REPRODUCE OR ALTER NOT - DO MATERIAL - UCLouvain · 2013-05-05 · METHODOLOGY AND SUMMARY OF NEW RECOMMENDATION, 2010 UPDATE vi INTRODUCTION x CHAPTER 1. DEFINITION AND OVERVIEW

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GLOBAL STRATEGY FORASTHMA MANAGEMENT AND PREVENTION

UPDATED 2010

© 2010 Global Initiative for AsthmaCOPYRIG

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Global Strategy for Asthma Management and Prevention The GINA reports are available on www.ginasthma.org. COPY

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GINA EXECUTIVE COMMITTEE*

Eric D. Bateman, MD, Chair University Cape Town Lung Institute Cape Town, South Africa

Louis-Philippe Boulet, MD Hôpital Laval Sainte-Foy , Quebec, Canada

Alvaro A. Cru , MD Federal University of Bahia School of Medicine Salvador, Brazil

Mark FitzGerald, MD University of British Columbia Vancouver, BC, Canada

Tari Haahtela, MD Helsinki University Central Hospital Helsinki, Finland

Mark L. Levy, MD University of Edinburgh London England, UK

Paul O’Byrne, MD McMaster University Ontario, Canada

Ken Ohta, MD, PhD Teikyo University School of Medicine Tokyo, Japan

Pierluigi Paggiaro, MD University of Pisa Pisa, Italy

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

Manuel Soto-Quiro, MD Hospital Nacional de Niños San José, Costa Rica

Gary W. Wong, MD Chinese University of Hong Kong Hong Kong ROC

GINA EXECUTIVE COMMITTEE*

Mark FitzGerald, MD, Chair University of British Columbia Vancouver, BC, Canada

Neil Barnes, MD London Chest Hospital London, England, UK

Peter J. Barnes, MD National Heart and Lung Institute London, England, UK

Eric D. Bateman, MD University Cape Town Lung Institute Cape Town, South Africa

Allan Becker, MD University of Manitoba Winnipeg, Manitoba, Canada

Jeffrey M. Drazen, MD Harvard Medical School Boston, Massachusetts, USA

Robert F. Lemanske, Jr., M.D. University of Wisconsin School of Medicine Madison, Wisconsin, USA

Paul O’Byrne, MD McMaster University Ontario, Canada

Ken Ohta, MD, PhD Teikyo University School of Medicine Tokyo, Japan

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

Emilio Pizichini, MD Universidade Federal de Santa Catarina Florianópolis, SC, Brazil

Helen K. Reddel, MD Woolcock Institute of Medical Research Camperdown, NSW, Australia

Sean D. Sullivan, PhD Professor of Pharmacy, Public Health University of Washington Seattle, Washington, USA

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

Global Strategy for Asthma Management and Prevention 2010 (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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PREFACEAsthma is a serious global health problem. People of all ages in countries throughout the world are affected by this chronic airway disorder that, when uncontrolled, can place severe 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 lost productivity and reduced participation in family life.

During the past two decades, we have witnessed many scientific advances that have improved our understanding of asthma and our ability to manage and control it effectively. However, the diversity of national health care service systems and variations in the availability of asthma therapies require that recommendations for asthma care be adapted to local conditions throughout the global community. In addition, public health officials require information about the costs of asthma care, how to effectively manage this chronic disorder, and education methods to develop asthma care services and programs responsive to the particular needs and circumstances within their countries.

In 1993, the National Heart, Lung, and Blood Institute collaborated with the World Health Organization to convene a workshop that led to a Workshop Report: Global Strategy for Asthma Management and Prevention. This presented a comprehensive plan to manage asthma with the goal of reducing chronic disability and premature deaths 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 disseminate information about the care of patients with asthma while at the same time assuring a mechanism to incorporate the results of scientific investigations into asthma care. Publications based on the GINA Report were prepared and have been translated into languages to promote international collaboration and dissemination of information. To disseminate information about asthma care, a GINA Assembly was initiated, comprised of asthma care experts from many countries to conduct workshops with local doctors and national opinion leaders and to hold seminars at national and international meetings. In addition, GINA initiated an annual World Asthma Day (in 2001) which has gained increasing attention each year to raise awareness about the burden of asthma, and to initiate activities at the local/national level to educate families and health care professionals about effective methods to manage and control asthma.

In spite of these dissemination efforts, international surveys provide direct evidence for suboptimal asthma control in many countries, despite the availability of effective therapies. It is clear that if recommendations contained within this report are to improve care of people with asthma, every effort must be made to encourage health care leaders to assure availability of and access to medications, and develop means to implement effective asthma management programs including the use of appropriate tools to measure success.

In 2002, the GINA Report stated that “It is reasonable to expect that in most patients with asthma, control of the disease can, and should be achieved and maintained.” To meet this challenge, in 2005, Executive Committee recommended preparation of a new report not only to incorporate updated scientific information but to implement an approach to asthma management based on asthma control, rather than asthma severity. Recommendations to assess, treat and maintain asthma control are provided in this document. The methods used to prepare this document are described in the Introduction.

It is a privilege for me to acknowledge the work of the many people who participated in this update project, as well as to acknowledge the superlative work of all who have 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 Tanabe Pharma, Novartis, Nycomed, PharmAxis and Schering-Plough. The generous contributions of these companies assured that Committee members could meet together to discuss issues and reach consensus in a constructive and timely manner. The members of the GINA Committees are, however, solely responsible for the statements and conclusions presented in this publication.

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

Eric Bateman, MD Chair, GINA Executive Committee University of CapeTown Lung Institute Cape Town, South AfricaCOPY

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GLOBAL STRATEGY FOR ASTHMA MANAGEMENT AND PREVENTIONTable of Contents

PREFACE ii

METHODOLOGY AND SUMMARY OF NEW RECOMMENDATION, 2010 UPDATE vi

INTRODUCTION x

CHAPTER 1. DEFINITION AND OVERVIEW 1

KEYPOINTS 2

DEFINITION 2

THEBURDENOFASTHMA 3 Prevalence,MorbidityandMortality 3 SocialandEconomicBurden 3

FACTORSINFLUENCINGTHEDEVELOPMENTAND EXPRESSIONOFASTHMA 4 HostFactors 4 Genetic 4 Obesity 5 Sex 5 EnvironmentalFactors 5 Allergens 5 Infections 5 Occupationalsensitizers 6 Tobaccosmoke 6 Outdoor/Indoorairpollution 7 Diet 7

MECHANISMSOFASTHMA 7 AirwayInflammationInAsthma 8 Inflammatorycells 8 Structuralchangesinairways 8 Pathophysiology 8 Airwayhyperresponsiveness 8 SpecialMechanisms 9 Acuteexacerbations 9 NocturnalAsthma 9 Irreversibleairflowasthma 9 Difficult-to-treatasthma 9 Diet 9

REFERENCES 9

CHAPTER 2. DIAGNOSIS AND CLASSIFICATION 15

KEYPOINTS 16

INTRODUCTION 16CLINICALDIAGNOSIS 16

MedicalHistory 16 Symptoms 16 Coughvariantasthma 16 Exercise-Inducedbronchospasm 17 PhysicalExamination 17 TestsforDiagnosisandMonitoring 17 Measurementsoflungfunction 17 Spirometry 18 Peakexpiratoryflow 18 Measurementofairwayresponsiveness 19 Non-Invasivemarkersofairwayinflammation 19 Measurementsofallergicstatus 19

DIAGNOSTICCHALLENGESAND DIFFERENTIALDIAGNOSIS 20 Children5YearsandYounger 20 OlderChildrenandAdults 20 TheElderly 21 OccupationalAsthma 21 DistinguishingAsthmafromCOPD 21

CLASSIFICATIONOFASTHMA 21 Etiology 21 Phenotype 22 AsthmaControl 22 AsthmaSeverity 23 REFERENCES 24

CHAPTER 3. ASTHMA MEDICATIONS 28

KEYPOINTS 29

INTRODUCTION 29

ASTHMAMEDICATIONS:ADULTS 29 RouteofAdministration 29 ControllerMedications 30 Inhaledglucocorticosteroids 30 Leukotrienemodifiers 31 Long-actinginhaledβ2-agonists 32 Theophylline 32 Cromones:sodiumcromoglycateand nedocromilsodium 33 Long-actingoralβ2-agonists 33 Anti-IgE 33 Systemicglucocorticosteroids 33 Oralanti-allergiccompounds 34 Othercontrollertherapies 34 Allergen-specificimmunotherapy 35

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RelieverMedications 35 Rapid-actinginhaledβ2-agonists 35 Systemicglucocorticosteroids 35 Anticholinergics 36 Theophylline 36 Short-actingoralβ2-agonists 36

ASTHMATREATMENT:CHILDREN 37 RouteofAdministration 37 ControllerMedications 37 Inhaledglucocorticosteroids 37 Leukotrienemodifiers 40 Long-actinginhaledβ2-agonists 40 Theophylline 40 Anti-IgE 41 Cromones:sodiumcromoglycateand nedocromilsodium 41 Systemicglucocorticosteroids 42 RelieverMedications 42 Rapid-actinginhaledβ2-agonistsandshort-acting oralβ2-agonists 42 Anticholinergics 42

REFERENCES 42

CHAPTER 4. ASTHMA MANAGEMENT AND PREVENTION 52

INTRODUCTION 53

COMPONENT 1: DEVELOP PATIENT/ DOCTOR PARTNERSHIP 53

KEYPOINTS 53

INTRODUCTION 53

ASTHMAEDUCATION 54 AttheInitialConsultation 55 PersonalAsthmaActionPlans 55 Follow-upandReview 55 ImprovingAdherence 56 Self-ManagementinChildren 56

THEEDUCATIONOFOTHERS 56

COMPONENT 2: IDENTIFY AND REDUCE EXPOSURE TO RISK FACTORS 57

KEYPOINTS 57

INTRODUCTION 57

ASTHMAPREVENTION 57

PREVENTIONOFASTHMASYMPTOMSAND EXACERBATIONS 58 IndoorAllergens 58 Domesticmites 58 Furredanimals 58 Cockroaches 59 Fungi 59 OutdoorAllergens 59 IndoorAirPollutants 59 OutdoorAirPollutants 59 OccupationalExposures 59 FoodandDrugAdditives 60 Drugs 60 InfluenzaVaccination 60 Obesity 60 EmotionalStress 60 OtherFactorsThatMayExacerbateAsthma 60

COMPONENT 3: ASSESS,TREAT AND MONITOR ASTHMA 61

KEYPOINTS 61

INTRODUCTION 61

ASSESSINGASTHMACONTROL 61

TREATMENTTOACHIEVECONTROL 61 TreatmentStepstoAchievingControl 16 Step1:As-neededrelievermedication 62 Step2:Relievermedicationplusasingle controller 64 Step3:Relievermedicationplusoneortwo controllers 64 Step4:Relievermedicationplustwoormore controllers 65 Step5:Relievermedicationplusadditional controlleroptions 65

MONITORINGTOMAINTAINCONTROL 65 DurationandAdjustmentstoTreatment 65 SteppingDownTreatmentWhenAsthmaIs Controlled 66 SteppingUpTreatmentInResponsetoLoss ofControl 66 Difficult-to-Treat-Asthma 67

COMPONENT 4: MANAGE ASTHMA EXACERBATIONS 69

KEYPOINTS 69

INTRODUCTION 69

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ASSESSINGOFSEVERITY 70

MANAGEMENT-COMMUNITYSETTINGS 70 Treatment 71 Bronchodilators 71 Glucocorticosteroids 71

MANAGEMENT-ACUTECARESETTINGS 71 Assessment 71 Treatment 73 Oxygen 73 Rapid-actinginhaledβ2-agonists 73 Epinephrine 73 Additionalbronchodilators 73 Systemicglucocorticosteroids 73 Inhaledglucocorticosteroids 74 Magnesium 74 Heliumoxygentherapy 74 Leukotrienemodifiers 74 Sedatives 74 CriteriaforDischargefromtheEmergency Departmentvs.Hospitalization 74

COMPONENT 5: SPECIAL CONSIDERATIONS 76 Pregnancy 76 Obesity 76 Surgery 76 Rhinitis,Sinusitis,andNasalPolyps 77 Rhinitis 77 Sinusitis 77 Nasalpolyps 77 OccupationalAsthma 77 RespiratoryInfections 77 GastroesophagealReflux 78 Aspirin-InducedAsthma 78 AnaphylaxisandAsthma 79

REFERENCES 79

CHAPTER 5. IMPLEMENTATION OF ASTHMA GUIDELINES IN HEALTH SYSTEMS 98

KEYPOINTS 99

INTRODUCTION 99

GUIDELINEIMPLEMENTATIONSTRATEGIES 99

ECONOMICVALUEOFINTERVENTIONSAND GUIDELINEIMPLEMENTATIONINASTHMA 100 UtilizationandCostofHealthCareResources 101 DeterminingtheEconomicValueofInterventionsin Asthma 101

GINADISSEMINATION/IMPLEMENTATION RESOURCES 102

REFERENCES 102

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Background: When the Global Initiative for Asthma (GINA) program was initiated in 1993, the primary goal was to produce recommendations for the management of asthma based on the best scientific information available. Its first report, NHLBI/WHO Workshop Report: Global Strategy for Asthma Management and Prevention was issued in 1995 and revised in 2002 and 2006. In 2002 and in 2006 revised documents were prepared based on published research.

The GINA Science Committee2 was established in 2002 to review published research on asthma management and prevention, to evaluate the impact of this research on recommendations in the GINA documents related to management and prevention, and to post yearly updates on the GINA website. Its members are recognized leaders in asthma research and clinical practice with the scientific credentials to contribute to the task of the Committee, and are invited to serve for a limited period and in a voluntary capacity. The Committee is broadly representative of adult and pediatric disciplines as well from diverse geographic regions.

Updates of the 2006 report have been issued in December of each year with each update based on the impact of publications from July 1 of the previous year through June 30 of the year the update was completed. Posted on the website along with the updated documents is a list of all the publications reviewed by the Committee.

Process: To produce the updated documents a Pub Med search is done using search fields established by the Committee: 1) asthma, All Fields, All ages, only items with abstracts, Clinical Trial, Human, sorted by Authors; and 2) asthma AND systematic, All fields, ALL ages, only items with abstracts, Human, sorted by author. The first search includes publications for July 1-December 30 for review by the Committee during the ATS meeting. The second search includes publications for January 1 – June 30 for review by the Committee during the ERS meeting. (Publications that appear after June 30 are considered in the first phase of the following year.) To ensure publications in peer review journals not captured by this search methodology are not missed, the respiratory community are invited to submit papers to the Chair, GINA Science Committee providing an abstract and the full paper are submitted in (or translated into) English.

All members of the Committee receive a summary of citations and all abstracts. Each abstract is assigned to at least two Committee members, although all members are offered the opportunity to provide an opinion on all abstracts. Members evaluate the abstract or, up to

her/his judgment, the full publication, and answer four specific written questions from a short questionnaire, and to indicate if the scientific data presented impacts on recommendations in the GINA report. If so, the member is asked to specifically identify modifications that should be made.

The entire GINA Science Committee meets twice yearly to discuss each publication that was considered by at least 1 member of the Committee to potentially have an impact on the management of asthma. The full Committee then reaches a consensus on whether to include it in the report, either as a reference supporting current recommendations, or to change the report. In the absence of consensus, disagreements are decided by an open vote of the full Committee. Recommendations by the Committee for use of any medication are based on the best evidence available from the literature and not on labeling directives from government regulators. The Committee does not make recommendations for therapies that have not been approved by at least one regulatory agency.

For the 2010 update, between July 1, 2009 and June 30, 2010, 402 articles met the search criteria. Of the 402, 23 papers were identified to have an impact on the GINA report. The changes prompted by these publications were posted on the website in December 2010. These were either: A) modifying, that is, changing the text or introducing a concept requiring a new recommendation to the report; or B) confirming, that is, adding to or replacing an existing reference.

Summary of Recommendations in the 2010 Update:

A. Additions to the text:

Pg 5, left column, delete current information about obesity and insert: Asthma is more frequently observed in obese subjects (Body Mass Index > 30 kg/m2) and is more difficult to control127-130. Obese people with asthma have lower lung function and more co-morbidities compared with normal weight people with asthma131. The use of systemic glucocorticosteroids and a sedentary lifestyle may promote obesity in severe asthma patients, but in most instances, obesity precedes the development of asthma.

How obesity promotes the development of asthma is still uncertain but it may result from the combined effects of various factors. It has been proposed that obesity could influence airway function due to its effect on lung mechanics, development of a pro-inflammatory state, in addition to genetic, developmental, hormonal or neurogenic influences35, 132-133. In this regard, obese patients have a reduced

Methodology and Summary of New Recommendations Global Strategy for Asthma Management and Prevention:

2010 Update1

1The Global Strategy for Asthma Management and Prevention (updated 2010), the updated Pocket Guides and the complete list of references examined by the Committee are available on the GINA website www.ginasthma.org.2Members (2009-20010): M. FitzGerald, Chair; P. Barnes, N. Barnes, E. Bateman, A. Becker, J. DeJongste, J. Drazen, R. Lemanske, P. O’Byrne, K. Ohta, S. Pedersen, E. Pizzichini, H. Reddel, S. Sullivan, S. Wenzel.

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expiratory reserve volume, a pattern of breathing which may possibly alter airway smooth muscle plasticity and airway function34. Furthermore, the release by adipocytes of various pro-inflammatory cytokines and mediators such as interleukin-6, tumor necrosis factor (TNF)-β eotaxin, and leptin, combined with a lower level of anti-inflammatory adipokines in obese subjects can favour a systemic inflammatory state although it is unknown how this could influence airway function134-135. Reference 127. Beuther DA, Sutherland ER. Overweight, obesity, and incident asthma: a meta-analysis of prospective epidemiologic studies. Am J Respir Crit Care Med 2007;175(7):661-6. Reference 128. Ford ES. The epidemiology of obesity and asthma. J Allergy Clin Immunol 2005;115(5):897-909. Reference 129. Saint-Pierre P, Bourdin A, Chanez P, Daures JP, Godard P. Are overweight asthmatics more difficult to control? Allergy 2006;61(1):79-84. Reference 130. Lavoie KL, Bacon SL, Labrecque M, Cartier A, Ditto B. Higher BMI is associated with worse asthma control and quality of life but not asthma severity. Respir Med 2006;100(4):648-57. Reference 131. Pakhale S, Doucette S, Vandemheen K, Boulet LP, McIvor RA, Fitzgerald JM, et al. A comparison of obese and nonobese people with asthma: exploring an asthma-obesity interaction. Chest. 2010;137(6): 1316-23. Reference 132. Schaub B, von ME. Obesity and asthma, what are the links? Curr Opin Allergy Clin Immunol 2005;5(6):185-93. Reference 133. Weiss ST, Shore S. Obesity and asthma: directions for research. Am J Respir Crit Care Med 2004;169(8):963-8. Reference 134. Shore SA. Obesity and asthma: possible mechanisms. J Allergy Clin Immunol. 2008;121(5):1087-93. Reference 135. Juge-Aubry CE, Henrichot E, Meier CA. Adipose tissue: a regulator of inflammation. Best Pract Res Clin Endocrinol Metab 2005;19(4):547-66.

Pg 17, right column, paragraph 3, insert: If precision is needed, for example, in the conduct of a clinical trial, use of a more rigorous definition (lower limit of normal -LLN) should be considered.

Pg 32, modifications of segment on side effects of long-acting β2-agonists.

Pg 33, right column, line 12 insert: Withdrawal of glucocorticosteroids facilitated by anti-IgE therapy has led to unmasking the presence of Churg Strauss syndrome in a small number of patients221. Clinicians successful in initiating steroid withdrawal using anti-IgE should be aware of this side effect. Reference 222. Wechsler ME, Wong DA, Miller MK, Lawrence-Miyasaki L. Churg-strauss syndrome in patients treated with omalizumab. Chest 2009;136(2):507-18.

Pg 36, right column, insert: Evidence from the most rigorous studies available to date indicates that spinal manipulation is not an effective treatment for asthma121. Systematic reviews indicate that homeopathic medicines have no effects beyond placebo222.. Reference 121. Ernst E. Spinal manipulation for asthma: a systematic review of randomised clinical trials.

Respir Med 2009;103(12):1791-5. Reference 222. Ernst E. Homeopathy: what does the “best” evidence tell us? Med J Aust 2010;192(8):458-60.

Page 36, right column, last paragraph, replace segment on Butyeko breathing: Several studies of breathing and/or relaxation techniques for asthma and/or dysfunctional breathing, including the Buteyko method and the Papworth method210, have shown improvements in symptoms, short-acting β2-agonist use, quality of life and/or psychological measures, but not in physiological outcomes. A study of two physiologically-contrasting breathing techniques, in which contact with health professionals and instructions about rescue inhaler use were matched, showed similar improvements in reliever and inhaled glucocorticosteroid use in both groups122. This suggests that perceived improvement with breathing techniques may be largely due to factors such as relaxation, voluntary reduction in use of rescue medication, or engagement of the patient in their care. Breathing techniques may thus provide a useful supplement to conventional asthma management strategies, particularly in anxious patients or those habitually over-using rescue medication. The cost of some programs may be a potential limitation.

Pg 54, left column, paragraph 1 insert: “…community health workers371…” Reference 371. Postma J, Karr C, Kieckhefer G. Community health workers and environmental interventions for children with asthma: a systematic review. J Asthma 2009;46(6):564-76.

Pg 54, left column, insert end of paragraph 2: “…but regional issues and the developmental stage of the children may affect the outcomes of such programs373. Reference 373. Clark NM, Shah S, Dodge JA, Thomas LJ, Andridge RR, Little RJ. An evaluation of asthma interventions for preteen students. J Sch Health 2010;80(2):80-7.

Pg 55, right column, fourth paragraph replace current sentence: Patients should be asked to demonstrate their inhaler device technique at every visit, with correction and re-checking if it is inadequate33,375. Reference 375. Bosnic-Anticevich SZ, Sinha H, So S, Reddel HK. Metered-dose inhaler technique: the effect of two educational interventions delivered in community pharmacy over time. J Asthma 2010;47(3):251-6.

Pg 56, right column, line 4 insert: Short questionnaires can assist with identification of poor adherence376. Reference 376. Cohen JL, Mann DM, Wisnivesky JP, Home R, Leventhal H, Musumeci-Szabó TJ, Halm EA. Assessing the validity of self-reported medication adherence among inner-city asthmatic adults: the Medication Adherence Report Scale for Asthma. Ann Allergy Asthma Immunol 2009;103(4):325-31.

Pg 56, right column, end of paragraph 2 insert: School-based asthma education improves knowledge of asthma, self-efficacy, COPY

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and self-management behaviors377. Reference 377. Coffman JM, Cabana MD, Yelin EH. Do school-based asthma education programs improve self-management and health outcomes? Pediatrics 2009;124(2):729-42.

Pg 59, left column, last paragraph add: Asthma patients who smoke, and are not treated with inhaled glucocorticosteroids, have a greater decline in lung function than asthma patients who do not smoke378. Smoking cessation needs to be vigorously encouraged for all patients with asthma who smoke. Reference 378. O’Byrne PM, Lamm CJ, Busse WW, Tan WC, Pedersen S; START Investigators Group. The effects of inhaled budesonide on lung function in smokers and nonsmokers with mild persistent asthma. Chest 2009;136(6):1514-20.

Pg 60, left column, paragraph 3 insert: There is some evidence that exposure to acetaminophen increases the risk of asthma and wheezing in both children and adults but further studies are needed379. Reference 379. Etminan M, Sadatsafavi M, Jafari S, Doyle-Waters M, Aminzadeh K, Fitzgerald JM. Acetaminophen use and the risk of asthma in children and adults: a systematic review and metaanalysis. Chest 2009;136(5):1316-23.

Pg 65, right column, insert at end of paragraph 2: General practitioners should be encouraged to assess asthma control at every visit, not just when the patient presents because of their asthma380. Reference 380. Mintz M, Gilsenan AW, Bui CL, Ziemiecki R, Stanford RH, Lincourt W, Ortega H. Assessment of asthma control in primary care. Curr Med Res Opin 2009;25(10):2523-31.

Pg 66, right column, paragraph on inhaled glucocorticosteroids, insert: However, there is emerging evidence that quadrupling the dose of inhaled glucocorticosteroid might be effective when asthma control starts to deteriorate, if doubling the does not work381. Reference 381. Oborne J, Mortimer K, Hubbard RB, Tattersfield AE, Harrison TW. Quadrupling the dose of inhaled corticosteroid to prevent asthma exacerbations: a randomized, double-blind, placebo-controlled, parallel-group clinical trial. Am J Respir Crit Care Med 2009;180(7):598-602.

Pg 67, left column, add new paragraph: For children (6 to 17 years) who have uncontrolled asthma despite the use of low-dose inhaled glucocorticosteroids, step-up therapy with long-acting β2-agonist bronchodilator was significantly more likely to provide the best response than either step-up therapy with inhaled glucocorticosteroids or leukotriene receptor antagonist. However, many children had a best response to inhaled glucocorticosteroids or leukotriene receptor antagonist step-up therapy, highlighting the need to regularly monitor and appropriately adjust each child’s asthma therapy382. Reference 382: Lemanske RF Jr, Mauger DT, Sorkness CA, Jackson DJ, Boehmer SJ, Martinez FD, et al.; Childhood Asthma Research and Education (CARE) Network of the National Heart, Lung, and Blood Institute. Step-

up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med 2010;362(11):975-85.

Pg 73, left column, fourth paragraph insert: The most cost effective and efficient delivery is by meter dose inhaler and a spacer device64, 211.

Pg 77, right column, last paragraph insert: … and are commonly found in children with asthma exacerbation380. Reference 391. Leung TF, To MY, Yeung AC, Wong YS, Wong GW, Chan PK. Multiplex molecular detection of respiratory pathogens in children with asthma exacerbation. Chest 2010;137(2):348-54.

B. References that provided confirmation or update of previous recommendations.Pg 6, right column, paragraph 2, insert reference 136. O’Byrne PM, Lamm CJ, Busse WW, Tan WC, Pedersen S; START Investigators Group. The effects of inhaled budesonide on lung function in smokers and nonsmokers with mild persistent asthma. Chest 2009;136(6):1514-20.

Pg 11, left column, replace reference 54 with: Sly PD, Kusel M, Holt PG. Do early-life viral infections cause asthma? J Allergy Clin Immunol 2010;125(6):1202-5.

Pg 32, right column, insert reference 221. Wechsler ME, Kunselman SJ, Chinchilli VM, Bleecker E, Boushey HA, Calhoun WJ, et al. National Heart, Lung and Blood Institute’s Asthma Clinical Research Network Effect of beta2-adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Lancet 2009;374(9073):1754-64.

Pg 54, left column, line 6, insert reference 372. van der Meer V, Bakker MJ, van den Hout WB, Rabe KF, Sterk PJ, Kievit J, Assendelft WJ, Sont JK; SMASHING (Self-Management in Asthma Supported by Hospitals, ICT, Nurses and General Practitioners) Study Group. Internet-based self-management plus education compared with usual care in asthma: a randomized trial. Ann Intern Med 2009;151(2):110-20.

Pg 55, left column, second paragraph, add reference 374. Wilson SR, Strub P, Buist AS, Knowles SB, Lavori PW, Lapidus J, Vollmer WM; Better Outcomes of Asthma Treatment (BOAT) Study Group. Shared treatment decision making improves adherence and outcomes in poorly controlled asthma. Am J Respir Crit Care Med 2010;181(6):566-77.

Pg 84, replace current reference 116 with: Fogel RB, Rosario N, Aristizabal G, Loeys T, Noonan G, Gaile S, Smugar SS, Polos PG. Effect of montelukast or salmeterol added to inhaled fluticasone on exercise-induced bronchoconstriction in children. Ann Allergy Asthma Immunol 2010;104(6):511-7. COPY

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Pg 86, replace current reference 148 with: Rodrigo GJ, Neffen H, Colodenco FD, Castro-Rodriguez JA. Formoterol for acute asthma in the emergency department: a systematic review with meta-analysis. Ann Allergy Asthma Immunol 2010;104(3):247-52.

Pg 88, delete reference 187.

C. Inserts related to special topics covered by the Committee1. Asthma Control: Figure 2-4, page 22 (and the identical Figure 4.3-1, page 62) has been modified. Segment A: Assessment of Current Clinical Control was inadvertently omitted in the 2009 update and has been added. The text that describes the purpose of the Figure as a clinical tool has been embedded.

2. Statement on Anti-IgE for use in children. Pg 41, insert new statement on anti-IgE with supporting references.

3. Special Considerations: Obesity. Page 76, insert new statement about asthma and obesity with supporting references.

4. Special Considerations: Gastroesophageal Reflux. Pg 78, insert new statement with supporting references to update segment on gastroesophageal reflux.

D. GRADE Evidence Statements. The GINA Science identified two issues for evaluation using GRADE evidence technology, one related to an expensive medication, anti-IgE, and one related to a inexpensive medication, magnesium sulfate. The methodology, the evidence statements, and the consensus statements can be found on the GINA website, www.ginasthma.org.

Pg 33. Question: “In adults with asthma, does monoclonal anti-IgE, omalizumab, compared to placebo improve patient outcomes?” The consensus recommendation:

For allergic patients, with an elevated IgE, not controlled on high dose inhaled glucocortico-steroids and a long acting β2-agonist and who continue to have exacerbations, a trial of omalizumab can be considered. This recommendation is based on a modest response rate for the main endpoint exacerbations, and its high cost.

Pg 74: Question: “In adults with acute exacerbations of asthma, does intravenous magnesium sulphate compared to placebo improve patient important outcomes?” The consensus recommendation:

In patients with severe, acute asthma, who have received maximal inhaled bronchodilator therapy and systemic glucocorticosteroids and who have not responded adequately, a single dose of magnesium sulphate (two grams IV) is recommended. This recommendation, in this population, is based on the poor case definition in studies, as well as its efficacy, low cost and safety.COPY

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Asthma is a serious public health problem throughout the world, affecting people of all ages. When uncontrolled, asthma can place severe limits on daily life, and is sometimes fatal.

In 1993, the Global Initiative for Asthma (GINA) was formed. Its goals and objectives were described in a 1995 NHLBI/WHO Workshop Report, Global Strategy for Asthma Management and Prevention. This Report (revised in 2002 and 2006), and its companion documents, have been widely distributed and translated into many languages. A network of individuals and organizations interested in asthma care has been created and several country-specific asthma management programs have been initiated. Yet much work is still required to reduce morbidity and mortality from this chronic disease.

In 2006, the Global Strategy for Asthma Management and Prevention was revised to emphasize asthma management based on clinical control, rather than classification of the patient by severity. This important paradigm shift for asthma care reflected the progress made in pharmacologic care of patients. Many asthma patients are receiving, or have received, some asthma medications. The role of the health care professional is to establish each patient’s current level of treatment and control, then adjust treatment to gain and maintain control. Asthma patients should experience no or minimal symptoms (including at night), have no limitations on their activities (including physical exercise), have no (or minimal) requirement for rescue medications, have near normal lung function, and experience only very infrequent exacerbations.

The recommendations for asthma care based on clinical control described in the 2006 report have been updated annually. This 2010 update reflects a number of modifications, described in “Methodology and Summary of New Recommendations.” As with all previous GINA reports, levels of evidence (Table A) are assigned to management recommendations where appropriate in Chapter 4, the Five Components of Asthma Management. Evidence levels are indicated in boldface type enclosed in parentheses after the relevant statement—e.g., (Evidence A). The methodological issues concerning the use of evidence from meta-analyses were carefully considered1. The GINA Science Committee used the GRADE approach2 to examine use of anti-IgE, omalizumab and intravenous magnesium sulphate; recommendations are presented on the website, www.ginasthma.org.

FUTURE CHALLENGES

In spite of laudable efforts to improve asthma care over the past decade, a majority of patients have not benefited from advances in asthma treatment and many lack even the rudiments of care. A challenge for the next several years is 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 a difficult task and, to aid in this work, has formed several groups of global experts, including: a Dissemination and Implementation Committee; the GINA Assembly, a network of individuals who care for asthma patients in many different health care settings; and two regional programs, GINA Mesoamerica and GINA Mediterranean. These efforts aim to enhance communication with asthma specialists, primary-care health professionals, other health care workers, and patient support organizations. The Executive Committee continues to examine barriers to implementation of the asthma management recommendations, especially the challenges that arise in primary-care settings and in developing countries.

While early diagnosis of asthma and implementation of appropriate therapy significantly reduce the socioeconomic burdens of asthma and enhance patients’ quality of life, medications continue to be the major component of the cost of asthma treatment. For this reason, the pricing of asthma medications continues to be a topic for urgent need and a growing area of research interest, as this has important implications for the overall costs of asthma management. Moreover, a large segment of the world’s population lives in areas with inadequate medical facilities and meagerfinancial resources. The GINA Executive Committee recognizes that “fixed” international guidelines and “rigid” scientific protocols will not work in many locations. Thus, the recommendations found in this Report must be adapted to fit local practices and the availability of health care resources.

INTRODUCTION

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As the GINA Committees expand their work, every effort will be made to interact with patient and physician groups at national, district, and local levels, and in multiple health care settings, to continuously examine new and innovative approaches that will ensure the delivery of the best asthma care possible. GINA is a partner organization in a program launched in March 2006 by the World Health Organization, the Global Alliance Against Chronic Respiratory Diseases (GARD). Through the work of the GINA Committees, and in cooperation with GARD, progress toward better care for all patients with asthma should be substantial in the next decade.

Table A. Description of Levels of EvidenceEvidence Category

Sources of Evidence Definition

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

Evidence is from endpoints of well designed RCTs that provide a consistent pattern of findings in the population for which the recommendation is made. Category A requires substantial numbers of studies involving substantial numbers of participants.

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

Evidence is from endpoints of intervention studies that include only a limited number of patients, posthoc or subgroup analysis of RCTs, or meta-analysis of RCTs. In general, Category B pertains when few randomized trials exist, they are small in size, they were under-taken in a population that differs from the target population of the recommendation, or the results are somewhat inconsistent.

C Nonrandomized trials. Observational studies.

Evidence is from outcomes of uncontrolled or non-randomized trials or from observational studies.

D Panel consensus judg-ment.

This category is used only in cases where the provision of some guidance was deemed valuable but the clinical literature addressing the subject was insufficient to justify placement in one of the other categories. The Panel Consensus is based on clinical experience or knowledge that does not meet the above listed criteria.

REFERENCES1. Jadad AR, Moher M, Browman GP, Booker L, Sigouis C, Fuentes M, et al. Systematic reviews and meta-analyses on treatment of asthma: critical evaluation. BMJ 2000;320:537-40.2. Guyatt G, Vist G, Falck-Ytter Y, Kunz R, Magrini N, Schunemann H. An emerging consensus on grading recommendations? Available from URL: http://www.evidence-basedmedicine.com.

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2DEFINITIONANDOVERVIEW

KEYPOINTS:

• Asthmaisachronicinflammatorydisorderoftheairwaysinwhichmanycellsandcellularelementsplayarole.Thechronicinflammationisassociatedwithairwayhyperresponsivenessthatleadstorecurrentepisodesofwheezing,breathlessness,chesttightness,andcoughing,particularlyatnightorintheearlymorning.Theseepisodesareusuallyassociatedwithwidespread,butvariable,airflowobstructionwithinthelungthatisoftenreversibleeitherspontaneouslyorwithtreatment.

• Clinicalmanifestationsofasthmacanbecontrolledwithappropriatetreatment.Whenasthmaiscontrolled,thereshouldbenomorethanoccasionalflare-upsandsevereexacerbationsshouldberare.

• Asthmaisaproblemworldwide,withanestimated300millionaffectedindividuals.

• Althoughfromtheperspectiveofboththepatientandsocietythecosttocontrolasthmaseemshigh,thecostofnottreatingasthmacorrectlyisevenhigher.

• Anumberoffactorsthatinfluenceaperson’sriskofdevelopingasthmahavebeenidentified.Thesecanbedividedintohostfactors(primarilygenetic)andenvironmentalfactors.

• Theclinicalspectrumofasthmaishighlyvariable,anddifferentcellularpatternshavebeenobserved,butthepresenceofairwayinflammationremainsaconsistentfeature.

Thischaptercoversseveraltopicsrelatedtoasthma,includingdefinition,burdenofdisease,factorsthatinfluencetheriskofdevelopingasthma,andmechanisms.Itisnotintendedtobeacomprehensivetreatmentofthesetopics,butratherabriefoverviewofthebackgroundthatinformstheapproachtodiagnosisandmanagementdetailedinsubsequentchapters.Furtherdetailsarefoundinthereviewsandotherreferencescitedattheendofthechapter.

Asthmaisadisorderdefinedbyitsclinical,physiological,andpathologicalcharacteristics.Thepredominantfeatureoftheclinicalhistoryisepisodicshortnessofbreath,particularlyatnight,oftenaccompaniedbycough.

Wheezingappreciatedonauscultationofthechestisthemostcommonphysicalfinding.

Themainphysiologicalfeatureofasthmaisepisodicairwayobstructioncharacterizedbyexpiratoryairflowlimitation.Thedominantpathologicalfeatureisairwayinflammation,sometimesassociatedwithairwaystructuralchanges.

Asthmahassignificantgeneticandenvironmentalcomponents,butsinceitspathogenesisisnotclear,muchofitsdefinitionisdescriptive.Basedonthefunctionalconsequencesofairwayinflammation,anoperationaldescriptionofasthmais:

Asthmaisachronicinflammatorydisorderoftheairwaysinwhichmanycellsandcellularelementsplayarole.Thechronicinflammationisassociatedwithairwayhyperresponsivenessthatleadstorecurrentepisodesofwheezing,breathlessness,chesttightness,andcoughing,particularlyatnightorintheearlymorning.Theseepisodesareusuallyassociatedwithwidespread,butvariable,airflowobstructionwithinthelungthatisoftenreversibleeitherspontaneouslyorwithtreatment.

Becausethereisnocleardefinitionoftheasthmaphenotype,researchersstudyingthedevelopmentofthiscomplexdiseaseturntocharacteristicsthatcanbemeasuredobjectively,suchasatopy(manifestedasthepresenceofpositiveskin-pricktestsortheclinicalresponsetocommonenvironmentalallergens),airwayhyperresponsiveness(thetendencyofairwaystonarrowexcessivelyinresponsetotriggersthathavelittleornoeffectinnormalindividuals),andothermeasuresofallergicsensitization.Althoughtheassociationbetweenasthmaandatopyiswellestablished,thepreciselinksbetweenthesetwoconditionshavenotbeenclearlyandcomprehensivelydefined.

Thereisnowgoodevidencethattheclinicalmanifestationsofasthma—symptoms,sleepdisturbances,limitationsofdailyactivity,impairmentoflungfunction,anduseofrescuemedications—canbecontrolledwithappropriatetreatment.Whenasthmaiscontrolled,thereshouldbenomorethanoccasionalrecurrenceofsymptomsandsevereexacerbationsshouldberare1.

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Prevalence, Morbidity, and Mortality

Asthmaisaproblemworldwide,withanestimated300millionaffectedindividuals2,3.Despitehundredsofreportsontheprevalenceofasthmainwidelydifferingpopulations,thelackofapreciseanduniversallyaccepteddefinitionofasthmamakesreliablecomparisonofreportedprevalencefromdifferentpartsoftheworldproblematic.Nonetheless,basedontheapplicationofstandardiedmethodstomeasuretheprevalenceofasthmaandwheezingillnessinchildren3andadults4,itappearsthattheglobalprevalenceofasthmarangesfrom1%to18%ofthepopulationindifferentcountries(Figure 1-1)2,3.Thereisgoodevidencethatinternationaldifferencesinasthmasymptomprevalencehavebeenreduced,particularlyinthe13-14yearagegroup,withdecreasesinprevalenceinNorthAmericaandWesternEuropeandincreasesinprevalenceinregionswhereprevalencewaspreviouslylow.Althoughtherewaslittlechangeintheoverallprevalenceofcurrentwheeze,thepercentageofchildrenreportedtohavehadasthmaincreasedsignificantly,possiblyreflectinggreaterawarenessofthisconditionand/orchangesindiagnosticpractice.TheincreasesinasthmasymptomprevalenceinAfrica,LatinAmericaandpartsofAsiaindicatethattheglobalburdenofasthmaiscontinuingtorise,buttheglobalprevalencedifferencesarelessening126.TheWorldHealthOrganizationhasestimatedthat15milliondisability-adjustedlifeyears(DALYs)arelostannuallyduetoasthma,representing1%ofthetotalglobaldiseaseburden2.Annualworldwidedeathsfromasthmahavebeenestimatedat250,000andmortalitydoesnotappeartocorrelatewellwithprevalence(Figure 1-1)2,3.Thereareinsufficientdatatodeterminethelikelycausesofthedescribedvariationsinprevalencewithinandbetweenpopulations.

Social and Economic Burden Socialandeconomicfactorsareintegraltounderstandingasthmaanditscare,whetherviewedfromtheperspectiveoftheindividualsufferer,thehealthcareprofessional,orentitiesthatpayforhealthcare.AbsencefromschoolanddayslostfromworkarereportedassubstantialsocialandeconomicconsequencesofasthmainstudiesfromtheAsia-Pacificregion,India,LatinAmerica,theUnitedKingdom,andtheUnitedStates9-12.

Themonetarycostsofasthma,asestimatedinavarietyofhealthcaresystemsincludingthoseoftheUnitedStates13-15andtheUnitedKingdom16aresubstantial.Inanalysesofeconomicburdenofasthma,attentionneedstobepaidtobothdirectmedicalcosts(hospitaladmissionsandcostofmedications)andindirect,non-medicalcosts(timelostfromwork,prematuredeath)17.Forexample,asthmaisamajorcauseofabsencefromworkinmanycountries4-6,121,includingAustralia,Sweden,theUnitedKingdom,andtheUnitedStates16,18-20.Comparisonsofthecostofasthmaindifferentregionsleadtoaclearsetofconclusions:

• Thecostsofasthmadependontheindividualpatient’slevelofcontrolandtheextenttowhichexacerbationsareavoided.

• Emergencytreatmentismoreexpensivethanplannedtreatment.

• Non-medicaleconomiccostsofasthmaaresubstantial.Guideline-determinedasthmacarecanbecosteffective.Familiescansufferfromthefinancialburdenoftreatingasthma.

Althoughfromtheperspectiveofboththepatientandsocietythecosttocontrolasthmaseemshigh,thecostofnottreatingasthmacorrectlyisevenhigher122.Propertreatmentofthediseaseposesachallengeforindividuals,healthcareprofessionals,healthcareorganizations,andgovernments.Thereiseveryreasontobelievethatthesubstantialglobalburdenofasthmacanbedramaticallyreducedthrougheffortsbyindividuals,theirhealthcareproviders,healthcareorganizations,andlocalandnationalgovernmentstoimproveasthmacontrol.

