key: cord-0738073-z19gfrh0
authors: Almutairi, Nawaf; Almutairi, Abdulrahman N.; Almazyad, Moneerah; Alwazzan, Sabika
title: Herpes zoster in the era of COVID 19: A prospective observational study to probe the association of herpes zoster with COVID 19 infection and vaccination
date: 2022-04-29
journal: Dermatol Ther
DOI: 10.1111/dth.15521
sha: eea06c5b46a3714a0b5b39b24cea91066ebef284
doc_id: 738073
cord_uid: z19gfrh0

Herpes zoster (HZ) is caused by reactivation of the latent varicella zoster virus (VZV) following decline in cell‐mediated immunity. All over the world, in the past couple of years, the Corona Virus 2019 (COVID‐19) has emerged as a viral cause of severe acute respiratory syndrome corona virus 2 (SARS‐CoV‐2) infection. Based on the current limited evidence, co‐infection of COVID‐19 with VZV or reactivation of VZV after COVID‐19 vaccination has been sporadically reported. All patients diagnosed with HZ, in Farwaniya Hospital in Kuwait, from March 2020 to July 2021, having either (A) a positive COVID‐19 polymerase chain reaction (PCR) test, or (B) been vaccinated against SARS‐CoV‐2 were enrolled in the study. All patients' demographic information, medical history, laboratory findings, and vaccination status was documented. All statistical analyses were performed using SPSS Statistics version 21.0 software. Twelve cases infected with COVID‐19 with a positive PCR (group 1) and five cases vaccinated against SARS‐CoV‐2 (group 2) were documented. Out of the 12 COVID‐19 infected patients (group 1), only two patients (16.67%) required hospitalization, while the remaining 10 patients had mild/moderate lymphopenia. Furthermore, amongst the 12 positive COVID‐19 cases, four patients with HZ were diagnosed within the first week of COVID‐19, while the remaining eight cases were diagnosed within 8 weeks of COVID‐19. Thoracic segments were affected in five cases (41.67%), cervical in one case (8.33%), cranial in two cases (16.67%), lumbar in three cases (25%) and sacral in one case (8.33%). In group 2, three patients presented with HZ within 4 weeks of having received the first dose of the vaccine and two patients after the second dose. Blood investigations for all five vaccinated patients did not show any abnormalities. Cervical segments were affected in two patients (40%), and cranial, thoracic, and lumbar segment in the remaining patients respectively (20%). Experts must be aware of the probable increased risk of HZ during the COVID 19 pandemic. We propose appropriate curative and preventive measures against HZ infection, including a systematic follow‐up of these patients to ensure that they stick to extreme safety measures till the diagnosis of COVID‐19 is omitted.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been recognized as a pandemic by the World Health Organization (WHO). 1 The disease was acknowledged as COVID-19 (Coronavirus Disease 2019), and has become a public health hazard in almost every country across the world. 1 The disease most commonly manifests within the fifth day of exposure to the virus, but the incubation period can be as long as 14 days in some cases. The clinical features seen in patients with COVID-19 can be highly variable, with few cases being completely asymptomatic.

