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Viral Infections and asthma

Viral Infections and asthma. Sebastian L Johnston Professor of Respiratory Medicine Department of Respiratory Medicine National Heart and Lung Institute Imperial College of Science, Technology & Medicine London, UK. Causes of exacerbations. Poor underlying control Environmental factors

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Viral Infections and asthma

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  1. Viral Infections and asthma Sebastian L Johnston Professor of Respiratory Medicine Department of Respiratory Medicine National Heart and Lung Institute Imperial College of Science, Technology & Medicine London, UK

  2. Causes of exacerbations • Poor underlying control • Environmental factors • Virus infections • Allergen exposure • Air pollution • Bacterial infections • Stress • Exercise/cold air • Occupational exposure

  3. The common cold viruses • rhinoviruses • enteroviruses • influenza viruses A & B • coronaviruses • parainfluenza viruses • respiratory syncytial virus

  4. Virus infections and asthma exacerbations Johnston BMJ 1995;310:1225

  5. Positive virus detection No virus detected Epidemiology • Association of viruses with exacerbations Children Adults

  6. RV infection of the lower airways • A crucial question in asthma pathogenesis • Direct vs indirect hypotheses • Implications in treatment research

  7. 33°C 37°C Temperature preferences of rhinoviruses • RVs can successfully replicate at 37°C and some strains may even prefer it. 33° 37° a b c d titer e f g h Papadopoulos et al. J Med Virol. 1999;58:100

  8. 0 6 24 48 RV infection of primary bronchial epithelial cells • Increase of viral titres • Increase of viral RNA • New viral protein synthesis • Cytopathic effect 38kD 28kD Papadopoulos et al. J Infect Dis 2000;181:1875

  9. Localization of RVs in the bronchi • In-situ hybridization in biopsies of experimentally infected volunteers • Co-localization of genomic and replicative RNA strand Papadopoulos et al. J Infect Dis 2000;181:1875

  10. Asthmatic vs normal subjects - frequency, severity & duration of illness with rhinovirus infections • 74 atopic asthmatic & non atopic normal spouses • Regular NA sampling every 2 wks over 3 months, daily diary card + PEF • PCR for rhinoviruses • frequency of infection not different between groups • no difference in severity or duration of URT illness • LRT symptoms more severe and more prolonged in asthmatics (P<0.0001) • falls in PEF more severe (P<0.03) Corne, Johnston. Lancet 2002;359:831

  11. The immune response to viruses later in life • PBMC from • 7 atopic asthmatic • 7 non atopic non-asthmatic subjects • Incubated with rhinovirus in vitro • Supernatants assayed for type 1 and type 2 cytokines

  12. 1000 900 800 700 600 500 400 300 200 100 0 Normal (-) Asthmatic (-) Normal Asthmatic Normal + RV Asthmatic + RV The immune response to rhinoviruses • Type 1 response deficient in asthmatic subjects IFN-g/IL-4 ratio IFN-g Papadopoulos et al (Thorax in press)

  13. Type 1 deficiency in virus induced asthma <Picture> Gern et al AJRCCM 2000;162:2226

  14. IL-4/IFN-g IL-10/IL-12 Deficient type 1 immune response in RSV bronchiolitis • Birth cohort study through first winter • Proven RSV infections • Nasal lavage day 1-2 & 5-7, PBMCs day 5-7 • Divided clinically into URTI alone, or bronchiolitis P=0.01 P=0.01 Legg et al, AJRCCM in revision

  15. p=0.009 p=0.006 IFN-g : GAPDH (Mean&SD) VB RSV URTI VB RSV URTI 24h n=15 24h n=9 48h n=15 48h n=9 IFN-gmRNA production by PHA stimulated PBMCs 10000 1000 100 10 1 0 Legg et al, AJRCCM in revision

  16. 10000 p=0.066 p=0.008 1000 100 IL-18 : GAPDH (Mean&SD) 10 1 IL-18 mRNA production by LPS stimulated PBMCs VB RSV URTI VB RSV URTI 24h n=15 24h n=9 48h n=15 48h n=9 Legg et al, AJRCCM in revision

  17. 4/19 rose 6/9 rose 10000 1000 F protein Gene Copies 100 10 1 0 Day 1-2 Day 5-7 Day 1-2 Day 5-7 URTI Bronchiolitis Bronchiolitics cleared virus less rapidly 100000

  18. RSV bronchiolitis • Deficient type 1 immunity in RSV bronchiolitis • Associated with impaired virus clearance • Not related to age • Not likely to be a result of RSV infection as already present on days 1-2 • Genetic susceptibility or very early life environmental factors likely explanation • Similar mechanisms in virus induced asthma exacerbation?

  19. Role of IL-8 and neutrophils in virus induced asthma • IL-8 produced by epithelium and monocytes/macrophages after RV infection Johnston SL et al. J Infect Dis 1997;175:323 Johnston SL et al. J Immunol. 1998;160:6172

  20. Correlation between IL-8 and neutrophilia • IL-8 correlates with neutrophilia in virus-induced asthma: • sputum • nasal aspirates • correlation with MPO • severity of URT symptoms Asthmatic subjects % Neutrophils Sputum IL-8 (pg/ml) Teran, Johnston et al, AJRCCM 1997;155:1362 Pizzichini, Johnston et al, AJRCCM 1998;158:1178

  21. Inflammation • Induction of lymphocyte, neutrophil and eosinophil chemoattractants and activators • IL-1, IL-6, IL-8, IL-10, IL-11, IL-12, IL-13, IL-16, IL-18, interferons, RANTES, MIP-1a ...... Eotaxin Eotaxin-2 Papadopoulos et al. Clin Exp Allergy 2001;31:1060

  22. Respiratory virus Cytokines, LPS, Viruses ? I-kB degradation NF-kB / I-kB complex Increase of transcription Molecular mechanisms of virus-induced inflammation • NF-kB: A transcription factor mediating several virus-mediated responses • IL-6 • IL-8 • IL-11 • RANTES • ICAM-1 • VCAM-1

  23. Conclusions • Rhinoviruses are major cause of asthma exacerbations in adults and children • asthmatics may have deficient type 1 immunity • Major mechanisms • IL-8 • NFB • Lower airway infection and resulting inflammation likely the major mechanism • Therapy for rhinovirus induced LRT disease should ideally reach the lower airway

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