title: Decreased CX3CR1 messenger RNA expression is an independent molecular biomarker of early and late mortality in critically ill patients.
abstract: BACKGROUND
  Chemokine (C-X3-C motif) receptor 1 (CX3CR1) was identified as the most differentially expressed gene between survivors and non-survivors in two independent cohorts of septic shock patients and was proposed as a marker of sepsis-induced immunosuppression. Whether such a biomarker is associated with mortality in the heterogeneous group of critically ill patients is unknown. The primary objective of this study was to evaluate the association between CX3CR1 messenger RNA (mRNA) expression and mortality in intensive care unit (ICU) patients. The secondary objective was to evaluate similar endpoints in the subgroup of septic shock patients.
  
  
  METHODS
  We performed a prospective, multicentre, non-interventional study in six ICUs of university hospitals in Lyon, France. Every consecutive adult patient with systemic inflammatory response syndrome and an expected length of stay in the ICU over 2 days was included. Whole-blood CX3CR1 mRNA expression was measured by quantitative real-time polymerase chain reaction at day 1 (D1) and D3 after inclusion.
  
  
  RESULTS
  In ICU patients (n = 725), decreased CX3CR1 mRNA expression at D1 was associated with high D7 mortality (AUC 0.70, adjusted OR [aOR] 2.03, 95 % CI 1.19-3.46), while decreased expression at D3 was associated with increased D28 mortality (AUC 0.64, aOR 2.34, 95 % CI 1.45-3.77). In septic shock patients (n = 279), similar associations were observed between decreased D1 CX3CR1 mRNA expression and D7 mortality (AUC 0.69, aOR 2.76, 95 % CI 1.32-5.75) as well as decreased D3 expression and D28 mortality (AUC 0.72, aOR 3.98, 95 % CI 1.72-9.23). These associations were independent of lactacidaemia, Simplified Acute Physiology Score II, Sepsis-related Organ Failure Assessment score and Charlson comorbidity index.
  
