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Impact of COVID-19 Vaccination on Varicella Zoster Virus Reactivation: A Case Control Study

Authors:
  • Infectious Diseases hospital ,MOH -Kuwait

Abstract and Figures

Background: Herpes zoster (HZ) is a medical condition of a significant global impact, with millions of people affected and rising incidence. Some risk factors of this disease had been reported in previous literatures worldwide; however, studies that pool evidence to provide estimates of newly emerged risk have yet to be conducted, especially in the context of the current pandemic. Therefore, the purpose of this study is to examine the association between COVID-19 vaccination and the risk of developing HZ in Kuwait. Methods: Clinically diagnosed 186 HZ patients were enrolled, along with 186 controls (1:1) with matched age (± 5 years), sex and nationality. Data from cases and controls was collected using a predesigned interview questionnaire. The data was analyzed using logistic regression. Results: Most of cases and controls were non-Kuwaiti (61.8%) and male (69.4%). About one fifth (19.4%) of HZ cases developed HZ following vaccination against COVID-19 within the study period (two months). Cases were more likely than controls to have had COVID-19 vaccination history (adjusted matched odds ratio (OR) = 4.87; 95 percent confidence interval (CI): 2.40–9.89; P< 0.001). Vaccinated HZ cases experienced significantly more lateralization to the left side (χ2 = 12.146, P = 0.000). Conclusions: Vaccination with COVID-19 had significant statistical association with varicella zoster activation. Future studies may contemplate to verify the observed results.
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Volume 5 | Issue 4 | 1 of 6Microbiol Infect Dis, 2021
Impact of COVID-19 Vaccination on Varicella Zoster Virus Reactivation: A
Case Control Study
1Infectious Diseases hospital, Kuwait.
2Professor of Occupational and Environmental Medicine, Alexandria
University, Egypt.
3Neurology Department, Beni-Suef University, Egypt.
4Neurology Department, Ibnsina Hospital, Kuwait.
Almunther Alhasawi1*, Mohammad I Kamel, PhD2, Sameh Elmasry, MD1, Walaa A. Kamel, MD3,4 and
Alshimaa Hassan, MD1
Citation: Alhasawi A, Kamel MI, Elmasry S, et al. Impact of COVID-19 Vaccination on Varicella Zoster Virus Reactivation: A Case
Control Study. Microbiol Infect Dis. 2021; 5(4): 1-6.
Research Article
ABSTRACT
Background: Herpes zoster (HZ) is a medical condition of a signicant global impact, with millions of people
aected and rising incidence. Some risk factors of this disease had been reported in previous literatures worldwide;
however, studies that pool evidence to provide estimates of newly emerged risk have yet to be conducted, especially
in the context of the current pandemic. Therefore, the purpose of this study is to examine the association between
COVID-19 vaccination and the risk of developing HZ in Kuwait.
Methods: Clinically diagnosed 186 HZ patients were enrolled, along with 186 controls (1:1) with matched
age (± 5 years), sex and nationality. Data from cases and controls was collected using a predesigned interview
questionnaire. The data was analyzed using logistic regression.
Results: Most of cases and controls were non-Kuwaiti (61.8%) and male (69.4%). About one fth (19.4%) of HZ
cases developed HZ following vaccination against COVID-19 within the study period (two months). Cases were
more likely than controls to have had COVID-19 vaccination history (adjusted matched odds ratio (OR) = 4.87;
95 percent condence interval (CI): 2.40–9.89; P< 0.001). Vaccinated HZ cases experienced signicantly more
lateralization to the left side (χ2 = 12.146, P = 0.000).
Conclusions: Vaccination with COVID-19 had signicant statistical association with varicella zoster activation.
Future studies may contemplate to verify the observed results.
*Correspondence:
Almunther Alhasawi, Consultant in internal medicine and
Infectious diseases, Infectious Diseases hospital, Kuwait, Faiha,
P.O.box 14981, Postcode 72860 and Tel: 0096599519545 Fax:
0096524929500.
Received: 04 May 2021; Accepted: 02 June 2021
Microbiology & Infectious Diseases
ISSN 2639-9458
Keywords
Complications, COVID-19 vaccines, Herpes zoster, Reactivation.
