key: cord-0954914-0x4xweo0
authors: Zaladonis, Angela; Huang, Simo; Hsu, Sylvia
title: COVID-Toes or Pernio?
date: 2020-06-05
journal: Clin Dermatol
DOI: 10.1016/j.clindermatol.2020.06.002
sha: 4cc085a789f41b1df596a469e2cd119e3aef0ae0
doc_id: 954914
cord_uid: 0x4xweo0

Abstract “COVID toes” are a new phenomenon of pernio-like lesions that has been associated with COVID-19 infection. As dermatology practices reopen and increase patient volumes amidst the waning of the coronavirus pandemic, it is important to consider the finding of pernio and pernio-like lesions in the context of both COVID-19 and its other possible etiologies. This article will discuss possible causes of pernio and pernio-like lesions and offer suggestions for appropriate diagnostic work-up and management when indicated.

Pernio, also known as perniosis or chilblains, characteristically presents as painful or pruritic erythematous macules or papules on the digits lasting more than 24 hours. It is likely the result of vasospasm of the superficial vasculature and secondary inflammatory reaction (1) . It is most commonly seen on the feet but may be found on other sites like the hands, ears, and nose.

Primary pernio, also known as idiopathic pernio, is the most common cause of pernio and is usually associated with cool temperatures and vasospasm (2) . Secondary pernio is associated with systemic inflammatory conditions like chronic cutaneous lupus erythematosus and sarcoidosis. Secondary pernio likely accounts for less than 7% of all pernio conditions (2) . Other conditions, including myeloid leukemias and the coronavirus disease 2019 (COVID-19) have been associated with pernio-like skin lesions (3, 4) . Table 1 summarizes some distinguishing features of these etiologies.

Idiopathic pernio is typically associated with cold, but non-freezing, temperatures. It often appears during the cool, wet seasons of the year, like late fall and early spring. Although the exact etiology is unknown, it is suspected that vasospasm and a secondary inflammatory reaction contribute to its progression (1, 2) . Along with the fingers and toes, primary pernio lesions may be found on the ears and face. It is more common in women of reproductive age, J o u r n a l P r e -p r o o f those with a low body mass index, those who smoke, and those with Raynaud's phenomenon (1, 2) .

Physical exam and history are typically sufficient for a diagnosis of primary pernio. Patients report appearance of lesions within about 24 hours of exposure to cool temperatures. On histopathology, perniosis classically presents with a superficial and deep lymphoid vasculitis, dermal edema, and perieccrine lymphocytic infiltrates (5) . No laboratory tests are required for diagnosis (2) .

Management of primary pernio generally includes conservative measures like keeping the affected areas warm and dry, as well as smoking cessation. Idiopathic pernio typically will resolve in 1-3 weeks. For unresolving or more severe cases, topical corticosteroids or oral calcium channel blockers like nifedipine may be attempted, but success is variable (1, 2). Patients with unresolving or severe pernio are at risk of developing systemic lupus erythematosus (SLE) in the following months, and therefore should be monitored for systemic symptoms (1) . Additionally, in patients with unresolving, severe, or otherwise atypical pernio, it is important to consider secondary causes of pernio or a pernio-like syndrome as described below.

Secondary pernio results from an underlying systemic cause. This accounts for a small proportion of all patient with pernio. Additionally, these are generally rare cutaneous manifestations of the systemic cause.

Chilblain lupus erythematosus (CHLE) is a form of cutaneous lupus erythematosus (CLE) which presents with lesions of similar morphology and distribution to primary pernio (6) . It may be sporadic or familial. The familial form of CHLE is associated with a mutation in TREX1 (6) . Like primary pernio, the lesions of CHLE may appear with cold temperatures; however, the lesions are not seasonal and typically persist longer than a few weeks. Acral lesions and characteristic histopathologic or immunofluorescence findings are necessary for a diagnosis of CHLE. If CHLE is suspected, biopsy and immunofluorescence should be performed. Biopsies of CHLE will show findings similar to idiopathic pernio with superficial and deep perivascular lymphocytic infiltrates. However, CHLE is more likely to show a widespread vacuolar interface with scattered necrotic keratinocytes in the lower epidermis and is less likely to show perieccrine lymphocytic infiltration and significant dermal edema (5, 7) . Immunofluorescence can show deposition of immunoglobulins and complement proteins at the dermoepidermal junction in CHLE which is characteristically absent in idiopathic pernio (6) . CHLE is often associated with discoid lupus, another form of CLE (6) . Up to 18% of patients with CHLE will also develop SLE, although this may take years (6) . Many autoantibodies, including antiphospholipid antibodies, are associated with CHLE; however, there are no significant correlations between presence of autoantibodies and the risk of development of SLE (6) . Initial management of CHLE is the same as that of primary pernio. If the lesions are unresponsive, topical immunosuppressants, like tacrolimus, or systemic immunosuppressants, like mycophenolate mofetil, may be used (6) . Patients should continue to be monitored for symptoms of SLE (6).

