens to reduce methylprednisolone, but its effect may result from the
the dose of oral glucocorticosteroids required by patients macrolide decreasing metabolism of the glucocortico-
with severe asthma have been proposed. These steroid and therefore not improving safety. However, other
medications should be used only in selected patients effects of the long-term use of macrolides in asthma
under the supervision of an asthma specialist, as their remain under study108. The use of intravenous
potential steroid-sparing effects may not outweigh the risk immunoglobulin is not recommended109-111.
of serious side effects. Two meta-analyses of the steroid-
sparing effect of low-dose methotrexate showed a small Side effects - Macrolide use is frequently associated with
overall benefit, but a relatively high frequency of adverse nausea, vomiting, and abdominal pain and occasionally
effects102,103. This small potential to reduce the impact of liver toxicity. Methotrexate also causes gastrointestinal
glucocorticosteroid side effects is probably insufficient to symptoms, and on rare occasions hepatic and diffuse
offset the adverse effects of methotrexate104. Cyclosporin105 pulmonary parenchymal disease, and hematological and
and gold106,107 have also been shown to be effective in teratogenic effects.

ASTHMA TREATMENTS 33
Allergen-specific immunotherapy. salbutamol, terbutaline, fenoterol, levalbuterol HFA209,
reproterol, and pirbuterol. Formoterol, a long-acting ␤2-
Role in therapy - The role of specific immunotherapy in agonist, is approved for symptom relief because of its
adult asthma is limited. Appropriate immunotherapy rapid onset of action, but it should only be used for this
requires the identification and use of a single well-defined purpose in patients on regular controller therapy with
clinically relevant allergen. The later is administered in inhaled glucocorticosteroids.
progressively higher doses in order to induce tolerance. A
Cochrane review112 that examined 75 randomized controlled Rapid-acting inhaled ␤2-agonists should be used only on
trials of specific immunotherapy compared to placebo an as-needed basis at the lowest dose and frequency
confirmed the efficacy of this therapy in asthma in reducing required. Increased use, especially daily use, is a warning
symptom scores and medication requirements, and improving of deterioration of asthma control and indicates the need to
allergen-specific and non-specific airway hyperresponsiveness. reassess treatment. Similarly, failure to achieve a quick and
Similar modest effects were identified in a systematic review of sustained response to ␤2-agonist treatment during an exacer-
sublingual immunotherapy (SLIT)196. Specific immunotherapy bation mandates medical attention, and may indicate the
has long-term clinical effects and the potential of preventing need for short-term treatment with oral glucocorticosteroids.
development of asthma in children with allergic rhino
conjunctivitis up to 7 years after treatment termination208. Side effects - Use of oral ␤2-agonists given in standard
doses are associated with more adverse systemic effects
However, in view of the relatively modest effect of such as tremor and tachycardia than occur with inhaled
allergen-specific immunotherapy compared to other preparations.
treatment options, these benefits must be weighed against
the risk of adverse effects and the inconvenience of the Systemic glucocorticosteroids.
prolonged course of injection therapy, including the
minimum half-hour wait required after each injection. Role in therapy - Although systemic glucocorticosteroids
Specific immunotherapy should be considered only after are not usually thought of as reliever medications, they are
strict environmental avoidance and pharmacologic important in the treatment of severe acute exacerbations
intervention, including inhaled glucocorticosteroids, have because they prevent progression of the asthma
failed to control a patientʼs asth ma113. There are no studies exacerbation, reduce the need for referral to emergency
that compare specific immunotherapy with pharmacologic departments and hospitalization, prevent early relapse
therapy for asthma. The value of immunotherapy using after emergency treatment, and reduce the morbidity of the
multiple allergens does not have support. illness. The main effects of systemic glucocorticosteroids
in acute asthma are only evident after 4 to 6 hours. Oral
Side effects - Local and systemic side effects may occur in therapy is preferred and is as effective as intravenous
conjunction with specific immunotherapy administration. hydrocortisone114. A typical short course of oral gluco-
Reactions localized to the injection site may range from a corticosterods for an exacerbation is 40-50 mg115
minimal immediate wheal and flare to a large, painful, prednisolone given daily for 5 to 10 days depending on the
delayed allergic response. Systemic effects may include severity of the exacerbation. When symptoms have
anaphylactic reactions, which may be life threatening, as subsided and lung function has approached the patientʼs
well as severe exacerbations of asthma. Deaths from personal best value, the oral glucocorticosteroids can be
specific immunotherapy have occurred in patients with stopped or tapered, provided that treatment with inhaled
severe asthma. glucocorticosteroids continues116. Intramuscular injection
of glucocorticosteroids has no advantage over a short
Reliever Medications course of oral glucocorticosteroids in preventing relapse114,116.

Reliever medications act quickly to relieve Side effects - Adverse effects of short-term high-dose
bronchoconstriction and its accompanying acute symptoms. systemic therapy are uncommon but include reversible
abnormalities in glucose metabolism, increased appetite,
Rapid-acting inhaled ␤2-agonists. fluid retention, weight gain, rounding of the face, mood
alteration, hypertension, peptic ulcer, and aseptic necrosis
Role in therapy - Rapid-acting inhaled ␤2-agonists are the of the femur.
medications of choice for relief of bronchospasm during
acute exacerbations of asthma and for the pretreatment of
exercise-induced bronchoconstriction. They include

34 ASTHMA TREATMENTS
Anticholinergics. effectiveness is largely unproven. Generally, these
therapies have not been validated by conventional
Role in therapy - Anticholinergic bronchodilators used in standards. Although the psychotherapeutic role of the
asthma include ipratropium bromide and oxitropium therapist forms part of the placebo effect of all treatments,
bromide. Inhaled ipratropium bromide is a less effective this aspect is viewed as an integral part of the so-called
reliever medication in asthma than rapid-acting inhaled ␤2- holistic approach used by practitioners of complementary
agonists. A meta-analysis of trials of inhaled ipratropium and alternative methods, and mitigates against
bromide used in association with an inhaled ␤2-agonist in performance of the large, multicenter, placebo-controlled
acute asthma showed that the anticholinergic produces a randomized studies required to confirm efficacy. However,
statistically significant, albeit modest, improvement in without these the relative efficacy of these alternative
pulmonary function, and significantly reduces the risk of measures will remain unknown120.
hospital admission117. The benefits of ipratropium bromide
in the long-term management of asthma have not been Complementary and alternative therapies include
established, although it is recognized as an alternative acupuncture, homeopathy, herbal medicine, Ayurvedic
bronchodilator for patients who experience such adverse medicine, ionizers, osteopathy and chiropractic
effects as tachycardia, arrhythmia, and tremor from rapid- manipulation, and speleotherapy among others. Dietary
acting ␤2-agonists. supplements, including selenium therapy197 are not of
proven benefit. Apart from those mentioned below, there
Side effects - Inhalation of ipratropium or oxitropium can have been no satisfactory studies from which conclusions
cause a dryness of the mouth and a bitter taste. There is about their efficacy can be drawn.
no evidence for any adverse effects on mucus secretion118.
A single controlled trial of chiropractic spinal manipulation
failed to show benefit of this therapy in asthma121, and a
Theophylline. systematic review of homeopathy found only three relevant
trials with inconclusive results. Although one study of the
Role in therapy - Short-acting theophylline may be Butyeko breathing method suggested minor benefit, a later
considered for relief of asthma symptoms119. The role of study of two physiologically-contrasting breathing
theophylline in treating exacerbations remains controversial. techniques showed similar improvements in reliever and
Short-acting theophylline may provide no additive inhaled glucocorticosteroids use in both groups,
bronchodilator effect over adequate doses of rapid-acting suggesting that perceived improvement with these
␤2-agonists, but it may benefit respiratory drive. methods are the result of non-physiological factors122. A
randomized controlled trial indicated that the practice of
Side effects - Theophylline has the potential for significant Sahaja yoga has limited beneficial effects on asthma for
adverse effects, although these can generally be avoided some objective and subjective measures, although there
by appropriate dosing and monitoring. Short-acting were no significant differences between the intervention
theophylline should not be administered to patients already and control groups at the 2 month follow up assessment198.
on long-term treatment with sustained-release theophylline An integrated breathing and relaxation technique
unless the serum concentration of theophylline is known to (Papworth method) appears to ameliorate respiratory
be low and/or can be monitored. symptoms, dysfunctional breathing and adverse mood but
there is no evidence of effect on objective measures of
Short-acting oral ␤2-agonists. respiratory function210.

Short-acting oral ␤2-agonists are appropriate for use in the Side effects - Acupuncture-associated hepatitis B, bilateral
few patients who are unable to use inhaled medication. pneumothorax, and burns have been described. Side
However, their use is associated with a higher prevalence effects of other alternative and complementary medicines
of adverse effects. are largely unknown. However, some popular herbal
medicines could potentially be dangerous, as exemplified
Complementary And Alternative Medicine by the occurrence of hepatic veno-occlusive disease
associated with the consumption of the commercially
The roles of complementary and alternative medicine in available herb comfrey. Comfrey products are sold as
adult asthma treatment are limited because these herbal teas and herbal root powders, and their toxicity is
approaches have been insufficiently researched and their due to the presence of pyrrolizidine alkaloids.

**See also the “Asthma Medications: Adults” section at the beginning of this
chapter for more information on the therapeutic role and side effects of various
therapies. In this section, only information specific to children is provided. ASTHMA TREATMENTS 35
 correctly coordinate inhalation with actuation of the MDI.
ASTHMA TREATMENT: CHILDREN** Commercially produced spacers with well-characterized
drug output characteristics are preferable. If these are not
Route of Administration available or feasible, a homemade spacer (for example, one
made from a 500 ml plastic cold drink bottle) may be used126.
Inhaled therapy is the cornerstone of asthma treatment for Nebulizers have rather imprecise dosing, are expensive,
children of all ages. Almost all children can be taught to are time consuming to use and care for, and require
effectively use inhaled therapy. Different age groups maintenance. They are mainly reserved for children who
require different inhalers for effective therapy, so the cannot use other inhaler devices. In severe acute asthma
choice of inhaler must be individualized. Information about exacerbations a nebulizer is often used, although an MDI
the lung dose for a particular drug formulation is seldom with a spacer is equally effective127.
available for children, and marked differences exist
between the various inhalers. This should be considered Controller Medications
whenever one inhaler device is substituted with another.
In addition, the choice of inhaler device should include Controller medications for children include inhaled and
consideration of the efficacy of drug delivery, cost, safety, systemic glucocorticosteroids, leukotriene modifiers, long-
ease of use, convenience, and documentation of its use in acting inhaled ␤2-agonists, theophylline, cromones, and
the patientʼs age group123-125. In general, a metered-dose long-acting oral ␤2-agonists.
inhaler (MDI) with spacer is preferable to nebulized
therapy due to its greater convenience, more effective lung Inhaled glucocorticosteroids.
deposition, lower risk of side effects, and lower cost.
Based on these considerations, a general strategy for Role in Therapy - Inhaled glucocorticosteroids are the
choosing inhalers in children is given in Figure 3-3. most effective controller therapy, and are therefore the
recommended treatment for asthma for children of all
Figure 3-3: Choosing an Inhaler Device for ages. Figure 3-4 lists approximately equipotent doses of
Children with Asthma* different inhaled glucocorticosteroids administered via
different inhalation devices.
Age Group Preferred Device Alternate Device
Younger than 4 years Pressurized metered- Nebulizer with face Children older than 5 years. Dose-response studies and
dose inhaler plus mask
dedicated spacer dose titration studies in children128,129 demonstrate marked
with face mask and rapid clinical improvements in symptoms and lung
4 – 6 years Pressurized metered- Nebulizer with function at low doses of inhaled glucocorticosteroids (e.g.,
dose inhaler plus mouthpiece 100-200 ␮g budesonide daily)130-134, and mild disease is
dedicated spacer well controlled by such doses in the majority of patients132.
with mouthpiece
Early intervention with inhaled budesonide is associated
Older than 6 years Dry powder inhaler, Nebulizer with with improved asthma control and less additional asthma
or breath-actuated mouthpiece
pressurized metered- medication use211. Some patients require higher doses
dose inhaler, or (400 ␮g/day) to achieve optimal asthma control and
pressurized metered- effective protection against exercise-induced asthma.
dose inhaler with Only a minority of patients require treatment with high
spacer and mouthpiece
doses of inhaled glucocorticosteroids133,134. In children
*Based on efficacy of drug delivery, cost effectiveness, safety, ease of use, and older than 5 years, maintenance treatment with inhaled
convenience. glucocorticosteroids controls asthma symptoms, reduces
the frequency of acute exacerbations and the number of
Spacers retain large drug particles that would normally
hospital admissions, improves quality of life, lung function,
be deposited in the oropharynx, reducing oral and
and bronchial hyperresponsiveness, and reduces
gastrointestinal absorption and thus systemic availability of
exercise-induced bronchoconstriction10. Symptom control
the inhaled drug. This is mainly important when inhaled
and improvements in lung function occur rapidly (after 1 to
glucocorticosteroids with first-pass metabolism
2 weeks), although longer treatment (over the course of
(beclomethasone dipropionate, flunisolide, triamcinolone,
months) and sometimes higher doses may be required
and budesonide) are given via pressurized MDI. Use of a
to achieve maximum improvements in airway hyper-
spacer also reduces oropharyngeal side effects. During
responsiveness10. When glucocorticosteroid treatment
acute asthma attacks, an MDI should always be used with
a spacer, as in this situation a child may be unable to is discontinued, asthma control deteriorates within weeks
to months10.

36 ASTHMA TREATMENTS
 Figure 3-4. Estimated Equipotent Daily Doses of Inhaled Glucocorticosteroids for Children
Drug ␮g)
Low Daily Dose (␮ ␮g)
Medium Daily Dose (␮ ␮g)‡
High Daily Dose (␮
Beclomethasone dipropionate 100 - 200 >200 - 400 >400
Budesonide* 100 - 200 >200 - 400 >400
Budesonide-Neb 250 - 500 >500 - 1000 >1000
Ciclesonide* 80 - 160 >160 - 320 >320
Flunisolide 500 - 750 >750 - 1250 >1250
Fluticasone 100 - 200 >200 - 500 >500
Mometasone furoate* 100 - 200 >200 - 400 >400
Triamcinolone acetonide 400 - 800 >800 - 1200 >1200

† Comparisons based upon efficacy data.

‡ Patients considered for high daily doses except for short periods should be referred to a specialist for assessment to consider alternative combinations of
controllers. Maximum recommended doses are arbitrary but with prolonged use are associated with increased risk of systemic side effects.
* Approved for once-daily dosing in mild patients.

Notes
• The most important determinant of appropriate dosing is the clinicianʼ s judgment of the patientʼs re sponse to therapy. The clinician must monitor the
patientʼs response in terms of clinical control and adjust the dose accordingly. Once control of asthma is achieved, the dose of medication should be
carefully titrated to the minimum dose required to maintain control, thus reducing the potential for adverse effects.
• Designation of low, medium, and high doses is provided from manufacturersʼ recommendations wh ere possible. Clear demonstration of dose-
response relationships is seldom provided or available. The principle is therefore to establish the minimum effective controlling dose in each patient,
as higher doses may not be more effective and are likely to be associated with greater potential for adverse effects.
• As CFC preparations are taken from the market, medication inserts for HFA preparations should be carefully reviewed by the clinician for the correct
equivalent dosage.

Children 5 years and younger. Treatment with inhaled Growth. When assessing the effects of inhaled gluco-
glucocorticosteroids in children 5 years and younger with corticosteroids on growth in children with asthma, it
asthma generally produces similar clinical effects as in is important to consider potential confounding factors.
older children, but dose-response relationships have For example, many children with asthma receiving inhaled
been less well studied. The clinical response may differ glucocorticosteroids experience a reduction in growth rate
depending on the inhaler and the childʼs ability to use the toward the end of the first decade of life140. This reduced
inhaler correctly. With use of a spacer device, daily doses growth rate continues into the mid-teens and is associated
≤ 400 µg of budesonide or equivalent result in near- with a delay in the onset of puberty. The pre-pubertal
maximum benefits in the majority of patients136,137. Use of deceleration of growth velocity resembles growth
inhaled glucocorticosteroids does not induce remission of retardation. However, the delay in pubertal growth is also
asthma and it returns when treatment is stopped138. associated with a delay in skeletal maturation, so that the
childʼs bone age corresponds to his or her height140,141.
The clinical benefits of intermittent systemic or inhaled Ultimately, adult height is not decreased, although it is
glucocorticosteroids for children with intermittent, viral- reached at a later than normal age. The use of 400 µg
induced wheeze remain controversial. While some inhaled budesonide or equivalent per day to control
studies in older children found small benefits, a study in asthma has less impact on growth than does low
young children found no effects on wheezing symptoms139. socioeconomic status141. A summary of the findings of
There is no evidence to support the use of maintenance studies on inhaled glucocorticosteroids and growth is
low-dose inhaled glucocorticosteroids for preventing early provided in Figure 3-5.
transient wheezing136,139,199.
Bones. The potential clinically relevant adverse effects of
Side effects - The majority of studies evaluating the inhaled glucocorticosteroids on bones in children are
systemic effects of inhaled glucocorticosteroids have been osteoporosis and fracture. Several cross-sectional and
undertaken in children older than 5 years. longitudinal epidemiologic studies have assessed the
effects of long-term inhaled glucocorticosteroid treatment
on these outcomes132,135,143-149. The conclusions are
summarized in Figure 3-6.

