Factors associated with rate of multiple sclerosis onset in a cohort with prior infectious mononucleosis identified in administrative data

Background and objectives — Evidence suggests that Epstein-Barr virus (EBV) infection is a necessary, but not sufficient, exposure for developing multiple sclerosis (MS). Although many cases of EBV infection are asymptomatic, people with infectious mononucleosis (IM) often seek medical attention and thus can be studied on the population level. We aimed to characterize factors influencing the rate of MS development in a large population-based cohort with IM.

Methods — In this retrospective cohort study, outpatient and inpatient cases of IM (ICD-9 code 075 and ICD-10-CA code B27) were identified from health claims data in Ontario, Canada, from April 1, 1992, to March 31, 2017. MS cases after IM were identified using a validated algorithm from May 1, 1992, to March 31, 2022. We evaluated the rate of MS in an IM-exposed cohort using a cause-specific hazards model incorporating age at IM (younger than 10 years, 10–25 years, and older than 25 years), sex, rural vs urban residence, neighborhood income, immigrant status, and mental health care use.

Results — We identified 671,410 cases of IM, with mean (SD) age of 19.9 (18.8) years; 53.5% were female. Of the 671,410, 2,470 (0.4%) developed MS over a median (interquarile range [IQR]) follow-up of 16.7 (10.1–23.3) years. The median time from IM to MS was 11.4 (IQR 6.5–16.8) years. Female sex (hazard ratio [HR] 1.9, 95% CI 1.8–2.1), age at IM (age 10–25 years vs < 10 years: HR 6.0; 95% CI 5.2–6.9), and mental health care use (HR 1.2; 95% CI 1.1–1.3) were associated with a greater rate of developing MS after IM, while being an immigrant was associated with a lower rate (HR 0.5; 95% CI 0.4–0.7).

Discussion — In a population-based cohort, the median time from IM exposure to MS was just over 1 decade. Mental health conditions may be associated with a higher rate of developing MS, in addition to being a feature of the MS prodrome. Our results may inform risk stratification for developing MS after IM and thus facilitate secondary prevention in high-risk individuals. Limitations include the ability to capture only recognized infectious mononucleosis, which may limit generalizability to asymptomatic or mild cases of EBV infection.