Introduction
Varicella-zoster virus (VZV; human herpesvirus 3) is a human
neurotropic alpha herpes virus. Primary VZV infection is a
systemic infection that results in chickenpox. During primary
infection, the virus gains access to neurons through retrograde
transport from the site of cutaneous lesion [1]. Varicella-zoster
reactivation from latency, which lies dormant in the spinal and
cranial sensory ganglia after primary infection in childhood [2,3].
Herpes zoster (HZ) which is a vesicular skin eruption associated
with pain that respect the dermatomal distribution occur after VZV
reactivation. Through various mechanisms, VZV is reactivated to
cause HZ. Numerous studies have identied risk factors associated
with reactivation of VZV, many of which are related to a decrease
in T-cell immunity, such as aging and immunosuppression, but
some are related to family history or stress [4,5].
Volume 5 | Issue 4 | 2 of 6Microbiol Infect Dis, 2021
As of April 2021, 13 vaccines are authorized by at least one
national regulatory authority for public use: ve conventional
inactivated vaccines (BBIBP-CorV, CoronaVac, Covaxin, WIBP-
CorV and CoviVac), two RNA vaccines (the Pzer–BioNTech
vaccine and the Moderna vaccine), four viral vector vaccines
(Sputnik V, the Oxford–AstraZeneca vaccine, Convidecia, and
the Johnson & Johnson vaccine), and two protein subunit vaccines
(EpiVacCorona and RBD-Dimer) [6].
Recognizing the urgent need for the COVID-19 vaccine, the
analysis of the safety data of dierent COVID vaccines trials
and its post marketing use is of prime importance. Most of the
reactions reported resolved within days of receiving the vaccine
and were mild to moderate whereas a few with severe intensity.
The commonly reported local adverse events were pain at the site
of injection, redness, and swelling. The systemic reactions included
fever, headache, fatigue, and myalgia. Laboratory derangements
were reported in some trials like decreased hemoglobin, increased
bilirubin, altered SGOT and SGPT. None of these alterations were
clinically manifested and were self-limiting. Few clinical trials
reported serious adverse events, but they were reported as unrelated
to vaccination. However, long-term post-marketing surveillance
data, particularly in high-risk vulnerable populations (elderly
and those with co-morbidities, pregnant women, and children) is
warranted to ensure the safety of COVID-19 vaccines [7].
Although some researchers found that people with certain
autoimmune diseases were likely to develop VZV reactivation
after receiving BNT162b2 mRNA COVID-19 vaccination [8].
Earlier in this year a case of VZV in a 78-year-old man following
vaccination with inactivated COVID-19 vaccine was reported [9].
To the best of our knowledge this is the rst case control study
studying the risk of developing VZV after receiving dierent types
of COVID -19 vaccines, our study aimed to assess if there is an
association between COVID-19 vaccination and VZV reactivation.
Methods
At the outpatient department of infection disease hospital (IDH),
which is the tertiary level health care facility that deal with HZ
cases in Kuwait, a matched case control study was performed.
Suspected HZ cases seen in other Kuwaiti clinics/ hospitals
were referred to IDH for conrmation of diagnosis and care. All
participants provided informed consent to participate in the study
after MOH ethics committee approved it. To collect data from each
case and its matched control, a structured interview questionnaire
was used. Cases and controls were enrolled over a two-month
period (February and March 2021). The questionnaire addressed
demographic, social, and physical factors.
Cases of HZ was dened by presence of painful, blistering skin
eruption in a unilateral dermatomal distribution (Figures 1 - 3). The
diagnosis was made by the attending infectious disease specialist
with the presence of at least one clinical claim linked to HZ (ICD-
10 codes B02, B02.2, B02.3, B02.7, B02.8, and B02.9) consistent
with an antiviral drug prescription (as acyclovir or valaciclovir).
Controls were selected from patients and their relatives attended
IDH hospital for reasons other than HZ (etc. animal bite, brucella,
UTI). They were matched to each case based on age (5 years),
gender and nationality. Individuals with known allergic reaction of
any severity to vaccines or drugs, pregnant and lactating women,
children, and adolescents below age of 18 years and those with
history of recent COVID-19 infection (within the last 3 months)
were excluded from the study.
Figure 1: 58 years old man with HZ following dermatomal distribution
of ophthalmic branch of left trigeminal nerve 7 days after mRNA vaccine.
Figure 2: 43 years old man with HZ following the dermatomal distribution
of Rt. T11 10 days after viral vector vaccine.
