key: cord-0868312-o06a6xtb authors: Mashayekhi, Farzaneh; Seirafianpour, Farnoosh; Pour Mohammad, Arash; Goodarzi, Azadeh title: Severe and life‐threatening COVID‐19‐related mucocutaneous eruptions: A systematic review date: 2021-08-19 journal: Int J Clin Pract DOI: 10.1111/ijcp.14720 sha: 1463c74c4d47fbfdac2358f0744791662577f471 doc_id: 868312 cord_uid: o06a6xtb OBJECTIVES: Earlier diagnosis and the best management of virus‐related, drug‐related or mixed severe potentially life‐threatening mucocutaneous reactions of COVID‐19 patients are of great concern. These patients, especially hospitalized cases, are usually in a complicated situation (due to multi‐organ failures), which makes their management more challenging. In such consultant cases, achieving by the definite beneficial management strategies that therapeutically address all concurrent comorbidities are really hard to reach or even frequently impossible. METHODS: According to the lack of any relevant systematic review, we thoroughly searched the databases until October/5/2020and finally found 57 articles including 93 patients. It is needed to know clinical presentations of these severe skin eruptions, signs and symptoms of COVID in these patients, time of skin rash appearance, classifying drug‐related or virus‐related skin lesions, classifying the type of skin rash, patients’ outcome and concurrent both COVID‐19 therapy and skin rash treatment. RESULT: Severe and potential life‐threatening mucocutaneous dermatologic manifestations of COVID‐19 usually may be divided into three major categories: virus‐associated, drug‐associated, and those with uncertainty about the exact origin. Angioedema, vascular lesions, toxic shock syndrome, erythroderma, DRESS, hemorrhagic bulla, AGEP, EM, SJS and TEN, generalized pustular figurate erythema were the main entities found as severe dermatologic reactions in all categories. CONCLUSION: We can conclude vascular injuries may be the most common cause of severe dermatologic manifestations of COVID‐19, which is concordant with many proposed hypercoagulation tendency and systemic inflammatory response syndrome as one of the most important pathomechanism of COVID‐19so the skin may show these features in various presentations and degrees. In December 2019, the pandemic of novel coronavirus was reported in Wuhan province of China 1 .COVID-19 is a single-stranded RNA virus related to betacoronavirus genus, it is in the Orthocoronavirinae subfamily which is common between acute respiratory syndromeassociated coronavirus (SARS-CoV) and the Middle East respiratory syndrome-associated coronavirus (MERS-CoV) leading to previous epidemics or pandemics of severe and fatal coronavirus diseases in 2002 and 2012. 1, 2 The Virus attaches to the angiotensin-converting enzyme 2 (ACE2) receptor which is located in the cell membrane of the lungs, heart, kidney, and arteries, and then enters the host cells. 3 According to recent studies, both aerosols and droplets are modes of coronavirus disease transmission. 4 Clinical manifestation of COVID-19 is varied from flu-like syndrome and mild upper respiratory tract infection to acute respiratory distress syndrome and death. 5 Respiratory tract sampling by real-time PCR is a gold standard diagnostic method. 1 This article is protected by copyright. All rights reserved Besides the multi-systems involvement in COVID-19 diseases, dermatological manifestations have been poorly delineated. 2 In one study, 20% of the patients have skin presentation, and skin rash was the initial manifestation of COVID-19 in 44% of them. 6 Skin manifestations are divided into four groups: 1) virus-related skin lesion, 2) skin reaction due to protective equipment and hand sanitizer, 3) adverse drug reaction of therapies for COVID-19, 4) primary skin diseases which are affected by virus or its therapies. 3 The skin manifestations are diverse, such as urticarial, livedoid eruptions, purpuric eruptions, livedoid vasculopathy, varicella-like vesicles, photo-contact dermatitis, generalized pustular figurate erythema, lichenoid photodermatitis, and erythroderma. 3 Recently, Some COVID-19 studies reported severe and life-threatening cutaneous drug reactions like AGEP and DRESS. 7, 8 Widespread use of drugs such as hydroxychloroquine in treatment and prophylaxis of COVID-19, was associated with increased drug-induced skin reactions like AGEP and erythema multiforme. 7 Despite drug-induced severe mucocutaneous skin reactions, vasculitis and vasculopathy lesions due to endothelial damage with COVID-19 in clinically ill patients have been reported that should be considered as a severe form of skin lesions. 