key: cord-0712092-np3zs3j5 authors: Abuelgasim, Eyad; Dona, Ann Christine Modaragamage; Sondh, Rajan Singh; Harky, Amer title: Management of Urticaria in COVID‐19 Patients: A Systematic Review date: 2020-09-28 journal: Dermatol Ther DOI: 10.1111/dth.14328 sha: f7ff1b127da559e88aab0001b52bf00d4d4fa9c5 doc_id: 712092 cord_uid: np3zs3j5 OBJECTIVES: The global pandemic COVID‐19 has resulted in significant global morbidity, mortality and increased healthcare demands. There is now emerging evidence in of patients experiencing urticaria. We sought to systematically review current evidence, critique the literature and present out findings. METHODS: Allowing PRISMA guidelines, a comprehensive literature search was carried out with Medline, EMBASE, Scopus, Cochrane, and Google Scholar, using key MeSH words, which include “COVID‐19,” “Coronavirus”, “SARS‐Cov‐2”, “Urticaria,” “Angioedema,” “Skin rash” up to August, 01 2020. The key inclusion criteria were articles that reported on urticaria and/or angioedema due to COVID‐19 infection and reported management and outcome. Studies were excluded if no case or cohort outcomes were observed. RESULTS: Our search returned 169 articles, 25 of which met inclusion criteria. All studies were case reports, reporting 26 patients with urticaria and/or angioedema and COVID‐19 infection and their management and/or response. Majority of patients (n=16, 69%) were over 50 years old. However, urticaria in the younger ages was not uncommon, with reported case of 2 months old infant. Skin lesions resolved from less than 24 hours to up to 2 weeks following treatment with antihistamines and/or steroids. There have been no cases of recurrent urticaria or cases non‐responsive to steroids. CONCLUSIONS: Management of urticarial in COVID‐19 patients should involve antihistamines. Low dose prednisolone should be considered on an individualised basis. Further research is required in understanding urticarial pathogenesis in COVID‐19. This will aid early diagnostic assessment in patients with high index of suspicion and subsequent management in the acute phase. This article is protected by copyright. All rights reserved. The global pandemic COVID-19 is caused by severe acute respiratory syndrome coronavirus-2 (SARS-COV2). It has resulted in global morbidity, mortality and significantly increased healthcare demands. 1 It was originally reported that the main symptoms of COVID-19 to be a cough and fever. However, as the pandemic progressed, our understanding of COVID-19 increased, leading to anosmia and/or hyposmia established as a third symptom. As our understanding of this disease increases, it is reported that SARS-COV2 can present with clinical manifestations beyond the respiratory system. We are now aware that neurological manifestation can develop which encompasses acute skeletal muscle injury as well as an impaired consciousness. 2 Additionally, severe infections can have an impact on renal and cardiac function. 3 manifestation of COVID-19, which has been observed in just under 4% of COVID-19 patients. 32 Of note, most case reports have found skin manifestations to not be associated with disease severity 32,28 Conversely, a prospective Spanish cohort study reported that the presentation of urticaria and maculopapular skin lesions were associated with higher morbidity (severe COVID-19 illness) and higher mortality rate (2%). 33 Further observational studies will aid further understanding of the association of COVID-19 disease progression and dermatological manifestations. The pathophysiology was previously hypothesised to be attributed to drug-induced urticaria. Urticaria is a well-known cutaneous manifestation of a drug eruption [34] , however urticaria has been debated in COVID-19 patients as to whether the virus directly results in urticaria, or if urticaria is caused by a drug eruption. There have been reports of COVID-19 positive cases with urticaria, where there had been no changes in their medication regime. 25, 32 This may suggest that urticaria could be directly related to the pathogenesis of the SARS-CoV2. However, individual case reports have reported urticaria manifestation prior to commencement of therapy for COVID-19 as well as reports of remission from urticaria despite continuation of drug therapy. 28 This suggests that urticaria in COVID-19 is likely multifactorial and drug-associated skin manifestations to not account for all cases. This article is protected by copyright. All rights reserved. SARS-CoV-2 entry into a cell is mediated through binding to angiotensin-converting enzyme-2 (ACE2) protein and subsequent endocytosis in epithelial targets in the lung. 35 Of note, systemic response may be owed to the presentation of ACE2 on other tissues, including kidney, brain and importantly, the vasculature. Angiotensin (Ang) I and Ang II are deactivated by ACE2 Ang I and Ang II are associated with inflammation, oxidative stress and fibrotic scarring. 36 This includes activation of the complement system and adjustment of the cytokinechemokine milieu. 9 Consequently, this progresses to aberrant activation and sequential degranulation of mast cells. It is hypothesised that mast cell degranulation is the principal pathophysiology associated with subsequent systemic organ damage in COVID-19. 40 Of note, most patients with COVID-19 were reported to have elevated levels of circulating interleukin-6 (IL-6). 41 Furthermore, colocalization of SARS-CoV-2 glycoproteins and respective complement mediators have been reported in peripheral cutaneous blood vessels. 