An examination, with a meta-analysis, of studies of childhood leukaemia in relation to population mixing

Abstract

Background:Marked influxes of people into rural areas, termed rural population mixing (PM), have been associated with excesses of childhood leukaemia (CL), consistent with mini-epidemics of a mainly immunising, subclinical infection to which CL is a rare response. For such situations of rural PM would promote contacts between infected and susceptible individuals, the latter tending to have a higher than average prevalence in rural or isolated areas. Confusion has arisen from some workers applying the term PM to non-rural situations lacking known recent change.Methods:Available PM studies using the original definition of influxes were examined, a meta-analysis carried out of studies of CL in relation to exposure to high levels of rural PM, and also a detailed analysis by age group.Results:The meta-analysis of 17 studies shows a significant CL excess in association with rural PM: overall relative risk (RR) at ages 0–14: 1.57; 95% confidence interval 1.44–1.72; at 0–4 years 1.72 (1.54–1.91). This contrasts with the absence of an excess of CL in similarly exposed urban areas (RR 1.00; 0.93–1.07), pointing to a high level of immunity there. The mixed results of studies using other definitions of PM were summarised. The excess associated with rural PM below age 2 years (RR 1.51; 1.17, 1.92) was not appreciably different from that at later childhood ages.Conclusion:Much of the inconsistency among studies ostensibly about CL and PM reflects the use of definitions other than that originally proposed. The broad similarity of the CL excess below age 2 with that at older childhood ages is inconsistent with the Greaves' delayed infection hypothesis, since any infection underlying the former is difficult to consider as delayed.

Childhood leukemia and population mixing

“…As the authors acknowledge ''in Finland overall, there has not been any major population influx or increased residential mobility during the study period'' [1], so their study hardly warrants a conclusion about the validity of the rural population mixing hypothesis. In contrast, supporting evidence from studies of unusual population mixing in rural areas under various circumstances is now extensive [3].…”

Új és hagyományos irányok a gyermekkori akut lymphoblastos leukaemia biológiájában és ellátásában

“…A fertőzés leukaemogenesisben játszott szerepét valószínűsíti, hogy több független vizsgálatban is alátámasztották a vándor-lással járó populációkeveredés konzisztens kockázateme-lő hatását a gyermekkori akut leukaemiák megjelenésére. Röviddel az új lakosok betelepülése után átlagosan más-félszeres relatív kockázatot figyeltek meg, ami mögött a behurcolt, adott területen addig ismeretlen patogének megjelenését sejtik [11,12]. Régóta próbálkoznak humán ALL-es mintákban leukaemogenesissel összefüg-gésbe hozható infektív ágens kimutatásával, azonban exogén virális, illetve mikrobiális szekvenciákat még ér-zékeny módszerekkel sem találtak [9].…”

“…Az elmélet egybeesik a blastszintű molekuláris abnormitások többlépcsős (szekvenciális) kialakulásának modelljével (lásd a későbbiekben). A folyamat eredeté-nek pontosítására Kinlen és Greaves inkább egymást kiegészítő, mintsem kizáró hipotéziseket dolgozott ki [9,11]. Az immunmechanizmusok etiológiai szerepét erősítik azok az eredmények, hogy a gyermekkori ALL rizikója asszociál bizonyos hisztokompatibilitásért felelős humánleukocytaantigén (HLA)-konstellációkkal.…”

Population mixing and childhood leukaemia

“…In their recent study of childhood leukaemia (CL) in Switzerland, Lupatsch et al [1] imply that they have tested my population mixing (PM) hypothesis concerning an infective aetiology for CL [2]. This is misleading, since this hypothesis concerns marked rural PM, as I have always stressed, and their study does not address such PM.…”

“…In general, epidemics do not show a linear dose-response relation with the contact level between susceptible and infected individuals, but begin when this reaches some critical level, specific for the agent involved [4]. The examples of marked rural PM that my colleagues and I have studied have been specific and clearly identifiable [2], and those associated with CL excesses usually involved influxes much greater in size than the rural communities they affected. The meta-analysis [2] to which Lupatsch et al [1] refer included the most recent examples in the UK, of Seascale (18-fold excess of CL) and in the USA, of Fallon (26-fold) which followed influxes in size equivalent to about 10 and 27 times, respectively, that of the rural communities in question.…”