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Viral Infections and Asthma Exacerbations: Understanding the Link

Explore the correlation between viral infections and exacerbations in asthma patients. This comprehensive study delves into the causes, epidemiology, and immune responses associated with asthma exacerbations triggered by viruses.

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Viral Infections and Asthma Exacerbations: Understanding the Link

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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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