GLOBAL STRATEGY FOR ASTHMA MANAGEMENT AND PREVENTION · 2019. 1. 14. · Asthma is a serious global health problem. People of all ages in countries throughout the world are affected

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GLOBAL STRATEGY FOR ASTHMA MANAGEMENT AND PREVENTION

UPDATED 2007

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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, ChairMcMaster UniversityHamilton, Ontario, Canada

Eric D. Bateman, MDUniversity of Cape Town Cape 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 Medicine Tokyo, Japan

Pierluigi Paggiaro, MDUniversity of Pisa Pisa, 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, ChairUniversity of Cape Town Cape 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 School Boston, Massachusetts, USA

Mark FitzGerald, MDUniversity of British Columbia Vancouver, BC, Canada

Peter Gibson, MDJohn Hunter HospitalNSW, New Castle, Australia

Paul O'Byrne, MDMcMaster UniversityHamilton, Ontario, Canada

Ken Ohta. MD, PhDTeikyo University School of Medicine Tokyo, 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 Center Denver, Colorado, USA

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

REVIEWERS (2006 report)

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 Center Portland, 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 (2006 report)

Professor Nguygen Nang An Bachmai University Hospital Hanoi, Vietnam

Professor Richard BeasleyMedical Research Institute New ZealandWellington, New Zealand

Yu-Zi Chen, MD Children's Hospital of The Capital Institute ofPediatrics Beijing, China

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

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

Professor Amiran Gamkrelidze Tbilisi, Georgia

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

Dr. Carlos Adrian Jiménez San Luis Potosí, México

Sow-Hsong Kuo, MD National 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 Radu N. Malaxa Hospital Bucharest, 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 Program

Suzanne S. Hurd, PhDScientific Director

Sarah DeWeerdtMedical Editor

Global Strategy for Asthma Management and Prevention 2007 (update)

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 thischronic 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 requireinformation 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. Inaddition, 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, internationalsurveys provide direct evidence for suboptimal asthmacontrol 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 ofappropriate 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 implementan 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, aswell 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, Mitsubishi TanabePharma Corporation, Novartis, Nycomed, PharmAxis andSchering-Plough. The generous contributions of thesecompanies assured that Committee members could meettogether to discuss issues and reach consensus in aconstructive and timely manner. The members of theGINA Committees are, however, solely responsible for thestatements and conclusions presented in this publication.

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

Paul O'Byrne, MDChair, GINA Executive CommitteeMcMaster UniversityHamilton, Ontario, Canada

PREFACE

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

METHODOLOGY AND SUMMARY OF NEWRECOMMENDATION, 2007 UPDATE .........................vi

INTRODUCTION ..............................................................x

EXECUTIVE SUMMARY: MANAGING ASTHMA IN CHILDREN 5 YEARS AND YOUNGER ......................xiv

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 AND EXPRESSION 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 AND DIFFERENTIAL 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 ......................................................34Theophylline...........................................................35Short-acting oral �2-agonists..................................35

Complementary 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 ANDEXACERBATIONS....................................................55Indoor Allergens .......................................................55

Domestic mites.......................................................55Furred animals .......................................................55Cockroaches ..........................................................55Fungi ......................................................................56

Outdoor Allergens ......................................................56Indoor Air Pollutants ..................................................56Outdoor Air Pollutants ................................................56Occupational Exposures ............................................56Food and Food Additives ...........................................56Drugs .........................................................................57Influenza Vaccination .................................................57Obesity.......................................................................57Emotional Stress ........................................................57Other Factors That May Exacerbate Asthma .............57

COMPONENT 3: ASSESS, TREAT AND MONITOR ASTHMA......................................................................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 ..................58Step 2: Reliever medication plus a single

controller .........................................................60Step 3: Reliever medication plus one or two

controllers .......................................................60Step 4: Reliever medication plus two or more

controllers .......................................................61Step 5: Reliever medication plus additional

controller options ............................................61

MONITORING TO MAINTAIN CONTROL ......................61Duration and Adjustments to Treatment......................61Stepping Down Treatment When Asthma Is

Controlled.................................................................62Stepping Up Treatment In Response To Loss Of

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


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COMPONENT 4 - MANAGE ASTHMA EXACERBATIONS ......................................................64

KEY POINTS ..................................................................64

INTRODUCTION ............................................................64

ASSESSMENT OF SEVERITY.......................................65

MANAGEMENT–COMMUNITY SETTINGS ...................65Treatment...................................................................66

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

MANAGEMENT–ACUTE CARE SETTINGS ..................66Assessment ................................................................66Treatment....................................................................68

Oxygen...................................................................68Rapid-acting inhaled �2–agonists...........................68Epinephrine ............................................................68

Additional bronchodilators ...........................................68Systemic glucocorticosteroids ................................68Inhaled glucocorticosteroids ...................................69Magnesium.............................................................69Helium oxygen therapy...........................................69Leukotriene modifiers .............................................69Sedatives ...............................................................69

Criteria for Discharge from the EmergencyDepartment vs. Hospitalization.................................69

COMPONENT 5. SPECIAL CONSIDERATIONS ..........70Pregnancy.....................................................................70Surgery .........................................................................70Rhinitis, Sinusitis, And Nasal Polyps .............................71

Rhinitis ...................................................................71Sinusitis..................................................................71Nasal polyps...........................................................71

Occupational Asthma....................................................71Respiratory Infections ...................................................72Gastroesophageal Reflux..............................................72Aspirin-Induced Asthma ................................................72Anaphylaxis and Asthma...............................................73

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

CHAPTER 5. IMPLEMENTATION OF ASTHMA GUIDELINES IN HEALTH SYSTEMS .........................87

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

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

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

ECONOMIC VALUE OF INTERVENTIONS ANDGUIDELINE IMPLEMENTATION IN ASTHMA...........89Utilization and Cost of Health Care Resources.........89Determining the Economic Value of Interventions in Asthma ...................................................................90

GINA DISSEMINATION/IMPLEMENTATIONRESOURCES ............................................................90

REFERENCES ...............................................................91


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When the Global Initiative for Asthma (GINA) program wasinitiated in 1993, a goal was to produce recommendationsfor asthma management based on the best scientificinformation available. Its first report, NHLBI/WHOWorkshop Report: Global Strategy for AsthmaManagement and Prevention was issued in 1995 andrevised in 2002. These reports, and their companiondocuments, have been widely distributed and translatedinto many languages. The 2002 report was revised in 2006based on research published through June, 2006 and canbe found on the GINA website (www.ginasthma.org).

The GINA Science Committee† was established in 2002 toreview published research on asthma management andprevention, to evaluate the impact of this research onrecommendations in the GINA documents related tomanagement and prevention, and to post yearly updateson the GINA website. This first update of the 2006 reportincludes the impact of publications from July 1, 2006through June 30, 2007.

Methods: The process to produce this 2007 updateincluded a Pub Med search using search fields establishedby the Committee: 1) asthma, All Fields, All ages, onlyitems with abstracts, Clinical Trial, Human, sorted byAuthors; and 2) asthma AND systematic, All fields, ALLages, only items with abstracts, Human, sorted by author.In addition, publications in peer review journals notcaptured by Pub Med could be submitted to individualmembers of the Committee providing an abstract and thefull paper were submitted in (or translated into) English.

All members of the Committee received a summary ofcitations and all abstracts. Each abstract was assigned totwo Committee members, although all members wereoffered the opportunity to provide an opinion on anyabstract. Members evaluated the abstract or, up to her/hisjudgment, the full publication, by answering specific writtenquestions from a short questionnaire, and to indicate if thescientific data presented impacted on recommendations inthe GINA report. If so, the member was asked to specificallyidentify modifications that should be made. The entireGINA Science Committee met on a regular basis todiscuss each individual publication that was indicated tohave an impact on asthma management and preventionby at least 1 member of the Committee, and to reach a

consensus on the changes in the report. Disagreementswere decided by vote.

Summary of Recommendations in the 2007 Update:Between July 1, 2006 and June 30, 2007, 406 articles metthe search criteria; 5 additional publications were broughtto the attention of the committee. Of the 205 reviewed, 40papers were identified to have an impact on the GINAReport that was posted on the website in December 2006either by: 1) confirming, that is, adding or replacing anexisting reference, or 2) modifying, that is, changing thetext or introducing a concept requiring a new recommendationto the report. The summary is reported in three segments:A) Modifications in the text; B) References that providedconfirmation or an update of previous recommendations;and C) Changes to the text for clarification or to correcterrors.

