Human genetic dissection of papillomavirus-driven diseases: new insight into their pathogenesis.

Human papillomaviruses (HPVs) infect mucosal or cutaneous stratified epithelia. There are 5 genera and more than 200 types of HPV, each with a specific tropism and virulence. HPV infections are typically asymptomatic or result in benign tumors, which may be disseminated or persistent in rare cases, but a few oncogenic HPVs can cause cancers. This review deals with the human genetic and immunological basis of interindividual clinical variability in the course of HPV infections of the skin and mucosae. Typical epidermodysplasia verruciformis (EV) is characterized by ß-HPV-driven flat wart-like and pityriasis-like cutaneous lesions and non-melanoma skin cancers in patients with inborn errors of EVER1-EVER2-CIB1-dependent skin-intrinsic immunity. Atypical EV is associated with other infectious diseases in patients with inborn errors of T cells. Severe cutaneous or anogenital warts, including anogenital cancers, are also driven by certain α-, γ-, µ or ν-HPVs in patients with inborn errors of T lymphocytes and antigen-presenting cells. The genetic basis of HPV diseases at other mucosal sites, such as oral multifocal epithelial hyperplasia or juvenile recurrent respiratory papillomatosis (JRRP), remains poorly understood. The human genetic dissection of HPV-driven lesions will clarify the molecular and cellular basis of protective immunity to HPVs, and should lead to novel diagnostic, preventive, and curative approaches in patients.

Dermatological manifestations in patients with human T-cell lymphotropic virus at a reference service in Amazon.

INTRODUCTION: Individuals infected with the human T-cell lymphotropic virus type 1 (HTLV-1) commonly present skin lesions, which may be a warning sign for the diagnosis of infection. This study describes the most prevalent skin manifestations in HTLV carriers attended at the clinic of Núcleo de Medicina Tropical (NMT) of the Universidade Federal do Pará (UFPA) in Belém, Pará, Brazil. METHODS: This is a study of a series of cases of patients infected with human T-cell lymphotropic virus types 1 and 2 (HTLV-1/2) treated at NMT UFPA between 1999 and 2016. A descriptive analysis of data was applied. RESULTS: Among 788 surveyed medical records in the service, 15.10% (n = 119) were referred to the dermatology clinic. From the series of cases that presented with skin lesions, 66.39% were female and 33.61% were male, and the average age of this group was 48 years. There was a predominance of patients with noninfectious inflammatory manifestations (64.2%), followed by infectious ones (24.6%), and 1.58% with lymphoproliferative diseases. As for the group of lesions, 45.26% of the erythematous-squamous type were observed, followed by dyschromia (24.21%), and eczematous (14.74%). One patient with a diagnosis of adult T-cell leukemia/lymphoma, another with parapsoriasis, and four with infective dermatitis are highlighted. CONCLUSION: Skin disorders in the HLTV positive patient are important causes of referral to the dermatologist with etiological and skin lesions groups diversity. In the series of cases studied, lymphoproliferatives diseases and infective dermatitis associated with HTLV-1 were presented as a challenge for the diagnosis and clinical management of these patients.

Infective dermatitis associated with HTLV-1 infection in a girl from Trinidad: Case report and review of literature.

Infective dermatitis (ID) associated with Human T-cell leukemia virus type-1 (HTLV-1) is a rare form of severe superinfected eczema seen mostly in the Caribbean islands and Latin America. Although rapid response to antibiotic treatment is observed, patients should be monitored for development of complications associated with this retroviral infection, including T-cell leukemia/lymphoma (ATLL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Infective dermatitis is rarely seen in the United States and therefore may be under-recognized by physicians unfamiliar with this condition. Herein, we present an additional case report of an ID associated with HTLV-1 in an 11-year-old girl from Trinidad.

Spatio-temporal dynamics and aetiology of proliferative leg skin lesions in wild British finches.

