medicina

Article
Chronic and Recurrent Herpes Zoster Ophthalmicus
Soo Min Lee 1,2,† , Jisang Han 3,† , Chan Min Yang 2 , Chul Young Choi 3 , Ramin Khoramnia 4 ,
Tae-Young Chung 2, *,‡ and Dong Hui Lim 2,5, *,‡

1 Nunemiso Eye Center, Seoul 06241, Korea; [email protected]

2 Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine,
Seoul 06351, Korea; [email protected]
3 Department of Ophthalmology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine,
Seoul 03181, Korea; [email protected] (J.H.); [email protected] (C.Y.C.)
4 Department of Ophthalmology, University of Heidelberg, 69102 Heidelberg, Germany;
[email protected]
5 Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University,
Seoul 06355, Korea
* Correspondence: [email protected] (T.-Y.C.); [email protected] (D.H.L.);
Tel.: +82-2-3410-3569 (T.-Y.C.); +82-2-3410-3568 (D.H.L.);
Fax: +82-2-3410-0074 (T.-Y.C.); +82-2-3410-0074 (D.H.L.)
† Both authors are equally contributed as the first authors for this article.
‡ Both authors are co-correspondence for this article.

Abstract: Background and Objectives: This study sought to investigate the natural course, the chronic-
ity and recurrence rate, and the risk factors of chronic and recurrent herpes zoster ophthalmicus
(HZO). We also evaluated the effects of long-term treatment for HZO. Materials and Methods: Pa-





 tients diagnosed and treated for HZO were included in the retrospective medical chart review.
Multivariable-adjusted logistic and Cox regression models were used to show risk factors for chronic
Citation: Lee, S.M.; Han, J.; Yang,
and recurrent HZO along with hazard ratios (HRs) and 95% confidence intervals (CIs). Results:
C.M.; Choi, C.Y.; Khoramnia, R.;
Among a total 130 of HZO patients, 31 patients (23.85%) had chronic disease and 19 patients (14.62%)
Chung, T.-Y.; Lim, D.H. Chronic and
Recurrent Herpes Zoster
had recurrent disease. The rate of chronic disease was higher in HZO with conjunctivitis, epithelial
Ophthalmicus. Medicina 2021, 57, 999. keratitis, and stromal keratitis. The recurrence rate increased in patients with chronic HZO (HR: 34.4,
https://doi.org/10.3390/ 95% CI: 3.6–324.6), epithelial keratitis (HR: 5.5, 95% CI: 1.3–30.0), stromal keratitis (HR: 18.8, 95% CI:
medicina57100999 3.0–120.8), and increased intraocular pressure (IOP) (HR: 7.3, 95% CI: 1.6–33.2). Length of systemic
antiviral therapy and anti-inflammatory eyedrop treatment were not associated with recurrent HZO
Academic Editor: Esther (p = 0.847 and p = 0.660, respectively). The most common ocular manifestation for recurrent HZO
M. Hoffmann was stromal keratitis. Conclusions: This study demonstrated a considerable frequency of chronic
and recurrent HZO. Chronic HZO in the form of epithelial or stromal keratitis with increased IOP
Received: 16 August 2021
provoked a significant rise in the risk of recurrence.
Accepted: 16 September 2021
Published: 22 September 2021
Keywords: herpes zoster ophthalmicus; epidemiology; frequency

Publisher’s Note: MDPI stays neutral

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1. Introduction
iations.
Herpes zoster (HZ) is defined as the reactivation of the latent varicella zoster virus
(VZV) in people who have had chickenpox (varicella), the primary infection caused by
VZV. After the primary infection, the virus is latent for a period of time in the sensory
Copyright: © 2021 by the authors.
ganglia. If and when the latent virus is reactivated, rashes and vesicles occur along the
Licensee MDPI, Basel, Switzerland.
affected dermatomal distribution, with accompanying pain [1]. It is believed that viral
This article is an open access article
reactivation is a result of declining cell-mediated immunity, which can be associated with
distributed under the terms and aging, impaired immunity, trauma, and psychological stress [2]. Although the prevalence
conditions of the Creative Commons of HZ has not been clearly documented, it can be predicted that the prevalence of HZ
Attribution (CC BY) license (https:// will increase with the increasing age of the population and immune suppression therapy
creativecommons.org/licenses/by/ considering the risk factors of HZ [3–5]. It is estimated that one million episodes occur
4.0/). each year in the United States alone [5–7].

Medicina 2021, 57, 999. https://doi.org/10.3390/medicina57100999 https://www.mdpi.com/journal/medicina

Medicina 2021, 57, 999 2 of 9

HZ ophthalmicus (HZO) is defined as HZ involvement of the first branch of the

trigeminal nerve ganglion with ocular involvement. HZO accounts for 10% to 20% of all
HZ cases [8]. Decreased cellular immunity, advancing age, immunosuppressive medication,
and primary infection with the HZ virus in infancy have been found to increase the risk of
HZO [8–11].
The ocular manifestations of HZO include conjunctivitis, epithelial keratitis including
punctate erosion or pseudodendrites, stromal and endothelial keratitis, acute and pos-
therpetic neuralgia, vesicular dermatitis and preseptalcellulitis, orbital cellulitis, uveitis,
glaucoma, and optic neuritis [11,12].
Although long-term or recurrent HZO may persist in some patients, there is not much
known about the prevalence and treatment regimen for such. Thus, this study aimed
to identify the epidemiology of HZO in Koreans and the risk factors for prolonged or
recurrent HZO. We also aimed to elucidate the relationship between treatment duration
and the recurrence of HZO.

2. Methods
This is a retrospective cohort study of patients diagnosed with HZO using electronic
medical records from Samsung Medical Center in Seoul, Korea, between 26 July 2009 and
31 May 2016. The study was conducted in accordance with the tenets of the Declaration of
Helsinki and approved by Samsung Medical Center Institutional Review Board.
We reviewed all patients’ charts who received a diagnostic code of HZ and underwent
antiviral treatment in all departments of the hospital. Korean Standard Classification of
Disease (KCD) codes B02.0 to B02.9, which are associated with zoster, were used to screen
for HZO. Patients with HZO were identified from among the HZ patients. The medical
records of potential patients with HZO were reviewed to confirm the diagnosis of HZO.
The sex, age, medical history, ophthalmologic clinical findings, treatment period, and
immune status of all patients were investigated. Treatment period refers to the duration of
antiviral or anti-inflammatory treatment. Primary treatment duration means the treatment
duration for the first disease attack. We defined patients with an immunocompromised
state as follows: patients who underwent systemic chemotherapy within six months prior
to the diagnosis of HZO, who had actively treated malignancies, who had end-stage renal
disease, who had autoimmune diseases treated with immunosuppressive drugs, and/or
who had organ transplantation. None of the patients had an infection with the human
immunodeficiency virus, and none had congenital immunodeficiency disease.
Ophthalmologic clinical findings were classified according to the ophthalmologist’s
medical records in terms of conjunctivitis, epithelial keratitis including pseudodendritic
keratitis, stromal keratitis, endothelial keratitis, uveitis, glaucoma, and optic neuritis. All
patients underwent measurements of visual acuity and intraocular pressure (IOP) and
microscopic slit lamp examination at every visit.
The study participants were divided into two groups based on the duration of dis-
ease. Chronic HZO was defined as active disease requiring antiviral or anti-inflammatory
treatment persisting for more than 60 days. Therefore, acute HZO was defined as the
termination of treatment within 60 days. In addition, we defined recurrent HZO as a case
in which the clinical findings completely disappeared and the ocular involvement recurred
any time after termination of treatment.
Baseline characteristics of the study population and clinical findings were presented
as numbers with percentages (%) for categorical variables or mean values with standard
deviations for continuous variables. The chi-square test was used to calculate the statistical
difference between categorical variables. Univariable and multivariable-adjusted logistic
and Cox regression models were used to show risk factors for chronic and recurrent
HZO along with hazard ratios (HRs) and 95% confidence intervals (CIs). Kaplan–Meier
survival analysis was employed to characterize the HZO recurrence-free survival curve,
and p values of less than 0.05 were considered to be statistically significant. Statistical
Medicina 2021, 57, 999 3 of 9

analyses were performed using SAS version 9.4 software program (SAS Institute, Cary, NC,
USA).