DetailedreferenceinformationabouttheburdenofasthmacanbefoundinthereportGlobalBurdenofAsthma*.Furtherstudiesofthesocialandeconomicburdenofasthmaandthecosteffectivenessoftreatmentareneededinbothdevelopedanddevelopingcountries.

THE BURDEN OF ASTHMA

Figure 1-1. Asthma Prevalence and Mortality2, 3

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

*(http://www.ginasthma.org/ReportItem.asp?I1=2&I2=2&intld=94

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Factorsthatinfluencetheriskofasthmacanbedividedintothosethatcausethedevelopmentofasthmaandthosethattriggerasthmasymptoms;somedoboth.Theformerincludehostfactors(whichareprimarilygenetic)andthelatterareusuallyenvironmentalfactors(Figure 1-2)21.However,themechanismswherebytheyinfluencethedevelopmentandexpressionofasthmaarecomplexandinteractive.Forexample,geneslikelyinteractbothwithothergenesandwithenvironmentalfactorstodetermineasthmasusceptibility22,23.Inaddition,developmentalaspects—suchasthematurationoftheimmuneresponseandthetimingofinfectiousexposuresduringthefirstyearsoflife—areemergingasimportantfactorsmodifyingtheriskofasthmainthegeneticallysusceptibleperson.

Additionally,somecharacteristicshavebeenlinkedtoanincreasedriskforasthma,butarenotthemselvestruecausalfactors.Theapparentracialandethnicdifferencesintheprevalenceofasthmareflectunderlyinggeneticvarianceswithasignificantoverlayofsocioeconomicandenvironmentalfactors.Inturn,thelinksbetweenasthmaandsocioeconomicstatus—withahigherprevalenceofasthmaindevelopedthanindevelopingnations,inpoorcomparedtoaffluentpopulationsindevelopednations,

andinaffluentcomparedtopoorpopulationsindevelopingnations—likelyreflectlifestyledifferencessuchasexposuretoallergens,accesstohealthcare,etc.

Muchofwhatisknownaboutasthmariskfactorscomesfromstudiesofyoungchildren.Riskfactorsforthedevelopmentofasthmainadults,particularlydenovoinadultswhodidnothaveasthmainchildhood,arelesswelldefined.

Thelackofacleardefinitionforasthmapresentsasignificantprobleminstudyingtheroleofdifferentriskfactorsinthedevelopmentofthiscomplexdisease,becausethecharacteristicsthatdefineasthma(e.g.,airwayhyperresponsiveness,atopy,andallergicsensitization)arethemselvesproductsofcomplexgene-environmentinteractionsandarethereforebothfeaturesofasthmaandriskfactorsforthedevelopmentofthedisease.

Host Factors

Genetic.Asthmahasaheritablecomponent,butitisnotsimple.Currentdatashowthatmultiplegenesmaybeinvolvedinthepathogenesisofasthma24,25,anddifferentgenesmaybeinvolvedindifferentethnicgroups.Thesearchforgeneslinkedtothedevelopmentofasthmahasfocusedonfourmajorareas:productionofallergen-specificIgEantibodies(atopy);expressionofairwayhyperresponsiveness;generationofinflammatorymediators,suchascytokines,chemokines,andgrowthfactors;anddeterminationoftheratiobetweenTh1andTh2immuneresponses(asrelevanttothehygienehypothesisofasthma)26.Familystudiesandcase-controlassociationanalyseshaveidentifiedanumberofchromosomalregionsassociatedwithasthmasusceptibility.Forexample,atendencytoproduceanelevatedleveloftotalserumIgEisco-inheritedwithairwayhyperresponsiveness,andagene(orgenes)governingairwayhyperresponsivenessislocatednearamajorlocusthatregulatesserumIgElevelsonchromosome5q27.However,thesearchforaspecificgene(orgenes)involvedinsusceptibilitytoatopyorasthmacontinues,asresultstodatehavebeeninconsistent24,25.

Inadditiontogenesthatpredisposetoasthmatherearegenesthatareassociatedwiththeresponsetoasthmatreatments.Forexample,variationsinthegeneencodingthebeta-adrenoreceptorhavebeenlinkedtodifferencesinsubjects’responsestoβ2-agonists

28.Othergenesofinterestmodifytheresponsivenesstoglucocorticosteroids29andleukotrienemodifiers30.Thesegeneticmarkerswilllikelybecomeimportantnotonlyasriskfactorsinthepathogenesisofasthmabutalsoasdeterminantsofresponsivenesstotreatment28,30-33.

FACTORS INFLUENCING THE DEVELOPMENT AND EXPRESSION OF ASTHMA Factors that influence the risk of asthma can be dividedinto those that cause the development of asthma andthose that trigger asthma symptoms; some do both.The former include host factors (which are primarilygenetic) and the latter are usually environmental factors(Figure 1-2)21. However, the mechanisms whereby theyinfluence the development and expression of asthma arecomplex and interactive. For example, genes likelyinteract both with other genes and with environmentalfactors to determine asthma susceptibility22,23. In addition,developmental aspects—such as the maturation of theimmune response and the timing of infectious exposuresduring the first years of life—are emerging as importantfactors modifying the risk of asthma in the geneticallysusceptible person.

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

HOST FACTORSGenetic, e.g.,

Genes pre-disposing to atopyGenes pre-disposing to airway hyperresponsiveness

ObesitySex

ENVIRONMENTAL FACTORSAllergens

Indoor: Domestic mites, furred animals (dogs, cats,mice), cockroach allergen, fungi, molds, yeastsOutdoor: Pollens, fungi, molds, yeasts

Infections (predominantly viral)Occupational sensiti ersTobacco smoke

Passive smokingActive smoking

Outdoor/Indoor Air PollutionDiet

Additionally, some characteristics have been linked to anincreased risk for asthma, but are not themselves truecausal factors. The apparent racial and ethnic differencesin the prevalence of asthma reflect underlying geneticvariances with a significant overlay of socioeconomic andenvironmental factors. In turn, the links between asthmaand socioeconomic status—with a higher prevalence of

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

Much of what is known about asthma risk factors comesfrom studies of young children. Risk factors for thedevelopment of asthma in adults, particularly de novo inadults who did not have asthma in childhood, are lesswell defined.

The lack of a clear definition for asthma presents asignificant problem in studying the role of different riskfactors in the development of this complex disease,because the characteristics that define asthma (e.g.,airway hyperresponsiveness, atopy, and allergicsensiti ation) are themselves products of complexgene-environment interactions and are therefore bothfeatures of asthma and risk factors for the developmentof the disease.

Host Factors

Genetic. Asthma has a heritable component, but it is notsimple. Current data show that multiple genes may beinvolved in the pathogenesis of asthma24,25, and differentgenes may be involved in different ethnic groups. Thesearch for genes linked to the development of asthma hasfocused on four major areas: production of allergen-specific IgE antibodies (atopy); expression of airwayhyperresponsiveness; generation of inflammatorymediators, such as cytokines, chemokines, and growthfactors; and determination of the ratio between Th1 andTh2 immune responses (as relevant to the hygienehypothesis of asthma)26.

Family studies and case-control association analyses haveidentified a number of chromosomal regions associatedwith asthma susceptibility. For example, a tendency toproduce an elevated level of total serum IgE is co-inheritedwith airway hyperresponsiveness, and a gene (or genes)governing airway hyperresponsiveness is located near amajor locus that regulates serum IgE levels onchromosome 5q27. However, the search for a specificgene (or genes) involved in susceptibility to atopy orasthma continues, as results to date have beeninconsistent24,25.

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

4 DEFINITION AND OVERVIEW

FACTORS INFLUENCING THEDEVELOPMENT AND EXPRESSIONOF ASTHMA

Factors that influence the risk of asthma can be dividedinto those that cause the development of asthma andthose that trigger asthma symptoms; some do both.The former include host factors (which are primarilygenetic) and the latter are usually environmental factors(Figure 1-2)21. However, the mechanisms whereby theyinfluence the development and expression of asthma arecomplex and interactive. For example, genes likelyinteract both with other genes and with environmentalfactors to determine asthma susceptibility22,23. In addition,developmental aspects—such as the maturation of theimmune response and the timing of infectious exposuresduring the first years of life—are emerging as importantfactors modifying the risk of asthma in the geneticallysusceptible person.




ObesitySex










Host Factors





FACTORS INFLUENCING THEDEVELOPMENT AND EXPRESSIONOF ASTHMA

Factors that influence the risk of asthma can be dividedinto those that cause the development of asthma andthose that trigger asthma symptoms; some do both.The former include host factors (which are primarilygenetic) and the latter are usually environmental factors(Figure 1-2)21. However, the mechanisms whereby theyinfluence the development and expression of asthma arecomplex and interactive. For example, genes likelyinteract both with other genes and with environmentalfactors to determine asthma susceptibility22,23. In addition,developmental aspects—such as the maturation of theimmune response and the timing of infectious exposuresduring the first years of life—are emerging as importantfactors modifying the risk of asthma in the geneticallysusceptible person.




ObesitySex










Host Factors




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Obesity.Asthmaismorefrequentlyobservedinobesesubjects(BodyMassIndex>30kg/m2)andismoredifficulttocontrol127-130.Obesepeoplewithasthmahavelowerlungfunctionandmoreco-morbiditiescomparedwithnormalweightpeoplewithasthma131.Theuseofsystemicglucocorticosteroidsandasedentarylifestylemaypromoteobesityinsevereasthmapatients,butinmostinstances,obesityprecedesthedevelopmentofasthma.

Howobesitypromotesthedevelopmentofasthmaisstilluncertainbutitmayresultfromthecombinedeffectsofvariousfactors.Ithasbeenproposedthatobesitycouldinfluenceairwayfunctionduetoitseffectonlungmechanics,developmentofapro-inflammatorystate,inadditiontogenetic,developmental,hormonalorneurogenicinfluences.35,132-133Inthisregard,obesepatientshaveareducedexpiratoryreservevolume,apatternofbreathingwhichmaypossiblyalterairwaysmoothmuscleplasticityandairwayfunction34.Furthermore,thereleasebyadipocytesofvariouspro-inflammatorycytokinesandmediatorssuchasinterleukin-6,tumornecrosisfactor(TNF)-α,eotaxin,andleptin,combinedwithalowerlevelofanti-inflammatoryadipokinesinobesesubjectscanfavorasystemicinflammatorystatealthoughitisunknownhowthiscouldinfluenceairwayfunction134-135.

Sex.Malesexisariskfactorforasthmainchildren.Priortotheageof14,theprevalenceofasthmaisnearlytwiceasgreatinboysasingirls36.Aschildrengetolderthedifferencebetweenthesexesnarrows,andbyadulthoodtheprevalenceofasthmaisgreaterinwomenthaninmen.Thereasonsforthissex-relateddifferencearenotclear.However,lungsizeissmallerinmalesthaninfemalesatbirth37butlargerinadulthood.

Environmental Factors

Thereissomeoverlapbetweenenvironmentalfactorsthatinfluencetheriskofdevelopingasthma,andfactorsthatcauseasthmasymptoms—forexample,occupationalsensitiersbelonginbothcategories.However,therearesomeimportantcausesofasthmasymptoms—suchasairpollutionandsomeallergens—whichhavenotbeenclearlylinkedtothedevelopmentofasthma.RiskfactorsthatcauseasthmasymptomsarediscussedindetailinChapter 4.2.

Allergens.Althoughindoorandoutdoorallergensarewellknowntocauseasthmaexacerbations,theirspecificroleinthedevelopmentofasthmaisstillnotfullyresolved.Birth-cohortstudieshaveshownthatsensitizationtohousedustmiteallergens,catdander,dogdander38,39,andAspergillusmold40areindependentriskfactorsforasthma-likesymptomsinchildrenupto3yearsofage.However,therelationshipbetweenallergenexposureandsensitizationin

childrenisnotstraightforward.Itdependsontheallergen,thedose,thetimeofexposure,thechild’sage,andprobablygeneticsaswell.

Forsomeallergens,suchasthosederivedfromhousedustmitesandcockroaches,theprevalenceofsensitizationappearstobedirectlycorrelatedwithexposure38,41.However,althoughsomedatasuggestthatexposuretohousedustmiteallergensmaybeacausalfactorinthedevelopmentofasthma42,otherstudieshavequestionedthisinterpretation43,44.Cockroachinfestationhasbeenshowntobeanimportantcauseofallergicsensitization,particularlyininner-cityhomes45.

Inthecaseofdogsandcats,someepidemiologicstudieshavefoundthatearlyexposuretotheseanimalsmayprotectachildagainstallergicsensitizationorthedevelopmentofasthma46-48,butotherssuggestthatsuchexposuremayincreasetheriskofallergicsensitization47,49-51.Thisissueremainsunresolved.

Theprevalenceofasthmaisreducedinchildrenraisedinaruralsetting,whichmaybelinkedtothepresenceofendotoxinintheseenvironments52.

Infections.Duringinfancy,anumberofviruseshavebeenassociatedwiththeinceptionoftheasthmaticphenotype.Respiratorysyncytialvirus(RSV)andparainfluenzavirusproduceapatternofsymptomsincludingbronchiolitisthatparallelmanyfeaturesofchildhoodasthma53,514.Anumberoflong-termprospectivestudiesofchildrenadmittedtothehospitalwithdocumentedRSVhaveshownthatapproximately40%willcontinuetowheezeorhaveasthmaintolaterchildhood53.Ontheotherhand,evidencealsoindicatesthatcertainrespiratoryinfectionsearlyinlife,includingmeaslesandsometimesevenRSV,mayprotectagainstthedevelopmentofasthma55,56.Thedatadonotallowspecificconclusionstobedrawn.Parasiteinfectionsdonotingeneralprotectagainstasthma,butinfectionwithhookwormmayreducetherisk123.

The“hygienehypothesis”ofasthmasuggeststhatexposuretoinfectionsearlyinlifeinfluencesthedevelopmentofachild’simmunesystemalonga“nonallergic”pathway,leadingtoareducedriskofasthmaandotherallergicdiseases.Althoughthehygienehypothesiscontinuestobeinvestigated,thismechanismmayexplainobservedassociationsbetweenfamilysize,birthorder,day-careattendance,andtheriskofasthma.Forexample,youngchildrenwitholdersiblingsandthosewhoattenddaycareareatincreasedriskofinfections,butenjoyprotectionagainstthedevelopmentofallergicdiseases,includingasthmalaterinlife57-59.

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Theinteractionbetweenatopyandviralinfectionsappearstobeacomplexrelationship60,inwhichtheatopicstatecaninfluencethelowerairwayresponsetoviralinfections,viralinfectionscantheninfluencethedevelopmentofallergicsensitization,andinteractionscanoccurwhenindividualsareexposedsimultaneouslytobothallergensandviruses.

Occupational sensitizers.Over300substanceshavebeenassociatedwithoccupationalasthma61-65,whichisdefinedasasthmacausedbyexposuretoanagentencounteredintheworkenvironment.Thesesubstancesincludehighlyreactivesmallmoleculessuchasisocyanates,irritantsthatmaycauseanalterationinairwayresponsiveness,knownimmunogenssuchasplatinumsalts,andcomplexplantandanimalbiologicalproductsthatstimulatetheproductionofIgE(Figure 1-3).

Occupationalasthmaarisespredominantlyinadults66,67,andoccupationalsensitizersareestimatedtocauseabout1in10casesofasthmaamongadultsofworkingage68.Asthmaisthemostcommonoccupationalrespiratorydisorderinindustrializedcountries69.Occupationsassociatedwithahighriskforoccupationalasthmaincludefarmingandagriculturalwork,painting(includingspraypainting),cleaningwork,andplasticmanufacturing62.

Mostoccupationalasthmaisimmunologicallymediatedandhasalatencyperiodofmonthstoyearsaftertheonsetofexposure70.IgE-mediatedallergicreactionsandcell-mediatedallergicreactionsareinvolved71,72.

Levelsabovewhichsensitizationfrequentlyoccurshavebeenproposedformanyoccupationalsensitizers.However,thefactorsthatcausesomepeoplebutnototherstodevelopoccupationalasthmainresponsetothesameexposuresarenotwellidentified.Veryhighexposurestoinhaledirritantsmaycause“irritantinducedasthma”(formerlycalledthereactiveairwaysdysfunctionalsyndrome)eveninnon-atopicpersons.Atopyandtobaccosmokingmayincreasetheriskofoccupationalsensitization,butscreeningindividualsforatopyisoflimitedvalueinpreventingoccupationalasthma73.Themostimportantmethodofpreventingoccupationalasthmaiseliminationorreductionofexposuretooccupationalsensitizers.

Tobacco smoke.Tobaccosmokingisassociatedwithaccelerateddeclineoflungfunctioninpeoplewithasthma136,increasesasthmaseverity,mayrenderpatientslessresponsivetotreatmentwithinhaled74,124andsystemic75glucocorticosteroids,andreducesthelikelihoodofasthmabeingcontrolled76.

Exposuretotobaccosmokebothprenatallyandafterbirthisassociatedwithmeasurableharmfuleffectsincludingagreaterriskofdevelopingasthma-likesymptomsinearlychildhood.However,evidenceofincreasedriskofallergicdiseasesisuncertain77,78.Distinguishingtheindependentcontributionsofprenatalandpostnatalmaternalsmokingisproblematic79.However,studiesoflungfunctionimmediatelyafterbirthhaveshownthatmaternalsmokingduringpregnancyhasaninfluenceonlungdevelopment37.Furthermore,infantsofsmokingmothersare4timesmorelikelytodevelopwheezingillnessesinthefirstyearoflife80.Incontrast,thereislittleevidence(basedonmetaanalysis)thatmaternalsmokingduringpregnancyhasaneffectonallergicsensitization78.Exposuretoenvironmentaltobaccosmoke(passivesmoking)increasestheriskoflowerrespiratorytractillnessesininfancy81andchildhood82.

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

Occupation/occupational field AgentAnimal and Plant Proteins

Bakers Flour, amylaseDairy farmers Storage mitesDetergent manufacturing Bacillus subtilis enzymesElectrical soldering Colophony (pine resin)Farmers Soybean dustFish food manufacturing Midges, parasitesFood processing Coffee bean dust, meat tenderizer, tea, shellfish,

amylase, egg proteins, pancreatic enzymes,papain

Granary workers Storage mites, Aspergillus, indoor ragweed, grassHealth care workers Psyllium, latexLaxative manufacturing Ispaghula, psylliumPoultry farmers Poultry mites, droppings, feathersResearch workers, veterinarians Locusts, dander, urine proteinsSawmill workers, carpenters Wood dust (western red cedar, oak, mahogany,

ebrawood, redwood, Lebanon cedar, Africanmaple, eastern white cedar)

Shipping workers Grain dust (molds, insects, grain)Silk workers Silk worm moths and larvae

Inorganic chemicalsBeauticians PersulfatePlating Nickel saltsRefinery workers Platinum salts, vanadium

Organic chemicalsAutomobile painting Ethanolamine, dissocyanatesHospital workers Disinfectants (sulfathiazole, chloramines,

formaldehyde, glutaraldehyde), latexManufacturing Antibiotics, piperazine, methyldopa, salbutamol,

cimetidineRubber processing Formaldehyde, ethylene diamine, phthalic anhydridePlastics industry Toluene dissocyanate, hexamethyl dissocyanate,

dephenylmethyl isocyanate, phthalic anhydride,triethylene tetramines, trimellitic anhydride,hexamethyl tetramine, acrylates

*See http6//www.bohrf.org.uk for a comprehensive list of known sensitizing agents

Occupational asthma arises predominantly in adults66, 67,and occupational sensiti ers are estimated to cause about1 in 10 cases of asthma among adults of working age68.Asthma is the most common occupational respiratorydisorder in industriali ed countries69. Occupationsassociated with a high risk for occupational asthma includefarming and agricultural work, painting (including spraypainting), cleaning work, and plastic manufacturing62.

Most occupational asthma is immunologically mediatedand has a latency period of months to years after the onsetof exposure70. IgE-mediated allergic reactions and cell-mediated allergic reactions are involved71, 72.

Levels above which sensiti ation frequently occurs havebeen proposed for many occupational sensiti ers.However, the factors that cause some people but not

others to develop occupational asthma in response to thesame exposures are not well identified. Very highexposures to inhaled irritants may cause “irritant inducedasthma” (formerly called the reactive airways dysfunctionalsyndrome) even in non-atopic persons. Atopy andtobacco smoking may increase the risk of occupationalsensiti ation, but screening individuals for atopy is oflimited value in preventing occupational asthma73. Themost important method of preventing occupational asthmais elimination or reduction of exposure to occupationalsensiti ers.

tobacco smoke. Tobacco smoking is associated withaccelerated decline of lung function in people with asthma,increases asthma severity, may render patients lessresponsive to treatment with inhaled74,124 and systemic75

glucocorticosteroids, and reduces the likelihood of asthmabeing controlled76.

Exposure to tobacco smoke both prenatally and after birthis associated with measurable harmful effects including agreater risk of developing asthma-like symptoms in earlychildhood. However, evidence of increased risk of allergicdiseases is uncertain77, 78. Distinguishing the independentcontributions of prenatal and postnatal maternal smokingis problematic79. However, studies of lung functionimmediately after birth have shown that maternal smokingduring pregnancy has an influence on lung development37.Furthermore, infants of smoking mothers are 4 times morelikely to develop whee ing illnesses in the first year of life80.In contrast, there is little evidence (based on meta-analysis) that maternal smoking during pregnancy has aneffect on allergic sensiti ation78. Exposure toenvironmental tobacco smoke (passive smoking)increases the risk of lower respiratory tract illnesses ininfancy81 and childhood82.

outdoor/indoor air pollution. The role of outdoor airpollution in causing asthma remains controversial83.Children raised in a polluted environment have diminishedlung function84, but the relationship of this loss of functionto the development of asthma is not known.

Outbreaks of asthma exacerbations have been shown tooccur in relationship to increased levels of air pollution,and this may be related to a general increase in the levelof pollutants or to specific allergens to which individualsare sensiti ed85-87. However, the role of pollutants in thedevelopment of asthma is less well defined. Similarassociations have been observed in relation to indoorpollutants, e.g., smoke and fumes from gas and biomassfuels used for heating and cooling, molds, and cockroachinfestations.


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

Occupation/occupational field AgentAnimal and Plant Proteins

Bakers Flour, amylaseDairy farmers Storage mitesDetergent manufacturing Bacillus subtilis en ymesElectrical soldering Colophony (pine resin)Farmers Soybean dustFish food manufacturing Midges, parasitesFood processing Coffee bean dust, meat tenderi er, tea, shellfish,

amylase, egg proteins, pancreatic en ymes,papain

Granary workers Storage mites, Aspergillus, indoor ragweed, grassHealth care workers Psyllium, latexLaxative manufacturing Ispaghula, psylliumPoultry farmers Poultry mites, droppings, feathersResearch workers, veterinarians Locusts, dander, urine proteinsSawmill workers, carpenters Wood dust (western red cedar, oak, mahogany,

ebrawood, redwood, Lebanon cedar, Africanmaple, eastern white cedar)

Shipping workers Grain dust (molds, insects, grain)Silk workers Silk worm moths and larvae

Inorganic chemicalsBeauticians PersulfatePlating Nickel saltsRefinery workers Platinum salts, vanadium

Organic chemicalsAutomobile painting Ethanolamine, dissocyanatesHospital workers Disinfectants (sulfathia ole, chloramines,

formaldehyde, glutaraldehyde), latexManufacturing Antibiotics, pipera ine, methyldopa, salbutamol,

cimetidineRubber processing Formaldehyde, ethylene diamine, phthalic anhydridePlastics industry Toluene dissocyanate, hexamethyl dissocyanate,

dephenylmethyl isocyanate, phthalic anhydride,triethylene tetramines, trimellitic anhydride,hexamethyl tetramine, acrylates

*See http6//www.bohrf.org.uk for a comprehensive list of known sensitizing agents

Occupational asthma arises predominantly in adults66, 67,and occupational sensiti ers are estimated to cause about1 in 10 cases of asthma among adults of working age68.Asthma is the most common occupational respiratorydisorder in industriali ed countries69. Occupationsassociated with a high risk for occupational asthma includefarming and agricultural work, painting (including spraypainting), cleaning work, and plastic manufacturing62.

Most occupational asthma is immunologically mediatedand has a latency period of months to years after the onsetof exposure70. IgE-mediated allergic reactions and cell-mediated allergic reactions are involved71, 72.

Levels above which sensiti ation frequently occurs havebeen proposed for many occupational sensiti ers.However, the factors that cause some people but not

others to develop occupational asthma in response to thesame exposures are not well identified. Very highexposures to inhaled irritants may cause “irritant inducedasthma” (formerly called the reactive airways dysfunctionalsyndrome) even in non-atopic persons. Atopy andtobacco smoking may increase the risk of occupationalsensiti ation, but screening individuals for atopy is oflimited value in preventing occupational asthma73. Themost important method of preventing occupational asthmais elimination or reduction of exposure to occupationalsensiti ers.

tobacco smoke. Tobacco smoking is associated withaccelerated decline of lung function in people with asthma,increases asthma severity, may render patients lessresponsive to treatment with inhaled74,124 and systemic75

glucocorticosteroids, and reduces the likelihood of asthmabeing controlled76.

Exposure to tobacco smoke both prenatally and after birthis associated with measurable harmful effects including agreater risk of developing asthma-like symptoms in earlychildhood. However, evidence of increased risk of allergicdiseases is uncertain77, 78. Distinguishing the independentcontributions of prenatal and postnatal maternal smokingis problematic79. However, studies of lung functionimmediately after birth have shown that maternal smokingduring pregnancy has an influence on lung development37.Furthermore, infants of smoking mothers are 4 times morelikely to develop whee ing illnesses in the first year of life80.In contrast, there is little evidence (based on meta-analysis) that maternal smoking during pregnancy has aneffect on allergic sensiti ation78. Exposure toenvironmental tobacco smoke (passive smoking)increases the risk of lower respiratory tract illnesses ininfancy81 and childhood82.

outdoor/indoor air pollution. The role of outdoor airpollution in causing asthma remains controversial83.Children raised in a polluted environment have diminishedlung function84, but the relationship of this loss of functionto the development of asthma is not known.

Outbreaks of asthma exacerbations have been shown tooccur in relationship to increased levels of air pollution,and this may be related to a general increase in the levelof pollutants or to specific allergens to which individualsare sensiti ed85-87. However, the role of pollutants in thedevelopment of asthma is less well defined. Similarassociations have been observed in relation to indoorpollutants, e.g., smoke and fumes from gas and biomassfuels used for heating and cooling, molds, and cockroachinfestations.

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Outdoor/indoor air pollution.Theroleofoutdoorairpollutionincausingasthmaremainscontroversial83.Childrenraisedinapollutedenvironmenthavediminishedlungfunction84,buttherelationshipofthislossoffunctiontothedevelopmentofasthmaisnotknown.

Outbreaksofasthmaexacerbationshavebeenshowntooccurinrelationshiptoincreasedlevelsofairpollution,andthismayberelatedtoageneralincreaseinthelevelofpollutantsortospecificallergenstowhichindividualsaresensitized85-87.However,theroleofpollutantsinthedevelopmentofasthmaislesswelldefined.Similarassociationshavebeenobservedinrelationtoindoorpollutants,e.g.,smokeandfumesfromgasandbiomassfuelsusedforheatingandcooling,molds,andcockroachinfestations.

Diet.Theroleofdiet,particularlybreast-feeding,inrelationtothedevelopmentofasthmahasbeenextensivelystudiedand,ingeneral,thedatarevealthatinfantsfedformulasofintactcow’smilkorsoyproteinhaveahigherincidenceofwheezingillnessesinearlychildhoodcomparedwiththosefedbreastmilk88.

SomedataalsosuggestthatcertaincharacteristicsofWesterndiets,suchasincreaseduseofprocessedfoodsanddecreasedantioxidant(intheformoffruitsandvegetables),increasedn-6polyunsaturatedfattyacid(foundinmargarineandvegetableoil),anddecreasedn-3polyunsaturatedfattyacid(foundinoilyfish)intakeshavecontributedtotherecentincreasesinasthmaandatopicdisease89.

Asthmaisaninflammatorydisorderoftheairways,whichinvolvesseveralinflammatorycellsandmultiplemediatorsthatresultincharacteristicpathophysiologicalchanges21,90.Inwaysthatarestillnotwellunderstood,thispatternofinflammationisstronglyassociatedwithairwayhyper-responsivenessandasthmasymptoms.

Airway Inflammation In Asthma

Theclinicalspectrumofasthmaishighlyvariable,anddifferentcellularpatternshavebeenobserved,butthepresenceofairwayinflammationremainsaconsistentfeature.Theairwayinflammationinasthmaispersistenteventhoughsymptomsareepisodic,andtherelationshipbetweentheseverityofasthmaandtheintensityofinflammationisnotclearlyestablished91,92.Theinflammationaffectsallairwaysincludinginmostpatientstheupperrespiratorytractandnosebutitsphysiologicaleffectsaremostpronouncedinmedium-sizedbronchi.

MECHANISMS OF ASTHMA

diet. The role of diet, particularly breast-feeding, inrelation to the development of asthma has beenextensively studied and, in general, the data reveal thatinfants fed formulas of intact cow's milk or soy protein havea higher incidence of whee ing illnesses in early childhoodcompared with those fed breast milk88.

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

MECHANISMS OF ASTHMA

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


The clinical spectrum of asthma is highly variable, anddifferent cellular patterns have been observed, but thepresence of airway inflammation remains a consistentfeature. The airway inflammation in asthma is persistenteven though symptoms are episodic, and the relationshipbetween the severity of asthma and the intensity ofinflammation is not clearly established91,92. Theinflammation affects all airways including in most patientsthe upper respiratory tract and nose but its physiologicaleffects are most pronounced in medium-si ed bronchi.The pattern of inflammation in the airways appears to besimilar in all clinical forms of asthma, whether allergic,non-allergic, or aspirin-induced, and at all ages.

inflammatory cells. The characteristic pattern ofinflammation found in allergic diseases is seen in asthma,with activated mast cells, increased numbers of activatedeosinophils, and increased numbers of T cell receptorinvariant natural killer T cells and T helper 2 lymphocytes(Th2), which release mediators that contribute tosymptoms (Figure 1-4). Structural cells of the airwaysalso produce inflammatory mediators, and contribute to thepersistence of inflammation in various ways (Figure 1-5).

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

Figure 1-4: Inflammatory Cells in Asthmatic Airways

Mast cells: Activated mucosal mast cells releasebronchoconstrictor mediators (histamine, cysteinyl leukotrienes,prostaglandin D2)93. These cells are activated by allergensthrough high-affinity IgE receptors, as well as by osmotic stimuli(accounting for exercise-induced bronchoconstriction). Increasedmast cell numbers in airway smooth muscle may be linked toairway hyperresponsiveness94.

Eosinophils, present in increased numbers in the airways,release basic proteins that may damage airway epithelial cells.They may also have a role in the release of growth factors andairway remodeling95.

T lymphocytes, present in increased numbers in the airways,release specific cytokines, including IL-4, IL-5, IL-9, and IL-13,that orchestrate eosinophilic inflammation and IgE production byB lymphocytes96. An increase in Th2 cell activity may be due inpart to a reduction in regulatory T cells that normally inhibit Th2cells. There may also be an increase in inKT cells, which releaselarge amounts of T helper 1 (Th1) and Th2 cytokines97.

Dendritic cells sample allergens from the airway surface andmigrate to regional lymph nodes, where they interact withregulatory T cells and ultimately stimulate production of Th2cells from na ve T cells98.

Macrophages are increased in number in the airways and maybe activated by allergens through low-affinity IgE receptors torelease inflammatory mediators and cytokines that amplify theinflammatory response99.

Neutrophil numbers are increased in the airways and sputum ofpatients with severe asthma and in smoking asthmatics, but thepathophysiological role of these cells is uncertain and theirincrease may even be due to glucocorticosteroid therapy100.

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

Airway epithelial cells sense their mechanical environment,express multiple inflammatory proteins in asthma, and releasecytokines, chemokines, and lipid mediators. Viruses and airpollutants interact with epithelial cells.

Airway smooth muscle cells express similar inflammatoryproteins to epithelial cells101.

Endothelial cells of the bronchial circulation play a role inrecruiting inflammatory cells from the circulation into the airway.

Fibroblasts and myofibroblasts produce connective tissuecomponents, such as collagens and proteoglycans, that areinvolved in airway remodeling.

Airway nerves are also involved. Cholinergic nerves may beactivated by reflex triggers in the airways and causebronchoconstriction and mucus secretion. Sensory nerves,which may be sensiti ed by inflammatory stimuli includingneurotrophins, cause reflex changes and symptoms such ascough and chest tightness, and may release inflammatoryneuropeptides102.

diet. The role of diet, particularly breast-feeding, inrelation to the development of asthma has beenextensively studied and, in general, the data reveal thatinfants fed formulas of intact cow's milk or soy protein havea higher incidence of whee ing illnesses in early childhoodcompared with those fed breast milk88.

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

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


The clinical spectrum of asthma is highly variable, anddifferent cellular patterns have been observed, but thepresence of airway inflammation remains a consistentfeature. The airway inflammation in asthma is persistenteven though symptoms are episodic, and the relationshipbetween the severity of asthma and the intensity ofinflammation is not clearly established91,92. Theinflammation affects all airways including in most patientsthe upper respiratory tract and nose but its physiologicaleffects are most pronounced in medium-si ed bronchi.The pattern of inflammation in the airways appears to besimilar in all clinical forms of asthma, whether allergic,non-allergic, or aspirin-induced, and at all ages.

inflammatory cells. The characteristic pattern ofinflammation found in allergic diseases is seen in asthma,with activated mast cells, increased numbers of activatedeosinophils, and increased numbers of T cell receptorinvariant natural killer T cells and T helper 2 lymphocytes(Th2), which release mediators that contribute tosymptoms (Figure 1-4). Structural cells of the airwaysalso produce inflammatory mediators, and contribute to thepersistence of inflammation in various ways (Figure 1-5).

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

Figure 1-4: Inflammatory Cells in Asthmatic Airways

Mast cells: Activated mucosal mast cells releasebronchoconstrictor mediators (histamine, cysteinyl leukotrienes,prostaglandin D2)93. These cells are activated by allergensthrough high-affinity IgE receptors, as well as by osmotic stimuli(accounting for exercise-induced bronchoconstriction). Increasedmast cell numbers in airway smooth muscle may be linked toairway hyperresponsiveness94.

Eosinophils, present in increased numbers in the airways,release basic proteins that may damage airway epithelial cells.They may also have a role in the release of growth factors andairway remodeling95.

T lymphocytes, present in increased numbers in the airways,release specific cytokines, including IL-4, IL-5, IL-9, and IL-13,that orchestrate eosinophilic inflammation and IgE production byB lymphocytes96. An increase in Th2 cell activity may be due inpart to a reduction in regulatory T cells that normally inhibit Th2cells. There may also be an increase in inKT cells, which releaselarge amounts of T helper 1 (Th1) and Th2 cytokines97.

Dendritic cells sample allergens from the airway surface andmigrate to regional lymph nodes, where they interact withregulatory T cells and ultimately stimulate production of Th2cells from na ve T cells98.

Macrophages are increased in number in the airways and maybe activated by allergens through low-affinity IgE receptors torelease inflammatory mediators and cytokines that amplify theinflammatory response99.

Neutrophil numbers are increased in the airways and sputum ofpatients with severe asthma and in smoking asthmatics, but thepathophysiological role of these cells is uncertain and theirincrease may even be due to glucocorticosteroid therapy100.

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

Airway epithelial cells sense their mechanical environment,express multiple inflammatory proteins in asthma, and releasecytokines, chemokines, and lipid mediators. Viruses and airpollutants interact with epithelial cells.

Airway smooth muscle cells express similar inflammatoryproteins to epithelial cells101.

Endothelial cells of the bronchial circulation play a role inrecruiting inflammatory cells from the circulation into the airway.

Fibroblasts and myofibroblasts produce connective tissuecomponents, such as collagens and proteoglycans, that areinvolved in airway remodeling.

Airway nerves are also involved. Cholinergic nerves may beactivated by reflex triggers in the airways and causebronchoconstriction and mucus secretion. Sensory nerves,which may be sensiti ed by inflammatory stimuli includingneurotrophins, cause reflex changes and symptoms such ascough and chest tightness, and may release inflammatoryneuropeptides102.

DEFINITION AND OVERVIEW 7

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Thepatternofinflammationintheairwaysappearstobesimilarinallclinicalformsofasthma,whetherallergic,non-allergic,oraspirin-induced,andatallages.

Inflammatory cells.Thecharacteristicpatternofinflammationfoundinallergicdiseasesisseeninasthma,withactivatedmastcells,increasednumbersofactivatedeosinophils,andincreasednumbersofTcellreceptor

invariantnaturalkillerTcellsandThelper2lymphocytes(Th2),whichreleasemediatorsthatcontributetosymptoms(Figure 1-4).Structuralcellsoftheairwaysalsoproduceinflammatorymediators,andcontributetothepersistenceofinflammationinvariousways(Figure 1-5).Inflammatorymediators.Over100differentmediatorsarenowrecogniedtobeinvolvedinasthmaandmediatethecomplexinflammatoryresponseintheairways103(Figure 1-6).

Structural changes in the airways.Inadditiontotheinflammatoryresponse,therearecharacteristicstructuralchanges,oftendescribedasairwayremodeling,intheairwaysofasthmapatients(Figure 1-7).Someofthesechangesarerelatedtotheseverityofthediseaseandmayresultinrelativelyirreversiblenarrowingoftheairways109,110.Thesechangesmayrepresentrepairinresponsetochronicinflammation.

Pathophysiology Airwaynarrowingisthefinalcommonpathwayleadingtosymptomsandphysiologicalchangesinasthma.Severalfactorscontributetothedevelopmentofairwaynarrowinginasthma(Figure 1-8).

Airway hyperresponsiveness.Airwayhyperresponsiveness,thecharacteristicfunctionalabnormalityofasthma,resultsinairwaynarrowinginapatientwithasthmainresponsetoastimulusthatwouldbeinnocuousinanormalperson.Inturn,thisairwaynarrowingleadstovariableairflowlimitationandintermittentsymptoms.Airwayhyperresponsivenessislinkedtobothinflammationandrepairoftheairwaysandispartiallyreversiblewiththerapy.Itsmechanisms(Figure 1-9)areincompletelyunderstood.

Figure 1-6: Key Mediators of Asthma

Chemokines are important in the recruitment of inflammatorycells into the airways and are mainly expressed in airwayepithelial cells104. Eotaxin is relatively selective for eosinophils,whereas thymus and activation-regulated chemokines (TARC)and macrophage-derived chemokines (MDC) recruit Th2 cells.

Cysteinyl leukotrienes are potent bronchoconstrictors andproinflammatorymediatorsmainlyderived frommast cells andeosinophils.They are the only mediator whose inhibition has been associatedwith an improvement in lung function and asthma symptoms105.

Cytokines orchestrate the inflammatory response in asthma anddetermine its severity106. Key cytokines include IL-1[ and TNF-oc,which amplify the inflammatory response, and GM-CSF, whichprolongs eosinophil survival in the airways. Th2-derived cytokinesinclude IL-5, which is required for eosinophil differentiation andsurvival; IL-4, which is important for Th2 cell differentiation; andIL-13, needed for IgE formation.

Histamine is released from mast cells and contributes tobronchoconstriction and to the inflammatory response.

Nitric oxide (NO), a potent vasodilator, is produced predominantlyfrom the action of inducible nitric oxide synthase in airway epithelialcells107. Exhaled NO is increasingly being used to monitor theeffectiveness of asthma treatment, because of its reportedassociation with the presence of inflammation in asthma108.

Prostaglandin D2 is a bronchoconstrictor derived predominantlyfrom mast cells and is involved in Th2 cell recruitment to the airways.

Structural changes in the airways. In addition to theinflammatory response, there are characteristic structuralchanges, often described as airway remodeling, in theairways of asthma patients (Figure 1-7). Some of thesechanges are related to the severity of the disease and mayresult in relatively irreversible narrowing of the airways109, 110.These changes may represent repair in response tochronic inflammation.

Figure 1-7: Structural Changes in Asthmatic Airways

Subepithelial fibrosis results from the deposition of collagen fibersand proteoglycans under the basement membrane and is seen inall asthmatic patients, including children, even before the onset ofsymptoms but may be influenced by treatment. Fibrosis occurs inother layers for the airway wall, with deposition of collagen andproteoglycans.

Airway smooth muscle increases, due both to hypertrophy(increased si e of individual cells) and hyperplasia (increased celldivision), and contributes to the increased thickness of the airwaywall111. This process may relate to disease severity and is causedby inflammatory mediators, such as growth factors.

Blood vessels in airway walls proliferate the influence of growthfactors such as vascular endothelial growth factor (VEGF) andmay contribute to increased airway wall thickness.

Mucus hypersecretion results from increased numbers of gobletcells in the airway epithelium and increased si e of submucosalglands.

Pathophysiology

Airway narrowing is the final common pathway leading tosymptoms and physiological changes in asthma. Severalfactors contribute to the development of airway narrowingin asthma (Figure 1-8).

Figure 1-8: Airway Narrowing in Asthma

Airway smooth muscle contraction in response to multiplebronchoconstrictor mediators and neurotransmitters is thepredominant mechanism of airway narrowing and is largelyreversed by bronchodilators.

Airway edema is due to increased microvascular leakage inresponse to inflammatory mediators. This may be particularlyimportant during acute exacerbations.

Airway thickening due to structural changes, often termed“remodeling,” may be important in more severe disease and isnot fully reversible by current therapy.

Mucus hypersecretion may lead to luminal occlusion (“mucusplugging”) and is a product of increased mucus secretion andinflammatory exudates.

airway hyperresponsiveness. Airway hyperresponsive-ness, the characteristic functional abnormality of asthma,results in airway narrowing in a patient with asthma inresponse to a stimulus that would be innocuous in anormal person. In turn, this airway narrowing leads tovariable airflow limitation and intermittent symptoms. Airwayhyperresponsiveness is linked to both inflammation and re-pair of the airways and is partially reversible with therapy.Its mechanisms (Figure 1-9) are incompletely understood.

Figure 1-9: Mechanisms of Airway Hyperresponsiveness

Excessive contraction of airway smooth muscle may resultfrom increased volume and/or contractility of airway smoothmuscle cells112.

Uncoupling of airway contraction as a result of inflammatorychanges in the airway wall may lead to excessive narrowing of theairways and a loss of the maximum plateau of contraction found innormal ariways when bronchoconstrictor substances are inhaled113.

