Lessons from dermatology about inflammatory responses in Covid-19.

The SARS-Cov-2 is a single-stranded RNA virus composed of 16 non-structural proteins (NSP 1-16) with specific roles in the replication of coronaviruses. NSP3 has the property to block host innate immune response and to promote cytokine expression. NSP5 can inhibit interferon (IFN) signalling and NSP16 prevents MAD5 recognition, depressing the innate immunity. Dendritic cells, monocytes, and macrophages are the first cell lineage against viruses' infections. The IFN type I is the danger signal for the human body during this clinical setting. Protective immune responses to viral infection are initiated by innate immune sensors that survey extracellular and intracellular space for foreign nucleic acids. In Covid-19 the pathogenesis is not yet fully understood, but viral and host factors seem to play a key role. Important points in severe Covid-19 are characterized by an upregulated innate immune response, hypercoagulopathy state, pulmonary tissue damage, neurological and/or gastrointestinal tract involvement, and fatal outcome in severe cases of macrophage activation syndrome, which produce a 'cytokine storm'. These systemic conditions share polymorphous cutaneous lesions where innate immune system is involved in the histopathological findings with acute respiratory distress syndrome, hypercoagulability, hyperferritinemia, increased serum levels of D-dimer, lactic dehydrogenase, reactive-C-protein and serum A amyloid. It is described that several polymorphous cutaneous lesions similar to erythema pernio, urticarial rashes, diffuse or disseminated erythema, livedo racemosa, blue toe syndrome, retiform purpura, vesicles lesions, and purpuric exanthema or exanthema with clinical aspects of symmetrical drug-related intertriginous and flexural exanthema. This review describes the complexity of Covid-19, its pathophysiological and clinical aspects.

Systemic sporotrichosis in an alcoholic patient

Abstract A 44-year-old male patient presented with nodules that evolved with inflammation, following drainage of seropurulent secretion and ulceration. The patient had a 6 year-history of alcohol addiction and reported contact with cats. At the physical examination, the patient had skin-colored and erythematous nodules, and ulcers covered with thick, blackened crusts on the face, trunk and limbs. A culture of a nodule fluid revealed growth of Sporotrix sp. He also had pulmonary involvement and therefore the disease was classified as systemic sporotrichosis, a rare form that usually affect patients infected with HIV. Chronic alcohol abuse was considered the factor of immunosuppression for the patient.

Systemic sporotrichosis in an alcoholic patient.

A 44-year-old male patient presented with nodules that evolved with inflammation, following drainage of seropurulent secretion and ulceration. The patient had a 6 year-history of alcohol addiction and reported contact with cats. At the physical examination, the patient had skin-colored and erythematous nodules, and ulcers covered with thick, blackened crusts on the face, trunk and limbs. A culture of a nodule fluid revealed growth of Sporotrix sp. He also had pulmonary involvement and therefore the disease was classified as systemic sporotrichosis, a rare form that usually affect patients infected with HIV. Chronic alcohol abuse was considered the factor of immunosuppression for the patient.

Case Report: Acute Transverse Myelitis after Zika Virus Infection.

We report here one case of Zika virus (ZIKV) infection associated with auto-immunity directed against the central nervous system in a Brazilian woman who developed acute transverse myelitis 9 days after recovery from an acute episode of fever with generalized erythema. Imaging of the spinal cord showed an elongated area on the T1-T10 level with gadolinium uptake. The diagnostic of the ZIKV infection was confirmed by cerebrospinal fluid and serum analysis. This patient had serum positivity for autoantibodies against myelin oligodendrocyte glycoprotein (MOG), a specific antibody against the myelin sheath. We propose that a direct central nervous system infection by ZIKV could lead to a specific auto-immunity against MOG protein.

Llega la primavera y florecen los eritemas polimorfos solares / Spring arrives and with it the polymorphous light eruption

El eritema polimorfo solar es la fotodermatosis más frecuente y suele aparecer en primavera con la primera exposición intensa al sol. Sus manifestaciones cutáneas son variadas y el diagnóstico se basa en la clínica junto al antecedente de exposición solar. En los casos leves, la fotoprotección suele ser suficiente para el control de la enfermedad, pero en formas más graves se requieren otras terapéuticas, como corticoides, antihistamínicos, o fototerapia, que genera una "fotoadaptación" de las áreas de piel afectadas. Presentamos un caso típico de erupción polimorfa solar que respondió de forma adecuada a medidas de fotoprotección. (AU)

The polymorphic solar eruption is the most frequent photodermatosis, and usually appears in spring with the first intense exposure to the sun. It has multiple cutaneous manifestations, and its diagnosis is based on the clinic and the antecedent of solar exposition. In mild cases, photoprotection is usually enough to control the disease, but in more severe forms, other therapies are required, such as corticosteroids, antihistamines, or phototherapy to generate a "photo-adaptation" of the affected skin areas. We present a typical case of polymorphic solar eruption that responded adequately to photoprotection measurements. (AU)

Annular erythema associated with anti-Ro/SS-A and anti-La/SS-B antibodies: a new case in a Hispanic patient.

We describe an 18 year-old male patient who was anti-Ro/SS-A and anti-La/SS-B positive and presented with recurrent annular plaques on the trunk, arms, face, and scalp with evidence of associated patchy alopecia. The skin biopsy revealed a superficial perivascular and periappendegeal lymphocytic infiltrate and focal areas of vacuolar alteration and smudging of the dermoepidermal junction. The patient also presented with a history of xerophthalmia. Skin lesions as well as sicca symptoms responded to antimalarial treatment with hydroxychloroquine. This case demonstrates a new case of annular erythema indistinguishable from those previously described in patients of Asian descent occurring in a Hispanic patient.

Eritema elevatum diutinum e infección por HIV / Erythema elevatum diutinun and HIV infection

El eritema elevatum diutinum (EED) es una forma localizada, crónica e infrecuente de vasculitis leucocitoclástica cutánea, caracterizada clínicamente por lesiones papulonodulares de color eritematovioláceo, pardas o amarillentas. Histopatológicamente evoluciona hacia una fibrosis concéntrica. Su causa es desconocida, pero se presume que se debe al depósito de inmunocomplejos en los vasos. Se lo asocia a múltiples enfermedades y también a HIV. Describimos el primer paciente con esta asociación en la Argentina, actualizamos el tema efectuando una revisión bibliográfica y confrontamos las características clínicas, histopatológicas, inmunológicas y terapéuticas de nuestra paciente con los pacientes de la literatura.

Immunopathologic study of erythema dyschromicum perstans (ashy dermatosis).

Erythema dyschromicum perstans (EDP) is a pigmentary disease of unknown etiology in which damage to basal cells is thought to be mediated by adhesion molecules. The aim of this study was to characterize the histopathology and immunopathology of EDP. Forty-three patients from Medellín, Colombia, with the diagnosis of EDP were evaluated. Skin biopsy specimens were obtained for histopathology and immunohistochemistry, using monoclonal antibodies directed against the following markers: CD4, CD8, CD56, CD1a, CD68, CLA, HLA-DR, ICAM-1 and LFA-1alpha. A dermal lymphocytic infiltrate was observed in all cases, with a perivascular location in 86%. Other histologic features included melanophages in all specimens, vacuolization of the basement membrane zone (BMZ) 58% and exocytosis of lymphocytes (53.5%). The mean number of total leukocytes was 1510 cells mm-2 of tissue. There was a predominance of CD8+ T lymphocytes in the dermis and HLA-DR+, ICAM-1+ keratinocytes in the epidermis. Exocytosis of cutaneous lymphocyte antigen (CLA)+cells was observed in areas of BMZ damage, suggesting that response to antigenic stimulation may play a role in the development of EDP.

Eritema discrómico perstans (dermatosis cenicienta) / Erythema dyschromicum perstans (ashy dermatosis)

El Eritema Discrómico Perstans (EDP) o Dermatosis Cenicienta es una condición poco común y se caracteriza por máculas grisáceas bien definidas y de contornos policíclicos. En la histopatología los hallazgos son característicos, pero no patognomónicos, y corresponden a una dermatitis liquenoide. La causa del EDP continúa siendo un misterio; se han propuesto causas infecciosas, alteraciones del sistema inmune, e incluso, factores ambientales. Para el diagnóstico, la mayoría de las veces el cuadro clínico es muy típico. Aún no existe un tratamiento efectivo probado para el EDP, sin embargo, la clofazimina parece ser la mejor alternativa.

Involvement of cell adhesion and activation molecules in the pathogenesis of erythema dyschromicum perstans (ashy dermatitis). The effect of clofazimine therapy.

OBJECTIVES: To assess the expression of several cell adhesion and lymphocyte activation molecules in erythema dyschromicum perstans lesions, and to evaluate the effect of clofazimine therapy on the expression of these molecules. DESIGN AND METHODS: A prospective study. Skin biopsy samples were obtained from patients before and after 3 months of clofazimine therapy, and the expression of cell adhesion and activation molecules was assessed by an immunohistochemical technique. SETTING: This study was performed in a clinical referral center and an immunology research laboratory. PATIENTS: We studied 6 patients with erythema dyschromicum perstans. A diagnosis was made on the basis of clinical and histological criteria. Two patients discontinued participation in the study: one because of adverse effects and the other for unknown reasons. INTERVENTIONS: Patients were treated with clofazimine, 100 mg/d, for 3 months. MAIN OUTCOME MEASURES: Expression of cell adhesion and lymphocyte activation molecules in skin biopsy specimens before and after clofazimine therapy. RESULTS: Before clofazimine therapy, we detected a noticeable expression of intercellular adhesion molecule 1 and major histocompatibility complex class II molecules (HLA-DR) in the keratinocyte basal cell layer. In addition, CD36, a thrombospondin receptor that is not expressed by normal skin, was detected in the strata spinosum and granulosum. The dermal cell infiltrate expressed the activation molecule AIM/CD69 and the cytotoxic cell marker CD94. After clofazimine therapy, the expression of intercellular adhesion molecule 1 and HLA-DR disappeared, as well as the mononuclear cell infiltrate. CONCLUSIONS: Our results suggest that some cell adhesion and activation molecules are involved in the pathogenesis of erythema dyschromicum perstans. Clofazimine appears to have an important effect on the inflammatory phenomenon of erythema dyschromicum perstans.

Immunohistochemical study of linear gingival erythema from HIV-positive patients.

Severe forms of periodontal disease are frequent in patients with acquired immunodeficiency syndrome (AIDS). Linear gingival erythema (LGE) is a progressive disease described in HIV-positive patients and is considered to be an early stage of necrotizing periodontitis. Although clinical and microbiological differences are reported in LGE and non-specific gingivitis (NSG), a comparative immunopathological approach of both has not been performed yet. The purpose of this study was to compare relative populations of T-lymphocytes, B-lymphocytes, neutrophils, macrophages and IgG bearing plasma cells in gingival biopsies from sites exhibiting LGE and from sites exhibiting NSG. A biotin-streptavidin amplified system was used for identification of the following antigens: CD3 (T-lymphocytes), CD20 (B-lymphocytes), elastase (neutrophils), CD68 (macrophages) and IgG (plasma cell's secretors of IgG). The results have demonstrated decrease proportions of T-lymphocytes, macrophages and high percentage of neutrophils and IgG bearing plasma cells in LGE. In contrast with NSG, many neutrophils cells in LGE were found inside oral gingival epithelium. Our results highlight the idea that progressive periodontal disease is not only characterized by increased tissue inflammation, but, in addition, by significant changes in the proportion of specific inflammatory cells. The high number of neutrophils along the gingival epithelium is probably associated with the severe gingival necrosis reported in AIDS patients.

Development of giant reaction in response to PPD skin test in lepromatous leprosy patients.

The present study analyzes some clinical and immunological aspects of the giant reaction (GR) in lepromatous leprosy. Sixteen out of a total of 147 (10.9%) lepromatous patients developed the clinical features of GR upon the intradermal administration of PPD; most (14 of 16) GRs occurred in bacteriologically positive cases. GR precipitated an episode of erythema nodosum leprosum (ENL) in three patients. In addition, patients with GR showed enhanced in vitro response to PPD, by the lymphoproliferation test and interferon-gamma assay, as compared to either PPD-negative individuals or PPD-positive patients without GR. Therefore, cell-mediated-immune response to mycobacterial antigens is present in lepromatous patients with GR. It is suggested that the exacerbated in vivo response to PPD in lepromatous leprosy is the result of an increased immunoreactivity to the antigen, which well may be associated with the local and/or systemic release of cytokines [tumor necrosis factor-alpha (TNF alpha) and interferon-gamma (IFN gamma)] by the inflammatory cells. These episodes may, in fact, play an important role in determining the development of disabilities and reactional states, thereby interfering with the prognosis of leprosy disease.