3. Results
3.1. Baseline Characteristics
A total of 1875 patients were found to have been diagnosed with HZ during the study
period, with 163 having been specifically diagnosed with HZO. Through detailed medical
chart review, we excluded 33 patients who were misdiagnosed as having HZO, who had
undergone ophthalmic surgery less than a year before the manifestation of HZO, or who
had a history of ophthalmic disease that could affect the development and progress of
the disease; thus, 130 patients were included in the final analysis. Demographics and
characteristics of the study population are summarized in Table 1. The male to female
ratio was 1.03. No significant sex difference was observed (p = 0.8608). In male patients,
12 had chronic and five had relapsed HZO; among the female patients, 19 had chronic
and 14 had relapsed HZO. The mean age of the study participants was 55.18 ± 17.66 years
(range: 11–89 years). The majority of patients were immunocompetent (89.23%). The mean
treatment duration was 82.22 ± 199.56 days (range: 3–1575 days), and the median value of
treatment duration was 11 days. The distribution of HZO patients according to their age is
shown in Figure 1. Of all of the HZO patients, most were in their 60s, followed by in their
50s and 70s (35%, 25%, and 21%, respectively).

Figure 1. Age distribution of patients at first diagnosis of HZO. The number of patients for each age group is indicated
in each bar graph. There were significant differences between the various age groups (p < 0.0001 *). * Chi-squared test.
Abbreviations: HZO = herpes zoster ophthalmicus.
Medicina 2021, 57, 999 4 of 9

Table 1. Demographic and clinical characteristics of the study population.

Demographic No. (%) Mean ± SD or Range

Sex
Male 66 (50.77)
Female 64 (49.23)
Age at presentation (years)
Mean 55.18 ± 17.66
Range 11–89
Immune status
Immunocompetent 116 (89.23)
Immunocompromised 14 (10.77)
Treatment duration (days)
Mean 82.22 ± 199.56
Range 3–1575
Chronic HZO 31 (23.85)
Acute HZO 99 (76.15)
Recurrent HZO 19 (14.62)
No recurrent HZO 111 (85.38)
Abbreviations: HZO = herpes zoster ophthalmicus; SD = standard deviation.

3.2. Clinical Manifestations

Ocular manifestations were present in 104 (80%) patients. Twenty-six (20%) patients
had skin rash only in the V1 dermatome. The distribution of HZO-associated ocular
manifestations is summarized in Table 2. The most common ocular manifestations were
epithelial keratitis, followed by conjunctivitis/episcleritis and endothelial keratitis (46.15%,
37.69%, and 11.54%, respectively). Stromal keratitis was present in 10 patients (7.69%) and
uveitis was present in eight patients (6.15%). Five patients presented with increased IOP
in the first month and another five patients presented with increased IOP in the second
month after beginning treatment. There were two patients with cranial nerve palsy.

Table 2. Clinical manifestation of HZO (n = 130).

Clinical Manifestation Frequency (%)

No eye involvement, only rash 26 (20)
Conjunctivitis 49 (37.69)
Epithelial keratitis 60 (46.15)
Stromal keratitis 10 (7.69)
Endothelial keratitis 15 (11.54)
Uveitis 8 (6.15)
Increased IOP 10 (7.7)
Cranial nerve palsy 2 (1.5)
Abbreviations: HZO = herpes zoster ophthalmicus; IOP = intraocular pressure. Note: Patients were counted more
than once if they presented with multiple clinical findings of HZO.

3.3. Clinical Course

3.3.1. Chronic Disease
Of the 130 patients with HZO, 99 (76.15%) had an acute course and 31 (23.85%) had a
chronic course. The mean treatment duration of acute-course patients was 12.78 ± 10.27 days
(range: 3–50 days) and the median treatment duration was eight days. In comparison,
the mean treatment duration of chronic-course patients was 304.00 ± 322.74 days (range:
66–1575 days) and the median treatment duration was 210 days. In univariate logistic
regression analysis, age, sex, conjunctivitis, epithelial keratitis, stromal keratitis, corneal
endotheliitis, uveitis, and increased IOP were identified as possible risk factors with
p values of less than 0.2 for chronic HZO (Table 3). In multivariate logistic regression
analysis, conjunctivitis, epithelial keratitis, and stromal keratitis were associated with
chronic HZO (p = 0.0154, p = 0.0005, and p = 0.0005, respectively).
Medicina 2021, 57, 999 5 of 9

Table 3. Results from univariate and multivariate analyses of factors associated with chronic HZO (n = 31).

Univariate Analysis Multivariate Analysis

Variable OR (95% CI) p Value 1 OR (95% CI) p Value 1
Age (years) 0.985 (0.963–1.018) 0.1911 0.963 (0.927–1.001) 0.0530
Sex 1.900 (0.834–4.331) 0.1268 1.248 (0.344–4.533) 0.7124
Immune status 0.500 (0.106–2.367) 0.3823
Conjunctivitis 2.133 (0.941–4.839) 0.0698 8.698 (1.619–46.736) 0.0154
Epithelial keratitis 2.682 (1.160–6.200) 0.0211 41.495 (1.82–20.29) 0.0005
Stromal keratitis 40.070 (4.826–332.720) 0.0006 46.605 (2.597–836.357) 0.0005
Endotheliitis 13.062 (3.773–45.221) <0.0001 3.171 (0.401–25.079) 0.0693
Uveitis 11.640 (2.214–61.193) 0.0037 6.519 (0.324–131.281) 0.3798
Increased IOP 16.869 (3.356–84.800) 0.0006 4.815 (0.437–53.019) 0.1940
Abbreviations: HZO = herpes zoster ophthalmicus; OR = odds ratio; CI = confidence interval; IOP = intraocular pressure. Variables with
p < 0.20 were included in the multivariate analysis. Factors with statistical significance are shown in bold. 1 Logistic regression.

3.3.2. Recurrent Disease

Of the 130 patients with HZO, 19 (14.62%) had recurrent HZO. Of the 19 cases of
recurrent HZO, 18 also presented with chronic disease. The mean time from the end of
treatment to recurrence was 6.24 ± 8.76 months (range: 0.36–35.04 months). The median
time of recurrent HZO treatment was 8.93 months. In univariate analysis, sex, conjunc-
tivitis, epithelial keratitis, stromal keratitis, corneal endotheliitis, uveitis, increased IOP,
primary treatment duration, and chronic HZO were identified as possible risk factors for
recurrent HZO with p values of less than 0.2 (Table 4). Through multivariate analysis
using a Cox proportional hazards model, we determined that epithelial keratitis, stromal
keratitis, increased IOP, and chronic HZO (p = 0.0465, p = 0.0020, p = 0.0101, and p = 0.0020,
respectively) increased the risk of recurrent HZO. Conversely, gender, age, and immune
status did not increase the risk of chronic or recurrent HZO.

Table 4. Results from univariate and multivariate analyses of factors associated with recurrent HZO (n = 19).

