Chilblains Appear as a Manifestation of SARS-CoV-2 Infection and Reveal Features of Type I Interferonopathy and Micro-Vasculopathy

BACKGROUND: The spectrum of manifestations associated with Covid-19 infection is expanding continuously. Increasing cases of cutaneous lesions are reported and are suspected to be secondary to the Covid-19 infection. However, no prospective systematic examination and in-depth assessment of skin manifestations has been reported yet. METHODS: A COVID-19 multidisciplinary consultation was organized at the University Hospital of Nice due to an increasing request from patients and physicians. Forty-nine consecutive patients complaining from cutaneous manifestations were examined. Only patients having chilblains were included. Patients underwent thorough general and dermatological examination, including skin biopsies, vascular investigations as well as biological analysis, SARS-CoV-2 PCR and serologies. FINDINGS: A total of 40 consecutive chilblains were included. Most patients were young with a median age of 22(range 12-67) and a male/female ratio of 0.9. The clinical presentation was highly reproducible with chilblains mostly on toes, and rarely on heels and fingers. Bullous and necrotic evolution was observed. Acrosyndrome was reported in 47.5% of cases. Mild flu-like sympoms were noted in 27.5% in the 6 weeks before the eruption and the rest remained asymptomatic. Flu-like symptoms within the cluster was noted in 60% of patients. Simultaneous occurence of several cases in the same family was observed in two occasions. The PCR testing was negative in all cases. A SARS-CoV-2 serology was positive or doubtful in 4 patients(10%). D-Dimers were evaluated in 61.5% of cases. The major histological findings were lupus-like chilblain/type I interferonopathy lesions and thickening of venules wall with pericytes hyperplasia harboring profibrotic phenotype. INTERPRETATION: Taken together, our results expand the clinical manifestations associated with SARS-CoV-2 infection to chilblains. They also support a viral-induced type I interferonopathy and a microvasculopathy involving pericyte cells. These new data improve our knowledge on the potential mechanisms which could also explain some of the systemic manifestations observed with SARS-CoV-2 infection. TRIAL REGISTRATION: The study was disclosed on ClinicalTrials.gov under the reference: NCT04344119. FUNDING STATEMENT: None DECLARATION OF INTERESTS: None. ETHICS APPROVAL STATEMENT: The institutional review board at the Nice University hospital independently approved the study. Informed consent was obtained from all patients. Analyses were performed on anonymized data.