title: Serum Inflammatory Cytokine Markers of Invasive Fungal Infection in Previously Immunocompetent Battle Casualties.
abstract: BACKGROUND
  Invasive fungal infection (IFI) is described increasingly in individuals experiencing high-energy military trauma. Hallmarks of successful treatment involve aggressive surgical debridement and early initiation of systemic antimicrobial therapy. Currently, intravenous anti-fungal therapy commences based on appearance of wounds and patient's clinical course. Whereas some clinical protocols exist to predict which critically injured patients should receive anti-fungal therapies, there are no established serum markers associated with IFI. Our hypothesis is that serum inflammatory cytokines exist that can assist in identifying individuals at risk for IFI.
  
  
  METHODS
  This is a retrospective case control study at a single institution. Nine patients with IFI (Saksenaea vasiformis, Fusarium sp., Graphium sp., Scedosporium sp., Aspergillus sp., Mucor sp., and Alternaria sp.) after battlefield trauma were matched to nine individuals with similar injury patterns whose laboratory results were negative for IFI. The combination of serum inflammatory cytokines from the first and second debridements was examined with multiplex platform proteomic analysis. We defined statistical significance as a two-tailed α<0.05 after adjusting for multiple comparisons using the false discovery rate method. This model was refined further with correlation-based filter selection and the area under the curve of the receiver operating characteristics (AUROC) was tested.
  
  
  RESULTS
  Both groups had similar Injury Severity Scores (ISS) (mean±standard deviation [SD]) (26.8±15.5 vs. 29.2±16.8, p=0.766). Elevated RANTES (regulated on activation, normal T cell expressed and secreted) alone (10,492.8±4,450.1 vs. 5,333.3±4,162.2, p=0.006) correlated with IFI. Also, the combination of persistent elevations in RANTES, interleukin (IL)-2R, and IL-15 was a robust model for predicting IFI with the AUROC being 0.9.
  
  
  CONCLUSIONS
  Elevation in serum cytokines, particularly RANTES, correlated with IFI in this small group of patients. This demonstrates the potential of future rapid serum testing for early initiation and guidance of anti-fungal therapies.
authors.affiliation: 1 Department of General Surgery, Walter Reed National Military Medical Center, Bethesda , Maryland.|2 Naval Medical Research Center , Regenerative Medicine Department, Silver Spring, Maryland.|4 Norman M. Rich Department of Surgery, Uniformed Services University of the Health Sciences , Bethesda, Maryland.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Radowsky
authors.affiliation: 2 Naval Medical Research Center , Regenerative Medicine Department, Silver Spring, Maryland.|5 Surgical Critical Care Initiative (SC2i), Uniformed Services University of the Health Sciences , Department of Surgery, Bethesda, Maryland.
authors.forename: Trevor S
authors.initials: TS
authors.lastname: Brown
authors.affiliation: 2 Naval Medical Research Center , Regenerative Medicine Department, Silver Spring, Maryland.|4 Norman M. Rich Department of Surgery, Uniformed Services University of the Health Sciences , Bethesda, Maryland.|5 Surgical Critical Care Initiative (SC2i), Uniformed Services University of the Health Sciences , Department of Surgery, Bethesda, Maryland.
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Lisboa
authors.affiliation: 1 Department of General Surgery, Walter Reed National Military Medical Center, Bethesda , Maryland.|4 Norman M. Rich Department of Surgery, Uniformed Services University of the Health Sciences , Bethesda, Maryland.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Rodriguez
authors.affiliation: 2 Naval Medical Research Center , Regenerative Medicine Department, Silver Spring, Maryland.|3 Department of Orthopaedic Surgery, Walter Reed National Military Medical Center, Bethesda , Maryland.|5 Surgical Critical Care Initiative (SC2i), Uniformed Services University of the Health Sciences , Department of Surgery, Bethesda, Maryland.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Forsberg
authors.affiliation: 1 Department of General Surgery, Walter Reed National Military Medical Center, Bethesda , Maryland.|2 Naval Medical Research Center , Regenerative Medicine Department, Silver Spring, Maryland.|4 Norman M. Rich Department of Surgery, Uniformed Services University of the Health Sciences , Bethesda, Maryland.|5 Surgical Critical Care Initiative (SC2i), Uniformed Services University of the Health Sciences , Department of Surgery, Bethesda, Maryland.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Elster
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood*; D016022:Case-Control Studies; D016207:Cytokines / Q000097:blood*; D016469:Fungemia / Q000175:diagnosis* / Q000382:microbiology; D005658:Fungi / Q000145:classification / Q000302:isolation & purification; D006801:Humans; D010865:Pilot Projects; D012189:Retrospective Studies; D044967:Serum / Q000737:chemistry*; D000067398:War-Related Injuries / Q000150:complications*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016207:Cytokines