GINA COMPLETO

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GLOBALSTRATEGY FORASTHMAMANAGEMENT AND PREVENTION

UPDATED 2008


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


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GINA EXECUTIVE COMMITTEE*

Eric D. Bateman, MD, ChairUniversity Cape Town Lung InstituteCape Town, South Africa

Jean Bousquet, MD, PhDMontpellier University and INSERMMontpellier, France

Mark FitzGerald, MDUniversity of British ColumbiaVancouver, BC, Canada

Tari Haahtela, MDHelsinki University Central HospitalHelsinki, Finland

Paul O'Byrne, MDMcMaster UniversityOntario, Canada

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

Pierluigi Paggiaro, MDUniversity of PisaPisa, Italy

Soren Erik Pedersen, M.D.Kolding HospitalKolding, Denmark

Manuel Soto-Quiroz, MDHospital Nacional de NiosSan Jos, Costa Rica

Wan-Cheng Tan, MD

St Paul's HospitalVancouver, BC, Canada

Gary W. Wong, MDChinese University of Hong KongHong Kong ROC

GINA SCIENCE COMMITTEE*

Mark FitzGerald, MD, ChairUniversity of British ColumbiaVancouver, BC, Canada

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

Eric D. Bateman, MDUniversity Cape Town Lung InstituteCape Town, South Africa

Allan Becker, MDUniversity of ManitobaWinnipeg, Manitoba, Canada

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

Peter Gibson, MDJohn Hunter HospitalNSW, New Castle, Australia

Robert F. Lemanske, Jr., M.D.University of WisconsinSchool of MedicineMadison, Wisconsin, USA

Paul O'Byrne, MDMcMaster UniversityOntario, Canada

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

Soren Erik Pedersen, M.D.Kolding HospitalKolding, Denmark

Emilio Pizzichini, MDUniversidade Federal de Santa CatarinaFlorianpolis, SC, Brazil

Helen K. Reddel, MDWoolcock Institute of Medical ResearchCamperdown, NSW, Australia

Sean D. Sullivan, PhDProfessor of Pharmacy, Public HealthUniversity of WashingtonSeattle, Washington, USA

Sally E. Wenzel, M.D.University of PittsburghPittsburgh, Pennsylvania, USA

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

Global Strategy for Asthma Management and Prevention 2008 (update)

*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. The

prevalence 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 lead

productive 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 asthma

care 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 recommendations

contained 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 through

unrestricted educational grants from AstraZeneca,Boehringer Ingelheim, Chiesi Group, GlaxoSmithKline,Meda Pharma, Merck, Sharp & Dohme, Mitsubishi TanabePharma, 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).

Eric Bateman, MDChair, GINA Executive CommitteeUniversity of CapeTown Lung InstituteCape Town, South Africa

PREFACE

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

METHODOLOGY AND SUMMARY OF NEW

RECOMMENDATION, 2007 UPDATE.........................vi

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

EXECUTIVE SUMMARY: MANAGING ASTHMA INCHILDREN 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 ANDEXPRESSION OF ASTHMA..........................................4

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

Environmental Factors ................................................5Allergens..................................................................5Infections..................................................................5Occupational sensitizers...........................................5

Tobacco 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.................................................8

Nocturnal 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...................................................16

Medical History...........................................................16Symptoms..............................................................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.............................................30

Long-acting inhaled2-agonists.............................30Theophylline...........................................................31Cromones: sodium cromoglycate and

nedocromil sodium........................................31Long-acting oral2-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 inhaled2-agonists............................34Systemic glucocorticosteroids................................34Anticholinergics......................................................34Theophylline...........................................................35Short-acting oral2-agonists..................................35

Complementary and Alternative Medicine...................35

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

Inhaled glucocorticosteroids...................................36Leukotriene modifiers.............................................38Long-acting inhaled2-agonists.............................38Theophylline...........................................................39Cromones: sodium cromoglycate and nedocromil

sodium .........................................................39Long-acting oral2-agonists...................................39Systemic glucocorticosteroids................................39

Reliever Medications...................................................40Rapid-acting inhaled2-agonists and short-acting

oral2-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........................................................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.............................58

Treatment Steps for Achieving Control......................58Step 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......................61

Stepping Down Treatment When Asthma IsControlled.................................................................62

Stepping Up Treatment In Response To Loss OfControl .....................................................................62

Difficult-to-Treat-Asthma .............................................63


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COMPONENT 4 - MANAGE ASTHMAEXACERBATIONS......................................................64

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

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

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

MANAGEMENTCOMMUNITY SETTINGS ...................65Treatment...................................................................66

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

MANAGEMENTACUTE CARE SETTINGS ..................66Assessment ................................................................66Treatment....................................................................68

Oxygen...................................................................68Rapid-acting inhaled2agonists...........................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.....................................................................70

Surgery .........................................................................70Rhinitis, Sinusitis, And Nasal Polyps.............................71Rhinitis...................................................................71Sinusitis..................................................................71Nasal polyps...........................................................71

Occupational Asthma....................................................71Respiratory Infections ...................................................72

Gastroesophageal Reflux..............................................72Aspirin-Induced Asthma................................................72Anaphylaxis and Asthma...............................................73

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

CHAPTER 5. IMPLEMENTATION OF ASTHMAGUIDELINES 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 inAsthma...................................................................90

GINA DISSEMINATION/IMPLEMENTATION

RESOURCES ............................................................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 Preventionwas issued in 1995 andrevised in 2002 and 2006. These reports, and theircompanion documents, have been widely distributed andtranslated into many languages. The 2006 report wasbased 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. The first update of the 2006 report(2007 update) included the impact of publications fromJuly 1, 2006 through June 30, 2007. This second updateof the 2006 report (2008 update) includes the impact ofpublications from July 1, 2007 through June 30, 2008.

Methods: The process to produce this 2008 updateincluded a Pub Med search using search fields established

by 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 any

abstract. 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 tospecifically identify modifications that should be made. Theentire GINA Science Committee met on a regular basis todiscuss each individual publication that was indicated tohave an impact on asthma management and prevention

by at least 1 member of the Committee, and to reach aconsensus on the changes in the report. Disagreementswere decided by vote.

Summary of Recommendations in the 2008 Update:Between July 1, 2007 and June 30, 2008, 406 articles metthe search criteria; 10 additional publications were broughtto the attention of the committee. Of the 416 articles, 40papers were identified to have an impact on the GINAReport (updated 2007) that was posted on the website inDecember 2007 either by: 1) confirming, that is, adding orreplacing an existing reference, or 2) modifying, that is,changing the text or introducing a concept requiring a newrecommendation to the report. The summary is reportedin three segments: A) Modifications in the text; B)References that provided confirmation or an update ofprevious recommendations; and C) Changes ormodifications to the text.

Diagnosis and Management of Asthma in Children 5 Yearsand Younger: Throughout 2008, several pediatric expertshave been developing a report that will focus on asthmacare in children 5 years and younger. The document is ex-pected to be released in early 2009. Publications thatappeared during the 2008 update cycle that impact on this

young age group will be reviewed in preparation of thenew report (see section C.2.) and are not included in this2008 update.

Evidence Reviews: In preparation of GINA reports,including this 2008 update, grading of evidence has beencompleted using four categories as described on page xiii.However, a new methodology called the GRADE systemhas been described1 and is being widely adopted. GINA isconcerned with regard to the resource implications of thischange, especially given the already rigorous method ofreviewing the literature and updating recommendationsthat is already in place. Nonetheless, a system is being

developed to slowly make a transition to the GRADEmethodology by initially identifying key recommendationsthat require more in-depth evaluation, and to implementthe creation and evaluation of evidence tables. Attentionwill be paid to ensuring clarity of the recommendationsbased on these tables. The 2009 update will begin toreflect this work. (See section C.3.)

METHODOLOGY AND SUMMARYOF NEW RECOMMENDATIONS GLOBAL STRATEGYFOR ASTHMA MANAGEMENT AND PREVENTION:

2008 UPDATE*

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

Members (2007-2008): M. FitzGerald, Chair; P. Barnes, E. Bateman, A. Becker, J. Drazen, P. Gibson, R. Lemanske,P.OByrne, K. Ohta, S. Pedersen, E. Pizzichini, H. Reddel, S. Sullivan, S. Wenzel, H. Zar.


