title: Metabolomics in pneumonia and sepsis: an analysis of the GenIMS cohort study.
abstract: OBJECTIVE
  To determine the global metabolomic profile as measured in circulating plasma from surviving and non-surviving patients with community-acquired pneumonia (CAP) and sepsis.
  
  
  METHODS
  Random, outcome-stratified case-control sample from a prospective study of 1,895 patients hospitalized with CAP and sepsis. Cases (n = 15) were adults who died before 90 days, and controls (n = 15) were adults who survived, matched on demographics, infection type, and procalcitonin. We determined the global metabolomic profile in the first emergency department blood sample using non-targeted mass-spectrometry. We derived metabolite-based prognostic models for 90-day mortality. We determined if metabolites stimulated cytokine production by differentiated Thp1 monocytes in vitro, and validated metabolite profiles in mouse liver and kidney homogenates at 8 h in cecal ligation and puncture (CLP) sepsis.
  
  
  RESULTS
  We identified 423 small molecules, of which the relative levels of 70 (17 %) were different between survivors and non-survivors (p ≤ 0.05). Broad differences were present in pathways of oxidative stress, bile acid metabolism, and stress response. Metabolite-based prognostic models for 90-day survival performed modestly (AUC = 0.67, 95 % CI 0.48, 0.81). Five nucleic acid metabolites were greater in non-survivors (p ≤ 0.05). Of these, pseudouridine increased monocyte expression of TNFα and IL1β versus control (p < 0.05). Pseudouridine was also increased in liver and kidney homogenates from CLP mice versus sham (p < 0.05 for both).
  
  
  CONCLUSIONS
  Although replication is required, we show the global metabolomic profile in plasma broadly differs between survivors and non-survivors of CAP and sepsis. Metabolite-based prognostic models had modest performance, though metabolites of oxidative stress may act as putative damage-associated molecular patterns.
authors.affiliation: Department of Critical Care Medicine and Emergency Medicine, University of Pittsburgh School of Medicine, 3550 Terrace St, Scaife Hall, #639, Pittsburgh, PA 15261, USA. seymourcw@upmc.edu
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Seymour
authors.forename: Sachin
authors.initials: S
authors.lastname: Yende
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Scott
authors.forename: John
authors.initials: J
authors.lastname: Pribis
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mohney
authors.forename: Lauren N
authors.initials: LN
authors.lastname: Bell
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Chen
authors.forename: Brian S
authors.initials: BS
authors.lastname: Zuckerbraun
authors.forename: William L
authors.initials: WL
authors.lastname: Bigbee
authors.forename: Donald M
authors.initials: DM
authors.lastname: Yealy
authors.forename: Lisa
authors.initials: L
authors.lastname: Weissfeld
authors.forename: John A
authors.initials: JA
authors.lastname: Kellum
authors.forename: Derek C
authors.initials: DC
authors.lastname: Angus
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D015331:Cohort Studies; D017714:Community-Acquired Infections / Q000097:blood / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D055432:Metabolomics; D011014:Pneumonia / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D011446:Prospective Studies; D018805:Sepsis / Q000097:blood / Q000235:genetics / Q000378:metabolism*