Abstract Background Epstein-Barr virus (EBV) infects ~95% of adults globally and limited early life transmission opportunities can delay EBV exposure till adolescence/early adulthood, increasing the risk of severe EBV infection, which most commonly manifests as infectious mononucleosis (IM). This study sought to investigate a potential aetiological association between IM and inflammatory bowel disease (IBD). Methods In this longitudinal nested case-control study, Danish nationwide registries were used to identify 37,156 IBD patients and 222,936 sex- and age-matched healthy controls, between 2005-2021. Logistic regression was used to calculate the odds ratio (OR) for IM hospitalisation prior to IBD diagnosis stratified by sex, age at IM diagnosis, age at IBD diagnosis, and IBD subtype (Crohn’s disease [CD] or ulcerative colitis [UC]). Additionally, exposure-controlled time-to-event analyses were used to explore the association between IM hospitalization and poor IBD prognosis. This association was measured using the occurrence of IBD-related hospitalization, surgery, complication and/or anti-TNF therapy commencement up to 10 years post-IBD diagnosis. Results Previous IM hospitalisation was significantly associated with the development of both CD (OR: 1.44, 95% CI: 1.20-1.73) and UC (OR: 1.27, 95% CI: 1.09-1.47). Sex was not found to be a significant effect modifier of this association for either CD (p=0.4) or UC (p=0.9). Those hospitalised with IM at a younger age had a higher odd of developing CD than those hospitalised in early adulthood (0-14-years OR: 2.60 [95% CI: 1.41-4.59]; >20-years OR: 2.04 [95% CI: 1.23-3.25]). A similar pattern was observed for UC development (0-14-years OR: 2.62 [95% CI: 1.44-4.55]; >20-years OR: 1.50 [95% CI: 0.97-2.25]). Poor disease prognosis following hospitalisation with IM within 10 years post-IBD diagnosis was only seen in CD (CD IRR: 1.52 [95% CI: 1.20-1.92]; UC IRR: 0.87 [95% CI: 0.65-1.16]). Conclusion This study demonstrated an association between IBD development and prior hospitalisation with IM, indicating the possibility of EBV infection as a significant contributor to IBD development. Strengthening understanding of IBD development can contribute to the prevention of IBD and improve management.
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