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

Abstract 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 likely because of the increased occurrence, frequently in young patients with no cold exposure or prior history of pernio, and reports of skin biopsies with positive SARS-CoV-2 immunohistochemistry. PubMed was searched for 2020 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 (ACE2) mediated by transmembrane protease serine 2 (TMPRSS2), subsequently affecting the renin-angiotensin-aldosterone system (RAAS) with an increase in the vasoconstricting, proinflammatory, and prothrombotic angiotensin II pathway. 2) SARS-CoV-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 RAAS balance, and the IFN-I response.