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®

GLOBAL STRATEGY FOR

ASTHMA MANAGEMENT AND PREVENTION

REVISED 2006

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Global Strategy for Asthma Management and PreventionThe GINA reports are available on www.ginasthma.org.

inside front cover

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GINA EXECUTIVE COMMITTEE*

Paul O'Byrne, MD, Chair McMaster University

Hamilton, Ontario, CanadaEric D. Bateman, MDUniversity of Cape TownCape Town, South Africa.

Jean Bousquet, MD, PhDMontpellier University and INSERMMontpellier, France

Tim Clark, MDNational Heart and Lung InstituteLondon United Kingdom

Ken Ohta. MD, PhDTeikyo University School of MedicineTokyo, Japan

Pierluigi Paggiaro, MDUniversity of PisaPisa, Italy

Soren Erik Pedersen, MDKolding HospitalKolding, Denmark

Manuel Soto-Quiroz, MDHospital Nacional de NiñosSan José, Costa Rica

Raj B Singh MDApollo HospitalChennai, India

Wan-Cheng Tan, MDSt Paul's Hospital,Vancouver, BC, Canada

GINA SCIENCE COMMITTEE*

Eric D. Bateman, MD, Chair University of Cape TownCape Town, South Africa

Peter J. Barnes, MDNational Heart and Lung InstituteLondon, UK

Jean Bousquet, MD, PhDMontpellier University and INSERMMontpellier, France

Jeffrey M. Drazen, MDHarvard Medical SchoolBoston, Massachusetts, USA

Mark FitzGerald, MDUniversity of British ColumbiaVancouver, BC, Canada

Peter Gibson, MDJohn Hunter HospitalNSW, New Castle, Australia

Paul O'Byrne, MDMcMaster UniversityHamilton, Ontario, Canada

Ken Ohta. MD, PhDTeikyo University School of MedicineTokyo, Japan

Soren Erik Pedersen, MDKolding HospitalKolding, Denmark

Emilio Pizzichini. MDUniversidade Federal de Santa CatarinaFlorianópolis, SC, Brazil

Sean D. Sullivan, PhDUniversity of WashingtonSeattle, Washington, USA

Sally E. Wenzel, MDNational Jewish Medical/Research CenterDenver, Colorado, USA

Heather J. Zar, MDUniversity of Cape TownCape Town, South Africa

REVIEWERS

Louis P. Boulet, MDHopital LavalQuebec, QC, Canada

William W. Busse, MDUniversity of WisconsinMadison, Wisconsin USA

Neil Barnes, MDThe London Chest Hospital, Barts and theLondon NHS TrustLondon, United Kingdom

Yoshinosuke Fukuchi, MD, PhDPresident, Asian Pacific Society of RespirologyTokyo, Japan

John E. Heffner, MDPresident, American Thoracic SocietyProvidence Portland Medical CenterPortland, Oregon USA

Dr. Mark LevyKenton Bridge Medical CentreKenton, United Kingdom

Carlos M. Luna, MDPresident, ALATUniversity of Buenos AiresBuenos Aires, Argentina

Dr. Helen K. ReddelWoolcock Institute of Medical ResearchCamperdown, New South Wales, Australia

Stanley Szefler, MDNational Jewish Medical & Research CenterDenver, Colorado USA

GINA Assembly Members Who SubmittedComments

Professor Nguygen Nang AnBachmai University HospitalHanoi, Vietnam

Professor Richard BeasleyMedical Research Institute New ZealandWellington, New Zealand

Yu-Zi Chen, MDChildren's Hospital of The Capital Institute ofPediatricsBeijing, China

Ladislav Chovan, MD, PhDPresident, Slovak Pneumological andPhthisiological SocietyBratislava, Slovak Republic

Motohiro Ebisawa, MD, PhDNational Sagamihara Hospital/ Clinical Research Center for AllergologyKanagawa, Japan

Professor Amiran GamkrelidzeTbilisi, Georgia

Dr. Michiko HaidaHanzomon Hospital,Chiyoda-ku, Tokyo, Japan

Dr. Carlos Adrian JiménezSan Luis Potosí, México

Sow-Hsong Kuo, MDNational Taiwan University HospitalTaipei, Taiwan

Eva Mantzouranis, MDUniversity Hospital

Heraklion, Crete, Greece

Dr. Yousser MohammadTishreen University School of MedicineLattakia, Syria

Hugo E. Neffen, MDChildren HospitalSanta Fe, Argentina

Ewa Nizankowska-Mogilnicka, MDUniversity School of MedicineKrakow, Poland

Afshin Parsikia, MD, MPHAsthma and Allergy ProgramIran

Jose Eduardo Rosado Pinto, MDHospital Dona EstefaniaLisboa, Portugal

Joaquín Sastre, MDUniversidad Autonoma de MadridMadrid, Spain

Dr. Jeana Rodica RaduN. Malaxa HospitalBucharest, Romania

Mostafizur Rahman, MDDirector and Head, NIDCHDhaka, Bangladesh

Vaclav Spicak, MDCzech Initiative for AsthmaPrague, Czech Republic

G.W. Wong, MDChinese University of Hong KongHong Kong, China

GINA ProgramSuzanne S. Hurd, PhDScientific Director

Sarah DeWeerdtMedical Editor

Global Strategy for Asthma Management and Prevention 2006

i*Disclosures for members of GINA Executive and Science Committees can be found at:http://www.ginasthma.com/Committees.asp?l1=7&l2=2

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Asthma is a serious global health problem. People of allages in countries throughout the world are affected by this

chronic airway disorder that, when uncontrolled, can placesevere limits on daily life and is sometimes fatal. Theprevalence of asthma is increasing in most countries,especially among children. Asthma is a significant burden,not only in terms of health care costs but also of lostproductivity and reduced participation in family life.

During the past two decades, we have witnessed manyscientific advances that have improved our understandingof asthma and our ability to manage and control iteffectively. However, the diversity of national health careservice systems and variations in the availability of asthmatherapies require that recommendations for asthma carebe adapted to local conditions throughout the globalcommunity. In addition, public health officials require

information about the costs of asthma care, how toeffectively manage this chronic disorder, and educationmethods to develop asthma care services and programsresponsive to the particular needs and circumstanceswithin their countries.

In 1993, the National Heart, Lung, and Blood Institutecollaborated with the World Health Organization toconvene a workshop that led to a Workshop Report:Global Strategy for Asthma Management and Prevention .This presented a comprehensive plan to manage asthmawith the goal of reducing chronic disability and prematuredeaths while allowing patients with asthma to leadproductive and fulfilling lives.

At the same time, the Global Initiative for Asthma (GINA)was implemented to develop a network of individuals,organizations, and public health officials to disseminateinformation about the care of patients with asthma while atthe same time assuring a mechanism to incorporate theresults of scientific investigations into asthma care.Publications based on the GINA Report were preparedand have been translated into languages to promoteinternational collaboration and dissemination ofinformation. To disseminate information about asthmacare, a GINA Assembly was initiated, comprised of asthmacare experts from many countries to conduct workshopswith local doctors and national opinion leaders and to holdseminars at national and international meetings. In

addition, GINA initiated an annual World Asthma Day (in2001) which has gained increasing attention each year toraise awareness about the burden of asthma, and toinitiate activities at the local/national level to educatefamilies and health care professionals about effectivemethods to manage and control asthma.

In spite of these dissemination efforts, international

surveys provide direct evidence for suboptimal asthma

control in many countries, despite the availability ofeffective therapies. It is clear that if recommendationscontained within this report are to improve care of peoplewith asthma, every effort must be made to encouragehealth care leaders to assure availability of and access tomedications, and develop means to implement effectiveasthma management programs including the use of

appropriate tools to measure success.

In 2002, the GINA Report stated that “it is reasonable toexpect that in most patients with asthma, control of thedisease can, and should be achieved and maintained.”To meet this challenge, in 2005, Executive Committeerecommended preparation of a new report not only toincorporate updated scientific information but to implement

an approach to asthma management based on asthmacontrol, rather than asthma severity. Recommendations toassess, treat and maintain asthma control are provided inthis document. The methods used to prepare thisdocument are described in the Introduction.

It is a privilege for me to acknowledge the work of themany people who participated in this update project, as

well as to acknowledge the superlative work of all whohave contributed to the success of the GINA program.

