gms | German Medical Science

Background: By triggering the immune system, early childhood infections are assumed to be protective in cancer development, particularly non-solid tumors. However, a delayed exposure to these infections may lead to an increased cancer risk due to abnormal immune responses. Nonetheless, studies on this association are inconsistent and have not been summarized.

Methods: Using PubMed and Web of Science, we systematically searched for studies conducted in humans on the association between childhood infections and cancer. We only included studies that assigned the infection to childhood and where the infection occurred prior to cancer diagnosis. Common effect estimates were calculated using random effects models for specific research hypotheses if at least three studies were available.

Results: The systematic literature search identified 11,626 studies. Overall, 101 studies (6 retrospective cohorts, 91 case-control, and 4 ecological studies) fulfilled inclusion criteria for this review and allowed 70 analyses on 11 different cancer outcomes after exposure to 28 different childhood infections. Pooled odds ratios (OR) showed an increased leukemia risk after 2+ childhood infections (OR=1.47 (95%CI 1.03; 2.11)). The risk of acute myeloid leukemia was found to be increased after any infection in childhood (OR=1.80 (95%CI 1.04; 3.10)) as well as after tonsil infections (OR=1.30 (95%CI 1.03; 1.65)). Moreover, we observed an increased risk for acute lymphoblastic leukemia (ALL) after infections of the upper respiratory tract (OR=1.49 (95%CI 1.27; 1.74)). The risk of non-Hodgkin lymphoma was increased after infections of the respiratory tract (OR=1.70 (95%CI 1.15; 2.54)).

Contrarily, we observed a decreased risk for ALL after severe infections of the ear or high-grade infections (4+ in the first year of life or requiring surgery) of the ear, nose, and throat tract (OR=0.82 (95%CI 0.72; 0.94)). Additionally, the risk of B-cell ALL was found to be decreased after any kind of infection (OR=0.86 (95%CI 0.75; 0.98)). Regarding lymphomas, we observed a decreased risk for myeloma after chickenpox (OR=0.84 (95%CI 0.73; 0.97)), for Hodgkin lymphoma after scarlet fever (OR=0.47 (95%CI 0.30; 0.75)), and for non-Hodgkin lymphoma after pertussis (OR=0.81 (95%CI 0.73; 0.90)).

Conclusion: While milder infections of the respiratory tract or a low number of infections in our results tend to increase cancer risk, more frequent and severe infections such as chickenpox, scarlet fever, pertussis, or infections that required surgical intervention appear to reduce cancer risk. The existing hypothesis that mild infections make the immune system inattentive, while threatening infections could contribute to a better development of the immune system due to their stronger triggers, is therefore consistent with our results. However, the timing of the infection or the pathogen (e.g. virus versus bacteria) could also be an important factor, but this has not yet been conclusively clarified by the studies currently available. Additionally, most of the available studies are subject to methodological limitations and exposure misclassification, especially recall bias. Therefore, large studies with valid and detailed assessment of exposure and infection age are needed to investigate causal relationships between childhood infections and cancer risk in later life, particularly also for endpoints other than non-solid tumors.

The authors declare that they have no competing interests.

The authors declare that an ethics committee vote is not required.