gina report 2012

®

GLOBAL STRATEGY FORASTHMA MANAGEMENT AND PREVENTION

UPDATED 2012

© 2012 Global Initiative for Asthma

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

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GINA BOARD OF DIRECTORS*

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

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

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

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

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 Hamilton, Ontario, Canada

Ken Ohta, MD, PhD National Hospital Organization Tokyo National Hospital Tokyo, Japan

Pierluigi Paggiaro, MD University of Pisa Pisa, Italy

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

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

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 SCIENCE COMMITTEE*

Helen Reddel, MD, ChairWoolcock Institute of Medical ResearchCamperdown, NSW, Australia

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

Elisabeth Bel, MDUniversity of AmsterdamAmsterdam, The Netherlands

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

Mark FitzGerald, MDUniversity of British ColumbiaVancouver, BC, Canada

Johan C. de Jongste, MD, PhD Erasmas University Medical Center Rotterdam, The Netherlands

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

Paul O’Byrne, MD McMaster University Hamilton, Ontario, Canada

Ken Ohta, MD, PhD National Hospital Organization Tokyo National Hospital Tokyo, Japan

Soren Erik Pedersen, MD Kolding Hospital Kolding, Denmark

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

Sally E. Wenzel, MDUniversity of Pittsburgh Pittsburgh, Pennsylvania, USA

Global Strategy for Asthma Management and Prevention 2012 (update)

*Disclosures for members of GINA Board of Directors and Science Committees can be found at http://www.ginasthma.orgCOPY

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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 Almirall, AstraZeneca, Boehringer-Ingelheim, Chiesi, CIPLA, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Quintiles, Takeda. 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).

Mark FitzGerald, MDProfessor of MedicineHead, UBC and VGH Divisions of Respiratory MedicineDirector, Centre for Lung HealthCo-Director Institute for Heart and Lung HealthThe Lung Centre, 7th FloorGordon and Leslie Diamond Health Care Centre,2775 Laurel StreetVancouver, B.C. V5Z 1M9 Canada

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GLOBAL STRATEGY FOR ASTHMA MANAGEMENT AND PREVENTIONTable of Contents

PREFACE ii

METHODOLOGY AND SUMMARY OF NEW RECOMMENDATION, 2011 UPDATE vi

INTRODUCTION x

CHAPTER 1. DEFINITION AND OVERVIEW 1

KEY POINTS 2

DEFINITION 2

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

FACTORS INFLUENCING THE DEVELOPMENT AND EXPRESSION OF ASTHMA 4 Host Factors 4 Genetic 4 Obesity 5 Sex 5 Environmental Factors 5 Allergens 5 Infections 5 Occupational sensitizers 6 Tobacco smoke 6 Outdoor/Indoor air pollution 7 Diet 7

MECHANISMS OF ASTHMA 7 AirwayInflammationInAsthma 7 Inflammatory cells 8 Structural changes in airways 8 Pathophysiology 8 Airway hyperresponsiveness 8 SpecialMechanisms 9 Acute exacerbations 9 Nocturnal Asthma 9 Irreversible airflow asthma 9 Difficult-to-treat asthma 9 Smoking and asthma 9

REFERENCES 9

CHAPTER 2. DIAGNOSIS AND CLASSIFICATION 15

KEY POINTS 16

INTRODUCTION 16CLINICAL DIAGNOSIS 16

Medical History 16 Symptoms 16 Cough variant asthma 16 Exercise-Induced bronchospasm 17 PhysicalExamination 17 TestsforDiagnosisandMonitoring 17 Measurements of lung function 17 Spirometry 18 Peak expiratory flow 18 Measurement of airway responsiveness 19 Non-Invasive markers of airway inflammation 19 Measurements of allergic status 19

DIAGNOSTIC CHALLENGES AND DIFFERENTIAL DIAGNOSIS 20 Children5YearsandYounger 20 OlderChildrenandAdults 20 TheElderly 21 OccupationalAsthma 21 DistinguishingAsthmafromCOPD 21

CLASSIFICATION OF ASTHMA 21 Etiology 21 Phenotype 22 AsthmaControl 22 AsthmaSeverity 23 REFERENCES 24

CHAPTER 3. ASTHMA MEDICATIONS 29

KEY POINTS 30

INTRODUCTION 30

ASTHMA MEDICATIONS: ADULTS 30 Route of Administration 30 Controller Medications 31 Inhaled glucocorticosteroids 31 Leukotriene modifiers 32 Long-acting inhaled β2-agonists 33 Theophylline 33 Cromones: sodium cromoglycate and nedocromil sodium 34 Long-acting oral β2-agonists 34 Anti-IgE 34 Systemic glucocorticosteroids 34 Oral anti-allergic compounds 35 Other controller therapies 36 Allergen-specific immunotherapy 36

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Reliever Medications 36 Rapid-acting inhaled β2-agonists 36 Systemic glucocorticosteroids 37 Anticholinergics 37 Theophylline 37 Short-acting oral β2-agonists 37

ComplementaryandAlternativeMedicine 37

ASTHMA TREATMENT: CHILDREN 38 Route of Administration 38 Controller Medications 39 Inhaled glucocorticosteroids 39 Leukotriene modifiers 41 Long-acting inhaled β2-agonists 41 Theophylline 42 Anti-IgE 42 Cromones: sodium cromoglycate and nedocromil sodium 43 Systemic glucocorticosteroids 43 Reliever Medications 43 Rapid-acting inhaled β2-agonists and short-acting oral β2-agonists 43 Anticholinergics 43

REFERENCES 43

CHAPTER 4. ASTHMA MANAGEMENT AND PREVENTION 55

INTRODUCTION 56

COMPONENT 1: DEVELOP PATIENT/ DOCTOR PARTNERSHIP 56

KEY POINTS 56

INTRODUCTION 56

ASTHMA EDUCATION 57 AttheInitialConsultation 58 PersonalWrittenAsthmaActionPlans 58 Follow-upandReview 58 ImprovingAdherence 59 Self-ManagementinChildren 59

THE EDUCATION OF OTHERS 60

COMPONENT 2: IDENTIFY AND REDUCE EXPOSURE TO RISK FACTORS 61

KEY POINTS 61

INTRODUCTION 61

ASTHMA PREVENTION 61PREVENTION OF ASTHMA SYMPTOMS AND EXACERBATIONS 62 IndoorAllergens 62 Domestic mites 62 Furred animals 62 Cockroaches 63 Fungi 63 OutdoorAllergens 63 Indoor Air Pollutants 63 Outdoor Air Pollutants 63 OccupationalExposures 63 FoodandDrugAdditives 64 Drugs 64 InfluenzaVaccination 64 Obesity 64 Emotional Stress 64 OtherFactorsThatMayExacerbateAsthma 64

COMPONENT 3: ASSESS,TREAT AND MONITOR ASTHMA 65

KEY POINTS 65

INTRODUCTION 65

ASSESSING ASTHMA CONTROL 65

TREATMENT TO ACHIEVE CONTROL 65 TreatmentStepstoAchievingControl 66 Step 1: As-needed reliever medication 66 Step 2: Reliever medication plus a single controller 68 Step 3: Reliever medication plus one or two controllers 68 Step 4: Reliever medication plus two or more controllers 68 Step 5: Reliever medication plus additional controller options 69

MONITORING TO MAINTAIN CONTROL 69 Duration and Adjustments to Treatment 69 SteppingDownTreatmentWhenAsthmaIs Controlled 70 SteppingUpTreatmentInResponsetoLoss of Control 70 Difficult-to-Treat-Asthma 71

THERMOPLASTY 72

COMPONENT 4: MANAGE ASTHMA EXACERBATIONS 73

KEY POINTS 73

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INTRODUCTION 73ASSESSMENT OF SEVERITY 74

MANAGEMENT-COMMUNITY SETTINGS 74 Treatment 75 Bronchodilators 75 Glucocorticosteroids 75

MANAGEMENT-ACUTE CARE SETTINGS 75 Assessment 75 Treatment 77 Oxygen 77 Rapid-acting inhaled β2-agonists 77 Epinephrine 77 Additionalbronchodilators 77 Systemic glucocorticosteroids 77 Inhaled glucocorticosteroids 78 Magnesium 78 Helium oxygen therapy 78 Leukotriene modifiers 78 Sedatives 78 CriteriaforDischargefromtheEmergency Departmentvs.Hospitalization 78

COMPONENT 5: SPECIAL CONSIDERATIONS 80 Pregnancy 80 Obesity 80 Surgery 80 Rhinitis,Sinusitis,andNasalPolyps 81 Rhinitis 81 Sinusitis 81 Nasal polyps 81 OccupationalAsthma 81 RespiratoryInfections 81 GastroesophagealReflux 82 Aspirin-InducedAsthma 82 AnaphylaxisandAsthma 83

REFERENCES 83

CHAPTER 5. IMPLEMENTATION OF ASTHMA GUIDELINES IN HEALTH SYSTEMS 104

KEY POINTS 105

INTRODUCTION 105

GUIDELINE IMPLEMENTATION STRATEGIES 105

ECONOMIC VALUE OF INTERVENTIONS AND GUIDELINE IMPLEMENTATION IN ASTHMA 106 UtilizationandCostofHealthCareResources 107 DeterminingtheEconomicValueofInterventionsin Asthma 107

GINA DISSEMINATION/IMPLEMENTATION RESOURCES 108

REFERENCES 108

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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 is 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 2012 update, between July 1, 2011 and June 30, 2012, 386 articles met the search criteria. Of the 386, 19 papers were identified to have an impact on the GINA report. The changes prompted by these publications were posted on the website in December 2012. 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.

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

2012 Update1

1The Global Strategy for Asthma Management and Prevention (updated 2012), the updated Pocket Guides and the complete list of references examined by the Committee are available on the GINA website www.ginasthma.org.2Members (2011-2012): H. Reddel, Chair; P. Barnes, N. Barnes, E. Bateman, A. Becker, E. Bel, J. DeJongste, J. Drazen, M. FitzGerald, R. Lemanske, P. O’Byrne, K. Ohta, S. Pedersen, E. Pizzichini, S. Wenzel.

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SUMMARY OF RECOMMENDATIONS IN THE 2013 UPDATE

A. Additions to the text:

Page 33, right column, insert new paragraph: Tiotropium,a long-acting inhaled anticholinergic bronchodilator, has been studied in adults with uncontrolled asthma and compared with salmeterol, doubling the dose of inhaled glucocorticosteroid and as add-on to inhaled glucocorticosteroids and salmeterol231,233. One study showed comparable bronchodilator effects with no significant changes on asthma control232. Another study showed that adding tiotropium to patients not controlled on inhaled glucocorticosteroids and long-acting ß2-agonists improved lung function but not symptoms233. The studies have been relatively short-term and no effect on exacerbations has so far been reported. There are no data about these medications in children.Reference 231: Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT et al. National Heart, Lung, and Blood Institute Asthma Clinical Research Network. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med 2010;363:1715-26.Reference 232: Kerstjens HA, Disse B, Schroder-Babo W, Bantje TA, Gahlemann M, Sigmund R, Engel M, van Noord JA. Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J Allergy Clin Immunol. 2011 Aug;128(2):308-14. Reference 233: Bateman ED, Kornmann O, Schmidt P, Pivovarova A, Engel M, Fabbri LM. Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma. J Allergy Clin Immunol. 2011 Aug;128(2):315-22.

Page 34, right column, insert line 15: …. although this was not confirmed in all studies235.Reference 235: Hanania NA, Alpan O, Hamilos DL, et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Internal Med 2011;154:573-82.

Page 38, left column, first paragraph, add sentence and reference: A systematic review of yoga interventions for asthma found no convincing evidence of benefit; the quality of studies was generally poor236.Reference 236. Posadzki P, Ernst E. Yoga for asthma? A systematic review of randomized clinical trials. J Asthma. 2011 Aug;48(6):632-9.

Page 38, right column, last paragraph, add statement and reference: although spacer devices or face masks differ in their drug delivery, and therefore may not be interchangeable237. Reference 237. Lavorini F, Fontana GA. Targeting drugs to the airways: The role of spacer devices. Expert Opin Drug Deliv 2009;6:91-102.

Page 40, left column, first paragraph replace with: The clinical benefits of intermittent systemic or inhaled glucocorticosteroids for children with intermittent, viral-induced wheeze remain controversial. A one-year study of intermittent treatment with inhaled glucocorticosteroids was equally effective as daily treatment, and reduced the total glucocorticosteroid dose threefold in preschool children with frequent wheezing and a high asthma predictive index238. Some studies in older children found small benefits while another study in young children found no effects on wheezing symptoms139. There is no evidence to support the use of maintenance low-dose inhaled glucocorticosteroids for preventing early transient wheezing136, 139, 199.Reference 238: Zeiger RS, Mauger D, Bacharier LB, Guilbert TW, Martinez FD, Lemanske RF Jr, et al; CARE Network of the National Heart, Lung, and Blood Institute. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011 Nov 24;365(21):1990-2001

Page 40, Figure 3-5, bullet 6: Modify age range to 2-10 years; add reference in figure title.Reference 239: Guilbert TW, Mauger DT, Allen DB, Zeiger RS, Lemanske RF Jr, Szefler SJ, et al; Childhood Asthma Research and Education Network of the National Heart, Lung, and Blood Institute. Growth of preschool children at high risk for asthma 2 years after discontinuation of fluticasone. J Allergy Clin Immunol. 2011 Nov;128(5):956-63.

Page 71, right column, replace second bullet and add reference: Investigate and confirm adherence with treatment. Incorrect or inadequate use of medications and inhalers405 remains the most common reason for failure to achieve good control. In patients with difficult-to-treat asthma, improved adherence and improved health outcomes can be achieved with a comprehensive concordance intervention416. Reference 416: Gamble J, Stevenson M, Heaney LG. A study of a multi-level intervention to improve non-adherence in difficult to control asthma. Respir Med. 2011 Sep;105(9):1308-15.

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Page 72, left column insert in last paragraph: Extended follow-up on a small number of patients has provided some additional support for long-term safety of bronchial thermoplasty417. However, longer-term follow-up of larger number of control and active patients is needed to assess effectiveness and caution should be used in selecting patients for this procedure. Reference 417: Castro M, Rubin A, Laviolette M, Hanania NA, Armstrong B, Cox G; AIR2 Trial Study Group. Persistence of effectiveness of bronchial thermoplasty in patients with severe asthma. Ann Allergy Asthma Immunol. 2011 Jul;107(1):65-70.

Page 77, left column replace paragraph on oxygen: To achieve arterial oxygen saturation of 90% (95% in children), oxygen should be administered by nasal cannulae, by mask, or rarely by head box in some infants. For severe asthma exacerbations, controlled oxygen therapy using pulse oximetry to maintain oxygen saturation at 90 – 93% is associated with better physiological outcomes, compared to high flow 100% oxygen therapy218, 419. Oxygen therapy should be titrated against pulse oximetry to maintain a satisfactory oxygen saturation219. However, oxygen should not be withheld if oximetry is not available.Reference 419. Perrin K, Wijesinghe M, Healy B, Wadsworth K, Bowditch R, Bibby S, Baker T, Weatherall M, Beasley R. Randomised controlled trial of high concentration versus titrated oxygen therapy in severe exacerbations of asthma. Thorax. 2011Nov;66(11):937-41.

Page 78, left column, end of first paragraph, insert text and reference: Two days of oral dexamethasone can also be used to treat asthma exacerbations, but there are concerns about metabolic side-effects if dexamethasone is continued beyond two days420. Evidence suggests that there is no benefit to tapering the dose of oral glucocorticosteroids, either in the short-term245 or over several weeks, as long as the patient is on maintenance inhaled glucocorticosteroids246 (Evidence B).Reference 420: Kravitz J, Dominici P, Ufberg J, Fisher J, Giraldo P. Two days of dexamethasone versus 5 days of prednisone in the treatment of acute asthma: arandomized controlled trial. Ann Emerg Med. 2011 Aug;58(2):200-4.

Page 82, right column, paragraph 2, insert in line 4: …in adults392-394 or in children422.Reference 422. Holbrook JT, Wise RA, Gold BD, Blake K, Brown ED, Castro M, Dozor AJ, et al. Writing Committee for the American Lung Association Asthma Clinical Research Centers. Lansoprazole for children with

poorly controlled asthma: a randomized controlled trial. JAMA. 2012 Jan 25;307(4):373-81.

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

Page 6, right column, first sentence in paragraph four, add reference 136. Reference 136: Burke H, Leonardi-Bee J, Hashim A, Pine-Abata H, Chen Y, Cook DG, Britton JR, McKeever TM. Prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis. Pediatrics. 2012 Apr;129(4):735-44.

Page 33, right column, insert reference 234 after reference 215.Reference 234: Kemp J, Armstrong L, Wan Y, Alagappan VK, Ohlssen D, Pascoe S. Safety of formoterol in adults and children with asthma: a meta-analysis. Ann Allergy Asthma Immunol. 2011 Jul;107(1):71-8.

Page 41, right column, line 10, insert reference 234 after reference 75, and in line 17, after reference 169.Reference 234: Kemp J, Armstrong L, Wan Y, Alagappan VK, Ohlssen D, Pascoe S. Safety of formoterol in adults and children with asthma: a meta-analysis. Ann Allergy Asthma Immunol. 2011 Jul;107(1):71-8.

Page 57, right column, last paragraph, insert reference 414 after reference 22. Reference 414: Shah S, Sawyer SM, Toelle BG, Mellis CM, Peat JK, Lagleva M, Usherwood TP, Jenkins CR. Improving paediatric asthma outcomes in primary health care: a randomised controlled trial. Med J Aust. 2011 Oct 3;195(7):405-9.

Page 61, right column, paragraph 2 insert reference:Reference 415: Gehring U, de Jongste JC, Kerkhof M, Oldewening M, Postma D, van Strien RT, et al. The 8-year follow-up of the PIAMA intervention study assessing the effect of mite-impermeable mattress covers. Allergy. 2012 Feb;67(2):248-56

Page 73, right column end of first paragraph insert reference 418 after reference 349.Reference 418: Ortega H, Miller DP, Li H. Characterization of asthma exacerbations in primary care using cluster analysis. J Asthma. 2012 Mar;49(2):158-69.

Page 81, right column, last sentence under section on Occupational Asthma, insert insert (See also reference 421).

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Reference 421: Fishwick D, Barber CM, Bradshaw LM, Ayres JG, Barraclough R, Burge S, et al. Standards of care for occupational asthma: an update. Thorax. 2012 Mar;67(3):278-80.

C. Inserts to add clarification or additional information

Page 20, left column, insert new paragraph: In early life, the presence of sensitization to common allergens, atopy, is a major risk factor for subsequent development of asthma. In addition, atopy also predicts that asthma may be more severe when it does develop.

Page 32, left column last paragraph: correct dose to 1000 ug/day

Page 64, under heading of obesity, insert: ...including by bariatric surgery

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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 2011 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).

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 Board of Directors 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 Board of Directors 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 meager financial resources. The GINA Board of Directors 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.

As the GINA Board of Directors 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 Board of Directors, and in cooperation with GARD, progress toward better care for all patients with asthma should be substantial in the next decade.

INTRODUCTION

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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.

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CHAPTER

1

DEFINITION

AND

OVERVIEW

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2 DEFINITION AND OVERVIEW

KEY POINTS:

• 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:

Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread, but variable, airflow obstruction within the lung that is often reversible either spontaneously or with treatment.

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

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

DEFINITION

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DEFINITION AND OVERVIEW 3

Prevalence, Morbidity, and Mortality

Asthmaisaproblemworldwide,withanestimated300million affected individuals2,3.Despitehundredsofreportsontheprevalenceofasthmainwidelydifferingpopulations,thelackofapreciseanduniversallyaccepteddefinitionofasthmamakesreliablecomparisonofreportedprevalencefromdifferentpartsoftheworldproblematic.Nonetheless,basedontheapplicationofstandardizedmethodstomeasuretheprevalenceofasthmaandwheezingillnessinchildren4andadults,itappearsthattheglobalprevalenceofasthmarangesfrom1%to18%ofthepopulationindifferentcountries(Figure 1-1)2,3.Thereisgoodevidencethatinternationaldifferencesinasthmasymptomprevalencehavebeenreduced,particularlyinthe13-14yearagegroup,withdecreasesinprevalenceinNorthAmericaandWesternEuropeandincreasesinprevalenceinregionswhereprevalencewaspreviouslylow.Althoughtherewaslittlechangeintheoverallprevalenceofcurrentwheeze,thepercentageofchildrenreportedtohavehadasthmaincreasedsignificantly,possiblyreflectinggreaterawarenessofthisconditionand/orchangesindiagnosticpractice.TheincreasesinasthmasymptomprevalenceinAfrica,LatinAmericaandpartsofAsiaindicatethattheglobalburdenofasthmaiscontinuingtorise,buttheglobalprevalencedifferencesarelessening118.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,asestimatedinavarietyofhealthcaresystemsincludingthoseoftheUnitedStates13-15 andtheUnitedKingdom16aresubstantial.Inanalysesofeconomicburdenofasthma,attentionneedstobepaidtobothdirectmedicalcosts(hospitaladmissionsandcostofmedications)andindirect,non-medicalcosts(timelostfromwork,prematuredeath)17.Forexample,asthmaisamajorcauseofabsencefromworkinmanycountries4-6,includingAustralia,Sweden,theUnitedKingdom,andtheUnitedStates2,3,18,19.Comparisonsofthecostofasthmaindifferentregionsleadtoaclearsetofconclusions:

• Thecostsofasthmadependontheindividualpatient’slevelofcontrolandtheextenttowhichexacerbationsareavoided.