The means and standard deviations (SD) of quantitative variables
as well as the frequencies of qualitative variables were computed
using descriptive analysis. For comparison between categorical
variables, Fisher exact test was used. Using multinomial logistic
regression model, risk factors for HZ were analyzed. The adjusted
OR (mORadj) and their 95% condence intervals (CI) were
determined using the nal model’s parameter estimates. The 2-tailed
test was used to measure all of the probability values (P- value),
Volume 5 | Issue 4 | 3 of 6Microbiol Infect Dis, 2021
with a value of less than 0.05 indicating statistical signicance.
Independent variables tested were immunosuppressive diseases
or drugs, smoking, family history of HZ, comorbidities, stress
(subjective description), and history of COVID-19 vaccination.
Statistical analyses were conducted using SPSS 20.
Results
In the current study, a total of 190 HZ cases were asked to
participate and 186 (97.9%) accepted. In total, 362 subjects were
enrolled in the study: 186 HZ cases along with 186 controls (1:1)
with matched age (± 5 years), sex and nationality. The mean age
(± SD) was 46.31 (± 15.40) and 45.89 (± 15.17) for cases and
controls, respectively. Most of cases and controls were non-
Kuwaiti (61.8%) and male (69.4%). Among cases (table 1),
stress (39.8%) was the most prevalent risk factor followed by
family history of HZ (34.9%), comorbidities (34.4%), smoking
(23.1%), and immunosuppression (2.7%). Statistically signicant
dierences were shown between cases and controls regarding
the prevalence of family history of HZ 2 = 20.853, P < 0.000)
and stress 2 = 82.556, P < 0.000). About one fth (19.4%) of
cases had previous history of COVID-19 vaccination vs. 8.6%
of controls with statistically signicant dierence between both
groups (χ2 = 8.942, P = 0.003).
After adjusting for age, sex and nationality, the nal multinomial
logistic regression test revealed that cases were more likely than
controls to have had immunosuppression (mORadj = 6.34; 95%
CI: 1.08–37.09; p < 0.05), comorbidities (mORadj = 1.79; 95%
CI: 1.03–3.08; p < 0.05), family history of HZ (mORadj = 82.59;
95% CI: 24.30–280.66; p < 0.001), and stress (mORadj = 4.46; 95%
CI: 2.47–8.06; p < 0.001). Cases were more likely to have had
COVID-19 vaccination history compared to controls (mORadj =
4.87; 95% CI: 2.40–9.89; p < 0.001).
About one fth of HZ cases had history of COVID 19 vaccination
(36 person, 19.4% of cases). More than three quarters of them,
(77.8%) had onset of HZ following mRNA COVID-19 vaccination
and 22.2% had HZ following viral vector vaccine? About 72% of
vaccinated cases had onset of HZ after receiving 1st dose of vaccine
compared to 28% who showed onset of HZ after 2nd dose. Less than
two thirds of vaccinated cases (63.9%) had onset of HZ within seven
days of receiving the vaccine with mean duration of 8.5 ± 4.802 days.
Among vaccinated cases, HZ is signicantly more prevalent among
older age group (63.9% vs. 38% in non-vaccinated cases), Kuwaiti
citizens (72.2% vs. 30% in non-vaccinated cases), those with positive
family history of HZ (61.1% vs. 90.7% in non-vaccinated cases),
2 = 7.938, P < 0.005), 2 = 21.930, P < 0.000), (χ2 = 19.832, P <
0.000) respectively. Herpes zoster tended to signicantly aect left
side dermatomes in vaccinated cases in comparison to non-vaccinated
cases (75% vs. 42.7%, χ2 = 12.146, P = 0.000) (Table 3).
Figure 4: Dermatomal involvement in both vaccinated and non-
vaccinated HZ cases.