Majority of the symptomatic patients tend to develop milder symptoms, only 10%-15% develop severe symptoms requiring hospitalization, and approximately 10% of these severe cases may eventually succumb to the disease. 2 Thus, the clinical situation varies widely, with the majority of patients needing only supportive treatment, whereas others require admission to intensive care unit (ICU) for invasive mechanical ventilation or hemodynamic monitoring. 3 The diagnosis of COVID-19 disease is based on the clinical signs (fever, malaise, fatigue, dry cough, rhinorrhea, anosmia, dyspnea, anorexia, and diarrhea), vital signs (fever >38.0 C, pulse oximetry saturation <95%), and radiological findings (chest CT scan for the presence of ground glass opacity). 3 The diagnosis can be confirmed by detection of viral RNA by reverse-transcriptase polymerase chain reaction (RT-PCR) from nasopharyngeal swabs or bronchoalveolar fluid. 4 Coronavirus disease 2019 (COVID- 19) primarily presents with pulmonary symptoms, yet extrapulmonary symptoms involving cutaneous manifestations have been identified. Cutaneous manifestations in COVID-19 patients involve chilblain-like eruption (covid toe), petechiae and purpura, vesicles, urticaria, livedo reticularis, chicken-pox like lesions and erythematous maculopapular lesions and several other distinct patterns. 5, 6 This might be due to direct immune damage by SARS-COV2, or indirectly as an indicator of systemic involvement. 7, 8 Varicella zoster virus (VZV) is a human neurotropic virus that causes varicella. Herpes zoster (HZ) is an acute, viral infection which ensues after the reactivation of the VZV. The virus usually remains dormant inside the sensory ganglia, notably, the dorsal root ganglia, trigeminal ganglia, and enteric ganglia after the virus's initial exposure in the form of chicken pox infection. 9 The latent phase usually lasts for several decades before reactivation occurs. HZ possibly appears when the immune system fails to contain the dormant VZV replication. Consequently, it often occurs in the elderly people, HIV-infected patients, and is more common in severely immunocompromised patients. Trauma, radiation, certain medications, and stress, can similarly trigger HZ but have not been determined with certitude. 10, 11 HZ is characterized by occurrence of multiple, painful, unilateral vesicles and ulceration, and typically limited to a single dermatome innervated by single dorsal root or cranial sensory ganglion. 12 COVID-19 infection may represent a trigger for HZ reactivation.

Among the COVID-19 pandemic, several published laboratory-confirmed COVID-19 reports with coexisting clinical manifestations of HZ virus have been reported, suggesting a probable co-existence of the two viruses, or an increased frequency of HZ in this population. [13] [14] [15] [16] [17] [18] [19] [20] [21] COVID-19-associated lymphopenia, especially CD3 + CD8 +lymphocyte and functional impairment of CD4 + T cells, can render COVID patient more prone to evolving HZ by reactivating VZV. 22 It is also stated that HZ might be an indication of undiagnosed COVID-19 infection in younger age groups. 13, 18, 23 In a challenge to lessen the morbidity and mortality associated with COVID-19 and halt viral transmission, a variety of vaccines has been developed. Among these vaccines, messenger RNA (mRNA) vaccines that supposedly provide up to 95% protection from COVID-19 after a two-dose series have been prepared. 24 Common vaccinerelated side effects including pain, redness, and/or swelling at the injection site, fatigue, headache, fever, and chills have been commonly reported. 24 HZ reactivation was reported following trivalent influenza, hepatitis A and rabies vaccines, suggesting vaccine-mediated immunomodulation. 25 Several reports have demonstrated cases of VZV reactivation developing after vaccination with the mRNA COVID-19

vaccine. 26, 27 The aim of the report is to investigate clinical presentations of HZ infection in the era of Covid infection and mRNA-COVID 19 vaccination. 

A total of 12 cases were documented in Covid infected group (group 1) and five cases in the vaccinated group (group 2). The mean age of patients was 53 years in group 1 and 37 years in group 2. The age ranged from 24 to 76 years for both groups. The male: female ratio was 1.4:1 (7 male:5 female) in group 1 and 0.67: 1 in group 2 (2 male:3 female). In group 1, the highest number of cases (5 cases = 41.67%) were seen in the age group between 41 and 50 years, while in group 2, 60% (3 cases) were seen in the age between 31 and 40 years. The age and sex distribution are given in Table 1 . Laboratory findings for covid patients are summarized in Table 2 . Complete blood count revealed that most of the patients, 10 (79.24%) had mild/moderate lymphopenia with a mean lymphocyte count of 0.917 Â 10 9 /L (normal value: 1.1-3.2 Â 10 9 /L for adults), and anemia in seven (58.33%) patients. Furthermore, four (33.33%) patients had leukopenia. Platelets count was found to be reduced in two (16.67%) patients, while no change was noticed in neutrophil values.

