key: cord-0992683-ga625frn
authors: Freeman, Esther E.; McMahon, Devon E.; Lipoff, Jules B.; Rosenbach, Misha; Kovarik, Carrie; Desai, Seemal R.; Harp, Joanna; Takeshita, Junko; French, Lars E.; Lim, Henry W.; Thiers, Bruce H.; Hruza, George J.; Fox, Lindy P.
title: The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries
date: 2020-07-02
journal: J Am Acad Dermatol
DOI: 10.1016/j.jaad.2020.06.1016
sha: ff240ca7d60fef33cc320537caaa70cd984e377d
doc_id: 992683
cord_uid: ga625frn

Abstract Background Coronavirus disease 2019 (COVID-19) has associated cutaneous manifestations. Objective To characterize the diversity of cutaneous manifestations of COVID-19, and facilitate understanding of underlying pathophysiology. Methods Case series from an international registry from the American Academy of Dermatology and International League of Dermatological Societies. Results The registry collected 716 cases of new-onset dermatologic symptoms in patients with confirmed/suspected COVID-19. Of the 171 patients in the registry with laboratory-confirmed COVID-19, the most common morphologies were morbilliform (22%), pernio-like (18%), urticarial (16%), macular erythema (13%), vesicular (11%), papulosquamous (9.9%), and retiform purpura (6.4%). Pernio-like lesions were common in patients with mild disease, while retiform purpura presented exclusively in ill, hospitalized patients. Limitations We cannot estimate incidence or prevalence. Confirmation bias is possible. Conclusion This study highlights the array of cutaneous manifestations associated with COVID-19. Many morphologies were non-specific, while others may provide insight into potential immune or inflammatory pathways in COVID-19 pathophysiology.

• In this international registry, the most common dermatologic morphologies in 171 COVID-19 labconfirmed cases included morbilliform (22%), pernio-like (18%), urticarial (16%), macular erythema (13%), vesicular (11%), papulosquamous (9.9%), and retiform purpura (6.4%).

• Pernio-like lesions were noted in mild disease while retiform purpura was seen exclusively in critically ill patients.

Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has associated cutaneous manifestations. 1 Case series have documented pernio-like lesions, [2] [3] [4] [5] [6] [7] erythematous macules or papules, 5, 6, 8 urticarial, 8, 9 morbilliform, 9 varicelliform, 5, 6, 8-10 papulosquamous, 11 petechial eruptions, 9, 12 livedo reticularis-like rashes, 5, 9 purpuric lesions, 5 acro-ischemic lesions 13 and retiform purpura. 14 The timing of eruptions in the disease course and potential associations between morphological subtypes with different COVID-19-associated syndromes and/or outcomes remain unclear.

Dermatologic manifestations of infectious diseases are important for identifying and treating viral illnesses including HIV, dengue, and chikungunya. Expert guidance in recognizing these signs represents an opportunity to improve diagnosis and management. Identification and characterization of COVID-19 skin lesions, like the welldescribed association with anosmia, may prompt suspicion for SARS-CoV-2 infection. 15 Thus, dermatologists at

Harvard Medical School and Massachusetts General Hospital created the COVID-19 Dermatology Registry, and in collaboration with the American Academy of Dermatology and International League of Dermatologic Societies, invited healthcare workers globally to submit data for possible cutaneous manifestations of confirmed or suspected COVID- 19. 16 For this study, we aimed to: (1) characterize internationally representative cutaneous manifestations of confirmed/suspected COVID-19 and (2) identify cutaneous manifestations that may provide insight into pathophysiology and disease course of COVID-19.

In collaboration with the AAD and ILDS, we established an international registry to collect cases of years (IQR 28-61), and 54% were female (Table 1 ).

In the 171 laboratory-confirmed COVID-19 patients, the most common morphologies were morbilliform (22%), pernio-like (18%), urticarial (16%), macular erythema (13%), vesicular (11%), papulosquamous (9.9%), and retiform purpura (6.4%) (for clinical photos, see Supplemental Figure 1 ). A sub-group analysis of patients submitted by dermatologists showed similar distribution (Supplemental Table 2 ). A minority of patients presented with multiple morphologies, including 4 cases of morbilliform plus urticarial rash, and 2 cases of morbilliform plus pernio. Six reports involved mucous membranes (4 of oral mucosa and 2 of conjunctivae). Of 17 reports of edema, most (71%) were associated with another cutaneous finding.

Skin symptoms and affected body sites varied by morphology ( Table 3 ). The most common COVID-19 symptoms among laboratory-confirmed cases included fever (61%) and cough (59%) ( Table 3) . With respect to CDC-defined PCR-test qualifying symptoms, patients with pernio-like skin lesions met fewer CDC testing criteria, meeting three or more criteria in 29%, compared to morbilliform eruptions (55%), urticaria (70%), macular erythema (74%), or vesicular eruptions (61%). 17 An additional 8.8% of patients with laboratory-confirmed COVID-19 were asymptomatic aside from rash.

