Conditions That Simulate the Environment of Atopic Dermatitis Enhance Susceptibility of Human Keratinocytes to Vaccinia Virus.

Individuals with underlying chronic skin conditions, notably atopic dermatitis (AD), are disproportionately affected by infections from members of the herpesviridae, papovaviridae, and poxviridae families. Many patients with AD experience recurrent, widespread cutaneous viral infections that can lead to viremia, serious organ complications, and even death. Little is known about how the type 2 inflammatory environment observed in the skin of AD patients impacts the susceptibility of epidermal cells (keratinocytes) to viral pathogens. Herein, we studied the susceptibility of keratinocytes to the prototypical poxvirus, vaccinia virus (VV)-the causative agent of eczema vaccinatum-under conditions that simulate the epidermal environment observed in AD. Treatment of keratinocytes with type 2 cytokines (IL-4 and -13) to simulate the inflammatory environment or a tight junction disrupting peptide to mirror the barrier disruption observed in AD patients, resulted in a differentiation-dependent increase in susceptibility to VV. Furthermore, pan JAK inhibition was able to diminish the VV susceptibility occurring in keratinocytes exposed to type 2 cytokines. We propose that in AD, the increased viral susceptibility of keratinocytes leads to enhanced virus production in the skin, which contributes to the rampant dissemination and pathology seen within patients.

Erupción variceliforme de Kaposi y enfermedad de Darier / Kaposi's varicelliform rash and Darier's disease

La erupción variceliforme de Kaposi es una infección cutánea diseminada, causada en la mayor parte de los casos por el virus Herpes simple tipo 1. Se suele presentar en pacientes con alteraciones preexistentes de la barrera cutánea, especialmente en niños con dermatitis atópica. Se comunica el caso de un paciente de 84 años, quien negaba enfermedades cutáneas previas, que consultó por lesiones dolorosas y pruriginosas, en la piel del tórax y el abdomen, de 3 semanas de evolución. Con sospecha de una enfermedad infecciosa viral, bacteriana, ampollar o neutrofílica, se realizó inmunofluorescencia directa para herpes, cultivo y biopsia de piel para estudio histológico. La inmunofluorescencia fue positiva para Herpes simple tipo 1 y el estudio histopatológico mostró cambios compatibles con infección herpética y enfermedad de Darier. La enfermedad de Darier es una genodermatosis infrecuente que se suele manifestar en la adolescencia. Si bien su diagnóstico en la ancianidad es excepcional, este caso ilustra que se debe considerar en todos los pacientes que presenten erupción variceliforme. (AU)

Kaposi's varicelliform rash is a disseminated cutaneous infection, caused by Herpes virus 1. It usually presents in patients with pre-existing skin barrier disorders, especially in children with atopic dermatitis. We report the case of an 84-year-old patient, who reported having no previous skin diseases, who consulted for painful, itchy, 3-week-old skin lesions. As we suspected viral, bacterial, bullous or neutrophilic disease, direct immunofluorescence, culture, and skin biopsy for histological study were performed. Immunofluorescence was positive for Herpes simplex type 1 and the histopathological study showed changes compatible with herpetic infection and Darier's disease. Darier's disease is a rare genodermatosis that usually manifests in adolescence. Although its diagnosis in old age is anecdotal, it should be considered in patients with a varicelliform rash. (AU)

Atypical Varicella-Zoster Kaposi Varicelliform Eruption in Sézary Syndrome.

Patients with mycosis fungoides experience considerable morbidity and mortality from secondary bacterial and viral infections. Staphylococcus aureus, ß-hemolytic streptococci, herpes simplex virus, and herpes zoster virus remain the most common infectious pathogens in this group of patients. With depressed cellular immunity and diminished skin barrier as the main precipitating risk factors, immunocompromised patients can often present with an atypical presentation of a common dermatologic condition. The case herein discusses a clinically atypical nonvesicular Kaposi varicelliform eruption secondary to a varicella-zoster virus in a patient with Sézary syndrome. Concurrent polypharmacy in these patients is also a risk factor for development of drug hypersensitivity reactions. However, given their immunocompromised status, first and foremost, a careful inspection should be made of every atypical skin eruption in search of an infectious etiology, and afterward, an appropriate treatment should be promptly initiated.

Induction, treatment and prevention of eczema vaccinatum in atopic dermatitis mouse models.

Eczema vaccinatum is a severe and occasionally lethal complication of smallpox vaccine, characterized by systemic viral dissemination, distant from the initial inoculation site of the vaccine. A major risk factor for eczema vaccinatum is a background of atopic dermatitis, a chronic, common allergic, relapsing disorder, manifested by dry and inflamed skin, itchy rash, Th2 biased immune response and hypersensitivity to various antigens. Unlike the severe manifestations of eczema vaccinatum in humans, current models present only mild symptoms that limits examination of potential therapeutics for eczema vaccinatum. The atopic dermatitis and eczema vaccinatum models we present here, are the first to simulate the severity of the diseases in humans. Indeed, dermatitic mice display persistent severe dermatitis, characterized by dry and inflamed skin with barrier dysfunction, epidermal hyperplasia and significant elevation of serum IgE. By exposing atopic dermatitis mice to ectromelia virus, we generated eczema vaccinatum that mimic the human disease better than known eczema vaccinatum models. Similarly to humans, eczematous mice displayed enlarged and disseminated skin lesions, which correlated with elevated viral load. Cidofovir and antiviral antibodies conferred protection even when treatment started at a late eczematous stage. Moreover, we are the first to demonstrate that despite a severe background of atopic dermatitis, modified vaccinia Ankara virus (MVA) vaccination protects against lethal ectromelia virus exposure. We finally show that protection by MVA vaccination is dependent on CD4+ T cells and is associated with significant activation of CD8+ cytotoxic T cells and induction of humoral immunity.

