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Allergic vs. Non-Allergic Asthma

Allergic vs. Non-Allergic Asthma. Paul M O’Byrne EJ Moran Campbell Professor of Medicine Firestone Institute for Respiratory Health, St. Joseph’s Healthcare and McMaster University,Hamilton, Ontario , Canada. Potential for Conflict of Interest.

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Allergic vs. Non-Allergic Asthma

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  1. Allergic vs. Non-Allergic Asthma Paul M O’Byrne EJ Moran Campbell Professor of Medicine Firestone Institute for Respiratory Health, St. Joseph’s Healthcare and McMaster University,Hamilton, Ontario, Canada

  2. Potential for Conflict of Interest • Advisory Boards: AstraZeneca, GlaxoSmithKline, Merck, Nycomed, Resistentia, Topigen. • Speakers Fees:AstraZeneca, Chiesi, GlaxoSmithKline, Nycomed, Ono Pharma. • Grants-in-Aid:AstraZeneca, Alexion, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Medimmune, Merck, Pfizer, Schering Plough, Wyeth.

  3. Allergic vs. Non-Allergic Asthma Allergic Asthma Non-Allergic Asthma Adult onset Triggers often unknown Non-IgE mediated Non-allergic comorbidities T-cell dependence unclear Neutrophils involved Not responsive to ICS • Childhood onset • Allergic triggers • IgE mediated • Allergic co-morbidities • Th2 dependent • Mast cells, basophils, eosinophils involved. • Responsive to ICS

  4. What is Non-Allergic Asthma? Beeh KM, at al. Eur Respir J 2000; 16:609-14

  5. What is Non-Allergic Asthma? Beeh KM, at al. Eur Respir J 2000; 16:609-14

  6. Airway Inflammation in Non-Allergic Asthma EOSINOPHILS NEUTROPHILS Drews AC, at al. Eur Respir J 2009; 64:1597-1601

  7. Asthma Phenotypes Haldar P, et al. Am J Respir Crit Care Med 2008; 178:218-24

  8. Asthma Phenotypes Mild Atopic Moderate Atopic Non- Atopic Severe Atopic Severe Fixed AFO Moore W, et al. Am J Respir Crit Care Med 2010; in press

  9. ALLERGIC ASTHMA

  10. 8 0 8 4 4 -10 MCh PC 20 2 2 -20 (mg/ml) 1 1 .5 -30 .5 24h 2d 4d 7d 300 Sputum 200 Eosinophils 100 4 (x10 /ml) 0 20 15 Sputum MCC 10 5 4 (x10 /ml) 0 24h 2d 4d 7d Time Post Inhalation % Fall in FEV 1 Diluent Allergen * * * * * Baseline 7h * * * * * * Baseline 7h GAUVREAU GM et al Am J Resp Crit Care Med 1999: 160; 640-7

  11. 8 6 Sputum Basophils 4 4 2 (X10 /ml) 0 Baseline 7 hours 24 hours 0.20 0.15 Sputum Mast Cells 0.10 4 0.05 (X10 /ml) 0.00 Baseline 7 hours 24 hours Post Allergen Inhalation * Early Responders Dual Responders * * * * * GAUVREAU GM et al Am J Respir Crit Care Med 2000; 161: 1473-8

  12. Occupational Sensitizers Maestrelli P, et al. J Allergy Clin Immunol 2009; 123:531-42

  13. Occupational Sensitizers Mapp CE, et al. Am J Respir Crit Care Med 2005; 172:280-305

  14. Pharmacology of Allergen-Induced Responses TRUE POSITIVES TRUE NEGATIVES Esterase-sensitive steroids PAF antagonists Inhaled anti-LTs Thromboxane antagonists POSSIBLY TRUE NEGS ? selectin inhibitors ? VLA4 antagonists ? ISS • All conventional ICS • LABAs • Combination ICS/LABA • SABAs • Anti-LTs • Anti-IgE • Theophylline

  15. Pharmacology of Allergen-Induced Responses FALSE POSITIVES FALSE NEGATIVES Mepolizumab • Anti-CD11a • PGE2 • ? PDE4 antagonists • PGE1 analogue • ? Heparin derivitives

  16. Leigh R, et al. Am J Respir Crit Care Med 2002; 166: 1212-7

  17. Leigh R, et al. Am J Respir Crit Care Med 2002; 166:1212-7

  18. Leigh R, et al. Am J Respir Crit Care Med 2002; 166:1212-7

  19. Omalizumab in Severe Allergic Asthma Busse WW, et al. J Allergy Clin Immunol 2001; 108:184-90

  20. Lord Kelvin (1824-1907) “When you can measure what you are speaking about and express it in numbers, you know something about it; but when you cannot measure it, when you cannot express it in numbers, your knowledge is of a meager and unsatisfactory kind”.

  21. Induced Sputum Freddy Hargreave

  22. 120 BTS management group 100 80 Severe Exacerbations (number) 60 Sputum management group 40 20 0 0 2 4 6 8 10 12 Time (months) GREEN R, et al . LANCET 2002; 360: 1715-21

  23. LOMA study Jayaram L, et al. Eur Respir J 2006; 27:483-94

  24. Sputum and Blood Eosinophils Nair P, et al. N Engl J Med 2009; 360:985-93

  25. Prednisone Reduction n=9 n=10 100 80 prednisone reduction as % of maximum possible reduction 60 40 20 0 mepolizumab placebo p<0.05 Nair P, et al. N Engl J Med 2009; 360:985-93 .

  26. Asthma Exacerbations Nair P, et al. N Engl J Med 2009; 360:985-93 .

  27. Refractory Eosinophilic Asthma Haldar P et al. N Engl J Med 2009; 360:973-984

  28. Mepolizumab in Severe Asthma Haldar P et al. N Engl J Med 2009; 360:973-984

  29. CXCR2 Antagonists Holz O, et al. Eur Respir J 2010: in press

  30. Conclusions • IgE is necessary for the clinical expression of allergic asthma, but may have a role in all asthmatic patients. • Occupational asthma is a common cause of “non-allergic asthma” • Allergen-induced airway responses have been extensively studied, involve Th2 responses, mast cells, basophils and eosinophils. • Small molecular weight occupational sensitizers (particularly isocyanates) cause neutrophilic airway inflammation

  31. Conclusions • Omalizumab is the only specific therapy for allergic asthma. • Measuring sputum inflammatory cells is useful in establishing therapeutic responses to ICS. • Refractory eosinophilic asthma is improved by treatment with mepolizumab. • CXCR2 antagonists will be useful to establish the role of neutrophils in “non-allergic” asthma

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