The GINA program has been conducted throughunrestricted educational grants from AstraZeneca,Boehringer Ingelheim, Chiesi Group, GlaxoSmithKline,

Meda Pharma, Merck, Sharp & Dohme, MitsubishiPharma, Novartis, Nycomed, PharmAxis and Schering-

Plough. The generous contributions of these companiesassured that Committee members could meet together todiscuss issues and reach consensus in a constructive andtimely manner. The members of the GINA Committeesare, however, solely responsible for the statements andconclusions presented in this publication.

GINA publications are available through the Internet(http://www.ginasthma.org).

Paul O'Byrne, MDChair, GINA Executive CommitteeMcMaster University

Hamilton, Ontario, Canada

PREFACE

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PREFACE .........................................................................ii

INTRODUCTION..............................................................vi

EXECUTIVE SUMMARY: MANAGING ASTHMA INCHILDREN 5 YEARS AND YOUNGER.........................x

CHAPTER 1. DEFINITION AND OVERVIEW..................1

KEY POINTS ....................................................................2

DEFINITION .....................................................................2

THE BURDEN OF ASTHMA.............................................3Prevalence, Morbidity and Mortality .............................3Social and Economic Burden .......................................3

FACTORS INFLUENCING THE DEVELOPMENT ANDEXPRESSION OF ASTHMA..........................................4

Host Factors................................................................4Genetic .....................................................................4Obesity .....................................................................5Sex ...........................................................................5

Environmental Factors ................................................5Allergens ..................................................................5Infections ..................................................................5Occupational sensitizers ...........................................5Tobacco smoke ........................................................6Outdoor/Indoor air pollution ......................................6Diet ...........................................................................7

MECHANISMS OF ASTHMA............................................7Airway Inflammation In Asthma....................................7

Inflammatory cells ....................................................7Inflammatory mediators ............................................7Structural changes in the airways .............................8

Pathophysiology...........................................................8Airway hyperresponsiveness ....................................8

Special Mechanisms ....................................................8Acute exacerbations .................................................8Nocturnal asthma .....................................................9Irreversible airflow limitation .....................................9Difficult-to-treat asthma ............................................9Smoking and asthma ................................................9

REFERENCES .................................................................9

CHAPTER 2. DIAGNOSIS AND CLASSIFICATION .....15

KEY POINTS ..................................................................16

INTRODUCTION ............................................................16

CLINICAL DIAGNOSIS...................................................16Medical History...........................................................16

Symptoms ..............................................................16Cough variant asthma ............................................16Exercise-Induced bronchospasm ...........................17

Physical Examination .................................................17Tests for Diagnosis and Monitoring ............................17

Measurements of lung function ...............................17Spirometry ..............................................................18Peak expiratory flow ...............................................18Measurement of airway responsiveness ................19Non-Invasive markers of airway inflammation ........19Measurements of allergic status .............................19

DIAGNOSTIC CHALLENGES ANDDIFFERENTIAL DIAGNOSIS.......................................20Children 5 Years and Younger ...................................20Older Children and Adults ..........................................20The Elderly .................................................................21Occupational Asthma .................................................21Distinguishing Asthma from COPD ............................21

CLASSIFICATION OF ASTHMA.....................................22Etiology ......................................................................22Asthma Severity .........................................................22Asthma Control ..........................................................22

REFERENCES ...............................................................23

CHAPTER 3. ASTHMA MEDICATIONS ........................27

KEY POINTS ..................................................................28

INTRODUCTION ............................................................28

ASTHMA MEDICATIONS: ADULTS ...............................28Route of Administration ..............................................28Controller Medications................................................29

Inhaled glucocorticosteroids ...................................29Leukotriene modifiers .............................................30Long-acting inhaled 2 -agonists .............................30Theophylline ...........................................................31Cromones: sodium cromoglycate and

nedocromil sodium ........................................31Long-acting oral 2 -agonists ...................................32Anti-IgE ..................................................................32Systemic glucocorticosteroids ................................32Oral anti-allergic compounds ..................................32Other controller therapies .......................................32

GLOBAL STRATEGY FOR ASTHMA MANAGEMENT AND PREVENTIONTABLE OF CONTENTS


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Allergen-specific immunotherapy ............................33Reliever Medications...................................................34

Rapid-acting inhaled 2 -agonists ............................34Systemic glucocorticosteroids ................................34Anticholinergics ......................................................34

Theophylline ...........................................................35Short-acting oral 2 -agonists ..................................35Complementary and Alternative Medicine...................35

ASTHMA TREATMENT: CHILDREN.............................35Route of Administration ..............................................35Controller Medications................................................36

Inhaled glucocorticosteroids ...................................36Leukotriene modifiers .............................................38Long-acting inhaled 2 -agonists .............................38Theophylline ...........................................................39Cromones: sodium cromoglycate and nedocromil

sodium .........................................................39Long-acting oral 2 -agonists ...................................39Systemic glucocorticosteroids ................................39

Reliever Medications...................................................40Rapid-acting inhaled 2 -agonists and short-acting

oral 2 -agonists ..............................................40Anticholinergics ......................................................40

REFERENCES ...............................................................40

CHAPTER 4. ASTHMA MANAGEMENT ANDPREVENTION ................................................................49

INTRODUCTION ............................................................50

COMPONENT 1: DEVELOP PATIENT/DOCTOR PARTNERSHIP...........................................50

KEY POINTS ..................................................................50

INTRODUCTION ............................................................50

ASTHMA EDUCATION...................................................51At the Initial Consultation...........................................52Personal Asthma Action Plans ..................................52Follow-up and Review ...............................................52Improving Adherence ................................................52Self-Management in Children....................................52

THE EDUCATION OF OTHERS.....................................53

COMPONENT 2: IDENTIFY AND REDUCE EXPOSURETO RISK FACTORS ....................................................54

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

INTRODUCTION ............................................................54

ASTHMA PREVENTION.................................................54

PREVENTION OF ASTHMA SYMPTOMS AND

EXACERBATIONS....................................................55Indoor Allergens .......................................................55Domestic mites .......................................................55Furred animals .......................................................55Cockroaches ..........................................................55Fungi ......................................................................56

Outdoor Allergens ......................................................56Indoor Air Pollutants ..................................................56Outdoor Air Pollutants ................................................56

Occupational Exposures ............................................56Food and Food Additives ...........................................56Drugs .........................................................................57Influenza Vaccination .................................................57Obesity.......................................................................57Emotional Stress ........................................................57

Other Factors That May Exacerbate Asthma .............57

COMPONENT 3: ASSESS, TREAT AND MONITORASTHMA......................................................................57

KEY POINTS ..................................................................57

INTRODUCTION ............................................................57

ASSESSING ASTHMA CONTROL.................................58

TREATING TO ACHIEVE CONTROL.............................58Treatment Steps for Achieving Control ......................58

Step 1: As-needed reliever medication ..................58

Step 2: Reliever medication plus a singlecontroller .........................................................60

Step 3: Reliever medication plus one or twocontrollers .......................................................60

Step 4: Reliever medication plus two or morecontrollers .......................................................61

Step 5: Reliever medication plus additionalcontroller options ............................................61

MONITORING TO MAINTAIN CONTROL ......................61

Duration and Adjustments to Treatment......................61

Stepping Down Treatment When Asthma Is

Controlled.................................................................62

Stepping Up Treatment In Response To Loss Of

Control .....................................................................62Difficult-to-Treat-Asthma .............................................63


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Asthma is a serious public health problem throughout theworld, affecting people of all ages. When uncontrolled,

asthma can place severe limits on daily life, and issometimes fatal.

In 1993, the Global Initiative for Asthma (GINA) wasformed. Its goals and objectives were described in a 1995

NHLBI/WHO Workshop Report, Global Strategy for Asthma Management and Prevention. This Report(revised in 2002), and its companion documents, havebeen widely distributed and translated into manylanguages. A network of individuals and organizationsinterested in asthma care has been created and severalcountry-specific asthma management programs havebeen initiated. Yet much work is still required to reduce

morbidity and mortality from this chronic disease.

In January 2004, the GINA Executive Committeerecommended that the Global Strategy for Asthma Management and Prevention be revised to emphasizeasthma management based on clinical control, rather thanclassification of the patient by severity. This importantparadigm shift for asthma care reflects the progress that

has been made in pharmacologic care of patients. Manyasthma patients are receiving, or have received, someasthma medications. The role of the health careprofessional is to establish each patientʼs current level oftreatment and control, then adjust treatment to gain andmaintain control. This means that asthma patients shouldexperience no or minimal symptoms (including at night),have no limitations on their activities (including physical

exercise), have no (or minimal) requirement for rescuemedications, have near normal lung function, andexperience only very infrequent exacerbations.

FUTURE CHALLENGES

In spite of laudable efforts to improve asthma care over thepast decade, a majority of patients have not benefited fromadvances in asthma treatment and many lack even the

rudiments of care. A challenge for the next several yearsis to work with primary health care providers and publichealth officials in various countries to design, implement,and evaluate asthma care programs to meet local needs.The GINA Executive Committee recognizes that this is a

difficult task and, to aid in this work, has formed severalgroups of global experts, including: a Dissemination TaskGroup; the GINA Assembly, a network of individuals who

care for asthma patients in many different health caresettings; and regional programs (the first two being GINAMesoamerica and GINA Mediterranean). These efforts

aim to enhance communication with asthma specialists,primary-care health professionals, other health care

workers, and patient support organizations. The ExecutiveCommittee continues to examine barriers to implementationof the asthma management recommendations, especiallythe challenges that arise in primary-care settings and indeveloping countries.

While early diagnosis of asthma and implementation ofappropriate therapy significantly reduce the socioeconomicburdens of asthma and enhance patientsʼ quality of life,medications continue to be the major component of thecost of asthma treatment. For this reason, the pricing ofasthma medications continues to be a topic for urgentneed and a growing area of research interest, as this has

important implications for the overall costs of asthmamanagement.

Moreover, a large segment of the worldʼs population livesin areas with inadequate medical facilities and meagerfinancial resources. The GINA Executive Committeerecognizes that “fixed” international guidelines and “rigid”scientific protocols will not work in many locations. Thus,

the recommendations found in this Report must beadapted to fit local practices and the availability of healthcare resources.

As the GINA Committees expand their work, every effortwill be made to interact with patient and physician groupsat national, district, and local levels, and in multiple healthcare settings, to continuously examine new and innovative

approaches that will ensure the delivery of the best asthmacare possible. GINA is a partner organization in a programlaunched in March 2006 by the World Health Organization,the Global Alliance Against Chronic Respiratory Diseases(GARD). Through the work of the GINA Committees, andin cooperation with GARD initiatives, progress towardbetter care for all patients with asthma should besubstantial in the next decade.

METHODOLOGY

A. Preparation of yearly updates: Immediatelyfollowing the release of an updated GINA Report in 2002,the Executive Committee appointed a GINA Science

Committee, charged with keeping the Report up-to-dateby reviewing published research on asthma managementand prevention, evaluating the impact of this research on

the management and prevention recommendations in theGINA documents, and posting yearly updates of thesedocuments on the GINA website. The first update was

INTRODUCTION


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posted in October 2003, based on publications fromJanuary 2000 through December 2002. A second updateappeared in October 2004, and a third in October 2005,each including the impact of publications from Januarythrough December of the previous year.

The process of producing the yearly updates began with a

Pub Med search using search fields established by theCommittee: 1) asthma, All Fields, All ages, only items with abstracts, Clinical Trial, Human, sorted by Authors; and2) asthma AND systematic, All fields, ALL ages, only items with abstracts, Human, sorted by Author. In addition,peer-reviewed publications not captured by Pub Med couldbe submitted to individual members of the Committeeproviding an abstract and the full paper were submitted in

(or translated into) English.

All members of the Committee received a summary ofcitations and all abstracts. Each abstract was assigned to

two Committee members, and an opportunity to provide anopinion on any single abstract was offered to all members.Members evaluated the abstract or, up to her/his

judgment, the full publication, by answering specific written

questions from a short questionnaire, indicating whetherthe scientific data presented affected recommendations inthe GINA Report. If so, the member was asked tospecifically identify modifications that should be made.The entire GINA Science Committee met on a regularbasis to discuss each individual publication that was

judged by at least one member to have an impact onasthma management and prevention recommendations,

and to reach a consensus on the changes in the Report.Disagreements were decided by vote.

The publications that met the search criteria for eachyearly update (between 250 and 300 articles per year)mainly affected the chapters related to clinicalmanagement. Lists of the publications considered by theScience Committee each year, along with the yearlyupdated reports, are posted on the GINA website,

www.ginasthma.org.

B. Preparation of new 2006 report: In January 2005,the GINA Science Committee initiated its work on this newreport. During a two-day meeting, the Committeeestablished that the main theme of the new report shouldbe the control of asthma. A table of contents was

developed, themes for each chapter identified, and writingteams formed. The Committee met in May and September2005 to evaluate progress and to reach consensus onmessages to be provided in each chapter. Throughout itswork, the Committee made a commitment to develop adocument that would: reach a global audience, be basedon the most current scientific literature, and be as concise

as possible, while at the same time recognizing that one ofthe values of the GINA Report has been to providebackground information about asthma management andthe scientific information on which managementrecommendations are based.

In January 2006, the Committee met again for a two-day

session during which another in-depth evaluation of eachchapter was conducted. At this meeting, membersreviewed the literature that appeared in 2005—using thesame criteria developed for the update process. The listof 285 publications from 2005 that were considered isposted on the GINA website. At the January meeting, itwas clear that work remaining would permit the report tobe finished during the summer of 2006 and, accordingly,

the Committee requested that as publications appearedthroughout early 2006, they be reviewed carefully for theirimpact on the recommendations. At the Committeeʼs nextmeeting in May, 2006 publications meeting the search

criteria were considered and incorporated into the currentdrafts of the chapters, where appropriate. A final meetingof the Committee was held be held in September 2006, atwhich publications that appear prior to July 31, 2006 were

considered for their impact on the document.

Periodically throughout the preparation of this report,representatives from the GINA Science Committee havemet with members of the GINA Assembly (May andSeptember, 2005 and May 2006) to discuss the overalltheme of asthma control and issues specific to each of thechapters. The GINA Assembly includes representatives

from over 50 countries and many participated in theseinterim discussions. In addition, members of the Assembly

were invited to submit comments on a DRAFT documentduring the summer of 2006. Their comments, along withcomments received from several individuals who wereinvited to serve as reviewers, were considered by theCommittee in September, 2006.

Summary of Major Changes

The major goal of the revision was to present informationabout asthma management in as comprehensive manneras possible but not in the detail that would normally befound in a textbook. Every effort has been made to selectkey references, although in many cases, several otherpublications could be cited. The document is intended to

be a resource; other summary reports will be prepared,including a Pocket Guide specifically for the care of infantsand young children with asthma.


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Some of the major changes that have been made in thisreport include:

1. Every effort has been made to produce a morestreamlined document that will be of greater use to busyclinicians, particularly primary care professionals. Thedocument is referenced with the up-to-date sources so thatinterested readers may find further details on varioustopics that are summarized in the report.

2. The whole of the document now emphasizes asthmacontrol. There is now good evidence that the clinicalmanifestations of asthma—symptoms, sleep disturbances,limitations of daily activity, impairment of lung function, anduse of rescue medications—can be controlled withappropriate treatment.

3. Updated epidemiological data, particularly drawn fromthe report Global Burden of Asthma, are summarized.

Although from the perspective of both the patient andsociety the cost to control asthma seems high, the cost ofnot treating asthma correctly is even higher.

4. The concept of difficult-to-treat asthma is introduced anddeveloped at various points throughout the report. Patientswith difficult-to-treat asthma are often relatively insensitiveto the effects of glucocorticosteroid medications, and maysometimes be unable to achieve the same level of controlas other asthma patients.

5. Lung function testing by spirometry or peak expiratoryflow (PEF) continues to be recommended as an aid todiagnosis and monitoring. Measuring the variability ofairflow limitation is given increased prominence, as it is key to

both asthma diagnosis and the assessment of asthma control.

6. The previous classification of asthma by severity intoIntermittent, Mild Persistent, Moderate Persistent, and SeverePersistent is now recommended only for research purposes.

7. Instead, the document now recommends a classificationof asthma by level of control: Controlled, Partly Controlled,or Uncontrolled. This reflects an understanding that asthmaseverity involves not only the severity of the underlyingdisease but also its responsiveness to treatment, and thatseverity is not an unvarying feature of an individualpatientʼs asthma but may change over months or years.

8. Throughout the report, emphasis is placed on theconcept that the goal of asthma treatment is to achieveand maintain clinical control. Asthma control is defined as:

• No (twice or less/week) daytime symptoms• No limitations of daily activities, including exercise• No nocturnal symptoms or awakening because of asthma

• No (twice or less/week) need for reliever treatment• Normal or near-normal lung function results• No exacerbations

9. Emphasis is given to the concept that increased use,especially daily use, of reliever medication is a warning ofdeterioration of asthma control and indicates the need toreassess treatment.