ASTHMA TREATMENTS 37
 Figure 3-5. Summary: Glucocorticosteroids and Cataracts. Inhaled glucocorticosteroids have not been
Growth in Children140-142 associated with an increased occurrence of cataract
development in children30,135.
• Uncontrolled or severe asthma adversely affects growth and
final adult height. Central nervous system effects. Although isolated case
• No long-term controlled studies have reported any statistically or reports have suggested that hyperactive behavior,
clinically significant adverse effects on growth of 100 to 200 ␮g aggressiveness, insomnia, uninhibited behavior, and
per day of inhaled glucocorticosteroids. impaired concentration may be seen with inhaled
• Growth retardation may be seen with all inhaled glucocorticosteroid treatment, no increase in such effects
glucocorticosteroids when a high dose is administered.
has been found in two long-term controlled trials of inhaled
• Growth retardation in both short- and medium-term studies is
budesonide involving more than 10,000 treatment years132,135.
dose dependent.
• Important differences seem to exist between the growth-
retarding effects of various inhaled glucocorticosteroids and
Oral candidiasis, hoarseness, and bruising. Clinical thrush
inhalers. is seldom a problem in children treated with inhaled or
• Different age groups seem to differ in their susceptibility to the systemic glucocorticosteroids. This side effect seems to
growth-retarding effects of inhaled glucocorticosteroids; children be related to concomitant use of antibiotics, high daily
aged 4 to 10 are more susceptible than adolescents. doses, dose frequency, and inhaler device. Spacers
• Glucocorticosteroid-induced changes in growth rate during the reduce the incidence of oral candidiasis151. Mouth rinsing
first year of treatment appear to be temporary. is beneficial152. The occurrence of hoarseness or other
• Children with asthma treated with inhaled glucocorticosteroids noticeable voice changes during budesonide treatment is
attain normal adult height (predicted from family members) but at similar to placebo30. Treatment with an average daily dose
a later age. of 500 ␮g budesonide for 3 to 6 years is not associated
with an increased tendency to bruise30.
Figure 3-6. Summary: Bones and
Glucocorticosteroids in Children10,143,144 Dental side effects. Inhaled glucocorticosteroid treatment
is not associated with increased incidence of caries.
• No studies have reported any statistically significant increased of However, the increased level of dental erosion reported in
risk of fractures in children taking inhaled glucocorticosteroids. children with asthma153 may be due to a reduction in oral
• Oral or systemic glucocorticosteroid use increases the risk of pH that may result from inhalation of ␤2-agonists154.
fracture. The risk of fracture increases along with the number of
treatments, with a 32% increase at four courses ever. Use of Other local side effects. The long-term use of inhaled
inhaled glucocorticosteroids reduces the need for systemic courses.
glucocorticosteroids is not associated with an increased
• Controlled longitudinal studies of 2 to 5 yearsʼ duration and
incidence of lower respiratory tract infections, including
several cross-sectional studies found no adverse effects of
inhaled glucocorticosteroid treatment on bone mineral density.
tuberculosis.
• No prospective studies have followed children on inhaled
glucocorticosteroid treatment until peak bone mineral density
has been reached. Leukotriene modifiers.

Children older than 5 years. Leukotriene modifiers provide

Hypothalamic-pituitary-adrenal (HPA) axis. Though clinical benefit in children older than 5 years at all levels of
differences exist between the various inhaled severity155-159, but generally less than that of low-dose inhaled
glucocorticosteroids and inhaler devices, treatment with glucocorticosteroids160. Leukotriene modifiers provide partial
inhaled glucocorticosteroid doses of less than 200 ␮g protection against exercise-induced bronchoconstriction
budesonide or equivalent daily is normally not associated within hours after administration with no loss of
with any significant suppression of the HPA axis in bronchoprotective effect200. As add-on treatment in
children135. At higher doses, small changes in HPA axis children whose asthma is insufficiently controlled by low
function can be detected with sensitive methods148. The doses of inhaled glucocorticosteroids, leukotriene
clinical relevance of these findings is not known, since modifiers provide moderate clinical improvements,
there have not been reports of adrenal crisis in clinical including a significant reduction in exacerbations161,162.
trials of inhaled glucocorticosteroids in children. However, Combination therapy is less effective in controlling asthma
adrenal crisis has been reported in children treated with in children with moderate persistent asthma than
excessively high doses of inhaled glucocorticosteroids150. increasing to moderate doses of inhaled
glucocorticosteroids201.

38 ASTHMA TREATMENTS
 exacerbations of asthma, they are not the recommended
Children 5 years and younger. In addition to the efficacy option when more than one controller is required170. If
as described above163,164, leukotriene modifiers reduce viral- used, long-acting ␤2-agonists should only be used in
induced asthma exacerbations in children ages 2-5 with a combination with an appropriate dose of inhaled gluco-
history of intermittent asthma164. corticosteroid as determined by a physician, preferably in
a fixed combination inhaler.
Side effects - No safety concerns have been demonstrated
from the use of leukotriene modifiers in children. Theophylline.

Long-acting inhaled ␤2-agonists. Role in therapy - Theophylline has been shown to be

effective as monotherapy and as add-on treatment to
Role in therapy - Long-acting inhaled ␤2-agonists are inhaled or oral glucocorticosteroids in children older than
primarily used as add-on therapy in children older than 5 years. It is significantly more effective than placebo at
5 years whose asthma is insufficiently controlled by controlling day and night symptoms and improving lung
medium doses of inhaled glucocorticosteroids or as single- function172-174. Maintenance treatment offers a marginal
dose therapy before vigorous exercise. Monotherapy with protective effect against exercise-induced broncho-
long-acting inhaled ␤2-agonists should be avoided75. constriction175. Add-on treatment with theophylline has
been found to improve asthma control and reduce the
Children older than 5 years. Long-acting inhaled ␤2- maintenance glucocorticosteroid dose necessary in
agonists have mainly been studied in children older than children with severe asthma treated with inhaled or oral
5 years as add-on therapy for patients whose asthma is glucocorticosteroids176,177. A few studies in children 5 years
not controlled on low to high doses of inhaled glucocortico- and younger also suggest some clinical benefit. However,
steroids. Significant improvements in peak flow and other the efficacy of theophylline is less than that of low-dose
lung function measurements have been found in most inhaled glucocorticosteroids.
studies55,165-169. However, their effects on other outcomes
such as symptoms and need for reliever medication have Most clinical evidence regarding the use of theophylline in
been less consistent and have only been observed in children has been obtained from studies in which plasma
about half of the trials conducted. Add-on treatment with theophylline levels were maintained within the therapeutic
long-acting inhaled ␤2-agonists has not been shown to range of 55-110 µmol/L (5-10 µg/ml). Further studies
reduce the frequency of exacerbations170. Inhalation of a suggest that its controller functions may occur at lower
single dose of long-acting inhaled ␤2-agonist effectively plasma levels (corresponding to doses of around 10
blocks exercise-induced bronchoconstriction for several mg/kg/day). Sustained-release products are preferable
hours171. With daily therapy the duration of the protection is for maintenance therapy, since they enable twice-daily
somewhat reduced171, but is still longer than that provided dosing. Sustained-release products with reliable
by short-acting ␤2-agonists. absorption profiles and complete bioavailability with and
without concomitant food intake are preferred.

Combination products containing an inhaled glucocortico- Theophylline elimination may vary up to tenfold between
steroid and a long-acting inhaled ␤2-agonist are preferred individuals. Measurement of plasma theophylline levels is
to long-acting inhaled ␤2-agonist and inhaled glucocortico- not necessary in otherwise healthy children when doses
steroids administered by separate inhalers. Fixed less than 10 mg/kg/day are used. However, when higher
doses are used or when drugs that may increase
combination inhalers ensure that the long-acting ␤2-
theophylline levels are also used chronically, plasma
agonist is always accompanied by a glucocorticosteroid.
theophylline levels should be measured two hours before
administration of the next dose once steady state has
Children 5 years or younger. The effect of long-acting
been reached (after 3 days).
inhaled ␤2-agonists has not yet been adequately studied.
Combination therapy with budesonide and formoterol used
Side effects - The most common side effects of theophylline
both as maintenance and rescue has been shown to are anorexia, nausea, vomiting, and headache178. Mild
reduce asthma exacerbations in children ages 4 years and central nervous stimulation, palpitations, tachycardia,
older with moderate to severe asthma202. arrhythmias, abdominal pain, diarrhea, and, rarely, gastric
bleeding may also occur. These side effects are mainly seen at
Side effects - Although long-acting inhaled ␤2-agonists doses higher than 10 mg/kg/day. The risk of adverse effects
are well-tolerated in children, even after long-term use, is reduced if treatment is initiated with daily doses around
because of inconsistency of reports on their effects on
ASTHMA TREATMENTS 39
5 mg/kg/day and then gradually increased to 10 mg/kg/day. Reliever Medications
Severe overdosing with theophylline can be fatal.
Rapid-acting inhaled ß2-agonists and short-acting oral
Cromones: sodium cromoglycate and nedocromil sodium. ␤2-agonists.

Role in therapy - Sodium cromoglycate and nedocromil Role in therapy - Rapid-acting inhaled ␤2-agonists are the
sodium have a limited role in the long-term treatment of most effective bronchodilators available and therefore the
asthma in children. One meta-analysis has concluded that preferred treatment for acute asthma in children of all
long-term treatment with sodium cromoglycate is not ages. The inhaled route results in more rapid broncho-
significantly better than placebo for management of asthma dilation at a lower dose and with fewer side effects than
in children179. Another has confirmed superiority of low dose oral or intravenous administration186. Furthermore, inhaled
inhaled glucocorticosteroids over sodium cromoglycate in therapy offers significant protection against exercise-
persistent asthma, but as there were no placebo arms in induced bronchoconstriction and other challenges for 0.5 to
these studies, the efficacy of sodium cromoglycate cannot 2 hours (long acting ␤2-agonists offer longer protection)187.
be confirmed from the studies reviewed; no between This is not seen after systemic administration188. Oral therapy
treatment difference in safety was observed180. is rarely needed and reserved mainly for young children
who cannot use inhaled therapy.
Nedocromil sodium has been shown to reduce
exacerbations, but its effect on other asthma outcomes is Side effects - Skeletal muscle tremor, headache, palpitations,
not superior to placebo135. A single dose of sodium and some agitation are the most common complaints
cromoglycate or nedocromil sodium attenuates broncho- associated with high doses of ␤2-agonists in children.
spasm induced by exercise or cold air181. Studies of the These complaints are more common after systemic
use of these medications in children 5 years and younger administration and disappear with continued treatment189.
are sparse and results are conflicting.
Anticholinergics.
Side effects - Cough, throat irritation, and broncho-
constriction occur in a small proportion of patients treated Role in therapy - Inhaled anticholinergics are not recommended
with sodium cromoglycate. A bad taste, headache, and for long-term management of asthma in children190.
nausea are the most common side effects of nedocromil182.

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Epub 2008 Apr 11.

48 MECHANISMS OF ASTHMA
 CHAPTER

ASTHMA
MANAGEMENT
AND
PREVENTION
INTRODUCTION COMPONENT 1: DEVELOP
Asthma has a significant impact on individuals, their
PATIENT/DOCTOR PARTNERSHIP
families, and society. Although there is no cure for
asthma, appropriate management that includes a KEY POINTS:
partnership between the physician and the patient/family
most often results in the achievement of control. • The effective management of asthma requires the
development of a partnership between the person
The goals for successful management of asthma are to: with asthma and his or her health care professional(s)
(and parents/caregivers, in the case of children with
asthma).
• Achieve and maintain control of symptoms
• Maintain normal activity levels, including exercise • The aim of this partnership is guided self-
• Maintain pulmonary function as close to normal as management—that is, to give people with asthma
possible the ability to control their own condition with
• Prevent asthma exacerbations guidance from health care professionals.
• Avoid adverse effects from asthma medications
• Prevent asthma mortality. • The partnership is formed and strengthened as
patients and their health care professionals discuss
and agree on the goals of treatment, develop a
These goals for therapy reflect an understanding of
personalized, written self-management plan
asthma as a chronic inflammatory disorder of the airways
including self-monitoring, and periodically review the
characterized by recurrent episodes of wheezing,
patientʼs treatment and level of asthma control.
breathlessness, chest tightness, and coughing. Clinical
studies have shown that asthma can be effectively
• Education should be an integral part of all interactions
controlled by intervening to suppress and reverse the
between health care professionals and patients, and
inflammation as well as treating the bronchoconstriction
is relevant to asthma patients of all ages.
and related symptoms. Furthermore, early intervention to
stop exposure to the risk factors that sensitized the airway • Personal asthma action plans help individuals with
may help improve the control of asthma and reduce asthma make changes to their treatment in response
medication needs. Experience in occupational asthma to changes in their level of asthma control, as
indicates that long-standing exposure to sensitizing agents indicated by symptoms and/or peak expiratory flow,
may lead to irreversible airflow limitation. in accordance with written predetermined guidelines.

The management of asthma can be approached in

different ways, depending on the availability of the various INTRODUCTION
forms of asthma treatment and taking into account cultural
preferences and differing health care systems. The The effective management of asthma requires the
recommendations in this chapter reflect the current development of a partnership between the person with
scientific understanding of asthma. They are based as far asthma and his or her health care professional(s) (and
as possible on controlled clinical studies, and the text parents/caregivers in the case of children with asthma).
references many of these studies. For those aspects of The aim of this partnership is to enable patients with
the clinical management of asthma that have not been the asthma to gain the knowledge, confidence, and skills to
subject of specific clinical studies, recommendations are assume a major role in the management of their asthma.
based on literature review, clinical experience, and expert The partnership is formed and strengthened as patients
opinion of project members. and their health care professionals discuss and agree on
the goals of treatment, develop a personalized, written
The recommendations for asthma management are laid self-management action plan including self-monitoring,
out in five interrelated components of therapy: and periodically review the patientʼs treatment and level
of asthma control (Figure 4.1-1).
1. Develop Patient/Doctor Partnership
2. Identify and Reduce Exposure to Risk Factors This approach is called guided self-management and has
3. Assess, Treat, and Monitor Asthma been shown to reduce asthma morbidity in both adults
4. Manage Asthma Exacerbations (Evidence A) and children (Evidence A). A number of
5. Special Considerations. specific systems of guided self-management have been

50 ASTHMA MANAGEMENT AND PREVENTION

developed1-10 for use in a wide range of settings, including
primary care1,4,6, hospitals2,3,7,10, emergency departments8, Figure 4.1-2. Education and the Patient/Doctor
Partnership
and internet-based home monitoring340, and among such
diverse groups as pregnant women with asthma11, children Goal: To provide the person with asthma, their family, and other
and adolescents12,13, and in multi-racial populations14. caregivers with suitable information and training so that they can
Guided self-management may involve varying degrees of keep well and adjust treatment according to a medication plan
independence, ranging broadly from patient-directed self- developed with the health care professional.
management in which patients make changes without
reference to their caregiver, but in accordance with a prior Key components:

K Focus on the development of the partnership

written action plan, to doctor-directed self-management in
K Acceptance that this is a continuing process
which patients rely follow a written action plan, but refer
most major treatment changes to their physician at the K A sharing of information
time of planned or unplanned consultations. Cochrane K Full discussion of expectations
systematic reviews13,15-18 have examined the role of K Expression of fears and concerns
education and self-management strategies in the care of
asthma patients. Provide specific information, training, and advice about:

Figure 4.1-1. Essential Features of the K Diagnosis

Doctor-Patient Partnership to Achieve Guided K Difference between “relievers” and “controllers”
Self-Management in Asthma K Potential side effects of medications
K Use of inhaler devices
• Education K Prevention of symptoms and attacks
K Signs that suggest asthma is worsening and actions to take
K Monitoring control of asthma
• Joint setting of goals

K How and when to seek medical attention

• Self-monitoring. The person with asthma is taught to combine
assessment of asthma control with educated interpretation of
key symptoms
The person then requires:
• Regular review of asthma control, treatment, and skills by a
health care professional K A guided self-management plan
• Written action plan. The person with asthma is taught which K Regular supervision, revision, reward, and reinforcement
medications to use regularly and which to use as needed, and
how to adjust treatment in response to worsening asthma control Good communication is essential as the basis for
• Self-monitoring is integrated with written guidelines for both the subsequent good compliance/adherence19-22 (Evidence B).
long-term treatment of asthma and the treatment of asthma Key factors that facilitate good communication are23:
exacerbations.
• A congenial demeanor (friendliness, humor, and
attentiveness)
ASTHMA EDUCATION • Engaging in interactive dialogue
• Giving encouragement and praise
Education should be an integral part of all interactions • Empathy, reassurance, and prompt handling of
between health care professionals and patients, and is any concerns
relevant to asthma patients of all ages. Although the focus • Giving of appropriate (personalized) information
of education for small children will be on the parents and • Eliciting shared goals
caregivers, children as young as 3 years of age can be • Feedback and review
taught simple asthma management skills. Adolescents
may have some unique difficulties regarding adherence Teaching health care professionals to improve their
that may be helped through peer support group education in communication skills can result in measurably better
addition to education provided by the health care professional12. outcomes–including increased patient satisfaction, better
health, and reduced use of health care–and these benefits
Figure 4.1-2 outlines the key features and components of may be achieved without any increase in consultation
an asthma education program. The information and skills times24. Studies have also shown that patients can be
training required by each person may vary, and their ability trained to benefit more from consultations. Patients taught
or willingness to take responsibility similarly differs. Thus how to give information to doctors in a clearer manner,
all individuals require certain core information and skills, but information-seeking techniques, and methods of checking
most education must be personalized and given to the person their understanding of what the doctor had told them gained
in a number of steps. Social and psychological support may significant improvements in compliance and overall health25.
also be required to maintain positive behavioral change.

