key: cord-1040929-c7wp9lbf
authors: Marzano, A.V.; Cassano, N.; Genovese, G.; Moltrasio, C.; Vena, G.A.
title: Cutaneous manifestations in patients with COVID‐19: A preliminary review of an emerging issue
date: 2020-06-01
journal: Br J Dermatol
DOI: 10.1111/bjd.19264
sha: bc12aff10b0f16797a236610e7192061c80a6a0d
doc_id: 1040929
cord_uid: c7wp9lbf

BACKGROUND: The infection caused by the recently identified SARS‐CoV‐2, called COronaVIrus Disease‐19 (COVID‐19), has rapidly spread throughout the world. With the exponential increase of patients worldwide, the clinical spectrum of COVID‐19 is being better defined and new symptoms are emerging. Numerous reports are documenting the occurrence of different cutaneous manifestations in COVID‐19 patients. OBJECTIVES: To provide a brief overview of the COVID‐19‐associated cutaneous lesions. METHODS: Literature search was performed in the PubMed, Scopus and Web of Science databases up to 30 April 2020. This narrative review summarizes the available data regarding clinical and histological features of COVID‐19‐associated skin manifestations. RESULTS: Literature reports showed a great heterogeneity in COVID‐19‐associated cutaneous manifestations, as well as in their latency periods and associated extracutaneous symptoms. Pathogenic mechanisms are unknown, although the role of hyperactive immune response, complement activation and microvascular injury has been hypothesized. Based on our experience and the literature data, we subdivided the reported cutaneous lesions into six main clinical patterns: i) urticarial rash, ii) confluent erythematous/maculo‐papular/morbilliform rash, iii) papulovesicular exanthem, iv) chilblain‐like acral pattern, v) livedo reticularis/racemosa‐like pattern, vi) purpuric “vasculitic” pattern. These six patterns can be merged into two main settings: the first one – inflammatory/exanthematous – including the first three groups cited above and the second one including the vasculopathic/vasculitic lesions of the last three aforementioned groups. CONCLUSIONS: The possible presence of cutaneous findings leading to suspect COVID‐19 puts dermatologists in a relevant position. Further studies are needed to delineate the diagnostic and prognostic value of such cutaneous manifestations.

A novel zoonotic enveloped RNA virus of the Coronaviridae family, that has been named "Severe Acute Respiratory Syndrome Coronavirus 2" (SARS-CoV-2), was identified in hospitalized patients with pneumonia in Wuhan, China, in December 2019. The infection caused by the virus, called COronaVIrus Disease-19 , has rapidly spread throughout the world becoming pandemic in early March 2020. 1 The clinical spectrum of COVID-19 is rather heterogeneous, ranging from unapparent or mild symptoms to critical fatal forms with respiratory failure, septic shock or multiorgan dysfunction. The clinical features at illness onset vary, but, over the disease course, patients mainly present with fever and respiratory symptoms. However, various signs and symptoms can occur, and, among the most common are fever, cough, fatigue, anorexia, shortness of breath, sputum production, myalgia, dyspnea, rhinorrhea, ageusia, anosmia, pharyngodynia, headache and chills. 1 With the exponential increase of infected patients worldwide, clinical characteristics of COVID-19 are being better defined and new symptoms are emerging.

In most of the early reports from China, cutaneous lesions were not generally included in the COVID-19 clinical spectrum, apart from a few exceptions. For instance, Guan et al. described skin rash in 0.2% out of 1,099 hospitalized patients, without specifying clinical patterns or further details. 2 Hoehl et al. observed a faint rash and minimal pharyngitis in one traveler returning from Wuhan to Germany in February 2020 who tested positive for SARS-CoV-2 by real-time reverse-transcription-polymerasechain-reaction (RT-PCR) of her throat swab. 3 Subsequently, a case of COVID-19 presenting with purpuric lesions mimicking dengue has been reported. 4 In Iran, the clinical findings of COVID-19 found in a 15-day-old neonate were fever, lethargy, respiratory distress without cough and cutaneous mottling. 5 Another report, which analyzed a series of 88 COVID-19 patients to describe the rate and type of skin lesions, drew the attention of the scientific community to the COVID-19-associated cutaneous manifestations. 6 In all these patients, history of intake of any new drug in the previous 15 days was excluded. Cutaneous manifestations developed in 18 patients (20.4%) either at the onset of the disease (n=8) or after the admission (n=10) and consisted in erythematous rash (n=14), widespread urticaria (n=3) and chickenpox-like vesicles (n=1). The trunk was the most frequently affected area and itch was mild or absent. Skin lesions usually disappeared in a few days and did not show any apparent correlation with COVID-19 severity.

Subsequently, various reports of skin manifestations in patients with COVID-19 have been published. It should be kept in mind that, at the beginning of this tremendous outbreak, the rapidly increasing rate of infected patients and the parallel multitude of severe and critical patients could have hampered systematic skin assessments. Therefore, cutaneous lesions are likely to have been underestimated for obvious reasons, including the paucity of dermatology consultations in this group of patients. 7 Moreover, cutaneous lesions may have been neglected as their duration can be very short and local symptoms can be minimal or absent. The difficulty in determining the actual prevalence of COVID-19-associated skin manifestations has Accepted Article also been linked to the fact that in some countries only patients with respiratory illness or requiring hospitalization are screened. 8 The aim of our article is to provide a brief overview of the COVID-19-associated cutaneous manifestations, accepting the preliminary nature of such data.

A literature search in the electronic databases PubMed, Scopus and Web of Science was conducted up to the 30 th of April 2020, using the term "COVID-19" in combination with "skin", "cutaneous manifestations", "eruption", "rash", "exanthem", "urticarial", "chilblain", "livedo", and "purpura" in order to collect reports of skin manifestations described in patients with COVID-19. Given the limited number of papers, we included all the available clinical reports dealing with this very recent topic, most of which concerned individual cases or small case series. Articles were selected based on title and abstract. Full texts were then carefully read to evaluate the article content. Articles from the references cited in the retrieved papers were also manually searched as appropriate.

The present review was based upon the available literature to date, which consists predominantly of case reports and small case series, all graded by low quality evidence. Tables 1 and 2 contain a partial list of case reports, 4, corresponding only to the description of single cases with detailed information. Such reports refer to patients with laboratory-confirmed COVID-19. In only one case, 13 although multiple nucleic acid tests were negative, the infection was diagnosed on the basis of both chest computerized tomography (CT) scan findings and close contact with COVID-19 patients. Case series with more than three patients are not contained in these Tables and are described in depth throughout the text. The only report with higher quality evidence is that by Galván Casas et al. on a large cohort of patients, 32 which allowed the authors to stratify COVID-19-related skin manifestations in five categories. Overall, the case reports suggest that skin lesions developed more often after the onset of COVID-19 symptoms, with a variable latency period. A simultaneous onset was sometimes noted, especially for fever. More rarely skin lesions occurred in the prodromal phase, shortly before the appearance of typical COVID-19 symptoms. 9, 27 Reports concerning asymptomatic subjects also exist. Different clinical patterns were described.

A classification of cutaneous manifestations of COVID-19 has been proposed based on the results of a prospective nationwide consensus study in Spain using a representative sample of 375 cases. 32 Five clinical patterns were recognized: i) acral areas of erythema with vesicles or pustules (pseudo-chilblains) (19%), ii) other vesicular eruptions (9%), iii) urticarial lesions (19%), iv) maculopapular eruptions (47%), v) livedo or necrosis (6%). Vesicular eruptions were found to appear early in the course of the disease (before other symptoms in 15% of cases), chilblain-like lesions frequently appear late over the disease course, whereas the remaining patterns tend to develop during the illness phase. Chilblain-like lesions also tend to

