title: Do inflammatory markers portend heterotopic ossification and wound failure in combat wounds?
abstract: BACKGROUND
  After a decade of war in Iraq and Afghanistan, we have observed an increase in combat-related injury survival and a paradoxical increase in injury severity, mainly because of the effects of blasts. These severe injuries have a devastating effect on each patient's immune system resulting in massive upregulation of the systemic inflammatory response. By examining inflammatory mediators, preliminary data suggest that it may be possible to correlate complications such as wound failure and heterotopic ossification (HO) with distinct systemic and local inflammatory profiles, but this is a relatively new topic.
  
  
  OBJECTIVE
  We asked whether systemic or local markers of inflammation could be used as an objective means, independent of demographic and subjective factors, to estimate the likelihood of (1) HO and/or (2) wound failure (defined as wounds requiring surgical débridement after definitive closure, or wounds that were not closed or covered within 21 days of injury) in patients sustaining combat wounds.
  
  
  METHODS
  Two hundred combat wounded active-duty service members who sustained high-energy extremity injuries were prospectively enrolled between 2008 and 2012. Of these 200 patients, 189 had adequate followups to determine the presence or absence of HO, and 191 had adequate followups to determine the presence or absence of wound failure. In addition to injury-specific and demographic data, we quantified 24 cytokines and chemokines during each débridement. Patients were followed clinically for 6 weeks, and radiographs were obtained 3 months after definitive wound closure. Associations were investigated between these markers and wound failure or HO, while controlling for known confounders.
  
  
  RESULTS
  The presence of an amputation (p < 0.001; odds ratio [OR], 6.1; 95% CI. 1.63-27.2), Injury Severity Score (p = 0.002; OR, 33.2; 95% CI, 4.2-413), wound surface area (p = 0.001; OR, 1.01; 95% CI, 1.002-1.009), serum interleukin (IL)-3 (p = 0.002; OR, 2.41; 95% CI, 1.5-4.5), serum IL-12p70 (p = 0.01; OR, 0.49; 95% CI, 0.27-0.81), effluent IL-3 (p = 0.02; OR, 1.75; 95% CI, 1.2-2.9), and effluent IL-13 (p = 0.006; OR, 0.67; 95% CI, 0.50-0.87) were independently associated with HO formation. Injury Severity Score (p = 0.05; OR, 18; 95% CI, 5.1-87), wound surface area (p = 0.05; OR, 28.7; 95% CI, 1.5-1250), serum procalcitonin ([ProCT] (p = 0.03; OR, 1596; 95% CI, 5.1-1,758,613) and effluent IL-6 (p = 0.02; OR, 83; 95% CI, 2.5-5820) were independently associated with wound failure.
  
  
  CONCLUSIONS
  We identified associations between patients' systemic and local inflammatory responses and wound-specific complications such as HO and wound failure. However, future efforts to model these data must account for their complex, time dependent, and nonlinear nature.
  
  
  METHODS
  Level II, prognostic study. See the Instructions for Authors for a complete description of levels of evidence.
authors.affiliation: Regenerative Medicine Department, Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA, jaforsberg@me.com.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Forsberg
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Potter
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Polfer
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Safford
authors.forename: Eric A
authors.initials: EA
authors.lastname: Elster
mesh_terms: D015415:Biomarkers / Q000097:blood*; D016207:Cytokines / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000209:etiology; D015601:Injury Severity Score; D008297:Male; D008889:Military Personnel; D009999:Ossification, Heterotopic / Q000097:blood* / Q000000981:diagnostic imaging / Q000209:etiology; D011859:Radiography; D012189:Retrospective Studies; D014481:United States; D014857:Warfare; D014947:Wounds and Injuries / Q000097:blood / Q000150:complications* / Q000000981:diagnostic imaging; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016207:Cytokines