10. The roles in therapy of several medications haveevolved since previous versions of the report:

• Recent data indicating a possible increased risk ofasthma-related death associated with the use of long-acting 2-agonists in a small group of individuals hasresulted in increased emphasis on the message thatlong-acting 2-agonists should not be used as

monotherapy in asthma, and must only be used incombination with an appropriate dose of inhaledglucocorticosteroid.

• Leukotriene modifiers now have a more prominentrole as controller treatment in asthma, particularly inadults. Long-acting oral 2-agonists alone are nolonger presented as an option for add-on treatment atany step of therapy, unless accompanied by inhaled

glucocorticosteroids.• Monotherapy with cromones is no longer given as an

alternative to monotherapy with a low dose of inhaledglucocorticosteroids in adults.

• Some changes have been made to the tables ofequipotent daily doses of inhaled glucocorticosteroidsfor both children and adults.

12. The six-part asthma management program detailed in

previous versions of the report has been changed. Thecurrent program includes the following five components:

Component 1. Develop Patient/Doctor PartnershipComponent 2. Identify and Reduce Exposure to Risk

FactorsComponent 3. Assess, Treat, and Monitor AsthmaComponent 4. Manage Asthma ExacerbationsComponent 5. Special Considerations

13. The inclusion of Component 1 reflects the fact thateffective management of asthma requires the developmentof a partnership between the person with asthma and hisor her health care professional(s) (and parents/caregivers,in the case of children with asthma). The partnership is

formed and strengthened as patients and their health careprofessionals discuss and agree on the goals of treatment,

develop a personalized, written self-management actionplan including self-monitoring, and periodically review thepatientʼs treatment and level of asthma control. Educationremains a key element of all doctor-patient interactions.


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14. Component 3 presents an overall concept for asthmamanagement oriented around the new focus on asthmacontrol. Treatment is initiated and adjusted in a continuouscycle (assessing asthma control, treating to achievecontrol, and monitoring to maintain control) driven by thepatientʼs level of asthma control.

15. Treatment options are organized into five “Steps”reflecting increasing intensity of treatment (dosages and/ornumber of medications) required to achieve control. At allSteps, a reliever medication should be provided for as-needed use. At Steps 2 through 5 , a variety of controllermedications are available.

16. If asthma is not controlled on the current treatmentregimen, treatment should be stepped up until control isachieved. When control is maintained, treatment can bestepped down in order to find the lowest step and dose oftreatment that maintains control.

17. Although each component contains managementadvice for all age categories where these are considered

relevant, special challenges must be taken into account inmaking recommendations for managing asthma in childrenin the first 5 years of life. Accordingly, an ExecutiveSummary has been prepared—and appears at the end ofthis introduction—that extracts sections on diagnosis andmanagement for this very young age group.

18. It has been demonstrated in a variety of settings that

patient care consistent with evidence-based asthma guide-lines leads to improved outcomes. However, in order toeffect changes in medical practice and consequent

improvements in patient outcomes, evidence-basedguidelines must be implemented and disseminated atnational and local levels. Thus, a chapter has beenadded on implementation of asthma guidelines in healthsystems that details the process and economics ofguideline implementation.

LEVELS OF EVIDENCE

In this document, levels of evidence are assigned tomanagement recommendations where appropriate inChapter 4, the Five Components of Asthma Management.Evidence levels are indicated in boldface type enclosed inparentheses after the relevant statement—e.g., (Evidence A).

The methodological issues concerning the use of evidencefrom meta-analyses were carefully considered1.

This evidence level scheme (Table A) has been used inprevious GINA reports, and was in use throughout thepreparation of this document. The GINA ScienceCommittee was recently introduced to a new approach to

evidence levels2 and plans to review and consider thepossible introduction of this approach in future reports andextending it to evaluative and diagnostic aspects of care.

REFERENCES

1. Jadad AR, Moher M, Browman GP, Booker L, Sigouis C,Fuentes M, et al. Systematic reviews and meta-analyseson treatment of asthma: critical evaluation. BMJ 2000;320:537-40.2. Guyatt G, Vist G, Falck-Ytter Y, Kunz R, Magrini N,Schunemann H. An emerging consensus on gradingrecommendations? Available from URL:http://www.evidence-basedmedicine.com.

Table A. Description of Levels of Evidence

Evidence Sources of DefinitionCategory Evidence

A

B

C

D

Randomized controlled trials(RCTs). Rich body of data.

Evidence is from endpoints ofwell designed RCTs thatprovide a consistent pattern offindings in the population forwhich the recommendationis made. Category A requiressubstantial numbers of studiesinvolving substantial numbersof participants.

Randomized controlled trials(RCTs). Limited body of data.

Evidence is from endpoints ofintervention studies thatinclude only a limited numberof patients, posthoc orsubgroup analysis of RCTs, ormeta-analysis of RCTs. In

general, Category B pertainswhen few randomized trialsexist, they are small in size,they were undertaken in apopulation that differs from thetarget population of the recom-mendation, or the results aresomewhat inconsistent.

Nonrandomized trials.Observational studies.

Evidence is from outcomes ofuncontrolled or nonrandomizedtrials or from observationalstudies.

Panel consensus judgment. This category is used only incases where the provision ofsome guidance was deemedvaluable but the clinicalliterature addressing thesubject was insufficient to

justify placement in one of theother categories. The PanelConsensus is based onclinical experience orknowledge that does not meetthe above-listed criteria.


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‡ References and evidence levels are deleted from this extracted material but are provided in the main text.

INTRODUCTION

Since the first asthma guidelines were published morethan 30 years ago, there has been a trend towards produc-ing unified guidelines that apply to all age groups. Thishas been prompted by the recognition that commonpathogenic and inflammatory mechanisms underlie allasthma, evidence-based literature on the efficacy of key

controller and reliever medications, and an effort to unifytreatment approaches for asthma patients in different agecategories. This approach avoids repetition of details thatare common to all patients with asthma. There is relativelylittle age-specific data on management of asthma inchildren, and guidelines have tended to extrapolate from

evidence gained from adolescents and adults.

This revision of the Global Strategy for Asthma

Management and Prevention again provides a unified textas a source document. Each chapter contains separatesections containing details and management advice forspecific age categories where these are consideredrelevant. These age groups include children 5 years andyounger (sometimes called preschool age), children olderthan 5 years, adolescents, adults, and the elderly. Most ofthe differences between these age groups relate to natural

history and comorbidities, but there are also importantdifferences in the approach to diagnosis, measures forassessing severity and monitoring control, responses to

different classes of medications, techniques for engagingwith the patient and his/her family in establishing andmaintaining a treatment plan, and the psychosocialchallenges presented at different stages of life.

Special challenges that must be taken into account inmanaging asthma in children in the first 5 years of lifeinclude difficulties with diagnosis, the efficacy and safety ofdrugs and drug delivery systems, and the lack of data onnew therapies. Patients in this age group are oftenmanaged by pediatricians who are routinely faced with awide variety of issues related to childhood diseases.Therefore, for the convenience of readers this Executive

Summary extracts sections of the report that pertain to

diagnosis and management of asthma in children 5 yearsand younger. These extracts may also be found in themain text, together with detailed discussion of otherrelevant background data on asthma in this age group‡.

As emphasized throughout the report, for patients in allage groups with a confirmed diagnosis of asthma, the goal

of treatment should be to achieve and maintain control(see Figure 4.3-2) for prolonged periods, with due regardto the safety of treatment, potential for adverse effects,and the cost of treatment required to achieve this goal.

DIAGNOSIS OF ASTHMA IN CHILDREN 5 YEARS ANDYOUNGER

Wheezing and diagnosis of asthma: Diagnosis of asthmain children 5 years and younger presents a particularlydifficult problem. This is because episodic wheezing andcough are also common in children who do not haveasthma, particularly in those under age 3. Wheezing is

usually associated with a viral respiratory illness—predominantly respiratory syncytial virus in childrenyounger than age 2, and other viruses in older preschoolchildren. Three categories of wheezing have beendescribed in children 5 years and younger:

• Transient early wheezing, which is often outgrown inthe first 3 years. This is often associated withprematurity and parental smoking.

• Persistent early-onset wheezing (before age 3). Thesechildren typically have recurrent episodes of wheezingassociated with acute viral respiratory infections, noevidence of atopy, and no family history of atopy.Their symptoms normally persist through school ageand are still present at age 12 in a large proportion of

children. The cause of wheezing episodes is usuallyrespiratory syncytial virus in children younger than age 2,while other viruses predominate in children ages 2-5.

