Elsevier

Mayo Clinic Proceedings

Volume 96, Issue 4, April 2021, Pages 989-1005
Mayo Clinic Proceedings

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

https://doi.org/10.1016/j.mayocp.2021.01.009Get rights and content

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.

Section snippets

Dermatologic Manifestations of Coronavirus Disease 2019

The highly contagious and deadly coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome coronavirus (SARS-CoV) 2 (SARS-CoV-2), has profoundly affected all medical specialties, including dermatology, necessitating new perspectives on patient and provider safety. As with many other respiratory viruses, patients with COVID-19 may develop viral exanthemata and other cutaneous manifestations. Initially, limitations on in-person dermatology evaluations and the increased

Histopathology of Pernio

One reason for the nonuniform use of terminology for COVID-19–associated acral eruptions was the initial lack of understanding of the microscopic inflammatory pattern.8 However, the first report of the histopathologic findings10 and subsequent articles have confirmed the typical skin biopsy findings of pernio. These include a superficial and deep lymphocytic inflammatory infiltrate in a lichenoid, perivascular, and perieccrine distribution.10, 11, 12 The acral presentation of pernio frequently

Pathophysiology of Pernio

Pernio was recognized as a diagnostic entity well before the COVID-19 pandemic, although the pathogenesis of pernio is not entirely understood. Previous clues were found in familial chilblain lupus, which is an autosomal dominant form due to sequence variations in the 3′ repair exonuclease 1 that protects cells from innate immune activation, including induction of type I interferons (IFN-Is) (eg, interferon α [IFN-α] and interferon β), which, if constitutively activated, can interfere with

Pernio During the COVID-19 Pandemic

An international dermatology registry was created to assist in documenting the dermatologic manifestations associated with COVID-19.27 Of 505 patients with cutaneous eruptions, 318 (63%) were reported as having pernio-like eruptions, of whom 94% had on the feet, 98% received outpatient care only, 55% were asymptomatic, and 45% had respiratory COVID-19 symptoms (mostly mild).27 However, 6 patients were hospitalized, including 2 who died. Seven patients had dermatopathology, all reporting

Severe Acute Respiratory Syndrome Coronavirus 2 Testing in COVID-19‒Associated Pernio

It is unusual that most of the reported cases of COVID-19‒associated pernio have occurred in younger patients with no history of pernio and in warmer weather conditions than is typical of cold-induced pernio, pointing to COVID-19 as the most likely cause.30 One hypothesis is that an adequate early IFN-I response to COVID-19 occurs in younger patients,10 possibly explaining why SARS-CoV-2 PCR results are frequently negative when patients present with chilblains.30 For example, of 22 children and

Severe Acute Respiratory Syndrome Coronavirus 2 Testing in Skin Biopsies of COVID-19‒Associated Pernio

Coronavirus disease 2019‒associated chilblain-like lesions have exhibited perivascular and perieccrine lymphocytic infiltrates of predominantly CD3+ T cells, with collections of CD123+ or CD303+ plasmacytoid dendritic cells (pDCs).11,12 Plasmacytoid dendritic cells produce IFN-I and are thought to be involved in the pathogenesis of chilblain lupus and COVID-19–associated pernio.50 CD123+ pDCs51 and expression of myxovirus resistance protein A (MxA), a marker of IFN-I signaling, are found in

Role of Angiotensin-Converting Enzyme 2 in COVID-19

Angiotensin-converting enzyme 2 (ACE2) functions as the receptor on cells that mediate cellular entry for both SARS-CoV and SARS-CoV-2.64,65 First the viral protein subunit S1 binds to the receptor ACE2; the second step is protein cleavage of the S1 and S2 protein subunits, which is completed by the transmembrane protease serine 2 (TMPRSS2).66,67 After the S1 protein subunit separation, the remaining S2 protein subunit conformationally rearranges, which allows the fusion of the viral and

Cutaneous ACE2 and COVID-19‒Associated Pernio

Angiotensin-converting enzyme 2 messenger RNA expression occurs in the skin and is positively correlated with the expression of immune signature genes of lymphocytes and the IFN response.70 In addition, ACE2 protein expression in the skin has been revealed by immunohistochemistry, which exhibits strong staining of the basal layer of the epidermis and hair follicles, the dermal blood vessels, and the eccrine glands.71 In all forms of pernio, the lymphocytic infiltrate characteristically exhibits

Renin-Angiotensin-Aldosterone System Imbalance in COVID-19

Although cell-bound ACE2 allows cellular entry for SARS-CoV-2, ACE2 also provides a vasoprotective function by converting angiotensin (ANG) II (ANGII) to ANG-(1-7) (ANG1-7).67 Increased levels of ANGII lead to endothelial dysfunction by binding ANG type 1 receptor (AT1R) and resulting in increased aldosterone release, vasoconstriction, coagulation, immune cell activation, and inflammatory cytokines.67 These effects are opposed by ANG1-7 binding the ANG type 2 receptor (AT2R) and the Mas

