Recurrent papulonodular herpes zoster, with syringitis, folliculitis, and vasculitis as clues to the diagnosis.

Herpes zoster (HZ) may have atypical clinical presentations, particularly in immunosuppressed patients. Nodular HZ is an extremely rare condition. We report the first case of recurrent papulonodular HZ in an adult patient with inflammatory bowel disease (IBD) receiving biologic treatment. More interestingly, there was no epidermal involvement on histopathological examination, but the involvement of the adnexa and blood vessels was a clue to the diagnosis in view of the clinical context. We wish to raise awareness of this rare manifestation of HZ for early diagnosis and proper treatment.

Mpox virus and coinfections: An approach to rapid diagnosis.

We report a case of a 42-year-old immunocompromised (human immunodeficiency virus [HIV], CD4 count 86 cells/µL) Black male who presented with fever, oropharyngeal candidiasis, and phimosis, followed by eruption of umbilicated papulovesicles most concentrated on the face. The patient was diagnosed with Mpox (MPXV, formerly monkeypox), herpes simplex virus 1 (HSV1), varicella-zoster virus (VZV), and late latent syphilis. Tzanck smear of a Mpox lesion proved a useful and rapidly obtained pertinent negative test, lacking the typical changes of HSV/VZV (multinucleation, margination, and molding). A biopsy specimen showed viral changes consistent with both Mpox (ballooning degeneration and multinucleated keratinocytes) and herpesvirus (multinucleated epithelial giant cell within a zone of follicular necrosis). Lesion PCR was positive for HSV1 and MPXV, and negative for HSV2 and VZV. Immunohistochemistry was positive for VZV and orthopoxvirus. Empiric treatment for HSV/VZV in patients with suspected or confirmed Mpox should be considered for patients with HIV or other immunocompromised patients. It is important to recognize that MPXV, HSV, and VZV may all be present and difficult to distinguish clinically. More than one test modality (PCR, H&E, immunohistochemistry, and Tzanck) and multiple lesion samples may be required to thoroughly evaluate widespread papulovesicular eruptions, especially in immunocompromised patients.

Zosteriform cutaneous metastases from urothelial carcinoma: Report of a rare case and literature review.

Zosteriform cutaneous metastases from urothelial carcinoma are rare. Here, we report a 50-year-old male with urothelial carcinoma who presented with multiple tender, erythematous papulonodules in an L1-L3 distribution approximately 6 years after primary tumor diagnosis. He had no history of prior herpes zoster infection. Histopathology showed lobules and small nests of atypical epithelioid cells positive for GATA3, CK20, CK7, and p40 throughout the dermis and within lymphatic vessels highlighted by D2-40, consistent with cutaneous metastases from urothelial carcinoma. No perineural invasion or viral cytopathic change was present. The patient died approximately 8 months after diagnosis of cutaneous metastases. Since its first report in 1986, there have been only six cases of zosteriform cutaneous metastases from urothelial carcinoma. We review the prior literature including hypotheses of the pathogenesis of zosteriform cutaneous metastases, which remain incompletely understood.

Humanized Severe Combined Immunodeficient (SCID) Mouse Models for Varicella-Zoster Virus Pathogenesis.

Varicella-zoster virus (VZV) is a human-restricted virus, which raises obstacles to research. The strict human tropism limits knowledge about its pathogenesis and creates challenges for evaluating antiviral treatments and vaccines. The development of humanized mouse models was driven by the need to address these challenges. Here, we summarize the humanized mouse models with xenografts of thymus/liver organoids, skin, dorsal root ganglia, and lung tissues. These models revealed VZV ORFs involved in cell tropism and pathogenesis in differentiated tissues, and made it possible to evaluate antiviral compounds in a mammalian system. Further development of skin organ culture techniques have the added benefit of lower cost and greater speed than mouse models. Human tissues, both in humanized mice and in ex vivo models, will continue to be necessary to study VZV in the tissue microenvironements to which it is adapted.

Varicella Zoster Virus Neuronal Latency and Reactivation Modeled in Vitro.