Defective natural killer cell activity in a mouse model of eczema herpeticum.

BACKGROUND: Patients with atopic dermatitis (AD) are susceptible to several viruses, including herpes simplex virus (HSV). Some patients experience 1 or more episodes of a severe skin infection caused by HSV termed eczema herpeticum (EH). There are numerous mouse models of AD, but no established model exists for EH. OBJECTIVE: We sought to establish and characterize a mouse model of EH. METHODS: We infected AD-like skin lesions with HSV1 to induce severe skin lesions in a dermatitis-prone mouse strain of NC/Nga. Gene expression was investigated by using a microarray and quantitative PCR; antibody titers were measured by means of ELISA; and natural killer (NK) cell, cytotoxic T-cell, regulatory T-cell, and follicular helper T-cell populations were evaluated by using flow cytometry. The role of NK cells in HSV1-induced development of severe skin lesions was examined by means of depletion and adoptive transfer. RESULTS: Inoculation of HSV1 induced severe erosive skin lesions in eczematous mice, which had an impaired skin barrier, but milder lesions in small numbers of normal mice. Eczematous mice exhibited lower NK cell activity but similar cytotoxic T-cell activity and humoral immune responses compared with normal mice. The role of NK cells in controlling HSV1-induced skin lesions was demonstrated by experiments depleting or transferring NK cells. CONCLUSION: A murine model of EH with an impaired skin barrier was established in this study. We demonstrated a critical role of defective NK activities in the development of HSV1-induced severe skin lesions in eczematous mice.

Kaposi-Juliusberg varicelliform eruption in patients suffering from Darier-White Disease: a case report and review of the literature.

Darier-White Disease (DW), otherwise known as keratosis follicularis, is a rare genodermatosis with autosomal dominant inheritance, characterized by loss of adhesion between epidermal cells and abnormal keratinization. The distinctives lesions of DW Disease include rough papules in seborrheic areas, palmoplantar pits, mucosal involvement, and nail changes. DW Disease can be occasionally associated with bacterial complications, but rarely with viral ones. Kaposi's varicelliform eruption (KVE) is a secondary herpes simplex virus infection that affects patients in the setting of primary dermatologic conditions. KVE, frequently misdiagnosed as impetigo, can be severe, progressing to disseminated infections and potentially life threatening. It occurs with a variety of skin disorders, although association with DW Disease has rarely been reported in the literature. This report describes a case of KVE in a patient suffering from DW Disease, focusing on its clinical course. A review of the literature on KVE including disease associations, pathogenesis, and treatment has been also reported.

Filaggrin deficiency promotes the dissemination of cutaneously inoculated vaccinia virus.

BACKGROUND: Eczema vaccinatum is a life-threatening complication of smallpox vaccination in patients with atopic dermatitis (AD) characterized by dissemination of vaccinia virus (VV) in the skin and internal organs. Mutations in the filaggrin (FLG) gene, the most common genetic risk factor for AD, confer a greater risk for eczema herpeticum in patients with AD, suggesting that it impairs the response to cutaneous viral infections. OBJECTIVE: We sought to determine the effects of FLG deficiency on the response of mice to cutaneous VV inoculation. METHODS: VV was inoculated by means of scarification of unsensitized skin or skin topically sensitized with ovalbumin in FLG-deficient flaky tail (ft/ft) mice or wild-type (WT) control mice. The sizes of primary and satellite skin lesions were measured, and hematoxylin and eosin staining was performed. VV genome copy numbers and cytokine mRNA levels were measured by using quantitative PCR. RESULTS: VV inoculation in unsensitized skin of ft/ft mice, independent of the matted hair mutation, resulted in larger primary lesions, more abundant satellite lesions, heavier viral loads in internal organs, greater epidermal thickness, dermal cellular infiltration, and higher local Il17a, Il4, Il13, and Ifng mRNA levels than in WT control mice. VV inoculation at sites of topical ovalbumin application amplified all of these features in ft/ft mice but had no detectable effect in WT control mice. The number of satellite lesions and the viral loads in internal organs after cutaneous VV inoculation were significantly reduced in both unsensitized and topically sensitized ft/ftxIl17a(-/-) mice. CONCLUSION: FLG deficiency predisposes to eczema vaccinatum. This is mediated primarily through production of IL-17A.

Kaposi varicelliform eruption in patients with Darier disease: a 20-year retrospective study.

BACKGROUND: Kaposi varicelliform eruption (KVE), or herpes simplex virus (HSV) superinfection of pre-existing skin lesions, may complicate Darier disease. OBJECTIVE: We sought to compare the clinical features and outcomes of patients with Darier disease who developed KVE superinfection with those who did not. METHODS: A 20-year retrospective analysis of 79 patients with Darier disease treated at our institution was performed. RESULTS: Eleven (14%) patients developed KVE, of whom 45% required hospitalization for their skin disease during the follow-up period. Patients with KVE had more severe Darier disease (P = .030) and were more likely to be hospitalized (P = .015). HSV was detected in erosions without concomitant vesicles or pustules in 64% of confirmed cases. In all, 23 (55%) patients with erosions had HSV testing pursued. LIMITATIONS: Retrospective study design is a limitation. CONCLUSION: The majority of KVE occurs in painless or painful erosions that may also appear impetiginized without vesicle or pustule formation. As HSV superinfection is correlated with severe Darier disease and risk for hospitalization, increased recognition of this phenomenon may lead to better patient outcomes.