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.

The relationship of endotoxaemia to peripheral and central nervous system inflammatory responses in Human African Trypanosomiasis

“…The effectiveness of heat treatment was confirmed by inclusion of a control sample of plasma spiked with a 0·2 EU mL −1 final concentration of endotoxin standard. Because previous literature on endotoxaemia in HAT have presented endotoxin concentrations as lipopolysaccharide (LPS) equivalents, endotoxin concentrations were expressed as pg mL −1 LPS using the conversion 1 EU mL −1  = 100 pg mL −1 (Hurley, 2013). …”

Endotoxemia as a Diagnostic Tool for Patients with Suspected Bacteremia Caused by Gram-Negative Organisms: a Meta-Analysis of 4 Decades of Studies

“…In comparative studies with this model, a relatively avirulent strain of E. coli versus P. aeruginosa (48), Staphylococcus aureus (66), or a more virulent strain of E. coli (65) showed similar quantitative levels of bacteremia, whereas the associated hemodynamic changes and shortened survival times were in each case more severe than those observed in association with the avirulent E. coli strain, as would be expected (48,65,66). Surprisingly, despite these expected differences, in each study the levels of endotoxemia were 3-fold (65) to 10-fold (48) lower or even undetectable (46) versus the levels seen after challenge with the avirulent E. coli strain. Interestingly, endotoxins extracted and purified from the virulent and avirulent E. coli strains were equal with respect to potency and endotoxin amount per bacterium; hence, the lack of an association between endotoxemia and disease severity in this experimental model could not be explained on this basis (65).…”

“…Third, paradoxical observations among animal models of sepsis indicate that the concordance of endotoxemia with GN bacteremia and also with outcome is expected to differ for different GN bacteremia types (48). The detection of endotoxemia is of interest in relation to ongoing efforts to develop rapid detection methods for GN bacteremia and the possible application of emerging endotoxemia therapies (46). Finally, newer statistical methods have enabled a reappraisal over a broad range of assay breakpoints (49).…”

“…Moreover, in the evaluations of endotoxemia therapies over this time period, there has been a substantial and unexplained disconnect between the results of animal models of sepsis and the results of subsequent clinical trials of the same therapies (46).…”

Treatment of Meningococcal Disease

“…In a randomized study of antiendotoxin antibody (HA-1A) conducted in children with meningococcal septicemia, no significant reduction in mortality was observed in children treated with HA-1A compared with placebo [27]. Subsequent studies in adults with gram-negative septicemia also showed no benefit of therapy with HA-1A [28]. In a randomized controlled trial of recombinant bactericidal permeability-increasing protein (rBPI 21 ), which binds and neutralizes endotoxin and blocks the inflammatory cascade, patients treated with rBPI 21 suffered fewer amputations, fewer blood product transfusions, and improved functional outcomes compared with those treated with placebo [29].…”