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A. Modifications in the text:

Pg 3, right column, delete sentence (and references)"There is good evidence..may have stabilized inothers7,8" and insert: There is good evidence thatinternational differences in asthma symptom prevalencehave been reduced, particularly in the 13-14 year agegroup, with decreases in prevalence in North America andWestern Europe and increases in prevalence in regionswhere prevalence was previously low. Although there waslittle change in the overall prevalence of current wheeze,the percentage of children reported to have had asthmaincreased significantly, possibly reflecting greaterawareness of this condition and/or changes in diagnosticpractice. The increases in asthma symptom prevalence inAfrica, Latin America and parts of Asia indicate that theglobal burden of asthma is continuing to rise, but theglobal prevalence differences are lessening126.Reference 126. Pearce N, At-Khaled N, Beasley R,Mallol J, Keil U, Mitchell E, Robertson C; and the ISAAC

Phase Three Study Group. Worldwide trends in theprevalence of asthma symptoms: phase III of theInternational Study of Asthma and Allergies in Childhood(ISAAC). Thorax2007 Sep;62(9):758-66. Epub 2007May 15.

Pg 23, left column modify current sentence to read: Someare suitable for self-assessment of asthma control bypatients65, and some are available in ..". Reference 65.Schatz M, Mosen DM, Kosinski M, Vollmer WM, Magid DJ,O'Connor E, Zeiger RS. Validity of the Asthma ControlTest completed at home. Am J ManagCare 2007Dec;13(12):661-7.

Pg 30, right column insert: A controlled releaseformulation of zileuton allows this medication to be usedon a twice daily basis with effects equivalent to that ofstandard zileuton used four times a day203. Reference203. Nelson H, Kemp J, Berger W, Corren J, Casale T,Dube L, Walton-Bowen K, LaVallee N, Stepanians M.Efficacy of zileuton controlled-release tablets administeredtwice daily in the treatment of moderate persistent asthma:a 3-month randomized controlled study. Ann AllergyAsthma Immuno2007 Aug;99(2):178-84.

Pg 31, left column insert:A meta-analysis of all studies of

salmeterol added to inhaled glucocorticosteroids hasconcluded that this combination does not increase the riskfor asthma-related deaths or intubations when comparedto inhaled glucocorticosteroids alone205. Reference 205.Bateman E, Nelson H, Bousquet J, Kral K, Sutton L,Ortega H, Yancey S. Meta-analysis: effects of addingsalmeterol to inhaled corticosteroids on serious asthma-related events. Ann Intern Med2008 Jul 1;149(1):33-42.Epub 2008 Jun 3.

Pg 31, left column, delete last sentence (and references)and insert: No influence of 2-adrenergic receptorphenotypes upon the efficacy or safety of long-acting 2-agonist therapy has been observed when administeredin combination with inhaled glucocorticosteroids whether bythe single inhaler for maintenance and relief method or ata regular fixed dose in adults206. Reference 206. Bleecker

ER, Postma DS, Lawrance RM, Meyers DA, Ambrose HJ,Goldman M. Effect of ADRB2 polymorphisms onresponse to long-acting beta2-agonist therapy: apharmacogenetic analysis of two randomised studies.Lancet2007 Dec 22;370(9605):2118-25.

Pg 32, left column, modify statement "..between ages of 11and 50.." to read: "12 years and older207."Reference 207. Bousquet J, Cabrera P, Berkman N, BuhlR, Holgate S, Wenzel S, et al. The effect of treatment withomalizumab, an anti-IgE antibody, on asthmaexacerbations and emergency medical visits in patientswith severe persistent asthma. Allergy2005;60(3):302-8.

Pg 34, left column, insert: Specific immunotherapy haslong-term clinical effects and the potential of preventingdevelopment of asthma in children with allergic rhinoconjunctivitis up to 7 years after treatment termination208.Reference 208. Jacobsen L, Niggemann B, Dreborg S,Ferdousi HA, Halken S, Hst A, et al; (The PATinvestigator group). Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma:10-year follow-up on the PAT study. Allergy2007Aug;62(8):943-8.