Latency and reactivation in neurons are critical aspects of VZV pathogenesis that have historically been difficult to investigate. Viral genomes are retained in many human ganglia after the primary infection, varicella; and about one-third of the naturally infected VZV seropositive population reactivates latent virus, which most often clinically manifests as herpes zoster (HZ or Shingles). HZ is frequently complicated by acute and chronic debilitating pain for which there remains a need for more effective treatment options. Understanding of the latent state is likely to be essential in the design of strategies to reduce reactivation. Experimentally addressing VZV latency has been difficult because of the strict human species specificity of VZV and the fact that until recently, experimental reactivation had not been achieved. We do not yet know the neuron subtypes that harbor latent genomes, whether all can potentially reactivate, what the drivers of VZV reactivation are, and how immunity interplays with the latent state to control reactivation. However, recent advances have enabled a picture of VZV latency to start to emerge. The first is the ability to detect the latent viral genome and its expression in human ganglionic tissues with extraordinary sensitivity. The second, the subject of this chapter, is the development of in vitro human neuron systems permitting the modeling of latent states that can be experimentally reactivated. This review will summarize recent advances of in vitro models of neuronal VZV latency and reactivation, the limitations of the current systems, and discuss outstanding questions and future directions regarding these processes using these and yet to be developed models. Results obtained from the in vitro models to date will also be discussed in light of the recent data gleaned from studies of VZV latency and gene expression learned from human cadaver ganglia, especially the discovery of VZV latency transcripts that seem to parallel the long-studied latency-associated transcripts of other neurotropic alphaherpesviruses.

[Varicella-Zoster Virus Infection in the Central Nervous System].

Varicella-zoster virus (VZV) is known to causes various inflammatory disorders of the central nervous system (CNS) such as encephalitis, meningitis, and myelitis. Similar to the varicella rashes, these conditions are associated with the reactivation of VZV. Ganglionitis and vasculitis, in particular, may be linked to the pathogenesis of VZV infection in the CNS. This review provides an overview of the clinical presentation, diagnosis, treatment, and prognosis of VZV infection in the CNS based on its distinct pathophysiology.

Breast carcinoma metastasis and Wolf's isotopic response.

Wolf's isotopic phenomenon occurs when a new dermatosis appears on a site that has already healed from a previous dermatological disease of another etiology. This report describes the case of a 44-year-old female patient undergoing treatment for breast carcinoma who recently had brownish erythematous lesions appearing on the scar region of previous herpes zoster on the right hemithorax. Histopathology and immunohistochemistry examination confirmed skin metastasis of breast cancer. Herpes zoster scars require attention due to the possibility of an isotopic response as a facilitating factor in some dermatoses, sometimes severe ones, such as neoplasms.

Variable Gene Expression in Human Ganglia Latently Infected with Varicella-Zoster Virus.

Varicella-Zoster virus (VZV) is a pathogenic human herpes virus that causes varicella ("chicken pox") as a primary infection, following which it becomes latent in neuronal cells in human peripheral ganglia. It may then reactivate to cause herpes zoster ("shingles"). Defining the pattern of VZV gene expression during latency is an important issue, and four highly expressed VZV genes were first identified by Randall Cohrs in 1996 using cDNA libraries. Further studies from both his and other laboratories, including our own, have suggested that viral gene expression may be more widespread than previously thought, but a confounding factor has always been the possibility of viral reactivation after death in tissues obtained even at 24 h post-mortem. Recent important studies, which Randall Cohrs contributed to, have clarified this issue by studying human trigeminal ganglia at 6 h after death using RNA-Seq methodology when a novel spliced latency-associated VZV transcript (VLT) was found to be mapped antisense to the viral transactivator gene 61. Viral gene expression could be induced by a VLT-ORF 63 fusion transcript when VZV reactivated from latency. Prior detection by several groups of ORF63 in post-mortem-acquired TG is very likely to reflect detection of the VLT-ORF63 fusion and not canonical ORF63. The contributions to the VZV latency field by Randall Cohrs have been numerous and highly significant.

VZV Infection of Primary Human Adrenal Cortical Cells Produces a Proinflammatory Environment without Cell Death.

