key: cord-277110-e27lm7rr
authors: Iria, Neri; Annalucia, Virdi; Ilaria, Corsini; Alba, Guglielmo; Tiziana, Lazzarotto; Liliana, Gabrielli; Cosimo, Misciali; Annalisa, Patrizi; Marcello, Lanari
title: Major cluster of pediatric “ true ” primary chilblains during the COVID‐19 pandemic: a consequence of lifestyle changes due to lockdown
date: 2020-06-13
journal: J Eur Acad Dermatol Venereol
DOI: 10.1111/jdv.16751
sha: 
doc_id: 277110
cord_uid: e27lm7rr

BACKGROUND: Over the last months, during the COVID‐19 pandemic, a growing number of chilblain‐like lesions was reported mainly in children, rarely in young adults. The relationship with SARS‐CoV‐2 infection was postulated, often without any laboratory, instrumental or clinical confirmation. The disclosure of information about chilblain‐like lesions as a COVID‐19 manifestation in social media has created concern in children’s families and pediatricians OBJECTIVES: to verify whether the chilblain‐like lesions were caused by SARS‐CoV‐2 infection. METHODS: prospective study on a case series including children who presented with acral lesions at the Pediatric Dermatology Outpatient and Pediatric Emergency Unit of the University of Bologna, from April 1 to April 30, 2020. We reported demographical, laboratory and clinical features, history of close contact with COVID‐19 patients, presence of similar skin lesions in other family members, precipitating and risk factors for chilblain onset. RESULTS: We evaluated 8 patients (5 females, 3 males) aged between 11 and 15 years. We excluded acute or previous SARS‐CoV‐2 infection with RT‐PCR nasopharyngeal swab, serum antibody levels using chemiluminescent immunoassays. Other acute infections causing purpuric lesions at the extremities were negative in all patients. Skin lesion biopsy for histological and immunohistochemical evaluation was made in two cases and was consistent with chilblain. PCR‐assay on skin lesion biopsy for Parvovirus B19, Mycoplasma pneumoniae and SARS‐CoV‐2 was performed in a patient and resulted negative. We identified common precipitating and risk factors: physical (cold and wet extremities, low BMI), cold and wet indoor and outdoor environment, behaviors, habits, lifestyle. We therefore reached a diagnosis of primary chilblains. CONCLUSIONS: During the COVID‐19 pandemic, a “cluster” of primary chilblains developed in predisposed subjects, mainly teenagers, due to to cold exposure in the lockdown period. Laboratory findings support our hypothesis, although it is also possible that an unknown infectious trigger may have contributed to the pathogenesis.

Global public health is still challenged by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, the causative agent of Coronavirus disease 2019 (COVID-19).

The Emilia Romagna region, as well as Lombardy, is one of the largest and most serious clusters of COVID-19 in Italy. The transmission of SARS-CoV-2 occurs through airborne spread, droplets, aerosol, hand contact and fecal shedding. The main paths of transmission in pediatric age are through close contact with other infected family members (89%), exposure to epidemic areas (33%) or both. 1 Clinical manifestations in the pediatric age range from mild to critical; however, most patients are asymptomatic or present a mild disease with fever, fatigue, dry cough, myalgia and diarrhea.

Severe and critical forms are rarer if compared with adults or the elderly, although bilateral interstitial pneumonia and late-onset neonatal sepsis have been reported. 2, 3 Skin findings associated with SARS-CoV-2 infection represent a new hot topic. The dermatological manifestations range from viral exanthema-like rashes to vasculopathy-related lesions. 4 Although this debate is very lively in adults, little is known about the dermatological manifestations of the virus in the pediatric age. Genovese and Morey-Olivé reported different types of rash, such as varicella-like, maculopapular and urticaria-like eruptions, in children with confirmed or highly suspected COVID-19. 5, 6 In the last month an "outbreak" of chilblain-like lesions was reported, mainly in the pediatric population. 7, 8 The relationship with SARS-CoV-2 infection was postulated by several Authors.

The chilblain-like lesions were variably associated with the presence of respiratory and systemic symptoms or with the history of close contact with positive cases, though lacking the criteria for testing for SARS-CoV2 in the majority of cases. 8

This article is protected by copyright. All rights reserved In April 2020, we observed a growing number of chilblain-like manifestations similar to coldinduced lesions during the pandemic, with the opportunity to study 8 cases, 2 children and 6 adolescents, and report here our results.

The aim of this study is to verify whether the chilblain-like lesions were a cutaneous clue for SARS-CoV-2 infection or due to other causes. 

This article is protected by copyright. All rights reserved -PCR-assay on blood samples for Parvovirus B19 DNA and Enterovirus RNA -PCR-assay on skin biopsy for Parvovirus B19, Mycoplasma pneumoniae and SARS-CoV-2 was performed in a single patient (12.5%).

A second evaluation (time 1 = T1) was performed on all patients 8 to 20 days after T0, repeating routine analysis and serological tests for Parvovirus B19, CMV, EBV, Mycoplasma pneumonia.

Skin biopsy for histological and immunohistochemical evaluation was made in two cases on finger and toe lesions respectively.

Qualitative detection of COVID-19 was performed through RNA extraction from throat swab and biopsy using QIAsymphony SP/AS instruments with QIAsymphony DSP Virus/Pathogen Midi Kit (Qiagen, Hilden, Germany). Real-time reverse-transcription was carried out according to Corman VM et al. 9 using RNA-dependent RNA polymerase gene (RdRp) as amplicon target. The limit of detection for the RdRp assay is 3.6 copies per reaction (95%: 2.7-11.2). 9

The patients evaluated were 8, 5 females and 3 males. The age ranged from 11 to 15 years.

The mean time from the lesions onset to the visit was 19.6 days (9-30).

All patients were asymptomatic and their medical history was unremarkable. None of them, including all family members, referred history of close contact with COVID-19 patients.

Moreover, neither parents or siblings presented any cutaneous or systemic and respiratory symptoms.

Clinical aspect was the same in all cases, presenting multiple red-purple macules and/or patches patches or nodular type and 2) blistering type ( Figure 1 ).

Also PCR-assay skin biopsy for SARS-CoV-2 RNA of the chilblain lesion in one case was negative.

Regarding laboratory findings, all patients had normal blood count and biochemical profile; 3/8 (37.5%) showed only slight lymphocytosis (T0), then returning to normal value (T1).

Furthermore, the immune inflammatory parameters and cytokines considered to be related to

This article is protected by copyright. All rights reserved SARS-CoV-2 (IL6, LDH and ferritin) were unaltered. The ANA reflex titer was normal in all patients.

The values of homocysteine, lymphocyte subset, LAC, anti-cardiolipin and anti-beta2 glycoprotein I antibodies (IgM and IgG) were within range in all patients.

Concerning the serological tests, four patients (50%) showed an increased level of IgG for Mycoplasma Pneumoniae (nr <12 U/ml) at T0; at T1, IgG level was slightly decreased in two patients (25%), unchanged in one patient (12.5%), and slightly increased in one patient (12.5%).

Elevated IgM levels were not observed in any patients at any time.

Seven patients (87.5%) were immune (IgG positive, IgM negative) to EBV; IgM were observed in only one patient (12.5%) in association with IgG and EBNA, both at T0 and T1: these values are relatable to a previous infection. Three patients (37.5%) were immune to CMV, none showed active infection.

Regarding viral PCR examinations on blood, two patients (25%) showed a low viral load of Parvovirus B19 DNA (<250 copies/ml), which corresponds to residual copies from a past infection. Finally, enterovirus RNA was not found in any of the cases. 

Since laboratory tests excluded infectious or autoimmune etiology and considering the habits and behavior of the patients during the lockdown, a diagnosis of idiopathic or primary chilblains (PC) was made.

We recommended protection from the cold. Topical steroids were prescribed in all patients. After a 4-5 week follow-up, the patients denied any symptoms and the lesions healed.

Our primary aim was to investigate a potential link between SARS-CoV-2 infection and the occurrence of chilblain-like lesions in children. Various cutaneous findings were observed in adults infected with COVID-19 and, simultaneously, a marked increase of chilblain-like lesions occurred worldwide among children during the COVID-19 pandemic 10, 11 In our cases we exclude SARS-CoV-2 infection. The serology was performed in all cases three weeks after the appearance of the chilblains and both IgM and IgG were negative, and this led us 

This article is protected by copyright. All rights reserved infected patients. 13 Even in large study the virus was detected in less than half of patients with pseudo-chilblains. 7 COVID-19-related pseudo-chilblains has been supposed associated with younger age, less severe disease, and late appearance compared to COVID-19 onset. 7 Pseudo-chilblain late onset led to hypothesize a late manifestation of vascular damage secondary to antigen-antibody mechanism 7, 14 and according to some authors this might explain the frequently negative PCR results on nasopharingeal swab. 7, 8 Few pediatric cases with clinical, instrumental or virologic confirmation were included in these studies. 14, 15 The disclosure of chilblain information as a COVID-19 cutaneous sign in social media has created concern in children's families and paediatricians.

However many of the recently reported chilblains occurred in children without general symptoms of SARS-Cov-2 and coming from asymptomatic families. 16 As chilblains are not frequent in pediatric age and uncommon in 'Mediterranean' climate, the recent increasing number of cases could suggest an infectious aetiology. So after SARS-CoV-2, we ruled out other pathogens causing purpuric lesions at the extremities, such as in papular purpuric gloves and socks syndrome and/or atypical hand-foot-mouth disease, and viral infections which are rarely reported as precipitating factors of chilblains. 17 We tested for Mycoplasma pneumoniae, Epstain-Barr-Virus, Parvovirus B19, Enterovirus and Citomegalovirus. None of the 8 children involved in our study was found to be in the acute phase of any of these infections. In all cases a complete blood count and C-reactive protein were within normal limits.

Lockdown involving the main gathering places for children (kindergartens, schools, gyms, parks) from the end of February resulted in a reduction in the spread of typical childhood infectious diseases and a lower number of admissions to the pediatric health care facilities.

In 2 cases biopsy was performed to evaluate the histological characteristics of skin lesions and to exclude the presence of vasculitis or thrombi (reported by Colonna et al. 18 ), whose appearance in the late phase of COVID-19 has been discussed. 14 

This article is protected by copyright. All rights reserved consistent with a diagnosis of chilblain. 15, 16, 18, 21 Clinical examination, microbiological investigations, laboratory data (including ANA, LAC, fibrinogen, D-dimer) did not reveal any other underlying diseases (viral infection, lupus, hypercoagulation status). It is also possible that an unknown infectious trigger may have contributed to our cluster.

We therefore reached a diagnosis of idiopathic or primary chilblains.

The primary chilblain (PC), also called pernio, is a self-limiting inflammatory disorder, caused by prolonged exposure to cold temperatures and wet weather, especially during late winter or early spring. Cold may cause persistent or prolonged vasoconstriction in vulnerable people, with subsequent hypoxemia and secondary inflammatory reaction. 22 The pathogenesis of PC has been attributed to a defective vasodilatory reflex.

We observed typical PC lesions in bilateral acral areas of the hands and feet, especially on the dorsal aspect of toes and in 3/8 cases also on the heel and plantar surface. PC affects susceptible individuals, mainly young females between the ages of 15 and 30 years, and less frequently children and the old people. 23 At this point why a "cluster" of chilblains was taking place in children not only in Italy but also in other countries 14 remains to be clarified. Many other published cases were evaluated through teledermatology, 10 often without tests and the evaluation of other possible etiologies common to various countries, such as the drastic lifestyle changes due to lockdown.

We therefore investigated predisposing factors, including age, common characteristics in affected subjects (such as cold and wet extremities and familiarity for chilblains) and trigger factors in environmental conditions (indoor and outdoor). In the pediatric age, girls going through puberty seem to be more at risk, especially teenagers with thin body habitus. 19 Our cases were all adolescent, F:M=5:3 with a mean age of 12.8 years. BMI was <25th percentile in 4/8 patients and within 25-50 th percentile in 4/8.

Non-freezing weather and humidity represented triggering factors to be considered. In the late winter-early spring the climate is generally not rigid at our latitude, whereas pronounced temperature variations were registered in Bologna this March (Figure 3) . A marked humidity characterized the climate in Bologna and in one case also the home environment.

Around this time also many apartments are cooler because the heating has been turned off.

New behaviors, habits and/or lifestyles arising from the lockdown were evaluated. Toddlers and school-age children were forced to stay at home all day and changed their habits. We evaluated the

This article is protected by copyright. All rights reserved clothing, the new behaviors and the characteristics of the home. Some "domestic behaviors" already frequent among adolescents increased during the lockdown period, such as the tendency to isolation in their room with computers due to school needs and entertainment on social network with friends. An accurate personal history showed inadequate clothing in most cases and in fact many of them walked barefoot on cold marble or ceramic floors, or had prolonged incorrect postural habits such as staying with their legs bent or crossed on the floor or on a chair for many hours. Incorrect postural habits may have contributed to a reduction of blood flow and to lowering skin temperature. These data led us to assume that although the outside temperature was not rigid, these new behaviors, poor clothing, unheated apartments, and the characteristics of the indoor environments may have caused the cooling of extremities and feet.

This explains the unusual plantar localization of chilblains in 3 of our cases who walked barefoot, similar to 3 other reported cases who wore shoe boots. 24 In the literature recreational chilblains are reported with involvement of unusual areas. Unusual localization appears on the hips due to prolonged cold exposure, provoked by tight low-cut jeans. 25 We have assumed that in predisposed subjects, mainly teenagers, the changes in life style due to the COVID-19 lockdown, the weather conditions in March and April 2020 and the cold and wet indoor climate may justify the 'cluster' of PC. The longer course of the lesions in our patients compared to typically acute PC 23 might be explained by the persistence of the lockdown.

It would be interesting to verify whether in COVID-19 positive young adults the presence of chilblains is caused by exposure to cold in predisposed subjects and not linked to SARS-CoV-2 infection, as already suspected. 7 The major limitation of our study was the small sample size. We were not able to test other patients due to the difficulties to access the hospital. The observation of other cases, with a careful clinical examination and an accurate history will provide further diagnostic clues and will be necessary to verify our hypothesis.

In the literature, the reasons for the chilblain "cluster" during the COVID-19 pandemic have so far been not well identified, also on account of the difficulties to perform clinical and diagnostic evaluation.

Negative results of RT-PCR nasopharyngeal swab, serological tests and PCR-assay skin biopsy Accepted Article ruled out a SARS-CoV-2 infection in all of our cases.

It is also possible that an unknown infectious trigger may have contributed to our cluster of cases. Nevertheless, the exclusion of other more frequent infectious agents, the normality of laboratory tests, and the histologic findings led us to the diagnosis of chilblain, a benign acral inflammatory disorder.

We conclude that the chilblains observed in our cases are primary and affect predisposed subjects due to cold exposure in the lockdown period (March-April 2020), during a worldwide emergency. 

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The patients in this manuscript have given written informed consent to the publication of their

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