Pg 34, right column, insert: levalbuterol HFA209.Reference 209. Pearlman DS, Rees W, Schaefer K,Huang H, Andrews WT. An evaluation of levalbuterol HFAin the prevention of exercise-induced bronchospasm.J Asthma2007 Nov;44(9):729-33.

Pg 35, right column, insert: An integrated breathing andrelaxation technique (Papworth method) appears toameliorate respiratory symptoms, dysfunctional breathingand adverse mood but there is no evidence of effect onobjective measures of respiratory function210. Reference210. Holloway EA, West RJ. Integrated breathing andrelaxation training (the Papworth method) for adults withasthma in primary care: a randomised controlled trial.Thorax 2007 Dec;62(12):1039-42. Epub 2007 Jun 15.

Pg 36, left column, insert:Early intervention with inhaledbudesonide is associated with improved asthma control

and less additional asthma medication use211. Reference211. Busse WW, Pedersen S, Pauwels RA, Tan WC,Chen YZ, Lamm CJ, O'Byrne PM; START InvestigatorsGroup. The Inhaled Steroid Treatment As RegularTherapy in Early Asthma (START) study 5-year follow-up:effectiveness of early intervention with budesonide in mildpersistent asthma. J Allergy Clin Immunol2008May;121(5):1167-74. Epub 2008 Apr 11.

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Pg 52, right column, insert: Although interactivecomputerized asthma education programs may improvepatient asthma knowledge and symptoms, their effect onobjective clinical outcomes is less consistent353.Reference 353. Bussey-Smith KL, Rossen RD. Asystematic review of randomized control trials evaluatingthe effectiveness of interactive computerized asthmapatient education programs. Ann Allergy Asthma Immunol2007 Jun;98(6):507-16.

Pg 52, Right column, delete "The written self-management plan and its understanding are alsoreviewed" and insert: Routine follow-up visits may be aneffective time to review the written self-management planand its understanding354. Reference 354. Ring N,Malcolm C, Wyke S, Macgillivray S, Dixon D, Hoskins G,Pinnock H, Sheikh A. Promoting the use of PersonalAsthma Action Plans: a systematic review. Prim CareRespir J2007 Oct;16(5):271-83.

Pg 53, right column, insert: For children, symptom-basedaction plans are more effective than those based on peakflows355. Reference 355: Zemek RL, Bhogal SK,Ducharme FM. Systematic review of randomizedcontrolled trials examining written action plans in children:what is the plan? Arch Pediatr Adolesc Med2008Feb;162(2):157-63.

Pg 56, right column, insert:Occupational exposuresaccount for a substantial proportion of adult asthmaincidence357. Reference 357. Kogevinas M, Zock JP,Jarvis D, Kromhout H, Lillienberg L, Plana E, et al.Exposure to substances in the workplace and new-onset

asthma: an international prospective population-basedstudy (ECRHS-II). Lancet2007 Jul 28;370(9584):336-41.

Pg 57, right column, insert: A randomized clinical trial of aself-regulation, telephone counseling interventionemphasizing sex and gender role factors in themanagement of asthma indicated that a program with afocus on asthma management problems particular towomen can significantly assist female asthma patients358.Reference 358. Clark NM, Gong ZM, Wang SJ, Lin X,Bria WF, Johnson TR. A randomized trial of a self-regulation intervention for women with asthma. Chest2007 Jul;132(1):88-97. Epub 2007 May 15.

Pg 60, left column, insert: Information on treatment ofexercise-induced asthma in athletes can be found in aJoint Task Force Report prepared by the EuropeanRespiratory Society, the European Academy of Allergy andClinical Immunology, and GA(2)LEN359 and the World Anti-Doping Agency website (http://www.wada-ama.org).Reference 359. Carlsen KH, Anderson SD, Bjermer L,Bonini S, Brusasco V, Canonica W, Cummiskey J,Delgado L, Del Giacco SR, Drobnic F, Haahtela T,

Larsson K, Palange P, Popov T, van Cauwenberge P;European Respiratory Society; European Academy ofAllergy and Clinical Immunology; GA(2)LEN. Treatment ofexercise-induced asthma, respiratory and allergicdisorders in sports and the relationship to doping: Part II ofthe report from the Joint Task Force of EuropeanRespiratory Society (ERS) and European Academy ofAllergy and Clinical Immunology (EAACI) in cooperationwith GA(2)LEN. Allergy2008 May;63(5):492-505.

