Varicella-zoster virus early infection but not complete replication is required for the induction of chronic hypersensitivity in rat models of postherpetic neuralgia.

Herpes zoster, the result of varicella-zoster virus (VZV) reactivation, is frequently complicated by difficult-to-treat chronic pain states termed postherpetic neuralgia (PHN). While there are no animal models of VZV-induced pain following viral reactivation, subcutaneous VZV inoculation of the rat causes long-term nocifensive behaviors indicative of mechanical and thermal hypersensitivity. Previous studies using UV-inactivated VZV in the rat model suggest viral gene expression is required for the development of pain behaviors. However, it remains unclear if complete infection processes are needed for VZV to induce hypersensitivity in this host. To further assess how gene expression and replication contribute, we developed and characterized three replication-conditional VZV using a protein degron system to achieve drug-dependent stability of essential viral proteins. Each virus was then assessed for induction of hypersensitivity in rats under replication permissive and nonpermissive conditions. VZV with a degron fused to ORF9p, a late structural protein that is required for virion assembly, induced nocifensive behaviors under both replication permissive and nonpermissive conditions, indicating that complete VZV replication is dispensable for the induction of hypersensitivity. This conclusion was confirmed by showing that a genetic deletion recombinant VZV lacking DNA packaging protein ORF54p still induced prolonged hypersensitivities in the rat. In contrast, VZV with a degron fused to the essential IE4 or IE63 proteins, which are involved in early gene regulation of expression, induced nocifensive behaviors only under replication permissive conditions, indicating importance of early gene expression events for induction of hypersensitivity. These data establish that while early viral gene expression is required for the development of nocifensive behaviors in the rat, complete replication is dispensable. We postulate this model reflects events leading to clinical PHN, in which a population of ganglionic neurons become abortively infected with VZV during reactivation and survive, but host signaling becomes altered in order to transmit ongoing pain.

P2X7 receptor antagonist BBG inhibits endoplasmic reticulum stress and pyroptosis to alleviate postherpetic neuralgia.

Postherpetic neuralgia (PHN) is the most common complication of acute herpes zoster. The treatment of PHN remains a challenge for clinical pain management. The present study investigated the P2X7 receptor antagonist brilliant blue G (BBG) whether inhibits endoplasmic reticulum stress and pyroptosis (a necrotic form of cell death) and alleviates PHN. Varicella zoster virus (VZV)-infected CV-1 cells were used to induce PHN model. Mechanical paw withdrawal thresholds were measured using an ascending series of von Frey filaments. Immunohistochemistry was used to detect the expression of P2X7R in nerve tissues. Western blot was used to determine the expression of endoplasmic reticulum (ER) stress and pyroptosis-related molecules. The expression of IL-1ß and IL-18 in tissue homogenate was detected by ELISA. The PHN rat has the lower paw withdrawal threshold, but higher expression of P2X7 in nerve tissues. And, endoplasmic reticulum stress was activated and pyroptosis was increased in PHN rats. BBG can decrease pain thresholds and reduce ER stress and pyroptosis in PHN rats. In addition, ER stress activator tunicamycin (TM) can reverse the effect of BBG on the paw withdrawal thresholds, endoplasmic reticulum stress, and pyroptosis. Therefore, P2X7 receptor antagonist BBG alleviates PHN by activating ER stress and reducing pyroptosis.

Relationships of varicella zoster virus (VZV)-specific cell-mediated immunity and persistence of VZV DNA in saliva and the development of postherpetic neuralgia in patients with herpes zoster.

There are no surrogate markers for the development of postherpetic neuralgia (PHN) in patients with herpes zoster (HZ). All patients with HZ were prospectively enrolled to evaluate the associations of saliva varicella zoster virus (VZV) DNA persistence and VZV-specific cell-mediated immunity (CMI) with the development of PHN. Slow clearers were defined if salivary VZV DNA persisted after day 15. Salivary VZV was detected in 60 (85.7%) of a total of 70 patients with HZ on initial presentation. Of 38 patients for whom follow-up saliva samples were available, 26 (68.4%) were classified as rapid clearers and 12 (31.6%) as slow cleares. Initial VZV-specific CMI was lower in slow clearers than rapid clearers (median 45 vs 158 spot forming cells/10 6 cells, P = .02). Of the 70 patients with HZ, 22 (31.4%) eventually developed PHN. Multivariate analysis showed that slow clearers (OR, 15.7, P = .01) and lower initial VZV-specific CMI (OR, 13.8, P = .04) were independent predictors of the development of PHN, after adjustment for age and immunocompromised status. Initial low VZV CMI response and persistence of VZV DNA in saliva may be associated with the development of PHN.