Potential risk factors
of HZ
Cases
n = 186
Controls
n = 186 OR
{CI}
Test of
signicance
No. % No. %
Immunosuppression
No
Yes
181
5
97.3
2.7
184
2
98.9
1.1
2.541
{0.487-13.268} P = 0.449#
Comorbidities
No
Yes
122
64
65.6
34.4
134
52
72.0
28.0
1.352
{0.870-2.100 χ2 = 1.804
P = 0.1799
Family history of HZ
No
Yes
121
65
58.9
34.9
159
27
85.5
14.5
3.163
{1.905-5.254} χ2 = 20.853
P< 0.001*
Smoking
No
Yes
143
43
76.9
23.1
153
33
82.3
17.7
1.394
{0.839-2.316} χ2 = 1.654
P = 0.198
Stress
No
Yes
112
74
60.2
39.8
183
3
58.3
13.3
40.304
{12.409-130.901} χ2 = 82.556
P< 0.001*
COVID-19 vaccine
No
Yes
150
36
80.6
19.4
170
16
91.4
8.6
2.550
{1.360-4.781} χ2 = 8.942
P = 0.003*
OR: Odd’s ratio (crude), CI: Condence Interval, HZ: Herpes zoster, * Signicant (p<0.05), χ2: Chi squared test, # Fisher exact 2-tailed P-value.
Table 1: Distribution of potential risk factors in cases and controls enrolled in a case-control study of risk factors for HZ in Kuwait
(February-March 2021).
Volume 5 | Issue 4 | 4 of 6Microbiol Infect Dis, 2021
Table 2: Multivariable conditional logistic regression model of risk factors associated with HZ in Kuwait (February-March 2021).
OR: Odd’s ratio, CI: Condence Interval, HZ: Herpes zoster, * Signicant (p<0.05).
Potential risk factors of HZ Adjusted matched OR 95 % CI P value
Immunosuppression (yes vs. no) 6.34 1.08-37.09 P = 0.041*
Comorbidities (yes vs. no) 1.79 1.03-3.08 P = 0.040*
Family history of HZ (yes vs. no) 82.59 24.30-280.66 P< 0.001*
Smoking (yes vs. no) 0.78 0.39-1.59 P = 0.509
Stress (yes vs. no) 4.46 2.47-8.06 P< 0.001*
COVID-19 vaccine (yes vs. no) 4.87 2.40-9.89 P< 0.001*
Table 3: Distribution of HZ cases enrolled in a case-control study of risk factors for HZ in Kuwait (February-March 2021) according to some variables.
* Signicant (p<0.05), χ2 Chi squared test, HZ: Herpes zoster, # Fisher exact 2-tailed P-value.
Variable
Not vaccinated
n = 150
Vaccinated
n = 36 Test of
signicance
No. % No. %
Age
<50 years
≥ 50 years
93
57
62.0
38.0
13
23
36.1
63.9
χ2 = 7.938
P = 0.005*
Sex
Male
Female
102
48
68.0
32.0
27
9
75.0
25.0
χ2 = 0.669
P = 0.413
Nationality
Kuwaiti
Non-Kuwaiti
45
105
30.0
70.0
26
10
72.2
27.8
χ2 = 21.930
P< 0.001*
Family History of HZ
No
Yes
14
136
9.3
90.7
14
22
38.9
61.1
χ2 = 19.832
P< 0.001*
HZ required hospital admission.
No
Yes
113
37
75.3
24.7
26
10
72.2
27.8
χ2 = 0.149
P = 0.700
Lateralization of HZ
Right
Left
86
64
57.3
42.7
9
27
25.0
75.0
χ2 = 12.146
P< 0.001*
Complication
No
Yes
131
19
87.3
12.7
34
2
94.4
2.56 P = 0.377
Figure 3: 33 years old man with HZ following the dermatomal distribution of Lt. T7 5 days after viral mRNA vaccine..
Volume 5 | Issue 4 | 5 of 6Microbiol Infect Dis, 2021
Figure 4 compared the dermatomal involvement in both vaccinated
and non-vaccinated HZ cases with no statistical signicance
among those with ophthalmic 2 = 1.117, P = 0.291), thoracic
involvement (χ2 = 0.024, P = 0.878), and other dermatomal
involvement (χ2 = 1.001, P = 0.317).
Discussion
The need for safe and eective vaccination against COVID-19 was
urgent, thus multiple vaccines were developed and licensed under
emergency use. However, these vaccines are still in the fourth
phase and further side eects, other than those reported in the
earlier phases, may be reported [10]. The current study revealed
a rare side eect, HZ following vaccination against COVID-19.
