title: Mortality in patients with septic shock correlates with anti-inflammatory but not proinflammatory immunomodulatory molecules.
abstract: BACKGROUND
  Mortality in patients with septic shock remains unacceptably high and the attempts to antagonize certain proinflammatory cytokines based on the results of animal model studies have failed to improve survival rates. The objective of this article is to examine the pro-/anti-inflammatory cytokine balance in patients with septic shock and its connection with mortality.
  
  
  METHODS
  Serum levels of proinflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin 1β [IL-1β], interferonγ [IFN-γ], and IL-6) and soluble cytokine antagonists (soluble TNF receptor I [sTNF-RI], sTNF-RII, and IL-1Ra) were determined on admission to the intensive care unit (ICU) and 3, 7, 14, and 28 days later in 52 patients with septic shock and in 36 healthy controls. Specific sandwich enzyme-linked immunosorbent assay (ELISA) was used for all determinations.
  
  
  RESULTS
  Serum levels of most of the pro- and anti-inflammatory molecules examined (TNF-α, IL-6, sTNF-RI, sTNF-RII, and IL-1 receptor agonist [IL-1Ra]) were significantly elevated on admission and during the 28-day observation period in patients when compared to controls. Notably, the anti-inflammatory mediators sTNF-RI, sTNF-RII, and IL-1Ra were better predictors of mortality. Receiver-operating characteristic (ROC) analysis revealed that sTNF-RI or sTNF-RII concentrations over 2767 or 4619 pg/mL, respectively, determined a high risk of death (sensitivity: 100%-100%, specificity: 57.1%-71.4%, area under the curve [AUC] 0.759-0.841, respectively), whereas IL-1Ra concentrations below 7033 pg/mL determined a high probability of survival (sensitivity: 60%, specificity: 100%, AUC 0.724). In addition, IFN-γ levels were significantly higher in survivors than in controls during the initial 2 weeks of observation.
  
  
  CONCLUSIONS
  Our data show that serum cytokine disturbance patterns have prognostic significance in patients with septic shock admitted to the ICU. The pattern, defined by an early response to continuously elevated anti-inflammatory cytokine serum levels, is associated with an enhanced risk of a fatal outcome for patients.
authors.affiliation: Intensive Care Unit, Hospital Universitario Principe de Asturias, Alcala de Henares, Madrid, Spain. raul.depablo@uah.es
authors.forename: Raúl
authors.initials: R
authors.lastname: de Pablo
authors.forename: Jorge
authors.initials: J
authors.lastname: Monserrat
authors.forename: Eduardo
authors.initials: E
authors.lastname: Reyes
authors.forename: David
authors.initials: D
authors.lastname: Diaz-Martin
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodriguez Zapata
authors.forename: Fernando
authors.initials: F
authors.lastname: Carballo
authors.forename: Antonio
authors.initials: A
authors.lastname: de la Hera
authors.forename: Alfredo
authors.initials: A
authors.lastname: Prieto
authors.forename: Melchor
authors.initials: M
authors.lastname: Alvarez-Mon
mesh_terms: D000368:Aged; D003422:Critical Care; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D053590:Interleukin 1 Receptor Antagonist Protein / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012372:ROC Curve; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood; D012680:Sensitivity and Specificity; D012772:Shock, Septic / Q000097:blood* / Q000401:mortality* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma