BIOLOGICAL EFFECTS OF CORTICOSTEROIDS ON PNEUMOCOCCAL PNEUMONIA IN MICE AND HUMANS

Rationale: Streptococcus pneumoniae is the most common bacterial cause of community acquired pneumonia. Some clinical trials have demonstrated a beneficial effect of corticosteroid therapy in community acquired pneumonia, but the mechanisms of this benefit remain unclear. Objectives: To investigate the biologic effects of corticosteroids in pneumococcal pneumonia in mice and in patients Methods: We studied lower respiratory tract transcriptomes from an observational cohort of mechanically ventilated patients and from a pneumonia model in mice. We also carried out comprehensive physiologic, biochemical, and histological analyses in mice to identify mechanisms of lung injury in S. pneumoniae with and without adjunctive steroid therapy. Measurement and Main Results: Transcriptomic analysis identified pleiotropic effects of steroid therapy on the lower respiratory tract in critically ill patients with pneumococcal pneumonia, findings that were reproducible in mice. In mice with pneumonia, dexamethasone in combination with ceftriaxone reduced (1) pulmonary edema formation, (2) alveolar protein permeability, (3) proinflammatory cytokine release, (4) histopathology lung injury score, and (5) hypoxemia, but did not increase bacterial burden. Conclusions: In combination with appropriate antibiotics in mice, treatment of pneumococcal pneumonia with steroid therapy reduces hypoxemia, pulmonary edema, lung permeability, and histologic criteria of lung injury, and also altered inflammatory responses at the protein and gene expression level. The concordance of transcriptional data in the mouse model and in patients with pneumococcal pneumonia supports the translational relevance of this work. Humans: Tracheal aspirate samples were collected from an observational cohort of mechanically ventilated patients. 10 patients had S. pneuomoniae pneumonia and were treated with antibiotics prior to specimen collection. Of these 10 subjects, five were treated with corticosteroids. Tracheal aspirate samples were also available from five control subjects intubtaed neurological injury who had normal chest radiographs and were not immunosuppressed. Mice: Mice were assigned to one of six experimental groups: 1) Control, 2) Dexamethasone, 3) SP, 4) SP + Dexamethasone, 5) SP + Ceftriaxone, 6) SP + Ceftriaxone + Dexamethasone *** The records will be updated with the mouse data in a few weeks*** ***Please note that the UCSF IRB has restricted sharing the raw data because some of the samples were collected under a waiver of consent and could in theory be identifiable. Therefore, raw data is not provided***