ASTHMA MANAGEMENT AND PREVENTION 51

At the Initial Consultation adjustments of medication are made by a doctor15
(Evidence B). Thus, patients who are unable to undertake
Early in the consultation the person with asthma needs guided self-management can still achieve benefit from a
information about the diagnosis and simple information structured program of regular medical review. Although
about the types of treatment available, the rationale for the interactive computerized asthma education programs may
specific therapeutic interventions being recommended, and improve patient asthma knowledge and symptoms, their
strategies for avoiding factors that cause asthma symptoms. effect on objective clinical outcomes is less consistent353.
Different inhaler devices can be demonstrated, and the
person with asthma encouraged to participate in the Examples of self-management plans that have been
decision as to which is most suitable for them. Some of recommended can be found on several Websites
these devices and techniques for their use are illustrated (UK National Asthma Campaign Plan,
on the GINA Website (http://www.ginasthma.org). Criteria http://www.asthma.org.uk; International Asthma
for initial selection of inhaler device include device Management Plan “Zone System,”
availability and cost, patient skills, and preferences of the http://www.nhlbisupport.com/asthma/index.html;
health professional and patient26-28. Patients should be New Zealand “Credit Card” System,
given adequate opportunity to express their expectations http://www.asthmanz.co.nz.
of both their asthma and its treatment. A frank appraisal
should be made of how far their expectations may or may An example of the contents for an asthma plan for patients
not be met, and agreement should be made about specific to maintain control of asthma is shown in Figure 4.1-3.
goals for therapy.
Follow-Up and Review
At the initial consultation, verbal information should be
supplemented by the provision of written or pictorial29, 30 Follow-up consultations should take place at regular
information about asthma and its treatment. The GINA intervals. At these visits, the patientʼs questions are
Website (http://www.ginasthma.org) contains patient discussed, and any problems with asthma and its initial
educational materials, as well as links to several asthma treatment are reviewed. Inhaler device technique should
websites. The patient and his or her family should be be assessed regularly, and corrected if inadequate33.
encouraged to make a note of any questions that arise Follow-up consultations should also include checking the
from reading this information or as a result of the personʼs adherence/compliance to the medication plan
consultation, and should be given time to address these and recommendations for reducing exposure to risk
during the next consultation. factors. Symptoms (and where appropriate, home peak
flow recordings) noted in the diary are also reviewed
Personal Asthma Action Plans regularly. After a period of initial training, the frequency of
home peak flow and symptom monitoring depends in part
Personal asthma action plans help individuals with asthma on the level of control of the personʼs asthma. Routine
make changes to their treatment in response to changes in follow-up visits may be an effective time to review the
their level of asthma control, as indicated by symptoms written self-managment plan and its understanding354.
and/or peak expiratory flow, in accordance with written Educational messages should be reviewed and repeated
predetermined guidelines23,31,32. or added to if necessary. A single page prompt to
clinicians has been shown to improve the provision of
The effects were greatest where the intervention involved preventive care to children with asthma during office
each of the following elements: education, self-monitoring, visits341.
regular review, and patient-directed self-management
using a written self-management action plan (Evidence Improving Adherence
A). Patients experience a one-third to two-thirds reduction
in hospitalizations, emergency room visits, unscheduled Studies of adults and children34 have shown that around
visits to the doctor for asthma, missed days of work, and 50% of those on long-term therapy fail to take medications
nocturnal wakening. It has been estimated that the as directed at least part of the time. Patient concern about
implementation of a self-management program in 20 side-effects of inhaled glucocorticosteroids whether real or
patients prevents one hospitalization, and successful perceived may influence adherence342. Non-adherence
completion of such a program by eight patients prevents may be defined in a nonjudgmental way as the failure of
one emergency department visit16-18,23. Less intensive treatment to be taken as agreed upon by the patient and
interventions that involve self-management education but the health care professional. Non-adherence may be
not a written plan are less effective15. The efficacy is identified by prescription monitoring, pill counting, or drug
similar regardless of whether patients self-adjust their assay, but at a clinical level it is best detected by asking
medications according to an individual written plan or about therapy in a way that acknowledges the likelihood of

52 ASTHMA MANAGEMENT AND PREVENTION

incomplete adherence (e.g., “So that we may plan therapy, Self-Management in Children
do you mind telling me how often you actually take the
medicine?”). Specific drug and non-drug factors involved Children with asthma (with the help of their parents/
in non-adherence are listed in Figure 4.1-4. caregivers) also need to know how to manage their own
condition. Simple educational interventions (designed to
Fig 4.1-3 Example Of Contents Of An Action Plan To teach self-management skills) among children admitted to
Maintain Asthma Control the hospital with asthma have been shown to significantly
reduce the readmission rate and reduce morbidity13. A
Your Regular Treatment:
1. Each day take ___________________________
systematic review found that educational programs for the
2. Before exercise, take _____________________ self-management of asthma in children and adolescents
led to improvements in lung function and feelings of self-
WHEN TO INCREASE TREATMENT
Assess your level of Asthma Control
control, and reduced absences from school, the number of
In the past week have you had: days with restricted activity, and the number of emergency
Daytime asthma symptoms more than 2 times ? No Yes department visits13,343. For children, symptom-based action
Activity or exercise limited by asthma? No Yes
Waking at night because of asthma? No Yes
plans are more effective than those based on peak
The need to use your [rescue medication] more than 2 times? No Yes flows355..
If you are monitoring peak flow, peak flow less than______? No Yes
If you answered YES to three or more of these questions, your asthma is
uncontrolled and you may need to step up your treatment. THE EDUCATION OF OTHERS
HOW TO INCREASE TREATMENT
STEP-UP your treatment as follows and assess improvement every day: The education of the general public about asthma is
_________________________________ [Write in next treatment step here] helpful in that it enables members of the public to
Maintain this treatment for _____________ days [specify number]
recognize asthma symptoms and their consequences and
WHEN TO CALL THE DOCTOR/CLINIC. encourages those with asthma to seek medical attention
Call your doctor/clinic: _______________ [provide phone numbers] and follow their asthma management program. Greater
If you donʼt respond in _________ days [specify number]
____________________________ [optional lines for additional instruction]
awareness of asthma is also likely to help dispel
misconceptions that may exist about the condition and
EMERGENCY/SEVERE LOSS OF CONTROL reduce feelings of stigmatization on the part of patients.
If you have severe shortness of breath, and can only speak in short sentences,
If you are having a severe attack of asthma and are frightened,
If you need your reliever medication more than every 4 hours and are not Specific advice about asthma and its management should
improving. be offered to school teachers and physical education
1. Take 2 to 4 puffs ___________ [reliever medication]
instructors, and several organizations produce materials
2. Take ____mg of ____________ [oral glucocorticosteroid]
3. Seek medical help: Go to ________________; Address______________ for this purpose. Schools may need advice on improving
Phone: _______________________ the environment and air quality for children with asthma35.
4. Continue to use your _________[reliever medication] until you are able
It is also helpful for employers to have access to clear
to get medical help.
advice about asthma. Most occupations are as suitable for
those with asthma as for those without, but there may be
some circumstances where caution is needed.
Figure 4.1-4. Factors Involved in Non-Adherence

Drug factors Non-drug factors

Difficulties with inhaler Misunderstanding or lack of instruction
devices Fears about side effects
Awkward regimes (e.g., Dissatisfaction with health care professionals
four times daily or Unexpressed/undiscussed fears or concerns
multiple drugs) Inappropriate expectations
Side effects Poor supervision, training, or follow-up
Cost of medication Anger about condition or its treatment
Dislike of medication Underestimation of severity
Distant pharmacies Cultural issues
Stigmatization
Forgetfulness or complacency
Attitudes toward ill health
Religious issues

ASTHMA MANAGEMENT AND PREVENTION 53

 Other than preventing tobacco exposure both in utero and
COMPONENT 2: IDENTIFY AND REDUCE after birth, there are no proven and widely accepted
EXPOSURE TO RISK FACTORS interventions that can prevent the development of asthma.

Allergic sensitization can occur prenatally37,38. There is

KEY POINTS: currently insufficient information on the critical doses and
timing of allergen exposure to permit intervention in this
• Pharmacologic intervention to treat established process, and no strategies can be recommended to
asthma is highly effective in controlling symptoms prevent allergic sensitization prenatally. Prescription of
and improving quality of life. However, measures to
an antigen-avoidance diet to a high-risk woman during
prevent the development of asthma, asthma
pregnancy is unlikely to reduce substantially her risk of
symptoms, and asthma exacerbations by avoiding
or reducing exposure to risk factors should be giving birth to an atopic child39. Moreover, such a diet may
implemented wherever possible. have an adverse effect on maternal and/or fetal nutrition.

• At this time, few measures can be recommended for The role of diet, particularly breast-feeding, in relation to
prevention of asthma because the development of the development of asthma has been extensively studied
the disease is complex and incompletely understood. and, in general, infants fed formulas of intact cowʼs milk
or soy protein compared with breast milk have a higher
• Asthma exacerbations may be caused by a variety of incidence of wheezing illnesses in early childhood40.
risk factors, sometimes referred to as "triggers," including Exclusive breast-feeding during the first months after birth
allergens, viral infections, pollutants, and drugs. is associated with lower asthma rates during childhood41.

• Reducing a patientʼs exp osure to some categories The “hygiene hypothesis” of asthma, though controversial,
of risk factors improves the control of asthma and has led to the suggestion that strategies to prevent allergic
reduces medication needs. sensitization should focus on redirecting the immune
response of infants toward a Th1, nonallergic response
• The early identification of occupational sensitizers or on modulating T regulator cells42, but such strategies
and the removal of sensitized patients from any currently remain in the realm of hypothesis and require
further exposure are important aspects of the further investigation. The role of probiotics in the prevention
management of occupational asthma. of allergy and asthma is also unclear43. Exposure to cats
has been shown to reduce risk of atopy in some studies44.

INTRODUCTION Exposure to tobacco smoke both prenatally and

postnatally is associated with measurable harmful effects,
Although pharmacologic intervention to treat established including effects on lung development45 and a greater risk
asthma is highly effective in controlling symptoms and of developing wheezing illnesses in childhood46. Although
improving quality of life, measures to prevent the there is little evidence that maternal smoking during
development of asthma, asthma symptoms, and asthma pregnancy has an effect on allergic sensitization47, passive
by avoiding or reducing exposure to risk factors should be smoking increases the risk of allergic sensitization in
implemented wherever possible36. At this time, few children47,48. Both prenatal and postnatal maternal smoking
measures can be recommended for prevention of asthma is problematic49. Pregnant women and parents of young
because the development of the disease is complex and children should be advised not to smoke (Evidence B).
incompletely understood. This area is a focus of intensive
research, but until such measures are developed Once allergic sensitization has occurred, there are
prevention efforts must primarily focus on prevention of theoretically still opportunities to prevent the actual
asthma symptoms and attacks. development of asthma. Whether H1-antagonists
(antihistamines)50,51 or allergen-specific immunotherapy52,53
can prevent the development of asthma in children who
ASTHMA PREVENTION have other atopic diseases remains an area of investigation,
and these interventions cannot be recommended for wide
Measures to prevent asthma may be aimed at the prevention adoption in clinical practice at this time.
of allergic sensitization (i.e., the development of atopy,
likely to be most relevant prenatally and perinatally), or the
prevention of asthma development in sensitized people.

54 ASTHMA MANAGEMENT AND PREVENTION

 and reduction of microhabitats favorable to mites has been
PREVENTION OF ASTHMA suggested, although its efficacy at reducing symptoms
SYMPTOMS AND EXACERBATIONS has only been confirmed in deprived populations with a
specific environmental exposure58 (Evidence B) and a
Asthma exacerbations may be caused by a variety of recommendation for its widespread use cannot be made.
factors, sometimes referred to as “triggers,” including
allergens, viral infections, pollutants, and drugs. Reducing Furred animals. Complete avoidance of pet allergens is
a patientʼs exposure to some of these categories of risk impossible, as the allergens are ubiquitous and can be
factors (e.g., smoking cessation, reducing exposure to found in many environments outside the home64, including
secondhand smoke, reducing or eliminating exposure to schools65, public transportation, and cat-free buildings66.
occupational agents known to cause symptoms, and Although removal of such animals from the home is
avoiding foods/additives/drugs known to cause symptoms) encouraged, even after permanent removal of the animal it
improves the control of asthma and reduces medication can be many months before allergen levels decrease67 and
needs. In the case of other factors (e.g., allergens, viral the clinical effectiveness of this and other interventions
infections and pollutants), measures where possible remains unproven (Figure 4.2-1).
should be taken to avoid these. Because many asthma
patients react to multiple factors that are ubiquitous in Cockroaches. Avoidance measures for cockroaches
the environment, avoiding these factors completely is include eliminating suitable environments (restricting
usually impractical and very limiting to the patient. Thus, havens by caulking and sealing cracks in the plasterwork
medications to maintain asthma control have an important and flooring, controlling dampness, and reducing the
role because patients are often less sensitive to these risk availability of food), restricting access (sealing entry sources
factors when their asthma is under good control. such as around paperwork and doors), chemical control,
and traps. However, these measures are only partially
Indoor Allergens effective in removing residual allergens68 (Evidence C).

Among the wide variety of allergen sources in human Figure 4.2-1: Effectiveness of Avoidance Measures
dwellings are domestic mites, furred animals, for Some Indoor Allergens*
cockroaches, and fungi. However, there is conflicting Measure Evidence Evidence
evidence about whether measures to create a low-allergen of effect of clinical
environment in patientsʼ home s and reduce exposure to on allergen benefit
levels
indoor allergens are effective at reducing asthma
House dust mites
symptoms54,55. The majority of single interventions have
Encase bedding in impermeable covers Some None
failed to achieve a sufficient reduction in allergen load to
(adults)
lead to clinical improvement55-57. It is likely that no single Some
intervention will achieve sufficient benefits to be cost (children)
effective. However, among inner-city children with atopic Wash bedding in the hot cycle (55-60oC) Some None
asthma, an individualized, home-based, comprehensive Replace carpets with hard flooring Some None
environmental intervention decreased exposure to indoor Acaricides and/or tannic acid Weak None
allergens and resulted in reduced asthma-associated Minimize objects that accumulate dust None None
morbidity58. More properly powered and well-designed
Vacuum cleaners with integral HEPA filter Weak None
studies of combined allergen-reduction strategies in large and double-thickness bags
groups of patients are needed. Remove, hot wash, or freeze soft toys None None

Domestic mites. Domestic mite allergy is a universal Pets

health problem59. Since mites live and thrive in many sites
Remove cat/dog from the home Weak None
throughout the house, they are difficult to reduce and
Keep pet from main living areas/bedrooms Weak None
impossible to eradicate (Figure 4.2-1). No single measure
HEPA-filter air cleaners Some None
is likely to reduce exposure to mite allergens, and single
chemical and physical methods aimed at reducing mite Wash pet Weak None
allergens are not effective in reducing asthma symptoms Replace carpets with hard flooring None None
in adults55,60-62 (Evidence A). One study showed some Vacuum cleaners with integral HEPA filter None None
and double-thickness bags
efficacy of mattress encasing at reducing airway
hyperresponsiveness in children63 (Evidence B). An *Adapted from Custovic A, Wijk RG. The effectiveness of measures to change the
integrated approach including barrier methods, dust removal, indoor environment in the treatment of allergic rhinitis and asthma: ARIA update
(in collaboration with GA(2)LEN). Allergy 2005;60(9):1112-1115.