Virus infection of adrenal glands can disrupt secretion of mineralocorticoids, glucocorticoids, and sex hormones from the cortex and catecholamines from the medulla, leading to a constellation of symptoms such as fatigue, dizziness, weight loss, nausea, and muscle and joint pain. Specifically, varicella zoster virus (VZV) can produce bilateral adrenal hemorrhage and adrenal insufficiency during primary infection or following reactivation. However, the mechanisms by which VZV affects the adrenal glands are not well-characterized. Herein, we determined if primary human adrenal cortical cells (HAdCCs) infected with VZV support viral replication and produce a proinflammatory environment. Quantitative PCR showed VZV DNA increasing over time in HAdCCs, yet no cell death was seen at 3 days post-infection by TUNEL staining or Western Blot analysis with PARP and caspase 9 antibodies. Compared to conditioned supernatant from mock-infected cells, supernatant from VZV-infected cells contained significantly elevated IL-6, IL-8, IL-12p70, IL-13, IL-4, and TNF-α. Overall, VZV can productively infect adrenal cortical cells in the absence of cell death, suggesting that these cells may be a potential reservoir for ongoing viral replication and proinflammatory cytokine production, leading to chronic adrenalitis and dysfunction.

Development of Robust Varicella Zoster Virus Luciferase Reporter Viruses for In Vivo Monitoring of Virus Growth and Its Antiviral Inhibition in Culture, Skin, and Humanized Mice.

There is a continued need to understand varicella-zoster virus (VZV) pathogenesis and to develop more effective antivirals, as it causes chickenpox and zoster. As a human-restricted alphaherpesvirus, the use of human skin in culture and mice is critical in order to reveal the important VZV genes that are required for pathogenesis but that are not necessarily observed in the cell culture. We previously used VZV-expressing firefly luciferase (fLuc), under the control of the constitutively active SV40 promoter (VZV-BAC-Luc), to measure the VZV spread in the same sample. However, the fLuc expression was independent of viral gene expression and viral DNA replication programs. Here, we developed robust reporter VZV viruses by using bacterial artificial chromosome (BAC) technology, expressing luciferase from VZV-specific promoters. We also identified two spurious mutations in VZV-BAC that were corrected for maximum pathogenesis. VZV with fLuc driven by ORF57 showed superior growth in cells, human skin explants, and skin xenografts in mice. The ORF57-driven luciferase activity had a short half-life in the presence of foscarnet. This background was then used to investigate the roles for ORF36 (thymidine kinase (TK)) and ORF13 (thymidylate synthase (TS)) in skin. The studies reveal that VZV-∆TS had increased sensitivity to brivudine and was highly impaired for skin replication. This is the first report of a phenotype that is associated with the loss of TS.

Altered gray matter volume and functional connectivity in patients with herpes zoster and postherpetic neuralgia.

Numerous neuroimaging studies on postherpetic neuralgia (PHN) and herpes zoster (HZ) have revealed abnormalities in brain structure/microstructure and function. However, few studies have focused on changes in gray matter (GM) volume and intrinsic functional connectivity (FC) in the transition from HZ to PHN. This study combined voxel-based morphometry and FC analysis methods to investigate GM volume and FC differences in 28 PHN patients, 25 HZ patients, and 21 well-matched healthy controls (HCs). Compared to HCs, PHN patients exhibited a reduction in GM volume in the bilateral putamen. Compared with HZ patients, PHN patients showed decreased GM volume in the left parahippocampal gyrus, putamen, anterior cingulate cortex, and right caudate and increased GM volume in the right thalamus. However, no regions with significant GM volume changes were found between the HZ and HC groups. Correlation analysis revealed that GM volume in the right putamen was positively associated with illness duration in PHN patients. Furthermore, lower FCs between the right putamen and right middle frontal gyrus/brainstem were observed in PHN patients than in HCs. These results indicate that aberrant GM volumes and FC in several brain regions, especially in the right putamen, are closely associated with chronification from HZ to PHN; moreover, these changes profoundly affect multiple dimensions of pain processing. These findings may provide new insights into the pathophysiological mechanisms of PHN.

Herpes zoster epidemiology in Latin America: A systematic review and meta-analysis.

