Immunophenotypic profiling reveals selective activation and differentiation-associated immune perturbations in acute herpes zoster and exploratory correlates of postherpetic neuralgia risk

Herpes zoster (HZ) is caused by varicella–zoster virus (VZV) reactivation and can be complicated by postherpetic neuralgia (PHN). Although cellular immunity is central to VZV control, early peripheral immune correlates associated with PHN risk remain incompletely defined. In this age- and sex-comparable case–control study, we performed flow-cytometric immunophenotyping of peripheral blood lymphocyte subsets in 86 patients with acute HZ (within 7 days after rash onset) and 86 healthy controls. Patients were followed longitudinally, and PHN was defined as pain persisting for ≥90 days after rash onset. Immune subsets across T, B, NK and γδ T-cell compartments were compared by Mann–Whitney U tests. Principal component analysis (PCA) was used as a descriptive visualization of coordinated immune patterns, and univariable logistic regression was used to generate exploratory associations with HZ status and PHN risk. Total circulating CD3⁺ T-cell counts and proportions did not differ significantly between acute HZ and controls. However, acute HZ was associated with selective activation/differentiation-associated changes, including reduced frequencies of double-negative T cells, CD4⁺ central-memory T cells, CD28 + CD4⁺ T cells, cTfh2 cells, CD28⁺CD8⁺ T cells, CD8⁺ central-memory T cells and Tc2-like cells, together with increased CD4⁺ TEMRA, CD28 − CD4⁺ T cells, Tph cells, cTfh17-like cells, CD28⁻CD8⁺ T cells and HLA–DR⁺CD38⁺CD8⁺ T cells. NK-cell analysis showed reduced total NK and CD56 dim NK-cell frequencies, with increased CD56 bright and NKp46⁺ NK-cell frequencies. B-cell and γδ T-cell frequencies were largely preserved. PCA provided a descriptive summary of these coordinated patterns, with the first two components explaining 31.5% of variance. During follow-up, 22 of 86 patients developed PHN. Compared with non-PHN patients, PHN cases showed higher CD4⁺ central-memory T cells and NKp30⁺ Vδ2⁺ γδ T-cell frequencies, but lower naïve CD8⁺ T cells, transitional B cells, and NKG2D⁺ Vδ2⁺ γδ T cells. In univariable analyses, age, reduced naïve CD8⁺ T cells and reduced transitional B cells were associated with higher PHN odds. Acute HZ is characterized by selective peripheral immune perturbations involving T-cell activation/differentiation states and NK-cell reduction/redistribution rather than global lymphocyte depletion. Early immune features, particularly naïve CD8⁺ T cells and transitional B cells, may provide exploratory information for PHN risk stratification and warrant validation in prospective cohorts with virological confirmation and VZV-specific functional assays.