DataSheet_1_Risk of malignancy following exposure to Epstein-Barr Virus associated infectious mononucleosis: A nationwide population-based cohort study.docx

PurposeEpstein-Barr virus (EBV) infection has been shown to contribute to oncogenesis and often causes acute clinical manifestation of Infectious mononucleosis (IM). It is unknown whether IM could increase the risk of subsequent malignancies. We aimed to evaluate the association of IM caused by EBV (EBV-IM) with overall and subtypes of malignancy in a large population-based cohort study.MethodsThis study included 1,419,407 individuals born in Denmark between 1973 and 2016 identified from national registers and 23,057 individuals had IM. The 5,394 of them had confirmed EBV-IM and they were birth date- and sex- matched (1:63) to 1,396,350 non-IM individuals. Cox regression was used to examine the associations of EBV-IM with malignancy.ResultsIndividuals with a history of confirmed EBV-IM had an 88% increased overall risk of malignancy (hazard ratio [HR]:1·88, 95% confidence interval [CI]: 1·42–2·49) and a five-fold risk of hematologic malignancies (HR 5·04, 95% CI: 3·07–8·25), compared to those without IM. Similar estimates were observed in the sibling analysis. The overall risk of malignancy was greater for EBV-IM with complications (HR 8·93, 95% CI: 3·35–23·81) than that for EBV-IM without complications (HR 1·35, 95% CI: 1·20–1·53). EBV-IM duration was related to increased risk of malignancy in a dose-response way. Notably, the significant elevated risk of overall malignancy was observed in the first two years after EBV-IM onset (rate ratio [RR] 4·44, 95% CI: 2·75–7·17) and attenuated thereafter.ConclusionEBV-IM was associated with an increased risk in malignancy, particularly hematologic malignancies and in the first two years following IM exposure. Our findings suggest an important time-window for early screening of the EBV-attributed malignancy.