key: cord-0882191-78zezh2a
authors: Marzano, Angelo Valerio; Genovese, Giovanni; Moltrasio, Chiara; Gaspari, Valeria; Vezzoli, Pamela; Maione, Vincenzo; Misciali, Cosimo; Sena, Paolo; Patrizi, Annalisa; Offidani, Annamaria; Quaglino, Pietro; Arco, Renato; Caproni, Marzia; Rovesti, Miriam; Bordin, Giorgio; Recalcati, Sebastiano; Potenza, Concetta; Guarneri, Claudio; Fabbrocini, Gabriella; Tomasini, Carlo; Sorci, Mariarita; Lombardo, Maurizio; Gisondi, Paolo; Conti, Andrea; Casazza, Giovanni; Peris, Ketty; Calzavara-Pinton, Piergiacomo; Berti, Emilio
title: The clinical spectrum of COVID-19-associated cutaneous manifestations: an Italian multicentre study of 200 adult patients
date: 2021-01-18
journal: J Am Acad Dermatol
DOI: 10.1016/j.jaad.2021.01.023
sha: 86a52b9d1d219b2bf988d966b17da31facabce01
doc_id: 882191
cord_uid: 78zezh2a

Background COVID-19 is associated with a wide range of skin manifestations. Objective To describe the clinical characteristics of COVID-19-associated skin manifestations, and explore the relationships between the six main cutaneous phenotypes and systemic findings. Methods Twenty-one Italian Dermatology Units were asked to collect the demographic, clinical and histopathological data of 200 patients with COVID-19-associated skin manifestations. The severity of COVID-19 was classified as asymptomatic, mild, moderate, or severe. Results A chilblain-like acral pattern significantly associated with a younger age (p<0.0001) and, after adjusting for age, significantly associated with less severe COVID-19 (p=0.0009). However, the median duration of chilblain-like lesions was significantly longer than that of the other cutaneous manifestations taken together (p <0.0001). Patients with moderate/severe COVID-19 were more represented than those with asymptomatic/mild COVID-19 among the patients with cutaneous manifestations other than chilblain-like lesions, but only the confluent erythematous/maculo-papular/morbilliform phenotype significantly associated with more severe COVID-19 (p=0.015), and this significance disappeared after adjusting for age. Limitations Laboratory confirmation of COVID-19 was not possible in all cases. Conclusions After adjusting for age, there was no clear-cut spectrum of COVID-19 severity in patients with COVID-19-related skin manifestations although chilblain-like acral lesions were more frequent in younger patients with asymptomatic/paucisymptomatic COVID-19.

identified six main phenotypes: i) urticarial rash; ii) confluent erythematous/maculo-100 papular/morbilliform rash; iii) papulovesicular exanthem; iv) a chilblain-like acral pattern; v) a livedo 101 reticularis/racemosa-like pattern; and vi) a purpuric "vasculitic" pattern. 3 However, there have been 102

reports of a miscellany of other cutaneous presentations that cannot be included in this 103 classification, including erythema multiforme-like 4 , pityriasis rosea-like 5 , and Grover's disease-like 104 manifestations. 6 Galván Casas et al. found maculopapular eruptions accounted for almost half of the 105 cutaneous manifestations in their study, 2 but the majority of published studies have focused on 106 chilblain-like acral lesions, 7-10 which are generally associated with a benign clinical course and more 107 frequently reported in children. 11-13 108

The aim of this nationwide multicentre study was to provide clinical data concerning COVID-19-109 associated skin manifestations in order to improve the clinical and demographic characterisation of 110 the cutaneous phenotypes that have previously been defined only on the basis of previously 111 published preliminary data. 3 The main study objective was to explore the possible associations 112 between these phenotypes, extra-cutaneous symptoms, and the severity of COVID-19. Each participating centre was asked to provide data on the basis of the following patient inclusion 124 criteria: i) an age of ≥18 years; ii) probable or laboratory-confirmed COVID-19; and iii) the presence of 125 COVID-19-related skin manifestations confirmed by an expert dermatologist. A COVID-19 diagnosis 126 was considered to be laboratory-confirmed in the case of a nasopharyngeal swab positive for SARS-127