The epidemiology and burden of Herpes Zoster (HZ) are largely unknown, and there are no recent reviews summarizing the available evidence from the Latin America and Caribbean (LAC) region. We conducted a systematic review and meta-analysis to characterize the epidemiology and burden of HZ in LAC. Bibliographic databases and grey literature sources were consulted to find studies published (January 2000 -February 2020) with epidemiological endpoints: cumulative incidence and incidence density (HZ cases per 100,000 person-years), prevalence, case-fatality rates, HZ mortality, hospitalization rates, and rates of each HZ complication. Twenty-six studies were included with most studies coming from Brazil. No studies reported the incidence of HZ in the general population. In population at higher risk, the cumulative incidence ranged from 318-3,423 cases of HZ per 100,000 persons per year of follow-up. The incidence density was 6.4-36.5 cases per 1,000 person-years. Age was identified as a major risk factor towards HZ incidence which increase significantly in people >50 years of age. Hospitalization rates ranged from 3%-35.7%. The in-hospital HZ mortality rate ranged from 0%-36%. Overall, HZ mortality rates were found to be higher in females across all age groups and countries. The incidence of HZ complications (such as post-herpetic neuralgia, ophthalmic herpes zoster, and Ramsay Hunt syndrome) was higher in the immunosuppressed compared to the immunocompetent population. Acyclovir was the most frequently used therapy. Epidemiological data from Ministry of Health databases (Argentina, Brazil, Colombia, Chile y Mexico) and Institute for Health Metrics and Evaluation's Global Burden of Disease project reported stable rates of hospitalizations and deaths over the last 10 years. High-risk groups for HZ impose a considerable burden in LAC. They could benefit from directed healthcare initiatives, including adult immunization, to prevent HZ occurrence and its complications.

The Role of Autophagy in Varicella Zoster Virus Infection.

Autophagy is an evolutionary conserved cellular process serving to degrade cytosolic organelles or foreign material to maintain cellular homeostasis. Autophagy has also emerged as an important process involved in complex interactions with viral pathogens during infection. It has become apparent that autophagy may have either proviral or antiviral roles, depending on the cellular context and the specific virus. While evidence supports an antiviral role of autophagy during certain herpesvirus infections, numerous examples illustrate how herpesviruses may also evade autophagy pathways or even utilize this process to their own advantage. Here, we review the literature on varicella zoster virus (VZV) and autophagy and describe the mechanisms by which VZV may stimulate autophagy pathways and utilize these to promote cell survival or to support viral egress from cells. We also discuss recent evidence supporting an overall antiviral role of autophagy, particularly in relation to viral infection in neurons. Collectively, these studies suggest complex and sometimes opposing effects of autophagy in the context of VZV infection. Much remains to be understood concerning these virus-host interactions and the impact of autophagy on infections caused by VZV.

Severe infection including disseminated herpes zoster triggered by subclinical Cushing's disease: a case report.

BACKGROUND: Subclinical Cushing's disease (SCD) is defined by corticotroph adenoma-induced mild hypercortisolism without typical physical features of Cushing's disease. Infection is an important complication associated with mortality in Cushing's disease, while no reports on infection in SCD are available. To make clinicians aware of the risk of infection in SCD, we report a case of SCD with disseminated herpes zoster (DHZ) with the mortal outcome. CASE PRESENTATION: An 83-year-old Japanese woman was diagnosed with SCD, treated with cabergoline in the outpatient. She was hospitalized for acute pyelonephritis, and her fever gradually resolved with antibiotics. However, herpes zoster appeared on her chest, and the eruptions rapidly spread over the body. She suddenly went into cardiopulmonary arrest and died. Autopsy demonstrated adrenocorticotropic hormone-positive pituitary adenoma, renal abscess, and DHZ. CONCLUSIONS: As immunosuppression caused by SCD may be one of the triggers of severe infection, the patients with SCD should be assessed not only for the metabolic but also for the immunodeficient status.

[Granuloma annulare after herpes zoster: Wolf's isotopic response]. / Granuloma annulare na herpes zoster.

BACKGROUND: The term Wolf's isotopic response has been used to describe the occurrence of a new skin disorder at the site of another, unrelated and already healed skin disease. CASE DESCRIPTION: A 74-year-old man with type 2 diabetes mellitus and prostate carcinoma with osseous and lymphatic metastases developed a herpes zoster infection of the left shoulder after palliative radiation therapy of this area. After several months multiple lenticular erythematous papules and some plaques were seen at the previously infected location. The diagnosis granuloma annulare was confirmed by a punch biopsy. CONCLUSION: This case report will increase clinical awareness and will thereby prevent the prescription of unnecessary repeated antiviral medication.

Herpes Zoster and Subsequent Cancer Risk: A Nationwide Population-Based Cohort Study in Korea.