Regarding inflammatory indicators, both erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) was raised in nine (75%) patients, and interleukin-6 (IL-6) was high in eight (66.67%) patients. Evaluating the levels of lymphocyte subsets by flow cytometry, in whole blood of COVID-19 patients indicated that there was reduction in range of various lymphocyte subclasses (CD3 + T cells, CD4 + T cells and CD8 + T cells). However, the CD4+/CD8+ ratio did not change significantly over the course of the illness. (Table 3 ). 32 To date, it is not possible to establish the exact incidence of skin lesions in COVID-19. 33 Despite an increase in significance, much remains unknown regarding the characterization, incidence, and pathogenesis of these dermatological symptoms. 30 The cases per million inhabitants during the current pandemic, which suggests a correlation between these diseases. 34 The incubation time of COVID-19 can be up to 14 days and the majority of cases only exhibit mild to moderate symptoms. 35 Elsaie et al. 15 involvement, usually scattered distribution, and mild/absent pruritus. 36 Compared to the Italian study, the lesions of our COVID-19 patients were associated with less itching, and were mostly found on trunk and limbs and rarely on the face.

Another Spanish study series, 37 should be carefully monitored and reported for further assessment. 23 Packwood et al. 38 The basis for the increased vulnerability to HZ reactivation in COVID-19 patients most likely points toward the tendency of COVID-19 virus to produce an immunosuppressive state secondary to the functional impairment, and the relative quantitative decrease in T lymphocytes, particularly CD4+ T cells, CD8+ T cells, and natural killer cells. 44 It was confirmed that COVID-19 infection is associated with a decrease in lymphocytes, monocytes, and eosinophils, along with a significant reduction of CD4/CD8 T cells, B cells, and natural killer cells. It was further disclosed that non-survivor COVID-19 patients continued to show a reduction in lymphocyte counts along the course of their disease until death. [45] [46] [47] According to our patient's laboratory tests, the total value of lymphocytes in 10 patients in COVID-19 infected group was reduced, indicating an impairment of the immune system during the course of COVID-19 infection, which might have effect to the termination of varicella dormancy. In our patients, these findings persisted for several weeks after COVID-19, which may have led to VZV reactivation.

In some reported cases, as well as in our patients, both lymphopenia and decrease in absolute lymphocyte number, especially CD3+, CD4+, and CD8+ T cells due to SARS-CoV-2 infection were observed. 13, 15 Thus, lymphopenia and decreased CD4 + T cells, might possibly lead to impaired antiviral response. 15 that still requires to be further explored was direct damage to lymphatic organs, such as the thymus and spleen. Also, direct lymphocyte apoptosis mediated by tumor necrosis factor-α, IL-6, and other proinflammatory cytokines; and direct inhibition of lymphocytes by metabolic disruption, such as acidosis have also been considered. 8, 50 Reactivation of VZV is a failure of the T cell component of the immune system to sustain control of the infection. It also has been hypothesized that the functional damage of CD4+ T cells may predispose patients with COVID-19 to severe disease. 44 Such immune variations can render a patient more vulnerable to developing shingles by reactivating VZV, which might be a mark of undiagnosed COVID-19 infection in younger age groups.

Intensified psychological stress can precipitate the occurrence of HZ. As COVID-19 survivors can suffer from remarkable psychological stress, they may be at risk of HZ. 51 Pona et al. 40 In COVID-19, the minority of cases present with severe symptoms and a hyper-inflammatory state. 52 Once a body is exposed to a foreign microbe, activation of the pattern recognition receptors presented on the surface of the immune cells directs the host to initiate a sepsis-like response. 53 Annotations on patients with mild disease have demonstrated a meaningfully decreased T cell and CD8 levels, indicating a possibility of SARS-CoV-2 directly infecting lymphocytes, which is ultimately represented in dysfunctional antiviral effects. 44 HZ may as well occur in completely asymptomatic COVID-19 patients. 18 HZ is reactivated when the host's cell-mediated immunity decreases. However, while the many studies propose that COVID-19

impairs T cell function, the intensity and interval of immunosuppression needed to trigger HZ is not yet known. 20 The 60 The authors mentioned that immune dysregulation created by the vaccine played a role in the reactivation of latent HZV infection in their case. 60 Psichogiou et al. 27 reported seven immunocompetent patients aged >50 years age, who had presented with HZ in a median of 9 days (range 7-20) after mRNA vaccination against SARS-CoV-2.

In contrast to our case series, Furer et al. 26 reported a six immunocompromised patients with autoimmune inflammatory diseases, who developed first episode of HZ closely after the first BNT162b2 mRNA vaccine; five developed HZ after the first dose and one after the second. The prevalence of HZ was 1.2% (n = 6) in patients with autoimmune inflammatory rheumatic diseases, compared with none in controls. 26 The occurrence of HZ within the time window 1-21 days after vaccination defined for increased risk and the reported T cellmediated immunity involvement suggest that COVID-19 vaccination is a probable cause of HZ. 27 Català et al., 61 Potential mechanisms that might explain the pathogenetic link between mRNA-COVID19 vaccination and HZ reactivation are related to stimulation of innate immunity through toll-like receptors (TLRs) 3,7 by mRNA-based vaccines. 62 Sahin U et al. 63 reported in healthy adults, vaccination with

BNT162b2 induces a coordinated humoral and cellular adaptive immunity. Seven days after the booster dose, a strong cellular response with spike-specific CD8+ T cell and T helper type 1 (Th1) CD4+ T cells was expanding with a high fraction of them producing interferon-γ (IFNγ), a cytokine responsible for several antiviral responses. 63 TLR signaling has been implicated during reactivation of herpesviruses, a process essential for these viruses to maintain themselves in the host. 64 Defects in TLR expression in patients suffering from diseases caused directly by herpes virus infection highlight the importance of these signaling pathways during infection and eventual disease progression. 64 Thus, the vaccine stimulates induction of type I INFs and potent inflammatory cytokines, which instigate T and B immune responses, but may negatively affect antigen expression potentially contributing to HZ reactivation. 26 These case reports support the importance of continuing assessment of vaccine safety during the ongoing massive vaccination for the COVID-19 pandemic and encourage reporting and communication of any vaccination-associated adverse event. 27 

We have noted numerous case reports of HZ infection at the time of the current pandemic either in patients infected with COVID-19, even in patients with mild or no respiratory symptoms, and after COVID-19

vaccination. Experts must be aware of the probable increased hazard of HZ during the pandemic and propose appropriate curative and preventive steps against HZ infection. Correspondingly, we ought to consider that HZ infection may be accompanied by undetectable COVID-19. A systematic follow-up of these patients would be assumed to stick to extreme safety measures till the diagnosis of COVID-19 is omitted.

The authors declare no potential conflict of interest.

All authors, namely Nawaf, Abdulrahman, Moneerah, and Sabika have contributed equally in carrying out the study as well as in preparation of the manuscript.

The data is available on request from the corresponding author, due to privacy/ethical restrictions.

A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)

WHO scientific and technical advisory Group for Infectious Hazards. COVID-19: what is next for public health?

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China

A genomic perspective on the origin and emergence of sars-cov-2

Cutaneous signs in COVID-19 patients: a review

Cutaneous manifestations of COVID-19: report of three cases and a review of literature

High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa

Clinical Features of COVID-19 and Factors Associated with Severe Clinical Course: A Systematic Review and Meta-Analysis

Herpes zoster in immunocompromised patients: incidence, timing, and risk factors

Recommendations for the management of herpes zoster

The epidemiology of herpes zoster in immunocompetent, unvaccinated adults ≥50 years old: incidence, complications, hospitalization, mortality, and recurrence

Herpes zoster-typical and atypical presentations

Herpes zoster in COVID-19-positive patients

Herpes zoster ophthalmicus in COVID-19 patients

Herpes zoster might be an indicator for latent COVID 19 infection

Herpes zoster and severe acute herpetic neuralgia as a complication of COVID-19 infection

Herpes zoster cases increased during COVID-19 outbreak. Is it possible a relation?

