key: cord-0916005-vxk118ia
authors: Rekhtman, Sergey; Tannenbaum, Rachel; Strunk, Andrew; Birabaharan, Morgan; Wright, Shari; Grbic, Nicole; Joseph, Ashna; Lin, Stephanie K.; Zhang, Aaron C.; Lee, Eric C.; Rivera, Erika; Qiu, Michael; Chelico, John; Garg, Amit
title: Eruptions and Related Clinical Course Among 296 Hospitalized Adults with Confirmed COVID-19
date: 2020-12-25
journal: J Am Acad Dermatol
DOI: 10.1016/j.jaad.2020.12.046
sha: 3016c2c85f1f745cd5f85e27d467fb33ed4e3f74
doc_id: 916005
cord_uid: vxk118ia

Background Limited information exists on mucocutaneous disease and its relation to course of COVID-19. Objective To estimate prevalence of mucocutaneous findings, characterize morphologic patterns, and describe relationship to course in hospitalized adults with COVID-19. Methods Prospective cohort study at two tertiary hospitals (Northwell Health) between May 11, 2020 and June 15, 2020. Results Among 296 hospitalized adults with COVID-19, 35 (11.8%) had at least one disease-related eruption. Patterns included ulcer (13/35, 37.1%), purpura (9/35, 25.7%), necrosis (5/35, 14.3%), non-specific erythema (4/35, 11.4%), morbilliform eruption (4/35, 11.4%), pernio-like lesions (4/35, 11.4%), and vesicles (1/35, 2.9%). Patterns also demonstrated anatomic site-specificity. A greater proportion of patients with mucocutaneous findings used mechanical ventilation [61% vs. 30%], used vasopressors [77% vs. 33%], initiated dialysis [31% vs. 9%], had thrombosis [17% vs. 11%], and had in-hospital mortality [34% vs. 12%] compared to those without mucocutaneous findings. Patients with mucocutaneous disease were more likely to use mechanical ventilation [adjusted PR 1.98 (1.37-2.86); P<0.001]. Differences for other outcomes were attenuated after covariate adjustment and did not reach statistical significance. Limitations Skin biopsies were not performed. Conclusions Distinct mucocutaneous patterns were identified in hospitalized adults with COVID-19. Mucocutaneous disease may be linked to more severe clinical course.

Little is understood about the morphologic spectrum of eruptions and their relation to clinical 86 course among acutely-ill adults infected with severe acute respiratory syndrome coronavirus 2 (SARS-87

CoV-2), the pathogen in COVID-19. A number of knowledge gaps, including estimating prevalence of 88 mucocutaneous disease, its detailed description, and its related outcomes have been discussed in a call to 89 action to develop high quality prospective studies on mucocutaneous disease in COVID-19. 1 In spring of 90 2020, the New York metropolitan area was an epicenter for the COVID-19 pandemic in the United 91

States, 2 and this provided an opportunity to characterize disease-related integumentary findings. These photographs were independently evaluated by two dermatologist raters (SR and AG) who classified 107 morphologic patterns and locations of SARS-CoV-2 related findings. These raters also assessed whether 108 each cutaneous observation was pre-existing or likely to be unrelated to SARS-CoV-2 infection. Consortium, and separately a sample of the dataset was verified against electronic medical records for 116 accuracy. This study was approved by the institutional review board at the Feinstein Institutes for Medical 117

Research at Northwell Health. 118

Prevalence of mucocutaneous manifestations was estimated by the percentage of eligible patients 120 with at least one COVID-19-related rash. Medians (IQR) were reported for continuous variables, and 121 frequencies (%) were reported for categorical variables. Summary statistics for laboratory values were 122 calculated based on the maximum value during hospitalization. Hypothesis tests were two-sided, and 123 statistical significance was assessed at the .05 alpha level. Analysis was performed using R version 3.6.3. 124

Acute kidney injury was defined according to the KDIGO Clinical Practice Guideline for Acute 125

