The Case for Immunotherapy Against Endotoxin in Sepsis and Septicemia
Conventionally treated severe gram-negative infection has an unpredictable outcome. Institution of appropriate antibiotic therapy, drainage of septic foci and adequate ventilatory, fluid and inotropic support where needed will result in survival of roughly half of the septic individuals [1, 2]. The remainder will develop a variety of potentially lethal sequelae including profound hypotension, coagulopathy and progressive organ failure and most of these patients will die. Mortality in this latter group has not improved significantly in the last two decades and the enormous cost of caring for such patients is associated with a poor reward. Furthermore a “cure” for septicemia progressing to multiple organ failure might have a greater impact on total patient survival than a cure for breast cancer according to some calculations. It might be considered that following publication of a Phase III clinical trial in a premier journal that demonstrated a 39% reduction in mortality in those with gram-negative sepsis when treated with a human moncolonal antibody against the Lipid A (a component of the endotoxin of all gram-negative strains of bacteria) this approach might be adopted with considerable enthusiasm and a desire to make such therapy available to all appropriate patients as rapidly as possible . The reality is that this therapy has attracted an almost unprecedented degree of controversy [4–7]. In this chapter, only the human monoclonal anti-endotoxin antibody HA-1A (CentoxinR) will be considered in depth. The other anti-endotoxin antibody E5 (a murine antibody) has been evaluated in two Phase III clinical trials. In neither study taken individually has it been shown to increase survival in the group of patients with gram-negative sepsis and hypotension, the clinical scenario most likely to be attributable to circulating endotoxin and where an IgM antibody against endotoxin would, on theoretical grounds, be most likely to be effective . For this reason, the author cannot find any compelling case for further evaluation of this agent.
KeywordsPlacebo Heparin Polypeptide Stratification
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