• Emergencytreatmentismoreexpensivethanplannedtreatment.

• Non-medicaleconomiccostsofasthmaaresubstantial.Guideline-determinedasthmacarecanbecosteffective.Familiescansufferfromthefinancialburdenoftreatingasthma.

Althoughfromtheperspectiveofboththepatientandsocietythecosttocontrolasthmaseemshigh,thecostofnottreatingasthmacorrectlyisevenhigher119.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,inpoor

comparedtoaffluentpopulationsindevelopednations,andinaffluentcomparedtopoorpopulationsindevelopingnations—likelyreflectlifestyledifferencessuchasexposuretoallergens,accesstohealthcare,etc.

Muchofwhatisknownaboutasthmariskfactorscomesfromstudiesofyoungchildren.Riskfactorsforthedevelopmentofasthmainadults,particularlyde novo in adultswhodidnothaveasthmainchildhood,arelesswelldefined.

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

Host Factors

Genetic.Asthmahasaheritablecomponent,butitisnotsimple.Currentdatashowthatmultiplegenesmaybeinvolvedinthepathogenesisofasthma24,25, and different genesmaybeinvolvedindifferentethnicgroups.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.Othergenesofinterestmodifytheresponsivenesstoglucocorticosteroids29 andleukotrienemodifiers30.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


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



Infections (predominantly viral)Occupational sensitizersTobacco smoke







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



Infections (predominantly viral)Occupational sensiti ersTobacco smoke







Host Factors




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Obesity.Asthmaismorefrequentlyobservedinobesesubjects(BodyMassIndex>30kg/m2)andismoredifficultto control124-127,134.Obesepeoplewithasthmahavelowerlungfunctionandmoreco-morbiditiescomparedwithnormalweightpeoplewithasthma131.Theuseofsystemicglucocorticosteroidsandasedentarylifestylemaypromoteobesityinsevereasthmapatients,butinmostinstances,obesityprecedesthedevelopmentofasthma.

Howobesitypromotesthedevelopmentofasthmaisstilluncertainbutitmayresultfromthecombinedeffectsofvariousfactors.Ithasbeenproposedthatobesitycouldinfluenceairwayfunctionduetoitseffectonlungmechanics,developmentofapro-inflammatorystate,inadditiontogenetic,developmental,hormonalorneurogenicinfluences35,129,130.Inthisregard,obesepatientshaveareducedexpiratoryreservevolume,apatternofbreathingthatmaypossiblyalterairwaysmoothmuscleplasticityandairway function34.Furthermore,thereleasebyadipocytesofvariouspro-inflammatorycytokinesandmediatorssuchasinterleukin-6,tumornecrosisfactor(TNF)-α, eotaxin, andleptin,combinedwithalowerlevelofanti-inflammatoryadipokinesinobesesubjectscanfavorasystemicinflammatorystatealthoughitisunknownhowthiscouldinfluenceairwayfunction131,132.

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

Environmental Factors

Thereissomeoverlapbetweenenvironmentalfactorsthatinfluencetheriskofdevelopingasthma,andfactorsthatcauseasthmasymptoms—forexample,occupationalsensitizersbelonginbothcategories.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)andparainfluenzavirusproduceapatternofsymptomsincludingbronchiolitisthatparallelmanyfeaturesofchildhoodasthma53,54.Anumberoflong-termprospectivestudiesofchildrenadmittedtothehospitalwithdocumentedRSVhaveshownthatapproximately40%willcontinuetowheezeorhaveasthmaintolaterchildhood53.Ontheotherhand,evidencealsoindicatesthatcertainrespiratoryinfectionsearlyinlife,includingmeaslesandsometimesevenRSV,mayprotectagainstthedevelopmentofasthma55,56.Thedatadonotallowspecificconclusionstobedrawn.Parasiteinfectionsdonotingeneralprotectagainstasthma,butinfectionwithhookwormmayreducetherisk120.

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.Tobaccosmokingisassociatedwithaccelerateddeclineoflungfunctioninpeoplewithasthma133,increasesasthmaseverity,mayrenderpatientslessresponsivetotreatmentwithinhaled121,122 and systemic74glucocorticosteroids,andreducesthelikelihoodofasthmabeingcontrolled75.

Exposuretotobaccosmokebothprenatally135,136 and afterbirthisassociatedwithmeasurableharmfuleffectsincludingagreaterriskofdevelopingasthma-likesymptomsinearlychildhood.However,evidenceofincreasedriskofallergicdiseasesisuncertain77, 78.Distinguishingtheindependentcontributionsofprenatalandpostnatalmaternalsmokingisproblematic79.However,studiesoflungfunctionimmediatelyafterbirthhaveshownthatmaternalsmokingduringpregnancyhasaninfluenceonlungdevelopment37.Furthermore,infantsofsmokingmothersare4timesmorelikelytodevelopwheezingillnessesinthefirstyearoflife79.Incontrast,thereislittleevidence(basedonmetaanalysis)thatmaternalsmokingduringpregnancyhasaneffectonallergicsensitization78.Exposuretoenvironmentaltobaccosmoke(passivesmoking)increasestheriskoflowerrespiratorytractillnesses in infancy80andchildhood81.

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.Theroleofoutdoorairpollutionincausingasthmaremainscontroversial82.Childrenraisedinapollutedenvironmenthavediminishedlungfunction83,buttherelationshipofthislossoffunctiontothedevelopmentofasthmaisnotknown.

Outbreaksofasthmaexacerbationshavebeenshowntooccurinrelationshiptoincreasedlevelsofairpollution,andthismayberelatedtoageneralincreaseinthelevelofpollutantsortospecificallergenstowhichindividualsaresensitized84-86.However,theroleofpollutantsinthedevelopmentofasthmaislesswelldefined.Similarassociationshavebeenobservedinrelationtoindoorpollutants,e.g.,smokeandfumesfromgasandbiomassfuelsusedforheatingandcooling,molds,andcockroachinfestations.

Diet.Theroleofdiet,particularlybreast-feeding,inrelationtothedevelopmentofasthmahasbeenextensivelystudiedand,ingeneral,thedatarevealthatinfantsfedformulasofintactcow’smilkorsoyproteinhaveahigherincidenceofwheezingillnessesinearlychildhoodcomparedwiththosefedbreastmilk87.

SomedataalsosuggestthatcertaincharacteristicsofWesterndiets,suchasincreaseduseofprocessedfoodsanddecreasedantioxidant(intheformoffruitsandvegetables),increasedn-6polyunsaturatedfattyacid(foundinmargarineandvegetableoil),anddecreasedn-3polyunsaturatedfattyacid(foundinoilyfish)intakeshavecontributedtotherecentincreasesinasthmaandatopicdisease88.

Asthmaisaninflammatorydisorderoftheairways,whichinvolvesseveralinflammatorycellsandmultiplemediatorsthatresultincharacteristicpathophysiologicalchanges89.Inwaysthatarestillnotwellunderstood,thispatternofinflammationisstronglyassociatedwithairwayhyper-responsivenessandasthmasymptoms.

Airway Inflammation In Asthma

Theclinicalspectrumofasthmaishighlyvariable,anddifferentcellularpatternshavebeenobserved,butthepresenceofairwayinflammationremainsaconsistentfeature.Theairwayinflammationinasthmaispersistenteventhoughsymptomsareepisodic,andtherelationshipbetweentheseverityofasthmaandtheintensityofinflammationisnotclearlyestablished90,91.Theinflammationaffectsallairwaysincludinginmostpatientstheupperrespiratorytractandnosebutitsphysiologicaleffectsaremostpronouncedinmedium-sizedbronchi.

MECHANISMS OF ASTHMA

Figure 1-4: Inflammatory Cells in Asthmatic Airways

Mast cells: Activated mucosal mast cells release bronchoconstrictor mediators (histamine, cysteinyl leukotrienes, prostaglandin D2)92. These cells are activated by allergens through high-affinity IgE receptors, as well as by osmotic stimuli (accounting for exercise-induced bronchoconstriction). Increased mast cell numbers in airway smooth muscle may be linked to airway hyperresponsiveness93.

Eosinophils, present in increased numbers in the airways, release basic proteins that may damage airway epithelial cells. They may also have a role in the release of growth factors and airway remodeling94.

T lymphocytes, present in increased numbers in the airways, release specific cytokines, including IL-4, IL-5, IL-9, and IL-13, that orchestrate eosinophilic inflammation and IgE production by B lymphocytes95. An increase in Th2 cell activity may be due in part to a reduction in regulatory T cells that normally inhibit Th2 cells. There may also be an increase in inKT cells, which release large amounts of T helper 1 (Th1) and Th2 cytokines96.

Dendritic cells sample allergens from the airway surface and migrate to regional lymph nodes, where they interact with regulatory T cells and ultimately stimulate production of Th2 cells from na ve T cells97.

Macrophages are increased in number in the airways and may be activated by allergens through low-affinity IgE receptors to release inflammatory mediators and cytokines that amplify the inflammatory response98.

Neutrophil numbers are increased in the airways and sputum of patients with severe asthma and in smoking asthmatics, but the pathophysiological role of these cells is uncertain and their increase may even be due to glucocorticosteroid therapy99 .

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

Airway epithelial cells sense their mechanical environment, express multiple inflammatory proteins in asthma, and release cytokines, chemokines, and lipid mediators. Viruses and air pollutants interact with epithelial cells.

Airway smooth muscle cells express similar inflammatory proteins to epithelial cells100.

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

Fibroblasts and myofibroblasts produce connective tissue components, such as collagens and proteoglycans, that are involved in airway remodeling.

Airway nerves are also involved. Cholinergic nerves may be activated by reflex triggers in the airways and cause bronchoconstriction and mucus secretion. Sensory nerves, which may be sensiti ed by inflammatory stimuli including neurotrophins, cause reflex changes and symptoms such as cough and chest tightness, and may release inflammatory neuropeptides101.

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).

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.


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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.Over100differentmediatorsarenowrecognizedtobeinvolvedinasthmaandmediatethecomplexinflammatoryresponseintheairways(Figure 1-6).

Structural changes in the airways.Inadditiontotheinflammatoryresponse,therearecharacteristicstructuralchanges,oftendescribedasairwayremodeling,intheairwaysofasthmapatients(Figure 1-7).Someofthesechangesarerelatedtotheseverityofthediseaseandmayresultinrelativelyirreversiblenarrowingoftheairways107,108.Thesechangesmayrepresentrepairinresponsetochronicinflammation.

Pathophysiology Airwaynarrowingisthefinalcommonpathwayleadingtosymptomsandphysiologicalchangesinasthma.Severalfactorscontributetothedevelopmentofairwaynarrowinginasthma109-111(Figure 1-8).

Airway hyperresponsiveness. Airway hyperresponsiveness,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 cells102. 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 andproinflammatory mediators mainly derived from mast cells and eosinophils.They are the only mediator whose inhibition has been associatedwith an improvement in lung function and asthma symptoms103.

Cytokines orchestrate the inflammatory response in asthma anddetermine its severity104. 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 epithelialcells105. Exhaled NO is increasingly being used to monitor theeffectiveness of asthma treatment, because of its reportedassociation with the presence of inflammation in asthma106.

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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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.










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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 airwaywall109. This process may relate to disease severity and is causedby inflammatory mediators, such as growth factors.


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

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Acute exacerbations.Transientworseningofasthmamay occurasaresultofexposuretoriskfactorsforasthmasymptoms113,or“triggers,”suchasexercise,airpollutants,andevencertainweatherconditions,e.g.,thunderstorms86.Moreprolongedworseningisusuallyduetoviralinfectionsoftheupperrespiratorytract(particularlyrhinovirusandrespiratorysyncytialvirus)114orallergenexposurewhichincreaseinflammationinthelowerairways(acuteorchronicinflammation)thatmaypersistforseveraldaysorweeks.

Nocturnal asthma.Themechanismsaccountingfortheworseningofasthmaatnightarenotcompletelyunderstoodbutmaybedrivenbycircadianrhythmsofcirculatinghormonessuchasepinephrine,cortisol,andmelatoninandneuralmechanismssuchascholinergictone.Anincreaseinairwayinflammationatnighthasbeenreported.Thismightreflectareductioninendogenousanti-inflammatorymechanisms115.

Irreversible airflow limitation.Somepatientswithsevereasthmadevelopprogressiveairflowlimitationthatisnotfullyreversiblewithcurrentlyavailabletherapy.Thismayreflectthechangesinairwaystructureinchronicasthma116.

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

Smoking and asthma.Tobaccosmokingmakesasthmamoredifficulttocontrol,resultsinmorefrequentexacerbationsandhospitaladmissions,andproducesamorerapiddeclineinlungfunctionandanincreasedriskofdeath117.Asthmapatientswhosmokemayhaveaneutrophil-predominantinflammationintheirairwaysandarepoorlyresponsivetoglucocorticosteroids121,122.

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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 airways when bronchoconstrictor substances are inhaled.


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

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102.BarnesPJ,ChungKF,PageCP.Inflammatorymediatorsofasthma:anupdate.Pharmacol Rev1998;50(4):515-96.MillerAL,LukacsNW.Chemokinereceptors:understandingtheirroleinasthmaticdisease.Immunol Allergy Clin North Am 2004;24(4):667-83,vii.

103.LeffAR.Regulationofleukotrienesinthemanagementof

asthma:biologyandclinicaltherapy.Annu Rev Med2001;52:1-14.

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105.RicciardoloFL,SterkPJ,GastonB,FolkertsG.Nitricoxideinhealthanddiseaseoftherespiratorysystem.Physiol Rev 2004;84(3):731-65.

106.BarnesPJ,DweikRA,GelbAF,GibsonPG,GeorgeSC,Grasemann H, et al.Exhalednitricoxideinpulmonarydiseases:acomprehensivereview.Chest.2010Sep;138(3):682-92.

107.JamesA.Airwayremodelinginasthma.Curr Opin Pulm Med 2005;11(1):1-6.

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109.HirstSJ,MartinJG,BonacciJV,ChanV,FixmanED,HamidQA,et al.Proliferativeaspectsofairwaysmoothmuscle.JAllergyClinImmunol2004;114(2Suppl):S2-17.

110.BlackJL.Asthma--moremusclecellsormoremuscularcells?Am J RespirCritCareMed2004;169(9):980-1.

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P,CollierC.Acuteasthmaepidemics,weatherandpolleninEngland,1987-1994.Eur Respir J1998;11(3):694-701.

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117.ThomsonNC,ChaudhuriR,LivingstonE.Asthmaandcigarettesmoking.Eur Respir J2004;24(5):822-33.

118.AsherMI,MontefortS,BjorkstenB,LaiCK,StrachanDP,WeilandSK,WilliamsH;ISAACPhaseThreeStudyGroup.Worldwidetimetrendsintheprevalenceofsymptomsofasthma,allergicrhinoconjunctivitis,andeczemainchildhood:ISAACPhasesOneandThreerepeatmulticountrycross-sectionalsurveys.Lancet2006Aug26;368(9537):733-43.

119.AccordiniS,BugianiM,ArossaW,GerzeliS,MarinoniA,OlivieriM,PirinaP,CarroiL,DallariR,DeTogniA,deMarcoR.Poorcontrolincreasestheeconomiccostofasthma.Amulticentrepopulation-basedstudy.Int Arch Allergy Immunol 2006;141(2):189-98.

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124.BeutherDA,SutherlandER.Overweight,obesity,andincidentasthma:ameta-analysisofprospectiveepidemiologicstudies.Am J Respir Crit Care Med2007;175(7):661-6.

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2

DIAGNOSIS

AND

CLASSIFICATION

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16 DIAGNOSIS AND CLASSIFICATION

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-No exacerbations

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

UsefulquestionstoconsiderwhenestablishingadiagnosisofasthmaaredescribedinFigure 2-1.

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,and vocal cord dysfunction6.

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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DIAGNOSIS AND CLASSIFICATION 17

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.

Predicted values of FEV1,FVC,andPEFbasedonage,sex,andheighthavebeenobtainedfrompopulationstudies.Thesearebeingcontinuallyrevised,andwiththeexceptionofPEFforwhichtherangeofpredictedvaluesistoowide,theyareusefulforjudgingwhetheragivenvalueisabnormalornot.Ifprecisionisneeded,forexample,intheconductofaclinicaltrial,useofamorerigorousdefinition(lowerlimitofnormal-LLN)shouldbeconsidered.

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

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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, a useful assessmentofairflowlimitationistheratioofFEV1toFVC.TheFEV1/FVCratioisnormallygreaterthan0.75to0.80,andpossiblygreaterthan0.90inchildren.Anyvalueslessthanthesesuggestairflowlimitation.

Peak expiratory flowmeasurementsaremadeusingapeakflowmeterandcanbeanimportantaidinbothdiagnosisandmonitoringofasthma.ModernPEFmetersarerelativelyinexpensive,portable,plastic,andidealforpatientstouseinhomesettingsforday-to-dayobjectivemeasurementofairflowlimitation.However,measurementsofPEFarenotinterchangeablewithothermeasurementsoflungfunctionsuchasFEV1ineitheradults

16orchildren17.PEFcanunderestimatethedegreeofairflowlimitation,particularlyasairflowlimitationandgastrappingworsen.BecausevaluesforPEFobtainedwithdifferentpeakflowmetersvaryandtherangeofpredictedvaluesistoowide,PEFmeasurementsshouldpreferablybecomparedtothepatient’sownpreviousbestmeasurements18usinghis/herownpeakflowmeter.Thepreviousbestmeasurementisusuallyobtainedwhenthepatientisasymptomaticoronfulltreatmentandservesasareferencevalueformonitoringtheeffectsofchangesintreatment.

Careful instruction is required to reliably measure PEF becausePEFmeasurementsareeffort-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:

• To confirm the diagnosis of asthma.Althoughspirometryisthepreferredmethodofdocumentingairflowlimitation,a60L/min(or20%ormoreofpre-bronchodilatorPEF)improvementafterinhalationofabronchodilator20, or diurnal variation in PEF of more than20%(withtwicedailyreadings,morethan10%21)suggestsadiagnosisofasthma.

• To improve control of asthma, particularly in patients with poor perception of symptoms10.Asthmamanagementplanswhichincludeself-monitoringofsymptomsorPEFfortreatmentofexacerbationshavebeenshowntoimproveasthmaoutcomes22.ItiseasiertodiscerntheresponsetotherapyfromaPEFchartthanfromaPEFdiary,providedthesamechartformat is consistently used23.

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

PE

F L

/min

-1 0

310/700= 44%

1 2 3 4 5 6 7 8 9 10

Inhaled glucocorticosteroidscommenced

500/710= 70%

620/720= 86%

0

100

200

300

400

500

600

700

800

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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• To identify environmental (including occupational) causes of asthma symptoms.ThisinvolvesthepatientmonitoringPEFdailyorseveraltimeseachdayoverperiodsofsuspectedexposuretoriskfactorsinthehomeorworkplace,orduringexerciseorotheractivitiesthatmaycausesymptoms,andduringperiodsofnon-exposure.

Measurement of airway responsiveness.Forpatientswithsymptomsconsistentwithasthma,butnormallungfunction,measurementsofairwayresponsivenesstodirectairwaychallengessuchasinhaledmethacholineandhistamineorindirectairwaychallengessuchasinhaledmannitol83 orexercisechallengemayhelpestablishadiagnosisofasthma24.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)32 havebeensuggestedasnon-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

Inearlylife,thepresenceofsensitizationtocommonallergens,atopy,isamajorriskfactorforsubsequentdevelopmentofasthma.Inaddition,atopyalsopredictsthatasthmamaybemoreseverewhenitdoesdevelop.

Thediagnosisofasthmainearlychildhoodischallengingandhastobebasedlargelyonclinicaljudgmentandanassessmentofsymptomsandphysicalfindings.Sincetheuseofthelabel“asthma”forwheezinginchildrenhasimportantclinicalconsequences,itmustbedistinguishedfromothercausespersistentandrecurrentwheeze.

Episodicwheezingandcoughisverycommoneveninchildrenwhodonothaveasthmaandparticularlyinthoseunderage336.Threecategoriesofwheezinghavebeendescribedinchildren5yearsandyounger:

• Transient early wheezing,whichisoftenoutgrowninthefirst3years.Thisisoftenassociatedwithprematurityandparentalsmoking.

• Persistent early-onset wheezing(beforeage3).Thesechildrentypicallyhaverecurrentepisodesofwheezingassociatedwithacuteviralrespiratoryinfections,havenoevidenceofatopy37and,unlikechildreninthenextcategoryoflateonsetwheezing/asthma,havenofamilyhistoryofatopy.Thesymptomsnormallypersistthroughschoolageandarestillpresentatage12inalargeproportionofchildren.Thecauseoftheepisodeisusuallytherespiratorysyncytialvirusinchildrenyoungerthanage2,whileothervirusespredominateinolderpreschoolchildren.

• Late-onset wheezing/asthma.Thesechildrenhaveasthmawhichoftenpersiststhroughoutchildhoodand into adult life38, 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:

DIAGNOSTIC CHALLENGES ANDDIFFERENTIAL DIAGNOSIS

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• Upperairwayobstructionandinhaledforeignbodies43 • Vocal cord dysfunction44 • Otherformsofobstructivelungdisease,particularly

COPD

• 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.Detectionofasthmaofoccupationaloriginrequiresasystematicinquiryabout

workhistoryandexposures.Thediagnosisrequiresadefinedhistoryofoccupationalexposuretoknownorsuspectedsensitizingagents;anabsenceofasthmasymptomsbeforebeginningemployment;oradefiniteworseningofasthmaafteremployment.Arelationshipbetweensymptomsandtheworkplace(improvementinsymptomsawayfromworkandworseningofsymptomsonreturningtowork)canbehelpfulinestablishingalinkbetweensuspectedsensitizingagentsandasthma45.

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

Distinguishing Asthma from COPD

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

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Etiology

Manyattemptshavebeenmadetoclassifyasthmaaccordingtoetiology,particularlywithregardtoenvironmentalsensitizingagents.However,suchaclassificationislimitedbytheexistenceofpatientsinwhomnoenvironmentalcausecanbeidentified.Despitethis,anefforttoidentifyanenvironmentalcauseforasthma(forexample,occupationalasthma)shouldbepartoftheinitialassessmenttoenabletheuseofavoidancestrategiesinasthmamanagement.Describingpatientsashavingallergicasthmaisusuallyoflittlebenefitinguidingtreatment,unlessasinglespecifictriggeragentcanbeidentified. Phenotype

Thereisincreasingawarenessofheterogeneityinthemanifestationsofasthmaandinitsresponsetotreatment.Thisisoftendescribedintermsof‘phenotypes’57,58,thecharacteristicswhichresultfromtheinteractionbetweenapatient’sgeneticmakeupandtheirenvironment.Several

differentclinicalphenotypesarerecognizedonthebasisofclusteranalysisofclinicalandotherfeaturesofasthma,e.g.aspirin-inducedasthma,exacerbation-proneasthmaandthesearchfordistinctivepathologicalormolecularfeaturesthatcouldexplaintheseclinicalpatternscontinues.Mostworkhasbeendoneoninflammatoryphenotypes,identifiedusingsputuminduction.Patientswitheosinophilicandnon-eosinophilicphenotypeshavebeenshowntodifferintheirclinicalresponsetoinhaledglucocorticosteroids59,60, andatagrouplevel,inflammatorymarkersmaybepredictiveofriskofexacerbationafterglucocorticosteroidreduction61.Inflammatoryphenotypesappeartobemoderatelystableovertime,althoughdataarelimited62,63.Atpresent,sincefewclinicianshaveaccesstoqualifiedsputumlaboratories,identificationoftheinflammatoryphenotypeismostlikelytobeusefulforpatientswithsevereasthmaorinthecontextofresearch.

Asthma Control

Asthmacontrolmaybedefinedinavarietyofways.Inlayterms,controlmayindicatediseaseprevention,orevencure.However,inasthma,whereneitherofthesearerealisticoptionsatpresent,itreferstocontrolofthemanifestationsofdisease.Theaimoftreatmentshouldbe

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 (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 definition, 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

CLASSIFICATION OF ASTHMA

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toachieveandmaintaincontrolforprolongedperiods64withdueregardtothesafetyoftreatment,potentialforadverseeffects,andthecostoftreatmentrequiredtoachievethisgoal.Therefore,theassessmentofasthmacontrolshouldincludenotonlycontroloftheclinicalmanifestations(symptoms,nightwaking,relieveruse,activitylimitation,lungfunction),butalsocontroloftheexpectedfuturerisktothepatientsuchasexacerbations,accelerateddeclineinlungfunction,andside-effectsoftreatment.Ingeneral,theachievementofgoodclinicalcontrolofasthmaleadstoreducedriskofexacerbations65.However,certainpatientsmaycontinuetoexperienceexacerbationsinspiteofadequateintervalcontrol.Smokersarelesslikelytoachievecontrolandremainatriskofexacerbations66.Itshouldbenotedthatinhaledglucocorticosteroidsbothimproveclinicalcontrolandreducefuturerisk,butsomepharmacologicalagentsaremoreeffectiveinimprovingfeaturesofclinicalcontrol,whileothersarerelativelymoreeffectiveatreducingexacerbations.Thus,forsomepatientphenotypes,treatmentmaybeselectedtoaddressthepredominantproblem.

Figure 2-4describestheclinicalcharacteristicsofControlled, Partly Controlled and Uncontrolledasthma.Thisisaworkingschemebasedoncurrentopinionandhasnotbeenformallyvalidated.However,thisclassificationhasbeenshowntocorrelatewellwiththeAsthmaControlTest67 andwithassessmentofasthmacontrolaccordingtotheUSNationalExpertPanelReport3guidelines68,69.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, and some areavailableinmanylanguages,ontheInternet,andinpaperformandmaybecompletedbypatientspriorto,orduring,consultationswiththeirhealthcareprovider.Theyhavethepotentialtoimprovetheassessmentofasthmacontrol,providingareproducibleobjectivemeasurethatmaybechartedovertime(weekbyweekormonthby

month)andrepresentinganimprovementincommunicationbetweenpatientandhealthcareprofessional.Theirvalueinclinicaluse,asdistinctfromresearchsettings,hasyettobedemonstratedbutwilllikelybecomeevidentincomingyears.Allofthesetoolsaresubjecttocopyrightrestrictions,andsomehavefeesassociatedwiththeiruseinresearch.

Thereisconsiderableinterestincontrollingnotonlytheclinicalmanifestationsofasthma,butalsotheinflammatoryandpatho-physiologicalfeaturesofthedisease.Thereisevidencethatreducinginflammationwithcontrollertherapyachievesgoodclinicalcontrolandreducestheriskofexacerbations.Inaddition,inflammatoryandpatho-physiologicalmarkersmaybepredictorsoffutureriskofexacerbationsanddeclineinlungfunction,independentofthepatient’slevelofclinicalcontrol66,76.Biomarker-guidedtreatmentappears,primarily,tobeofvalueinasthmaphenotypesinwhichthereisdissociationbetweenmeasuresofclinicalcontrolandairwayinflammation.Forexample,treatmentbasedontheproportionofeosinophilsinsputumhasresultedinareductionofexacerbationsorminimizationofdosesofinhaledglucocorticosteroidsinpatientswithuncontrolledasthmainspiteofmoderatelevels of treatment77,78.

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

Asthma Severity

Forpatientsnotreceivinginhaledglucocorticosteroidtreatment,previousGINAdocumentssubdividedasthmabyseveritybasedonthelevelofsymptoms,airflowlimitation,andlungfunctionvariabilityintofourcategories:Intermittent, Mild Persistent, Moderate Persistent, or SeverePersistent,althoughthisclassificationwasoftenerroneouslyappliedtopatientsalreadyontreatment79.Acopyofthisclassificationsystemisarchivedatwww.ginasthma.org.Itisimportanttorecognize,however,thatasthmaseverityinvolvesboththeseverityoftheunderlyingdiseaseanditsresponsivenesstotreatment80.Thus,asthmacouldpresentwithseveresymptomsandairflowobstruction,butbecomecompletelycontrolledwithlow-dosetreatment.Inaddition,severityisnotastaticfeatureofanindividualpatient’sasthma,butmaychangeovermonthsoryears.Themainlimitationofthispreviousmethodofclassificationofasthmaseveritywasitspoorvalueinpredictingwhattreatmentwouldberequiredandwhatapatient’sresponsetothattreatmentmightbe.Forthisreason,anassessmentofasthmacontrolatinitial

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presentationandperiodicallyduringtreatmentismorerelevant and useful81.

Inviewoftheselimitations,asthmaseverityisnowbyconsensusclassifiedonthebasisoftheintensityoftreatmentrequiredtoachievegoodasthmacontrol79,80.Mildasthmaisasthmathatcanbewell-controlledwithlowintensitytreatmentsuchaslow-doseinhaledglucocorticosteroids,leukotrienemodifiersorcromones.Severeasthmaisasthmathatrequireshighintensitytreatment,e.g.GINAStep4,tomaintaingoodcontrol,orwheregoodcontrolisnotachieveddespitehighintensity treatment82.Itisrecognizedthatdifferentasthmaphenotypesmayhavedifferentlevelsofresponsivenesstoconventionaltreatment.Asphenotype-specifictreatmentbecomesavailable,asthmapreviouslyconsideredtobeseverecouldbecomemild.

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

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34. SmithAD,CowanJO,BrassettKP,HerbisonGP,TaylorDR.Useofexhalednitricoxidemeasurementstoguidetreatmentinchronicasthma.N Engl J Med2005;352(21):2163-73.

35. HoeppnerVH,MurdockKY,KoonerS,CockcroftDW.Severeacute“occupationalasthma!causedbyaccidentalallergenexposureinanallergenchallengelaboratory.Ann Allergy 1985;55:36-7.

36. WilsonNM.Wheezybronchitisrevisited.Arch Dis Child 1989;64(8):1194-9.

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39. SearsMR,GreeneJM,WillanAR,WiecekEM,TaylorDR,Flannery EM, et al.Alongitudinal,population-based,cohortstudyofchildhoodasthmafollowedtoadulthood.N Engl J Med 2003;349(15):1414-22.

40. GuilbertTW,MorganWJ,ZeigerRS,MaugerDT,BoehmerSJ,SzeflerSJ,et al.Long-terminhaledcorticosteroidsinpreschoolchildrenathighriskforasthma.N Engl J Med 2006;354(19):1985-97.

41. FreyU,StocksJ,SlyP,BatesJ.Specificationforsignalprocessinganddatahandlingusedforinfantpulmonaryfunctiontesting.ERS/ATSTaskForceonStandardsforInfantRespiratoryFunctionTesting.EuropeanRespiratorySociety/AmericanThoracicSociety.Eur Respir J2000;16(5):1016-22.

42. SlyPD,CahillP,WilletK,BurtonP.Accuracyofminipeakflowmetersinindicatingchangesinlungfunctioninchildrenwithasthma.BMJ1994;308(6928):572-4.

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46. TarloSM.Laboratorychallengetestingforoccupationalasthma.J Allergy Clin Immunol2003;111(4):692-4.

47. Chan-YeungM,DesjardinsA.Bronchialhyperresponsivenessandlevelofexposureinoccupationalasthmaduetowesternredcedar(Thujaplicata).Serialobservationsbeforeandafterdevelopmentofsymptoms.Am Rev Respir Dis 1992;146(6):1606-9.

48. CoteJ,KennedyS,Chan-YeungM.SensitivityandspecificityofPC20andpeakexpiratoryflowrateincedarasthma.J Allergy Clin Immunol1990;85(3):592-8.

49. VandenplasO,MaloJL.Inhalationchallengeswithagentscausingoccupationalasthma.Eur Respir J1997;10(11):2612-29.

50. BrightP,BurgePS.Occupationallungdisease.8.Thediagnosisofoccupationalasthmafromserialmeasurementsoflungfunctionatandawayfromwork.Thorax1996;51(8):857-63.

51. Chan-YeungM,MacLeanL,PaggiaroPL.Follow-upstudyof232patientswithoccupationalasthmacausedbywesternredcedar(Thujaplicata).J Allergy Clin Immunol1987;79(5):792-6.

52. NicholsonPJ,CullinanP,TaylorAJ,BurgePS,BoyleC.Evidencebasedguidelinesfortheprevention,identification,andmanagementofoccupationalasthma.Occup Environ Med 2005;62(5):290-9.

53. PriceDB,TinkelmanDG,HalbertRJ,NordykeRJ,IsonakaS,NonikovD,et al.Symptom-basedquestionnaireforidentifyingCOPDinsmokers.Respiration2006;73(3):285-95.

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

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

56. ShawDE,BerryMA,ThomasM,GreenRH,BrightlingCE,WardlawAJ,PavordID.Theuseofexhalednitricoxidetoguideasthmamanagement:arandomizedcontrolledtrial.Am J Respir Crit Care Med2007;176:231-7.

57. BelEH.Clinicalphenotypesofasthma. Curr Opin Pulm Med 2004;10:44-50.

58. WenzelSE.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.Lancet 1999;353:2213-4.

61. JatakanonA,LimS,BarnesPJ.Changesinsputumeosinophilspredictlossofasthmacontrol.Am J Respir Crit Care Med 2000;161:64-72.

62. SimpsonJL,ScottR,BoyleMJ,GibsonPG.Inflammatorysubtypesinasthma:assessmentandidentificationusinginducedsputum. Respirology2006;11:54-61.

63. vanVeenIH,TenBrinkeA,GauwSA,SterkPJ,RabeKF,BelEH.Consistencyofsputumeosinophiliaindifficult-to-treatasthma:a5-yearfollow-upstudy.J Allergy Clin Immunol 2009;124:615-7,617e1-2.

64. BatemanED,BousheyHA,BousquetJ,BusseWW,ClarkTJ,PauwelsRA,PedersenSE.Canguideline-definedasthmacontrolbeachieved?TheGainingOptimalAsthmaControLstudy.Am J Respir Crit Care Med2004;170:836-44.

65. BatemanED,BousquetJ,KeechML,BusseWW,ClarkTJ,PedersenSE.Thecorrelationbetweenasthmacontrolandhealthstatus:theGOALstudy.Eur Respir J2007;29:56-62.

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.Prim Care Respir J 2009;18:41-9.

68. NationalHeart,Lung,andBloodInstitute.NationalAsthmaEducationandPreventionProgram.ExpertPanelReport3:GuidelinesfortheDiagnosisandManagementofAsthma.August2007.Availablefrom: www.nhlbi.nih.gov/guidelines/asthma/asthgdln

69. KhaliliB,BoggsPB,ShiR,BahnaSL.Discrepancybetweenclinicalasthmacontrolassessmenttoolsandfractionalexhalednitricoxide.Ann Allergy Asthma Immunol2008;101:124-9.

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71. NathanRA,SorknessCA,KosinskiM,SchatM,LiJT,MarcusP,MurrayJJ,PendergraftTB.Developmentoftheasthmacontroltest:asurveyforassessingasthmacontrol.J Allergy Clin Immunol2004;113:59-65.

72. LiuAH,ZeigerR,SorknessC,MahrT,OstromN,BurgessS,RosenzweigJC,ManjunathR.Developmentandcross-sectionalvalidationoftheChildhoodAsthmaControlTest.J Allergy Clin Immunol2007;119:817-25.

73. VollmerWM,MarksonLE,O’ConnorE,SanockiLL,FittermanL,BergerM,BuistAS.Associationofasthmacontrolwithhealthcareutilizationandqualityoflife.Am J Respir Crit Care Med 1999;160:1647-52.

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

75. SchatzM,MosenDM,KosinskiM,VollmerWM,MagidDJ,O’ConnorE,ZeigerRS.ValidityoftheAsthmaControlTestcompletedathome.Am J Manag Care2007;13:661-7.

76. vanRensenEL,SontJK,EvertseCE,WillemsLN,MauadT,HiemstraPS,SterkPJ.BronchialCD8cellinfiltrateandlungfunctiondeclineinasthma.Am J Respir Crit Care Med 2005;172:837-41.

77. HaldarP,PavordID,ShawDE,BerryMA,ThomasM,BrightlingCE,WardlawAJ,GreenRH.Clusteranalysisandclinicalasthmaphenotypes.Am J Respir Crit Care Med2008;178:218-24.

78. JayaramL,PizichiniMM,CookRJ,BouletLP,LemiereC,PizichiniE,CartierA,HussackP,GoldsmithCH,LavioletteM,ParameswaranK,HargreaveFE.Determiningasthmatreatmentbymonitoringsputumcellcounts:effectonexacerbations.Eur Respir J2006;27:483-94.

79. TaylorDR,BatemanED,BouletLP,BousheyHA,BusseWW,CasaleTB,ChaneP,EnrightPL,GibsonPG,deJongsteJC,KerstjensHA,LazarusSC,LevyML,O’ByrnePM,PartridgeMR,PavordID,SearsMR,SterkPJ,StoloffSW,SzeflerSJ,SullivanSD,ThomasMD,WenzelSE,ReddelHK.Anewperspectiveonconceptsofasthmaseverityandcontrol.Eur Respir J2008;32:545-54.

80. CockcroftDW,SwystunVA.Asthmacontrolversusasthmaseverity.J Allergy Clin Immunol1996;98:1016-8.

81. ChenH,GouldMK,BlancPD,MillerDP,KamathTV,LeeJH,SullivanSD.Asthmacontrol,severity,andqualityoflife:quantifyingtheeffectofuncontrolleddisease.J Allergy Clin Immunol2007;120:396-402.

82. ProceedingsoftheATSworkshoponrefractoryasthma:currentunderstanding,recommendations,andunansweredquestions.AmericanThoracicSociety.Am J Respir Crit Care Med 2000;162:2341-51.

83. AndersonSD.Indirectchallengetests:Airwayhyperresponsivenessinasthma:itsmeasurementandclinicalsignificance.Chest 2010;138:25S-30S.

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30 ASTHMA TREATMENTS

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.Controllers are medicationstakendailyonalong-termbasistokeepasthmaunderclinicalcontrolchieflythroughtheiranti-inflammatoryeffects.Theyincludeinhaledandsystemicglucocorticosteroids,leukotrienemodifiers,long-actinginhaledβ2-agonistsincombinationwithinhaledglucocorticosteroids,sustained-releasetheophylline,cromones,andanti-IgE.Inhaledglucocorticosteroidsarethemosteffectivecontrollermedicationscurrentlyavailable.Relievers are medications used on an as-needed basisthatactquicklytoreversebronchoconstrictionandrelieveitssymptoms.Theyincluderapid-actinginhaledβ2-agonists,inhaledanticholinergics,short-actingtheophylline,andshort-actingoralβ2-agonists.

Route of Administration

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

Inhaledmedicationsforasthmaareavailableaspressurizedmetered-doseinhalers(MDIs),breath-actuatedMDIs,drypowderinhalers(DPIs),softmistinhalers,andnebulizedor“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,andmayreducelocal and systemic side effects1.However,CFCinhalerdevicesarebeingphasedoutduetotheimpactofCFCsupontheatmosphericozonelayer,andarebeingreplacedbyHFAdevices.ForpMDIscontainingbronchodilators,theswitchfromCFCtoHFAinhalersdoesnotresultinachangeinefficacyatthesamenominaldose2.However,forsomeglucocorticosteroids,theHFAformulationsprovideanaerosolofsmallerparticlesizethatresultsinlessoraldeposition(withassociatedreductioninoralsideeffects),andcorrespondinglygreaterlungdeposition3-5.Cliniciansareadvisedtoconsultthepackageinsertsofeachproducttoconfirmtherecommendeddoseequivalenttocurrentlyuseddrugs.SomeofthesecomparisonsareprovidedinFigure 3-1.

INTRODUCTION

ASTHMA MEDICATIONS: ADULTS

*InformationonvariousinhalerdevicesavailablecanbefoundontheGINAWebsite(http://www.ginasthma.org).

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PressurizedMDIsmaybeusedbypatientswithasthmaofanyseverity,includingduringexacerbations.Breath-actuatedaerosolsmaybehelpfulforpatientswhohavedifficultyusingthe“pressandbreathe”pressurizedMDI6.Softmistinhalersappeartorequirelesscoordination.Drypowderinhalersaregenerallyeasiertouse,buttheyrequireaminimalinspiratoryflowrateandmayprovedifficultforsomepatients.DPIsdifferwithrespecttothefractionofex-actuatordosedeliveredtothelung.Forsomedrugs,thedosemayneedtobeadjustedwhenswitchingfrom an MDI6 to a DIP7.Nebulizedaerosolsarerarelyindicatedforthetreatmentofchronicasthmainadults8.

Inhaled glucocorticosteroids*

Role in therapy-Inhaledglucocorticosteroidsarecurrentlythemosteffectiveanti-inflammatorymedicationsforthetreatmentofpersistentasthma.Studieshavedemonstratedtheirefficacyinreducingasthmasymptoms9,improvingquality of life9,improvinglungfunction9,decreasingairwayhyperresponsiveness10,controllingairwayinflammation11, reducingfrequencyandseverityofexacerbations12, and reducingasthmamortality13.However,theydonotcureasthma,andwhentheyarediscontinueddeterioration

ofclinicalcontrolfollowswithinweekstomonthsinaproportionofpatients14,15.

Inhaledglucocorticosteroidsdifferinpotencyandbioavailability,butbecauseofrelativelyflatdose-responserelationshipsinasthmarelativelyfewstudieshavebeenabletoconfirmtheclinicalrelevanceofthesedifferences191.Figure 3-1listsapproximatelyequipotentdosesofdifferentinhaledglucocorticosteroidsbasedupontheavailableefficacyliterature,butthecategorizationintodosagecategoriesdoesnotimplythatcleardose-responserelationshipshavebeendemonstratedforeachdrug.Theefficacyofsomeproductsvarieswhenadministeredviadifferentinhalerdevices16.Mostofthebenefitfrominhaledglucocorticosteroidsisachievedinadultsatrelativelylowdoses,equivalentto400ugofbudesonideperday17.Increasingtohigherdosesprovideslittlefurtherbenefitintermsofasthmacontrolbutincreasestheriskof side effects17,18.However,thereismarkedindividualvariabilityofresponsivenesstoinhaledglucocorticosteroidsandbecauseofthisandtherecognizedpooradherencetotreatmentwithinhaledglucocorticosteroids,manypatientswillrequirehigherdosestoachievefulltherapeuticbenefit.Astobaccosmokingreducestheresponsivenesstoinhaledglucocorticosteroids,higherdosesmayberequiredinpatientswhosmoke240.

