Influence of Mannose Binding Lectin (MBL) Gene Polymorphisms on Infectious Complications during Treatment for Childhood Malignancy.

Infection remains a major cause of morbidity and hospitalisation in children receiving chemotherapy. At present clinical parameters provide a guide to risk of severe infection but it has become increasingly apparent that, among patients with the same diagnosis and treatment regimen, not all suffer equally from infectious complications. Mannose binding lectin is a pattern recognition molecule of the innate immune system which, upon binding to a wide range of microorganisms, activates the lectin pathway of complement. Polymorphisms in the MBL2 gene result in low levels of MBL protein and are frequently associated with increased susceptibility to infection. Studies investigating the role of MBL in defence against infection following chemotherapy have reported conflicting findings to date. MBL replacement therapy is a potential treatment option in the future and we consider it imperative that we clarify the role of MBL in this clinical setting. Clinical data from episodes of febrile neutropenia (FN) in children aged 0−16 receiving chemotherapy for childhood cancer was recorded prospectively from April 2004−March 2005, including clinical and microbiological evidence of infection, antibiotic days and duration of admission. MBL genotyping was performed using a reverse hybridisation technique and results were analysed against FN outcome. 269 children were recruited into the study. A total of 513 episodes of FN were captured over the study period from 211 patients. 58 patients had no recorded episodes of FN. There was no association between age, sex, ethnicity or diagnosis and MBL genotype. 75% of subjects had a haematological malignancy and of these 84% had acute lymphoblastic leukaemia (ALL). Overall, patients with MBL2 polymorphisms experienced more episodes of FN than wildtype individuals (median 2 and 1, respectively, p=0.074). Analysis of episodes with documented clinical/microbiological infection revealed that the proportion of patients with ≥ 3 episodes was 14.6% in those with polymorphisms and 8% in wildtype, p=0.045. This trend was also true for the supgroup of patients with ALL. The duration of inpatient stay for FN, used as a surrogate measure of severity, was influenced by MBL genotype in some groups of patients. Longer inpatient stays and antibiotic days were most apparent in the MBL deficient patients with high risk diagnoses e.g. AML and B NHL who spent up to 4.5 days longer/per episode in hospital than high risk wildtype patients. These results suggest that MBL deficiency influences both susceptibility to FN and outcome of FN episodes in this study cohort. The effect of MBL deficiency differs between diagnostic groups and may be most important in those patients who are at higher risk of severe FN by virtue of their underlying diagnosis and treatment regime.