1. Interactions between viral infections and allergy in exacerbating asthma

2. Asthma exacerbations The tip of the iceberg  Sensitization  Inflammation  Remodeling  Signal transduction  Genes  Evident  Dangerous  Consequences  Therapeutic target

3. Viruses induce most exacerbations Children Adults Johnston et al. BMJ (1995) 310:1225 Nicholson et al. BMJ (1993) 307:982

4. Virus-induced exacerbations Johnston et al. AJRCCM (1996) 154:654 Nicholson et al. BMJ (1993) 307:982

5. Allergens exacerbate asthma Pollen, pet allergy Soya, storm epidemics Allergen challenges Reid et al. JACI (1986) 78:590-6

6. Individual factors in a complicated Universe Viral infections Atopy Pollution Food allergy Aspirin Stress Exercise Weather changes  % of asthma exacerbations explainable 60 - 85% 40 - 80% 5 - 20% 2 - 9% 4 - 28% 4 - 12% 7 - 18% 1 - 4% 123 - 256% (!)

7. Viral infections predispose to an altered response to non-specific and specific stimuli

8. Virus-induced hyperresponsiveness Increase in non-specific hyperresponsiveness Preferential increase in allergic subjects and subjects with decreased FEV 1 Increased response to allergen Calhoun et al. Am Rev Respir Dis (1991) 144:1267 Gern et al Am J Respir Crit Care Med (1997) 155:1872 Calhoun et al. JCI (1994) 94:2200 Normal Allergic * * * *

9. Mechanisms of hyperresponsiveness Epithelial damage Inflammatory mediators Cells recruited Neural reflexes Immunological mechanisms (eg IgE)

10. Allergy may lead to an abnormal response to viruses

11. Th1 Th2 Flu

12. 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. J Exp Med (1995) 181:1229

13. An “allergic” response to virus Normal (-) Normal + RV Atopic (-) Atopic + RV IFN-  IL-10 IFN-γ/IL-4 NG Papadopoulos et al. Thorax (2002) 57:328

14. Defective costimulation ** * CD14 / CD80 NormalAsthmatic * CTLA-4 on CD4+ cells NG Papadopoulos et al. Clin Exp Allergy (2002) 32:537

15. Outcome of RV infection DE Parry et al. J Allergy Clin Immunol (2000) 105:692

16. Eosinophilia persists in atopics Experimental infection with RV Increase in bronchial hyperreactivity Infiltration with lymphocytes and eosinophils Fraenkel DJ et al Am J Respir Crit Care Med (1995) 151:879

17. Virus-induced hyperresponsiveness persists in atopics Time to PC 20 return to baseline Days 3002001000 % patients 1,0 0,8 0,6 0,4 0,2 0,0 Non- atopic Atopic Xepapadaki, Papadopoulos et al. unpublished

18. Could allergens protect from colds ?! Avila PC et al. JACI (2000) 105:923

19. Natural history: combined effects

20. 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 SO 2, NO, than asthma alone No correlation of pollen/spore counts with asthma exacerbations or colds Tarlo SM et al JACI (2001) 108:52

21. Viruses and mites in asthma exacerbations Synergistic interaction between –allergen sensitization –allergen exposure –virus infection Sensitized + - - + - + + Exposed - + - - + + + Virus - - + + + - + OR for asthma admission Green, Custovic, Johnston, Woodcock et al. BMJ (2002) 324:763 ** *

22. Exacerbations in seasonal asthma * # * NG Papadopoulos et al. XXI EAACI proceedings

23. Conclusions Viruses induce hyperresponsiveness Atopy is a risk factor In the allergic environment, virus-induced inflammation persists A vicious circle…