A Childhood Leukaemia Cluster in Milan: Possible Role of Pandemic AH1N1 Swine Flu Virus.
Authors: Cazzaniga Giovanni , Bisanti Luigi A. , Palmi Chiara , Randi Giorgia , Pregliasco Fabrizio , Deandrea Silvia , Bungaro Silvia , Valsecchi Maria Grazia , Masera Giuseppe , Biondi Andrea , Greaves Mel 
Published: October 2019

Abstract
Abstract 2496
Cases of childhood leukemia very rarely present as a significant time/space cluster. Clusters offer a unique opportunity to identify a point source causal exposure but, in practice, this is extremely difficult. We herewith report an apparent cluster of seven cases of childhood B cell precursor acute lymphoblastic leukaemia (ALL) occurring over a four week period (December 2009/January 2010) in Milan, Lombardy, Italy. Over the prior ten years (1999–2008), the mean number of cases per year in Milan was 7.3±1.3. The seven cases in the cluster were of varying ages at diagnosis (2–11 years); analysis of chromosomal abnormalities did not reveal recurrent features; inherited leukemia associated alleles did not show an augmented risk. Given the protracted natural history of ALL, initiated in utero, and the variable ages at diagnosis in this cluster, an exposure to a causal trigger or promotional factor focused proximally to the diagnostic time frame was suspected. Three cases attended one school and a fourth was the younger sibling of a student at this same school. No cases of leukemia were recorded in the previous ten years at the school. All four cases lived in the same small area of Milan. A space-time permutation scan statistic was applied to the whole series of data and revealed a clustering for the one month period of diagnosis and the small city area of the four cases (p-value=0.017). As the school had undergone extensive refurbishment 3–24 months prior to the diagnoses, exposure to chemicals and physical agents (including EMF) as well as leukemogenic paint solvents was considered but no supportive evidence for this was obtained. An outbreak of the AH1N1 influenza virus pandemic occurred in Milan 8–10 weeks prior to the diagnoses. All seven cases of ALL were later found to be AH1N1 antibody-positive, in contrast to 32.3% (95% confidence interval: 26,96% – 37,96%) of age-matched children in Milan. Interestingly, positivity was found in only one out of four children from Lombardy with kidney tumor for whom we could retrieve PB collected at that time. Additionally, all seven cases had features indicative of a likely paucity of infectious exposure in the first year of life (high birth order and lack of social contacts). These data do not establish causality but are compatible with the ‘delayed infection’ hypothesis for childhood ALL in which an abnormal immune or inflammatory response to a common infection promotes ALL in susceptible individuals (Greaves M., Nat Rev Cancer, 2006;6:193–203).
This is the first time that a significant cluster of childhood leukemia cases has been linked, albeit tentatively, to a known infectious agent. Prior, descriptive epidemiological data have however indicated an association between increased rates of childhood ALL and epidemics of seasonal influenza in the UK (Kroll ME et al, J Natl Cancer Inst, 2006;98:417-20). The credibility of flu viruses as potential triggers of ALL requires further exploration including functional assessment in model systems.

Disclosures:
No relevant conflicts of interest to declare.