Proliferative leg skin lesions have been described in wild finches in Europe although there have been no large-scale studies of their aetiology or epizootiology to date. Firstly, disease surveillance, utilising public reporting of observations of live wild finches was conducted in Great Britain (GB) and showed proliferative leg skin lesions in chaffinches (Fringilla coelebs) to be widespread. Seasonal variation was observed, with a peak during the winter months. Secondly, pathological investigations were performed on a sample of 39 chaffinches, four bullfinches (Pyrrhula pyrrhula), one greenfinch (Chloris chloris) and one goldfinch (Carduelis carduelis) with proliferative leg skin lesions and detected Cnemidocoptes sp. mites in 91% (41/45) of affected finches and from all species examined. Fringilla coelebs papillomavirus (FcPV1) PCR was positive in 74% (23/31) of birds tested: a 394 base pair sequence was derived from 20 of these birds, from all examined species, with 100% identity to reference genomes. Both mites and FcPV1 DNA were detected in 71% (20/28) of birds tested for both pathogens. Histopathological examination of lesions did not discriminate the relative importance of mite or FcPV1 infection as their cause. Development of techniques to localise FcPV1 within lesions is required to elucidate the pathological significance of FcPV1 DNA detection.

A Case-Control Study in Primary Care Settings on the Roles of Dermatoscopy in Infectious Diseases Affecting the Skin, Part 1: Viral and Bacterial Infections.

We aimed to investigate roles of dermatoscopy in skin infections, with Part 1 of our report covering viral and bacterial infections. A case-control study was conducted on the medical records of all patients with skin infections who had had dermatoscopy performed over a period of 3 months. Our control participants were all patients with skin infections in two 3-month periods, and sex-pair-matched patients with the same infections, who had not undergone dermatoscopy. Records of 523 study subjects were analyzed. Our first new finding was that dermatoscopy brought forward the diagnosis of herpes zoster by 1.62 days (95% confidence interval [CI] 0.29 to 0.34 days; z-score -2.18). Second, dermatoscopy facilitated the diagnosis of genital (P<.01) and small extragenital risk ratio [RR] 1.28, 95% CI 1.03 to 1.59) viral warts. Third, patients with genital herpes and/or genital warts and/or genital molluscum contagiosum diagnosed by clinical examination and dermatoscopy were significantly more willing to pay US$300 to investigate for other sexually transmitted infections (STIs) (RR 2.52, 95% CI 1.32 to 3.18), and bring partners for investigation (RR 1.32, 95% CI 1.12 to 1.55), compared to patients diagnosed by clinical examination alone. We performed dermatoscope-guided laser ablation on viral warts, and dermatoscopy-guided excisional biopsy to confirm molluscum contagiosum. We conclude that dermatoscopy contributes to the diagnosis of some viral and bacterial infections. In addition, it may modify the help-seeking behaviour of patients with STIs.

Mouse papillomavirus infection persists in mucosal tissues of an immunocompetent mouse strain and progresses to cancer.

Mouse papillomavirus has shown broad tissue tropism in nude mice. Previous studies have tested cutaneous infections in different immunocompromised and immunocompetent mouse strains. In the current study, we examined mucosal infection in several immunocompetent and immunocompromised mouse strains. Viral DNA was monitored periodically by Q-PCR of lavage samples. Immunohistochemistry and in situ hybridization were used to determine viral capsid protein and viral DNA respectively. All athymic nude mouse strains showed active infections at both cutaneous and mucosal sites. Interestingly, NOD/SCID mice, which have a deficiency in T, B, and NK cells, showed minimal disease at cutaneous sites but developed persistent infection at the mucosal sites including those of the anogenital region and the oral cavity. Three strains of immunocompetent mice supported mucosal infections. Infections of the lower genital tract in heterozygous (immunocompetent) mice of the NU/J strain progressed to high grade dysplasia and to carcinoma in situ. Anti-MmuPV1 neutralizing antibodies were detected in the sera of all immunocompetent animals. Our findings demonstrate that the mucosae may be the preferred sites for this virus in mice. The mouse model is expected to be a valuable model for the study of mucosal papillomavirus disease, progression, and host immune control.

Skin diseases of the vulva: Infectious diseases.

