key: cord-296128-kjoi54ea
authors: Balestri, Riccardo; Magnano, Michela; Rizzoli, Laura; Rech, Giulia
title: Do we have serological evidences that chilblain‐like lesions are related to SARS‐CoV‐2? A review of the literature
date: 2020-08-26
journal: Dermatol Ther
DOI: 10.1111/dth.14229
sha: 
doc_id: 296128
cord_uid: kjoi54ea

The outbreak of chilblain‐like lesions (CLL) coincidentally to the COVID‐19 pandemic is a topic of great concern. SARS‐CoV‐2 was initially hypothesized as the etiologic agent of CLL, but, since nasopharyngeal swabs seldom resulted positive, dermatologists’ attention focused on the search for specific SARS‐CoV‐2 antibodies. Many papers were published contemporarily on this topic, reporting limited case series. We reviewed the English literature up to the 1(st) July 2020 and, excluding single case reports, we considered 13 studies that serologically investigated 220 patients. The presence of specific antibodies was detected in 18 subjects (8,2%): isolated IgA were found in 6 patients, IgA and IgG in 1, isolated IgG in 5, and IgM in 2. In 4 patients, isotypes were not specified. Our review demonstrated a high prevalence of negative serological results in CLL: antibodies were observed only in a few patients, that are even less excluding those with positive IgA, not clearly involved in the pathogenesis of the disease. In conclusion, although it is still uncertain whether CLL are related to SARS‐CoV‐2 infection, patients affected by CLL seem not to be prone to shedding the virus, hence, if they are asymptomatic, we can reassure them, thus avoiding hospital referral This article is protected by copyright. All rights reserved.

The outbreak of chilblain-like lesions (CLL) coincidentally to the COVID-19 pandemic is a topic of great concern 1 SARS-CoV-2 was hypothesized as the etiologic agent of CLL, initially on the basis of the temporal correlation between the "burst" of skin manifestations and the viral pandemic.

However, it has been shown that CLL are not related to an acute infection, since real-time reverse transcription polymerase chain reaction (rt-PCR) tests from nasopharyngeal swabs seldom resulted positive 1-9- Therefore, dermatologists' attention shifted to the search for specific SARS-CoV-2 antibodies.

Many papers were published contemporarily on this topic, reporting limited case series. The aim of our review is to collect more data concerning seroprevalence and to better understand the role of SARS-CoV-2 in the development of CLL.

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We reviewed the English literature up to the 1 st July 2020 in the PubMed MEDLINE database using combinations of the key search terms "acral", "acro-ischemic", "acro-syndrome", "chilblain", "chilblain-like", "COVID-19", "pernio", "pernio-like", "perniosis", "pseudochilblain", "SARS-CoV-2". Search terms were used in combinations.

The search was limited to articles published in English We included only case series, clearly declaring that a search for SARS-CoV-2 specific antibodies had been performed. Single case reports were excluded.

Data were independently extracted by two Authors (MM and RB), then the results of data extraction were compared.

The initial research on PubMed returned 72 papers focusing on CLL and SARS-CoV-2.

We retrieved 13 articles reporting serological studies performed on case series that included at least 8 patients (Table 1) .

Twelve studies took place in Europeand the last one is an observational survey conducted in 8 US states. A total of 220 patients were serologically investigated.

Testing methods were various: chemiluminescent immunoassays were used in 3 studies, chromatographic immunoassay was used by 2 groups, enzyme linked immunosorbent assays (ELISA) in other 2, one study used both a chemiluminescent immunoassay and an ELISA and one both chromatographic and ELISA. In 4 papers test types were not specified.

Performances declared in the manufacturers' package insert of each test are reported in Table 2 .

The presence of specific antibodies was detected in 18/220 (8.2%) cases. The detected isotypes were: isolated IgA 6 (2.7%); IgA and IgG 1 (0.4%), isolated IgG 5 (2.3%); IgM 2 (0.9%). In 4 cases, the isotype was not specified. 1, 7, 11, 12 . One study declared only the total median (25 days) 6 . One hundred and ninety-two patients also underwent rt-PCR, resulted negative in all cases.

