Volume 26 Number 12| December 2020 Dermatology Online Journal || Review 26(12):2 Cutaneous manifestations of COVID-19: a systematic review and analysis of individual patient-level data David S Lee1 MD, Paradi Mirmirani2,3 MD, Patrick E McCleskey4 MD, Majid Mehrpouya5 PhD, Farzam Gorouhi6,7 MD Affiliations: 1Department of Dermatology, The Permanente Medical Group, Pleasanton, California, USA, 2Department of Dermatology, University of California, San Francisco, California, USA, 3Department of Dermatology, The Permanente Medical Group, Vallejo, California, USA, 4Department of Dermatology, The Permanente Medical Group, Oakland, California, USA, 5Faculty of Engineering, University of Calgary, Calgary, Alberta, Canada, 6Department of Dermatology, The Permanente Medical Group, South Sacramento, California, USA, 7Department of Dermatology, University of California, Davis, California, USA Corresponding Author: Farzam Gorouhi MD FAAD, Kaiser Permanente, South Sacramento, 6600 Bruceville Road, Sacramento, CA 95823, Tel: 415-298-1345, Email: [email protected] Introduction Abstract In December 2019, reports from Wuhan, China Distinctive patterns in the cutaneous manifestations described new clusters of patients with severe of COVID-19 have been recently reported. We pneumonia linked to a novel coronavirus strain, now conducted a systematic review to identify case reports and case series characterizing cutaneous referred to as severe acute respiratory syndrome manifestations of confirmed COVID-19. Key coronavirus 2 (SARS-CoV-2), [1]. Coronavirus disease demographic and clinical data from each case were 2019 (COVID-19) has since reached pandemic extracted and analyzed. The primary outcome proportions, with over 12·7 million cases worldwide, measure was risk factor analysis of skin related 566,000 deaths, and 188 countries affected at the outcomes for severe COVID-19 disease. Seventy-one time of this article’s submission [2]. Primarily a case reports and series comprising 144 cases of respiratory disease, COVID-19 is now known to have cutaneous involvement in COVID-19 were included. a wide spectrum of clinical phenotypes, ranging The most frequently occurring morphologies were: from asymptomatic carriage to multi-system organ morbilliform (30.6%), varicelliform (18.8%), urticarial failure. (13.2%), chilblains-like (12.5%), and acro-ischemic (9%). The median age of patients was 51 years (mean: The first report of cutaneous involvement in COVID- 45.9, range: 0 to 91). Patients with chilblains-like 19 was in February 2020, when Guan et al. listed rash eruptions had lower frequencies of extracutaneous as a sign of infection in two of 1099 patients with COVID-19 symptoms (5/18, 27.8%, P<0.05) and were laboratory-confirmed COVID-19 in China [3]. Multiple less likely to have severe COVID-19 disease (2/18, subsequent case reports and series have described 11%, 95% CI 1.4% to 34.7%, P=0.02). Patients with COVID-19 with cutaneous involvement. It is now livedoid and acro-ischemic morphologies had severe understood that coagulopathy and thrombotic COVID-19 more frequently than those with other events can be observed in more severe cases of morphologies (17/21, 81%, 95% CI 58.0% to 94.5%, COVID-19 infection [4,5]. This trend has also been P<0.0001). The most frequently observed cutaneous manifestations of COVID-19 (morbilliform, varicella- recently reflected in a large-scale registry-based case form, and urticarial) are well-described patterns of series in which livedo racemosa, retiform purpura, viral exanthems. However, chilblains-like, livedoid, and acral ischemia were exclusively observed in and acro-ischemic morphologies are not traditionally critically ill patients [6]. We conducted a systematic associated with viral infections and were significantly review of the literature to characterize the cutaneous associated with severity of COVID-19 disease. manifestations of COVID-19 and analysis of individual patient-level data to identify potential associations between skin presentation and severity Keywords: cutaneous manifestation, SARS-CoV-2 of COVID-19 infection. - 1 - Volume 26 Number 12| December 2020 Dermatology Online Journal || Review 26(12):2 Methods Study selection Eligibility criteria The search results were screened independently by All case reports and case series that provided two investigators. Duplicate publications were patient-level data and characterized cutaneous removed by FG. Two investigators (PM & FG) manifestations of COVID-19 were included in this independently screened all the results of searches systematic review. The search was conducted from and selected the potentially eligible studies based on October 1, 2019 to May 21, 2020. There were no title and abstract. language, publication status, or publication