Interactions between viral infections and allergy in

exacerbating asthma

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

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

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

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

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% (!)

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

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

**

Mechanisms of hyperresponsiveness

• Epithelial damage• Inflammatory mediators• Cells recruited• Neural reflexes• Immunological mechanisms (eg

IgE)

Allergy may lead to an abnormal response to

viruses

Allergy may lead to an abnormal response to

viruses

Th1

Th2

Flu

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

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

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

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

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

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

Could allergens protect from colds ?!

Avila PC et alAvila PC et al. JACI . JACI (2000) 105:923(2000) 105:923

Natural history:Natural history:combined effectscombined effectsNatural history:Natural history:

combined effectscombined effects

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

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

**

*

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

Conclusions

• Viruses induce hyperresponsiveness• Atopy is a risk factor• In the allergic environment, virus-

induced inflammation persists• A vicious circle…