COVID toes: where do we stand with the current evidence?

BACKGROUND: Numerous of cases of chilblains have been observed, mainly in young subjects with no or mild symptoms compatible with COVID-19. The pathophysiology of these lesions is still widely debated and an association with SARS-CoV-2 infection remains unconfirmed.
OBJECTIVES: This paper focus on the unresolved issues about these COVID toes and in particular whether or not they are associated with COVID-19. ARGUMENTS: The temporal link between the outbreak of chilblains and the COVID-19 pandemic is a first suggests a link between the two events. Positive anti-SARS-CoV/SARS-CoV-2 immunostaining on skin biopsy of chilblains seem to confirm the presence of the virus in the lesions, but lack specificity and must be interpreted with caution. Conversely, RT-PCR and anti-SARS-CoV-2 serology were negative in the majority of patients with chilblains. Therefore, SARS-CoV-2 infection can be excluded, with relative certainty, even after accounting for possible lower immunization in mild/asymptomatic patients and for some differences in sensitivity/specificity between the tests used. Some authors hypothesize that chilblains could be the cutaneous expression of a strong type I interferon (IFN-I) response. High production of IFN-I is suggested to be associated with early viral control and may suppress antibody response. However, the absence of other cutaneous or extracutaneous symptoms as observed in other interferonopathies raises unanswered questions. To date, a direct link between chilblains and COVID-19 still seems impossible to confirm. A more indirect association due to lifestyle changes induced by lockdown is a possible explanation. Improvement of chilblains when protective measures were adopted and after lifting of lockdown, support this hypothesis.
CONCLUSION: Conflicting current evidence highlights the need for systematic and repeated testing of larger numbers of patients and the need for valid follow-up data that take into consideration epidemic curves and evolution of lockdown measures.

Perspective

Skin manifestations are considered infrequent presentations of COVID-19 but no causal link has been formally demonstrated to date (Daneshgaran et al., 2020, Freeman et al., 2020a). A significant number of cases of chilblains have been observed, mainly in adolescents and young adults with no or mild symptoms compatible with SARS-CoV-2 infection. An association between chilblains and COVID-19 is suspected but the pathophysiology of these lesions is still widely debated. Although numerous publications on the subject of chilblains, pseudo-chilblains, chilblain-like lesions, covid-toes, or acral ischemic lesions exist, an association with SARS-CoV-2 infection remains currently unconfirmed.

The prevalence of these COVID-toes observed in several European countries but also in the United States is difficult to assess, with some authors drawing attention to possible SALAMI publishing and to overlapping cases reported in scientific literature and social networks (Kluger, 2020). These lesions seem to mainly affect feet of children, adolescents and young adults who are otherwise in good health and who have no particular medical history (Fig.1 ). However, in our series, blood tests revealed isolated positive anti-nuclear antibodies in one third of patients and these lesions seem to preferentially affect patients with a low BMI (Median:19.13) (Herman et al., 2020, Baeck et al., 2020a). Several patients report symptoms consistent with SARS-CoV-2 infection in the days and weeks prior to the onset of chilblains or contact with people who experienced such symptoms.

Fig. 1

Clinical aspect of the COVID toes in an otherwise healthy teenager, with purplish-erythematous macules located on the toes.

In most reported series, other causes of chilblains such as coagulopathy or systemic diseases were excluded. Several authors performed histopathological and/or immunofluorescence analyses that confirm the diagnosis of chilblains sometimes with vasculitis and microthromboses (Herman et al., 2020, Kanitakis et al., 2020). These features are classically encountered in chilblains and should not lead to confusion with the ischemic acral lesions due to thrombotic vasculopathy and systemic procoagulant state observed in patients with severe or critical COVID-19 and mainly triggered by endothelial damage (probably due to direct viral effect and perivascular inflammation) (Baeck et al., 2020b, Zhang et al., 2020, Magro et al., 2020).

The discussion focuses on whether or not chilblains are associated with COVID-19:

The temporal link between the outbreak of chilblains and the COVID-19 pandemic (moreover during an unusual season for this type of lesion) is a first argument to suggest a link between the two events.

Some authors have also shown positive anti-SARS-CoV/SARS-CoV-2 immunostaining on skin biopsy specimens of chilblains, which seem to confirm the presence of the virus in the lesions (Colmenero et al., 2020, Santonja et al., 2020). However, due to lack specificity, these immunostainings should be interpreted with caution. (Baeck et al., 2020c, Ko et al., 2020).

Conversely, RT-PCR and anti-SARS-CoV-2 serology were mostly negative (Herman et al., 2020, Baeck et al., 2020a, Caselli et al., 2020, El Hachem et al., 2020, Neri et al., 2020, Roca-Ginés et al., 2020, Rouanet et al., 2020, Rizzoli et al., 2020, Mahieu et al., 2020, García-Legaz Martínez et al., 2020, Garcia-Lara et al., 2020, Freeman et al., 2020b, Colonna et al., 2020, Le Cleach et al., 2020, Lesort et al., 2020, Stavert et al., 2020, Denina et al., 2020). Negative RT-PCR on nasopharyngeal swabs could suggest that chilblains are a late symptom of COVID-19. However, serological tests were often negative. A few publications reported positive serology for anti-SARS-CoV-2 IgA (El Hachem et al., 2020, Hubiche et al., 2020). However, the sensitivity of these antibodies is questionable and it cannot be ruled out that false positives may be due to excessive sensitivity (Jääskeläinen et al., 2020). Negative RT-PCR and serological tests in the majority of patients with chilblains allow to exclude, with relative certainty, SARS-CoV-2 infection, even accounting for possible lower immunization in mild/asymptomatic patients and for some differences in sensitivity/specificity between the tests used. For a viral associated phenomenon, the strikingly low rate of testing positivity raises questions.

Some authors hypothesize that chilblains could be the cutaneous expression of a strong type I interferon (IFN-I) response (Lipsker, 2020, Battesti et al., 2020, Damsky et al., 2020, Rodríguez-Villa Lario et al., 2020). A high production of IFN-I is suggested to be associated with early viral control and mild course of SARS-CoV-2 infection. IFN-I may also suppress antibody response which could explain why these patients would not develop antibodies and fail serologic detection. However, some questions remain unanswered with regard to the sometimes-long delay between the suspected COVID-19 symptoms and the appearance of the skin lesions or the absence of other cutaneous or extracutaneous symptoms as observed in other interferonopathies (Rodero and Crow, 2016, Papa et al., 2020).

To date, a direct link between chilblains and COVID-19 still seems impossible to confirm. Our study, like others, points towards a more indirect association due to lifestyle changes induced by lockdown, in particular sedentary lifestyles and bare-feet exposure to cool indoors (Freeman et al., 2020a, Kluger, 2020, Caselli et al., 2020, El Hachem et al., 2020). Patient follow-up support this hypothesis with the observed improvement of chilblains when protective and warm-up measures were adopted and containment restrictions relaxed. It should also be noted that we have observed no new cases of chilblains since lifting of lockdown measures despite recent new infections.

Shedding light on unanswered questions would be significant for patient management and information, testing strategies and implementation of isolation measures. Only data on large series of patients with systematic and repeated testing, as well as follow-up information considering epidemic curves and evolution of lockdown measures, will make it possible to strengthen any one hypothesis.

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Conflict of Interest Statement

The authors have no conflicts of interest.

Funding Source

The authors disclose no financial associations nor funding.

Ethical Approval

The data have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Specific national laws have also been observed.

Authors contributions

Marie Baeck and Anne Herman performed literature searches, prepared the manuscript, reviewed and approved the manuscript and decided to submit the manuscript for publication.