title: A molecular biomarker to diagnose community-acquired pneumonia on intensive care unit admission.
abstract: BACKGROUND
  Community-acquired pneumonia (CAP) accounts for a major proportion of intensive care unit (ICU) admissions for respiratory failure and sepsis. Diagnostic uncertainty complicates case management, which may delay appropriate cause-specific treatment.
  
  
  OBJECTIVE
  To characterize the blood genomic response in patients with suspected CAP and identify a candidate biomarker for the rapid diagnosis of CAP on ICU admission.
  
  
  METHODS
  The study comprised two cohorts of consecutively enrolled patients treated for suspected CAP on ICU admission. Patients were designated CAP (cases) and no-CAP patients (control subjects) by post hoc assessment. The first (discovery) cohort (101 CAP and 33 no-CAP patients) was enrolled between January 2011 and July 2012; the second (validation) cohort (70 CAP and 30 no-CAP patients) between July 2012 and June 2013. Blood was collected within 24 hours of ICU admission.
  
  
  RESULTS
  Blood microarray analysis of CAP and no-CAP patients revealed shared and distinct gene expression patterns. A 78-gene signature was defined for CAP, from which a FAIM3:PLAC8 gene expression ratio was derived with area under curve of 0.845 (95% confidence interval, 0.764-0.917) and positive and negative predictive values of 83% and 81%, respectively. Robustness of the FAIM3:PLAC8 ratio was ascertained by quantitative polymerase chain reaction in the validation cohort. The FAIM3:PLAC8 ratio outperformed plasma procalcitonin and IL-8 and IL-6 in discriminating between CAP and no-CAP patients.
  
  
  CONCLUSIONS
  CAP and no-CAP patients presented shared and distinct blood genomic responses. We propose the FAIM3:PLAC8 ratio as a candidate biomarker to assist in the rapid diagnosis of CAP on ICU admission. Clinical trial registered with www.clinicaltrials.gov (NCT 01905033).
authors.affiliation: 1 Center for Experimental Molecular Medicine and Center for Infection and Immunity Amsterdam.
authors.forename: Brendon P
authors.initials: BP
authors.lastname: Scicluna
authors.affiliation: 2 Department of Intensive Care Medicine.|3 Department of Medical Microbiology, and.|4 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; and.
authors.forename: Peter M C
authors.initials: PM
authors.lastname: Klein Klouwenberg
authors.affiliation: 1 Center for Experimental Molecular Medicine and Center for Infection and Immunity Amsterdam.
authors.forename: Lonneke A
authors.initials: LA
authors.lastname: van Vught
authors.affiliation: 1 Center for Experimental Molecular Medicine and Center for Infection and Immunity Amsterdam.
authors.forename: Maryse A
authors.initials: MA
authors.lastname: Wiewel
authors.affiliation: 2 Department of Intensive Care Medicine.|3 Department of Medical Microbiology, and.|4 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; and.
authors.forename: David S Y
authors.initials: DS
authors.lastname: Ong
authors.affiliation: 5 Clinical Epidemiology Biostatistics and Bioinformatics.
authors.forename: Aeilko H
authors.initials: AH
authors.lastname: Zwinderman
authors.affiliation: 6 Cologne Center for Genomics.|7 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, and.
authors.forename: Marek
authors.initials: M
authors.lastname: Franitza
authors.affiliation: 6 Cologne Center for Genomics.
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Toliat
authors.affiliation: 6 Cologne Center for Genomics.|7 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, and.|8 Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: 1 Center for Experimental Molecular Medicine and Center for Infection and Immunity Amsterdam.
authors.forename: Arie J
authors.initials: AJ
authors.lastname: Hoogendijk
authors.affiliation: 9 Department of Intensive Care Medicine, and.
authors.forename: Janneke
authors.initials: J
authors.lastname: Horn
authors.affiliation: 2 Department of Intensive Care Medicine.
authors.forename: Olaf L
authors.initials: OL
authors.lastname: Cremer
authors.affiliation: 9 Department of Intensive Care Medicine, and.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Schultz
authors.affiliation: 3 Department of Medical Microbiology, and.|4 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; and.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Bonten
authors.affiliation: 1 Center for Experimental Molecular Medicine and Center for Infection and Immunity Amsterdam.|10 Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D015415:Biomarkers / Q000097:blood*; D002116:Calcitonin / Q000097:blood; D015740:Calcitonin Gene-Related Peptide; D017714:Community-Acquired Infections / Q000175:diagnosis*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007362:Intensive Care Units; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D008875:Middle Aged; D011014:Pneumonia / Q000175:diagnosis*; D011498:Protein Precursors / Q000097:blood; D011506:Proteins / Q000235:genetics*; D046888:Tissue Array Analysis
chemical_list: D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; C000606589:CALCA protein, human; C421307:FAIM protein, human; D015850:Interleukin-6; D016209:Interleukin-8; C506004:PLAC8 protein, human; D011498:Protein Precursors; D011506:Proteins; D002116:Calcitonin; D015740:Calcitonin Gene-Related Peptide
keywords: biomarker; blood; microarray; pneumonia; sepsis