A systematic review and meta-analysis of the association between childhood infections and the risk of childhood acute lymphoblastic leukaemia

Abstract

Background: To determine whether childhood infections were associated with the development of childhood acute lymphoblastic leukaemia (ALL).

Methods: We included studies that assessed any infection in childhood prior to the diagnosis of ALL in children aged 0-19 years compared to children without cancer. The primary analysis synthesised any infection against the odds of ALL, and secondary analyses assessed the frequency, severity, timing of infections, and specific infectious agents against the odds of ALL. Subgroup analyses by data source were investigated.

Results: In our primary analysis of 12 496 children with ALL and 2 356 288 children without ALL from 38 studies, we found that any infection was not associated with ALL (odds ratio (OR)=1.10, 95% CI: 0.95-1.28). Among studies with laboratory-confirmed infections, the presence of infections increased the odds of ALL by 2.4-fold (OR=2.42, 95% CI: 1.54-3.82). Frequency, severity, and timing of infection were not associated with ALL.

Conclusions: The hypothesis put forward by Greaves and others about an infectious aetiology are neither confirmed nor refuted and the overall evidence remains inadequate for good judgement. The qualitative difference in the subgroup effects require further study, and future research will need to address the challenges in measuring infectious exposures.

Figure 1

Study selection flow diagram.

Figure 2

Random-effects model examining the association between common infections and risk of childhood acute lymphoblastic leukaemia. CI represents confidence interval. Common infections are reported as a two-class variable, or highest vs lowest in more than two categories. The secondary analysis for frequency of infections is a combined maximum likelihood effect estimate that estimates a trend from summarised dose–response data. The presence of parvovirus B19 was measured as a dichotomous variable, presence of IgG antibodies vs no IgG antibodies for parvovirus B19. All other studies, the reference was no infections.