Hospital-treated infectious diseases, infection burden, and subsequent risk of demyelinating diseases: a prospective cohort study

Abstract Background and Objectives Epstein-Barr virus infection is an established risk factor for multiple sclerosis (MS). However, associations between a wider range of infections and MS remain unclear, particularly among middle-aged and older adults. Risk factors for other (non-MS) demyelinating diseases are also poorly understood. We examined whether hospital-treated infectious diseases and infection burden were associated with subsequent risk of demyelinating diseases. Methods This prospective cohort study included 484,292 UK Biobank participants (mean age 56.5 [SD 8.1] years; 54.3% women). Participants with demyelinating diseases at baseline were excluded. Hospital-treated infectious diseases and incident demyelinating diseases were ascertained from linked inpatient records. The primary outcome was any incident demyelinating disease; secondary outcomes were MS and other demyelinating diseases (not mutually exclusive). Infection burden was assessed by episode count, maximum number of concurrent infections, and number of affected anatomical sites. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for sociodemographic, lifestyle, and clinical factors. Results During a median follow-up of 12.7 years (IQR, 12.0-13.4), 592 participants (0.12%) developed demyelinating diseases, including 436 with MS and 194 with other demyelinating diseases. Hospital-treated infectious diseases were associated with higher risks of all demyelinating diseases (HR 1.80, 95% CI 1.49-2.17), MS (HR 1.88, 95% CI 1.51-2.35), and other demyelinating diseases (HR 1.65, 95% CI 1.18-2.31). For all demyelinating diseases, greater infection burden across all 3 measures was associated with progressively higher risk (all P for trend <0.001); HRs were 1.45 (95% CI 1.16-1.81) for 1 infection episode and 2.97 (95% CI 2.22-3.97) for ≥2 episodes versus none. Discussion Hospital-treated infectious diseases and greater infection burden were associated with higher subsequent risk of demyelinating diseases among middle-aged and older adults. These findings broaden current understanding of infection-related risk and may inform future prevention research.