A clinicopathological description of COVID-19-induced chilblains (COVID-toes) correlated with a published literature review.

BACKGROUND: The abundance of publications of COVID-19-induced chilblains has resulted in a confusing situation. METHODS: This is a prospective single-institution study from 15 March to 13 May 2020. Thirty-two patients received PCR nasopharyngeal swabs. Of these, 28 patients had a thoracic CT-scan, 31 patients had blood and urine examinations, 24 patients had skin biopsies including immunohistochemical and direct immunofluorescence studies, and four patients had electron microscopy. RESULTS: COVID-19-induced chilblains are clinically and histopathologically identical to chilblains from other causes. Although intravascular thrombi are sometimes observed, no patient had a systemic coagulopathy or severe clinical course. The exhaustive clinical, radiological, and laboratory work-up in this study ruled-out other primary and secondary causes. Electron microscopy revealed rare, probable viral particles whose core and spikes measured from 120 to 133 nm within endothelium and eccrine glands in two cases. CONCLUSION: This study provides further clinicopathologic evidence of COVID-19-related chilblains. Negative PCR and antibody tests do not rule-out infection. Chilblains represent a good prognosis, occurring later in the disease course. No systemic coagulopathy was identified in any patient. Patients presenting with acral lesions should be isolated, and chilblains should be distinguished from thrombotic lesions (livedo racemosa, retiform purpura, or ischemic acral necrosis).

Clinicopathologic correlations of COVID-19-related cutaneous manifestations with special emphasis on histopathologic patterns.

Skin is one of target organs affected by the novel coronavirus SARS-CoV-2, and in response to the current COVID-19 pandemic, a fast body of literature has emerged on related cutaneous manifestations. Current perspective is that the skin is not only a bystander of the general cytokines storm with thrombophilic multiorgan injury, but it is directly affected by the epithelial tropism of the virus, as confirmed by the detection of SARS-CoV-2 in endothelial cells and epithelial cells of epidermis and eccrine glands. In contrast with the abundance of epidemiologic and clinical reports, histopathologic characterization of skin manifestations is limited. Without an adequate clinicopathologic correlation, nosology of clinically similar conditions is confusing, and effective association with COVID-19 remains presumptive. Several patients with different types of skin lesions, including the most specific acral chilblains-like lesions, showed negative results at SARS-CoV-2 nasopharyngeal and serologic sampling. The aim of this review is to provide an overview of what has currently been reported worldwide, with a particular emphasis on microscopic patterns of the skin manifestations in patients exposed to or affected by COVID-19. Substantial breakthroughs may occur in the near future from more skin biopsies, improvement of immunohistochemistry studies, RNA detection of SARS-CoV-2 strain by real-time polymerase chain reaction-based assay, and electron microscopic studies.

[Cutaneous Manifestations Associated with COVID-19: A Narrative Review]. / Manifestações Cutâneas Associadas à COVID-19: Uma Revisão Narrativa.

INTRODUCTION: COVID-19 is an infectious disease caused by the new coronavirus, SARS-CoV-2, that has spread rapidly throughout the world. This has resulted in an urgent need to obtain information regarding its pathogenesis, diagnosis and clinical manifestations. More specifically, skin manifestations, seldom reported initially, have been increasingly described. MATERIAL AND METHODS: We performed a literature search in the PubMed database, regarding cutaneous manifestations associated with COVID-19. This article describes the clinical and histological findings of the main skin lesions observed in the context of SARS-CoV-2 infection. DISCUSSION: Cutaneous manifestations associated with COVID-19 have been described in multiple retrospective and prospective studies, case series and case reports. The reported incidence reached 20.4%. Although there was substantial heterogeneity in terms of clinical patterns, the main ones include: erythematous/maculopapular, urticarial, papulovesicular, and purpuric/petechial eruptions, chilblain-like lesions and livedoid/acro-ischemic lesions. In the vast majority, the underlying pathophysiologic mechanisms are not fully understood, although histopathological findings and biomolecular studies can add relevant data. CONCLUSION: The recognition of cutaneous manifestations associated with COVID-19 is of utmost importance. They may help establishing an early diagnosis, namely in oligosymptomatic patients or when confirmatory tests are impossible to perform. Moreover, chilblain-like lesions and acro-ischemia, also seem to play an important role in terms of prognosis.