A. Modifications in the text:

Pg 5 insert: Parasite infections do not in general protectagainst asthma, but infection with hookworm may reducethe risk123. Reference 123: Leonardi-Bee J, Pritchard D,Britton J. Asthma and current intestinal parasite infection:systematic review and meta-analysis. Am J Respir CritCare Med 2006 Sep 1;174(5):514-23.

Pg 19 insert: “…measurements of airway responsivenessto direct airway challenges such as inhaled methcholineand histamine or indirect airway challenges such asinhaled mannitol60, or exercise challenge…” Reference 60:Brannan JD, Anderson SD, Perry CP, Freed-Martens R,Lassig AR, Charlton B. The safety and efficacy of inhaleddry powered mannitol as a bronchial provocation test forairway hyperresponsiveness: a phase 3 comparison studywith hypertonic (4.5%) saline. Respiratory Research 2005;6:144.

Pg 21 replace current sentence with: Recent publicationsprovide an evidence-based approach to the identificationof occupational asthma and compare specific inhalationchallenge testing with alternative tests for confirming theresponsible agents52,61. Reference 61: Beach J, RussellK, Blitz S, Hooton N, Spooner C, Lemiere C, Tarlo SM,Rowe BH. Systematic review of the diagnosis ofoccupational asthma. Chest 2007 Feb;131(2):569-78.

METHODOLOGY AND SUMMARY OF NEW RECOMMENDATIONS GLOBAL STRATEGY FOR ASTHMA MANAGEMENT AND PREVENTION:

2007 UPDATE*

vi*The Global Strategy for Asthma Management and Prevention (updated 2007), the updated Pocket Guides and thecomplete list of references examined by the Committee are available on the GINA website www.ginasthma.org.

†Members (2006-2007): E. Bateman, Chair; P. Barnes, J. Drazen, M. FitzGerald, P. Gibson, R. Lemanske, P. OʼByrne,K. Ohta, S. Pedersen, E. Pizzichini, H. Reddel, S. Sullivan, S. Wenzel, H. Zar.


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Pg 23 insert: “…the Childhood Asthma Control Test (C-ACT)62… Reference 62: Liu AH, Zeiger R, Sorkness C,Mahr T, Ostrom N, Burgess S, Rosenzweig JC,ManjunathR. Development and cross-sectional validation of theChildhood Asthma Control Test. J Allergy Clin Immunol2007 Apr;119(4):817-25.

Pg 31 insert: “…but another study concludes that thismay not be the case195.” Reference 195: Bleecker ER,Yancey SW, Baitinger LA, Edwards LD, Klotsman M,Anderson WH, Dorinsky PM. Salmeterol response is notaffected by beta2-adrenergic receptor genotype in subjectswith persistent asthma. J Allergy Clin Immunol 2006Oct;118(4):809-16.

Pg 33 insert: Similar modest effects were identified in asystematic review of sublingual immunotherapy (SLIT)196.Reference196: Calamita Z, Saconato H, Pela AB, Atallah AN.Efficacy of sublingual immunotherapy in asthma: systematicreview of randomized-clinical trials using the CochraneCollaboration method. Allergy 2006 Oct;61(10):1162-72.

Pg 35 insert: Dietary supplements, including seleniumtherapy197 are not of proven benefit. Reference 197:Shaheen SO, Newson RB, Rayman MP, Wong AP,Tumilty MK, Phillips JM, Potts JF, Kelly FJ, White PT,Burney PG. Randomised, double blind, placebo-controlledtrial of selenium supplementation in adult asthma. Thorax2007 Jun;62(6):483-90.

Pg 35 insert: A randomized controlled trial indicated thatthe practice of Sahaja yoga has limited beneficial effectson asthma for some objective and subjective measures, although there were no significant differences between theintervention and control groups at the 2 month follow upassessment198. Reference 198: Manocha R, Marks GB,Kenchington P, Peters D, Salome CM. Sahaja yoga in themanagement of moderate to severe asthma: a randomisedcontrolled trial. Thorax 2002;57:110-5.

