NATURAL CYTOKINE ANTAGONISTS AND ENDOGENOUS ANTIENDOTOXIN CORE ANTIBODIES IN SEPSIS SYNDROME

Objective.-To assess the value of measuring circulating concentrations of mediators (endotoxin, tumor necrosis factor-alpha [TNF-alpha], interleukin-1 beta [IL-1 beta], and interleukin-6 [IL-6]) and their endogenous antagonists (antiendotoxin core antibody [EndoCAb], interleukin-1 receptor antagonist [lL-1ra], and soluble TNF receptors [sTNF-R]) in predicting mortality and organ failure in sepsis syndrome. Design.-Cohort study with a follow-up period of 30 days. Setting.-Intensive therapy units of five tertiary referral centers in Scotland. Subjects.-A total of 146 intensive therapy unit patients with sepsis syndrome underwent repeated sampling during a 10-day period following admission to an intensive therapy unit. Main Outcome Measures.-Circulating concentrations of mediators and antagonists were compared in survivors and nonsurvivors. Results.-Median Acute Physiology and Chronic Health Evaluation II score was 23 (range, 8 to 40). Mortality at 30 days was 49%. On entry to the study, circulating endotoxin was detected in 66% of patients, TNF-alpha in 14%, and IL-1 beta in 29%. Levels did not predict mortality or organ failure. Patients with IL-6 concentrations in excess of 3000 pg/mL had an increased mortality rate (64% vs 40%, P=.02). The incidence of IgG EndoCAb depletion on entry to the study was 26% in nonsurvivors and 10% in survivors (P=.02). Initial concentrations of both type I and type II sTNF-R were significantly higher in nonsurvivors (P<.01). Initial circulating IL-1ra concentrations were not of value in predicting mortality, Cytokine antagonists were present in concentrations 30- to 100 000-fold greater than their corresponding cytokine. Conclusion.-The observed high circulating levels of the cytokine antagonists IL-1ra and sTNF-R and the relatively small proportion of patients developing EndoCAb depletion may contribute to the limitations of therapies that aim to augment natural defenses against endotoxin or the proinflammatory cytokines.