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 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.

Allergic vs. Non-Allergic Asthma Childhood onset Allergic triggers IgE mediated Allergic co-morbidities Th2 dependent Mast cells, basophils, eosinophils involved. Responsive to ICS Adult onset Triggers often unknown Non-IgE 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 Atopic Severe Fixed AFO Moore W, et al. Am J Respir Crit Care Med 2010; in press

ALLERGIC ASTHMA This cartoon of a cross setion through an airway wall illustrates several factors that have been implicated in causing airway hyperresponsiveness. The point to be made here is that steroid treatment may reduce only the acute inflammatory events in the airway, but that airway hyperresponsiveness to MCh and Hist would still be present, dut to all of the other pathologic events, that may not be affected by steroids

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

* * * * * * Basophils Sputum Mast Cells Post Allergen Inhalation Baseline 7 hours 24 hours Post Allergen Inhalation 0.00 0.05 0.10 0.15 0.20 Sputum Mast Cells (X10 4 /ml) 2 6 8 Basophils * Early Responders Dual Responders * * * * * 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 TRUE NEGATIVES All conventional ICS LABAs Combination ICS/LABA SABAs Anti-LTs Anti-IgE Theophylline Esterase-sensitive steroids PAF antagonists Inhaled anti-LTs Thromboxane antagonists POSSIBLY TRUE NEGS ? selectin inhibitors ? VLA4 antagonists ? ISS

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

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 Numerous low-affinity bonds 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

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

Jayaram L, et al. Eur Respir J 2006; 27:483-94 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 as % of maximum possible reduction 100 80 prednisone reduction as % of maximum possible reduction 60 40 20 mepolizumab placebo p<0.05 Nair P, et al. N Engl J Med 2009; 360:985-93 .

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

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

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

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