Herpes zoster incidence in Germany - an indirect validation study for self-reported disease data from pretest studies of the population-based German National Cohort.

BACKGROUND: Until now, herpes zoster (HZ)-related disease burden in Germany has been estimated based on health insurance data and clinical findings. However, the validity of self-reported HZ is unclear. This study investigated the validity of self-reported herpes zoster (HZ) and its complication postherpetic neuralgia (PHN) using data from the pretest studies of the German National Cohort (GNC) in comparison with estimates based on health insurance data. METHODS: Data of 4751 participants aged between 20 and 69 years from two pretest studies of the GNC carried out in 2011 and 2012 were used. Based on self-reports of physician-diagnosed HZ and PHN, age- and sex-specific HZ incidence rates and PHN proportions were estimated. For comparison, estimates based on statutory health insurance data from the German population were considered. RESULTS: Eleven percent (95%-CI, 10.4 to 12.3, n = 539) of the participants reported at least one HZ episode in their lifetime. Our estimated age-specific HZ incidence rates were lower than previous estimates based on statutory health insurance data. The PHN proportion in participants older than 50 years was 5.9% (1.9 to 13.9%), which was in line with estimates based on health insurance data. CONCLUSION: As age- and sex-specific patterns were comparable with that in health insurance data, self-reported diagnosis of HZ seems to be a valid instrument for overall disease trends. Possible reasons for observed differences in incidence rates are recall bias in self-reported data or overestimation in health insurance data.

What are the new vaccination recommendations for herpes zoster?

A new vaccine to prevent herpes zoster (shingles) has been included in the 2018 Advisory Committee on Immunization Practices' adult immunization schedule as the preferred herpes zoster vaccination for all immunocompetent adults age 50 years and older. This article discusses new vaccination recommendations for herpes zoster.

FV-100 versus valacyclovir for the prevention of post-herpetic neuralgia and the treatment of acute herpes zoster-associated pain: A randomized-controlled trial.

This prospective, parallel-group, randomized, double-blind, multicenter study compared the efficacy and safety of FV-100 with valacyclovir for reducing pain associated with acute herpes zoster (HZ). Patients, ≥50 years of age, diagnosed with HZ within 72 h of lesion appearance who had HZ-associated pain, were randomized 1:1:1 to a 7-day course of either FV-100 200 mg QD (n = 117), FV-100 400 mg QD (n = 116), or valacyclovir 1000 mg TID (n =117). Efficacy was evaluated on the basis of the burden of illness (BOI; Zoster Brief Pain Inventory scores); incidence and duration of clinically significant pain (CSP); pain scores; incidence and severity of post-herpetic neuralgia (PHN); and times to full lesion crusting and to lesion healing. Safety was evaluated on the basis of adverse event (AE)/SAE profiles, changes in laboratory and vital signs values, and results of electrocardiograms. The burden of illness scores for pain through 30 days were 114.5, 110.3, and 118.0 for FV-100 200 mg, FV-100 400 mg, and valacyclovir 3000 mg, respectively. The incidences of PHN at 90 days for FV-100 200 mg, FV-100 400 mg, and valacyclovir 3000 mg were 17.8%, 12.4%, and 20.2%, respectively. Adverse event and SAE profiles of the two FV-100 and the valacyclovir groups were similar and no untoward signals or trends were evident. These results demonstrate a potential for FV-100 as an antiviral for the treatment of shingles that could both reduce the pain burden of the acute episode and reduce the incidence of PHN compared with available treatments.

A Rare Presentation of Cranial Polyneuropathy Without Rash Caused by Varicella Zoster Virus.