Tipicidad y atipicidad del eritema discromico perstans / Typical and aty[ical erythema dyschromicum perstans

Los autores evalúan un grupo de pacientes (49), referidos en los últimos 10 años con el diagnóstico clínico de Eritema Discrómico Perstans a la consulta externa del Hospital Vargas (Instituto de Biomedicina). Se tomaron los siguientes parámetros: clínico, histopatológico, M. electrónica, subpoblaciones celulares en tejido, inmunofluorescencia, anticuerpos antinucleares y otros exámenes paraclínicos. Todos estos parámetros fueron tomados en cuenta con la finalidad de precisar aquellos pacientes con EDP típico en contraposición con aquellos pacientes atípico. Hacen consideraciones para reconocer el EDP típico como una entidad aparte, mientras que los pacientes con EDP atípico podrían ser una expresión de otra nosología

Pruebas de inmunofluorescencia en enfermedades ampollosas / Immunofluorescence tests in skin bullous diseases

Los estudios serologicos para inmunofluorescencia indirecta (IFD) como las bipsias de la piel para inmunofluorescencia directa (IFD) en las enfermedades vesicampollosas nos pueden dar una informacion diagnostica. Se describen las principales enfermedades ampollosas, como dermatitis herperiforme, penfigos, penfigoide, herpes gestationis, dermatits ampollosa de IgA lineal, etc., haciendo enfasis en la clase, caracteristicas y localizacion de los diferentes anticuerpos a nivel de la piel de estas entidades, como tambien la presencia de antigenos de histocompatibilidad. Se menciona como la toma de la biopsia de piel y mucosas difere para cada entidad para lograr una mayor positividad

Clinical trial with clofazimine for treating erythema dyschromicum perstans. Evaluation of cell-mediated immunity.

Eight patients were studied to determine the possible use of clofazimine for treating erythema dyschromicum perstans (EDP). The T-helper/T-suppressor cytotoxic ratio (CD-4/CD-8) and the in vitro lymphoproliferative response on stimulation with phytohemaglutin (PHA) and concanavalin A (Con A) were determined in peripheral blood before and after treatment. Of the eight patients studied, seven had excellent to good responses, whereas only one had a marginal response. The immunologic evaluation before and after treatment showed a significant change in the CD-4/CD-8 ratio, a decrease of the response to PHA, and no change in the response to Con A. The results obtained show that clofazimine is useful for treating this nosologic entity because of its cosmetic effect, and also because it induces changes in cell-mediated response, which could be very important therapeutically.

studio in vitro e in situ de la respuesta inmune en el eritema discrómico perstans y vitiligo / Study in vitro e in situ of the immune responsein the Erythema dyschromicum perstans and vitiligo

El eritema discrómico perstans (EDP) y el vitiligo son dermatosis pigmentarias cutáneas de etiología desconocida, en las que existen evidencias que sugieren una importante participación del sistema inmune. En el presente trabajo, se estudiaron los infiltrados leucocitarios de ambas enfermedades. La caracterización linfocitaria in situ se realizó en pacientes con EDP mas clofazima y piel de voluntarios sin lesiones cutáneas aparentes. Los resultados obtenidos muestran que la administración de la droga estimula la acumulación de linfocitos T cooperador de las zonas afectadas de la piel

Mononuclear cell subpopulations and infiltrating lymphocytes in erythema dyschromicum perstans and vitiligo.

