All-cause mortality
In the overall matched cohort, patients diagnosed with HZ within one year following COVID-19 exhibited a higher all-cause mortality rate of 8.0%, compared to 6.1% in those without HZ. However, Kaplan–Meier survival analysis showed no significant difference in overall survival curves between the two groups over the full three-year follow-up period (log-rank p = 0.260), and the corresponding HR was 1.04 (95% CI: 0.97–1.11) (Fig. 2A).
Kaplan–Meier survival curves comparing COVID-19 patients with and without herpes zoster (HZ) infection for (A) all-cause mortality, (B) MACE, (C) AKI, and (D) decline in eGFR to less than 60 mL/min/1.73 m² over a three-year follow-up period. The blue line represents patients with HZ development, and the red line represents patients without HZ. The log-rank test was used to compare survival distributions between groups, with p-values provided in each panel. Abbreviation: AKI, acute kidney injury; eGFR, estimated glomerular filtration rate; HZ, herpes zoster; MACE, major adverse cardiovascular events.
Notably, the proportional hazards assumption was violated (global test p < 0.001), suggesting that the effect of post-COVID HZ on mortality varied over time. Time-stratified survival analyses were therefore performed (Supplementary Table S1). During the first 90 days after COVID-19 diagnosis, patients with HZ had a significantly lower mortality risk (HR = 0.30, 95% CI: 0.25–0.36, p < 0.001), potentially reflecting increased medical attention during acute HZ episodes (Supplementary Table S2). From day 91 onward, this early survival advantage reversed. Between day 91 and three years, the mortality risk became significantly higher in the HZ group (HR = 1.33, 95% CI: 1.24–1.44; log-rank p < 0.001), and the proportional hazards assumption was no longer violated (p = 0.897) (Supplementary Figure S1). Further stratified analyses showed that the excess risk emerged most prominently between days 181–270 (HR = 1.45, 95% CI: 1.13–1.87) and 271–360 (HR = 1.55, 95% CI: 1.24–1.94), indicating a delayed but persistent adverse impact of HZ on long-term survival.
In subgroup analyses (Fig. 3A), several factors were associated with increased all-cause mortality among COVID-19 patients who developed HZ, including older age (HR: 3.83; 95% CI: 3.42–4.29), diabetes mellitus (HR: 1.39; 95% CI: 1.25–1.54), hypertension (HR: 1.34; 95% CI: 1.15–1.54), smoking (HR: 1.45; 95% CI: 1.25–1.69), chronic obstruction pulmonary disease (COPD) (HR: 1.85; 95% CI: 1.63–2.11), reduced eGFR < 60 mL/min/1.73 m² (HR: 2.08; 95% CI: 1.85–2.34), CRP ≥ 10 mg/L (HR: 3.10; 95% CI: 2.68–3.58), and vitamin D deficiency < 30 ng/mL (HR: 1.77; 95% CI: 1.43–2.20). In contrast, female sex (HR: 0.69; 95% CI: 0.62–0.77) and higher body mass index (BMI) (HR: 0.65 for BMI ≥ 30; 95% CI: 0.57–0.74) were associated with lower mortality risk.
Subgroup analysis of adverse clinical outcomes in COVID-19 patients with herpes zoster (HZ). Hazard ratios (HRs) with 95% confidence intervals (CIs) are shown for key risk factors associated with (A) all-cause mortality, (B) MACE, (C) AKI, and (D) renal function decline (eGFR < 60 mL/min/1.73 m²). Abbreviations: AKI, acute kidney injury; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HTN, hypertension; MACE, major adverse cardiovascular events.
Major adverse cardiovascular events
Patients diagnosed with HZ within one year after COVID-19 exhibited a higher risk of MACE compared to those without HZ. The MACE incidence was 18.1% in the post-COVID HZ group versus 10.6% in the non-HZ group. Kaplan–Meier analysis demonstrated a significantly lower MACE-free survival probability in the HZ group (80.27%) relative to the non-HZ group (84.95%), with a log-rank p < 0.001. The corresponding HR was 1.38 (95% CI: 1.30–1.46), indicating a sustained increase in cardiovascular risk throughout the follow-up period (Fig. 2B).
