A rich and consistent set of research has shown that patterns of infection influence childhood acute lymphoblastic leukemia (ALL) risk. For instance: being a first born child carries a higher risk of ALL as the younger children are exposed to more infections brought home by the older children. Also, a normal course of vaccinations proveides decreased risk of leukemia (compared to unvaccinated children), showing that immune “exercise” decreases risk. The most compelling data shows that exposure to childhood contacts in a daycare setting reduces leukemia risk – this seen in many studies (see the Figure 1). Children who lack this early immune “education” will eventually be exposed to common childhood infections, but their “uneducated” immune systems are more likely to react too strongly, leading to damaging mutations and therefore increased risk. Daycare is good and healthy! This mirrors research concerning allergies and asthma, which also show that increased exposure early to immune stimulants decreases these diseases as children grow older. The fact that immune deprivation increases risk is often called the hygiene hypothesis when referring to immune related diseases and when referring to leukemia is called the Greaves’ hypothesis, after Mel Greaves who first described this for ALL in the 1980s.
Studies of population mixing within new towns provides evidence that specificinfections may influence risk however, no particular infection has been identified that precedes ALL despite many searches. The United Kingdom Childhood Cancer Study (UKCCS) showed that daycare exposure reduced ALL risk, but unexpectedly showed that the number of physician-diagnosed infections during the first year of life was higher among case children (OR = 1.4, 95% CI: 1.1-1.9; p < 0.05) relative to healthy controls . A subsequent UKCCS analysis on the same data found that the rate of infectious illnesses during the first year of life was associated with the probability of developing ALL after age 2 years. The result from the UKCCS has been corroborated by our population-based analysis of national health records in Taiwan. When compared with controls, Taiwanese children who contracted leukemia were more likely to have had infections diagnosed by a physician in their first year of life (OR = 3.18, 95% CI: 2.17-4.66) and in any period before diagnosis (censored one year prior to diagnosis, OR = 3.90, 95% CI: 2.61-5.81) with a dose-response relationship.
We are therefore left with two observations: increased exposure to infection early in life protects against ALL, but having severe infections requiring a doctor visit increases risk of ALL! Both of these observations do not point to specific infections playing a role, but generally suggest that early infections are good for you and when you are not exposed early, your infections can result in strong after effects that increase risk to leukemia.