42 Therefore, it is possible that these mediators may be attributed to urticarial pathogenesis. This article is protected by copyright. All rights reserved. Urticaria has sometimes been associated with eosinophilia (>500 eosinophils/mm 3 ), which has been observed in a number of COVID-19 cases [43] . Moreover, eosinophilia seems to have a protective mechanism and has been associated with a better prognosis. 44 There have also been some cases where patients initially presented with urticaria only before experiencing the typical COVID-19 symptoms and testing positive. What was evident in these cases was that they had been taking some form of prescribed medication prior to testing positive to 46 Despite some patients having no medication changes, they still were taking medication at the time of onset of urticaria, suggesting that COVID-19 may cause eosinophilia, resulting in drug hypersensitivity and thus urticaria. However, more research is needed to formally establish this relation. It is important to ensure that urticaria is correctly diagnosed so that appropriate treatment can be administered. A diagnostic characteristic of urticaria is that the cutaneous lesions must be evanescent. Multiple case reports have not detailed this characteristic in their studies, so it is important this is taken into consideration. Furthermore, some case reports have mentioned how a skin biopsy for histopathological studies may aid in a diagnosis of urticaria. 47 One case report has discussed that a skin biopsy of a COVID-19 patient with urticaria revealed perivascular infiltrate of lymphocytes, some eosinophils and upper dermal oedema. 48 A skin biopsy and awareness of evanescent lesions may allow for the differentiation to be made This article is protected by copyright. All rights reserved. between urticaria and other cutaneous manifestations, limiting the chance of a misdiagnosis. On clinical assessment clinicians should consider the possibility of glucose-6-pyruvate dehydrogenase (G6PD) deficiency in COVID-19 patients as this group of patients may have a dominance of high-producing IL-6 allele. In one study group, this correlation has been reported in 71% of patients 49 . Classically, the recommended algorithm for treating urticaria includes the use of second-generation antihistamines, and if inadequate control within 2-4 weeks, the dose can be increased up to four times the original dose. If this is still inadequate control after a further 2-4 weeks, specialist referral should be considered, where specialists can consider prescribing omalizumab and ciclosporin to help alleviate symptoms. 50 However, in most patients, second generation oral antihistamines provide adequate control of urticaria. 51 The pathophysiology of COVID-19 related urticaria demonstrates that antihistamines alone will not stop mast cell histamine degranulation but will only act to reduce the severity of urticaria. Low systemic steroids, on the other hand, targets the COVID-19 inflammatory storm, which prevents mast cell activation, and thus histamine release. Therefore, low dose systemic steroids may be able to effectively manage urticaria in COVID-19 through their proposed mechanism of action. Combining this with antihistamines can improve patients' clinical response to urticaria 9 . A further benefit of low dose steroids, shown through a randomised control trial, has demonstrated an increase in survival rate in COVID-19 patients (Randomised Evaluation of COVID-19 Therapy (RECOVERY), ClinicalTrials.gov Identifier: NCT04381936). Although corticosteroids are promising, it may increase the risk of prolonged viral replication, so it may be best to use them for the shortest duration possible until symptoms are controlled. After this, consideration should be made to promptly switch to omalizumab. Ciclosporin is currently not recommended in COVID-19 patients. 51 All included articles were case. Only three case reports detailed pathological study results. 8, 12, 27 A diagnostic characteristic of urticaria is that the cutaneous lesions must be evanescent (no one lesion should last more than 24 hours), however this was only noted by Falkenhain-López et al. 13 Urticaria is a significant manifestation of COVID-19, notably affecting patient morbidity. As such the clinical presentation of urticaria can aid diagnostic assessment, whist considering risk factors, such as G6PD deficiency and aberrant IL-6 expression. This article is protected by copyright. All rights reserved. COVID-19: Unique public health issues facing Black, Asian and minority ethnic communities COVID-19 and anosmia: A review based on up-to-date knowledge Neurological Manifestations of COVID-19: A systematic review and current update This article is protected by copyright. All rights reserved Clinical Characteristics of Coronavirus Disease 2019 in China Diagnosis and treatment of urticaria in primary care Urticaria in an Infant with SARS-CoV-2 Positivity Erythematous Papular Rash: A Dermatological Feature of COVID-19 Atypical Skin Manifestations During Immune Checkpoint Blockage in Coronavirus Disease 2019-Infected Patients With Lung Cancer Low-dose systemic steroids, an emerging therapeutic option for COVID-19 related urticaria Urticaria and angioedema as a prodromal cutaneous manifestation of SARS-CoV-2 (COVID-19) infection This article is protected by copyright. All rights reserved Urticaria (angioedema) and COVID-19 infection Urticarial vasculitis in COVID-19 infection: a vasculopathy-related symptom SARS-Coronavirus-2 and acute urticaria Fever with rash in COVID-19: viral exanthema or secondary lesions Urticaria in a patient with COVID-19: Therapeutic and diagnostic difficulties Skin involvement in SARS-CoV-2 infection: Case series Follow-up of skin lesions during the evolution of COVID-19: a case report This article is protected by copyright. All rights reserved. Discharged home in stable condition. 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.