Thickening of the airway wall by edema and structural changesamplifies airway narrowing due to contraction of airway smoothmuscle for geometric reasons114.

Sensory nerves may be sensiti ed by inflammation, leading toexaggerated bronchoconstriction in response to sensory stimuli.

Special Mechanisms

acute exacerbations. Transient worsening of asthmamay occur as a result of exposure to risk factors forasthma symptoms, or “triggers,” such as exercise, air


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Airway smooth muscle increases, due both to hypertrophy(increased size of individual cells) and hyperplasia (increased celldivision), and contributes to the increased thickness of the airwaywall111. This process may relate to disease severity and is causedby inflammatory mediators, such as growth factors.



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Special Mechanisms

Acute exacerbations.Transientworseningofasthmamayoccurasaresultofexposuretoriskfactorsforasthmasymptoms,or“triggers,”suchasexercise,airpollutants115,andevencertainweatherconditions,e.g.,thunderstorms116.Moreprolongedworseningisusuallyduetoviralinfectionsoftheupperrespiratorytract(particularlyrhinovirusandrespiratorysyncytialvirus)117orallergenexposurewhichincreaseinflammationinthelowerairways(acuteorchronicinflammation)thatmaypersistforseveraldaysorweeks.

Nocturnal asthma.Themechanismsaccountingfortheworseningofasthmaatnightarenotcompletelyunderstoodbutmaybedrivenbycircadianrhythmsofcirculatinghormonessuchasepinephrine,cortisol,andmelatoninandneuralmechanismssuchascholinergictone.Anincreaseinairwayinflammationatnighthasbeenreported.Thismightreflectareductioninendogenousanti-inflammatorymechanisms118.

Irreversible airflow limitation.Somepatientswithsevereasthmadevelopprogressiveairflowlimitationthatisnotfullyreversiblewithcurrentlyavailabletherapy.Thismayreflectthechangesinairwaystructureinchronicasthma119.

Difficult-to-treat asthma.Thereasonswhysomepatientsdevelopasthmathatisdifficulttomanageandrelativelyinsensitivetotheeffectsofglucocorticosteroidsarenotwellunderstood.Commonassociationsarepoorcompliancewithtreatmentandpsychologicalandpsychiatricdisorders.However,geneticfactorsmaycontributeinsome.Manyofthesepatientshavedifficult-to-treatasthmafromtheonsetofthedisease,ratherthanprogressingfrommilderasthma.Inthesepatientsairwayclosureleadstoairtrappingandhyperinflation.Althoughthepathologyappearsbroadlysimilartootherformsofasthma,thereisanincreaseinneutrophils,moresmallairwayinvolvement,andmore

structuralchanges100.

Smoking and asthma.Tobaccosmokingmakesasthmamoredifficulttocontrol,resultsinmorefrequentexacerbationsandhospitaladmissions,andproducesamorerapiddeclineinlungfunctionandanincreasedriskofdeath120.Asthmapatientswhosmokemayhaveaneutrophil-predominantinflammationintheirairwaysandarepoorlyresponsivetoglucocorticosteroids125.

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2. MasoliM,FabianD,HoltS,BeasleyR.Theglobalburdenofasthma:executivesummaryoftheGINADisseminationCommitteereport.Allergy2004;59(5):469-78.

3. BeasleyR.TheGlobalBurdenofAsthmaReport,GlobalInitiativeforAsthma(GINA).Availablefromhttp://www.ginasthma.org2004.

4. YanDC,OuLS,TsaiTL,WuWF,HuangJL.Prevalenceandseverityofsymptomsofasthma,rhinitis,andeczemain13-to14-year-oldchildreninTaipei,Taiwan.AnnAllergyAsthmaImmunol2005;95(6):579-85.

5. KoFW,WangHY,WongGW,LeungTF,HuiDS,ChanDP,etal.WheezinginChineseschoolchildren:diseaseseveritydistributionandmanagementpractices,acommunity-basedstudyinHongKongandGuanghou.ClinExpAllergy2005;35(11):1449-56.

6. Carvajal-UruenaI,Garcia-MarcosL,Busquets-MongeR,MoralesSuare-VarelaM,GarciadeAndoinN,Batlles-GarridoJ,etal.[GeographicvariationintheprevalenceofasthmasymptomsinSpanishchildrenandadolescents.InternationalStudyofAsthmaandAllergiesinChildhood(ISAAC)Phase3,Spain].ArchBronconeumol2005;41(12):659-66.

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9. MahapatraP.Social,economicandculturalaspectsofasthma:anexploratorystudyinAndraPradesh,India.Hyderbad,India:InstituteofHealthSystems;1993.

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Pathophysiology













Special Mechanisms



Pathophysiology













Special Mechanisms















Pathophysiology








Special Mechanisms
















Pathophysiology










Uncoupling of airway contraction as a result ofi nflammatorychanges in the airway wall may lead to excessive narrowing of theairways and a loss of the maximum plateau of contraction found innormal ariways when bronchoconstrictor substances are inhaled113.


Sensory nerves may be sensitized by inflammation, leading toexaggerated bronchoconstriction in response to sensory stimuli.

Special Mechanisms



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16DIAGNOSISANDCLASSIFICATION

KEY POINTS: • Aclinicaldiagnosisofasthmaisoftenprompted

bysymptomssuchasepisodicbreathlessness,wheezing,cough,andchesttightness.

• Measurementsoflungfunction(spirometryorpeakexpiratoryflow)provideanassessmentoftheseverityofairflowlimitation,itsreversibility,anditsvariability,andprovideconfirmationofthediagnosisofasthma.

• Measurementsofallergicstatuscanhelptoidentifyriskfactorsthatcauseasthmasymptomsinindividualpatients.

• Extrameasuresmayberequiredtodiagnoseasthmainchildren5yearsandyoungerandintheelderly,andoccupationalasthma.

• Forpatientswithsymptomsconsistentwithasthma,butnormallungfunction,measurementofairwayresponsivenessmayhelpestablishthediagnosis.

• Asthmahasbeenclassifiedbyseverityinpreviousreports.However,asthmaseveritymaychangeovertime,anddependsnotonlyontheseverityoftheunderlyingdiseasebutalsoitsresponsivenesstotreatment.

• Toaidinclinicalmanagement,aclassificationofasthmabylevelofcontrolisrecommended.

• Clinicalcontrolofasthmaisdefinedas:

-No(twiceorless/week)daytimesymptoms-Nolimitationsofdailyactivities,includingexercise-Nonocturnalsymptomsorawakeningbecauseofasthma-No(twiceorless/week)needforrelievertreatment-Normalornear-normallungfunction-Noexacerbations

Acorrectdiagnosisofasthmaisessentialifappropriatedrugtherapyistobegiven.Asthmasymptomsmaybeintermittentandtheirsignificancemaybeoverlookedbypatientsandphysicians,or,becausetheyarenon-specific,theymayresultinmisdiagnosis(forexampleofwheezybronchitis,COPD,orthebreathlessnessofoldage).Thisisparticularlytrueamongchildren,wheremisdiagnosesincludevariousformsofbronchitisorcroup,andleadtoinappropriatetreatment.

Medical History

Symptoms.Aclinicaldiagnosisofasthmaisoftenpromptedbysymptomssuchasepisodicbreathlessness,wheezing,cough,andchesttightness1.Episodicsymptomsafteranincidentalallergenexposure,seasonalvariabilityofsymptomsandapositivefamilyhistoryofasthmaandatopicdiseasearealsohelpfuldiagnosticguides.Asthmaassociatedwithrhinitismayoccurintermittently,withthepatientbeingentirelyasymptomaticbetweenseasonsoritmayinvolveseasonalworseningofasthmasymptomsorabackgroundofpersistentasthma.Thepatternsofthesesymptomsthatstronglysuggestanasthmadiagnosisarevariability;precipitationbynon-specificirritants,suchassmoke,fumes,strongsmells,orexercise;worseningatnight;andrespondingtoappropriateasthmatherapy.UsefulquestionstoconsiderwhenestablishingadiagnosisofasthmaaredescribedinFigure 2-1.

Insomesensitizedindividuals,asthmamaybeexacerbatedbyseasonalincreasesinspecificaeroallergens2.ExamplesincludeAlternaria,andbirch,grass,andragweedpollens.

Cough-variant asthma.Patientswithcough-variantasthma3havechroniccoughastheirprincipal,ifnotonly,symptom.Itisparticularlycommoninchildren,andisoftenmoreproblematicatnight;evaluationsduringthedaycanbenormal.Forthesepatients,documentationofvariabilityinlungfunctionorofairwayhyperresponsiveness,andpossiblyasearchforsputumeosinophils,areparticularlyimportant4.Cough-variantasthmamustbedistinguishedfromso-calledeosinophilicbronchitisinwhichpatientshavecoughandsputumeoinophilsbutnormalindicesoflungfunctionwhenassessedbyspirometryandairwayhyperresponsiveness5.

Otherdiagnosestobeconsideredarecough-inducedbyangiotensin-converting-enzyme(ACE)inhibitors,gastroesophagealreflux,postnasaldrip,chronicsinusitis,andvocalcorddysfunction6.

INTRODUCTION

CLINICAL DIAGNOSIS

Figure 2-1. Questions to Consider in the Diagnosis of Asthma

• Has the patient had an attack or recurrent attacks of wheezing? • Does the patient have a troublesome cough at night? • Does the patient wheeze or cough after exercise? • Does the patient experience wheezing, chest tightness, or

cough after exposure to airborne allergens or pollutants? • Do the patient's colds “go to the chest” or take more than 10

days to clear up?• Are symptoms improved by appropriate asthma treatment?

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Exercise-induced bronchoconstriction.Physicalactivityisanimportantcauseofasthmasymptomsformostasthmapatients,andforsomeitistheonlycause.Exercise-inducedbronchoconstrictiontypicallydevelopswithin5-10minutesaftercompletingexercise(itrarelyoccursduringexercise).Patientsexperiencetypicalasthmasymptoms,orsometimesatroublesomecough,whichresolvespontaneouslywithin30-45minutes.Someformsofexercise,suchasrunning,aremorepotenttriggers7.Exercise-inducedbronchoconstrictionmayoccurinanyclimaticcondition,butitismorecommonwhenthepatientisbreathingdry,coldairandlesscommoninhot,humidclimates8.

Rapidimprovementofpost-exertionsymptomsafterinhaledβ2-agonistuse,ortheirpreventionbypretreatmentwithaninhaledβ2-agonistbeforeexercise,supportsadiagnosisofasthma.Somechildrenwithasthmapresentonlywithexercise-inducedsymptoms.Inthisgroup,orwhenthereisdoubtaboutthediagnosis,exercisetestingishelpful.An8-minuterunningprotocoliseasilyperformedinclinicalpracticeandcanestablishafirmdiagnosisofasthma9.

Physical Examination

Becauseasthmasymptomsarevariable,thephysicalexaminationoftherespiratorysystemmaybenormal.Themostusualabnormalphysicalfindingiswheezingonauscultation,afindingthatconfirmsthepresenceofairflowlimitation.However,insomepeoplewithasthma,wheezingmaybeabsentoronlydetectedwhenthepersonexhalesforcibly,eveninthepresenceofsignificantairflowlimitation.Occasionally,insevereasthmaexacerbations,wheezingmaybeabsentowingtoseverelyreducedairflowandventilation.However,patientsinthisstateusuallyhaveotherphysicalsignsreflectingtheexacerbationanditsseverity,suchascyanosis,drowsiness,difficultyspeaking,tachycardia,hyperinflatedchest,useofaccessorymuscles,andintercostalrecession.

Otherclinicalsignsareonlylikelytobepresentifpatientsareexaminedduringsymptomaticperiods.Featuresofhyperinflationresultfrompatientsbreathingatahigherlungvolumeinordertoincreaseoutwardretractionoftheairwaysandmaintainthepatencyofsmallerairways(whicharenarrowedbyacombinationofairwaysmoothmusclecontraction,edema,andmucushypersecretion).Thecombinationofhyperinflationandairflowlimitationinanasthmaexacerbationmarkedlyincreasestheworkofbreathing.

Tests for Diagnosis and Monitoring

Measurements of lung function.Thediagnosisofasthmaisusuallybasedonthepresenceofcharacteristicsymptoms.However,measurementsoflungfunction,andparticularlythedemonstrationofreversibilityoflungfunctionabnormalities,greatlyenhancediagnosticconfidence.Thisisbecausepatientswithasthmafrequentlyhavepoorrecognitionoftheirsymptomsandpoorperceptionofsymptomseverity,especiallyiftheirasthmaislong-standing10.Assessmentofsymptomssuchasdyspneaandwheezingbyphysiciansmayalsobeinaccurate.Measurementoflungfunctionprovidesanassessmentoftheseverityofairflowlimitation,itsreversibilityanditsvariability,andprovidesconfirmationofthediagnosisofasthma.Althoughmeasurementsoflungfunctiondonotcorrelatestronglywithsymptomsorothermeasuresofdiseasecontrolineitheradults11orchildren12,thesemeasuresprovidecomplementaryinformationaboutdifferentaspectsofasthmacontrol.

Variousmethodsareavailabletoassessairflowlimitation,buttwomethodshavegainedwidespreadacceptanceforuseinpatientsover5yearsofage.Thesearespirometry,particularlythemeasurementofforcedexpiratoryvolumein1second(FEV1)andforcedvitalcapacity(FVC),andpeakexpiratoryflow(PEF)measurement.

PredictedvaluesofFEV1,FVC,andPEFbasedonage,sex,andheighthavebeenobtainedfrompopulationstudies.Thesearebeingcontinuallyrevised,andwiththeexceptionofPEFforwhichtherangeofpredictedvaluesistoowide,theyareusefulforjudgingwhetheragivenvalueisabnormalornot.Ifprecisionisneeded,forexample,intheconductofaclinicaltrial,useofamorerigorousdefinition(lowerlimitofnormal-LLN)shouldbeconsidered.

Thetermsreversibilityand variabilityrefertochangesinsymptomsaccompaniedbychangesinairflowlimitationthatoccurspontaneouslyorinresponsetotreatment.ThetermreversibilityisgenerallyappliedtorapidimprovementsinFEV1(orPEF),measuredwithinminutesafterinhalationofarapid-actingbronchodilator—forexampleafter200-400ugsalbutamol(albuterol)13—ormoresustainedimprovementoverdaysorweeksaftertheintroductionofeffectivecontrollertreatmentsuchasinhaledglucocorticosteroids13.Variabilityreferstoimprovementordeteriorationinsymptomsandlungfunctionoccurringovertime.Variabilitymaybeexperiencedoverthecourseofoneday(whenitiscalleddiurnalvariability),fromdaytoday,frommonthtomonth,orseasonally.Obtainingahistoryofvariabilityisanessentialcomponentofthediagnosisofasthma.Inaddition,variabilityformspartoftheassessmentofasthmacontrol.COPY

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Spirometryistherecommendedmethodofmeasuringairflowlimitationandreversibilitytoestablishadiagnosisofasthma.MeasurementsofFEV1andFVCareundertakenduringaforcedexpiratorymaneuverusingaspirometer.Recommendationsforthestandardizationofspirometryhavebeenpublished13-15.ThedegreeofreversibilityinFEV1whichindicatesadiagnosisofasthmaisgenerallyacceptedas12%and200mlfromthepre-bronchodilatorvalue13.Howevermostasthmapatientswillnotexhibitreversibilityateachassessment,particularlythoseontreatment,andthetestthereforelackssensitivity.Repeatedtestingatdifferentvisitsisadvised.

Spirometryisreproducible,buteffort-dependent.Therefore,properinstructionsonhowtoperformtheforcedexpiratorymaneuvermustbegiventopatients,andthehighestvalueofthreerecordingstaken.Asethnicdifferencesinspirometricvalueshavebeendemonstrated,appropriatepredictiveequationsforFEV1andFVCshouldbeestablishedforeachpatient.Thenormalrangeofvaluesiswiderandpredictedvaluesarelessreliableinyoungpeople(<age20)andintheelderly(>age70).BecausemanylungdiseasesmayresultinreducedFEV1,ausefulassessmentofairflowlimitationistheratioofFEV1toFVC.TheFEV1/FVCratioisnormallygreaterthan0.75to0.80,andpossiblygreaterthan0.90inchildren.Anyvalueslessthanthesesuggestairflowlimitation.

Peak expiratory flowmeasurementsaremadeusingapeakflowmeterandcanbeanimportantaidinbothdiagnosisandmonitoringofasthma.ModernPEFmetersarerelativelyinexpensive,portable,plastic,andidealforpatientstouseinhomesettingsforday-to-dayobjectivemeasurementofairflowlimitation.However,measurementsofPEFarenotinterchangeablewithothermeasurementsoflungfunctionsuchasFEV1ineitheradults16orchildren

17.PEFcanunderestimatethedegreeofairflowlimitation,particularlyasairflowlimitationandgastrappingworsen.BecausevaluesforPEFobtainedwithdifferentpeakflowmetersvaryandtherangeofpredictedvaluesistoowide,PEFmeasurementsshouldpreferablybecomparedtothepatient’sownpreviousbestmeasurements18usinghis/herownpeakflowmeter.Thepreviousbestmeasurementisusuallyobtainedwhenthepatientisasymptomaticoronfulltreatmentandservesasareferencevalueformonitoringtheeffectsofchangesintreatment.

CarefulinstructionisrequiredtoreliablymeasurePEFbecausePEFmeasurementsareeffort-dependent.Mostcommonly,PEFismeasuredfirstthinginthemorningbeforetreatmentistaken,whenvaluesareoftenclosetotheirlowest,andlastthingatnightwhenvaluesareusuallyhigher.OnemethodofdescribingdiurnalPEFvariabilityisastheamplitude(thedifferencebetweenthemaximum

andtheminimumvaluefortheday),expressedasapercentageofthemeandailyPEFvalue,andaveragedover1-2weeks19.AnothermethodofdescribingPEFvariabilityistheminimummorningpre-bronchodilatorPEFover1week,expressedasapercentoftherecentbest(Min%Max)(Figure 2-2)19.ThislattermethodhasbeensuggestedtobethebestPEFindexofairwaylabilityforclinicalpracticebecauseitrequiresonlyaonce-dailyreading,correlatesbetterthananyotherindexwithairwayhyperresponsiveness,andinvolvesasimplecalculation.

PEFmonitoringisvaluableinasubsetofasthmaticpatientsandcanbehelpful:

• Toconfirmthediagnosisofasthma.Althoughspirometryisthepreferredmethodofdocumentingairflowlimitation,a60L/min(or20%ormoreofpre-bronchodilatorPEF)improvementafterinhalationofabronchodilator20,ordiurnalvariationinPEFofmorethan20%(withtwicedailyreadings,morethan10%21)suggestsadiagnosisofasthma.

• Toimprovecontrolofasthma,particularlyinpatientswithpoorperceptionofsymptoms10.Asthmamanagementplanswhichincludeself-monitoringofsymptomsorPEFfortreatmentofexacerbationshavebeenshowntoimproveasthmaoutcomes22.ItiseasiertodiscerntheresponsetotherapyfromaPEFchartthanfromaPEFdiary,providedthesamechartformatisconsistentlyused23.

Weeks of Inhaled Glucocorticosteroid Treatment

PEF L/min

-1 0310/700= 44% 1 2 3 4 5 6 7 8 9 10

Inhaled glucocorticosteroidscommenced

500/710= 70% 620/720= 86%0100200300400500600700800

Weeks of Inhaled Glucocorticosteroid Treatment

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620/720= 86%

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Figure 2-2. Measuring PEF Variability*

*PEF chart of a 27-year-old man with long-standing, poorly controlled asthma, beforeand after the start of inhaled glucocorticosteroid treatment. With treatment, PEFlevels increased, and PEF variability decreased, as seen by the increase in Min%Max(lowest morning PEF/highest PEF %) over 1 week.

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• Toidentifyenvironmental(includingoccupational)causesofasthmasymptoms.ThisinvolvesthepatientmonitoringPEFdailyorseveraltimeseachdayoverperiodsofsuspectedexposuretoriskfactorsinthehomeorworkplace,orduringexerciseorotheractivitiesthatmaycausesymptoms,andduringperiodsofnon-exposure.

Measurement of airway responsiveness.Forpatientswithsymptomsconsistentwithasthma,butnormallungfunction,measurementsofairwayresponsivenesstodirectairwaychallengessuchasinhaledmethacholineandhistamineorindirectairwaychallengessuchasinhaledmannitol60orexercisechallengemayhelpestablishadiagnosisofasthma24.Measurementsofairwayresponsivenessreflectthe“sensitivity”oftheairwaystofactorsthatcancauseasthmasymptoms,sometimescalled“triggers,”andthetestresultsareusuallyexpressedastheprovocativeconcentration(ordose)oftheagonistcausingagivenfall(often20%)inFEV1(Figure 2-3).Thesetestsaresensitiveforadiagnosisofasthma,buthavelimitedspecificity25.Thismeansthatanegativetestcanbeusefultoexcludeadiagnosisofpersistentasthmainapatientwhoisnottakinginhaledglucocorticosteroidtreatment,butapositivetestdoesnotalwaysmeanthatapatienthasasthma26.Thisisbecauseairwayhyperresponsivenesshasbeendescribedinpatientswithallergicrhinitis27andinthosewithairflowlimitationcausedbyconditionsotherthanasthma,suchascysticfibrosis28,bronchiectasis,andchronicobstructivepulmonarydisease(COPD)29.

Non-invasive markers of airway inflammation.Theevaluationofairwayinflammationassociatedwithasthmamaybeundertakenbyexaminingspontaneouslyproducedorhypertonicsaline-inducedsputumforeosinophilicorneutrophilicinflammation30.Inaddition,levelsofexhalednitricoxide(FeNO)31andcarbonmonoxide(FeCO)32havebeensuggestedasnon-invasivemarkersofairwayinflammationinasthma.LevelsofFeNOareelevatedinpeoplewithasthma(whoarenottakinginhaledglucocorticosteroids)comparedtopeoplewithoutasthma,yetthesefindingsarenotspecificforasthma.NeithersputumeosinophilianorFeNOhavebeenevaluatedprospectivelyasanaidinasthmadiagnosis,butthesemeasurementsarebeingevaluatedforpotentialuseindeterminingoptimaltreatment33,34,56,althoughithasbeenshownthattheuseofFeNOasameasureofasthmacontroldoesnotimprovecontrolorenablereductionindoseofinhaledglucocorticosteroid55.

Measurements of allergic status.Becauseofthestrongassociationbetweenasthmaandallergicrhinitis,thepresenceofallergies,allergicdiseases,andallergicrhinitisinparticular,increasestheprobabilityofadiagnosisofasthmainpatientswithrespiratorysymptoms.Moreover,thepresenceofallergiesinasthmapatients(identifiedbyskintestingormeasurementofspecificIgEinserum)canhelptoidentifyriskfactorsthatcauseasthmasymptomsinindividualpatients.Deliberateprovocationoftheairwayswithasuspectedallergenorsensitizingagentmaybehelpfulintheoccupationalsetting,butisnotroutinelyrecommended,becauseitisrarelyusefulinestablishingadiagnosis,requiresconsiderableexpertiseandcanresultinlife-threateningbronchospasm35.Skintestswithallergensrepresenttheprimarydiagnostictoolindeterminingallergicstatus.Theyaresimpleandrapidtoperform,andhavealowcostandhighsensitivity.However,whenimproperlyperformed,skintestscanleadtofalselypositiveornegativeresults.MeasurementofspecificIgEinserumdoesnotsurpassthereliabilityofresultsfromskintestsandismoreexpensive.Themainlimitationofmethodstoassessallergicstatusisthatapositivetestdoesnotnecessarilymeanthatthediseaseisallergicinnatureorthatitiscausingasthma,assomeindividualshavespecificIgEantibodieswithoutanysymptomsanditmaynotbecausallyinvolved.Therelevantexposureanditsrelationtosymptomsmustbeconfirmedbypatienthistory.MeasurementoftotalIgEinserumhasnovalueasadiagnostictestforatopy.

Figure 2-3. Measuring Airway Responsiveness*

*Airway responsiveness to inhaled methacholine or histamine in a normal subject, andin asthmatics with mild, moderate, and severe airway hyperresponsiveness.Asthmatics have an increased sensitivity and an increased maximal broncho- constric-tor response to the agonist. The response to the agonist is usually expressed as theprovocative concentration causing a 20% decline in FEV1 (PC20).

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Thedifferentialdiagnosisinpatientswithsuspectedasthmadiffersamongdifferentagegroups:infants,children,youngadults,andtheelderly.

Children 5 years and Younger

Thediagnosisofasthmainearlychildhoodischallengingandhastobebasedlargelyonclinicaljudgmentandanassessmentofsymptomsandphysicalfindings.Sincetheuseofthelabel“asthma”forwheezinginchildrenhasimportantclinicalconsequences,itmustbedistinguishedfromothercausespersistentandrecurrentwheeze.

Episodicwheezingandcoughisverycommoneveninchildrenwhodonothaveasthmaandparticularlyinthoseunderage336.Threecategoriesofwheezinghavebeendescribedinchildren5yearsandyounger:

• Transientearlywheezing,whichisoftenoutgrowninthefirst3years.Thisisoftenassociatedwithprematurityandparentalsmoking.

• Persistentearly-onsetwheezing(beforeage3).Thesechildrentypicallyhaverecurrentepisodesofwheezingassociatedwithacuteviralrespiratoryinfections,havenoevidenceofatopy37and,unlikechildreninthenextcategoryoflateonsetwheezing/asthma,havenofamilyhistoryofatopy.Thesymptomsnormallypersistthroughschoolageandarestillpresentatage12inalargeproportionofchildren.Thecauseoftheepisodeisusuallytherespiratorysyncytialvirusinchildrenyoungerthanage2,whileothervirusespredominateinolderpreschoolchildren.

• Late-onsetwheezing/asthma.Thesechildrenhaveasthmawhichoftenpersiststhroughoutchildhoodandintoadultlife38,39.Theytypicallyhaveanatopicbackground,oftenwitheczema,andairwaypathologyischaracteristicofasthma.

Thefollowingcategoriesofsymptomsarehighlysuggestiveofadiagnosisofasthma:frequentepisodesofwheeze(morethanonceamonth),activity-inducedcoughorwheeze,nocturnalcoughinperiodswithoutviralinfections,absenceofseasonalvariationinwheeze,andsymptomsthatpersistafterage3.Asimpleclinicalindexbasedonthepresenceofawheezebeforetheageof3,andthepresenceofonemajorriskfactor(parentalhistoryofasthmaoreczema)ortwoofthreeminorriskfactors

(eosinophilia,wheezingwithoutcolds,andallergicrhinitis)hasbeenshowntopredictthepresenceofasthmainlaterchildhood38.However,treatingchildrenatriskwithinhaledglucocorticosteroidshasnotbeenshowntoaffectthedevelopmentofasthma40.Alternativecausesofrecurrentwheezingmustbeconsideredandexcluded.Theseinclude:

• Chronicrhino-sinusitis• Gastroesophagealreflux• Recurrentvirallowerrespiratorytractinfections• Cysticfibrosis• Bronchopulmonarydysplasia• Tuberculosis• Congenitalmalformationcausingnarrowingofthe• intrathoracicairways• Foreignbodyaspiration• Primaryciliarydyskinesiasyndrome• Immunedeficiency• Congenitalheartdisease

Neonatalonsetofsymptoms(associatedwithfailuretothrive),vomiting-associatedsymptoms,orfocallungorcardiovascularsignssuggestanalternativediagnosisandindicatetheneedforfurtherinvestigations.

Ausefulmethodforconfirmingthediagnosisofasthmainchildren5yearsandyoungerisatrialoftreatmentwithshort-actingbronchodilatorsandinhaledglucocorticosteroids.Markedclinicalimprovementduringthetreatmentanddeteriorationwhentreatmentisstoppedsupportsadiagnosisofasthma.Useofspirometryandothermeasuresrecommendedforolderchildrenandadultssuchasairwayresponsivenessandmarkersofairwayinflammationisdifficultandseveralrequirecomplexequipment41makingthemunsuitableforroutineuse.However,children4to5yearsoldcanbetaughttouseaPEFmeter,buttoensurereliabilityparentalsupervisionisrequired42.

Older Children and Adults

Acarefulhistoryandphysicalexamination,togetherwiththedemonstrationofreversibleandvariableairflowobstruction(preferablybyspirometry),willinmostinstancesconfirmthediagnosis.Thefollowingcategoriesofalternativediagnosesneedtobeconsidered:

• Hyperventilationsyndromeandpanicattacks• Upperairwayobstructionandinhaledforeignbodies43• Vocalcorddysfunction44• Otherformsofobstructivelungdisease,particularly

COPD

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• Non-obstructiveformsoflungdisease(e.g.,diffuseparenchymallungdisease)

• Non-respiratorycausesofsymptoms(e.g.,leftventricularfailure)

Becauseasthmaisacommondisease,itcanbefoundinassociationwithanyoftheabovediagnoses,whichcomplicatesthediagnosisaswellastheassessmentofseverityandcontrol.Thisisparticularlytruewhenasthmaisassociatedwithhyperventilation,vocalcorddysfunction,orCOPD.Carefulassessmentandtreatmentofboththeasthmaandthecomorbidityisoftennecessarytoestablishthecontributionofeachtoapatient’ssymptoms.

The Elderly

Undiagnosedasthmaisafrequentcauseoftreatablerespiratorysymptomsintheelderly,andthefrequentpresenceofcomorbiddiseasescomplicatesthediagnosis.Wheezing,breathlessness,andcoughcausedbyleftventricularfailureissometimeslabeled“cardiacasthma,”amisleadingterm,theuseofwhichisdiscouraged.Thepresenceofincreasedsymptomswithexerciseandatnightmayaddtothediagnosticconfusionbecausethesesymptomsareconsistentwitheitherasthmaorleftventricularfailure.Useofbeta-blockers,eventopically(forglaucoma)iscommoninthisagegroup.Acarefulhistoryandphysicalexamination,combinedwithanECGandchestX-ray,usuallyclarifiesthepicture.Intheelderly,distinguishingasthmafromCOPDisparticularlydifficult,andmayrequireatrialoftreatmentwithbronchodilatorsand/ororal/inhaledglucocorticosteroids.

Asthmatreatmentandassessmentandattainmentofcontrolintheelderlyarecomplicatedbyseveralfactors:poorperceptionofsymptoms,acceptanceofdyspneaasbeing“normal”inoldage,andreducedexpectationsofmobilityandactivity.

Occupational Asthma

Asthmaacquiredintheworkplaceisadiagnosisthatisfrequentlymissed.Becauseofitsinsidiousonset,occupationalasthmaisoftenmisdiagnosedaschronicbronchitisorCOPDandisthereforeeithernottreatedatallortreatedinappropriately.Thedevelopmentofnewsymptomsofrhinitis,cough,and/orwheezeparticularlyinnon-smokersshouldraisesuspicion.Detectionofasthmaofoccupationaloriginrequiresasystematicinquiryaboutworkhistoryandexposures.Thediagnosisrequiresadefinedhistoryofoccupationalexposuretoknownorsuspectedsensitizingagents;anabsenceofasthmasymptomsbeforebeginningemployment;oradefiniteworseningofasthmaafteremployment.Arelationship

betweensymptomsandtheworkplace(improvementinsymptomsawayfromworkandworseningofsymptomsonreturningtowork)canbehelpfulinestablishingalinkbetweensuspectedsensitizingagentsandasthma45.

Sincethemanagementofoccupationalasthmafrequentlyrequiresthepatienttochangehisorherjob,thediagnosiscarriesconsiderablesocioeconomicimplicationsanditisimportanttoconfirmthediagnosisobjectively.Thismaybeachievedbyspecificbronchialprovocationtesting46,althoughtherearefewcenterswiththenecessaryfacilitiesforspecificinhalationtesting.AnothermethodistomonitorPEFatleast4timesadayforaperiodof2weekswhenthepatientisworkingandforasimilarperiodawayfromwork47-50.Theincreasingrecognitionthatoccupationalasthmacanpersist,orcontinuetodeteriorate,evenintheabsenceofcontinuedexposuretotheoffendingagent51,emphasizestheneedforanearlydiagnosissothatappropriatestrictavoidanceoffurtherexposureandpharmacologicinterventionmaybeapplied.Recentpublicationsprovideanevidence-basedapproachtotheidentificationofoccupationalasthmaandcomparespecificinhalationchallengetestingwithalternativetestsforconfirmingtheresponsibleagents52,61.

Distinguishing Asthma from COPD

BothasthmaandCOPDaremajorchronicobstructiveairwaysdiseasesthatinvolveunderlyingairwayinflammation.COPDischaracterizedbyairflowlimitationthatisnotfullyreversible,isusuallyprogressive,andisassociatedwithanabnormalinflammatoryresponseofthelungstonoxiousparticlesorgases.Individualswithasthmawhoareexposedtonoxiousagents(particularlycigarettesmoking)maydevelopfixedairflowlimitationandamixtureof“asthma-like”inflammationand“COPD-like”inflammation.Thus,eventhoughasthmacanusuallybedistinguishedfromCOPD,insomeindividualswhodevelopchronicrespiratorysymptomsandfixedairflowlimitation,itmaybedifficulttodifferentiatethetwodiseases.Asymptom-basedquestionnairefordifferentiatingCOPDandasthmaforusebyprimaryhealthcareprofessionalsisavailable53,54.

Etiology

Manyattemptshavebeenmadetoclassifyasthmaaccordingtoetiology,particularlywithregardtoenvironmentalsensitizingagents.However,suchaclassificationislimitedbytheexistenceofpatientsinwhomnoenvironmentalcausecanbeidentified.Despitethis,

CLASSIFICATION OF ASTHMA

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anefforttoidentifyanenvironmentalcauseforasthma(forexample,occupationalasthma)shouldbepartoftheinitialassessmenttoenabletheuseofavoidancestrategiesinasthmamanagement.Describingpatientsashavingallergicasthmaisusuallyoflittlebenefitinguidingtreatment,unlessasinglespecifictriggeragentcanbeidentified.Phenotype

Thereisincreasingawarenessofheterogeneityinthemanifestationsofasthmaandinitsresponsetotreatment.Thisisoftendescribedintermsof‘phenotypes’57,58,thecharacteristicswhichresultfromtheinteractionbetweenapatient’sgeneticmakeupandtheirenvironment.Severaldifferentclinicalphenotypesarerecognizedonthebasisofclusteranalysisofclinicalandotherfeaturesofasthma,e.g.aspirin-inducedasthma,exacerbation-proneasthmaandthesearchfordistinctivepathologicalormolecularfeatureswhichcouldexplaintheseclinicalpatternscontinues.Mostworkhasbeendoneoninflammatoryphenotypes,identifiedusingsputuminduction.Patientswitheosinophilicandnon-eosinophilicphenotypeshavebeenshowntodifferintheirclinicalresponsetoinhaledglucocorticosteroids59,60,andatagrouplevel,inflammatory

markersmaybepredictiveofriskofexacerbationafterglucocorticosteroidreduction61.Inflammatoryphenotypesappeartobemoderatelystableovertime,althoughdataarelimited62,63.Atpresent,sincefewclinicianshaveaccesstoqualifiedsputumlaboratories,identificationoftheinflammatoryphenotypeismostlikelytobeusefulforpatientswithsevereasthmaorinthecontextofresearch.

Asthma Control

Asthmacontrolmaybedefinedinavarietyofways.Inlayterms,controlmayindicatediseaseprevention,orevencure.However,inasthma,whereneitherofthesearerealisticoptionsatpresent,itreferstocontrolofthemanifestationsofdisease.Theaimoftreatmentshouldbetoachieveandmaintaincontrolforprolongedperiods64withdueregardtothesafetyoftreatment,potentialforadverseeffects,andthecostoftreatmentrequiredtoachievethisgoal.Therefore,theassessmentofasthmacontrolshouldincludenotonlycontroloftheclinicalmanifestations(symptoms,nightwaking,relieveruse,activitylimitation,lungfunction),butalsocontroloftheexpectedfuturerisktothepatientsuchasexacerbations,accelerateddeclineinlungfunction,andside-effectsoftreatment.Ingeneral,theachievementofgoodclinicalcontrolofasthmaleads

Figure 2-4. LEVELS OF ASTHMA CONTROL

A. Assessment of current clinical control (preferably over 4 weeks)

Characteristic Controlled (All of the following)

Partly Controlled(Any measure present)

Uncontrolled

Daytime symptoms None(twiceorless/week)

Morethantwice/week Threeormorefeaturesofpartlycontrolledasthma*†

Limitation of activities None Any

Nocturnal symptoms/awakening

None Any

Need for reliever/ rescue treatment

None(twiceorless/week)

Morethantwice/week

Lung function (PEF or FEV1)‡

Normal <80%predictedorpersonalbest(ifknown)

B. Assessment of Future Risk (riskofexacerbations,instability,rapiddeclineinlungfunction,side-effects)

Featuresthatareassociatedwithincreasedriskofadverseeventsinthefutureinclude:Poorclinicalcontrol,frequentexacerbationsinpastyear*,everadmissiontocriticalcareforasthma,lowFEV1,exposuretocigarettesmoke,highdosemedications*Anyexacerbationshouldpromptreviewofmaintenancetreatmenttoensurethatitisadequate† By definition, an exacerbation in any week makes that an uncontrolled asthma week‡ Without administration of bronchodilator,lungfunctionisnotareliabletestforchildren5yearsandyounger

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toreducedriskofexacerbations65.However,certainpatientsmaycontinuetoexperienceexacerbationsinspiteofadequateintervalcontrol.Smokersarelesslikelytoachievecontrolandremainatriskofexacerbations66.Itshouldbenotedthatinhaledglucocorticosteroidsbothimproveclinicalcontrolandreducefuturerisk,butsomepharmacologicalagentsaremoreeffectiveinimprovingfeaturesofclinicalcontrol,whileothersarerelativelymoreeffectiveatreducingexacerbations.Thus,forsomepatientphenotypes,treatmentmaybeselectedtoaddressthepredominantproblem.

Figure 2-4describestheclinicalcharacteristicsofControlled,PartlyControlledandUncontrolledasthma.Thisisaworkingschemebasedoncurrentopinionandhasnotbeenformallyvalidated.However,thisclassificationhasbeenshowntocorrelatewellwiththeAsthmaControlTest67andwithassessmentofasthmacontrolaccordingtotheUSNationalExpertPanelReport3guidelines68,69.Inclinicalpractice,thisclassificationshouldbeusedinconjunctionwithanassessmentofthepatient’sclinicalconditionandthepotentialrisksandbenefitsofchangingtreatment.Severalstandardizedmeasuresforassessingclinicalcontrolofasthmahavebeendeveloped,whichscorethegoalsoftreatmentascontinuousvariablesandprovidenumericalvaluestodistinguishdifferentlevelsofcontrol.ExamplesofvalidatedinstrumentsaretheAsthmaControlQuestionnaire(ACQ)(www.qoltech.co.uk/Asthma1.htm)70,theAsthmaControlTest(ACT)(www.asthmacontrol.com)71,theChildhoodAsthmaControlTest(C-ACT)72,theAsthmaTherapyAssessmentQuestionnaire(ATAQ)(www.ataqinstrument.com)73,andtheAsthmaControlScoringSystem74.Fewoftheseinstrumentsincludeameasureoflungfunction.Theyarebeingpromotedforusenotonlyinresearchbutforpatientcareaswell,evenintheprimarycaresetting.Somearesuitableforself-assessmentofasthmacontrolbypatients75,andsomeareavailableinmanylanguages,ontheInternet,andinpaperformandmaybecompletedbypatientspriorto,orduring,consultationswiththeirhealthcareprovider.Theyhavethepotentialtoimprovetheassessmentofasthmacontrol,providingareproducibleobjectivemeasurethatmaybechartedovertime(weekbyweekormonthbymonth)andrepresentinganimprovementincommunicationbetweenpatientandhealthcareprofessional.Theirvalueinclinicaluse,asdis¬tinctfromresearchsettings,hasyettobedemonstratedbutwilllikelybecomeevidentincomingyears.Allofthesetoolsaresubjecttocopyrightrestrictions,andsomehavefeesassociatedwiththeiruseinresearch.

Thereisconsiderableinterestincontrollingnotonlytheclinicalmanifestationsofasthma,butalsotheinflammatoryandpatho-physiologicalfeaturesofthedisease.There

isevidencethatreducinginflammationwithcontrollertherapyachievesgoodclinicalcontrolandreducestheriskofexacerbations.Inaddition,inflammatoryandpatho-physiologicalmarkersmaybepredictorsoffutureriskofexacerbationsanddeclineinlungfunction,independentofthepatient’slevelofclinicalcontrol66,76.Biomarker-guidedtreatmentappears,primarily,tobeofvalueinasthmaphenotypesinwhichthereisdissociationbetweenmeasuresofclinicalcontrolandairwayinflammation.Forexample,treatmentbasedontheproportionofeosinophilsinsputumhasresultedinareductionofexacerbationsorminimizationofdosesofinhaledglucocorticosteroidsinpatientswithuncontrolledasthmainspiteofmoderatelevelsoftreatment77,78.

However,inprimarycare,becauseofthecostand/orunavailabilityoftestssuchasendobronchialbiopsyandmeasurementofsputumeosinophilsandexhalednitricoxide30-34,thecurrentrecommendationisthattreatmentshouldbeaimedatcontrollingtheclinicalfeaturesofdisease,includinglungfunctionabnormalities.

Asthma Severity

Forpatientsnotreceivinginhaledglucocorticosteroidtreatment,previousGINAdocumentssubdividedasthmabyseveritybasedonthelevelofsymptoms,airflowlimitation,andlungfunctionvariabilityintofourcategories:Intermittent,MildPersistent,ModeratePersistent,orSeverePersistent,althoughthisclassificationwasoftenerroneouslyappliedtopatientsalreadyontreatment79.Acopyofthisclassificationsystemisarchivedatwww.ginasthma.com.Itisimportanttorecognize,however,thatasthmaseverityinvolvesboththeseverityoftheunderlyingdiseaseanditsresponsivenesstotreatment80.Thus,asthmacouldpresentwithseveresymptomsandairflowobstruction,butbecomecompletelycontrolledwithlow-dosetreatment.Inaddition,severityisnotastaticfeatureofanindividualpatient’sasthma,butmaychangeovermonthsoryears.Themainlimitationofthispreviousmethodofclassificationofasthmaseveritywasitspoorvalueinpredictingwhattreatmentwouldberequiredandwhatapatient’sresponsetothattreatmentmightbe.Forthisreason,anassessmentofasthmacontrolatinitialpresentationandperiodicallyduringtreatmentismorerelevantanduseful81.