ASTHMA MANAGEMENT AND PREVENTION 55

Fungi. Fungal exposure has been associated with matter–and symptoms or exacerbations of asthma. On
exacerbations from asthma and the number of fungal occasion, certain weather and atmospheric conditions,
spores can best be reduced by removing or cleaning mold- e.g., thunderstorms79 favor the development of asthma
laden objects69. In tropical and subtropical climates, fungi exacerbations by a variety of mechanisms, including dust
may grow on the walls of the house due to water seepage and pollution, increases in respirable allergens, and
and humidity. To avoid this, the walls could be tiled or changes in temperature/humidity.
cleaned as necessary. Air conditioners and dehumidifiers
may be used to reduce humidity to levels less than 50% Avoidance of unfavorable environmental conditions is
and to filter large fungal spores. However, air conditioning usually unnecessary for patients whose asthma is
and sealing of windows have also been associated with controlled. For patients with asthma that is difficult to
increases in fungal and house dust mite allergens70. control, practical steps to take during unfavorable
environmental conditions include avoiding strenuous
Outdoor Allergens physical activity in cold weather, low humidity, or high air
pollution; avoiding smoking and smoke-filled rooms; and
Outdoor allergens such as pollens and molds are impossible staying indoors in a climate-controlled environment.
to avoid completely. Exposure may be reduced by closing Occupational Exposures
windows and doors, remaining indoors when pollen and
mold counts are highest, and using air conditioning if Occupational exposures account for a substantial
possible. Some countries use radio, television, and the proportion of adult asthma incidence357. The early
Internet to provide information on outdoor allergen levels. identification of occupational sensitizers and the removal
The impact of these measures is difficult to assess. of sensitized patients from any further exposure are
important aspects of the management of occupational
Indoor Air Pollutants asthma (Evidence B). Once a patient has become
sensitized to an occupational allergen, the level of exposure
The most important measure in controlling indoor air necessary to induce symptoms may be extremely low, and
pollutants is to avoid passive and active smoking. resulting exacerbations become increasingly severe.
Secondhand smoke increases the frequency and severity Attempts to reduce occupational exposure have been
of symptoms in children with asthma. Parents/caregivers successful especially in industrial settings, and some potent
of children with asthma should be advised not to smoke sensitizers, such as soy castor bean, have been replaced by
and not to allow smoking in rooms their children use. In less allergenic substances80 (Evidence B). Prevention of
addition to increasing asthma symptoms and causing long- latex sensitization has been made possible by the production
term impairments in lung function, active cigarette smoking of hypoallergenic gloves, which are powder free and have
reduces the efficacy of inhaled and systemic glucocorticos- a lower allergen content81,82 (Evidence C). Although more
teroids71,72 (Evidence B), and smoking cessation needs to be expensive than untreated gloves, they are cost effective.
vigorously encouraged for all patients with asthma who smoke.
Other major indoor air pollutants include nitric oxide, Food and Food Additives
nitrogen oxides, carbon monoxide, carbon dioxide, sulfur Food allergy as an exacerbating factor for asthma is
dioxide, formaldehyde, and biologicals (endotoxin)73. uncommon and occurs primarily in young children. Food
However, methods to control or prevent exposure to these avoidance should not be recommended until an allergy has
pollutants, such as venting all furnaces to the outdoors, and been clearly demonstrated (usually by oral challenges)83.
maintaining heating systems adequately, have not been When food allergy is demonstrated, food allergen avoidance
adequately evaluated and can be expensive (Evidence D). can reduce asthma exacerbations84 (Evidence D).
Outdoor Air Pollutants Sulfites (common food and drug preservatives found in
such foods as processed potatoes, shrimp, dried fruits,
Several studies have suggested that outdoor pollutants beer, and wine) have often been implicated in causing
aggravate asthma symptoms74, 356, possibly having an addi- severe asthma exacerbations but the likelihood of a
tive effect with allergen exposure75. Outbreaks of asthma reaction is dependent on the nature of the food, the level
exacerbations have been shown to occur in relationship to of residual sulfite, the sensitivity of the patient, the form of
increased levels of air pollution, and this may be related to residual sulfite and the mechanism of the sulfite-induced
a general increase in pollutant levels or to an increase in reaction85. The role of other dietary substances—including
specific allergens to which individuals are sensitized76-78. the yellow dye tartrazine, benzoate, and monosodium
Most epidemiological studies show a significant glutamate—in exacerbating asthma is probably minimal;
association between air pollutants–such as ozone, confirmation of their relevance requires double-blind
nitrogen oxides, acidic aerosols, and particulate challenge before making specific dietary restrictions.

56 ASTHMA MANAGEMENT AND PREVENTION

Drugs A randomized clinical trial of a self-regulation, telephone
counseling intervention emphasizing sex and gender role factors
Some medications can exacerbate asthma. Aspirin and in the management of asthma indicated that a program with a
other nonsteroidal anti-inflammatory drugs can cause focus on asthma management problems particular to women
severe exacerbations and should be avoided in patients can significantly assist female asthma patients358.
with a history of reacting to these agents86. Beta-blocker
drugs administered orally or intraocularly may exacerbate
bronchospasm (Evidence A) and close medical supervision
COMPONENT 3: ASSESS, TREAT,
is essential when these are used by patients with asthma87. AND MONITOR ASTHMA
Influenza Vaccination
KEY POINTS:
Patients with moderate to severe asthma should be advised • The goal of asthma treatment, to achieve and
to receive an influenza vaccination every year88 or at least maintain clinical control, can be reached in a
when vaccination of the general population is advised. majority of patients with a pharmacologic
However, routine influenza vaccination of children89 and intervention strategy developed in partnership
adults90 with asthma does not appear to protect them from between the patient/family and the doctor.
asthma exacerbations or improve asthma control. Inactivated
influenza vaccines are associated with few side effects • Treatment should be adjusted in a continuous cycle
and are safe to administer to asthmatic adults and children driven by the patientsʼ asthma control status. If
over the age of 3 years, including those with difficult-to-treat asthma is not controlled on the current treatment
asthma91. There are data to suggest that intranasal regimen, treatment should be stepped up until
vaccination in children under age 3 may be associated control is achieved. When control is maintained for at
with an increased incidence of asthma exacerbations92. least three months, treatment can be stepped down.

Obesity • In treatment-naïve patients with persistent asthma,

treatment should be started at Step 2, or, if very sympto-
Increases in body mass index (BMI) have been associated with matic (uncontrolled), at Step 3. For Steps 2 through 5,
increased prevalence of asthma, although the mechanisms behind a variety of controller medications are available.
this association are unclear93. Weight reduction in obese
patients with asthma has been demonstrated to improve lung • At each treatment step, reliever medication should
function, symptoms, morbidity, and health status94 (Evidence B). be provided for quick relief of symptoms as needed.

Emotional Stress • Ongoing monitoring is essential to maintain control

and to establish the lowest step and dose of
Emotional stress may lead to asthma exacerbations, primarily treatment to minimize cost and maximize safety.
because extreme emotional expressions (laughing, crying,
anger, or fear) can lead to hyperventilation and hypocapnia,
which can cause airway narrowing95,96. Panic attacks, which INTRODUCTION
are rare but not exceptional in some patients with asthma,
have a similar effect97,98. However, it is important to note that The goal of asthma treatment, to achieve and maintain
asthma is not primarily a psychosomatic disorder. clinical control, can be reached in a majority of patients104,344
with a pharmacologic intervention strategy developed in
Other Factors That May Exacerbate Asthma partnership between the patient/family and the doctor.
Each patient is assigned to one of five “treatment steps”
Rhinitis, sinusitis, and polyposis are frequently associated
depending on their current level of control and treatment is
with asthma and need to be treated. In children, antibiotic
adjusted in a continuous cycle driven by changes in their
treatment of bacterial sinusitis has been shown to reduce
the severity of asthma99. However, sinusitis and asthma asthma control status. This cycle involves:
may simply coexist. Apart from sinusitis, there is little • Assessing Asthma Control
evidence that bacterial infections exacerbate asthma. • Treating to Achieve Control
Gastroesophageal reflux can exacerbate asthma, especially • Monitoring to Maintain Control
in children, and asthma sometimes improves when the reflux
is corrected100,101. Many women complain that their asthma In this Component, this cycle is described for long-term
is worse at the time of menstruation, and premenstrual treatment of asthma. Treatment for exacerbations is
exacerbations have been documented102. Similarly, asthma detailed in Component 4.
may improve, worsen, or remain unchanged during pregnancy103.

ASTHMA MANAGEMENT AND PREVENTION 57

 of possible treatment options, and the patientʼs satisfaction
ASSESSING ASTHMA CONTROL with the level of control achieved. The scheme presented
in Figure 4.3-2 is based upon these principles, but the
Each patient should be assessed to establish his or her range and sequence of medications used in each clinical
current treatment regimen, adherence to the current setting will vary depending on local availability (for cost or
regimen, and level of asthma control. A simplified other reasons), acceptability, and preference.
scheme for recognizing controlled, partly controlled, and
uncontrolled asthma in a given week is provided in Treatment Steps for Achieving Control
Figure 4.3-1. This is a working scheme based on current
opinion and has not been validated. Several composite Most of the medications available for asthma patients,
control measures (e.g., Asthma Control Test105, Asthma when compared with medications used for other chronic
Control Questionnaire106-108, Asthma Therapy Assessment diseases, have extremely favorable therapeutic ratios.
Questionnaire109, Asthma Control Scoring System110) Each step represents treatment options that, although not
have been developed and are being validated for various of identical efficacy, are alternatives for controlling asthma.
applications, including use by health care providers to Steps 1 to 5 provide options of increasing efficacy, except
assess the state of control of their patientsʼ ast hma and for Step 5 where issues of availability and safety influence
the selection of treatment. Step 2 is the initial treatment for
by patients for self-assessments as part of a written
most treatment-naïve patients with persistent asthma
personal asthma action plan. Uncontrolled asthma may
symptoms. If symptoms at the initial consultation suggest
progress to the point of an exacerbation, and immediate
that asthma is severely uncontrolled (Figure 4.3-1),
steps, described in Component 4, should be taken to
treatment should be commenced at Step 3.
regain control.
At each treatment step, a reliever medication (rapid-onset
TREATING TO ACHIEVE CONTROL bronchodilator, either short-acting or long-acting) should
be provided for quick relief of symptoms. However,
regular use of reliever medication is one of the elements
The patientʼ s current level of asthma control and current defining uncontrolled asthma, and indicates that controller
treatment determine the selection of pharmacologic treatment should be increased. Thus, reducing or eliminating
treatment. For example, if asthma is not controlled on the the need for reliever treatment is both an important goal
current treatment regimen, treatment should be stepped and measure of success of treatment. For Steps 2
up until control is achieved. If control has been maintained through 5, a variety of controller medications are available.
for at least three months, treatment can be stepped down
with the aim of establishing the lowest step and dose of Step 1: As-needed reliever medication. Step 1
treatment that maintains control (see Monitoring to treatment with an as-needed reliever medication is
Maintain Control below). If asthma is partly controlled, an reserved for untreated patients with occasional daytime
increase in treatment should be considered, subject to symptoms (cough, wheeze, dyspnea occurring twice or
whether more effective options are available (e.g., less per week, or less frequently if nocturnal) of short
increased dose or an additional treatment), safety and cost duration (lasting only a few hours) comparable with

Figure 4.3-1. Levels of Asthma Control

Characteristic Controlled Partly Controlled Uncontrolled
(All of the following) (Any measure present in any week)
Daytime symptoms None (twice or less/week) More than twice/week Three or more features
of partly controlled
Limitations of activities None Any asthma present in
Nocturnal symptoms/awakening None Any any week
Need for reliever/ None (twice or less/week) More than twice/week
rescue treatment
Lung function (PEF or FEV1)‡ Normal < 80% predicted or personal best
(if known)
Exacerbations None One or more/year* One in any week†

* Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate.
† By definition, an exacerbation in any week makes that an uncontrolled asthma week.
‡ Lung function is not a reliable test for children 5 years and younger.

58 ASTHMA MANAGEMENT AND PREVENTION

 Management Approach Based On Control
Figure 4.3-2.

For Children Older Than 5 Years, Adolescents and Adults

Level of Control Treatment Action

Reduce
Controlled Maintain and find lowest controlling step

Partly controlled Consider stepping up to gain control

Uncrontrolled Step up until controlled

Increase
Uncontrolled

Exacerbation Treat as exacerbation

Reduce Treatment Steps Increase

Step 1 Step 2 Step 3 Step 4 Step 5

Asthma education
Environmental control

As needed rapid-
As needed rapid-acting β2-agonist
acting β2-agonist

Select one Select one Add one or more Add one or both

Medium-or high-dose
Low-dose inhaled Low-dose ICS plus Oral glucocorticosteroid
ICS plus long-acting
ICS* long-acting β2-agonist
β2-agonist (lowest dose)

Controller
options Leukotriene Medium-or Leukotriene Anti-IgE
*** modifier Ü
** high-dose ICS modifier treatment

Low-dose ICS plus Sustained release

leukotriene modifier theophylline

Low-dose ICS plus

sustained release
theophylline

**ICS=inhaled
ICS=inhaledglucocorticosteroids
glucocorticosteroids
Ü=Receptor
** antagonistororsynthesis
=Receptor antagonist synthesisinhibitors
inhibitors
***Preferred controller options are shown in shaded boxes

Alternative reliever treatments include inhaled anticholinergics, short-acting oral ␤2-agonists, some long-acting ␤2-agonists, and short-acting theophylline.
Regular dosing with short and long-acting ␤2-agonist is not advised unless accompanied by regular use of an inhaled glucocorticosteroid.

Figure 4.3-2: Management Approach Based on Control For Children 5 Years and Younger

The available literature on treatment of asthma in children 5 years and younger precludes detailed treatment recommendations. The best
documented treatment to control asthma in these age groups is inhaled glucocorticosteroids and at Step 2, a low-dose inhaled glucocortico-
steroid is recommended as the initial controller treatment. Equivalent doses of inhaled glucocorticosteroids, some of which may be given as
a single daily dose, are provided in Chapter 3 (Figure 3-4).

