Managing Community-acquired Pneumonia and Hospital-acquired Pneumonia - Professor Francesco Blasi
Antiinflammatory treatment in community-acquired pneumonia
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Transcript of Antiinflammatory treatment in community-acquired pneumonia
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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
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Introduction
The mortality rate in ICU hospitalized patients is 20-50%.
New antibiotics has not changed mortality rates significantly!
New strategies are needed.
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Pro-inflammatory Cytokines
IFN-γ TNF-αIL-6IL-8IL-1β
Lung Inflammatory Response During Pneumonia
Anti-inflammatorycytokinesTGF-sTNFrp55sTNFrp75IL-1 receptor antagIL-10
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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
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6Monton C, Crit Care Med 1999
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7Monton C, Crit Care Med 1999
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8Monton C, Crit Care Med 1999
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9Monton C, Crit Care Med 1999
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Systemic cytokine levels in CAP and their association with disease severity
Antunes G, Eur Respir J 2002
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11Antunes G, Eur Respir J 2002
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12Antunes G, Eur Respir J 2002
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13Antunes G, Eur Respir J 2002
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14Antunes G, Eur Respir J 2002
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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
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16Serrano SF, Clin Diagn Lab Immunol 2003
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17Serrano SF, Clin Diagn Lab Immunol 2003
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18Serrano SF, Clin Diagn Lab Immunol 2003
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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
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20Salluh JI, Intensive Care Med 2006
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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
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22Monton C, Eur Respir J 1999
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23Monton C, Eur Respir J 1999
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Hydrocortisone Infusion for Severe CAP
Confalonieri M, Am J Respir Crit Care Med 2005
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25Confalonieri M, Am J Respir Crit Care Med 2005
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26Confalonieri M, Am J Respir Crit Care Med 2005
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27Confalonieri M, Am J Respir Crit Care Med 2005
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28Confalonieri M, Am J Respir Crit Care Med 2005
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29Confalonieri M, Am J Respir Crit Care Med 2005
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30Confalonieri M, Am J Respir Crit Care Med 2005
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Adjunctive Corticosteroids for PCP: A Meta-Analysis
Briel M, BMC Infect Dis 2005
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32Briel M, BMC Infect Dis 2005
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33Briel M, BMC Infect Dis 2005
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34Sung JJY, Thorax 2004
Glucocorticoids in SARS
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35Sung JJY, Thorax 2004
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36Sung JJY, Thorax 2004
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37Sung JJY, Thorax 2004
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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
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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
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Systemic Administration of Cytokines Systemic administration of cytokines
Significant, dose-limiting toxicitySpecific, undesirable immune effects
Local, compartmentalized delivery
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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
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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
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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
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Adjunctive Effect of IFN-γ in P. aeruginosa pneumonia
Babalola CP, Int J Antimicrob Agents 2004
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45Babalola CP, Int J Antimicrob Agents 2004
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46Babalola CP, Int J Antimicrob Agents 2004
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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
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Adjunctive Efficacy of G-CSF in P. aeruginosa pneumonia
Babalola CP, Int J Antimicrob Agents 2004
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49Babalola CP, Int J Antimicrob Agents 2004
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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
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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
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52Root RK, Crit Care Med 2003
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53Root RK, Crit Care Med 2003
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54Root RK, Crit Care Med 2003
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55Root RK, Crit Care Med 2003
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56Root RK, Crit Care Med 2003
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57Root RK, Crit Care Med 2003
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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?
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There is no current evidence supporting the routine use of cytokines in the treatment of pneumonia.
Conclusion-2
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