Common Polymorphisms of the Interleukin-6 and Chitotriosidase Genes Are Associated with the Risk for Infection with Gram-Negative Bacteria in Children Undergoing Therapy for Acute Myeloid Leukemia.

Purpose: Infectious complications remain a substantial cause of morbidity and mortality in patients with acute myeloid leukemia (AML). Candidate gene studies have identified common polymorphisms in genes of molecules of innate immunity as risk factors for susceptibility and/or outcome to a spectrum of pathogens in various populations. This study was performed to investigate whether common polymorphism in genes of innate immunity might influence the risk for serious infection during therapy for pediatric AML.

Patients and Methods: Genotype analysis was performed in 168 children treated on clinical trial AML-BFM 93. Infectious events were categorized as microbiologically or clinically documented infections and as fever without an identifiable source. Candidate gene polymorphisms included tumor necrosis factor-alpha, interleukin 6 and 8 (IL6 and IL8), myeloperoxidase, chitotriosidase (CHIT), the low affinity Fc receptor 2A, and the toll like-receptors 2 and 4.

Results: The 168 children treated according to clinical trial AML-BFM 93 experienced a total of 508 infectious episodes. Only three patients escaped significant infectious complication. One-hundred-and-ten patients had a least one microbiologically documented infection. Gram-positive bacteria were isolated in the bloodstream of 84 children, whereas Gram-negative bacteria were recovered from the bloodstream of 24 patients. There was an association between Gram-negative bacterial infection and each of the IL6 and CHIT genetic variants. The risk of bacteremia with Gram-negative organisms was significantly higher in patients with the G allele in the IL6 promoter at 174bp [22/123 (17.9%) vs 0/25 (0%); P=.022 (OR 11.31, 95% CI 1.41–90.6)] and in patients with the H allele (24-bp duplication in exon 10) of CHIT [13/56 (23.25) vs 11/112 (9.8%); P=.020 (OR 2.78; 95% CI 1.18–6.54)]. No significant association of the other variant genotypes with any of the clinical endpoints analyzed was observed.

Conclusion: The data suggest that variant alleles of both IL6 and CHIT influence susceptibility to infection with Gram-negative bacteria in children undergoing therapy for AML. Further studies are warranted to confirm our findings and to investigate underlying mechanisms.