Polmoniti: Steroidi sì, no, quando. Alfredo Chetta Clinica Pneumologica Università degli Studi di Parma

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1 Polmoniti: Steroidi sì, no, quando Alfredo Chetta Clinica Pneumologica Università degli Studi di Parma

2 Number of patients Epidemiology and outcome of severe pneumococcal pneumonia admitted to intensive care unit: a multicenter study Mongardon N, et al. Crit Care. 2012;16:R155. Causes of ICU admission in 222 patients with severe pneumococcal CAP Acute Respiratory Failure Septic shock Coma Others Measured criteria Although antibiotherapy was adequate in 92% of cases, hospital mortality reached 29% Age, male sex and need for renal replacement therapy are associated with an unfavourable outcome

3 Epidemiology and outcome of severe pneumococcal pneumonia admitted to intensive care unit: a multicenter study Mongardon N, et al. Crit Care. 2012;16:R155. Seasonal variation in ICU admission for severe pneumococcal community-acquired pneumonia

4 Molecular Inflammatory Responses Measured in Blood of Patients with Severe Community-Acquired Pneumonia Fernandez-Serrano S, et al. Clin Diag Lab Immunol 2003: IL-6 IL-10 Total mortality : 11/38 (29%)

5 In regression logistic analyses, high levels of CRP and IL6 showed an independent predictive value for predicting 30-day mortality, after adjustment for prognostic scales (PSI, CURB65 and CRB65)

6 Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease Corrales-Medina VF et al, JAMA. 2015;313: CONCLUSIONS AND RELEVANCE Hospitalization for pneumonia was associated with increased short-term and long-term risk of CVD, suggesting that pneumonia may be a risk factor for CVD.

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9 Nie W, Zhang Y, Cheng J, Xiu Q (2012) Corticosteroids in the Treatment of Community-Acquired Pneumonia in Adults: A Meta-Analysis. PLoS ONE 7(10): e Characteristics of included trials

10 Nie W, Zhang Y, Cheng J, Xiu Q (2012) Corticosteroids in the Treatment of Community-Acquired Pneumonia in Adults: A Meta-Analysis. PLoS ONE 7(10): e Meta-analysis for the association between mortality and corticosteroids

11 Nie W, Zhang Y, Cheng J, Xiu Q (2012) Corticosteroids in the Treatment of Community-Acquired Pneumonia in Adults: A Meta-Analysis. PLoS ONE 7(10): e Subgroup analysis according to the severity of CAP

12 Nie W, Zhang Y, Cheng J, Xiu Q (2012) Corticosteroids in the Treatment of Community-Acquired Pneumonia in Adults: A Meta-Analysis. PLoS ONE 7(10): e47926 Subgroup analysis according to the duration of corticosteroids treatment Results from this meta-analysis did not suggest a benefit for corticosteroids treatment in patients with CAP. However, the use of corticosteroids was associated with improved mortality in severe CAP. In addition, prolonged corticosteroids therapy suggested a beneficial effect on mortality. These results should be confirmed by future adequately powered randomized trials.

13 Corticosteroid Therapy for Patients Hospitalized With Community-Acquired Pneumonia: A Systematic Review and Meta-analysis Reed A.C. Siemieniuk et al, Ann Intern Med. 2015;163: Effect of corticosteroids on all-cause mortality in patients hospitalized with community-acquired pneumonia, by severity of pneumonia. For hospitalized adults with CAP, systemic corticosteroid therapy may reduce mortality by approximately 3%, need for mechanical ventilation by approximately 5%, and hospital stay by approximately 1 day.

14 Efficacy and Safety of Corticosteroids for Community-Acquired Pneumonia A Systematic Review and Meta-Analysis You-Dong Wan et al, CHEST 2016 Nine eligible RCTs (1,667 patients) were identified. Corticosteroids did not have a statistically significant effect on mortality in patients with CAP. Corticosteroids treatment was associated with a decreased risk of ARDS and may reduce lengths of hospital and ICU stay, duration of IV antibiotic treatment, and time to clinical stability. Corticosteroids were not associated with increased rates of adverse events.

15 Pitfalls in RCT s Studying Corticosteroids in CAP 1. Selection of non-severe CAP in most of the studies 2. Inclusion of patients independently of the initial systemic inflammation (CRP) 3. Low or high dosages of corticosteroids 4. Different primary end-points between studies

16 Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults Lionel A. Mandell et al. Clin Infect Dis. 2007;44:S27-S72 Criteria for severe community-acquired pneumonia.