  
  CONCLUSIONS
  This study represents the largest evaluation of such an mRNA marker in a heterogeneous cohort of severely injured patients. Our results show that decreased CX3CR1 mRNA expression is associated with increased mortality in ICU patients. This suggests a link between injury-induced immunosuppression and mortality in critically ill patients. In this context, the monitoring of such a host response molecular biomarker could prove very helpful for the identification of patients at high risk of death in the ICU.
authors.affiliation: Hospices Civils de Lyon, Intensive Care Unit, Centre Hospitalier Lyon Sud, Pierre Bénite, France.|Hospices Civils de Lyon-bioMérieux Joint Research Unit, Groupement Hospitalier Edouard Herriot, Lyon, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Friggeri
authors.affiliation: Hospices Civils de Lyon-bioMérieux Joint Research Unit, Groupement Hospitalier Edouard Herriot, Lyon, France.
authors.forename: Marie-Angélique
authors.initials: MA
authors.lastname: Cazalis
authors.affiliation: Hospices Civils de Lyon-bioMérieux Joint Research Unit, Groupement Hospitalier Edouard Herriot, Lyon, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Pachot
authors.affiliation: Hospices Civils de Lyon, Medical Intensive Care Unit, Groupement Hospitalier Edouard Herriot, Lyon, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Cour
authors.affiliation: Hospices Civils de Lyon, Medical Intensive Care Unit, Groupement Hospitalier Edouard Herriot, Lyon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Argaud
authors.affiliation: Hospices Civils de Lyon, Intensive Care Unit, Centre Hospitalier Lyon Sud, Pierre Bénite, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Allaouchiche
authors.affiliation: Hospices Civils de Lyon, Department of Anaesthesiology and Critical Care Medicine, Groupement Hospitalier Edouard Herriot, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Floccard
authors.affiliation: Hospices Civils de Lyon, Intensive Care Unit, Hôpital de la Croix Rousse, Lyon, France.
authors.forename: Zoé
authors.initials: Z
authors.lastname: Schmitt
authors.affiliation: Hospices Civils de Lyon, Department of Anaesthesiology and Critical Care Medicine, Groupement Hospitalier Edouard Herriot, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Martin
authors.affiliation: Hospices Civils de Lyon-bioMérieux Joint Research Unit, Groupement Hospitalier Edouard Herriot, Lyon, France.|Hospices Civils de Lyon, Department of Anaesthesiology and Critical Care Medicine, Groupement Hospitalier Edouard Herriot, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rimmelé
authors.affiliation: Hospices Civils de Lyon, Intensive Care Unit, Centre Hospitalier Lyon Sud, Pierre Bénite, France.
authors.forename: Oriane
authors.initials: O
authors.lastname: Fontaine-Kesteloot
authors.affiliation: Hospices Civils de Lyon, Department of Anaesthesiology and Critical Care Medicine, Groupement Hospitalier Edouard Herriot, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Page
authors.affiliation: Hospices Civils de Lyon, Intensive Care Unit, Centre Hospitalier Lyon Sud, Pierre Bénite, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Piriou
authors.affiliation: Hospices Civils de Lyon, Intensive Care Unit, Centre Hospitalier Lyon Sud, Pierre Bénite, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Bohé
authors.affiliation: Hospices Civils de Lyon-bioMérieux Joint Research Unit, Groupement Hospitalier Edouard Herriot, Lyon, France.|Hospices Civils de Lyon, Immunology Laboratory, Groupement Hospitalier Edouard Herriot, Lyon, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Monneret
authors.affiliation: Hospices Civils de Lyon-bioMérieux Joint Research Unit, Groupement Hospitalier Edouard Herriot, Lyon, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Morisset
authors.affiliation: Hospices Civils de Lyon-bioMérieux Joint Research Unit, Groupement Hospitalier Edouard Herriot, Lyon, France.|Hospices Civils de Lyon, Department of Anaesthesiology and Critical Care Medicine, Groupement Hospitalier Edouard Herriot, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Textoris
authors.affiliation: Hospices Civils de Lyon, Intensive Care Unit, Centre Hospitalier Lyon Sud, Pierre Bénite, France.|Hospices Civils de Lyon-bioMérieux Joint Research Unit, Groupement Hospitalier Edouard Herriot, Lyon, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Vallin
authors.affiliation: Hospices Civils de Lyon-bioMérieux Joint Research Unit, Groupement Hospitalier Edouard Herriot, Lyon, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Blein
authors.affiliation: Hospices Civils de Lyon, Université Lyon 1, CNRS, UMR5558, Service de Biostatistique et Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Lyon, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Maucort-Boulch
authors.affiliation: Hospices Civils de Lyon, Intensive Care Unit, Centre Hospitalier Lyon Sud, Pierre Bénite, France.|Hospices Civils de Lyon-bioMérieux Joint Research Unit, Groupement Hospitalier Edouard Herriot, Lyon, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Lepape
authors.affiliation: Hospices Civils de Lyon-bioMérieux Joint Research Unit, Groupement Hospitalier Edouard Herriot, Lyon, France. fabienne.venet@chu-lyon.fr.|Hospices Civils de Lyon, Immunology Laboratory, Groupement Hospitalier Edouard Herriot, Lyon, France. fabienne.venet@chu-lyon.fr.|Immunology Laboratory, Hôpital E. Herriot - Hospices Civils de Lyon, 5 place d'Arsonval, 69437, Lyon Cedex 03, France. fabienne.venet@chu-lyon.fr.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Venet
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D000073883:CX3C Chemokine Receptor 1 / Q000032:analysis* / Q000097:blood; D015331:Cohort Studies; D016638:Critical Illness; D005260:Female; D005602:France; D017052:Hospital Mortality; D006801:Humans; D007362:Intensive Care Units / Q000458:organization & administration; D007902:Length of Stay; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012333:RNA, Messenger / Q000032:analysis* / Q000097:blood; D012372:ROC Curve; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012307:Risk Factors; D012772:Shock, Septic / Q000097:blood / Q000150:complications / Q000503:physiopathology; D017741:Survivors / Q000706:statistics & numerical data; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood / Q000150:complications / Q000503:physiopathology*
chemical_list: D015415:Biomarkers; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D012333:RNA, Messenger
keywords: Biomarker; CX3CR1 mRNA; Immunosuppression; Intensive care unit; Mortality; Prognosis; Transcriptomics