Kidney Injury (AKI, increase in serum creatinine by > 0.3mg/dl within 48 hours; or increase in serum 126 creatinine to > 1.5 times baseline), or based on initiation of dialysis during hospitalization. 3 Baseline 127 serum creatinine was estimated using the most recent value in the year prior to the present admission, if 128 available, or otherwise the median value during hospitalization. Patients with a history of chronic kidney 129 disease were not included in calculations of AKI incidence. 130

Pre-specified primary outcomes for comparison between patients with rash and without rash 131 included the following: 1) requirement for invasive mechanical ventilation; 2) requirement for 132 vasopressors; 3) initiation of dialysis during hospitalization; 4) thrombosis or venous thromboembolism 133 (VTE) diagnosed by duplex or computed tomography angiography; and 5) in-hospital mortality. 134

Prevalence of each outcome during hospitalization was compared between groups using Poisson 135 regression with robust variance estimates, 4 adjusting for age, sex, race, body mass index (BMI), Charlson 136 J o u r n a l P r e -p r o o f Comorbidity Index (CCI), and use of invasive mechanical ventilation (except when ventilation was itself 137 the outcome). Multiple imputation was used to account for missing race and BMI data in the analysis of 138 primary outcomes, with m=10 imputations. 139

Pre-specified secondary outcomes of interest for comparison between those with and without rash 140 included age, BMI, maximum neutrophil-to-lymphocyte ratio (NLR), and maximum D-dimer during 141 hospitalization. Mann-Whitney U tests were used to compare variable distributions between groups, 142 stratified by use of mechanical ventilation during hospitalization. 143

In exploratory analyses, we also compared length of stay and presence of acute kidney injury in 144 patients with and without rash, stratified by ventilation status. Hypothesis tests were not performed for 145 exploratory analyses. 146

Among 338 hospitalized patients identified as possibly having COVID-19 during the study 148 period, 10 did not have laboratory confirmation of SARS-CoV-2 infection and 32 others were not 149 available for examination or declined examination. Demographic characteristics and comorbidities of 150 patients with and without rash are summarized in Table I 11.4%), morbilliform pattern (4/35, 11.4%), pernio-like lesions (4/35, 11.4%), and vesicles (1/35, 2.9%). 158

All 13 (100%) of the ulcers involved the face, lips, or tongue. All 9 (100%) of the purpuric lesions 159 involved the extremities. All 5 (100%) of the necrotic lesions involved the toes. Red erythema most 160 frequently involved the face, neck, and chest. The morbilliform pattern was most frequently observed on 161 the trunk. All 4 (100%) of the pernio-like lesions involved the hands or feet. The vesicular eruption, noted 162 in one patient, involved the abdomen. 163

All 13 (100%), 6 of 9 (66.7%), and 4 of 5 (80%) patients with ulcer, purpura, and necrosis, 164 respectively, were mechanically ventilated. Clinical course for adult COVID-19 patients with and without 165 mucocutaneous disease is described in Table III In this study of consecutively examined patients with confirmed COVID-19, we estimate the 186 prevalence of related mucocutaneous eruptions among a racially diversified cohort of hospitalized adults 187 to be 11.8%. No distinct morphologic pattern emerged among hospitalized patients, rendering the 188 appearance of mucocutaneous disease less pertinent to diagnosing COVID-19 among suspected cases. It 189

is noteworthy that morphologic patterns demonstrated site specificity. For example, all ulcers appeared on 190 the face, lips, and tongue. All patients who developed these ulcers were also mechanically ventilated. 191

Ulcer locations corresponded to areas of increased pressure from endotracheal tubes or medical devices 192 used to hold tubes in place. This occurrence has also been described in case series of COVID-19 patients 193 with ulcerated and/or necrotic lesions at sites in direct contact with medical devices. 5,6 Whether this is 194 simply a pressure phenomenon related to devices used to secure endotracheal tubes with or without 195 prolonged intubation, 7 or whether microvascular injury with COVID-19 predisposed patients to ulceration 196 warrants further investigation. The majority of patients in our study with purpura or necrosis were also 197 mechanically ventilated, which raises the question of whether this presentation is the result of reported observations of acral ischemia, livedo racemosa, purpura, petechiae, and erythema multiforme 216 (EM)-like lesions. However, these were selected cases for whom a dermatology consult was requested. 9 217