• Late-onset wheezing/asthma. These children haveasthma that often persists throughout childhood andinto adult life. They typically have an atopicbackground, often with eczema, and airway pathologythat is characteristic of asthma.

The following categories of symptoms are highlysuggestive of a diagnosis of asthma: frequent episodes ofwheeze (more than once a month), activity-induced coughor wheeze, nocturnal cough in periods without viralinfections, absence of seasonal variation in wheeze, and

symptoms that persist after age 3. A simple clinical indexbased on the presence of a wheeze before the age of 3,and the presence of one major risk factor (parental historyof asthma or eczema) or two of three minor risk factors(eosinophilia, wheezing without colds, and allergic rhinitis)has been shown to predict the presence of asthma inlater childhood.

EXECUTIVE SUMMARY

MANAGING ASTHMA IN CHILDREN 5 YEARS AND YOUNGER

x


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Alternative causes of recurrent wheezing must be

considered and excluded. These include:

• Chronic rhino-sinusitis• Gastroesophageal reflux• Recurrent viral lower respiratory tract infections

• Cystic fibrosis• Bronchopulmonary dysplasia• Tuberculosis• Congenital malformation causing narrowing of the

intrathoracic airways• Foreign body aspiration• Primary ciliary dyskinesia syndrome• Immune deficiency

• Congenital heart disease

Neonatal onset of symptoms (associated with failure tothrive), vomiting-associated symptoms, or focal lung orcardiovascular signs suggest an alternative diagnosis andindicate the need for further investigations.

Tests for diagnosis and monitoring. In children 5 years

and younger, the diagnosis of asthma has to be basedlargely on clinical judgment and an assessment ofsymptoms and physical findings. A useful method forconfirming the diagnosis of asthma in this age group is atrial of treatment with short-acting bronchodilators andinhaled glucocorticosteroids. Marked clinical improvementduring the treatment and deterioration when it is stoppedsupports a diagnosis of asthma. Diagnostic measures

recommended for older children and adults such asmeasurement of airway responsiveness, and markers ofairway inflammation is difficult, requiring complexequipment41 that makes them unsuitable for routine use.Additionally, lung function testing—usually a mainstay ofasthma diagnosis and monitoring—is often unreliable in

young children. Children 4 to 5 years old can be taught to

use a PEF meter, but to ensure accurate results parentalsupervision is required.

ASTHMA CONTROL

Asthma control refers to control of the clinicalmanifestations of disease. A working scheme based oncurrent opinion that has not been validated provides thecharacteristics of controlled, partly controlled anduncontrolled asthma. Complete control of asthma iscommonly achieved with treatment, the aim of whichshould be to achieve and maintain control for prolongedperiods, with due regard to the safety of treatment,

potential for adverse effects, and the cost of treatmentrequired to achieve this goal.

ASTHMA MEDICATIONS(Detailed background information on asthma medications for children of all ages is included in Chapter 3.)

Inhaled therapy is the cornerstone of asthma treatment forchildren of all ages. Almost all children can be taught toeffectively use inhaled therapy. Different age groups requiredifferent inhalers for effective therapy, so the choice ofinhaler must be individualized (Chapter 3, Figure 3-3).

Controller Medications

Inhaled glucocorticosteroids: Treatment with inhaledglucocorticosteroids in children 5 years and younger withasthma generally produces similar clinical effects as inolder children, but dose-response relationships havebeen less well studied. The clinical response to inhaledglucocorticosteroids may depend on the inhaler chosen

Figure 4.3-1. Levels of Asthma Control

Characteristic Controlled(All of the following)

Partly Controlled(Any measure present in any week)

Uncontrolled

Daytime symptoms None (twice or less/week) More than twice/week Three or more featuresof partly controlledasthma present inany week

Limitations of activities None Any

Nocturnal symptoms/awakening None Any

Need for reliever/rescue treatment

None (twice or less/week) More than twice/week

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.


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and the childʼs ability to use the inhaler correctly. With useof a spacer device, daily doses ≤ 400 µg of budesonide orequivalent result in near-maximum benefits in the majorityof patients. Use of inhaled glucocorticosteroids does notinduce remission of asthma, and symptoms return when

treatment is stopped.

The clinical benefits of intermittent systemic or inhaledglucocorticosteroids for children with intermittent, viral-induced wheeze remain controversial. While some studiesin older children have found small benefits, a study inyoung children found no effects on wheezing symptoms.There is no evidence to support the use of maintenancelow-dose inhaled glucocorticosteroids for preventingtransient early wheezing.

Leukotriene modifiers: Clinical benefits of monotherapywith leukotriene modifiers have been shown in childrenolder than age 2. Leukotriene modifiers reduce viral-

induced asthma exacerbations in children ages 2-5 with ahistory of intermittent asthma. No safety concerns havebeen demonstrated from the use of leukotriene modifiersin children.

Theophylline: A few studies in children 5 years andyounger suggest some clinical benefit of theophylline.However, the efficacy of theophylline is less than that oflow-dose inhaled glucocorticosteroids and the side effectsare more pronounced.

Other controller medications: The effect of long-actinginhaled 2-agonists or combination products has not yetbeen adequately studied in children 5 years and younger.Studies on the use of cromones in this age group are

sparse and the results generally negative. Because of theside effects of prolonged use, oral glucocorticosteroids inchildren with asthma should be restricted to the treatmentof severe acute exacerbations, whether viral-inducedor otherwise.

Reliever Medications

Rapid-acting inhaled 2-agonists are the most effectivebronchodilators available and therefore the preferredtreatment for acute asthma in children of all ages.

ASTHMA MANAGEMENT AND PREVENTION

To achieve and maintain asthma control for prolongedperiods an asthma management and prevention strategyincludes five interrelated components: (1) DevelopPatient/Parent/Caregiver/Doctor Partnership; (2) Identifyand Reduce Exposure to Risk Factors; (3) Assess, Treat,and Monitor Asthma; (4) Manage Asthma Exacerbations;and (5) Special Considerations.

Component 1 - Develop Patient/Doctor Partnership: Education should be an integral part of all interactionsbetween health care professionals and patients. Althoughthe focus of education for small children will be on theparents and caregivers, children as young as 3 years of

age can be taught simple asthma management skills.

Component 2 - Identify and Reduce Exposure to Risk

Factors: Although pharmacologic interventions to treatestablished asthma are highly effective in controllingsymptoms and improving quality of life, measures toprevent the development of asthma, asthma symptoms,and asthma exacerbations by avoiding or reducingexposure to risk factors—in particular exposure to tobacco

smoke—should be implemented wherever possible.

Children over the age of 3 years with severe asthmashould be advised to receive an influenza vaccinationevery year, or at least when vaccination of the general

population is advised. However, routine influenzavaccination of children with asthma does not appear toprotect them from asthma exacerbations or improve

asthma control.

Component 3 - Assess, Treat, and Monitor Asthma:

The goal of asthma treatment, to achieve and maintainclinical control, can be reached in a majority of patientswith a pharmacologic intervention strategy developed inpartnership between the patient/family and the doctor. Atreatment strategy is provided in Chapter 4, Component 3- Figure 4.3-2.

The available literature on treatment of asthma in children

5 years and younger precludes detailed treatmentrecommendations. The best documented treatment tocontrol asthma in these age groups is inhaled glucocortico-steroids and at Step 2, a low-dose inhaled glucocortico-steroid is recommended as the initial controller treatment.

Equivalent doses of inhaled glucocorticosteroids, some ofwhich may be given as a single daily dose, are provided inChapter 3 (Figure 3-4) for children 5 years and younger.

If low doses of inhaled glucocorticosteroids do not controlsymptoms, an increase in glucocorticosteroid dose may bethe best option. Inhaler techniques should be carefullymonitored as they may be poor in this age group.

Combination therapy, or the addition of a long-acting 2-agonist, a leukotriene modifier, or theophylline when apatientʼs asthma is not controlled on moderate doses ofinhaled glucocorticosteroids, has not been studied inchildren 5 years and younger.


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Intermittent treatment with inhaled glucocorticosteroids isat best only marginally effective. The best treatment ofvirally induced wheeze in children with transient earlywheezing (without asthma) is not known. None of thecurrently available anti-asthma drugs have shown

convincing effects in these children.

Duration of and Adjustments to Treatment

Asthma like symptoms spontaneously go into remission ina substantial proportion of children 5 years and younger.Therefore, the continued need for asthma treatment in thisage group should be assessed at least twice a year.