CONTROLLER MEDICATIONS

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

Drug Low Daily Dose (µg) Medium Daily Dose (µg) High Daily Dose (µg)‡

Beclomethasone dipropionate - CFC 200-500 >500-1000 >1000-2000Beclomethasone dipropionate - HFA 100 - 250 >250 - 500 >500 - 1000

Budesonide* 200-400 >400-800 >800-1600Ciclesonide* 80-160 >160-320 >320-1280Flunisolide 500-1000 >1000-2000 >2000

Fluticasone propionate 100-250 >250-500 >500-1000Mometasone furoate* 200 ≥400 ≥800

Triamcinolone acetonide 400-1000 >1000-2000 >2000†Comparisons based on 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 approprioate dosing is the clinician’s judgement of the patient’s response 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 carefully be 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 equivalent correct dosage.

*In this section recommendations for doses of inhaled glococorticosteriods are given as “µ/day budesonide or equivalent,” because a majority of the clinical literature on these medications uses this standard

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Toreachclinicalcontrol,add-ontherapywithanotherclassofcontrollerispreferredoverincreasingthedoseofinhaledglucocorticosteroids211.Thereis,however,aclearrelationshipbetweenthedoseofinhaledglucocorticosteroidsandthepreventionofsevereacuteexacerbationsofasthma12,althoughthereappeartobedifferencesinresponseaccordingtosymptom/inflammationphenotype212.Therefore,somepatientswithsevereasthmamaybenefitfromlong-termtreatmentwithhigherdosesofinhaledglucocorticosteroids. Side effects: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,andfluticasonepropionateatequipotentdoseshavelesssystemic effect20-23.Currentevidencesuggeststhatinadults,systemiceffectsofinhaledglucocorticosteroidsarenotaproblematdosesof400µgorlessbudesonideorequivalentdaily.

Thesystemicsideeffectsoflong-termtreatmentwithhighdosesofinhaledglucocorticosteroidsincludeeasybruising24,adrenalsuppression1,20, and decreased bone mineral density25,26.Ameta-analysisofcase-controlstudiesofnon-vertebralfracturesinadultsusinginhaledglucocorticosteroids(BDPorequivalent)indicatedthatinolderadults,therelativeriskofnon-vertebralfracturesincreasesbyabout12%foreach1000µg/dayincreaseinthedoseBDPorequivalentbutthatthemagnitudeofthisriskwasconsiderablylessthanothercommonriskfactorsforfractureintheolderadult213.Inhaledglucocorticosteroidshavealsobeenassociatedwithcataracts27,29andglaucomain cross-sectional studies28,butthereisnoevidenceofposterior-subcapsularcataractsinprospectivestudies30-32.

Onedifficultyinestablishingtheclinicalsignificanceofsuchadverseeffectsliesindissociatingtheeffectofhigh-doseinhaledglucocorticosteroidsfromtheeffectofcoursesoforalglucocorticosteroidstakenbypatientswithsevereasthma.Thereisnoevidencethatuseofinhaledglucocorticosteroidsincreasestheriskofpulmonaryinfections,includingtuberculosis,andinhaledglucocorticosteroidsarenotcontraindicatedinpatientswithactive tuberculosis33.

Leukotriene modifiers.

Role in therapy-Leukotrienemodifiersincludecysteinyl-leukotriene1(CysLT1)receptorantagonists(montelukast,pranlukast,andzafirlukast)anda5-lipoxygenaseinhibitor(zileuton).Clinicalstudieshavedemonstratedthatleukotrienemodifiershaveasmallandvariablebronchodilatoreffect,reducesymptomsincludingcough34, improvelungfunction,andreduceairwayinflammationandasthmaexacerbations35-37.Theymaybeusedasanalternativetreatmentforadultpatientswithmildpersistentasthma38-40,andsomepatientswithaspirin-sensitiveasthmarespondwelltoleukotrienemodifiers41.However,whenusedaloneascontroller,theeffectofleukotrienemodifiersaregenerallylessthanthatoflowdosesofinhaledglucocorticosteroids,and,inpatientsalreadyoninhaledglucocorticosteroids,leukotrienemodifierscannotsubstituteforthistreatmentwithoutriskingthelossofasthmacontrol42,43.

Leukotrienemodifiersusedasadd-ontherapymayreducethedoseofinhaledglucocorticosteroidsrequiredbypatientswithmoderatetosevereasthma44, and mayimproveasthmacontrolinpatientswhoseasthmaisnotcontrolledwithloworhighdosesofinhaledglucocorticosteroids43,45-47.Withtheexceptionofonestudythatdemonstratedequivalenceinpreventingexacerbations48,severalstudieshavedemonstratedthatleukotrienemodifiersarelesseffectivethanlong-actinginhaledβ2-agonistsasadd-ontherapy

49-51,192.Acontrolledreleaseformulationofzileutonallowsthismedicationtobeusedonatwicedailybasiswitheffectsequivalenttothatofstandardzileutonusedfourtimesaday203.

Side effects-Leukotrienemodifiersarewelltolerated,andfewifanyclass-relatedeffectshavesofarbeenrecognized.Zileutonhasbeenassociatedwithlivertoxicity204,andmonitoringoflivertestsisrecommendedduringtreatmentwiththismedication.NoassociationwasfoundbetweenChurg-Strausssyndromeandleukotrienemodifiersaftercontrollingforasthmadruguse,althoughitisnotpossibletoruleoutmodestassociationsgiventhatChurg-Strausssyndromeissorareandsohighlycorrelatedwithasthmaseverity52.

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Long-acting inhaled bronchodilators

Role in therapy -Long-actinginhaledβ2-agonists,includingformoterolandsalmeterol,shouldnotbeusedasmonotherapyinasthmaasthesemedicationsdonotappeartoinfluenceairwayinflammationinasthma.Theyaremosteffectivewhencombinedwithinhaledglucocorticosteroids55,56,193,andthiscombinationtherapyisthepreferredtreatmentwhenamediumdoseofinhaledglucocorticosteroidalonefailstoachievecontrolofasthma.Theadditionoflong-actinginhaledβ2-agoniststoadailyregimenofinhaledglucocorticosteroidsimprovessymptomscores,decreasesnocturnalasthmasymptoms,improveslungfunction,decreasestheuseofrapid-actinginhaledβ2-agonists

57-59,reducesthenumberof exacerbations12,57-62,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-agonistswhenusedasacombinationmedicationwithinhaledglucocorticosteroidsmayalsobeusedtopreventexercise-inducedbronchospasm,andforthispurposemayprovidelongerprotectionthanrapid-actinginhaledβ2-agonists

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

Tiotropium,along-actinginhaledanticholinergicbronchodilator,hasbeenstudiedinadultswithuncontrolledasthmaandcomparedwithsalmeterol,doublingthedoseofinhaledglucocorticosteroidandasadd-ontoinhaledglucocorticosteroidsandsalmeterol231,233.Onestudyshowedcomparablebronchodilatoreffectswithnosignificantchangesonasthmacontrol232.Anotherstudyshowedthataddingtiotropiumtopatientsnotcontrolledoninhaledglucocorticosteroidsandlong-actingβ2-agonistsimprovedlungfunctionbutnotsymptoms233.Thestudieshavebeenrelativelyshort-termandnoeffectonexacerbationshassofarbeenreported.Therearenodataaboutthesemedicationsinchildren.

Side effects-Therapywithlong-actinginhaledβ2-agonistscausesfewersystemicadverseeffects—suchascardiovascularstimulation,skeletalmuscletremor,andhypokalemia—thanoraltherapy.Theregularuseofrapid-actingβ2-agonistsinbothshortandlongactingformsmaylead to relative refractoriness to β2-agonists

74.Basedondataindicatingapossibleincreasedriskofasthma-relateddeathassociatedwiththeuseofsalmeterolinasmallgroupofindividuals75long-actingβ2-agonistsshouldnotbeusedasasubstituteforinhaledororalglucocorticosteroids,andshouldonlybeusedincombinationwithanappropriatedoseofinhaledglucocorticosteroidasdeterminedbyaphysician215,234.Somemeta-analysesofstudiesoflong-actingβ2-agonistshaveshownnumericallyverysmallincreasesinthenumberofdeathsinpatientsreceivinglong-actingβ2-agonistsincombinationwithinhaledglucocorticosteroids,whencomparedtoinhaledglucocorticosteroidsalone.Wherepresent,theeffectsizesareextremelysmallandneedtobebalancedagainstthebenefitsinimprovedasthmacontrolandreductioninexacerbationsthatthesemedicationsbringwhencombinedwithinhaledglucocorticosteroids205,214.Noinfluenceofβ2-adrenergicreceptorphenotypesupontheefficacyorsafetyoflong-actingβ2-agonisttherapyhasbeenobservedwhenadministeredincombinationwithinhaledglucocorticosteroidswhetherbythesingleinhalerformaintenanceandreliefmethodorataregularfixeddoseinadults206,220.

Theophylline

Role in therapy-Theophyllineisabronchodilatorand,whengiveninalowerdose,hasmodestanti-inflammatoryproperties77-79.Itisavailableinsustained-releaseformulationsthataresuitableforonce-ortwice-dailyInaddition,combinationinhalerscontainingformoterolanddosing.Dataontherelativeefficacyoftheophyllineasalong-termcontrollerislacking.However,availableevidencesuggeststhatithaslittleeffectasafirst-linecontroller80.Itmayusedasadd-ontherapyinpatientswhodonotachievecontroloninhaledglucocorticosteroidsalone81-83.

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Additionallyinsuchpatientsthewithdrawalofsustained-releasetheophyllinehasbeenassociatedwithdeteriorationof control84.Asadd-ontherapy,theophyllineislesseffectivethanlong-actinginhaledβ2-agonists

85,86.

Side effects-Sideeffectsoftheophylline,particularlyathigherdoses(10mg/kgbodyweight/dayormore),aresignificantandreducetheirusefulness.Sideeffectscanbereducedbycarefuldoseselectionandmonitoring,andgenerallydecreaseordisappearwithcontinueduse.Adverseeffectsincludegastrointestinalsymptoms,loosestools,cardiacarrhythmias,seizures,andevendeath.Nauseaandvomitingarethemostcommonearlyevents.Monitoringisadvisedwhenahighdoseisstarted,ifthepatientdevelopsanadverseeffectontheusualdose,whenexpectedtherapeuticaimsarenotachieved,andwhenconditionsknowntoaltertheophyllinemetabolismexist.Forexample,febrileillness,pregnancy,andanti-tuberculosismedications87reducebloodlevelsoftheophylline,whileliverdisease,congestiveheartfailure,andcertaindrugsincludingcimetidine,somequinolones,andsomemacrolidesincreasetheriskoftoxicity.Lowerdosesoftheophylline,whichhavebeendemonstratedtoprovidethefullanti-inflammatorybenefitofthisdrug82, are associated withlessfrequentsideeffects,andplasmatheophyllinelevelsinpatientsonlow-dosetherapyneednotbemeasuredunlessoverdoseissuspected.

Cromones: sodium cromoglycate and nedocromil sodium.

Role in therapy–Theroleofsodiumcromoglycateandnedocromilsodiuminlong-termtreatmentofasthmainadultsislimited.Efficacyhasbeenreportedinpatientswithmildpersistentasthmaandexercise-inducedbronchospasm.Theiranti-inflammatoryeffectisweakandtheyarelesseffectivethanalowdoseofinhaledglucocorticosteroid88.

Side effects -Side effects are uncommon and include coughinguponinhalationandsorethroat.Somepatientsfindthetasteofnedocromilsodiumunpleasant.

Long-acting oral β2-agonists.

Role in therapy -Longactingoralβ2-agonistsincludeslow release formulations of salbutamol, terbutaline, and bambuterol,aprodrugthatisconvertedtoterbutalineinthebody.Theyareusedonlyonrareoccasionswhenadditionalbronchodilationisneeded.

Side effects-Thesideeffectprofileoflong-actingoralβ2-agonistsishigherthanthatofinhaledβ2-agonists,andincludescardiovascularstimulation(tachycardia),anxiety,

andskeletalmuscletremor.Adversecardiovascularreactionsmayalsooccurwiththecombinationoforalβ2-agonistsandtheophylline.Regularuseoflong-actingoralβ2-agonistsasmonotherapyislikelytobeharmfulandthesemedicationsmustalwaysbegivenincombinationwithinhaledglucocorticosteroids.

Anti-IgE*

Role in therapy-Anti-IgE(omalizumab)isatreatmentoptionlimitedtopatientswithelevatedserumlevelsofIgE.Itscurrentindicationisforpatientswithsevereallergicasthma89whoareuncontrolledoninhaledglucocorticosteroids,althoughthedoseofconcurrenttreatmenthasvariedindifferentstudies.Improvedasthmacontrolisreflectedbyfewersymptoms,lessneedfor reliever medications, and fewer exacerbations90,91, althoughthiswasnotconfirmedinallstudies235.Furtherinvestigationswilllikelyprovideadditionalclarificationoftheroleofanti-IgEinotherclinicalsettings.

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

89, anti-IgEappearstobesafeasadd-ontherapy92-94,includingpatientsgenerallyconsideredtobeathighriskforexacerbations229 .Withdrawalofglucocorticosteroidsfacilitatedbyanti-IgEtherapyhasledtounmaskingthepresenceofChurg-Strausssyndromeinasmallnumberofpatients221.Clinicianssuccessfulininitiatingglucocorticosteroidwithdrawalusinganti-IgEshouldbeawareofthissideeffect.

Systemic glucocorticosteroids.

Role in therapy-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.

*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?”COPY

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Side effects-Thesystemicsideeffectsoflong-termoralorparenteralglucocorticosteroidtreatmentincludeosteoporosis,arterialhypertension,diabetes,hypothalamic-pituitary-adrenalaxissuppression,obesity,cataracts,glaucoma,skinthinningleadingtocutaneousstriaeandeasybruising,andmuscleweakness.Patientswithasthmawhoareonlong-termsystemicglucocorticosteroidsinanyformshouldreceivepreventivetreatmentforosteoporosis(Figure 3-2)97-99.Althoughitisrare,withdrawaloforalglucocorticosteroidscanelicitadrenalfailureorunmaskunderlyingdisease,suchasChurg-StraussSyndrome100.Cautionandclosemedicalsupervisionarerecommendedwhenconsideringtheuseofsystemicglucocorticosteroidsinpatientswithasthmawhoalsohavetuberculosis,parasiticinfections,osteoporosis,glaucoma,diabetes,severedepression,orpepticulcers.Fatalherpesvirus

infectionshavebeenreportedamongpatientswhoareexposedtotheseviruseswhiletakingsystemicglucocorticosteroids,evenshortbursts.

Oral anti-allergic compounds.

Role in therapy-Severaloralanti-allergiccompoundshavebeenintroducedinsomecountriesforthetreatmentofmildtomoderateallergicasthma.Theseincludetranilast,repirinast,tazanolast,pemirolast,ozagrel,seratrodast,amlexanox,andibudilast.Ingeneral,theiranti-asthmaeffectappearstobelimited101,butstudiesontherelativeefficacyofthesecompoundsareneededbeforerecommendationscanbemadeabouttheirroleinthelong-termtreatmentofasthma.

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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Side effects-Sedationisapotentialsideeffectofsomeofthesemedications.

Other controller therapies.

Role in therapy-Varioustherapeuticregimenstoreducethedoseoforalglucocorticosteroidsrequiredbypatientswithsevereasthmahavebeenproposed.Thesemedicationsshouldbeusedonlyinselectedpatientsunderthesupervisionofanasthmaspecialist,astheirpotentialsteroid-sparingeffectsmaynotoutweightheriskofserioussideeffects.Twometa-analysesofthesteroid-sparingeffectoflow-dosemethotrexateshowedasmalloverallbenefit,butarelativelyhighfrequencyofadverseeffects102,103.Thissmallpotentialtoreducetheimpactofglucocorticosteroidsideeffectsisprobablyinsufficienttooffsettheadverseeffectsofmethotrexate104.Cyclosporin105 andgold106,107havealsobeenshowntobeeffectiveinsomepatients.Themacrolide,troleandomycin,hasasmallsteroid-sparingeffectwhenusedwithsystemicmethylprednisolone,butitseffectmayresultfromthemacrolidedecreasingmetabolismoftheglucocorticosteroidandthereforenotimprovingsafety.However,othereffectsofthelong-termuseofmacrolidesinasthmaremainunderstudy108.Theuseofintravenousimmunoglobulinisnotrecommended109-111.Dataonahumanmonoclonalantibodyagainsttumornecrosisfactor(TNF)-alphasuggestthattheriskbenefitequationdoesnotfavortheuseofthisclassoftreatmentsinsevereasthma216.

Side effects-Macrolideuseisfrequentlyassociatedwithnausea,vomiting,andabdominalpainandoccasionallylivertoxicity.Methotrexatealsocausesgastrointestinalsymptoms,andonrareoccasionshepaticanddiffusepulmonaryparenchymaldisease,andhematologicalandteratogeniceffects.

Allergen-specific immunotherapy.

Role in therapy-Theroleofspecificimmunotherapyinadultasthmaislimited.Appropriateimmunotherapyrequirestheidentificationanduseofasinglewell-definedclinicallyrelevantallergen.Thelaterisadministeredinprogressivelyhigherdosesinordertoinducetolerance.ACochranereview112thatexamined75randomizedcontrolledtrialsofspecificimmunotherapycomparedtoplaceboconfirmedtheefficacyofthistherapyinasthmainreducingsymptomscoresandmedicationrequirements,andimprovingallergen-specificandnon-specificairwayhyperresponsiveness.Similarmodesteffectswereidentifiedinasystematicreviewofsublingualimmunotherapy(SLIT)196.Specificimmunotherapyhaslong-termclinicaleffectsandthepotentialofpreventingdevelopmentofasthmainchildrenwithallergicrhino

conjunctivitisupto7yearsaftertreatmenttermination208.However,inviewoftherelativelymodesteffectofallergen-specificimmunotherapycomparedtoothertreatmentoptions,thesebenefitsmustbeweighedagainsttheriskofadverseeffectsandtheinconvenienceoftheprolongedcourseofinjectiontherapy,includingtheminimumhalf-hourwaitrequiredaftereachinjection.Specificimmunotherapyshouldbeconsideredonlyafterstrictenvironmentalavoidanceandpharmacologicintervention,includinginhaledglucocorticosteroids,havefailedtocontrolapatient’sasthma113.Therearenostudiesthatcomparespecificimmunotherapywithpharmacologictherapyforasthma.Thevalueofimmunotherapyusingmultipleallergensdoesnothavesupport.Side effects -Local and systemic side effects may occur in conjunctionwithspecificimmunotherapyadministration.Reactionslocalizedtotheinjectionsitemayrangefromaminimalimmediatewhealandflaretoalarge,painful,delayedallergicresponse.Systemiceffectsmayincludeanaphylacticreactions,whichmaybelifethreatening,aswellassevereexacerbationsofasthma.Deathsfromspecificimmunotherapyhaveoccurredinpatientswithsevereasthma.

Reliever Medications

Relievermedicationsactquicklytorelievebronchoconstrictionanditsaccompanyingacutesymptoms. Rapid-acting inhaled β2-agonists.

Role in therapy -Rapid-actinginhaledβ2-agonistsarethemedicationsofchoiceforreliefofbronchospasmduringacuteexacerbationsofasthmaandforthepretreatmentofexercise-inducedbronchoconstriction.Theyincludesalbutamol, terbutaline, fenoterol, levalbuterol HFA209, reproterol,andpirbuterol.Formoterol,along-actingβ2-agonist,isapprovedforsymptomreliefbecauseofitsrapidonsetofaction,butitshouldonlybeusedforthispurposeinpatientsonregularcontrollertherapywithinhaledglucocorticosteroids230.

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

Side effects -Use of oral β2-agonistsgiveninstandarddosesareassociatedwithmoreadversesystemiceffects

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Role in therapy-Althoughsystemicglucocorticosteroidsarenotusuallythoughtofasrelievermedications,theyareimportantinthetreatmentofsevereacuteexacerbationsbecausetheypreventprogressionoftheasthmaexacerbation,reducetheneedforreferraltoemergencydepartmentsandhospitalization,preventearlyrelapseafteremergencytreatment,andreducethemorbidityoftheillness.Themaineffectsofsystemicglucocorticosteroidsinacuteasthmaareonlyevidentafter4to6hours.Oraltherapyispreferredandisaseffectiveasintravenoushydrocortisone114.Atypicalshortcourseoforalglucocorticosterodsforanexacerbationis40-50mg115 prednisolonegivendailyfor5to10daysdependingontheseverityoftheexacerbation.Whensymptomshavesubsidedandlungfunctionhasapproachedthepatient’spersonalbestvalue,theoralglucocorticosteroidscanbestoppedortapered,providedthattreatmentwithinhaledglucocorticosteroidscontinues116.Intramuscularinjectionofglucocorticosteroidshasnoadvantageoverashortcourseoforalglucocorticosteroidsinpreventingrelapse114,116.

