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
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

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:

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
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

12. * * * * * * * * * * * 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;

13. * * * * * * 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:

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

15. Occupational Sensitizers
Mapp CE, et al. Am J Respir Crit Care Med 2005; 172:

16. 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

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

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

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

20. 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

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

22. Lord Kelvin ( )
“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”.

23. Induced Sputum
Freddy Hargreave

24. 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:

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

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

28. 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:

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

30. Refractory Eosinophilic Asthma
Haldar P et al. N Engl J Med 2009; 360:

31. Mepolizumab in Severe Asthma
Haldar P et al. N Engl J Med 2009; 360:

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

33. 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

34. 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