Leukemia cutis (LC) is any specific cutaneous manifestation of leukemia which may be identified by the presence of leukemic cells within the skin lesion upon histological exam (8) . Leukemia cutis may have many different morphologies, including a chilblain-like LC. This is a rare manifestation, which is most often associated with myeloid leukemias (3, 9) . In addition to biopsy, chilblain-like LC may be diagnosed by peripheral blood smear and complete blood counts, which provide evidence of leukemia (8) .

COVID-19 has been associated with many different cutaneous manifestations, including a chilblain-like eruption on the feet, thus the nickname of "COVID toes." This cutaneous manifestation seems to appear in younger patients (4, 10, 11). These patients typically do not have other symptoms of the virus upon presentation and will not go on to develop further symptoms (4) . One study showed that about one quarter of those with chilblain-like lesions will have other symptoms of COVID-19 (10) . If patients do report symptoms of COVID-19, they usually occur prior to the chilblain lesions (11) . It has been suggested that patients with chilblainlike lesions may be contagious, and they should be counseled to use all social distancing precautions (4, 11) . Interestingly, patients with severe cases of COVID-19 have been found to develop ischemic lesions of the extremities, including acral regions (12) . These patients demonstrate elevated antiphospholipid antibodies, similar to CHLE (12) . This may suggest vascular dysfunction similar to that of pernio. Histology of "COVID toes" has shown similarities as well. Superficial and deep perivascular lymphocytic infiltrates with perieccrine involvement, vacuolar interface, and scattered necrotic keratinocytes have been described (10, 13) . Focal thrombosis can be seen which is not characteristic of CHLE or idiopathic pernio. Most lesions associated with COVID-19 do not require treatment and will resolve within a few days (12) . At this time, the Centers for Disease Control and Prevention (CDC) do not specifically list the chilblain-like eruption or any cutaneous manifestation of COVID-19 as stand-alone symptomatology warranting nasopharyngeal swab testing (14) . However, the CDC does say that clinicians should use their judgment to determine if a patient has symptomatology consistent with COVID-19 in deciding whether the patient should be tested (14) . Figure 1 depicts suspected COVID toes in a 20s-year-old man hospitalized for symptoms of COVID-19. Interestingly, the patient's reverse transcriptase-polymerase chain reaction (RT-PCR) test results were negative. This case illustrates a challenge related to the diagnosis of COVID-19: a significant risk of false-negative RT-PCR tests (15) . For this reason, negative RT-PCR test results should be interpreted cautiously and in the context of the patient's symptoms and possible exposures to the virus (15) . Alternative testing using serum antibodies may be a useful tool for confirming previous infection with COVID-19 and further establishing the link between pernio-like lesions known as COVID toes and infection with COVID-19. Antibody testing is best conducted at least one week after onset of symptoms and has also been associated with a significant false-positive test result (16) .

Pernio and pernio-like lesions represent a constellation of clinical conditions ranging from idiopathic to malignant and life threatening. The first step in evaluation of pernio and pernio-like lesions should include obtaining a patient history for exposure to cold temperatures. If this is the case, the lesions are likely primary (idiopathic) pernio. If the pernio lesions are found in atypical locations, do not resolve after a few weeks of conservative management, or are not associated with cool temperatures, secondary pernio or causes of pernio-like lesions should be considered. Biopsy of a lesion and histological exam can be helpful for diagnosis. Table 1 includes an overview of common histological findings, as well as other laboratory findings and associations which may be helpful in determining the etiology of pernio.

The clinical significance of chilblain-like lesions in COVID-19 is still to be determined; however, as dermatology clinics reopen, dermatologists are likely to encounter more pernio-like lesions than before. It is important to interpret these findings in the context of all etiologies of pernio. Negative RT-PCR or antibody tests should be interpreted cautiously, as the risk of false negative is well established. Physicians should continue to look for updates regarding the significance and management protocols for cutaneous manifestations of COVID-19.

Clinical characteristics, etiologic associations, laboratory findings, treatment, and proposal of diagnostic criteria of pernio (chilblains) in a series of 104 patients at Mayo Clinic

Chilblain-like leukemia cutis

Characterization of acute acro-ischemic lesions in non-hospitalized patients: a case series of 132 patients during the COVID-19 outbreak

Weedons Skin Pathology

Chilblain lupus erythematosus--a review of literature

A histologic and immunohistochemical study of chilblains

Leukemia cutis -epidemiology, clinical presentation, and differential diagnoses

Chilblain-like leukaemia cutis

COVID-19) infection-induced chilblains: A case report with histopathologic findings. JAAD Case Rep

Chilblain-like lesions during COVID-19 epidemic: a preliminary study on 63 patients

COVID-19 Pandemic: Are There Unique Cutaneous Manifestations in Patients Infected with SARS-CoV-2?

Chilblains in children in the setting of COVID-19 pandemic

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