antiinflammatory treatment in community-acquired pneumonia

1

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

Pro-inflammatory Cytokines

IFN-γ TNF-αIL-6IL-8IL-1β

Lung Inflammatory Response During Pneumonia

Anti-inflammatorycytokinesTGF-sTNFrp55sTNFrp75IL-1 receptor antagIL-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

6Monton C, Crit Care Med 1999

7Monton C, Crit Care Med 1999

8Monton C, Crit Care Med 1999

9Monton C, Crit Care Med 1999

10

Systemic cytokine levels in CAP and their association with disease severity

Antunes G, Eur Respir J 2002

11Antunes G, Eur Respir J 2002

12Antunes G, Eur Respir J 2002

13Antunes G, Eur Respir J 2002

14Antunes 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

16Serrano SF, Clin Diagn Lab Immunol 2003

17Serrano SF, Clin Diagn Lab Immunol 2003

18Serrano 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

20Salluh JI, Intensive Care Med 2006

21

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.

Role of GC on Inflammatory Response in Pneumonia

Monton C, Eur Respir J 1999

22Monton C, Eur Respir J 1999

23Monton C, Eur Respir J 1999

24

Hydrocortisone Infusion for Severe CAP

Confalonieri M, Am J Respir Crit Care Med 2005

25Confalonieri M, Am J Respir Crit Care Med 2005

26Confalonieri M, Am J Respir Crit Care Med 2005

27Confalonieri M, Am J Respir Crit Care Med 2005

28Confalonieri M, Am J Respir Crit Care Med 2005

29Confalonieri M, Am J Respir Crit Care Med 2005

30Confalonieri M, Am J Respir Crit Care Med 2005

31

Adjunctive Corticosteroids for PCP: A Meta-Analysis

Briel M, BMC Infect Dis 2005

32Briel M, BMC Infect Dis 2005

33Briel M, BMC Infect Dis 2005

34Sung JJY, Thorax 2004

Glucocorticoids in SARS

35Sung JJY, Thorax 2004

36Sung JJY, Thorax 2004

37Sung 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

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.

Glucocorticoids in Other Viral Pneumonias

40

Systemic Administration of Cytokines Systemic administration of cytokines

Significant, dose-limiting toxicitySpecific, 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 1995Kolls JK, J Infect Dis 1995Takashima 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 2001Standiford TJ, Hum Gene Ther 1999Laichalk 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 2001Condos R, Lancet 1997

44

Adjunctive Effect of IFN-γ in P. aeruginosa pneumonia

Babalola CP, Int J Antimicrob Agents 2004

45Babalola CP, Int J Antimicrob Agents 2004

46Babalola 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 2000Smith WS, Blood 1995

48

Adjunctive Efficacy of G-CSF in P. aeruginosa pneumonia

Babalola CP, Int J Antimicrob Agents 2004

49Babalola 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

51

Use of Filgrastim in Patients Hospitalized with Pneumonia and Severe SepsisMulticenter, double-blind, placebo-controlled study

Primary end point: mortality through day 29

Secondary end point: subsequent organ dysfunction, time to discharge, number of days on MV, time to death

Root RK, Crit Care Med 2003

52Root RK, Crit Care Med 2003

53Root RK, Crit Care Med 2003

54Root RK, Crit Care Med 2003

55Root RK, Crit Care Med 2003

56Root RK, Crit Care Med 2003

57Root RK, Crit Care Med 2003

58

Conclusion-1

Low doses of hydrocortisone in severe CAP reduces morbidity and may improve survival.

Confirmatory randomized clinical trials are needed.

Which patients can benefit?

Optimal doses?

Duration of glucocorticoids?

59

There is no current evidence supporting the routine use of cytokines in the treatment of pneumonia.

Conclusion-2

60