Management of urticaria in COVID‐19 patients: A systematic review

Abstract The global pandemic COVID‐19 has resulted in significant global morbidity, mortality and increased healthcare demands. There is now emerging evidence of patients experiencing urticaria. We sought to systematically review current evidence, critique the literature, and present our findings. 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,” and “Skin rash” up to 01 August 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. Our search returned 169 articles, 25 of which met inclusion criteria. All studies were case reports, reporting 26 patients with urticaria and/or angioedema, COVID‐19 infection and their management and/or response. ajority 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 nonresponsive to steroids. Management of urticarial in COVID‐19 patients should involve antihistamines. Low dose prednisolone should be considered on an individualized 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.

morbidity, mortality and significantly increased healthcare demands. 1,2 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. 3 Additionally, severe infections can have an impact on renal and cardiac function. 4 More recently, there has been a growing interest regarding the dermatological manifestations in patients with COVID-19. Skin manifestations during the course of a COVID-19 infection was first reported in China, however the prevalence was low at 0.2% cases out of 1099 cases. 5 There is now emerging evidence in literature making reference to some patients experiencing urticaria. Urticaria manifests itself as urticarial plaques that affect the upper dermis which can cover the skin and mucous membranes. It is described as erythematous and pruritic, and can sometimes present with angioedema, a type of swelling of the dermis subcutaneous tissue, the mucosa, and submucosal tissues. 6 The objective of this systematic review is to review the current literature on urticaria in COVID-19 patients. Furthermore, we aim to provide insight into urticarial pathogenesis and management in such patients.

| Literature search
This study was done according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method identifying published literature on urticaria and/or angioedema due to  infection and its management and outcomes. The comprehensive literature search was carried out with Medline, EMBASE, Scopus, Cochrane database, and Google Scholar, using key MeSH words, which include "COVID-19," "Coronavirus," "SARS-Cov-2," "Urticaria," "Angioedema," and "Skin rash." Manual cross checking of reference lists of relevant articles was performed. All published articles have been reviewed, and the findings have been included in this study. The relevant articles have been cited and referenced within this study. The limits included studies in English and articles published after December 2019 until 01 August 2020. All the relevant articles identified were analyzed by two authors, and the results were appropriately summarized and reported.

| Inclusion and exclusion criteria
The key inclusion criteria were articles that reported on urticaria and/or angioedema due to COVID-19 infection and reported management and outcome, and studies were excluded if no case or cohort outcomes were observed. Other exclusion criteria were consensus documents, editorials, commentaries, and narrative reviews.

| Data extraction
All studies were screened by two authors independently (E.A. and A. D); disagreement was resolved by consensus or involvement of other authors (R.S. and A.H.). The extracted data then were crosschecked by a third author to validate their accuracy (A.H.).

| RESULTS
Following an extensive database search, 169 articles were identified.
Of these, 34 were selected for full text review based on their title and  Table 1 includes the summarized key findings of the studies included in this review. All included articles were case reports.
However, urticaria in the younger ages was not uncommon, with reported case of 2 months old girl. Skin lesions were reported resolve 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 nonresponsive to steroids.

| Demographic of COVID-19 patients with urticaria development
The review population revealed that the majority of patients (18 patients) affected by urticaria were over 50 years old. However, urticaria in the younger ages was not uncommon. Typically, urticaria has a peak onset of 20-40 years and affects females more than males, which was found to be the case in this review. Lifetime incidence of urticaria is reported to be 15%. 32 It has been reported that urticaria may be a rare manifestation of COVID-19, which has been observed in just under 4% of COVID-19 patients. 33 Of note, most case reports have found skin manifestations to not be associated with disease severity 33,29 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%). 34 Further observational studies will aid further understanding of the association of COVID-19 disease progression and dermatological manifestations.

| Pathophysiology of urticaria in COVID-19
The pathophysiology was previously hypothesized to be attributed to drug-induced urticaria. Urticaria is a well-known cutaneous manifestation of a drug eruption, 35 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. 26,33 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. 29 This suggests that urticaria in COVID-19 is likely multifactorial and drug-associated skin manifestations to not account for all cases.
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. 36 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. 37 In the instance of coronavirus infection, the binding of SARS-CoV-2 with ACE2 disrupts normal ACE2 activity. This may result in increased activity of Ang II, leading to formation of reactive oxygen species, disrupt antioxidant and vasodilatory molecules, and result in complement activation. 38 Such disrupted physiological processes were observed in a rat model with aberrant expression of Ang II. 39 COVID-19 associated skin manifestations may be mediated by the systemic inflammatory response that follows the human body's response to an acute infection. 40 This includes activation of the complement system and adjustment of the cytokine-chemokine milieu. 10 Consequently, this progresses to aberrant activation and sequential degranulation of mast cells. It is hypothesized that mast cell degranulation is the principal pathophysiology associated with subsequent systemic organ damage in COVID-19. 41 Of note, most patients with COVID-19 were reported to have elevated levels of circulating interleukin-6 (IL-6). 42 Furthermore, colocalization of SARS-CoV-2 glycoproteins and respective complement mediators have been reported in peripheral cutaneous blood vessels. 43 Therefore, it is possible that these mediators may be attributed to urticarial pathogenesis.  Urticaria has sometimes been associated with eosinophilia (>500 eosinophils/mm 3 ), which has been observed in a number of COVID-19 cases. 44 Moreover, eosinophilia seems to have a protective mechanism and has been associated with a better prognosis. 45 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 COVID-19. 46 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. 52

| Limitations
All included articles were case. Only three case reports detailed pathological study results. 9,13,28 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. 14

| CONCLUSION
Urticaria is a significant manifestation of COVID-19, notably affecting