key: cord-0981829-re8hyjqs authors: Sachdeva, Muskaan; Gianotti, Raffaele; Shah, Monica; Lucia, Bradanini; Tosi, Diego; Veraldi, Stefano; Ziv, Michael; Leshem, Eyal; Dodiuk-Gad, Roni P. title: Cutaneous manifestations of COVID-19: Report of three cases and a review of literature date: 2020-04-29 journal: J Dermatol Sci DOI: 10.1016/j.jdermsci.2020.04.011 sha: 78e68426a54ef9394b6072221a12fb603d64f857 doc_id: 981829 cord_uid: re8hyjqs ABSTRACT Background Various cutaneous manifestations have been observed in patients with COVID-19 infection. However, overall similarities in the clinical presentation of these dermatological manifestations have not yet been summarized. Objective This review aims to provide an overview of various cutaneous manifestations in patients with COVID-19 through three case reports and a literature review. Methods A literature search was conducted using PubMed, OVID, and Google search engines for original and review articles. Studies written in the English language that mentioned cutaneous symptoms and COVID-19 were included. Results Eighteen articles and three additional cases reported in this paper were included in this review. Of these studies, 6 are case series and 12 are case report studies. The most common cutaneous manifestation of COVID-19 was found to be maculopapular exanthem (morbilliform), presenting in 36.1% (26/72) patients. The other cutaneous manifestations included: a papulovesicular rash (34.7%, 25/72), urticaria (9.7%, 7/72), painful acral red purple papules (15.3%, 11/72) of patients, livedo reticularis lesions (2.8%, 2/72) and petechiae (1.4%, 1/72). Majority of lesions were localized on the trunk (66.7%, 50/72), however, 19.4% (14/72) of patients experienced cutaneous manifestations in the hands and feet. Skin lesion development occurred after the onset of respiratory symptoms or before COVID-19 diagnosis in 12.5% (9/72) of the patients, and lesions spontaneously healed in all patients within 10 days. Majority of the studies reported no correlation between COVID-19 severity and skin lesions. Conclusion Infection with COVID-19 may result in dermatological manifestations with various clinical presentations, which may aid in the timely diagnosis of this infection. As of April 20 th , 2020, COVID-19 (severe acute respiratory syndrome coronavirus 2 [SARS- or, previously called 2019-nCoV) initially reported in Wuhan, China 1 has been diagnosed in more than 2.4 million people worldwide. 2 The high rate of infectivity, low virulence and asymptomatic transmission have resulted in its rapid spread across geographic boundaries, leading to a pandemic. 3 The outbreak of COVID-19 has been declared a Public Health Emergency of International Concern by the World Health Organization (WHO) and presents a great challenge for the health care communities across the globe. 4 SARS-CoV 2 is an enveloped virus composed of positive sense single-stranded RNA and belongs to the coronavirus family. 1 The virus enters cells through the angiotensin converting enzyme 2 (ACE2) receptor, found on the surface of cells. 1 The lungs are the primary site of infection for COVID-19, with patients presenting symptoms ranging from a mild flu-like symptoms to fulminant pneumonia and potentially lethal respiratory distress. 5 Interestingly, there have been many COVID-19 cases reporting cutaneous manifestations. [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] The purpose of this article is to report three relevant cases and provide a literature review of various cutaneous manifestation in patients with COVID-19. A 71-year-old Caucasian woman presented to the Emergency Department in Milan, complaining of fever, productive cough and worsening shortness of breath which started 10 days before. The patient J o u r n a l P r e -p r o o f 4 of 15 was otherwise healthy with no co-morbidities, medications or previous adverse drug reactions. She was living in Milan with her husband, who was diagnosed with COVID-19. Laboratory tests revealed a normal white blood cells and platelet count (WBC 6470/mm, PLT 290.000/mmc), normal liver and kidney function and an increased C-reactive protein (49.4 mg/L). Blood cultures were negative. Bilateral interstitial pneumonia was found on chest x-ray. Naso-pharyngeal swab tested for SARS-CoV-2 RNA amplification resulted positive. She was admitted to the Infectious Disease Department and started off-label antiviral therapy with lopinavir/ritonavir and hydroxychloroquine, following Italian Society of Infectious and Tropical Diseases (SIMIT) guidelines and empiric antibiotic therapy with third generation cephalosporin (ceftriaxone). Other drugs administered during hospitalization were: rabeprazole, paracetamol, metoclopramide, dihydrocodeine, lactulose and subcutaneous low molecular weight heparin. In the subsequent days, she promptly recovered: she never had fever, we have been able to gradually decrease oxygen flow and on the 30 th of march, antiviral and antibiotic therapies were discontinued. Over the following days a maculo-papular itchy rash appeared on the trunk resembling a Grover disease ( Figure 1 ). A 77-year-old Caucasian woman was admitted to the hospital in Milan, due to neck lymphonodal enlargement, fever, cough and diffuse maculopapular exanthem (morbilliform) on the trunk ( Figure 2a ). One day later during hospitalization, she also developed macular hemorrhagic rash on the legs ( Figure 2b) . Naso-pharyngeal swab tested for SARS-CoV-2 RNA amplification were positive. No signs of pneumonia were found on the chest x ray. Treatment consisted of antiviral therapy using lopinavir/ritonavir and hydroxychloroquine and subcutaneous low molecular weight heparin. Gradual spontaneous improvement of skin lesions appeared. A 72-year-old Caucasian woman, otherwise healthy, presented to the Emergency Department in Milan with