A multitude of infectious diseases of viral (genital herpes, herpes zoster, genital warts and molluscum contagiosum), bacterial (syphilis, chancroid, lymphogranuloma venereum, donovanosis, erysipelas, cellulitis and necrotising fasciitis, folliculitis, impetigo, bartholin gland abscess, trichomycosis and erythrasma), fungal (candidiasis and dermatophytosis) and parasitic (pediculosis pubis) origin may affect the vulvar area. Herein, we review the infections and their skin manifestations in the vulvar area.

Human papilloma virus dermatosis in human immunodeficiency virus-positive patients: A 14-year retrospective study in 965 patients. / Dermatosis por virus de papiloma humano (VPH) en pacientes infectados por el virus de la inmunodeficiencia humana (VIH): estudio retrospectivo de 965 pacientes durante 14 años.

INTRODUCTION: The incidence of the human papilloma virus (HPV) has not dropped in HIV-positive patients despite the discovery of antiretroviral therapy (ART). Our goal is to assess the prevalence of HPV in HIV patients and its relationship with the epidemiological and virological characteristics of HIV patients. PATIENTS AND METHODS: Retrospective cohort of 965 patients diagnosed with HIV from 1998 to 2012. We analyzed patients' demographic factors and factors related to the HPV. RESULTS: Of the 965 patients examined, 333 consulted a dermatologist. Of these, 52 patients had genital warts (15.6%), 43 had common warts (12.9%) and 8% had both conditions. In total, 28.5% of patients had a skin lesion caused by HPV. DISCUSSION AND CONCLUSION: This is the first longitudinal observational study carried out on HIV-positive patients in the era of ART in which HPV infection is the most common skin pathology. We observed a similar trend in countries with access to ART. This study spreads awareness on the importance of preventing HPV and the difficulty of treating it in HIV-positive patients.

[Cutaneous infection with Orthopoxvirus bovis in a German Spaniel]. / Kutane Infektion mit Orthopoxvirus bovis bei einem Wachtelhund.

A 4-year-old female German Spaniel was presented with anorexia. Clinically, the dog showed papular to ulcerative lesions on the nasal planum and on the tongue. Hematological, bacteriological and mycological examinations did not contribute any evidence for the etiology of the lesions. Histopathological examination of skin biopsies revealed a proliferative dermatitis and folliculitis with hydropic degeneration of keratinocytes and cytoplasmatic inclusion bodies. Cowpox virus antigen was detected by immunohistochemistry, and electron microscopy showed pox virus particles in the cytoplasm of the epithelial cells. DNA of Orthopoxvirus bovis was identified by polymerase chain reaction. Consequently, in dogs with papular to ulcerative lesions in the face or on the tongue, infection with cowpoxvirus should be considered as an etiological differential diagnosis. Infected dogs represent a potential risk of infection for humans and other animals with close contact.

Epstein-Barr virus: dermatologic associations and implications: part I. Mucocutaneous manifestations of Epstein-Barr virus and nonmalignant disorders.

Epstein-Barr virus (EBV) is a ubiquitous virus that has been implicated in a wide range of human diseases, many of which have mucocutaneous manifestations. As a member of the herpesviridae family, EBV causes lifelong infection by establishing latency in B lymphocytes. An intact immune response is critical in preventing progression of EBV disease, and the clinical manifestations of infection are dependent on the intricate relationship between virus and host immune system. This review provides a comprehensive overview of the epidemiology, pathophysiology, and diagnostic testing in EBV infection. In part I of this continuing medical education article, the mucocutaneous manifestations of EBV infection are reviewed with an emphasis on pathophysiology and management.

Risk factors for complicated varicella infection in pediatric oncology patients at a tertiary health care facility in Pakistan.

