Herpes Zoster after COVID-19 Infection or Vaccination: A Prospective Cohort Study in a Tertiary Dermatology Clinic

Background Herpes zoster (HZ) has been observed to occur after COVID-19 infection and vaccination; however, knowledge regarding the demographic data, clinical presentations, and treatment outcomes of HZ is limited. Objective To compare the demographic data, clinical manifestations, treatments, and outcomes of patients with and without HZ within 14 days of COVID-19 infection or vaccination. Methods This prospective cohort study involving patients diagnosed with cutaneous HZ was conducted at a dermatology clinic from October 2021 to January 2023. Results Among a total of 232 patients with HZ, the median age was 62.0 years and 59.1% were female. HZ developed in 23 (9.9%) and four (1.7%) patients after COVID-19 vaccination and infection, respectively. The mean duration from vaccination and the median duration from infection to HZ onset were 5.7 and 8.5 days, respectively. The proportion of female patients was significantly higher in the group of patients with COVID-19 vaccination or infection than in those without such a history (P = 0.035). Patients who developed HZ following the recent COVID-19 infection had a median age of 42.5 years, which was lower than that of the other groups. Dissemination occurred in 8.7% of the patients after COVID-19 vaccination. HZ recurrence was reported in five cases, of which 80% had been vaccinated or infected with COVID-19 during the previous 21 days. All patients had similar durations of antiviral treatment, crust-off time, and duration of neuralgia. Conclusions HZ after COVID-19 vaccination is more frequently observed in females, while HZ after COVID-19 infection tends to occur in younger patients. Disseminated HZ is more common in patients recently vaccinated against COVID-19. COVID-19 vaccination or infection may trigger recurrent HZ infection.


Introduction
Herpes zoster (HZ) is the reactivation of the varicella-zoster virus (VZV) in the sensory ganglia after a long latency period of the primary varicella infection.It presents as a group of painful, erythematous, maculopapular, or vesicular rashes with a unilateral dermatomal distribution [1,2].Te prevalence of HZ increases with advancing age [3,4] and is more common among individuals with an immunocompromised status [5] due to a decline in cell-mediated immunity (CMI) [1,6,7].Furthermore, there have been reports of an increase in the prevalence of HZ during the coronavirus disease (COVID- 19) pandemic [8,9].COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is transmitted through respiratory droplets, direct contact, and the fecaloral route [10][11][12].Te clinical manifestations of COVID-19 range from asymptomatic to severe forms and mainly involve the respiratory system, in which patients commonly present with fever, cough, and dyspnea [13,14].Several studies have reported lymphopenia (absolute lymphocyte counts <1000/mm 3 ) as one of the signs of COVID-19 infection; yet, the exact underlying mechanism remains unclear [15][16][17][18][19].While most patients have a return of lymphocyte counts to normal within the frst seven days after admission, some patients may have lymphopenia lasting for 2-4 weeks [15,16].While specifc treatments for COVID-19 are still under research and development, numerous types of COVID-19 vaccines have been introduced and widely distributed worldwide [20][21][22].Tese vaccines cannot completely prevent infection in vaccinated people; however, they can alter the severity of the infection and associated complications [23][24][25].Several skin manifestations have been reported after COVID-19 infection and vaccination, including HZ.A systematic review reported that 3.4% of new-onset skin diseases after COVID-19 infection were cases of HZ [8,9].
To the best of our knowledge, there remains a gap in our understanding of whether HZ that occurs following COVID-19 infection or vaccination difers in its clinical course from HZ in the general population.Tis prospective study aimed to compare the demographic data, clinical manifestations, treatments, and outcomes between patients with HZ occurring within 14 days after COVID-19 infection or vaccination and patients with HZ who had no history of COVID-19 infection or vaccination within 14 days.

Methods
Tis prospective observational cohort study was conducted at Siriraj Hospital Dermatology Clinic between October 2021 and January 2023.Te inclusion criteria were (i) patients diagnosed with HZ by clinical and/or laboratory fndings, (ii) age of 18 years or older, and (iii) no previous treatment of this HZ episode.Patients who were lost to follow-up were excluded from the study.Informed consent was obtained from patients who agreed to participate, including the publication of the case details.Demographic data, clinical manifestations, pain scores using a numerical rating scale, and history of COVID-19 infection and COVID-19 vaccination were collected during the frst visit.Te duration of antiviral treatment, crusting of all lesions (days), and pain scores were recorded at each visit until the patients had no pain and their lesions healed.Disseminated herpes zoster was defned according to the Centers for Disease Control and Prevention's (CDC) defnition, which involves the presence of primary lesions in 1-3 dermatomes and the presence of lesions outside the primary or adjacent dermatomes or visceral involvement [26].Confrmation was achieved through an indirect immunofuorescence assay for VZV using a commercial reagent kit containing VZV monoclonal antibodies (Merck, Ltd.).Postherpetic neuralgia was defned as constant pain, intermittent pain without stimulus, and hyperalgesia lasting for at least three months after the healing of skin lesions of HZ [27].Te protocol was approved by the Siriraj Institutional Review Board (Si 799/ 2021).

Data and Statistical
Analysis.Descriptive statistics were used to describe the demographic data.Chi-square and Fisher's exact tests were used to compare the diferences in the clinical characteristics between groups.Continuous data with normal and nonnormal distributions were compared using an independent t-test and the Mann-Whitney U test, respectively.A Kaplan-Meier survival curve was applied to show the diferences between the survival curves for crust-of time and duration of neuralgia, which were compared using the log-rank test.A P value (P < 0.05) was considered statistically signifcant.All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 28.0 (IBM Corp., Armonk, NY, USA).
Te demographic data, clinical characteristics, and treatment outcomes of patients with or without COVID-19 vaccination or infection are shown in Table 1.Te proportion of female patients with a history of COVID-19 vaccination or infection was signifcantly higher than that of those without a history (P � 0.035).Patients with a recent COVID-19 infection seemed to have a younger median age (IQR) (42.5 [36.3, 58.5]    Dermatology Research and Practice 3 without a history of COVID-19 vaccination or infection (1817.4(749.2) vs. 1720.9(784.9),P � 0.775).Nine patients were lost to follow-up after their initial visit.Te treatment outcomes tended to be worse in patients with HZ and a recent history of COVID-19 infection or vaccination.Te median duration to crust-of was prolonged, and there was the higher proportion of scar development; however, this diference was not statistically signifcant (Table 1 and Figure 1).Te duration of neuralgia after the onset of HZ was similar between the two groups, as shown in Figure 2.
Te subgroup comparison of demographic data, clinical characteristics, and treatment outcomes between patients with a history of COVID-19 vaccination (N � 23) and those with no history of COVID-19 infection or vaccination (N � 205) revealed a signifcantly higher proportion of females in the former group (78.3%) than in the latter group (56.6%,P � 0.045).Other parameters, including age, immunological status, pain score at the frst visit, clinical presentation, duration to crust-of, healing outcomes, duration of postherpetic neuralgia, and the proportion of cases with postherpetic neuralgia, did not show any statistically signifcant diferences.
Five patients (2.2%) in this study experienced these episodes as second recurrent episodes of HZ.Teir mean age (SD) was 62.8 (10) years, and 80% were women.None of the patients had received a herpes zoster vaccine previously.Te mean duration (SD) between the frst HZ episode and these recurrent episodes was 170.2 (107.9)weeks.Four patients had recurrent HZ within six weeks post-COVID-19 vaccination; two had received mRNA vaccines, and two had received ChAdOx1 nCoV-19 vaccines.Te mean duration (SD) from vaccination to the development of HZ was 12.5 (9.7) days.One patient experienced recurrent HZ 21 days after the onset of COVID-19.

Discussion
Tis prospective cohort study provides comprehensive comparisons of demographic data, clinical manifestations, treatments, and treatment outcomes among three groups of patients with HZ divided according to the onset of HZ after COVID-19 infection or vaccination within 14 days.Of the 232 patients in this study, 9.9% of HZ patients had a history of recent booster doses of COVID-19 vaccination and 1.7% had a history of recent COVID-19 infection.A signifcantly higher proportion of patients with HZ, who had a history of recent COVID-19 vaccination or infection, were women compared to those with no history.Te median age of patients with recent COVID-19 infections tended to be lower than that of other patients.Prodrome symptoms, lesion morphology, dermatomal involvement, complication rates, duration of antiviral drug use, duration to crust-of, and time to remission of postherpetic neuropathic pain were similar among the three groups.Te dissemination and recurrence rates of HZ after COVID-19 vaccination were higher than those in controls.