Subgroup analysis among COVID-19 patients with HZ (Fig. 3B) revealed that several risk factors were significantly associated with elevated MACE risk. These included older age (HR: 2.94; 95% CI: 2.72–3.18), diabetes mellitus (HR: 1.67; 95% CI: 1.53–1.83), hypertension (HR: 2.18; 95% CI: 1.96–2.42), smoking (HR: 1.58; 95% CI: 1.51–1.98), COPD (HR: 2.03; 95% CI: 1.81–2.27), reduced eGFR < 60 mL/min/1.73 m² (HR: 1.70; 95% CI: 1.52–1.89), and elevated CRP ≥ 10 mg/L (HR: 1.41; 95% CI: 1.26–1.59). Conversely, female sex was associated with a lower MACE risk (HR: 0.77; 95% CI: 0.71–0.84). BMI ≥ 30 (HR: 0.95; 95% CI: 0.87–1.05) and vitamin D deficiency < 30 ng/mL (HR: 1.01; 95% CI: 0.86–1.18) were not significantly associated with MACE.
Acute kidney injury
Patients diagnosed with HZ within one year after COVID-19 had a significantly higher risk of AKI compared to those without HZ. The incidence of AKI was 9.5% in the post-COVID HZ group versus 4.6% in the non-HZ group. Kaplan–Meier analysis showed a lower AKI-free survival probability in the HZ group (89.71%) compared to the non-HZ group (93.55%), with a significant difference confirmed by the log-rank test (p < 0.001). The HR for AKI associated with HZ was 1.67 (95% CI: 1.55–1.80), suggesting a sustained increased renal risk following the occurrence of HZ during the post-acute COVID-19 phase (Fig. 2C).
Subgroup analysis (Fig. 3C) demonstrated that the risk of AKI was markedly elevated among patients aged ≥ 65 years (HR: 3.04; 95% CI: 2.75–3.37), those with diabetes mellitus (HR: 2.10; 95% CI: 1.90–2.33), hypertension (HR: 3.02; 95% CI: 2.59–3.53), smoking history (HR: 1.67; 95% CI: 1.43–1.96), and COPD (HR: 1.96; 95% CI: 1.72–2.24). Furthermore, pre-existing eGFR < 60 mL/min/1.73 m² (HR: 4.24; 95% CI: 3.76–4.81) and elevated CRP ≥ 10 mg/L (HR: 2.35; 95% CI: 2.06–2.67) were strongly associated with increased AKI risk. Vitamin D deficiency < 30 ng/mL was also significantly associated (HR: 1.37; 95% CI: 1.14–1.64). In contrast, female sex was protective (HR: 0.63; 95% CI: 0.57–0.70), and BMI ≥ 30 was not significantly associated with AKI (HR: 1.07; 95% CI: 0.95–1.20).
Renal function decline by eGFR < 60 mL/min/1.73 m²
Among patients with a diagnosis of HZ within one year following COVID-19, the incidence of renal function decline (defined as eGFR < 60 mL/min/1.73 m²) was 12.2%, compared to 7.6% in the matched COVID-19 cohort without HZ. Kaplan–Meier survival analysis demonstrated a lower renal function preservation rate in the HZ group, with 86.56% of patients maintaining eGFR ≥ 60 mL/min/1.73 m² at three years, compared to 89.23% in the non-HZ group. The log-rank test indicated a significant difference in renal outcomes between groups (p < 0.001), with a corresponding HR of 1.28 (95% CI: 1.20–1.37) (Fig. 2D).
Subgroup analysis (Fig. 3D) showed that renal function decline was more pronounced in patients aged ≥ 65 years (HR: 2.86; 95% CI: 2.62–3.13), those with diabetes mellitus (HR: 1.47; 95% CI: 1.33–1.63), hypertension (HR: 1.80; 95% CI: 1.60–2.04), smoking history (HR: 1.18; 95% CI: 1.03–1.36), COPD (HR: 1.25; 95% CI: 1.10–1.43), and elevated CRP ≥ 10 mg/L (HR: 1.41; 95% CI: 1.24–1.60). Female sex (HR: 0.91; 95% CI: 0.82–1.00) showed a marginal protective effect. Notably, BMI ≥ 30 (HR: 1.05; 95% CI: 0.94–1.17) and vitamin D deficiency (HR: 1.03; 95% CI: 0.87–1.22) were not significantly associated with eGFR decline in this subgroup.