Pg 38 insert: “…with no loss of bronchoprotectiveeffect200.” Reference 200: de Benedictis FM, del GiudiceMM, Forenza N, Decimo F, de Benedictis D, Capristo A.Lack of tolerance to the protective effect of montelukast inexercise-induced bronchoconstriction in children. EurRespir J 2006 Aug;28(2):291-5.

Pg 38 insert: Combination therapy is less effective incontrolling asthma in children with moderate persistentasthma than increasing to moderate doses of inhaledglucocorticosteroids201. Reference 201: Jat GC, MathewJL, Singh M. Treatment with 400 microg of inhaledbudesonide vs 200 microg of inhaled budesonide and oralmontelukast in children with moderate persistent asthma:randomized controlled trial. Ann Allergy Asthma Immunol2006 Sep;97(3):397-401.

Pg 39 modify to read: The effect of long-acting inhaled�2-agonists has not yet been adequately studied.Combination therapy with budesonide and formoterol usedboth as maintenance and rescue has been shown toreduce asthma exacerbations in children ages 4 years andolder with moderate to severe asthma202. Reference 202:Bisgaard H, Le Roux P, Bjamer D, Dymek A, VermeulenJH, Hultquist C. Budesonide/formoterol maintenance plusreliever therapy: a new strategy in pediatric asthma. Chest2006 Dec;130(6):1733-43.

Pg 51 insert: ”… and internet-based home monitoring340,”Reference 340: Chan DS, Callahan CW, Hatch-PigottVB, Lawless A, Proffitt HL, Manning NE, Schweikert M,Malone FJ. Internet-based home monitoring andeducation of children with asthma is comparable to idealoffice-based care: results of a 1-year asthma in-homemonitoring trial. Pediatrics 2007 Mar;119(3):569-78.

Pg 52 insert: A single page prompt to clinicians has beenshown to improve provision of preventive care to childrenwith asthma during office visits341. Reference 341:Halterman JS, Fisher S, Conn KM, Fagnano M, Lynch K,Marky A, Szilagyi PG. Improved preventive care forasthma: a randomized trial of clinician prompting inpediatric offices. Arch Pediatr Adolesc Med 2006Oct;160(10):1018-25.

Pg 52 insert: Patient concern about side-effects of inhaledglucocorticosteroids whether real or perceived mayinfluence adherence342. Reference 342: Boulet LP.Perception of the role and potential side effects of inhaledcorticosteroids among asthmatic patients. Chest1998;113:587-92.

Pg 62 replace current wording: Combination therapy withbudesonide and formoterol used both as maintenance andrescue has been shown to reduce asthma exacerbationsin children ages 4 years and older with moderate to severeasthma347. Reference 347: Bisgaard H, Le Roux P,Bjamer D, Dymek A, Vermeulen JH, Hultquist C.Budesonide/formoterol maintenance plus reliever therapy:a new strategy in pediatric asthma. Chest 2006Dec;130(6):1733-43.

Pg 64 insert: A clinically useful tool to assess thelikelihood of asthma-related hospitalizations or emergencydepartment visits in adults with severe or difficult to treatasthma has been described349. Reference 349: Miller MK,Lee JH, Blanc PD, Pasta DJ, Gujrathi S, Barron H, WenzelSE, Weiss ST; TENOR Study Group. TENOR risk scorepredicts healthcare in adults with severe or difficult-to-treatasthma. Eur Respir J 2006 Dec;28(6):1145-55.

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B. References that provided confirmation or update of previous recommendations:

Pg 3: Reference 121. Asher MI, Montefort S, Bjorksten B,Lai CK, Strachan DP, Weiland SK, Williams H; ISAACPhase Three Study Group. Worldwide time trends in theprevalence of symptoms of asthma, allergicrhinoconjunctivitis, and eczema in childhood: ISAACPhases One and Three repeat multicountry cross-sectional surveys. Lancet 2006 Aug 26;368(9537):733-43.

Pg 3: Reference 122. Accordini S, Bugiani M, Arossa W,Gerzeli S, Marinoni A, Olivieri M, Pirina P, Carrozzi L,Dallari R, De Togni A, de Marco R. Poor control increasesthe economic cost of asthma. A multicentre population-based study. Int Arch Allergy Immunol 2006;141(2):189-98.

Pg 6: Reference 124. Lazarus SC, Chinchilli VM, RollingsNJ, Boushey HA, Cherniack R, Craig TJ, Deykin A,DiMango E, Fish JE, Ford JG, Israel E, Kiley J, Kraft M,Lemanske RF Jr, Leone FT, Martin RJ, Pesola GR, PetersSP, Sorkness CA, Szefler SJ, Wechsler ME, Fahy JV;National Heart Lung and Blood Institute's Asthma ClinicalResearch Network. Smoking affects response to inhaledcorticosteroids or leukotriene receptor antagonists inasthma. Am J Respir Crit Care Med 2007 Apr15;175(8):783-90.

Pg 9: Reference 125. Chaudhuri R, Livingston E,McMahon AD, Lafferty J, Fraser I, Spears M, McSharryCP, Thomson NC. Effects of smoking cessation on lungfunction and airway inflammation in smokers with asthma.Am J Respir Crit Care Med 2006 Jul 15;174(2):127-33.

Pg 9: Replace existing reference 1. Reddel H, Ware S,Marks G, et al. Differences between asthma exacerbationsand poor asthma control. Lancet 1999; 353: 364-9.

Pg 29: Reference 191. Adams NP, Jones PW. The dose-response characteristics of inhaled corticosteroids whenused to treat asthma: an overview of Cochrane systematicreviews. Respir Med 2006 Aug;100(8):1297-306.

Pg 30: Reference 192. Deykin A, Wechsler ME, BousheyHA, Chinchilli VM, Kunselman SJ, Craig TJ, DiMango E,Fahy JV, Kraft M, Leone F, Lazarus SC, Lemanske RF Jr,Martin RJ, Pesola GR, Peters SP, Sorkness CA, SzeflerSJ, Israel E; National Heart, Lung, and Blood Institute'sAsthma Clinical Research Network. Combination therapywith a long-acting beta-agonist and a leukotrieneantagonist in moderate asthma. Am J Respir Crit CareMed 2007 Feb 1;175(3):228-34.

Pg 30: Reference 193. Gibson PG, Powell H, DucharmeFM. Differential effects of maintenance long-acting beta-agonist and inhaled corticosteroid on asthma control andasthma exacerbations. J Allergy Clin Immunol 2007Feb;119(2):344-50.

Pg 31: Reference 194. Rabe KF, Atienza T, Magyar P,Larsson P, Jorup C, Lalloo UG. Effect of budesonide incombination with formoterol for reliever therapy in asthmaexacerbations: a randomised controlled, double-blindstudy. Lancet 2006 Aug 26;368(9537):744-53.

Pg 37: Reference 199: Murray CS, Woodcock A, LangleySJ, Morris J, Custovic A; IFWIN study team. Secondaryprevention of asthma by the use of Inhaled Fluticasonepropionate in Wheezy INfants (IFWIN): double-blind,randomised, controlled study. Lancet 2006 Aug26;368(9537):754-62.

Pg 44: Replace current reference 122: Slader CA, ReddelHK, Spencer LM, Belousova EG, Armour CL, Bosnic-Anticevich SZ, Thien FC, Jenkins CR. Double blindrandomised controlled trial of two different breathingtechniques in the management of asthma. Thorax 2006Aug;61(8):651-6.

Pg 53: Reference 343. Bhogal S, Zemek R, DucharmeFM. Written action plans for asthma in children. CochraneDatabase Syst Rev 2006 Jul 19;3:CD005306.

Pg 57: Reference 344. Bateman ED, Bousquet J, KeechML, Busse WW, Clark TJ, Pedersen SE. The correlationbetween asthma control and health status: the GOALstudy. Eur Respir J 2007 Jan;29(1):56-62.

Pg 60: Reference 345. Pearlman DS, van Adelsberg J,Philip G, Tilles SA, Busse W, Hendeles L, Loeys T, DassSB, Reiss TF. Onset and duration of protection againstexercise-induced bronchoconstriction by a single oral doseof montelukast. Ann Allergy Asthma Immunol 2006Jul;97(1):98-104.

