title: Microvesicle Tissue Factor Activity and Interleukin-8 Levels are Associated with Mortality in Patients with Influenza A/H1N1 Infection.
abstract: OBJECTIVE
  To identify plasma biomarkers that can be early predictors of mortality in critically ill patients with primary influenza A/H1N1.
  
  
  METHODS
  A prospective, multicenter, case-cohort pilot study.
  
  
  METHODS
  Three academic ICUs.
  
  
  METHODS
  Fifteen patients with primary influenza A/H1N1 that included seven survivors and eight nonsurvivors. For comparison, age- and gender-matched healthy controls (n = 27) were also studied.
  
  
  METHODS
  Plasma was prepared from whole blood drawn on ICU admission in patients with influenza (ICU day 1). Microvesicle tissue factor activity, thrombin-antithrombin complexes, and D-dimers were measured as procoagulant markers and markers of activation of coagulation. Plasma cytokine levels were measured on the same blood samples in a subset of 12 patients with influenza using the Luminex Multi-Analyte Profiling system (Luminex Corporation, DeSoto, TX). Patients were followed up for the primary outcome of 28-day mortality.
  
  
  RESULTS
  The average admission Acute Physiology and Chronic Health Evaluation II score of the patients was 25.5 ± 9.3, 60% of patients had shock, and the 28-day mortality rate was 53.3% (n = 8/15). Patients with influenza had dysregulated indices of coagulation and inflammation compared with controls. Among the markers of activation of coagulation measured on ICU day 1, only increased microvesicle tissue factor activity was significantly associated with subsequent influenza-related mortality (5.6 ± 1.2 pg/mL in nonsurvivors vs 1.8 ± 0.8 pg/mL in survivors; p < 0.05). Interleukin-8 was significantly higher in nonsurvivors compared with survivors (71.8 ± 29.1 pg/mL, n = 5 vs 17.3 ± 3.7 pg/mL, n = 7; p < 0.05). In addition, microvesicle tissue factor activity and interleukin-8 levels were significantly and positively correlated (r = 0.60; p = 0.003). Other cytokines, thrombin-antithrombin complexes, and D-dimer were not different between nonsurvivors and survivors and did not correlate with illness severity or mortality.
  
  
  CONCLUSIONS
  This study identifies an association between plasma interleukin-8 and microvesicle tissue factor activity measured on admission in patients with severe, primary influenza A/H1N1 infection and subsequent mortality. Thus, these biomarkers may serve as very early prognostic markers for patients with influenza A/H1N1.
authors.affiliation: 1Divisions of General Internal Medicine, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT. 2Molecular Medicine Program at the University of Utah School of Medicine, Salt Lake City, UT. 3Department of Internal Medicine at the George E. Wahlen Salt Lake City VAMC, Salt Lake City, UT. 4Division of Hematology/Oncology, Department of Medicine, UNC McAllister Heart Institute, University of North Carolina at Chapel Hill, NC. 5Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Rondina
authors.forename: Kohei
authors.initials: K
authors.lastname: Tatsumi
authors.forename: Julie A
authors.initials: JA
authors.lastname: Bastarache
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D016207:Cytokines / Q000097:blood; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D007251:Influenza, Human / Q000097:blood / Q000378:metabolism* / Q000401:mortality; D007362:Intensive Care Units; D016209:Interleukin-8 / Q000097:blood*; D055806:Microvessels / Q000378:metabolism*; D011379:Prognosis; D011446:Prospective Studies; D013925:Thromboplastin / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D016209:Interleukin-8; D013925:Thromboplastin