This article is protected by copyright. All rights reserved have a longer duration as compared to the other forms. A gradient of severity of COVID-19 could be observed ranging from less severe disease in acral lesions to most severe in the case of livedoid presentations. 32 Nevertheless, transient livedoid eruptions have also been reported in the literature. 28 Based on our experience, review of the literature and the classification by Galván Casas et al. who studied a cohort of 375 Spanish patients, 32 we subdivided the reported cutaneous lesions into six main clinical patterns: i) urticarial rash ( Figure 1A) , 6, [8] [9] [10] [11] [12] [13] [14] [15] [16] , ii) confluent erythematous/maculopapular/morbilliform rash ( Figure 1B) , 3, 6, 14, 15, [17] [18] [19] [21] [22] [23] [24] [25] [26] [27] iii) papulovesicular exanthem ( Figure 1D ), 6,20,33-35 iv) chilblain-like acral pattern ( Figure 1C) , 8, 29 ,30,33,36-41 v) livedo reticularis/racemosa-like pattern ( Figure 1F ), 28,31 vi) purpuric "vasculitic" pattern ( Figure 1E ). 31,33 Although livedo reticularis/racemosa and purpura could be included in the same setting, we decided to split them into two separate categories, keeping in mind the hypothesis that the former has a vasculopathic origin, while the latter admits a true vasculitic pathogenesis.

For clarity of exposition, the six patterns were assigned to two broader categories: inflammatory/exanthematous eruptions, including urticarial rash, confluent erythematous/maculopapular/morbilliform rash and papulovesicular exanthem (Table 1) , and vasculopathic/vasculitic lesions, including chilblain-like acral pattern, livedo reticularis/racemosa-like pattern and purpuric "vasculitic" pattern ( Table 2) .

These encompass confluent erythematous, maculopapular, morbilliform and urticarial presentations, similar to non-specific rashes in the course of common viral infections. In the large cohort of 375 patients by as well as localized plaques on the heels, 23 and a papulosquamous eruption, clinically reminiscent of pityriasis rosea. 26 Gisondi et al. gave a brief mention of a diffuse papular eruption seen in a woman with COVID-19 febrile infection. 44 Lesions resembling erythema multiforme have also been described. 32

In some case reports (Table 1) , the outcomes were not specified. When available, the data on the natural evolution generally indicated an overall short duration of skin involvement.

Hedou et al. analyzed, in a prospective study, the incidence and types of cutaneous manifestations associated with COVID-19 in France. 8 In total, 103 patients with confirmed infection (71 women) with a mean age of 47 yrs were evaluated. Among them, 76 were treated at home, 23 were admitted to conventional hospital wards and 4 to intensive care units. Only 5 (5%) presented with skin manifestations:

erythematous rash (n=2) and urticaria (n=2), mainly located on the face and the upper body, and one case Accepted Article of oral herpes simplex virus reactivation in an intubated patient. Cutaneous signs appeared during the prodromal phase in a patient with urticaria and during the illness in the remaining subjects. All eruptions were associated with itching and disappeared within 6 days (median: 2 days).

A further retrospective observational study recorded the occurrence of inflammatory lesions, usually a few days after the onset of COVID-19 systemic symptoms, in 7 patients, including exanthem (n=4), varicellalike vesicles (n=2) and cold urticaria (n=1). 33

An eruption worthy of separate comments is that characterized by vesicular or papulovesicular lesions resembling varicella (Table 1) . 6, 20, 34, 35 In the cohort observed by Galván Some cutaneous rashes encountered in association with COVID-19 were characterized by a petechial component, 15, 19, 24, 25 which may have been secondary to thrombocytopenia. 4 These cases were not included in the purpuric "vasculitic" pattern of our classification because, in our opinion, petechial lesions in such circumstances were only an accompanying finding of inflammatory non-vasculitic eruptions which were predominantly characterized by macular or maculo-papular lesions. Petechial lesions could also represent a secondary phenomenon during the natural evolution of the exanthem, as described in a case in which a maculopapular rash became purpuric one week later. 15 Erythematous-purpuric, maculopapular and petechial lesions with a tendency toward a flexural or periflexural distribution have also been reported. 24, 25 Vasculopathic/vasculitic lesions