Pg 61: Reference 346. American Lung AssociationAsthma Clinical Research Centers. Clinical trial of low-dose theophylline and montelukast in patients with poorlycontrolled asthma. Am J Respir Crit Care Med 2007 Feb1;175(3):235-42.

Pg 63: Reference 348: Smith JR, Mugford M, Holland R,Noble MJ, Harrison BD. Psycho-educational interventionsfor adults with severe or difficult asthma: a systematicreview. J Asthma 2007 Apr;44(3):219-41.

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Pg 64: Reference 350. Serrano J, Plaza V, Sureda B, dePablo J, Picado C, Bardagi S, Lamela J, Sanchis J;Spanish High Risk Asthma Research Group. Alexithymia:a relevant psychological variable in near-fatal asthma. Eur Respir J 2006 Aug;28(2):296-302.

Pg 70: Reference 351. Rahimi R, Nikfar S, Abdollahi M.Meta-analysis finds use of inhaled corticosteroids duringpregnancy safe: a systematic meta-analysis review. HumExp Toxicol 2006 Aug;25(8):447-52.

Pg 73: Reference 352. El Miedany Y, Youssef S, AhmedI, El Gaafary M. Safety of etoricoxib, a specificcyclooxygenase-2 inhibitor, in asthmatic patients withaspirin-exacerbated respiratory disease. Ann AllergyAsthma Immunol 2006 Jul;97(1):105-9.

Pg 80: Replace reference 187. Reddel HK, Jenkins CR,Marks GB, et al. Optimal asthma control, starting with highdoses of inhaled budesonide. Eur Respir J 2000; 16: 226-35.

Pg 80: Replace reference 194. FitzGerald JM, Becker A,Sears MR, Mink S, Chung K, Lee J, et al. Doubling thedose of budesonide versus maintenance treatment inasthma exacerbations. Thorax 2004;59:550-56.

Pg 82: Replace reference 251. FitzGerald JM, Shragge D,Haddon J, Jennings B, Lee J, Bai T, et al. A randomizedcontrolled trial of high dose, inhaled budesonide versusoral prednisone in patients discharged from the emergencydepartment following an acute asthma exacerbation. CanRespir J 2000;7(1):61-7.

Pg 82: Replace reference 257. Colebourn CL, Barber V,Young JD. Use of helium-oxygen mixture in adult patientspresenting with exacerbations of asthma and chronicobstructive pulmonary disease: a systematic review.Anaesthesia 2007 Jan;62(1):34-42.

C. The committee recommended changes to text:

Pg 17: Modification of units (from mg to µg) salbutamol

Pg 18: Modification of wording - FEV1 > 12% and > 200 ml.

Pg 22: Add a footnote to Figure 2-4: *The worst featuredetermines the severity classification.

Pg 29: Modification of units (from mg to µg) budesonide

Pg 51: insert in Figure 4.1-2: Potential side effects ofmedications

Pg 59: A clarification of the shaded boxes as “preferredoptions” in Figure 4.3-2,

Pg 65: Place citation for reference 187 after "PEF" ratherthan after pulse oximetry.

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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 1995NHLBI/WHO Workshop Report, Global Strategy forAsthma 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 reducemorbidity and mortality from this chronic disease.

In January 2004, the GINA Executive Committeerecommended that the Global Strategy for AsthmaManagement 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 thathas 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 physicalexercise), 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 therudiments 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 adifficult task and, to aid in this work, has formed severalgroups of global experts, including: a Dissemination TaskGroup; the GINA Assembly, a network of individuals whocare 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 careworkers, 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 hasimportant 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 innovativeapproaches 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 ScienceCommittee, charged with keeping the Report up-to-dateby reviewing published research on asthma managementand prevention, evaluating the impact of this research onthe 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 aPub Med search using search fields established by theCommittee: 1) asthma, All Fields, All ages, only items withabstracts, Clinical Trial, Human, sorted by Authors; and2) asthma AND systematic, All fields, ALL ages, only itemswith 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 totwo 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/hisjudgment, the full publication, by answering specific writtenquestions 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 wasjudged 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 wasdeveloped, 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-daysession 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 list of 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 searchcriteria 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 wereconsidered 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 representativesfrom over 50 countries and many participated in theseinterim discussions. In addition, members of the Assemblywere 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 tobe 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 toboth 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 underlying disease 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 asmonotherapy 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 inhaledglucocorticosteroids.