headache, arthralgia, myalgia and fever. Four days later, a papular-vesicular, pruritic eruption appeared on sub-mammary folds, trunk and hips ( Figure 3 ). Laboratory examination J o u r n a l P r e -p r o o f conducted revealed mild increase in WBC, C-reactive protein and erythrosedimentation rate (ESR). COVID-19, tested with naso-pharyngeal swab, was positive. Chest X ray was negative for pneumonia. Complete remission of both general and cutaneous manifestations was observed approximately ten days after the beginning of the clinical picture. A literature search was conducted using PubMed, OVID and Google search engines for original and review articles published since the onset of the current COVID-19 epidemic to April 20, 2020. Search terms "COVID-19", "2019-nCoV", "SARS-CoV-2" and "coronavirus" were used in combination with "skin", "dermatology", "cutaneous", "urticaria" and "rash". We also performed extensive hand searching of reference lists of relevant papers and reports. The studies that did not mention cutaneous symptoms or did not include any relevant information in the English language were excluded. We extracted the following data from included studies: author, publication year, region, number of participants with skin signs, age, sex, suspected or confirmed status for COVID-19, cutaneous signs and its location, timeline and healing duration, associated symptoms, correlation with COVID-19 severity with skin lesions and treatments for COVID-19 infection. When extracting information from the studies, pairs of researchers conferred to compare findings and reach consensus. Where consensus was not reached, an independent researcher was consulted. We also searched for grey literature including advisories from professional societies, expert commentaries, blogposts, magazine articles, newspaper articles and social media posts to retrieve relevant information. The information from grey literature was not included in the results section, however, it has been summarized in the Supplemental File 1. Eighteen articles and three additional cases (reported in this review) that met the aforementioned inclusion criteria were summarized in this review. All studies were published during February and April 2020, with 61.1% of articles published in April. There are 6 case series 6-9,16,20 and 12 case reports [10] [11] [12] [13] [14] [15] [17] [18] [19] [21] [22] [23] . The mean patient age was 53.6 years, with patients between 15 days and 84 years J o u r n a l P r e -p r o o f of age. Males accounted for 38.9% of reported cases, females accounted for 27.8% of cases, and the sex of 37.5% cases was not reported. In terms of COVID-19 diagnosis, 2.8% patients were suspected cases and 97.2% were confirmed cases. Table 1 Cutaneous manifestations are important in the diagnosis of various infectious diseases, such as toxic shock syndrome, meningococcemia, rickettsial diseases, measles, and scarlet fever. [27] [28] [29] [30] [31] As COVID-19 has a tendency to produce asymptomatic cases for up to 14 days after infection, cutaneous manifestations may serve as an indicator of infection, aiding in timely diagnosis. In this review, 12.5% (9/72) of patients presented with cutaneous lesions at onset. Furthermore, physicians' awareness of the cutaneous symptoms related to COVID-19 infection is critical in preventing misdiagnosis of disease, such as the misdiagnosis of dengue as reported by Joob et al. 10 The mechanisms of COVID-19 cutaneous disturbances are not yet well known, but some common theories are prevalent. It can be postulated that the viral particles present in the cutaneous blood vessels in patients with COVID19 infection could lead to a lymphocytic vasculitis similar to those observed in thrombophilic arteritis induced by blood immune complexes that activate cytokines. Keratinocytes may be a secondary target after Langerhans cells activation, inducing a spectrum of different clinical manifestation. 6, 32 It can be postulated that the virus does not target the keratinocyte, but rather immune response to infection leads to Langerhans cells activation, resulting in a state of vasodilation and spongiosis. 32 Further theories suggest livedo reticularis-resembling manifestations J o u r n a l P r e -p r o o f can result due the accumulation of microthromboses originating in other organs, thus reducing blood flow to the cutaneous microvasculature system. 8 Similarly, low grade disseminated intravascular coagulation and hypoxia-related accumulation of deoxygenated blood in venous plexes may further explain such manifestations. 8 Additionally, pauci-inflammatory thrombogenic vasculopathy with deposition of C5b-9 and C4d as well as co-localization of these with COVID-19 spike glycoproteins was reported by Magro et al. 33 It is still unclear whether cutaneous symptoms are a secondary consequence of respiratory-related infection or a primary infection of the skin itself. It is more likely that a combination of such mechanisms is responsible for the cutaneous manifestations found in COVID-19+ individuals. There are several limitations that must be considered for this literature review. Firstly, the small sample size used in this analysis restricts the ability to draw strong conclusion applicable to whole populations. Additionally, since scientific understanding of COVID-19 and associated dermatological symptoms is currently evolving at this stage, the information contained in this review is based mainly The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak-an update on the status World Health Organization. Coronavirus disease (COVID-19) outbreak situation World Health Organization The transmission and diagnosis of 2019 novel coronavirus infection disease (COVID-19): A Chinese perspective Rolling updates on coronavirus disease (COVID-19). 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