M P Fink1. 1. Department of Surgery and Anesthesiology, University of Massachusetts Medical Center, Boston.
Abstract
OBJECTIVE: To provide a succinct overview of the scientific rationale for adoptive immunotherapy of Gram-negative sepsis using antibodies directed at epitopes in the core region of the lipopolysaccharide molecule. DATA SOURCES: Relevant, English-language primary and secondary (i.e., review) articles dealing with the structure or toxicity of lipopolysaccharide or adoptive anti-endotoxin immunotherapy in animals or man. STUDY SELECTION AND DATA EXTRACTION: The review emphasizes the findings obtained in several recent multicenter, randomized, prospective trials of monoclonal antibodies to core determinants of lipopolysaccharide. DATA SYNTHESIS: Lipopolysaccharide, a component of the outer cell wall of Gram-negative bacteria, is a complex molecule consisting of three regions: lipid A, core polysaccharide, and O-antigenic side chains. Epitopes in the lipid A and core polysaccharide regions are highly conserved across species and strains of Gram-negative bacteria. Because of the availability of mutant strains of bacteria that synthesize lipopolysaccharides lacking O-specific side chains and, in some instances, portions of the core polysaccharide moiety, investigators have been able to develop polyclonal and monoclonal antibodies to core-region determinants. In experimental animals, many of these antibodies have been shown to protect against the deleterious effects of either purified heterologous lipopolysaccharides or viable heterologous Gram-negative bacteria. Recently, two different monoclonal "anti-core" antibodies (HA-1A and E5) were evaluated in prospective, placebo-controlled, double-blind, randomized trials. In the pivotal trial of HA-1A, a human monoclonal IgM, no treatment effect was discernible when data from all patients enrolled in the study were analyzed. However, in a subset of patients with positive blood cultures for Gram-negative organisms, there was a decrease in all-cause mortality over a 28-day observation period in patients treated with HA-1A, as compared with those patients treated with placebo (p = .014). Interpretation of this finding, however, is confounded because multiple other subsets and end-points also were analyzed, necessitating an adjustment in the p value necessary to reject the null hypothesis. A murine monoclonal IgM called E5 was evaluated in two separate trials. In the first trial, improved survival over a 30-day observation period was observed in a subset of patients with Gram-negative sepsis without refractory shock (p = .01). However, in a second trial of E5, which focused on this subset, a statistically significant improvement in survival was not observed in patients with documented Gram-negative sepsis without shock. CONCLUSIONS: Adoptive immunotherapy using monoclonal anticore antibodies seems to improve survival rate in selected patients with Gram-negative sepsis. Nevertheless, because of concerns about costs and the interpretation of the results from the completed clinical trials, these new agents have generated enormous controversy. The precise role of adoptive immunotherapy against lipopolysaccharide in the practice of critical care medicine in the United States remains unclear.
OBJECTIVE: To provide a succinct overview of the scientific rationale for adoptive immunotherapy of Gram-negative sepsis using antibodies directed at epitopes in the core region of the lipopolysaccharide molecule. DATA SOURCES: Relevant, English-language primary and secondary (i.e., review) articles dealing with the structure or toxicity of lipopolysaccharide or adoptive anti-endotoxin immunotherapy in animals or man. STUDY SELECTION AND DATA EXTRACTION: The review emphasizes the findings obtained in several recent multicenter, randomized, prospective trials of monoclonal antibodies to core determinants of lipopolysaccharide. DATA SYNTHESIS: Lipopolysaccharide, a component of the outer cell wall of Gram-negative bacteria, is a complex molecule consisting of three regions: lipid A, core polysaccharide, and O-antigenic side chains. Epitopes in the lipid A and core polysaccharide regions are highly conserved across species and strains of Gram-negative bacteria. Because of the availability of mutant strains of bacteria that synthesize lipopolysaccharides lacking O-specific side chains and, in some instances, portions of the core polysaccharide moiety, investigators have been able to develop polyclonal and monoclonal antibodies to core-region determinants. In experimental animals, many of these antibodies have been shown to protect against the deleterious effects of either purified heterologous lipopolysaccharides or viable heterologous Gram-negative bacteria. Recently, two different monoclonal "anti-core" antibodies (HA-1A and E5) were evaluated in prospective, placebo-controlled, double-blind, randomized trials. In the pivotal trial of HA-1A, a human monoclonal IgM, no treatment effect was discernible when data from all patients enrolled in the study were analyzed. However, in a subset of patients with positive blood cultures for Gram-negative organisms, there was a decrease in all-cause mortality over a 28-day observation period in patients treated with HA-1A, as compared with those patients treated with placebo (p = .014). Interpretation of this finding, however, is confounded because multiple other subsets and end-points also were analyzed, necessitating an adjustment in the p value necessary to reject the null hypothesis. A murine monoclonal IgM called E5 was evaluated in two separate trials. In the first trial, improved survival over a 30-day observation period was observed in a subset of patients with Gram-negative sepsis without refractory shock (p = .01). However, in a second trial of E5, which focused on this subset, a statistically significant improvement in survival was not observed in patients with documented Gram-negative sepsis without shock. CONCLUSIONS: Adoptive immunotherapy using monoclonal anticore antibodies seems to improve survival rate in selected patients with Gram-negative sepsis. Nevertheless, because of concerns about costs and the interpretation of the results from the completed clinical trials, these new agents have generated enormous controversy. The precise role of adoptive immunotherapy against lipopolysaccharide in the practice of critical care medicine in the United States remains unclear.