Gina report 2012_feb13

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Gina report 2012_feb13

  1. 1. ®GLOBAL STRATEGY FORASTHMA MANAGEMENT AND PREVENTIONUPDATED 2012© 2012 Global Initiative for AsthmaCOPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE
  2. 2. Global Strategy for Asthma Management and PreventionThe GINA reports are available on www.ginasthma.org.COPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE
  3. 3. iGINA BOARD OF DIRECTORS*Mark FitzGerald, MD, ChairUniversity of British ColumbiaVancouver, BC, CanadaEric D. Bateman, MDUniversity Cape Town Lung InstituteCape Town, South AfricaLouis-Philippe Boulet, MDHôpital LavalSainte-Foy, Quebec, CanadaAlvaro A. Cruz, MDFederal University of BahiaSchool of MedicineSalvador, BrazilTari Haahtela, MDHelsinki University Central HospitalHelsinki, FinlandMark L. Levy, MDUniversity of EdinburghLondon, England, UKPaul O’Byrne, MDMcMaster UniversityHamilton, Ontario, CanadaKen Ohta, MD, PhDNational Hospital Organization Tokyo National HospitalTokyo, JapanPierluigi Paggiaro, MDUniversity of PisaPisa, ItalySoren Erik Pedersen, M.D.Kolding HospitalKolding, DenmarkHelen Reddel, MDWoolcock Institute of Medical ResearchCamperdown, NSW, AustraliaManuel Soto-Quiro, MDHospital Nacional de NiñosSan José, Costa RicaGary W. Wong, MDChinese University of Hong KongHong Kong ROCGINA SCIENCE COMMITTEE*Helen Reddel, MD, ChairWoolcock Institute of Medical ResearchCamperdown, NSW, AustraliaNeil Barnes, MDLondon Chest HospitalLondon, England, UKPeter J. Barnes, MDNational Heart and Lung InstituteLondon, England, UKEric D. Bateman, MDUniversity Cape Town Lung InstituteCape Town, South AfricaAllan Becker, MDUniversity of ManitobaWinnipeg, Manitoba, CanadaElisabeth Bel, MDUniversity of AmsterdamAmsterdam, The NetherlandsJeffrey M. Drazen, MDHarvard Medical SchoolBoston, Massachusetts, USAMark FitzGerald, MDUniversity of British ColumbiaVancouver, BC, CanadaJohan C. de Jongste, MD, PhDErasmas University Medical CenterRotterdam, The NetherlandsRobert F. Lemanske, Jr., MDUniversity of Wisconsin School of MedicineMadison, Wisconsin, USAPaul O’Byrne, MDMcMaster UniversityHamilton, Ontario, CanadaKen Ohta, MD, PhDNational Hospital Organization Tokyo National HospitalTokyo, JapanSoren Erik Pedersen, MDKolding HospitalKolding, DenmarkEmilio Pizzichini, MDUniversidade Federal de Santa CatarinaFlorianópolis, SC, BrazilSally E. Wenzel, MDUniversity of PittsburghPittsburgh, Pennsylvania, USAGlobal Strategy for Asthma Management and Prevention 2012 (update)*Disclosures for members of GINA Board of Directors and Science Committees can befound at http://www.ginasthma.orgCOPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE
  4. 4. iiPREFACEAsthma is a serious global health problem. People of allages in countries throughout the world are affected bythis chronic airway disorder that, when uncontrolled, canplace 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 lostproductivity and reduced participation in family life.During the past two decades, we have witnessed manyscientific advances that have improved our understandingof asthma and our ability to manage and control iteffectively. However, the diversity of national healthcare service systems and variations in the availabilityof asthma therapies require that recommendations forasthma care be adapted to local conditions throughoutthe global community. In addition, public health officialsrequire information about the costs of asthma care, howto effectively manage this chronic disorder, and educationmethods to develop asthma care services and programsresponsive to the particular needs and circumstanceswithin their countries.In 1993, the National Heart, Lung, and Blood Institutecollaborated with the World Health Organization toconvene a workshop that led to a Workshop Report:Global Strategy for Asthma Management and Prevention.This presented a comprehensive plan to manage asthmawith the goal of reducing chronic disability and prematuredeaths while allowing patients with asthma to leadproductive and fulfilling lives.At the same time, the Global Initiative for Asthma (GINA)was implemented to develop a network of individuals,organizations, and public health officials to disseminateinformation about the care of patients with asthma whileat the same time assuring a mechanism to incorporatethe results of scientific investigations into asthmacare. Publications based on the GINA Report wereprepared and have been translated into languages topromote international collaboration and dissemination ofinformation. To disseminate information about asthmacare, a GINA Assembly was initiated, comprised of asthmacare experts from many countries to conduct workshopswith local doctors and national opinion leaders and tohold seminars at national and international meetings. Inaddition, GINA initiated an annual World Asthma Day (in2001) which has gained increasing attention each yearto raise awareness about the burden of asthma, and toinitiate activities at the local/national level to educatefamilies and health care professionals about effectivemethods to manage and control asthma.In spite of these dissemination efforts, internationalsurveys provide direct evidence for suboptimal asthmacontrol in many countries, despite the availability ofeffective therapies. It is clear that if recommendationscontained within this report are to improve care of peoplewith asthma, every effort must be made to encouragehealth care leaders to assure availability of and access tomedications, and develop means to implement effectiveasthma management programs including the use ofappropriate tools to measure success.In 2002, the GINA Report stated that “It is reasonableto expect that in most patients with asthma, controlof the disease can, and should be achieved andmaintained.” To meet this challenge, in 2005, ExecutiveCommittee recommended preparation of a new reportnot only to incorporate updated scientific informationbut to implement an approach to asthma managementbased on asthma control, rather than asthma severity.Recommendations to assess, treat and maintain asthmacontrol are provided in this document. The methods usedto prepare this document are described in the Introduction.It is a privilege for me to acknowledge the work of themany people who participated in this update project, aswell as to acknowledge the superlative work of all whohave contributed to the success of the GINA program.The GINA program has been conducted throughunrestricted educational grants from Almirall, AstraZeneca,Boehringer-Ingelheim, Chiesi, CIPLA, GlaxoSmithKline,Merck Sharp & Dohme, Novartis, Quintiles, Takeda. Thegenerous contributions of these companies assured thatCommittee members could meet together to discussissues and reach consensus in a constructive and timelymanner. The members of the GINA Committees are,however, solely responsible for the statements andconclusions 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 CanadaCOPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE
  5. 5. iiiGLOBAL STRATEGY FOR ASTHMA MANAGEMENT AND PREVENTIONTable of ContentsPREFACE iiMETHODOLOGY AND SUMMARY OF NEW  RECOMMENDATION, 2011 UPDATE viINTRODUCTION xCHAPTER 1. DEFINITION AND OVERVIEW 1KEY POINTS 2DEFINITION 2THE BURDEN OF ASTHMA 3 Prevalence, Morbidity and Mortality 3 Social and Economic Burden 3FACTORS 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 7MECHANISMS OF ASTHMA 7 Airway Inflammation In Asthma 7 Inflammatory cells 8 Structural changes in airways 8 Pathophysiology 8 Airway hyperresponsiveness 8 Special Mechanisms 9 Acute exacerbations 9 Nocturnal Asthma 9 Irreversible airflow asthma 9 Difficult-to-treat asthma 9 Smoking and asthma 9REFERENCES 9CHAPTER 2. DIAGNOSIS AND CLASSIFICATION 15KEY POINTS 16INTRODUCTION 16CLINICAL DIAGNOSIS 16 Medical History 16 Symptoms 16 Cough variant asthma 16 Exercise-Induced bronchospasm 17 Physical Examination 17 Tests for Diagnosis and Monitoring 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 19DIAGNOSTIC CHALLENGES AND  DIFFERENTIAL DIAGNOSIS 20 Children 5 Years and Younger 20 Older Children and Adults 20 The Elderly 21 Occupational Asthma 21 Distinguishing Asthma from COPD 21CLASSIFICATION OF ASTHMA 21 Etiology 21 Phenotype 22 Asthma Control 22 Asthma Severity 23 REFERENCES 24CHAPTER 3. ASTHMA MEDICATIONS 29KEY POINTS 30INTRODUCTION 30ASTHMA 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 COPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE
  6. 6. ivReliever Medications 36 Rapid-acting inhaled β2-agonists 36 Systemic glucocorticosteroids 37 Anticholinergics 37 Theophylline 37 Short-acting oral β2-agonists 37Complementary and Alternative Medicine 37ASTHMA 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 43REFERENCES 43CHAPTER 4. ASTHMA MANAGEMENT AND  PREVENTION 55INTRODUCTION 56COMPONENT 1: DEVELOP PATIENT/  DOCTOR PARTNERSHIP 56KEY POINTS 56INTRODUCTION 56ASTHMA EDUCATION 57 At the Initial Consultation 58 Personal Written Asthma Action Plans 58 Follow-up and Review 58 Improving Adherence 59 Self-Management in Children 59THE EDUCATION OF OTHERS 60COMPONENT 2: IDENTIFY AND REDUCE EXPOSURE  TO RISK FACTORS 61KEY POINTS 61INTRODUCTION 61ASTHMA PREVENTION 61PREVENTION OF ASTHMA SYMPTOMS AND EXACERBATIONS 62 Indoor Allergens 62 Domestic mites 62 Furred animals 62 Cockroaches 63 Fungi 63 Outdoor Allergens 63 Indoor Air Pollutants 63 Outdoor Air Pollutants 63 Occupational Exposures 63 Food and Drug Additives 64 Drugs 64 Influenza Vaccination 64 Obesity 64 Emotional Stress 64 Other Factors That May Exacerbate Asthma 64COMPONENT 3: ASSESS,TREAT AND MONITOR  ASTHMA 65KEY POINTS 65INTRODUCTION 65ASSESSING ASTHMA CONTROL 65TREATMENT TO ACHIEVE CONTROL 65 Treatment Steps to Achieving Control 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 69MONITORING TO MAINTAIN CONTROL 69 Duration and Adjustments to Treatment 69 Stepping Down Treatment When Asthma Is  Controlled 70 Stepping Up Treatment In Response to Loss   of Control 70 Difficult-to-Treat-Asthma 71THERMOPLASTY 72COMPONENT 4: MANAGE ASTHMAEXACERBATIONS 73KEY POINTS 73COPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE
  7. 7. vINTRODUCTION 73ASSESSMENT OF SEVERITY 74MANAGEMENT-COMMUNITY SETTINGS 74 Treatment 75 Bronchodilators 75 Glucocorticosteroids 75MANAGEMENT-ACUTE CARE SETTINGS 75 Assessment 75 Treatment 77 Oxygen 77 Rapid-acting inhaled β2-agonists 77 Epinephrine 77 Additional bronchodilators 77 Systemic glucocorticosteroids 77 Inhaled glucocorticosteroids 78 Magnesium 78 Helium oxygen therapy 78 Leukotriene modifiers 78 Sedatives 78 Criteria for Discharge from the Emergency   Department vs. Hospitalization 78COMPONENT 5: SPECIAL CONSIDERATIONS 80  Pregnancy 80 Obesity 80  Surgery 80  Rhinitis, Sinusitis, and Nasal Polyps 81 Rhinitis 81 Sinusitis 81 Nasal polyps 81  Occupational Asthma 81  Respiratory Infections 81  Gastroesophageal Reflux 82  Aspirin-Induced Asthma 82  Anaphylaxis and Asthma 83REFERENCES 83CHAPTER 5. IMPLEMENTATION OF ASTHMA  GUIDELINES IN HEALTH SYSTEMS 104KEY POINTS 105INTRODUCTION 105GUIDELINE IMPLEMENTATION STRATEGIES 105ECONOMIC VALUE OF INTERVENTIONS AND  GUIDELINE IMPLEMENTATION IN ASTHMA 106 Utilization and Cost of Health Care Resources 107 Determining the Economic Value of Interventions in Asthma 107GINA DISSEMINATION/IMPLEMENTATION RESOURCES 108REFERENCES 108COPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE
  8. 8. viBackground: When the Global Initiative for Asthma(GINA) program was initiated in 1993, the primary goalwas to produce recommendations for the management ofasthma based on the best scientific information available.Its first report, NHLBI/WHO Workshop Report: GlobalStrategy for Asthma Management and Prevention wasissued in 1995 and revised in 2002 and 2006. In 2002and in 2006 revised documents were prepared based onpublished research.The GINA Science Committee2was established in 2002to review published research on asthma managementand prevention, to evaluate the impact of this researchon recommendations in the GINA documents related tomanagement and prevention, and to post yearly updateson the GINA website. Its members are recognizedleaders in asthma research and clinical practice withthe scientific credentials to contribute to the task of theCommittee, and are invited to serve for a limited periodand in a voluntary capacity. The Committee is broadlyrepresentative of adult and pediatric disciplines as wellfrom diverse geographic regions.Updates of the 2006 report have been issued inDecember of each year with each update based on theimpact of publications from July 1 of the previous yearthrough June 30 of the year the update was completed.Posted on the website along with the updateddocuments is a list of all the publications reviewed by theCommittee.Process: To produce the updated documents a PubMed search is done using search fields established bythe Committee: 1) asthma, All Fields, All ages, only itemswith abstracts, Clinical Trial, Human, sorted by Authors;and 2) asthma AND systematic, All fields, ALL ages, onlyitems with abstracts, Human, sorted by author. The firstsearch includes publications for July 1-December 30 forreview by the Committee during the ATS meeting. Thesecond search includes publications for January 1 – June30 for review by the Committee during the ERS meeting.(Publications that appear after June 30 are consideredin the first phase of the following year.) To ensurepublications in peer review journals not captured bythis search methodology are not missed, the respiratorycommunity is invited to submit papers to the Chair, GINAScience Committee, providing an abstract and the fullpaper are submitted in (or translated into) English.All members of the Committee receive a summary ofcitations and all abstracts. Each abstract is assigned toat least two Committee members, although all membersare offered the opportunity to provide an opinion onall abstracts. Members evaluate the abstract or, up toher/his judgment, the full publication, and answer fourspecific written questions from a short questionnaire, andto indicate if the scientific data presented impacts onrecommendations in the GINA report. If so, the memberis asked to specifically identify modifications that shouldbe made.The entire GINA Science Committee meets twice yearlyto discuss each publication that was considered by atleast 1 member of the Committee to potentially havean impact on the management of asthma. The fullCommittee then reaches a consensus on whether toinclude it in the report, either as a reference supportingcurrent recommendations, or to change the report. In theabsence of consensus, disagreements are decided byan open vote of the full Committee. Recommendationsby the Committee for use of any medication are basedon the best evidence available from the literature andnot on labeling directives from government regulators.The Committee does not make recommendations fortherapies that have not been approved by at least oneregulatory 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 GINAreport. The changes prompted by these publicationswere posted on the website in December 2012. Thesewere either: A) modifying, that is, changing the text orintroducing a concept requiring a new recommendationto the report; or B) confirming, that is, adding to orreplacing an existing reference.Methodology and Summary of New RecommendationsGlobal Strategy for Asthma Management and Prevention:2012 Update11The 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 websitewww.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.COPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE
  9. 9. viiSUMMARY OF RECOMMENDATIONS IN THE 2013UPDATEA. 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 asthmaand compared with salmeterol, doubling the dose ofinhaled glucocorticosteroid and as add-on to inhaledglucocorticosteroids and salmeterol231,233. One studyshowed comparable bronchodilator effects with nosignificant changes on asthma control232. Another studyshowed that adding tiotropium to patients not controlledon inhaled glucocorticosteroids and long-acting ß2-agonists improved lung function but not symptoms233.The studies have been relatively short-term and no effecton exacerbations has so far been reported. There are nodata about these medications in children.Reference 231: Peters SP, Kunselman SJ, Icitovic N,Moore WC, Pascual R, Ameredes BT et al. NationalHeart, Lung, and Blood Institute Asthma ClinicalResearch Network. Tiotropium bromide step-up therapyfor adults with uncontrolled asthma. N Engl J Med2010;363:1715-26.Reference 232: Kerstjens HA, Disse B, Schroder-BaboW, Bantje TA, Gahlemann M, Sigmund R, Engel M,van Noord JA. Tiotropium improves lung function inpatients with severe uncontrolled asthma: a randomizedcontrolled trial. J Allergy Clin Immunol. 2011Aug;128(2):308-14.Reference 233: Bateman ED, Kornmann O, SchmidtP, Pivovarova A, Engel M, Fabbri LM. Tiotropium isnoninferior to salmeterol in maintaining improved lungfunction in B16-Arg/Arg patients with asthma. J AllergyClin Immunol. 2011 Aug;128(2):315-22.Page 34, right column, insert line 15: …. although thiswas not confirmed in all studies235.Reference 235: Hanania NA, Alpan O, Hamilos DL, etal. Omalizumab in severe allergic asthma inadequatelycontrolled with standard therapy: a randomized trial. AnnInternal Med 2011;154:573-82.Page 38, left column, first paragraph, add sentence andreference: A systematic review of yoga interventionsfor asthma found no convincing evidence of benefit; thequality of studies was generally poor236.Reference 236. Posadzki P, Ernst E. Yoga for asthma? Asystematic review of randomized clinical trials. J Asthma.2011 Aug;48(6):632-9.Page 38, right column, last paragraph, add statementand reference: although spacer devices or face masksdiffer in their drug delivery, and therefore may not beinterchangeable237.Reference 237. Lavorini F, Fontana GA. Targeting drugsto the airways: The role of spacer devices. Expert OpinDrug Deliv 2009;6:91-102.Page 40, left column, first paragraph replace with: Theclinical benefits of intermittent systemic or inhaledglucocorticosteroids for children with intermittent, viral-induced wheeze remain controversial. A one-year studyof intermittent treatment with inhaled glucocorticosteroidswas equally effective as daily treatment, and reducedthe total glucocorticosteroid dose threefold in preschoolchildren with frequent wheezing and a high asthmapredictive index238. Some studies in older children foundsmall benefits while another study in young childrenfound no effects on wheezing symptoms139. There is noevidence to support the use of maintenance low-doseinhaled glucocorticosteroids for preventing early transientwheezing136, 139, 199.Reference 238: Zeiger RS, Mauger D, Bacharier LB,Guilbert TW, Martinez FD, Lemanske RF Jr, et al; CARENetwork of the National Heart, Lung, and Blood Institute.Daily or intermittent budesonide in preschool childrenwith recurrent wheezing. N Engl J Med. 2011 Nov24;365(21):1990-2001Page 40, Figure 3-5, bullet 6: Modify age range to 2-10years; add reference in figure title.Reference 239: Guilbert TW, Mauger DT, Allen DB,Zeiger RS, Lemanske RF Jr, Szefler SJ, et al; ChildhoodAsthma Research and Education Network of theNational Heart, Lung, and Blood Institute. Growth ofpreschool children at high risk for asthma 2 years afterdiscontinuation of fluticasone. J Allergy Clin Immunol.2011 Nov;128(5):956-63.Page 71, right column, replace second bullet and addreference: Investigate and confirm adherence withtreatment. Incorrect or inadequate use of medicationsand inhalers405remains the most common reason forfailure to achieve good control. In patients with difficult-to-treat asthma, improved adherence and improvedhealth outcomes can be achieved with a comprehensiveconcordance 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.COPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE
  10. 10. viiiPage 72, left column insert in last paragraph: Extendedfollow-up on a small number of patients has providedsome additional support for long-term safety of bronchialthermoplasty417. However, longer-term follow-up oflarger number of control and active patients is neededto assess effectiveness and caution should be used inselecting patients for this procedure.Reference 417: Castro M, Rubin A, Laviolette M,Hanania NA, Armstrong B, Cox G; AIR2 Trial StudyGroup. Persistence of effectiveness of bronchialthermoplasty in patients with severe asthma. AnnAllergy 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 nasalcannulae, by mask, or rarely by head box in someinfants. For severe asthma exacerbations, controlledoxygen therapy using pulse oximetry to maintainoxygen saturation at 90 – 93% is associated with betterphysiological outcomes, compared to high flow 100%oxygen therapy218, 419. Oxygen therapy should be titratedagainst pulse oximetry to maintain a satisfactory oxygensaturation219. However, oxygen should not be withheld ifoximetry is not available.Reference 419. Perrin K, Wijesinghe M, Healy B,Wadsworth K, Bowditch R, Bibby S, Baker T, WeatherallM, Beasley R. Randomised controlled trial of highconcentration versus titrated oxygen therapy in severeexacerbations of asthma. Thorax. 