ASTHMA MANAGEMENT AND PREVENTION 59

controlled asthma (Figure 4.3-1). Between episodes, the
patient is asymptomatic with normal lung function and Other options are available but not recommended for
there is no nocturnal awakening. When symptoms are routine use as initial or first-line controllers in Step 2.
more frequent, and/or worsen periodically, patients require Sustained-release theophylline has only weak anti-
regular controller treatment (see Steps 2 or higher) in inflammatory and controller efficacy126-130 (Evidence B) and
addition to as-needed reliever medication111-113 (Evidence B). is commonly associated with side effects that range from
trivial to intolerable131,132. Cromones (nedocromil sodium
For the majority of patients in Step 1, a rapid-acting inhaled and sodium cromoglycate) have comparatively low
␤2-agonist is the recommended reliever treatment114 efficacy, though a favorable safety profile133-136 (Evidence A).
(Evidence A). An inhaled anticholinergic, short-acting oral
␤2-agonist, or short-acting theophylline may be considered Step 3: Reliever medication plus one or two
as alternatives, although they have a slower onset of controllers. At Step 3, the recommended option for
action and higher risk of side effects (Evidence A). adolescents and adults is to combine a low-dose of
inhaled glucocorticosteroid with an inhaled long-acting
Exercise-induced bronchoconstriction. Physical activity is ␤2-agonist, either in a combination inhaler device or as
an important cause of asthma symptoms for most asthma separate components137-144 (Evidence A). Because of
patients, and for some it is the only cause. However, the additive effect of this combination, the low-dose of
exercise-induced bronchoconstriction often indicates that glucocorticosteroid is usually sufficient, and need only
the patient's asthma is not well controlled, and stepping be increased if control is not achieved within 3 or 4
up controller therapy generally results in the reduction of months with this regimen (Evidence A). The long-acting
exercise-related symptoms. For those patients who still ␤2-agonist formoterol, which has a rapid onset of action
experience exercise-induced bronchoconstriction despite whether given alone145-148 or in combination inhaler with
otherwise well-controlled asthma, and for those in whom budesonide149,150, has been shown to be as effective as
exercise-induced bronchoconstriction is the only mani- short-acting ␤2-agonist in acute asthma exacerbation.
festation of asthma, a rapid-acting inhaled ␤2-agonist However its use as monotherapy as a reliever medication
(short- or long-acting), taken prior to exercise or to relieve is strongly discouraged since it must always be used in
symptoms that develop after exercise, is recommended115. association with an inhaled glucocorticosteroid.
A leukotriene modifier116,345 or cromone117 are alternatives
(Evidence A). Training and sufficient warm-up also For all children but particularly those 5 years and younger,
reduce the incidence and severity of exercise-induced combination therapy has been less well studied and the
bronchoconstriction118,119 (Evidence B). Information on addition of a long-acting ␤2-agonist may not be as
treatment of exercise-induced asthma in athletes can be effective as increasing the dose of inhaled glucocortico-
found in a Joint Task Force Report prepared by the steroids in reducing exacerbations151-153. However, the
European Respiratory Society, the European Academy of interpretation of some studies is problematic as not all
Allergy and Clinical Immunology, and GA(2)LEN359 and the children received concurrent inhaled glucocorticosteroids152,153.
World Anti-Doping Agency website
(http://www.wada-ama.org). If a combination inhaler containing formoterol and
budesonide is selected, it may be used for both rescue
Step 2: Reliever medication plus a single controller. and maintenance. This approach has been shown to
Treatment Steps 2 through 5, combine an as-needed result in reductions in exacerbations and improvements in
reliever treatment with regular controller treatment. At asthma control in adults and adolescents at relatively low
Step 2, a low-dose inhaled glucocorticosteroid is doses of treatment154-157 (Evidence A). Whether this
recommended as the initial controller treatment for asthma approach can be employed with other combinations of
patients of all ages111,120 (Evidence A). Equivalent doses of controller and reliever requires further study.
inhaled glucocorticosteroids, some of which may be given
as a single daily dose, are provided in Figure 3-1 for Another option for both adults and children, but the one
adults and in Figure 3-4 for children 5 years and younger. recommended for children158, is to increase to a medium-
dose of inhaled glucocorticosteroids104,159-161 (Evidence A).
Alternative controller medications include leukotriene For patients of all ages on medium- or high-dose of
modifiers121-123 (Evidence A), appropriate particularly for inhaled glucocorticosteroid delivered by a pressurized
patients who are unable or unwilling to use inhaled metered-dose inhaler, use of a spacer device is
glucocorticosteroids, or who experience intolerable side recommended to improve delivery to the airways, reduce
effects such as persistent hoarseness from inhaled oropharyngeal side effects, and reduce systemic
glucocorticosteroid treatment and those with concomitant absorption162-164 (Evidence A).
allergic rhinitis124,125 (Evidence C).

60 ASTHMA MANAGEMENT AND PREVENTION

Another option at Step 3 is to combine a low-dose inhaled daily limitation of activities and frequent exacerbations.
glucocorticosteroid with leukotriene modifiers165-173 Patients should be counseled about potential side effects
(Evidence A). Alternatively, the use of sustained-release and all other alternative treatments must be considered.
theophylline given at low-dose may be considered129
(Evidence B). These options have not been fully studied Addition of anti-IgE treatment to other controller medications
in children 5 years and younger. has been shown to improve control of allergic asthma
Step 4: Reliever medication plus two or more when control has not been achieved on combinations of
controllers. The selection of treatment at Step 4 depends other controllers including high-doses of inhaled or oral
on prior selections at Steps 2 and 3. However, the order in glucocorticosteroids181-186 (Evidence A).
which additional medications should be added is based, as
far as possible, upon evidence of their relative efficacy in MONITORING TO MAINTAIN CONTROL
clinical trials. Where possible, patients who are not
controlled on Step 3 treatments should be referred to a
health professional with expertise in the management When asthma control has been achieved, ongoing
of asthma for investigation of alternative diagnoses and/or monitoring is essential to maintain control and to establish
the lowest step and dose of treatment necessary, which
causes of difficult-to-treat asthma.
minimizes the cost and maximizes the safety of treatment.
On the other hand, asthma is a variable disease, and treat-
The preferred treatment at Step 4 is to combine a
ment has to be adjusted periodically in response to loss of
medium- or high-dose of inhaled glucocorticosteroid
control as indicated by worsening symptoms or the
with a long-acting inhaled ␤2-agonist. However, in development of an exacerbation.
most patients, the increase from a medium- to a high-dose
of inhaled glucocorticosteroid provides relatively little Asthma control should be monitored by the health care
additional benefit104,159-161,174 (Evidence A), and the high- professional and preferably also by the patient at regular
dose is recommended only on a trial basis for 3 to 6 intervals, using either a simplified scheme as presented in
months when control cannot be achieved with medium- Figure 4.3-1 or a validated composite measure of control.
dose inhaled glucocorticosteroid combined with a long- The frequency of health care visits and assessments
acting ␤2-agonist and/or a third controller (e.g. leukotriene depends upon the patientʼs initial clinical severity, and the
modifiers or sustained-release theophylline )130,175,346 patientʼs training and confidence in playing a role in the on-
(Evidence B). Prolonged use of high-dose inhaled going control of his or her asthma. Typically, patients are
glucocorticosteroids is also associated with increased seen one to three months after the initial visit, and every
potential for adverse effects. At medium- and high-doses, three months thereafter. After an exacerbation, follow-up
twice-daily dosing is necessary for most but not all inhaled should be offered within two weeks to one month
glucocorticosteroids176 (Evidence A). With budesonide, (Evidence D).
efficacy may be improved with more frequent dosing (four
times daily)177 (Evidence B). (Refer to Figure 3-1 for Duration and Adjustments to Treatment
adults and Figure 3-4 for children 5 years and younger for
recommendations on dosing and frequency for different For most classes of controller medications, improvement
inhaled glucocorticosteroids.) begins within days of initiating treatment, but the full benefit
may only be evident after 3 or 4 months187, 360. In severe and
Leukotriene modifiers as add-on treatment to medium-to chronically undertreated disease, this can take even longer188.
high-dose inhaled glucocorticosteroids have been shown
to provide benefit (Evidence A), but usually less than that The reduced need for medication once control is achieved
achieved with the addition of a long-acting ␤2-agonist165-168,175,178 is not fully understood, but may reflect the reversal of
(Evidence A). The addition of a low-dose of sustained- some of the consequences of long-term inflammation of
the airways. Higher doses of anti-inflammatory medication
release theophylline130 to medium- or high-dose inhaled
may be required to achieve this benefit than to maintain it.
glucocorticosteroid and long-acting ␤2-agonist may also
Alternatively, the reduced need for medication might
provide benefit (Evidence B)129.
simply represent spontaneous improvement as part of the
cyclical natural history of asthma. Rarely, asthma may go
Step 5: Reliever medication plus additional controller into remission particularly in children aged 5 years and
options. Addition of oral glucocorticosteroids to other younger and during puberty. Whatever the explanation,
controller medications may be effective179 (Evidence D) in all patients the minimum controlling dose of treatment
but is associated with severe side effects180 (Evidence A) must be sought through a process of regular follow-up and
and should only be considered if the patientʼs asthma staged dose reductions.
remains severely uncontrolled on Step 4 medications with

ASTHMA MANAGEMENT AND PREVENTION 61

At other times treatment may need to be increased either • Controller treatment may be stopped if the patientʼs
in response to loss of control or threat of loss of control asthma remains controlled on the lowest dose of
(return of symptoms) or an acute exacerbation, which is controller and no recurrence of symptoms occurs for
defined as a more acute and severe loss of control that one year (Evidence D).
requires urgent treatment. (An approach to exacerbations
is provided in Component 4.4.) Stepping Up Treatment In Response To Loss Of Control

Stepping Down Treatment When Asthma Is Controlled Treatment has to be adjusted periodically in response to
worsening control, which may be recognized by the minor
There is little experimental data on the optimal timing, recurrence or worsening of symptoms195. Treatment
sequence, and magnitude of treatment reductions in options are as follows:
asthma, and the approach will differ from patient to patient
depending on the combination of medications and the • Rapid-onset, short-acting or long-acting ␤2-
doses that were needed to achieve control. These agonist bronchodilators. Repeated dosing with
changes should ideally be made by agreement between bronchodilators in this class provides temporary relief
patient and health care professional, with full discussion of until the cause of the worsening symptoms passes.
potential consequences including reappearance of The need for repeated doses over more than one or
symptoms and increased risk of exacerbations. two days signals the need for review and possible
increase of controller therapy.
Although further research on stepping down asthma
• Inhaled glucocorticosteroids. Temporarily doubling
treatment is needed, some recommendations can be
the dose of inhaled glucocorticosteroids has not been
made based on the current evidence:
demonstrated to be effective, and is no longer
• When inhaled glucocorticosteroids alone in medium- recommended194,196 (Evidence A). A four-fold or
to high-doses are being used, a 50% reduction in dose greater increase has been demonstrated to be
should be attempted at 3 month intervals189-191 (Evidence B). equivalent to a short course of oral glucocorticosteroids
in adult patients with an acute deterioration195
• Where control is achieved at a low-dose of inhaled (Evidence A). The higher dose should be maintained
glucocorticosteroids alone, in most patients treatment for seven to fourteen days but more research is needed
may be switched to once-daily dosing192,193 (Evidence A). in both adults and children to standardize the approach.

• When asthma is controlled with a combination of • Combination of inhaled glucocorticosteroids and

inhaled glucocorticosteroid and long-acting rapid and long-acting ␤2-agonist bronchodilator
␤2-agonist, the preferred approach to is to begin by (e.g. formoterol) for combined relief and control.
reducing the dose of inhaled glucocorticosteroid by The use of the combination of a rapid and long-acting
approximately 50% while continuing the long-acting ␤2-agonist (formoterol) and an inhaled glucocortico-
␤2-agonist150 (Evidence B). If control is maintained, steroid (budesonide) in a single inhaler both as a
further reductions in the glucocorticosteroid should be controller and reliever is effective in maintaining a high
attempted until a low-dose is reached, when the long- level of asthma control and reduces exacerbations
acting ␤2-agonist may be stopped (Evidence D). An requiring systemic glucocorticosteroids and
alternative is to switch the combination treatment to hospitalization111,156,157,197 (Evidence A). The benefit
once-daily dosing194. A second alternative is to in preventing exacerbations appears to be the
discontinue the long-acting ␤2-agonist at an earlier consequence of early intervention at a very early stage
stage and substitute the combination treatment with of a threatened exacerbation since studies involving
inhaled glucocorticosteroid monotherapy at the same doubling or quadrupling doses of combination
dose contained in the combination inhaler. However, treatment once deterioration is established (for 2 or
for some patients these alternative approaches lead to more days) show some benefit but results are
loss of asthma control137,150 (Evidence B). inconsistent195. Because there are no studies using
this approach with other combinations of controller
• When asthma is controlled with inhaled gluco- and relievers, other than budesonide/formoterol, the
corticosteroids in combination with controllers alternative approaches described in this section should
other than long-acting ␤2-agonists, the dose of be used for patients on other controller therapies.
inhaled glucocorticosteroid should be reduced by 50% Combination therapy with budesonide and formoterol
until a low-dose of inhaled glucocorticosteroid is used both as maintenance and rescue has been shown
reached, then the combination treatment stopped as to reduce asthma exacerbations in children ages 4
described above (Evidence D). years and older with moderate to severe asthma347.

62 ASTHMA MANAGEMENT AND PREVENTION

 • The usual treatment for an acute exacerbation is a • Investigate the presence of comorbidities that may
high-dose of ␤2-agonist and a burst of systemic aggravate asthma. Chronic sinusitis, gastroesophageal
glucocorticosteroids administered orally or reflux, and obesity/obstructive sleep apnea have been
intravenously. (Refer to Component 4 for more reported in higher percentages in patients with difficult-
information.) to-treat asthma. Psychological and psychiatric
disorders should also be considered. If found, these
Following treatment for an exacerbation of asthma, comorbidities should be addressed and treated as
maintenance treatment can generally be resumed at appropriate, although the ability to improve asthma
previous levels unless the exacerbation was associated control by doing so remains unconfirmed200,348.
with a gradual loss of control suggesting chronic
undertreatment. In this case, provided inhaler technique When these reasons for lack of treatment response have
has been checked, a step-wise increase in treatment been considered and addressed, a compromise level of
(either in dose or number of controllers) is indicated. control may need to be accepted and discussed with the
patient to avoid futile over-treatment (with its attendant
Difficult-to-Treat Asthma cost and potential for adverse effects). The objective is
then to minimize exacerbations and need for emergency
Although the majority of asthma patients can obtain the medical interventions while achieving as high a level of
targeted level of control (Figure 4.3-1), some patients will clinical control with as little disruption of activities and as
not do so even with the best therapy104. Patients who do few daily symptoms as possible. For these difficult-to-treat
not reach an acceptable level of control at Step 4 (reliever patients, frequent use of rescue medication is accepted, as
medication plus two or more controllers) can be is a degree of chronic lung function impairment.
considered to have difficult-to-treat asthma198. These Although lower levels of control are generally associated
patients may have an element of poor glucocorticosteroid with an increased risk of exacerbations, not all patients
responsiveness, and require higher doses of inhaled with chronically impaired lung function, reduced activity
glucocorticosteroids than are routinely used in patients levels, and daily symptoms have frequent exacerbations.
whose asthma is easy to control. However, there is In such patients, the lowest level of treatment that retains
currently no evidence to support continuing these high-
the benefits achieved at the higher doses of treatment
doses of inhaled glucocorticosteroids beyond 6 months in
should be employed. Reductions should be made
the hope of achieving better control. Instead, dose
cautiously and slowly at intervals not more frequent than 3
optimization should be pursued by stepping down to a
to 6 months, as carryover of the effects of the higher dose
dose that maintains the maximal level of control achieved
may last for several months and make it difficult to assess
on the higher dose.
the impact of the dose reduction (Evidence D). Referral to
a physician with an interest in and/or special focus on
Because very few patients are completely resistant to
asthma may be helpful and patients may benefit from
glucocorticosteroids, these medications remain a mainstay
phenotyping into categories such as allergic, aspirin-
of therapy for difficult-to-treat asthma, while additional
sensitive, and/or eosinophilic asthma201. Patients
diagnostic and generalized therapeutic options can and
categorized as allergic might benefit from anti-IgE
should also be considered:
therapy183, and leukotriene modifiers can be helpful for
patients determined to be aspirin sensitive (who are often
• Confirm the diagnosis of asthma. In particular, the
eosinophilic as well)172.
presence of COPD must be excluded. Vocal cord
dysfunction must be considered.
• Investigate and confirm compliance with treatment.
Incorrect or inadequate use of medications remains
the most common reason for failure to achieve control.
• Consider smoking, current or past, and encourage
complete cessation. A history of past tobacco smoking
is associated with a reduced likelihood of complete
asthma control, and this is only partly attributable to
the presence of fixed airflow obstruction. In addition,
current smoking reduces the effectiveness of inhaled
and oral glucocorticosteroids199. Counseling and smok-
ing cessation programs should be offered to all asthma
patients who smoke.

ASTHMA MANAGEMENT AND PREVENTION 63

 patients with a history of near-fatal asthma and also appears
COMPONENT 4: MANAGE ASTHMA to be more likely in males. A clinically useful tool to assess
EXACERBATIONS the likelihood of asthma-related hospitalizations or
emergency department visits in adults with severe or
KEY POINTS: difficult to treat asthma has been described349.