COVID-19 and herpes zoster co-infection presenting with trigeminal neuropathy

Herpes zoster and Postherpetic neuralgia in an elderly patient with critical COVID-19: a case report

Can COVID-19 increase the risk of herpes zoster? Narrative

A rare case of varicella-zoster virus reactivation following recovery from COVID-19

Herpes zoster co-infection in an immunocompetent patient with COVID-19

Herpes zoster may be a marker for COVID-19 infection during pregnancy

Safety and efficacy of the BNT162b2 mMRNA COVID-19 vaccine

Reactivation of herpesvirus infections after vaccinations?

Herpes zoster following BNT162b2 mRNA Covid-19 vaccination in patients with autoimmune inflammatory rheumatic diseases: a case series

Reactivation of varicella zoster virus after vaccination for SARS-CoV-2. Vaccines (Basel)

Mixed viral infections: detection and management

Skin manifestations associated with COVID-19: current knowledge and future perspectives

Cutaneous manifestations of COVID-19: a systematic review

Cutaneous manifestations in COVID-19: a first perspective

Clinical characteristics of coronavirus disease 2019 in China

Skin manifestations in COVID-19 patients, state of the art

Increased number of herpes zoster cases in Brazil related to the COVID-19 pandemic

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Varicella-like exanthem as a specific COVID-19-associated skin manifestation: multicenter case series of 22 patients

Comment on: "to consider varicella-like exanthem associated with COVID-19, virus varicella zoster and virus herpes simplex must be ruled out. Characterization of herpetic lesions in hospitalized COVID-19 patients

An unusual case report of COVID-19 presenting with meningitis symptoms and shingles

Out-patient management of patients with COVID-19 on home isolation

Herpes zoster as a potential complication of coronavirus disease 2019

Serum LD1 isoenzyme and blood lymphocyte subsets as prognostic indicators for severe acute respiratory syndrome

Imbalance between Th17 and regulatory T cells in patients with systemic lupus erythematosus combined EBV/-CMV viraemia

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Functional exhaustion of antiviral lymphocytes in COVID-19 patients

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China

Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis

COVID-19 in a designated infectious diseases hospital outside Hubei Province

T-cell immunity of SARS-CoV: implications for vaccine development against MERS-CoV

Human herpesvirus-6, 7, and Epstein-Barr virus reactivation in pityriasis rosea during COVID-19

High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa

Survivors of COVID-19 are at high risk of post traumatic stress disorder

COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal

The immune system's role in sepsis progression, resolution, and long-term outcome

A review of the progress and challenges of developing a vaccine for COVID-19

Maintaining safety with SARS-CoV-2 vaccines

Reaktivierung von herpesviren-infektionen durch impfungen: evidenz oder koinzidenz? (reactivation of herpes virus infections by vaccination: evidence or coincidence?)

Herpes zoster after yellow fever vaccination

Herpes zoster following inactivated COVID-19 vaccine: a coexistence or coincidence?

Herpes zoster emergence following mRNA COVID-19 vaccine

Ipsilateral herpes zoster after the first dose of BNT162b2 mRNA COVID-19 vaccine

Cutaneous reactions after SARS-COV-2 vaccination: a cross-sectional Spanish nationwide study of 405 cases

Advances in mRNA vaccines for infectious diseases

BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans

How to cite this article: Almutairi N, Almutairi AN, Almazyad M, Alwazzan S. Herpes zoster in the era of COVID 19: A prospective observational study to probe the association of herpes zoster with COVID 19 infection and vaccination