title: Improvement of prognostic performance in severely injured patients by integrated clinico-transcriptomics: a translational approach.
abstract: BACKGROUND
  Severe trauma triggers a systemic inflammatory response that contributes to secondary complications, such as nosocomial infections, sepsis or multi-organ failure. The present study was aimed to identify markers predicting complications and an adverse outcome of severely injured patients by an integrated clinico-transcriptomic approach.
  
  
  METHODS
  In a prospective study, RNA samples from circulating leukocytes from severely injured patients (injury severity score ≥ 17 points; n = 104) admitted to a Level I Trauma Center were analyzed for dynamic changes in gene expression over a period of 21 days by quantitative RT-PCR. Transcriptomic candidates were selected based on whole genome screening of a representative discovery set (n = 10 patients) or known mechanisms of the immune response, including mediators of inflammation (IL-8, IL-10, TNF-α, MIF, C5, CD59, SPHK1), danger signaling (HMGB1, TLR2, CD14, IL-33, IL-1RL1), and components of the heme degradation pathway (HP, CD163, HMOX1, BLVRA, BLVRB). Clinical markers comprised standard physiological and laboratory parameters and scoring systems routinely determined in trauma patients.
  
  
  RESULTS
  Leukocytes, thrombocytes and the expression of sphingosine kinase-1 (SPHK1), complement C5, and haptoglobin (HP) have been identified as markers with the best performance. Leukocytes showed a biphasic course with peaks on day 0 and day 11 after trauma, and patients with sepsis exhibited significantly higher leukocyte levels. Thrombocyte numbers showed a typical profile with initial thrombopenia and robust thrombocytosis in week 3 after trauma, ranging 2- to 3-fold above the upper normal value. 'Relative thrombocytopenia' was associated with multi-organ dysfunction, the development of sepsis, and mortality, the latter of which could be predicted within 3 days prior to the time point of death. SPHK1 expression at the day of admission indicated mortality with excellent performance. C5-expression on day 1 after trauma correlated with an increased risk for the development of nosocomial infections during the later course, while HP was found to be a marker for the development of sepsis.
  
  
  CONCLUSIONS
  The combination of clinical and transcriptomic markers improves the prognostic performance and may represent a useful tool for individual risk stratification in trauma patients.
authors.affiliation: Division of Trauma Surgery, Department of Surgery, University Hospital Zurich, University of Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland. daniel.rittirsch@usz.ch.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rittirsch
authors.affiliation: Division of Trauma Surgery, Department of Surgery, University Hospital Zurich, University of Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland. veitschoenborn@googlemail.com.
authors.forename: Veit
authors.initials: V
authors.lastname: Schoenborn
authors.affiliation: Department of Anaesthesiology and Intensive Care Therapy, Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany. sandro.lindig@med.uni-jena.de.
authors.forename: Sandro
authors.initials: S
authors.lastname: Lindig
authors.affiliation: Division of Trauma Surgery, Department of Surgery, University Hospital Zurich, University of Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland. elisabeth.wanner@usz.ch.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Wanner
authors.affiliation: Division of Trauma Surgery, Department of Surgery, University Hospital Zurich, University of Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland. kai.sprengel@usz.ch.
authors.forename: Kai
authors.initials: K
authors.lastname: Sprengel
authors.affiliation: Division of Trauma Surgery, Department of Surgery, University Hospital Zurich, University of Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland. sebguenkel@web.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Günkel
authors.affiliation: Department of Anaesthesiology and Intensive Care Therapy, Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany. barbara.schaarschmidt@med.uni-jena.de.|Center for Sepsis Control and Care, Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany. barbara.schaarschmidt@med.uni-jena.de.
authors.forename: Barbara
authors.initials: B
authors.lastname: Schaarschmidt
authors.affiliation: Division of Trauma Surgery, Department of Surgery, University Hospital Zurich, University of Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland. albers.sonja@web.de.
authors.forename: Sonja
authors.initials: S
authors.lastname: Märsmann
authors.affiliation: Division of Trauma Surgery, Department of Surgery, University Hospital Zurich, University of Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland. hanspeter.simmen@usz.ch.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Simmen
authors.affiliation: Division of Trauma Surgery, Department of Surgery, University Hospital Zurich, University of Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland. paolo.cinelli@usz.ch.
authors.forename: Paolo
authors.initials: P
authors.lastname: Cinelli
authors.affiliation: Department of Anaesthesiology and Intensive Care Therapy, Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany. michael.bauer@med.uni-jena.de.|Center for Sepsis Control and Care, Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany. michael.bauer@med.uni-jena.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Department of Anaesthesiology and Intensive Care Therapy, Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany. ralf.claus@med.uni-jena.de.|Center for Sepsis Control and Care, Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany. ralf.claus@med.uni-jena.de.
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Claus
authors.affiliation: Division of Trauma Surgery, Department of Surgery, University Hospital Zurich, University of Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland. guido.wanner@usz.ch.
authors.forename: Guido A
authors.initials: GA
authors.lastname: Wanner
mesh_terms: D015415:Biomarkers / Q000032:analysis / Q000097:blood; D003182:Complement C5 / Q000032:analysis / Q000096:biosynthesis; D006242:Haptoglobins / Q000032:analysis / Q000096:biosynthesis; D006801:Humans; D015601:Injury Severity Score; D009102:Multiple Organ Failure / Q000097:blood / Q000175:diagnosis*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000032:analysis / Q000097:blood; D011446:Prospective Studies; D018570:Risk Assessment / Q000379:methods*; D018805:Sepsis / Q000097:blood / Q000175:diagnosis*; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood / Q000175:diagnosis*; D000099157:Sphingosine Kinase
chemical_list: D015415:Biomarkers; D003182:Complement C5; D006242:Haptoglobins; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase