Chilblains and COVID-19: why SARS-CoV-2 endothelial infection is questioned.

Dear Editor, Chilblains observed during the COVID‐19 pandemic have led to numerous reports and to a suggested link with COVID.

Recently, Colmenero et al. demonstrated, by immunohistochemistry and by electron microscopy (EM), the presence of SARS‐CoV‐2 in endothelial cells of skin biopsy specimens of chilblains in seven patients. These results raise some questions.

The presence of the virus at cutaneous and vascular levels in otherwise asymptomatic patients with negative reverse‐transcription polymerase chain reaction (RT‐PCR) is unexpected. Vascular damage by direct viral effect is expected to be a sign of severity. It is also surprising that only feet are affected.

As mentioned by the authors, immunohistochemistry for detection of SARS‐CoV/SARS‐CoV‐2 remains restricted and subject to cautious interpretation. It would be interesting to show the comparative images of controls. In our limited experience, the immunohistochemistry for SARS‐CoV‐2 (anti‐SARS‐CoV‐2 NP Antibody, BioVision, Inc. Milpitas, CA, USA) in pulmonary specimens from patients with COVID‐19 and those without COVID‐19 shows similar diffuse and homogeneous nonspecific staining of the vascular endothelium (Figure 1a, b). The staining observed by Colmenero et al. concerns vessels that appear to be relatively healthy with no vasculitis or significant perivascular inflammatory infiltrates. Positive and identical immunohistochemistry for SARS‐CoV‐2 in all seven patients (despite time differences between chilblain onset and biopsies) is also puzzling. We compared SARS‐CoV‐2 immunostaining in skin biopsy specimens of chilblains observed in patients prior to and during the COVID‐19 pandemic. The staining was similar in both cases (Figure 1c, d).

Figure 1

Immunohistochemistry for SARS‐CoV‐2 [using anti‐SARS‐CoV‐2 NP Antibody (Clone# 6F10) BioVision, Inc. Milpitas, CA, USA]. (a) Surgical pulmonary resection specimen of a patient without COVID‐19 who underwent thoracic surgery in 2019 before the COVID‐19 pandemic (original magnification × 20). (b) Autopsy pulmonary specimen of a patient with critical COVID‐19 (original magnification × 20). Diffuse endothelial staining of pulmonary vessels can be observed in both cases. (c) Skin biopsy specimens of chilblain lesions during the COVID‐19 pandemic (original magnification × 20). (d) Skin biopsy specimens of classical chilblains observed in 2015 prior to any cases of COVID‐19 (original magnification × 20). Diffuse endothelial staining of dermal vessels is present in both cases.

We feel that the EM image of a single patient presented by Colmenero et al. is not typical of coronavirus particles. Indeed, coronavirus particles have been described by Goldsmith et al. as spherical structures clustered within a membrane that separates them from the cytoplasm. Black dots, corresponding to cross‐sections through the nucleocapsid, are affixed to the inside of the viral envelope, and the interior of the particles is usually eletron‐lucent., The structures observed by Colmenero et al. seem isolated and free within the cytoplasm, although we would expect to see accumulation of viral particles in membrane‐bound areas. Moreover, they are surrounded by dark dots that may be interpreted as spikes of the coronavirus, whereas the spikes would normally be located on the inside of the cisternal space.

Colmenero et al. argue that the negative nasopharyngeal and oropharyngeal PCR in six of their patients may be attributed to low positive rates of PCR in children with symptoms of COVID‐19. However, several publications confirmed not only negative PCR, but also negative serological tests in patients with chilblains. Additionally, RT‐PCR performed on skin biopsy specimens from 21 patients with chilblains failed to detect SARS‐CoV‐2 RNA.

In light of the questions raised, in our opinion, these findings seem insufficient to establish definitive infection by SARS‐CoV‐2 or a direct link with COVID‐19 in patients with ‘COVID toes’.

Author Contribution

Marie Baeck: Conceptualization (lead); Data curation (lead); Formal analysis (lead); Investigation (lead); Methodology (lead); Resources (lead); Supervision (lead); Validation (lead); Writing‐original draft (lead); Writing‐review & editing (lead). Delphine Hoton: Data curation (equal); Formal analysis (equal); Investigation (supporting); Methodology (supporting); Resources (equal); Validation (equal); Writing‐review & editing (supporting). Liliane Marot: Conceptualization (equal); Data curation (equal); Formal analysis (equal); Investigation (supporting); Methodology (supporting); Resources (equal); Supervision (supporting); Writing‐review & editing (supporting). Anne Herman: Conceptualization (equal); Data curation (equal); Formal analysis (equal); Investigation (equal); Methodology (equal); Project administration (equal); Resources (equal); Supervision (supporting); Validation (equal); Writing‐original draft (supporting); Writing‐review & editing (equal).