Erythema dyschromicum perstans (EDP) and vitiligo are two cutaneous pigmentary dermatoses of unknown etiology. In the present study, the leukocyte infiltrates in the affected skin of EDP and vitiligo patients were studied using the avidin-biotin (ABC) immunoperoxidase technique and monoclonal antibodies which recognise the following mononuclear cell subgroups: T-suppressor/cytotoxic (CD8-Leu-2), T-helper (CD4 = OKT4), T-suppressor + macrophages (Leu-15), Pan T (CD3 = Leu-4), macrophages (Leu-M3) and Langerhans cells (CD1 = Leu-6), and other cellular markers such as Ia antigens and the Interleukin-2 receptor (CD25 = TAC). The immunocytochemical analysis showed a selective accumulation of CD3+, CD8+, Leu-15-, T-cytotoxic cells in the epidermis of both EDP and early lesions of vitiligo. In addition, an increase in the number of epidermal Langerhans cells (CD1+) was observed in some cases of EDP and vitiligo. The CD4/CD8 ratios in affected and uninvolved skin for both disorders were not significantly different, although values lower than unity were only observed in the infiltrates of affected skin. Ia antigen positivity was observed in the dendritic cells of the dermis and epidermis, as well as in most of the lymphoid cells within the infiltrates for both diseases. Macrophages (Leu-M3) in EDP dermal infiltrates were generally found adjacent to extracellular melanin pigment. Lymphocytes expressing TAC (CD25) surface antigens were also present in the dermal infiltrates. These morphological observations suggest a possible immune cell participation in the dyschromia of such cutaneous disorders.

Estudio de la inmunidad celular in situ en eritema discrómico perstans y vitiligo / Study in situ of the cellular immunity in erythema dyschromicum perstans and vitiligo

El Eritema Discrómico Perstans (EDP) y el Vitiligo son dos dermatosis pigmentarias cutáneas de etiología desconocida. En el presente estudio los infiltrados leucocitarios de EDP (n=10) y de Vitiligo (n=5) fueron estudiados, usando la técnica de la inmunoperoxidasa de avidinabiotina (ABC) y anticuerpos monoclonales que reconocen las siguientes subpoblaciones celulares: T-Supresor-Citotóxico (CD8=Leu-2), T-cooperadores (CD4=OKT4), T-Supresores (Leu-15), Pan T (Leu-4), Macrófagos (Leu-M3) y células de Langerhans (CD1=Leu-6); y marcadores celulares para antígeno la, Gamma Interferón, Interleucina-2 y receptor para Interleucina-2. El análisis inmunocitoquímico mostró una acumulación selectiva de células T-Citotóxicas Leu-4+, Leu-2+, Leu-15-en la epidermis tanto de EDP como de lesiones recientes de Vitiligo. Además, un aumento en el número de células de Langerhans epidérmicas Leu-6 se observó en algunos de los casos de EDP y de Vitiligo. La relación CD4/CD8 en las lesiones y en la piel no envuelta para ambos desórdenes no mostró diferencias significativas, no obstante valores menores que uno se apreciaron sólo en los infiltrados de piel lesionada. Los macrófagos en los infiltrados dérmicos de EDP se encontraban generalmente yuxtapuestos al pigmento melánico. Los linfocitos que expresaban en su superficie antígenos tipo TAC, IL-2 y Gamma Interferón, fueron muy pocas en los infiltrados dérmicos. Algunas células NK se encontraban también presentes en la epidermis enferma. Estas observaciones morfológicas sugieren una importante participación de la inmunidad celular en la discromia de diversos desórdenes pigmentarios cutáneos

Eritema infeccioso: una parvovirosis / Infectious erythema: a parvovirosis

Se realizó una actualización de eritema infeccioso, una enfermedad exantemática de la infancia que recientemente se ha asociado a parvovirus humanos y se presentan 2 casos en que se comprobó el diagnóstico por alza de IgM específica, mediante la técnica de Radioinmunoanálisis

Human parvovirus (B19) and erythema infectiosum.

An outbreak of erythema infectiosum ("fifth disease") was studied in Fukuoka, Japan, in 1980-1981. Human parvovirus (HPV) antigen was not detected in any patients, but anti-HPV, measured by countercurrent immunoelectrophoresis, was found in 33 of 34 affected children and in 21 (15%) of 141 children of the same ages without the disease. Immunoglobulin M class anti-HPV was present in all 25 children with erythema infectiosum tested. In a survey of hospital patients, the prevalence of anti-HPV detected by CIE was 12% in the cohort 5 to 9 years of age, 19% in the cohort 10 to 14 years, and 32 to 55% in the cohorts greater than or equal to 30 years. The antibody reactions in the cases of erythema infectiosum, which were already well established at the onset of disease, indicate that HPV was the cause of the outbreak.