2011Nov;66(11):937-41.Page 78, left column, end of first paragraph, insert textand reference: Two days of oral dexamethasone canalso be used to treat asthma exacerbations, but there areconcerns about metabolic side-effects if dexamethasoneis continued beyond two days420. Evidence suggeststhat there is no benefit to tapering the dose of oralglucocorticosteroids, either in the short-term245or overseveral weeks, as long as the patient is on maintenanceinhaled glucocorticosteroids246(Evidence B).Reference 420: Kravitz J, Dominici P, Ufberg J, Fisher J,Giraldo P. Two days of dexamethasone versus 5 days ofprednisone in the treatment of acute asthma: arandomized controlled trial. Ann Emerg Med. 2011Aug;58(2):200-4.Page 82, right column, paragraph 2, insert in line 4: …inadults392-394or in children422.Reference 422. Holbrook JT, Wise RA, Gold BD,Blake K, Brown ED, Castro M, Dozor AJ, et al. WritingCommittee for the American Lung Association AsthmaClinical Research Centers. Lansoprazole for children withpoorly controlled asthma: a randomized controlled trial.JAMA. 2012 Jan 25;307(4):373-81.B. References that provided confirmation or update ofprevious 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, McKeeverTM. Prenatal and passive smoke exposure and incidenceof asthma and wheeze: systematic review and meta-analysis. Pediatrics. 2012 Apr;129(4):735-44.Page 33, right column, insert reference 234 afterreference 215.Reference 234: Kemp J, Armstrong L, Wan Y,Alagappan VK, Ohlssen D, Pascoe S. Safety offormoterol in adults and children with asthma: ameta-analysis. Ann Allergy Asthma Immunol. 2011Jul;107(1):71-8.Page 41, right column, line 10, insert reference 234 afterreference 75, and in line 17, after reference 169.Reference 234: Kemp J, Armstrong L, Wan Y,Alagappan VK, Ohlssen D, Pascoe S. Safety offormoterol in adults and children with asthma: ameta-analysis. Ann Allergy Asthma Immunol. 2011Jul;107(1):71-8.Page 57, right column, last paragraph, insert reference414 after reference 22.Reference 414: Shah S, Sawyer SM, Toelle BG, MellisCM, Peat JK, Lagleva M, Usherwood TP, Jenkins CR.Improving paediatric asthma outcomes in primary healthcare: a randomised controlled trial. Med J Aust. 2011 Oct3;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-yearfollow-up of the PIAMA intervention study assessing theeffect of mite-impermeable mattress covers. Allergy. 2012Feb;67(2):248-56Page 73, right column end of first paragraph insertreference 418 after reference 349.Reference 418: Ortega H, Miller DP, Li H.Characterization of asthma exacerbations in primary careusing cluster analysis. J Asthma. 2012 Mar;49(2):158-69.Page 81, right column, last sentence under section onOccupational Asthma, insert insert (See also reference 421).COPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE
  11. 11. ixReference 421: Fishwick D, Barber CM, Bradshaw LM,Ayres JG, Barraclough R, Burge S, et al. Standards ofcare for occupational asthma: an update. Thorax. 2012Mar;67(3):278-80.C. Inserts to add clarification or additional informationPage 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 ofasthma. In addition, atopy also predicts that asthma maybe more severe when it does develop.Page 32, left column last paragraph: correct dose to 1000ug/dayPage 64, under heading of obesity, insert: ...including bybariatric surgery.COPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE
  12. 12. xAsthma is a serious public health problem throughout theworld, affecting people of all ages. When uncontrolled,asthma can place severe limits on daily life, and issometimes fatal.In 1993, the Global Initiative for Asthma (GINA) wasformed. Its goals and objectives were described in a 1995NHLBI/WHO Workshop Report, Global Strategy for AsthmaManagement and Prevention. This Report (revised in 2002and 2006), and its companion documents, have beenwidely distributed and translated into many languages.A network of individuals and organizations interested inasthma care has been created and several country-specificasthma management programs have been initiated.Yet much work is still required to reduce morbidity andmortality from this chronic disease.In 2006, the Global Strategy for Asthma Management andPrevention was revised to emphasize asthma managementbased on clinical control, rather than classification ofthe patient by severity. This important paradigm shift forasthma care reflected the progress made in pharmacologiccare of patients. Many asthma patients are receiving, orhave received, some asthma medications. The role ofthe health care professional is to establish each patient’scurrent level of treatment and control, then adjusttreatment to gain and maintain control. Asthma patientsshould experience no or minimal symptoms (includingat night), have no limitations on their activities (includingphysical exercise), have no (or minimal) requirement forrescue medications, have near normal lung function, andexperience only very infrequent exacerbations.The recommendations for asthma care based onclinical control described in the 2006 report have beenupdated annually. This 2011 update reflects a number ofmodifications, described in “Methodology and Summary ofNew Recommendations.” As with all previous GINA reports,levels of evidence (Table A) are assigned to managementrecommendations where appropriate in Chapter 4, the FiveComponents of Asthma Management. Evidence levels areindicated in boldface type enclosed in parentheses after therelevant statement—e.g., (Evidence A).FUTURE CHALLENGESIn spite of laudable efforts to improve asthma care over thepast decade, a majority of patients have not benefited fromadvances in asthma treatment and many lack even therudiments of care. A challenge for the next several yearsis to work with primary health care providers and publichealth officials in various countries to design, implement,and evaluate asthma care programs to meet local needs.The GINA Board of Directors recognizes that this is adifficult task and, to aid in this work, has formed severalgroups of global experts, including: a Dissemination andImplementation Committee; the GINA Assembly, a networkof individuals who care for asthma patients in manydifferent health care settings; and two regional programs,GINA Mesoamerica and GINA Mediterranean. These effortsaim to enhance communication with asthma specialists,primary-care health professionals, other health careworkers, and patient support organizations. The Board ofDirectors continues to examine barriers to implementationof the asthma management recommendations, especiallythe challenges that arise in primary-care settings and indeveloping countries.While early diagnosis of asthma and implementation ofappropriate therapy significantly reduce the socioeconomicburdens of asthma and enhance patients’ quality of life,medications continue to be the major component of thecost of asthma treatment. For this reason, the pricing ofasthma medications continues to be a topic for urgentneed and a growing area of research interest, as this hasimportant implications for the overall costs of asthmamanagement. Moreover, a large segment of the world’spopulation lives in areas with inadequate medical facilitiesand meager financial resources. The GINA Board ofDirectors recognizes that “fixed” international guidelinesand “rigid” scientific protocols will not work in manylocations. Thus, the recommendations found in this Reportmust be adapted to fit local practices and the availability ofhealth care resources.As the GINA Board of Directors expand their work, everyeffort will be made to interact with patient and physiciangroups at national, district, and local levels, and in multiplehealth care settings, to continuously examine new andinnovative approaches that will ensure the delivery of thebest asthma care possible. GINA is a partner organizationin a program launched in March 2006 by the WorldHealth Organization, the Global Alliance Against ChronicRespiratory Diseases (GARD). Through the work of theGINA Board of Directors, and in cooperation with GARD,progress toward better care for all patients with asthmashould be substantial in the next decade.INTRODUCTIONCOPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE
  13. 13. xiTable A. Description of Levels of EvidenceEvidenceCategorySources of Evidence DefinitionA Randomized controlledtrials (RCTs). Rich bodyof data.Evidence is from endpoints of well designed RCTs that provide a consistentpattern of findings in the population for which the recommendation is made.Category A requires substantial numbers of studies involving substantial numbersof participants.B Randomized controlledtrials (RCTs). Limitedbody of data.Evidence is from endpoints of intervention studies that include only a limitednumber of patients, posthoc or subgroup analysis of RCTs, or meta-analysis ofRCTs. In general, Category B pertains when few randomized trials exist, they aresmall in size, they were under-taken in a population that differs from the targetpopulation 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 fromobservational studies.D Panel consensus judg-ment.This category is used only in cases where the provision of some guidance wasdeemed valuable but the clinical literature addressing the subject was insufficientto justify placement in one of the other categories. The Panel Consensus isbased on clinical experience or knowledge that does not meet the above listedcriteria.COPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE
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  15. 15. CHAPTER1DEFINITIONANDOVERVIEWCOPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE
  16. 16. 2 DEFINITION AND OVERVIEWKEY POINTS:• Asthma is a chronic inflammatory disorder of theairways in which many cells and cellular elementsplay a role. The chronic inflammation is associatedwith airway hyperresponsiveness that leads torecurrent episodes of wheezing, breathlessness,chest tightness, and coughing, particularly at nightor in the early morning. These episodes are usuallyassociated with widespread, but variable, airflowobstruction within the lung that is often reversibleeither spontaneously or with treatment.• Clinical manifestations of asthma can be controlledwith appropriate treatment. When asthma iscontrolled, there should be no more than occasionalflare-ups and severe exacerbations should be rare.• Asthma is a problem worldwide, with an estimated300 million affected individuals.• Although from the perspective of both the patient andsociety the cost to control asthma seems high, thecost of not treating asthma correctly is even higher.• A number of factors that influence a person’s risk ofdeveloping asthma have been identified. These canbe divided into host factors (primarily genetic) andenvironmental factors.• The clinical spectrum of asthma is highly variable,and different cellular patterns have been observed,but the presence of airway inflammation remains aconsistent feature.This chapter covers several topics related to asthma,including definition, burden of disease, factors thatinfluence the risk of developing asthma, and mechanisms.It is not intended to be a comprehensive treatment ofthese topics, but rather a brief overview of the backgroundthat informs the approach to diagnosis and managementdetailed in subsequent chapters. Further details are foundin the reviews and other references cited at the end of thechapter.Asthma is a disorder defined by its clinical, physiological,and pathological characteristics. The predominant featureof the clinical history is episodic shortness of breath,particularly at night, often accompanied by cough.Wheezing appreciated on auscultation of the chest is themost common physical finding.The main physiological feature of asthma is episodic airwayobstruction characterized by expiratory airflow limitation.The dominant pathological feature is airway inflammation,sometimes associated with airway structural changes.Asthma has significant genetic and environmentalcomponents, but since its pathogenesis is not clear, muchof its definition is descriptive. Based on the functionalconsequences of airway inflammation, an operationaldescription of asthma is:Asthma is a chronic inflammatory disorder of the airwaysin which many cells and cellular elements play a role.The chronic inflammation is associated with airwayhyperresponsiveness that leads to recurrent episodes ofwheezing, breathlessness, chest tightness, and coughing,particularly at night or in the early morning. Theseepisodes are usually associated with widespread, butvariable, airflow obstruction within the lung that is oftenreversible either spontaneously or with treatment.Because there is no clear definition of the asthmaphenotype, researchers studying the development ofthis complex disease turn to characteristics that canbe measured objectively, such as atopy (manifested asthe presence of positive skin-prick tests or the clinicalresponse to common environmental allergens), airwayhyperresponsiveness (the tendency of airways to narrowexcessively in response to triggers that have little orno effect in normal individuals), and other measures ofallergic sensitization. Although the association betweenasthma and atopy is well established, the precise linksbetween these two conditions have not been clearly andcomprehensively defined.There is now good evidence that the clinical manifestationsof asthma—symptoms, sleep disturbances, limitationsof daily activity, impairment of lung function, and use ofrescue medications—can be controlled with appropriatetreatment. When asthma is controlled, there should be nomore than occasional recurrence of symptoms and severeexacerbations should be rare1.DEFINITIONCOPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE
  17. 17. DEFINITION AND OVERVIEW 3Prevalence, Morbidity, and MortalityAsthma is a problem worldwide, with an estimated 300million affected individuals2,3. Despite hundreds of reportson the prevalence of asthma in widely differing populations,the lack of a precise and universally accepted definition ofasthma makes reliable comparison of reported prevalencefrom different parts of the world problematic. Nonetheless,based on the application of standardized methods tomeasure the prevalence of asthma and wheezing illness inchildren4and adults, it appears that the global prevalenceof asthma ranges from 1% to 18% of the population indifferent countries (Figure 1-1)2,3. There is good evidencethat international differences in asthma symptomprevalence have been reduced, particularly in the 13-14year age group, with decreases in prevalence in NorthAmerica and Western Europe and increases in prevalencein regions where prevalence was previously low. Althoughthere was little change in the overall prevalence of currentwheeze, the percentage of children reported to have hadasthma increased significantly, possibly reflecting greaterawareness of this condition and/or changes in diagnosticpractice. The increases in asthma symptom prevalencein Africa, Latin America and parts of Asia indicate thatthe global burden of asthma is continuing to rise, butthe global prevalence differences are lessening118. TheWorld Health Organization has estimated that 15 milliondisability-adjusted life years (DALYs) are lost annually dueto asthma, representing 1% of the total global diseaseburden2. Annual worldwide deaths from asthma havebeen estimated at 250,000 and mortality does not appearto correlate well with prevalence (Figure 1-1)2,3. Thereare insufficient data to determine the likely causes of thedescribed variations in prevalence within and betweenpopulations.Social and Economic BurdenSocial and economic factors are integral to understandingasthma and its care, whether viewed from the perspectiveof the individual sufferer, the health care professional,or entities that pay for health care. Absence from schooland days lost from work are reported as substantial socialand economic consequences of asthma in studies fromthe Asia-Pacific region, India, Latin America, the UnitedKingdom, and the United States9-12.The monetary costs of asthma, as estimated in a variety ofhealth care systems including those of the United States13-15and the United Kingdom16are substantial. In analyses ofeconomic burden of asthma, attention needs to be paid toboth direct medical costs (hospital admissions and cost ofmedications) and indirect, non-medical costs (time lost fromwork, premature death)17. For example, asthma is a majorcause of absence from work in many countries4-6, includingAustralia, Sweden, the United Kingdom, and the UnitedStates2,3,18,19. Comparisons of the cost of asthma in differentregions lead to a clear set of conclusions:• The costs of asthma depend on the individual patient’slevel of control and the extent to which exacerbationsare avoided.• Emergency treatment is more expensive than plannedtreatment.• Non-medical economic costs of asthma are substantial.Guideline-determined asthma care can be costeffective.Families can suffer from the financial burdenof treating asthma.Although from the perspective of both the patient andsociety the cost to control asthma seems high, the costof not treating asthma correctly is even higher119. Propertreatment of the disease poses a challenge for individuals,health care professionals, health care organizations, andgovernments. There is every reason to believe that thesubstantial global burden of asthma can be dramaticallyreduced through efforts by individuals, their health careproviders, health care organizations, and local and nationalgovernments to improve asthma control.Detailed reference information about the burden of asthmacan be found in the report Global Burden of Asthma*.Further studies of the social and economic burden ofasthma and the cost effectiveness of treatment are neededin both developed and developing countries.THE BURDEN OF ASTHMAFigure 1-1. Asthma Prevalence and Mortality2, 3Permission for use of this figure obtained from J. Bousquet.*(http://www.ginasthma.org/ReportItem.asp?I1=2&I2=2&intld=94COPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE
  18. 18. 4 DEFINITION AND OVERVIEWFactors that influence the risk of asthma can be dividedinto those that cause the development of asthma andthose that trigger asthma symptoms; some do both. Theformer include host factors (which are primarily genetic)and the latter are usually environmental factors (Figure1-2)21. However, the mechanisms whereby they influencethe development and expression of asthma are complexand interactive. For example, genes likely interact both withother genes and with environmental factors to determineasthma susceptibility22,23. In addition, developmentalaspects—such as the maturation of the immune responseand the timing of infectious exposures during the first yearsof life—are emerging as important factors modifying the riskof asthma in the genetically susceptible person.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 ofasthma 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 as exposureto 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 less welldefined.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., airwayhyperresponsiveness, atopy, and allergic sensitization)are themselves products of complex gene-environmentinteractions and are therefore both features of asthma andrisk factors for the development of the disease.Host FactorsGenetic. 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 asthmahas focused 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 Th1and Th2 immune responses (as relevant to the hygienehypothesis of asthma)26. Family studies and case-control association analyses have identified a numberof chromosomal regions associated with asthmasusceptibility. For example, a tendency to produce anelevated level of total serum IgE is co-inherited with airwayhyperresponsiveness, and a gene (or genes) governingairway hyperresponsiveness is located near a major locusthat regulates serum IgE levels on chromosome 5q27.However, the search for a specific gene (or genes) involvedin susceptibility to atopy or asthma continues, as results todate have been inconsistent24,25.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 differencesin subjects’ responses to β2-agonists28. Other genes ofinterest modify the responsiveness to glucocorticosteroids29and leukotriene modifiers30. These genetic markers willlikely become important not only as risk factors in thepathogenesis of asthma but also as determinants ofresponsiveness to treatment28,30-33.FACTORS INFLUENCING THEDEVELOPMENT AND EXPRESSIONOF ASTHMAFactors 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 AsthmaHOST FACTORSGenetic, e.g.,Genes pre-disposing to atopyGenes pre-disposing to airway hyperresponsivenessObesitySexENVIRONMENTAL FACTORSAllergensIndoor: Domestic mites, furred animals (dogs, cats,mice), cockroach allergen, fungi, molds, yeastsOutdoor: Pollens, fungi, molds, yeastsInfections (predominantly viral)Occupational sensiti ersTobacco smokePassive smokingActive smokingOutdoor/Indoor Air PollutionDietAdditionally, 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 ofasthma 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 FactorsGenetic. 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 in4 DEFINITION AND OVERVIEWFACTORS INFLUENCING THEDEVELOPMENT AND EXPRESSIONOF ASTHMAFactors 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 AsthmaHOST FACTORSGenetic, e.g.,Genes pre-disposing to atopyGenes pre-disposing to airway hyperresponsivenessObesitySexENVIRONMENTAL FACTORSAllergensIndoor: Domestic mites, furred animals (dogs, cats,mice), cockroach allergen, fungi, molds, yeastsOutdoor: Pollens, fungi, molds, yeastsInfections (predominantly viral)Occupational sensitizersTobacco smokePassive smokingActive smokingOutdoor/Indoor Air PollutionDietAdditionally, 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 ofasthma 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 FactorsGenetic. 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 in4 DEFINITION AND OVERVIEWFACTORS INFLUENCING THEDEVELOPMENT AND EXPRESSIONOF ASTHMAFactors 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 AsthmaHOST FACTORSGenetic, e.g.,Genes pre-disposing to atopyGenes pre-disposing to airway hyperresponsivenessObesitySexENVIRONMENTAL FACTORSAllergensIndoor: Domestic mites, furred animals (dogs, cats,mice), cockroach allergen, fungi, molds, yeastsOutdoor: Pollens, fungi, molds, yeastsInfections (predominantly viral)Occupational sensiti ersTobacco smokePassive smokingActive smokingOutdoor/Indoor Air PollutionDietAdditionally, 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 ofasthma 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 FactorsGenetic. 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 inCOPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE
  19. 19. DEFINITION AND OVERVIEW 5Obesity. Asthma is more frequently observed in obesesubjects (Body Mass Index > 30 kg/m2) and is more difficultto control124-127,134. Obese people with asthma have lowerlung function and more co-morbidities compared withnormal weight people with asthma131. The use of systemicglucocorticosteroids and a sedentary lifestyle may promoteobesity in severe asthma patients, but in most instances,obesity precedes the development of asthma.How obesity promotes the development of asthma isstill uncertain but it may result from the combined effectsof various factors. It has been proposed that obesitycould influence airway function due to its effect on lungmechanics, development of a pro-inflammatory state, inaddition to genetic, developmental, hormonal or neurogenicinfluences35,129,130. In this regard, obese patients have areduced expiratory reserve volume, a pattern of breathingthat may possibly alter airway smooth muscle plasticity andairway function34. Furthermore, the release by adipocytesof various pro-inflammatory cytokines and mediators suchas interleukin-6, tumor necrosis factor (TNF)-α, eotaxin,and leptin, combined with a lower level of anti-inflammatoryadipokines in obese subjects can favor a systemicinflammatory state although it is unknown how this couldinfluence airway function131,132.Sex. Male sex is a risk factor for asthma in children. Priorto the age of 14, the prevalence of asthma is nearly twiceas great in boys as in girls36. As children get older thedifference between the sexes narrows, and by adulthoodthe prevalence of asthma is greater in women than in men.The reasons for this sex-related difference are not clear.However, lung size is smaller in males than in females atbirth37but larger in adulthood.Environmental FactorsThere is some overlap between environmental factorsthat influence the risk of developing asthma, and factorsthat cause asthma symptoms—for example, occupationalsensitizers belong in both categories. However, there aresome important causes of asthma symptoms—such as airpollution and some allergens—which have not been clearlylinked to the development of asthma. Risk factors that causeasthma symptoms are discussed in detail in Chapter 4.2.Allergens. Although indoor and outdoor allergens are wellknown to cause asthma exacerbations, their specific role inthe development of asthma is still not fully resolved. Birth-cohort studies have shown that sensitization to house dustmite allergens, cat dander, dog dander38,39, and Aspergillusmold40are independent risk factors for asthma-likesymptoms in children up to 3 years of age. However, therelationship between allergen exposure and sensitization inchildren is not straightforward. It depends on the allergen,the dose, the time of exposure, the child’s age, andprobably genetics as well.For some allergens, such as those derived from house dustmites and cockroaches, the prevalence of sensitizationappears to be directly correlated with exposure38,41.However, although some data suggest that exposure tohouse dust mite allergens may be a causal factor in thedevelopment of asthma42, other studies have questionedthis interpretation43,44. Cockroach infestation has beenshown to be an important cause of allergic sensitization,particularly in inner-city homes45.In the case of dogs and cats, some epidemiologicstudies have found that early exposure to these animalsmay protect a child against allergic sensitization orthe development of asthma46-48, but others suggestthat such exposure may increase the risk of allergicsensitization47,49-51. This issue remains unresolved.The prevalence of asthma is reduced in children raisedin a rural setting, which may be linked to the presence ofendotoxin in these environments52.Infections. During infancy, a number of viruses have beenassociated with the inception of the asthmatic phenotype.Respiratory syncytial virus (RSV) and parainfluenzavirusproduce a pattern of symptoms including bronchiolitis thatparallel many features of childhood asthma53,54. A numberof long-term prospective studies of children admittedto the hospital with documented RSV have shown thatapproximately 40% will continue to wheeze or have asthmainto later childhood53. On the other hand, evidence alsoindicates that certain respiratory infections early in life,including measles and sometimes even RSV, may protectagainst the development of asthma55,56. The data do notallow specific conclusions to be drawn. Parasite infectionsdo not in general protect against asthma, but infection withhookworm may reduce the risk120.The “hygiene hypothesis” of asthma suggests thatexposure to infections early in life influences thedevelopment of a child’s immune system along a“nonallergic” pathway, leading to a reduced risk ofasthma and other allergic diseases. Although the hygienehypothesis continues to be investigated, this mechanismmay explain observed associations between family size,birth order, day-care attendance, and the risk of asthma.For example, young children with older siblings and thosewho attend day care are at increased risk of infections,but enjoy protection against the development of allergicdiseases, including asthma later in life57-59.COPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE
  20. 20. 6 DEFINITION AND OVERVIEWThe interaction between atopy and viral infections appearsto be a complex relationship60, in which the atopic state caninfluence the lower airway response to viral infections, viralinfections can then influence the development of allergicsensitization, and interactions can occur when individualsare exposed simultaneously to both allergens and viruses.Occupational sensitizers. Over 300 substances have beenassociated with occupational asthma61-65, which is definedas asthma caused by exposure to an agent encounteredin the work environment. These substances include highlyreactive small molecules such as isocyanates, irritants thatmay cause an alteration in airway responsiveness, knownimmunogens such as platinum salts, and complex plantand animal biological products that stimulate the productionof IgE (Figure 1-3).Occupational asthma arises predominantly in adults66, 67,and occupational sensitizers are estimated to cause about1 in 10 cases of asthma among adults of working age68.Asthma is the most common occupational respiratorydisorder in industrialized countries69. Occupationsassociated with a high risk for occupational asthma includefarming and agricultural work, painting (including 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 sensitization frequently occurshave been proposed for many occupational sensitizers.However, the factors that cause some people but notothers to develop occupational asthma in response tothe same 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 occupationalsensitization, 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 occupationalsensitizers.Tobacco smoke. Tobacco smoking is associated withaccelerated decline of lung function in people withasthma133, increases asthma severity, may render patientsless responsive to treatment with inhaled121,122andsystemic74glucocorticosteroids, and reduces the likelihoodof asthma being controlled75.Exposure to tobacco smoke both prenatally135,136andafter birth is associated with measurable harmfuleffects including a greater risk of developing asthma-like symptoms in early childhood. However, evidenceof increased risk of allergic diseases is uncertain77, 78.Distinguishing the independent contributions of prenataland postnatal maternal smoking is problematic79. However,studies of lung function immediately after birth have shownthat maternal smoking during pregnancy has an influenceon lung development37. Furthermore, infants of smokingmothers are 4 times more likely to develop wheezingillnesses in the first year of life79. In contrast, there is littleevidence (based on metaanalysis) that maternal smokingduring pregnancy has an effect on allergic sensitization78.Exposure to environmental tobacco smoke (passivesmoking) increases the risk of lower respiratory tractillnesses in infancy80and childhood81.Figure 1-3. Examples of Agents Causing Asthma inSelected Occupations*Occupation/occupational field AgentAnimal and Plant ProteinsBakers 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,papainGranary 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 larvaeInorganic chemicalsBeauticians PersulfatePlating Nickel saltsRefinery workers Platinum salts, vanadiumOrganic 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 agentsOccupational 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 includeothers 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 inhaled74,124and systemic75glucocorticosteroids, 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 ininfancy81and 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.Figure 1-3. Examples of Agents Causing Asthma inSelected Occupations*Occupation/occupational field AgentAnimal and Plant ProteinsBakers 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,papainGranary 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 larvaeInorganic chemicalsBeauticians PersulfatePlating Nickel saltsRefinery workers Platinum salts, vanadiumOrganic 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 agentsOccupational 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 includeothers 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 inhaled74,124and systemic75glucocorticosteroids, 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 ininfancy81and 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.COPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE
  21. 21. DEFINITION AND OVERVIEW 7Outdoor/indoor air pollution. The role of outdoor airpollution in causing asthma remains controversial82.Children raised in a polluted environment have diminishedlung function83, but the relationship of this loss of function tothe 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 sensitized84-86. However, the role of pollutants inthe development of asthma is less well defined. Similarassociations have been observed in relation to indoorpollutants, e.g., smoke and fumes from gas and biomassfuels used for heating and cooling, molds, and cockroachinfestations.Diet. The role of diet, particularly breast-feeding, in relationto the development of asthma has been extensively studiedand, in general, the data reveal that infants fed formulas ofintact cow’s milk or soy protein have a higher incidence ofwheezing illnesses in early childhood compared with thosefed breast milk87.Some data also suggest that certain characteristicsof Western diets, such as increased use of processedfoods and decreased antioxidant (in the form of fruits andvegetables), increased n-6 polyunsaturated fatty acid(found in margarine and vegetable oil), and decreased n-3polyunsaturated fatty acid (found in oily fish) intakes havecontributed to the recent increases in asthma and atopicdisease88.Asthma is an inflammatory disorder of the airways, whichinvolves several inflammatory cells and multiple mediatorsthat result in characteristic pathophysiological changes89.In ways that are still not well understood, this pattern ofinflammation is strongly associated with airway hyper-responsiveness and asthma symptoms.Airway Inflammation In AsthmaThe clinical spectrum of asthma is highly variable,and different cellular patterns have been observed,but the presence of airway inflammation remains aconsistent feature. The airway inflammation in asthmais persistent even though symptoms are episodic, andthe relationship between the severity of asthma and theintensity of inflammation is not clearly established90,91. Theinflammation affects all airways including in most patientsthe upper respiratory tract and nose but its physiologicaleffects are most pronounced in medium-sized bronchi. MECHANISMS OF ASTHMAFigure 1-4: Inflammatory Cells in Asthmatic AirwaysMast cells: Activated mucosal mast cells releasebronchoconstrictor mediators (histamine, cysteinyl leukotrienes,prostaglandin D2)92. 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 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 andairway 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 byB lymphocytes95. 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 cytokines96.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 cells97.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 response98.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 therapy99.Figure 1-5: Airway Structural Cells Involved in thePathogenesis of AsthmaAirway 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 cells100.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 inflammatoryneuropeptides101.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 cows 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 ASTHMAAsthma 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.Airway Inflammation In AsthmaThe 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 cows 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.Airway Inflammation In AsthmaFigure 1-4: Inflammatory Cells in Asthmatic AirwaysMast 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.COPYRIGHTEDMATERIAL-DONOTALTERORREPRODUCE

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