Agbeko, RS; (2013) Characterization of the acute phase response in critically ill children. Doctoral thesis (PhD), UCL (University College London).

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Abstract

Humans come into contact and interact with potential infective agents. The innate immune system is the first line of response to ward off infection. Innate immunity is, in part, under genetic control. This genetic control may help us understand the differences between individuals in preventing infection or limiting infectious and inflammatory illness. Systemic inflammation is a complex disorder that is difficult to define. Current definitions are derived from consensus meetings. A need has been expressed for a more useful definition of systemic inflammation. The work presented here identifies some of the underlying hereditability in limiting or being more vulnerable to severe infectious and injurious insults. Individual differences in complement activation potential and endotoxin recognition underlie part of the observed differences in a systemic inflammatory response to severe infection and injury. An exploratory study using heart rate variability as a non-invasive method to distinguish infectious systemic inflammation from sterile systemic inflammation was inconclusive. Chapter 1 gives the background to this study and an introduction to the approaches taken in this thesis. Chapter 2 describes in detail the methods used in the genetic association study and physiological systems analysis. Chapter 3 goes into some detail about the potential pitfalls in genotyping association studies and how these were addressed in the current study. The areas of genotypi ng quality, linkage disequilibrium, ethnicity, sample size and validation of previously done work are discussed using MBL-2 and ACE as examples. Chapter 4 is a description of the work done on genetic variability in the endotoxin receptor complex and how in may result in the host response to severe infection and physical insults. TLR4 polymorphisms were associated with lower platelet counts in severe inflammation. The reasons for this are unclear but may point to a direct effect of the TLR4 pathways on platelets or indicate that platelet counts are a more sensitive marker of systemic inflammation than SIRS criteria. These data support the view that variation in TLR4 function influences the early inflammatory response. This phenomenon may be one aspect of reduced fitness in the capacity to respond appropriately to an insult. Chapter 5 reports the central role of complement in the acute phase response. Polymorphisms in two out of the three complement activation pathways were shown to have potential modifying effects in paediatric systemic inflammation. This chapter reports that polymorphisms in the CFH gene may modulate the acute inflammatory response and corroborates the previously reported finding that MBL-2 variant genotypes are a risk factor for the early occurrence of SIRS/sepsis in a large cohort of paediatric critical care patients, independent of other potentially important functional polymorphisms in the complement and innate immunity system. A better understanding of how these polymorphisms operate at the pathophysi ol ogi cal level is needed before these findings can be translated to clinically useful therapeutic modalities. This study demonstrates that genetic polymorphisms associated with reduced complement activation may be associated with early SIRS/sepsis. This is consistent with a view that appropriate complement activation occurring early following an infectious or inflammatory insult protects children from early SIRS/sepsis. Chapter 6 assesses the usefulness of full MBL-2 genotyping and compares the MBL-2 genotype and M BL serum levels between a cohort of healthy children and a cohort of critically ill paediatric patients. MBL2 genotyping did not render more information with regards to M BL serum level when all promoter and structural polymorphisms were identified over and above structural polymorphisms and the XY promoter polymorphism. The children admitted with infection did not have a surplus of M BL deficient genotypes as compared with healthy children. This suggests that M BL deficient genotypes do not predispose to severe infection. M BL serum levels in SIRS or sepsis were lower compared with critically ill children without systemic inflammation. M BL levels were most reduced in the acute phase response in those genotypes with intermediate serum levels, which may reflect a consumption of M BL in critical illness and an inability to maintain pre-insult M BL serum levels. Chapter 7 explores a novel way to discriminate SIRS from sepsis by means of heart rate variability analysis. In this small paired sample study no differences were seen in LF metrics to differentiate sterile SIRS from sepsis. Neither was there a difference in LF metrics between those children who went on to develop a nosocomial infection and those who did not. Normalised HF was significantly higher in sterile SIRS vs. sepsis. These preliminary finding require further validation and a longitudinal approach in a larger cohort. Finally, Chapter 8 discusses the findings of this thesis in the context of interpretation and of the findings and potential future approaches. This thesis supports the view that better metrics are required to discriminate systemic inflammation as well as the concept that in children control of an inflammatory threat is aided by a vigorous capacity to respond.

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