key: cord-0776041-i4a6nf7l
authors: Freeman, Esther E.; McMahon, Devon E.; Lipoff, Jules B.; Rosenbach, Misha; Kovarik, Carrie; Takeshita, Junko; French, Lars E.; Thiers, Bruce H.; Hruza, George J.; Fox, Lindy P.
title: Pernio-like skin lesions associated with COVID-19: a case series of 318 patients from 8 countries
date: 2020-05-30
journal: J Am Acad Dermatol
DOI: 10.1016/j.jaad.2020.05.109
sha: ff3d2bcd031df5d74b21bd5407d77ef521afe356
doc_id: 776041
cord_uid: i4a6nf7l

Abstract Background Increasing evidence suggests pernio-like lesions are cutaneous manifestations of COVID-19. Objective To describe clinical and pathologic findings of pernio-like lesions in confirmed or suspected COVID-19 cases. Methods An international dermatology registry was circulated to healthcare providers worldwide through the American Academy of Dermatology (AAD), International League of Dermatologic Societies (ILDS), and other organizations. Results We documented 505 patients with dermatologic manifestations associated with COVID-19, including 318 (63%) with pernio-like lesions. Patients with pernio-like lesions were generally young and healthy, with relatively mild COVID-19. Of 318 cases confirmed or suspected as COVID-19 by providers, twenty-three cases (7%) were laboratory-confirmed COVID-19 positive, and 20 others (6%) were close contacts of confirmed COVID-19 cases. Given current testing criteria, many patients lacked COVID-19 testing access. For 55% of patients, pernio-like lesions were their only symptom. In patients with other COVID-19 symptoms, pernio-like lesions typically appeared after other symptoms. Pernio-like lesions lasted a median of 14 days (IQR 10-21). Limitations A case series cannot estimate population level incidence or prevalence. Additionally, there may be confirmation bias in reporting. We cannot exclude an epiphenomenon. Conclusions Pernio-like skin changes of the feet and hands, without another explanation, may suggest COVID-19 infection and should prompt confirmatory testing.

Emerging evidence suggests that coronavirus infectious disease 2019 (COVID-19) has associated dermatologic manifestations. Many cutaneous findings of COVID-19 are non-specific, such as morbilliform exanthems, urticarial eruptions, and vesicular lesions, and are often seen in the context of other viral infections. [1] [2] [3] In contrast, recent reports from around the globe highlight a striking pernio-like phenomenon in association with 4, 5 Pernio, or chilblains, is a superficial inflammatory vascular response that occurs on acral skin, usually after cold exposure, typically in children and young to middle-aged women. 6 In this large international registry-based case series, we evaluate clinical characteristics of patients with suspected or confirmed COVID-19

who presented with pernio-like lesions on acral surfaces. Our objectives were to assess location, timing, and duration of the pernio-like lesions, and to analyze patients' comorbidities, COVID-19 severity, and disease outcomes.

We established a registry to collect cases of COVID-19 with dermatologic manifestations reported by medical professionals, with data collected from April 8, 2020 to May 2, 2020. The registry was widely promoted to members of the American Academy of Dermatology (AAD), major dermatology subspecialty groups, the International League of Dermatologic Societies (ILDS), and dermatology and general medicine groups on social media. The website (www.aad.org/covidregistry) was hosted through a Massachusetts General Hospital (MGH)

REDCap database. The registry queried patient demographics, dermatologic symptoms, COVID-19 history and symptoms, and past medical history. For this sub-analysis, we included patients with new onset pernio-like skin changes in the setting of confirmed or suspected COVID-19 and excluded patients with prior history of pernio.

The de-identified patient data was analyzed using Stata (Version 16, College Station, Texas). The registry was reviewed by Partners Healthcare Institutional Review Board, and was determined to not meet the definition of Human Subjects Research.

The registry compiled 505 cases of dermatologic manifestations associated with COVID-19 over 25 days, reported by dermatologists (50%), other physicians (37%), and mid-level practitioners (8%). Three hundred eighteen cases (63%) identified pernio-like changes in the setting of confirmed or suspected COVID-19 (Table 1) . Pernio-like lesions affected only the feet in 84% of cases, only the hands in 5.1% of cases, and a combination of the hands and feet in 10% of cases ( Figure 1 ). Associated acrocyanosis was seen in 9.2% and acral desquamation in 4.4%. Notably, 29% of patients lived in geographic regions with average March 2020 temperatures above 10°C, temperatures at which idiopathic pernio is less likely.

Dermatopathology was available for one PCR positive case, demonstrating mild vacuolar interface dermatitis with dense superficial and deep lymphocytic inflammation, consistent with pernio versus connective tissue disease. No thrombi were noted. Six other pathology reports from patients without laboratory confirmation showed findings consistent with pernio-like changes: i) one with mild spongiosis, vacuolar interface change, few apoptotic epidermal keratinocytes, and perivascular and perieccrine lymphoid infiltrate, ii) three reporting superficial and deep perivascular, peri-eccrine lymphocytic or lymphohistiocytic infiltrate without evidence of vasculitis, iii) one reporting a subepidermal blister with small vessel lymphocytic vasculitis without microthrombi, and iv) one reporting lymphocytic vasculitis with rare microthrombi and overlying epidermal necrosis.