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

Anticholinergics.

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

Side effects-Inhalationofipratropiumoroxitropiumcancauseadrynessofthemouthandabittertaste.Thereisnoevidence for any adverse effects on mucus secretion118.

Theophylline.

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

Side effects-Theophyllinehasthepotentialforsignificantadverseeffects,althoughthesecangenerallybeavoidedbyappropriatedosingandmonitoring.Short-actingtheophyllineshouldnotbeadministeredtopatientsalreadyonlong-termtreatmentwithsustained-releasetheophyllineunlesstheserumconcentrationoftheophyllineisknowntobelowand/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,withoutthesetherelativeefficacyofthesealternativemeasureswillremainunknown.

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

Dietarysupplements,includingseleniumtherapy197 are not ofprovenbenefitandtheuseofalowsodiumdietasanadjunctivetherapytonormaltreatmenthasnoadditionaltherapeuticbenefitinadultswithasthma.Inaddition,ithasnoeffectonbronchialreactivitytomethacholine217.

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Evidencefromthemostrigorousstudiesavailabletodateindicatesthatspinalmanipulationisnotaneffectivetreatmentforasthma121.Systematicreviewsindicatethathomeopathicmedicineshavenoeffectsbeyondplacebo222.Asystematicreviewofyogainterventionsforasthmafoundnoconvincingevidenceofbenefit;thequalityofstudieswasgenerallypoor236.

Severalstudiesofbreathingand/orrelaxationtechniquesforasthmaand/ordysfunctionalbreathing,includingtheButeykomethodandthePapworthmethod210,haveshownimprovementsinsymptoms,short-actingβ2-agonistuse,qualityoflifeand/orpsychologicalmeasures,butnotinphysiologicaloutcomes.Astudyoftwophysiologically-contrastingbreathingtechniques,inwhichcontactwithhealthprofessionalsandinstructionsaboutrescueinhalerusewerematched,showedsimilarimprovementsinrelieverandinhaledglucocorticosteroiduseinbothgroups122.Thissuggeststhatperceivedimprovementwithbreathingtechniquesmaybelargelyduetofactorssuchasrelaxation, voluntary reduction in use of rescue medication, orengagementofthepatientintheircare.Breathingtechniquesmaythusprovideausefulsupplementtoconventionalasthmamanagementstrategies,particularlyinanxiouspatientsorthosehabituallyover-usingrescuemedication.Thecostofsomeprogramsmaybeapotentiallimitation.

Side effects-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)aregivenviapressurizedMDI.Useofaspaceralsoreducesoropharyngealsideeffects.Duringacuteasthmaattacks,anMDIshouldalwaysbeusedwithaspacer,asinthissituationachildmaybeunabletocorrectlycoordinateinhalationwithactuationoftheMDI.

Commerciallyproducedspacerswithwell-characterizeddrugoutputcharacteristicsarepreferable,althoughspacerdevicesorfacemasksdifferintheirdrugdeliveryandthereforemaynotbeinterchangable237.Ifthesearenotavailableorfeasible,ahomemadespacer(forexample,onemadefroma500mlplasticcolddrinkbottle)maybe used126.Nebulizershaveratherimprecisedosing,areexpensive,aretimeconsumingtouseandcarefor,andrequiremaintenance.Theyaremainlyreservedforchildrenwhocannotuseotherinhalerdevices.Insevereacuteasthmaexacerbationsanebulizerisoftenused,althoughanMDIwithaspacerisequallyeffective127.

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. COPY

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Controller Medications

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

Inhaled glucocorticosteroids.

Role in Therapy-Inhaledglucocorticosteroidsarethemosteffectivecontrollertherapy,andarethereforetherecommendedtreatmentforasthmaforchildrenofallages.Figure 3-4listsapproximatelyequipotentdosesofdifferentinhaledglucocorticosteroidsadministeredviadifferentinhalationdevicesforchildrenolderthan5years.

Childrenolderthan5years.Dose-responsestudiesanddosetitrationstudiesinchildren128,129demonstratemarkedandrapidclinicalimprovementsinsymptomsandlungfunctionatlowdosesofinhaledglucocorticosteroids(e.g.,100-200µgbudesonidedaily)130-134, and mild diseaseiswellcontrolledbysuchdosesinthemajorityofpatients132.Earlyinterventionwithinhaledbudesonideisassociatedwithimprovedasthmacontrolandlessadditionalasthmamedicationuse132.Somepatientsrequirehigherdoses(400µg/day)toachieveoptimalasthmacontrolandeffectiveprotectionagainstexercise-inducedasthma.Onlyaminorityofpatientsrequiretreatment

withhighdosesofinhaledglucocorticosteroids133,134.Inchildrenolderthan5years,maintenancetreatmentwithinhaledglucocorticosteroidscontrolsasthmasymptoms,reducesthefrequencyofacuteexacerbationsandthenumberofhospitaladmissions,improvesqualityoflife,lungfunction,andbronchialhyperresponsiveness,andreducesexercise-inducedbronchoconstriction10.Symptomcontrolandimprovementsinlungfunctionoccurrapidly(after1to2weeks),althoughlongertreatment(overthecourseofmonths)andsometimeshigherdosesmayberequiredtoachievemaximumimprovementsinairwayhyperresponsiveness10.Whenglucocorticosteroidtreatmentisdiscontinued,asthmacontroldeteriorateswithinweekstomonths10.

Children5yearsandyounger.Treatmentwithinhaledglucocorticosteroidsinchildren5yearsandyoungerwithasthmagenerallyproducessimilarclinicaleffectsasinolderchildren,butdose-responserelationshipshavebeenlesswellstudied.Theclinicalresponsemaydifferdependingontheinhalerandthechild’sabilitytousetheinhalercorrectly.Withuseofaspacerdevice,alow-doseinhaledglucocorticosteroidresultsinnear-maximumbenefitsinthemajorityofpatients136,137.Useofinhaledglucocorticosteroidsdoesnotinduceremissionofasthmaanditreturnswhentreatmentisstopped138.

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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Theclinicalbenefitsofintermittentsystemicorinhaledglucocorticosteroidsforchildrenwithintermittent,viral-inducedwheezeremaincontroversial.Aoneyearstudyofintermittenttreatmentwithinhaledglucocorticosteroidswas equally effective as daily treatment, and reduced thetotalglucocorticosteroiddosethreefoldinpreschoolchildrenwithfrequentwheezingandahighasthmapredictiveindex238.Somestudiesinolderchildrenfoundsmallbenefitswhileanotherstudyinyoungchildrenfoundnoeffectsonwheezingsymptoms139.Thereisnoevidencetosupporttheuseofmaintenancelow-doseinhaledglucocorticosteroidsforpreventingearlytransientwheezing136,139,199.

Side effects-Themajorityofstudiesevaluatingthesystemiceffectsofinhaledglucocorticosteroidshavebeenundertakeninchildrenolderthan5years.

Growth.Whenassessingtheeffectsofinhaledglucocorticosteroidsongrowthinchildrenwithasthma,itisimportanttoconsiderpotentialconfoundingfactors.Forexample,manychildrenwithasthmareceivinginhaledglucocorticosteroidsexperienceareductioningrowthratetowardtheendofthefirstdecadeoflife140.Thisreducedgrowthratecontinuesintothemid-teensandisassociatedwithadelayintheonsetofpuberty.Thepre-pubertaldecelerationofgrowthvelocityresemblesgrowthretardation.However,thedelayinpubertalgrowthisalsoassociatedwithadelayinskeletalmaturation,sothat

thechild’sboneagecorrespondstohisorherheight140,141 Ultimately,adultheightisnotdecreased,althoughitisreachedatalaterthannormalage.Theuseof400µginhaledbudesonideorequivalentperdaytocontrolasthmahaslessimpactongrowththandoeslowsocioeconomicstatus141.AsummaryofthefindingsofstudiesoninhaledglucocorticosteroidsandgrowthisprovidedinFigure 3-5.

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

Hypothalamic-pituitary-adrenal(HPA)axis.Thoughdifferencesexistbetweenthevariousinhaledglucocorticosteroidsandinhalerdevices,treatmentwithinhaledglucocorticosteroiddosesoflessthan200µgbudesonide or equivalent daily is normally not associated withanysignificantsuppressionoftheHPAaxisinchildren.Athigherdoses,smallchangesinHPAaxisfunctioncanbedetectedwithsensitivemethods148.Theclinicalrelevanceofthesefindingsisnotknown,sincetherehavenotbeenreportsofadrenalcrisisinclinicaltrialsofinhaledglucocorticosteroidsinchildren.However,adrenalcrisishasbeenreportedinchildrentreatedwithexcessivelyhighdosesofinhaledglucocorticosteroids150.

Cataracts.Inhaledglucocorticosteroidshavenotbeenassociatedwithanincreasedoccurrenceofcataractdevelopmentinchildren30.

• Uncontrolled or severe asthma adversely affects growth and final adult height.

• No long-term controlled studies have reported any statistically or clinically significant adverse effects on growth of 100 to 200 µg per day of inhaled glucocorticosteroids.

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

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

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

• Different age groups seem to differ in their susceptibility to the growth-retarding effects of inhaled glucocorticosteroids; children aged 2 to 10 are more susceptible than adolescents.

• Glucocorticosteroid-induced changes in growth rate during the first year of treatment appear to be temporary. Children with asthma treated with inhaled glucocorticosteroids attain normal adult height (predicted from family members) but at a later age.

Figure 3-5. Summary: Glucocorticosteroids and Growth in Children140-142,239

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

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

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

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

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

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Centralnervoussystemeffects.Althoughisolatedcasereportshavesuggestedthathyperactivebehavior,aggressiveness,insomnia,uninhibitedbehavior,andimpairedconcentrationmaybeseenwithinhaledglucocorticosteroidtreatment,noincreaseinsucheffectshasbeenfoundinalong-termcontrolledtrialofinhaledbudesonide132.

Oralcandidiasis,hoarseness,andbruising.Clinicalthrushisseldomaprobleminchildrentreatedwithinhaledorsystemicglucocorticosteroids.Thissideeffectseemstoberelatedtoconcomitantuseofantibiotics,highdailydoses,dosefrequency,andinhalerdevice.Spacersreducetheincidenceoforalcandidiasis151.Mouthrinsingisbeneficial152.Theoccurrenceofhoarsenessorothernoticeablevoicechangesduringbudesonidetreatmentissimilartoplacebo30.Treatmentwithanaveragedailydoseof500µgbudesonidefor3to6yearsisnotassociatedwithan increased tendency to bruise30.

Dentalsideeffects.Inhaledglucocorticosteroidtreatmentisnotassociatedwithincreasedincidenceofcaries.However,theincreasedlevelofdentalerosionreportedinchildrenwithasthma153maybeduetoareductioninoralpHthatmayresultfrominhalationofβ2-agonists

154.

Otherlocalsideeffects.Thelong-termuseofinhaledglucocorticosteroidsisnotassociatedwithanincreasedincidenceoflowerrespiratorytractinfections,includingtuberculosis.

Leukotriene modifiers.

Childrenolderthan5years.Leukotrienemodifiersprovideclinicalbenefitinchildrenolderthan5yearsatalllevelsof severity155-159,butgenerallylessthanthatoflow-doseinhaledglucocorticosteroids160.Leukotrienemodifiersprovidepartialprotectionagainstexercise-inducedbronchoconstrictionwithinhoursafteradministrationwithnolossofbronchoprotectiveeffect200.Asadd-ontreatmentinchildrenwhoseasthmaisinsufficientlycontrolledbylowdosesofinhaledglucocorticosteroids,leukotrienemodifiersprovidemoderateclinicalimprovements,includingasignificantreductioninexacerbations162.Combinationtherapyislesseffectiveincontrollingasthmainchildrenwithmoderatepersistentasthmathanincreasingtomoderatedosesofinhaledglucocorticosteroids201.Montelukasthasnotbeendemonstratedtobeaneffectiveinhaledglucocorticosteroidsparingalternativeinchildrenwithmoderate-to-severepersistentasthma219.

Children5yearsandyounger.Inadditiontotheefficacyasdescribed above163,164,leukotrienemodifiersreduceviral-inducedasthmaexacerbationsinchildrenages2-5withahistoryofintermittentasthma164.

Side effects-Nosafetyconcernshavebeendemonstratedfromtheuseofleukotrienemodifiersinchildren.

Long-acting inhaled β2-agonists.

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

75,234.

Childrenolderthan5years.Long-actinginhaledβ2-agonistshavemainlybeenstudiedinchildrenolderthan5yearsasadd-ontherapyforpatientswhoseasthmaisnotcontrolledonlowtohighdosesofinhaledglucocorticosteroids.Significantimprovementsinpeakflowandotherlungfunctionmeasurementshavebeenfound in most studies55,165-169, 234.However,theeffectsonotheroutcomessuchassymptomsandneedforrelievermedicationhavebeenlessconsistentandhaveonlybeenobservedinabouthalfofthetrialsconducted.Add-ontreatmentwithlong-actinginhaledβ2-agonistshasnotbeenshowntoreducethefrequencyofexacerbations170.Inhalationofasingledoseoflong-actinginhaledβ2-agonistseffectivelyblocksexercise-inducedbronchoconstrictionforseveralhours171.Withdailytherapythedurationoftheprotectionissomewhatreduced171, but is stilllongerthanthatprovidedbyshort-actingβ2-agonists.Combinationproductscontaininganinhaledglucocorticosteroidandalong-actinginhaledβ2-agonistsarepreferredtolong-actinginhaledβ2-agonistsandinhaledglucocorticosteroidsadministeredbyseparateinhalers.Fixedcombinationinhalersensurethatthelong-actingβ2-agonistsisalwaysaccompaniedbyaglucocorticosteroid.

Children5yearsandyounger.Theeffectoflong-actinginhaledβ2-agonistshasnotyetbeenadequatelystudied.Combinationtherapywithbudesonideandformoterolusedbothasmaintenanceandrescuehasbeenshowntoreduceasthmaexacerbationsinchildrenages4yearsandolderwithmoderatetosevereasthma202.

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

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Theophylline.

Role in therapy-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.Theophyllineeliminationmayvaryuptotenfoldbetweenindividuals.Measurementofplasmatheophyllinelevelsisnotnecessaryinotherwisehealthychildrenwhendoseslessthan10mg/kg/dayareused.However,whenhigherdosesareusedorwhendrugsthatmayincreasetheophyllinelevelsarealsousedchronically,plasmatheophyllinelevelsshouldbemeasuredtwohoursbeforeadministrationofthenextdoseoncesteadystatehasbeenreached(after3days).

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

Anti-IgE.

Role in therapy -Anti-IgE(omalizumab)hasprovenefficacyinchildrenage6to12yearswithmoderate-to-severeandseverepersistentallergic(IgE-mediated)asthma.A

28week,randomized,double-blind,placebo-controlledstudy223, 224included334childrenwithmoderatetosevereallergicasthmawhowerewellcontrolledoninhaledglucocorticosteroiddosesequivalentto200-500µg/dayofbeclomethasone.Therewasnodifferenceinclinicaleffectsbetweenplaceboandanti-IgEduringa16-weekstableinhaledglucocorticosteroiddoseperiod.Duringa12-weektaperingperiodurgent,unscheduledphysicianvisitsweresignificantlyreducedfromby30.3%intheanti-IgEcomparedwithplacebo(12.9%)group223, and thereweresignificantimprovementsinqualityoflifeinthepatientsreceivinganti-IgE,bothduringstableinhaledglucocorticosteroiddosingandduringtapering224.Theremainingoutcomeswereverysimilarinthetwotreatmentgroups.

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

AsubstantialnumberofchildrenwithdifficultasthmawillhavehigherIgElevelsthantheupperlimitofIgErecommendedfortherapy(1,300IU)226.Itisunknownifthesepatientswillstillbenefitfromomalizumabtherapy.Therearenoteststhatcancurrentlyberecommendedinordertopredictwhowillrespond227.

Anti-IgEtherapyisexpensiveandrequiresregularinjectionsandobservationaftereachinjection.Acostbenefitanalysissuggestedthattherewouldbeafiscalsavingifthistreatmentisgiventochildrenwithfiveormorehospitaladmissionsandcumulativelytwentydaysormoreinhospital228.

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

Cromones: sodium cromoglycate and nedocromil sodium.

Role in therapy-Sodiumcromoglycateandnedocromilsodiumhavealimitedroleinthelong-termtreatmentofasthmainchildren.Onemeta-analysishasconcludedthatlong-termtreatmentwithsodiumcromoglycateisnotsignificantlybetterthanplaceboformanagementofasthmainchildren179.Anotherhasconfirmedsuperiorityoflowdose

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inhaledglucocorticosteroidsoversodiumcromoglycateinpersistentasthma,butastherewerenoplaceboarmsinthesestudies,theefficacyofsodiumcromoglycatecannotbeconfirmedfromthestudiesreviewed;nobetweentreatment difference in safety was observed180.

Nedocromilsodiumhasbeenshowntoreduceexacerbations,butitseffectonotherasthmaoutcomesisnotsuperiortoplacebo.Asingledoseofsodiumcromoglycateornedocromilsodiumattenuatesbroncho-spasminducedbyexerciseorcoldair181.Studiesoftheuseofthesemedicationsinchildren5yearsandyoungeraresparseandresultsareconflicting.

Side effects-Cough,throatirritation,andbroncho-constrictionoccurinasmallproportionofpatientstreatedwithsodiumcromoglycate.Abadtaste,headache,andnauseaarethemostcommonsideeffectsofnedocromil182.

Long-acting oral β2-agonists.

Treatmentwithlong-actingoralβ2-agonistsuchasslowrelease formulations of salbutamol, terbutaline, and bambuterolreducesnocturnalsymptomsofasthma183,184.Duetotheirpotentialsideeffectsofcardiovascularstimulation,anxiety,andskeletalmuscletremor,theiruseisnotencouraged.Ifused,dosingshouldbeindividualied,andthetherapeuticresponsemonitoredtolimitsideeffects185.Long-actingoralβ2-agonisttherapyofferslittleornoprotectionagainstexercise-inducedbronchoconstriction.


Becauseofthesideeffectsofprolongeduse,oralglucocorticosteroidsinchildrenwithasthmashouldberestrictedtothetreatmentofacutesevereexacerbations,whetherviral-inducedorotherwise.

Reliever Medications

Rapid-acting inhaled ß2-agonists and short-acting oral ß2-agonists.

Role in therapy-Rapid-actinginhaledß2-agonistsarethemosteffectivebronchodilatorsavailableandthereforethepreferredtreatmentforacuteasthmainchildrenofallages.Theinhaledrouteresultsinmorerapidbronchodilationatalowerdoseandwithfewersideeffectsthanoralorintravenous administration186.Furthermore,inhaledtherapyofferssignificantprotectionagainstexercise-inducedbronchoconstrictionandotherchallengesfor0.5to2hours(long-actingß2-agonistsofferlongerprotection)

187.Thisisnot seen after systemic administration188.Oraltherapyisrarelyneededandreservedmainlyforyoungchildrenwhocannotuseinhaledtherapy.

Side effects-Skeletalmuscletremor,headache,palpitations,andsomeagitationarethemostcommoncomplaintsassociatedwithhighdosesofß2-agonistsinchildren.Thesecomplaintsaremorecommonaftersystemicadministrationanddisappearwithcontinuedtreatment189.

Anticholinergics.

Role in therapy-Inhaledanticholinergicsarenotrecommendedforlong-termmanagementofasthmainchildren190.

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4. HarrisonLI,SoriaI,ClineAC,EkholmBP.Pharmacokineticdifferencesbetweenchlorofluorocarbonandchlorofluorocarbon-freemetereddoseinhalersofbeclomethasonedipropionateinadultasthmatics.J Pharm Pharmacol1999;51(11):1235-40.

5. JuniperEF,PriceDB,StamponePA,CreemersJP,MolSJ,FiremanP.Clinicallyimportantimprovementsinasthma-specificqualityoflife,butnodifferenceinconventionalclinicalindexesinpatientschangedfromconventionalbeclomethasonedipropionatetoapproximatelyhalfthedoseofextrafinebeclomethasonedipropionate.Chest 2002;121(6):1824-32.

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7. NewmanSP.Acomparisonoflungdepositionpatternsbetweendifferentasthmainhalers. J Aerosol Med1995;8Suppl3:21-6S.

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CHAPTER

4

ASTHMA MANAGEMENT

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56 ASTHMA MANAGEMENT AND PREVENTION

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.

KEY POINTS:

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

• Theaimofthispartnershipisguidedself-management—thatis,togivepeoplewithasthmatheabilitytocontroltheirownconditionwithguidancefromhealthcareprofessionals.

• Thepartnershipisformedandstrengthenedaspatientsandtheirhealthcareprofessionalsdiscussandagreeonthegoalsoftreatment,developapersonalized,writtenasthmaactionplanincludingself-monitoring,andperiodicallyreviewthepatient’streatmentandlevelofasthmacontrol.

• Educationshouldbeanintegralpartofallinteractionsbetweenhealthcareprofessionalsandpatients,andisrelevanttoasthmapatientsofallages.