CoV-2 RNA or positive serology for anti-SARS-CoV-2 IgG/IgM antibodies. COVID-19 was considered 128 probable in any patient meeting the clinical criteria (dry cough, fever, dyspnea, the sudden onset of 129 hyposmia or hypogeusia) who had been in close contact with someone with confirmed COVID-19 in 130 the 14 days before symptom onset. A history of new medications in the 15 days before the onset of 131 the skin manifestations was considered an exclusion criterion. 132

Systemic symptoms were taken from the charts of hospitalised patients or reported by outpatients, 134 and assessed by a physician (pulmonologist, or a specialist in internal/emergency medicine or 135 infectious diseases). The duration of the skin manifestations was directly evaluated by a 136 dermatologist in the case of hospitalised patients, or reported by outpatients. Each patient was 137 examined at least twice (during the period of skin manifestations and after their resolution). 138

The severity of COVID-19 was classified as asymptomatic, mild (in the presence of fever, cough dyspnea and/or radiological findings of pneumonia) or severe (a need for invasive assisted 141 ventilation, the occurrence of thromboembolic events, or death), 14 and was assessed by considering 142 the worst systemic symptoms over the entire course of the disease as shown in hospital records or 143 self-reported by outpatients. 144

Continuous variables are expressed as median values and interquartile ranges (IQR), and 146 dichotomous variables as absolute numbers and percentages. Quantitative variables (disease 147 severity, symptoms, cutaneous phenotypes) were compared between groups using the non-148 parametric Wilcoxon-Mann-Whitney test. 149

Logistic regression analysis was used to assess the role of the six predefined skin phenotypes as risk 150 factors for extra-cutaneous symptoms (fever, cough, dyspnea, pneumonia, gastrointestinal 151 symptoms, hyposmia/hypogeusia) and the severity of COVID-19 (dichotomised as asymptomatic or 152 mild vs moderate or severe). Univariate logistic regression models of each cutaneous phenotype 153 were fitted by considering the severity of COVID-19 and the six extra-cutaneous symptoms as 154 dependent variables (seven separate models); the phenotype was considered an independent 155 variable. In addition, age-adjusted logistic regression analyses were made because of the possible 156 confounding effect of age on symptoms and the severity of COVID-19. Odds ratios (ORs) and their 157 95% confidence intervals (CI) were obtained from the estimates of the logistic model parameters. 158

Differences in the prevalence of symptoms between phenotypes were assessed using chi-square 159 tests. Given the small number of patients with a livedo reticularis-like/racemosa-like pattern, only 160 five phenotypes were considered (the purpuric and reticularis/racemosa-like patterns were merged). 161

Patients with more than one cutaneous phenotype were not included in the statistical analyses, 162 which were made using SAS statistical software (release 9.4, SAS Institute, Inc., Cary, North Carolina). 163

The study was conducted in accordance with the Declaration of Helsinki, and the full protocol was 166 approved by the Institutional Review Board of the Ethics Committee of the Principal Investigator's 167 centre (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Protocol No. 168 464_2020). All of the subjects enrolled in the study gave their written informed consent. 169 J o u r n a l P r e -p r o o f RESULTS 170

The demographic and clinical features of the 200 patients are summarised in Table 1. The patients  172 were predominantly males (n=108; 54%), and their median age at the time of the diagnosis of COVID-173 19 was 57 years ). Eighty-six of the 195 patients with available data (43%) had 174 experienced at least one co-morbidity. 175