Our registry-based, international collaborative series of patients presents the largest and most comprehensive collection of cases reported of pernio-like lesions as a cutaneous manifestation of confirmed or suspected COVID-19. Based on this data, we propose that this finding should prompt evaluation for the active or While there is a possibility that IgM positivity represents a false positive, if reliable, it instead supports the theory that antibody testing would be an important part of the evaluation of pernio-like lesions to rule out COVID-19.

Further, if pernio is indeed a later disease course phenomenon in at least a subset of patients, then it may be prudent to repeat antibody testing and/or seek delayed IgG testing for suspected patients.

We must critically examine with further investigation why some patients with COVID-19 associated It is also possible that many COVID-19 patients may have a delayed antibody responses. Another, more worrisome, explanation is that patients with relatively mild disease tend not to have as brisk of an antibody response. 7,10 This explanation is concerning because it would question both the validity of our current antibody testing and suggest that patients with mild or asymptomatic disease may not generate antibodies (and possible immunity) upon infection with SARS-Cov-2. Lastly, reliable testing combined with coordination of timing of these skin changes with COVID-19 PCR, IgG, and IgM testing results is imperative in order to better establish selfisolation recommendations for patients presenting with pernio-like lesions.

There are multiple potential pathophysiologic mechanisms underpinning pernio-like lesions in COVID-19.

In non-epidemic settings, pernio is often idiopathic or related to underlying disease (e.g. systemic lupus erythematosus, antiphospholipid antibody syndrome), and cannot easily be ascertained with histopathology alone. 11 The histopathology reported for one of the COVID-19 PCR positive cases, as well as 4 of 6 suspected cases, demonstrated features consistent with pernio without evidence of vascular damage, suggesting COVID-19-associated pernio-like lesions may be simply inflammatory. The other 2 of 6 suspected cases with histopathology reported vascular changes, including lymphocytic vasculitis, that can sometimes be seen in conjunction with variants of pernio. Indeed, interferon response to viral infection appears to be a clue as to why some patients do poorly while others fare well. 12, 13 Less likely, but worthy of consideration, is that pro-thrombotic coagulopathy may be a contributing factor, as suggested by COVID-19 cases complicated by venous thromboembolism, pathologic reports of microvascular thrombosis, 14 and laboratory abnormalities including elevated D-dimer and high fibrinogen. [15] [16] [17] Furthermore, antiphospholipid antibodies have been implicated in a small case series of acutely ill COVID-19 patients 18 and have previously been associated with pernio. With greater clinical-pathologic correlation, we hope to better understand the pathophysiology, including understanding how, if at all, hypercoagulability plays a role in COVID-19-associated pernio-like lesions. Importantly, although young patients with COVID-19 have presented with stroke, we are not aware of any cases of concomitant perniolike lesions and strokes. 19 Limitations of this case series include incomplete testing for COVID-19, especially in otherwise asymptomatic patients. We are also unable to estimate the incidence or prevalence of this condition. There may be confirmation bias in reporting of cases. Additionally, the background incidence of pernio from other causes in March and April is not well documented. 6 We cannot exclude an epiphenomenon, as this case series cannot establish causation. Future studies are needed to assess the histopathology of pernio-like lesions to inform understanding of the disease process.

In conclusion, our case series demonstrates pernio-like skin lesions as a manifestation of COVID-19.

Patients with pernio-like lesions of COVID-19 may still be infectious and pose a public health risk, as at least four patients in this report developed skin lesions prior to COVID-19 PCR confirmation, and 14 developed the lesions while still PCR positive. We propose that pernio-like lesions be added to the testing criteria for COVID-19 and prompt consideration of testing for both PCR and IgM and IgG antibodies. This information will be critical to understanding the significance of these cutaneous lesions and empowering physicians and other healthcare providers to counsel patients appropriately. 

Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases

Cutaneous manifestations in COVID-19: a first perspective

A Dermatologic Manifestation of COVID-19: Transient Livedo Reticularis

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

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

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

Viral Kinetics and Antibody Responses in Patients with COVID-19

The Promise and Peril of Antibody Testing for COVID-19

Test performance evaluation of SARS-CoV-2 serological assays

Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications

Idiopathic perniosis and its mimics: a clinical and histological study of 38 cases

Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with disease severity in COVID-19

Familial Chilblain Lupus -What Can We Learn from Type I Interferonopathies?

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan

Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19

Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young

The authors would like to thank Drs. Philippe Dieude, Cynthia Yalowitz, Rachel Hub, Emily

Arch, Ambrose Su and Haydee Knott for providing photographs, as well as Drs. Rina Allawh, Graeme Lipper, Lynda Kauls, Lee Albert, Shannon Keiser, and Sarah Smilow for providing pathology. We thank Dr. Mariko Yasuda for her input on pathophysiologic mechanisms. We thank Dr. Marlys Fassett for her contributions regarding antibody testing. We would like to thank the American Academy of Dermatology Ad Hoc Task Force on Covid-19 and staff at the American Academy of Dermatology for their logistical and administrative support. We would like to thank the International League of Dermatological Societies for their international collaboration. We also appreciate the COVID-19 Global Rheumatology Alliance for sharing their experience with registry development.