Inviewoftheselimitations,asthmaseverityisnowbyconsensusclassifiedonthebasisoftheintensityoftreatmentrequiredtoachievegoodasthmacontrol79,80.Mildasthmaisasthmathatcanbewell-controlledwithlowintensitytreatmentsuchaslow-doseinhaledglucocorticosteroids,leukotrienemodifiersorcromones.SevereasthmaisasthmathatrequireshighintensityCOPY

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treatment,e.g.GINAStep4,tomaintaingoodcontrol,orwheregoodcontrolisnotachieveddespitehighintensitytreatment82.Itisrecognizedthatdifferentasthmaphenotypesmayhavedifferentlevelsofresponsivenesstoconventionaltreatment.Asphenotype-specifictreatmentbecomesavailable,asthmawhichwaspreviouslyconsideredtobeseverecouldbecomemild.

Terminologyaroundasthmaseverityisconfusingbecause“severity”isalsousedtodescribethemagnitudeofairwayobstructionortheintensityofsymptoms.Patientswilloftenperceivetheirasthmaassevereiftheyhaveintenseorfrequentsymptoms,butitisimportanttoconveythatthismaymerelyrepresentinadequatetreatment.Becausetheterms“control”and“severity”areusedinothercontextsinlaylanguage,itisimportantthathealthprofessionalscommunicateclearlyhowthewordsareusedinthecontextofasthma.

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54. TinkelmanDG,PriceDB,NordykeRJ,HalbertRJ,IsonakaS,NonikovD,etal.Symptom-basedquestionnairefordifferentiatingCOPDandasthma.Respiration2006;73(3):296-305.

55. SzeflerSJ,MitchellH,SorknessCA,GergenPJ,O’ConnorGT,MorganWJ,etal.Managementofasthmabasedonexhalednitricoxideinadditiontoguideline-basedtreatmentforinner-cityadolescentsandyoungadults:arandomisedcontrolledtrial.Lancet.2008Sep20;372(9643):1065-72.

56. ShawDE,BerryMA,ThomasM,GreenRH,BrightlingCE,WardlawAJ,PavordID.Theuseofexhalednitricoxidetoguideasthmamanagement:arandomizedcontrolledtrial.AmJRespirCritCareMed2007;176:231-7.

57. BelEH.Clinicalphenotypesofasthma.CurrOpinPulmMed2004;10:44-50.

58. WenelSE.Asthma:definingofthepersistentadultphenotypes.Lancet2006;368:804-13.

59. BerryM,MorganA,ShawDE,ParkerD,GreenR,BrightlingC,BraddingP,WardlawAJ,PavordID.Pathologicalfeaturesandinhaledcorticosteroidresponseofeosinophilicandnon-eosinophilicasthma.Thorax2007;62:1043-9.

60. PavordID,BrightlingCE,WoltmannG,WardlawAJ.Non-eosinophiliccorticosteroidunresponsiveasthma.Lancet1999;353:2213-4.

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63. vanVeenIH,TenBrinkeA,GauwSA,SterkPJ,RabeKF,BelEH.Consistencyofsputumeosinophiliaindifficult-to-treatasthma:a5-yearfollow-upstudy.JAllergyClinImmunol2009;124:615-7,617e1-2.

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66. OsborneML,PedulaKL,O’HollarenM,EttingerKM,StiboltT,BuistAS,VollmerWM.Assessingfutureneedforacutecareinadultasthmatics:theProfileofAsthmaRiskStudy:aprospectivehealthmaintenanceorganization-basedstudy.Chest2007;132:1151-61.

67. ThomasM,KayS,PikeJ,WilliamsA,RosenweigJR,HillyerEV,PriceD.TheAsthmaControlTest(ACT)asapredictorofGINAguideline-definedasthmacontrol:analysisofamultinationalcross-sectionalsurvey.PrimCareRespirJ2009;18:41-9.

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72. LiuAH,ZeigerR,SorknessC,MahrT,OstromN,BurgessS,RosenweigJC,ManjunathR.Developmentandcross-sectionalvalidationoftheChildhoodAsthmaControlTest.JAllergyClinImmunol2007;119:817-25.COPY

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74. BouletLP,BouletV,MilotJ.Howshouldwequantifyasthmacontrol?Aproposal.Chest2002;122:2217-23.

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77. HaldarP,PavordID,ShawDE,BerryMA,ThomasM,BrightlingCE,WardlawAJ,GreenRH.Clusteranalysisandclinicalasthmaphenotypes.AmJRespirCritCareMed2008;178:218-24.

78. JayaramL,PizichiniMM,CookRJ,BouletLP,LemiereC,PizichiniE,CartierA,HussackP,GoldsmithCH,LavioletteM,ParameswaranK,HargreaveFE.Determiningasthmatreatmentbymonitoringsputumcellcounts:effectonexacerbations.EurRespirJ2006;27:483-94.

79. TaylorDR,BatemanED,BouletLP,BousheyHA,BusseWW,CasaleTB,ChaneP,EnrightPL,GibsonPG,deJongsteJC,KerstjensHA,LaarusSC,LevyML,O’ByrnePM,PartridgeMR,PavordID,SearsMR,SterkPJ,StoloffSW,SzeflerSJ,SullivanSD,ThomasMD,WenelSE,ReddelHK.Anewperspectiveonconceptsofasthmaseverityandcontrol.EurRespirJ2008;32:545-54.

80. CockcroftDW,SwystunVA.Asthmacontrolversusasthmaseverity.JAllergyClinImmunol1996;98:1016-8.

81. ChenH,GouldMK,BlancPD,MillerDP,KamathTV,LeeJH,SullivanSD.Asthmacontrol,severity,andqualityoflife:quantifyingtheeffectofuncontrolleddisease.JAllergyClinImmunol2007;120:396-402.

82. ProceedingsoftheATSworkshoponrefractoryasthma:currentunderstanding,recommendations,andunansweredquestions.AmericanThoracicSociety.AmJRespirCritCareMed2000;162:2341-51.

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KEY POINTS:

• Medicationstotreatasthmacanbeclassifiedascontrollersorrelievers.Controllersaremedicationstakendailyonalong-termbasistokeepasthmaunderclinicalcontrolchieflythroughtheiranti-inflammatoryeffects.Relieversaremedicationsusedonanas-neededbasisthatactquicklytoreversebronchoconstrictionandrelieveitssymptoms.

• Asthmatreatmentcanbeadministeredindifferentways—inhaled,orally,orbyinjection.Themajoradvantageofinhaledtherapyisthatdrugsaredelivereddirectlyintotheairways,producinghigherlocalconcentrationswithsignificantlylessriskofsystemicsideeffects.

• Inhaledglucocorticosteroidsarethemosteffectivecontrollermedicationscurrentlyavailable.

• Rapid-actinginhaledβ2-agonistsarethemedicationsofchoiceforreliefofbronchoconstrictionandforthepretreatmentofexercise-inducedbronchoconstriction,inbothadultsandchildrenofallages.

• Increaseduse,especiallydailyuse,ofrelievermedicationisawarningofdeteriorationofasthmacontrolandindicatestheneedtoreassesstreatment.

Thegoalofasthmatreatmentistoachieveandmaintainclinicalcontrol.Medicationstotreatasthmacanbeclassifiedascontrollersorrelievers.Controllersaremedicationstakendailyonalong-termbasistokeepasthmaunderclinicalcontrolchieflythroughtheiranti-inflammatoryeffects.Theyincludeinhaledandsystemicglucocorticosteroids,leukotrienemodifiers,long-actinginhaledβ2-agonistsincombinationwithinhaledglucocorticosteroids,sustained-releasetheophylline,cromones,andanti-IgE.Inhaledglucocorticosteroidsarethemosteffectivecontrollermedicationscurrentlyavailable.Relieversaremedicationsusedonanas-neededbasisthatactquicklytoreversebronchoconstrictionandrelieveitssymptoms.Theyincluderapid-actinginhaledβ2-agonists,inhaledanticholinergics,short-actingtheophylline,andshort-actingoralβ2-agonists.

Route of Administration

Asthmatreatmentforadultscanbeadministeredindifferentways—inhaled,orallyorparenterally(bysubcutaneous,intramuscular,orintravenousinjection).Themajoradvantageofinhaledtherapyisthatdrugsaredelivereddirectlyintotheairways,producinghigherlocalconcentrationswithsignificantlylessriskofsystemicsideeffects.

Inhaledmedicationsforasthmaareavailableaspressuriedmetered-doseinhalers(MDIs),breath-actuatedMDIs,drypowderinhalers(DPIs),softmistinhalers,andnebuliedor“wet”aerosols*.Inhalerdevicesdifferintheirefficiencyofdrugdeliverytothelowerrespiratorytract,dependingontheformofthedevice,formulationofmedication,particlesize,velocityoftheaerosolcloudorplume(whereapplicable),andeasewithwhichthedevicecanbeusedbythemajorityofpatients.Individualpatientpreference,convenience,andeaseofusemayinfluencenotonlytheefficiencyofdrugdeliverybutalsopatientadherencetotreatmentandlong-termcontrol.

PressurizedMDIs(pMDIs)requiretrainingandskilltocoordinateactivationoftheinhalerandinhalation.Medicationsinthesedevicescanbedispensedasasuspensioninchlorofluorocarbons(CFCs)orasasolutioninhydrofluoroalkanes(HFAs).ForapMDIcontainingCFCs,theuseofaspacer(holdingchamber)improvesdrugdelivery,increaseslungdeposition,andmayreducelocalandsystemicsideeffects1.However,CFCinhalerdevicesarebeingphasedoutduetotheimpactofCFCsupontheatmosphericozonelayer,andarebeingreplacedbyHFAdevices.ForpMDIscontainingbronchodilators,theswitchfromCFCtoHFAinhalersdoesnotresultinachangeinefficacyatthesamenominaldose2.However,forsomeglucocorticosteroids,theHFAformulationsprovideanaerosolofsmallerparticlesizethatresultsinlessoraldeposition(withassociatedreductioninoralsideeffects),andcorrespondinglygreaterlungdeposition3-5.Cliniciansareadvisedtoconsultthepackageinsertsofeachproducttoconfirmtherecommendeddoseequivalenttocurrentlyuseddrugs.SomeofthesecomparisonsareprovidedinFigure 3-1.

INTRODUCTION

ASTHMA MEDICATIONS: ADULTS

*InformationonvariousinhalerdevicesavailablecanbefoundontheGINAWebsite(http6//www.ginasthma.org).

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PressurizedMDIsmaybeusedbypatientswithasthmaofanyseverity,includingduringexacerbations.Breath-actuatedaerosolsmaybehelpfulforpatientswhohavedifficultyusingthe“pressandbreathe”pressurizedMDI6.Softmistinhalersappeartorequirelesscoordination.Drypowderinhalersaregenerallyeasiertouse,buttheyrequireaminimalinspiratoryflowrateandmayprovedifficultforsomepatients.DPIsdifferwithrespecttothefractionofex-actuatordosedeliveredtothelung.Forsomedrugs,thedosemayneedtobeadjustedwhenswitchingfromanMDItoaDPI7.Nebulizedaerosolsarerarelyindicatedforthetreatmentofchronicasthmainadults8.

Inhaled glucocorticosteroids*

Roleintherapy-Inhaledglucocorticosteroidsarecurrentlythemosteffectiveanti-inflammatorymedicationsforthetreatmentofpersistentasthma.Studieshavedemonstratedtheirefficacyinreducingasthmasymptoms9,improvingqualityoflife9,improvinglungfunction9,decreasingairwayhyperresponsiveness10,controllingairwayinflammation11,reducingfrequencyandseverityofexacerbations12,andreducingasthmamortality13.However,theydonotcureasthma,andwhentheyarediscontinueddeterioration

ofclinicalcontrolfollowswithinweekstomonthsinaproportionofpatients14,15.

Inhaledglucocorticosteroidsdifferinpotencyandbioavailability,butbecauseofrelativelyflatdose-responserelationshipsinasthmarelativelyfewstudieshavebeenabletoconfirmtheclinicalrelevanceofthesedifferences191.Figure 3-1listsapproximatelyequipotentdosesofdifferentinhaledglucocorticosteroidsbasedupontheavailableefficacyliterature,butthecategoriationintodosagecategoriesdoesnotimplythatcleardose-responserelationshipshavebeendemonstratedforeachdrug.Theefficacyofsomeproductsvarieswhenadministeredviadifferentinhalerdevices16.Mostofthebenefitfrominhaledglucocorticosteroidsisachievedinadultsatrelativelylowdoses,equivalentto400ugofbudesonideperday17.Increasingtohigherdosesprovideslittlefurtherbenefitintermsofasthmacontrolbutincreasestheriskofsideeffects17,18.However,thereismarkedindividualvariabilityofresponsivenesstoinhaledglucocorticosteroidsandbecauseofthisandtherecognizedpooradherencetotreatmentwithinhaledglucocorticosteroids,manypatientswillrequirehigherdosestoachievefulltherapeuticbenefit.Astobaccosmokingreducestheresponsivenesstoinhaledglucocorticosteroids,higherdosesmayberequiredinpatientswhosmoke.

CONTROLLER MEDICATIONS

Figure 3-1. Estimated Equipotent Daily Doses of Inhaled Glucocorticosteroids for Adults†

Drug Low Daily Dose (�g) Medium Daily Dose (�g) High Daily Dose (�g)‡

Beclomethasone dipropionate 200 - 500 >500 - 1000 >1000 - 2000Budesonide* 200 - 400 >400 - 800 >800 - 1600Ciclesonide* 80 - 160 >160 - 320 >320 - 1280Flunisolide 500 - 1000 >1000 - 2000 >2000Fluticasone propionate 100 - 250 >250 - 500 >500 - 1000Mometasone furoate* 200 - 400 >400 - 800 >800 - 1200Triamcinolone acetonide 400 - 1000 >1000 - 2000 >2000

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

Notes• The most important determinant of appropriate dosing is the clinician’s judgment of the patient’s response to therapy. The clinician must monitor the patient’s

response in terms of clinical control and adjust the dose accordingly. Once control of asthma is achieved, the dose of medication should be carefully titrated tothe minimum dose required to maintain control, thus reducing the potential for adverse effects.

• Designation of low, medium, and high doses is provided from manufacturers’ recommendations where possible. Clear demonstration of dose-responserelationships is seldom provided or available. The principle is therefore to establish the minimum effective controlling dose in each patient, as higher dosesmay not be more effective and are likely to be associated with greater potential for adverse effects.

• As CFC preparations are taken from the market, medication inserts for HFA preparations should be carefully reviewed by the clinician for the equivalentcorrect dosage.

*In this section recommendations for doses of inhaled glucocorticosteroids are given as “�/day budesonide orequivalent,” because a majority of the clinical literature on these medications uses this standard.

200 ≥400

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Toreachclinicalcontrol,add-ontherapywithanotherclassofcontrollerispreferredoverincreasingthedoseofinhaledglucocorticosteroids211.Thereis,however,aclearrelationshipbetweenthedoseofinhaledglucocorticosteroidsandthepreventionofsevereacuteexacerbationsofasthma12,althoughthereappeartobedifferencesinresponseaccordingtosymptom/inflammationphenotype212.Therefore,somepatientswithsevereasthmamaybenefitfromlong-termtreatmentwithhigherdosesofinhaledglucocorticosteroids.Sideeffects:Localadverseeffectsfrominhaledglucocorticosteroidsincludeoropharyngealcandidiasis,dysphonia,andoccasionallycoughingfromupperairwayirritation.ForpressurizedMDIstheprevalenceoftheseeffectsmaybereducedbyusingcertainspacerdevices1.Mouthwashing(rinsingwithwater,gargling,andspittingout)afterinhalationmayreduceoralcandidiasis.Theuseofprodrugsthatareactivatedinthelungsbutnotinthepharynx(e.g.,ciclesonide19andbeclometasone),andnewformulationsanddevicesthatreduceoropharyngealdeposition,mayminimizesucheffectswithouttheneedforaspacerormouthwashing.

Inhaledglucocorticosteroidsareabsorbedfromthelung,accountingforsomedegreeofsystemicbioavailability.Theriskofsystemicadverseeffectsfromaninhaledglucocorticosteroiddependsuponitsdoseandpotency,thedeliverysystem,systemicbioavailability,first-passmetabolism(conversiontoinactivemetabolites)intheliver,andhalf-lifeofthefractionofsystemicallyabsorbeddrug(fromthelungandpossiblygut)20.Therefore,thesystemiceffectsdifferamongthevariousinhaledglucocorticosteroids.Severalcomparativestudieshavedemonstratedthatciclesonide,budesonide,andfluticasonepropionateatequipotentdoseshavelesssystemiceffect20.23.Currentevidencesuggeststhatinadults,systemiceffectsofinhaledglucocorticosteroidsarenotaproblematdosesof400µgorlessbudesonideorequivalentdaily.

Thesystemicsideeffectsoflong-termtreatmentwithhighdosesofinhaledglucocorticosteroidsincludeeasybruising24,adrenalsuppression1,20,anddecreasedbonemineraldensity25,26.Ameta-analysisofcase-controlstudiesofnon-vertebralfracturesinadultsusinginhaledglucocorticosteroids(BDPorequivalent)indicatedthatinolderadults,therelativeriskofnon-vertebralfracturesincreasesbyabout12%foreach1000g/dayincreaseinthedoseBDPorequivalentbutthatthemagnitudeofthisriskwasconsiderablylessthanothercommonriskfactorsforfractureintheolderadult213.Inhaledglucocorticosteroidshavealsobeenassociatedwithcataracts27andglaucomaincross-sectionalstudies28,29,butthereisnoevidenceof

posterior-subcapsularcataractsinprospectivestudies30-32.Onedifficultyinestablishingtheclinicalsignificanceofsuchadverseeffectsliesindissociatingtheeffectofhigh-doseinhaledglucocorticosteroidsfromtheeffectofcoursesoforalglucocorticosteroidstakenbypatientswithsevereasthma.Thereisnoevidencethatuseofinhaledglucocorticosteroidsincreasestheriskofpulmonaryinfections,includingtuberculosis,andinhaledglucocorticosteroidsarenotcontraindicatedinpatientswithactivetuberculosis33.

Leukotriene modifiers.

Roleintherapy-Leukotrienemodifiersincludecysteinyl-leukotriene1(CysLT1)receptorantagonists(montelukast,pranlukast,andafirlukast)anda5-lipoxygenaseinhibitor(zileuton).Clinicalstudieshavedemonstratedthatleukotrienemodifiershaveasmallandvariablebronchodilatoreffect,reducesymptomsincludingcough34,improvelungfunction,andreduceairwayinflammationandasthmaexacerbations35-37.Theymaybeusedasanalternativetreatmentforadultpatientswithmildpersistentasthma38-40,andsomepatientswithaspirin-sensitiveasthmarespondwelltoleukotrienemodifiers41.However,whenusedaloneascontroller,theeffectofleukotrienemodifiersaregenerallylessthanthatoflowdosesofinhaledglucocorticosteroids,and,inpatientsalreadyoninhaledglucocorticosteroids,leukotrienemodifierscannotsubstituteforthistreatmentwithoutriskingthelossofasthmacontrol42,43.Leukotrienemodifiersusedasadd-ontherapymayreducethedoseofinhaledglucocorticosteroidsrequiredbypatientswithmoderatetosevereasthma44,andmayimproveasthmacontrolinpatientswhoseasthmaisnotcontrolledwithloworhighdosesofinhaledglucocorticosteroids43,45-47.Withtheexceptionofonestudythatdemonstratedequivalenceinpreventingexacerbations48,severalstudieshavedemonstratedthatleukotrienemodifiersarelesseffectivethanlong-actinginhaledβ2-agonistsasadd-ontherapy49-51,192.Acontrolledreleaseformulationofzileutonallowsthismedicationtobeusedonatwicedailybasiswitheffectsequivalenttothatofstandardzileutonusedfourtimesaday203.

Sideeffects-Leukotrienemodifiersarewelltolerated,andfewifanyclass-relatedeffectshavesofarbeenrecognized.Zileutonhasbeenassociatedwithlivertoxicity204,andmonitoringoflivertestsisrecommendedduringtreatmentwiththismedication.NoassociationwasfoundbetweenChurg-Strausssyndromeandleukotrienemodifiersaftercontrollingforasthmadruguse,althoughitisnotpossibletoruleoutmodestassociationsgiventhatChurg-Strausssyndromeissorareandsohighlycorrelatedwithasthmaseverity52.COPY

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Long-acting inhaled β2-agonists.

Roleintherapy-Long-actinginhaledβ2-agonists,includingformoterolandsalmeterol,shouldnotbeusedasmonotherapyinasthmaasthesemedicationsdonotappeartoinfluenceairwayinflammationinasthma.Theyaremosteffectivewhencombinedwithinhaledglucocortico-steroids55,56,193,andthiscombinationtherapyisthepreferredtreatmentwhenamediumdoseofinhaledglucocorticosteroidalonefailstoachievecontrolofasthma.Theadditionoflong-actinginhaledβ2-agoniststoadailyregimenofinhaledglucocorticosteroidsimprovessymptomscores,decreasesnocturnalasthmasymptoms,improveslungfunction,decreasestheuseofrapid-actinginhaledβ2-agonists

57-59,reducesthenumberofexacerbations12,57-62,doesnotincreasetheriskofasthma-relatedhospitalizations214,andachievesclinicalcontrolofasthmainmorepatients,morerapidly,andatalowerdoseofinhaledglucocorticosteroidsthaninhaledglucocorticosteroidsgivenalone63.

Thisgreaterefficacyofcombinationtreatmenthasledtothedevelopmentoffixedcombinationinhalersthatdeliverbothglucocorticosteroidandlong-actingβ2-agonistsimultaneously(fluticasonepropionateplussalmeterol,budesonideplusformoterol,mometasoneplusformoterol,beclometasoneplusformoterol).Controlledstudieshaveshownthatdeliveringthistherapyinacombinationinhalerisaseffectiveasgivingeachdrugseparately64,65.Fixedcombinationinhalersaremoreconvenientforpatients,mayincreasecompliance66,andensurethatthelong-actingβ2-agonistisalwaysaccompaniedbyaglucocorticosteroid.Inaddition,combinationinhalerscontainingformoterolandbudesonidemaybeusedforbothrescueandmaintenance.Bothcomponentsofbudesonide-formoterolgivenasneededcontributetoenhancedprotectionfromsevereexacerbationsinpatientsreceivingcombinationtherapyformaintenance67,194andprovideimprovementsinasthmacontrolatrelativelylowdosesofinhaledglucocorticosteroids67-70.(SeeAppendixB,GINAPocketGuideupdated2009forinformationonAsthmaCombinationMedicationsForAdultsandChildren5YearsandOlder.)

Long-actingβ2-agonistswhenusedasacombinationmedicationwithinhaledglucocortico-steroids,mayalsobeusedtopreventexercise-inducedbronchospasm,andforthispurposemayprovidelongerprotectionthanrapid-actinginhaledβ2-agonists

71.Salmeterolandformoterolprovideasimilardurationofbronchodilationandprotectionagainstbronchoconstrictors,buttherearepharmacologicaldifferencesbetweenthem.Formoterolhasamorerapidonsetofactionthansalmeterol72,73,whichmaymakeformoterolsuitableforsymptomreliefaswellassymptomprevention68.

Sideeffects-Therapywithlong-actinginhaledβ2-agonistscausesfewersystemicadverseeffects—suchascardiovascularstimulation,skeletalmuscletremor,andhypokalemia—thanoraltherapy.Theregularuseofrapid-actingβ2-agonistsinbothshortandlongactingformsmayleadtorelativerefractorinesstoβ2-agonists

74.Basedondataindicatingapossibleincreasedriskofasthma-relateddeathassociatedwiththeuseofsalmeterolinasmallgroupofindividuals75long-actingβ2-agonistsshouldnotbeusedasasubstituteforinhaledororalglucocorticosteroids,andshouldonlybeusedincombinationwithanappropriatedoseofinhaledglucocorticosteroidasdeterminedbyaphysician215.Somemeta-analysesofstudiesoflong-actingβ2-agonistshaveshownnumericallyverysmallincreasesinthenumberofdeathsinpatientsreceivinglong-actingβ2-agonistsincombinationwithinhaledglucocorticosteroids,whencomparedtoinhaledglucocorticosteroidsalone.Wherepresent,theeffectsizesareextremelysmallandneedtobebalancedagainstthebenefitsinimprovedasthmacontrolandreductioninexacerbationsthatthesemedicationsbringwhencombinedwithinhaledglucocorticosteroids205,214.Noinfluenceofβ2-adrenergicreceptorphenotypesupontheefficacyorsafetyoflong-actingβ2-agonisttherapyhasbeenobservedwhenadministeredincombinationwithinhaledglucocorticosteroidswhetherbythesingleinhalerformaintenanceandreliefmethodorataregularfixeddoseinadults206,221.

Theophylline

Roleintherapy-Theophyllineisabronchodilatorand,whengiveninalowerdose,hasmodestanti-inflammatoryincreasecompliance66,andensurethatthelong-actingβ2-properties

77-79.Itisavailableinsustained-releaseformulationsthataresuitableforonce-ortwice-dailyInaddition,combinationinhalerscontainingformoterolanddosing.Dataontherelativeefficacyoftheophyllineasalong-termcontrollerislacking.However,availableevidencesuggeststhatlittleeffectasafirst-linecontroller80.Itmayprovideasadd-ontherapyinpatientswhodonotachievecontroloninhaledglucocorticosteroidsalone81-83.Additionallyinsuchpatientsthewithdrawalofsustained-releasetheophyllinehasbeenassociatedwithdeteriorationofcontrol84.Asadd-ontherapy,theophyllineislesseffectivethanlong-actinginhaledβ2-agonists

85,86.

Sideeffects-Sideeffectsoftheophylline,particularlyathigherdoses(10mg/kgbodyweight/dayormore),aresignificantandreducetheirusefulness.Sideeffectscanbereducedbycarefuldoseselectionandmonitoring,andgenerallydecreaseordisappearwithcontinueduse.Adverseeffectsincludegastrointestinalsymptoms,looselstools,cardiacarrhythmias,seizures,andevendeath.COPY

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Nauseaandvomitingarethemostcommonearlyevents.Monitoringisadvisedwhenahighdoseisstarted,ifthepatientdevelopsanadverseeffectontheusualdose,whenexpectedtherapeuticaimsarenotachieved,andwhenconditionsknowntoaltertheophyllinemetabolismexist.Forexample,febrileillness,pregnancy,andanti-tuberculosismedications87reducebloodlevelsoftheophylline,whileliverdisease,congestiveheartfailure,andcertaindrugsincludingcimetidine,somequinolones,andsomemacrolidesincreasetheriskoftoxicity.Lowerdosesoftheophylline,whichhavebeendemonstratedtoprovidethefullanti-inflammatorybenefitofthisdrug82,areassociatedwithlessfrequentsideeffects,andplasmatheophyllinelevelsinpatientsonlow-dosetherapyneednotbemeasuredunlessoverdoseissuspected.

Cromones: sodium cromoglycate and nedocromil sodium.

Roleintherapy–Theroleofsodiumcromoglycateandnedocromilsodiuminlong-termtreatmentofasthmainadultsislimited.Efficacyhasbeenreportedinpatientswithmildpersistentasthmaandexercise-inducedbronchospasm.Theiranti-inflammatoryeffectisweakandtheyarelesseffectivethanalowdoseofinhaledglucocorticosteroid88.

Sideeffects-Sideeffectsareuncommonandincludecoughinguponinhalationandsorethroat.Somepatientsfindthetasteofnedocromilsodiumunpleasant.

Long-acting oral β2-agonists.

Roleintherapy-Longactingoralβ2-agonistsincludeslowreleaseformulationsofsalbutamol,terbutaline,andbambuterol,aprodrugthatisconvertedtoterbutalineinthebody.Theyareusedonlyonrareoccasionswhenadditionalbronchodilationisneeded.

Sideeffects-Thesideeffectprofileoflongactingoralβ2-agonistsishigherthanthatofinhaledβ2-agonists,andincludescardiovascularstimulation(tachycardia),anxiety,andskeletalmuscletremor.Adversecardiovascularreactionsmayalsooccurwiththecombinationoforalβ2-agonistsandtheophylline.Regularuseoflong-actingoralβ2-agonistssasmonotherapyislikelytobeharmfulandthesemedicationsmustalwaysbegivenincombinationwithinhaledglucocorticosteroids.

Anti-IgE*

Roleintherapy-Anti-IgE(omalizumab)isatreatmentoptionlimitedtopatientswithelevatedserumlevelsofIgE.Itscurrentindicationisforpatientswithsevere

allergicasthma89whoareuncontrolledoninhaledglucocorticosteroids,althoughthedoseofconcurrenttreatmenthasvariedindifferentstudies.Improvedasthmacontrolisreflectedbyfewersymptoms,lessneedforrelievermedications,andfewerexacerbations90,91.Furtherinvestigationswilllikelyprovideadditionalclarificationoftheroleofanti-IgEinotherclinicalsettings.

Sideeffects:Asindicatedbyseveralstudiesinvolvingasthmapatientsages12yearsandolder207,whowerealreadyreceivingtreatmentwithglucocorticosteroids(inhaledand/ororal)andlong-actingβ2-agonists

89,anti-IgEappearstobesafeasadd-ontherapy92-94.Withdrawalofglucocorticosteroidsfacilitatedbyanti-IgEtherapyhasledtounmaskingthepresenceofChurgStrausssyndromeinasmallnumberofpatients222.Clinicianssuccessfulininitiatingglucocorticosteroidwithdrawalusinganti-IgEshouldbeawareofthissideeffect.

Systemic glucocorticosteroids.

Roleintherapy-Long-termoralglucocorticosteroidtherapy(thatis,forperiodslongerthantwoweeksasaglucocorticosteroid“burst”)mayberequiredforseverelyuncontrolledasthma,butitsuseislimitedbytheriskofsignificantadverseeffects.Thetherapeuticindex(effect/sideeffect)oflong-terminhaledglucocortico-steroidsisalwaysmorefavorablethanlong-termsystemicglucocorticosteroidsinasthma95,96.Iforalglucocorticosteroidshavetobeadministeredonalong-termbasis,attentionmustbepaidtomeasuresthatminimiethesystemicsideeffects.Oralpreparationsarepreferredoverparenteral(intramuscularorintravenous)forlong-termtherapybecauseoftheirlowermineralocorticoideffect,relativelyshorthalf-life,andlessereffectsonstriatedmuscle,aswellasthegreaterflexibilityofdosingthatpermitstitrationtothelowestacceptabledosethatmaintainscontrol.

Sideeffects-Thesystemicsideeffectsoflong-termoralorparenteralglucocorticosteroidtreatmentincludeosteoporosis,arterialhypertension,diabetes,hypothalamic-pituitary-adrenalaxissuppression,obesity,cataracts,glaucoma,skinthinningleadingtocutaneousstriaeandeasybruising,andmuscleweakness.Patientswithasthmawhoareonlong-termsystemicglucocorticosteroidsinanyformshouldreceivepreventivetreatmentforosteoporosis(Figure 3-2)97-99.Althoughitisrare,withdrawaloforalglucocorticosteroidscanelicitadrenalfailureorunmaskunderlyingdisease,suchasChurg-StraussSyndrome54,100.Cautionandclosemedicalsupervisionarerecommendedwhenconsideringtheuseofsystemicglucocorticosteroidsinpatientswithasthmawhoalsohavetuberculosis,parasiticinfections,osteoporosis,glaucoma,diabetes,

*Visit GINA website, www.ginasthma.org for GRADE review of question “In adults with asthma, does monoclonal anti-IgE, omalizumab, compared to placebo improve patient outcomes?”

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severedepression,orpepticulcers.Fatalherpesvirusinfectionshavebeenreportedamongpatientswhoareexposedtotheseviruseswhiletakingsystemicglucocorticosteroids,evenshortbursts.

Oral anti-allergic compounds.

Roleintherapy-Severaloralanti-allergiccompoundshavebeenintroducedinsomecountriesforthetreatmentofmildtomoderateallergicasthma.Theseincludetranilast,repirinast,tazanolast,pemirolast,ozagrel,celatrodast,amlexanox,andibudilast.Ingeneral,theiranti-asthmaeffectappearstobelimited101,butstudiesontherelativeefficacyofthesecompoundsareneededbeforerecommendationscanbemadeabouttheirroleinthelong-termtreatmentofasthma.

Sideeffects-Sedationisapotentialsideeffectofsomeofthesemedications.

Other controller therapies.

Roleintherapy-Varioustherapeuticregimenstoreducethedoseoforalglucocorticosteroidsrequiredbypatientswithsevereasthmahavebeenproposed.Thesemedicationsshouldbeusedonlyinselectedpatientsunderthesupervisionofanasthmaspecialist,astheirpotentialsteroid-sparingeffectsmaynotoutweightheriskofserioussideeffects.Twometa-analysesofthesteroid-sparingeffectoflow-dosemethotrexateshowedasmalloverallbenefit,butarelativelyhighfrequencyofadverseeffects102,103.Thissmallpotentialtoreducetheimpactofglucocorticosteroidsideeffectsisprobablyinsufficientto

Figure 3-2. Glucocorticosteroids and Osteoporosis

Asthma patients on high-dose inhaled glucocorticosteroids or oral glucocorticosteroids at any dose are considered at risk of developingosteoporosis and fractures, but it is not certain whether this risk exists for patients on lower doses of inhaled glucocorticosteroids1. Physiciansshould consider monitoring patients who are at risk. The following summarizes monitoring and management but more detailed guidelines forthe management of steroid-induced osteoporosis are available2,3.

Screening - Chest X-rays should be reviewed for the presence of vertebral fractures. Wedging, compressions, and cod-fishing of vertebralbodies are synonymous with fractures, and indicate those who are at the highest risk for future fractures. In men, this may be a better predictorof fracture risk than bone mineral density (BMD). BMD measurements by dual energy X-ray absorptiomety (DXA scan) should be undertaken in:

• Any patient with asthma who has been taking oral glucocorticosteroids for over 6 months duration at a mean daily dose of 7.5 mgprednisone/prednisolone or above.

• Post-menopausal women taking over 5 mg prednisone/prednisolone daily for more than 3 months. • Any patient with asthma and a history of vertebral or other fractures that may be related to osteoporosis.

Bone density measurements should also be offered to:• Post-menopausal women taking > 2 mg inhaled BDP or equivalent daily• Any patient who is receiving frequent short courses of high-dose oral glucocorticosteroids

Osteoporosis is present if the bone density in lumbar spine or femoral neck shows :• T-score below -2.5 (2.5 standard deviations below the mean value of young normal subjects of the same sex in patients 19-69 years).• Z-score below -1 (1 standard deviation below the predicted value for age and sex).

follow-up scanning - Repeat scanning should be done:• In 2 years in those whose initial scan was not osteoporotic but in whom treatment (as above) with oral glucocorticosteroids continues.• In 1 year for those with osteoporosis on the first scan who are started on osteoporosis treatment.

Management• General measures include avoidance of smoking, regular exercise, use of the lowest dose of oral glucocorticosteroid possible, and a good

dietary intake of calcium.• For women with osteoporosis up to 10 years post-menopausal offer bisphosphonates or hormone therapy4,5,6 (Evidence A).• For men, pre-menopausal women, and women more than 10 years since menopause consider treatment with a bisphosphonate7 (Evidence A).

References1. Goldstein MF, Fallon JJ, Jr., Harning R. Chronic glucocorticoid therapy-induced osteoporosis in patients with obstructive lung disease. Chest 1999; 116:1733-1749.2. Eastell R, Reid DM, Compston J, Cooper C, Fogelman I, Francis RM et al. A UK Consensus Group on management of glucocorticoid-induced osteoporosis:

an update. J Intern Med 1998; 244:271-292.3. Sambrook PN, Diamond T, Ferris L, Fiatarone-Singh M, Flicker L, MacLennan A et al. Corticosteroid induced osteoporosis. Guidelines for treatment. Aust Fam

Physician 2001; 30:793-796.4. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML et al. Risks and benefits of estrogen plus progestin in healthy

postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-33.5. Cauley JA, Robbins J, Chen Z, Cummings SR, Jackson RD, LaCroix AZ, LeBoff M, Lewis CE, McGowan J, Neuner J, Pettinger M, Stefanick ML, Wactawski-

Wende J, Watts NB. "Effects of Estrogen Plus Progestin on Risk of Fracture and Bone Mineral Density." JAMA 2003;290(13):1729-1738. 6. Brown JP, Josse RG. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ. 2002;167:S1-34.7. Homik J, Cranney A, Shea B, Tugwell P, Wells G, Adachi R et al. Bisphosphonates for steroid induced osteoporosis. Cochrane Database Syst Rev 2000;CD001347.

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offsettheadverseeffectsofmethotrexate104.Cyclosporin105andgold106,107havealsobeenshowntobeeffectiveinsomepatients.Themacrolide,troleandromycin,hasasmallsteroid-sparingeffectwhenusedwithsystemicmethylprednisolone,butitseffectmayresultfromthemacrolidedecreasingmetabolismoftheglucocorticosteroidandthereforenotimprovingsafety.However,othereffectsofthelong-termuseofmacrolidesinasthmaremainunderstudy108.Theuseofintravenousimmunoglobulinisnotrecommended109-111.Dataonahumanmonoclonalantibodyagainsttumornecrosisfactor(TNF)-alphasuggestthattheriskbenefitequationdoesnotfavortheuseofthisclassoftreatmentsinsevereasthma216.

Sideeffects-Macrolideuseisfrequentlyassociatedwithnausea,vomiting,andabdominalpainandoccasionallylivertoxicity.Methotrexatealsocausesgastrointestinalsymptoms,andonrareoccasionshepaticanddiffusepulmonaryparenchymaldisease,andhematologicalandteratogeniceffects.

Allergen-specific immunotherapy.

Roleintherapy-Theroleofspecificimmunotherapyinadultasthmaislimited.Appropriateimmunotherapyrequirestheidentificationanduseofasinglewell-definedclinicallyrelevantallergen.Thelaterisadministeredinprogressivelyhigherdosesinordertoinducetolerance.ACochranereview112thatexamined75randomizedcontrolledtrialsofspecificimmunotherapycomparedtoplaceboconfirmedtheefficacyofthistherapyinasthmainreducingsymptomscoresandmedicationrequirements,andimprovingallergen-specificandnon-specificairwayhyperresponsiveness.Similarmodesteffectswereidentifiedinasystematicreviewofsublingualimmunotherapy(SLIT)196.Specificimmunotherapyhaslong-termclinicaleffectsandthepotentialofpreventingdevelopmentofasthmainchildrenwithallergicrhinoconjunctivitisupto7yearsaftertreatmenttermination208.However,inviewoftherelativelymodesteffectofallergen-specificimmunotherapycomparedtoothertreatmentoptions,thesebenefitsmustbeweighedagainsttheriskofadverseeffectsandtheinconvenienceoftheprolongedcourseofinjectiontherapy,includingtheminimumhalf-hourwaitrequiredaftereachinjection.Specificimmunotherapyshouldbeconsideredonlyafterstrictenvironmentalavoidanceandpharmacologicintervention,includinginhaledglucocorticosteroids,havefailedtocontrolapatient’sasthma113.Therearenostudiesthatcomparespecificimmunotherapywithpharmacologictherapyforasthma.Thevalueofimmunotherapyusingmultipleallergensdoesnothavesupport.

Sideeffects-Localandsystemicsideeffectsmayoccurin

conjunctionwithspecificimmunotherapyadministration.Reactionslocalizedtotheinjectionsitemayrangefromaminimalimmediatewhealandflaretoalarge,painful,delayedallergicresponse.Systemiceffectsmayincludeanaphylacticreactions,whichmaybelifethreatening,aswellassevereexacerbationsofasthma.Deathsfromspecificimmunotherapyhaveoccurredinpatientswithsevereasthma.

Reliever Medications

Relievermedicationsactquicklytorelievebronchoconstrictionanditsaccompanyingacutesymptoms.Rapid-acting inhaled β2-agonists.

Roleintherapy-Rapid-actinginhaledβ2-agonistsarethemedicationsofchoiceforreliefofbronchospasmduringacuteexacerbationsofasthmaandforthepretreatmentofexercise-inducedbronchoconstriction.Theyincludesalbutamol,terbutaline,fenoterol,levalbuterolHFA209,reproterol,andpirbuterol.Formoterol,along-actingβ2-agonists,isapprovedforsymptomreliefbecauseofitsrapidonsetofaction,butitshouldonlybeusedforthispurposeinpatientsonregularcontrollertherapywithinhaledglucocorticosteroids.

Rapid-actinginhaledβ2-agonistsshouldbeusedonlyonanas-neededbasisatthelowestdoseandfrequencyrequired.Increaseduse,especiallydailyuse,isawarningofdeteriorationofasthmacontrolandindicatestheneedtoreassesstreatment.Similarly,failuretoachieveaquickandsustainedresponsetoβ2-agoniststreatmentduringanexacerbationmandatesmedicalattention,andmayindicatetheneedforshort-termtreatmentwithoralglucocorticosteroids.

Sideeffects-Useoforalβ2-agonistsgiveninstandarddosesareassociatedwithmoreadversesystemiceffectssuchastremorandtachycardiathanoccurwithinhaledpreparations.


Roleintherapy-Althoughsystemicglucocorticosteroidsarenotusuallythoughtofasrelievermedications,theyareimportantinthetreatmentofsevereacuteexacerbationsbecausetheypreventprogressionoftheasthmaexacerbation,reducetheneedforreferraltoemergencydepartmentsandhospitaliation,preventearlyrelapseafteremergencytreatment,andreducethemorbidityoftheillness.Themaineffectsofsystemicglucocorticosteroidsinacuteasthmaareonlyevidentafter4to6hours.OraltherapyispreferredandisaseffectiveCOPY

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asintravenoushydrocortisone114.Atypicalshortcourseoforalglucocorticosterodsforanexacerbationis40-50mg115prednisolonegivendailyfor5to10daysdependingontheseverityoftheexacerbation.Whensymptomshavesubsidedandlungfunctionhasapproachedthepatient’spersonalbestvalue,theoralglucocorticosteroidscanbestoppedortapered,providedthattreatmentwithinhaledglucocorticosteroidscontinues116.Intramuscularinjectionofglucocorticosteroidshasnoadvantageoverashortcourseoforalglucocorticosteroidsinpreventingrelapse114,116.

Sideeffects-Adverseeffectsofshort-termhigh-dosesystemictherapyareuncommonbutincludereversibleabnormalitiesinglucosemetabolism,increasedappetite,fluidretention,weightgain,roundingoftheface,moodalteration,hypertension,pepticulcer,andasepticnecrosisofthefemur.

Anticholinergics.