The current study revealed that immunosuppression, associated
comorbidities, positive family history of HZ, and stress were
signicantly more likely encountered among HZ cases than their
matched controls. Age, sex and nationality could not be studied
as these factors were matched. What is really important is that
receiving COVID-19 vaccination was also more signicantly
encountered among cases with HZ than their controls. Several risk
factors were recorded to predispose to HZ. Progress in age is the
most important factor [11]. In addition to diseases with impaired
cell mediate immunity (CMI) such as diabetes mellitus, systemic
lupus erythematosus, and rheumatoid arthritis in addition to organ
transplant and psychological stress [12].
Few case series studies reported individual cases suering from
dierent forms of HZ reactivation in the thoracic or cranial
sensory ganglia [13-20]. The main involved mechanisms included
lymphopenia and functional impairment of CD4 + T cells [21,22].
Reviewing the current available literature revealed that just only
two studies have reported reactivation of VZV after vaccination
against COVID-19. One study involved only six cases in a case
series study, while the other one involved just only one case
reported in a letter to the editor [8,9]. The current study revealed
36 HZ cases following vaccination against COVID-19 within
the study period (two months). Herpes Zoster cases appeared
within a short period following vaccination. The majority of HZ
cases (63.9%) developed the disease within one week following
receiving the vaccine with a mean duration of 8.5 + 4.8 days. A
case series of six females developing reactivation of VZV after
receiving mRNA vaccine against COVID-19 had a median
duration of 5 days for appearance of HZ [8]. Another case series
involving just only one HZ patient following inactivated vaccine
against COVID-19 developed the disease after 5 days [9].
This study also showed that 72% of cases developed HZ after
receiving the rst dose. This similar to other reports that revealed
5/6 cases developed after receiving the rst dose. Although the
majority of cases (77.8%) received mRNA while the rest received
non replicating viral vector vaccine yet, this dierence could be
attributed to the dierences in the mechanism of action of the two
vaccines or the availability of the vaccine. In Kuwait, mRNA was
the rst vaccine introduced into the country. Several theories can be
forwarded to explain the relationship between VZV reactivation and
vaccination against COVID-19. Vaccines can occasionally induce
an acute autoimmune disease [23]. Vaccine enhanced disease was
suggested to be caused by a cellular response to the vaccine involving
T cells and eosinophils as well as inammatory mediators [24-26].
Stimulation of innate immunity through toll-Like receptors (TLR)
might be the link between vaccination against COVID-19 and
reactivation of VZV.[27] These receptors stimulation has been
linked with reactivation of VZV so that the dormant virus can
stay dormant in the aected individuals [28]. The vaccination
process against COVID-19 may stimulate secretion of type I INFs
and other inammatory cytokines which activates T and B cell
immunity and may negatively aect antigen expression leading to
HZ reactivation [9,29-30].
Comparing characteristics of COVID-19 vaccinated and
unvaccinated HZ cases revealed several ndings. The vaccinated
cases were signicantly more likely encountered among those
aged more than 50 years (63.9% compared with 38.0%) and were
also more commonly encountered among the Kuwaitis (72.2%
compared with 30.0%). These ndings can be attributed to
priorities of vaccination process adopted in Kuwait. On contrast
family history of HZ was more likely encountered among the
non-vaccinated (90.7% compared with 61.1%). This may add
evidence to the co-existence relationship between vaccination
against COVID-19 and reactivation of VZV. No signicant
dierence could be revealed between the vaccinated and non-
vaccinated HZ cases with regard to severity of HZ infection as
measured by hospitalization and occurrence of complications and
the dermatomal distribution. However, lateralization to the left
side was signicantly more encountered among the vaccinated.
The preferred site of vaccination (left arm) may be related to this
lateralization however, the exact mechanism still needs more
research and explanation.
The current study has some limitations due to the design adopted.
In hospital based studies; mild cases of the disease may be missed
and not presented to the clinical setting. Diagnosis of HZ was
not based on molecular or histological investigation but mainly
depended on the clinical diagnosis. Conrmation of a cause-eect
relationship can not depend on a single research study but need
multiple ones with large number of cases (this study dealt with
only 36 cases). However, large scale epidemiological, clinical and
immunological studies are highly recommended to establish such
cause-eect relationship. The wide population vaccination could
provide a unique opportunity for such studies.
Acknowledgment
All thanks and appreciation to the management of the Infectious
Diseases Hospital for granting permissions, as well as to some of
our collages and nurse sta in the outpatient department for their
assistance in gathering data from study participants.
Volume 5 | Issue 4 | 6 of 6Microbiol Infect Dis, 2021
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