INTRODUCTION: Varicella Zoster Virus (VZV) is associated with many disorders of the central and peripheral nervous systems including neuralgia, meningitis, meningoencephalitis, cerebellitis, vasculopathy, myelopathy, Ramsay-Hunt syndrome, and polyneuritis cranialis. Cranial nerves V, VI, VII, VIII, IX, X, XI, and/or XII may be affected. The neurological disorders caused by VZV usually present with rash, but may rarely present without rash. CASE REPORT: We herein present a case of polyneuritis cranialis without rash caused by VZV affecting cranial nerves VII, VIII, IX, and X. After excluding other causes of the condition, we diagnosed VZV infection based on VZV DNA in the CSF and an elevated anti-VZV IgG level in serum. The patient responded well to antiviral therapy. CONCLUSION: VZV infection should be kept in mind during the differential diagnosis of polyneuritis cranialis; it is important to note that VZV re-activation may occur without rash.

Efficacy of low dose gabapentin in acute herpes zoster for preventing postherpetic neuralgia: a prospective controlled study.

Postherpetic neuralgia (PHN) is a sequela of herpes zoster that adversely affects quality of life seriously. The risk factors for PHN are well known but the effective interventions that reduce the incidence of PHN are less studied. The objective of this study is to evaluate the efficacy of treatment with gabapentin in patients with acute herpes zoster for preventing PHN. We performed a prospective randomized controlled study of 120 participants diagnosed with acute herpes zoster, aged 50 and over and complaining moderate to severe pain. All patients were treated with valacyclovir and acetaminophen. Half of the participants were assigned to the gabapentin group and received gabapentin 300 mg three times a day additionally. The intensity of pain at every visit and the incidence of PHN in both groups were measured. Total 52 and 49 patients in the gabapentin group and the control group, respectively, had completed 12 weeks of follow-up period. Although the incidence of PHN was higher in the control group, the difference was not statistically significant (6.1% vs. 3.8%, p = 0.67). Our results indicate that the use of low-dose gabapentin in acute herpes zoster seems not effective in the prevention of PHN.

[Herpes zoster and postherpetic neuralgia]. / Herpes zoster und postzosterische Neuralgie.

Herpes zoster develops by endogenous reactivation of varizella zoster virus (VZV). Incidence increases with age. Females are more frequently affected than males. The reactivation rate in seropositive individuals is about 20 %. After a short prodromal stage, herpetiform-grouped vesicles appear in segmental arrangement. Pain and paresthesia are typical zoster symptoms. Complications like bacterial superinfections, vasculopathy, paresis, and oculopathy may occur. During pregnancy herpes zoster is a threat for mother and child. Among elderly patients, cardiovascular risk is increased during the first week of herpes zoster infection. Postherpetic neuropathy is feared. Diagnosis can be made clinically and by the use of polymerase chain reaction. First-line treatment is systemic antiviral drug therapy with either acyclovir or brivudine. Adjuvant therapies consist of pain management and topical treatment.

Incidence of herpes zoster and associated events including stroke--a population-based cohort study.

BACKGROUND: More detailed understanding of herpes zoster (HZ) is called for in the context of an increasing observed frequency of disease, and ongoing discussions regarding potential consequences of the disease. Thus, population-based data on incidence and complications of HZ are needed. METHODS: We conducted a register-based cohort study in Västra Götaland County (population 1.5 million) in Sweden. We collected data on all patients diagnosed with HZ during the years 2008 to 2010 from population-based registers. Incidence rates (IR) of HZ and related complications were calculated and stratified by age and sex. RESULTS: There were 13 269 new HZ cases during the study period. Overall, the IR of herpes zoster in both genders was 3.25 (95% CI: 3.16-3.34) per 1000 person years in 2010. The incidence was consistently higher in women than in men and in older than in young. A history of immunosuppression was more common than in the general population. The incidence was highest in individuals over 80 years of age (IR 9.2 per 1000 person years, 95% CI: 8.8-9.6) during 2008-2010. The most common complications to HZ were ocular engagement and postherpetic neuralgia; risks for stroke and sepsis were significantly elevated during the one year following diagnosis, especially in the youngest age group of patients 0-39 years. CONCLUSIONS: Herpes zoster is more common in women, the elderly and immunosuppressed individuals. We verify a population-based association between herpes zoster and risk for stroke and sepsis, which may merit concern.

Varicella-zoster reactivation after allogeneic stem cell transplantation without routine prophylaxis--the incidence remains high.