year Data collection process limits. Papers published in Chinese and Spanish were All full texts were retrieved. DL & FG independently initially translated with the Google Translate tool, appraised and extracted data from the selected then proofread by a Chinese- or Spanish-speaking studies. Any differences between the data sets were medical professional. discussed and a consensus reached. If case details Information sources were insufficient, corresponding authors were PubMed, Embase, Cochrane databases, and Google solicited for further details when their contact Scholar were searched. The following trial registries information was available. Figure 1 demonstrates were also searched: Cochrane Central Register of the flow diagram of the study. Controlled Trials, the World Health Organization International Clinical Trials Registry Platform. Elsevier Study aims and Wiley websites were also searched separately. Our primary outcome measure was risk factor Moreover, medRxiv and Research Square as pre-print analysis of skin related outcomes for severe COVID- databases were searched and only one eligible study 19 disease. A patient was defined as COVID-19 was identified. positive if having a positive real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for Search strategy SARS-CoV-2, IgG or IgM anti-SARS-CoV-2 serology The search strategy (Appendix 1) was developed by testing by enzyme-linked immunosorbent assay author FG. Detailed search strategy for all databases (ELISA), or radiological features characteristic for is provided in Appendix 1. We performed the entire search on May 21, 2020. COVID-19 on computed tomography or chest X-ray. Severe COVID-19 disease was defined as infection that required intensive care unit (ICU) care or mechanical ventilation or infection that resulted in death. Secondary outcomes included the frequency of different morphologies of cutaneous eruptions in COVID-19 patients. Other secondary outcomes included timing of cutaneous manifestations relative to other COVID-19 symptoms and presence of drug administration prior to rash onset. Cutaneous morphology characterization When clinical images of cutaneous manifestations were available, the images were independently evaluated by three board-certified dermatologists and assigned one or more primary cutaneous morphologies and/or secondary descriptors (Table 1). Of note, cases of retiform purpura were classified as livedoid morphology owing to their overlapping Figure 1. Flow diagram of the study. pathophysiology. Targetoid morphology included - 2 - Volume 26 Number 12| December 2020 Dermatology Online Journal || Review 26(12):2 typical and atypical targetoid lesions similar to those Mann-Whitney U test for continuous variables such seen in erythema multiforme. Assigned as age owing to lack of normal distribution. Given morphologies and descriptors were included in the their overlapping pathophysiology, livedo and acro- final assessment if consensus on a given variable was ischemic cutaneous morphologies were combined reached by two or more dermatologists. When to form a new category of “Livedo/Acro-ischemia” clinical images were unavailable, the morphology prior to the primary outcome measure analysis. and/or descriptor were assigned based on the Multivariate binary logistic regression analysis was author’s written description. utilized to model the prognostic factors associated Country of affiliation, demography (age, gender), with severe COVID-19 disease. Odds ratios and anatomical site of skin involvement, non-cutaneous relevant 95% confidence intervals (CIs) were reported accordingly. Violin plots, bar charts, and COVID-19 symptoms (Figure 2), duration of skin heatmaps were used to present the data. eruption, latency between other COVID-19 symptoms and rash onset, and medication exposures relative to rash onset were extracted from the studies. Results A total of 1352 records were identified through Statistical methods database searching and reference screening (Figure Details of statistical methods are described in Appendix 1. 1). After exclusion of duplicate records and screening We performed analyses using Python (Python of articles for eligibility, 71 unique publications software foundation, version 3·7) and SPSS (IBM (Appendix 2) meeting inclusion criteria were Corp., Armonk, N.Y., USA), version 26. The proportion included for qualitative assessment and data of patients with severe COVID-19 disease as the main extraction. Large case series without detailed outcome measure was reported with binomial 95% reporting of individual patient-level data were confidence intervals (CIs). Kolmogorov-Smirnov excluded from this study. Cases for which COVID-19 analysis was used to test the normality of the was not confirmed or skin findings