Background: Infectious mononucleosis (IM) is a largely self-limiting syndrome mainly affecting adolescents and young adults but can present as a more severe disease requiring hospitalisation. The infectious agent most commonly causing IM, Epstein-Barr virus (EBV) has been associated with the development of several immune-mediated and inflammatory diseases. Objective: To investigate the risk of inflammatory bowel disease (IBD) following hospitalisation with severe IM. Methods: Danish nationwide registries were used to identify severe IM patients and sex-, age- and municipality- matched non-IM hospitalised controls, from 1st January 1977 to 31st December 2022. We undertook Cox regression modelling to calculate the hazards (HR) and 95% CI of IBD diagnosis, including Crohn's disease (CD) and ulcerative colitis (UC). Analyses were stratified by sex and age at IM hospitalisation. Results: We identified 39,684 patients with severe IM who were sex-, age-, and municipality-matched to 396,840 non-IM hospitalised controls. Severe IM was significantly associated with the development of IBD (HR:1.35; 95% CI: 1.22-1.49) and this was seen particularly in CD (HR: 1.56; 95% CI: 1.34-1.83) and to a lesser extent in UC (HR: 1.23; 95% CI: 1.08-1.40). Sex at severe IM diagnosis was not found to be a significant modifier to the risk of IBD development with risk increased in both females (HR: 1.36; 95% CI: 1.20-1.55) and males (HR: 1.34; 95% CI: 1.17-1.54). Only those receiving a severe IM diagnosis at 10-16 years (HR: 1.42; 95% CI:1.22-1.64) or 17-29 years (HR: 1.34; 95% CI:1.15-1.56) were at increased risk of IBD development. Conclusion: This study demonstrated an association between IM hospitalisation and later IBD development, indicating an association between severe EBV disease and IBD development. Further exploration of factors contributing to IBD susceptibility following EBV infection is warranted.

The authors have declared no competing interest.

This work was supported by the Danish National Research Foundation (grant no: DNRF148), the Novo Nordisk Foundation (grant no: NNF21OC0068631) and the Lundbeck Foundation (grant no: R403-2022-1531).

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