One-year prophylaxis with acyclovir has been shown to effectively prevent varicella-zoster virus (VZV) reactivation after allogeneic hematopoietic stem cell transplantation (HSCT) in a cohort that underwent transplantation in the beginning of the 2000s. Transplantation procedures have since changed considerably and reduced-intensity conditioning (RIC) is nowadays common. We investigated VZV reactivation without routine prophylaxis in a cohort of HSCT patients, 50% of whom had received RIC. The cumulative 2-year incidence of VZV reactivation was 20.7%. Risk factors in a multivariate analysis were treatment with mesenchymal stromal cells (relative hazard [RH], 1.65; confidence interval [CI], 1.07 to 2.54; P = .02), total body irradiation ≥6 Gy (RH, 1.55; CI, 1.14 to 2.13; P = .006), engraftment later than day 16 (RH, 1.46; CI, 1.07 to 2.00; P = .02), and age 0 to 19 years (RH, 1.68; CI, 1.21 to 2.35; P = .002). There was no difference in VZV reactivation between patients receiving myeloablative conditioning or RIC. VZV-related complications occurred in 29% of the patients with reactivation; most common were disseminated disease and postherpetic neuralgia. No single low-risk group for VZV reactivation could be identified. We conclude that VZV reactivation remains common after HSCT and carries a high complication rate, warranting prophylaxis.

[Herpes Zoster and its prevention in Italy. Scientific consensus statement]. / L'Herpes Zoster e la prevenzione vaccinale in Italia. Documento scientifico di consenso.

In this paper, an Italian group of experts presents a revision of the available data about epidemiology and prevention of Herpes Zoster (HZ). HZ is an acute viral diseases caused by the reactivation of Varicella Zoster Virus (VZV). HZ is characterized by neurological and dermatological symptoms with a dermatomeric localization. The reactivation of the virus from the latent status in the sensitive ganglia increases with age and failing cell mediated immunity. In Europe, more than 95% of adults presents antibodies against VZV. Incidence of HZ is similar all over the world, related to the age of the population: from 2-3/1000 persons/year in the age group 20 to 50 years to 5/1000 in the 60 years old, 6-7/1000 between 70 and 80 up to >1/100 in older than 80. In Italy, about 157,000 new cases of HZ are estimated every year with an incidence of 6.3/1000 persons/year mostly in older adults. Among the hospitalized cases, 60% are over 65 years of age. The more frequent and severe complication of HZ is post herpetic neuralgia (PHN), characterized by severe localized pain lasting at least 3 month after the beginning of the acute phase. The pain is responsible for a sharp decrease in the quality of life. In Europe, PHN is described in 2.6-27% of HZ cases. In Italy, data obtained by a network of General Practitioner show PHN in 20.6% of HZ patients, while 9.2% of the patients still presents PHN at 6 months. The more frequent localization is thoracic; when the virus reactivate at the level of the ophthalmic division of the trigeminal nerve most patients develop ocular complications. The clinical and therapeutical managements of HZ patients is difficult and the results are often poor. Prevention of HZ e PHN in the population over 50 years is possible using a live attenuated vaccine containing VZV (Oka/Merck strain, not less than 19.400 plaque forming units), available since 2006. Efficacy of anti-HZ vaccine was demonstrated in two large clinical trials that showed a 51% reduction in the incidence of HZ and a 61% decrease of the burden of illness. Incidence of PHN showed a reduction of 67% in immunized subjects. Long-term follow-up showed a persistence of the protection even if a decrease was noted in older subjects and with time. Effectiveness studies confirm the data of clinical trials and numerous pharmaco-economical evaluation show a favorable profile of HZ vaccine. The vaccine is recommended in USA, Canada and some European countries for people over 60. The expert group concluded that HZ and PHN represent an important clinical and Public Health problem in Italy and that the possibility to prevent them should be carefully evaluated.

The variegate neurological manifestations of varicella zoster virus infection.

Varicella zoster virus (VZV) is an exclusively human neurotropic alphaherpesvirus. Primary infection causes varicella (chickenpox), after which the virus becomes latent in ganglionic neurons along the entire neuraxis. With advancing age or immunosuppression, cell-mediated immunity to VZV declines, and the virus reactivates to cause zoster (shingles), dermatomal distribution, pain, and rash. Zoster is often followed by chronic pain (postherpetic neuralgia), cranial nerve palsies, zoster paresis, vasculopathy, meningoencephalitis, and multiple ocular disorders. This review covers clinical, laboratory, and pathological features of neurological complications of VZV reactivation, including diagnostic testing to verify active VZV infection in the nervous system. Additional perspectives are provided by discussions of VZV latency, animal models to study varicella pathogenesis and immunity, and of the value of vaccination of elderly individuals to boost cell-mediated immunity to VZV and prevent VZV reactivation.

Beyond zoster: sensory and immune changes in zoster-affected dermatomes: a review*.

Neuroepidermal tropism of varicella-zoster virus accounts for cutaneous and nerve lesions following herpes zoster. Skin lesions heal in a few weeks and may or may not leave visible scars. Nerve lesions involve peripheral sensory fibres, sometimes causing permanent damage that results in partial denervation of the affected dermatome. The effects of the nerve injury involve the sensibility function, thus causing neuralgia, itch, allodynia, hypo- or anaesthesia, as well as the immune function that is related to neuropeptide release, thus altering immune control in the affected dermatome. The neuro-immune destabilization in the zoster-infected site paves the way for the onset of many and various immunity-related disorders along the affected dermatome.

Clinical recognition of varicella zoster virus vasculopathy.

INTRODUCTION: It is important to recognize acutely evolving ischemic stroke attributable to reactivation of varicella zoster virus vasculopathy since antiviral agents are effective. METHODS: Three cases seen by the author over a 2-year period are highlighted. RESULTS: All patients presented with an evolving arterial or venous ischemia in the background of postherpetic neuralgia proceeding for weeks to months. CONCLUSION: Chronic neuralgic pain in a dermatomal distribution of an evolving central nervous system vasculopathy is an important clue to its recognition.

A case of rheumatoid arthritis presenting with postherpetic neuralgia and abdominal-wall pseudohernia.

Postherpetic neuralgia is a common complication, while the postherpetic abdominal-wall pseudohernia (AWP) is a quite rare complication of herpes zoster (HZ). We report a patient >45 years of age with a history of rheumatoid arthritis (RA) who presented with two chronic HZ complications. A 75-year-old woman was admitted with neuralgia following cutaneous herpes zoster 6 weeks before. She was on long-term glucocorticoid, antimalarial and non-steroidal anti-inflammatory treatment. Confluent ulcers began to fill with granulation tissue, crusts, scars and skin discoloration in the area of the left T12-L2 dermatomes and reducible, painless swelling of the left flank, 20 × 20 cm, without palpable defect in abdominal-wall. There were typical joint deformity and positive rheumatoid factor. On neurological examination superficial abdominal reflexes were diminished in the left side, with hypesthesia of the overlying skin. Needle electromyography revealed denervational changes limited to the left-side muscles (on affected dermatomes T12-L2). Thoracoabdominal CT did not reveal the presence of existing hernia. There was an abdominal distension, the left abdominal-wall was thinner than the right side. The patient was treated with an oral preparation containing benfotiamine and vitamins B6 and B12, carbamazepine, amitriptyline, gabapentin, and local lidocaine. Skin rash left with scarring and pigmentary changes and the abdominal-wall swelling resolved within 8 months, however, the pain still persisted. To our best knowledge, this is the first observation of RA-associated postherpetic AWP. This rare motor complication appears to be self-limited with a good prognosis for recovery, while postherpetic neuralgia may require a combination of treatments for adequate pain relief. Older age, female sex, greater rash and acute pain severity are considered as risk factors associated with severe postherpetic neuralgia. In addition, patients with RA, mainly those treated with oral corticosteroids, are also at increased risk of HZ complications.

Persistence of varicella zoster virus DNA in saliva after herpes zoster.

Analysis of saliva samples from individuals aged ≥ 60 years who had a history of zoster (group 1), zoster and postherpetic neuralgia (PHN; group 2), or no history of zoster (group 3) revealed varicella zoster virus (VZV) DNA in saliva samples from 11 of 17 individuals in group 1, 10 of 15 individuals in group 2, and 2 of 17 individuals in group 3. The frequency of VZV DNA detection was significantly higher (P = .001) in saliva of subjects with a history of zoster, with or without PHN (21 [67%] of 32 subjects in groups 1 and 2), than in saliva of age-matched subjects with no zoster history (2 [12%] of 17 subjects in group 3). Thus, persistence of VZV DNA in saliva is the outcome of zoster, independent of PHN. Because VZV infection can produce neurological and ocular disease without zoster rash, future studies are needed to establish whether VZV DNA can be detected in the saliva of such patients.

