key: cord-0992284-916bm0f0 authors: Atzori, Laura; Recalcati, Sebastiano; Ferreli, Caterina; Hoenig, Leonard; Rongioletti, Franco title: COVID-19-related skin manifestations: Update on therapy date: 2020-12-14 journal: Clin Dermatol DOI: 10.1016/j.clindermatol.2020.12.003 sha: 49a053030e4cdac3f76abc861cdd91387540976f doc_id: 992284 cord_uid: 916bm0f0 An increasing body of evidence has been produced in a very limited period of time to improve the understanding of skin involvement in the current Coronavirus 2019 disease pandemic, and how this novel disease impacts the management of dermatologic patients. A little explored area is represented by the therapeutic approach adopted for the different skin manifestations associated with the infection. An overview of the current scenario is provided, through review of the English-language literature published through October 30, 2020, and comparison with the personal experience of the authors. As dermatologists, our primary aim is to support patients with the highest standard of cares and relieve sufferance, even with lesions not being life-threatening. With asymptomatic COVID-19 patients, patients discomfort related to skin lesions should not be undervalued, and intervention to accelerate healing should be provided. Consensus protocols are warranted to assess the best skin targeted treatments in COVID-19 patients. From the March 11, 2020 declaration of coronavirus 2019 disease (COVID-19) as a pandemic, 1 skin involvement has progressively gained the attention of the medical community, from early limited case series to now a significant body of evidence. [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] Although actual worldwide prevalence is still far from being clearly defined, it has been estimated to approach 1-2% of the world's population. 19 The presentation is very polymorphic, and according to the Spanish prospective nationwide consensus, 4 three patterns are most characteristics: chilblain-pernio like lesions, ischemic-livedoid/necrotic lesions. and the varicelliform-like/vesicular eruption. Less specific manifestations include erythematous, urticarial, purpuric, maculopapular, or papulo-squamous eruptions. There is even a peculiar Kawasaki-like presentation in children, named multisystem inflammatory syndrome (MIS). [20] [21] [22] Interpretation of the underlying pathogenetic mechanisms is a current challenge that commits numerous research groups around the world to distinguish among specific viral skin injuries and the consequences of the multisystemic involvement. [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] Substantial breakthroughs will occur, with the development of specific SARS-CoV-2 assays for histopathologic, immunohistochemical, and ultrastructural study of the skin. However, a little explored area is represented by the treatment options adopted to manage these cutaneous manifestations. It may depend on the tendency to the spontaneous recovery of most conditions; alternatively, the therapy of skin lesions may have received less attention in view of the greater severity of lung and multiorgan involvement. We have reviewed English-language literature published through 2020 and augmented our findings with the personal experience of the authors because symptomatic and supportive treatment are important to relieve the patient discomfort and accelerate skin lesions healing A retrieval of published English-language literature was performed through October 30, 2020, collecting original cases or case series of cutaneous manifestations related to COVID-19, with specific information on the treatment adopted. The following databases were consulted: PubMed, Google Scholar, and Research Gate. Key terms included severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or COVID-19 combined with each of the following: We then analysed the descriptions of skin manifestations and the related treatments Treatment of adverse skin reactions to COVID-19 therapies were excluded. Management of common chronic inflammatory skin diseases, as well as skin cancers or consequences of personal protective devices Very few reports explicitly included as keywords or title the therapeutic use were also discarded. approach for the occurrence of skin lesions associated with COVID-19 infection, 35,36 and several expert reviews were also considered to collect information on recommended treatment. [13] [14] [15] [16] In parallel, an observational retrospective study was performed on all patients presenting to the Dermatology Unit of the Alessandro Manzoni Hospital in Lecco (Italy). Data collected included demographics, type of skin manifestations, systemic and topical treatment employed, and outcome. Our findings are summarized in table 1. The majority of reports concerned chilblain/pernio-like cutaneous manifestations and specify that no treatment was needed. 