Genetic determinants of sepsis in haematological malignancy.
Doctoral thesis, UCL (University College London).
Background: Sepsis is a systemic illness caused by microbial invasion of normally sterile parts of the body. In haematological malignancies, patients are more prone to developing infections due to defects in the neutrophil count and function which occur as a part of the neoplastic process or due to chemotherapy. The presence of neutropenia calls for other means of defence including the innate immune system. Genetic studies have attempted to examine the relationship between particular genes involved in innate immunity and susceptibility to infections. Genes involved in the host defence mechanism such as pathogen presentation, recognition and phagocytosis result in the initiation of a cascade of events ending in the innate immune system activation. Chitotriosidase and nucleotide oligmerization domain (NOD2) are two genes suggested to have a possible role in the innate immune response against bacterial and fungal infections. Studies of acute lymphoblastic leukaemia (ALL) and NOD2 mutations have been conducted in allogenic transplant patients in order to examine any association with the incidence of relapse, survival and graft versus host disease. The occurrence of NOD2 variants are also implicated in the onset or progression of different malignancies via its effect on immune system. Purpose gene: The aim of our study was to explore the effect of mutations in genes involved in the innate immune system in relation to incidence and outcome of sepsis, prevalence of particular microorganism, and depth and duration of neutropenia in patients with haematological malignancies. The study aimed to identify mutations in chitotriosidase and NOD2, individually, and then looked at the synergetic effect of both mutations, given previous evidence of molecular interaction between the gene products. We also looked at NOD2 mutation in non-transplanted ALL patients so as to evaluate the effect of this mutation on outcome and prognosis. Methods: The study was carried out in the RFH in patients diagnosed with haematological malignancies. Blood was collected and DNA extracted. Genotyping identified chitotriosidase mutations while NOD2 missense mutations (SNP8 and SNP12) were determined by pyrosequencing. In the study of NOD2 mutations and ALL outcome, samples were collected as a part of UKALL-12 trial-MRD study in patients with the diagnosis of ALL. The NOD2 mutations (SNP8, SNP12 and SNP13) were identified by genescanning. Results: The incidence of febrile events with positive (p=0.031) or negative growth for any organism cultures (p=0.029) was increased in patients with chitotriosidase mutations. These results were most significant during periods of neutropenia; febrile events with bacterial isolates (p=0.015) and without (p=0.007). During periods of normal neutrophil count the incidence of fevers with positive bacterial cultures was also increased in patients with NOD2 mutation,(p=0.017). The incidence of fevers without positive cultures was decreased (p=0.029). There were no significant differences in CR, incidence of relapse or OS in ALL patients with NOD2 mutations. Conclusions: This study suggests an association between chitotriosidase mutations and the incidence of febrile events (with or without positive bacterial cultures) in neutropenic patients. The NOD2 mutation was found in association with an increased incidence of fevers with bacterial organisms identified and a decreased incidence of fever of unknown origin in non-neutropenic patients.
|Title:||Genetic determinants of sepsis in haematological malignancy|
|Open access status:||An open access version is available from UCL Discovery|
|Additional information:||The first two pages, the title page and the declaration of originality, are not included in this copy|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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