key: cord-0978471-d08se82o authors: Sharma, Surabhi; Raby, Edward; Prasad Kumarasinghe, Sujith title: Cutaneous manifestations and dermatological sequelae of Covid‐19 infection compared to those from other viruses date: 2021-02-17 journal: Australas J Dermatol DOI: 10.1111/ajd.13561 sha: 668002551e4bd9d47731e478c2761227076e25be doc_id: 978471 cord_uid: d08se82o In the last few months, there have been numerous reports describing a variety of cutaneous signs associated with COVID‐19. Clinicians from Italy were the first to describe the cutaneous manifestations of COVID‐19, which were later observed in other parts of the globe. In some cases, cutaneous signs were the only manifestation of COVID‐19 rather than the typical syndrome of fever and upper respiratory tract symptoms. However, there is considerable heterogeneity amongst the cutaneous signs described so far, which has been published extensively. Our aim is to summarise the latest studies that have reported the early and late cutaneous signs of COVID‐19 and compare them to the most common established viral exanthems. Viruses can cause distinctive exanthems which help the clinician hypothesise a diagnosis even before the results of diagnostic investigations become available. Contrary to the initial belief, severe acute respiratory syndrome caused by a new coronavirus (SARS-CoV2; also known as COVID- 19) doesn't have a specific exanthem but can present with various cutaneous manifestations which are important to recognise. Erythema infectiosum, varicella, infectious mononucleosis and measles are some examples of specific viral exanthems which are well established and share some similarities with the cutaneous signs of COVID-19. Our aims are twofold, firstly to describe the various cutaneous manifestations of COVID-19 that have been observed so far based on their morphology and time of onset, and secondly, to compare their similarities and differences with other established viral exanthems. A comprehensive literature review was conducted via PubMed for the search terms 'COVID-19 and skin'; 'COVID-19 and dermatology'; 'coronavirus and skin' and 'coronavirus and dermatology'. Additional studies were sourced through a Google search and reference lists of a few recent review articles. A total of 576 articles were carefully screened, and 55 articles were further evaluated for cutaneous signs of COVID-19. Only patients with a confirmed diagnosis of COVID-19 using polymerase chain reaction diagnostic assay of nasopharyngeal (NP) swab samples and/ or antibody testing were included in the study. Eight studies were further excluded as they used a clinical diagnosis of COVID-19 without confirmatory laboratory investigations. Information on confirmed cases of COVID-19 was extracted from the study if it reported both suspected and confirmed cases. Our search included articles in different languages, which had translations available. The exanthems were divided into broad clinical categories of (1) generalised maculopapular or morbilliform eruption (2) varicella-like or vesicular lesions (3) vascular ischaemic lesions or chilblains (4) acute urticaria and (5) others. We only included established viral exanthems known to be associated with respiratory symptoms in prominent dermatology and virology textbooks for comparison with COVID-19. 1-3 Literature review identified 406 reported cases of COVID-19 with cutaneous signs meeting the inclusion criteria ( Table 1) . The most common type of manifestations ( COVID-19 can present as a syndrome of dry cough, fever, rhinorrhoea, anosmia and fatigue with radiological evidence of bilateral pneumonia seen on chest x-ray and CT chest. 6 Recalcati and colleagues were the first to describe the cutaneous manifestations of COVID-19 infection observed in Italy in 20% of their cohort. 6 Subsequently, new reports have come from many countries confirming the widespread cutaneous signs related to the virus which has been observed sporadically in COVID-19 patients. A recent review by Tang et al. analysed 16 studies with 88 confirmed COVID-19 related cutaneous manifestations and concluded that they can be categorised as erythematous, urticarial, and vesicular (chicken pox-like or varicelliform) which most commonly affected the trunk. 7 Some individual reports of a petechial eruption, livedo reticularis, pityriasis rosea and reactivation of herpes simplex virus-1 have also been reported. 8, 9 There has also been reports of outbreaks of peculiar perniosis-like acral lesions (chilblains) that have occurred in Spain and Italy amidst the pandemic believed to be a late manifestation of the COVID-19 infection; however, its relevance is questionable as discussed later in the article. 10,11 COVID-19 associated Kawasaki syndrome or paediatric multisystem inflammatory syndrome temporarily associated with COVID-19 (PIMS-TS), also known as multisystem inflammatory syndrome in children (MIS-C) has emerged in Europe and America, with very few cases observed in Asia, especially Japan where the usual incidence is 20 times higher than the Western world. 12 One report recorded significant differences in the COVID-19 triggered Kawasaki disease to the traditional entity, in that COVID-19 was associated with Kawasaki in older children (mean age: 7.5 years) and caused haemodynamic instability in 20% of the affected children as compared to the usual 7%. 12 According to the analysis done by Tang et al., the latency period between the prodromal clinical symptoms such as cough and fever and cutaneous presentation was À2 to 21 days, with some reports suggesting that the cutaneous manifestation was the only symptom of COVID-19 in otherwise asymptomatic patients. 7, 13 The pathogenesis of the skin signs of COVID-19 remains poorly understood and warrants further investigation via large scale prospective studies analysing the serological profile of the antibody response to the infection supported by histopathological diagnosis through biopsies. A study reporting the clinical patterns and sequalae of COVID-19 skin lesions suggested that chilblains affected younger patients, lasted longer and presented later in the disease and were associated with less severe disease. 14 Similar observations have been reported by Andina et al. and Recalcalti et al. 10, 15 In comparison, urticarial and maculopapular lesions occurred earlier in the disease and were associated with more severe COVID-19 disease. 14 Necrotic lesions mainly affected older patients who had severe COVID-19 disease, which is also evident from the data summarised in Table 1 . 