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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. - PowerPoint PPT Presentation
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Allergic vs. Non-Allergic Asthma
Paul M O’ByrneEJ 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
Allergic Asthma
• Childhood onset• Allergic triggers• IgE mediated• Allergic co-morbidities• Th2 dependent• Mast cells, basophils,
eosinophils involved.• Responsive to ICS
Non-Allergic Asthma
• 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
Moore W, et al. Am J Respir Crit Care Med 2010; in press
Mild Atopic
Moderate Atopic
Non- Atopic
Severe Atopic
Severe Fixed AFO
Goblet cell hyperplasia, mucus production &
epithelial desquamationAltered neural
mediators
Increasedsmooth muscle
&altered function
Edema and lossof airway
tethering to parenchyma
Myofibroblasthyperplasia &
fibrosis
Dendritic cell, lymphocyte & mast cell
mediated events
Inflammatory cell production,recruitment andmediator release
Initial antigen recognition, T-cell orientation
and IgE production
AHRALLERGICASTHMA
FEV1
(L)
FEV1
(L)
Time Post-Inhalation (h)
0 1 2 3 4 5 6 7 8
3.0
3.5
4.0
4.5
5.0
3.0
3.5
4.0
4.5
5.0
Grass Pollen
D. Pteronyssinus
CARTIER A , et al. J Allergy Clin Immunol 1982; 70:170-7
16
8
4
2
1
0.5
4
2
1
0.5
Days after Allergen Inhalation
0 1 2 3 4 5 6 7 8 9 17 19 45 73 129
Ratio Change
in Histamine
PC20
+2
0 SD
-2
+2
0 SD
-2
24h 2d 4d 7dTime Post Inhalation
0
5
10
15
20
SputumMCC
(x10 4 /ml)
0
100
200
300
SputumEosinophils
(x10 4 /ml)
24h 2d 4d 7d.5
1
2
4
8
MCh PC 20
(mg/ml)
-30
-20
-10
0
.5
1
2
4
8
GAUVREAU GM et al Am J Resp Crit Care Med 1999: 160; 640-7
Diluent Allergen
Baseline
Baseline
7h
7h
% Fall in FEV1
*
**
**
*
* * * **
Baseline 7 hours 24 hours
Post Allergen Inhalation
0.00
0.05
0.10
0.15
0.20
SputumMast Cells
(X10 4 /ml)
Baseline 7 hours 24 hours
0
2
4
6
8
SputumBasophils
(X10 4
/ml)
GAUVREAU GM et al Am J Respir Crit Care Med 2000; 161: 1473-8
*
*
*
*
*
*
Early RespondersDual Responders
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-IgE
• Theophylline
TRUE NEGATIVES• 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
• Anti-CD11a
• PGE2
• ? PDE4 antagonists
• PGE1 analogue
• ? Heparin derivitives
FALSE NEGATIVES
• Mepolizumab
Time Post Allergen (h)
1 54320 76
Combination
MontelukastBudesonide
Placebo
5
0
-30
-20
-15
-10
-5
-25
-35
Leigh R, et al. Am J Respir Crit Care Med 2002; 166: 1212-7
BudesonidePlacebo
Combination
Montelukast
Pre-allergen Post-allergen
*
Pre-treatment
Leigh R, et al. Am J Respir Crit Care Med 2002; 166:1212-7
0
5
10
15
20
Pre-treatment Pre-allergen 7 h post-allergen 24 h post-allergen
PlaceboBudesonideMontelukastCombination
*
*
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
0
20
40
60
80
100
120
BTSmanagement group
Sputummanagement group
SevereExacerbations
(number)
2 4 6 8 10 120
GREEN R, et al . LANCET 2002; 360: 1715-21
Time (months)
Nu
mb
er/
ex
ac
erb
ati
on
s/y
ea
r(m
ed
ian
)
Clinical Strategy
Sputum Strategy
Very Mild - Mild
Moderate - Severe
All subjects
0
1.5
1.0
0.5
0.77
0.46
1.0
0.50
p=0.01
p=0.03
Pizzichini MMM et al. ERS meeting 2003
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
0
20
40
60
80
100
mepolizumab placebo
prednisone reduction as % of maximum possible
reduction
n=9 n=10
Prednisone Reduction
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
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