Abstract
Sequence variants in genes involved in the immune system have previously been linked to neutropenia as well as infections in cancer patients. Sequence variants in genes coding for TLR4, MBL, and IL-1Ra were investigated in relation to clinical utility of identifying severe episodes of febrile neutropenia (FN) in a cohort of children undergoing treatment for acute lymphoblastic leukemia. The study included 122 children, where data on FN and microbiological findings were retrospectively collected from medical records. Sequence variants in genes coding for MBL, TLR4, and IL-1Ra were identified by pyrosequencing, TaqMan SNP genotyping assay, and gel electrophoresis. A total of 380 episodes of FN were identified and in 139 episodes, there was a microbiological defined infection. Age and treatment intensity were all associated with the risk of developing FN. No sequence variant was associated to increased numbers of FN episodes. Two sequence variants in the TLR4 gene increased the risk of viral infection, whilst sequence variants in the IL-1Ra gene were associated to a decreased risk of bacterial blood-stream infection (BSI). The investigated sequence variants did not associate with increased risk for FN or to severe infections, as to why the clinical utility as a risk-stratification tool is low. Most episodes of FN were classified as fever with unknown origin, emphasizing the need for improved microbial detection methods.
Highlights
Acute lymphoblastic leukemia (ALL) is the most frequent cancer in children
All infectious episodes were analyzed as only bacterial bloodstream infections (BSI) and only viral infections
Risk-stratification could improve management of febrile neutropenia (FN) in the immunosuppressed child and previous studies have indicated a role for Toll-like receptor 4 (TLR4), mannose-binding lectin (MBL), and IL-IRa sequence variants as risk factors for serious infections in immunocompromised children
Summary
The long-term survival of children with ALL has increased considerably [1], complications associated with chemotherapy are common. Infections remain as a cause of increased morbidity and mortality [2,3]. Data on febrile neutropenia (FN) and microbiological defined infections (MDI) during the entire pediatric ALL treatment period is limited. Recent studies have reported that bacterial bloodstream infections (BSI) and invasive fungal disease (IFD) still account for most infection-related deaths. Mainly respiratory infections, are commonly detected in FN [3,4,5,6].
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