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.
The etiology of childhood acute lymphoblastic leukemia (ALL) has long been studied piecemeal with investigations leading to a lengthy list of putative risk factors including several with immune modulatory effects. The ubiquity of many of these factors (e.g., daycare attendance, low parity, breastfeeding, normal vaccinations) belies the rarity of ALL as an outcome. In this commentary, Pombo-de-Oliveira and colleagues show that a key feature may be the combination of particular risk factors, as the birth characteristics “cesarean section” and “birth order” when combined interact to impart higher risk of ALL than would be suggested by the additive risk of both factors. This statistical interaction would be predicted by the “delayed infection hypothesis” wherein infant immune isolation promotes developmental vulnerability to ALL upon infection exposure later in childhood. Pombo-de-Oliveira and colleagues show further that lack of breastfeeding, a postnatal factor leading to further immune isolation, induces additional risk. In sum, the data reveal a combination of factors that together could impart a healthy “trained” immune system allowing for moderated responses to later exposures with microbial and viral antigens. Such priming of the immune system avoids maladaptive immunologic consequences of delayed antigenic stimulation leading to ALL and other diseases. Further research utilizing biomarkers of specific exposures (in addition to the proxy measures used here) will be helpful to realize the full potential for immune modification for ALL prevention.
See related article by Pombo-de-Oliveira et al., p. 371
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