title: A Transcriptomic Biomarker to Quantify Systemic Inflammation in Sepsis - A Prospective Multicenter Phase II Diagnostic Study.
abstract: Development of a dysregulated immune response discriminates sepsis from uncomplicated infection. Currently used biomarkers fail to describe simultaneously occurring pro- and anti-inflammatory responses potentially amenable to therapy. Marker candidates were screened by microarray and, after transfer to a platform allowing point-of-care testing, validated in a confirmation set of 246 medical and surgical patients. We identified up-regulated pathways reflecting innate effector mechanisms, while down-regulated pathways related to adaptive lymphocyte functions. A panel of markers composed of three up- (Toll-like receptor 5; Protectin; Clusterin) and 4 down-regulated transcripts (Fibrinogen-like 2; Interleukin-7 receptor; Major histocompatibility complex class II, DP alpha1; Carboxypeptidase, vitellogenic-like) described the magnitude of immune alterations. The created gene expression score was significantly greater in patients with definite as well as with possible/probable infection than with no infection (median (Q25/Q75): 80 (60/101)) and 81 (58/97 vs. 49 (27/66), AUC-ROC=0.812 (95%-CI 0.755-0.869), p<0.0001). Down-regulated lymphocyte markers were associated with prognosis with good sensitivity but limited specificity. Quantifying systemic inflammation by assessment of both pro- and anti-inflammatory innate and adaptive immune responses provides a novel option to identify patients-at-risk and may facilitate immune interventions in sepsis.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Erlanger Allee 101, 07646 Jena, Germany; Center for Sepsis Control & Care, Jena University Hospital, Erlanger Allee 101, 07646 Jena, Germany. Electronic address: michael.bauer@med.uni-jena.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Center for Sepsis Control & Care, Jena University Hospital, Erlanger Allee 101, 07646 Jena, Germany; 4th Department of Internal Medicine, University of Athens, Medical School, 1 Rimini Str, 12462 Athens, Greece.
authors.forename: Evangelos J
authors.initials: EJ
authors.lastname: Giamarellos-Bourboulis
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Erlanger Allee 101, 07646 Jena, Germany; Center for Sepsis Control & Care, Jena University Hospital, Erlanger Allee 101, 07646 Jena, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kortgen
authors.affiliation: Analytik-Jena AG Germany, Sepsis diagnostics expert group (previously SIRS-Lab GmbH Jena), Konrad-Zuse-Strasse 1, 07745 Jena, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Möller
authors.affiliation: Analytik-Jena AG Germany, Sepsis diagnostics expert group (previously SIRS-Lab GmbH Jena), Konrad-Zuse-Strasse 1, 07745 Jena, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Felsmann
authors.affiliation: Unit Cytokines & Inflammation, Institute Pasteur, 75015 Paris, France.
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Cavaillon
authors.affiliation: Department of Otolaryngology and the Institute of Phoniatry and Pedaudiology, Jena University Hospital, Lessingstrasse 2, 07740 Jena, Germany.
authors.forename: Orlando
authors.initials: O
authors.lastname: Guntinas-Lichius
authors.affiliation: Division of Emergency Medicine, Department of Community, Primary Care and Emergency Medicine, Geneva University Hospitals and Faculty of Medicine, 2, rue Gabrielle Perret-Gentil, 1211 Geneva 14, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rutschmann
authors.affiliation: Center for Sepsis Control & Care, Jena University Hospital, Erlanger Allee 101, 07646 Jena, Germany.
authors.forename: Andriy
authors.initials: A
authors.lastname: Ruryk
authors.affiliation: Faculty of Medical and Life Sciences, Furtwangen University, Jakob-Kienzle-Str. 17, 78054 Villingen-Schwenningen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kohl
authors.affiliation: State Development Corporation of Thuringia, Mainzerhofstraße 12, 99084 Erfurt, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Wlotzka
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Erlanger Allee 101, 07646 Jena, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rußwurm
authors.affiliation: University of Toronto, St. Michael's Hospital, 30 Bond Street, Bond 4-014, Toronto, Ontario M5B 1W8, Canada.
authors.forename: John C
authors.initials: JC
authors.lastname: Marshall
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Erlanger Allee 101, 07646 Jena, Germany; Center for Sepsis Control & Care, Jena University Hospital, Erlanger Allee 101, 07646 Jena, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Reinhart
mesh_terms: D056704:Adaptive Immunity; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D005819:Genetic Markers / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D019095:Point-of-Care Systems; D011379:Prognosis; D011446:Prospective Studies; D012680:Sensitivity and Specificity; D018805:Sepsis / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology
chemical_list: D005819:Genetic Markers
keywords: Adaptive immunity; Clinical utility; Host response; Point-of-care; RT-qPCR; Transcriptomic profiling