Dermatology Research and Practice
With regard to HZ after COVID-19 vaccination, this association remains controversial.Some studies found an increased risk of HZ after COVID-19 vaccination [28,29], and some did not [30][31][32][33][34].HZ could be reactivated after receiving several types of COVID-19 vaccines, such as inactivated, nonreplicating viral vector, and mRNA vaccine [34][35][36].Te most commonly reported type includes mRNA vaccines, especially BNT162b2, which could be caused by diferent proportions of COVID-19 vaccine types, available in diferent countries.Studies in Hong Kong reported that almost half of the HZ events occurred from inactivated vaccines [35], while studies in Italy reported that more than 90% of HZ cases presented after mRNA vaccines [37].Similarly, in these studies, a nearly equivalent percentage of patients received mRNA and nonreplicating viral vector vaccines prior to HZ reactivation.
Tis study demonstrated that among cases with HZ who had a recent history of COVID-19 vaccination or infection, the proportion of females was signifcantly higher than that of those without a history.Similarly, previous studies have reported that the female sex is an additional risk factor for the development of HZ [1,38].Additional studies are needed to understand whether women are more likely to develop HZ after COVID-19 vaccination or infection.Te mean age of patients with HZ after COVID-19 vaccination was comparable to that of previous studies [35,36,39] (range 58.9-62 years).A previous systematic review reported a higher percentage of cases of autoimmune diseases (13.2%) [39], whereas the current study observed only 4.3% cases.Tree studies reported that the mean or median duration after COVID-19 vaccination, regardless of the number of doses, to the onset of HZ ranged from 5.8 to 8 days [36,39,40].Tis is consistent with this study, which reported a duration of 5.7 days after the second to fourth dose of vaccination.
Te association of HZ reactivation and COVID-19 might be caused by the reaction between SARS-CoV-2 virus infection and T-cell immune dysfunction, which contributes to a decrease in VZV-specifc CMI and subsequently reactivates HZ [41][42][43].When patients are infected with COVID-19, a cytokine storm (releasing a large amount of several proinfammatory cytokines) often occurs [44] and is followed by lymphopenia, functional impairment of CD4+ T cells, and a quantitative decrease in monocytes, eosinophils, and especially, CD3+ and CD8+ T cells [37,41].Tis study showed that the age of HZ patients with a recent history of COVID-19 infection was lower than that of the other two groups, which may be explained by the extreme immune response in the young population compared to the elderly.Furthermore, since this study did not fnd a signifcant diference in the total lymphocyte count between individuals with and without a history of COVID-19, this suggests that the problem may be related to functional defects rather than the quantity.
Te median time from COVID-19 symptoms to the onset of HZ was approximately one week in both this study and a systematic review by Czech and Nishimura [45].Te current study demonstrated that the clinical manifestations of HZ after COVID-19 infection and vaccination did not seem to be more severe than those in the control group.In addition, the treatment duration and the duration of neuralgia were similar.Oral thymidine kinase-dependent antiviral drugs are still the main specifc monotherapy in this study and in previous studies [36,39,40,46].Regarding the treatment outcomes, HZ patients with a recent history of COVID-19 vaccination or infection tend to have a prolonged median duration to crust-of and scar development; however, this diference was not statistically signifcant.Close observation and prolonged follow-up may be required in cases with HZ and a history of COVID-19 vaccination or infection.
Disseminated HZ was more likely to be reported in patients with recent COVID-19 vaccinations than in controls; however, this fnding was not statistically signifcant.Several previous studies have reported that HZ was disseminated after COVID-19 vaccination, including inactivated vaccines, nonreplicating viral vectors, and mRNA vaccines, in patients older than 65 years of age or in immunocompromised hosts [47][48][49][50][51].However, this study reported that only one patient with disseminated HZ after vaccination was immunocompromised, and only 28.6% of patients were older than 65 years of age.Future studies should investigate whether COVID-19 vaccination increases the risk of disseminated HZ.However, physicians should be vigilant about the development of disseminated HZ after COVID-19 vaccination, especially in elderly or immunosuppressed patients.
Te rate of recurrence of HZ was reported to be ranging from 5.3 to 6.4% of patients with initial HZ, and the signifcant risk factors were older age, female sex, and immunosuppressed status [38,52,53].Tis fnding is consistent with the current study, where four of fve cases of recurrence were in women.A study with the longest followup period of 13 years reported that the mean interval between episodes was 1,062.9days or 151.8 weeks, which was slightly diferent from that in this study, in which the interval was 170.2 weeks.Notably, four out of fve patients with a history of HZ had been vaccinated or infected with COVID-19 prior to this episode, within a range of 1-21 days.Te mean interval between HZ episodes in patients with a recent COVID-19 vaccination was less than that in those without by approximately 10 weeks.Tis raises the question of whether vaccination or COVID-19 is associated with HZ recurrence.

4.1.
Limitations.Tis prospective cohort study was conducted in an outpatient dermatology clinic.Hospitalized patients, such as those with HZ prior to or simultaneously diagnosed with COVID-19, were not included.Te association interval between COVID-19 infection or vaccination and HZ has varied in previous studies.Tis study examined the period within 14 days of COVID-19 vaccination/infection to elucidate the efect of COVID-19 and HZ.Terefore, a small sample size was allocated to the post-COVID-19 group, which may have occurred during hospitalization.Near the end of the study period, booster vaccinations were not encouraged, resulting in a limited sample size of patients with HZ receiving recent vaccinations.Dermatology Research and Practice

Conclusions
HZ after COVID-19 vaccination was more common in females compared to those without a history, while HZ after COVID-19 infection tended to occur in younger patients.Most patients developed HZ after COVID-19 vaccination or infection within 5-10 days.Although the clinical manifestations, treatment outcomes, and complications were not signifcantly diferent from those of patients with HZ and without recent infection or vaccination, recurrent HZ and HZ dissemination were reported in a higher proportion of patients with HZ after COVID-19 vaccination or infection.Physicians should be aware of the potential for disseminated or recurrent HZ infection following COVID-19 vaccination or infection, especially in elderly or immunocompromised patients.

Figure 1 :Figure 2 :
Figure 1: Kaplan-Meier curve of the duration to crust-of of herpes zoster patients with and without a history of recent COVID-19 infection or vaccination within 2 weeks (log rank of the P value � 0.151).

Table 1 :
Comparison between herpes zoster patients with and without a history of recent COVID-19 infection or vaccination within 2 weeks.