%L discovery1333965
%T Genetic determinants of sepsis in haematological malignancy
%D 2011
%O The first two pages, the title page and the declaration of originality, are not included in this copy
%A L.S.A.M. Saeed
%X 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.
%I UCL (University College London)