Associations between early‐life and in utero infections and cytomegalovirus‐positive acute lymphoblastic leukemia in children

Abstract

Childhood infections and cytomegalovirus (CMV) are associated with pediatric acute lymphoblastic leukemia (ALL). CMV dysregulates the host immune system and alters the immune response to subsequent antigenic exposures. We suspect that this immune dysregulation contributes to increased numbers of symptomatic infections in childhood allowing for expansion of pre‐leukemic clones. We explored the association between childhood infections, maternal infections during pregnancy and CMV‐positive ALL. Using a droplet digital PCR assay, we screened diagnostic ALL bone marrow samples from the California Childhood Leukemia Study (1995‐2015) for the presence of CMV DNA identifying CMV‐positive and CMV‐negative cases. We performed a case‐only analysis (n = 524) comparing the number and types of childhood infections and maternal infections during pregnancy between CMV‐positive and CMV‐negative ALL cases using logistic regression. With increasing numbers of infections in the first 12 months of life, children were more likely to classify to the highest tertile of CMV DNA in the bone marrow at diagnosis (OR: 1.04, 95% CI: 1.01‐1.08). Specifically, those reporting cough or flu in the first 12 months were more likely to be CMV‐positive at ALL diagnosis (OR: 2.15, 95% CI: 1.06‐4.37 and OR: 2.06, 95% CI: 1.17‐3.63 respectively). Furthermore, those with a history of maternal infection during pregnancy were more likely to be CMV‐positive (OR: 2.12, 95% CI: 1.24‐3.62). We hypothesize that children with underlying immune dysregulation develop more symptomatic infections in childhood and ultimately CMV‐positive ALL; this underlying immune dysregulation may be due to early immune system alterations via CMV exposure (in utero or early infancy) proposing a potential link between CMV and ALL etiology.

Association between medically diagnosed postnatal infection and childhood cancers: A matched case‐control study in Denmark, 1978 to 2016

“…1 In the same year, Kinlen proposed that childhood leukemia was caused by an abnormal immune response in a susceptible population due to migration and population mixing related to a lack of herd immunity. 2 Currently, many studies have suggested a positive association between postnatal infection and acute lymphoblastic leukemia (ALL), [3][4][5] as some literature has proposed protective effects or no evidence for any connection between infection and ALL. 6,7 On the other hand, there is little detailed research on specific types of infections 8,9 and on subtypes of leukemia such as acute myeloid leukemia (AML).…”