title: Activation of the tryptophan/serotonin pathway is associated with severity and predicts outcomes in pneumonia: results of a long-term cohort study.
abstract: BACKGROUND
  As part of the immune defense during infection, an increase in enzyme activity of indoleamine 2,3-dioxygenase (IDO) leads to a breakdown of tryptophan to kynurenine. In previous animal studies, therapeutic antagonism of IDO resulted in reduced sepsis mortality. We investigated the prognostic ability of tryptophan, serotonin, kynurenine and IDO (represented by the ratio of kynurenine/tryptophan) to predict adverse clinical outcomes in patients with community-acquired pneumonia (CAP).
  
  
  METHODS
  We measured tryptophan, serotonin and kynurenine on admission plasma samples from CAP patients included in a previous multicenter trial by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). We studied their association with inflammation (C-reactive protein), infection (procalcitonin) and clinical outcome.
  
  
  RESULTS
  Mortality in the 268 included patients was 45% within 6 years of follow-up. IDO and kynurenine showed a strong positive correlation with markers of infection (procalcitonin) and inflammation (C-reactive protein) as well as sepsis and CAP severity scores. Tryptophan showed similar, but negative correlations. In a multivariate regression analysis adjusted for age and comorbidities, higher IDO activity and lower tryptophan levels were strongly associated with short-term adverse outcome defined as death and/or ICU admission within 30 days with adjusted odds ratios of 9.1 [95% confidence interval (CI) 1.4-59.5, p=0.021] and 0.11 (95% CI 0.02-0.70, p=0.021). Multivariate analysis did not reveal significant associations for kynurenine and serotonin.
  
  
  CONCLUSIONS
  In hospitalized CAP patients, higher IDO activity and lower tryptophan levels independently predicted disease severity and short-term adverse outcome. Whether therapeutic modulation of IDO has positive effects on outcome needs further investigation.
authors.affiliation: .
authors.forename: Marc A
authors.initials: MA
authors.lastname: Meier
authors.affiliation: .
authors.forename: Manuel
authors.initials: M
authors.lastname: Ottiger
authors.affiliation: .
authors.forename: Alaadin
authors.initials: A
authors.lastname: Vögeli
authors.affiliation: .
authors.forename: Christian
authors.initials: C
authors.lastname: Steuer
authors.affiliation: .
authors.forename: Luca
authors.initials: L
authors.lastname: Bernasconi
authors.affiliation: .
authors.forename: Robert
authors.initials: R
authors.lastname: Thomann
authors.affiliation: .
authors.forename: Mirjam
authors.initials: M
authors.lastname: Christ-Crain
authors.affiliation: .
authors.forename: Christoph
authors.initials: C
authors.lastname: Henzen
authors.affiliation: .
authors.forename: Claus
authors.initials: C
authors.lastname: Hoess
authors.affiliation: .
authors.forename: Werner
authors.initials: W
authors.lastname: Zimmerli
authors.affiliation: .
authors.forename: Andreas
authors.initials: A
authors.lastname: Huber
authors.affiliation: .
authors.forename: Beat
authors.initials: B
authors.lastname: Mueller
authors.affiliation: .
authors.forename: Philipp
authors.initials: P
authors.lastname: Schuetz
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007737:Kynurenine / Q000097:blood; D008297:Male; D008875:Middle Aged; D010343:Patient Admission; D011014:Pneumonia / Q000097:blood* / Q000175:diagnosis* / Q000201:enzymology / Q000401:mortality; D011379:Prognosis; D012701:Serotonin / Q000097:blood*; D014364:Tryptophan / Q000097:blood*
chemical_list: D015415:Biomarkers; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012701:Serotonin; D007737:Kynurenine; D014364:Tryptophan
keywords: community-acquired pneumonia; indoleamine 2,3-dioxygenase; kynurenine; long-term; mortality; prediction; serotonin; tryptophan