Pernio-like lesions were not associated with other COVID-19 symptoms in 19%.

The most common medical co-morbidities included hypertension (16%), diabetes (12%), and smoking (12%). Most patients did not receive COVID-19-specific treatment (60%). For the 69 patients receiving COVID-19 treatment, 55% received antimalarials and 50% antibiotics including azithromycin (56%), ceftriaxone (37%), vancomycin (37%), piperacillin-tazobactam (29%), and doxycycline (27%). Treatment preceded the COVID-19associated dermatologic condition in 56%. For morbilliform rashes, 37% received no treatment, 15% received treatment before morbilliform rashes started, and 48% received treatment after morbilliform rash onset.

Hospitalization varied: 16% of patients with pernio-like lesions were hospitalized, compared to 35% for all other COVID-19 dermatologic manifestations. Patients with retiform purpura tended to be sicker; 100% were hospitalized and 82% had Acute Respiratory Distress Syndrome (ARDS) ( Table 3 ) (Figure 1 ). For the 60 hospitalized patients with laboratory-confirmed COVID-19, 24 (40%) required invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO), and 17 (28%) required supplemental oxygen. The most common complication was ARDS, in 23 (38%). Ten patients died, including those with morbilliform rash and macular erythema (2), urticaria (1), acrocyanosis and pernio-like lesions (1), acrocyanosis (1), livedo-reticularis (1), retiform purpura (2), livedo racemosa (1), retiform purpura and livedo racemosa (1), and pernio-like lesions, acrocyanosis and petechiae (1).

Dermatopathology (Table 4 ) was available from fourteen laboratory-confirmed cases (fifteen total biopsies). Six cases with clinical retiform purpura and/or livedo racemosa demonstrated thrombotic vasculopathy.

One case clinically described as buttock pressure injury also showed thrombotic vasculopathy. Another patient with complicated hospital course also developed buttock pressure injury and retiform purpura, but the biopsy only showed clotting and pressure necrosis. One palpable purpura case with ulceration demonstrated leukocytoclastic vasculitis. Two patients with papulosquamous morphologies demonstrated spongiosis and dermal inflammation.

One case with pernio-like lesions had vacuolar interface dermatitis, subepidermal edema, and superficial and deep lymphocytic inflammation. One case with an acrally distributed petechial, macular and urticarial eruption demonstrated diffuse vacuolar interface dermatitis with numerous dyskeratotic keratinocytes, sparse perivascular lymphohistiocytic inflammation, and rare dermal eosinophils.

This study highlights the wide variety of cutaneous manifestations of COVID-19 reported concurrently with or after COVID-19 diagnosis. The most common morphologies in laboratory-confirmed cases in our registry include morbilliform, pernio-like, urticarial, macular erythematous, vesicular, papulosquamous, and retiform purpura. Many of these morphologies occur with different viral infections and thus may not provide specific insight into pathophysiology or treatment targets. However, others may suggest potential immune or inflammatory pathways involved in COVID-19 pathogenesis. Further, by documenting this constellation of cutaneous manifestations, we hope to inform providers to more accurately identify signs of COVID-19. Cutaneous COVID-19

manifestations generally presented simultaneous to or after other COVID-19 symptoms. However, 12% occurred before other COVID-19 signs, highlighting their importance in assisting COVID-19 detection.

Similar to previous reports, pernio-like lesions were reported more than other dermatologic manifestations. 1, 7, 9 The high frequency of these reports may reflect the media attention pernio-like lesions received, especially in April/May 2020, with providers potentially sensitized to enter cases even without laboratory-confirmation. 18, 19 However, restricted to laboratory-confirmed sub-group analysis, morbilliform and/or macular erythema presentations were more common. Similarly, a Spanish case series reported half of laboratoryconfirmed COVID-19 dermatologic manifestations as "maculopapular," 19% pernio-like, and 19% urticarial. 6 Thirty-one patients with pernio-like lesion had laboratory-confirmed COVID-19, including 16 who were PCR positive, and therefore possibly infectious. Given public health risks posed by COVID-19, new onset of pernio-like lesions should prompt patient-provider discussions regarding both testing with PCR and/or antibody assays and the role of self-isolation in concordance with local and national guidelines. patients may extend to the skin in patients with livedo racemosa/retiform purpura/acro-ischemia, with a morphology distinct from pernio. 14 One study implicated activation of the alternative complement pathway cutaneous thrombosis pathophysiology. 14 present with pernio-like lesions, suggesting a robust interferon response in the pathogenesis of perniosis. 23 Type I interferon is critical for anti-viral immunity, and thus its heightened production in young, healthy people exposed to SARS-CoV-2 is expected and would lead to successful viral control but also, hypothetically, could trigger pernio. 24 Indeed, a low/delayed interferon response might allow for uncontrolled viral replication and a subsequent cytokine storm leading to severe illness and low incidence of pernio. 24 SARS-CoV-2-infected Chinese patients with interferon-induced transmembrane protein-3 gene polymorphism may develop worsening disease in an agedependent fashion, suggesting an interferon-driven anti-viral response could be necessary for early viral control. 25 Our study is limited by the constraints of a case series, which cannot accurately estimate prevalence nor incidence of these findings. The incidence of COVID-19 dermatologic manifestation remains unclear, with studies reporting 0.2% to 20%. 8, 26, 27 There also remains the possibility of bias due to attribution error, given reliance on providers' judgment entering data, if findings were virus-related or from a medication or other causes. Although providers were prompted for case updates, most reports represent a single snapshot, preventing full observation of dermatologic manifestations, disease complications, and follow-up testing. Limited testing of COVID-19 remains a persistent issue. Only 25% of our patients had laboratory-confirmed disease. It is difficult to parse the effects of poor test access and false negative tests on our data. Furthermore, this registry represents a small sample of global dermatologic manifestations; American dermatology networks received the most promotion, as our results reflect. Additionally, providers may have been more likely to enter more severe cases.

