Understanding Clostridium difficile Infection Outcomes, through Host Clinical Variables, and Bacterial Whole Genome and Phenotypic Analysis
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Thesis or dissertation
University of Exeter
Reason for embargo
I wish to publish data from the content of this thesis.
Clostridium difficile is a clinically problematic pathogen and continues to persist within the healthcare system. Presentation of disease symptoms ranges from mild to severe diarrhoea, through to fulminant pseudomembranous colitis. Approximately 20% of patients will suffer from recurrent episodes and of all patients who die from C. difficile related causes, approximately 41% of death certificates mention C. difficile as an underlying cause of death, and this poses a significant burden on healthcare facilities. Three methods of investigation were employed to develop a more comprehensive understanding of both the host and isolate association with the outcomes of C. difficile infection; mortality and recurrence. These methods were; analysing patient clinical data to try and identify host markers of infection outcomes, evaluating C. difficile type association with infection outcomes, and genetically and phenotypically characterising the clinically relevant C. difficile isolates associated to these outcomes. During this study statistical analysis of clinical data revealed that there were four variables; white cell count, serum albumin, C-reactive protein and respiratory rate, which were prognostic of mortality in patients with C. difficile infection. Threshold levels of these variables were used to create a clinical prediction rule to classify patients with C. difficile infection who were more 'at risk' from mortality, with statistical significance in both a derivation and validation cohort. However, analysis was unable to determine variables prognostic of recurrent infection. Due to small sample sizes of some groups of isolates, no groups of C. difficile isolates were significantly associated with increased recurrent infection or mortality during this study. Some groups of isolates were associated with primary only infection and/or low mortality. There was a non-significant trend in particular C. difficile isolate groups being associated with infection outcome; a panel of representative isolates was therefore chosen to be characterised in more detail. Phenotypic and genetic analysis of a panel of sixteen C. difficile isolates revealed isolate specific differences in toxin production, conservation of transposable elements and SNP abundances, which may have played a role in infection outcome. Isolate motility and antibiotic resistance profiles were not statistically significantly different between isolates within a particular group of C. difficile types. One hypothesis from the collective results obtained during this study suggests that the phenotypic and genotypic changes in isolates may have facilitated differences in their interaction with the host. In turn, the host specific inflammatory response to the infecting C. difficile isolate may have played a role in host outcomes. Research conducted during this study has begun to assess which host specific responses may be important in determining the outcome of C. difficile infection, and which C. difficile isolate characteristics may in part also contribute. However, the assessment of both host and isolate association to infection outcomes would benefit from further investigation in a larger cohort, in order to prove or refute conclusively any hypothesises generated in this study.
University of Exeter
Doctor of Philosophy in Biological Sciences