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Asthma in Adults

Asthma in Adults. A/Prof Alan James Dept Pulmonary Physiology, Sir Charles Gairdner Hospital University Western Australia NHMRC Practitioner Fellow. Photo Sam James - Sydney. Asthma - Definition.

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Asthma in Adults

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  1. Asthmain Adults A/Prof Alan James Dept Pulmonary Physiology, Sir Charles Gairdner Hospital University Western Australia NHMRC Practitioner Fellow Photo Sam James - Sydney

  2. Asthma - Definition “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 and 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.” (Global Initiative for Asthma – GINA 2008) Variable symptoms and variable, excessive airway narrowing. There is no gold standard for diagnosis.

  3. Asthma - Pathology B Araujo et al. Eur Respir J 2008;32:61-69

  4. Airway Hyper-responsiveness

  5. Excessive Airway Narrowing James et al. ARRD 1992;146:895-9

  6. Lung Function Deficit and Decline in Asthma Males James A et al. AJRCCM 2005;171:109

  7. Lung Function and Severity are Stable from Child to Adult Lung function by classification at recruitment Phelan et al. JACI 2002;109:189-94

  8. Allergic sensitisation Perinatal influences Persistent Wheezers at Age 16 Years have Persistently Abnormal Lung Function Morgan et al. AJRCCM 2005;355:1253

  9. Airway Smooth Muscle

  10. Airway Smooth Muscle AreaRelated to Severity, not Duration n = 312 James et al. ERJ 2009;34:1040-5 James et al. ERJ 2009

  11. Airway Inflammation and Remodeling in Preschoolers Atopic Atopic S Saglani et al. AJRCCM 2007;176:858

  12. Inflammation and Remodeling

  13. Eosinophils and Neutrophils

  14. Mast Cells and Mucus Secretion

  15. Excessive Airway Narrowing

  16. Corticosteroids Relievers Pathophysiology and Treatment

  17. How Much Treatment ? Photo Sam James - Sydney

  18. Maintenance TreatmentAsthma Severity “Emergency Treatment of Asthma” S. Lazarus NEJM 2010;363:755 • Taylor DR, et al. Eur Respir J. 2008 Sep;32(3):545-54.

  19. Maintenance TreatmentAsthma Control • "Asthma control" refers to the extent to which the manifestationsof asthma have been reduced or removed by treatment - • Current clinical control(e.g. symptoms, reliever use and clinic lung function) • Futurerisk (e.g. exacerbations and rapid decline in lung function, side effects of treatment). • Taylor DR, et al. Eur Respir J. 2008 Sep;32(3):545-54.

  20. How Long to Treat ? Photo Sam James - Sydney

  21. Responses to Treatment Jenkins et al. Symptoms Lung Function Airway Responsiveness

  22. Asthma - Response to Treatment Haahtela et al NEJM 1994; 331: 700-705.

  23. Therapies Fail to Alter the Natural History of Lung Function in Asthma • Childhood Asthma Management Program* • > 1000 children 4-6 years age • Randomised: Budesonide, Nedocromil, Placebo • Age 6-8 years: 31-35% had FEV/FVC < LLN, regardless of treatment • Age 18 years: 52% had FEV/FVC < LLN Sub-group Analysis 60% of lung function deficit at 18 years were present at age 6-8 years 25% more rapid decline, not related to asthma severity Bai et al. Eur Respir J 2007 CAMP Research Group. NEJM 2000;343:1054

  24. Asthma – Persistent, Local Airway Inflammation • Long-term treatment required • Severity generally unchanged • Localised inflammation • Withdrawal of treatment often leads to recurrence • Inflammation present even when symptoms are absent • Use of induced sputum, eNO, AHR to monitor

  25. What’s New in Asthma? • Natural History • Role of Inflammation vs Airway Remodelling • Genetics • Monitoring Therapy • Neutrophilic Asthma • Macrolides, Omalizumab (IgE), Mepolizumab (IL-5) • Anti-tumour necrosis factor • Thermoplasty (Steam?) • Phenotyping!

  26. Omalizumab • Pooled data from seven studies • Omalizumab added to current therapy, compared with placebo (5 trials) or current therapy alone (2 trials) • N = 4308 patients (2511 with omalizumab), 93% severe peristent • Exacerbation rate reduced by 38% (p < 0.0001) • Emergency visits reduced by 47% (p < 0.0001) • Effect not related to patient age, gender, baseline IgE, dosing schedule (2 or 4 weeks) • More absolute benefit in more severe asthma (lower FEV1) Bousquet et al. Allergy 2005;60:302

  27. OmalizumabTrial in Inner-City Children • Children, adolescents and young adults (n = 419) • 73% with moderate or severe disease • Omalizumab added to current therapy, 60 weeks • Outcomes – asthma symptoms • Days with symptoms decreased by 24% (p < 0.001) • Exacerbations reduced 49% to 30% of subjects (p < 0.001) • Reduced use of ICS and LABAs • Effect greatest in those sensitised and exposed to cockroach or house dust mite Busse et al. NEJM 2011;364:1005

  28. Leukotriene Receptor Antagonists • Montelukast, zafirlukast, pranlukast - block leukotrienes (LT) C4, D4, E4 • Onset – 6 hours (oral), maximal effect – days • Reduce eosinophils in blood • Less consistent effect on airway inflammation • Add-on therapy to ICS (less effective than ICS) • May have a role in acute asthma as add-on therapy • Zileuton – block LT B4, C4, D4, E4, - Churg-Strauss S.

  29. Treatment of Remodeling • Thermoplasty • Pharmacological - ?

  30. Genetics in Asthma Genome-wide Association ORMLD 3 Moffat et al. Nature July 2007

  31. Asthma Phenotype A Population Study: Cases #1 and #2 “Has a doctor ever told you that you have asthma?” Yes Wheeze in last 12 months? Yes Symptoms with exercise? Yes Ever smoked cigarettes? No Use asthma medications? Yes FEV1 post b/d > 80% Yes AHR - PC20 < 8umol methacholine Yes

  32. Case #1

  33. Asthma – Case #1 Age 27 Asthma onset < 5 years of age Occupation – lawyer in a city practice Intermittent symptoms well controlled with ICS plus LABA Otherwise well

  34. Case #2

  35. Asthma – Case #2 Age 65 Asthma onset 45 years of age Occupation – farmer Frequent symptoms, partly controlled with ICS plus LABA BMI = 45 History of reflux, sleep apnoea, diabetes, hypertension, coronary artery disease... Otherwise well

  36. Cluster Analysis

  37. Clinical phenotypes of asthma. A summary of phenotypes identified using cluster analysis in primary- and secondary-care asthma populations.

  38. Busselton Cluster Phenotypes

  39. Non-eosinophilic asthma: importance and possible mechanismsDouwes J et al Thorax 2002;57:643-648 Pathways leading to IL-5 mediated eosinophil inflammation (Acquired) or IL-8 mediated neutrophil inflammation (Innate) and asthma. Receptors for triggers (FcRI, FcRII, TLR4, CD14) and transcription factors (NFAT, API, GATA, NF-{kappa}B) are intermediate steps.

  40. Macrolides in AsthmaMeta-Analysis “Not enough evidence to recommend as treatment for asthma.” (Recheldi et al. Cochrane Data Syst Rev 2005;Issue, 4:CD002997)

  41. ‘AMAZES’ Double-blind, randomised, placebo-controlled trial of azithromycin 500mg three times a week in patients with asthma who are symptomatic on ICS, or LABA + ICS

  42. Management of Asthma – My way • Patient’s history of asthma • Consider diagnosis • Assess Severity – in past and more recently • Address patient questions • Educate - treatment in relation to natural history • Consider further investigation – eNO, sputum, AHR • Aim for complete control before reducing • Reassess - 2-4 weeks, 3 months, 6-12 months - monitor symptoms (ACQ), FEV, other

  43. IN ACQ > 1.0 - despite adequate therapy Variable airflow - AHR, B/D >12% or 200ml Stable for 4 weeks OUT FEV1 < 1.3L Smokers Current Rx macros/ tetras Hypersensitivity Pregnant Other resp. disease Emphysema (DLCO<75%) AMAZES - Criteria Photos Sam James - Sydney

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