• Exacerbations of asthma (asthma attacks or acute Strategies for treating exacerbations, though generalizable,
asthma) are episodes of progressive increase in are best adapted and implemented at a local level204,205.
shortness of breath, cough, wheezing, or chest Severe exacerbations are potentially life threatening, and
tightness, or some combination of these symptoms. their treatment requires close supervision. Patients with
severe exacerbations should be encouraged to see their
• Exacerbations are characterized by decreases in physician promptly or, depending on the organization of
expiratory airflow that can be quantified and monitored local health services, to proceed to the nearest clinic or
by measurement of lung function (PEF or FEV1). hospital that provides emergency access for patients with
acute asthma. Close objective monitoring (PEF) of the
• The primary therapies for exacerbations include the response to therapy is essential.
repetitive administration of rapid-acting inhaled
bronchodilators, the early introduction of systemic
The primary therapies for exacerbations include—in the
glucocorticosteroids, and oxygen supplementation.
order in which they are introduced, depending on severity—
repetitive administration of rapid-acting inhaled bronchodilators,
• The aims of treatment are to relieve airflow
early introduction of systemic glucocorticosteroids, and
obstruction and hypoxemia as quickly as possible,
and to plan the prevention of future relapses. oxygen supplementation202. The aims of treatment are to
relieve airflow obstruction and hypoxemia as quickly as
• Severe exacerbations are potentially life possible, and to plan the prevention of future relapses.
threatening, and their treatment requires close
supervision. Most patients with severe asthma Patients at high risk of asthma-related death require closer
exacerbations should be treated in an acute care attention and should be encouraged to seek urgent care
facility. Patients at high risk of asthma-related early in the course of their exacerbations. These patients
death also require closer attention. include those:

• Milder exacerbations, defined by a reduction in • With a history of near-fatal asthma requiring intubation
peak flow of less than 20%, nocturnal awakening, and mechanical ventilation206
and increased use of short acting ␤2-agonists can • Who have had a hospitalization or emergency care
usually be treated in a community setting. visit for asthma in the past year
• Who are currently using or have recently stopped
using oral glucocorticosteroids
INTRODUCTION • Who are not currently using inhaled
glucocorticosteroids207
Exacerbations of asthma (asthma attacks or acute asthma) • Who are overdependent on rapid-acting inhaled
are episodes of progressive increase in shortness of breath, ␤2-agonists, especially those who use more than one
cough, wheezing, or chest tightness, or some combination canister of salbutamol (or equivalent) monthly208
of these symptoms. Exacerbations usually have a • With a history of psychiatric disease or psychosocial350
progressive onset but a subset of patients (mostly adults) problems, including the use of sedatives209
present more acutely361. Respiratory distress is common. • With a history of noncompliance with an asthma
Exacerbations are characterized by decreases in expiratory medication plan.
airflow that can be quantified by measurement of lung
function (PEF or FEV1)202. These measurements are more Response to treatment may take time and patients should
reliable indicators of the severity of airflow limitation than is be closely monitored using clinical as well as objective
the degree of symptoms. The degree of symptoms may, measurements. The increased treatment should continue
however, be a more sensitive measure of the onset of an until measurements of lung function (PEF or FEV1) return
exacerbation because the increase in symptoms usually to their previous best (ideally) or plateau, at which time a
precedes the deterioration in peak flow rate203. Still, a decision to admit or discharge can be made based upon
minority of patients perceive symptoms poorly, and may these values. Patients who can be safely discharged will
have a significant decline in lung function without a significant have responded within the first two hours, at which time
change in symptoms. This situation especially affects decisions regarding patient disposition can be made.

64 ASTHMA MANAGEMENT AND PREVENTION

ASSESSMENT OF SEVERITY MANAGEMENT–COMMUNITY SETTINGS

The severity of the exacerbation (Figure 4.4-1) determines Most patients with severe asthma exacerbations should
the treatment administered. Indices of severity, particularly be treated in an acute care facility (such as a hospital
PEF187 (in patients older than 5 years), pulse rate, emergency department) where monitoring, including
respiratory rate, and pulse oximetry210, should be objective measurement of airflow obstruction, oxygen
monitored during treatment. saturation, and cardiac function, is possible. Milder
exacerbations, defined by a reduction in peak flow of less
than 20%, nocturnal awakening, and increased use of

Figure 4.4-1. Severity of Asthma Exacerbations*

Mild Moderate Severe Respiratory arrest
imminent

Breathless Walking Talking At rest

Infant—softer Infant stops feeding
shorter cry;
difficulty feeding

Can lie down Prefers sitting Hunched forward

Talks in Sentences Phrases Words
Alertness May be agitated Usually agitated Usually agitated Drowsy or confused
Respiratory rate Increased Increased Often > 30/min
Normal rates of breathing in awake children:
Age Normal rate
< 2 months < 60/min
2-12 months < 50/min
1-5 years < 40/min
6-8 years < 30/min
Accessory muscles Usually not Usually Usually Paradoxical thoraco-
and suprasternal abdominal movement
retractions
Wheeze Moderate, often only Loud Usually loud Absence of wheeze
end expiratory
Pulse/min. < 100 100-120 >120 Bradycardia
Guide to limits of normal pulse rate in children:
Infants 2-12 months–Normal Rate < 160/min
Preschool 1-2 years < 120/min
School age 2-8 years < 110/min
Pulsus paradoxus Absent May be present Often present Absence suggests
< 10 mm Hg 10-25 mm Hg > 25 mm Hg (adult) respiratory muscle
20-40 mm Hg (child) fatigue
PEF Over 80% Approx. 60-80% < 60% predicted or
after initial personal best
bronchodilator (< 100 L/min adults)
% predicted or or
% personal best response lasts < 2hrs
PaO2 (on air)† Normal > 60 mm Hg < 60 mm Hg
Test not usually
necessary Possible cyanosis
and/or
PaCO2† < 45 mm Hg < 45 mm Hg > 45 mm Hg;
Possible respiratory
failure (see text)
SaO2% (on air)† > 95% 91-95% < 90%
Hypercapnea (hypoventilation) develops more readily in young children than in
adults and adolescents.

*Note: The presence of several parameters, but not necessarily all, indicates the general classification of the exacerbation.
†Note: Kilopascals are also used internationally; conversion would be appropriate in this regard.

ASTHMA MANAGEMENT AND PREVENTION 65

short acting ␤2-agonists can usually be treated in a Assessment
community setting. If the patient responds to the increase
in inhaled bronchodilator treatment after the first few A brief history and physical examination pertinent to the
doses, referral to an acute care facility is not required, but exacerbation should be conducted concurrently with the
further management under the direction of a primary care prompt initiation of therapy. The history should include:
physician may include the use of systemic glucocortico- severity and duration of symptoms, including exercise
steroids. Patient education and review of maintenance limitation and sleep disturbance; all current medications,
therapy should also be undertaken. including dose (and device) prescribed, dose usually
taken, dose taken in response to the deterioration, and the
Treatment patientʼs response (or lack thereof) to this therapy; time of
onset and cause of the present exacerbation; and risk
Bronchodilators. For mild to moderate exacerbations, factors for asthma-related death.
repeated administration of rapid-acting inhaled ␤2-agonists
(2 to 4 puffs every 20 minutes for the first hour) is usually The physical examination should assess exacerbation
the best and most cost-effective method of achieving rapid severity by evaluating the patientʼs ability to complete a
reversal of airflow limitation. After the first hour, the dose sentence, pulse rate, respiratory rate, use of accessory
of ␤2-agonist required will depend on the severity of the muscles, and other signs detailed in Figure 4.4-2. Any
exacerbation. Mild exacerbations respond to 2 to 4 puffs complicating factors should be identified (e.g., pneumonia,
every 3 to 4 hours; moderate exacerbations will require 6 atelectasis, pneumothorax, or pneumomediastinum).
to 10 puffs every 1 or 2 hours. Treatment should also be
titrated depending upon the individual patientʼs res ponse, Functional assessments such as PEF or FEV1 and arterial
and if there is a lack of response or other concern about oxygen saturation measurements are strongly recommended
how the patient is responding, the patient should be as physical examination alone may not fully indicate the
referred to an acute care facility. severity of the exacerbation, particularly the degree of
hypoxemia213,214. Without unduly delaying treatment, a
Many patients will be able to monitor their PEF after the baseline PEF or FEV1 measurement should be made
initiation of increased bronchodilator therapy. before treatment is initiated. Subsequent measurements
Bronchodilator therapy delivered via a metered-dose should be made at intervals until a clear response to
inhaler (MDI), ideally with a spacer, produces at least an treatment has occurred.
equivalent improvement in lung function as the same dose
Oxygen saturation should be closely monitored, preferably
delivered via nebulizer164,211. At the clinic level, this route of
by pulse oximetry. This is especially useful in children
delivery is the most cost effective212, provided patients are
because objective measurements of lung function may be
able to use an MDI. No additional medication is necessary
difficult. Oxygen saturation in children should normally be
if the rapid-acting inhaled ␤2-agonist produces a complete
greater than 95%, and oxygen saturation less than 92% is
response (PEF returns to greater than 80% of predicted or
a good predictor of the need for hospitalization210
personal best) and the response lasts for 3 to 4 hours.
(Evidence C).
Glucocorticosteroids. Oral glucocorticosteroids (0.5 to 1
In adults a chest X-ray is not routinely required, but should
mg of prednisolone/kg or equivalent during a 24-hour
be carried out if a complicating cardiopulmonary process is
period) should be used to treat exacerbations, especially if
suspected, in patients requiring hospitalization, and in
they develop after instituting the other short-term treatment
those not responding to treatment where a pneumothorax
options recommended for loss of control (see “Stepping up
may be difficult to diagnose clinically215. Similarly, in children
treatment in response to loss of control” in Component 3).
routine chest X-rays are not recommended unless there
If patients fail to respond to bronchodilator therapy, as
are physical signs suggestive of parenchymal disease216.
indicated by persistent airflow obstruction, prompt transfer
to an acute care setting is recommended, especially if they
Although arterial blood gas measurements are not
are in a high risk group.
routinely required216, they should be completed in patients
with a PEF of 30 to 50% predicted, those who do not
MANAGEMENT–ACUTE CARE SETTINGS respond to initial treatment, or when there is concern
regarding deterioration. The patient should continue on
Severe exacerbations of asthma are life-threatening medical supplemental oxygen while the measurement is made.
emergencies, treatment of which is often most safely undertaken A PaO2 < 60 mm Hg (8 kPa) and a normal or increased
in an emergency department. Figure 4.4-2 illustrates the PaCO2 (especially > 45 mm Hg, 6 kPa) indicates the
approach to acute care-based management of exacerbations. presence of respiratory failure.

66 ASTHMA MANAGEMENT AND PREVENTION

 Figure 4.4-2: Management of Asthma Exacerbations in Acute Care Setting

Initial Assessment (see Figure 4.4-1)

• History, physical examination (auscultation, use of accessory muscles, heart rate, respiratory rate, PEF or FEV1, oxygen
saturation, arterial blood gas if patient in extremis)
Initial Treatment
• Oxygen to achieve O2 saturation ≥ 90% (95% in children)
• Inhaled rapid-acting ␤2-agonist continuously for one hour.
• Systemic glucocorticosteroids if no immediate response, or if patient recently took oral glucocorticosteroid, or if episode is severe.

M
• Sedation is contraindicated in the treatment of an exacerbation.

Reassess after 1 Hour

Physical Examination, PEF, O2 saturation and other tests as needed

M M
Criteria for Severe Episode:
Criteria for Moderate Episode: • History of risk factors for near fatal asthma
• PEF 60-80% predicted/personal best • PEF < 60% predicted/personal best
• Physical exam: moderate symptoms, accessory muscle use • Physical exam: severe symptoms at rest, chest retraction
Treatment: • No improvement after initial treatment
• Oxygen
Treatment:
• Inhaled ␤2-agonist and inhaled anticholinergic every 60 min • Oxygen
• Oral glucocorticosteroids • Inhaled ␤2-agonist and inhaled anticholinergic
• Continue treatment for 1-3 hours, provided there is improvement • Systemic glucocorticosteroids
• Intravenous magnesium
M M
Reassess after 1-2 Hours

M M M
Incomplete Response within 1-2 Poor Response within 1-2 Hours:
Good Response within 1-2 Hours: • Risk factors for near fatal asthma
• Response sustained 60 min after last Hours:
• Risk factors for near fatal asthma • Physical exam: symptoms severe,
treatment • Physical exam: mild to moderate signs
• Physical exam normal: No distress drowsiness, confusion
• PEF < 60% • PEF < 30%
• PEF > 70%
• O2 saturation not improving • PCO2 > 45 mm Hg
• O2 saturation > 90% (95% children)
• P O2 < 60mm Hg
Admit to Intensive Care
Admit to Acute Care Setting • Oxygen
• Oxygen • Inhaled ␤2-agonist + anticholinergic
• Inhaled ␤2-agonist ± anticholinergic
• Intravenous glucocorticosteroids
• Systemic glucocorticosteroid • Consider intravenous ␤2-agonist
• Intravenous magnesium • Consider intravenous theophylline
• Monitor PEF, O2 saturation, pulse • Possible intubation and mechanical
ventilation

M M
M

M M
Reassess at intervals

Improved: Criteria for Discharge Home Poor Response (see above):

• PEF > 60% predicted/personal best • Admit to Intensive Care
• Sustained on oral/inhaled medication
Home Treatment: Incomplete response in 6-12 hours
• Continue inhaled ␤2-agonist (see above)
• Consider, in most cases, oral glucocorticosteroids • Consider admission to Intensive Care

M
• Consider adding a combination inhaler if no improvement within 6-12 hours
• Patient education: Take medicine correctly
Review action plan
M

Close medical follow-up Improved (see opposite)

ASTHMA MANAGEMENT AND PREVENTION 67

Treatment Additional bronchodilators.

The following treatments are usually administered Ipratropium bromide. A combination of nebulized ␤2-
concurrently to achieve the most rapid resolution of the agonist with an anticholinergic (ipratropium bromide)
exacerbation217: may produce better bronchodilation than either drug
alone231 (Evidence B) and should be administered before
Oxygen. To achieve arterial oxygen saturation of ≥ 90% methylxanthines are considered. Combination ␤2-
(≥ 95% in children), oxygen should be administered by agonist/anticholinergic therapy is associated with lower
nasal cannulae, by mask, or rarely by head box in some hospitalization rates212,232,233 (Evidence A) and greater
infants. PaCO2 may worsen in some patients on 100 improvement in PEF and FEV1233 (Evidence B). Similar
percent oxygen, especially those with more severe airflow data have been reported in the pediatric literature212
obstruction218. Oxygen therapy should be titrated against (Evidence A). However, once children with asthma are
pulse oximetry to maintain a satisfactory oxygen saturation219. hospitalized following intensive emergency department
treatment, the addition of nebulized ipratropium bromide to
Rapid-acting inhaled ß2–agonists. Rapid-acting inhaled nebulized ␤2-agonist and systemic glucocorticosteroids
␤2-agonists should be administered at regular intervals220-222 appears to confer no extra benefit234.
(Evidence A). Although most rapid-acting ␤2-agonists
have a short duration of effect, the long-acting broncho- Theophylline. In view of the effectiveness and relative
dilator formoterol, which has both a rapid onset of action safety of rapid-acting ␤2-agonists, theophylline has a
and a long duration of effect, has been shown to be minimal role in the management of acute asthma235. Its
equally effective without increasing side effects, though use is associated with severe and potentially fatal side
it is considerably more expensive148. The importance of effects, particularly in those on long-term therapy with
this feature of formoterol is that it provides support and sustained-release theophylline, and their bronchodilator
reassurance regarding the use of a combination of effect is less than that of ␤2-agonists. The benefit as
formoterol and budesonide early in asthma exacerbations. add-on treatment in adults with severe asthma exacer-
bations has not been demonstrated. However, in one
A modestly greater bronchodilator effect has been shown study of children with near-fatal asthma, intravenous
with levabuterol compared to racemic albuterol in both theophylline provided additional benefit to patients also
adults and children with an asthma exacerbation223-226. In a receiving an aggressive regimen of inhaled and
large study of acute asthma in children227, and in adults not intravenous ␤2-agonists, inhaled ipatropium bromide, and
previously treated with glucocorticosteroids226, levabuterol intravenous systemic glucocorticosteroids236.
treatment resulted in lower hospitalization rates compared
to racemic albuterol treatment, but in children the length of Systemic glucocorticosteroids. Systemic
hospital stay was no different227. glucocorticosteroids speed resolution of exacerbations and
should be utilized in the all but the mildest
Studies of intermittent versus continuous nebulized short- exacerbations237,238 (Evidence A), especially if:
acting ␤2-agonists in acute asthma provide conflicting
results. In a systematic review of six studies228, there were • The initial rapid-acting inhaled ␤2-agonist therapy fails
no significant differences in bronchodilator effect or to achieve lasting improvement
hospital admissions between the two treatments. In • The exacerbation develops even though the patient
patients who require hospitalization, one study229 found was already taking oral glucocorticosteroids
that intermittent on-demand therapy led to a significantly • Previous exacerbations required oral
shorter hospital stay, fewer nebulizations, and fewer glucocorticosteroids.
palpitations when compared with intermittent therapy given
every 4 hours. A reasonable approach to inhaled therapy Oral glucocorticosteroids are usually as effective as those
in exacerbations, therefore, would be the initial use of administered intravenously and are preferred because this
continuous therapy, followed by intermittent on-demand route of delivery is less invasive and less expensive239,240.
therapy for hospitalized patients. There is no evidence to If vomiting has occurred shortly after administration of oral
support the routine use of intravenous ␤2-agonists in glucocorticosteroids, then an equivalent dose should be
patients with severe asthma exacerbations230. re-administered intravenously. In patients discharged from
the emergency department, intramuscular administration
Epinephrine. A subcutaneous or intramuscular injection may be helpful241, especially if there are concerns about
of epinephrine (adrenaline) may be indicated for acute compliance with oral therapy. Oral glucocorticosteroids
treatment of anaphylaxis and angioedema, but is not require at least 4 hours to produce clinical improvement.
routinely indicated during asthma exacerbations. Daily doses of systemic glucocorticosteroids equivalent to
68 ASTHMA MANAGEMENT AND PREVENTION
60-80 mg methylprednisolone as a single dose, or 300-400 Leukotriene modifiers. There is little data to suggest a
mg hydrocortisone in divided doses, are adequate for role for leukotriene modifiers in acute asthma258.
hospitalized patients, and 40 mg methylprednisolone or
200 mg hydrocortisone is probably adequate in most Sedatives. Sedation should be strictly avoided during
cases238,242 (Evidence B). An oral glucocorticosteroid dose exacerbations of asthma because of the respiratory
of 1 mg/kg daily is adequate for treatment of exacerbations depressant effect of anxiolytic and hypnotic drugs. An
in children with mild persistent asthma243. A 7-day course association between the use of these drugs and avoidable
in adults has been found to be as effective as a 14-day asthma deaths209,259 has been demonstrated.
course244, and a 3- to 5-day course in children is usually
considered appropriate (Evidence B). Current evidence Criteria for Discharge from the Emergency Department
suggests that there is no benefit to tapering the dose of vs. Hospitalization
oral glucocorticosteroids, either in the short-term245 or over
several weeks246 (Evidence B). Criteria for determining whether a patient should be
discharged from the emergency department or admitted to
Inhaled glucocorticosteroids. Inhaled glucocortico- the hospital have been succinctly reviewed and stratified
steroids are effective as part of therapy for asthma based on consensus260. Patients with a pre-treatment
exacerbations. In one study, the combination of high-dose FEV1 or PEF < 25% percent predicted or personal best, or
inhaled glucocorticosteroids and salbutamol in acute those with a post-treatment FEV1 or PEF < 40% percent
asthma provided greater bronchodilation than salbutamol predicted or personal best, usually require hospitalization.
alone247 (Evidence B), and conferred greater benefit than Patients with post-treatment lung function of 40-60%
the addition of systemic glucocorticosteroids across all predicted may be discharged, provided that adequate
parameters, including hospitalizations, especially for follow-up is available in the community and compliance is
patients with more severe attacks248. assured. Patients with post-treatment lung function
≥ 60 % predicted can be discharged.
Inhaled glucocorticosteroids can be as effective as oral
glucocorticosteroids at preventing relapses249,250. Patients Management of acute asthma in the intensive care unit is
discharged from the emergency department on prednisone beyond the scope of this document and readers are
and inhaled budesonide have a lower rate of relapse than referred to recent comprehensive reviews261.
those on prednisone alone237 (Evidence B). A high-dose
of inhaled glucocorticosteroid (2.4 mg budesonide daily in For patients discharged from the emergency department:
four divided doses) achieves a relapse rate similar to 40
mg oral prednisone daily251 (Evidence A). Cost is a • At a minimum, a 7-day course of oral glucoco-
significant factor in the use of such high-doses of inhaled rticosteroids for adults and a shorter course
glucocorticosteroids, and further studies are required to (3-5 days) for children should be prescribed, along with
document their potential benefits, especially cost continuation of bronchodilator therapy.
effectiveness, in acute asthma252. • The bronchodilator can be used on an as-needed
basis, based on both symptomatic and objective
Magnesium. Intravenous magnesium sulphate (usually improvement, until the patient returns to his or her pre-
given as a single 2 g infusion over 20 minutes) is not exacerbation use of rapid-acting inhaled ␤2-agonists.
recommended for routine use in asthma exacerbations, • Ipratropium bromide is unlikely to provide additional
benefit beyond the acute phase and may be quickly
but can help reduce hospital admission rates in certain
discontinued.
patients, including adults with FEV1 25-30% predicted at
• Patients should initiate or continue inhaled gluco-
presentation, adults and children who fail to respond to
corticosteroids.
initial treatment, and children whose FEV1 fails to improve
• The patientʼs inhaler technique and use of peak flow
above 60% predicted after 1 hour of care253,254 (Evidence A). meter to monitor therapy at home should be reviewed.
Nebulized salbutamol administered in isotonic magnesium Patients discharged from the emergency department
sulfate provides greater benefit than if it is delivered in with a peak flow meter and action plan have a better
normal saline255,256 (Evidence A). Intravenous magnesium response than patients discharged without these
sulphate has not been studied in young children. resources8.
• The factors that precipitated the exacerbation should
Helium oxygen therapy. A systematic survey of studies be identified and strategies for their future avoidance
that have evaluated the effect of a combination of helium implemented.
and oxygen, compared to helium alone, suggests there is • The patientʼs response to the exacerbation should be
no routine role for this intervention. It might be considered evaluated. The action plan should be reviewed and
for patients who do not respond to standard therapy257. written guidance provided.