28, 36,, 39-42 For isolated cases, 37,38 two expert opinion leaders suggested that high-potency topical corticosteroids may be helpful if the lesions were causing discomfort. 16, 43 For acro-ischemic lesions, medication with topical corticosteroids, alone or in combination with topical antibiotics, is more widely reported. 4, 5, 18, 44 As these manifestations occur in severely ill patients, due to the pro-thrombotic setting, treatment with low molecular weight heparin can be beneficial. 31 This has been included in standard COVID-19 protocols. 45 For exanthematous eruption associated with COVID-19, the most specific finding represented by the varicelliform-like/vesicular lesions is usually not specifically treated or discussed in general COVID-19 protocols. 3, 4 A prospective observational study from China and Italy documented an overall rate of 7.8% inflammatory cutaneous findings in confirmed COVID-19 patients. These have a self-limiting course and resolution without specific therapy. 6 Several authors have suggested the use of corticosteroids, other topically and orally, plus the administration of oral antihistamines. 4, 46-49 One reported recommended the use of vitamin C. 49 A systematic review, and case series of acute urticaria in COVID-19 patients recommend treatment with antihistamines. [50] [51] [52] [53] with additional low dose prednisone to be considered on an individualized basis. 54 The skin lesions resolved within 24 hours or up to 2 weeks. Low dose systemic steroid was also suggested to treat COVID-19 related anagen effluvium, in a 35-year-old Iranian woman, with a concomitant mixed urticarial and maculopapular rash. 55 Purpuric, petechial and/or livedoid eruptions are associated with severe COVID-19 and thus again, beneficiate of same supportive measures and anticoagulant treatment of the systemic disease. 30, 56, 57 More severe erythema multiforme-like eruptions can be treated with systemic steroids, 58,59 as well as leucocytoclastic vasculitis associated with COVID-19. A dose of 0.5 mg/Kg/daily has been reported as efficacious, 60, 61 although a patient already under steroids developed a purpuric leukocytoclastic vasculitis. 62 Further isolated anecdotal case reports were not included in this review. Additional information includes both inpatient (36 patients) and outpatients (48 patients), as well as the recovery times, ranging from 1 to 8 weeks. An example of chilblain/pernio-like lesions (Fig.1) , and erythema polymorphous lesions (Fig. 2, 3 ) are provided. The exponential rise of pandemic COVID-19 affects all of medicine, notwithstanding dermatology. The disease is so new and different from any previous viral outbreak that protocols and guidelines are lacking. 63 Granted, there is a wide body of evidence is being rapidly produced from case reports, observational studies, and systematic reviews. Skin manifestations are often mild and self-limited, except for the severely ill COVID-19 patients who may have experienced disseminated thromboembolic events, accompanied by purpuric eruptions and acro-ischemic lesions. Unfortunately, both from the literature review and the authors' personal experience found at the Lecco Hospital, skin disease has been relegated to a general wait and see approach. Dealing with a very new disease, priority has been given not to worsen the infection course. For example, the use of systemic corticosteroids was initially avoided for fear of prolonging the COVID-19 disease duration and increasing the mortality rate. 45. Actual guidelines derived from randomized clinical trials now include strong recommendations for the use of corticosteroids in critically ill patients with COVID-19. 64, 65 Another controversial point concerned antihistamines and their effect on the QT interval, especially mizolastine and ebastine, which might trigger cardiac arrhythmias if hydroxychloroquine or azithromycin were concomitantly administered. 