Immunotherapy of endotoxemia and septicemia

Neutralization of endotoxin (lipopolysaccharide, LPS) would be of considerable benefit in the treatment of Gram-negative sepsis. Administration of anti-LPS antibodies is an old approach which has been renewed by improvements in monoclonal antibody technology. The antibodies directed at the conserved core region of LPS or at the lipid A which have been studied in humans are discussed in this review. Some of these antibodies appeared to be protective in animal models or in clinical trials, but discrepant results have been reported and the mechanism of the postulated protection was not clarified. The polyclonal antibody preparations have given variable results in patients. The clinical studies of anti-lipid A monoclonal antibodies seemed promising because both antibodies appeared to protect subsets of patients. However, the studies gave discrepant results concerning the type of patients reported to benefit from the administration of these antibodies. One of these antibodies, E5, appeared to improve the survival of patients with Gram-negative sepsis provided they were not in shock, but a second trial failed to confirm this. The other antibody, HA-1A, appeared to protect patients with Gram-negative sepsis who were in refractory shock, but only when they were bacteremic. This antibody was recently released on the market in some european countries. However, the FDA agency decided that a confirmatory study should be done before it could consider to approve HA-1A because a careful reanalysis suggested that the observed differences were only of marginal statistical significance. Therefore, this type of treatment has not yet clearly been shown to benefit patients. More studies are needed to delineate the role of core LPS antibodies in the management of Gram-negative sepsis.