Reflectance confocal microscopy for the early diagnosis of herpes zoster.

For herpes zoster (HZ) infection, early diagnosis and treatment are important in order to shorten the course of the disease and reduce sequelae, however, there is a lack of non-invasive diagnostic methods. Reflectance confocal microscopy (RCM) is a non-invasive technique often used to diagnose dyspigmented dermatosis, skin tumours, human papillomavirus infectious dermatosis, etc. To evaluate the clinical value of RCM for the early diagnosis of HZ. We collected RCM images from 30 HZ patients with typical vesicles in order to analyse their features. We then utilized RCM to analyse early lesions of another 12 HZ patients, who presented with localized erythema or papules, but not typical vesicles. In addition, we recruited one patient with HZ and observed the lesions over 14 days also using RCM. RCM images showed that the typical lesions of HZ mainly involved oedema of the spinous layer, intraepidermal blister formation, ballooning multinucleated giant (BMG) cells, and dermal papillary oedema. Among them, BMG cells were of specific diagnostic value. Early lesions of HZ patients without typical vesicles showed BMG cells under RCM. A few BMG cells were observed during the early stage of HZ. However, the number of BMG cells increased significantly as typical clustered blisters gradually appeared in the lesions. With the regression of the lesions, the number of BMG cells decreased gradually. RCM, with the advantages of being non-invasive, rapid, and convenient, has an important role in monitoring the evolution of HZ.

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.

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.

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.

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.

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.

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.

A Novel Human Skin Tissue Model To Study Varicella-Zoster Virus and Human Cytomegalovirus.

The herpesviruses varicella-zoster virus (VZV) and human cytomegalovirus (HCMV) are endemic to humans. VZV causes varicella (chicken pox) and herpes zoster (shingles), while HCMV causes serious disease in immunocompromised patients and neonates. More effective, less toxic antivirals are needed, necessitating better models to study these viruses and evaluate antivirals. Previously, VZV and HCMV models used fetal tissue; here, we developed an adult human skin model to study VZV and HCMV in culture and in vivo While VZV is known to grow in skin, it was unknown whether skin could support an HCMV infection. We used TB40/E HCMV and POka VZV strains to evaluate virus tropism in skin organ culture (SOC) and skin xenograft mouse models. Adult human skin from reduction mammoplasties was prepared for culture on NetWells or mouse implantation. In SOC, VZV infected the epidermis and HCMV infected the dermis. Specifically, HCMV infected fibroblasts, endothelial cells, and hematopoietic cells, with some infected cells able to transfer infection. VZV and HCMV mouse models were developed by subcutaneous transplantation of skin into SCID/beige or athymic nude mice at 2 independent sites. Viruses were inoculated directly into one xenograft, and widespread infection was observed for VZV and HCMV. Notably, we detected VZV- and HCMV-infected cells in the contralateral, uninoculated xenografts, suggesting dissemination from infected xenografts occurred. For the first time, we showed HCMV successfully grows in adult human skin, as does VZV. Thus, this novel system may provide a much-needed preclinical small-animal model for HCMV and VZV and, potentially, other human-restricted viruses.IMPORTANCE Varicella-zoster virus and human cytomegalovirus infect a majority of the global population. While they often cause mild disease, serious illness and complications can arise. Unfortunately, there are few effective drugs to treat these viruses, and many are toxic. To complicate this, these viruses are restricted to replication in human cells and tissues, making them difficult to study in traditional animal models. Current models rely heavily on fetal tissues, can be prohibitively expensive, and are often complicated to generate. While fetal tissue models provide helpful insights, it is necessary to study human viruses in human tissue systems to fully understand these viruses and adequately evaluate novel antivirals. Adult human skin is an appropriate model for these viruses because many target cells are present, including basal keratinocytes, fibroblasts, dendritic cells, and lymphocytes. Skin models, in culture and xenografts in immunodeficient mice, have potential for research on viral pathogenesis, tissue tropism, dissemination, and therapy.

Acute zoster plasma contains elevated amyloid, correlating with Aß42 and amylin levels, and is amyloidogenic.

Herpes zoster is associated with an increased dementia and neovascular macular degeneration risk and a decline in glycemic control in diabetes mellitus. Because amyloid is present and pathogenic in these diseases, we quantified amyloid, Aß40, Aß42, and amylin in 14 zoster and 10 control plasmas. Compared with controls, zoster plasma had significantly elevated amyloid that correlated with Aß42 and amylin levels and increased amyloid aggregation with addition of exogenous Aß42 or amylin. These results suggest that zoster plasma contains factor(s) that promotes aggregation of amyloidogenic peptides, potentially contributing to the toxic amyloid burden and explaining accelerated disease progression following zoster.

Herpes zoster granulomatous dermatitis in metastatic lung cancer treated with nivolumab: A case report.

Granulomatous dermatitis (GD) is the most common among a variety of skin reactions that may occur in the varicella-zoster virus (VZV) reactivation area. It is thought that the formation of granulomas may be the result of a delayed hypersensitivity reaction to viral envelope glycoproteins. Immune checkpoint inhibitors (ICIs), such as nivolumab stimulate T cells and promote hypersensitivity reactions, leading to the formation of granulomas in VZV wrapping proteins, thus triggering VZV-GD. Few cases of the use of ICIs in patients diagnosed with VZV-GD have been reported in the literature. Here, we report the clinical case of a patient with metastatic lung cancer which was treated with nivolumab who subsequently developed VZV-GD. Accurate clinical diagnosis and prompt treatment with antiviral agents have resulted in a complete resolution of the clinical picture. KEY POINTS: Significant findings Treatment with ICIs may result in VZV reactivation. Accurate differential diagnosis and early treatment led to the resolution of VZV-GD. WHAT THIS STUDY ADDS: Few cases of ICI and VZV reactivation have been reported in the literature. Full and timely resolution of VZV-GD allowed the continuation of ICI treatment.

Wolf's Isotopic Response after Herpes Zoster Infection: A Study of 24 New Cases and Literature Review.

Wolf's isotopic response refers to the occurrence of a new skin disease at the exact site of an unrelated skin disease that had previously healed. Various cutaneous lesions have been described after herpes zoster. This study included 24 patients with Wolf's isotopic response after herpes zoster infection, which presented as manifestations ranging from inflammatory disease to carcinoma. Histopathological examinations in 12 patients and immunohistochemical analyses in 10 patients allowed exploration of secondary microscopic changes in the lesions. CD4+/CD8+ T-cell ratios were normal and infiltrating cells included mast cells, eosinophils, and tumour cells. Our study has described additional patients with confirmed Wolf's isotopic response following herpes zoster infection; moreover, it has extended the spectrum of Wolf's isotopic response to include impetigo. We suggest Wolf's isotopic response classification categories for herpes zoster-associated Wolf's isotopic response. Additionally, clinicians should consider the possibilities of different diseases in Wolf's isotopic response, especially malignancies.