title: Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome.
abstract: OBJECTIVE
  Immunoparalysis defined by prolonged monocyte human leukocyte antigen DR depression is associated with adverse outcomes in adult severe sepsis and can be reversed with granulocyte macrophage colony-stimulating factor (GM-CSF). We hypothesized that immunoparalysis defined by whole-blood ex vivo lipopolysaccharide-induced tumor necrosis factor-alpha (TNFα) response <200 pg/mL beyond day 3 of multiple organ dysfunction syndrome (MODS) is similarly associated with nosocomial infection in children and can be reversed with GM-CSF.
  
  
  METHODS
  In study period 1, we performed a multicenter cohort trial of transplant and nontransplant multiple organ dysfunction syndrome (MODS) patients (≥2 organ failure). In study period 2, we performed an open-label randomized trial of GM-CSF therapy for nonneutropenic, nontransplant, severe MODS patients (≥3 organ failure) with TNFα response <160 pg/mL.
  
  
  RESULTS
  Immunoparalysis was observed in 34% of MODS patients (n = 70) and was associated with increased nosocomial infection (relative risk [RR] 3.3, 95% confidence interval [1.8-6.0] p < 0.05) and mortality (RR 5.8 [2.1-16] p < 0.05). TNFα response <200 pg/mL throughout 7 days after positive culture was associated with persistent nosocomial infection, whereas recovery above 200 pg/mL was associated with resolution of infection (p < 0.05). In study period 2, GM-CSF therapy facilitated rapid recovery of TNFα response to >200 pg/mL by 7 days (p < 0.05) and prevented nosocomial infection (no infections in seven patients versus eight infections in seven patients) (p < 0.05).
  
  
  CONCLUSIONS
  Similar to in adults, immunoparalysis is a potentially reversible risk factor for development of nosocomial infection in pediatric MODS. Whole-blood ex vivo TNFα response is a promising biomarker for monitoring this condition.
authors.affiliation: Department of Pediatrics, Section of Critical Care Medicine, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Hall
authors.forename: Nina L
authors.initials: NL
authors.lastname: Knatz
authors.forename: Carol
authors.initials: C
authors.lastname: Vetterly
authors.forename: Steven
authors.initials: S
authors.lastname: Tomarello
authors.forename: Mark D
authors.initials: MD
authors.lastname: Wewers
authors.forename: Hans Dieter
authors.initials: HD
authors.lastname: Volk
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Carcillo
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D016001:Confidence Intervals; D003428:Cross Infection / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D016867:Immunocompromised Host / Q000187:drug effects*; D007223:Infant; D015850:Interleukin-6 / Q000097:blood; D009102:Multiple Organ Failure / Q000276:immunology / Q000503:physiopathology; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014481:United States
chemical_list: D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor