key: cord-1016891-r2xm164s
authors: Gallizzi, Romina; Sutera, Diana; Spagnolo, Alessandra; Bagnato, Anna Maria; Cannavò, Serafinella Patrizia; Grasso, Loredana; Guarneri, Claudio; Nunnari, Giuseppe; Mazza, Francesca; Pajno, Giovanni Battista
title: Management of pernio‐like cutaneous manifestations in children during the outbreak of covid‐19.
date: 2020-09-19
journal: Dermatol Ther
DOI: 10.1111/dth.14312
sha: fda520238fb80840f75b758949898e414c9b5ec3
doc_id: 1016891
cord_uid: r2xm164s

BACKGROUND: During the outbreak of COVID‐19 many pernio‐like lesions have been increasingly reported. The aim of the study is to describe our management of these skin manifestations and to evaluate a possible correlation to SARS‐CoV‐2 infection. METHODS: All patients underwent clinical and laboratory tests to detect a possible underlying connective disease and also to specific SARS‐CoV‐2 investigations such as oropharyngeal swab and IgG‐IgM serology. RESULTS: Nine patients aged between five and fifteen years old were evaluated. Skin lesions observed were purplish, erythematous and oedematous, in some cases painful and itchy. Six out of nine had respiratory and systemic symptoms (cough, nasal congestion, chills, fever, asthenia) that preceded cutaneous findings of approximately two weeks. Concerning blood exams, three out of nine had D‐dimer weakly increased, four had ANA positivity: two with a title 1:160, one with 1:320 and one with 1:5120 and a speckled pattern. The latter patient had also ENA SS‐A positive and RF positivity, confirmed at a second check, so as to allow us to make a diagnosis of connective tissue disease. Four out of nine had aPL positivity (IgM). Reactants acute phase were all negative. Oropharyngeal swabs and serology tests for SARS‐CoV‐2 was negative (borderline in one patient for IgM). No treatment was needed. CONCLUSIONS: Even if we do not have enough data to prove it, we hypothesize a correlation between pernio‐like lesions and SARS‐CoV‐2 infection for an increased number of these lesions described during the pandemic and also because such manifestations appeared when temperatures were mild and patients were at home in isolation for the lockdown. Many questions remain open about interaction host‐virus. This article is protected by copyright. All rights reserved.

During the outbreak of COVID-19 many skin manifestations have been reported, and among these, in very significant numbers, newly vascular eruptions and peculiar pernio-like skin lesions have been described in observational studies 1, 2, 3, 4 . Pernio, also referred to as chilblains, is a rare inflammatory condition.

Chilblains derives from two Old English words "chill" (cold) and "blegen" (sore). Most commonly, pernio affects acral skin and develops among susceptible individuals who are exposed to cold, the lesions usually appear in fall or winter and disappear in spring or early summer. It is typically idiopathic and acute, nevertheless chronic forms also exist 5 . The diagnosis of pernio is largely clinical and based on a thorough history and physical exam. The differential diagnosis must exclude diseases that can often be confused with other forms of pernio or vasculitis processes like Systemic Lupus This article is protected by copyright. All rights reserved.

Erythematous (SLE) or other conditions as Raynaud phenomenon, acrocyanosis, cryoglobulinemia, cold panniculitis and Interferonopathies. The prognosis of pernio is good with minimal chronic sequelae. Single or multiple erythematous, purplish, edematous lesions appear, accompanied by intense pain, itching, or burning. Usually, pernio affects the toes and dorsum of the proximal phalanges 6 . The mainstay of treatment is the avoidance of the cold and, in some cases, drugs as nifedipine and other calcium channel blockers are needed for the resolution of existing lesions 5 .

Since March 2020, children with acral red and painful skin lesions, referable to chilblain have come to our attention. The increased number of cases of pernio-like lesions compared to the cases per year we usually observe, the mild temperatures of those months in Southern Italy and the concomitant lockdown, led us to hypothesize a possible correlation with SARS-CoV-2 infection.

We evaluated the personal history and photographs of skin lesions of 26 patients, sent to us by their pediatrician, through multidisciplinary telematic meetings with dermatologists, rheumatological pediatricians, infectious disease specialist. We only included patients with pernio-like skin lesions (nine patients). Patients who could not perform the oropharyngeal swab for SARS-CoV-2 were not admitted to the hospital. We collected informed consent to obtain clinical information and photos of patients and to perform blood chemistry sampling. Therefore, we evaluated 9 cases of children who 

In our group of patients no significant difference in gender was detected (5 Females and 4 Males).

The median age was 11,4 years (from 5 to 15 years). Two patients were siblings. All patients were from the South of Italy coming from the town of Messina and surrounding. Their family histories and their personal histories were negative for autoimmune disorders, Raynaud's phenomenon, acrocyanosis, chilblains or photosensitivity except for one child who had suffered from an episode of Raynaud's phenomenon a few years earlier. No family member of these patients presented symptoms attributable to SARS-CoV-2 infection but, for work reasons, their parents were in contact with public.

Only two siblings had both parents with compatible symptoms and confirmed SARS-CoV-2 infection by positive nasal swab. The cutaneous manifestations observed were purplish, erythematous and edematous, four children reported subjective symptoms, painful and pruritus localized to the sole of the feet or to the toes and/or fingers or heels ( Fig. 1,2,3 ). Feet alone were mostly affected (6 out of 9), hands alone (3 out of 9) (Fig.1) . Six patients had respiratory and systemic symptoms (cough, nasal congestion, chills, fever, asthenia) that preceded the skin lesions by about two weeks (Table1). This article is protected by copyright. All rights reserved.

We evaluated 9 cases of children who presented pernio-like lesions, since March to April 2020 during the outbreak of COVID-19. We performed first level tests, all negative except for D-dimer weakly increased in three of our patients. D-dimer is a marker of activation of coagulation and fibrinolysis and it provides a rapid evaluation of thrombotic activity. Its level correlated to coagulopathy have been described as prognostic factors in the evolution of SARS-CoV-2 infection, especially in more severe patients. Zhang's study developed a triage, testing D-dimer levels at the admission, on the first and third day to predict survival in a cohort of patients and to evaluate management and follow up.

The result was that a regulatory level of D-dimer at the presentation is highly predictive for survival 7 .

This is useful to highlight, as in our case, the D-dimer of our patients was weakly increased, a condition perfectly correlated with the mild symptoms of SARS-CoV-2 putative infection presented.

We have also performed autoimmunity tests, three out of nine had ANA positivity (speckled pattern):

two with a title of 1:160, one 1:320 not confirmed at a subsequent check after two months, another asymptomatic cases generated specific antibody responses for SARS-CoV-2 9 . The case of our family is emblematic: two parents presented striking symptoms of SARS-CoV-2 infection, high fever and This article is protected by copyright. All rights reserved. difficulty in breathing, and three positive swabs; the father had positive serology with high IgG, such as to allow donation of his plasma for therapeutic purposes and the mother was surprisingly negative.

Sons who came to our observation, both with chilblain, presented mild respiratory symptoms and they were negative for both swabs and IgG serology, while in one of the two cases, the IgM were borderline. Despite the negativities of diagnostic test for SARS-CoV-2, we are still convinced that there is a correlation between this infection and the development of pernio-like lesions, as described Nasopharyngeal swab for SARS-CoV-2 gave negative results 4 . In a report of 19 adolescent patients with a clinical diagnosis of pernio-like lesions nasopharyngeal swab and IgG serology for SARS-CoV-2 nucleocapsid protein were negative. Importantly, IgA serology for S1 domain of SARS-CoV-2 spike protein was positive in 6 patients and borderline in 3 patients 10 . In a study performed in Sicily (Italy) via teledermatology a total of 22 patients complaining of perniosis-like lesions were screened, mainly in the pediatric age (≤18yrs). All of them were tested with rhino-pharyngeal swabs and SARS-CoV-2 was detected in 6 patients, 5 of whom were children 11 . The understanding of the immunopathogenetic mechanisms of interaction between the SARS-CoV-2 infection and children is very intriguing but current knowledge does not seem to be sufficient. Why some children who come into contact with the SARS-CoV-2 do not develop striking respiratory symptoms but present pernio-like lesions with negativity on diagnostic tests?

Matricardi et al developed the first model of interaction between the human immune system and SARS-CoV-2, as an attempt to produce a synthesis of the actual knowledge 12 . What emerges is that innate immunity represents the first line of defense against the new SARS-CoV-2 and this first comparison establishes the natural history of the pathology: either the infection will effectively block in the upper airways or if the virus manages to reach the lungs. Innate immunity is essential for controlling virus replication before an adaptive immune response is generated 13 . Type I Interferones (IFN-I) are major components of the innate immune system and it represents critical antiviral molecules 14 . It is hypothesized that the IFN-I response may induce microangiopathic changes, producing chilblains and lupus-like erythematous eruption.

A mechanism has recently been considered to explain the appearance of autoimmune phenomena following the whole SARS-CoV-2 infection: molecular mimicry 16, 17, 18 . Lucchesi and Floel 19 have hypothesized a molecular mimicry mechanism between neuronal proteins present in the brain stem respiratory pacemaker neurons (DAB1, AIFM and SURF1) and viral epitopes of SARS-CoV-2 treated antigenic. The same mechanism, according to Angileri et al., could be responsible of anosmia, leukopenia and multi-organ failure caused by vascular damage, assuming they are associated with the molecular mimicry 20 . A type 3 hypersensitivity therefore occurs with the deposition of antibody antigen complexes precipitating inside the tissues, in particular the blood vessels, inducing a serious inflammatory state by the action of the complement anaphylatoxins (C3a and C5a), which in turn stimulate the release of histamine from mast cells and the recruitment of phagocytes, first in neutrophils, the main cause of tissue damage and following «leukocytoclastic vasculitis» (LCV), also reported in the English medical literature from the term «hypersensitivity vasculitis 21, 22 ».

This pathogenic mechanism could explain the appearance of pernio-like lesions due to SARS-CoV-2 infection.

In conclusion, we think there is a correlation between pernio-like lesions and SARS-CoV-2 infection, but further studies are needed to prove it. This, for the increased number of these lesions described during this short time, as in our experience, and because such manifestations appeared when temperatures were mild in Southern Italy and patients were at home for the lockdown.

To our knowledge, this is one of the few studies that collects a series of pediatric patients with perniolike lesions, evaluating the possible association with COVID 19 (oropharyngeal swab and serology test) but also for rheumatological diseases. This article is protected by copyright. All rights reserved. 

Chilblain-like lesions during COVID-19 epidemic: a preliminary study on 63 patients

Chilblain-like lesions on feet and hands during the COVID-19 Pandemic

Acral cutaneous lesions in the time of COVID-19

Pernio (Chilblains) StatPearls

Treasure Island (FL): StatPearls Publishing

D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19

Autoantibodies in nonautoimmune individuals during infections

Yuxin Chen & Bing Gu (2020) Different longitudinal patterns of nucleic acid and serology testing results based on disease severity of COVID-19 patients

A clinical, histopathological and laboratory study of 19 consecutive Italian paediatric patients with chilblain-like lesions: lights and shadows on the relationship with COVID-19 infection

Diversity of clinical appearance of cutaneous manifestations in the course of COVID-19

The first, holistic immunological model of COVID-19: implications for prevention, diagnosis, and public health measures

Type I interferons (a/b) in immunity and autoimmunity

COVID-19) infection-induced chilblains: A case report with histopathologic findings

COVID-19 a proteiform disease inducing also molecular mimicry phenomena?

Guillain Barre syndrome associated with COVID-19 infection: A case report

COVID-19 and molecular mimicry: The Columbus' egg?

Molecular mimicry between SARS-CoV-2 and respiratory pacemaker neurons

Molecular mimicry may explain multi-organ damage in COVID-19

Immunobiology: the immune system in health and disease

Leukocytoclastic vasculitis

LIST OF ABBREVIATIONS aCL: anti-cardiolipin antibodies AIFM: Apoptosis-inducing factor 1, mitochondrial ANA: antinuclear antibodies anti-β2GP1: anti β-2-glycoprotein1 antibodies aPL: antiphospholipid antibodies C3a: complement factor 3 anaphylotoxin C5a: complement factor 5 anaphylotoxin CBC: complete blood count CLIA: chemiluminescent microparticle immunoassay COVID