ReviewPernio (Chilblains), SARS-CoV-2, and COVID Toes Unified Through Cutaneous and Systemic Mechanisms
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.
References (139)
- et al.
Clinical characteristics, etiologic associations, laboratory findings, treatment, and proposal of diagnostic criteria of pernio (chilblains) in a series of 104 patients at Mayo Clinic, 2000 to 2011
Mayo Clin Proc
(2014) - et al.
SNDV (French National Union of Dermatologists-Venereologists). Chilblains is a common cutaneous finding during the COVID-19 pandemic: a retrospective nationwide study from France
J Am Acad Dermatol
(2020) - et al.
Characterization of acute acral skin lesions in nonhospitalized patients: a case series of 132 patients during the COVID-19 outbreak
J Am Acad Dermatol
(2020) - et al.
Coronavirus (COVID-19) infection-induced chilblains: a case report with histopathologic findings
JAAD Case Rep
(2020) - et al.
Chilblain-like acral lesions during the COVID-19 pandemic (“COVID toes”): histologic, immunofluorescence and immunohistochemical study of 17 cases
J Am Acad Dermatol
(2020) - et al.
Role of interferon alpha in endothelial dysfunction: insights into endothelial nitric oxide synthase-related mechanisms
Am J Med Sci
(2014) - et al.
American Academy of Dermatology Ad Hoc Task Force on COVID-19. Pernio-like skin lesions associated with COVID-19: a case series of 318 patients from 8 countries
J Am Acad Dermatol
(2020) - et al.
The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries
J Am Acad Dermatol
(2020) - et al.
Timing of PCR and antibody testing in patients with COVID-19-associated dermatologic manifestations
J Am Acad Dermatol
(2021) A chilblain epidemic during the COVID-19 pandemic: a sign of natural resistance to SARS-CoV-2?
Med Hypotheses
(2020)
Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Geneva, Switzerland (SEROCoV-POP): a population-based study
Lancet
New insights in COVID-19-associated chilblains: a comparative study with chilblain lupus erythematosus
J Am Acad Dermatol
Paraviral eruptions in the era of COVID-19: do some skin manifestations point to a natural resistance to SARS-CoV-2?
Clin Dermatol
The pivotal link between ACE2 deficiency and SARS-CoV-2 infection
Eur J Intern Med
Skin is a potential host of SARS-CoV-2: a clinical, single-cell transcriptome-profiling and histologic study
J Am Acad Dermatol
Estradiol, acting through ERα, induces endothelial non-classic renin-angiotensin system increasing angiotensin 1-7 production
Mol Cell Endocrinol
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is likely to be androgen mediated
J Am Acad Dermatol
Estrogen downregulates gp130 expression in HUVECs by regulating ADAM10 and ADAM17 via the estrogen receptor
Biochem Biophys Res Commun
Florida Health website
Wiktionary website
Chilblain lupus erythematosus (lupus pernio): clinical review of the Mayo Clinic experience and proposal of diagnostic criteria
Cutis
Sarcoidosis of the upper respiratory tract and its association with lupus pernio
Thorax
Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases
Br J Dermatol
Coronavirus hijacks the body from head to toe, perplexing doctors
The Wall Street Journal
A clinical, histopathological and laboratory study of 19 consecutive Italian paediatric patients with chilblain-like lesions: lights and shadows on the relationship with COVID-19 infection
J Eur Acad Dermatol Venereol
Acral purpuric lesions (erythema multiforme type) associated with thrombotic vasculopathy in a child during the COVID-19 pandemic
J Eur Acad Dermatol Venereol
A distinctive variant of pernio: clinical and histopathologic study of nine cases
Arch Dermatol
Perniosis: clinical and histopathological analysis
Am J Dermatopathol
Nomenclature of cutaneous vasculitis: dermatologic addendum to the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides
Arthritis Rheumatol
Retiform purpura as a dermatological sign of coronavirus disease 2019 (COVID-19) coagulopathy
J Eur Acad Dermatol Venereol
Acro-ischaemia and COVID-19 infection: clinical and histopathological features
J Eur Acad Dermatol Venereol
Catastrophic acute bilateral lower limbs necrosis associated with COVID-19 as a likely consequence of both vasculitis and coagulopathy
J Eur Acad Dermatol Venereol
The differing pathophysiologies that underlie COVID-19 associated perniosis and thrombotic retiform purpura: a case series
Br J Dermatol
Assessment of clinical response to janus kinase inhibition in patients with familial chilblain lupus and TREX1 mutation
JAMA Dermatol
Vasospasm is a consistent finding in pernio (chilblains) and a possible clue to pathogenesis
Dermatology
Childhood pernio and cryoproteins
Pediatr Dermatol
TREX-1-related disease associated with the presence of cryofibrinogenemia
J Clin Immunol
High prevalence of cryofibrinogenemia in patients with chilblains during the COVID-19 outbreak
Int J Dermatol
Chilblains in children in the setting of COVID-19 pandemic
Pediatr Dermatol
Chilblain-like lesions in children following suspected COVID-19 infection
Pediatr Dermatol
Chilblains in children in the time of COVID-19: new evidence with serology assay
Pediatr Dermatol
Are chilblain-like acral skin lesions really indicative of COVID-19? A prospective study and literature review
J Eur Acad Dermatol Venereol
Major cluster of paediatric ‘true’ primary chilblains during the COVID-19 pandemic: a consequence of lifestyle changes due to lockdown
J Eur Acad Dermatol Venereol
Negative SARS-CoV-2 PCR in patients with chilblain-like lesions
No antibody response in acral cutaneous manifestations associated with COVID-19?
J Eur Acad Dermatol Venereol
Antibody responses to SARS-CoV-2 in patients with COVID-19
Nat Med
Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections
Nat Med
Rapid decay of anti-SARS-CoV-2 antibodies in persons with mild Covid-19
N Engl J Med
Decline in SARS-CoV-2 antibodies after mild infection among frontline health care personnel in a multistate hospital network—12 states, April-August 2020
MMWR Morb Mortal Wkly Rep
Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals
Cell
Cited by (26)
Renal, cardiac, neurological, cutaneous and coagulopathic long-term manifestations of COVID-19 after recovery; A review
2022, Epidemiology and InfectionThe impact on the scientific community of the 2018 addendum to the CHCC
2022, Frontiers in MedicineSARS-CoV-2 Vaccination and Chilblain-like Lesions: What Do We Know so Far?
2022, Dermatology Practical and Conceptual
Potential Competing Interests: The authors report no competing interests.