Antiinflammatory treatment in community-acquired pneumonia

1. Antiinflammatory treatment in community-acquired pneumonia Doç.Dr. Aykut Çilli Akdeniz Üniversitesi Tıp Fakültesi Göğüs Hastalıkları AD.

2. Plan • Introduction • Lung inflammatory response during pneumonia • Role of corticosteroids on inflammatory response in pneumonia • Administering cytokines in experimental model of pneumonia and in patients with pneumonia. • Conclusion

3. Introduction • The mortality rate in ICU hospitalized patients is 20-50%. • New antibiotics has not changed mortality rates significantly! • New strategies are needed.

4. Lung Inflammatory Response During Pneumonia Pro-inflammatory Cytokines IFN-γ TNF-α IL-6 IL-8 IL-1β Anti-inflammatory cytokines TGF- sTNFrp55 sTNFrp75 IL-1 receptor antag IL-10

5. Cytokine Expression in Severe Pneumonia • 30 mechanically ventilated patients (>48 hrs) were allocated to either the pneumonia group (n=20) or a control group (n=10). • Serum and BAL fluid TNF-α, IL-1β and IL-6 levels were measured on days 1, 3 and 7. Monton C, Crit Care Med 1999

6. Monton C, Crit Care Med 1999

7. Monton C, Crit Care Med 1999

8. Monton C, Crit Care Med 1999

9. Monton C, Crit Care Med 1999

10. Systemic cytokine levels in CAP and their association with disease severity Antunes G, Eur Respir J 2002

11. Antunes G, Eur Respir J 2002

12. Antunes G, Eur Respir J 2002

13. Antunes G, Eur Respir J 2002

14. Antunes G, Eur Respir J 2002

15. Cytokine profile and clinical outcome in pneumonia • 38 patients with severe CAP. • Blood samples were collected at study entry and on days 1, 2, 3, 5 and 7. • The concentrations of TNF-α, IL-1β, IL-6, IL-8 and IL-10 cytokines were determined. Serrano SF, Clin Diagn Lab Immunol 2003

16. Serrano SF, Clin Diagn Lab Immunol 2003

17. Serrano SF, Clin Diagn Lab Immunol 2003

18. Serrano SF, Clin Diagn Lab Immunol 2003

19. Cortisol Levels in Patients with Severe CAP • Retrospective cohort study in ICU. • 40 patients with severe CAP. • Random cortisol levels were measured up to 72 h after ICU admission. Salluh JI, Intensive Care Med 2006

20. Salluh JI, Intensive Care Med 2006

21. Role of GC on Inflammatory Response in Pneumonia • 20 mechanically ventilated patients with severe pneumonia. • All patients received prior antimicrobial treatment. • Serum and BAL TNF-α, IL-1β, IL-6 and CRP levels were measured. Monton C, Eur Respir J 1999

22. Monton C, Eur Respir J 1999

23. Monton C, Eur Respir J 1999

24. Hydrocortisone Infusion for Severe CAP Confalonieri M, Am J Respir Crit Care Med 2005

25. Confalonieri M, Am J Respir Crit Care Med 2005

26. Confalonieri M, Am J Respir Crit Care Med 2005

27. Confalonieri M, Am J Respir Crit Care Med 2005

28. Confalonieri M, Am J Respir Crit Care Med 2005

29. Confalonieri M, Am J Respir Crit Care Med 2005

30. Confalonieri M, Am J Respir Crit Care Med 2005

31. Adjunctive Corticosteroids for PCP: A Meta-Analysis Briel M, BMC Infect Dis 2005

32. Briel M, BMC Infect Dis 2005

33. Briel M, BMC Infect Dis 2005

34. Glucocorticoids in SARS Sung JJY, Thorax 2004

35. Sung JJY, Thorax 2004

36. Sung JJY, Thorax 2004

37. Sung JJY, Thorax 2004

38. A placebo-controlled clinical trial of corticosteroids is needed. • Corticosteroids are not indicated for the routine care of patients with uncomplicated SARS. • Pulse-dose steroid therapy could be used for patients with clinical deterioration. • Benefit / risk analysis! Levy MM, Am J Respir Crit Care Med 2005

39. Glucocorticoids in Other Viral Pneumonias • No randomised clinical trial has been conducted. • GCs may have some benefit in patients with ARDS due to hantavirus, human influenza virus and varicella-zoster virus.

40. Systemic Administration of Cytokines Systemic administration of cytokines Significant, dose-limiting toxicity Specific, undesirable immune effects Local, compartmentalized delivery

41. Augmenting TNFα Expression • The inhibition of TNFα: • impair lung bacterial clearance • attenuate lung neutrophil influx in response to administered P. aeruginosa, K. pneumonia and S. pneumoniae • markedly decrease survival in animals with bacterial pneumonia Gosselin D, Infect Immun 1995 Kolls JK, J Infect Dis 1995 Takashima K, Infect Immun 1997

42. Administration or induction of TNFα: • reverses sepsis-induced suppression of lung antibacteriel host defense • improves survival of infected animals • augments antibacterial host defense in murine Klebsiella pneumonia Nelson S, Chest 2001 Standiford TJ, Hum Gene Ther 1999 Laichalk LL, Infect Immun 1998

43. Administration or Expression of IFN-γ • Augments bacterial clearance in immunocompetent hosts in vivo. • Decreased the size of cavitary lesions and reduced time to negative culture in MDR TB. Deng JC, Infect Immun 2001 Condos R, Lancet 1997

44. Adjunctive Effect of IFN-γin P. aeruginosa pneumonia Babalola CP, Int J Antimicrob Agents 2004

45. Babalola CP, Int J Antimicrob Agents 2004

46. Babalola CP, Int J Antimicrob Agents 2004

47. G-CSF Treatment • G-CSF administered into the lung has systemic effects. • Animal studies indicate that rG-CSF might accelerate clearance of pathogens from the lungs. • Early survival benefit in a rabbit model of pneumonia/sepsis. Rodriguez FH, Curr Pharm Des 2000 Smith WS, Blood 1995

48. Adjunctive Efficacy of G-CSF in P. aeruginosa pneumonia Babalola CP, Int J Antimicrob Agents 2004

49. Babalola CP, Int J Antimicrob Agents 2004

50. Effect of Single Dose of G-CSF in CAP • Prolonged survival and increased activation of neutrophils. • Sustained release of anti-inflammatory cytokines. Droemann D, Respiration 2005