interactions between viral infections and allergy in exacerbating asthma
TRANSCRIPT
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Interactions between viral infections and allergy in
exacerbating asthma
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Asthma exacerbationsAsthma exacerbations The tip of the icebergThe tip of the iceberg
SensitizationSensitization InflammationInflammation RemodelingRemodeling Signal transductionSignal transduction GenesGenes
EvidentEvident DangerousDangerous ConsequencesConsequences Therapeutic targetTherapeutic target
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Viruses induce most exacerbations
15%
85%
15%
85%
Ch
ildre
nC
hild
ren
40%
60%
40%
60%
Ad
ult
sA
du
lts
Johnston et al. Johnston et al. BMJ BMJ (1995) 310(1995) 310::11222255
Nicholson et al. Nicholson et al. BMJBMJ (1993) 307:982 (1993) 307:982
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Virus-induced exacerbations
0
5
10
15
20
Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar
No of Viruses
Hospitalizations
0
20
40
60
80
100
120
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Days after onset of symptoms
Dec
reas
e in
pea
k flo
w
Virus found No pathogen found
Johnston et al. Johnston et al. AJRCCM AJRCCM (1996) (1996) 1154:654:65544
Nicholson et al. Nicholson et al. BMJBMJ (1993) 307:982 (1993) 307:982
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Allergens exacerbate asthma
• Pollen, pet allergy• Soya, storm
epidemics• Allergen challenges 0
200
400
600
800
1000
1981 1982 1983 1984
Asthma score
Grass pollen
Reid et al. JACI (1986) 78:590-6
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Individual factors in a complicated Universe
• Viral infections• Atopy• Pollution• Food allergy• Aspirin• Stress• Exercise• Weather changes
% of asthma exacerbations % of asthma exacerbations explainableexplainable
60 - 85% 40 - 80% 5 - 20% 2 - 9% 4 - 28% 4 - 12% 7 - 18% 1 - 4% 123 - 256% (!)123 - 256% (!)
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Viral infectionsViral infectionspredispose to predispose to
an altered responsean altered response to non-specific and to non-specific and
specific stimulispecific stimuli
Viral infectionsViral infectionspredispose to predispose to
an altered responsean altered response to non-specific and to non-specific and
specific stimulispecific stimuli
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Virus-induced hyperresponsiveness
• Increase in non-specific hyperresponsiveness
• Preferential increase in allergic subjects and subjects with decreased FEV1
• Increased response to allergen
Calhoun et al. Calhoun et al. Am Rev Respir Dis Am Rev Respir Dis (1991) 144(1991) 144:1267:1267
Gern et al Gern et al Am J Respir Crit Care MedAm J Respir Crit Care Med (1997) 155:1872 (1997) 155:1872
Calhoun et al. Calhoun et al. JCIJCI (1994) 94:2200 (1994) 94:2200
0
2
4
6
8
pre acute conv pre acute conv
BAL H
ista
min
e
Normal Allergic
*
*
0
0,5
1
1,5
2
Meth PD20 Hist PD20
Pre-coldCold
**
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Mechanisms of hyperresponsiveness
• Epithelial damage• Inflammatory mediators• Cells recruited• Neural reflexes• Immunological mechanisms (eg
IgE)
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Allergy may lead to an abnormal response to
viruses
Allergy may lead to an abnormal response to
viruses
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Th1
Th2
Flu
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Virus-specific CD8+ cells• In an atopic environment, virus-
specific CD8 cells can switch to Th2 cytokine production and induce eosinophilia
Coyle AJ et al. Coyle AJ et al. J Exp Med J Exp Med (1995) 181:1229(1995) 181:1229
0 200 400 600 800 1000
IFN-γ
IL-5
ShamOVA
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An “allergic” response to virus
Normal (-)
Normal + RV
Atopic (-)
Atopic + RV
0
200
400
600
800
1000
1200
6h 24h 48h
IFN-IFN-
0
50
100
150
200
250
6h 24h 48h
IL-10IL-10
0
400
800
1200
Normal Atopic
IFNIFN-γ/-γ/IL-IL-44
NG Papadopoulos et al. NG Papadopoulos et al. ThoraxThorax (2002) 57:328 (2002) 57:328
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Defective costimulation
Control RV16
%
0
20
40
60
80
100
Control RV16
**** *
CD
14 /
CD
80
Normal Asthmatic
0
1
2
3
4
5
6
Normal Asthmatic
%
Control
RV16
*
CTLA-4 on CD4+ CTLA-4 on CD4+ cellscells
NG Papadopoulos et al. NG Papadopoulos et al. Clin Exp Allergy Clin Exp Allergy (2002) 32:537 (2002) 32:537
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Outcome of RV infection
DE Parry et al. DE Parry et al. J Allergy Clin ImmunolJ Allergy Clin Immunol (2000) 105:692 (2000) 105:692
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Eosinophilia persists in atopics
• Experimental infection with RV• Increase in bronchial hyperreactivity• Infiltration with lymphocytes and eosinophils
0
0,4
0,8
Baseline Cold Convalescence
NormalAtopic
Fraenkel DJ et al Fraenkel DJ et al Am J Respir Crit Care MedAm J Respir Crit Care Med (1995) 151:879 (1995) 151:879
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Virus-induced hyperresponsiveness persists
in atopicsTime to PC20 return to baseline
Days3002001000
% p
atie
nts
1,0
0,8
0,6
0,4
0,2
0,0
Non- atopic
Atopic
Xepapadaki, Papadopoulos et alXepapadaki, Papadopoulos et al. unpublished. unpublished
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Could allergens protect from colds ?!
Avila PC et alAvila PC et al. JACI . JACI (2000) 105:923(2000) 105:923
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Natural history:Natural history:combined effectscombined effectsNatural history:Natural history:
combined effectscombined effects
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Colds – pollution – allergy • 57 asthmatics - diary cards for 1 year• Colds, pollution and pollen/spore
levels• Comparison of the days with
cold+asthma vs either alone• Asthma+cold= more SO2, NO, than
asthma alone • No correlation of pollen/spore counts
with asthma exacerbations or colds
Tarlo SM et al Tarlo SM et al JACI JACI (2001) 108:52(2001) 108:52
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Viruses and mites in asthma exacerbations
• Synergistic interaction between– allergen
sensitization– allergen exposure– virus infection
0
1
2
3
4
5
6
Sensitized + - - + - + +Exposed - + - - + + +Virus - - + + + - +
OR
for
ast
hma
adm
issi
on
Green, Custovic, Johnston, Woodcock et al. BMJ (2002) 324:763
**
*
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Exacerbations in seasonal asthma
1
2
3
4
Upper Lower
severi
ty
With virusNo virus
*
#
0
2
4
6
8
10
Duration
day
s
With virusNo virus
*
With virus
No virus
OtherRV
NG Papadopoulos et al. NG Papadopoulos et al. XXI EAACI XXI EAACI proceedings proceedings
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Conclusions
• Viruses induce hyperresponsiveness• Atopy is a risk factor• In the allergic environment, virus-
induced inflammation persists• A vicious circle…