The lack of a clear definition for COVID-19-associated skin findings may restrict extrapolation from these data, e.g. the non-specific term "Covid toes," which may incorporate a variety of acral lesions. Only half of medical professionals entering cases were dermatologists, making morphologic misclassification possible; without photographs to confirm, we cannot ensure consistent description. As more data emerge, we should examine specific subsets (e.g. such as angulated distal purpura, erythema multiforme-like lesions, and true pernio-like lesions) that may have distinct clinical morphologies, histologic patterns, and pathophysiology. Nevertheless, we believe that better recognition of these manifestations, whether from the disease itself or from medications for COVID-19, will provide insight into disease characterization and management. 28 Our cases lacked diversity in representation, with only 34 Hispanic/Latino and 13 Black/African-American patients. This poor racial/ethnic diversity in the classification of COVID-19 dermatologic manifestations is problematic, especially given that photos of these lesions in darker skin types may help patients and providers identify early signs of COVID-19. 29 Disparities in number of COVID-19 hospitalizations and outcomes demonstrate disproportionate impact on these populations. 30 Lack of race and ethnicity data reporting in state health department registries of COVID-19 cases has complicated this issue. 31 *Defined as sex assigned at birth **Cases determined to be due to a drug have been excluded from this table, and are included in the Supplement ***Leg and buttocks were combined due to questionnaire design, which changed slightly over the course of the study † Because providers could select more than one rash morphology, some patients are double counted (i.e. Patient had both morbilliform rash and pernio) 

Cutaneous Manifestations of COVID-19: A Preliminary Review

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

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

Acral cutaneous lesions in the Time of COVID-19

Vascular skin symptoms in COVID-19: a french observational study

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

Pernio-like skin lesions associated with COVID-19: a case series of 318 patients from 8 countries

Cutaneous manifestations in COVID-19: a first perspective

Chilblains are a common cutaneous finding during the COVID-19 pandemic: a retrospective nationwide study from France

Varicella-like exanthem as a specific COVID-19-associated skin manifestation: multicenter case series of 22 patients

Digitate Papulosquamous Eruption Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Infection

Petechial Skin Rash Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Infection

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

The Prevalence of Olfactory and Gustatory Dysfunction in COVID-19 Patients: A Systematic Review and Meta-analysis

Registry: Crowdsourcing Dermatology in the Age of COVID-19

Evaluating and Testing Persons for Coronavirus Disease

What Is 'Covid Toe'? Maybe a Strange Sign of Coronavirus Infection

Frostbite' toes and other peculiar rashes may be signs of hidden coronavirus infection, especially in the young

Pernio-like skin lesions associated with COVID-19: a case series of 318 patients from 8 countries

Cutaneous manifestations in COVID-19: Lessons learned from current evidence

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

Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions

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

Cutaneous manifestations related to coronavirus disease 2019 (COVID-19): A prospective study from China and Italy

Clinical Characteristics of Coronavirus Disease 2019 in China

How Dermatologists Can Learn and Contribute at the Leading Edge of the COVID-19 Global Pandemic

Absence of Skin of Colour Images in Publications of COVID-19 Skin Manifestations

Covid-19: Black people and other minorities are hardest hit in US

The COVID-19 Pandemic: a Call to Action to Identify and Address Racial and Ethnic Disparities

Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study

Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19

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

Test performance evaluation of SARS-CoV-2 serological assays

Neutralizing Antibodies Responses to SARS-CoV-2 in COVID-19 Inpatients and Convalescent Patients

cough (35%);19% asymptomatic • 16% hospitalized • Extremities and buttocks • Often asymptomatic (73%) • After other COVID -19 symptoms (91%) • Fever (64%), cough (73%), and shortness of breath (73%)

65-74%), cough (52-66%), sore throat (39-50%), shortness of breath

• 22-45% hospitalized across groups

We Cokonis, Laura Jerome, Edward Butler, and Tess Peters for providing dermatopathology results. We appreciate all the healthcare providers worldwide who entered cases in this registry.