key: cord-0994493-xgjqwtxm
authors: Torrelo, Antonio; Andina, David; Santonja, Carlos; Noguera‐Morel, Lucero; Bascuas‐Arribas, Marta; Gaitero‐Tristán, Jara; Alonso‐Cadenas, José Antonio; Escalada‐Pellitero, Silvia; Hernández‐Martín, Ángela; de la Torre‐Espi, Mercedes; Colmenero, Isabel
title: Erythema multiforme‐like lesions in children and COVID‐19
date: 2020-05-23
journal: Pediatr Dermatol
DOI: 10.1111/pde.14246
sha: f664d71ead5a2fd000909558144ac53a6dec023b
doc_id: 994493
cord_uid: xgjqwtxm

During examination of cases of chilblains in children and adolescents, we identified four patients who also showed skin lesions similar to erythema multiforme (EM). They had no other known triggers for EM. One of them had a positive PCR for SARS‐CoV‐2, while the other 3 were negative. Skin biopsies from two patients showed features not typical of EM, such as deep perivascular and perieccrine infiltrate and absence of necrosis of keratinocytes. Immunohistochemistry for SARS‐CoV/SARS‐CoV‐2 spike protein showed granular positivity in endothelial cells and epithelial cells of eccrine glands in both biopsies. All patients had an excellent outcome, and had minimal or no systemic symptoms. The coincidence of EM, a condition commonly related to viruses, and chilblains in the setting of COVID‐19, as well as the positivity for SARS‐CoV/SARS‐CoV‐2 spike protein by immunohistochemistry strongly suggest a link between EM‐like lesions and SARS‐CoV‐2.

Skin manifestations including urticarial, morbilliform, vesicular and petechial exanthems, and vasospastic manifestations such as livedo reticularis and acral ischemic lesions (1) (2) (3) (4) (5) have been reported in association with coronavirus disease 2019 . In particular, chilblains on the feet and hands have being extensively documented worldwide during the peak incidence of the pandemic (6) (7) (8) . During our examination of 22 cases of chilblains in children and adolescents (9) we identified four patients who also showed skin lesions similar to erythema multiforme. We report these cases and discuss their clinical and histopathologic features, as well as the possible relationship to COVID-19.

The four children (3 male, 1 female; age 11-17 years) had been referred from the emergency department as part of a study to record acral skin lesions during the peak period of incidence of COVID-19 in Madrid, Spain (9) . Clinical examination confirmed chilblains on the feet (four cases) and also on the hands (two cases). In addition, complete examination disclosed different skin lesions involving the hands, feet, forearms, elbows, arms, ankles, legs, thighs and ears (Table 1) . They consisted of target (three rings) and targetoid (two rings), confluent macules, papules and plaques, with different sizes, some with hemorrhage Accepted Article or a small central crust (Figures 1 and 2) . Three patients complained of itch, and mild pain in the lesions was noted by one of them.

None of the patients had a previous history of erythema multiforme. A recent lip sore was not recalled, and no patient had been taken any new drug or had been vaccinated within 30 days before the onset of the skin lesions. One patient was on treatment with methylphenidate at the same dose for more than one year. SARS-CoV-2 PCR from oropharyngeal and nasopharyngeal swabs was performed in all the cases, and only one was positive. Routine hematological and biochemical analyses were normal, when done.

Skin biopsies were taken in two cases ( Figure 3 One patient was given a short course of oral corticosteroids and another patient received topical corticosteroids. All patients experienced complete remission of their skin lesions within one to three weeks and had no complications.

We present four patients with lesions clinically consistent with erythema multiforme (EM) and histopathological features not specific or typical for EM. These lesions were located on the most common cutaneous sites of involvement of classical EM. They appeared in patients with COVID-19-related chilblains, similar to those extensively described in social networks in

This article is protected by copyright. All rights reserved most countries affected by the pandemic, and also in medical journals (6) (7) (8) (9) . The outbreak of these acral ischemic lesions, very rarely seen before in children and adolescents, coinciding with the peak incidence of COVID-19, strongly suggest a causal role for SARS-CoV-2. In patients with chilblains the rate of positivity for SARS-Cov-2 PCR has been consistently very low (8, 9) , a reason why some authors have argued against a viral causality.

The presence of EM lesions in adolescents with chilblains in the setting of COVID-19 has been rarely reported (10), but may have been overlooked, possibly because chilblains in case series were reported via photographs and may have not been seen in an ideal clinical setting by dermatologists. One report describes "erythemato-papular targetoid lesions on the hands and elbows after few days" (10) in 2 out of 11 children, and biopsies were described as "mild superficial perivascular dermatitis" (10). In our series, 18 % of children (4 of 22) with COVID-19-related chilblains were also affected with EM-like lesions.

Infections, usually viral, are the most common cause of EM in children and adults (11).

Among viruses, herpes simplex virus is most frequently found, followed by Epstein-Barr Despite the clinical diagnosis, histopathology failed to demonstrate the typical features of EM. Both cases showed variable degrees of interface dermatitis, without necrotic keratinocytes, and a deep extension of the inflammatory infiltrate extending into the subcutis with vasculopatic changes. Necrotic keratinocytes, which are commonly seen in EM biopsies, were not identified, and spongiosis was mild to moderate in our patients. Similarly, the deep extension of the inflammatory process to involve the deep vascular plexus and eccrine glands is not a feature of EM. However, the overall histopathological features are Accepted Article similar to those found in chilblains, including those described during COVID-19 pandemic (7, 9) .

All four patients had an excellent outcome, without complications or severe disease involvement, and lesions eventually disappeared within 1-3 weeks of follow-up.

Treatment with oral corticosteroids was well tolerated in one of them.

In conclusion, EM-like lesions may appear together with chilblains in adolescents in the setting of the COVID-19 pandemic. This coincidence and the positivity for SARS-CoV/SARS-CoV-2 spike protein by immunohistochemistry strongly suggest a link between EM-like lesions and SARS-CoV-2.

The authors wish to thank Bárbara Quintela Bravo for her work with the immunohistochemistries in this study 

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