9 Several numbers of life-threatening mucocutaneous reactions are: 10 The mortality rate is varied from less than 5% to higher than 14.8%. 17, 18 Accepted Article This article is protected by copyright. All rights reserved Severe skin reactions are potentially life-threatening, and delayed diagnosis is associated with high mortality rates and internal organ damage which has permanent sequelae in patients. Earlier diagnosis is even more important for proper medical management of COVID-19 patients with severe mucocutaneous reactions; since these patients especially hospitalized ones are usually in a complicated situation (due to multi-organ failures), management of any potential life-threatening reactions is more challenging. In these challenging cases, make a definite beneficial managing decision− therapeutically addresses all concurrent comorbidities (COVID-19 and its systemic consequences) and the emerging concomitant severe and potential life-threatening dermatologic reactions (virus or drug-related)−is hard to approach, in addition to some further proposed controversies. According to the lack of relevant systematic review, there is an obvious requirement for diagnosing, assessing, and treatment in the case of severe and life-threatening mucocutaneous reactions; so the purpose of this study was to systematically review the literature on clinical presentations of severe potential life-threatening skin eruptions, primary symptoms of COVID-19, time of skin rash appearance, categorized drug-related or virus related skin lesions, classifying type of skin rash, patients' outcome and handling both COVID-19 therapy and skin rash treatment. To our best knowledge, this is the first systematic review to address this important topic and may have really practical points for specialists (dermatologists and first-line physicians manage these patients).. This study is implemented according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. The PRISMA flow chart is shown in Figure- 1. A search was carried out in Medline (PubMed) (http://ncbi.nlm.nih.gov/pubmed), Scopus This article is protected by copyright. All rights reserved coronavirus dermatology resource of Nottingham University (https://www.nottingham.ac.uk/). The search strategy for databases is shown in Figure-2 in the supplement file. It should be noted that all articles resulting from this search in PubMed, Scopus, and Embase were included, but in Google Scholar, only the 100 newest articles were selected from a total of 2289 articles. The search was not limiting the entries to any condition. The search was performed by keywords COVID-19 and alternative names have been called, and all the severe skin manifestations such as Stevens-Johnson syndrome, erythema multiforme major, toxic epidermal necrolysis, toxic shock syndrome, acute generalized exanthematous pustulosis, dress syndrome, angioedema, serum sickness, and their synonyms separately. The search was completed onOctober5 th , 2020; and all related articles were included. Inclusion criteria comprised all studies about COVID-19 virus-related or drug-related severe or life-threatening cutaneous manifestations of cutaneous involvements in this global pandemic. The exclusion criteria consisted of all publications not meeting the above, studies not mentioning skin manifestations of COVID-19 or mild skin manifestations in the n-cov2019 pandemic, animal studies, in-vitro studies, and review articles. Endnote® X8 (Clarivate Analytics, Philadelphia, USA) was used for study screening and data extraction. Overall, there were 754 articles, with 247 being duplicates; therefore, 507 articles were screened and categorized by two independent reviewers and any potential conflicts were resolved by consulting a third reviewer. Finally, 57 articles were reviewed completely. It is shown in detail in the PRISMA flow diagram (Figure1 in the supplement file). All articles whose data were extracted have been shown in Tables 1-6 in three different categories: virus-related skin manifestations, drug reactions, skin manifestations, and skin manifestations that are not known to be virus-related or drug-related. This article is protected by copyright. All rights reserved After the final screening of the databases, 57 studies were included. 47 studies were case reported and 10 studies were case series. A total data of 93 patients were extracted. All studies were published during December 2019 and October 2020; the mean patient age was 55.62 years old. The age of three cases was not reported. Fifty-two cases (59.77%) were males and 35 cases (40.22%) were females. The gender of 6 cases was not reported. Gender of the male is top of the virus-related list 68.3% (41/60) and female in drug-related group is in majority of 60% (12/20) that may indicate women's susceptibility to drug reactions. 