Stephens, RCM; (2014) The human response to endotoxin. Doctoral thesis , UCL (University College London).

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Abstract

Many patients undergoing high-risk major surgery suffer complications. Previous studies have shown that patients with low IgM Endotoxin Core Antibodies (EndoCAb) are more likely to have a complication, for relatively unknown reasons. Studying EndoCAb directly is difficult as it is a polyclonal group of antibodies. This thesis explored the relationship between EndoCAb and different measures of outcome using samples from previously conducted clinical trials and a series of basic laboratory studies. A pilot human volunteer study was conducted to try to improve ways of assessing the response to an endotoxin challenge. An observational study on adults undergoing 1st time Coronary Artery Bypass Grafting was conducted using samples from a previous trial to see if the association between outcome and low EndoCAb IgM extended to this comparatively low-risk group and to examine whether this was clearly mediated by an exaggerated inflammatory response. Patients with low EndoCAb IgM had more complications, but had less interleukin-6 at 6 hours. To assess the relationship between low EndoCAb IgM and other antibodies a series of studies was conducted to examine the hypothesis that EndoCAb IgM is part of a wider ‘natural IgM antibody group’. Blood donors with low EndoCAb IgM had lower concentrations of the ‘natural IgM antibodies’. Furthermore, EndoCAb IgM and the ‘natural IgM antibody group’ had similar temporal patterns and were present at low concentrations in some umbilical cord blood. To further understand the clinical relevance of EndoCAb, the association between EndoCAb and the systemic inflammatory response syndrome was retrospectively measured in critically ill children undergoing another clinical trial. Low EndoCAb IgG was associated with early development of the systemic inflammatory response syndrome. The difficulty in determining which factors affect the response to an inflammatory challenge led me to develop a new low-dose endotoxin human volunteer model: one in which there is the largest range of change, variability or dispersion in inflammatory markers.

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