Pg 64, left column, insert: Exacerbations usually have aprogressive onset but a subset of patients (mostly adults)present more acutely361. Reference 361. Ramnath VR,Clark S, Camargo CA Jr. Multicenter study of clinicalfeatures of sudden-onset versus slower-onset asthmaexacerbations requiring hospitalization. Respir Care. 2007Aug;52(8):1013-20.

Pg 88, left column, modify last line: "medications (e.g.,inhaled preparations), suboptimal use of medications21,

and lack of physician use of guidelines." Reference 21.Cazzoletti L, Marcon A, Janson C, Corsico A, Jarvis D, PinI, Accordini S, Almar E, Bugiani M, Carolei A, Cerveri I,Duran-Tauleria E, Gislason D, Gulsvik A, Jgi R, MarinoniA, Martnez-Moratalla J, Vermeire P, de Marco R; Therapyand Health Economics Group of the European CommunityRespiratory Health Survey. Asthma control in Europe: areal-world evaluation based on an international population-based study. J Allergy Clin Immunol2007Dec;120(6):1360-7. Epub 2007 Nov 5.

Pg 88, right column, insert: Integrated care pathways arebeing explored as a mean to improve asthma care in

specific settings, such as patients coming to emergencydepartments22. Reference 22. Cunningham S, Logan C,Lockerbie L, Dunn MJ, McMurray A, Prescott RJ. Effect ofan integrated care pathway on acute asthma/wheeze inchildren attending hospital: cluster randomized trial. JPediatr2008 Mar;152(3):315-20. Epub 2007 Nov 26.

B. References that provided confirmation or update ofprevious recommendations:

Pg 19: left column, insert: Reference 63. Shaw DE, BerryMA, Thomas M, Green RH, Brightling CE, Wardlaw AJ,Pavord ID. The use of exhaled nitric oxide to guide

asthma management: a randomized controlled trial. Am JRespir Crit Care Med. 2007 Aug 1;176(3):231-7. Epub2007 May 11.

Pg 22: left column insert: Reference 64. Chen H, GouldMK, Blanc PD, Miller DP, Kamath TV, Lee JH, SullivanSD; for the TENOR Study Group. Asthma control,severity, and quality of life: quantifying the effect ofuncontrolled disease. J Allergy Clin Immunol. 2007Aug;120(2):396-402. Epub 2007 Jun 11.

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Pg 30: right column, insert: Reference 204. Watkins PB,Dube LM, Walton-Bowen K, Cameron CM, Kasten LE.Clinical pattern of zileuton-associated liver injury: results ofa 12-month study in patients with chronic asthma. DrugSaf2007;30(9):805-15.

Pg 56: left column, insert: Reference 356. McCreanor J,Cullinan P, Nieuwenhuijsen MJ, Stewart-Evans J,Malliarou E, Jarup L, Harrington R, Svartengren M, HanIK, Ohman-Strickland P, Chung KF, Zhang J. Respiratoryeffects of exposure to diesel traffic in persons with asthma.N Engl J Med. 2007 Dec 6;357(23):2348-58.

Pg 61: right column, delete reference 104 and replacewith Reference 360: Bateman ED, Clark TJ, Frith L,Bousquet J, Busse WW, Pedersen SE; Goal InvestigatorsGroup. Rate of response of individual asthma controlmeasures varies and may overestimate asthma control: ananalysis of the goal study. J Asthma2007 Oct;44(8):667-73.

Pg 74: Substitute this for reference 24: Clark NM,Cabana MD, Nan B, Gong ZM, Slish KK, Birk NA, KacirotiN. The clinician-patient partnership paradigm: outcomesassociated with physician communication behavior. ClinPediatr (Phila). 2008 Jan;47(1):49-57. Epub 2007 Sep 27.

Pg 76: Substitute this for reference 90: Cates CJ,Jefferson TO, Rowe BH. Vaccines for preventing influenzain people with asthma. Cochrane Database Syst Rev2008 Apr 16;(2):CD000364.

C. Committee recommended changes:

1. A new table showing current combination therapies willbe prepared, posted on the website, and updated as newformulations become available.

2. In early 2009, GINA will publish a report on Diagnosisand Management of Asthma in Children 5 years andYounger. Several publications that appeared during thisupdate cycle will be reviewed in preparation of this newdocument, including:

a. Bisgaard H, Pedersen S, Anhj J, Agertoft L, HedlinG, Gulsvik A, et al. Weiss ST. Determinants of lungfunction and airway hyperresponsiveness in asthmatic

children. Respir Med2007 Jul;101(7):1477-82. Epub2007 Mar 2.b. Johnston NW, Mandhane PJ, Dai J, Duncan JM,

Greene JM, Lambert K, Sears MR. Attenuation of theSeptember epidemic of asthma exacerbations inchildren: a randomized, controlled trial of montelukastadded to usual therapy. Pediatric. 2007Sep;120(3):e702-12.

c. Kramer MS, Matush L, Vanilovich I, Platt R,Bogdanovich N, Sevkovskaya Z, et al; Promotion of

Breastfeeding Intervention Trial (PROBIT) StudyGroup. Effect of prolonged and exclusive breastfeeding on risk of allergy and asthma: clusterrandomised trial. BMJ2007 Oct 20;335(7624):815.

d. Ozdemir C, Yazi D, Gocmen I, Yesil O, Aydogan M,Semic-Jusufagic A, Bahceciler NN, Barlan IB.Efficacy of long-term sublingual immunotherapy as anadjunct to pharmacotherapy in house dust mite-allergic children with asthma. Pediatr AllergyImmunol. 2007 Sep;18(6):508-15.

e. Ducharme FM, Chalut D, Plotnick L, Savdie C,Kudirka D, Zhang X, Meng L, McGillivray D. ThePediatric Respiratory Assessment Measure: a validclinical score for assessing acute asthma severity fromtoddlers to teenagers. J Pediatr2008 Apr;152(4):476-80, 480.e1. Epub 2007 Oct 31.

f. Schokker S, Kooi EM, de Vries TW, Brand PL, MulderPG, Duiverman EJ, van der Molen T. Inhaledcorticosteroids for recurrent respiratory symptoms inpreschool children in general practice: randomized

controlled trial. Pulm Pharmacol Ther2008;21(1):88-97. Epub 2007 Jan 23.

g. Sedik HA, Barr RG, Clark S, Camargo CA Jr.Prospective study of sudden-onset asthmaexacerbations in children. Pediatr Emerg Care2007Jul;23(7):439-44.

3. Grading Evidence: The GINA document GlobalStrategy for Asthma Management and Prevention willcontinue to include background information and willeventually include a series of specific recommendationsbased on evidence tables1 (included as an appendix to thevolume and/or on the GINA website.) The GINA ScienceCommittee will develop a system to identify

recommendations that are relatively controversial andhave a less robust evidence base, to assemble andanalyze the evidence, and to routinely update theevidence. Three questions that have been identified tobegin the work include:

a. In adults with acute exacerbations of asthma, doesintravenous magnesium sulphate compared toplacebo improve patient important outcomes?

b. In adults with asthma, does monoclonal anti-IgE,omalazumab, compared to placebo improve patientoutcomes?

c. In adults with asthma, does sublingual immunotherapy

compared to placebo improve patient importantoutcomes?

The analysis of the data from these questions is underreview and will be available in the 2009 update.