Thirteen patients (6.5%) presented with more than one cutaneous phenotype. Of the 187 patients 176 with only one phenotype, 19 (10.2%) developed urticarial rash; 48 (25.7%) confluent 177 erythematous/maculo-papular/morbilliform rash; 29 (15.5%) papulovesicular exanthem; 46 (24.6%) 178 a chilblain-like acral pattern; 4 (2.1%) a livedo reticularis/racemosa-like pattern; and 13 (6.9%) a 179 purpuric "vasculitic" pattern (Supplemental Fig. 1 ). Cutaneous manifestations other than those 180 included in the classification mentioned above 3 were observed in 28 patients (15.0%): pityriasis 181 rosea-like lesions in 10; erythema multiforme-like lesions in eight; erythema nodosum-like lesions in 182 four; panniculitis in four; and angioedema in two. No mucosal lesions were recorded. The most 183 frequent skin-related symptom was pruritus (n=81; 40.5%), followed by pain/burning (n=22; 11%). 184

Among the 168 patients for whom data were available, the median duration of the skin 185 manifestations was 12 days . However, the median duration of chilblain-like acral lesions 186 was significantly longer than that of the other cutaneous manifestations taken together ( 

As shown in Table 2 , COVID-19 was laboratory-confirmed in 124 patients, and regarded as probable 210 in the remaining 73. Thirty-one patients (15.5%) were asymptomatic; 51 (25.5%) had mild disease; 95 211 (47.5%) had moderate disease; and 23 (11.5% had severe disease. Among the 124 patients for whom 212 the data were available, the median duration of systemic symptoms was 23 days (IQR: 12-31). 213

Skin signs pre-dated systemic symptoms in 11 patients; among the remaining 189, they followed 214 (n=186) or were concomitant with systemic symptoms (n=3). Fever was the most frequent systemic 215 symptom (n=146; 73%), followed by cough (n=108; 54%), pneumonia (n=106; 53%), dyspnea (n=77; 216 38.5%), gastrointestinal symptoms (n=46; 23%), and hypogeusia/hyposmia (n=44; 22%). 217 Thromboembolic complications occurred in 11 patients (5.5%), and death in seven (3.5%). 218

The median duration of systemic symptoms by each cutaneous phenotype is detailed in Table 2 . 219 220 J o u r n a l P r e -p r o o f

It is worth noting that, after adjusting for age, chilblain-like acral lesions were associated with a 223 decreased risk of experiencing more severe COVID-19 (OR = 0.23, 95% CI 0.09-0.55; p=0.0009). On 224 the other hand, confluent erythematous/maculopapular/morbilliform rash was associated with more 225 severe COVID-19 before (OR = 2.49, 95% CI 1.19-5.18; p=0.015) but not after adjusting for age (OR = 226 1.9, 95% CI 0.83-4.37; p=0.1307). 227

Although patients with moderate/severe COVID-19 were more represented than those with 228 asymptomatic/mild COVID-19 among the patients with cutaneous phenotypes other than chilblain-229 like lesions, there was no statistically significant association with the severity of COVID-19. 230

After adjusting for age, confluent erythematous/maculo-papular/morbilliform rash was identified as 231 a significant risk factor for cough (OR = 2.25, 95% CI 1.1-4.63; p=0.0269); the urticarial pattern as a 232 significant risk factor for gastrointestinal symptoms (OR = 6.10, 95% CI 2.25-16.59; p= 0.0004); and 233 the livedo-like/vasculitic pattern as a significant risk factor for dyspnea (OR =4.17, 95% CI 1.05-16. The most frequent cutaneous phenotypes were confluent erythematous/maculo-242 papular/morbilliform rash and a chilblain-like acral pattern, which affected respectively 25.7% and 243 24.6% of the 187 patients included in the statistical analysis, whereas the least frequent was a livedo 244 reticularis-like/racemosa-like pattern (2.1%). The median latency between the onset of the 245 cutaneous manifestations and systemic symptoms was 14 days (varying from four days in the case of 246 papulovesicular exanthem to 24.5 days in the case of a livedo reticularis-like/racemosa-like pattern). 247

The median duration of the cutaneous manifestations was 12 days (ranging from eight days in the 248 case of urticarial rash to 22 days in the case of a chilblain-like acral pattern). 249