Component 4 - Manage Asthma Exacerbations:Exacerbations of asthma (asthma attacks or acute

asthma) are episodes of progressive increase in shortnessof breath, cough, wheezing, or chest tightness, or somecombination of these symptoms. Severe exacerbations

are potentially life threatening, and their treatment requiresclose supervision. Patients with severe exacerbationsshould be encouraged to see their physician promptly or,depending on the organization of local health services, toproceed to the nearest clinic or hospital that provides

emergency access for patients with acute asthma.

Assessment: Several differences in lung anatomy andphysiology place infants at theoretically greater risk thanolder children for respiratory failure. Despite this,respiratory failure is rare in infancy. Close monitoring,using a combination of the parameters other than PEF(Chapter 4, Component 4: Figure 4.4-1), will permit a

fairly accurate assessment. Breathlessness sufficiently

severe to prevent feeding is an important symptom ofimpending respiratory failure.

Oxygen saturation, which should be measured in infantsby pulse oximetry, is normally greater than 95 percent.Arterial or arterialized capillary blood gas measurementshould be considered in infants with oxygen saturation

less than 90 percent on high-flow oxygen whosecondition is deteriorating. Routine chest X-rays are notrecommended unless there are physical signs suggestiveof 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 atregular intervals. Combination 2-agonist/anticholinergictherapy is associated with lower hospitalization rates andgreater improvement in PEF and FEV1. However, oncechildren with asthma are hospitalized following intensiveemergency department treatment, the addition of nebulized

ipratropium bromide to nebulized 2-agonist and systemicglucocorticosteroids appears to confer no extra benefit.

In view of the effectiveness and relative safety of rapid-acting 2-agonists, theophylline has a minimal role in the

management of acute asthma. Its use is associated withsevere and potentially fatal side effects, particularly in

those on long-term therapy with slow-release theophylline,and its bronchodilator effect is less than that of 2-agonists.In one study of children with near-fatal asthma, intravenoustheophylline provided additional benefit to patients alsoreceiving an aggressive regimen of inhaled and intravenous2-agonists, inhaled ipatropium bromide, and intravenoussystemic glucocorticosteroids. Intravenous magnesiumsulphate has not been studied in children 5 years andyounger.

An oral glucocorticosteroid dose of 1 mg/kg daily isadequate for treatment of exacerbations in children with

mild persistent asthma. A 3- to 5-day course is usuallyconsidered appropriate. Current evidence suggests thatthere is no benefit to tapering the dose of oral gluco-corticosteroids, either in the short-term or over severalweeks. Some studies have found that high doses of

inhaled glucocorticosteroids administered frequentlyduring the day are effective in treating exacerbations,but more studies are needed before this strategy canbe recommended.

For children admitted to an acute care facility for anexacerbation, criteria for determining whether they shouldbe discharged from the emergency department or

admitted to the hospital are provided in Chapter 4,

Component 4.


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CHAPTER

1

DEFINITION

AND

OVERVIEW

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This chapter covers several topics related to asthma,including definition, burden of disease, factors that influencethe risk of developing asthma, and mechanisms. It is notintended to be a comprehensive treatment of these topics,but rather a brief overview of the background that informsthe approach to diagnosis and management detailed insubsequent chapters. Further details are found in the

reviews and other references cited at the end of the chapter.

DEFINITION

Asthma is a disorder defined by its clinical, physiological,and pathological characteristics. The predominant featureof the clinical history is episodic shortness of breath,

particularly at night, often accompanied by cough.

Wheezing appreciated on auscultation of the chest is themost common physical finding.

The main physiological feature of asthma is episodic airway

obstruction characterized by expiratory airflow limitation.The dominant pathological feature is airway inflammation,sometimes associated with airway structural changes.

Asthma has significant genetic and environmentalcomponents, but since its pathogenesis is not clear, muchof its definition is descriptive. Based on the functionalconsequences of airway inflammation, an operational

description of asthma is:

Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role.The chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing,

particularly at night or in the early morning. These episodes are usually associated with widespread, but variable, airflow obstruction within the lung that is often reversible either spontaneously or with treatment.

Because there is no clear definition of the asthmaphenotype, researchers studying the development of thiscomplex disease turn to characteristics that can bemeasured objectively, such as atopy (manifested as the

presence of positive skin-prick tests or the clinicalresponse to common environmental allergens), airwayhyperresponsiveness (the tendency of airways to narrowexcessively in response to triggers that have little or noeffect in normal individuals), and other measures of

allergic sensitization. Although the association betweenasthma and atopy is well established, the precise linksbetween these two conditions have not been clearly and

comprehensively defined.

There is now good evidence that the clinical manifestationsof asthma—symptoms, sleep disturbances, limitations ofdaily activity, impairment of lung function, and use ofrescue medications—can be controlled with appropriatetreatment. When asthma is controlled, there should be nomore than occasional recurrence of symptoms and severe

exacerbations should be rare1.

KEY POINTS:

• Asthma is a chronic inflammatory disorder of theairways in which many cells and cellular elements

play a role. The chronic inflammation is associatedwith airway hyperresponsiveness that leads torecurrent episodes of wheezing, breathlessness,chest tightness, and coughing, particularly at night

or in the early morning. These episodes are usuallyassociated with widespread, but variable, airflowobstruction within the lung that is often reversibleeither spontaneously or with treatment.

• Clinical manifestations of asthma can be controlledwith appropriate treatment. When asthma iscontrolled, there should be no more than occasional

flare-ups and severe exacerbations should be rare.

• Asthma is a problem worldwide, with an estimated300 million affected individuals.

• Although from the perspective of both the patient andsociety the cost to control asthma seems high, thecost of not treating asthma correctly is even higher.

• A number of factors that influence a personʼs risk ofdeveloping asthma have been identified. These canbe divided into host factors (primarily genetic) andenvironmental factors.

• The clinical spectrum of asthma is highly variable,and different cellular patterns have been observed,

but the presence of airway inflammation remains a

consistent feature.

2 DEFINITION AND OVERVIEW


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THE BURDEN OF ASTHMA

Prevalence, Morbidity, and Mortality

Asthma is a problem worldwide, with an estimated 300million affected individuals2,3. Despite hundreds of reportson the prevalence of asthma in widely differing populations,the lack of a precise and universally accepted definition ofasthma makes reliable comparison of reported prevalencefrom different parts of the world problematic. Nonetheless,based on the application of standardized methods to

measure the prevalence of asthma and wheezing illness inchildren3 and adults4, it appears that the global prevalenceof asthma ranges from 1% to 18% of the population indifferent countries (Figure 1-1)2,3. There is good evidencethat asthma prevalence has been increasing in somecountries4-6 and has recently increased but now may havestabilized in others7,8. The World Health Organization has

estimated that 15 million disability-adjusted life years(DALYs) are lost annually due to asthma, representing1% of the total global disease burden2. Annual worldwidedeaths from asthma have been estimated at 250,000 andmortality does not appear to correlate well with prevalence(Figure 1-1)2,3. There are insufficient data to determine thelikely causes of the described variations in prevalencewithin and between populations.

Social and Economic Burden

Social and economic factors are integral to understandingasthma and its care, whether viewed from the perspectiveof the individual sufferer, the health care professional, or

entities that pay for health care. Absence from school and

days lost from work are reported as substantial social andeconomic consequences of asthma in studies from theAsia-Pacific region, India, Latin America, the UnitedKingdom, and the United States9-12.

The monetary costs of asthma, as estimated in a varietyof health care systems including those of the United

States13-15 and the United Kingdom16 are substantial.In analyses of economic burden of asthma, attentionneeds to be paid to both direct medical costs (hospitaladmissions and cost of medications) and indirect, non-medical costs (time lost from work, premature death) 17.For example, asthma is a major cause of absence fromwork in many countries, including Australia, Sweden,the United Kingdom, and the United States16,18-20.

Comparisons of the cost of asthma in different regionslead to a clear set of conclusions:

• The costs of asthma depend on the individual patientʼs

level of control and the extent to which exacerbationsare avoided.

• Emergency treatment is more expensive than plannedtreatment.

• Non-medical economic costs of asthma are substantial.

• Guideline-determined asthma care can be cost effective.

• Families can suffer from the financial burden of treatingasthma.