REFERENCES

1. Guyatt GH, Oxman AD, Kunz R, et al. Going fromevidence to recommendations. BMJ2008;336:1049-51.

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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 Preventionbe 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 patients current level oftreatment and control, then adjust treatment to gain andmaintain control. This means that asthma patients should

experience 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 public

health 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 implementation

of 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 patientsquality 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 worlds population livesin areas with inadequate medical facilities and meagerfinancial resources. The GINA Executive Committeerecognizes that fixed international guidelines and rigidscientific 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 groups

at 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 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 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 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 new

report. 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 2005using 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 Committees 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 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 be

found 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. The

document 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 asthmasymptoms, sleep disturbances,limitations of daily activity, impairment of lung function, anduse of rescue medicationscan 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 to

diagnosis and monitoring. Measuring the variabilityofairflow 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 underlyingdisease but also its responsiveness to treatment, and that

severity is not an unvarying feature of an individualpatients 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 of

deterioration 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.

11. 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

12. The inclusion of Component 1 reflects the fact thateffective management of asthma requires the development

of 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 thepatients treatment and level of asthma control. Educationremains a key element of all doctor-patient interactions.


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13. 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 thepatients level of asthma control.

14. Treatment options are organized into five Stepsreflecting 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 2through 5, a variety of controllermedications are available.

15. 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.

16. 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 preparedand appears at the end ofthis introductionthat extracts sections on diagnosis andmanagement for this very young age group.

17. 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 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 in

Chapter 4, the Five Components of Asthma Management.Evidence levels are indicated in boldface type enclosed inparentheses after the relevant statemente.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 CFuentes 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 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 incaseswhere the provision ofsome guidancewas deemedvaluable but the clinical

literature addressing thesubject was insufficient tojustify placement in one of theother categories. ThePanelConsensus 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 t

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 from

evidence gained from adolescents and adults.

This revision of the Global Strategy for AsthmaManagement and Preventionagain 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 for

assessing 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 a

wide 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 is

usually associated with a viral respiratory illnesspredominantly 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 of

wheeze (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 inlater childhood.

EXECUTIVE SUMMARY

MANAGING ASTHMA IN CHILDREN 5 YEARS AND YOUNGER

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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 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 and

inhaled 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 testingusually a mainstay ofasthma diagnosis and monitoringis 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 asthmamedications 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 controlled

asthma 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

* Anyexacerbation 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 childs ability to use the inhaler correctly. With useof a spacer device, daily doses 400 g 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-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 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 factorsin particular exposure to tobaccosmokeshould 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 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 in

Chapter 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 be

the 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 apatients 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 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 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 a

fairly 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 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 themanagement of acute asthma. Its use is associated with

severe and potentially fatal side effects, particularly inthose on long-term therapy with slow-release theophyllineand its bronchodilator effect is less than that of 2-agonistsIn 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 ofinhaled 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 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, but

variable, 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 asthmasymptoms, sleep disturbances, limitations ofdaily activity, impairment of lung function, and use ofrescue medicationscan 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 elementsplay a role. The chronic inflammation is associatedwith airway hyperresponsiveness that leads to

recurrent episodes of wheezing, breathlessness,chest tightness, and coughing, particularly at nightor 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 persons 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 reports

on the prevalence of asthma in widely differingpopulations, the lack of a precise and universally accepteddefinition of asthma makes reliable comparison of reportedprevalence from different parts of the world problematic.Nonetheless, based on the application of standardizedmethods to measure the prevalence of asthma andwheezing illness in children3 and adults4, it appears thatthe global prevalence of asthma ranges from 1% to 18% ofthe population in different countries (Figure 1-1)2,3. Thereis good evidence that international differences in asthmasymptom prevalence have been reduced, particularly inthe 13-14 year age group, with decreases in prevalence inNorth America and Western Europe and increases in

prevalence in regions where prevalence was previouslylow. Although there was little change in the overallprevalence of current wheeze, the percentage of childrenreported to have had asthma increased significantly, possi-bly reflecting greater awareness of this condition and/orchanges in diagnostic practice. The increases in asthmasymptom prevalence in Africa, Latin America and parts ofAsia indicate that the global burden of asthma iscontinuing to rise, but the global prevalence differencesare lessening126. The World Health Organization hasestimated 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 varietyof 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 from

work 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 patientslevel 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 higher122. 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 dramaticallyreduced through efforts by individuals, their health careproviders, health care organizations, and local and

national 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 asth

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