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At the beginning of the CLL epidemic, a role of SARS-CoV-2 was hypothesized only on the basis of the temporal correlation with the COVID-19 pandemic, searching for evidence from nasopharyngeal swabs. It is now clear that CLL do not represent an acute cutaneous manifestation of SARS-CoV-2, hence swabs are completely useless to confirm the infection. The attention of the scientific community therefore shifted to serology, assuming that specific antibodies may validate thishypothesis.

The present review shows a high prevalence of negative serological results in CLL, indicating that this is a wrong strategy to demonstrate the role of coronavirus in CLL. In fact, antibodies were observed only in a limited percentage of patients, which becomes very low (5,45%) if we exclude patients with IgA, whose role remains doubtful in the pathogenesis of the disease.

Some considerations and hypotheses can be raised to explain this finding:

Three groups support this theory, considering these skin lesions caused by lifestyle changes due to containment and lockdown measures 7, 11, 12 . However, although this may be true for some of these cases, given the large number of new reports of CLL coincidentally with the COVID-19 pandemic, it is not sufficient to explain all the cases. Moreover, mean European temperatures during the first months of 2020 were similar or higher compared to those of the last 29 years, and solely the sedentary habits and barefoot walking at home seem inadequate to justify an epidemic of CLL.

This was particularly true with the initially-available tests, since they had been rapidly developed and placed on the market with limited validationHowever, we can exclude this hypothesis because This article is protected by copyright. All rights reserved.

serological tests showed excellent clinical performance in real life 1 and the authors used 8 different types of test, achieving similar findings.

Higher levels of IgM and IgG have been found in the second and third week of illness, then IgM begins to decline and almost disappears by week 7, while IgG persists 14 . The duration of their persistence still remains unknown: data suggest a serological profile similar to SARS-CoV 14 , although asymptomatic/paucisymptomatic patients seem to present lower levels of specific antibodies compared to severe disease 22 . Lower levels do not mean an absence of antibodies, hence we can also exclude this hypothesis.

Another issue could be the timing in which tests had been performed, since a sufficient time lapse is necessary to develop antibodies. This information is reported only in 4 studies, and the timing proved adequate to detect antibodies in most cases.

Locally recruited cytotoxic CD8 T cells could be the effector of skin lesions. During mild forms of the disease, such as those developing CLL, T cell exhaustion and viral-associated immunosuppression may reduce the production of SARS-CoV-2 specific antibodies, therefore an incomplete viral clearing may induce delayed cutaneous lesions without detectable antibodies 9 .

In genetically predisposed individuals the contact with SARS-CoV-2 triggers a robust interferon response, of which chilblains are the cutaneous expression. This hypothesis is supported by the fact that chilblains are a prototypical sign of a few inherited disorders of innate immunity, characterized by a strong interferon signature and a severe microangiopathy (i.e. interferonopathies). This strong This article is protected by copyright. All rights reserved.

IFN-I response would mute early viral replication, clearing the virus without intervention of the adaptive immune system, thus avoiding the development of detectable IgM/IgG 1 .

Finally, we could consider the involvement of another viral agent in the epidemic of CLL, and the seldom test-positivity to SARS-CoV-2 may therefore be only a casual finding. However, a viral outbreak during another viral pandemic seems highly improbable.

In conclusion, while recent findings seem to suggest that SARS-CoV-2 could have a pathogenetic role in the development of CLL, also serological screening failed to prove that acral skin lesions are a specific marker of SARS-CoV-2 infection. Further studies are needed to obtain a definitive confirmation. In the meanwhile, it seems that patients affected by CLL are not prone to shedding the virus; consequently, in the case of otherwise asymptomatic patients, we canreassure them, without referring them to hospital to perform any sort of COVID-19 test, or quarantining them. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

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