Blood transcriptomic immune signatures in herpes zoster and postherpetic neuralgia: parallel cohort analyses of IFN-related pathway patterns

Herpes zoster (HZ) results from reactivation of latent varicella-zoster virus (VZV), and postherpetic neuralgia (PHN) is a major chronic pain complication. We performed parallel analyses of two independent public blood transcriptomic cohorts: GSE242252 (n=80; HZ onset, 1-year recovery, and controls) and PRJNA1142765 (n=23; 15 HZ and 8 PHN). Because the cohorts differed in platform, library preparation, design, and sampling structure, expression matrices were not merged; cross-cohort interpretation was restricted to within-cohort results and pathway-level directional concordance. HZ onset showed strong type I interferon (IFN)-dominated activation (HALLMARK_INTERFERON_ALPHA_RESPONSE, NES = 2.21, adjusted p=4.4x10-10), with recovery-associated attenuation of the sample-level IFN score (onset vs. recovery, p=0.005). In the smaller PHN cohort, only two genes met the strict differential-expression threshold, but Hallmark GSEA showed positive IFN-alpha and IFN-gamma enrichment. Ranking-sensitivity analysis confirmed IFN-alpha and IFN-gamma as the top two positively enriched Hallmark pathways using either log2 fold change or the DESeq2 Wald statistic, with leading-edge Jaccard similarities of 0.848 and 0.897, respectively. Exact patient-label permutation of the sample-level IFN score was not significant (two-sided p=0.297), although the PHN-minus-HZ direction remained positive in all 23 leave-one-out iterations. The new biological information is therefore an asymmetry of evidence: acute HZ IFN activation and recovery-associated attenuation are strongly supported, whereas the PHN-associated IFN pattern is stable at the pathway-ranking level but statistically uncertain at the patient level. Accordingly, the prior interpretation of persistent IFN activation in PHN is narrowed rather than reinforced. A structured external-replication search did not identify a suitable independent public human blood/PBMC transcriptomic cohort containing PHN samples; external evidence was therefore treated as literature-based concordance and supportive context rather than validation. Restricted computational prioritization highlighted IFN-related and CCL5/CCR5-associated axes for future study.