INTRODUCTION: Varicella zoster infection (VZI) is well recognized as a potential cause of morbidity and mortality in immunocompromised pediatric oncology patients (POP). The purpose of this study was to describe the clinical profile and risk factors for complications and outcomes of VZI in POP treated with acyclovir. METHODOLOGY: Medical records of all POP with a discharge diagnosis of VZI over a period of seven years (2005-2011) were reviewed. The demographic features, underlying malignancy, risk factors for VZI, complications, and outcomes were recorded. RESULTS: Thirty-six POP with VZI were identified. Leukemia was the most common underlying malignancy (n = 20, 58.8%), followed by lymphoma (n = 7, 20.6%) and solid organ tumors (n = 7, 20.6%). Most of the cases (41%) were observed in children under five. All patients were treated with acyclovir. Varicella-related complications developed in 10 (29%) patients. The most frequent complication was bloodstream infection (n = 3, 8.8%), followed by pneumonia (n = 2, 5.9%), skin infection (n = 2, 5.9%), hepatitis, renal failure, and encephalitis. Independent risk factors associated with complications were age < five years, weight for age < fifth percentile, delay in seeking care (> seven days after onset of symptoms) and severe neutropenia (ANC < 500/cm). One child died secondary to varicella encephalitis. CONCLUSION: Our data suggests that young age, poor health-seeking behavior, severe neutropenia, and being underweight are the major risk factors for the development of varicella-related complications in POP in developing countries. These complications could be favorably modified through active immunization of immunocompetent children.

Detection of six novel papillomavirus sequences within canine pigmented plaques.

In dogs, papillomaviruses are thought to cause oral and cutaneous papillomas and pigmented plaques. Eight canine papillomaviruses have been fully sequenced to date. Four of these canine papillomaviruses, including Canis familiaris papillomavirus (CPV)-3, CPV-4, CPV-5, and CPV-8, were amplified from pigmented plaques. Given the identification of several different canine papillomaviruses within pigmented plaques, it is likely that there are additional papillomavirus sequences that have not been previously identified. The aim of the present study was to amplify papillomavirus DNA from pigmented plaques and identify potentially novel papillomavirus sequences through nucleotide sequence analysis. Polymerase chain reaction was used to amplify DNA sequences of the papillomavirus L1 gene from 27 pigmented plaques. Identification of novel papillomavirus sequences was based on less than 90% shared DNA homology to any known papillomavirus. DNA from 10 different papillomaviruses was identified within the pigmented plaques, including 6 putative novel papillomavirus sequences. CPV-4 was detected within 41% (11/27) of the pigmented plaques, while CPV-5 was identified within 2 pigmented plaques and CPV-3 within a single pigmented plaque. A previously identified novel papillomavirus sequence was identified within 2 pigmented plaques. The remaining 11 pigmented plaques contained 6 papillomavirus DNA sequences that have not been previously reported. These putative novel PV sequences were most similar to the canine papillomaviruses that have been detected within canine pigmented plaques.

Geriatric dermatoses: a clinical review of skin diseases in an aging population.

Geriatric dermatoses are a challenging job for the physician in terms of diagnosis, management, and followup. Since skin of the elderly population is going through a lot of changes from both an intrinsic and extrinsic point of view, it is imperative for the physician to have a better understanding of the pathophysiology of geriatric skin disorders and their specific management, which differs slightly from an adult population. This review focuses on a brief introduction to the pathophysiological aspects of skin disorders in elderly, the description of some common geriatric skin disorders and their management and the new emerging role of psychodermatological aspects of geriatric dermatoses is also discussed. At the end, ten multiple choice questions are also added to further enhance the knowledge base of the readers.

Infective dermatitis associated with human T-cell lymphotropic virus type 1: evaluation of 42 cases observed in Bahia, Brazil.