ASTHMA MANAGEMENT AND PREVENTION 69

 • Use of controller therapy during the exacerbation should Pregnancy
be reviewed: whether this therapy was increased
promptly, by how much, and, if appropriate, why oral During pregnancy the severity of asthma often changes,
glucocorticosteroids were not added. Consider and patients may require close follow-up and adjustment
providing a short course of oral glucocorticosteroids to of medications. In approximately one-third of women
be on hand for subsequent exacerbations. asthma becomes worse; in one-third asthma becomes
• The patient or family should be instructed to contact less severe; and in the remaining one-third it remains
the primary health care professional or asthma unchanged during pregnancy265-267.
specialist within 24 hours of discharge. A follow-up
appointment with the patient's usual primary care Although concern exists with the use of medications in
professional or asthma specialist should be made pregnancy, poorly controlled asthma can have an adverse
within a few days of discharge to assure that treatment effect on the fetus, resulting in increased perinatal
is continued until baseline control parameters, mortality, increased prematurity, and low birth weight266,267.
including personal best lung function, are reached. The overall perinatal prognosis for children born to women
Prospective data indicate that patients discharged from with asthma that is well-managed during pregnancy is
the emergency department for follow-up with specialist comparable to that for children born to women without
care do better that patients returned to routine care262. asthma268. For this reason, using medications to obtain
optimal control of asthma is justified even when their
An exacerbation severe enough to require hospitalization safety in pregnancy has not been unequivocally proven.
may reflect a failure of the patientʼs se lf-management plan. For most medications used to treat asthma there is little
Hospitalized patients may be particularly receptive to evidence to suggest an increased risk to the fetus.
information and advice about their illness. Health care Appropriately monitored use of theophylline, inhaled
providers should take the opportunity to review patient glucocorticosteroids351, ␤2-agonists, and leukotriene
understanding of the causes of asthma exacerbations, modifiers (specifically montelukast) are not associated with
avoidance of factors that may cause exacerbations an increased incidence of fetal abnormalities. Inhaled
(including, where relevant smoking cessation), the glucocorticosteroids have been shown to prevent
purposes and correct uses of treatment, and the actions exacerbations of asthma during pregnancy269,270 (Evidence B).
to be taken to respond to worsening symptoms or peak As in other situations, the focus of asthma treatment must
flow values263 (Evidence A). remain on control of symptoms and maintenance of normal
lung function271. Acute exacerbations should be treated
Referral to an asthma specialist should be considered for aggressively in order to avoid fetal hypoxia. Treatment
hospitalized patients. Following discharge from should include nebulized rapid-acting ␤2-agonists and
continuous supervision, the patient should be reviewed by oxygen and systemic glucocorticosteroids should be
the family health care professional or asthma specialist instituted when necessary.
regularly over the subsequent weeks until personal best
lung function is reached. Use of incentives improves While all patients should have adequate opportunity to
primary care follow up but has shown no effect on long discuss the safety of their medications, pregnant patients
term outcomes264. Patients who come to the emergency with asthma should be advised that the greater risk to their
department with an acute exacerbation should be baby lies with poorly controlled asthma, and the safety of
especially targeted for an asthma education program, if most modern asthma treatments should be stressed. Even
one is available. with a good patient/health care professional relationship,
independent printed material, such as a statement from
COMPONENT 5: SPECIAL the US National Asthma Education and Prevention
Program on the treatment of asthma during pregnancy272,
CONSIDERATIONS will provide important additional reassurance265,273.
Special considerations are required in managing asthma
Surgery
in relation to pregnancy; surgery; rhinitis, sinusitis, and
nasal polyps; occupational asthma; respiratory infections;
Airway hyperresponsiveness, airflow limitation, and
gastroesophageal reflux; aspirin-induced asthma; and
mucus hypersecretion predispose patients with asthma to
anaphylaxis.
intraoperative and postoperative respiratory complications.
The likelihood of these complications depends on the

70 ASTHMA MANAGEMENT AND PREVENTION

severity of asthma at the time of surgery, the type of Treatment of rhinitis may improve asthma symptoms286,287
surgery (thoracic and upper abdominal surgeries pose the (Evidence A). Anti-inflammatory agents including
greatest risks), and type of anesthesia (general anesthesia glucocorticosteroids and cromones as well as leukotriene
with endotracheal intubation carries the greatest risk). modifiers and anticholinergics can be effective in both
These variables need to be assessed prior to surgery and conditions. However, some medications are selectively
pulmonary function should be measured. If possible, this effective against rhinitis (e.g., H1-antagonists) and others
evaluation should be undertaken several days before against asthma (e.g., ␤2-agonists)288 (Evidence A). Use of
surgery to allow time for additional treatment. In particular, intra-nasal glucocorticosteroids for concurrent rhinitis has
if the patientʼs F EV1 is less than 80% of personal best, a been found to have a limited benefit in improving asthma
brief course of oral glucocorticosteroids should be and reducing asthma morbidity in some but not all
considered to reduce airflow limitation274,275 (Evidence C). studies289-291. Leukotriene modifiers125,292, allergen-specific
Furthermore, patients who have received systemic immunotherapy284,293, and anti-IgE therapy294,295 are effective
glucocorticosteroids within the past 6 months should have in both conditions (Evidence A).
systemic coverage during the surgical period (100 mg
hydrocortisone every 8 hours intravenously). This should Additional information on this topic from the Allergic
be rapidly reduced 24 hours following surgery, as Rhinitis and its Impact on Asthma (ARIA) initiative can be
prolonged systemic glucocorticosteroid therapy may inhibit found at http://www.whiar.org284.
wound healing276 (Evidence C).
Sinusitis. Sinusitis is a complication of upper respiratory
Rhinitis, Sinusitis, and Nasal Polyps infections, allergic rhinitis, nasal polyps, and other forms of
nasal obstruction. Both acute and chronic sinusitis can
Upper airway diseases can influence lower airway function worsen asthma. Clinical features of sinusitis lack
in some patients with asthma. Although the mechanisms diagnostic precision296, and CT Scan confirmation is
behind this relationship have not been established, recommended when available. In children with suspected
inflammation likely plays a similarly critical role in the rhinosinusitis, antibiotic therapy for 10 days is
pathogenesis of rhinitis, sinusitis, and nasal polyps as recommended297 (Evidence B). Treatment should also
in asthma. include medications to reduce nasal congestion, such as
topical nasal decongestants or topical nasal or even
Rhinitis. The majority of patients with asthma have a systemic glucocorticosteroids. These agents remain
history or evidence of rhinitis and up to 30% of patients secondary to primary asthma therapies279,288.
with persistent rhinitis have or develop asthma277,278.
Rhinitis frequently precedes asthma, and is both a risk Nasal polyps. Nasal polyps associated with asthma and
factor for the development of asthma279 and is associated rhinitis, and sometimes with aspirin hypersensitivity298, are
with increased severity and health resource use in seen primarily in patients over 40 years old. Between 36%
asthma280. Rhinitis and asthma share several risk factors: and 96% of aspirin-intolerant patients have polyps, and
common indoor and outdoor allergens such as house dust 29% to 70% of patients with nasal polyps may have
mites, animal dander, and, less commonly, pollen affecting asthma298,299. Children with nasal polyps should be
both the nose and bronchi281,282, occupational sensitizers283, assessed for cystic fibrosis and immotile cilia syndrome.
and non-specific factors like aspirin. For these reasons,
the Allergic Rhinitis and its Impact on Asthma (ARIA) Nasal polyps are quite responsive to topical
initiative recommends that the presence of asthma must glucocorticosteroids288. A limited number of patients with
be considered in all patients with rhinitis, and that in glucocorticosteroid-refractory polyps may benefit from surgery.
planning treatment, both should be considered together284.
Occupational Asthma
Both asthma and rhinitis are considered to be
inflammatory disorders of the airway, but there are some Once a diagnosis of occupational asthma is established,
differences between the two conditions in mechanisms, complete avoidance of the relevant exposure is ideally an
clinical features, and treatment approach. Although the important component of management300-302. Occupational
inflammation of the nasal and bronchial mucosa may be asthma may persist even several years after removal from
similar, nasal obstruction is largely due to hyperemia in exposure to the causative agent, especially when the
rhinitis, while airway smooth muscle contraction plays a patient has had symptoms for a long time before cessation
dominant role in asthma285. of exposure303,304. Continued exposure may lead to increasingly
severe and potentially fatal asthma exacerbations305, a

ASTHMA MANAGEMENT AND PREVENTION 71

lower probability of subsequent remission, and, ultimately, Gastroesophageal Reflux
permanently impaired lung function306. Pharmacologic
therapy for occupational asthma is identical to therapy for The relationship of increased asthma symptoms,
other forms of asthma, but it is not a substitute for particularly at night, to gastroesophageal reflux remains
adequate avoidance. Consultation with a specialist in uncertain, although this condition is nearly three times as
asthma management or occupational medicine is advisable. prevalent in patients with asthma compared to the general
population 318,319. Some of these patients also have a hiatal
The British Occupational Health Research Foundation hernia; furthermore, theophylline and oral ␤2-agonists may
Guidelines for the prevention, identification, and increase the likelihood of symptoms by relaxing the lower
management of occupational asthma are available at esophageal ring.
http://www.bohrf.org.uk/downloads/asthevre.pdf.
A diagnosis of gastroesophageal reflux in patients with
Respiratory Infections asthma can best be made by simultaneously monitoring
esophageal pH and lung function. Medical management
Respiratory infections have an important relationship to should be given for the relief of reflux symptoms as it is
asthma as they provoke wheezing and increased often effective. Patients may be advised to eat smaller,
symptoms in many patients307. Epidemiological studies more frequent meals; avoid food or drink between meals
have found that infectious microorganisms associated and especially at bedtime; avoid fatty meals, alcohol,
with increased asthma symptoms are often respiratory theophylline, and oral ␤2-agonists; use proton pump
viruses308, but seldom bacteria309. Respiratory syncytial inhibitors or H2-antagonists; and elevate the head of the
virus is the most common cause of wheezing in infancy45, bed. However, the role of anti-reflux treatment in asthma
while rhinoviruses (which cause the common cold), are the control is unclear, as it does not consistently improve lung
principal triggers of wheezing and worsening of asthma in function, asthma symptoms, nocturnal asthma, or the use
older children and adults310. Other respiratory viruses, of asthma medications in subjects with asthma but without
such as parainfluenza, influenza, adenovirus, and clear reflux-associated respiratory symptoms. Subgroups
of patients may benefit, but it appears difficult to predict
coronavirus, are also associated with increased wheezing
which patients will respond to this therapy320.
and asthma symptoms311.
Surgery for gastroesophageal reflux is reserved for the
A number of mechanisms have been identified that explain
severely symptomatic patient with well-documented
why respiratory infections trigger wheezing and increased
esophagitis and failure of medical management. In patients
airway responsiveness, including damage to airway
with asthma, it should be demonstrated that the reflux
epithelium, stimulation of virus-specific IgE antibody,
causes asthma symptoms before surgery is advised321,322.
enhanced mediator release, and the appearance of a late
asthmatic response to inhaled antigen312. Thus, there is
Aspirin-Induced Asthma (AIA)
evidence that viral infections are an “adjuvant” to the
inflammatory response and promote the development of Up to 28% of adults with asthma, but rarely children with
airway injury by enhancing airway inflammation313. asthma, suffer from asthma exacerbations in response to
aspirin and other nonsteroidal anti-inflammatory drugs
Treatment of an infectious exacerbation follows the same (NSAIDs). This syndrome is more common in severe
principles as treatment of other asthma exacerbations— asthma323.
that is, rapid-acting inhaled ␤2-agonists and early
introduction of oral glucocorticosteroids or increases in The clinical picture and course of aspirin-induced asthma
inhaled glucocorticosteroids by at least four-fold are (AIA) are characteristic324. The majority of patients first
recommended. Because increased asthma symptoms experience symptoms, which may include vasomotor
can often persist for weeks after the infection is cleared, rhinitis and profuse rhinorrhea, during the third to fourth
anti-inflammatory treatment should be continued for this decade of life. Chronic nasal congestion evolves, and
full period to ensure adequate control. physical examination often reveals nasal polyps. Asthma
and hypersensitivity to aspirin often develop subsequently.
The role of chronic infection with Chlamydia pneumoniae The hypersensitivity to aspirin presents a unique picture:
and Mycoplasma pneumoniae in the pathogenesis or within minutes to one or two hours following ingestion of
worsening of asthma is currently uncertain314. The benefit aspirin, an acute, often severe, asthma attack develops,
from macrolide antibiotics remains unclear315-317. and is usually accompanied by rhinorrhea, nasal
obstruction, conjunctival irritation, and scarlet flush of the
head and neck. This may be provoked by a single aspirin

