Dissecting the Causal Pathway from Herpes Zoster to Postherpetic Neuralgia: A Multi-Stage Mendelian Randomization Study Implicating VZV-Specific IgE and Cerebrospinal Fluid Metabolites.

Background: Postherpetic neuralgia (PHN) develops in 10-20% of herpes zoster (HZ) patients, yet the causal mechanisms driving this transition from acute infection to chronic neuropathic pain remain elusive. VZV-specific immunoglobulin E (IgE) and cerebrospinal fluid (CSF) metabolites represent candidate intermediate phenotypes that may mediate neuroimmune dysfunction, but their sequential causal relationships remain unexplored. We hypothesized that IgE and CSF metabolites constitute a hierarchical causal pathway from HZ exposure to PHN risk. Methods: We conducted a multi-stage Mendelian randomization study. First, two-sample Mendelian Randomization (MR) with MRlap correction established causal effects of HZ on IgE and screened 435 CSF metabolites for PHN associations. Given substantial HZ-PHN sample overlap precluding total effect estimation, multivariable MR (MVMR) evaluated whether metabolites mediate IgE effects on PHN. Results: HZ exhibited a significant causal effect on VZV-specific IgE (IVW: β = 0.237, 95% CI: 0.104-0.371, Conclusion: These findings support a sequential causal pathway from HZ to PHN involving IgE and CSF metabolites, identifying 5-methyluridine as a potential modifiable protective factor and highlighting neuroimmune-metabolic crosstalk in chronic pain pathogenesis.