BACKGROUND: Infective dermatitis associated with human T-cell lymphotropic virus type 1 (HTLV-1; IDH) is a chronic recurrent eczema affecting HTLV-1-infected children. The epidemiological and dermatological characteristics of IDH are described, and their principal diagnostic criteria are reevaluated. METHODS: Forty-two patients were included: 40 patients serologically positive for HTLV-1 and 2 seronegative patients who tested positive in polymerase chain reaction (PCR) assays. RESULTS: The mean age at onset of the disease was 2.6 ± 2.4 years (range, 2 months-11 years). The mean duration of breast-feeding was 24.2 months. The lesions were erythematous, scaly, and crusted, always affecting the scalp and retroauricular regions. Crusting of the nostrils was observed in 64.3% of the patients. Of the 36 patients followed up, 23 had the active disease. The age at which IDH disappeared in the others was 10-20 years. CONCLUSIONS: The onset of IDH may occur earlier than reported in the literature. The scalp and retroauricular regions are always affected, and lesions are invariably present in ≥3 areas. Crusting of the nostrils cannot be considered an obligatory factor for the diagnosis of IDH. The recurring nature of IDH was a characteristic found in all cases. Patients with classic IDH lesions who are serologically negative should be investigated by PCR. Therefore, the indispensable criteria for diagnosis are (1) presence of erythematous-scaly, exudative, and crusted lesions involving ≥3 areas, including the scalp and retroauricular regions; (2) recurring nature of the lesions; and (3) a finding of HTLV-1 infection by serology or molecular biology.

Accelerated dendritic cell differentiation from migrating Ly6C(lo) bone marrow monocytes in early dermal West Nile virus infection.

No study has investigated the participation of Ly6C(+) monocytes in the earliest phase of skin infection with the mosquito-borne West Nile virus. In a novel murine model mimicking natural dermal infection, CCL2-dependent bone marrow (BM)-derived monocyte migration, differentiation into Ly6C(+) dendritic cells (DC), and accumulation around dermal deposits of infected fibroblasts by day 1 postinfection were associated with increasing numbers of monocyte-derived TNF/inducible NO synthase-producing DC by day 2 postinfection in draining auricular lymph nodes (ALN). Adoptive transfer demonstrated simultaneous migration of bone marrow-derived Ly6C(lo) monocytes to virus-infected dermis and ALN, where they first become Ly6C(hi) DC within 24 h and then Ly6C(lo) DC by 72 h. DC migration from the infected dermis to the ALN derived exclusively from Ly6C(lo) BM monocytes. This demonstrates that Ly6C(hi) and Ly6C(lo) BM-derived monocytes have different fates in vivo and suggests that BM may be a reservoir of preinflammatory monocytes for rapid deployment as inflammatory DC during virus infection.

EBV positive mucocutaneous ulcer--a study of 26 cases associated with various sources of immunosuppression.

We describe a series of Epstein Barr virus (EBV)-positive circumscribed, ulcerative lesions associated with various types of immunosuppression (IS). The study group (26 patients) comprised 10 males and 16 females, median age 77 years (range 42 to 101). IS in 9 cases included azathioprine (AZA), methotrexate (MTX) or cyclosporin-A (CyA). Seventeen patients had age-related immunosenescence. Patients presented with isolated sharply circumscribed ulcers involving oropharyngeal mucosa (16), skin (6), and gastrointestinal tract (4). Lesions were histologically characterized by a polymorphous infiltrate and atypical large B-cell blasts often with Hodgkin/Reed-Sternberg (HRS) cell-like morphology. The B cells showed strong CD30 and EBER positivity, some with reduced CD20 expression, in a background of abundant T cells. CD15 was positive in 43% of cases (10/23). The pathologic features were identical regardless of the anatomic site or cause of IS. Polymerase chain reaction revealed 39% (7/18) clonal Ig gene rearrangements with 38% (6/16) and 31% (5/16) clonal and restricted T-cell patterns, respectively. Twenty-five percent of patients (5/20) received standard chemotherapy and/or radiotherapy. Forty-five percent (9/20) regressed spontaneously with no treatment and 15% (3/20) were characterized by a relapsing and remitting course. All of the iatrogenic lesions (6/6) with available follow-up responded to reduction of IS. All patients achieved complete remission with no disease-associated deaths over a median follow-up period of 22 months (range 3 to 72). We propose EBV-positive mucocutaneous ulcer as a newly recognized clinicopathologic entity with Hodgkin-like features and a self-limited, indolent course, generally responding well to conservative management. Association with various forms of IS implies a common pathogenetic mechanism. The localized nature of the disease may be owing to a minimal and localized lapse in immunosurveillance over EBV.