Introdução: A COVID-19, doença infeciosa causada por um novo coronavírus, SARS-CoV-2, propagou-se rapidamente pelo mundo inteiro, resultando numa necessidade emergente de obtenção de conhecimentos alusivos à sua patogénese, diagnóstico e sintomatologia. Mais especificamente, um número cada vez maior de casos relativos a manifestações cutâneas, previamente desconhecidas, tem vindo a ser descrito.Material e Métodos: Foi realizada uma pesquisa de literatura, através da base de dados PubMed, referente às manifestações dermatológicas associadas à COVID-19. O presente artigo descreve os achados clínicos e histológicos das principais lesões cutâneas observadas em contexto da infeção por SARS-CoV-2.Discussão: Manifestações cutâneas associadas à COVID-19 foram descritas em múltiplos estudos retrospetivos e prospetivos, séries de casos e casos clínicos isolados. A incidência reportada atingiu os 20,4%, verificando-se uma heterogeneidade de padrões clínicos substancial. Destes destacam-se as erupções eritematosas/maculopapulares, urticariformes, papulovesiculares, purpúricas/petequiais, lesões tipo-perniose e lesões livedóides/acro-isquémicas. O conhecimento dos mecanismos fisiopatológicos subjacentes tem vindo a ser enriquecido com achados os histológicos e de biologia molecular.Conclusão: É essencial o reconhecimento das manifestações dermatológicas associadas à COVID-19, uma vez que podem permitir o diagnóstico precoce da infeção, nomeadamente em casos oligossintomáticos ou quando não é possível a realização de testes confirmatórios. Embora menos estabelecido, lesões tipo-perniose e acro-isquémicas, parecem ter também um papel importante a nível prognóstico.

Skin Manifestations Associated with COVID-19: Current Knowledge and Future Perspectives.

BACKGROUND: Coronavirus disease-19 (COVID-19) is an ongoing global pandemic caused by the "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), which was isolated for the first time in Wuhan (China) in December 2019. Common symptoms include fever, cough, fatigue, dyspnea and hypogeusia/hyposmia. Among extrapulmonary signs associated with COVID-19, dermatological manifestations have been increasingly reported in the last few months. SUMMARY: The polymorphic nature of COVID-19-associated cutaneous manifestations led our group to propose a classification, which distinguishes the following six main clinical patterns: (i) urticarial rash, (ii) confluent erythematous/maculopapular/morbilliform rash, (iii) papulovesicular exanthem, (iv) chilblain-like acral pattern, (v) livedo reticularis/racemosa-like pattern, (vi) purpuric "vasculitic" pattern. This review summarizes the current knowledge on COVID-19-associated cutaneous manifestations, focusing on clinical features and therapeutic management of each category and attempting to give an overview of the hypothesized pathophysiological mechanisms of these conditions.

COVID Purpura (Toes) Case Series: A Chilblains-Like Vasculopathy.

ABSTRACT: Biopsies were taken from 4 patients who presented to their dermatologist with violaceous papules and plaques of the dorsal toes (COVID Toes) associated with varying degrees of severe acute respiratory syndrome coronavirus 2 exposure and COVID-19 testing. Major histopathologic findings were lymphocytic eccrine inflammation and a spectrum of vasculopathic findings to include superficial and deep angiocentric-perivascular lymphocytic inflammation, lymphocytes in vessel walls (lymphocytic vasculitis), endothelial swelling, red blood cell extravasation, and focal deposits of fibrin in both vessel lumina, and vessel walls. Interface changes were observed to include vacuolopathy and apoptotic keratinocytes at the basement membrane. Immunostains showed a dominant T-cell lineage (positive for T-cell receptor beta, CD2, CD3, CD5, and CD7). B-cells were rare and clusters of CD123-positive dermal plasmacytoid dendritic cells were observed surrounding eccrine clusters and some perivascular zones. The consistent perieccrine and vasculopathic features represent important pathologic findings in the diagnosis of COVID toes and are suggestive of pathogenetic mechanisms. Clinicopathologic correlation, the epidemiological backdrop, and the current worldwide COVID-19 pandemic favor a viral causation and should alert the physician to initiate a workup and the appropriate use of COVID-19 testing.

