title: A Dysregulated Balance of Proinflammatory and Anti-Inflammatory Host Cytokine Response Early During Therapy Predicts Persistence and Mortality in Staphylococcus aureus Bacteremia.
abstract: OBJECTIVE
  The contribution of individual immune response to Staphylococcus aureus bacteremia on outcome has not been well studied. The objective was to relate the host cytokine response to outcome of Staphylococcus aureus bacteremia.
  
  
  METHODS
  Prospective observational study.
  
  
  METHODS
  Three U.S. university-affiliated medical centers.
  
  
  METHODS
  Adult patients infected with Staphylococcus aureus bacteremia hospitalized between July 2012 and August 2014.
  
  
  METHODS
  Blood specimens were obtained at Staphylococcus aureus bacteremia onset and 72 hours after therapy initiation. Levels of tissue necrosis factor, interleukin-6, interleukin-8, interleukin-17A, and interleukin-10 were measured by enzyme-linked immunosorbent assay at each time point and compared between those with persistent bacteremia (≥ 4 d) and resolving bacteremia. Primary outcome was persistent bacteremia after 4 days of effective therapy. Secondary outcomes were 30-day mortality and 30-day recurrence.
  
  
  RESULTS
  A total of 196 patients were included (mean age, 59 yr); of them, 33% had methicillin-resistant Staphylococcus aureus bacteremia. Forty-seven percent of the methicillin-resistant Staphylococcus aureus strains were staphylococcal cassette chromosome mec IV. Persistent bacteremia occurred in 24% of patients (47/196); they were more likely to die than resolving bacteremia group (28% vs 5%; p < 0.001). Compared with resolving bacteremia group, persistent bacteremia patients had higher initial median levels of tissue necrosis factor (44.73 vs 21.68 pg/mL; p < 0.001), interleukin-8 (124.76 vs 47.48 pg/mL; p = 0.028), and interleukin-10 (104.31 vs 29.72 pg/mL; p < 0.001). Despite 72 hours of treatment, levels remained higher for the persistent bacteremia group than for the resolving bacteremia group (tissue necrosis factor: 26.95 vs 18.38 pg/mL, p = 0.02; interleukin-8: 70.75 vs 27.86 pg/mL, p = 0.002; interleukin-6: 67.50 vs 21.81 pg/mL, p = 0.005; and interleukin-10: 30.98 vs 12.60 pg/mL, p < 0.001). Interleukin-17A levels were similar between groups at both time points. After controlling for confounding variables by multivariate analysis, interleukin-10/tissue necrosis factor ratio at 72 hours most significantly predicted persistence (odds ratio, 2.98; 95% CI, 1.39-6.39; p = 0.005) and mortality (odds ratio, 9.87; 95% CI, 2.64-36.91; p < 0.001) at values more than 1.00 and more than 2.56, respectively.
  
  
  CONCLUSIONS
  Sustained elevation of interleukin-10/tissue necrosis factor ratio at 72 hours suggests a dysregulated immune response and may be used to guide management to improve outcomes.
authors.affiliation: 1Department of Pharmacy, University of Southern California, Los Angeles, CA. 2Department of Pathology, Keck School of Medicine, Los Angeles, CA. 3Department of Preventative Medicine, Keck School of Medicine, Los Angeles, CA. 4Department of Pharmacy, Huntington Hospital, Pasadena, CA. 5Department of Medicine, Huntington Hospital, Pasadena, CA.
authors.forename: Emi
authors.initials: E
authors.lastname: Minejima
authors.forename: Joyce
authors.initials: J
authors.lastname: Bensman
authors.forename: Rosemary C
authors.initials: RC
authors.lastname: She
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Mack
authors.forename: Martin
authors.initials: M
authors.lastname: Tuan Tran
authors.forename: Pamela
authors.initials: P
authors.lastname: Ny
authors.forename: Mimi
authors.initials: M
authors.lastname: Lou
authors.forename: Jason
authors.initials: J
authors.lastname: Yamaki
authors.forename: Paul
authors.initials: P
authors.lastname: Nieberg
authors.forename: Joyce
authors.initials: J
authors.lastname: Ho
authors.forename: Annie
authors.initials: A
authors.lastname: Wong-Beringer
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D016470:Bacteremia / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D006801:Humans; D007378:Interleukins / Q000097:blood*; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification; D008875:Middle Aged; D011446:Prospective Studies; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000276:immunology / Q000401:mortality*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*; D014481:United States
chemical_list: D000900:Anti-Bacterial Agents; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha