key: cord-0845753-v994acb6 authors: Hubiche, T; Phan, A; Leducq, S; Rapp, J; Fertitta, L; Aubert, H; Barbarot, S; Chiaverini, C; Giraudeau, B; Lasek, A; Mallet, S; Labarelle, A; Piram, M; McCuaig, C; Martin, L; Monitor, L; Nicol, I; Bissuel, M; Bellissen, A; Jullien, D; Lesort, C; Vabres, P; Maruani, A title: Acute acral eruptions in children during the COVID-19 pandemic: characteristics of 103 children and their family clusters date: 2021-01-09 journal: Ann Dermatol Venereol DOI: 10.1016/j.annder.2020.11.005 sha: da21bfedd841140fef988da9e57fe79722171b79 doc_id: 845753 cord_uid: v994acb6 Background: A marked increase in frequency of acute acral eruptions (AAE) was observed in children during the COVID-19 pandemic in the spring period. Objectives: In this observational multicenter study, based on children with AAE, we aimed to assess the proportion of household members possibly infected by SARS-CoV-2. Methods: We collected data from all children observed with AAE, prospectively from April 7, 2020 to June 22, 2020, and retrospectively since February 28, 2020. The primary outcome was the household infection rate, defined as the proportion of family clusters having at least one member with COVID-19 infection other than the child with AAE (“index child”). The definition of a case was based on characteristic clinical signs and a positive PCR or serology. Results: The study included 103 children in 10 French departments and in Quebec. The median age was 13 years and the interquartile range [8-15], with a female-to-male ratio of 1/1.15. In children with AAE, all PCR tests were negative (n=18), and serology was positive in 2/14 (14.3%) cases. We found no significant anomalies in the lab results. 66 of the 103 families (64.1%) of included children had at least one other infected member apart from the index child. The total number of household members was 292, of whom 119 (40.8%) were considered possibly infected by SARS-CoV-2. No index children or households exhibited severe COVID-19. Discussion: Among the 103 households included, 64.1% had at least one infected member. Neither children with AAE nor their households showed severe COVID-19. J o u r n a l P r e -p r o o f 4 Several cutaneous signs are associated with COVID-19, but the mechanisms are not fully understood [1, 2] . They have been observed in both adults and children. Severe COVID-19 is less frequent in children than adults. Davies et al. showed that general clinical symptoms manifest in only 21% of young people aged 10 to 19 years with COVID-19 versus 69% of people aged > 70 years old [3] . However, numerous cutaneous signs have been reported in children with COVID-19, such as acute acral eruptions (AAE) [4, 5] . Published cases of AAE display heterogeneous features, including pseudo-chilblains, acral vesicles or papules, and papular-purpuric gloves and socks syndrome [1, 2, 4, 5] . These signs appear late in the course of COVID-19 [5] . Identified risk factors for severe COVID-19 include increased age, male gender, being overweight, and chronic diseases. Genetic risk factors have also been suspected [6] . The high contagiousness of the disease warrants the study of family clusters [7] . Intrafamilial transmission is still incompletely understood and requires documentation, particularly as children have been more exposed since the reopening of schools as of May 2020 in several European countries [3, 8] . In this study, based on children with AAE, we aimed to assess the proportion of household members possibly infected by SARS-CoV-2 with COVID-19 and to describe demographic, clinical, biological and histological signs in these entities. This multicenter observational study included centers in France and Quebec, Canada. The study involved all dermatologists belonging to the Group of Research of the French Society of Pediatric Dermatology (GRSFDP) and began on April 7, 2020. We collected data from all children with observed AAE prospectively from April 7, 2020 to June 22, 2020 and retrospectively since February 28, 2020. Data comprised demographic and clinical data (cutaneous and extracutaneous signs) for the child and the household at baseline (at the consultation) and at approximately 1-month of follow-up (all parents were contacted by telephone). Parents were then orally informed about the study and gave their oral consent to participate. Results were also collected for additional examiantions, including lab results, virology (SARS-Cov-2 PCR and serology), imaging, and microscopy of skin biopsy. Investigators entered the data into a standardized electronic case report form (e-CRF). Using the criteria of the European Centre for Disease Prevention and Control, we defined a COVID-19 case as any person presenting fever, cough, shortness of breath, sudden onset of anosmia, ageusia or dysgeusia, or having characteristic CT-scan pulmonary images, or exhibiting positivity for SARS-Cov-2 on PCR (from nasopharyngeal or oropharyngeal swabs) or serology [9] . We used the WHO scale for progression of COVID-19 infection to assess severity (from 0, no infection, to 8, death): severe infection was defined as stage > 3 [10] . All children (< 18 years old) assessed for AAE were eligible. We excluded children for whom personal or family data was available. The study was approved by the Ethics Committee of Nice, France. The primary outcome was the proportion of household members possibly infected by SARS-CoV-2 with COVID-19 other than the child with AAE ("index child"). Secondary outcomes were the proportion of severe COVID-19 within the family cluster and the description of demographic, clinical, virology and microscopy data for children with AAE. Quantitative data are expressed using mean, standard deviation (SD), median and interquartile range (IQR); categorical data are described with frequency (%). We used the Wilcoxon test to compare cutaneous features of AAE by age of the children. P<0.05 was considered statistically significant. We used R v3.6.2 for calculations. The study included 103 children from 10 French departments and from Quebec ( Fig. 1 Fig. 2 ) [8] . Among these 119 households, 77 had signs of infection before the index child was seen for AAE, and 16 had signs after the 1-month follow-up for the index child (data missing for 26 cases, Table 3 ). Cutaneous signs were present in 8 children other than the index cases in 7 families. No significant differences in age or sex were observed between these 8 children and those without cutaneous signs in their families. In total, all household members were aged < 60 years. No children or household members exhibited severe infection (no hospitalizations). 3 cases among household members were in stage 1 of the WHO scale (2.5%), 113 were in stage 2 (95.0%) and 3 were in stage 3 (2.5%). No children showed multisystem inflammatory disease of childhood [11] . The semiological characteristics of cutaneous signs in the 103 children ( (Table 4) . Regarding complementary examinations in children with AAE, standard lab results and levels of inflammatory markers and coagulation markers were all either normal or not significantly increased (Table 5) . Antinuclear antibodies were detected in 13 of 54 (24.1%) children. SARS-Cov-2 serology was positive for IgG in 2 of 14 (14.3%) children, and PCR results were negative in all children (n=18). Skin samples of chilblains were analyzed in 5 children (Table 6 ). Microscopy showed dermal perivascular lymphocytic infiltrates of differing intensity in all 5 children, as well as spongiosis (n=4) and lymphocytic vasculitis (n=2). Two children exhibited mucinosis. Since the beginning of the COVID-19 pandemic, many cases of AAE were observed during the same period in different areas in France and Quebec. A causal link between COVID-19 and AAE has not yet been demonstrated and remains debated. Such a link appears likely since the period during which we observed AAE in France and Quebec was associated with COVID-19 progression and was chiefly during the spring months [12, 13] . Evidence of the presence of COVID-19 in skin biopsies of chilblains has recently been reported [14, 15] . However, several studies based on serological results have found no evidence of a causal link between COVID-19 and AAE [16] [17] [18] . Confirmation of COVID-19 in patients presenting AAE may not be based on classical tests such as PCR (since AAE usually occur after the infectious symptoms) or serology. Indeed, serology appears to have diagnostic efficacy, especially in asymptomatic and paucisymptomatic patients [19] . Neither index children nor households showed severe signs of COVID-19. Where available, laboratory data showed no significant abnormalities. The types of clinical manifestations associated with COVID-19 were associated with host factors, with age being the most important [20] . Severe COVID-19 is more frequent in older people. Neither chilblains nor other acral eruptions have been reported in older people but are associated rather with younger subjects [16, 18] . These data underline the importance of host characteristics in COVID-19-associated medical conditions. Efficient innate immune response and/or cross T-cell immunity induced by previous infection with  coronavirus were explored in patients and relatives presenting such dermatological conditions [21] [22] [23] . [4, 17, 24, 25] . Of note is the fact that this skin condition has not been reported in severe COVID-19 patients, who might have impaired IFN type I activity compared to mild COVID-19 cases and to controls [26] . Furthermore, it has been reported that patients with chilblains observed during the COVID-19 pandemic had a significantly higher IFN alpha response compared to severe COVID-19 patients [25] . Some authors have thus hypothesized that patients with chilblains might present an efficient antiviral response triggered by SARS-CoV-2 [27] . Furthermore, in our young population, clinical presentation differed according to age. Host factors play a central role in the clinical presentation of COVID-19. Vessel characteristics and immune status in the host may play a key role. Vessel characteristics and IFN type I response vary according to host characteristics, including age [28] . Such factors could account for the differences between dermatological presentations observed between children and adults as well as those between infants and adolescents. We observed no acral ischemia in our study. This serious complication reported in adults is associated with a pro-thrombotic condition. Values for coagulation markers in the children in our study were normal. Such thrombotic complications observed in COVID-19 may be driven by other factors related to host characteristics. Only scant data are available on the evolution of acral lesions. Unlike general signs, such as fever or anosmia, which are presenting symptoms of COVID-19, AAE seems to occur later during the disease, from 0 to several weeks after the first symptoms of suspected viral infection or after presumed contact with a carrier of the virus, as reported in previous studies [5, 17, 29] . This finding could account for the negative PCR results in our study and in most previously reported cases. However, 3 adolescents with chilblains recently proved positive on RT-PCR with nasopharyngeal swabs [30] . Most lesions had a long but benign course, with complete spontaneous regression after a median of 47 days. The main limitation of the study is the absence of a control group to confirm intrafamilial contamination. Further, COVID-19 was based on serology, PCR or clinical symptoms according to criteria of the European Centre for Disease Prevention and Control, which may have either over-or underestimated the proportion of households infected. Family members did not undergo systematic PCR testing with nasopharyngeal swabs, which was only performed in hospitalized patients or in patients with severe respiratory symptoms during the inclusion period. In addition, not all patients or household members underwent serology testing, and the serologic techniques themselves were heterogeneous. * Individual patients may present several signs ** Data are missing for 18 patients in the "Children from household having at least one case" group and 14 patients in the "Children from household having no cases" group Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases Cutaneous manifestations in COVID-19: a first perspective. Safety concerns of clinical images and skin biopsies CMMID COVID-19 working group, Eggo RM. 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