Herein we also describe clinical course among hospitalized adults with COVID-19 and 218 mucocutaneous disease. Patients with eruptions had nearly twice the prevalence of mechanical 219 ventilation, suggesting that presence of rash in adults may be related to more severe course. While values 220 for laboratory markers of inflammation and severity of illness were increased among mechanically 221 ventilated patients, we did not observe a pattern of differences between patients with and without 222 mucocutaneous disease, after stratifying by ventilation status. Other clinical outcomes which may be 223 associated with rash, including acute kidney injury, coagulopathy, length of stay, and mortality may 224 19 are limited to case series 8,10,11 and one cross sectional study 12 including 53 hospitalized patients with 230 rash from China and Italy. Study methods and clinical outcomes were not described in detail in the cross-231 sectional study, however a link between mucocutaneous disease and COVID-19 severity was not 232 established. 12 The AAD's series described worse prognosis among 11 patients with retiform purpura. 8 In a 233

Spanish series of 375 patients with cutaneous manifestations, those having livedo, necrosis, and 234 maculopapular eruptions experienced pneumonia, hospital admission, ICU admission, and mortality more 235 frequently than with other patterns. 10 However, maculopapular eruptions comprised approximately half of 236 the cases, for which drug induced eruptions could not be ruled out. Over one third of cases in the series 237 did not have confirmation of COVID-19, and there was limited follow-up time for data on disease course. 238

There are limitations which warrant consideration when interpreting observations in this study. 239

Our cohort may not be representative of those with milder disease or those who do not require 240 hospitalization. We could not ascertain exact onset of rash from acutely-ill patients, and as such, cannot 241 describe the temporal relationship between rash and clinical course. Duration of illness prior to admission 242 was not established for patients, and the variability between time from admission to mucocutaneous 243 examination was also not captured. Accordingly, we could not describe the temporal relationship between 244 rash onset and clinical course. It is also possible that some patients developed integumentary findings 245 after their examination. Oral mucosal examination was not possible for all patients, as a significant 246

proportion were intubated and some could not adequately cooperate in the context of their acute illness. 247

The extent to which these limitations influences the prevalence estimate or spectrum of disease is unclear. 248

We did not perform skin biopsy of the patterns observed, and as such we cannot provide histopathologic 249 correlations for the eruptions observed. It was not clear that biopsy, beyond clinical impression, would 250 result in changes to management. Safety of study personnel was also an important consideration in 251 deciding not to systematically pursue skin biopsies. Face

8 (22.9) -4 5 --2 a Location counts within each rash may sum to more than the overall frequency of the rash due to patients 315

having the same rash in multiple locations. Sum of patients with individual rashes exceeds the number 316 with any rash due to patients who had multiple types of rash. 317 b Percentages for morphology locations are not presented for each rash individually due to small numbers. 318 c In addition to the rashes presented in the table above, one patient had conjunctivitis, and one patient had 319 desquamation, with both rashes considered COVID-19-related. 320 Abbreviations: PR, Prevalence Ratio; Adj., Adjusted * Based on multivariable Poisson regression models with robust (sandwich) standard errors. Covariates included age, sex, race, BMI, Charlson Comorbidity Index, and use of invasive mechanical ventilation (for the four other outcomes). a -12 patients who had ulcers of the cheek or chin were excluded from the analysis of the ventilation outcome, as it was difficult to discern whether these cutaneous manifestations were directly related to COVID-19 infection, patients being ventilated for a prolonged period, or a combination of both b -3 patients who were not discharged as of the date of data extraction were excluded from the analysis of in-hospital mortality.

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