Infectious Etiologies of Childhood Leukemia: Plausibility and Challenges to Proof

Abstract

Infections as well as environmental exposures are proposed determinants of childhood acute lymphoblastic leukemia (ALL), particularly common precursor B-cell ALL (cALL). Lines of investigation test hypotheses that cALL is a rarer result of common infection, that it results from uncommon infection, or that it ensues from abnormal immune development; perhaps it requires a preceding prenatal or early childhood insult. Ideally, studies should document that particular infections precede leukemia and induce malignant transformation. However, limited detection studies have not directly linked specific human or nonhuman infectious agents with ALL or cALL. Primarily based on surrogate markers of infectious exposure, indirect evidence from ecologic and epidemiologic studies varies widely, but some suggest that infancy or early childhood infectious exposures might protect against childhood ALL or cALL. Several others suggest that maternal infection during pregnancy might increase risk or that certain breast-feeding practices decrease risk. To date, evidence cannot confirm or refute whether at least one infection induces or is a major co-factor for developing ALL or cALL, or perhaps actually protects against disease. Differences in methodology and populations studied may explain some inconsistencies. Other challenges to proof include the likely time lag between infection and diagnosis, the ubiquity of many infections, the influence of age at infection, and the limitations in laboratory assays; small numbers of cases, inaccurate background leukemia rates, and difficulty tracking mobile populations further affect cluster investigations. Nevertheless, existing evidence partially supports plausibility and warrants further investigation into potential infectious determinants of ALL and cALL, particularly in the context of multifactorial or complex systems.

Breastfeeding and Childhood Leukemia Incidence

“…Further support is drawn from the population-mixing theory that an excess of childhood leukemia has been found in rural, potentially immunologically naive, populations that have undergone an influx of permanent residents. [8][9][10][11][12] Breast milk is a total food meant to exclusively supply all the nutritional needs of infants. Current recommendations of leading health organizations, including the American Academy of Pediatrics 13 and the World Health Organization, 14 state that "infants should be exclusively breastfed for the first six months of life to achieve optimal growth, development and health.…”

HLA-DP genetic variation, proxies for early life immune modulation and childhood acute lymphoblastic leukemia risk

“…1 However, unlike leukemia in some animals 2 and HTLV-associated adult T-cell leukemia, 3 studies have not been able to show a direct pathologic involvement of specific infection(s) for leukemia in children. 4 It has been suggested that for childhood leukemia, particularly for precursor B-cell acute lymphoblastic leukemia (ALL), a delay in exposure to common childhood infections leaves the immune network undermodulated, and subsequent exposure to infections results in an unfavorable immune response; specifically, a proliferative advantage to preleukemia cells. 5 This "delayed infection" hypothesis suggests that exposure to infections or other immune-modulatory factors early in life may result in a protective effect against childhood ALL.…”

Breastfeeding and early infection in the aetiology of childhood leukaemia in Down syndrome

“…Correspondingly, early infections have a protective effect in ALL by promoting the physiological maturation of the immune system, whereas late infections promote an excessive proliferation of the lymphocytes (McNally and Eden, 2004;Menegaux et al, 2004;Greaves, 2006;O'Connor and Boneva, 2007).…”