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

Abstract

Endotoxin is a potent mediator of a broad range of patho-physiological effects in humans. It is present in all Gram negative (GN) bacteria. It would be expected that anti-endotoxin therapies, whether antibody based or not, would have an important adjuvant therapeutic role along with antibiotics and other supportive therapies for GN infections. Indeed there is an extensive literature relating to both pre-clinical and clinical studies of anti-endotoxin antibodies. However, the extent of disconnect between the generally successful pre-clinical studies versus the failures of the numerous large clinical trials of antibody based and other anti-endotoxin therapies is under-appreciated and unexplained. Seeking a reconciliation of this disconnect is not an abstract academic question as clinical trials of interventions to reduce levels of endotoxemia levels are ongoing. 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. Several new factors to consider in this reappraisal include the frequency and types of GN bacteremia and the underlying mortality risk in the various study populations. For a range of reasons, endotoxemia can no longer be considered as a single entity. There are old clinical trials which warrant a re-appraisal in light of these recent advances in the understanding of the structure-function relationship of endotoxin. Fundamentally however, the disconnect not only remains, it has enlarged.

Figure 1

The location of the lipopolysaccharide (endotoxin) molecule in the cell wall of Gram negative bacteria.

Figure 2

The components of the lipopolysaccharide (endotoxin) molecule.

Figure 3

Simplified diagram of TLR4-MD-2 receptor complex dimerization upon ligation of hexa-acyl lipid A. See text for description. Copyright ^© 2013 Maeshima and Fernandez. From reference [13], an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited.

Figure 4

L’Abbé plots of study specific mortality rates from 35 studies. Each figure shows mortality rates for studies undertaken in an ICU (triangles) or non-ICU (circles) setting with symbols proportional to group size with the line of no difference (y = x; dotted line) shown for visual reference purposes. Shown are (a) Groups 1 (endotoxemia and GN bacteremia detected) versus groups 4 (neither detected); (b) Groups 2 (GN bacteremia alone) versus groups 4 (neither detected); and (c) Groups 3 (endotoxemia alone) versus groups 4 (neither detected). GN, gram negative. From [77] ^© 2012 Hurley et al.; licensee BioMed Central Ltd., an open access article distributed under the terms of the Creative Commons Attribution License.