key: cord-353756-lm2qs6ev authors: Massey, Paul R.; Jones, Krystal M. title: Going viral: A brief history of Chilblain-like skin lesions (“COVID toes”) amidst the COVID-19 pandemic date: 2020-05-23 journal: Semin Oncol DOI: 10.1053/j.seminoncol.2020.05.012 sha: doc_id: 353756 cord_uid: lm2qs6ev Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the respiratory illness COVID-19, has led to a global pandemic. In a rapidly evolving medical literature its manifestations are expanding and now include coagulopathies renal dysfunction, cardiac arrests, multisystem inflammatory syndrome in children as well as cutaneous manifestations commonly observed with viral illnesses and chilblain-like skin lesions often referred to as “COVID toes”. Driven in large part by the internet-facilitated communication, dermatologists around the world now report a marked increase in the frequency of chilblain-like diagnoses, not infrequently in members of the same family, amidst the COVID-19 pandemic. While a mechanistic explanation has yet to be proven a robust antiviral immune response in young patients that simultaneously truncates the clinical course and induces the microangiopathic changes could lead to chilblain-like skin lesions. This or a similar explanation would then posit that chilblain-like lesions would be most likely to appear only after a successful viral response is mounted with lesions detected only when symptoms are likely to be subsiding. We review the rapid evolution of the chilblain-like presentation in patients with COVID 19 beginning with its first description in early March 2020 and summarize the evolving but rapidly self-confirming data. family, amidst the COVID-19 pandemic. While a mechanistic explanation has yet to be proven a robust antiviral immune response in young patients that simultaneously truncates the clinical course and induces the microangiopathic changes could lead to chilblain-like skin lesions. This or a similar explanation would then posit that chilblain-like lesions would be most likely to appear only after a successful viral response is mounted with lesions detected only when symptoms are likely to be subsiding. We review the rapid evolution of the chilblain-like presentation in patients with COVID 19 beginning with its first description in early March 2020 and summarize the evolving but rapidly selfconfirming data. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the respiratory illness COVID-19, has led to a global pandemic. COVID-19 is the focus of a nascent and rapidly evolving medical literature. Amidst a panoply of unusual findings for a viral respiratory illness including induced coagulopathies, 1 renal dysfunction 2 and cardiac arrests, 3, 4 a suspected cutaneous manifestation of COVID-19, chilblain-like skin lesions -"COVID toes"has garnered particular attention both in the medical literature and in the national media. [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] While COVID-19 was initially reported to have few or no cutaneous findings, 15 a multitude of skin manifestations have now been described. Purported cutaneous manifestations of COVID-19 range from those commonly observed with viral illnesses, e.g., maculopapular and urticarial eruptions, 7, 16 to the more unusual, e.g., varicella-like eruptions 7 or livedoid and necrotic skin lesions. 5, 7 These findings merit further study to parse true viral associations from those of potential confounders including acute or latent co-infections, medical complications of disease and adverse reactions to medication. Similarly, the chilblain-like presentation is an unexpected association with COVID-19. Historically chilblains, or pernio, has been defined as an exaggerated skin response to cold in predisposed individuals. 17 It is characterized clinically by pink to violaceous papules arising on acral surfaces, most commonly the hands and feet (Figures 1 and 2) . Histologically, chilblains is an inflammatory disorder showing dermal edema along with a superficial and deep perivascular lymphocytic infiltrate. Chilblains may be idiopathic or associated with systemic disease, such as autoimmune conditions, certain genetic mutations, hematologic malignancy and less commonly infections, such as Epstein-Barr virus (EBV). 17 Cold agglutinins appear to play a role in chilblains associated with EBV. 17 Chilblains is a relatively rare condition; a Minnesota case series recorded an average of 9-10 diagnoses per year across an entire tertiary academic department. 17 In early March 2020, nearly 3 weeks after community spread of COVID-19 was documented in Italy, a 13-year-old boy developed pruritic red-violet lesions on the toes in the setting of fever, myalgia and headache. 11 Family members were reported to have had fever, cough and dyspnea six days prior. While testing for COVID-19 was not possible in this case an association was suspected. Shortly after this index report, images of similar acral lesions in the feet of children with suspected COVID-19 were circulated on "Amici DermPed," an Italian pediatric dermatology forum. 11 In mid-March, the French Union of Dermatologists and Venereologists (SNDV) created a text messaging group on WhatsApp® to share information. 6 One week later, a case of chilblain-like lesions was reported via WhatsApp® and with the help of "re-posts" through Facebook® between the two platforms, 146 individual chilblain-like cases were subsequently circulated. 6 Intensified medical and lay interest in this phenomenon was reflected in unprecedented Google searches for "coronavirus toes". 18 In the second week in April, just one month after the initial report of chilblain-like lesions in Italy, the American Academy of Dermatology, the Pediatric Dermatology Research Alliance and the Spanish General Council of Podiatrists announced registries that would facilitate the study of chilblain-like lesions and COVID-19. 10, 19, 20 This month-long evolution from first informal reports to national specialty-level registry formation is striking. A detailed timeline is presented in Figure 2 . Dermatologists in the United States and around the world now report a dramatically increased frequency of chilblain-like diagnoses, not infrequently in members of the same family, amidst the COVID-19 pandemic. The increased incidence, 6 coupled with the temporal association with viral symptoms, has led to the colloquialization "COVID toes." Chilblain-like lesions appear to have a predilection for younger patients who are often minimally or asymptomatic and do not require hospitalization. 10 patients, and only 2 (18%) were positive. 10 Recalcati et al reported no positive cases in a separate Italian series of 14 patients. 21 In a Spanish series of 12 cases with available PCR data, again no patients were found to be positive. 23 The strongest correlation between COVID-19 and chilblain-like lesions is provided by a Spanish study in which 71 cases were reported, 41% with confirmed COVID-19. 7 At the time of this writing in early May 2020, 17 reports have detailed a pooled 566 patients with new-onset chilblain-like lesions suspected to be related to COVID-19 ( Table 1) The initial report by Mazzota is not formally published as of this writing. Most assessments for active COVID-19 infection were by PCR. 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