14 Given the variety of cutaneous presentations and their timing with respect to stage of disease, it is likely that there are distinct underlying mechanisms potentially including direct endothelial infection, coagulopathy with microthrombosis and immune complex deposition. 16 SARS-CoV-2 virus shows endothelial tropism due to the including coagulopathy. 16 Furthermore, the deposition of immune complexes on vessels has been implicated in COVID-19 vasculitis with some reports describing leukocytoclastic vasculitis on histopathology. 17 The cutaneous side effects of medications used to treat COVID-19 such as hydroxychloroquine need to be reported as they can be similar to the cutaneous manifestations of COVID-19. 18 Moreover, the pandemic has resulted in cutaneous signs for up to 97% of the frontline healthcare workers due to the strict personal protective equipment requirements, with the most common eruptions being desquamation, erythema and maceration over the nasal bridge, cheek and face from wearing the N95 facial masks. 19, 20 The maculopapular (Fig. 1 ) and morbilliform exanthem is quite commonly observed with other viral infections associated with respiratory symptoms such as infectious mononucleosis, measles, rubella, human immunodeficiency virus (HIV) and roseola, which can also present with a similar prodrome of fever, nasal congestion, cough followed by the skin signs. 1-3 Measles, pityriasis rosea, erythema multiforme and Kawasaki disease are some examples of non-specific viral exanthems that are similar to the reported cutaneous signs of COVID-19. 8, 12 The vesicular eruption observed in COVID-19 patients is similar to varicella, hand foot and mouth (HFM) and acute generalised exanthematous pustulosis (AGEP). 1,2 Chilblains, also known as pernio, are quite unusual in other viral upper respiratory tract infections and the mechanism by which SARS-CoV-2 leads to this manifestation is still being investigated. Chilblains can be primary (idiopathic or cold related) or secondary (connective tissue disorders, haematological malignancies, cryopathies, blood hyper viscosities and genetic conditions). 1,2 A study of children from Spain, reported mild symptomatic chilblains as a late manifestation of COVID-19 based on a single case which was positive for COVID-19 via nasopharyngeal swabs. 10 We have not included the patients with chilblains who had negative swab results and thus the prevalence of chilblains may be underrepresented in the summary we have provided. However, given that the PCR result was negative for SARS-CoV-2 in most patients with chilblains, many clinicians question the reliability of this clinical sign in the diagnosis of COVID-19. Other vascular manifestations of COVID-19 such as acro-ischaemic lesion have been reported by Yang et al. with a median latency period of 19 days. 21 Table 3 summarises the key similarities and differences between the different viral exanthems (Fig. 2, Fig. 3 Rook's Textbook of Dermatology Principles and Practice of Clinical Virology Two cases of COVID-19 presenting with a clinical picture resembling chilblain: first report from the Middle East Urticarial exanthem as early diagnostic clue for COVID-19 infection Cutaneous manifestations in COVID-19: a first perspective Cutaneous manifestations of the Coronavirus Disease 2019 (COVID-19): A brief review Pityriasis rosea as a cutaneous manifestation of COVID-19 infection Comment on 'Cutaneous manifestations in COVID-19: a first perspective' by Recalcati S Chilblains in children in the setting of COVID-19 pandemic. Pediatric Dermatol Histologic features of long-lasting chilblain-like lesions in a paediatric COVID-19 patient An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS CoV-2 epidemic: an observational cohort study SARS-CoV-2 infection presenting as a febrile rash Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases Acral cutaneous lesions in the time of COVID-19 Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science Type 3 hypersensitivity in COVID-19 vasculitis Increased cutaneous reactions to hydroxychloroquine (Plaquenil) possibly associated with formulation change: Comment on the letter by Alarc on Occupational skin disease among health care workers during the coronavirus (COVID-19) epidemic The adverse skin reactions of health care workers using personal protective equipment for COVID-19 Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia Cutaneous manifestations of COVID-19: Report of three cases and a review of literature Varicella-like exanthem as a specific COVID-19-associated skin manifestation: Multicentere case series of 22 patients COVID-19) infection-induced chilblains: A case report with histopathologic findings Morbilliform exanthem associated with COVID-19 Novel coronavirus in a 15-day-old neonate with clinical signs of sepsis, a case report Urticarial eruption in COVID-19 infection Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China Cutaneous manifestations in COVID-19: a new contribution A distinctive skin rash associated with Coronavirus Disease A case of COVID-19 pneumonia in a young male with full body rash as a presenting symptom. 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Brit Cutaneous manifestations in COVID-19: familial cluster of urticarial rash Characterization of acute acral skin lesions in non-hospitalized patients: A case series of 132 patients during the COVID-19 outbreak Varicella-like exanthem associated with COVID-19 in an 8-year-old girl: A diagnostic clue? Periorbital erythema as a presenting sign of Covid-19 A case of COVID-19 pneumonia presenting with acute urticaria Dermatologic findings in two patients with COVID-19 Chilblainlike lesions on feet and hands during the COVID-19 Pandemic Cutaneous small vessel vasculitis secondary to COVID-19 infection: a case report Acute maculopapular eruption in Covid-19 patient: a case report Pernio-like skin lesions associated with COVID-19: a case series of 318 patients from 8 countries Cutaneous manifestations in COVID-19: a skin rash in a child Acro-ischemia and COVID-19 infection: clinical and histopathological features Retiform purpura as a dermatological sign of coronavirus disease 2019 (COVID-19) coagulopathy Rash as a presenting complaint in a child with COVID-19 Relapsing symmetric livedo reticularis in a patient with COVID-19 infection Catastrophic acute bilateral lower limbs necrosis associated with COVID-19 as a likely consequence of both vasculitis and coagulopathy Skin manifestations in COVID-19: A case series of 5 patients from Elazı G, Turkey