Association Between Post-COVID-19 Herpes Zoster Reactivation and Peripheral Nervous System Disorders: Multinational Real-World Evidence from TriNetX.

Background: The increased incidence of herpes zoster (HZ) following coronavirus disease 2019 (COVID-19) suggests a period of immune dysregulation, but the associated long-term neuro-immunological risks remain unclear. Methods: Utilizing de-identified electronic health records from the TriNetX Global Collaborative Network, we established 1:1 propensity score-matched cohorts of COVID-19 survivors, comparing HZ-exposed and unexposed groups over a three-year follow-up. Primary endpoints included the incidence of peripheral nervous system disorders: Bell's palsy, Guillain-Barré syndrome (GBS), and myasthenia gravis (MG). Analyses included Cox proportional hazards models, landmark analyses, and multiple sensitivity analyses. Results: HZ reactivation was associated with increased three-year risks of all outcomes. The risk of Bell's palsy was elevated early and remained sustained (hazard ratio 3.625, 95% confidence interval 3.151-4.170). In contrast, the risks of GBS (hazard ratio 1.858, 95% confidence interval 1.243-2.779) and MG (hazard ratio 1.640, 95% confidence interval 1.178-2.284) showed delayed increases emerging after the first year. These associations remained consistent across sensitivity analyses and were more pronounced in individuals with metabolic comorbidities. COVID-19 vaccination was not associated with an increased risk of these outcomes, although subgroup findings should be interpreted with caution due to limited event counts. Conclusions: Post-COVID-19 HZ is associated with an increased risk of peripheral nervous system disorders, highlighting the need for symptom-based neurological awareness during both early and delayed post-infectious periods.