BACKGROUND: It is well known that an immunosuppressed status such as cancer is a risk factor for herpes zoster (HZ), but little is known about whether HZ affects cancer development. OBJECTIVES: This study aimed to investigate the association between HZ and subsequent cancer risk by cancer type. METHODS: We conducted a nationwide retrospective cohort study using the Korean National Health Insurance claims database. The study enrolled 1,568,818 patients: 784,409 diagnosed with HZ between 2010 and 2015 were included in the HZ group, and 784,409 matched controls without HZ were included in the non-HZ group, with 1:1 exact matching for age, sex, and index year. Hazard ratios (HRs) were calculated for the risk of cancers based on anatomical site according to the HZ status using the Cox proportional hazards regression models. RESULTS: During a mean follow-up period of 6 years, 22,235 and 22,316 patients in the HZ group and the non-HZ group, respectively, developed cancer (incidence rate: 7.6 vs. 7.7 per 1,000 person-years). After adjusting for age, sex, and comorbidities, the overall risk of cancers was slightly decreased in the HZ group compared with the non-HZ group (HR, 0.999; 95% confidence interval [CI], 0.98-1.02). In post hoc analyses on organ site, the HZ group had significantly increased risk of hematologic malignancies, including multiple myeloma (HR, 1.63; 95% CI, 1.37-1.95), leukemia (HR, 1.20; 95% CI, 1.03-1.39), and lymphoma (HR, 1.15; 95% CI, 1.02-1.30) compared with the non-HZ group. Conversely, the risk of cancers in the liver (HR, 0.87; 95% CI, 0.82-0.93) and larynx (HR, 0.73; 95% CI, 0.58-0.92) were significantly decreased in the HZ group compared with the non-HZ group. CONCLUSIONS: Although the risk of developing some hematological cancers increased in patients with HZ, solid cancers including liver and laryngeal cancers showed a negative association with HZ.

Clinicopathologic Features of Varicella Zoster Virus Infection of the Upper Gastrointestinal Tract.

Reactivation of latent varicella zoster virus (VZV) may be limited to a dermatome or involve multiple organs, including the gastrointestinal tract. Although gastrointestinal manifestations of disseminated zoster have been likened to those of herpes simplex virus (HSV), histologic features of VZV-related injury to the tubular gut are not well-documented. We performed this study to describe the clinicopathologic features of VZV-related gastrointestinal injury. We identified 6 such patients with VZV infection. All involved the upper gastrointestinal tract, affecting the esophagus (n=3), stomach (n=2), or both (n=1). All patients were immunocompromised adults with hematologic malignancies (n=5) or a heart transplant (n=1); 3 with hematologic malignancies had received stem cell transplants. Five patients had cutaneous and gastrointestinal zoster; 1 had gastrointestinal disease alone. When compared with 14 HSV-related esophagitis controls, there were several notable differences. VZV caused hemorrhagic ulcers with nodularity or erythema, whereas HSV produced round, shallow ulcers on a background of nearly normal mucosa (P=0.01). VZV-related ulcers featured fibrin-rich, pauci-inflammatory exudates compared with the macrophage-rich exudates of HSV (P=0.003). The cytopathic changes of VZV were present at all levels of the squamous epithelium, especially in a peripapillary distribution. In contrast, HSV inclusions were located in the superficial layers (P=0.003) and detached keratinocytes. Unlike HSV, VZV involved the stomach, producing hemorrhage accompanied by striking apoptosis in the deep glands. We conclude that VZV produces unique patterns of gastrointestinal injury that facilitate its diagnosis. Recognition of gastrointestinal VZV infection is important because it heralds potentially life-threatening disseminated disease.

A Case of Eosinophilic Pustular Folliculitis Associated With Herpes Zoster.

ABSTRACT: Patients with eosinophilic pustular folliculitis (EPF), a sterile eosinophilic infiltration of hair follicles, often present with papulopustules that tend to form annular plaques. Histopathologic examination revealed eosinophilic infiltration around the pilosebaceous units and eosinophilic microabscess formation. Although the pathogenesis of EPF is unknown, T-helper type 2 immune responses were suggested to be important based on their stimulating effect on the sebaceous glands. Here, we report the first case of EPF associated with herpes zoster, indicating that herpes zoster and EPF are correlated with T-helper type 2 immune responses.