The differing pathophysiologies that underlie COVID-19-associated perniosis and thrombotic retiform purpura: a case series.

BACKGROUND: There are two distinctive acral manifestations of COVID-19 embodying disparate clinical phenotypes. One is perniosis occurring in mildly symptomatic patients, typically children and young adults; the second is the thrombotic retiform purpura of critically ill adults with COVID-19. OBJECTIVES: To compare the clinical and pathological profiles of these two different cutaneous manifestations of COVID-19. METHODS: We compared the light microscopic, phenotypic, cytokine and SARS-CoV-2 protein and RNA profiles of COVID-19-associated perniosis with that of thrombotic retiform purpura in critical patients with COVID-19. RESULTS: Biopsies of COVID-19-associated perniosis exhibited vasocentric and eccrinotropic T-cell- and monocyte-derived CD11c+ , CD14+ and CD123+ dendritic cell infiltrates. Both COVID-associated and idiopathic perniosis showed striking expression of the type I interferon-inducible myxovirus resistance protein A (MXA), an established marker for type I interferon signalling in tissue. SARS-CoV-2 RNA, interleukin-6 and caspase 3 were minimally expressed and confined to mononuclear inflammatory cells. The biopsies from livedo/retiform purpura showed pauci-inflammatory vascular thrombosis without any MXA decoration. Blood vessels exhibited extensive complement deposition with endothelial cell localization of SARS-CoV-2 protein, interleukin-6 and caspase 3; SARS-CoV-2 RNA was not seen. CONCLUSIONS: COVID-19-associated perniosis represents a virally triggered exaggerated immune reaction with significant type I interferon signaling. This is important to SARS-CoV-2 eradication and has implications in regards to a more generalized highly inflammatory response. We hypothesize that in the thrombotic retiform purpura of critically ill patients with COVID-19, the vascular thrombosis in the skin and other organ systems is associated with a minimal interferon response. This allows excessive viral replication with release of viral proteins that localize to extrapulmonary endothelium and trigger extensive complement activation.

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases.

Acute respiratory failure and a systemic coagulopathy are critical aspects of the morbidity and mortality characterizing infection with severe acute respiratory distress syndrome-associated coronavirus-2, the etiologic agent of Coronavirus disease 2019 (COVID-19). We examined skin and lung tissues from 5 patients with severe COVID-19 characterized by respiratory failure (n= 5) and purpuric skin rash (n = 3). COVID-19 pneumonitis was predominantly a pauci-inflammatory septal capillary injury with significant septal capillary mural and luminal fibrin deposition and permeation of the interalveolar septa by neutrophils. No viral cytopathic changes were observed and the diffuse alveolar damage (DAD) with hyaline membranes, inflammation, and type II pneumocyte hyperplasia, hallmarks of classic acute respiratory distress syndrome, were not prominent. These pulmonary findings were accompanied by significant deposits of terminal complement components C5b-9 (membrane attack complex), C4d, and mannose binding lectin (MBL)-associated serine protease (MASP)2, in the microvasculature, consistent with sustained, systemic activation of the complement pathways. The purpuric skin lesions similarly showed a pauci-inflammatory thrombogenic vasculopathy, with deposition of C5b-9 and C4d in both grossly involved and normally-appearing skin. In addition, there was co-localization of COVID-19 spike glycoproteins with C4d and C5b-9 in the interalveolar septa and the cutaneous microvasculature of 2 cases examined. In conclusion, at least a subset of sustained, severe COVID-19 may define a type of catastrophic microvascular injury syndrome mediated by activation of complement pathways and an associated procoagulant state. It provides a foundation for further exploration of the pathophysiologic importance of complement in COVID-19, and could suggest targets for specific intervention.