Pityriasis rosea-like and erythema multiforme-like patterns were the most frequently reported skin 250 manifestations falling outside our classification, but it is still debated whether the former is directly 251 mediated by SARS-CoV-2 or caused by COVID-19-related immune system dysfunction leading to 252 human herpes virus(HHV)-6/HHV-7 reactivation, 5,15,18 and whether the latter is triggered by SARS-253

CoV-2 or other viruses. 4 254

In line with previous observations, none of our patients experienced mucosal membrane lesions. 16 255

Although the angiotensin-converting enzyme 2 (ACE2) receptor of the spike protein of SARS-CoV-2 256 has been described as being not only expressed on keratinocytes 17 but also in the oral cavity, 18 257 mucosal membrane lesions have very rarely been reported in patients with COVID-19 16 . 258

The main strength of this study is our exploration of the relationships between cutaneous 259 phenotypes and the severity of COVID-19. Two studies of large cohorts of patients with COVID-19-260 related skin manifestations have found a gradient of increasingly severe systemic symptoms going 261 from chilblain-like lesions to a livedo/necrotic pattern. 3, 19 However, unlike these studies, our study adjusted for patient age and failed to confirm this spectrum. Only the chilblain-like acral phenotype 263 significantly associated with less severe COVID-19 and, although patients with severe disease were 264 prevalent in each of the other five phenotypic categories, none of them significantly associated with 265 an increased risk of more severe Moreover, in line with the findings of other studies, 7 the chilblain-like acral phenotype was associated 267 with a younger age at the time of COVID-19 diagnosis, whereas the livedo-like/vasculitic and maculo-268 papular phenotypes were associated with an older age at the time COVID-19 diagnosis. The 269 pathological mechanisms underlying these relationships remain unclear but, in line with the 270 acknowledged correlation between age and COVID-19 severity, 20 we found that patients with more 271 severe disease, fever or respiratory symptoms (cough, dyspnea and pneumonia) had a higher median 272 age, thus confirming the need for careful observation and an early intervention in order to prevent 273 the development of severe COVID-19 in the elderly. 274

The close association between the urticarial phenotype and gastrointestinal symptoms found in our 275 study is intriguing, and suggests that this phenotype is predictive of COVID-19-related 276 gastrointestinal involvement. The pathophysiological link between skin and digestive manifestations 277 needs further investigation, but it is likely that SARS-CoV-2 is a triggering factor for both. 278

The main limitation of this study is the absence of laboratory confirmation of COVID-19 in 73 patients 279 (36.5%), which was mainly due to the fact that asymptomatic and paucisymptomatic patients did not 280 undergo SARS-CoV-2 testing during the first wave of COVID-19 in Italy for economic reasons. 281

Selection bias due to the fact that the study only included patients whose COVID-19-related skin 282 lesions had been evaluated by an expert dermatologist may be considered another limitation, but we 283 believe that this is actually a strength insofar as it avoided the misdiagnoses that may have been 284 made by non-specialists. 285

In conclusion, this study further defines the demographic and clinical features of the six main clinical 286 phenotypes of COVID-19-associated skin manifestations by assessing the relationship between them 287 and the extra-cutaneous symptoms and severity of COVID-19. The only correlation between the cutaneous phenotype and the severity of COVID-19 was observed in the case of chilblain-like acral 289 lesions, a phenotype that is generally associated with the benign/sub-clinical course of Acknowledgement 291

The authors would like to thank the following collaborators for their help in data collection and 292 

The spectrum of COVID-19-associated dermatologic 354 manifestations: An international registry of 716 patients from 31 countries

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan

Skin-related symptoms, n (%) patients: * 155, ** 171

*Data available for 195 patients

• There are six main COVID-19-related cutaneous phenotypes, but only the chilblain-like acral pattern significantly associated with younger age.• After adjusting for patient age, there was no spectrum of COVID-19 severity in relation to cutaneous phenotypes, although the longer-lasting chilblain-like acral pattern significantly associated with milder disease.J o u r n a l P r e -p r o o f