Although from the perspective of both the patient andsociety the cost to control asthma seems high, the cost ofnot treating asthma correctly is even higher. Propertreatment of the disease poses a challenge for individuals,

health care professionals, health care organizations, andgovernments. There is every reason to believe that thesubstantial global burden of asthma can be dramatically

reduced through efforts by individuals, their health careproviders, health care organizations, and local andnational governments to improve asthma control.

Detailed reference information about the burden of asthmacan be found in the report Global Burden of Asthma * .Further studies of the social and economic burden ofasthma and the cost effectiveness of treatment are neededin both developed and developing countries.

DEFINITION AND OVERVIEW 3

Figure 1-1. Asthma Prevalence and Mortality2, 3

Permission for use of this figure obtained from J. Bousquet.

*(http://www.ginasthma.org/ReportItem.asp?l1=2&l2=2&intId=94).


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FACTORS INFLUENCING THE

DEVELOPMENT AND EXPRESSION

OF ASTHMA

Factors that influence the risk of asthma can be dividedinto those that cause the development of asthma andthose that trigger asthma symptoms; some do both.The former include host factors (which are primarilygenetic) and the latter are usually environmental factors(Figure 1-2)21. However, the mechanisms whereby they

influence the development and expression of asthma arecomplex and interactive. For example, genes likelyinteract both with other genes and with environmentalfactors to determine asthma susceptibility22,23. In addition,developmental aspects—such as the maturation of theimmune response and the timing of infectious exposuresduring the first years of life—are emerging as important

factors modifying the risk of asthma in the geneticallysusceptible person.

Additionally, some characteristics have been linked to an

increased risk for asthma, but are not themselves truecausal factors. The apparent racial and ethnic differencesin the prevalence of asthma reflect underlying geneticvariances with a significant overlay of socioeconomic andenvironmental factors. In turn, the links between asthma

and socioeconomic status—with a higher prevalence of

asthma in developed than in developing nations, in poorcompared to affluent populations in developed nations,and in affluent compared to poor populations in developingnations—likely reflect lifestyle differences such asexposure to allergens, access to health care, etc.

Much of what is known about asthma risk factors comes

from studies of young children. Risk factors for thedevelopment of asthma in adults, particularly de novo inadults who did not have asthma in childhood, are lesswell defined.

The lack of a clear definition for asthma presents asignificant problem in studying the role of different riskfactors in the development of this complex disease,because the characteristics that define asthma (e.g.,

airway hyperresponsiveness, atopy, and allergicsensitization) are themselves products of complexgene-environment interactions and are therefore both

features of asthma and risk factors for the developmentof the disease.

Host Factors

Genetic. Asthma has a heritable component, but it is notsimple. Current data show that multiple genes may beinvolved in the pathogenesis of asthma24,25, and differentgenes may be involved in different ethnic groups. Thesearch for genes linked to the development of asthma hasfocused on four major areas: production of allergen-specific IgE antibodies (atopy); expression of airwayhyperresponsiveness; generation of inflammatory

mediators, such as cytokines, chemokines, and growth

factors; and determination of the ratio between Th1 andTh2 immune responses (as relevant to the hygienehypothesis of asthma)26.

Family studies and case-control association analyses haveidentified a number of chromosomal regions associatedwith asthma susceptibility. For example, a tendency to

produce an elevated level of total serum IgE is co-inheritedwith airway hyperresponsiveness, and a gene (or genes)governing airway hyperresponsiveness is located near amajor locus that regulates serum IgE levels onchromosome 5q27. However, the search for a specificgene (or genes) involved in susceptibility to atopy orasthma continues, as results to date have beeninconsistent24,25.

In addition to genes that predispose to asthma there aregenes that are associated with the response to asthmatreatments. For example, variations in the gene encodingthe beta-adrenoreceptor have been linked to differences in


Figure 1-2. Factors Influencing the Developmentand Expression of Asthma

HOST FACTORSGenetic, e.g.,• Genes pre-disposing to atopy

• Genes pre-disposing to airway hyperresponsivenessObesitySex

ENVIRONMENTAL FACTORSAllergens• Indoor: Domestic mites, furred animals (dogs, cats,

mice), cockroach allergen, fungi, molds, yeasts• Outdoor: Pollens, fungi, molds, yeasts

Infections (predominantly viral)Occupational sensitizersTobacco smoke• Passive smoking• Active smoking

Outdoor/Indoor Air PollutionDiet


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subjectsʼ responses to 2-agonists28. Other genes of

interest modify the responsiveness to glucocorticosteroids29

and leukotriene modifiers30. These genetic markers willlikely become important not only as risk factors in thepathogenesis of asthma but also as determinants of

responsiveness to treatment28,30-33.

Obesity. Obesity has also been shown to be a risk factorfor asthma. Certain mediators such as leptins may affectairway function and increase the likelihood of asthmadevelopment34,35.

Sex. Male sex is a risk factor for asthma in children. Priorto the age of 14, the prevalence of asthma is nearly twiceas great in boys as in girls36. As children get older thedifference between the sexes narrows, and by adulthoodthe prevalence of asthma is greater in women than in men.The reasons for this sex-related difference are not clear.However, lung size is smaller in males than in females at

birth37

but larger in adulthood.

Environmental Factors

There is some overlap between environmental factors thatinfluence the risk of developing asthma, and factors thatcause asthma symptoms—for example, occupationalsensitizers belong in both categories. However, there aresome important causes of asthma symptoms—such as airpollution and some allergens—which have not been clearlylinked to the development of asthma. Risk factors thatcause asthma symptoms are discussed in detail inChapter 4.2.

Allergens. Although indoor and outdoor allergens are wellknown to cause asthma exacerbations, their specific rolein the development of asthma is still not fully resolved.Birth-cohort studies have shown that sensitization to housedust mite allergens, cat dander, dog dander38,39, andAspergillus mold40 are independent risk factors for asthma-like symptoms in children up to 3 years of age. However,the relationship between allergen exposure andsensitization in children is not straightforward. It dependson the allergen, the dose, the time of exposure, the childʼsage, and probably genetics as well.

For some allergens, such as those derived from housedust mites and cockroaches, the prevalence ofsensitization appears to be directly correlated with

exposure38,41. However, although some data suggest thatexposure to house dust mite allergens may be a causalfactor in the development of asthma42, other studies havequestioned this interpretation43,44. Cockroach infestationhas been shown to be an important cause of allergicsensitization, particularly in inner-city homes45.

In the case of dogs and cats, some epidemiologic studieshave found that early exposure to these animals may protecta child against allergic sensitization or the development ofasthma46-48, but others suggest that such exposure mayincrease the risk of allergic sensitization47,49-51. This issue

remains unresolved.

The prevalence of asthma is reduced in children raised ina rural setting, which may be linked to the presence ofendotoxin in these environments52.

Infections. During infancy, a number of viruses have beenassociated with the inception of the asthmatic phenotype.Respiratory syncytial virus (RSV) and parainfluenza virusproduce a pattern of symptoms including bronchiolitis thatparallel many features of childhood asthma53,54. A numberof long-term prospective studies of children admitted to thehospital with documented RSV have shown thatapproximately 40% will continue to wheeze or have

asthma into later childhood53

. On the other hand, evidencealso indicates that certain respiratory infections early in life,including measles and sometimes even RSV, may protectagainst the development of asthma55,56. The data do notallow specific conclusions to be drawn.

The “hygiene hypothesis” of asthma suggests thatexposure to infections early in life influences thedevelopment of a childʼs immune system along a“nonallergic” pathway, leading to a reduced risk of asthmaand other allergic diseases. Although the hygienehypothesis continues to be investigated, this mechanismmay explain observed associations between family size,birth order, day-care attendance, and the risk of asthma.For example, young children with older siblings and thosewho attend day care are at increased risk of infections,but enjoy protection against the development of allergicdiseases, including asthma later in life57-59.

The interaction between atopy and viral infections appearsto be a complex relationship60, in which the atopic state caninfluence the lower airway response to viral infections, viralinfections can then influence the development of allergicsensitization, and interactions can occur when individualsare exposed simultaneously to both allergens and viruses.

Occupational sensitizers. Over 300 substances havebeen associated with occupational asthma61-65, which isdefined as asthma caused by exposure to an agent

encountered in the work environment. These substancesinclude highly reactive small molecules such asisocyanates, irritants that may cause an alteration inairway responsiveness, known immunogens such asplatinum salts, and complex plant and animal biologicalproducts that stimulate the production of IgE (Figure 1-3).



