Towards clinical applications of anti-endotoxin antibodies; a re-appraisal of the disconnect.

Abstract

Endotoxin is a potent mediator of a broad range of path-physiological effects in humans and present in all Gram negative (GN) bacteria. It would be expected that anti-endotoxin therapies, antibody based or not, would play an important adjuvant therapeutic role along with antibiotics and other supportive therapies for GN infections. There is an extensive literature relating to pre-clinical and clinical studies of anti-endotoxin antibodies however there is a unknown and unexplained disconnect between generally successful pre-clinical studies versus the failures of the many large clinical trials of antibody based and other anti-endotoxin therapies. This disconnect is not merely an abstract academic question as there are ongoing clinical trials of interventions to reduce levels of endotoxemia levels. The aim of this review is to examine new insights into the complex relationship between endotoxemia and sepsis in an attempt to bridge this disconnect. New factors to consider in this reappriasal include the frequency and types of GN bateremia and the underlying mortality risk in the different study populations. Endoxemia can no longer be considered a single entity for a range of reasons. Old clinical trials warrant a re-appraisal in light of recent advances in the understanding of the structure-fuction relationship of endotoxin. The disconnect not only remains however, it has enlarged.