Cutaneous Pathology of COVID-19 as a Window into Immunologic Mechanisms of Disease.

Many skin manifestations of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection reflect activation of cutaneous and systemic immune responses involving effector pathways of both the innate and adaptive arms of the immune system. This article reviews evidence from the recent clinical and scientific literature that informs the current understanding of the consequences of coronavirus disease 2019 (COVID-19)-induced immune cell activation, as relevant to dermatology. Topics include the clinical consequences of autoantibody production in patients with COVID-19, immunologic evidence for chilblains as a manifestation of SARS-CoV-2 infection, and the relationship between type I interferons and COVID-19 disease severity.

Cutaneous Manifestations of COVID-19.

Patients with coronavirus disease 2019 (COVID-19) present with multisystem signs and symptoms, including dermatologic manifestations. The recent literature has revealed that dermatologic manifestations of COVID-19 often are early onset and provide helpful cues to a timely diagnosis. We compiled the relevant emerging literature regarding the dermatologic manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) so that physicians can be aware of the various clinical cutaneous presentations in this time of high incidence of COVID-19.

Chilblain-Like Lesions (CLL) Associated With COVID-19 ("COVID Toes"): A Systematic Review.

Reports of chilblain-like lesions (CLL) coinciding with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been described in the literature, but this phenomenon has not been critically summarized. The aim of this paper is to summarize reports of CLL coinciding with SARS-CoV-2 infection to clarify the prevalence, clinical relevance, and prognostic value of these lesions. A literature search was conducted using the Embase, Pubmed, and Scopus databases from December 2019 to June 16, 2020 using the search terms ("COVID-19" OR "coronavirus" OR "2019-nCoV" OR "SARS-CoV-2") AND ("chilblain-like" OR "COVID toes" OR "acral"). Papers that described skin changes in patients with suspected or confirmed COVID-19 were included. A total of 31 papers were summarized, representing 813 cases of CLL. Available data suggests an equal gender distribution, mean age of 21 years, and median age of 14 years. Mild extracutaneous symptoms were reported in 53% of cases and 47% were asymptomatic. CLL occurred an average of 16 days after extracutaneous symptoms. Patients with CLL were positive for SARS-CoV-2 in 15% of cases. Lesions were mainly described as asymptomatic and/or pruritic erythematous to violaceous acral macules and plaques. Partial or complete resolution occurred in 85% of cases in a mean of 13 days. The most common histologic findings were perivascular and perieccrine superficial and deep lymphocytic infiltrates. Although a causal relationship between CLL and SARS-CoV-2 has not been confirmed, the temporal association and 15% positive SARS-CoV-2 rate in affected individuals should not be ignored.

Cutaneous manifestations of COVID-19.

The severe acute respiratory syndrome coronavirus two (SARS-CoV-2), which causes the 2019 coronavirus disease (COVID-19), has infected patients worldwide. Physicians have increasingly identified cutaneous findings as a significant clinical manifestation of COVID-19. In this review, we describe the clinical presentation, onset, duration, associated symptoms, treatment, and outcome of cutaneous manifestations thus far reported to be related to COVID-19. We have included data from 63 studies and subdivided reported cutaneous manifestations into the categories of viral exanthem, urticarial, vesicular, chilblains/chilblains-like, non-chilblains vasculopathy-related, pityriasis rosea-like, erythema multiforme-like, Kawasaki/Kawasaki-like disease, and others. Physicians should be aware of the known common cutaneous manifestations of COVID-19 and future research is required to better understand the pathophysiology and prognosis of each COVID-19-related skin manifestation.

Pernio (Chilblains), SARS-CoV-2, and COVID Toes Unified Through Cutaneous and Systemic Mechanisms.

Pernio or chilblains is characterized by erythema and swelling at acral sites (eg, toes and fingers), typically triggered by cold exposure. Clinical and histopathologic features of pernio are well described, but the pathogenesis is not entirely understood; vasospasm and a type I interferon (IFN-I) immune response are likely involved. During the coronavirus disease 2019 (COVID-19) pandemic, dermatologists have observed an increase in pernio-like acral eruptions. Direct causality of pernio due to COVID-19 has not been established in many cases because of inconsistent testing methods (often negative results) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a form of COVID-19‒associated pernio (also called COVID toes) is probable because of increased occurrence, frequently in young patients with no cold exposure or a history of pernio, and reports of skin biopsies with positive SARS-CoV-2 immunohistochemistry. PubMed was searched between January 1, 2020, and December 31, 2020 for publications using the following keywords: pernio, chilblain, and acral COVID-19. On the basis of our review of the published literature, we speculate that several unifying cutaneous and systemic mechanisms may explain COVID-19‒associated pernio: (1) SARS-CoV-2 cell infection occurs through the cellular receptor angiotensin-converting enzyme 2 mediated by transmembrane protease serine 2, subsequently affecting the renin-angiotensin-aldosterone system with an increase in the vasoconstricting, pro-inflammatory, and prothrombotic angiotensin II pathway. (2) Severe acute respiratory syndrome coronavirus 2 cell infection triggers an immune response with robust IFN-I release in patients predisposed to COVID-19‒associated pernio. (3) Age and sex discrepancies correlated with COVID-19 severity and manifestations, including pernio as a sign of mild disease, are likely explained by age-related immune and vascular differences influenced by sex hormones and genetics, which affect susceptibility to viral cellular infection, the renin-angiotensin-aldosterone system balance, and the IFN-I response.