• Personalwrittenasthmaactionplanshelpindividualswithasthmamakechangestotheirtreatmentinresponsetochangesintheirlevelofasthmacontrol,asindicatedbysymptomsand/orpeakexpiratoryflow,inaccordancewithwrittenpredeterminedguidelines.

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

COMPONENT 1: DEFINITION

INTRODUCTION COMPONENT 1: DEVELOP PATIENT/DOCTOR PARTNERSHIP

INTRODUCTION

CHAPTER 4: ASTHMA MANAGEMENT AND PREVENTIONCOPY

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Thisapproachiscalledguidedself-managementandhasbeenshowntoreduceasthmamorbidityinbothadults(Evidence A)andchildren(Evidence A).Anumberofspecificsystemsofguidedself-managementhavebeendeveloped1-10foruseinawiderangeofsettings:primarycare1,4,6,hospitals2,3,7,10,andemergencydepartments8.Internet-basedhomemonitoring340,372,andmobilephones395 havebeenshowntobesuccessfulmodestoimproveasthmacontrol.Self-managementprogramshavebeentestedindiversegroups,includingcommunityhealthworkers371,pregnantwomenwithasthma11,childrenandadolescents12,13,andinmulti-racialpopulations14.

Guidedself-managementmayinvolvevaryingdegreesofindependence,rangingbroadlyfrompatient-directedself-managementinwhichpatientsmakechangeswithoutreferencetotheircaregiver,butinaccordancewithapriorwrittenactionplan,todoctor-directedself-managementinwhichpatientsrelyfollowawrittenactionplan,butrefermostmajortreatmentchangestotheirphysicianatthe

timeofplannedorunplannedconsultations.Cochranesystematic reviews13,15-18haveexaminedtheroleofeducationandself-managementstrategiesinthecareofasthmapatients.

Educationshouldbeanintegralpartofallinteractionsbetweenhealthcareprofessionalsandpatients,andisrelevanttoasthmapatientsofallages.Althoughthefocusofeducationforsmallchildrenwillbeontheparentsandcaregivers,childrenasyoungas3yearsofagecanbetaughtsimpleasthmamanagementskills.Adolescentsmayhavesomeuniquedifficultiesregardingadherence

thatmaybehelpedthroughpeersupportgroupeducationinadditiontoeducationprovidedbythehealthcareprofessional12 butregionalissuesandthedevelopmentalstageofthechildrenmayaffecttheoutcomesofsuchprograms373.

Figure 4.1-2outlinesthekeyfeaturesandcomponentsofanasthmaeducationprogram.Theinformationandskillstrainingrequiredbyeachpersonmayvary,andtheirability

orwillingnesstotakeresponsibilitysimilarlydiffers.Thusallindividualsrequirecertaincoreinformationandskills,butmosteducationmustbepersonalizedandgiventothepersoninanumberofsteps.Socialandpsychologicalsupportmayalsoberequiredtomaintainpositivebehavioralchange.

Good communicationisessentialasthebasisforsubsequentgoodcompliance/adherence19-22,414(Evidence B).Keyfactorsthatfacilitategoodcommunicationare23:

• Acongenialdemeanor(friendliness,humor,andattentiveness)

• Engagingininteractivedialogue• Givingencouragementandpraise

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 Doctor PartnershipGoal: To provide the person with asthma, their family, and other caregivers with suitable information and training so that they can keep well and adjust treatment according to a medication plan developed with the health care professional.

Key Components:o Focus on the development of the partnershipo Acceptance that this is a continuing processo A sharing of informationo Full discussion of expectationso Expression of fears and concerns

Key Components:o Diagnosiso Difference between “relievers” and “controllers”o Potential side effects of medicationso Use of inhaler deviceso Prevention of symptoms and attackso Signs that suggest asthma is worsening and actions to takeo Monitoring control of asthmao How and when to seek medical attention

The person then requires:o A written asthma action plano Regular supervision, revision, reward, and reinforcement

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• Empathy,reassurance,andprompthandlingofanyconcerns

• Givingofappropriate(personalized)information• Elicitingsharedgoals• Feedbackandreview

Teaching health care professionals to improve their communication skills can result in measurably better outcomes–includingincreasedpatientsatisfaction,betterhealth,andreduceduseofhealthcare–andthesebenefitsmaybeachievedwithoutanyincreaseinconsultationtimes24.Studieshavealsoshownthatpatientscanbetrainedtobenefitmorefromconsultations.Patientstaughthowtogiveinformationtodoctorsinaclearermanner,andhowtoseekinformationandchecktheirunderstandingofwhatthedoctorhadtoldthemgainedsignificantimprovementsincompliancewithtreatmentrecommendations25.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, 30 informationaboutasthmaanditstreatment.TheGINAWebsite(http://www.ginasthma.org)containspatienteducationalmaterials,aswellaslinkstoseveralasthmawebsites.Thepatientandhisorherfamilyshouldbeencouragedtomakeanoteofanyquestionsthatarisefromreadingthisinformationorasaresultoftheconsultation,andshouldbegiventimetoaddresstheseduringthenextconsultation.

Personal Written Asthma Action Plans

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

Theeffectsweregreatestwheretheinterventioninvolvedeachofthefollowingelements:education,self-monitoring,regularreview,andpatient-directedmanagementusingawrittenasthmaactionplan(Evidence A).Withinthesestudies,theeffectswerealsogreaterwhentheactionplansthemselvesbothsteppedupinhaledglucocorticosteroidsandaddedoralglucocorticosteroids,andforpeakflow-basedplans,whentheywerebasedonpersonalbestratherthanpercentpredictedpeakflow32.Patientsexperienceaone-thirdtotwo-thirdsreductioninhospitalizations,emergencyroomvisits,unscheduledvisitstothedoctorforasthma,misseddaysofwork,andnocturnalwakening.Ithasbeenestimatedthattheimplementationofaself-managementprogramin20patientspreventsonehospitalization,andsuccessfulcompletionofsuchaprogrambyeightpatientspreventsoneemergencydepartmentvisit16-18,23.Lessintensiveinterventionsthatinvolveself-managementeducationbutnotawrittenplanarelesseffective15.Theefficacyissimilarregardlessofwhetherpatientsself-adjusttheirmedicationsaccordingtoanindividualwrittenplanoradjustmentsof medication are made by a doctor15(Evidence B).Thus,patientswhoareunabletoundertakeguidedself-managementcanstillachievebenefitfromastructuredprogramofregularmedicalreview.Althoughinteractivecomputerizedasthmaeducationprogramsmayimprovepatientasthmaknowledgeandsymptoms,theireffectonobjective clinical outcomes is less consistent353. ExamplesofwrittenasthmaactionplansthathavebeenrecommendedcanbefoundonseveralWebsites(UKNationalAsthmaCampaignPlan,www.asthma.org.uk;InternationalAsthmaManagementPlan“ZoneSystem,”www.nhlbisupport.com/asthma/index.html;NewZealand“CreditCard”System,www.asthmanz.co.nz.Anexampleofthecontentsforanasthmaplanforpatientstomaintaincontrolofasthma,andrespondtoworseningasthma,isshowninFigure 4.1-3.

Follow-Up and Review

Follow-upconsultationsshouldtakeplaceatregularintervals.Atthesevisits,thepatient’squestionsarediscussed,andanyproblemswithasthmaanditsinitialtreatmentarereviewed.Patientsshouldbeaskedtodemonstratetheirinhalerdevicetechniqueateveryvisit,withcorrectionandre-checkingifitisinadequate33,375.

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Follow-upconsultationsshouldalsoincludecheckingtheperson’sadherence/compliancetothemedicationplanandrecommendationsforreducingexposuretoriskfactors.Ifthepatienthasbeenaskedtokeepadiaryofsymptoms(andwhereappropriate,homepeakflowrecordings)this

shouldalsobereviewedregularly.Afteraperiodofinitialtraining,thefrequencyofhomepeakflowandsymptommonitoringdependsinpartonthelevelofcontroloftheperson’sasthma.Routinefollow-upvisitsmaybeaneffectivetimetoreviewthewrittenasthmaactionplananditsunderstanding354.Educationalmessagesshouldbereviewedandrepeatedoraddedtoifnecessary.Asinglepageprompttoclinicianshasbeenshowntoimprovetheprovisionofpreventivecaretochildrenwithasthmaduringofficevisits341.Telehealthcarefollow-upisunlikelytobenefitinmildasthmabutmaybeofbenefitinthosewithseverediseaseatriskofhospitaladmission397. Improving Adherence

Althoughinterventionsforenhancingmedicationadherencehavebeendeveloped363,studiesofadultsandchildrenwithasthma34haveshownthataround50%ofthoseonLong-termtherapyfailtotakemedicationsasdirectedatleastpartofthetime.Patientconcernaboutside-effectsofinhaledglucocorticosteroidswhetherrealorperceivedmayinfluenceadherence342.Non-adherencemaybedefinedinanonjudgmentalwayasthefailureoftreatmenttobetakenasagreeduponbythepatientandthehealthcareprofessional. Non-adherencemaybeidentifiedbyprescriptionmonitoring,pillcounting,ordrugassay,butataclinicallevelitisbestdetectedbyaskingabouttherapyinawaythatacknowledgesthelikelihoodofincompleteadherence(e.g.,“Sothatwemayplantherapy,doyoumindtellingmehowoftenyouactuallytakethemedicine?”).Shortquestionnairescanassistwithidentificationofpooradherence376.Providingadherenceinformationtocliniciansdoesnotimproveuseofinhaledglucocorticosteroidamongpatientswithasthmaunlesscliniciansaresufficientlyinterestedinadherencetoviewthedetailsofthismedicationuse398.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-basedasthmaeducationimprovesknowledgeof

Figure 4.1-3 Example of Contents of Written AsthmaAction Plan to Maintain 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 Poor 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 issues

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asthma,self-efficacy,andself-managementbehaviors377.Acomprehensiveschool-basedprogramforadolescentsandacademicdetailingfortheirphysicianswasassociatedwithsignificantlyimprovedasthmaoutcomesincludingreducedhospitalizations399.

THE EDUCATION OF OTHERS

Theeducationofthegeneralpublicaboutasthmaishelpfulinthatitenablesmembersofthepublictorecognizeasthmasymptomsandtheirconsequencesandencouragesthosewithasthmatoseekmedicalattentionandfollowtheirasthmamanagementprogram.Greaterawarenessofasthmaisalsolikelytohelpdispelmisconceptionsthatmayexistabouttheconditionandreducefeelingsofstigmatizationonthepartofpatients.

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

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KEY POINTS: • 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.Otherthanpreventingtobaccoexposurebothin uteroandafterbirth,therearenoprovenandwidelyacceptedinterventionsthatcanpreventthedevelopmentofasthma.

Allergicsensitzationcanoccurprenatally37,38.Thereiscurrentlyinsufficientinformationonthecriticaldosesandtimingofallergenexposuretopermitinterventioninthisprocess,andnostrategiescanberecommendedtopreventallergicsensitizationprenatally415.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-specificimmunotherapy52,53 canpreventthedevelopmentofasthmainchildrenwhohaveotheratopicdiseasesremainsanareaofinvestigation,andtheseinterventionscannotberecommendedforwideadoptioninclinicalpracticeatthistime.

Asthmaexacerbationsmaybecausedbyavarietyoffactors,sometimesreferredtoas“triggers,”includingallergens,viralinfections400,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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itcanbemanymonthsbeforeallergenlevelsdecrease67 andtheclinicaleffectivenessofthisandotherinterventionsremainsunproven(Figure 4.2-1).

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

Fungi.Fungalexposurehasbeenassociatedwithexacerbationsfromasthmaandthenumberoffungalsporescanbestbereducedbyremovingorcleaningmold-laden objects69.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.,thunderstorms78favorthedevelopmentofasthmaexacerbationsbyavarietyofmechanisms,includingdustandpollution,increasesinrespirableallergens,andchangesintemperature/humidity.

Avoidance of unfavorable environmental conditions isusuallyunnecessaryforpatientswhoseasthmaiscontrolled.Forpatientswithasthmathatisdifficulttocontrol,practicalstepstotakeduringunfavorableenvironmentalconditionsincludeavoidingstrenuousphysicalactivityincoldweather,lowhumidity,orhighairpollution;avoidingsmokingandsmoke-filledrooms;andstayingindoorsinaclimate-controlledenvironment.

Occupational Exposures

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

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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.Thereissomeevidencethatexposuretoacetaminophenincreasestheriskofasthmaandwheezinginchildren401 and adults but furtherstudiesareneeded379.

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

Influenza Vaccination

Patientswithmoderatetosevereasthmashouldbeadvisedtoreceiveaninfluenzavaccinationeveryyear88 oratleastwhenvaccinationofthegeneralpopulationisadvised.However,routineinfluenzavaccinationofchildren89 and adults90withasthmadoesnotappearto

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

Obesity

Increasesinbodymassindex(BMI)havebeenassociatedwithincreasedprevalenceofasthma93.Weightreductioninobesepatientswithasthma,includingbybariatricsurgery,hasbeenhasbeendemonstratedtoimprovelungfunction,symptoms,morbidity,andhealthstatus94(Evidence B).

Emotional Stress

Emotionalstressmayleadtoasthmaexacerbationsinchildren402andadults.Extremeemotionalexpressions(laughing,crying,anger,orfear)canleadtohyperventilationandhypocapniathatcancauseairwaynarrowing95,96.Panicattacks,thatarerarebutnotexceptionalinsomepatientswithasthma,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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KEY POINTS:

• Thegoalofasthmatreatment,toachieveandmaintainclinicalcontrol,canbereachedinamajorityofpatientswithapharmacologicinterventionstrategydevelopedinpartnershipbetweenthepatient/familyandthedoctor.

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

• Intreatment-naïvepatientswithpersistentasthma,treatmentshouldbestartedatStep 2, or, if very symptomatic(uncontrolled),atStep 3.ForSteps 2 through5, a variety of controller medications are available.

• Ateachtreatmentstep,relievermedicationshouldbeprovidedforquickreliefofsymptomsasneeded.

• Ongoingmonitoringisessentialtomaintaincontrolandtoestablishtheloweststepanddoseoftreatmenttominimizecostandmaximizesafety.

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

• AssessingAsthmaControl• TreatingtoAchieveControl• MonitoringtoMaintainControl

InthisComponent,thiscycleisdescribedforlong-termtreatmentofasthma.TreatmentforexacerbationsisdetailedinComponent4.

Eachpatientshouldbeassessedtoestablishhisorhercurrenttreatmentregimen,adherencetothecurrentregimen,andlevelofasthmacontrol.Asimplifiedschemeforrecognizingcontrolled,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 4.3-2 is basedupontheseprinciples,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.Steps 1 to 5provideoptionsofincreasingefficacy,exceptfor Step 5whereissuesofavailabilityandsafetyinfluencetheselectionoftreatment.Step 2istheinitialtreatmentformosttreatment-naïvepatientswithpersistentasthmasymptoms.Ifsymptomsattheinitialconsultationsuggestthatasthmaisseverelyuncontrolled(Figure 4.3-1),treatmentshouldbecommencedatStep 3.

Ateachtreatmentstep,arelievermedication(rapid-onset bronchodilator,eithershort-actingorlong-acting)shouldbeprovidedforquickreliefofsymptoms.However,regularuseofrelievermedicationisoneoftheelementsdefininguncontrolledasthma,andindicatesthatcontrollertreatmentshouldbeincreased.Thus,reducingoreliminatingtheneedforrelievertreatmentisbothanimportantgoalandmeasureofsuccessoftreatment.ForSteps 2through5, a variety of controller medications are

available.

Step 1: as-needed reliever medication. Step 1 treatment withanas-neededrelievermedicationisreservedforuntreatedpatientswithoccasionaldaytimesymptoms(cough,wheeze,dyspneaoccurringtwiceorlessperweek,orlessfrequentlyifnocturnal)ofshortduration(lastingonlyafewhours)comparablewithcontrolledasthma(Figure 4.3-1).Betweenepisodes,thepatientisasymptomaticwithnormallungfunctionandthereisnonocturnalawakening.Whensymptomsaremorefrequent,and/orworsenperiodically,patientsrequireregularcontrollertreatment(seeSteps 2orhigher)inadditiontoas-needed reliever medication111-113(Evidence B).

ForthemajorityofpatientsinStep 1, 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 definition, 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 StepsAs needed rapid-acting β2-agonistAs needed rapid-acting β2-agonistLow-dose ICS pluslong-acting β2-agonistSelect one

Leukotrienemodifier**Select oneMedium-orhigh-dose ICSMedium-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 eitherAsthma educationEnvironmental control

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

ControlledMaintain and find lowest controlling stepPartly controlledConsider stepping up to gain controlUncontrolledStep up until controlledExacerbationTreat as exacerbation

Treatment ActionLevel of ControlReduce

Reduce IncreaseI nc re ase

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

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 education. Environmental control.(If step-up treatment is being considered for poor symptom control, first check inhaler technique, check adherence, and confirm symptoms are due to asthma.)

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

*** = Recommended treatment (shaded boxes) based on group mean data. Individual patient needs, preferences, and circumstances (including costs) should be considered.

Figure 4.3-2.

For management of asthma in children 5 years and younger, refer to the Global Strategy for the Diagnosis and Management of Asthma in Children 5 Years and Younger, available at http://www.ginasthma.org.

Alternative reliever treatments include inhaled anticholinergics, short-acting oral β2-agonists, some long-acting β2-agonists, and short-acting theophylline.Regular dosing with short and long-acting β2-agonists is not advised unless accompanied by regular use of an inhaled glucocorticorsteriod.

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Exercise-induced bronchoconstriction.Physicalactivityisanimportantcauseofasthmasymptomsformostasthmapatients,andforsomeitistheonlycause.However,exercise-inducedbronchoconstrictionoftenindicatesthatthepatient’sasthmaisnotwellcontrolled,andsteppingupcontrollertherapygenerallyresultsinthereductionofexercise-relatedsymptoms.Forthosepatientswhostillexperienceexercise-inducedbronchoconstrictiondespiteotherwisewell-controlledasthma,andforthoseinwhomexercise-inducedbronchoconstrictionistheonlymanifestationofasthma,arapid-actinginhaledβ2-agonist(short-orlong-acting),takenpriortoexerciseortorelievesymptomsthatdevelopafterexercise,isrecommended115.Aleukotrienemodifier116,345 or cromone117 are alternatives (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. Treatment Steps 2through5, combine an as-needed relievertreatmentwithregularcontrollertreatment.At Step 2,a low-dose inhaled glucocorticosteroid is recommendedastheinitialcontrollertreatmentforasthmapatientsofallages111,120(Evidence A).Equivalentdosesofinhaledglucocorticosteroids,someofwhichmaybegivenasasingledailydose,areprovidedinFigure 3-1 for adults and in Figure 3-4forchildrenolderthan5years.

Alternative controller medications include leukotriene modifiers121-123(Evidence A),appropriateparticularlyforpatientswhoareunableorunwillingtouseinhaledglucocorticosteroids,orwhoexperienceintolerablesideeffectssuchaspersistenthoarsenessfrominhaledglucocorticosteroidtreatmentandthosewithconcomitantallergicrhinitis124,125(Evidence C).

Otheroptionsareavailablebutnotrecommendedforroutineuseasinitialorfirst-linecontrollersinStep 2.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. At Step 3,therecommendedoptionforchildren403 and adolescents and adults is to combine a low-dose of inhaled glucocorticosteroid with an inhaled long-

acting ß2-agonist,eitherinacombinationinhalerdeviceorasseparatecomponents137-144(Evidence A).Becauseoftheadditiveeffectofthiscombination,thelow-doseofglucocorticosteroidisusuallysufficient,andneedonlybeincreasedifcontrolisnotachievedwithin3or4monthswiththisregimen(Evidence A).Thelong-actingβ2-agonistformoterol,whichhasarapidonsetofactionwhethergivenalone145,146,148orincombinationinhalerwithbudesonide149,hasbeenshowntobeaseffectiveasshort-actingβ2-agonistinacuteasthmaexacerbation.Howeveritsuseasmonotherapyasarelievermedicationisstronglydiscouragedsinceitmustalwaysbeusedinassociationwithaninhaledglucocorticosteroid.

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

Ifacombinationinhalercontainingformoterolandbudesonideisselected,itmaybeusedforbothrescueandmaintenance.Thisapproachhasbeenshowntoresultinreductionsinexacerbationsandimprovementsinasthmacontrolinadultsandadolescentsatrelativelylow doses of treatment154-157(Evidence A).Whetherthisapproachcanbeemployedwithothercombinationsofcontrollerandrelieverrequiresfurtherstudy.

Anotheroptionforbothadultsandchildren,buttheonerecommendedforchildren158, is to increase to a medium-dose of inhaled glucocorticosteroids104,159-161 (Evidence A).Forpatientsofallagesonmedium-orhigh-doseofinhaledglucocorticosteroiddeliveredbyapressurizedmetered-doseinhaler,useofaspacerdeviceisrecommendedtoimprovedeliverytotheairways,reduceoropharyngealsideeffects,andreducesystemicabsorption162-164(Evidence A).

AnotheroptionatStep 3istocombinealow-doseinhaledglucocorticosteroidwithleukotrienemodifiers165-173 (Evidence A).Alternatively,theuseofsustained-releasetheophyllinegivenatlow-dosemaybeconsidered129 (Evidence B).Theseoptionshavenotbeenfullystudiedinchildren5yearsandyounger.

Step 4: Reliever medication plus two or more controllers. TheselectionoftreatmentatStep 4dependsonpriorselectionsatSteps 2 and 3.However,theorderinwhichadditionalmedicationsshouldbeaddedisbased,asfaraspossible,uponevidenceoftheirrelativeefficacyinclinicaltrials.Wherepossible,patientswhoarenot

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controlled on Step 3treatmentsshouldbereferred to a health professional with expertise in the management of asthmaforinvestigationofalternativediagnosesand/orcausesofdifficult-to-treatasthma.

ThepreferredtreatmentatStep 4 is to combine a medium-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 3-1 for adults and Figure 3-4forchildrenolderthan5yearsforrecommendationsondosingandfrequencyfordifferentinhaledglucocorticosteroids.)

Leukotriene modifiers as add-on treatment to medium-tohigh-doseinhaledglucocorticosteroidshavebeenshowntoprovidebenefit(Evidence A),butusuallylessthanthatachievedwiththeadditionofalong-actingβ2-agonist165-168,175,178(Evidence A).Theadditionofalow-dose of sustained-release theophylline130 to medium-or high-doseinhaledglucocorticosteroidandlong-actingβ2-agonistmayalsoprovidebenefit(Evidence B)129.

Step 5: Reliever medication plus additional controller options. Addition of oral glucocorticosteroidstoothercontroller medications may be effective179(Evidence D)butisassociatedwithseveresideeffects180(Evidence A)andshouldonlybeconsideredifthepatient’sasthmaremains severely uncontrolled on Step 4medicationswithdailylimitationofactivitiesandfrequentexacerbations.Patientsshouldbecounseledaboutpotentialsideeffectsandallotheralternativetreatmentsmustbeconsidered.

Addition of anti-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,butthefullbenefitmayonlybeevidentafter3or4months 360.Insevereandchronicallyundertreateddisease,thiscantakeevenlonger188.

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

Atothertimestreatmentmayneedtobeincreasedeitherinresponsetolossofcontrolorthreatoflossofcontrol(returnofsymptoms)oranacuteexacerbation,whichisdefinedasamoreacuteandseverelossofcontrolthat

MONITORING TO MAINTAINCONTROL

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requiresurgenttreatment.(AnapproachtoexacerbationsisprovidedinComponent4.4.)

Stepping Down Treatment When Asthma Is Controlled

Thereislittleexperimentaldataontheoptimaltiming,sequence,andmagnitudeoftreatmentreductionsinasthma,andtheapproachwilldifferfrompatienttopatientdependingonthecombinationofmedicationsandthedosesthatwereneededtoachievecontrol.Thesechangesshouldideallybemadebyagreementbetweenpatientandhealthcareprofessional,withfulldiscussionofpotentialconsequencesincludingreappearanceofsymptomsandincreasedriskofexacerbations.Althoughfurtherresearchonsteppingdownasthmatreatment is needed, some recommendations can be madebasedonthecurrentevidence:

• Wheninhaled glucocorticosteroids alone in medium-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

(Evidence B).Ifcontrolismaintained,furtherreductionsintheglucocorticosteroidshouldbeattempteduntilalow-doseisreached,whenthelong-actingβ2-agonistmaybestopped(Evidence D).Analternativeistoswitchthecombinationtreatmenttoonce-dailydosing187,194.Asecondalternativeistodiscontinuethelong-actingβ2-agonistatanearlierstageandsubstitutethecombinationtreatmentwithinhaledglucocorticosteroidmonotherapyatthesamedosecontainedinthecombinationinhaler.However,thisismorelikelytoleadtolossofasthmacontrol368 (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’s

asthmaremainscontrolledonthelowestdoseofcontrollerandnorecurrenceofsymptomsoccursforoneyear(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.

• Inthecontextofasthmaself-managementstudies,actionplansinwhichthedoseofinhaledglucocorticosteroidswasatleastdoubledwereassociatedwithimprovedasthmaoutcomesandreducedhealthcareutilisation32.Inplacebo-controlledtrials,temporarilydoublingthedoseofinhaledglucocorticosteroidswasnoteffective404 (Evidence A),butanaverageintervalof5-7daysbetweentheonsetofworseningsymptomsandincreaseoftheinhaledglucocorticosteroiddose194, 196 mayhavebeenafactor.Thereisemergingevidencethathigherdosesofinhaledglucocorticosteroidmightbeeffectiveforpreventingprogressionto severe exacerbation195,404.Patientswhoquadrupledtheirdoseofinhaledglucocorticosteroidaftertheirpeakflowfellweresignificantlylesslikelytorequireoralglucocorticosteroids381.Inadultpatientswithanacutedeterioration,high-doseinhaledglucocorticosteroidshavebeendemonstratedtobeequivalenttoashortcourseoforalglucocorticosteroids195(Evidence A).Inthesestudies,thehigherdosewasmaintainedforseventofourteendays.Moreresearchisneededinbothadultsandchildrentostandardizetheapproach.

• 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

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(Evidence A).Thebenefitinpreventingexacerbationsappearstobetheconsequenceofearlyinterventionataveryearlystageofathreatenedexacerbationsincestudiesinvolvingdoublingorquadruplingdosesofcombinationtreatmentoncedeteriorationisestablished(for2ormoredays)showsomebenefitbutresultsareinconsistent195.Becausetherearenostudiesusingthisapproachwithothercombinationsofcontrollerandrelievers,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.PatientswhodonotreachanacceptablelevelofcontrolatStep 4 (reliever medication plus two or more controllers)canbeconsideredtohavedifficult-to-treatasthma198.Thesepatientsmayhaveanelementofpoorglucocorticosteroidresponsiveness,andrequirehigherdosesofinhaled

glucocorticosteroidsthanareroutinelyusedinpatientswhoseasthmaiseasytocontrol.However,thereiscurrentlynoevidencetosupportcontinuingthesehigh-dosesofinhaledglucocorticosteroidsbeyond6monthsinthehopeofachievingbettercontrol.Instead,doseoptimizationshouldbepursuedbysteppingdowntoadosethatmaintainsthemaximallevelofcontrolachievedonthehigherdose.

Becauseveryfewpatientsarecompletelyresistanttoglucocorticosteroids,thesemedicationsremainamainstayoftherapyfordifficult-to-treatasthma,whileadditionaldiagnosticandgeneralizedtherapeuticoptionscanandshouldalsobeconsidered:

• Confirmthediagnosisofasthma.Inparticular,thepresenceofCOPDmustbeexcluded.Vocalcorddysfunctionmustbeconsidered.

• Investigateandconfirmadherencewithtreatment.Incorrect or inadequate use of medications and inhalers405remainsthemostcommonreasonforfailuretoachievegoodcontrol.Inpatientswithdifficult-to-treatasthma,improvedadherenceandimprovedhealthoutcomescanbeachievedwithacomprehensiveconcordanceintervention416.

• Consider smoking, current or past, and encouragecompletecessation.Ahistoryofpasttobaccosmokingisassociatedwithareducedlikelihoodofcompleteasthmacontrol,andthisisonlypartlyattributabletothepresenceoffixedairflowobstruction.Inaddition,currentsmokingreducestheeffectivenessofinhaledandoralglucocorticosteroids71,72,378.Counselingandsmokingcessationprogramsshouldbeofferedtoallasthmapatientswhosmoke.

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

Whenthesereasonsforlackoftreatmentresponsehavebeenconsideredandaddressed,acompromiselevelofcontrolmayneedtobeacceptedanddiscussedwiththepatienttoavoidfutileover-treatment(withitsattendantcostandpotentialforadverseeffects).Theobjectiveisthentominimizeexacerbationsandneedforemergencymedicalinterventionswhileachievingashighalevelof

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clinicalcontrolwithaslittledisruptionofactivitiesandasfewdailysymptomsaspossible.Forthesedifficult-to-treatpatients,frequentuseofrescuemedicationisaccepted,asisadegreeofchroniclungfunctionimpairment.Althoughlowerlevelsofcontrolaregenerallyassociatedwithanincreasedriskofexacerbations,notallpatientswithchronicallyimpairedlungfunction,reducedactivitylevels,anddailysymptomshavefrequentexacerbations.Insuchpatients,thelowestleveloftreatmentthatretainsthebenefitsachievedatthehigherdosesoftreatmentshouldbeemployed.Reductionsshouldbemadecautiouslyandslowlyatintervalsnotmorefrequentthan3to6months,ascarryoveroftheeffectsofthehigherdosemaylastforseveralmonthsandmakeitdifficulttoassesstheimpactofthedosereduction(Evidence D).Referraltoaphysicianwithaninterestinand/orspecialfocusonasthmamaybehelpfulandpatientsmaybenefitfromphenotypingintocategoriessuchasallergic,aspirin-sensitive,and/oreosinophilicasthma201.Patientscategorizedasallergicmightbenefitfromanti-IgEtherapy183,andleukotrienemodifierscanbehelpfulforpatientsdeterminedtobeaspirinsensitive(whoareofteneosinophilicaswell)172.

Thermoplasty

GRADEevidencetechnologywasusedtoevaluateresearchonthermoplasty:

Question: “In adult patient whose asthma is uncontrolled despite recommended therapeutic regimens, does thermoplasty, compared to placebo improve patient outcomes?” The consensus recommendation:

• Foradultpatientswhoseasthmaremainsuncontrolleddespiteapplicationofthistherapeuticparadigm,andreferraltoanasthmaspecialtycenter,bronchialthermoplastyisnowapossibleoptioninsomecountries406-408.Inthisbronchoscopictreatment,airwaysaretreatedonthreeoccasionswithalocalizedradiofrequencypulse.Thetreatment,whichitselfisassociatedwithasthmaexacerbationsinthemonthspostbronchoscopy,resultsinasubsequentdecreaseinexacerbations.Therearenosignificanteffectsonlungfunctionorasthmasymptoms.Extendedfollow-uponasmallnumberofpatientshasprovidedsomeadditionalsupportforlong-termsafetyofbronchialthermoplasty417.However,longer-termfollow-upoflargernumberofcontrolandactivepatientsisneededtoassesseffectivenessandcautionshouldbeusedinselectingpatientsforthisprocedure.

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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-relatedhospitalizationsoremergencydepartmentvisitsinadultswithsevereordifficulttotreatasthmahavebeendescribed349,418.

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

• Withahistoryofpsychiatricdiseaseorpsychosocial350 problems,includingtheuseofsedatives209

• Withahistoryofpooradherencewithasthmamedicationsand/orawrittenasthmaactionplan.

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.

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

Treatment

Bronchodilators. For mild to moderate exacerbations, repeatedadministrationofrapid-actinginhaledβ-agonists(2to4puffsevery20minutesforthefirsthour)isusuallythebestandmostcost-effectivemethodofachievingrapidreversalofairflowlimitation.Afterthefirsthour,thedoseof β-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).FunctionalassessmentssuchasPEForFEV1 and arterialoxygensaturationmeasurementsarestronglyrecommendedasphysicalexaminationalonemaynotfullyindicatetheseverityoftheexacerbation,particularlythedegreeofhypoxemia213,214.Withoutundulydelayingtreatment, a baseline PEF or FEV1measurementshouldbemadebeforetreatmentisinitiated,althoughspirometrymaynotbepossibleinchildrenwithacuteasthma.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.Forsevereasthmaexacerbations,controlledoxygentherapyusingpulseoximetrytomaintainoxygensaturationat90–93%isassociatedwithbetterphysiologicaloutcomes,comparedtohighflow100%oxygentherapy218,

419.Oxygentherapyshouldbetitratedagainstpulseoximetrytomaintainasatisfactoryoxygensaturation219.However,oxygenshouldnotbewithheldifoximetryisnotavailable.

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

220-222 (Evidence A).Themostcosteffectiveandefficientdeliveryisbymetereddoseinhalerandaspacerdevice164, 211.Althoughmostrapid-actingβ2-agonistshaveashortdurationofeffect,thelong-actingbronchodilatorformoterol,whichhasbotharapidonsetofactionandalongdurationofeffect,hasbeenshowntobeequallyeffectivewithoutincreasingsideeffects,thoughitisconsiderablymoreexpensive148.Theimportanceofthisfeatureofformoterolisthatitprovidessupportandreassuranceregardingtheuse of a combination of formoterol and budesonide early in asthmaexacerbations. Amodestlygreaterbronchodilatoreffecthasbeenshownwithlevabuterolcomparedtoracemicalbuterolinbothadultsandchildrenwithanasthmaexacerbation223-226.Inalargestudyofacuteasthmainchildren227, and in adults not previouslytreatedwithglucocorticosteroids226, levabuterol treatmentresultedinlowerhospitalizationratescomparedtoracemicalbuteroltreatment,butinchildrenthelengthofhospitalstaywasnodifferent227.

Studiesofintermittentversuscontinuousnebulizedshort-actingβ2-agonistsinacuteasthmaprovideconflictingresults.Inasystematicreviewofsixstudies228,therewere

nosignificantdifferencesinbronchodilatoreffectorhospitaladmissionsbetweenthetwotreatments.Inpatientswhorequirehospitalization,onestudy229foundthatintermittenton-demandtherapyledtoasignificantlyshorterhospitalstay,fewernebulizations,andfewerpalpitationswhencomparedwithintermittenttherapygivenevery4hours.Areasonableapproachtoinhaledtherapyinexacerbations,therefore,wouldbetheinitialuseofcontinuoustherapy,followedbyintermittenton-demandtherapyforhospitalizedpatients.Thereisnoevidencetosupporttheroutineuseof intravenous β2-agonistsinpatientswithsevereasthmaexacerbations230.

Epinephrine. A subcutaneous or intramuscular injection ofepinephrine(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. Systemic glucocorticosteroidsspeedresolutionofexacerbationsandshouldbeutilizedintheallbutthemildestexacerbations237,238(Evidence A),especiallyif:

• Theinitialrapid-actinginhaledβ2-agonisttherapyfailstoachievelastingimprovement

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• Theexacerbationdevelopseventhoughthepatientwasalreadytakingoralglucocorticosteroids

• Previous exacerbations required oral glucocorticosteroids.

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).Twodaysoforaldexamethasonecanalsobeusedtotreatasthmaexacerbations,butthereareconcernsaboutmetabolicside-effectsifdexamethasoneiscontinuedbeyondtwodays420.Evidencesuggeststhatthereisnobenefittotaperingthedoseoforalglucocorticosteroids,eitherintheshort-term245oroverseveralweeks,aslongasthepatientisonmaintenanceinhaledglucocorticosteroids246 (Evidence B).

Inhaled glucocorticosteroids.Inhaledglucocorticosteroidsareeffectiveaspartoftherapyforasthmaexacerbations.Inonestudy,thecombinationofhigh-doseinhaledglucocorticosteroidsandsalbutamolinacuteasthmaprovidedgreaterbronchodilationthansalbutamol alone247(Evidence B),andconferredgreaterbenefitthantheadditionofsystemicglucocorticosteroidsacrossallparameters,includinghospitalizations,especiallyforpatientswithmoresevereattacks248.

Inhaledglucocorticosteroidscanbeaseffectiveasoralglucocorticosteroidsatpreventingrelapses249,250.Patientsdischargedfromtheemergencydepartmentonprednisoneandinhaledbudesonidehavealowerrateofrelapsethanthoseonprednisonealone237(Evidence B).Ahigh-doseofinhaledglucocorticosteroid(2.4mgbudesonidedailyinfourdivideddoses)achievesarelapseratesimilarto40mgoralprednisonedaily251(Evidence A).Costisasignificantfactorintheuseofsuchhigh-dosesofinhaled

glucocorticosteroids,andfurtherstudiesarerequiredtodocumenttheirpotentialbenefits,especiallycosteffectiveness,inacuteasthma252.

Magnesium*.Intravenousmagnesiumsulphate(usuallygivenasasingle2ginfusionover20minutes)isnotrecommendedforroutineuseinasthmaexacerbations,butcanhelpreducehospitaladmissionratesincertainpatients,includingadultswithFEV125-30%predictedatpresentation,adultsandchildrenwhofailtorespondtoinitialtreatment,andchildrenwhoseFEV1failstoimproveabove60%predictedafter1hourofcare253,254,409(Evidence A).Nebulizedsalbutamoladministeredinisotonicmagnesiumsulfateprovidesgreaterbenefitthanifitisdelivered in normal saline255,256(Evidence A).Intravenousmagnesiumsulphatehasnotbeenstudiedinyoungchildren.

Helium oxygen therapy. A systematic survey of studies thathaveevaluatedtheeffectofacombinationofheliumandoxygen,comparedtoheliumalone,suggeststhereisnoroutineroleforthisintervention.Itmightbeconsideredforpatientswhodonotrespondtostandardtherapy257.

Leukotriene modifiers.Therearelittledatatosuggestaroleforleukotrienemodifiersinacuteasthma258.SmallinvestigationshavedemonstratedimprovementinPEF410, butclinicalrelevancerequiresmorestudy.

Sedatives.Sedationshouldbestrictlyavoidedduringexacerbationsofasthmabecauseoftherespiratorydepressanteffectofanxiolyticandhypnoticdrugs.Anassociationbetweentheuseofthesedrugsandavoidableasthmadeaths209,259hasbeendemonstrated.

Criteria for Discharge from the Emergency Department vs. Hospitalization

Criteriafordeterminingwhetherapatientshouldbedischargedfromtheemergencydepartmentoradmittedtothehospitalhavebeensuccinctlyreviewedandstratifiedbased on consensus260.Patientswithapre-treatmentFEV1 orPEF<25%percentpredictedorpersonalbest,orthosewithapost-treatmentFEV1orPEF<40%percentpredictedorpersonalbest,usuallyrequirehospitalization.Patientswithpost-treatmentlungfunctionof40-60%predictedmaybedischarged,providedthatadequatefollow-upisavailableinthecommunityandcomplianceisassured.Patientswithpost-treatmentlungfunction60%predictedcanbedischarged.

Managementofacuteasthmaintheintensivecareunitisbeyondthescopeofthisdocumentandreadersarereferredtorecentcomprehensivereviews261.*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?”COPY

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Forpatientsdischargedfromtheemergencydepartment:

• At a minimum, a 7-day course of oral glucocorticosteroidsforadultsandashortercourse(3-5days)forchildrenshouldbeprescribed,alongwithcontinuationofbronchodilatortherapy.

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

• Ipratropiumbromideisunlikelytoprovideadditionalbenefitbeyondtheacutephaseandmaybequicklydiscontinued.

• Patientsshouldinitiateorcontinueinhaledglucocorticosteroids.

• Thepatient’sinhalertechniqueanduseofpeakflowmetertomonitortherapyathomeshouldbereviewed.Patientsdischargedfromtheemergencydepartmentwithapeakflowmeterandactionplanhaveabetterresponsethanpatientsdischargedwithouttheseresources8.

• Thefactorsthatprecipitatedtheexacerbationshouldbeidentifiedandstrategiesfortheirfutureavoidanceimplemented.

• Thepatient’sresponsetotheexacerbationshouldbeevaluated.Theactionplanshouldbereviewedandwrittenguidanceprovided411.

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

• Thepatientorfamilyshouldbeinstructedtocontacttheprimaryhealthcareprofessionalorasthmaspecialistwithin24hoursofdischarge.Afollow-upappointmentwiththepatient’susualprimarycareprofessionalorasthmaspecialistshouldbemadewithinafewdaysofdischargetoassurethattreatmentiscontinueduntilbaselinecontrolparameters,includingpersonalbestlungfunction,arereached.Prospectivedataindicatethatpatientsdischargedfromtheemergencydepartmentforfollow-upwithspecialistcaredobetterthanpatientsreturnedtoroutine care262.

Anexacerbationsevereenoughtorequirehospitalizationmayreflectafailureofthepatient’sasthmamanagementorlackofawrittenasthmaactionplan.Hospitalizedpatientsmaybeparticularlyreceptivetoinformationandadviceabouttheirillness.Healthcareprovidersshouldtakethe

opportunitytoreviewpatientunderstandingofthecausesofasthmaexacerbations,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-IgEtherapy294,295 are effective inbothconditions(Evidence A).

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

Sinusitis.Sinusitisisacomplicationofupperrespiratoryinfections,allergicrhinitis,nasalpolyps,andotherforms

ofnasalobstruction.Bothacuteandchronicsinusitiscanworsenasthma.Clinicalfeaturesofsinusitislackdiagnosticprecision296,andCTScanconfirmationisrecommendedwhenavailable.Inchildrenwithsuspectedrhinosinusitis,antibiotictherapyfor10daysisrecommended(Evidence B).Treatmentshouldalsoincludemedicationstoreducenasalcongestion,suchastopicalnasaldecongestantsortopicalnasalorevensystemicglucocorticosteroids.Theseagentsremainsecondarytoprimaryasthmatherapies279,288.

Nasal polyps.Nasalpolypsassociatedwithasthmaandrhinitis,andsometimeswithaspirinhypersensitivity298, are seenprimarilyinpatientsover40yearsold.Between36%and96%ofaspirin-intolerantpatientshavepolyps,and29%to70%ofpatientswithnasalpolypsmayhaveasthma298,299.Childrenwithnasalpolypsshouldbeassessedforcysticfibrosisandimmotileciliasyndrome.Nasalpolypsarequiteresponsivetotopicalglucocorticosteroids288.Alimitednumberofpatientswithglucocorticosteroid-refractorypolypsmaybenefitfromsurgery.

