Infections as part of the multiple sclerosis prodrome: A systematic review

Background and aim: Evidence has highlighted the prodromal phase of multiple sclerosis (MS), reflected in increased healthcare usage, hospital admissions and prescriptions. Despite increasing interest in the role of infections in MS susceptibility and severity, infections in the prodrome have not been systematically reviewed. We examined how infections are defined and measured within the MS prodrome and synthesised existing evidence. Methods: We conducted a systematic review of studies investigating infection-related events in the 10 years preceding MS onset. Results: 3523 papers were screened; 40 papers underwent full-text review with eight studies meeting inclusion criteria. MS case definitions varied, ranging from a single diagnostic code to neurologist-confirmed diagnoses. Most papers (75%) examined a five-year period prior to diagnosis. Findings were heterogeneous. One study reported higher self-reported upper respiratory tract infections, while UK and French healthcare data showed increased rates of cystitis and urinary tract infections in people with subsequent MS (P < 0.05). Some infections were less frequent in the MS cohort (e.g., tonsillitis). Higher infection-related healthcare usage was observed in a Canadian administrative cohort compared with controls, whereas no significant differences were found in a clinically defined cohort. Conclusion: Differences in how cases are defined, including criteria for the prodrome and infections, limit comparability across studies. While some evidence suggests increased infections prior to MS onset, findings are inconsistent. We highlight the need for further investigation including across MS subtypes and more diverse populations. © 2026 The Authors