Roleintherapy-Anticholinergicbronchodilatorsusedinasthmaincludeipratropiumbromideandoxitropiumbromide.Inhaledipratropiumbromideisalesseffectiverelievermedicationinasthmathanrapid-actinginhaledβ2-agonists.Ameta-analysisoftrialsofinhaledipratropiumbromideusedinassociationwithaninhaledβ2-agonistsinacuteasthmashowedthattheanticholinergicproducesastatisticallysignificant,albeitmodest,improvementinpulmonaryfunction,andsignificantlyreducestheriskofhospitaladmission117.Thebenefitsofipratropiumbromideinthelong-termmanagementofasthmahavenotbeenestablished,althoughitisrecognizedasanalternativebronchodilatorforpatientswhoexperiencesuchadverseeffectsastachycardia,arrhythmia,andtremorfromrapid-actingβ2-agonists.

Sideeffects-Inhalationofipratropiumoroxitropiumcancauseadrynessofthemouthandabittertaste.Thereisnoevidenceforanyadverseeffectsonmucussecretion118.

Theophylline.

Roleintherapy-Short-actingtheophyllinemaybeconsideredforreliefofasthmasymptoms119.Theroleoftheophyllineintreatingexacerbationsremainscontroversial.Short-actingtheophyllinemayprovidenoadditivebronchodilatoreffectoveradequatedosesofrapid-actingβ2-agonists,butitmaybenefitrespiratorydrive.

Sideeffects-Theophyllinehasthepotentialforsignificantadverseeffects,althoughthesecangenerallybeavoidedbyappropriatedosingandmonitoring.Short-actingtheophyllineshouldnotbeadministeredtopatientsalreadyonlong-termtreatmentwithsustained-releasetheophylline

unlesstheserumconcentrationoftheophyllineisknowntobelowand/orcanbemonitored.

Short-acting oral β2-agonists.

Short-actingoralβ2-agonistsareappropriateforuseinthefewpatientswhoareunabletouseinhaledmedication.However,theiruseisassociatedwithahigherprevalenceofadverseeffects.

Complementary And Alternative Medicine

Therolesofcomplementaryandalternativemedicineinadultasthmatreatmentarelimitedbecausetheseapproacheshavebeeninsufficientlyresearchedandtheireffectivenessislargelyunproven.Generally,thesetherapieshavenotbeenvalidatedbyconventionalstandards.Althoughthepsychotherapeuticroleofthetherapistformspartoftheplaceboeffectofalltreatments,thisaspectisviewedasanintegralpartoftheso-calledholisticapproachusedbypractitionersofcomplementaryandalternativemethods,andmitigatesagainstperformanceofthelarge,multicenter,placebo-controlledrandomizedstudiesrequiredtoconfirmefficacy.However,withoutthesetherelativeefficacyofthesealternativemeasureswillremainunknown120.

Complementaryandalternativetherapiesincludeacupuncture,homeopathy,herbalmedicine,Ayurvedicmedicine,ionizers,osteopathyandchiropracticmanipulation,andspeleotherapyamongothers.Apartfromthosementionedbelow,therehavebeennosatisfactorystudiesfromwhichconclusionsabouttheirefficacycanbedrawn.

Dietarysupplements,includingseleniumtherapy197arenotofprovenbenefitandtheuseofalowsodiumdietasanadjunctivetherapytonormaltreatmenthasnoadditionaltherapeuticbenefitinadultswithasthma.Inaddition,ithasnoeffectonbronchialreactivitytomethacholine217.Evidencefromthemostrigorousstudiesavailabletodateindicatesthatspinalmanipulationisnotaneffectivetreatmentforasthma121.Systematicreviewsindicatethathomeopathicmedicineshavenoeffectsbeyondplacebo222.

Severalstudiesofbreathingand/orrelaxationtechniquesforasthmaand/ordysfunctionalbreathing,includingtheButeykomethodandthePapworthmethod210,haveshownimprovementsinsymptoms,short-actingβ2-agonistuse,qualityoflifeand/orpsychologicalmeasures,butnotinphysiologicaloutcomes.Astudyoftwophysiologically-contrastingbreathingtechniques,inwhichcontactwithhealthprofessionalsandinstructionsaboutrescueinhalerusewerematched,showedsimilarimprovementsCOPY

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inrelieverandinhaledglucocorticosteroiduseinbothgroups122.Thissuggeststhatperceivedimprovementwithbreathingtechniquesmaybelargelyduetofactorssuchasrelaxation,voluntaryreductioninuseofrescuemedication,orengagementofthepatientintheircare.Breathingtechniquesmaythusprovideausefulsupplementtoconventionalasthmamanagementstrategies,particularlyinanxiouspatientsorthosehabituallyover-usingrescuemedication.Thecostofsomeprogramsmaybeapotentiallimitation.

Sideeffects-Acupuncture-associatedhepatitisB,bilateralpneumothorax,andburnshavebeendescribed.Sideeffectsofotheralternativeandcomplementarymedicinesarelargelyunknown.However,somepopularherbalmedicinescouldpotentiallybedangerous,asexemplifiedbytheoccurrenceofhepaticveno-occlusivediseaseassociatedwiththeconsumptionofthecommerciallyavailableherbcomfrey.Comfreyproductsaresoldasherbalteasandherbalrootpowders,andtheirtoxicityisduetothepresenceofpyrroliidinealkaloids.

Route of Administration

Inhaledtherapyisthecornerstoneofasthmatreatmentforchildrenofallages.Almostallchildrencanbetaughttoeffectivelyuseinhaledtherapy.Differentagegroupsrequiredifferentinhalersforeffectivetherapy,sothechoiceofinhalermustbeindividualized.Informationaboutthelungdoseforaparticulardrugformulationisseldomavailableforchildren,andmarkeddifferencesexistbetweenthevariousinhalers.Thisshouldbeconsideredwheneveroneinhalerdeviceissubstitutedwithanother.Inaddition,thechoiceofinhalerdeviceshouldincludeconsiderationoftheefficacyofdrugdelivery,cost,safety,easeofuse,convenience,anddocumentationofitsuseinthepatient’sagegroup123-125.Ingeneral,ametered-doseinhaler(MDI)withspacerispreferabletonebulizedtherapyduetoitsgreaterconvenience,moreeffectivelungdeposition,lowerriskofsideeffects,andlowercost.Basedontheseconsiderations,ageneralstrategyforchoosinginhalersinchildrenisgiveninFigure 3-3.Spacersretainlargedrugparticlesthatwouldnormallybedepositedintheoropharynx,reducingoralandgastrointestinalabsorptionandthussystemicavailabilityoftheinhaleddrug.Thisismainlyimportantwheninhaledglucocorticosteroidswithfirst-passmetabolism(beclomethasonedipropionate,flunisolide,triamcinolone,andbudesonide)aregivenviapressuriedMDI.Useofaspaceralsoreducesoropharyngealsideeffects.Duringacuteasthmaattacks,

anMDIshouldalwaysbeusedwithaspacer,asinthissituationachildmaybeunabletocorrectlycoordinateinhalationwithactuationoftheMDI.Commerciallyproducedspacerswithwell-characterizeddrugoutputcharacteristicsarepreferable.Ifthesearenotavailableorfeasible,ahomemadespacer(forexample,onemadefroma500mlplasticcolddrinkbottle)maybeused126.Nebulizershaveratherimprecisedosing,areexpensive,aretimeconsumingtouseandcarefor,andrequiremaintenance.Theyaremainlyreservedforchildrenwhocannotuseotherinhalerdevices.Insevereacuteasthmaexacerbationsanebulierisoftenused,althoughanMDIwithaspacerisequallyeffective127.

Controller Medications

Controllermedicationsforchildrenincludeinhaledandsystemicglucocorticosteroids,leukotrienemodifiers,long-actinginhaledβ2-agonists,theophylline,cromones,andlong-actingoralβ2-agonists.

Inhaled glucocorticosteroids.

RoleinTherapy-Inhaledglucocorticosteroidsarethemosteffectivecontrollertherapy,andarethereforetherecommendedtreatmentforasthmaforchildrenofallages.Figure 3-4listsapproximatelyequipotentdosesofdifferentinhaledglucocorticosteroidsadministeredviadifferentinhalationdevicesforchildrenolderthan5years..

Childrenolderthan5years.Dose-responsestudiesanddosetitrationstudiesinchildren128,129demonstratemarkedandrapidclinicalimprovementsinsymptomsandlungfunctionatlowdosesofinhaledglucocorticosteroids

ASTHMA TREATMENT: CHILDREN**

Figure 3-3: Choosing an Inhaler Device for Children with Asthma*

Age Group Preferred Device Alternate DeviceYounger than 4 years Pressurized metered-

dose inhaler plusdedicated spacer with face mask

Nebulizer with facemask

4 – 6 years Pressurized metered-dose inhaler plusdedicated spacer with mouthpiece

Nebulizer with mouthpiece

Older than 6 years Dry powder inhaler,or breath-actuatedpressurized metered-dose inhaler, orpressurized metered-dose inhaler withspacer and mouthpiece

Nebulizer with mouthpiece

*Based on efficacy of drug delivery, cost effectiveness, safety, ease of use, andconvenience.

**See also the “Asthma Medications: Adults” section at the beginning of this chapter for more information on the therapeutic role and side effects of various therapies. In this section, only information specific to children is provided.

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(e.g.,100-200µgbudesonidedaily)130-134,andmilddiseaseiswellcontrolledbysuchdosesinthemajorityofpatients132.Earlyinterventionwithinhaledbudesonideisassociatedwithimprovedasthmacontrolandlessadditionalasthmamedicationuse211.Somepatientsrequirehigherdoses(400µg/day)toachieveoptimalasthmacontrolandeffectiveprotectionagainstexercise-inducedasthma.Onlyaminorityofpatientsrequiretreatmentwithhighdosesofinhaledglucocorticosteroids133,134.Inchildrenolderthan5years,maintenancetreatmentwithinhaledglucocorticosteroidscontrolsasthmasymptoms,reducesthefrequencyofacuteexacerbationsandthenumberofhospitaladmissions,improvesqualityoflife,lungfunction,andbronchialhyperresponsiveness,andreducesexercise-inducedbronchoconstriction10.Symptomcontrolandimprovementsinlungfunctionoccurrapidly(after1to2weeks),althoughlongertreatment(overthecourseofmonths)andsometimeshigherdosesmayberequiredtoachievemaximumimprovementsinairwayhyperresponsiveness10.Whenglucocorticosteroidtreatmentisdiscontinued,asthmacontroldeteriorateswithinweekstomonths10.

Children5yearsandyounger.Treatmentwithinhaledglucocorticosteroidsinchildren5yearsandyoungerwithasthmagenerallyproducessimilarclinicaleffectsasinolderchildren,butdose-responserelationshipshavebeenlesswellstudied.Theclinicalresponsemaydiffer

dependingontheinhalerandthechild’sabilitytousetheinhalercorrectly.Withuseofaspacerdevice,alow-doseinhaledglucocorticosteroidresultsinnear-maximumbenefitsinthemajorityofpatients136,137.Useofinhaledglucocorticosteroidsdoesnotinduceremissionofasthmaanditreturnswhentreatmentisstopped138.

Theclinicalbenefitsofintermittentsystemicorinhaledglucocorticosteroidsforchildrenwithintermittent,viral-inducedwheezeremaincontroversial.Whilesomestudiesinolderchildrenfoundsmallbenefits,astudyinyoungchildrenfoundnoeffectsonwheeingsymptoms139.Thereisnoevidencetosupporttheuseofmaintenancelow-doseinhaledglucocorticosteroidsforpreventingearlytransientwheezing136,139,199.

Sideeffects-Themajorityofstudiesevaluatingthesystemiceffectsofinhaledglucocorticosteroidshavebeenundertakeninchildrenolderthan5years.

Growth.Whenassessingtheeffectsofinhaledglucocorticosteroidsongrowthinchildrenwithasthma,itisimportanttoconsiderpotentialconfoundingfactors.Forexample,manychildrenwithasthmareceivinginhaledglucocorticosteroidsexperienceareductioningrowthratetowardtheendofthefirstdecadeoflife140.Thisreducedgrowthratecontinuesintothemid-teensandisassociatedwithadelayintheonsetofpuberty.Thepre-

Figure 3-4. Estimated Equipotent Daily Doses of Inhaled Glucocorticosteroids for Children Older than 5 Years

Drug Low Daily Dose (�g) Medium Daily Dose (�g) High Daily Dose (�g)‡

Beclomethasone dipropionate 100 - 200 >200 - 400 >400 Budesonide* 100 - 200 >200 - 400 >400 Budesonide-Neb 250 - 500 >500 - 1000 >1000 Ciclesonide* 80 - 160 >160 - 320 >320 Flunisolide 500 - 750 >750 - 1250 >1250 Fluticasone propionate 100 - 200 >200 - 500 >500 Mometasone furoate* 100 - 200 >200 - 400 >400 Triamcinolone acetonide 400 - 800 >800 - 1200 >1200

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

Notes • The most important determinant of appropriate dosing is the clinician’s judgment of the patient’s response to therapy. The clinician must monitor the

patient’s response in terms of clinical control and adjust the dose accordingly. Once control of asthma is achieved, the dose of medication should be carefully titrated to the minimum dose required to maintain control, thus reducing the potential for adverse effects.

• Designation of low, medium, and high doses is provided from manufacturers’ recommendations where possible. Clear demonstration of dose- response relationships is seldom provided or available. The principle is therefore to establish the minimum effective controlling dose in each patient, as higher doses may not be more effective and are likely to be associated with greater potential for adverse effects.

• As CFC preparations are taken from the market, medication inserts for HFA preparations should be carefully reviewed by the clinician for the correct equivalent dosage.

100 ≥200

≥400

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pubertaldecelerationofgrowthvelocityresemblesgrowthretardation.However,thedelayinpubertalgrowthisalsoassociatedwithadelayinskeletalmaturation,sothatthechild’sboneagecorrespondstohisorherheight140,141Ultimately,adultheightisnotdecreased,althoughitisreachedatalaterthannormalage.Theuseof400µginhaledbudesonideorequivalentperdaytocontrolasthmahaslessimpactongrowththandoeslowsocioeconomicstatus141.AsummaryofthefindingsofstudiesoninhaledglucocorticosteroidsandgrowthisprovidedinFigure 3-5.

Bones.Thepotentialclinicallyrelevantadverseeffectsofinhaledglucocorticosteroidsonbonesinchildrenareosteoporosisandfracture.Severalcross-sectionalandlongitudinalepidemiologicstudieshaveassessedtheeffectsoflong-terminhaledglucocorticosteroidtreatmentontheseoutcomes132,135,143-149.TheconclusionsaresummariedinFigure 3-6.

Hypothalamic-pituitary-adrenal(HPA)axis.Thoughdifferencesexistbetweenthevariousinhaledglucocorticosteroidsandinhalerdevices,treatmentwithinhaledglucocorticosteroiddosesoflessthan200µgbudesonideorequivalentdailyisnormallynotassociatedwithanysignificantsuppressionoftheHPAaxisinchildren135.Athigherdoses,smallchangesinHPAaxisfunctioncanbedetectedwithsensitivemethods148.Theclinicalrelevanceofthesefindingsisnotknown,sincetherehavenotbeenreportsofadrenalcrisisinclinicaltrialsofinhaledglucocorticosteroidsinchildren.However,adrenalcrisishasbeenreportedinchildrentreatedwithexcessivelyhighdosesofinhaledglucocorticosteroids150.

Cataracts.Inhaledglucocorticosteroidshavenotbeenassociatedwithanincreasedoccurrenceofcataractdevelopmentinchildren30,135.

Centralnervoussystemeffects.Althoughisolatedcasereportshavesuggestedthathyperactivebehavior,aggressiveness,insomnia,uninhibitedbehavior,andimpairedconcentrationmaybeseenwithinhaledglucocorticosteroidtreatment,noincreaseinsucheffectshasbeenfoundintwolong-termcontrolledtrialsofinhaledbudesonideinvolvingmorethan10,000treatmentyears132,135.

Oralcandidiasis,hoarseness,andbruising.Clinicalthrushisseldomaprobleminchildrentreatedwithinhaledorsystemicglucocorticosteroids.Thissideeffectseemstoberelatedtoconcomitantuseofantibiotics,highdailydoses,dosefrequency,andinhalerdevice.Spacersreducetheincidenceoforalcandidiasis151.Mouthrinsingisbeneficial152.Theoccurrenceofhoarsenessorothernoticeablevoicechangesduringbudesonidetreatmentissimilartoplacebo30.Treatmentwithanaveragedailydoseof500µgbudesonidefor3to6yearsisnotassociatedwithanincreasedtendencytobruise30.

Dentalsideeffects.Inhaledglucocorticosteroidtreatmentisnotassociatedwithincreasedincidenceofcaries.However,theincreasedlevelofdentalerosionreportedinchildrenwithasthma153maybeduetoareductioninoralpHthatmayresultfrominhalationofβ2-agonists

154.

Otherlocalsideeffects.Thelong-termuseofinhaledglucocorticosteroidsisnotassociatedwithanincreasedincidenceoflowerrespiratorytractinfections,includingtuberculosis.

Figure 3-5. Summary: Glucocorticosteroids andGrowth in Children140-142

• Uncontrolled or severe asthma adversely affects growth andfinal adult height.

• No long-term controlled studies have reported any statistically orclinically significant adverse effects on growth of 100 to 200 �gper day of inhaled glucocorticosteroids.

• Growth retardation may be seen with all inhaledglucocorticosteroids when a high dose is administered.

• Growth retardation in both short- and medium-term studies isdose dependent.

• Important differences seem to exist between the growth-retarding effects of various inhaled glucocorticosteroids andinhalers.

• Different age groups seem to differ in their susceptibility to thegrowth-retarding effects of inhaled glucocorticosteroids; childrenaged 4 to 10 are more susceptible than adolescents.

• Glucocorticosteroid-induced changes in growth rate during thefirst year of treatment appear to be temporary.

• Children with asthma treated with inhaled glucocorticosteroidsattain normal adult height (predicted from family members) but ata later age.

Figure 3-6. Summary: Bones andGlucocorticosteroids in Children10,143,144

• No studies have reported any statistically significant increased ofrisk of fractures in children taking inhaled glucocorticosteroids.

• Oral or systemic glucocorticosteroid use increases the risk offracture. The risk of fracture increases along with the number oftreatments, with a 32% increase at four courses ever. Use ofinhaled glucocorticosteroids reduces the need for systemic courses.

• Controlled longitudinal studies of 2 to 5 years’ duration andseveral cross-sectional studies found no adverse effects ofinhaled glucocorticosteroid treatment on bone mineral density.

• Inhaled glucocorticosteroid use has the potential for reducingbone mineral accretion in male children progressing throughpuberty, but this risk is likely to be outweighed by the ability to re-duce the amount of oral corticosteroids used in these children218.

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Leukotriene modifiers.

Childrenolderthan5years.Leukotrienemodifiersprovideclinicalbenefitinchildrenolderthan5yearsatalllevelsofseverity155-159,butgenerallylessthanthatoflow-doseinhaledglucocorticosteroids160.Leukotrienemodifiersprovidepartialprotectionagainstexercise-inducedbronchoconstrictionwithinhoursafteradministrationwithnolossofbronchoprotectiveeffect200.Asadd-ontreatmentinchildrenwhoseasthmaisinsufficientlycontrolledbylowdosesofinhaledglucocorticosteroids,leukotrienemodifiersprovidemoderateclinicalimprovements,includingasignificantreductioninexacerbations161,162.Combinationtherapyislesseffectiveincontrollingasthmainchildrenwithmoderatepersistentasthmathanincreasingtomoderatedosesofinhaledglucocorticosteroids201.Montelukasthasnotbeendemonstratedtobeaneffectiveinhaledglucocorticosteroidsparingalternativeinchildrenwithmoderate-to-severepersistentasthma219.

Children5yearsandyounger.Inadditiontotheefficacyasdescribedabove163,164,leukotrienemodifiersreduceviral-inducedasthmaexacerbationsinchildrenages2-5withahistoryofintermittentasthma164.

Sideeffects-Nosafetyconcernshavebeendemonstratedfromtheuseofleukotrienemodifiersinchildren.

Long-acting inhaled β2-agonists.

Roleintherapy-Long-actinginhaledβ2-agonistsareprimarilyusedasadd-ontherapyinchildrenolderthan5yearswhoseasthmaisinsufficientlycontrolledbymediumdosesofinhaledglucocorticosteroidsorassingle-dosetherapybeforevigorousexercise.Monotherapywithlong-actinginhaledβ2-agonistsshouldbeavoided

75.

Childrenolderthan5years.Long-actinginhaledβ2-agonistshavemainlybeenstudiedinchildrenolderthan5yearsasadd-ontherapyforpatientswhoseasthmaisnotcontrolledonlowtohighdosesofinhaledglucocorticosteroids.Significantimprovementsinpeakflowandotherlungfunctionmeasurementshavebeenfoundinmoststudies55,165-169.However,theireffectsonotheroutcomessuchassymptomsandneedforrelievermedicationhavebeenlessconsistentandhaveonlybeenobservedinabouthalfofthetrialsconducted.Add-ontreatmentwithlong-actinginhaledβ2-agonistshasnotbeenshowntoreducethefrequencyofexacerbations170.Inhalationofasingledoseoflong-actinginhaledβ2-agonistseffectivelyblocksexercise-inducedbronchoconstrictionforseveralhours171.Withdailytherapythedurationoftheprotectionissomewhatreduced171,butisstilllongerthanthatprovidedbyshort-actingβ2-agonists.

Combinationproductscontaininganinhaledglucocorticosteroidandalong-actinginhaledβ2-agonistsarepreferredtolong-actinginhaledβ2-agonistsandinhaledglucocorticosteroidsadministeredbyseparateinhalers.Fixedcombinationinhalersensurethatthelong-actingβ2-agonistsisalwaysaccompaniedbyaglucocorticosteroid.

Children5yearsandyounger.Theeffectoflong-actinginhaledβ2-agonistshasnotyetbeenadequatelystudied.Combinationtherapywithbudesonideandformoterolusedbothasmaintenanceandrescuehasbeenshowntoreduceasthmaexacerbationsinchildrenages4yearsandolderwithmoderatetosevereasthma202.

Sideeffects-Althoughlong-actinginhaledβ2-agonistsarewell-toleratedinchildren,evenafterlong-termuse,becauseofinconsistencyofreportsontheireffectsonexacerbationsofasthma,theyarenottherecommendedoptionwhenmorethanonecontrollerisrequired170.Ifused,long-actingβ2-agonistsshouldonlybeusedincombinationwithanappropriatedoseofinhaledglucocorticosteroidasdeterminedbyaphysician,preferablyinafixedcombinationinhaler.

Theophylline.

Roleintherapy-Theophyllinehasbeenshowntobeeffectiveasmonotherapyandasadd-ontreatmenttoinhaledororalglucocorticosteroidsinchildrenolderthan5years.Itissignificantlymoreeffectivethanplaceboatcontrollingdayandnightsymptomsandimprovinglungfunction172-174.Maintenancetreatmentoffersamarginalprotectiveeffectagainstexercise-inducedbroncho-constriction175.Add-ontreatmentwiththeophyllinehasbeenfoundtoimproveasthmacontrolandreducethemaintenanceglucocorticosteroiddosenecessaryinchildrenwithsevereasthmatreatedwithinhaledororalglucocorticosteroids176,177.Afewstudiesinchildren5yearsandyoungeralsosuggestsomeclinicalbenefit.However,theefficacyoftheophyllineislessthanthatoflow-doseinhaledglucocorticosteroids.

Mostclinicalevidenceregardingtheuseoftheophyllineinchildrenhasbeenobtainedfromstudiesinwhichplasmatheophyllinelevelsweremaintainedwithinthetherapeuticrangeof55-110µmol/L(5-10µg/ml).Furtherstudiessuggestthatitscontrollerfunctionsmayoccuratlowerplasmalevels(correspondingtodosesofaround10mg/kg/day).Sustained-releaseproductsarepreferableformaintenancetherapy,sincetheyenabletwice-dailydosing.Sustained-releaseproductswithreliableabsorptionprofilesandcompletebioavailabilitywithandwithoutconcomitantfoodintakearepreferred.COPY

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Theophyllineeliminationmayvaryuptotenfoldbetweenindividuals.Measurementofplasmatheophyllinelevelsisnotnecessaryinotherwisehealthychildrenwhendoseslessthan10mg/kg/dayareused.However,whenhigherdosesareusedorwhendrugsthatmayincreasetheophyllinelevelsarealsousedchronically,plasmatheophyllinelevelsshouldbemeasuredtwohoursbeforeadministrationofthenextdoseoncesteadystatehasbeenreached(after3days).

Sideeffects-Themostcommonsideeffectsoftheophyllineareanorexia,nausea,vomiting,andheadache178.Mildcentralnervousstimulation,palpitations,tachycardia,arrhythmias,abdominalpain,diarrhea,and,rarely,gastricbleedingmayalsooccur.Thesesideeffectsaremainlyseenatdoseshigherthan10mg/kg/day.Theriskofadverseeffectsisreducediftreatmentisinitiatedwithdailydosesaround5mg/kg/dayandthengraduallyincreasedto10mg/kg/day.Severeoverdosingwiththeophyllinecanbefatal.

Anti-IgE.

Roleintherapy-Anti-IgE(omalizumab)hasprovenefficacyinchildrenage6to12yearswithmoderate-to-severeandseverepersistentallergic(IgE-mediated)asthma.A28week,randomized,double-blind,placebo-controlledstudy223,224included334childrenwithmoderatetosevereallergicasthmawhowerewellcontrolledoninhaledglucocorticosteroiddosesequivalentto200-500µg/dayofbeclomethasone.Therewasnodifferenceinclinicaleffectsbetweenplaceboandanti-IgEduringa16-weekstableinhaledglucocorticosteroiddoseperiod.Duringa12-weektaperingperiodurgent,unscheduledphysicianvisitsweresignificantlyreducedfromby30.3%intheanti-IgEcomparedwithplacebo(12.9%)group223,andthereweresignificantimprovementsinqualityoflifeinthepatientsreceivinganti-IgE,bothduringstableinhaledglucocorticosteroiddosingandduringtapering224.Theremainingoutcomeswereverysimilarinthetwotreatmentgroups.

Aone-yearstudyevaluatedtheefficacyandsafetyofanti-IgEin627childrenwithIgE-mediatedasthmainadequatelycontrolledondosesofinhaledglucocorticosteroidequivalentto200µg/dayfluticasonepropionateorhigher(meandose500µg/day)225.Anti-IgEtreatmentwasassociatedwithasignificantlylowerexacerbationrateandtheoverallincidenceofseriousadverseeventswassignificantlylowerinthechildrenreceivinganti-IgEthanplacebo.

AsubstantialnumberofchildrenwithdifficultasthmawillhavehigherIgElevelsthantheupperlimitofIgErecommendedfortherapy(1,300IU)226.Itisunknownif

thesepatientswillstillbenefitfromomalizumabtherapy.Therearenotestswhichcancurrentlyberecommendedinordertopredictwhowillrespond227.

Anti-IgEtherapyisexpensiveandrequiresregularinjectionsandobservationaftereachinjection.Acostbenefitanalysissuggestedthattherewouldbeafiscalsavingifthistreatmentisgiventochildrenwithfiveormorehospitaladmissionsandcumulativelytwentydaysormoreinhospital228.

Sideeffects:Drug-relatedadverseeventsinanti-IgEtreatedpatientsaremildtomoderateinseverityandincludeurticaria,rash,flushing,andpruritus223.Thelong-term(beyondoneyear)safetyandefficacyhasnotyetbeenstudied.

Cromones: sodium cromoglycate and nedocromil sodium.

Roleintherapy-Sodiumcromoglycateandnedocromilsodiumhavealimitedroleinthelong-termtreatmentofasthmainchildren.Onemeta-analysishasconcludedthatlong-termtreatmentwithsodiumcromoglycateisnotsignificantlybetterthanplaceboformanagementofasthmainchildren179.Anotherhasconfirmedsuperiorityoflowdoseinhaledglucocorticosteroidsoversodiumcromoglycateinpersistentasthma,butastherewerenoplaceboarmsinthesestudies,theefficacyofsodiumcromoglycatecannotbeconfirmedfromthestudiesreviewed;nobetweentreatmentdifferenceinsafetywasobserved180.

Nedocromilsodiumhasbeenshowntoreduceexacerbations,butitseffectonotherasthmaoutcomesisnotsuperiortoplacebo135.Asingledoseofsodiumcromoglycateornedocromilsodiumattenuatesbroncho-spasminducedbyexerciseorcoldair181.Studiesoftheuseofthesemedicationsinchildren5yearsandyoungeraresparseandresultsareconflicting.

Sideeffects-Cough,throatirritation,andbroncho-constrictionoccurinasmallproportionofpatientstreatedwithsodiumcromoglycate.Abadtaste,headache,andnauseaarethemostcommonsideeffectsofnedocromil182.

Long-acting oral β2-agonists. Treatmentwithlong-actingoralβ2-agonistsuchasslowreleaseformulationsofsalbutamol,terbutaline,andbambuterolreducesnocturnalsymptomsofasthma183,184.Duetotheirpotentialsideeffectsofcardiovascularstimulation,anxiety,andskeletalmuscletremor,theiruseisnotencouraged.Ifused,dosingshouldbeindividualied,andthetherapeuticresponsemonitoredtolimitsideeffects185.Long-actingoralβ2-agonisttherapyofferslittleornoprotectionagainstexercise-inducedbronchoconstriction.COPY

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Becauseofthesideeffectsofprolongeduse,oralglucocorticosteroidsinchildrenwithasthmashouldberestrictedtothetreatmentofacutesevereexacerbations,whetherviral-inducedorotherwise.

Reliever Medications

Rapid-actinginhaledß2-agonistsandshort-actingoralß2-agonists.

Roleintherapy-Rapid-actinginhaledß2-agonistssarethemosteffectivebronchodilatorsavailableandthereforethepreferredtreatmentforacuteasthmainchildrenofallages.Theinhaledrouteresultsinmorerapidbronchodilationatalowerdoseandwithfewersideeffectsthanoralorintravenousadministration186.Furthermore,inhaledtherapyofferssignificantprotectionagainstexercise-inducedbronchoconstrictionandotherchallengesfor0.5to2hours(longacting[ß2-agonistsofferlongerprotection)

187.Thisisnotseenaftersystemicadministration188.Oraltherapyisrarelyneededandreservedmainlyforyoungchildrenwhocannotuseinhaledtherapy.

Sideeffects-Skeletalmuscletremor,headache,palpitations,andsomeagitationarethemostcommoncomplaintsassociatedwithhighdosesofß2-agonistsinchildren.Thesecomplaintsaremorecommonaftersystemicadministrationanddisappearwithcontinuedtreatment189.

Anticholinergics.

Roleintherapy-Inhaledanticholinergicsarenotrecommendedforlong-termmanagementofasthmainchildren190.

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ANDPREVENTION

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ASTHMAMANAGEMENTANDPREVENTION53

Asthmahasasignificantimpactonindividuals,theirfamilies,andsociety.Althoughthereisnocureforasthma,appropriatemanagementthatincludesapartnershipbetweenthephysicianandthepatient/familymostoftenresultsintheachievementofcontrol.

Thegoalsforsuccessfulmanagementofasthmaareto:

• Achieveandmaintaincontrolofsymptoms• Maintainnormalactivitylevels,includingexercise• Maintainpulmonaryfunctionasclosetonormalas• possible• Preventasthmaexacerbations• Avoidadverseeffectsfromasthmamedications• Preventasthmamortality.

Thesegoalsfortherapyreflectanunderstandingofasthmaasachronicinflammatorydisorderoftheairwayscharacterizedbyrecurrentepisodesofwheezing,breathlessness,chesttightness,andcoughing.Clinicalstudieshaveshownthatasthmacanbeeffectivelycontrolledbyinterveningtosuppressandreversetheinflammationaswellastreatingthebronchoconstrictionandrelatedsymptoms.Furthermore,earlyinterventiontostopexposuretotheriskfactorsthatsensitizedtheairwaymayhelpimprovethecontrolofasthmaandreducemedicationneeds.Experienceinoccupationalasthmaindicatesthatlong-standingexposuretosensitizingagentsmayleadtoirreversibleairflowlimitation.

Themanagementofasthmacanbeapproachedindifferentways,dependingontheavailabilityofthevariousformsofasthmatreatmentandtakingintoaccountculturalpreferencesanddifferinghealthcaresystems.Therecommendationsinthischapterreflectthecurrentscientificunderstandingofasthma.Theyarebasedasfaraspossibleoncontrolledclinicalstudies,andthetextreferencesmanyofthesestudies.Forthoseaspectsoftheclinicalmanagementofasthmathathavenotbeenthesubjectofspecificclinicalstudies,recommendationsarebasedonliteraturereview,clinicalexperience,andexpertopinionofprojectmembers.

Therecommendationsforasthmamanagementarelaidoutinfiveinterrelatedcomponentsoftherapy:

1.DevelopPatient/DoctorPartnership2.IdentifyandReduceExposuretoRiskFactors3.Assess,Treat,andMonitorAsthma4.ManageAsthmaExacerbations5.SpecialConsiderations.

KEYPOINTS:

• Theeffectivemanagementofasthmarequiresthedevelopmentofapartnershipbetweenthepersonwithasthmaandhisorherhealthcareprofessional(s)(andparents/caregivers,inthecaseofchildrenwithasthma).

• Theaimofthispartnershipisguidedself-management—thatis,togivepeoplewithasthmatheabilitytocontroltheirownconditionwithguidancefromhealthcareprofessionals.

• Thepartnershipisformedandstrengthenedaspatientsandtheirhealthcareprofessionalsdiscussandagreeonthegoalsoftreatment,developapersonalized,writtenself-managementplanincludingself-monitoring,andperiodicallyreviewthepatient’streatmentandlevelofasthmacontrol.

• Educationshouldbeanintegralpartofallinteractionsbetweenhealthcareprofessionalsandpatients,andisrelevanttoasthmapatientsofallages.

• Personalasthmaactionplanshelpindividualswithasthmamakechangestotheirtreatmentinresponsetochangesintheirlevelofasthmacontrol,asindicatedbysymptomsand/orpeakexpiratoryflow,inaccordancewithwrittenpredeterminedguidelines.

Theeffectivemanagementofasthmarequiresthedevelopmentofapartnershipbetweenthepersonwithasthmaandhisorherhealthcareprofessional(s)(andparents/caregiversinthecaseofchildrenwithasthma).Theaimofthispartnershipistoenablepatientswithasthmatogaintheknowledge,confidence,andskillstoassumeamajorroleinthemanagementoftheirasthma.Thepartnershipisformedandstrengthenedaspatientsandtheirhealthcareprofessionalsdiscussandagreeonthegoalsoftreatment,developapersonalized,writtenself-managementactionplanincludingself-monitoring,andperiodicallyreviewthepatient’streatmentandlevelofasthmacontrol(Figure 4.1-1).

CHAPTER 1: DEFINITION

INTRODUCTION COMPONENT 1: DEVELOP PATIENT/DOCTOR PARTNERSHIP

INTRODUCTION

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54ASTHMAMANAGEMENTANDPREVENTION

Thisapproachiscalledguidedself-managementandhasbeenshowntoreduceasthmamorbidityinbothadults(Evidence A)andchildren(Evidence A).Anumberofspecificsystemsofguidedself-managementhavebeendeveloped1-10foruseinawiderangeofsettings,includingprimarycare1,4,6,hospitals2,3,7,10,emergencydepartments8,andinternet-basedhomemonitoring340,372,communityhealthworkers371,andamongsuchdiversegroupsaspregnantwomenwithasthma11,childrenandadolescents12,13,andinmulti-racialpopulations14.Guidedself-managementmayinvolvevaryingdegreesofindependence,rangingbroadlyfrompatient-directedself-managementinwhichpatientsmakechangeswithoutreferencetotheircaregiver,butinaccordancewithapriorwrittenactionplan,todoctor-directedself-managementinwhichpatientsrelyfollowawrittenactionplan,butrefermostmajortreatmentchangestotheirphysicianatthetimeofplannedorunplannedconsultations.Cochranesystematicreviews13,15-18haveexaminedtheroleofeducationandself-managementstrategiesinthecareofasthmapatients.

Educationshouldbeanintegralpartofallinteractionsbetweenhealthcareprofessionalsandpatients,andisrelevanttoasthmapatientsofallages.Althoughthefocusofeducationforsmallchildrenwillbeontheparentsandcaregivers,childrenasyoungas3yearsofagecanbetaughtsimpleasthmamanagementskills.Adolescentsmayhavesomeuniquedifficultiesregardingadherencethatmaybehelpedthroughpeersupportgroupeducationinadditiontoeducationprovidedbythehealthcareprofessional12butregionalissuesandthedevelopmentalstageofthechildrenmayaffecttheoutcomesofsuchprograms373.

Figure 4.1-2outlinesthekeyfeaturesandcomponentsofanasthmaeducationprogram.Theinformationandskillstrainingrequiredbyeachpersonmayvary,andtheirabilityorwillingnesstotakeresponsibilitysimilarlydiffers.Thusallindividualsrequirecertaincoreinformationandskills,butmosteducationmustbepersonalizedandgiventothepersoninanumberofsteps.Socialandpsychologicalsupportmayalsoberequiredtomaintainpositivebehavioralchange.

Goodcommunicationisessentialasthebasisforsubsequentgoodcompliance/adherence19-22(Evidence B).Keyfactorsthatfacilitategoodcommunicationare23:

• Acongenialdemeanor(friendliness,humor,andattentiveness)

• Engagingininteractivedialogue• Givingencouragementandpraise• Empathy,reassurance,andprompthandlingofany

concerns• Givingofappropriate(personalized)information• Elicitingsharedgoals• Feedbackandreview

Teachinghealthcareprofessionalstoimprovetheircommunicationskillscanresultinmeasurablybetter

ASTHMA EDUCATION

Figure 4.1-1. Essential Features of the Doctor-Patient Partnership to Achieve Guided Self-Management in Asthma

• Education• Joint setting of goals• Self-monitoring. The person with asthma is taught to combine

assessment of asthma control with educated interpretation ofkey symptoms

• Regular review of asthma control, treatment, and skills by ahealth care professional

• Written action plan. The person with asthma is taught whichmedications to use regularly and which to use as needed, andhow to adjust treatment in response to worsening asthma control

• Self-monitoring is integrated with written guidelines for both thelong-term treatment of asthma and the treatment of asthmaexacerbations.

Figure 4.1-2. Education and the Patient/DoctorPartnership

Goal: To provide the person with asthma, their family, and othercaregivers with suitable information and training so that they cankeep well and adjust treatment according to a medication plandeveloped with the health care professional.

Key components:

q Focus on the development of the partnershipq Acceptance that this is a continuing processq A sharing of informationq Full discussion of expectationsq Expression of fears and concerns

Provide specific information, training, and advice about:

q Diagnosisq Difference between “relievers” and “controllers”q Potential side effects of medicationsq Use of inhaler devicesq Prevention of symptoms and attacksq Signs that suggest asthma is worsening and actions to takeq Monitoring control of asthmaq How and when to seek medical attention

The person then requires:

q A guided self-management planq Regular supervision, revision, reward, and reinforcement

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outcomes–includingincreasedpatientsatisfaction,betterhealth,andreduceduseofhealthcare–andthesebenefitsmaybeachievedwithoutanyincreaseinconsultationtimes24.Studieshavealsoshownthatpatientscanbetrainedtobenefitmorefromconsultations.Patientstaughthowtogiveinformationtodoctorsinaclearermanner,information-seekingtechniques,andmethodsofcheckingtheirunderstandingofwhatthedoctorhadtoldthemgainedsignificantimprovementsincomplianceandoverallhealth25.Layeducatorscanberecruitedandtrainedtodeliveradiscreteareaofrespiratorycare(forexample,asthmaself-managementeducation)withcomparableoutcomestothoseachievedbyprimarycarebasedpracticenurses362(Evidence B).

At the Initial Consultation

Earlyintheconsultationthepersonwithasthmaneedsinformationaboutthediagnosisandsimpleinformationaboutthetypesoftreatmentavailable,therationaleforthespecifictherapeuticinterventionsbeingrecommended,andstrategiesforavoidingfactorsthatcauseasthmasymptoms374.Differentinhalerdevicescanbedemonstrated,andthepersonwithasthmaencouragedtoparticipateinthedecisionastowhichismostsuitableforthem.SomeofthesedevicesandtechniquesfortheiruseareillustratedontheGINAWebsite(http://www.ginasthma.org).Criteriaforinitialselectionofinhalerdeviceincludedeviceavailabilityandcost,patientskills,andpreferencesofthehealthprofessionalandpatient26-28.Patientsshouldbegivenadequateopportunitytoexpresstheirexpectationsofboththeirasthmaanditstreatment.Afrankappraisalshouldbemadeofhowfartheirexpectationsmayormaynotbemet,andagreementshouldbemadeaboutspecificgoalsfortherapy.

Attheinitialconsultation,verbalinformationshouldbesupplementedbytheprovisionofwrittenorpictorial29,30informationaboutasthmaanditstreatment.TheGINAWebsite(www.ginasthma.org)containspatienteducationalmaterials,aswellaslinkstoseveralasthmawebsites.Thepatientandhisorherfamilyshouldbeencouragedtomakeanoteofanyquestionsthatarisefromreadingthisinformationorasaresultoftheconsultation,andshouldbegiventimetoaddresstheseduringthenextconsultation.

Personal Asthma Action Plans

Personalasthmaactionplanshelpindividualswithasthmamakechangestotheirtreatmentinresponsetochangesintheirlevelofasthmacontrol,asindicatedbysymptomsand/orpeakexpiratoryflow,inaccordancewithwrittenpredeterminedguidelines23,31,32.

Theeffectsweregreatestwheretheinterventioninvolvedeachofthefollowingelements:education,self-monitoring,regularreview,andpatient-directedself-managementusingawrittenself-managementactionplan(Evidence A).Patientsexperienceaone-thirdtotwo-thirdsreductioninhospitalizations,emergencyroomvisits,unscheduledvisitstothedoctorforasthma,misseddaysofwork,andnocturnalwakening.Ithasbeenestimatedthattheimplementationofaself-managementprogramin20patientspreventsonehospitalization,andsuccessfulcompletionofsuchaprogrambyeightpatientspreventsoneemergencydepartmentvisit16-18,23.Lessintensiveinterventionsthatinvolveself-managementeducationbutnotawrittenplanarelesseffective15.Theefficacyissimilarregardlessofwhetherpatientsself-adjusttheirmedicationsaccordingtoanindividualwrittenplanoradjustmentsofmedicationaremadebyadoctor15(Evidence B).Thus,patientswhoareunabletoundertakeguidedself-managementcanstillachievebenefitfromastructuredprogramofregularmedicalreview.Althoughinteractivecomputeriedasthmaeducationprogramsmayimprovepatientasthmaknowledgeandsymptoms,theireffectonobjectiveclinicaloutcomesislessconsistent353.Examplesofself-managementplansthathavebeenrecommendedcanbefoundonseveralWebsites(UKNationalAsthmaCampaignPlan,www.asthma.org.uk;InternationalAsthmaManagementPlan“ZoneSystem,”www.nhlbisupport.com/asthma/index.html;NewZealand“CreditCard”System,www.asthmanz.co.nz.AnexampleofthecontentsforanasthmaplanforpatientstomaintaincontrolofasthmaisshowninFigure 4.1-3.