66 To avoid such risks, antihistamines devoid of these hazardous drug interactions should be prescribed for maculo-papular und urticarial eruption. While hospitalized patients usually beneficiate of the general supportive cares and constant specialized assistance, outpatients should be offered targeted skin therapies to shorten the duration of symptoms when skin manifestations tend to persist longer than expected. Exanthematous eruption could beneficiate of medication with topical steroids, alone or in combination with topical antibiotics to relieve tissue inflammation, and accelerate the healing. Same medications are indicated both in mild chilblain/pernio-like lesion, and more severe acro-ischemic manifestations. Lesions with consistent vascular damage, in the setting of hypercoagulation disease (acro-ischemic, purpuric and livedoid lesions, leucocytoclastic vasculitis) beneficiate of current COVID-19 standard of care, which includes subcutaneous low molecular weight heparins and systemic steroids. As dermatologists, our primary aim is to support patients with the highest standard of care and to relieve the associated discomfort, even though the lesions are not life-threatening. Patients with mild or asymptomatic disease might benefit from a targeted skin treatment, to shorten its duration and reduce discomfort. WHO declares COVID-19 a pandemic Cutaneous manifestations in COVID-19: a first perspective Varicella-like exanthem as a specific COVID-19-associated skin manifestation: multicenter case series of 22 patients Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases Characterization of acute acro-ischemic lesions in nonhospitalized patients: a case series of 132 patients during the COVID-19 outbreak Cutaneous manifestations related to coronavirus disease 2019 (COVID-19): A prospective study from China and Italy Viral exanthem in COVID-19, a clinical enigma with biological significance Cutaneous manifestations in COVID-19: the experiences of Barcelona and Rome COVID-19 and cutaneous manifestations Diversity of clinical appearance of cutaneous manifestations in the course of COVID-19 Special dermatological presentation of paediatric multisystem inflammatory syndrome related to COVID-19: erythema multiforme An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study Clinical and Histopathological Features and Potential Pathological Mechanisms of Skin Lesions in COVID-19: Review of the Literature Erythema multiforme-like lesions in children and COVID-19 Assessment of Acute Acral Lesions in a Case Series of Children and Adolescents During the COVID-19 Pandemic No evidence of SARS-CoV-2 infection by polymerase chain reaction or serology in children with pseudo-chilblain COVID-19) infection-induced chilblains: A case report with histopathologic findings A clinical, histopathological and laboratory study of 19 consecutive Italian paediatric patients with chilblain-like lesions: lights and shadows on the relationship with COVID-19 infection SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases Lesiones pernióticas y acrales en Espa˜na durante el confinamiento por COVID: análisis retrospectivo de 12 casos Approach to Chilblains During the COVID-19 Pandemic Novel outbreak of acral lesions intimes of COVID-19: a description of 74 cases from a tertiary university hospital in Spain A Comprehensive Literature Review on the Clinical Presentation, and Management of the Pandemic Coronavirus Disease 2019 (COVID-19) Pityriasis rosea as a cutaneous manifestation of COVID-19 infection A distinctive skin rash associated with coronavirus disease 2019? Cutaneous clinico-pathological findings in three COVID-19-positive patients observed in the metropolitan area of Viral exanthema as manifestation of SARS-CoV-2 infection: A case report Management of urticaria in COVID-19 patients: A systematic review Urticarial eruption in COVID-19 infection Acute urticaria with pyrexia as the first manifestations of a COVID-19infection Urticarial exanthem as early diagnostic clue for COVID-19 infec-tion Low-dose systemic steroids, an emerging therapeutic option for COVID-19 related urticaria COVID-19 related anagen effluvium Venous thrombosis and arterioscle-rosis obliterans of lower extremities in a very severe patientwith 2019 novel coronavirus disease: a case report A dermatologic manifestation of COVID-19: transient livedo reticularis Erythema multiforme-like eruption in patients with COVID-19 infection: clinical and histological findings A case of erythema multiforme major in a patient with COVID 19: The role of corticosteroid treatment Cutaneous small vessel vasculitis secondary to COVID-19 infection: a case report Leucocytoclastic vasculitis in a patient with COVID-19 with positive SARS-CoV-2 PCR in skin biopsy A generalized purpuric eruption with histopathologic features of leucocytoclastic vasculitis in a patient severely ill with COVID-19 Creating dermatology guidelines for COVID-19: The pitfalls of applying evidence-based medicine to an emerging infectious disease Dexamethasone in hospitalized patients with COVID-19 -preliminary report Corticosteroids in COVID-19 ARDS: Evidence and Hope During the Pandemic Cutaneous drug eruptions associated with COVID-19 therapy