Discrepancies in COVID-19 Severity by Sex and Age

Severe COVID-19 occurs more frequently in male patients73,74 and older patients.75 Differences in the RAAS may be one explanation, as in male patients and older adults the angiotensin-converting enzyme–driven ANGII-AT1R axis is favored,76,77 whereas in female patients the balance is shifted toward increased activity of ACE2 and the positive effects of ANG1-7 binding AT2R and the Mas receptor.76 Estradiol increases ANG1-7 production through estrogen receptor α and increases ACE2 expression and

Type I Interferons and pDCs in COVID-19

Type I interferons are primarily produced by pDCs, which provide an important link between innate and adaptive immunity.101 Plasmacytoid dendritic cells are considered sentinel cells102 that are stimulated upon physical contact with virally infected cells at an adhesion site (an interferogenic synapse).103 Through this contact synapse, viral RNA transfer to pDCs leads to TLR7 signaling and production of IFN-I by pDCs, which may be locally secreted on infected cells.103 However, in chronic viral

Relation of Antiphospholipid Antibodies in COVID-19‒Associated Pernio

Lupus anticoagulant and antiphospholipid antibodies have been reported to be frequently positive in hospitalized patients with COVID-19.111, 112, 113, 114 Viral infections can trigger the development of antiphospholipid antibodies, probably through molecular mimicry, with most cases being transient and nonpathogenic; however, catastrophic antiphospholipid syndrome has been associated with some viral infections.115

Antiphospholipid antibodies have been proposed as a factor in a subset of pernio

Coagulopathy, Thrombosis, T Lymphocytes, and COVID-19‒Associated Pernio

Coronavirus disease 2019 has been associated with several coagulation defects, including elevated D-dimer levels, pulmonary thrombosis, venous thromboembolism, and disseminated intravascular coagulation.118 In a prospective cohort study, patients with acute respiratory distress syndrome due to COVID-19 had increased thrombotic complications, including pulmonary embolism, despite anticoagulation.119 Some have suggested that COVID-19 may result in distinct sepsis-induced coagulopathy owing to

Hypoxia as a Factor in COVID-19‒Associated Pernio

Hypoxia in COVID-19 is not surprising given patients’ related pneumonia with ground glass opacities on radiologic imaging studies, although some have hypothesized that hemoglobin dysfunction may also be involved.129 Additionally, relative hypoxia may occur within other tissues, in part because of the vasoconstricting and prothrombotic effects of unopposed ANGII. The subsequent endothelial dysfunction could then, for example, result in local hypoxia of the skin and be an additional contributing

Cutaneous Endothelial Function and RAAS in COVID-19‒Associated Pernio

Coronavirus disease 2019‒associated pernio may more commonly affect younger patients because of age-related differences in cutaneous endothelial function. The complete RAAS resides in human skin and includes ANGII, which can be synthesized locally, and its receptors AT1R and AT2R, which are found in epidermal keratinocytes and dermal vessels.132 Cutaneous vascular responses to ANGII are age-related.77,133 In young adults, reflex cutaneous vasoconstriction to cold exposure is primarily dependent

Proposed Mechanism for COVID-19‒Associated Pernio (COVID Toes)

On the basis of a review of the published literature, we speculate that the mechanism for COVID-19‒associated pernio (COVID toes) involves an interplay of SARS-CoV-2 cell infection through ACE2, the RAAS, sex hormones, and the IFN-I immune response (Figure 364, 65, 66, 67, 68, 69,76,81,82,86,87,94,97,123, 124, 125, 126,128,130,136). These interconnected mechanisms provide a rationale for some of the therapeutics studied in the context of COVID-19 infection, including RAAS inhibitors,

Limitations

The caveats of this review include the retrospective nature of most published studies; the lack of prospective data thus far is due to the novel nature of the current SARS-CoV-2 pandemic. For example, SARS-CoV-2 testing methods and results have been highly variable, as the best practices for proving infection in patients with possible cutaneous manifestations have yet to be determined. We also acknowledge that from a review of the published literature, we have made speculative hypotheses about

Conclusion

Pernio or chilblains is the most common diagnosis to explain COVID toes, because affected patients present with erythema and swelling involving acral surfaces and consistent lymphocyte-rich histopathology, fulfilling the previously proposed diagnostic criteria.3 However, it is critical to distinguish pernio from other cutaneous acral eruptions that can also be associated with COVID-19, particularly pauci-inflammatory thrombo-occlusive vasculopathy, which presents with livedoid to retiform

Acknowledgments

Editing, proofreading, reference verification, and illustration formatting assistance was provided by Scientific Publications, Mayo Clinic.

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