Severe community-acquired pneumonia as a cause of severe sepsis: Data from the PROWESS study*

Abstract

To investigate community-acquired pneumonia (CAP) as a cause of severe sepsis in the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial and to evaluate the effect of drotrecogin alfa (activated) (DrotAA) in this subgroup. Retrospective analysis of the severe CAP subgroup in the PROWESS trial. Tertiary care institutions in 11 countries. DrotAA (n = 850), 24 microg.kg.hr for 96 hrs, or placebo (n = 840). The 1,690 patients with severe sepsis enrolled in the PROWESS trial. Patients were classified as having CAP if lung was the primary site of infection and if they were enrolled directly from home (private residence) with </=4 days in the hospital before receipt of study drug in the PROWESS trial. Survival at 28 days, hospital discharge, and 90 days was compared in DrotAA and placebo groups in the CAP subgroup of PROWESS and CAP subgroups based on disease severity. Of the 1,690 PROWESS patients, 35.6% (DrotAA, n = 324; placebo, n = 278) were classified as severe CAP. Of these severe CAP patients, 26.1% had Streptococcus pneumoniae infections. Within CAP, 79.1% were enrolled by the end of the second calendar day in the hospital, and approximately 90% of CAP patients were at high risk of death according to the Pneumonia Severity Index category. Based on their dependence on vasopressors, 59% of CAP patients were judged at high risk of death. Biomarkers of coagulation and inflammation were markedly abnormal in severe CAP patients. In severe CAP patients treated with DrotAA, a relative risk reduction in mortality of 28% was observed at 28 days, with a relative risk reduction in mortality of 14% observed at 90 days from the start of study drug infusion. The survival benefit was most pronounced in severe CAP patients with S. pneumoniae and in severe CAP patients at high risk of death as indicated by Acute Physiology and Chronic Health Evaluation II score of >/=25, Pneumonia Severity Index score of >/=4, or CURB-65 (confusion, urea, respiratory rate, blood pressure, age) score of >/=3. CAP associated with a high Pneumonia Severity Index score, bacteremia, or an intense coagulation and inflammatory response requiring intensive care unit care were indicators of a high risk of death from severe sepsis. In patients with severe sepsis resulting from CAP, a readily identifiable disease, DrotAA, improved survival compared with placebo.