72 ASTHMA MANAGEMENT AND PREVENTION

or other cyclooxygnease-1 (COX-1) inhibitor and include Generally, asthma patients, especially those with adult
violent bronchospasm, shock, loss of consciousness, and onset asthma and associated upper airway disease (nasal
even respiratory arrest325,326. polyposis), should be counseled to avoid NSAIDs, taking
acetominophen/paracetemol instead.
Persistent marked eosinophilic inflammation, epithelial
disruption, cytokine production, and upregulation of Anaphylaxis and Asthma
adhesion molecules are found in the airways of patients
with AIA327,328. Airway expression of interleukin-5 (IL-5), Anaphylaxis is a potentially life-threatening condition that
which is involved in recruitment and survival of eosinophils, can both mimic and complicate severe asthma. Effective
is also increased328. AIA is further characterized by treatment of anaphylaxis demands early recognition of the
increased activation of cysteinyl leukotriene pathways, event. The possibility of anaphylaxis should be considered
which may be partly explained by a genetic polymorphism in any setting where medication or biological substances
of the LTC4 synthase gene found in about 70% percent of are given, especially by injection. Examples of documented
patients329. However, the exact mechanism by which causes of anaphylaxis include the administration of
aspirin triggers bronchoconstriction remains unknown330. allergenic extracts in immunotherapy, food intolerance
(nuts, fish, shellfish, eggs, milk), avian-based vaccines,
The ability of a cyclooxygenase inhibitor to trigger reactions insect stings and bites, latex hypersensitivity, drugs (␤-
depends on the drug's cyclooxygenase inhibitory potency, lactam antibiotics, aspirin and NSAIDs, and angiotensin
as well as on the individual sensitivity of the patient329. converting enzyme (ACE) inhibitors), and exercise.
A characteristic history of reaction is considered adequate Symptoms of anaphylaxis include flushing, pruritis,
for initiating avoidance strategies. However, the diagnosis urticaria, and angioedema; upper and lower airway
can only be confirmed by aspirin challenge, as there are involvement such as stridor, dyspnea, wheezing, or apnea;
no suitable in vitro tests for diagnosis. The aspirin challenge dizziness or syncope with or without hypotension; and
test is not recommended for routine practice as it is associated
gastrointestinal symptoms such as nausea, vomiting,
with a high risk of potentially fatal consequences and must
cramping, and diarrhea. Exercise-induced anaphylaxis,
only be conducted in a facility with cardiopulmonary
often associated with medication or food allergy, is a
resuscitation capabilities331. Further safeguards are that
unique physical allergy and should be differentiated from
patients should only be challenged when their asthma is in
exercise-induced bronchoconstriction338.
remission and their FEV1 is greater than 70% of predicted
or personal best. Bronchial (inhalational) and nasal
Airway anaphylaxis could account for the sudden onset of
challenges with lysine aspirin are safer than oral challenges
asthma attacks in severe asthma and the relative
and may be performed in specialized centers332,333.
resistance of these attacks to increased doses of ␤2-
Once aspirin or NSAID hypersensitivity develops, it is
agonists180. If there is a possibility that anaphylaxis is
present for life. Patients with AIA should avoid aspirin,
involved in an asthma attack, epinephrine should be the
products containing it, other analgesics that inhibit COX-1,
and often also hydrocortisone hemisuccinate334. Avoid- bronchodilator of choice. Prompt treatment for
ance does not prevent progression of the inflammatory anaphylaxis is crucial and includes oxygen, intramuscular
disease of the respiratory tract. Where an NSAID is epinephrine, injectable antihistamine, intravenous
indicated, a cyclooxygenase-2 (COX-2) inhibitor may be hydrocortisone, oropharyngeal airway, and intravenous
considered352 with appropriate physician supervision and fluid. Preventing a recurrence of anaphylaxis depends on
observation for at least one hour after administration335 identifying the cause and instructing the patient on
(Evidence B). Glucocorticosteroids continue to be the avoidance measures and self-administered emergency
mainstay of asthma therapy, but leukotriene modifiers may treatment with pre-loaded epinephrine syringes339.
also be useful for additional control of the underlying
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86 ASTHMA MANAGEMENT AND PREVENTION

 CHAPTER

IMPLEMENTATION
OF ASTHMA
GUIDELINES IN
HEALTH SYSTEMS
 An important barrier to the successful translation of
KEY POINTS: asthma guidelines into clinical practice is access to
available and affordable medication especially for patients
• In order to effect changes in medical practice and in less developed economies where the cost of treatment
consequent improvements in patient outcomes, is high in comparison to income and assets.
evidence-based guidelines must be implemented
and disseminated at the national and local levels.
GUIDELINE IMPLEMENTATION
• Implementation of asthma guidelines should involve STRATEGIES
a wide variety of professional groups and other
stakeholders, and take into account local cultural Implementation of asthma guidelines should begin with the
and economic conditions. setting of goals and development of strategies for asthma
care through collaboration among diverse professional
• An important part of the implementation process is groups including both primary and secondary health care
to establish a system to evaluate the effectiveness professionals, public health officials, patients, asthma
and quality of care. advocacy groups, and the general public. Goals and
implementation strategies will vary from country to
• Those involved in the adaptation and implementation country–and within countries–for reasons of economics,
of asthma guidelines require an understanding of the culture, and environment. However, common issues are
cost and cost effectiveness of various management shown in Figure 5-1.
recommendations in asthma care.
The next step is adaptation of guidelines on asthma
management for local use by teams of local primary and
• GINA has developed a number of resources and
secondary care health professionals. Many low- and
programs to aid in guideline implementation and
middle income countries do not consider asthma a high-
dissemination. priority health concern because other, more common
respiratory diseases such as tuberculosis and pneumonia
are of greater public health importance1. Therefore,
INTRODUCTION practical asthma guidelines for implementation in low-
income countries should have a simple algorithm for
It has been demonstrated in a variety of settings that separating non-infectious from infectious respiratory
patient care consistent with recommendations in evidence- illnesses; simple objective measurements for diagnosis
based asthma guidelines leads to improved outcomes. and management such as peak flow variability2; available,
Guidelines are designed to ensure that all members of a affordable, and low-risk medications recommended for
patientʼs healt h care team are aware of the goals of asthma control; a simple regime for recognizing severe
treatment and of the different ways of achieving these asthma; and simple diagnosis and management approaches
goals. They help set standards of clinical care, may serve relevant to the facilities and limited resources available.
as a basis for audit and payment, and act as a starting
point for the education of health professionals and patients. Next, adapted guidelines must be widely disseminated in
multiple venues and using multiple formats. This can be
However, in order to effect changes in medical practice accomplished, for example, by publication in professional
and consequent improvements in patient outcomes, journals, accompanied by multidisciplinary symposia,
evidence-based guidelines must be implemented and workshops, and conferences involving national and local
disseminated at national and local levels. Dissemination experts with involvement of the professional and mass
involves educating clinicians to improve their awareness, media to raise awareness of the key messages3. The
knowledge, and understanding of guideline most effective interventions to improve professional
recommendations. It is one part of implementation, practice are multifaceted and interactive4,5. However, little
which involves the translation of evidence-based asthma is known of the cost effectiveness of these interventions6.
guidelines into real-life practice with improvement of health Integrated care pathways are being explored as a mean to
outcomes for the patient. Implementation remains a improve asthma care in specific settings, such as patients
difficult problem worldwide. Barriers to implementation coming to emergency departments22.
range from poor infrastructure that hampers delivery of
medicines to remote parts of a country, to cultural factors In some countries, implementation of asthma guidelines
that make patients reluctant to use recommended has been done at a national level with government health
medications (e.g., inhaled preparations), suboptimal use of department collaboration. A model for an implementation
medications21, and lack of physician use of guidelines. program that has improved patient outcomes is provided

88 IMPLEMENTATION OF ASTHMA GUIDELINES IN HEALTH SYTEMS

 and outcome within different sectors of the health care
Figure 5-1. Checklist of Issues for National or Local system. Each country should determine its own minimum
Asthma Implementation
sets of data to audit health outcomes. There are a variety
• What is the size of the problem and burden of asthma in this of assessment tools which provide a consistent and
country or district? objective assessment of asthma morbidity or control (e.g.,
• What arrangements will be made for shared care among
Asthma Control Test9, Asthma Control Questionnaire10-12,
different health care providers (doctors and nurses, hospital Asthma Therapy Assessment Questionnaire13). Results of
and primary care)? these assessments should be recorded at each visit,
• How will medical care be linked with community health facilities providing a record of the long-term clinical response of the
and educational initiatives? patient to treatment. Direct feedback provides several
• What are the major preventable factors in this country or district
benefits—a means for the patient/caregiver to become
that could help prevent asthma from developing or could familiar with, and sensitized to, satisfactory versus poor
prevent asthma exacerbations from occurring in those who control of asthma; a reference point from which to evaluate
already have asthma? deteriorating asthma; and an indicator of changes in
• What preconceived assumptions about asthma and its treatment asthma control in response to changes in treatment. The
and what cultural factors will need special attention? strategy of culturally appropriate direct feedback of clinical
• What treatments are currently used? outcomes to physicians about specific health care results
of their patients may be important for general practitioners
• How affordable and accessible are medications and services to
the patient? who treat many diseases in addition to asthma and thus
could not be expected to know guidelines in detail and
• What other treatments are available, cheap enough for
purchase, and stable in local climatic conditions?
handle patients accordingly.
• Can inhaler devices and medicines be standardized to reduce
cost/storage/availability problems? ECONOMIC VALUE OF
• Who will provide emergency care? INTERVENTIONS AND GUIDELINE
• Which groups of the population are at special risk (e.g., inner-
city, poor, teenage, minority)?
IMPLEMENTATION IN ASTHMA
• Whom can we enlist to help in education (community health
workers/health-promotion facilitators/trained educators currently
Cost is recognized as an important barrier to the delivery
working on other programs/self-help support groups)? of optimal evidence-based health care in almost every
country, although its impact on patientsʼ ac cess to
• Who will take responsibility for the education of health care
professionals? treatments varies widely both between and within
countries. At the country or local level, health authorities
• Who will take responsibility for the education of people with
asthma and their family members/caregivers?
make resource availability and allocation decisions
affecting populations of asthma patients by considering
• How can asthma education and treatment be integrated into
the balance and tradeoffs between costs and clinical
other programs (e.g., child health)?
outcomes (benefits and harms), often in relation to
competing public health and medical needs. Treatment
by the national asthma program in Finland, a long-term, costs must also be explicitly considered at each
comprehensive, multifaceted public health initiative with consultation between health care provider and patient to
well-defined targets for asthma guideline implementation7,8. assure that cost does not present a barrier to achieving
asthma control. Thus, those involved in the adaptation
Public health strategies involving a broad coalition of and implementation of asthma guidelines require an
stakeholders in asthma care, including medical societies,
understanding of the cost and cost effectiveness of various
health care professionals, patient support groups,
management recommendations in asthma care. To this
government, and the private sector, have been
end, a short discussion of cost-effectiveness evaluation for
implemented in Australia (Australian National Asthma
asthma care follows.
Campaign, http://www.nationalasthma.org.au), and the
United States (National Asthma Education and Prevention
Utilization and Cost of Health Care Resources
Program, http://www.nhlbi.nih.gov).
Between 35 and 50% of medical expenditures for asthma
An important part of the implementation process is to are a consequence of exacerbations14, an asthma outcome
establish a system to evaluate the effectiveness and most view as representing treatment failure. Hospitalization,
quality of care. Evaluation involves surveillance of emergency department and unscheduled clinic visits,
traditional epidemiological parameters, such as morbidity and use of rescue medication comprise the majority of
and mortality, as well as the specific audit of both process exacerbation-related treatment costs. In clinical trials of

IMPLEMENTATION OF ASTHMA GUIDELINES IN HEALTH SYTEMS 89

asthma treatments, exacerbations are customarily Determining the Economic Value of Interventions in
characterized by use of health care resources, alone or in Asthma
combination with symptom and lung function data,
especially when the primary study outcome is reduction in Economic evaluations require the selection of three main
the exacerbation frequency or time to an exacerbation outcome parameters–estimates of treatment-related health
event. Routine collection of health care resource benefits, treatment-related risks, and treatment-related costs.
consumption data can be undertaken in the field through These parameters can be determined directly from clinical
patient or caregiver self-report. In some circumstances, studies or through the application of modeling studies.
automated data from clinical or billing records can Local evidence requirements for economic evaluations
substitute for self-report and are more reliable and valid13,15. determine the choices of health benefit measures. When
the decision to be considered is at the macro-level, for
Composite definitions of asthma control16,17 may include
example the inclusion of a new treatment in a government-
one or more health care utilization items. These items
typically describe the presence of an exacerbation or an sponsored health care program or the benefits package of
exacerbation-related treatment in precise and valid terms. a health insurer, economic evaluations require the use of a
Many of the published composite measures of asthma common metric such as life years gained, improvement in
control have included hospitalization and emergency generic quality of life, or quality-adjusted life years (QALY)
treatment data, such as unscheduled or urgent care visits or gained18. These outcomes support comparison of cost-
use of nebulized ␤2-agonists and/or oral glucocorticosteroids17. effectiveness ratios across different disease states and
Although health care utilization elements are essential to any patient populations. However, in asthma, QALYs are
pragmatic definition of asthma control, as yet unanswered difficult to measure, particularly in children where validated
in the literature is which of the number of possible health preference measures are not available. Some have
care options (single items or combinations of items) can advocated the use of clinical measures such as
contribute to an acceptable definition of control, and the symptom-free days or asthma control as the denominator
values of each that might be viewed as acceptable control. in economic evaluations19. A unified definition of asthma
control would substantially improve the acceptance of
For studies to evaluate the cost impact of guideline non-QALY economic evaluations among those interested
implementation or of specific asthma interventions, data on
in their design and application.
costs of implementation (e.g., costs related to dissemination
and publication of guidelines, costs of health professional
education), preventive pharmacotherapy, diagnostic and GINA DISSEMINATION AND
follow-up spirometry, use of devices (spacers, peak flow
meters), and routine office visits are required to supplement
IMPLEMENTATION RESOURCES
data on exacerbation-related treatments. Together, these
data provide a comprehensive profile of health care resource Educational materials based on this Global Strategy for
consumption. These data can be acquired in a similar Asthma Management and Prevention are available in
fashion using self-report or from automated databases. several forms, including a pocket guide for health care
professionals and one for patients and families. These are
Once data on use of health care resources are collected, available on the GINA Website (http://www.ginasthma.org).
costs can be determined by assigning local currency price Each year, the GINA Science Committee examines peer-
weights to health care resources consumed. Unit price reviewed literature on asthma management and updates
weights are normally collected from government reports, various GINA documents. A report of a GINA Working
price audits of local payers, billing records, claims Group20 provides a blueprint for implementation strategies.
databases, and patient surveys.
Other activities to assist with implementation of asthma
Assessment of patient and caregiver travel and waiting management recommendations through the GINA
time for medical visits, as well as absences from and program include:
productivity while at school or work, comprise additional
and important outcome measures in asthma. These
GINA Website - http://www.ginasthma.org. The Internet
indirect costs of asthma are substantial, in estimated to be
is creating a conduit for the access, sharing, and exchange
roughly 50% of the overall disease burden14. However,
there are no standardized, validated, and culturally of information and permits the global distribution of
adapted instruments for assessing these measures in a medical information. Although it is still not widely
variety of populations. available, especially in low-income countries, the global
trend is for increasing use of the Internet for medical
education by asthma patients and their health care
providers. Thus, to facilitate communication with health

90 IMPLEMENTATION OF ASTHMA GUIDELINES IN HEALTH SYTEMS

professionals, health policy experts, patients, and their procurement through an Asthma Drug Facility
families internationally, GINA has maintained a Website (http://www.GlobalADF.org) are among the goals of GARD
since 1995 to provides access to the GINA guideline and are being pursued actively by one of the partner
documents and educational materials for patients and the groups, the International Union Against Tuberculosis and
public as well as updates of activities and information about Lung Diseases (IUATLD).
collaborating groups and contacts throughout the world.
World Asthma Day. Initiated in 1998, and held on the REFERENCES
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92 IMPLEMENTATION OF ASTHMA GUIDELINES IN HEALTH SYTEMS

NOTES
NOTES
The Global Initiative for Asthma is supported by educational grants from:

Visit the GINA Web site at www.ginasthma.org

© 2006 Medical Communications Resources, Inc.

Copies of this document are available at www.us-health-network.com