Herpes zoster: A Review of Clinical Manifestations and Management.

The Varicella-zoster virus (VZV) or human herpes virus 3 is a neurotropic human alpha herpes virus responsible for chickenpox/varicella and shingles/Herpes zoster (HZ). This review will focus on HZ. Since HZ is secondary to varicella, its incidence increases with age. In children and youngsters, HZ is rare and associated to metabolic and neoplastic disorders. In adults, advanced age, distress, other infections (such as AIDS or COVID-19), and immunosuppression are the most common risk factors. HZ reactivation has recently been observed after COVID-19 vaccination. The disease shows different clinical stages of variable clinical manifestations. Some of the manifestations bear a higher risk of complications. Among the possible complications, postherpetic neuralgia, a chronic pain disease, is one of the most frequent. HZ vasculitis is associated with morbidity and mortality. Renal and gastrointestinal complications have been reported. The cornerstone of treatment is early intervention with acyclovir or brivudine. Second-line treatments are available. Pain management is essential. For (secondary) prophylaxis, currently two HZV vaccines are available for healthy older adults, a live attenuated VZV vaccine and a recombinant adjuvanted VZV glycoprotein E subunit vaccine. The latter allows vaccination also in severely immunosuppressed patients. This review focuses on manifestations of HZ and its management. Although several articles have been published on HZ, the literature continues to evolve, especially in regard to patients with comorbidities and immunocompromised patients. VZV reactivation has also emerged as an important point of discussion during the COVID-19 pandemic, especially after vaccination. The objective of this review is to discuss current updates related to clinical presentations, complications, and management of HZ.

Characterization of the host immune response in human Ganglia after herpes zoster.

Varicella-zoster virus (VZV) causes varicella (chicken pox) and establishes latency in ganglia, from where it reactivates to cause herpes zoster (shingles), which is often followed by postherpetic neuralgia (PHN), causing severe neuropathic pain that can last for years after the rash. Despite the major impact of herpes zoster and PHN on quality of life, the nature and kinetics of the virus-immune cell interactions that result in ganglion damage have not been defined. We obtained rare material consisting of seven sensory ganglia from three donors who had suffered from herpes zoster between 1 and 4.5 months before death but who had not died from herpes zoster. We performed immunostaining to investigate the site of VZV infection and to phenotype immune cells in these ganglia. VZV antigen was localized almost exclusively to neurons, and in at least one case it persisted long after resolution of the rash. The large immune infiltrate consisted of noncytolytic CD8(+) T cells, with lesser numbers of CD4(+) T cells, B cells, NK cells, and macrophages and no dendritic cells. VZV antigen-positive neurons did not express detectable major histocompatibility complex (MHC) class I, nor did CD8(+) T cells surround infected neurons, suggesting that mechanisms of immune control may not be dependent on direct contact. This is the first report defining the nature of the immune response in ganglia following herpes zoster and provides evidence for persistence of non-latency-associated viral antigen and inflammation beyond rash resolution.

Review: The neurobiology of varicella zoster virus infection.

Varicella zoster virus (VZV) is a neurotropic herpesvirus that infects nearly all humans. Primary infection usually causes chickenpox (varicella), after which virus becomes latent in cranial nerve ganglia, dorsal root ganglia and autonomic ganglia along the entire neuraxis. Although VZV cannot be isolated from human ganglia, nucleic acid hybridization and, later, polymerase chain reaction proved that VZV is latent in ganglia. Declining VZV-specific host immunity decades after primary infection allows virus to reactivate spontaneously, resulting in shingles (zoster) characterized by pain and rash restricted to one to three dermatomes. Multiple other serious neurological and ocular disorders also result from VZV reactivation. This review summarizes the current state of knowledge of the clinical and pathological complications of neurological and ocular disease produced by VZV reactivation, molecular aspects of VZV latency, VZV virology and VZV-specific immunity, the role of apoptosis in VZV-induced cell death and the development of an animal model provided by simian varicella virus infection of monkeys.