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 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.

Identification, Mechanism, and Treatment of Skin Lesions in COVID-19: A Review

“…These lesions are more frequent in adolescents and young adults, with involvement of the feet and fingers in 71% of the cases and in the same proportion in men and women [20]. In this way, Cappel et al [43] showed that 63% of patients with cutaneous manifestations presented lesions similar to chilblains and 94% of patients were located on the feet. The appearance of chilblain-like lesions follows the onset of systemic symptoms of COVID-19, with the mean duration of these lesions being around 13 days [20,22].…”

“…According to Freeman et al [44], 16% of patients with pernio-type lesions were hospitalized, compared with 35% for all other dermatologic manifestations of SARS-CoV-2 associated disease. In a study by Cappel et al [43], 98% of patients with these lesions received only outpatient care, 55% had no symptoms of the disease, and 45% developed respiratory manifestations [33]. The clinical finding of chilblain-like or pernio-like lesions is an unusual manifestation of COVID-19, suggesting it to be an effective host antiviral response by the host [19].…”

“…The causes attributed to COVID-19-associated chilblain-like lesions raise a hypothesis that SARS-CoV-2 causes coagulation disorders (increased D-dimer and fibrinogen degradation products), thrombosis, generalized endothelial infection (endothelial damage) [43], and dysregulation of immune pathways (early IFN-1 response) [19]. In addition, chilblains could be a paraviral rash associated with COVID-19 [45].…”

Nail Manifestations in COVID-19: Insight into a Systemic Viral Disease

“…These isolated case reports, however, are not yet sufficient to establish this finding as a unique characteristic of COVID-19 infection. COVID “pernio” accounts for 2/3 of skin findings in patients with COVID-19 and is associated with a lymphocytic vasculitis of small dermal vessels with fibrin thrombi [ 17 ]. Similarly, complement-mediated vascular injury results in thrombus formation in small vessels in lung tissue, and complement binding to COVID-19 spike glycoproteins has been identified in purpuric skin lesions of COVID-19 patients [ 18 ].…”

Mucocutaneous lesions associated with SARS‑CoV‑2 infection (Review)

“…The current hypotheses consider that the vasculitic/vasculopathic manifestations could be the result of small vessel occlusion, or it could be a neurogenic, microthrombotic, immune complex-mediated mechanism. A direct correlation with the SARS-CoV-2 virus has yet to be demonstrated (37,38). a) Ischemic acral lesions.…”