Univariate Analysis Multivariate Analysis

Variable HR (95% CI) p Value 1 HR (95% CI) p Value 1
Age (years) 1.000 (0.974–1.025) 0.9723 1.027 (0.980–1.067) 0.1661
Sex 3.161(1.138–8.777) 0.0272 2.606 (0.690–9.837) 0.1576
Immune status 1.052 (0.243–4.556) 0.9455
Conjunctivitis 2.321 (0.933–5.771) 0.0700 2.671 (0.654–10.910) 0.1713
Epithelial keratitis 2.876 (1.092–7.571) 0.0324 5.550 (1.207–29.993) 0.0465
Stromal keratitis 14.924 (5.460–40.795) <0.0001 18.811 (2.929–120.824) 0.0020
Endotheliitis 5.638 (2.214–14.353) 0.0003 0.221 (0.039–1.246) 0.0871
Uveitis 5.441 (1782–16.612) 0.0029 1.484 (0.218–10.094) 0.6863
Increased IOP 14.925 (5.818–38.286) <0.0001 7.306 (1.606–33.242) 0.0101
Primary Tx duration 1.003 (1.002–1.004) <0.0001 0.999 (0.997–1.001) 0.4745
Chronic course 32.146 (3.473–297.543) 0.0022 34.405 (3.647–324.611) 0.0020
Abbreviations: HZO = herpes zoster ophthalmicus; HR = hazard ratio; CI = confidence interval; Tx = treatment duration; IOP = intraocular
pressure. Variables with p < 0.20 were included in the multivariate analysis. Factors with statistical significance are shown in bold. 1 Cox
proportional hazards regression.

The distribution of recurrent HZO-associated ocular manifestations is summarized

in Table 5. The most common recurrent HZ ocular manifestation was stromal keratitis,
followed by epithelial keratitis, endotheliitis, and conjunctivitis/scleritis (50.00%, 29.17%,
12.50%, and 8.33%, respectively). Of the 12 recurrent herpes zoster patients with stromal
keratitis, three patients did not have stromal keratitis at the initial visit.
Medicina 2021, 57, 999 6 of 9

Table 5. Clinical manifestation of recurrent herpes zoster ophthalmicus (n = 19).

Patient Age Immune First Ocular Recurred Ocular

Sex
Number (Years) Status Manifestation Manifestation
1 F 40 competent S,U S
2 M 35 competent S,I S
3 F 22 competent E S
4 F 58 competent C,E,I C
5 M 76 competent C,E,S,e E,S,e
6 F 57 competent E S
7 F 54 competent C,e E
8 M 63 competent E,S,I S, I
9 F 61 competent C,S,e,U S,e
10 F 59 competent C,E S
11 F 62 compromised C,E S,e
12 F 71 competent C,E,e S
13 F 23 competent E,S S
14 F 44 compromised C,E,S E,S
15 M 53 competent C C
16 F 71 competent E,e,U E
17 F 62 competent C,E E
18 F 67 competent C,E E
19 M 70 competent E E
Abbreviations: C = conjunctival keratitis; E = epithelial keratitis; S = stromal keratitis; e = endothelial keratitis;
U = uveitis, I = increased intraocular pressure. Note: Of the ocular manifestations of recurrent HZO, stromal
keratitis was the most common clinical finding. Only two patients had an immunocompromised status. Three
recurrent stromal keratitis patients did not have stromal keratitis at the initial visit.

4. Discussion
This study identified a considerable frequency of chronic (23.8%) and recurrent (14.6%)
HZO. In the risk factor analysis of our study, we found that chronic HZO was associated
with conjunctivitis (odds ratio (OR): 8.7; p = 0.0154), epithelial keratitis (OR: 41.5; p = 0.0005),
and stromal keratitis (OR: 46.6; p = 0.0005), while recurrent HZO was associated with
epithelial keratitis (HR: 5.5; p = 0.0465), stromal keratitis (HR: 18.8; p = 0.002), increased
IOP (HR: 7.3; p = 0.010), and chronic HZO (HR: 34.4; p = 0.002). Especially, most of the
recurrences were seen within 8.6 months after the end of treatment (Figure 2). In the
Kaplan–Meier survival analysis demonstrating cumulative recurrence-free survival over
time, the overall one-, two-, and three-year recurrence rates were 12.56%, 14.5%, and 15.62%,
respectively. Even patients with suspected simple conjunctival involvement can develop a
chronic disease, so careful treatment and follow-up are needed. This might be explained
by the fact that it is not always easy to distinguish between a simple conjunctivitis and
episcleritis or scleritis. Therefore, patients with these risk factors should be treated with
consideration of the possibility of chronicity or recurrence of the disease.
In the United States, several studies have demonstrated an increased incidence of
HZ [5,13–15]. HZ affects approximately 20% to 30% of the general population at some
point in their lifetime in the United States [16]. Considering this large prevalence rate, the
Centers for Disease Control and Prevention recommended a vaccine (Zostavax® (zoster
vaccine live), Merck & Co., Kenilworth, NJ, USA) be given to aged immunocompetent
people older than 60 years. HZO accounts for approximately 10% to 20% of all cases of HZ.
The spectrum of ocular manifestation of HZO is diverse.
Medicina 2021, 57, 999 7 of 9

Figure 2. Kaplan–Meier survival analysis demonstrating cumulative recurrence-free survival over time. Within one year,
89.5% of all events recurred; the curved point (bold arrow) of the graph corresponds to 8.6 months. * One-year survival was
87.44%. † Two-year survival was 85.5%. ‡ Three-year survival was 84.38%.

There have been few previous studies conducted to date regarding the recurrence of
HZO. To our knowledge, there has only been one investigation published by Tran et al.,
who evaluated potential risk factors such as demographics, immune status, vaccination
status, and ophthalmic involvement for recurrent and chronic HZO using South Florida
Veterans Administration Healthcare System (MIAVHS) medical data between 1 January
2010 and 31 December 2014 [17]. Of the 1358 patients with HZ, a total of 90 HZO patients
were included in their study. Only increased IOP and uveitis raised the risk of recurrent
and chronic disease. Thus, the risk factors for recurrent and chronic disease identified in the
study of MIAVHS and in our study are different. However, this may be due to differences
in the study populations (e.g., Western vs. Korean); furthermore, while we are a single
hospital center, we are a tertiary hospital to which severe cases are referred. Regardless, it
is meaningful that both in the previous study and in our assessment, sex, age, and immune
status did not increase the risk for a recurrent or chronic HZO.
Of note, there was also an article published regarding the recurrence of HZ, not HZO,
by Yawn et al. In Olmsted County, Minnesota, of the 1669 patients with HZ, 105 experienced
HZ recurrence between one day and 11.7 years from 1996 to 2001. In this study, recurrence
of HZ was defined as a characteristic vesicular rash with pain at three months after the
first episode. Episodes of recurrence were more likely to present in individuals with zoster-
associated pain of 30 days or longer, immunocompromised status, female sex, and older
age (≥50 years) [18]. However, this article differs from our paper because we analyzed the
risk factors for HZO, not HZ.
While there has not been enough research studying the long-term disease progress
of HZO completed in the past, a large-scale clinical study has been recently started. The
Zoster Eye Disease Study (ZEDS) started in the United States in August 2017 to determine
whether prolonged suppressive oral antiviral treatment with valacyclovir reduces the
complications of HZO.
Medicina 2021, 57, 999 8 of 9

