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July 12, 1995

Natural Cytokine Antagonists and Endogenous Antiendotoxin Core Antibodies in Sepsis Syndrome

Author Affiliations

Royal Infirmary, Edinburgh; Western Infirmary, Glasgow; City Hospital, Edinburgh; Western General Hospital, Edinburgh; Victoria Infirmary, Glasgow; Department of Medical Microbiology, Medical School, Edinburgh; Academisch Ziekenhuis, Maastricht, the Netherlands
From the University Department of Surgery, Royal Infirmary (Drs Goldie, Fearon, and Ross), Scottish National Blood Transfusion Service (Dr Barclay), and Intensive Therapy Unit, Western General Hospital (Dr Grant), Edinburgh, Scotland; Department of Anaesthetics, Western Infirmary (Drs Jackson and Blyth), and Department of Anaesthetics, Victoria Infirmary (Dr Howie), Glasgow, Scotland; and Academisch Zeikenhuis (Dr Ramsay), Maastricht, the Netherlands.

JAMA. 1995;274(2):172-177. doi:10.1001/jama.1995.03530020090038

Objective.  —To assess the value of measuring circulating concentrations of mediators (endotoxin, tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], and interleukin-6 [IL-6]) and their endogenous antagonists (antiendotoxin core antibody [EndoCAb], interleukin-1 receptor antagonist [IL-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-α in 14%, and IL-1β 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.(JAMA. 1995;274:172-177)