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SUMMARY: OBJECTIVE This article aims to review all relevant genetic polymorphism studies that may contribute to the pathogenesis of sepsis with emphasis on polymorphisms of the innate immunity, pro- and anti-inflammatory cytokines, and coagulation mediators.DATA SOURCE Published articles reporting on studies of associations between genetic polymorphisms, sepsis, septic shock, and other relevant infectious disease models.DATA ANALYSIS Research into the pathogenesis of sepsis has led to the development of many potential therapeutic strategies. Several therapeutic agents and treatment modalities have been shown to decrease mortality rates in large, prospective, and randomized clinical trials. However, although these advances have resulted in improved survival for certain patient populations, the overall mortality rate for septic patients remains high. With the rapid development of molecular and genetic techniques, substantial interests have developed in using genomic information to define disease-mediating genetic variants in sepsis. Combined with microarray technology, it is anticipated in the near future that one will be able to tailor drug selection and dosage and predict outcome by correlating genetic profile with disease presentation. Numerous genetic association studies in sepsis have already been reported and more are likely to be published.CONCLUSIONS Although studies examined in this review are of small heterogeneous populations, the identification of strong associations between certain genetic polymorphisms and increased mortality rate or susceptibility to severe sepsis is intriguing and supports further research using this approach. The establishment of these associations does not equal causation, and further research is required in both genetic and molecular aspect of sepsis. [ABSTRACT FROM AUTHOR]

OBJECTIVE:: To evaluate whether administration of afelimomab, an anti-tumor necrosis factor F(ab'')2 monoclonal antibody fragment, would reduce 28-day all-cause mortality in patients with severe sepsis and elevated serum levels of IL-6. DESIGN:: Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial. SETTING:: One hundred fifty-seven intensive care units in the United States and Canada. PATIENTS:: Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels. INTERVENTIONS:: Patients were stratified into two groups by means of a rapid qualitative interleukin-6 test kit designed to identify patients with serum interleukin-6 levels above (test positive) or below (test negative) approximately 1000 pg/mL. Of the 2,634 patients, 998 were stratified into the test-positive group, 1,636 into the test-negative group. They were then randomly assigned 1:1 to receive afelimomab 1 mg/kg or placebo for 3 days and were followed for 28 days. The a priori population for efficacy analysis was the group of patients with elevated baseline interleukin-6 levels as defined by a positive rapid interleukin-6 test result. MEASUREMENTS AND MAIN RESULTS:: In the group of patients with elevated interleukin-6 levels, the mortality rate was 243 of 510 (47.6%) in the placebo group and 213 of 488 (43.6%) in the afelimomab group. Using a logistic regression analysis, treatment with afelimomab was associated with an adjusted reduction in the risk of death of 5.8% (p = .041) and a corresponding reduction of relative risk of death of 11.9%. Mortality rates for the placebo and afelimomab groups in the interleukin-6 test negative population were 234 of 819 (28.6%) and 208 of 817 (25.5%), respectively. In the overall population of interleukin-6 test positive and negative patients, the placebo and afelimomab mortality rates were 477 of 1,329 (35.9%)and 421 of 1,305 (32.2%), respectively. Afelimomab resulted in a significant reduction in tumor necrosis factor and interleukin-6 levels and a more rapid improvement in organ failure scores compared with placebo. The safety profile of afelimomab was similar to that of placebo. CONCLUSIONS:: Afelimomab is safe, biologically active, and well tolerated in patients with severe sepsis, reduces 28-day all-cause mortality, and attenuates the severity of organ dysfunction in patients with elevated interleukin-6 levels. [ABSTRACT FROM AUTHOR]