Follow-Up and Review

Follow-upconsultationsshouldtakeplaceatregularintervals.Atthesevisits,thepatient’squestionsarediscussed,andanyproblemswithasthmaanditsinitialtreatmentarereviewed.Patientsshouldbeaskedtodemonstratetheirinhalerdevicetechniqueateveryvisit,withcorrectionandre-checkingifitisinadequate33,375.Follow-upconsultationsshouldalsoincludecheckingtheperson’sadherence/compliancetothemedicationplanandrecommendationsforreducingexposuretoriskfactors.Symptoms(andwhereappropriate,homepeakflowrecordings)notedinthediaryarealsoreviewedregularly.Afteraperiodofinitialtraining,thefrequencyofhomepeakflowandsymptommonitoringdependsinpartonthelevelofcontroloftheperson’sasthma.Routinefollow-upvisitsmaybeaneffectivetimetoreviewthewrittenself-managementplananditsunderstanding354.Educationalmessagesshouldbereviewedandrepeatedoraddedtoifnecessary.Asinglepageprompttoclinicianshasbeenshowntoimprovetheprovisionofpreventivecaretochildrenwithasthmaduringofficevisits341.COPY

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Improving Adherence Althoughinterventionsforenhancingmedicationadherencehavebeendeveloped363,studiesofadultsandchildrenwithasthma34haveshownthataround50%ofthoseon

long-termtherapyfailtotakemedicationsasdirectedatleastpartofthetime.Patientconcernaboutside-effectsofinhaledglucocorticosteroidswhetherrealorperceivedmayinfluenceadherence342.Non-adherencemaybedefinedinanonjudgmentalwayasthefailureoftreatmenttobetakenasagreeduponbythepatientandthehealthcareprofessional.Non-adherencemaybeidentifiedbyprescriptionmonitoring,pillcounting,ordrugassay,butataclinicallevelitisbestdetectedbyaskingabouttherapyinawaythatacknowledgesthelikelihoodofincompleteadherence(e.g.,“Sothatwemayplantherapy,doyoumindtellingmehowoftenyouactuallytakethemedicine?”).Shortquestionnairescanassistwithidentificationofpooradherence376.Specificdrugandnon-drugfactorsinvolvedinnon-adherencearelistedinFigure 4.1-4.

Self-Management in Children

Childrenwithasthma(withthehelpoftheirparents/caregivers)alsoneedtoknowhowtomanagetheirowncondition.Simpleeducationalinterventions(designedtoteachself-managementskills)amongchildrenadmittedtothehospitalwithasthmahavebeenshowntosignificantlyreducethereadmissionrateandreducemorbidity13.Asystematicreviewfoundthateducationalprogramsfortheself-managementofasthmainchildrenandadolescentsledtoimprovementsinlungfunctionandfeelingsofself-control,andreducedabsencesfromschool,thenumberofdayswithrestrictedactivity,andthenumberofemergencydepartmentvisits13,343.Forchildren,symptom-basedactionplansaremoreeffectivethanthosebasedonpeakflows355.School-basedasthmaeducationimprovesknowledgeofasthma,self-efficacy,andself-managementbehaviors377.THE EDUCATION OF OTHERS

Theeducationofthegeneralpublicaboutasthmaishelpfulinthatitenablesmembersofthepublictorecognizeasthmasymptomsandtheirconsequencesandencouragesthosewithasthmatoseekmedicalattentionandfollowtheirasthmamanagementprogram.Greaterawarenessofasthmaisalsolikelytohelpdispelmisconceptionsthatmayexistabouttheconditionandreducefeelingsofstigmatizationonthepartofpatients.Specificadviceaboutasthmaanditsmanagementshouldbeofferedtoschoolteachersandphysicaleducationinstructors,andseveralorganizationsproducematerialsforthispurpose.Schoolsmayneedadviceonimprovingtheenvironmentandairqualityforchildrenwithasthma35.Itisalsohelpfulforemployerstohaveaccesstoclearadviceaboutasthma.Mostoccupationsareassuitableforthosewithasthmaasforthosewithout,buttheremaybesomecircumstanceswherecautionisneeded.

Fig 4.1-3 Example Of Contents Of An Action Plan ToMaintain Asthma Control

Your Regular Treatment:1. Each day take ___________________________2. Before exercise, take _____________________

WHEN TO INCREASE TREATMENTAssess your level of Asthma ControlIn the past week have you had:

Daytime asthma symptoms more than 2 times ? No YesActivity or exercise limited by asthma? No YesWaking at night because of asthma? No YesThe need to use your [rescue medication] more than 2 times? No YesIf you are monitoring peak flow, peak flow less than______? No Yes

if you answered YeS to three or more of these questions, your asthma isuncontrolled and you may need to step up your treatment.

HOW TO INCREASE TREATMENTSTEP-UP your treatment as follows and assess improvement every day:_________________________________ [Write in next treatment step here] Maintain this treatment for _____________ days [specify number]

WHEN TO CALL THE DOCTOR/CLINIC.Call your doctor/clinic: _______________ [provide phone numbers]If you don’t respond in _________ days [specify number]____________________________ [optional lines for additional instruction]

EMERGENCY/SEVERE LOSS OF CONTROL3If you have severe shortness of breath, and can only speak in short sentences,3 If you are having a severe attack of asthma and are frightened,3 If you need your reliever medication more than every 4 hours and are not

improving.1. Take 2 to 4 puffs ___________ [reliever medication] 2. Take ____mg of ____________ [oral glucocorticosteroid]3. Seek medical help: Go to ________________; Address______________

Phone: _______________________4. Continue to use your _________[reliever medication] until you are able

to get medical help.

Figure 4.1-4. Factors Involved in Non-Adherence

Drug factors

Difficulties with inhaler devices

Awkward regimes (e.g., four times daily ormultiple drugs)

Side effectsCost of medicationDislike of medicationDistant pharmacies

Non-drug factors

Misunderstanding or lack of instructionFears about side effectsDissatisfaction with health care professionalsUnexpressed/undiscussed fears or concernsInappropriate expectationsPoor supervision, training, or follow-upAnger about condition or its treatmentUnderestimation of severityCultural issuesStigmatizationForgetfulness or complacencyAttitudes toward ill healthReligious issuesCOPY

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KEYPOINTS:• Pharmacologicinterventiontotreatestablished

asthmaishighlyeffectiveincontrollingsymptomsandimprovingqualityoflife.However,measurestopreventthedevelopmentofasthma,asthmasymptoms,andasthmaexacerbationsbyavoidingorreducingexposuretoriskfactorsshouldbeimplementedwhereverpossible.

• Atthistime,fewmeasurescanberecommendedforpreventionofasthmabecausethedevelopmentofthediseaseiscomplexandincompletelyunderstood.

• Asthmaexacerbationsmaybecausedbyavarietyofriskfactors,sometimesreferredtoas"triggers",includingallergens,viralinfections,pollutants,anddrugs.

• Reducingapatient’sexposuretosomecategoriesofriskfactorsimprovesthecontrolofasthmaandreducesmedicationneeds.

• Theearlyidentificationofoccupationalsensitizersandtheremovalofsensitizedpatientsfromanyfurtherexposureareimportantaspectsofthemanagementofoccupationalasthma.

Althoughpharmacologicinterventiontotreatestablishedasthmaishighlyeffectiveincontrollingsymptomsandimprovingqualityoflife,measurestopreventthedevelopmentofasthma,asthmasymptoms,andasthmabyavoidingorreducingexposuretoriskfactorsshouldbeimplementedwhereverpossible36.Atthistime,fewmeasurescanberecommendedforpreventionofasthmabecausethedevelopmentofthediseaseiscomplexandincompletelyunderstood.Thisareaisafocusofintensiveresearch,butuntilsuchmeasuresaredevelopedpreventioneffortsmustprimarilyfocusonpreventionofasthmasymptomsandattacks.

Measurestopreventasthmamaybeaimedatthepreventionofallergicsensitization(i.e.,thedevelopmentof

atopy,likelytobemostrelevantprenatallyandperinatally),orthepreventionofasthmadevelopmentinsensitizedpeople.Otherthanpreventingtobaccoexposurebothinuteroandafterbirth,therearenoprovenandwidelyacceptedinterventionsthatcanpreventthedevelopmentofasthma.

Allergicsensitzationcanoccurprenatally37,38.Thereiscurrentlyinsufficientinformationonthecriticaldosesandtimingofallergenexposuretopermitinterventioninthisprocess,andnostrategiescanberecommendedtopreventallergicsensitizationprenatally.Prescriptionofanantigen-avoidancediettoahigh-riskwomanduringpregnancyisunlikelytoreducesubstantiallyherriskofgivingbirthtoanatopicchild39.Moreover,suchadietmayhaveanadverseeffectonmaternaland/orfetalnutrition.

Theroleofdiet,particularlybreast-feeding,inrelationtothedevelopmentofasthmahasbeenextensivelystudiedand,ingeneral,infantsfedformulasofintactcow’smilkorsoyproteincomparedwithbreastmilkhaveahigherincidenceofwheezingillnessesinearlychildhood40.Exclusivebreast-feedingduringthefirstmonthsafterbirthisassociatedwithlowerasthmaratesduringchildhood41.The“hygienehypothesis”ofasthma,thoughcontroversial,hasledtothesuggestionthatstrategiestopreventallergicsensitizationshouldfocusonredirectingtheimmuneresponseofinfantstowardaTh1,nonallergicresponseoronmodulatingTregulatorcells42,butsuchstrategiescurrentlyremainintherealmofhypothesisandrequirefurtherinvestigation.Theroleofprobioticsinthepreventionofallergyandasthmaisalsounclear43.Exposuretocatshasbeenshowntoreduceriskofatopyinsomestudies44.Exposuretotobaccosmokebothprenatallyandpostnatallyisassociatedwithmeasurableharmfuleffects,includingeffectsonlungdevelopment45andagreaterriskofdevelopingwheezingillnessesinchildhood46.Althoughthereislittleevidencethatmaternalsmokingduringpregnancyhasaneffectonallergicsensitization47,passivesmokingincreasestheriskofallergicsensitizationinchildren47,48.Bothprenatalandpostnatalmaternalsmokingisproblematic49.Pregnantwomenandparentsofyoungchildrenshouldbeadvisednottosmoke(Evidence B).

Onceallergicsensitizationhasoccurred,therearetheoreticallystillopportunitiestopreventtheactual

COMPONENT 2: IDENTIFY AND REDUCEEXPOSURE TO RISK FACTORS

INTRODUCTION

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developmentofasthma.WhetherH1-antagonists(antihistamines)50,51orallergen-specificimmunotherapy52,53canpreventthedevelopmentofasthmainchildrenwhohaveotheratopicdiseasesremainsanareaofinvestigation,andtheseinterventionscannotberecommendedforwideadoptioninclinicalpracticeatthistime.

Asthmaexacerbationsmaybecausedbyavarietyoffactors,sometimesreferredtoas“triggers,”includingallergens,viralinfections,pollutants,anddrugs.Reducingapatient’sexposuretosomeofthesecategoriesofriskfactors(e.g.,smokingcessation,reducingexposuretosecondhandsmoke,reducingoreliminatingexposuretooccupationalagentsknowntocausesymptoms,andavoidingfoods/additives/drugsknowntocausesymptoms)improvesthecontrolofasthmaandreducesmedicationneeds.Inthecaseofotherfactors(e.g.,allergens,viralinfectionsandpollutants),measureswherepossibleshouldbetakentoavoidthese.Becausemanyasthmapatientsreacttomultiplefactorsthatareubiquitousintheenvironment,avoidingthesefactorscompletelyisusuallyimpracticalandverylimitingtothepatient.Thus,medicationstomaintainasthmacontrolhaveanimportantrolebecausepatientsareoftenlesssensitivetotheseriskfactorswhentheirasthmaisundergoodcontrol.Patientswithwell-controlledasthmaarelesslikelytoexperienceexacerbationsthanthosewhoseasthmaisnotwell-controlled364.

Indoor Allergens

Amongthewidevarietyofallergensourcesinhumandwellingsaredomesticmites,furredanimals,cockroaches,andfungi.However,thereisconflictingevidenceaboutwhethermeasurestocreatealow-allergenenvironmentinpatients'homesandreduceexposuretoindoorallergensareeffectiveatreducingasthmasymptoms54,55.Themajorityofsingleinterventionshavefailedtoachieveasufficientreductioninallergenloadtoleadtoclinicalimprovement55-57.Itislikelythatnosingleinterventionwillachievesufficientbenefitstobecosteffective.However,amonginner-citychildrenwithatopicasthma,anindividualized,home-based,comprehensiveenvironmentalinterventiondecreasedexposuretoindoorallergensandresultedinreducedasthma-associatedmorbidity58.Moreproperlypoweredandwell-designedstudiesofcombinedallergen-reductionstrategiesinlargegroupsofpatientsareneeded.

Figure 4.2-1: Effectiveness of Avoidance Measuresfor Some Indoor Allergens*

Measure Evidenceof effect

on allergenlevels

Evidence of clinical

benefit

House dust mitesEncase bedding in impermeable covers Some None

(adults)Some

(children)

Wash bedding in the hot cycle (55-60oC) Some NoneReplace carpets with hard flooring Some NoneAcaricides and/or tannic acid Weak NoneMinimize objects that accumulate dust None NoneVacuum cleaners with integral HEPA filterand double-thickness bags

Weak None

Remove, hot wash, or freeze soft toys None None

PetsRemove cat/dog from the home Weak NoneKeep pet from main living areas/bedrooms Weak NoneHEPA-filter air cleaners Some NoneWash pet Weak NoneReplace carpets with hard flooring None NoneVacuum cleaners with integral HEPA filterand double-thickness bags

None None

*Adapted from Custovic A, Wijk RG. The effectiveness of measures to change theindoor environment in the treatment of allergic rhinitis and asthma: ARIA update(in collaboration with GA(2)LEN). Allergy 2005;60(9):1112-1115.

Domestic mites.Domesticmiteallergyisauniversalhealthproblem59.Sincemitesliveandthriveinmanysitesthroughoutthehouse,theyaredifficulttoreduceandimpossibletoeradicate(Figure 4.2-1).Nosinglemeasureislikelytoreduceexposuretomiteallergens,andsinglechemicalandphysicalmethodsaimedatreducingmiteallergensarenoteffectiveinreducingasthmasymptomsinadults55,60-62(Evidence A).Onestudyshowedsomeefficacyofmattressencasingatreducingairwayhyperresponsivenessinchildren63(Evidence B).Anintegratedapproachincludingbarriermethods,dustremoval,andreductionofmicrohabitatsfavorabletomiteshasbeensuggested,althoughitsefficacyatreducingsymptomshasonlybeenconfirmedindeprivedpopulationswithaspecificenvironmentalexposure58(Evidence B)andarecommendationforitswidespreadusecannotbemade.

Furred animals.Completeavoidanceofpetallergensisimpossible,astheallergensareubiquitousandcanbefoundinmanyenvironmentsoutsidethehome64,includingschools65,publictransportation,andcat-freebuildings66.Althoughremovalofsuchanimalsfromthehomeisencouraged,evenafterpermanentremovaloftheanimal

PREVENTION OF ASTHMA SYMPTOMS AND EXACERBATIONS

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itcanbemanymonthsbeforeallergenlevelsdecrease67andtheclinicaleffectivenessofthisandotherinterventionsremainsunproven(Figure 4.2-1).

Cockroaches.Avoidancemeasuresforcockroachesincludeeliminatingsuitableenvironments(restrictinghavensbycaulkingandsealingcracksintheplasterworkandflooring,controllingdampness,andreducingtheavailabilityoffood),restrictingaccess(sealingentrysourcessuchasaroundpaperworkanddoors),chemicalcontrol,andtraps.However,thesemeasuresareonlypartiallyeffectiveinremovingresidualallergens68(Evidence C).

Fungi.Fungalexposurehasbeenassociatedwithexacerbationsfromasthmaandthenumberoffungalsporescanbestbereducedbyremovingorcleaningmold-ladenobjects69.Intropicalandsubtropicalclimates,fungimaygrowonthewallsofthehouseduetowaterseepageandhumidity.Toavoidthis,thewallscouldbetiledorcleanedasnecessary.Airconditionersanddehumidifiersmaybeusedtoreducehumiditytolevelslessthan50%andtofilterlargefungalspores.However,airconditioningandsealingofwindowshavealsobeenassociatedwithincreasesinfungalandhousedustmiteallergens70.

Outdoor Allergens

Outdoorallergenssuchaspollensandmoldsareimpossibletoavoidcompletely.Exposuremaybereducedbyclosingwindowsanddoors,remainingindoorswhenpollenandmoldcountsarehighest,andusingairconditioningifpossible.Somecountriesuseradio,television,andtheInternettoprovideinformationonoutdoorallergenlevels.Theimpactofthesemeasuresisdifficulttoassess.

Indoor Air Pollutants

Themostimportantmeasureincontrollingindoorairpollutantsistoavoidpassiveandactivesmoking.Secondhandsmokeincreasesthefrequencyandseverityofsymptomsinchildrenwithasthma.Parents/caregiversofchildrenwithasthmashouldbeadvisednottosmokeandnottoallowsmokinginroomstheirchildrenuse.Inadditiontoincreasingasthmasymptomsandcausinglong-termimpairmentsinlungfunction,activecigarettesmokingreducestheefficacyofinhaledandsystemicglucocorticosteroids71,72(Evidence B),Asthmapatientswhosmoke,andarenottreatedwithinhaledglucocorticosteroids,haveagreaterdeclineinlungfunctionthanasthmaticpatientswhodonotsmoke378.Smokingcessationneedstobevigorouslyencouragedforallpatientswithasthmawhosmoke.

Othermajorindoorairpollutantsincludenitricoxide,nitrogenoxides,carbonmonoxide,carbondioxide,sulfurdioxide,formaldehyde,andbiologicals(endotoxin)73.Installationofnon-polluting,moreeffectiveheating(heatpump,woodpelletburner,fluedgas)inthehomesofchildrenwithasthmadoesnotsignificantlyimprovelungfunctionbutdoessignificantlyreducesymptomsofasthma,daysoffschool,healthcareutilization,andvisitstoapharmacist365.

Outdoor Air Pollutants

Severalstudieshavesuggestedthatoutdoorpollutantsaggravateasthmasymptoms74,356,possiblyhavinganadditiveeffectwithallergenexposure75.Outbreaksofasthmaexacerbationshavebeenshowntooccurinrelationshiptoincreasedlevelsofairpollution,andthismayberelatedtoageneralincreaseinpollutantlevelsortoanincreaseinspecificallergenstowhichindividualsaresensitized76-78.Mostepidemiologicalstudiesshowasignificantassociationbetweenairpollutants–suchasozone,nitrogenoxides,acidicaerosols,andparticulatematter–andsymptomsorexacerbationsofasthma.Onoccasion,certainweatherandatmosphericconditions,e.g.,thunderstorms79favorthedevelopmentofasthmaexacerbationsbyavarietyofmechanisms,includingdustandpollution,increasesinrespirableallergens,andchangesintemperature/humidity.

Avoidanceofunfavorableenvironmentalconditionsisusuallyunnecessaryforpatientswhoseasthmaiscontrolled.Forpatientswithasthmathatisdifficulttocontrol,practicalstepstotakeduringunfavorableenvironmentalconditionsincludeavoidingstrenuousphysicalactivityincoldweather,lowhumidity,orhighairpollution;avoidingsmokingandsmoke-filledrooms;andstayingindoorsinaclimate-controlledenvironment.

Occupational Exposures

Occupationalexposuresaccountforasubstantialproportionofadultasthmaincidence357.Theearlyidentificationofoccupationalsensitizersandtheremovalofsensitizedpatientsfromanyfurtherexposureareimportantaspectsofthemanagementofoccupationalasthma(Evidence B).Onceapatienthasbecomesensitizedtoanoccupationalallergen,thelevelofexposurenecessarytoinducesymptomsmaybeextremelylow,andresultingexacerbationsbecomeincreasinglysevere.Attemptstoreduceoccupationalexposurehavebeensuccessfulespeciallyinindustrialsettings,andsomepotentsensitizers,suchassoycastorbean,havebeenreplacedbylessallergenicsubstances80(Evidence B).PreventionoflatexsensitizationhasbeenmadepossiblebytheCOPY

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productionofhypoallergenicgloves,whicharepowderfreeandhavealowerallergencontent81,82(Evidence C).Althoughmoreexpensivethanuntreatedgloves,theyarecosteffective.

Food and Food Additives

Foodallergyasanexacerbatingfactorforasthmaisuncommonandoccursprimarilyinyoungchildren.Foodavoidanceshouldnotberecommendeduntilanallergyhasbeenclearlydemonstrated(usuallybyoralchallenges)83.Whenfoodallergyisdemonstrated,foodallergenavoidancecanreduceasthmaexacerbations84(Evidence D).Sulfites(commonfoodanddrugpreservativesfoundinsuchfoodsasprocessedpotatoes,shrimp,driedfruits,beer,andwine)haveoftenbeenimplicatedincausingsevereasthmaexacerbationsbutthelikelihoodofareactionisdependentonthenatureofthefood,thelevelofresidualsulfite,thesensitivityofthepatient,theformofresidualsulfiteandthemechanismofthesulfite-inducedreaction85.Theroleofotherdietarysubstances—includingtheyellowdyetartrazine,benzoate,andmonosodiumglutamate—inexacerbatingasthmaisprobablyminimal;confirmationoftheirrelevancerequiresdouble-blindchallengebeforemakingspecificdietaryrestrictions.

Drugs

Somemedicationscanexacerbateasthma.Aspirinandothernonsteroidalanti-inflammatorydrugscancausesevereexacerbationsandshouldbeavoidedinpatientswithahistoryofreactingtotheseagents86.Thereissomeevidencethatexposuretoacetaminophenincreasestheriskofasthmaandwheezinginbothchildrenandadultsbutfurtherstudiesareneeded379.

Beta-blockerdrugsadministeredorallyorintraocularlymayexacerbatebronchospasm(Evidence A)andclosemedicalsupervisionisessentialwhentheseareusedbypatientswithasthma87.Betablockershaveaprovenbenefitinthemanagementofpatientswithacutecoronarysyndromesandforsecondarypreventionofcoronaryevents.Datasuggestthatpatientswithasthmawhoreceivenewermorecardio-selectivebetablockerswithin24hoursofhospitaladmissionforanacutecoronaryeventhavelowerin-hospitalmortalityrates366,367.

Influenza Vaccination

Patientswithmoderatetosevereasthmashouldbeadvisedtoreceiveaninfluenzavaccinationeveryyear88oratleastwhenvaccinationofthegeneralpopulationisadvised.However,routineinfluenzavaccinationofchildren89andadults90withasthmadoesnotappearto

protectthemfromasthmaexacerbationsorimproveasthmacontrol.Inactivatedinfluenzavaccinesareassociatedwithfewsideeffectsandaresafetoadministertoasthmaticadultsandchildrenovertheageof3years,includingthosewithdifficult-to-treatasthma91.Therearedatatosuggestthatintranasalvaccinationinchildrenunderage3maybeassociatedwithanincreasedincidenceofasthmaexacerbations92.

Obesity

Increasesinbodymassindex(BMI)havebeenassociatedwithincreasedprevalenceofasthma93.Weightreductioninobesepatientswithasthmahasbeendemonstratedtoimprovelungfunction,symptoms,morbidity,andhealthstatus94(Evidence B).

Emotional Stress

Emotionalstressmayleadtoasthmaexacerbations,primarilybecauseextremeemotionalexpressions(laughing,crying,anger,orfear)canleadtohyperventilationandhypocapnia,whichcancauseairwaynarrowing95,96.Panicattacks,whicharerarebutnotexceptionalinsomepatientswithasthma,haveasimilareffect97,98.However,itisimportanttonotethatasthmaisnotprimarilyapsychosomaticdisorder.

Other Factors That May Exacerbate Asthma

Rhinitis,sinusitis,andpolyposisarefrequentlyassociatedwithasthmaandneedtobetreated.Inchildren,antibiotictreatmentofbacterialsinusitishasbeenshowntoreducetheseverityofasthma99.However,sinusitisandasthmamaysimplycoexist.Apartfromsinusitis,thereislittleevidencethatbacterialinfectionsexacerbateasthma.Gastroesophagealrefluxcanexacerbateasthma,especiallyinchildren,andasthmasometimesimproveswhentherefluxiscorrected100,101.Manywomencomplainthattheirasthmaisworseatthetimeofmenstruation,andpremenstrualexacerbationshavebeendocumented102.Similarly,asthmamayimprove,worsen,orremainunchangedduringpregnancy103.Arandomizedclinicaltrialofaself-regulation,telephonecounselinginterventionemphasizingsexandgenderrolefactorsinthemanagementofasthmaindicatedthataprogramwithafocusonasthmamanagementproblemsparticulartowomencansignificantlyassistfemaleasthmapatients358.

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KEYPOINTS:

• Thegoalofasthmatreatment,toachieveandmaintainclinicalcontrol,canbereachedinamajorityofpatientswithapharmacologicinterventionstrategydevelopedinpartnershipbetweenthepatient/familyandthedoctor.

• Treatmentshouldbeadjustedinacontinuouscycledrivenbythepatients’asthmacontrolstatus.Ifasthmaisnotcontrolledonthecurrenttreatmentregimen,treatmentshouldbesteppedupuntilcontrolisachieved.Whencontrolismaintainedforatleastthreemonths,treatmentcanbesteppeddown.

• Intreatment-naïvepatientswithpersistentasthma,treatmentshouldbestartedatStep2,or,ifverysymptomatic(uncontrolled),atStep3.ForSteps2through5,avarietyofcontrollermedicationsareavailable.

• Ateachtreatmentstep,relievermedicationshouldbeprovidedforquickreliefofsymptomsasneeded.

• Ongoingmonitoringisessentialtomaintaincontrolandtoestablishtheloweststepanddoseoftreatmenttominimizecostandmaximizesafety.

Thegoalofasthmatreatment,toachieveandmaintainclinicalcontrol,canbereachedinamajorityofpatients104,344withapharmacologicinterventionstrategydevelopedinpartnershipbetweenthepatient/familyandthedoctor.Eachpatientisassignedtooneoffive“treatmentsteps”dependingontheircurrentlevelofcontrolandtreatmentisadjustedinacontinuouscycledrivenbychangesintheirasthmacontrolstatus.Thiscycleinvolves:

• AssessingAsthmaControl• TreatingtoAchieveControl• MonitoringtoMaintainControl

InthisComponent,thiscycleisdescribedforlong-termtreatmentofasthma.TreatmentforexacerbationsisdetailedinComponent4.

Eachpatientshouldbeassessedtoestablishhisorhercurrenttreatmentregimen,adherencetothecurrentregimen,andlevelofasthmacontrol.Asimplifiedschemeforrecogniingcontrolled,partlycontrolled,anduncontrolledasthmainagivenweekisprovidedinFigure 4.3-1.Thisisaworkingschemebasedoncurrentopinionandhasnotbeenvalidated.Severalcompositecontrolmeasures(e.g.,AsthmaControlTest105,AsthmaControlQuestionnaire106-108,AsthmaTherapyAssessmentQuestionnaire109,AsthmaControlScoringSystem110)havebeendevelopedandarebeingvalidatedforvariousapplications,includingusebyhealthcareproviderstoassessthestateofcontroloftheirpatients'asthmaandbypatientsforself-assessmentsaspartofawrittenpersonalasthmaactionplan.Uncontrolledasthmamayprogresstothepointofanexacerbation,andimmediatesteps,describedinComponent4,shouldbetakentoregaincontrol.

Thepatient’scurrentlevelofasthmacontrolandcurrenttreatmentdeterminetheselectionofpharmacologictreatment.Forexample,ifasthmaisnotcontrolledonthecurrenttreatmentregimen,treatmentshouldbesteppedupuntilcontrolisachieved.Ifcontrolhasbeenmaintainedforatleastthreemonths,treatmentcanbesteppeddownwiththeaimofestablishingtheloweststepanddoseoftreatmentthatmaintainscontrol(seeMonitoringtoMaintainControlbelow).Ifasthmaispartlycontrolled,anincreaseintreatmentshouldbeconsidered,subjecttowhethermoreeffectiveoptionsareavailable(e.g.,increaseddoseoranadditionaltreatment),safetyandcostofpossibletreatmentoptions,andthepatient’ssatisfactionwiththelevelofcontrolachieved.TheschemepresentedinFigure 4.3-2isbasedupontheseprinciples,buttherangeandsequenceofmedicationsusedineachclinicalsettingwillvarydependingonlocalavailability(forcostorotherreasons),acceptability,andpreference.

COMPONENT 3: ASSESS, TREAT, AND MONITOR ASTHMA

INTRODUCTION

ASSESSING ASTHMA CONTROL

TREATING TO ACHIEVE CONTROL

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Treatment Steps for Achieving Control

Mostofthemedicationsavailableforasthmapatients,whencomparedwithmedicationsusedforotherchronicdiseases,haveextremelyfavorabletherapeuticratios.Eachsteprepresentstreatmentoptionsthat,althoughnotofidenticalefficacy,arealternativesforcontrollingasthma.Steps1to5provideoptionsofincreasingefficacy,exceptforStep5whereissuesofavailabilityandsafetyinfluencetheselectionoftreatment.Step2istheinitialtreatmentformosttreatment-naïvepatientswithpersistentasthmasymptoms.Ifsymptomsattheinitialconsultationsuggestthatasthmaisseverelyuncontrolled(Figure 4.3-1),treatmentshouldbecommencedatStep3.

Ateachtreatmentstep,arelievermedication(rapid-onset bronchodilator,eithershort-actingorlong-acting)shouldbeprovidedforquickreliefofsymptoms.However,regularuseofrelievermedicationisoneoftheelementsdefininguncontrolledasthma,andindicatesthatcontrollertreatmentshouldbeincreased.Thus,reducingoreliminatingtheneedforrelievertreatmentisbothanimportantgoalandmeasureofsuccessoftreatment.ForSteps2through5,avarietyofcontrollermedicationsare

available.

Step 1: as-needed reliever medication.Step1treatmentwithanas-neededrelievermedicationisreservedforuntreatedpatientswithoccasionaldaytimesymptoms(cough,wheeze,dyspneaoccurringtwiceorlessperweek,orlessfrequentlyifnocturnal)ofshortduration(lastingonlyafewhours)comparablewithcontrolledasthma(Figure 4.3-1).Betweenepisodes,thepatientisasymptomaticwithnormallungfunctionandthereisnonocturnalawakening.Whensymptomsaremorefrequent,and/orworsenperiodically,patientsrequireregularcontrollertreatment(seeSteps2orhigher)inadditiontoas-neededrelievermedication111-113(Evidence B).

ForthemajorityofpatientsinStep1,a rapid-acting inhaled β2-agonististherecommendedrelievertreatment114(Evidence A).Aninhaledanticholinergic,short-actingoralβ2-agonist,orshort-actingtheophyllinemaybeconsideredasalternatives,althoughtheyhaveasloweronsetofactionandhigherriskofsideeffects(Evidence A).

Figure 4.3-1. LEVELS OF ASTHMA CONTROL

A. Assessment of current clinical control (preferably over 4 weeks)

Characteristic Controlled (All of the following)

Partly Controlled(Any measure present)

Uncontrolled

Daytime symptoms None (twice or less/week)

More than twice/week Three or more features of partly controlled asthma*†

Limitation 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)

B. Assessment of Future Risk (risk of exacerbations, instability, rapid decline in lung function, side-effects)

Features that are associated with increased risk of adverse events in the future include:

Poor clinical control, frequent exacerbations in past year*, ever admission to critical care for asthma, low FEV1, exposure to cigarette smoke, high dose medications

* Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate† By de�nition, an exacerbation in any week makes that an uncontrolled asthma week‡ Without administration of bronchodilator, lung function is not a reliable test for children 5 years and younger

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Management Approach Based On ControlFor Children Older Than 5 Years, Adolescents and Adults

Controlleroptions***

* ICS = inhaled glucocorticosteroids**= Receptor antagonist or synthesis inhibitors *** = Preferred controller options are shown in shaded boxes

Treatment Steps

As needed rapid-acting β2-agonist As needed rapid-acting β2-agonistLow-dose ICS pluslong-acting β2-agonistSelect one

Leukotrienemodifier**

Select one

Medium-orhigh-dose ICS Medium-or high-doseICS plus long-actingβ2-agonistLow-dose ICS plusleukotriene modifierLow-dose ICS plussustained releasetheophylline

To Step 3 treatment,select one or more To Step 4 treatment,add either

Asthma educationEnvironmental control

Low-dose inhaledICS* Oral glucocorticosteroid(lowest dose)Anti-IgEtreatmentLeukotrienemodifierSustained releasetheophylline

Controlled Maintain and find lowest controlling stepPartly controlled Consider stepping up to gain controlUncontrolled Step up until controlledExacerbation Treat as exacerbation

Treatment ActionLevel of Control Reduce

Reduce Increase

Increase

2Step1Step 3Step 4Step 5Step

Management Approach Based On ControlFor Children Older Than 5 Years, Adolescents and Adults

Controlleroptions***

* ICS = inhaled glucocorticosteroids**= Receptor antagonist or synthesis inhibitors *** = Preferred controller options are shown in shaded boxes

Treatment Steps

As needed rapid-acting β2-agonist

As needed rapid-acting β2-agonist

Low-dose ICS pluslong-acting β2-agonist

Select one

Leukotrienemodifier**

Select one

Medium-orhigh-dose ICS

Medium-or high-doseICS plus long-acting

β2-agonist

Low-dose ICS plusleukotriene modifier

Low-dose ICS plussustained release

theophylline

To Step 3 treatment,select one or more

To Step 4 treatment,add either

Asthma educationEnvironmental control

Low-dose inhaledICS*

Oral glucocorticosteroid(lowest dose)

Anti-IgEtreatment

Leukotrienemodifier

Sustained releasetheophylline

Controlled Maintain and find lowest controlling step

Partly controlled Consider stepping up to gain control

Uncontrolled Step up until controlled

Exacerbation Treat as exacerbation

Treatment ActionLevel of Control

Red

uce

Reduce Increase

Incr

ease

2Step1Step 3Step 4Step 5Step

Figure 4.3-2.

For guidelines on management of asthma in children 5 years and younger, please refer to the Global Strategy for the Diagnosis and management of Asthma in children 5 Years and Younger, available at www.ginasthma.org.

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

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Exercise-inducedbronchoconstriction.Physicalactivityisanimportantcauseofasthmasymptomsformostasthmapatients,andforsomeitistheonlycause.However,exercise-inducedbronchoconstrictionoftenindicatesthatthepatient’sasthmaisnotwellcontrolled,andsteppingupcontrollertherapygenerallyresultsinthereductionofexercise-relatedsymptoms.Forthosepatientswhostillexperienceexercise-inducedbronchoconstrictiondespiteotherwisewell-controlledasthma,andforthoseinwhomexercise-inducedbronchoconstrictionistheonlymanifestationofasthma,arapid-actinginhaledβ2-agonist(short-orlong-acting),takenpriortoexerciseortorelievesymptomsthatdevelopafterexercise,isrecommended115.Aleukotrienemodifier116,345orcromone117arealternatives(Evidence A).Trainingandsufficientwarm-upalsoreducetheincidenceandseverityofexercise-inducedbronchoconstriction118,119(Evidence B).Informationontreatmentofexercise-inducedasthmainathletescanbefoundinaJointTaskForceReportpreparedbytheEuropeanRespiratorySociety,theEuropeanAcademyofAllergyandClinicalImmunology,andGA(2)LEN359andtheWorldAnti-DopingAgencywebsite(www.wada-ama.org).

Step 2: Reliever medication plus a single controller.TreatmentSteps2through5,combineanas-neededrelievertreatmentwithregularcontrollertreatment.AtStep2,alow-dose inhaled glucocorticosteroidisrecommendedastheinitialcontrollertreatmentforasthmapatientsofallages111,120(Evidence A).Equivalentdosesofinhaledglucocorticosteroids,someofwhichmaybegivenasasingledailydose,areprovidedinFigure 3-1foradultsandinFigure 3-4forchildrenolderthan5years.

Alternativecontrollermedicationsincludeleukotrienemodifiers121-123(Evidence A),appropriateparticularlyforpatientswhoareunableorunwillingtouseinhaledglucocorticosteroids,orwhoexperienceintolerablesideeffectssuchaspersistenthoarsenessfrominhaledglucocorticosteroidtreatmentandthosewithconcomitantallergicrhinitis124,125(Evidence C).

Otheroptionsareavailablebutnotrecommendedforroutineuseasinitialorfirst-linecontrollersinStep2.Sustained-release theophyllinehasonlyweakanti-inflammatoryandcontrollerefficacy126-130(Evidence B)andiscommonlyassociatedwithsideeffectsthatrangefromtrivialtointolerable131,132.Cromones (nedocromil sodium and sodium cromoglycate)havecomparativelylowefficacy,thoughafavorablesafetyprofile133-136(Evidence A).

Step 3: Reliever medication plus one or two controllers. AtStep3,therecommendedoptionforadolescentsandadultsistocombinealow-dose of inhaled

glucocorticosteroid with an inhaled long-acting ß2-agonist,eitherinacombinationinhalerdeviceorasseparatecomponents137-144(Evidence A).Becauseoftheadditiveeffectofthiscombination,thelow-doseofglucocorticosteroidisusuallysufficient,andneedonlybeincreasedifcontrolisnotachievedwithin3or4monthswiththisregimen(Evidence A).Thelong-actingβ2-agonistformoterol,whichhasarapidonsetofactionwhethergivenalone145-148orincombinationinhalerwithbudesonide149,150,hasbeenshowntobeaseffectiveasshort-actingβ2-agonistinacuteasthmaexacerbation.Howeveritsuseasmonotherapyasarelievermedicationisstronglydiscouragedsinceitmustalwaysbeusedinassociationwithaninhaledglucocorticosteroid.

Forallchildrenbutparticularlythose5yearsandyounger,combinationtherapyhasbeenlesswellstudiedandtheadditionofalong-actingβ2-agonistmaynotbeaseffectiveasincreasingthedoseofinhaledglucocorticosteroidsinreducingexacerbations151-153.However,theinterpretationofsomestudiesisproblematicasnotallchildrenreceivedconcurrentinhaledglucocorticosteroids152,153.

Ifacombinationinhalercontainingformoterolandbudesonideisselected,itmaybeusedforbothrescueandmaintenance.Thisapproachhasbeenshowntoresultinreductionsinexacerbationsandimprovementsinasthmacontrolinadultsandadolescentsatrelativelylowdosesoftreatment154-157(Evidence A).Whetherthisapproachcanbeemployedwithothercombinationsofcontrollerandrelieverrequiresfurtherstudy.

Anotheroptionforbothadultsandchildren,buttheonerecommendedforchildren158,istoincreasetoamedium-dose of inhaled glucocorticosteroids104,159-161(Evidence A).Forpatientsofallagesonmedium-orhigh-doseofinhaledglucocorticosteroiddeliveredbyapressurizedmetered-doseinhaler,useofaspacerdeviceisrecommendedtoimprovedeliverytotheairways,reduceoropharyngealsideeffects,andreducesystemicabsorption162-164(Evidence A).

AnotheroptionatStep3istocombinealow-doseinhaledglucocorticosteroidwithleukotrienemodifiers165-173(Evidence A).Alternatively,theuseofsustained-releasetheophyllinegivenatlow-dosemaybeconsidered129(Evidence B).Theseoptionshavenotbeenfullystudiedinchildren5yearsandyounger.

Step 4: Reliever medication plus two or more controllers. TheselectionoftreatmentatStep4dependsonpriorselectionsatSteps2and3.However,theorderinwhichadditionalmedicationsshouldbeaddedisbased,asfaraspossible,uponevidenceoftheirrelativeefficacyCOPY

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inclinicaltrials.Wherepossible,patientswhoarenotcontrolledonStep3treatmentsshouldbereferred to a health professional with expertise in the management of asthmaforinvestigationofalternativediagnosesand/orcausesofdifficult-to-treatasthma.

ThepreferredtreatmentatStep4istocombineamedium-or high-dose of inhaled glucocorticosteroid with a long-acting inhaled β2-agonist.However,inmostpatients,theincreasefromamedium-toahigh-doseofinhaledglucocorticosteroidprovidesrelativelylittleadditionalbenefit104,159-161,174(Evidence A),andthehigh-doseisrecommendedonlyonatrialbasisfor3to6monthswhencontrolcannotbeachievedwithmedium-doseinhaledglucocorticosteroidcombinedwithalong-actingβ2-agonistand/orathirdcontroller(e.g.leukotrienemodifiersorsustained-releasetheophylline)130,175,346(Evidence B).Prolongeduseofhigh-doseinhaledglucocorticosteroidsisalsoassociatedwithincreasedpotentialforadverseeffects.Atmedium-andhigh-doses,twice-dailydosingisnecessaryformostbutnotallinhaledglucocorticosteroids176(Evidence A).Withbudesonide,efficacymaybeimprovedwithmorefrequentdosing(fourtimesdaily)177(Evidence B).(RefertoFigure 3-1foradultsandFigure 3-4forchildrenolderthan5yearsforrecommendationsondosingandfrequencyfordifferentinhaledglucocorticosteroids.)

Leukotriene modifiersasadd-ontreatmenttomedium-tohigh-doseinhaledglucocorticosteroidshavebeenshowntoprovidebenefit(Evidence A),butusuallylessthanthatachievedwiththeadditionofalong-actingβ2-agonist165-168,175,178(Evidence A).Theadditionofalow-doseofsustained-release theophylline130tomedium-orhigh-doseinhaledglucocorticosteroidandlong-actingβ2-agonistmayalsoprovidebenefit(Evidence B)129.

Step 5: Reliever medication plus additional controller options.Additionoforal glucocorticosteroidstoothercontrollermedicationsmaybeeffective179(Evidence D)butisassociatedwithseveresideeffects180(Evidence A)andshouldonlybeconsideredifthepatient’sasthmaremainsseverelyuncontrolledonStep4medicationswithdailylimitationofactivitiesandfrequentexacerbations.Patientsshouldbecounseledaboutpotentialsideeffectsandallotheralternativetreatmentsmustbeconsidered.

Additionofanti-IgE treatment toothercontrollermedicationshasbeenshowntoimprovecontrolofallergicasthmawhencontrolhasnotbeenachievedoncombinationsofothercontrollersincludinghigh-dosesofinhaledororalglucocorticosteroids181-186(Evidence B).

Whenasthmacontrolhasbeenachieved,ongoingmonitoringisessentialtomaintaincontrolandtoestablishtheloweststepanddoseoftreatmentnecessary,whichminimizesthecostandmaximizesthesafetyoftreatment.Ontheotherhand,asthmaisavariabledisease,andtreatmenthastobeadjustedperiodicallyinresponsetolossofcontrolasindicatedbyworseningsymptomsorthedevelopmentofanexacerbation.

Asthmacontrolshouldbemonitoredbythehealthcareprofessionalandpreferablyalsobythepatientatregularintervals,usingeitherasimplifiedschemeaspresentedinFigure 4.3-1 oravalidatedcompositemeasureofcontrol.Thefrequencyofhealthcarevisitsandassessmentsdependsuponthepatient’sinitialclinicalseverity,andthepatient’strainingandconfidenceinplayingaroleintheon-goingcontrolofhisorherasthma.Typically,patientsareseenonetothreemonthsaftertheinitialvisit,andeverythreemonthsthereafter.Afteranexacerbation,follow-upshouldbeofferedwithintwoweekstoonemonth(Evidence D).Generalpractitionersshouldbeencouragedtoassessasthmacontrolateveryvisit,notjustwhenthepatientpresentsbecauseoftheirasthma380.

Duration and Adjustments to Treatment

Formostclassesofcontrollermedications,improvementbeginswithindaysofinitiatingtreatment,butthefullbenefitmayonlybeevidentafter3or4months187,360.Insevereandchronicallyundertreateddisease,thiscantakeevenlonger188.

Thereducedneedformedicationoncecontrolisachievedisnotfullyunderstood,butmayreflectthereversalofsomeoftheconsequencesoflong-terminflammationoftheairways.Higherdosesofanti-inflammatorymedicationmayberequiredtoachievethisbenefitthantomaintainit.Alternatively,thereducedneedformedicationmightsimplyrepresentspontaneousimprovementaspartofthecyclicalnaturalhistoryofasthma.Rarely,asthmamaygointoremissionparticularlyinchildrenaged5yearsandyoungerandduringpuberty.Whatevertheexplanation,inallpatientstheminimumcontrollingdoseoftreatmentmustbesoughtthroughaprocessofregularfollow-upandstageddosereductions.

Atothertimestreatmentmayneedtobeincreasedeitherinresponsetolossofcontrolorthreatoflossofcontrol(returnofsymptoms)oranacuteexacerbation,whichis

MONITORING TO MAINTAINCONTROL

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definedasamoreacuteandseverelossofcontrolthatrequiresurgenttreatment.(AnapproachtoexacerbationsisprovidedinComponent4.4.)

Stepping Down Treatment When Asthma Is Controlled

Thereislittleexperimentaldataontheoptimaltiming,sequence,andmagnitudeoftreatmentreductionsinasthma,andtheapproachwilldifferfrompatienttopatientdependingonthecombinationofmedicationsandthedosesthatwereneededtoachievecontrol.Thesechangesshouldideallybemadebyagreementbetweenpatientandhealthcareprofessional,withfulldiscussionofpotentialconsequencesincludingreappearanceofsymptomsandincreasedriskofexacerbations.Althoughfurtherresearchonsteppingdownasthmatreatmentisneeded,somerecommendationscanbemadebasedonthecurrentevidence:

• Wheninhaled glucocorticosteroids aloneinmedium-tohigh-dosesarebeingused,a50%reductionindoseshouldbeattemptedat3monthintervals189-191(Evidence B).

• Wherecontrolisachievedatalow-doseofinhaledglucocorticosteroidsalone,inmostpatientstreatmentmaybeswitchedtoonce-dailydosing192,193(Evidence A).

• Whenasthmaiscontrolledwithacombination of inhaled glucocorticosteroid and long-acting ß2-agonist,thepreferredapproachtoistobeginbyreducingthedoseofinhaledglucocorticosteroidbyapproximately50%whilecontinuingthelong-actingβ2-agonist

150(Evidence B).Ifcontrolismaintained,furtherreductionsintheglucocorticosteroidshouldbeattempteduntilalow-doseisreached,whenthelong-actingβ2-agonistmaybestopped(Evidence D).Analternativeistoswitchthecombinationtreatmenttoonce-dailydosing194.Asecondalternativeistodiscontinuethelong-actingβ2-agonistatanearlierstageandsubstitutethecombinationtreatmentwithinhaledglucocorticosteroidmonotherapyatthesamedosecontainedinthecombinationinhaler.However,thisismorelikelytoleadtolossofasthmacontrol137,368(Evidence B).

• Whenasthmaiscontrolledwithinhaled glucocorticosteroids in combination with controllers other than long-acting β2-agonists,thedoseofinhaledglucocorticosteroidshouldbereducedby50%untilalow-doseofinhaledglucocorticosteroidisreached,thenthecombinationtreatmentstoppedasdescribedabove(Evidence D).

• Controller treatment may be stoppedifthepatient’sasthmaremainscontrolledonthelowestdoseofcontrollerandnorecurrenceofsymptomsoccursforoneyear(Evidence D).

Stepping Up Treatment In Response To Loss Of Control

Treatmenthastobeadjustedperiodicallyinresponsetoworseningcontrol,whichmayberecognizedbytheminorrecurrenceorworseningofsymptoms195.Treatmentoptionsareasfollows:

• Rapid-onset, short-acting or long-acting ß2-agonist bronchodilators.Repeateddosingwithbronchodilatorsinthisclassprovidestemporaryreliefuntilthecauseoftheworseningsymptomspasses.Theneedforrepeateddosesovermorethanoneortwodayssignalstheneedforreviewandpossibleincreaseofcontrollertherapy.

• Inhaled glucocorticosteroids.Temporarilydoublingthedoseofinhaledglucocorticosteroidshasnotbeendemonstratedtobeeffective,andisnolongerrecommended194,196(Evidence A).However,thereisemergingevidencethatquadruplingthedoseofinhaledglucocorticosteroidmightbeeffectivewhenasthmacontrolstartstodeteriorate,ifdoublingthedoesnotwork381.Afour-foldorgreaterincreasehasbeendemonstratedtobeequivalenttoashortcourseoforalglucocorticosteroidsinadultpatientswithanacutedeterioration195(Evidence A).Thehigherdoseshouldbemaintainedforseventofourteendaysbutmoreresearchisneededinbothadultsandchildrentostandardizetheapproach.

• Combination of inhaled glucocorticosteroids and rapid and long-acting ß2-agonist bronchodilator (e.g. formoterol) for combined relief and control.Theuseofthecombinationofarapidandlong-actingβ2-agonist(formoterol)andaninhaledglucocorticosteroid(budesonide)inasingleinhalerbothasacontrollerandrelieveriseffectiveinmaintainingahighlevelofasthmacontrolandreducesexacerbationsrequiringsystemicglucocorticosteroidsandhospitalization111,156,157,197(Evidence A).Thebenefitinpreventingexacerbationsappearstobetheconsequenceofearlyinterventionataveryearlystageofathreatenedexacerbationsincestudiesinvolvingdoublingorquadruplingdosesofcombinationtreatmentoncedeteriorationisestablished(for2ormoredays)showsomebenefitbutresultsareinconsistent195.BecausetherearenostudiesusingCOPY

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thisapproachwithothercombinationsofcontrollerandrelievers,otherthanbudesonide/formoterol,thealternativeapproachesdescribedinthissectionshouldbeusedforpatientsonothercontrollertherapies.

Forchildren(6to17years)whohaveuncontrolledasthmadespitetheuseoflow-doseinhaledglucocorticosteroids,step-uptherapywithlong-actingβ2-agonistbronchodilatorwassignificantlymorelikelytoprovidethebestresponsethaneitherstep-uptherapywithinhaledglucocorticosteroidsorleukotrienereceptorantagonist.However,manychildrenhadabestresponsetoinhaledglucocorticosteroidsorleukotrienereceptorantagoniststep-uptherapy,highlightingtheneedtoregularlymonitorandappropriatelyadjusteachchild’sasthmatherapy382.

Combinationtherapywithbudesonideandformoterolusedbothasmaintenanceandrescuehasbeenshowntoreduceasthmaexacerbationsinchildrenages4yearsandolderwithmoderatetosevereasthma347.

Theusualtreatmentforanacuteexacerbationisahigh-doseofβ2-agonistandaburstofsystemicglucocorticosteroidsadministeredorallyorintravenously.(RefertoComponent4formoreinformation.)

Followingtreatmentforanexacerbationofasthma,maintenancetreatmentcangenerallyberesumedatpreviouslevelsunlesstheexacerbationwasassociatedwithagraduallossofcontrolsuggestingchronicundertreatment.Inthiscase,providedinhalertechniquehasbeenchecked,astep-wiseincreaseintreatment(eitherindoseornumberofcontrollers)isindicated.

Difficult-to-Treat Asthma

• Althoughthemajorityofasthmapatientscanobtainthetargetedlevelofcontrol(Figure 4.3-1),somepatientswillnotdosoevenwiththebesttherapy104.PatientswhodonotreachanacceptablelevelofcontrolatStep4(reliever medication plus two or more controllers)canbeconsideredtohavedifficult-to-treatasthma198.Thesepatientsmayhaveanelementofpoorglucocorticosteroidresponsiveness,andrequirehigherdosesofinhaledglucocorticosteroidsthanareroutinelyusedinpatientswhoseasthmaiseasytocontrol.However,thereiscurrentlynoevidencetosupportcontinuingthesehigh-dosesofinhaledglucocorticosteroidsbeyond6monthsinthehopeofachievingbettercontrol.Instead,doseoptimizationshouldbepursuedbysteppingdowntoadosethatmaintainsthemaximallevelofcontrolachievedonthehigherdose.

Becauseveryfewpatientsarecompletelyresistanttoglucocorticosteroids,thesemedicationsremainamainstayoftherapyfordifficult-to-treatasthma,whileadditionaldiagnosticandgeneralizedtherapeuticoptionscanandshouldalsobeconsidered:

• Confirmthediagnosisofasthma.Inparticular,thepresenceofCOPDmustbeexcluded.Vocalcorddysfunctionmustbeconsidered.

• Investigateandconfirmcompliancewithtreatment.Incorrectorinadequateuseofmedicationsremainsthemostcommonreasonforfailuretoachievecontrol.

• Considersmoking, current or past,andencouragecompletecessation.Ahistoryofpasttobaccosmokingisassociatedwithareducedlikelihoodofcompleteasthmacontrol,andthisisonlypartlyattributabletothepresenceoffixedairflowobstruction.Inaddition,currentsmokingreducestheeffectivenessofinhaledandoralglucocorticosteroids199.Counselingandsmokingcessationprogramsshouldbeofferedtoallasthmapatientswhosmoke.

• Investigatethepresenceofcomorbiditiesthatmayaggravateasthma.Chronicsinusitis,gastroesophagealreflux,andobesity/obstructivesleepapneahavebeenreportedinhigherpercentagesinpatientswithdifficult-to-treatasthma.Psychologicalandpsychiatricdisordersshouldalsobeconsidered.Iffound,thesecomorbiditiesshouldbeaddressedandtreatedasappropriate,althoughtheabilitytoimproveasthmacontrolbydoingsoremainsunconfirmed200,348.

Whenthesereasonsforlackoftreatmentresponsehavebeenconsideredandaddressed,acompromiselevelofcontrolmayneedtobeacceptedanddiscussedwiththepatienttoavoidfutileover-treatment(withitsattendantcostandpotentialforadverseeffects).Theobjectiveisthentominimizeexacerbationsandneedforemergencymedicalinterventionswhileachievingashighalevelofclinicalcontrolwithaslittledisruptionofactivitiesandasfewdailysymptomsaspossible.Forthesedifficult-to-treatpatients,frequentuseofrescuemedicationisaccepted,asisadegreeofchroniclungfunctionimpairment.

Althoughlowerlevelsofcontrolaregenerallyassociatedwithanincreasedriskofexacerbations,notallpatientswithchronicallyimpairedlungfunction,reducedactivitylevels,anddailysymptomshavefrequentexacerbations.Insuchpatients,thelowestleveloftreatmentthatretainsthebenefitsachievedatthehigherdosesoftreatmentshouldbeemployed.ReductionsshouldbemadeCOPY

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cautiouslyandslowlyatintervalsnotmorefrequentthan3to6months,ascarryoveroftheeffectsofthehigherdosemaylastforseveralmonthsandmakeitdifficulttoassesstheimpactofthedosereduction(Evidence D).Referraltoaphysicianwithaninterestinand/orspecialfocusonasthmamaybehelpfulandpatientsmaybenefitfromphenotypingintocategoriessuchasallergic,aspirin-sensitive,and/oreosinophilicasthma201.Patientscategorizedasallergicmightbenefitfromanti-IgEtherapy183,andleukotrienemodifierscanbehelpfulforpatientsdeterminedtobeaspirinsensitive(whoareofteneosinophilicaswell)172.

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KEY POINTS:

• Exacerbationsofasthma(asthmaattacksoracuteasthma)areepisodesofprogressiveincreaseinshortnessofbreath,cough,wheezing,orchesttightness,orsomecombinationofthesesymptoms.

• Exacerbationsarecharacterizedbydecreasesinexpiratoryairflowthatcanbequantifiedandmonitoredbymeasurementoflungfunction(PEForFEV1).

• Theprimarytherapiesforexacerbationsincludetherepetitiveadministrationofrapid-actinginhaledbronchodilators,theearlyintroductionofsystemicglucocorticosteroids,andoxygensupplementation.

• Theaimsoftreatmentaretorelieveairflowobstructionandhypoxemiaasquicklyaspossible,andtoplanthepreventionoffuturerelapses.

• Severeexacerbationsarepotentiallylifethreatening,andtheirtreatmentrequiresclosesupervision.Mostpatientswithsevereasthmaexacerbationsshouldbetreatedinanacutecarefacility.Patientsathighriskofasthma-relateddeathalsorequirecloserattention.

• Milderexacerbations,definedbyareductioninpeakflowoflessthan20%,nocturnalawakening,andincreaseduseofshortactingβ2-agonistscanusuallybetreatedinacommunitysetting.

Exacerbationsofasthma(asthmaattacksoracuteasthma)areepisodesofprogressiveincreaseinshortnessofbreath,cough,wheezing,orchesttightness,orsomecombinationofthesesymptoms.Exacerbationsusuallyhaveaprogressiveonsetbutasubsetofpatients(mostlyadults)presentmoreacutely361.Respiratorydistressiscommon.Exacerbationsarecharacterizedbydecreasesinexpiratoryairflowthatcanbequantifiedbymeasurementoflungfunction(PEForFEV1)

202.Thesemeasurementsaremorereliableindicatorsoftheseverityofairflowlimitationthanisthedegreeofsymptoms.Thedegreeofsymptomsmay,however,beamoresensitivemeasureoftheonsetofanexacerbationbecausetheincreaseinsymptomsusuallyprecedesthedeteriorationinpeakflowrate203.Still,aminorityofpatientsperceivesymptomspoorly,andmayhaveasignificantdeclineinlungfunctionwithoutasignificantchangeinsymptoms.Thissituationespeciallyaffectspatientswithahistoryofnear-fatalasthmaandalso

appearstobemorelikelyinmales.Aclinicallyusefultooltoassessthelikelihoodofasthma-relatedhospitalizationsoremergencydepartmentvisitsinadultswithsevereordifficulttotreatasthmahasbeendescribed349.

Strategiesfortreatingexacerbations,thoughgeneralizable,arebestadaptedandimplementedatalocallevel204,205.Severeexacerbationsarepotentiallylifethreatening,andtheirtreatmentrequiresclosesupervision.Patientswithsevereexacerbationsshouldbeencouragedtoseetheirphysicianpromptlyor,dependingontheorganizationoflocalhealthservices,toproceedtothenearestclinicorhospitalthatprovidesemergencyaccessforpatientswithacuteasthma.Closeobjectivemonitoring(PEF)oftheresponsetotherapyisessential.

Theprimarytherapiesforexacerbationsinclude—intheorderinwhichtheyareintroduced,dependingonseverity—repetitiveadministrationofrapid-actinginhaledbronchodilators,earlyintroductionofsystemicglucocorticosteroids,andoxygensupplementation202.Theaimsoftreatmentaretorelieveairflowobstructionandhypoxemiaasquicklyaspossible,andtoplanthepreventionoffuturerelapses.

Patientsathighriskofasthma-relateddeathrequirecloserattentionandshouldbeencouragedtoseekurgentcareearlyinthecourseoftheirexacerbations.Thesepatientsincludethose:

• Withahistoryofnear-fatalasthmarequiringintubationandmechanicalventilation206

• Whohavehadahospitalizationoremergencycarevisitforasthmainthepastyear

• Whoarecurrentlyusingorhaverecentlystoppedusingoralglucocorticosteroids

• Whoarenotcurrentlyusinginhaledglucocorticosteroids207

• Whoareoverdependentonrapid-actinginhaledβ2-agonists,especiallythosewhousemorethanonecanisterofsalbutamol(orequivalent)monthly208

• Withahistoryofpsychiatricdiseaseorpsychosocial350problems,includingtheuseofsedatives209

• Withahistoryofnoncompliancewithanasthmamedicationplan.

Responsetotreatmentmaytaketimeandpatientsshouldbecloselymonitoredusingclinicalaswellasobjectivemeasurements.Theincreasedtreatmentshouldcontinue

COMPONENT 4: MANAGE ASTHMA EXACERBATIONS

INTRODUCTION

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untilmeasurementsoflungfunction(PEForFEV1)returntotheirpreviousbest(ideally)orplateau,atwhichtimeadecisiontoadmitordischargecanbemadebaseduponthesevalues.Patientswhocanbesafelydischargedwillhaverespondedwithinthefirsttwohours,atwhichtimedecisionsregardingpatientdispositioncanbemade.

Theseverityoftheexacerbation(Figure 4.4-1)determinesthetreatmentadministered.Indicesofseverity,particularly

PEF(inpatientsolderthan5years),pulserate,respiratoryrate,andpulseoximetry210,shouldbemonitoredduringtreatment.

Mostpatientswithsevereasthmaexacerbationsshouldbetreatedinanacutecarefacility(suchasahospitalemergencydepartment)wheremonitoring,including

ASSESSMENT OF SEVERITY

MANAGEMENT—COMMUNITY SETTINGS

Figure 4.4-1. Severity of Asthma Exacerbations*

Mild Moderate Severe Respiratory arrestimminent

Breathless Walking Talking At restInfant—softer Infant stops feedingshorter cry;difficulty feeding

Can lie down Prefers sitting Hunched forwardTalks in Sentences Phrases WordsAlertness May be agitated Usually agitated Usually agitated Drowsy or confusedRespiratory rate Increased Increased Often > 30/min

Normal rates of breathing in awake children:Age Normal rate< 2 months < 60/min2-12 months < 50/min1-5 years < 40/min6-8 years < 30/min

Accessory muscles Usually not Usually Usually Paradoxical thoraco-and suprasternal abdominal movementretractionsWheeze Moderate, often only Loud Usually loud Absence of wheeze

end expiratoryPulse/min. < 100 100-120 >120 Bradycardia

Guide to limits of normal pulse rate in children:Infants 2-12 months–Normal Rate < 160/minPreschool 1-2 years < 120/minSchool age 2-8 years < 110/min

Pulsus paradoxus Absent May be present Often present Absence suggests< 10 mm Hg 10-25 mm Hg > 25 mm Hg (adult) respiratory muscle

20-40 mm Hg (child) fatiguePEF Over 80% Approx. 60-80% < 60% predicted orafter initial personal bestbronchodilator (< 100 L/min adults)% predicted or or% personal best response lasts < 2 hrsPaO2 (on air)† Normal > 60 mm Hg < 60 mm Hg

Test not usuallynecessary Possible cyanosis

and/orPaCO2† < 45 mm Hg < 45 mm Hg > 45 mm Hg;

Possible respiratoryfailure (see text)

SaO2% (on air)† > 95% 91-95% < 90%Hypercapnea (hypoventilation) develops more readily in young children than inadults and adolescents.

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

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objectivemeasurementofairflowobstruction,oxygensaturation,andcardiacfunction,ispossible.Milderexacerbations,definedbyareductioninpeakflowoflessthan20%,nocturnalawakening,andincreaseduseofshortactingβ2-agonistscanusuallybetreatedinacommunitysetting.Ifthepatientrespondstotheincreaseininhaledbronchodilatortreatmentafterthefirstfewdoses,referraltoanacutecarefacilityisnotrequired,butfurthermanagementunderthedirectionofaprimarycarephysicianmayincludetheuseofsystemicglucocorticosteroids.Patienteducationandreviewofmaintenancetherapyshouldalsobeundertaken.

Treatment

Bronchodilators.Formildtomoderateexacerbations,repeatedadministrationofrapid-actinginhaledβ-agonists(2to4puffsevery20minutesforthefirsthour)isusuallythebestandmostcost-effectivemethodofachievingrapidreversalofairflowlimitation.Afterthefirsthour,thedoseofβ-agonistrequiredwilldependontheseverityoftheexacerbation.Mildexacerbationsrespondto2to4puffsevery3to4hours;moderateexacerbationswillrequire6to10puffsevery1or2hours.Treatmentshouldalsobetitrateddependingupontheindividualpatient’sresponse,andifthereisalackofresponseorotherconcernabouthowthepatientisresponding,thepatientshouldbereferredtoanacutecarefacility.

ManypatientswillbeabletomonitortheirPEFaftertheinitiationofincreasedbronchodilatortherapy.Bronchodilatortherapydeliveredviaametered-doseinhaler(MDI),ideallywithaspacer,producesatleastanequivalentimprovementinlungfunctionasthesamedose164,211deliveredvianebulizer.Atthecliniclevel,thisrouteofdeliveryisthemostcosteffective212,providedpatientsareabletouseanMDI.Noadditionalmedicationisnecessaryiftherapid-actinginhaledβ-agonistproducesacompleteresponse(PEFreturnstogreaterthan80%ofpredictedorpersonalbest)andtheresponselastsfor3to4hours.

Glucocorticosteroids.Oralglucocorticosteroids(0.5to1mgofprednisolone/kgorequivalentduringa24-hourperiod)shouldbeusedtotreatexacerbations,especiallyiftheydevelopafterinstitutingtheothershort-termtreatmentoptionsrecommendedforlossofcontrol(see“Steppinguptreatmentinresponsetolossofcontrol”inComponent3).Ifpatientsfailtorespondtobronchodilatortherapy,asindicatedbypersistentairflowobstruction,prompttransfertoanacutecaresettingisrecommended,especiallyiftheyareinahighriskgroup.

Severeexacerbationsofasthmaarelife-threateningmedicalemergencies,treatmentofwhichisoftenmostsafelyundertakeninanemergencydepartment.Figure 4.4-2illustratestheapproachtoacutecare-basedmanagementofexacerbations.

Assessment

Abriefhistoryandphysicalexaminationpertinenttotheexacerbationshouldbeconductedconcurrentlywiththepromptinitiationoftherapy.Thehistoryshouldinclude:severityanddurationofsymptoms,includingexerciselimitationandsleepdisturbance;allcurrentmedications,includingdose(anddevice)prescribed,doseusuallytaken,dosetakeninresponsetothedeterioration,andthepatient’sresponse(orlackthereof)tothistherapy;timeofonsetandcauseofthepresentexacerbation;andriskfactorsforasthma-relateddeath.

Thephysicalexaminationshouldassessexacerbationseveritybyevaluatingthepatient’sabilitytocompleteasentence,pulserate,respiratoryrate,useofaccessorymuscles,andothersignsdetailedinFigure 4.4-2.Anycomplicatingfactorsshouldbeidentified(e.g.,pneumonia,atelectasis,pneumothorax,orpneumomediastinum).FunctionalassessmentssuchasPEForFEV1andarterialoxygensaturationmeasurementsarestronglyrecommendedasphysicalexaminationalonemaynotfullyindicatetheseverityoftheexacerbation,particularlythedegreeofhypoxemia213,214.Withoutundulydelayingtreatment,abaselinePEForFEV1measurementshouldbemadebeforetreatmentisinitiated.Subsequentmeasurementsshouldbemadeatintervalsuntilaclearresponsetotreatmenthasoccurred.

Oxygensaturationshouldbecloselymonitored,preferablybypulseoximetry.Thisisespeciallyusefulinchildrenbecauseobjectivemeasurementsoflungfunctionmaybedifficult.Oxygensaturationinchildrenshouldnormallybegreaterthan95%,andoxygensaturationlessthan92%isagoodpredictoroftheneedforhospitalization210(Evidence C).

InadultsachestX-rayisnotroutinelyrequired,butshouldbecarriedoutifacomplicatingcardiopulmonaryprocessissuspected,inpatientsrequiringhospitalization,andinthosenotrespondingtotreatmentwhereapneumothoraxmaybedifficulttodiagnoseclinically215.Similarly,inchildrenroutinechestX-raysarenotrecommendedunlesstherearephysicalsignssuggestiveofparenchymaldisease216.

MANAGEMENT—ACUTE CARE SETTINGS

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

Reassess after 1-2 Hours

Reassess at intervals

Improved (see opposite)

Initial Assessment (see Figure 4.4-1)• History, physical examination (auscultation, use of accessory muscles, heart rate, respiratory rate, PEF or FEV1, oxygen

saturation, arterial blood gas if patient in extremis)

Reassess after 1 HourPhysical Examination, PEF, O2 saturation and other tests as needed

Initial Treatment• Oxygen to achieve O2 saturation ≥ 90% (95% in children)• Inhaled rapid-acting �2-agonist continuously for one hour.• Systemic glucocorticosteroids if no immediate response, or if patient recently took oral glucocorticosteroid, or if episode is severe.• Sedation is contraindicated in the treatment of an exacerbation.

Criteria for Moderate Episode:• PEF 60-80% predicted/personal best• Physical exam: moderate symptoms, accessory muscle useTreatment:• Oxygen• Inhaled �2-agonist and inhaled anticholinergic every 60 min• Oral glucocorticosteroids• Continue treatment for 1-3 hours, provided there is improvement

Good Response within 1-2 Hours:• Response sustained 60 min after last

treatment• Physical exam normal: No distress• PEF > 70% • O2 saturation > 90% (95% children)

Incomplete Response within 1-2Hours:• Risk factors for near fatal asthma• Physical exam: mild to moderate signs• PEF < 60%• O2 saturation not improving

Poor Response within 1-2 Hours:• Risk factors for near fatal asthma• Physical exam: symptoms severe,

drowsiness, confusion• PEF < 30%• PCO2 > 45 mm Hg• P O2 < 60mm HgAdmit to Intensive Care• Oxygen • Inhaled �2-agonist + anticholinergic • Intravenous glucocorticosteroids • Consider intravenous �2-agonist • Consider intravenous theophylline• Possible intubation and mechanical

ventilation

Poor Response (see above):• Admit to Intensive CareIncomplete response in 6-12 hours(see above)• Consider admission to Intensive Care

if no improvement within 6-12 hours

Admit to Acute Care Setting• Oxygen• Inhaled �2-agonist ± anticholinergic• Systemic glucocorticosteroid• Intravenous magnesium• Monitor PEF, O2 saturation, pulse

Improved: Criteria for Discharge Home• PEF > 60% predicted/personal best• Sustained on oral/inhaled medicationHome Treatment:• Continue inhaled �2-agonist• Consider, in most cases, oral glucocorticosteroids• Consider adding a combination inhaler• Patient education: Take medicine correctly

Review action planClose medical follow-up

Criteria for Severe Episode:• History of risk factors for near fatal asthma• PEF < 60% predicted/personal best• Physical exam: severe symptoms at rest, chest retraction• No improvement after initial treatmentTreatment:• Oxygen• Inhaled �2-agonist and inhaled anticholinergic• Systemic glucocorticosteroids• Intravenous magnesium

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Althougharterialbloodgasmeasurementsarenotroutinelyrequired216,theyshouldbecompletedinpatientswithaPEFof30to50%predicted,thosewhodonotrespondtoinitialtreatment,orwhenthereisconcernregardingdeterioration.Thepatientshouldcontinueonsupplementaloxygenwhilethemeasurementismade.APaO2<60mmHg(8kPa)andanormalorincreasedPaCO2(especially>45mmHg,6kPa)indicatesthepresenceofrespiratoryfailure.

Treatment

Thefollowingtreatmentsareusuallyadministeredconcurrentlytoachievethemostrapidresolutionoftheexacerbation217:

Oxygen.Toachievearterialoxygensaturationof90%(95%inchildren),oxygenshouldbeadministeredbynasalcannulae,bymask,orrarelybyheadboxinsomeinfants.PaCO2mayworseninsomepatientson100percentoxygen,especiallythosewithmoresevereairflowobstruction218.Oxygentherapyshouldbetitratedagainstpulseoximetrytomaintainasatisfactoryoxygensaturation219.

Rapid-acting inhaled ß2–agonists.Rapid-actinginhaledβ2-agonistsshouldbeadministeredatregularintervals

220-222(Evidence A).Themostcosteffectiveandefficientdeliveryisbymeterdoseinhalerandaspacerdevice64,211.Althoughmostrapid-actingβ2-agonistshaveashortdurationofeffect,thelong-actingbronchodilatorformoterol,whichhasbotharapidonsetofactionandalongdurationofeffect,hasbeenshowntobeequallyeffectivewithoutincreasingsideeffects,thoughitisconsiderablymoreexpensive148.Theimportanceofthisfeatureofformoterolisthatitprovidessupportandreassuranceregardingtheuseofacombinationofformoterolandbudesonideearlyinasthmaexacerbations.Amodestlygreaterbronchodilatoreffecthasbeenshownwithlevabuterolcomparedtoracemicalbuterolinbothadultsandchildrenwithanasthmaexacerbation223-226.Inalargestudyofacuteasthmainchildren227,andinadultsnotpreviouslytreatedwithglucocorticosteroids226,levabuteroltreatmentresultedinlowerhospitalizationratescomparedtoracemicalbuteroltreatment,butinchildrenthelengthofhospitalstaywasnodifferent227.

Studiesofintermittentversuscontinuousnebulizedshort-actingβ2-agonistsinacuteasthmaprovideconflictingresults.Inasystematicreviewofsixstudies228,therewerenosignificantdifferencesinbronchodilatoreffectorhospitaladmissionsbetweenthetwotreatments.Inpatientswhorequirehospitalization,onestudy229foundthatintermittent

on-demandtherapyledtoasignificantlyshorterhospitalstay,fewernebulizations,andfewerpalpitationswhencomparedwithintermittenttherapygivenevery4hours.Areasonableapproachtoinhaledtherapyinexacerbations,therefore,wouldbetheinitialuseofcontinuoustherapy,followedbyintermittenton-demandtherapyforhospitalizedpatients.Thereisnoevidencetosupporttheroutineuseofintravenousβ2-agonistsinpatientswithsevereasthmaexacerbations230.

Epinephrine.Asubcutaneousorintramuscularinjectionofepinephrine(adrenaline)maybeindicatedforacutetreatmentofanaphylaxisandangioedema,butisnotroutinelyindicatedduringasthmaexacerbations.

Additional bronchodilators.

Ipratropiumbromide.Acombinationofnebulizedβ2-agonistwithananticholinergic(ipratropiumbromide)mayproducebetterbronchodilationthaneitherdrugalone231(Evidence B)andshouldbeadministeredbeforemethylxanthinesareconsidered.Combinationβ2-agonist/anticholinergictherapyisassociatedwithlowerhospitalizationrates212,232,233(Evidence A)andgreaterimprovementinPEFandFEV1

233(Evidence B).Similardatahavebeenreportedinthepediatricliterature212(Evidence A).However,oncechildrenwithasthmaarehospitalizedfollowingintensiveemergencydepartmenttreatment,theadditionofnebulizedipratropiumbromidetonebulizedβ2-agonistandsystemicglucocorticosteroidsappearstoconfernoextrabenefit234.Theophylline.Inviewoftheeffectivenessandrelativesafetyofrapid-actingβ2-agonists,theophyllinehasaminimalroleinthemanagementofacuteasthma235.Itsuseisassociatedwithsevereandpotentiallyfatalsideeffects,particularlyinthoseonlong-termtherapywithsustained-releasetheophylline,andtheirbronchodilatoreffectislessthanthatofβ2-agonists.Thebenefitasadd-ontreatmentinadultswithsevereasthmaexacerbationshasnotbeendemonstrated.However,inonestudyofchildrenwithnear-fatalasthma,intravenoustheophyllineprovidedadditionalbenefittopatientsalsoreceivinganaggressiveregimenofinhaledandintravenousβ2-agonists,inhaledipatropiumbromide,andintravenoussystemicglucocorticosteroids236.

Systemic glucocorticosteroids. Systemicglucocorticosteroidsspeedresolutionofexacerbationsandshouldbeutilizedintheallbutthemildestexacerbations237,238(Evidence A),especiallyif:

• Theinitialrapid-actinginhaledβ2-agonisttherapyfailstoachievelastingimprovement

• TheexacerbationdevelopseventhoughthepatientwasalreadytakingoralglucocorticosteroidsCOPY

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• Previousexacerbationsrequiredoralglucocorticosteroids.

Oralglucocorticosteroidsareusuallyaseffectiveasthoseadministeredintravenouslyandarepreferredbecausethisrouteofdeliveryislessinvasiveandlessexpensive239,240.Ifvomitinghasoccurredshortlyafteradministrationoforalglucocorticosteroids,thenanequivalentdoseshouldbere-administeredintravenously.Inpatientsdischargedfromtheemergencydepartment,intramuscularadministrationmaybehelpful241,especiallyifthereareconcernsaboutcompliancewithoraltherapy.Oralglucocorticosteroidsrequireatleast4hourstoproduceclinicalimprovement.Dailydosesofsystemicglucocorticosteroidsequivalentto60-80mgmethylprednisoloneasasingledose,or300-400mghydrocortisoneindivideddoses,areadequateforhospitalizedpatients,and40mgmethylprednisoloneor200mghydrocortisoneisprobablyadequateinmostcases238,242(Evidence B).Anoralglucocorticosteroiddoseof1mg/kgdailyisadequatefortreatmentofexacerbationsinchildrenwithmildpersistentasthma243.A7-daycourseinadultshasbeenfoundtobeaseffectiveasa14-daycourse244,anda3-to5-daycourseinchildrenisusuallyconsideredappropriate(Evidence B).Currentevidencesuggeststhatthereisnobenefittotaperingthedoseoforalglucocorticosteroids,eitherintheshort-term245oroverseveralweeks246(Evidence B).

Inhaled glucocorticosteroids.Inhaledglucocorticosteroidsareeffectiveaspartoftherapyforasthmaexacerbations.Inonestudy,thecombinationofhigh-doseinhaledglucocorticosteroidsandsalbutamolinacuteasthmaprovidedgreaterbronchodilationthansalbutamolalone247(Evidence B),andconferredgreaterbenefitthantheadditionofsystemicglucocorticosteroidsacrossallparameters,includinghospitalizations,especiallyforpatientswithmoresevereattacks248.

Inhaledglucocorticosteroidscanbeaseffectiveasoralglucocorticosteroidsatpreventingrelapses249,250.Patientsdischargedfromtheemergencydepartmentonprednisoneandinhaledbudesonidehavealowerrateofrelapsethanthoseonprednisonealone237(Evidence B).Ahigh-doseofinhaledglucocorticosteroid(2.4mgbudesonidedailyinfourdivideddoses)achievesarelapseratesimilarto40mgoralprednisonedaily251(Evidence A).Costisasignificantfactorintheuseofsuchhigh-dosesofinhaledglucocorticosteroids,andfurtherstudiesarerequiredtodocumenttheirpotentialbenefits,especiallycosteffectiveness,inacuteasthma252.

Magnesium*.Intravenousmagnesiumsulphate(usuallygivenasasingle2ginfusionover20minutes)isnotrecommendedforroutineuseinasthmaexacerbations,

butcanhelpreducehospitaladmissionratesincertainpatients,includingadultswithFEV125-30%predictedatpresentation,adultsandchildrenwhofailtorespondtoinitialtreatment,andchildrenwhoseFEV1failstoimproveabove60%predictedafter1hourofcare253,254(Evidence A).Nebulizedsalbutamoladministeredinisotonicmagnesiumsulfateprovidesgreaterbenefitthanifitisdeliveredinnormalsaline255,256(Evidence A).Intravenousmagnesiumsulphatehasnotbeenstudiedinyoungchildren.

Helium oxygen therapy.Asystematicsurveyofstudiesthathaveevaluatedtheeffectofacombinationofheliumandoxygen,comparedtoheliumalone,suggeststhereisnoroutineroleforthisintervention.Itmightbeconsideredforpatientswhodonotrespondtostandardtherapy257.

Leukotriene modifiers.Thereislittledatatosuggestaroleforleukotrienemodifiersinacuteasthma258.

Sedatives.Sedationshouldbestrictlyavoidedduringexacerbationsofasthmabecauseoftherespiratorydepressanteffectofanxiolyticandhypnoticdrugs.Anassociationbetweentheuseofthesedrugsandavoidableasthmadeaths209,259hasbeendemonstrated.

Criteria for Discharge from the Emergency Department vs. Hospitalization

Criteriafordeterminingwhetherapatientshouldbedischargedfromtheemergencydepartmentoradmittedtothehospitalhavebeensuccinctlyreviewedandstratifiedbasedonconsensus260.Patientswithapre-treatmentFEV1orPEF<25%percentpredictedorpersonalbest,orthosewithapost-treatmentFEV1orPEF<40%percentpredictedorpersonalbest,usuallyrequirehospitalization.Patientswithpost-treatmentlungfunctionof40-60%predictedmaybedischarged,providedthatadequatefollow-upisavailableinthecommunityandcomplianceisassured.Patientswithpost-treatmentlungfunction60%predictedcanbedischarged.

Managementofacuteasthmaintheintensivecareunitisbeyondthescopeofthisdocumentandreadersarereferredtorecentcomprehensivereviews261.

Forpatientsdischargedfromtheemergencydepartment:

• Ataminimum,a7-daycourseoforalglucocorticosteroidsforadultsandashortercourse(3-5days)forchildrenshouldbeprescribed,alongwithcontinuationofbronchodilatortherapy.

*Visit GINA website, www.ginasthma.org for GRADE review of question “In adults with acute exacerbations of asthma, does intravenous magnesium sulphate compared to placebo improve patient important outcomes?”

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• Thebronchodilatorcanbeusedonanas-neededbasis,basedonbothsymptomaticandobjectiveimprovement,untilthepatientreturnstohisorherpre-exacerbationuseofrapid-actinginhaledβ2-agonists.

• Ipratropiumbromideisunlikelytoprovideadditionalbenefitbeyondtheacutephaseandmaybequicklydiscontinued.

• Patientsshouldinitiateorcontinueinhaledglucocorticosteroids.

• Thepatient’sinhalertechniqueanduseofpeakflowmetertomonitortherapyathomeshouldbereviewed.Patientsdischargedfromtheemergencydepartmentwithapeakflowmeterandactionplanhaveabetterresponsethanpatientsdischargedwithouttheseresources8.

• Thefactorsthatprecipitatedtheexacerbationshouldbeidentifiedandstrategiesfortheirfutureavoidanceimplemented.

• Thepatient’sresponsetotheexacerbationshouldbeevaluated.Theactionplanshouldbereviewedandwrittenguidanceprovided.

• Useofcontrollertherapyduringtheexacerbationshouldbereviewed:whetherthistherapywasincreasedpromptly,byhowmuch,and,ifappropriate,whyoralglucocorticosteroidswerenotadded.Considerprovidingashortcourseoforalglucocorticosteroidstobeonhandforsubsequentexacerbations.

• Thepatientorfamilyshouldbeinstructedtocontacttheprimaryhealthcareprofessionalorasthmaspecialistwithin24hoursofdischarge.Afollow-upappointmentwiththepatient’susualprimarycareprofessionalorasthmaspecialistshouldbemadewithinafewdaysofdischargetoassurethattreatmentiscontinueduntilbaselinecontrolparameters,includingpersonalbestlungfunction,arereached.Prospectivedataindicatethatpatientsdischargedfromtheemergencydepartmentforfollow-upwithspecialistcaredobetterthanpatientsreturnedtoroutinecare262.

Anexacerbationsevereenoughtorequirehospitalizationmayreflectafailureofthepatient’sself-managementplan.Hospitalizedpatientsmaybeparticularlyreceptivetoinformationandadviceabouttheirillness.Healthcareprovidersshouldtaketheopportunitytoreviewpatientunderstandingofthecausesofasthmaexacerbations,avoidanceoffactorsthatmaycauseexacerbations(including,whererelevantsmokingcessation),thepurposesandcorrectusesoftreatment,andtheactionstobetakentorespondtoworseningsymptomsorpeakflowvalues263(Evidence A).

Referraltoanasthmaspecialistshouldbeconsideredforhospitalizedpatients.Followingdischargefromcontinuoussupervision,thepatientshouldbereviewedbythefamilyhealthcareprofessionalorasthmaspecialistregularlyoverthesubsequentweeksuntilpersonalbestlungfunctionisreached.Useofincentivesimprovesprimarycarefollowupbuthasshownnoeffectonlongtermoutcomes264.Patientswhocometotheemergencydepartmentwithanacuteexacerbationshouldbeespeciallytargetedforanasthmaeducationprogram,ifoneisavailable.

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Specialconsiderationsarerequiredinmanagingasthmainrelationtopregnancy;obesity;surgery;rhinitis,sinusitis,andnasalpolyps;occupationalasthma;respiratoryinfections;gastroesophagealreflux;aspirin-inducedasthma;andanaphylaxis.

Pregnancy

Duringpregnancytheseverityofasthmaoftenchanges,andpatientsmayrequireclosefollow-upandadjustmentofmedications.Inapproximatelyone-thirdofwomenasthmabecomesworse;inone-thirdasthmabecomeslesssevere;andintheremainingone-thirditremainsunchangedduringpregnancy265-267.

Althoughthereisageneralconcernabouttheuseofanymedicationinpregnancy,poorlycontrolledasthmacanhaveanadverseeffectonthefetus,resultinginincreasedperinatalmortality,increasedprematurity,andlowbirthweight266,267.Theoverallperinatalprognosisforchildrenborntowomenwithasthmathatiswell-managedduringpregnancyiscomparabletothatforchildrenborntowomenwithoutasthma268.Forthisreason,usingmedicationstoobtainoptimalcontrolofasthmaisjustifiedevenwhentheirsafetyinpregnancyhasnotbeenunequivocallyproven.Formostmedicationsusedtotreatasthmathereislittleevidencetosuggestanincreasedrisktothefetus.Appropriatelymonitoreduseoftheophylline,inhaledglucocorticosteroids351,β2-agonists,andleukotrienemodifiers(specificallymontelukast)isnotassociatedwithanincreasedincidenceoffetalabnormalities369.Inhaledglucocorticosteroidshavebeenshowntopreventexacerbationsofasthmaduringpregnancy269,270(Evidence B).Asinothersituations,thefocusofasthmatreatmentmustremainoncontrolofsymptomsandmaintenanceofnormallungfunction271.Acuteexacerbationsshouldbetreatedaggressivelyinordertoavoidfetalhypoxia.Treatmentshouldincludenebulizedrapid-actingβ2-agonistsandoxygenandsystemicglucocorticosteroidsshouldbeinstitutedwhennecessary.

Whileallpatientsshouldhaveadequateopportunitytodiscussthesafetyoftheirmedications,pregnantpatientswithasthmashouldbeadvisedthatthegreaterrisktotheirbabylieswithpoorlycontrolledasthma,andthesafetyofmostmodernasthmatreatmentsshouldbestressed.Evenwithagoodpatient/healthcareprofessionalrelationship,independentprintedmaterial,suchasastatementfromtheUSNationalAsthmaEducationandPreventionProgramonthetreatmentofasthmaduringpregnancy272,willprovideimportantadditionalreassurance265,273.

Obesity

Asthmaismoredifficulttocontrolintheobesepatient383-386.Thismaybeduetoadifferenttypeofairwayinflammation(lesseosinophilic),obesity-relatedco-morbiditiessuchasobstructivesleepapneaandgastroesophagealreflux,mechanicalfactorsorotherasyetundefinedfactors.Thereisnotsufficientevidencetosuggestthatthemanagementofasthmaintheobeseshouldbedifferentthaninpatientswithnormalweight.However,thereseemstobeareducedresponsetoinhaledglucocorticosteroidsintheobesepatient,andalthoughthisseemstobelessevidentwithleukotrieneantagonists,inhaledglucocorticosteroidsareconsideredthemainstayofasthmatreatmentinthispopulation385,386.

Althoughasthmaisnotmoreoftenover-diagnosedinobesecomparedtonon-obesepatients,itisparticularlyimportanttoconfirmthediagnosisbyobjectivemeasuresofvariableairwayobstructionorbronchialhyper-responsiveness,asrespiratorysymptomsassociatedtoobesitymaymimicasthma388.Weightlossintheobesepatientimprovesasthmacontrol,lungfunctionandreducesmedicationneedsandshouldbeincludedinthetreatmentplan94,389,390

Surgery

Airwayhyperresponsiveness,airflowlimitation,andmucushypersecretionpredisposepatientswithasthmatointraoperativeandpostoperativerespiratorycomplications.Thelikelihoodofthesecomplicationsdependsontheseverityofasthmaatthetimeofsurgery,thetypeofsurgery(thoracicandupperabdominalsurgeriesposethegreatestrisks),andtypeofanesthesia(generalanesthesiawithendotrachealintubationcarriesthegreatestrisk).Thesevariablesneedtobeassessedpriortosurgeryandpulmonaryfunctionshouldbemeasured.Ifpossible,thisevaluationshouldbeundertakenseveraldaysbeforesurgerytoallowtimeforadditionaltreatment.Inparticular,ifthepatient’sFEV1islessthan80%ofpersonalbest,abriefcourseoforalglucocorticosteroidsshouldbeconsideredtoreduceairflowlimitation274,275(Evidence C).Furthermore,patientswhohavereceivedsystemicglucocorticosteroidswithinthepast6monthsshouldhavesystemiccoverageduringthesurgicalperiod(100mghydrocortisoneevery8hoursintravenously).Thisshouldberapidlyreduced24hoursfollowingsurgery,asprolongedsystemicglucocorticosteroidtherapymayinhibitwoundhealing276(Evidence C).

COMPONENT 5: SPECIAL CONSIDERATIONS

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Rhinitis, Sinusitis, and Nasal Polyps

Upperairwaydiseasescaninfluencelowerairwayfunctioninsomepatientswithasthma.Althoughthemechanismsbehindthisrelationshiphavenotbeenestablished,inflammationlikelyplaysasimilarlycriticalroleinthepathogenesisofrhinitis,sinusitis,andnasalpolypsasinasthma.

Rhinitis.Themajorityofpatientswithasthmahaveahistoryorevidenceofrhinitisandupto30%ofpatientswithpersistentrhinitishaveordevelopasthma277,278.Rhinitisfrequentlyprecedesasthma,andisbothariskfactorforthedevelopmentofasthma279andisassociatedwithincreasedseverityandhealthresourceuseinasthma280.Rhinitisandasthmashareseveralriskfactors:commonindoorandoutdoorallergenssuchashousedustmites,animaldander,and,lesscommonly,pollenaffectingboththenoseandbronchi281,282,occupationalsensitizers283,andnon-specificfactorslikeaspirin.Forthesereasons,theAllergicRhinitisanditsImpactonAsthma(ARIA)initiativerecommendsthatthepresenceofasthmamustbeconsideredinallpatientswithrhinitis,andthatinplanningtreatment,bothshouldbeconsideredtogether284.

Bothasthmaandrhinitisareconsideredtobeinflammatorydisordersoftheairway,buttherearesomedifferencesbetweenthetwoconditionsinmechanisms,clinicalfeatures,andtreatmentapproach.Althoughtheinflammationofthenasalandbronchialmucosamaybesimilar,nasalobstructionislargelyduetohyperemiainrhinitis,whileairwaysmoothmusclecontractionplaysadominantroleinasthma285.

Treatmentofrhinitismayimproveasthmasymptoms286,287(Evidence A).Anti-inflammatoryagentsincludingglucocorticosteroidsandcromonesaswellasleukotrienemodifiersandanticholinergicscanbeeffectiveinbothconditions.However,somemedicationsareselectivelyeffectiveagainstrhinitis(e.g.,H1-antagonists)andothersagainstasthma(e.g.,β2-agonists)

288(Evidence A).Useofintra-nasalglucocorticosteroidsforconcurrentrhinitishasbeenfoundtohavealimitedbenefitinimprovingasthmaandreducingasthmamorbidityinsomebutnotallstudies289-291.Leukotrienemodifiers125,292,allergen-specificimmunotherapy284,293,andanti-IgEtherapy294,295areeffectiveinbothconditions(Evidence A).

AdditionalinformationonthistopicfromtheAllergicRhinitisanditsImpactonAsthma(ARIA)initiativecanbefoundathttp://www.whiar.org284.

Sinusitis.Sinusitisisacomplicationofupperrespiratoryinfections,allergicrhinitis,nasalpolyps,andotherforms

ofnasalobstruction.Bothacuteandchronicsinusitiscanworsenasthma.Clinicalfeaturesofsinusitislackdiagnosticprecision296,andCTScanconfirmationisrecommendedwhenavailable.Inchildrenwithsuspectedrhinosinusitis,antibiotictherapyfor10daysisrecommended297(Evidence B).Treatmentshouldalsoincludemedicationstoreducenasalcongestion,suchastopicalnasaldecongestantsortopicalnasalorevensystemicglucocorticosteroids.Theseagentsremainsecondarytoprimaryasthmatherapies279,288.

Nasal polyps.Nasalpolypsassociatedwithasthmaandrhinitis,andsometimeswithaspirinhypersensitivity298,areseenprimarilyinpatientsover40yearsold.Between36%and96%ofaspirin-intolerantpatientshavepolyps,and29%to70%ofpatientswithnasalpolypsmayhaveasthma298,299.Childrenwithnasalpolypsshouldbeassessedforcysticfibrosisandimmotileciliasyndrome.Nasalpolypsarequiteresponsivetotopicalglucocorticosteroids288.Alimitednumberofpatientswithglucocorticosteroid-refractorypolypsmaybenefitfromsurgery.

Occupational Asthma

Onceadiagnosisofoccupationalasthmaisestablished,completeavoidanceoftherelevantexposureisideallyanimportantcomponentofmanagement300-302.Occupationalasthmamaypersistevenseveralyearsafterremovalfromexposuretothecausativeagent,especiallywhenthepatienthashadsymptomsforalongtimebeforecessationofexposure303,304.Continuedexposuremayleadtoincreasinglysevereandpotentiallyfatalasthmaexacerbations305,aGastroesophagealRefluxlowerprobabilityofsubsequentremission,and,ultimately,permanentlyimpairedlungfunction306.Pharmacologictherapyforoccupationalasthmaisidenticaltotherapyforotherformsofasthma,butitisnotasubstituteforadequateavoidance.Consultationwithaspecialistinasthmamanagementoroccupationalmedicineisadvisable.

TheBritishOccupationalHealthResearchFoundationGuidelinesfortheprevention,identification,andmanagementofoccupationalasthmaareavailableathttp://www.bohrf.org.uk/downloads/asthevre.pdf.

Respiratory Infections

Respiratoryinfectionshaveanimportantrelationshiptoasthmaastheyprovokewheezingandincreasedsymptomsinmanypatients307andarecommonlyfoundinchildrenwithasthmaexacerbation391.Epidemiologicalstudieshavefoundthatinfectiousmicroorganismsassociatedwithincreasedasthmasymptomsareoftenrespiratoryviruses308,butseldombacteria309.RespiratoryCOPY

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syncytialvirusisthemostcommoncauseofwheezingininfancy45,whilerhinoviruses(whichcausethecommoncold),aretheprincipaltriggersofwheezingandworseningofasthmainolderchildrenandadults310.Otherrespiratoryviruses,suchasparainfluenza,influenza,adenovirus,andcoronavirus,arealsoassociatedwithincreasedwheezingandasthmasymptoms311.Adultswithasthmamaybeatincreasedriskofseriouspneumococcaldisease370.

Anumberofmechanismshavebeenidentifiedthatexplainwhyrespiratoryinfectionstriggerwheezingandincreasedairwayresponsiveness,includingdamagetoairwayepithelium,stimulationofvirus-specificIgEantibody,enhancedmediatorrelease,andtheappearanceofalateasthmaticresponsetoinhaledantigen312.Thus,thereisevidencethatviralinfectionsarean“adjuvant”totheinflammatoryresponseandpromotethedevelopmentofairwayinjurybyenhancingairwayinflammation313.

Treatmentofaninfectiousexacerbationfollowsthesameprinciplesastreatmentofotherasthmaexacerbations—thatis,rapid-actinginhaledβ2-agonistsandearlyintroductionoforalglucocorticosteroidsorincreasesininhaledglucocorticosteroidsbyatleastfour-foldarerecommended.Becauseincreasedasthmasymptomscanoftenpersistforweeksaftertheinfectioniscleared,anti-inflammatorytreatmentshouldbecontinuedforthisfullperiodtoensureadequatecontrol.

TheroleofchronicinfectionwithChlamydiapneumoniaeandMycoplasmapneumoniaeinthepathogenesisorworseningofasthmaiscurrentlyuncertain314.Thebenefitfrommacrolideantibioticsremainsunclear315-317.

Gastroesophageal Reflux.

Thereisconsiderableevidencethatgastroesophagealrefluxismorecommoninpatientswithasthmathaninthegeneralpopulation392.Thishasledtoresearchtodeterminewhethertreatmentofgastroesophagealrefluxcanimproveasthmasymptomsorcontrol.Gastroesophagealrefluxisundoubtedlyacauseofdrycoughandsomeoftheconfusionintheliteratureisprobablyduetopatientswithdrycoughsymptomsbeingattributedtoasthma.Thisrelationshipmayinpartrelatetotheuseofmedicationstomanageasthma,suchasβ2-agonistsandtheophyllinewhichcauserelaxationoftheloweroesophagealsphincter.

ACochranereview320oftheeffectivetreatmentsofgastroesophagealrefluxwithavarietyofmeasuresincludingprotonpumpinhibitors,H2antagonists,andsurgeryfailedtoshowbenefit.Astudyonadultpatientswithsymptomaticasthmawithoutsymptomsof

gastroesophagealrefluxfoundthattreatmentwithhighdoseprotonpumpinhibitorsdidnotimprovesymptomsorexacerbationsofasthma393.Inpatientswithmoderatetosevereasthmatreatedwithanti-inflammatoryasthmamedicationsandsymptomaticgastroesophagealreflux,treatmentwithprotonpumpinhibitorsdemonstratedasmallandprobablyclinicallynon-significantimprovementinlungfunctionandqualityoflife392.Fewdataareavailableonstudiesoftreatmentforchildrenwithasthmasymptomsandsymptomsofgastroesophagealreflux394.

Insummary,despiteahighprevalenceofasymptomaticgastroesophagealrefluxamongpatientswithpoorlycontrolledasthma,treatmentwithproton-pumpinhibitorsdoesnotimproveasthmacontrol.Asymptomaticgastroesophagealrefluxisnotalikelycauseofpoorlycontrolledasthma.Surgeryforgastroesophagealrefluxisreservedfortheseverelysymptomaticpatientwithwell-documentedesophagitisandfailureofmedicalmanagement.Inpatientswithasthma,itshouldbedemonstratedthattherefluxcausesasthmasymptomsbeforesurgeryisadvised321,322.

Aspirin-Induced Asthma (AIA)

Upto28%ofadultswithasthma,butrarelychildrenwithasthma,sufferfromasthmaexacerbationsinresponsetoaspirinandothernonsteroidalanti-inflammatorydrugs(NSAIDs).Thissyndromeismorecommoninsevereasthma323.

Theclinicalpictureandcourseofaspirin-inducedasthma(AIA)arecharacteristic324.Themajorityofpatientsfirstexperiencesymptoms,whichmayincludevasomotorrhinitisandprofuserhinorrhea,duringthethirdtofourthdecadeoflife.Chronicnasalcongestionevolves,andphysicalexaminationoftenrevealsnasalpolyps.Asthmaandhypersensitivitytoaspirinoftendevelopsubsequently.Thehypersensitivitytoaspirinpresentsauniquepicture:withinminutestooneortwohoursfollowingingestionofaspirin,anacute,oftensevere,asthmaattackdevelops,andisusuallyaccompaniedbyrhinorrhea,nasalobstruction,conjunctivalirritation,andscarletflushoftheheadandneck.Thismaybeprovokedbyasingleaspirinorothercyclooxygnease-1(COX-1)inhibitorandincludeviolentbronchospasm,shock,lossofconsciousness,andevenrespiratoryarrest325,326.

Persistentmarkedeosinophilicinflammation,epithelialdisruption,cytokineproduction,andupregulationofadhesionmoleculesarefoundintheairwaysofpatientswithAIA327,328.Airwayexpressionofinterleukin-5(IL-5),whichisinvolvedinrecruitmentandsurvivalofeosinophils,isalsoincreased328.AIAisfurthercharacterizedbyCOPY

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increasedactivationofcysteinylleukotrienepathways,whichmaybepartlyexplainedbyageneticpolymorphismoftheLTC4synthasegenefoundinabout70%percentofpatients329.However,theexactmechanismbywhichaspirintriggersbronchoconstrictionremainsunknown330.Theabilityofacyclooxygenaseinhibitortotriggerreactionsdependsonthedrug’scyclooxygenaseinhibitorypotency,aswellasontheindividualsensitivityofthepatient329.

Acharacteristichistoryofreactionisconsideredadequateforinitiatingavoidancestrategies.However,thediagnosiscanonlybeconfirmedbyaspirinchallenge,astherearenosuitableinvitrotestsfordiagnosis.Theaspirinchallengetestisnotrecommendedforroutinepracticeasitisassociatedwithahighriskofpotentiallyfatalconsequencesandmustonlybeconductedinafacilitywithcardiopulmonaryresuscitationcapabilities331.FurthersafeguardsarethatpatientsshouldonlybechallengedwhentheirasthmaisinremissionandtheirFEV1isgreaterthan70%ofpredictedorpersonalbest.Bronchial(inhalational)andnasalchallengeswithlysineaspirinaresaferthanoralchallengesandmaybeperformedinspecializedcenters332,333.OnceaspirinorNSAIDhypersensitivitydevelops,itispresentforlife.PatientswithAIAshouldavoidaspirin,productscontainingit,otheranalgesicsthatinhibitCOX-1,andoftenalsohydrocortisonehemisuccinate334.Avoidancedoesnotpreventprogressionoftheinflammatorydiseaseoftherespiratorytract.WhereanNSAIDisindicated,acyclooxygenase-2(COX-2)inhibitormaybeconsidered352withappropriatephysiciansupervisionandobservationforatleastonehourafteradministration335(Evidence B).Glucocorticosteroidscontinuetobethemainstayofasthmatherapy,butleukotrienemodifiersmayalsobeusefulforadditionalcontroloftheunderlyingdisease332,336(Evidence B).ForNSAID-sensitivepatientswithasthmawhorequireNSAIDsforothermedicalconditions,desensitizationmaybeconductedinthehospitalunderthecareofaspecialist337.AspirindesensitizationhasalsobeenusedasatreatmentforAIA,butlong-termimprovementsappeartobemorecommonwithsinussymptomsthanwithlowerairwaydisease.Afteraspirindesensitization,dailyingestionof600-1200mgofaspirinmayreduceinflammatorymucosaldiseasesymptoms,especiallyinthenose,inmostpatientswithAIA332.Generally,asthmapatients,especiallythosewithadultonsetasthmaandassociatedupperairwaydisease(nasalpolyposis),shouldbecounseledtoavoidNSAIDs,takingacetominophen/paracetemolinstead.

Anaphylaxis and Asthma

Anaphylaxisisapotentiallylife-threateningconditionthatcanbothmimicandcomplicatesevereasthma.Effective

treatmentofanaphylaxisdemandsearlyrecognitionoftheevent.Thepossibilityofanaphylaxisshouldbeconsideredinanysettingwheremedicationorbiologicalsubstancesaregiven,especiallybyinjection.Examplesofdocumentedcausesofanaphylaxisincludetheadministrationofallergenicextractsinimmunotherapy,foodintolerance(nuts,fish,shellfish,eggs,milk),avian-basedvaccines,insectstingsandbites,latexhypersensitivity,drugs(β-lactamantibiotics,aspirinandNSAIDs,andangiotensinconvertingenzyme(ACE)inhibitors),andexercise.

Symptomsofanaphylaxisincludeflushing,pruritis,urticaria,andangioedema;upperandlowerairwayinvolvementsuchasstridor,dyspnea,wheezing,orapnea;dizzinessorsyncopewithorwithouthypotension;andgastrointestinalsymptomssuchasnausea,vomiting,cramping,anddiarrhea.Exercise-inducedanaphylaxis,oftenassociatedwithmedicationorfoodallergy,isauniquephysicalallergyandshouldbedifferentiatedfromexercise-inducedbronchoconstriction338.

Airwayanaphylaxiscouldaccountforthesuddenonsetofasthmaattacksinsevereasthmaandtherelativeresistanceoftheseattackstoincreaseddosesofβ2-agonists180.Ifthereisapossibilitythatanaphylaxisisinvolvedinanasthmaattack,epinephrineshouldbethebronchodilatorofchoice.Prompttreatmentforanaphylaxisiscrucialandincludesoxygen,intramuscularepinephrine,injectableantihistamine,intravenoushydrocortisone,oropharyngealairway,andintravenousfluid.Preventingarecurrenceofanaphylaxisdependsonidentifyingthecauseandinstructingthepatientonavoidancemeasuresandself-administeredemergencytreatmentwithpre-loadedepinephrinesyringes339.

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5

IMPLEMENTATION OF ASTHMA

GUIDELINES INHEALTH SYSTEMS

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99IMPLEMENTATIONOFASTHMAGUIDELINESINHEALTHSYSTEMS

KEYPOINTS:

• Inordertoeffectchangesinmedicalpracticeandconsequentimprovementsinpatientoutcomes,evidence-basedguidelinesmustbeimplementedanddisseminatedatthenationalandlocallevels.

• Implementationofasthmaguidelinesshouldinvolveawidevarietyofprofessionalgroupsandotherstakeholders,andtakeintoaccountlocalculturalandeconomicconditions.

• Animportantpartoftheimplementationprocessistoestablishasystemtoevaluatetheeffectivenessandqualityofcare.

• Thoseinvolvedintheadaptationandimplementationofasthmaguidelinesrequireanunderstandingofthecostandcosteffectivenessofvariousmanagementrecommendationsinasthmacare.

• GINAhasdevelopedanumberofresourcesandprogramstoaidinguidelineimplementationanddissemination.

Ithasbeendemonstratedinavarietyofsettingsthatpatientcareconsistentwithrecommendationsinevidence-basedasthmaguidelinesleadstoimprovedoutcomes.Guidelinesaredesignedtoensurethatallmembersofapatient’shealthcareteamareawareofthegoalsoftreatmentandofthedifferentwaysofachievingthesegoals.Theyhelpsetstandardsofclinicalcare,mayserveasabasisforauditandpayment,andactasastartingpointfortheeducationofhealthprofessionalsandpatients.However,inordertoeffectchangesinmedicalpracticeandconsequentimprovementsinpatientoutcomes,evidence-basedguidelinesmustbeimplementedanddisseminatedatnationalandlocallevels.Disseminationinvolveseducatingclinicianstoimprovetheirawareness,knowledge,andunderstandingofguidelinerecommendations.Itisonepartofimplementation,whichinvolvesthetranslationofevidence-basedasthmaguidelinesintoreal-lifepracticewithimprovementofhealthoutcomesforthepatient.Implementationremainsadifficult

problemworldwide.Barrierstoimplementationrangefrompoorinfrastructurethathampersdeliveryofmedicinestoremotepartsofacountry,toculturalfactorsthatmakepatientsreluctanttouserecommendedmedications(e.g.,inhaledpreparations),suboptimaluseofmedications21,andlackofphysicianuseofguidelines.

Animportantbarriertothesuccessfultranslationofasthmaguidelinesintoclinicalpracticeisaccesstoavailableandaffordablemedicationespeciallyforpatientsinlessdevelopedeconomieswherethecostoftreatmentishighincomparisontoincomeandassets.

Implementationofasthmaguidelinesshouldbeginwiththesettingofgoalsanddevelopmentofstrategiesforasthmacarethroughcollaborationamongdiverseprofessionalgroupsincludingbothprimaryandsecondaryhealthcareprofessionals,publichealthofficials,patients,asthmaadvocacygroups,andthegeneralpublic.Goalsandimplementationstrategieswillvaryfromcountrytocountry-andwithincountries-forreasonsofeconomics,culture,andenvironment.However,commonissuesareshowninFigure 5-1.

Thenextstepisadaptationofguidelinesonasthmamanagementforlocalusebyteamsoflocalprimaryandsecondarycarehealthprofessionals.Manylow-andmiddleincomecountriesdonotconsiderasthmaahigh-priorityhealthconcernbecauseother,morecommonrespiratorydiseasessuchastuberculosisandpneumoniaareofgreaterpublichealthimportance1.Therefore,practicalasthmaguidelinesforimplementationinlow-incomecountriesshouldhaveasimplealgorithmforseparatingnon-infectiousfrominfectiousrespiratoryillnesses;simpleobjectivemeasurementsfordiagnosisandmanagementsuchaspeakflowvariability2;available,affordable,andlow-riskmedicationsrecommendedforasthmacontrol;asimpleregimeforrecogniingsevereasthma;andsimplediagnosisandmanagementapproachesrelevanttothefacilitiesandlimitedresourcesavailable.Next,adaptedguidelinesmustbewidelydisseminatedinmultiplevenuesandusingmultipleformats.Thiscanbeaccomplished,forexample,bypublicationinprofessional

CHAPTER 5: IMPLEMENTATION OF ASTHMA GUIDELINES IN HEALTH SYSTEMS

INTRODUCTION

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Figure 5-1. Checklist of Issues for National or LocalAsthma Implementation

• What is the size of the problem and burden of asthma in thiscountry or district?

• What arrangements will be made for shared care amongdifferent health care providers (doctors and nurses, hospital and primary care)?

• How will medical care be linked with community health facilitiesand educational initiatives?

• What are the major preventable factors in this country or districtthat could help prevent asthma from developing or couldprevent asthma exacerbations from occurring in those whoalready have asthma?

• What preconceived assumptions about asthma and its treatmentand what cultural factors will need special attention?

• What treatments are currently used?• How affordable and accessible are medications and services to

the patient? • What other treatments are available, cheap enough for

purchase, and stable in local climatic conditions? • Can inhaler devices and medicines be standardized to reduce

cost/storage/availability problems? • Who will provide emergency care? • Which groups of the population are at special risk (e.g., inner-

city, poor, teenage, minority)? • Whom can we enlist to help in education (community health

workers/health-promotion facilitators/trained educators currentlyworking on other programs/self-help support groups)?

• Who will take responsibility for the education of health careprofessionals?

• Who will take responsibility for the education of people withasthma and their family members/caregivers?

• How can asthma education and treatment be integrated intoother programs (e.g., child health)?

journals,accompaniedbymultidisciplinarysymposia,workshops,andconferencesinvolvingnationalandlocalexpertswithinvolvementoftheprofessionalandmassmediatoraiseawarenessofthekeymessages3.Themosteffectiveinterventionstoimproveprofessionalpracticearemultifacetedandinteractive4,5.However,littleisknownofthecosteffectivenessoftheseinterventions6.Integratedcarepathwaysarebeingexploredasameantoimproveasthmacareinspecificsettings,suchaspatientscomingtoemergencydepartments22.

Insomecountries,implementationofasthmaguidelineshasbeendoneatanationallevelwithgovernmenthealthdepartmentcollaboration.AmodelforanimplementationprogramthathasimprovedpatientoutcomesisprovidedbythenationalasthmaprograminFinland,along-term,comprehensive,multifacetedpublichealthinitiativewithwell-definedtargetsforasthmaguidelineimplementation7,8.

Publichealthstrategiesinvolvingabroadcoalitionofstakeholdersinasthmacare,includingmedicalsocieties,healthcareprofessionals,patientsupportgroups,government,andtheprivatesector,havebeenimplementedinAustralia(AustralianNationalAsthmaCampaign,http://www.nationalasthma.org.au),andtheUnitedStates(NationalAsthmaEducationandPreventionProgram,http://www.nhlbi.nih.gov).

Animportantpartoftheimplementationprocessistoestablishasystemtoevaluatetheeffectivenessandqualityofcare.Evaluationinvolvessurveillanceoftraditionalepidemiologicalparameters,suchasmorbidityandmortality,aswellasthespecificauditofbothprocessandoutcomewithindifferentsectorsofthehealthcaresystem.Eachcountryshoulddetermineitsownminimumsetsofdatatoaudithealthoutcomes.Thereareavarietyofassessmenttoolswhichprovideaconsistentandobjectiveassessmentofasthmamorbidityorcontrol(e.g.,AsthmaControlTest9,AsthmaControlQuestionnaire10-12,AsthmaTherapyAssessmentQuestionnaire13).Resultsoftheseassessmentsshouldberecordedateachvisit,providingarecordofthelong-termclinicalresponseofthepatienttotreatment.Directfeedbackprovidesseveralbenefits-ameansforthepatient/caregivertobecomefamiliarwith,andsensitiedto,satisfactoryversuspoorcontrolofasthma;areferencepointfromwhichtoevaluatedeterioratingasthma;andanindicatorofchangesinasthmacontrolinresponsetochangesintreatment.Useofadministrativedatasets(e.g.,dispensingrecords)orurgenthealthcareutilizationcanhelptoidentifyat-riskpatientsortoauditthequalityofhealthcare23.Thestrategyofculturallyappropriatedirectfeedbackofclinicaloutcomestophysiciansaboutspecifichealthcareresultsoftheirpatientsmaybeimportantforgeneralpractitionerswhotreatmanydiseasesinadditiontoasthmaandthuscouldnotbeexpectedtoknowguidelinesindetailandhandlepatientsaccordingly.

Costisrecognizedasanimportantbarriertothedeliveryofoptimalevidence-basedhealthcareinalmosteverycountry,althoughitsimpactonpatients’accesstotreatmentsvarieswidelybothbetweenandwithincountries.Atthecountryorlocallevel,healthauthoritiesmakeresourceavailabilityandallocationdecisionsaffectingpopulationsofasthmapatientsbyconsideringthebalanceandtradeoffsbetweencostsandclinicaloutcomes(benefitsandharms),ofteninrelationtocompetingpublichealthandmedicalneeds.Treatmentcostsmustalsobe

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explicitlyconsideredateachconsultationbetweenhealthcareproviderandpatienttoassurethatcostdoesnotpresentabarriertoachievingasthmacontrol.Thus,thoseinvolvedintheadaptationandimplementationofasthmaguidelinesrequireanunderstandingofthecostandcosteffectivenessofvariousmanagementrecommendationsinasthmacare.Tothisend,ashortdiscussionofcost-effectivenessevaluationforasthmacarefollows.

Utilization and Cost of Health Care Resources

Between35and50%ofmedicalexpendituresforasthmaareaconsequenceofexacerbations14,anasthmaoutcomemostviewasrepresentingtreatmentfailure.Hospitalization,emergencydepartmentandunscheduledclinicvisits,anduseofrescuemedicationcomprisethemajorityofexacerbation-relatedtreatmentcosts.Inclinicaltrialsofasthmatreatments,exacerbationsarecustomarilycharacterizedbyuseofhealthcareresources,aloneorincombinationwithsymptomandlungfunctiondata,especiallywhentheprimarystudyoutcomeisreductionintheexacerbationfrequencyortimetoanexacerbationevent.Routinecollectionofhealthcareresourceconsumptiondatacanbeundertakeninthefieldthroughpatientorcaregiverself-report.Insomecircumstances,automateddatafromclinicalorbillingrecordscansubstituteforself-reportandaremorereliableandvalid13,15.

Compositedefinitionsofasthmacontrol16,17mayincludeoneormorehealthcareutilizationitems.Theseitemstypicallydescribethepresenceofanexacerbationoranexacerbation-relatedtreatmentinpreciseandvalidterms.Manyofthepublishedcompositemeasuresofasthmacontrolhaveincludedhospitalizationandemergencytreatmentdata,suchasunscheduledorurgentcarevisitsoruseofnebulizedβ2-agonistsand/ororalglucocorticosteroids17.Althoughhealthcareutilizationelementsareessentialtoanypragmaticdefinitionofasthmacontrol,asyetunansweredintheliteratureiswhichofthenumberofpossiblehealthcareoptions(singleitemsorcombinationsofitems)cancontributetoanacceptabledefinitionofcontrol,andthevaluesofeachthatmightbeviewedasacceptablecontrol.

Forstudiestoevaluatethecostimpactofguidelineimplementationorofspecificasthmainterventions,dataoncostsofimplementation(e.g.,costsrelatedtodisseminationandpublicationofguidelines,costsofhealthprofessionaleducation),preventivepharmacotherapy,diagnosticandfollow-upspirometry,useofdevices(spacers,peakflowmeters),androutineofficevisitsarerequiredtosupplementdataonexacerbation-relatedtreatments.Together,thesedataprovideacomprehensiveprofileofhealthcareresourceconsumption.Thesedata

canbeacquiredinasimilarfashionusingself-reportorfromautomateddatabases.

Oncedataonuseofhealthcareresourcesarecollected,costscanbedeterminedbyassigninglocalcurrencypriceweightstohealthcareresourcesconsumed.Unitpriceweightsarenormallycollectedfromgovernmentreports,priceauditsoflocalpayers,billingrecords,claimsdatabases,andpatientsurveys.

Assessmentofpatientandcaregivertravelandwaitingtimeformedicalvisits,aswellasabsencesfromandproductivitywhileatschoolorwork,compriseadditionalandimportantoutcomemeasuresinasthma.Theseindirectcostsofasthmaaresubstantial,inestimatedtoberoughly50%oftheoveralldiseaseburden14.However,therearenostandardized,validated,andculturallyadaptedinstrumentsforassessingthesemeasuresinavarietyofpopulations.

Determining the Economic Value of Interventions in Asthma

Economicevaluationsrequiretheselectionofthreemainoutcomeparameters-estimatesoftreatment-relatedhealthbenefits,treatment-relatedrisks,andtreatment-relatedcosts.Theseparameterscanbedetermineddirectlyfromclinicalstudiesorthroughtheapplicationofmodelingstudies.Localevidencerequirementsforeconomicevaluationsdeterminethechoicesofhealthbenefitmeasures.Whenthedecisiontobeconsideredisatthemacro-level,forexampletheinclusionofanewtreatmentinagovernment-sponsoredhealthcareprogramorthebenefitspackageofahealthinsurer,economicevaluationsrequiretheuseofacommonmetricsuchaslifeyearsgained,improvementingenericqualityoflife,orquality-adjustedlifeyears(QALY)gained18.Theseoutcomessupportcomparisonofcost-effectivenessratiosacrossdifferentdiseasestatesandpatientpopulations.However,inasthma,QALYsaredifficulttomeasure,particularlyinchildrenwherevalidatedpreferencemeasuresarenotavailable.Somehaveadvocatedtheuseofclinicalmeasuressuchassymptom-freedaysorasthmacontrolasthedenominatorineconomicevaluations19.Aunifieddefinitionofasthmacontrolwouldsubstantiallyimprovetheacceptanceofnon-QALYeconomicevaluationsamongthoseinterestedintheirdesignandapplication.

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EducationalmaterialsbasedonthisGlobalStrategyforAsthmaManagementandPreventionareavailableinseveralforms,includingapocketguideforhealthcareprofessionalsandoneforpatientsandfamilies.TheseareavailableontheGINAWebsite(http://www.ginasthma.org).Eachyear,theGINAScienceCommitteeexaminespeer-reviewedliteratureonasthmamanagementandupdatesvariousGINAdocuments.AreportofaGINAWorkingGroup20providesablueprintforimplementationstrategies.OtheractivitiestoassistwithimplementationofasthmamanagementrecommendationsthroughtheGINAprograminclude:

Gina Website -www.ginasthma.org.TheInternetiscreatingaconduitfortheaccess,sharing,andexchangeofinformationandpermitstheglobaldistributionofmedicalinformation.Althoughitisstillnotwidelyavailable,especiallyinlow-incomecountries,theglobaltrendisforincreasinguseoftheInternetformedicaleducationbyasthmapatientsandtheirhealthcareproviders.Thus,tofacilitatecommunicationwithhealthprofessionals,healthpolicyexperts,patients,andtheirfamiliesinternationally,GINAhasmaintainedaWebsitesince1995toprovidesaccesstotheGINAguidelinedocumentsandeducationalmaterialsforpatientsandthepublicaswellasupdatesofactivitiesandinformationaboutcollaboratinggroupsandcontactsthroughouttheworld.

World asthma day.Initiatedin1998,andheldonthefirstTuesdayinMay,WorldAsthmaDayisorganizedbyGINAincollaborationwithhealthcaregroupsandasthmaeducatorsthroughouttheworld.WorldAsthmaDayactivitiesfocusondisseminationofinformationaboutasthmaamongthegeneralpopulation,healthcareprofessionals,andgovernmentofficials.Forpatientswithasthmaandtheirrelatives,theseactivitiesfosteranappreciationoftheimportanceofasthmaonalocal,regional,national,andinternationallevel.Activitiesincludesportingevents;meetingsofpeoplewithasthmaandtheirfamilieswithhealthprofessionals;meetingswithlocalhealthofficialstodiscussprogressinasthmacare;andreportsinprintmedia,radio,andtelevision.InformationaboutWorldAsthmaDaycanbefoundontheGINAWebsite.

Regional initiatives.Toexaminetheformationofnetworkstofacilitatetheprocessofguidelineimplementation,twopilotinitiativeshavebeenimplementedintheMesoamericaandMediterraneanregions.GINAleadershavebeen

identifiedineachcountryineachregionwhowillsupervisecollaborationbetweenGINAandlocalgroupsandbringtheGINAguidelinesintoformsthatcanbereadilyusedbyhealthcareprofessionalsandpatientsineachregion.

GINA Assembly.Tomaximizeinteractionwithglobalasthma-carepractitioners,aGINAAssemblywasinitiatedinJanuary2005.TheAssemblyprovidesaforumfordialogueamongthesehealthcareprofessionalsandfacilitatessharingofinformationaboutscientificadvancesandimplementationofhealtheducation,management,andpreventionprogramsforasthma.

Global alliance against Chronic Respiratory diseases (GARD). GINAisapartnerorganizationoftheGlobalAllianceAgainstChronicRespiratoryDiseases(GARD),aWorldHealthOrganizationinitiative(http://www.who.int/respiratory/gard/en/).ThegoalofGARDistofacilitatecollaborationamongexistinggovernmentalandnongovernmentalprogramsinterestedinchronicrespiratorydiseasestoassuremoreefficientutilizationofresourcesandavoidduplicationofefforts.Theparticipatingorganizationswilldevelopacomprehensiveglobalapproachtothepreventionandcontrolofchronicrespiratorydiseases,withaspecialemphasisondevelopingcountries.StrategiesforaffordabledrugprocurementthroughanAsthmaDrugFacility(www.GlobalADF.org)areamongthegoalsofGARDandarebeingpursuedactivelybyoneofthepartnergroups,theInternationalUnionAgainstTuberculosisandLungDiseases(IUATLD).

REFERENCES

1. StewartAW,MitchellEA,PearceN,StrachanDP,WeilandonSK.Therelationshipofpercapitagrossnationalproducttotheprevalenceofsymptomsofasthmaandotheratopicdiseasesinchildren(ISAAC).IntJEpidemiol2001;30(1):173-9.

2. HigginsBG,BrittonJR,ChinnS,CooperS,BurneyPG,TattersfieldAE.Comparisonofbronchialreactivityandpeakexpiratoryflowvariabilitymeasurementsforepidemiologicstudies.AmRevRespirDis1992;145(3):588-93.

3. PartridgeMR,HarrisonBD,RudolphM,BellamyD,SilvermanM.TheBritishAsthmaGuidelines--theirproduction,disseminationandimplementation.BritishAsthmaGuidelinesCo-ordinatingCommittee.RespirMed1998;92(8):1046-52.

4. DavisDA,ThomsonMA,OxmanAD,HaynesRB.Changingphysicianperformance.Asystematicreviewoftheeffectofcontinuingmedicaleducationstrategies.JAMA1995;274(9):700-5.

5. BeroLA,GrilliR,GrimshawJM,HarveyE,OxmanAD,ThomsonMA.Closingthegapbetweenresearchandpractice:anoverviewofsystematicreviewsofinterventionstopromotetheimplementationofresearchfindings.TheCochraneEffectivePracticeandOrganizationofCareReviewGroup.BMJ1998;317(7156):465-8.

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6. SullivanSD,LeeTA,BloughDK,FinkelsteinJA,LozanoP,InuiTS,etal.AmultisiterandomizedtrialoftheeffectsofphysicianeducationandOrganizationalchangeinchronicasthmacare:cost-effectivenessanalysisofthePediatricAsthmaCarePatientOutcomesResearchTeamII(PAC-PORTII).ArchPediatrAdolescMed2005;159(5):428-34.

7. HaahtelaT,KlaukkaT,KoskelaK,ErholaM,LaitinenLA.AsthmaprogrammeinFinland:acommunityproblemneedscommunitysolutions.Thorax2001;56(10):806-14.

8. HaahtelaT,TuomistoLE,PietinalhoA,KlaukkaT,ErholaM,KailaM,etal.A10yearasthmaprogrammeinFinland:majorchangeforthebetter.Thorax2006;61(8):663-70.

9. NathanRA,SorknessCA,KosinskiM,SchatzM,LiJT,MarcusP,etal.Developmentoftheasthmacontroltest:asurveyforassessingasthmacontrol.JAllergyClinImmunol2004;113(1):59-65.

10. JuniperEF,BuistAS,CoxFM,FerriePJ,KingDR.ValidationofastandardizedversionoftheAsthmaQualityofLifeQuestionnaire.Chest1999;115(5):1265-70.

11. JuniperEF,BousquetJ,AbetL,BatemanED.Identifying‘wellcontrolled’and‘notwell-controlled’asthmausingtheAsthmaControlQuestionnaire.RespirMed2005.

12. JuniperEF,SvenssonK,MorkAC,StahlE.Measurementpropertiesandinterpretationofthreeshortenedversionsoftheasthmacontrolquestionnaire.RespirMed2005;99(5):553-8.

13. VollmerWM,MarksonLE,O’ConnorE,SanockiLL,FittermanL,BergerM,etal.Associationofasthmacontrolwithhealthcareutilizationandqualityoflife.AmJRespirCritCareMed1999;160(5Pt1):1647-52.

14. WeissKB,SullivanSD.Thehealtheconomicsofasthmaandrhinitis.I.Assessingtheeconomicimpact.JAllergyClinImmunol2001;107(1):3-8.

15. VollmerWM,MarksonLE,O’ConnorE,FrazierEA,BergerM,BuistAS.Associationofasthmacontrolwithhealthcareutilization:aprospectiveevaluation.AmJRespirCritCareMed2002;165(2):195-9.

16. Globalstrategyforasthmamanagementandprevention(updated2005):GlobalInitiativeforAsthma(GINA).URL:http://www.ginasthma.org;2005.


18. PriceMJ,BriggsAH.Developmentofaneconomicmodeltoassessthecosteffectivenessofasthmamanagementstrategies.Pharmacoeconomics2002;20(3):183-94.

19. SullivanS,ElixhauserA,BuistAS,LuceBR,EisenbergJ,WeissKB.NationalAsthmaEducationandPreventionProgramworkinggroupreportonthecosteffectivenessofasthmacare.AmJRespirCritCareMed1996;154(3Pt2):S84-95.

20. GlobalInitiativeforasthma:DisseminationandImplementationofasthmaguidelinesReport.Availablefromhttp://wwwginasthmaorg2002.

21. CazolettiL,MarconA,JansonC,CorsicoA,JarvisD,PinI,

etal;TherapyandHealthEconomicsGroupoftheEuropeanCommunityRespiratoryHealthSurvey.AsthmacontrolinEurope:areal-worldevaluationbasedonaninternationalpopulation-basedstudy.JAllergyClinImmunol2007Dec;120(6):1360-7.Epub2007Nov5

22. CunninghamS,LoganC,LockerbieL,DunnMJ,McMurrayA,PrescottRJ.Effectofanintegratedcarepathwayonacuteasthma/wheezeinchildrenattendinghospital:clusterrandomizedtrial.JPediatr2008Mar;152(3):315-20.Epub2007Nov26.

23. BereznickiBJ,PetersonGM,JacksonSL,WaltersEH,FitzmauriceKD,GeePR.Data-miningofmedicationrecordstoimproveasthmamanagement.MedJAust.2008Jul7;189(1):21-5

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REPRODUCE OR ALTER NOT - DO MATERIAL - UCLouvain · 2013-05-05 · METHODOLOGY AND SUMMARY OF NEW RECOMMENDATION, 2010 UPDATE vi INTRODUCTION x CHAPTER 1. DEFINITION AND OVERVIEW