• Monotherapy with cromones is no longer given as analternative 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 inprevious 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 isformed 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 treatment regimen, 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 consideredrelevant, 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 thatpatient care consistent with evidence-based asthma guide-lines leads to improved outcomes. However, in order toeffect changes in medical practice and consequentimprovements in patient outcomes, evidence-basedguidelines must be implemented and disseminated atnational and local levels. Thus, a chapter has been added 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.

REFERENCES1. Jadad AR, Moher M, Browman GP, Booker L, Sigouis C,Fuentes M, et al. Systematic reviews and meta-analyseson treatment of asthma: critical evaluation. BMJ2000;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 EvidenceEvidence 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. Ingeneral, 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 tojustify 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 keycontroller 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 fromevidence gained from adolescents and adults.

This revision of the Global Strategy for AsthmaManagement 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 naturalhistory and comorbidities, but there are also importantdifferences in the approach to diagnosis, measures forassessing severity and monitoring control, responses todifferent 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 ExecutiveSummary extracts sections of the report that pertain todiagnosis 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 isusually 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 ofchildren. 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, andsymptoms 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 in later childhood.

EXECUTIVE SUMMARYMANAGING ASTHMA IN CHILDREN 5 YEARS AND YOUNGER

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Alternative causes of recurrent wheezing must beconsidered 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 yearsand 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 measuresrecommended 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 touse 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 asthmamedications for children of all ages is included inChapter 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 have been 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 in any 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 whentreatment 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 aresparse 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-induced or 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 ofage can be taught simple asthma management skills.

Component 2 - Identify and Reduce Exposure to RiskFactors: 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 tobaccosmoke—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 generalpopulation is advised. However, routine influenzavaccination of children with asthma does not appear toprotect them from asthma exacerbations or improveasthma 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 children5 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 shownconvincing 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 acuteasthma) are episodes of progressive increase in shortnessof breath, cough, wheezing, or chest tightness, or somecombination of these symptoms. Severe exacerbationsare 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 providesemergency 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 afairly accurate assessment. Breathlessness sufficientlysevere 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 saturationless than 90 percent on high-flow oxygen whose condition 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 themanagement of acute asthma. Its use is associated withsevere and potentially fatal side effects, particularly inthose 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 intravenous�2-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 withmild 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 ofinhaled glucocorticosteroids administered frequentlyduring the day are effective in treating exacerbations, but more studies are needed before this strategy can be recommended.

For children admitted to an acute care facility for anexacerbation, criteria for determining whether they shouldbe discharged from the emergency department oradmitted to the hospital are provided in Chapter 4,Component 4.


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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 thereviews 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 airwayobstruction 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 operationaldescription of asthma is:

Asthma is a chronic inflammatory disorder of the airwaysin which many cells and cellular elements play a role.The chronic inflammation is associated with airwayhyperresponsiveness that leads to recurrent episodes ofwheezing, breathlessness, chest tightness, and coughing,particularly at night or in the early morning. Theseepisodes are usually associated with widespread, butvariable, airflow obstruction within the lung that is oftenreversible 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 thepresence 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 ofallergic sensitization. Although the association betweenasthma and atopy is well established, the precise linksbetween these two conditions have not been clearly andcomprehensively 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 severeexacerbations should be rare1.

KEY POINTS:

• Asthma is a chronic inflammatory disorder of theairways in which many cells and cellular elementsplay 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 occasionalflare-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 aconsistent 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 tomeasure 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 somecountries4-6,121 and has recently increased but now mayhave stabilized in others7,8. The World Health Organizationhas estimated that 15 million disability-adjusted life years(DALYs) are lost annually due to asthma, representing 1% 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, orentities 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 variety of health care systems including those of the UnitedStates13-15 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 countries4-6,121, 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 patientʼslev

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GLOBAL STRATEGY FOR ASTHMA MANAGEMENT AND PREVENTION · 2019. 1. 14. · Asthma is a serious global health problem. People of all ages in countries throughout the world are affected