17 Effect of Corticosteroids on Treatment Failure Among Hospitalized Patients With Severe Community-Acquired Pneumonia and High Inflammatory Response: A Randomized Clinical Trial A Torres et al, JAMA. 2015;313: Inclusion criteria Age 18 years old or older. Clinical symptoms suggesting for CAP (cough, fever, pleuritic chest pain or dyspnea). New consodilations on chest radiography. Severe CAP criteria, defined by ATS criteria modified by Ewig et al (1 major or two minor) or Pneumonia Severity Index (PSI) class V. C-reactive protein (CRP) level >150 mg/l at admission. Exclusion criteria Steroid previous treatment (chronic treatment or any dosage at admission). Nosocomial pneumonia. Reported severe immunosupression (HIV infection, use of immunosupressants). A preexisting medical condition with a life expectancy less than 3 months. Uncontrolled diabetes mellitus. A major gastrointestinal bleed within 3 months of the current hospitalization. A condition requiring more than 1 mg/kg/day of methylprednisolone or equivalent (i.e. severe bronchospasm). Dosage: 0.5 mg/kg/12h per 5 days

18 Effect of Corticosteroids on Treatment Failure Among Hospitalized Patients With Severe Community-Acquired Pneumonia and High Inflammatory Response: A Randomized Clinical Trial A Torres et al, JAMA. 2015;313: Primary clinical outcome Clinical outcomes. ITT population Methylprednisolone (N=61) Placebo (N=59) P value Treatment failure 8 (13%) 18 (31%) 0.02 Early treatment failure (0h to 72h) 6 (10%) 6 (10%) >0.9 Early mechanical ventilation 4 (7%) 5 (8%) 0.7 Early septic shock 2 (3%) 3 (5%) 0.7 Death 2 (3%) 2 (3%) >0.9 Late treatment failure (72h to 120h) 2 (3%) 15 (25%) Radiographic progression 1 (2%) 9 (15%) Respiratory failure 1 (2%) 5 (8%) 0.1 Late mechanical ventilation 1 (2%) 4 (7%) 0.2 Late septic shock 0 (0%) 4 (7%) 0.06 Death 0 (0%) 0 (0%) - Secondary clinical outcomes Time to clinical stability (days) 4.0 (3.0; 6.0) 5.0 (3.0; 7.0) 0.3 Length of stay (days) 11.0 (7.5; 14.0) 10.5 (8.0; 15.0) 0.8 In-hospital mortality 6 (10%) 9 (15%) 0.4 ICU admission 42 (69%) 46 (78%) 0.3 Length of stay in ICU (days) 5.0 (3.0; 8.0) 6.0 (4.0; 8.0) 0.6

19 Effect of Corticosteroids on Treatment Failure Among Hospitalized Patients With Severe Community-Acquired Pneumonia and High Inflammatory Response: A Randomized Clinical Trial A Torres et al, JAMA. 2015;313: Kaplan-Meier analysis of the effect of methylprednisolone on time to treatment failure. ITT population

20 Effect of Corticosteroids on Treatment Failure Among Hospitalized Patients With Severe Community-Acquired Pneumonia and High Inflammatory Response: A Randomized Clinical Trial A Torres et al, JAMA. 2015;313: Inflammatory response. ITT population p<0 001 p=0 033 p=0 55 p=0 37 N=45 N=50 N=34 N=36 N=44 N=51 N=34 N=34 p=0 13 p=0 47 p=0 11 p=0 94 p=0 047 p=0 24 N=40 N=37 N=28 N=32 N=36 N=42 N=28 N=34 N=41 N=47 N=31 N=35

21 Effect of Corticosteroids on Treatment Failure Among Hospitalized Patients With Severe Community-Acquired Pneumonia and High Inflammatory Response: A Randomized Clinical Trial A Torres et al, JAMA. 2015;313: Adverse events. ITT population Methylprednisolone (N=61) Placebo (N=59) Hyperglycemia 11 (18%) 7 (12%) 0.3 P value Super-infection 1 (2%) 0 (0%) >0.9 Gastrointestinal bleeding 0 (0%) 1 (2%) 0.5 Delirium 1 (2%) 0 (0%) >0.9 Acute kidney injury 8 (13%) 8 (14%) 0.9 Acute hepatic failure 1 (2%) 0 (0%) >0.9 Data are number of patients (%). CONCLUSIONS AND RELEVANCE Among patients with severe community-acquired pneumonia and high initial inflammatory response, the acute use of methylprednisolone compared with placebo decreased treatment failure. If replicated, these findings would support the use of corticosteroids as adjunctive treatment in this clinical population.

22 Neuraminidase inhibitors, superinfection and corticosteroids affect survival of influenza patients. Lee N et al, Eur Respir J. 2015;45: Kaplan Meier survival curves of adult patients hospitalised for confirmed influenza virus infections, censored at 30 days. Survival according to a) neuraminidase inhibitors (NAI) treatment status (log-rank test p=0.002), b) NAI initiation time (log-rank test p<0.001), c) systemic steroid use (log-rank test p=0.038) and d) chronic statin use (log-rank test p=0.013)

23 Corticosteroids as adjunctive therapy in the treatment of influenza Rodrigo C et al, 2016 Authors conclusions We did not identify any completed RCTs of adjunctive corticosteroid therapy for treating influenza. The available evidence from observational studies is of very low quality with confounding by indication a major potential concern. Although we found that adjunctive corticosteroid therapy was associated with increased mortality, this result should be interpreted with caution. In the context of clinical trials of adjunctive corticosteroid therapy in sepsis and pneumonia that report improved outcomes, including decreased mortality, more high-quality research is needed (both RCTs and observational studies). Currently, we do not have sufficient evidence in this review to determine the effectiveness of corticosteroids for patients with influenza.

24 Steps for the administration of corticosteroids in severe community-acquired pneumonia. A Torres & M Ferrer. Intensive Care Med. 2015