75 patients were confirmed COVID-19 with RT-PCR or serology, three cases were negative and 15 cases were not mentioned. Sixty-six cases were COVID-related cutaneous manifestations, 20 cases were drug-related skin reactions and seven cases were uncertain. Generally, among all included literature, necrosis and ischemic episode appeared to be the most common skin manifestation with 32.25% (30/93) of patients presenting such lesions on their skin. Vasculitis or vasculopathy lesions were seen in 17.2% (16/93) of patients. Angioedema occurred in 12.9% (12/93) of reported patients, and the presence of AGEP was seen in 8.6% (8/93). In the virus-related category, necrosis and ischemic phenomenon with the prevalence of 45.45% (30/66) are the most frequent presentation in patients. Vasculitis and vasculopathy lesions with 19.69% prevalence (13/66) were the second common skin reactions. The prevalence of angioedema, Toxic shock syndrome, EM, generalized Livedo reticularis, erythroderma was 9% (6/66), 7.5% (5/66),6% (4/66),6% (4/66), 3% (2/66),respectively. One case of hemorrhagic bullae, SJS, AGEP was also reported. In the virus-related category, four cases presented skin manifestations as an initial manifestation of COVID-19 infection before other symptoms. AGEP with 30% (6/20) was the most frequent skin lesion in the drug-related group and afterward EM 20% (4/20), angioedema 10% (2/20), DRESS 10% (2/20), Generalized pustular figurate erythema 10% (2/20), respectively. One case of vasculitis, TEN, and SJS was reported. This article is protected by copyright. All rights reserved In the uncertain group which there is no defined boundary between virus-related or drugrelated reasons, angioedema was the most common skin reaction 50% (4/7). One case of SJS, AGEP, vasculitis, and dissecting hematoma belong to this group. This study reveals a 19.7% (14/71) mortality rate within patients who reported outcomes. The majority of expired patients were men. In the uncertain group, no deaths were reported. In drug-related classification, both cases died of a massive pulmonary embolism. 53 This article is protected by copyright. All rights reserved category includes cases in which discrimination between the unusual reaction to the prescribed drug or skin manifestation associated with COVID-19 pathophysiology, was not possible. According to the Tables, some noticeable points have been presented, regarding severe and life-threatening mucocutaneous dermatologic manifestations' categories. healthy pediatrics between 5-19 years. 33 In adults there was also reporting of Kawasaki-like syndrome or Toxic shock-like syndrome associated with COVID-19. In this category, five patients with toxic shock syndrome presentation were mostly under the age of 50. One of the predominant characteristics of TSS is conjunctivitis and mostly appeared early in the disease course and triggered by bacterial superantigens. 33 In two cases, toxic shock syndrome was the first presentation besides the other COVID-19 symptoms. 27, 32 IVIG and steroid appeared to produce a better response than other options. SJS and TEN were also reported and initiation of intravenous Immunoglobulin as a therapeutic option for symptoms' attenuation was recommended. Four cases with erythema multiform associated with hydroxychloroquine, 5-30 days after treatment, were reported. Uncertain group; SJS/TEN syndrome was reported in a critically ill patient with several comorbidities.  Generalized pustular figurate erythema: Drug-related reactions; It is a combination of Stevens-Johnson syndrome/toxic epidermal necrolysis with its targetoid lesions and AGEP with its pustulosis. Two COVID-19 patients on hydroxychloroquine treatment developed generalized pustular figurate erythema, two and three weeks after the onset of hydroxychloroquine. This report is the first study delineating this type of skin reaction. 