Allergic vs. Non-Allergic Asthma

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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

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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

Transcript of Allergic vs. Non-Allergic Asthma

Page 1: Allergic vs. Non-Allergic Asthma

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

Page 2: Allergic vs. Non-Allergic Asthma

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.

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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

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What is Non-Allergic Asthma?

Beeh KM, at al. Eur Respir J 2000; 16:609-14

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What is Non-Allergic Asthma?

Beeh KM, at al. Eur Respir J 2000; 16:609-14

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Airway Inflammation in Non-Allergic Asthma

EOSINOPHILS NEUTROPHILS

Drews AC, at al. Eur Respir J 2009; 64:1597-1601

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Asthma Phenotypes

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

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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

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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

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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

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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

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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

*

**

**

*

* * * **

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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

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Occupational Sensitizers

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

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Occupational Sensitizers

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

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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

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Pharmacology of Allergen-Induced Responses

FALSE POSITIVES

• Anti-CD11a

• PGE2

• ? PDE4 antagonists

• PGE1 analogue

• ? Heparin derivitives

FALSE NEGATIVES

• Mepolizumab

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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

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BudesonidePlacebo

Combination

Montelukast

Pre-allergen Post-allergen

*

Pre-treatment

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

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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

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Omalizumab in Severe Allergic Asthma

Busse WW, et al. J Allergy Clin Immunol 2001; 108:184-90

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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”.

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Induced Sputum

Freddy Hargreave

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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)

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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

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Sputum and Blood Eosinophils

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

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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 .

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Asthma Exacerbations

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

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Refractory Eosinophilic Asthma

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

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Mepolizumab in Severe Asthma

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

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CXCR2 Antagonists

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

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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

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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