To Örebro University

Background: Viral infections, particularly Epstein-Barr virus (EBV), have been linked with risk of multiple sclerosis (MS). Given the evidence that SARS- CoV-2 infection can have consequences for the central nervous system (CNS) and autoimmune disorders, it might increase risk of MS and other demyelinating diseases of the CNS.

Objectives: We aimed to assess whether SARS- CoV-2 infection is associated with subsequent diagnoses of non-MS demyelinating CNS diseases, MS, and infectious mononucleosis (IM) due to EBV—an important MS risk factor.

Methods: All residents of Sweden aged 3–100 years were followed between 1st January 2020 and 30th November 2022, excluding those with demyelinating disease prior to 2020, resulting in 9,981,915 individuals. Exposure was classified as SARS- Cov-2 uninfected or infected, the latter divided by severity, and mod-elled as a time-varying covariate (uninfected, infection without hospital admission and infected with hospital admission). Cox regression assessed the risk of three separate outcomes: hospital-diagnosed non-MS demyelinating diseases; MS; and IM due t oEBV, adjusting for sex, year of birth (age), Charlson comorbidity index, healthcare region and country of birth.

Results: Hospital admission for COVID-19 was associated with raised risk of subsequent non-MS demyelinating disease. Rates per 100 000 person years (and 95% confidence intervals [CI]) were 3.8 (3.6– 4.1) among those without a COVID-19 diagnosis and 9.0 (5.1–15.9) among those admitted to hospital for COVID-19, with an adjusted hazard ratio (aHR) and 95% CI of 2.31 (1.30– 4.10). Equivalent associations with MS were rates of 9.5 (9.1–9.9) and 21.0 (14.5–30.5) per 100,000, and an aHR of 2.48 (1.70–3.61). For subsequent IM due to EBV, hospital admission for COVID-19 was associated with a rate of 10.5 (6.2–17.8) per 100,000 compared with 4.7 (4.4–5.0) for those without COVID-19, and an aHR of 5.63 (3.29–9.66).

Conclusions: There was increased risk of CNS demyelinating diseases among people admitted to hospital for COVID-19. COVID-19 was also associated with a raised risk of IM due to EBV, an established risk factor for MS. It is possible that at least a proportion of these associations is due to surveillance or referral bias (due to a previous hospital admission for infection), so future research should continue to follow the population that had COVID-19 for development of MS and other demyelinating diseases, which can have long asymptomatic and prodromal phases.