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Occupational asthma arises predominantly in adults66, 67,and occupational sensitizers are estimated to cause about1 in 10 cases of asthma among adults of working age68.Asthma is the most common occupational respiratorydisorder in industrialized countries69. Occupationsassociated with a high risk for occupational asthma includefarming and agricultural work, painting (including spray

painting), cleaning work, and plastic manufacturing62.

Most occupational asthma is immunologically mediatedand has a latency period of months to years after the onset

of exposure70. IgE-mediated allergic reactions and cell-mediated allergic reactions are involved71, 72.

Levels above which sensitization frequently occurs have

been proposed for many occupational sensitizers.However, the factors that cause some people but not

others to develop occupational asthma in response to thesame exposures are not well identified. Very highexposures to inhaled irritants may cause “irritant inducedasthma” (formerly called the reactive airways dysfunctionalsyndrome) even in non-atopic persons. Atopy and

tobacco smoking may increase the risk of occupationalsensitization, but screening individuals for atopy is of

limited value in preventing occupational asthma73. Themost important method of preventing occupational asthmais elimination or reduction of exposure to occupationalsensitizers.

Tobacco smoke. Tobacco smoking is associated with ac-celerated decline of lung function in people with asthma,increases asthma severity, may render patients lessresponsive to treatment with inhaled74 and systemic75

glucocorticosteroids, and reduces the likelihood of asthmabeing controlled76.

Exposure to tobacco smoke both prenatally and after birthis associated with measurable harmful effects including agreater risk of developing asthma-like symptoms in earlychildhood. However, evidence of increased risk of allergicdiseases is uncertain77, 78. Distinguishing the independent

contributions of prenatal and postnatal maternal smokingis problematic79. However, studies of lung functionimmediately after birth have shown that maternal smokingduring pregnancy has an influence on lung development37.Furthermore, infants of smoking mothers are 4 times morelikely to develop wheezing illnesses in the first year of life 80.In contrast, there is little evidence (based on meta-analysis) that maternal smoking during pregnancy has an

effect on allergic sensitization78. Exposure to

environmental tobacco smoke (passive smoking)increases the risk of lower respiratory tract illnesses ininfancy81 and childhood82.

Outdoor/indoor air pollution. The role of outdoor airpollution in causing asthma remains controversial83.Children raised in a polluted environment have diminished

lung function84, but the relationship of this loss of functionto the development of asthma is not known.

Outbreaks of asthma exacerbations have been shown tooccur in relationship to increased levels of air pollution,and this may be related to a general increase in the levelof pollutants or to specific allergens to which individualsare sensitized85-87. However, the role of pollutants in the

development of asthma is less well defined. Similarassociations have been observed in relation to indoorpollutants, e.g., smoke and fumes from gas and biomassfuels used for heating and cooling, molds, and cockroachinfestations.


Figure 1-3. Examples of Agents Causing Asthma inSelected Occupations*

Occupation/occupational field Agent

Animal and Plant Proteins

Bakers Flour, amylase

Dairy farmers Storage mites

Detergent manufacturing Bacillus subtilis enzymes

Electrical soldering Colophony (pine resin)

Farmers Soybean dust

Fish food manufacturing Midges, parasites

Food processing Coffee bean dust , meat tenderizer, tea, shell fish,amylase, egg proteins, pancreatic enzymes,papain

Granary workers Storage mites, Aspergillus , indoor ragweed, grass

Health care workers Psyllium, latex

Laxative manufacturing Ispaghula, psyllium

Poultry farmers Poultry mites, droppings, feathers

Research workers, veterinarians Locusts, dander, urine proteins

Sawmill workers, carpenters Wood dust (western red cedar, oak, mahogany,zebrawood, redwood, Lebanon cedar, Africanmaple, eastern white cedar)

Shipping workers Grain dust (molds, insects, grain)

Silk workers Silk worm moths and larvae

Inorganic chemicals

Beauticians Persulfate

Plating Nickel salts

Refinery workers Platinum salts, vanadium

Organic chemicals

Automobi le paint ing Ethanolamine, dissocyanates

Hospital workers Disinfectants (sul fath iazole, chloramines,formaldehyde, glutaraldehyde), latex

Manufacturing Antibiotics, piperazine, methyldopa, salbutamol,cimetidine

Rubber processing Formaldehyde, ethylene diamine, phthalic anhydride

Plastics industry Toluene dissocyanate, hexamethyl dissocyanate,dephenylmethyl isocyanate, phthalic anhydride,triethylene tetramines, trimellitic anhydride,

hexamethyl tetramine, acrylates

*See http://www.bohrf.org.uk for a comprehensive list of known sensitizing agents


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Diet. The role of diet, particularly breast-feeding, inrelation to the development of asthma has beenextensively studied and, in general, the data reveal thatinfants fed formulas of intact cow's milk or soy protein havea higher incidence of wheezing illnesses in early childhood

compared with those fed breast milk88.

Some data also suggest that certain characteristics ofWestern diets, such as increased use of processed foodsand decreased antioxidant (in the form of fruits and vegetables),increased n-6 polyunsaturated fatty acid (found in margarineand vegetable oil), and decreased n-3 polyunsaturatedfatty acid (found in oily fish) intakes have contributed tothe recent increases in asthma and atopic disease89.

MECHANISMS OF ASTHMA

Asthma is an inflammatory disorder of the airways, which

involves several inflammatory cells and multiple mediatorsthat result in characteristic pathophysiological changes21,90.In ways that are still not well understood, this pattern ofinflammation is strongly associated with airway hyper-responsiveness and asthma symptoms.

Airway Inflammation In Asthma

The clinical spectrum of asthma is highly variable, anddifferent cellular patterns have been observed, but thepresence of airway inflammation remains a consistentfeature. The airway inflammation in asthma is persistenteven though symptoms are episodic, and the relationshipbetween the severity of asthma and the intensity of

inflammation is not clearly established91,92

. Theinflammation affects all airways including in most patientsthe upper respiratory tract and nose but its physiologicaleffects are most pronounced in medium-sized bronchi.The pattern of inflammation in the airways appears to besimilar in all clinical forms of asthma, whether allergic,non-allergic, or aspirin-induced, and at all ages.

Inflammatory cells. The characteristic pattern ofinflammation found in allergic diseases is seen in asthma,with activated mast cells, increased numbers of activatedeosinophils, and increased numbers of T cell receptorinvariant natural killer T cells and T helper 2 lymphocytes(Th2), which release mediators that contribute to

symptoms (Figure 1-4). Structural cells of the airwaysalso produce inflammatory mediators, and contribute to thepersistence of inflammation in various ways (Figure 1-5).

Inflammatory mediators. Over 100 different mediators arenow recognized to be involved in asthma and mediate thecomplex inflammatory response in the airways103 (Figure 1-6).


Figure 1-4: Inflammatory Cells in Asthmatic Airways

Mast cells: Activated mucosal mast cells release

bronchoconstrictor mediators (histamine, cysteinyl leukotrienes,

prostaglandin D2)93. These cells are activated by allergens

through high-affinity IgE receptors, as well as by osmotic stimuli(accounting for exercise-induced bronchoconstriction). Increased

mast cell numbers in airway smooth muscle may be linked to

airway hyperresponsiveness94.

Eosinophils, present in increased numbers in the airways,

release basic proteins that may damage airway epithelial cells.

They may also have a role in the release of growth factors and

airway remodeling95.

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

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

large amounts of T helper 1 (Th1) and Th2 cytokines97.

Dendritic cells sample allergens from the airway surface and

migrate to regional lymph nodes, where they interact with

regulatory T cells and ultimately stimulate production of Th2

cells from naïve T cells98.

Macrophages are increased in number in the airways and may

be activated by allergens through low-affinity IgE receptors to

release inflammatory mediators and cytokines that amplify the

inflammatory response99.

Neutrophil numbers are increased in the airways and sputum of

patients with severe asthma and in smoking asthmatics, but the

pathophysiological role of these cells is uncertain and their

increase may even be due to glucocorticosteroid therapy100.

Figure 1-5: Airway Structural Cells Involved in thePathogenesis of Asthma

Airway epithelial cells sense their mechanical environment,

express multiple inflammatory proteins in asthma, and release

cytokines, chemokines, and lipid mediators. Viruses and air

pollutants interact with epithelial cells.

Airway smooth muscle cells express similar inflammatory

proteins to epithelial cells101.

Endothelial cells of the bronchial circulation play a role in

recruiting inflammatory cells from the circulation into the airway.

Fibroblasts and myofibroblasts produce connective tissue

components, such as collagens and proteoglycans, that are

involved in airway remodeling.

Airway nerves are also

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GINA Report 2006