title: An Endotoxin Tolerance Signature Predicts Sepsis and Organ Dysfunction at Initial Clinical Presentation.
abstract: BACKGROUND
  Sepsis involves aberrant immune responses to infection, but the exact nature of this immune dysfunction remains poorly defined. Bacterial endotoxins like lipopolysaccharide (LPS) are potent inducers of inflammation, which has been associated with the pathophysiology of sepsis, but repeated exposure can also induce a suppressive effect known as endotoxin tolerance or cellular reprogramming. It has been proposed that endotoxin tolerance might be associated with the immunosuppressive state that was primarily observed during late-stage sepsis. However, this relationship remains poorly characterised. Here we clarify the underlying mechanisms and timing of immune dysfunction in sepsis.
  
  
  METHODS
  We defined a gene expression signature characteristic of endotoxin tolerance. Gene-set test approaches were used to correlate this signature with early sepsis, both newly and retrospectively analysing microarrays from 593 patients in 11 cohorts. Then we recruited a unique cohort of possible sepsis patients at first clinical presentation in an independent blinded controlled observational study to determine whether this signature was associated with the development of confirmed sepsis and organ dysfunction.
  
  
  RESULTS
  All sepsis patients presented an expression profile strongly associated with the endotoxin tolerance signature (p < 0.01; AUC 96.1%). Importantly, this signature further differentiated between suspected sepsis patients who did, or did not, go on to develop confirmed sepsis, and predicted the development of organ dysfunction.
  
  
  CONCLUSIONS
  Our data support an updated model of sepsis pathogenesis in which endotoxin tolerance-mediated immune dysfunction (cellular reprogramming) is present throughout the clinical course of disease and related to disease severity. Thus endotoxin tolerance might offer new insights guiding the development of new therapies and diagnostics for early sepsis.
authors: Centre for Microbial Diseases and Immunity Research, 2259 Lower Mall Research Station, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors: Olga M
authors: OM
authors: Pena
authors: Flinders University Medical School, GPO Box 2100, Adelaide 5001, South Australia, Australia.
authors: David G
authors: DG
authors: Hancock
authors: Centre for Microbial Diseases and Immunity Research, 2259 Lower Mall Research Station, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors: Ngan H
authors: NH
authors: Lyle
authors: Division of Critical Care Medicine, University of British Columbia at St Paul's Hospital, P3311 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.
authors: Adam
authors: A
authors: Linder
authors: Centre for Microbial Diseases and Immunity Research, 2259 Lower Mall Research Station, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors: James A
authors: JA
authors: Russell
authors: Centre for Microbial Diseases and Immunity Research, 2259 Lower Mall Research Station, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors: Jianguo
authors: J
authors: Xia
authors: Centre for Microbial Diseases and Immunity Research, 2259 Lower Mall Research Station, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada ; Division of Critical Care Medicine, University of British Columbia at St Paul's Hospital, P3311 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.
authors: Christopher D
authors: CD
authors: Fjell
authors: Division of Critical Care Medicine, University of British Columbia at St Paul's Hospital, P3311 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.
authors: John H
authors: JH
authors: Boyd
authors: Centre for Microbial Diseases and Immunity Research, 2259 Lower Mall Research Station, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada ; Wellcome Trust Sanger Institute, Cambridgeshire, United Kingdom.
authors: Robert E W
authors: RE
authors: Hancock
keywords: Cellular reprogramming; Diagnosis; Endotoxin tolerance; Immune dysfunction; Sepsis; Severe sepsis; Signature