Allergic vs NonAllergic Asthma Paul M OByrne EJ
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 Mc. Master University, Hamilton, Ontario, Canada
Potential for Conflict of Interest • Advisory Boards: Astra. Zeneca, Glaxo. Smith. Kline, Merck, Nycomed, Resistentia, Topigen. • Speakers Fees: Astra. Zeneca, Chiesi, Glaxo. Smith. Kline, Nycomed, Ono Pharma. • Grants-in-Aid: Astra. Zeneca, Alexion, Boehringer Ingelheim, Genentech, Glaxo. Smith. Kline, Medimmune, Merck, Pfizer, Schering Plough, Wyeth.
Allergic vs. Non-Allergic Asthma • • • Childhood onset Allergic triggers Ig. E mediated Allergic co-morbidities Th 2 dependent Mast cells, basophils, eosinophils involved. • Responsive to ICS Non-Allergic Asthma • • • Adult onset Triggers often unknown Non-Ig. E mediated Non-allergic comorbidities T-cell dependence unclear • Neutrophils involved • Not responsive to ICS
What is Non-Allergic Asthma? Beeh KM, at al. Eur Respir J 2000; 16: 609 -14
What is Non-Allergic Asthma? Beeh KM, at al. Eur Respir J 2000; 16: 609 -14
Airway Inflammation in Non. Allergic Asthma EOSINOPHILS NEUTROPHILS Drews AC, at al. Eur Respir J 2009; 64: 1597 -1601
Asthma Phenotypes Haldar P, et al. Am J Respir Crit Care Med 2008; 178: 218 -24
Asthma Phenotypes Mild Atopic Moderate Atopic Non- Atopic Severe Fixed AFO Moore W, et al. Am J Respir Crit Care Med 2010; in press
ALLERGIC ASTHMA
Baseline 7 h 300 100 0 20 4 5 2 d 4 d 7 d 10 * 15 * Sputum MCC (x 10 /ml) 24 h * (x 10 /ml) 200 . 5 * 4 * Sputum Eosinophils Allergen 1 * -30 * . 5 -20 * 1 2 * (mg/ml) 4 -10 2 Diluent 8 * MCh PC 20 4 0 * 8 % Fall in FEV 1 0 24 h 2 d 4 d Time Post Inhalation 7 d GAUVREAU GM et al Am J Resp Crit Care Med 1999: 160; 640 -7
4 * * 4 (X 10 /ml) 6 Early Responders Dual Responders * Sputum Basophils * 8 Baseline 7 hours 24 hours Baseline 7 hours 2 0 * 0. 20 * 0. 15 Sputum Mast Cells 0. 10 4 (X 10 /ml) 0. 05 0. 00 24 hours Post Allergen Inhalation GAUVREAU GM et al Am J Respir Crit Care Med 2000; 161: 1473 -8
Occupational Sensitizers Maestrelli P, et al. J Allergy Clin Immunol 2009; 123: 531 -42
Occupational Sensitizers Mapp CE, et al. Am J Respir Crit Care Med 2005; 172: 280 -305
Pharmacology of Allergen-Induced Responses TRUE POSITIVES • All conventional ICS • LABAs • Combination ICS/LABA • SABAs • Anti-LTs • Anti-Ig. E • Theophylline TRUE NEGATIVES • Esterase-sensitive steroids • PAF antagonists • Inhaled anti-LTs • Thromboxane antagonists POSSIBLY TRUE NEGS • ? selectin inhibitors • ? VLA 4 antagonists • ? ISS
Pharmacology of Allergen-Induced Responses FALSE POSITIVES FALSE NEGATIVES • • • Mepolizumab Anti-CD 11 a PGE 2 ? PDE 4 antagonists PGE 1 analogue ? Heparin derivitives
Leigh R, et al. Am J Respir Crit Care Med 2002; 166: 1212 -7
Leigh R, et al. Am J Respir Crit Care Med 2002; 166: 1212 -7
Leigh R, et al. Am J Respir Crit Care Med 2002; 166: 1212 -7
Omalizumab in Severe Allergic Asthma Busse WW, et al. J Allergy Clin Immunol 2001; 108: 184 -90
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”.
Induced Sputum Freddy Hargreave
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
LOMA study Jayaram L, et al. Eur Respir J 2006; 27: 483 -94
Sputum and Blood Eosinophils Nair P, et al. N Engl J Med 2009; 360: 985 -93
Prednisone Reduction n=9 n=10 mepolizumab placebo 100 80 prednisone reduction as % of maximum possible reduction 60 40 20 0 p<0. 05 Nair P, et al. N Engl J Med 2009; 360: 985 -93.
Asthma Exacerbations Nair P, et al. N Engl J Med 2009; 360: 985 -93.
Refractory Eosinophilic Asthma Haldar P et al. N Engl J Med 2009; 360: 973 -984
Mepolizumab in Severe Asthma Haldar P et al. N Engl J Med 2009; 360: 973 -984
CXCR 2 Antagonists Holz O, et al. Eur Respir J 2010: in press
Conclusions • Ig. E 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 Th 2 responses, mast cells, basophils and eosinophils. • Small molecular weight occupational sensitizers (particularly isocyanates) cause neutrophilic airway inflammation
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. • CXCR 2 antagonists will be useful to establish the role of neutrophils in “non-allergic” asthma
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