Low vitamin D3 levels may be associated with herpes zoster reactivation

Introduction

Herpes zoster is a painful disease that is characterized by vesicles with involvement of the dermatome. The disease has the potential to cause significant acute morbidity and long-term sequelae, including chronic pain, which can have a markedly detrimental impact on the quality of life, even in those who are undergoing appropriate antiviral therapy. Herpes zoster occurs as a result of a decline in cell-mediated immunity directed specifically towards the varicella zoster virus (VZV). Consequently, the likelihood of developing herpes zoster is heightened among individuals with compromised cell-mediated immune capabilities [1, 2]. The most important risk factor for herpes zoster is advanced age. Aging reduces the skin’s ability to synthesize vitamin D, and increased skin pigmentation reduces the effectiveness of UVB to stimulate vitamin D synthesis [3, 4].
Cell-mediated immunity is known to decrease with age, and decreased cell-mediated immunity is associated with reactivation of VZV [5]. Vitamin D is important for calcium homeostasis, bone health, and prevention of fractures. Vitamin D has a clear impact on metabolic, neoplastic, inflammatory, and immune events [6, 7]. Vitamin D deficiency is considered to be a serum 25-hydroxyvitamin D (25-OH-D) level of less than 20 ng/ml. 25-OH-D vitamin values between 20 and 30 ng/ml are considered insufficient and are considered clinically important. The prevalence of vitamin D deficiency varies according to geographic regions with different levels of sunlight exposure [7, 8]. It has been found that vitamin D deficiency is frequently seen in various viral infectious diseases. Vitamin D has been demonstrated to influence the secretion of antimicrobial peptides associated with several toll-like receptors (TLRs), which have been shown to exert antiviral effects. Similarly, 1,25-(OH)-D strongly stimulates the release of human cathelicidins from neutrophils and possibly monocytes and natural killer cells. Human cathelicidin is induced by TLR1/2 activation and contributes to mucosal immunity and provides antiviral effects [7, 8]. The extant literature on the relationship between vitamin D levels and herpes zoster is limited. In a previous study, Chao et al. proposed that vitamin D may influence both the susceptibility of humans to varicella zoster virus reactivation and the clinical course of herpes zoster infection [6, 7].

Objective

The objective of this study was to compare the vitamin D levels in patients with herpes zoster to those of healthy controls and to investigate the potential role of vitamin D in the pathogenesis of herpes zoster.

Material and methods

A local ethics committee approval was obtained for the study (Decision number: 2020/185). In this study, 101 patients who applied to the Ordu State Hospital dermatology outpatient clinic between March 2019 and June 2020 and were diagnosed with herpes zoster and had a vitamin D result at the time of diagnosis and a control group of 100 healthy people were included. Data of the patient and control groups were recorded. The location of the disease and the season of admission were recorded in the patient group. Individuals with cardiovascular disease, gastrointestinal disease, kidney disease, malignancy, pregnancy, diabetes mellitus, autoimmune and inflammatory diseases, and individuals taking vitamin D supplements were not included in the control group. Informed consent was obtained.

Statistical analysis

The data were evaluated with IBM SPSS statistics 21 package program. Numerical variables were expressed as mean ± standard deviation, percentage. An evaluation was made after checking whether the parameters were normally distributed. In data analysis, Student’s t test was used for the group comparisons, and in cases where there was no normal distribution, Mann Whitney-U test was used. The relationship between the two variables was evaluated using the Pearson correlation test in parametric tests and the Spearman correlation test in non-parametric tests.
A value of p < 0.05 was accepted for the significance level of the tests.

Results

The study included 57 (56.4%) female and 44 (43.4%) male patients. The patients were aged between 18 and 77 years, with a mean age of 49.72 ±16.37 years. Of the 100 individuals in the control group, 64 (64%) were female and 36 (36%) were male. The ages of the control group ranged from 18 to 78 years, with a mean age of 49.16 ±17.61. There was no significant difference between the patient group and the control group in terms of age and gender (p = 0.83).
One herpes zoster patient had a history of lung cancer and 1 patient had a history of breast cancer in remission. Apart from this, there were no patients using immunosuppressive drugs or immunocompromised patients.
Thirty five (34.7%) of the herpes zoster patients referred to the outpatient clinic in winter, 5 (5%) in spring, 30 (29.7%) in summer and 31 (30.7%) in autumn. Herpes zoster developed in the thoracic region in 42 patients, in the lumbar region in 31 patients, in the ophthalmic region in 7 patients, in the leg region in 10 patients, in the arm region in 2 patients, in the cervical region in 8 patients, and in the mandibular region in 1 patient (table 1).
25-OH vitamin D levels were calculated as < 20 µg/l deficiency, 21–29 µg/l insufficiency and > 30 µg/l sufficient amount. The 25-OH vitamin D levels of the patients ranged from 2.37 to 32.98 µg/l and the mean value was 14.25 ±7.20 µg/l. In the patient group, the number of patients with deficiency of 25-OH vitamin D level was 82 (81.2%), the number of patients with an insufficient level was 15 (14.9%), and the number of patients with a sufficient level was 4 (4%). In the control group, 25-OH vitamin D levels ranged between 10.3 and 44.25 µg/l, and the mean value was 24.9 ±6.24 µg/l. In the control group, the number of individuals with 25-OH vitamin D deficiency was 20 (20%), the number of individuals with an insufficient level was 59 (59%), and the number of individuals with a sufficient level was 21 (21%). 25-OH vitamin D levels in the patient group were significantly lower than the levels in the control group (p < 0.001) (table 2).

Dıscussion

Herpes zoster is more common in women than men. Thoracic, lumbar, trigeminal and cervical dermatomes are the most frequently affected areas [3]. In our study, the most affected dermatome was thoracic dermatome.
With advanced age, the risk of developing severe shingles increases as a result of the decrease in the immune response specific to varicella zoster virus, especially in people with immunosuppressive disease or immunosuppressive drug use [1, 3, 9]. In humans, the main source of vitamin D is UVB-mediated synthesis in the skin. Certain foods, such as fatty fish and dairy products, contain vitamin D. Vitamin D activation involves two hydroxylation steps, one in the liver and the other in the kidneys. In particular, final activation of vitamin D by 1a-hydroxylase also occurs in extra kidney tissues, including epithelial and immune cells [10].
The identification of the vitamin D receptor in peripheral blood mononuclear cells has led to increased focus on the regulatory function of vitamin D in the immune system [6, 11]. 25(OH) – Vitamin D enters the monocyte and, after being converted to 1,25-(OH)2-D in the mitochondria, binds to the vitamin D receptor (VDR) and ultimately acts as a transcription factor for human cathelicidin, which is antimicrobial peptide. Defensins can also inhibit viral replication and cause direct degradation of the viral membrane [12]. Following exposure to a pathogen, monocytes and macrophages increase the number of vitamin D receptors, thereby enhancing the production of cathelicidin [13, 14]. Cathelicidin effectively inhibits herpes simplex virus type 1 and retrovirus replication in its peptide form, LL-37. In addition, severe 1,25-(OH)2-D deficiency has been associated with clinically advanced human immunodeficiency virus (HIV) infection, and vitamin D supplementation significantly inhibits hepatitis C virus (HCV) proliferation [7]. B cells infected with Epstein-Barr virus (EBV) exhibit significantly lower levels of VDR expression compared to uninfected cells [6, 7]. Activation of B and T lymphocytes has been shown to result in VDR expression. In addition, 1,25-(OH)2-D stimulates T lymphocyte maturation, increases the regulatory T lymphocyte ratio, and plays a role in limiting inflammation triggered by microbial invasion [6, 13]. It has been demonstrated that HIV infection results in a reduction of the activity of VDR. A reduction of VDR expression or activity levels results in the impairment of innate immunity, thereby facilitating the persistence of intracellular pathogens, such as viruses. Nevertheless, vitamin D has been demonstrated to possess antiviral properties in vitro [7]. A study examining the impact of vitamin D-related antimicrobial peptides on herpes viruses revealed that cathelicidine was effective in reducing HSV-1 viral titers isolated from patients with keratoconjunctivitis [13]. It has been shown that vitamin D deficiency correlates with increased mental stress, and has demonstrated that stress can influence the activation of CD8+T lymphocytes by inducing neuroendocrine factors that regulate the transition between viral latency and reactivation in neurons. In this manner, vitamin D deficiency results in the attenuation of immune function and an increased susceptibility to the development of herpes zoster [7]. In a study of patients undergoing dialysis for chronic kidney failure, it was found that the risk of herpes zoster reactivation was significantly lower in patients who received vitamin D supplements [6]. Chao et al. suggested that vitamin D may also play a role in controlling VZV replication during herpes zoster management as the control of most episodes of viral infection depends on cell-mediated immunity and related cytokines [7]. Vitamin D can inhibit neuroinflammation through down-regulation of pro-inflammatory cytokines and up-regulation of anti-inflammatory cytokines. Chen et al. showed in their study that hypovitaminosis D was significantly higher in postherpetic neuralgia patients compared to controls [15]. In a study by Han et al. with 30 herpes zoster patients, the incidence of herpes zoster decreased as 25 hydroxyvitamin D3 increased [16]. In our study, 25-(OH)-D vitamin levels were found to be lower in patients with herpes zoster than in the control group.
A cohort study concluded that while low vitamin D levels were associated with a higher risk of progression to AIDS in HIV-infected patients, vitamin D supplementation did not affect mortality, CD4 cell count, and viral load [13]. Chao et al. found that both serum total and bioavailable vitamin D levels were positively associated with herpes zoster antibody levels [7]. In a study conducted in Canada, low 25-OH-vitamin D levels were associated with an increased risk of viral upper respiratory tract infections in children [17]. In another study by Sabetta et al., including healthy adults, it was found that those with 25-OH-D vitamin over 38 ng/ml had a lower risk of acute viral respiratory tract infection [18]. In a meta-analysis by Bergman et al., vitamin D supplementation was found to have a protective effect against respiratory tract infections [10].
In a new study, it is stated that taking 50,000 IU vitamin D per month for 12 months in those with vitamin D deficiency and inadequacy can help to reach sufficient levels [19].
Nevertheless, the results of a recent study indicated that there was no evidence to suggest that the administration of vitamin D supplements or the presence of vitamin D deficiency was associated with an increased risk of herpes zoster [20].
As this study employs a retrospective design, the absence of VZV antibodies and a history of chickenpox in childhood represents a limitation of the study. This study revealed that 25-OH vitamin D levels were significantly lower in herpes zoster patients compared to the control group. 25-OH vitamin D deficiency may increase the risk of VZV reactivation and vitamin D supplementation may alleviate the course of the disease and complications such as postherpetic neuralgia in vitamin D-deficient patients with herpes zoster. It is imperative to conduct prospective studies on this topic.

Funding

No external funding.

Ethical approval

Approval number: 2020/185.

Conflict of interest

The authors declare no conflict of interest.

References