Occupational Asthma

Onceadiagnosisofoccupationalasthmaisestablished,completeavoidanceoftherelevantexposureisideallyanimportantcomponentofmanagement300-302,412.Occupationalasthmamaypersistevenseveralyearsafterremovalfromexposuretothecausativeagent,especiallywhenthepatienthashadsymptomsforalongtimebeforecessationofexposure303,304.Continuedexposuremayleadtoincreasinglysevereandpotentiallyfatalasthmaexacerbations305,aGastroesophagealRefluxlowerprobabilityofsubsequentremission,and,ultimately,permanentlyimpairedlungfunction306.Pharmacologictherapyforoccupationalasthmaisidenticaltotherapyforotherformsofasthma,butitisnotasubstituteforadequateavoidance.Consultationwithaspecialistinasthmamanagementoroccupationalmedicineisadvisable.

TheBritishOccupationalHealthResearchFoundationGuidelinesfortheprevention,identification,andmanagementofoccupationalasthmaareavailableathttp://www.bohrf.org.uk/downloads/asthevre.pdf.(Seealsoreference421.)

Respiratory Infections

Respiratoryinfectionshaveanimportantrelationshiptoasthmaastheyprovokewheezingandincreasedsymptomsinmanypatients307 and are commonly found inchildrenwithasthmaexacerbation391.Epidemiologicalstudieshavefoundthatinfectiousmicroorganismsassociatedwithincreasedasthmasymptomsareoften

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respiratoryviruses308, but seldom bacteria309.Respiratorysyncytialvirusisthemostcommoncauseofwheezingininfancy45,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.Thebenefitfrom macrolide antibiotics remains unclear315-317.Arelativelysmallbutwellconductedstudyshowednoevidenceofbenefitfromtheadditionofclarithromycintoadultswithmildtomoderatelysevereasthmaonlowdoseinhaledglucocorticosteroids413.However,furtherresearchinthisareaisrequired.

Gastroesophageal Reflux.

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

A review320oftheeffectivetreatmentsofgastroesophagealrefluxwithavarietyofmeasuresincludingprotonpumpinhibitors,H2antagonists,andsurgeryfailedtoshowbenefit.Astudyonadultpatientswithsymptomaticasthmawithoutsymptomsofgastroesophagealrefluxfoundthattreatmentwithhighdoseprotonpumpinhibitorsdidnotimprovesymptomsorexacerbationsofasthma393.Inpatientswithmoderatetosevereasthmatreatedwithanti-inflammatoryasthmamedicationsandsymptomaticgastroesophagealreflux,treatmentwithprotonpumpinhibitorsdemonstratedasmallandprobablyclinicallynon-significantimprovementinlungfunctionandqualityof life392.Fewdataareavailableonstudiesoftreatmentforchildrenwithasthmasymptomsandsymptomsofgastroesophagealreflux394.

Insummary,despiteahighprevalenceofasymptomaticgastroesophagealrefluxamongpatientswithpoorlycontrolledasthma,treatmentwithproton-pumpinhibitorsdoesnotimproveasthmacontrolinadults392-394 or children422.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.

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Persistentmarkedeosinophilicinflammation,epithelialdisruption,cytokineproduction,andupregulationofadhesionmoleculesarefoundintheairwaysofpatientswithAIA327,328.Airwayexpressionofinterleukin-5(IL-5),whichisinvolvedinrecruitmentandsurvivalofeosinophils,is also increased328.AIAisfurthercharacterizedbyincreasedactivationofcysteinylleukotrienepathways,whichmaybepartlyexplainedbyageneticpolymorphismoftheLTC4synthasegenefoundinabout70%percentofpatients329.However,theexactmechanismbywhichaspirintriggersbronchoconstrictionremainsunknown330. Theabilityofacyclooxygenaseinhibitortotriggerreactionsdependsonthedrug’scyclooxygenaseinhibitorypotency,aswellasontheindividualsensitivityofthepatient329.

Acharacteristichistoryofreactionisconsideredadequateforinitiatingavoidancestrategies.However,thediagnosiscanonlybeconfirmedbyaspirinchallenge,astherearenosuitableinvitrotestsfordiagnosis.Theaspirinchallengetestisnotrecommendedforroutinepracticeasitisassociatedwithahighriskofpotentiallyfatalconsequences and must only be conducted in a facility withcardiopulmonaryresuscitationcapabilities331.FurthersafeguardsarethatpatientsshouldonlybechallengedwhentheirasthmaisinremissionandtheirFEV1 is greaterthan70%ofpredictedorpersonalbest.Bronchial(inhalational)andnasalchallengeswithlysineaspirinaresaferthanoralchallengesandmaybeperformedinspecializedcenters332,333.OnceaspirinorNSAIDhypersensitivitydevelops,itispresentforlife.PatientswithAIAshouldavoidaspirin,productscontainingit,otheranalgesicsthatinhibitCOX-1,andoftenalsohydrocortisonehemisuccinate334.Avoidancedoesnotpreventprogressionoftheinflammatorydiseaseoftherespiratorytract.WhereanNSAIDisindicated,acyclooxygenase-2(COX-2)inhibitormaybeconsidered352 withappropriatephysiciansupervisionandobservationforatleastonehourafteradministration335(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.Effectivetreatmentofanaphylaxisdemandsearlyrecognitionoftheevent.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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382.LemanskeRFJr,MaugerDT,SorknessCA,JacksonDJ,BoehmerSJ,MartinezFD,etal.;ChildhoodAsthmaResearchandEducation(CARE)NetworkoftheNationalHeart,Lung,andBloodInstitute.Step-uptherapyforchildrenwithuncontrolledasthmareceivinginhaledcorticosteroids.N Engl J Med2010;362(11):975-85.

383.Saint-PierreP,BourdinA,ChanezP,DauresJP,GodardP.Areoverweightasthmaticsmoredifficulttocontrol?Allergy2006;61(1):79-84.

384.LavoieKL,BaconSL,LabrecqueM,CartierA,DittoB.HigherBMIisassociatedwithworseasthmacontrolandqualityoflifebutnotasthmaseverity.Respir Med 2006;100(4):648-57.

385.DixonAE,ShadeDM,CohenRIetal.Effectofobesityonclinicalpresentationandresponsetotreatmentinasthma.J Asthma 2006;43(7):553-8.

386.BouletLP,FranssenE.Influenceofobesityonresponsetofluticasonewithorwithoutsalmeterolinmoderateasthma.Respir Med 2007;101(11):2240-7

387.Peters-Golden M, Swern A, Bird SS, Hustad CM, Grant E,EdelmanJM.Influenceofbodymassindexontheresponsetoasthmacontrolleragents.Eur Respir J 2006;27(3):495-503.

388.AaronSD,VandemheenKL,BouletLP,McIvorRA,FitzgeraldJM,HernandezP,LemiereC,SharmaS,FieldSK,AlvarezGG,DalesRE,DoucetteS,FergussonD;CanadianRespiratoryClinicalResearchConsortium.Overdiagnosisofasthmainobeseandnonobeseadults. CMAJ2008;179(11):1121-31.

389.EneliIU,SkyboT,CamargoCAJr.Weightlossandasthma:asystematicreview.Thorax2008;63(8):671-6.

390.AaronSD,FergussonD,DentR,ChenY,VandemheenKL,DalesRE.Effectofweightreductiononrespiratoryfunctionandairwayreactivityinobesewomen. Chest 2004;125(6):2046-52.

391.LeungTF,ToMY,YeungAC,WongYS,WongGW,ChanPK.Multiplexmoleculardetectionofrespiratorypathogensinchildrenwithasthmaexacerbation.Chest 2010;137(2):348-54.

392.KiljanderTO,HardingSM,FieldSK,SteinMR,NelsonHS,EkelundJ,IlluecaM,BeckmanO,SostekMB.Effectsofesomeprazole40mgtwicedailyonasthma:arandomizedplacebo-controlledtrial.Am J Respir Crit Care Med 2006;173(10):1091-7.

393.MastronardeJG,AnthonisenNR,CastroM,HolbrookJT,LeoneFT,TeagueWG,WiseRA.Efficacyofesomeprazolefortreatmentofpoorlycontrolledasthma.N Engl J Med 2009;360(15):1487-99.

394.SopoSM,RadzikD,CalvaniM.Doestreatmentwithprotonpumpinhibitorsforgastroesophagealrefluxdisease(GERD)improveasthmasymptomsinchildrenwithasthmaandGERD?Asystematicreview.J Investig Allergol Clin Immunol2009;19(1):1-5.Review.

395.LiuWT,HuangCD,WangCH,LeeKY,LinSM,KuoHP.Amobiletelephone-basedinteractiveself-caresystemimprovesasthmacontrol.Eur Respir J. 2011 Feb;37(2):310-7.


397.McLeanS,ChandlerD,NurmatovU,LiuJ,PagliariC,CarJ,SheikhA.Telehealthcareforasthma.Cochrane Database Syst Rev.2010Oct6;(10):CD007717.

398.WilliamsLK,PetersonEL,WellsK,CampbellJ,WangM,ChowdhryVK,etal.Acluster-randomizedtrialtoprovidecliniciansinhaledcorticosteroidadherenceinformationfortheirpatientswithasthma.J Allergy Clin Immunol. 2010Aug;126(2):225-31,231.e1-4.

399.BruzzeseJM,ShearesBJ,VincentEJ,DuY,SadeghiH,LevisonMJ,MellinsRB,EvansD.Effectsofaschool-basedinterventionforurbanadolescentswithasthma.Acontrolledtrial.Am J Respir Crit Care Med.2011Apr15;183(8):998-1006.

400.BusseWW,LemanskeRFJr,GernJE.Roleofviralrespiratoryinfectionsinasthmaandasthmaexacerbations.Lancet.2010Sep4;376(9743):826-34.

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401.BeasleyRW,ClaytonTO,CraneJ,LaiCK,MontefortSR,MutiusE,StewartAW;ISAACPhaseThreeStudyGroup.Acetaminophenuseandriskofasthma,rhinoconjunctivitis,andeczemainadolescents:InternationalStudyofAsthmaandAllergiesinChildhoodPhaseThree.Am J Respir Crit Care Med. 2011Jan15;183(2):171-8.

402.TiboschMM,VerhaakCM,MerkusPJ.Psychologicalcharacteristicsassociatedwiththeonsetandcourseofasthmainchildrenandadolescents:asystematicreviewoflongitudinaleffects.Patient Educ Couns.2011Jan;82(1):11-9.

403.Vaessen-VerberneAA,vandenBergNJ,vanNieropJC,BrackelHJ,GerritsGP,HopWC,DuivermanEJ;COMBOStudyGroup.Combinationtherapysalmeterol/fluticasoneversusdoublingdoseoffluticasoneinchildrenwithasthma.Am J Respir Crit Care Med. 2010 Nov15;182(10):1221-7.

404.QuonBS,FitzGeraldJM,LemiereC,ShahidiN,DucharmeFM.Increasedversusstabledosesofinhaledcorticosteroidsforexacerbationsofchronicasthmainadultsandchildren.Cochrane Database Syst Rev.2010Oct6;(10):CD007524.

405.Melani AS, Bonavia M, Cilenti V, Cinti C, Lodi M, MartucciP,SerraM,ScichiloneN,SestiniP,AlianiM,NeriM;GruppoEducazionaleAssociazioneItalianaPneumologiOspedalieri.Inhalermishandlingremainscommoninreallifeandisassociatedwithreduceddiseasecontrol.Respir Med.2011Jun;105(6):930-8.

406.CastroM,RubinAS,LavioletteM,FitermanJ,DeAndradeLimaM,ShahPL,etal;AIR2TrialStudyGroup.Effectivenessandsafetyofbronchialthermoplastyinthetreatmentofsevereasthma:amulticenter,randomized,double-blind,sham-controlledclinicaltrial.Am J Respir Crit Care Med.2010Jan15;181(2):116-24.

407.ThomsonNC,RubinAS,NivenRM,CorrisPA,SierstedHC,OlivensteinR,etal;AIRTrialStudyGroup.Long-term(5year)safetyofbronchialthermoplasty:Asthma Intervention Research (AIR) trial.BMC Pulm Med.2011Feb11;11:8.

408.CoxG,ThomsonNC,RubinAS,etal.Asthmacontrolduringtheyearafterbronchialthermoplasty.N Engl J Med. 2007;356:1327-37.

409.Gallegos-SolorzanoMC,Perez-PadillaR,Hernandez-ZentenoRJ.Usefulnessofinhaledmagnesiumsulfateinthecoadjuvantmanagementofsevereasthmacrisisinanemergencydepartment.Pulm Pharmacol Ther. 2010 Oct;23(5):432-7.

410.RamsayCF,PearsonD,MildenhallS,WilsonAM.Oralmontelukastinacuteasthmaexacerbations:arandomised,double-blind,placebo-controlledtrial.Thorax. 2011 Jan;66(1):7-11.

411.DucharmeFM,ZemekRL,ChalutD,McGillivrayD,NoyaFJ,ResendesS,KhomenkoL,RouleauR,ZhangX.Writtenactionplaninpediatricemergencyroomimprovesasthmaprescribing,adherence,andcontrol.Am J Respir Crit Care Med.2011Jan15;183(2):195-203.

412.deGroeneGJ,PalTM,BeachJ,TarloSM,SpreeuwersD,Frings-DresenMH,MattioliS,VerbeekJH.Workplaceinterventionsfortreatmentofoccupationalasthma.Cochrane Database Syst Rev. 2011 May 11;5:CD006308.

413.SutherlandER,KingTS,IcitovicN,AmeredesBT,BleeckerE,BousheyHA,etal;NationalHeart,LungandBloodInstitute’sAsthmaClinicalResearchNetwork.Atrialofclarithromycinforthetreatmentofsuboptimallycontrolledasthma.J Allergy Clin Immunol. 2010 Oct;126(4):747-53.

414.ShahS,SawyerSM,ToelleBG,MellisCM,PeatJK.LaglevaM,et al.Improvingpaediatricasthmaoutcomesinprimaryhealthcare:arandomisedcontrolledtrial.Med J Aust.2011Oct3;195(7):405-9.

415.GehringU,deJongsteJC,KerkhofM,OldeweningM,Postma D, van Strien RT, et al.The8-yearfollow-upofthePIAMAinterventionstudyassessingtheeffectofmite-impermeablemattresscovers.Allergy. 2012 Feb;67(2):248-56

416.GambleJ,StevensonM,HeaneyLG.Astudyofamulti-levelinterventiontoimprovenon-adherenceindifficulttocontrolasthma.Respir Med.2011Sep;105(9):1308-15.

417.CastroM,RubinA,LavioletteM,HananiaNA,ArmstrongB,CoxG;AIR2TrialStudyGroup.Persistenceofeffectivenessofbronchialthermoplastyinpatientswithsevereasthma.Ann Allergy Asthma Immunol. 2011 Jul;107(1):65-70.

418.OrtegaH,MillerDP,LiH.Characterizationofasthmaexacerbationsinprimarycareusingclusteranalysis.J Asthma.2012Mar;49(2):158-69.

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419.PerrinK,WijesingheM,HealyB,WadsworthK,BowditchR,BibbyS,BakerT,WeatherallM,BeasleyR.Randomisedcontrolledtrialofhighconcentrationversustitratedoxygentherapyinsevereexacerbationsofasthma. Thorax.2011Nov;66(11):937-41.

420.KravitzJ,DominiciP,UfbergJ,FisherJ,GiraldoP.Twodaysofdexamethasoneversus5daysofprednisoneinthetreatmentofacuteasthma:arandomizedcontrolledtrial.Ann Emerg Med.2011Aug;58(2):200-4.

421.FishwickD,BarberCM,BradshawLM,AyresJG,BarracloughR,BurgeS,etal.Standardsofcareforoccupationalasthma:anupdate.Thorax.2012Mar;67(3):278-80.

422.HolbrookJT,WiseRA,GoldBD,BlakeK,BrownED,Castro M, et al.WritingCommitteefortheAmericanLungAssociationAsthmaClinicalResearchCenters.Lansoprazoleforchildrenwithpoorlycontrolledasthma:arandomizedcontrolledtrial.JAMA.2012Jan25;307(4):373-81.

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GUIDELINES INHEALTH SYSTEMS

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106 IMPLEMENTATION OF ASTHMA GUIDELINES IN HEALTH SYSTEMS

KEY POINTS:

• 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, and lackofphysicianuseofguidelines.

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;asimpleregimeforrecognizingsevereasthma;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.Themosteffectiveinterventionstoimproveprofessionalpracticearemultifaceted and interactive4,5.However,littleisknownofthecosteffectivenessoftheseinterventions6.Integratedcarepathwaysarebeingexploredasameantoimproveasthmacareinspecificsettings,suchaspatientscomingtoemergencydepartments22.

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

Publichealthstrategiesinvolvingabroadcoalitionofstakeholdersinasthmacare,includingmedicalsocieties,healthcareprofessionals,patientsupportgroups,government,andtheprivatesector,havebeenimplementedinAustralia(AustralianNationalAsthmaCouncil,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,andsensitizedto,satisfactoryversuspoorcontrolofasthma;areferencepointfromwhichtoevaluatedeterioratingasthma;andanindicatorofchangesinasthmacontrolinresponsetochangesintreatment.Useofadministrativedatasets(e.g.,dispensingrecords)orurgenthealthcareutilizationcanhelptoidentifyat-riskpatientsortoauditthequalityofhealthcare23.Thestrategyofculturallyappropriatedirectfeedbackofclinicaloutcomestophysiciansaboutspecifichealthcareresultsoftheirpatientsmaybeimportantforgeneralpractitionerswhotreatmanydiseasesinadditiontoasthmaandthuscouldnotbeexpectedtoknowguidelinesindetailandhandlepatientsaccordingly.

Costisrecognizedasanimportantbarriertothedeliveryofoptimalevidence-basedhealthcareinalmosteverycountry,althoughitsimpactonpatients’accesstotreatmentsvarieswidelybothbetweenandwithincountries.Atthecountryorlocallevel,healthauthoritiesmakeresourceavailabilityandallocationdecisionsaffectingpopulationsofasthmapatientsbyconsideringthebalanceand tradeoffs between costs and clinical outcomes (benefitsandharms),ofteninrelationtocompetingpublichealthandmedicalneeds.Treatmentcostsmustalsobe

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

Utilization and Cost of Health Care Resources

Between35and50%ofmedicalexpendituresforasthmaareconsequencesofexacerbations14,anasthmaoutcomemostviewasrepresentingtreatmentfailure.Hospitalization,emergencydepartmentandunscheduledclinicvisits,anduseofrescuemedicationcomprisethemajorityofexacerbation-relatedtreatmentcosts.Inclinicaltrialsofasthmatreatments,exacerbationsarecustomarilycharacterizedbyuseofhealthcareresources,aloneorincombinationwithsymptomandlungfunctiondata,especiallywhentheprimarystudyoutcomeisreductionintheexacerbationfrequencyortimetoanexacerbationevent.Routinecollectionofhealthcareresourceconsumptiondatacanbeundertakeninthefieldthroughpatientorcaregiverself-report.Insomecircumstances,automateddatafromclinicalorbillingrecordscansubstituteforself-reportandaremorereliableandvalid13,15.

Compositedefinitionsofasthmacontrol16,17 may include oneormorehealthcareutilizationitems.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.

Assessmentofpatientandcaregivertravelandwaitingtime for medical visits, as well as absences from and productivitywhileatschoolorwork,compriseadditionalandimportantoutcomemeasuresinasthma.Theseindirectcostsofasthmaaresubstantial,estimatedtoberoughly50%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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EducationalmaterialsbasedonthisGlobal Strategy for Asthma Management and Prevention are available in severalforms,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,GINAhasmaintainedaWebsitesince1995toprovideaccesstotheGINAdocumentsandeducationalmaterialsforpatientsandthepublicaswellasupdatesofactivitiesandinformationaboutcollaboratinggroupsandcontactsthroughouttheworld.

World Asthma Day.Initiatedin1998,andheldonthefirstTuesdayinMay,WorldAsthmaDayisorganizedbyGINAincollaborationwithhealthcaregroupsandasthmaeducatorsthroughouttheworld.WorldAsthmaDay activities focus on dissemination of information aboutasthmaamongthegeneralpopulation,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).Int J Epidemiol2001;30(1):173-9.

2. HigginsBG,BrittonJR,ChinnS,CooperS,BurneyPG,TattersfieldAE.Comparisonofbronchialreactivityandpeakexpiratoryflowvariabilitymeasurementsforepidemiologicstudies.Am Rev Respir Dis1992;145(3):588-93.

3. PartridgeMR,HarrisonBD,RudolphM,BellamyD,SilvermanM.TheBritishAsthmaGuidelines--theirproduction,disseminationandimplementation.BritishAsthmaGuidelinesCo-ordinatingCommittee.Respir Med1998;92(8):1046-52.

4. DavisDA,ThomsonMA,OxmanAD,HaynesRB.Changingphysicianperformance.Asystematicreviewoftheeffectofcontinuingmedicaleducationstrategies.JAMA 1995;274(9):700-5.

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

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Almirall

AstraZeneca

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