Sensitivity analysis
In the matched cohorts, excluding patients with CKD within one year prior to COVID-19 diagnosis, HZ was significantly associated with increased risks of MACE, AKI, and decreased renal function, but not with all-cause mortality (Supplementary Table S3). When patients with AKI within one year before COVID-19 were excluded, HZ remained significantly associated with increased risks of MACE, AKI, and reduced kidney function, while the association with all-cause mortality remained nonsignificant (Supplementary table S4). In a third sensitivity analysis excluding patients with influenza one year before or after COVID-19, the associations between HZ and both cardiovascular and renal outcomes persisted, whereas the association with all-cause mortality was not statistically significant (Supplementary Table S5).
Furthermore, in analyses using expanded covariate adjustment, HZ remained independently associated with elevated risks of MACE, AKI, and eGFR decline. In the model adjusted for age, sex, race, and major comorbidities (Supplementary Table S6), the HRs for MACE, AKI, and renal impairment ranged from 1.25 to 1.44, with no significant association for all-cause mortality (HR 0.98, p = 0.520). These findings remained consistent when key laboratory parameters (CRP, hemoglobin, and iron) were included in the matching algorithm (Supplementary Table S7), showing robust associations with cardiorenal outcomes and a nonsignificant association with mortality (HR 0.968, p = 0.310).
In an additional sensitivity analysis focused on the early post-COVID period (days 1–90), we assessed whether the observed short-term survival advantage among HZ patients was confounded by baseline renal vulnerability. After excluding individuals with CKD or AKI in the year prior to COVID-19, the early mortality benefit associated with post-COVID HZ remained statistically significant (HR = 0.36, 95% CI: 0.29–0.45, p < 0.001) compared to matched non-HZ controls (Supplementary Table S8).
In a further sensitivity analysis stratified by COVID-19 vaccination status, we evaluated whether vaccination modified the associations between post-COVID HZ and adverse outcomes. Among vaccinated patients, HZ was significantly associated with increased risks of all-cause mortality (HR = 1.25, 95% CI: 1.06–1.47, p < 0.05), MACE (HR = 1.36, 95% CI: 1.21–1.52, p < 0.05), AKI (HR = 1.38, 95% CI: 1.20–1.60, p = 0.07), and eGFR < 60 mL/min/1.73 m² (HR = 1.29, 95% CI: 1.14–1.46, p = 0.08), although the associations for AKI and renal impairment did not reach conventional statistical significance. In contrast, among unvaccinated individuals, HZ was significantly associated with increased risks of MACE (HR = 1.29, 95% CI: 1.22–1.37, p < 0.001), AKI (HR = 1.65, 95% CI: 1.53–1.77, p < 0.001), and renal function decline (HR = 1.20, 95% CI: 1.13–1.28, p < 0.05), while the association with all-cause mortality was not statistically significant (HR = 1.05, 95% CI: 0.98–1.12, p < 0.001) (Supplementary Table S9).
Risk estimates in the overall and age-restricted cohorts
Because the overall cohort included more than one million patients, conducting PSM across the full dataset was computationally infeasible. To provide a representative example of matched baseline characteristics, we selected the 40–50-year-old subgroup for presentation in Table 1. To support the generalizability of our findings, Table 2 presents outcome estimates from both the overall cohort and this age-restricted subgroup. In both groups, HZ was consistently associated with significantly increased risks of MACE, AKI, and renal function decline, while the association with all-cause mortality was not statistically significant. These concordant results support the validity of our matching approach and the robustness of the observed associations.
To further address concerns regarding the temporal alignment of COVID-19 diagnosis dates between groups, we evaluated the distributions of age at index (i.e., date of COVID-19 diagnosis) and current age before and after matching. As shown in Supplementary Table S10, the age at index was perfectly matched between HZ and non-HZ patients after PSM (mean 58.3 ± 15.6 years in both groups), resulting in nearly identical current age distributions (62.8 ± 15.6 years).
COVID-19 reinfection risk and frequency
To explore whether post-COVID HZ was associated with increased vulnerability to SARS-CoV-2 reinfection, we compared reinfection risk and frequency between matched cohorts. As shown in Supplementary Table S11, patients with HZ experienced a significantly higher risk of COVID-19 reinfection than those without HZ (71.0% vs. 53.2%). Moreover, the mean number of reinfection episodes was higher in the HZ group (2.90 ± 5.13) compared to the non-HZ group (1.66 ± 3.65), with a statistically significant difference (p < 0.001).