68 This article is protected by copyright. All rights reserved These cutaneous features linked to the COVID-19 infection interplay with the skin. It means that increased angiotensin-II levels occur with the binding and inhibition of ACE-2 receptors by COVID-19 which induces vascular injuries. It is unclear that the skin eruptions in COVID-19 patients could be specifically due to COVID-19 itself or not. Virus-related skin lesions may help identify COVID-19 patients earlier to avoid progression to disseminated infection and potentially life-threatening skin reactions. Generally, in the drug-related group, except for four cases (with AGEP, TEN, vasculitis, angioedema), hydroxychloroquine was suspected to be accountable for drug-induced skin reactions. According to the widespread use of corticosteroids and immunomodulatory agents in severe skin reactions in a setting of COVID-19 infection, we hypothesized that severe skin lesions, are mainly due to immune-mediated reaction and dysregulated host inflammatory responses affecting the skin and occasionally the mucosa. Therefore, COVID-19 as an important etiological agent activates the immune system rather than direct invasion. We underline that the lesions could present as a delayed immune-mediated reaction to the virus or an immediate response. The authors of this study have been worked on the most important hot topics of dermatologic issues in this pandemic area and now based on the experiences of the experts in academic centers and consultant complicated cases of mucocutaneous COVID-19 related reactions, they found that some holistic managing decision in these patients is challenging, even for expert dermatology professors, since these patients, especially hospitalized ones, many times show multiple laboratory abnormalities or organ failures that the handling of a severe and potential life-threatening mucocutaneous reaction or aggravation of a pre-existing severe chronic dermatologic disorder by COVID-19, which usually needs immunosuppressive immunomodulators, are hard and needing tomulti-aspect cautions. In addition, all drugs are not available in all situations like IVIG (e.g. in Iran), etc., which makes this condition more complicated, as well. We declare no competing interests. Not applicable. Dominguez-Santas M, Diaz-Guimaraens B, Garcia Abellas P, Moreno-Garcia del This article is protected by copyright. This article is protected by copyright. All rights reserved Tables submitted separately: Table 3 : drug-related skin manifestations case reports Table 4 : drug-related skin manifestations case series Table 6 : Skin manifestations that are not known to be virus-related or drug-related case series The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak-an update on the status Kawasaki disease shock syndrome or toxic shock syndrome in children and the relationship with COVID-19 Coronavirus Disease-2019 with Dermatologic Manifestations and Implications: An Unfolding Conundrum virus by droplets and aerosols: A critical review on the unresolved dichotomy SARS-CoV-2 positive patients: An observational study from North India Big data and cutaneous manifestations of COVID-19 Acute Generalized Exanthematous Pustulosis with Erythema Multiforme-Like lesions in a COVID-19 woman Drug reaction with eosinophilia and systemic symptoms syndrome to hydroxychloroquine, an old drug in the spotlight in the COVID-19 era A generalized purpuric eruption with histopathologic features of leucocytoclastic vasculitis in a patient severely ill with COVID-19 Treatments for severe cutaneous adverse reactions Diagnosis, classification, and management of erythema multiforme and Stevens-Johnson syndrome Accepted Article This article is protected by copyright. All rights reserved 12 Life-threatening severe allergic reactions: urticaria, angioedema, and anaphylaxis The evaluation and management of toxic shock syndrome in the emergency department: a review of the literature A Unique Case Report on Hypersensitivity Vasculitis as an Allergic Reaction to the Herpes Zoster Vaccine Severe erythrodermic reactions to the proton pump inhibitors omeprazole and lansoprazole Recent advances in managing and understanding Stevens Johnson syndrome and toxic epidermal necrolysis Ixekizumab for treatment of refractory acute generalized exanthematous pustulosis caused by hydroxychloroquine Polymorphic cutaneous manifestations of COVID-19 An unusual case of bullous haemorrhagic vasculitis in a COVID-19 patient. Article in Press Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases Acute urticaria with angioedema in the setting of coronavirus disease 2019. Article Coronavirus disease 2019-associated urticaria with angioedema in a morbidly obese man successfully treated with glucocorticoids Cutaneous small vessel vasculitis secondary to COVID This article is protected by copyright. All rights reservedThe authors would like to express their gratitude to Rasool Akram Medical Complex Clinical Research Development Center (RCRDC), Iran University of Medical Sciences for its technical and editorial assistance. This article is protected by copyright. All rights reserved.