In a retrospective observational French study, seven patients presented with vascular lesions as follows:

violaceous macules with "porcelain-like" appearance (n=1), livedo (n=1), non-necrotic purpura (n=1), necrotic purpura (n=1), eruptive cherry angiomas (n=1) chilblain-like lesions alone (n=1) and associated with Raynaud's phenomenon (n=1). 33

Manifestations defined as petechiae, tiny bruises or livedoid eruptions have been linked to COVID-19, as reported by an article in a newsmagazine published by the Society of Hospital Medicine. 45 Furthermore, it was speculated that these manifestations may be a result of small blood vessel occlusion whose pathogenic mechanisms (e.g., neurogenic, microthrombotic or immune complex-mediated) are as yet unknown.

Intriguingly, Magro et al. have documented the presence of thrombotic microvascular damage in the lung and/or skin of five critical COVID-19 patients. 31 In three of these patients, purpuric/livedoid skin lesions (Table 2 ) characterized by a pauci-inflammatory microthrombotic vasculopathy were described ( Table 3) .

Deposition of complement components within the skin and lung microvasculature ( In our classification, we distinguished a specific purpuric pattern that was defined as "vasculitic" in order to differentiate it from the petechial component of some exanthematous eruptions, as well as from livedo related to occlusive/microthrombotic vasculopathy. This pattern is likely to be extremely rare. 31,33 In our experience, we observed a case of palpable purpura on the knees ( Figure 1E ) and another patient with purpuric and necrotic lesions of the lower legs, clinically resembling cutaneous leukocytoclastic vasculitis (unpublished data). In such cases, a vasculitic aetiology might be implicated, although histopathological Accepted Article data were unavailable and further studies are required. Interestingly, among the three vasculopathic lesions in the setting of severe COVID-19 documented by Magro et al., the retiform purpura also showed prominent leukocytoclasia, suggesting the coexistence of a vasculitic process ( 

This article is protected by copyright. All rights reserved asymptomatic/pauci-symptomatic forms of COVID-9. 33,41 An increased type I interferon reaction has also been implicated. 30, 33 .

Histopathological examination of lesional skin was performed in a limited number of cases (Table 3) .

Inflammatory lesions generally showed non-specific features. 10 (Table 3 ). In two cases, a biopsy taken from the normal-appearing skin showed microvascular deposits of C5b-9 throughout the dermis.

Direct immunofluorescence studies were performed only in a case of erythematous-oedematous figurate plaques 16 and in a patient with chilblain-like acral lesions 30 , providing negative results in both cases.

RT-PCR for SARS-CoV-2 was very rarely performed on lesional skin samples, and again negative results were obtained. 22 

This article is protected by copyright. All rights reserved 

This article is protected by copyright. All rights reserved 

This article is protected by copyright. All rights reserved Livedo racemosa Modest perivascular lymphocytic infiltrate in the superficial dermis along with deeper seated small thrombi within

China Novel Coronavirus Investigating and Research Team. A novel Coronavirus from patients with pneumonia in China

China Medical Treatment Expert Group for Covid-19. Clinical characteristics of Coronavirus Disease 2019 in China

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Accepted Article This article is protected by copyright. All rights reserved 17. Najarian DJ. Morbilliform exanthem associated with COVID-19

A case of COVID-19 pneumonia in a young male with full body rash as a presenting symptom

Cutaneous manifestation of COVID-19 in images: A case report

Varicella-like exanthem associated with COVID-19 in an 8-year-old girl: A diagnostic clue?

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Digitate papulosquamous eruption associated with severe acute respiratory syndrome Coronavirus 2 infection

Cutaneous clinico-pathological findings in three COVID-19-positive patients observed in the metropolitan area of