In our study, the duration of medical treatment did not affect the course of the disease.
Endotheliitis and uveitis were not related with chronic and recurrent HZO. We can spec-
ulate that endotheliitis or uveitis are not common manifestations of initial attack among
recurred or chronic cases. Rather, endotheliitis, uveitis, or increased IOP become more
common with prolonged disease course or recurrence. Stromal keratitis and uveitis are
known to be the most common manifestation among recurred cases. [19] Because this
was a retrospective study, we could not analyze a variety of drugs individually. It is a
drawback of retrospective observational study that we could not investigate the exact
mechanism between various type of HZO and disease course. Therefore, prospective
studies are needed.
In addition, most of the recurrence cases occurred within one year of the initial
presentation. Thus, especially if patients have risk factors such as epithelial keratitis,
stromal keratitis, or increased IOP, ophthalmologists need to follow up on the progress of
the disease for at least one year.
Our study has several limitations. First, it analyzed hospital-based clinical data, so
only patients who visited to receive regular care were included in the study. Using data
from a single center may cause selection bias and, since our hospital is one of the largest
tertiary centers in South Korea, severely affected patients are often referred. Patients who
recover quickly or who have no complications may not be treated in a tertiary hospital.
Therefore, our chronic disease rate or recurrence rate may be higher than what is typical.
Thus, more research is needed to better understand the disease in the entire population.
Second, HZO was clinically diagnosed by ophthalmologists and most patients did not
undergo laboratory testing, including finding immunoglobulin M antibodies specific to
VZV, viral culture, or polymerase chain reaction. In general, the diagnosis of HZO is
performed clinically. However, since the clinical findings of HZO are very typical, this
clinical diagnostic method does not appear to cause a large bias. Third, we could not
always accurately identify whether HZO patients were vaccinated during the medical
chart review since the varicella vaccine was introduced in 1995 and the zoster vaccine was
introduced thereafter. Follow-up studies may need to investigate the relationship between
vaccination and the recurrence or chronicity of HZO.
In conclusion, this study demonstrates clinical characteristics of HZO. This is the first
study to analyze the relationship between the initial treatment period and recurrent HZO.
Sex, age, and immune status did not affect the disease course; however, conjunctivitis,
epithelial keratitis, and stromal keratitis could be risk factors for chronic HZO. Addition-
ally, epithelial keratitis, stromal keratitis, and increased IOP raised the rate of recurrence.
Therefore, clinicians must carefully look for these clinical manifestations.
HZO recurred after an average of 6.24 months and not many cases were observed
beyond one year. Therefore, especially if patients have risk factors such as epithelial
keratitis, stromal keratitis, or increased IOP, ophthalmologists need to follow up on the
disease progression for at least one year.

Author Contributions: Conception and design, D.H.L. and T-Y.C.; conduct of the study, S.M.L., J.H.,
C.M.Y., C.Y.C., D.H.L., and T-Y.C.; collection, management, and interpretation of data, S.M.L., J.H.,
C.M.Y., and C.Y.C.; data analysis, S.M.L. and J.H.; writing the article, S.M.L.; preparation, review,
and approval of the manuscript, J.H., R.K., D.H.L., and T.-Y.C. S.M.L. and J.H. contributed equally
to the manuscript as co-first authors. D.H.L. and T.-Y.C. contributed equally to the manuscript as
co-corresponding authors. All authors have reviewed the manuscript and approved the final version.
All authors have read and agreed to the published version of the manuscript.
Funding: This research was supported by a National Research Foundation of Korea grant funded by
the Korean government’s Ministry of Education (NRF-2019R1C1C1007917; Seoul, Korea) which was
received by J.H. The funding organization had no role in the design or conduct of this research.
Institutional Review Board Statement: The study was conducted according to the guidelines of the
Declaration of Helsinki, and approved by the Institutional Review Board of Samsung Medical Center
(protocol code 2018-03-065 and date of approval 16 March 2018).
Medicina 2021, 57, 999 9 of 9

Informed Consent Statement: Patient consent was waived for all subjects by Samsung Medical
Center Institutional Review Board because this is the retrospective chart review study.
Data Availability Statement: All datasets generated and/or analyzed during the current study are
available from the corresponding author upon reasonable request.
Acknowledgments: This research previously presented as a poster presentation at ARVO 2017
in Baltimore, Maryland, United States, and an oral presentation at the Annual Meeting of the
Korean Ophthalmology Society 2018 in Busan, Korea. The authors wish to give a special thanks to
Kyunga Kim, Professor of the Department of Statistics, Samsung Medical Center, Sungkyunkwan
University School of Medicine, Seoul, Korea, for her assistance commenting on the statistical analysis
of this study.
Conflicts of Interest: The authors declare no conflict of interest.

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