title: Biomarkers of thrombosis, fibrinolysis, and inflammation in patients with severe sepsis due to community-acquired pneumonia with and without Streptococcus pneumoniae.
abstract: BACKGROUND
  Severe Streptococcus pneumoniae (S. pneum) pneumonia has historically been associated with an acute presentation and increased mortality. Using data from patients with community-acquired pneumonia (CAP) and severe sepsis, we investigated: (1) the baseline patient characteristics and biomarkers of thrombosis, fibrinolysis, and inflammation in patients with CAP due to S. pneum infection (S. pneum CAP) or CAP due to infection with other or unidentified organisms (non-S. pneum CAP); (2) the behavior of these biomarkers over time and during treatment with drotrecogin alfa (activated) (DrotAA, recombinant activated protein C).
  
  
  METHODS
  Data from the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation on Severe Sepsis) trial were retrospectively analyzed by treatment (DrotAA or placebo) in patients with CAP.
  
  
  RESULTS
  Patients with S. pneum CAP (n = 157) tended to be younger and had fewer comorbid conditions than patients with non-S. pneum CAP (n = 445). Overall disease severity (median APACHE II scores) was not significantly different between the two groups at baseline. However, there were significant baseline differences in protein C and markers of coagulation, fibrinolysis, and inflammation. Although thrombosis markers were not different at baseline, D-dimer levels significantly increased from baseline to day 4 in placebo-treated patients with S. pneum compared to those with non-S. pneum. DrotAA treatment was associated with statistically significant improvements in protein C and markers of thrombosis in patients with S. pneum. In addition, the proportion of patients with severe protein C deficiency ( </= 40% activity) at baseline was significantly greater in patients with S. pneum than those with non-S. pneum. Among patients with S. pneum and severe protein C deficiency at baseline, a significantly greater proportion of patients were no longer severely protein C deficient after 4 days of DrotAA therapy.
  
  
  CONCLUSIONS
  In this population of patients with severe sepsis, patients with S. pneum CAP had a more severe dysregulation of coagulation, fibrinolysis, and inflammation than patients with non-S. pneum CAP; the former also developed significantly elevated levels of markers of thrombosis. Treatment with DrotAA was associated with significant improvements in protein C levels as well as markers of thrombosis. These characteristics may make patients with S. pneum CAP and severe sepsis particularly suited to derive a benefit from therapy with DrotAA.
authors.affiliation: Eli Lilly and Company, Indianapolis, IN 46285, USA. Vail_George_Matthew@lilly.com
authors.forename: G M
authors.initials: GM
authors.lastname: Vail
authors.forename: Y J
authors.initials: YJ
authors.lastname: Xie
authors.forename: D J
authors.initials: DJ
authors.lastname: Haney
authors.forename: C J
authors.initials: CJ
authors.lastname: Barnes
mesh_terms: D000368:Aged; D015415:Biomarkers; D017714:Community-Acquired Infections / Q000150:complications* / Q000473:pathology; D004311:Double-Blind Method; D005342:Fibrinolysis; D006801:Humans; D007249:Inflammation / Q000175:diagnosis* / Q000473:pathology; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D011008:Pneumococcal Infections / Q000150:complications* / Q000473:pathology; D018410:Pneumonia, Bacterial / Q000150:complications* / Q000473:pathology; D011486:Protein C / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D012189:Retrospective Studies; D018805:Sepsis / Q000473:pathology*; D013296:Streptococcus pneumoniae / Q000302:isolation & purification; D013927:Thrombosis / Q000175:diagnosis* / Q000473:pathology
chemical_list: D015415:Biomarkers; D010919:Placebos; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated