Clinical, Laboratory, and Interferon-Alpha Response Characteristics of Patients With Chilblain-like Lesions During the COVID-19 Pandemic

Abstract

IMPORTANCE Chilblain-like lesions have been reported during the coronavirus 2019 (COVID-19) pandemic. The pathophysiology of such manifestations remains largely unknown. OBJECTIVE To perform a systematic clinical, histologic, and biologic assessment in a cohort of patients with chilblain-like lesions occurring during the COVID-19 pandemic. DESIGN, SETTING, AND PARTICIPANTS In this prospective case series carried out with a COVID-19 multidisciplinary consultation group at the University Hospital of Nice, France, 40 consecutive patients presenting with chilblain-like lesions were included. MAIN OUTCOMES AND MEASURES Patients underwent a thorough general and dermatologic examination, including skin biopsies, vascular investigations, biologic analyses, interferon-alpha (IFN-α) stimulation and detection, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) and serologic analysis. RESULTS Overall, 40 consecutive patients with chilblain-like lesions were included. Most patients were young, with a median (range) age of 22 (12-67) years; 19 were male and 21 were female. The clinical presentation was highly reproducible with chilblain-like lesions mostly on the toes. Bullous and necrotic evolution was observed in 11 patients. Acrocyanosis or cold toes were reported in 19 (47.5%) cases. Criteria compatible with COVID-19 cases were noted in 11 (27.5%) within 6 weeks prior to the eruption. The real-time PCR (rt-PCR) testing results were negative in all cases. Overall, SARS-CoV-2 serology results were positive in 12 patients (30%). D-dimer concentration levels were elevated in 24 (60.0%) cases. Cryoglobulinemia and parvovirus B19 serologic results were negative for all tested patients. The major histologic findings were features of lymphocytic inflammation and vascular damage with thickening of venule walls and pericyte hyperplasia. A significant increase of IFN-α production after in vitro stimulation was observed in the chilblain population compared with patients with mild-severe acute COVID-19. CONCLUSIONS AND RELEVANCE Taken together, our results suggest that chilblain-like lesions observed during the COVID-19 pandemic represent manifestations of a viral-induced type I interferonopathy. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04344119

Relapse of chilblain‐like lesions during the second wave of coronavirus disease 19

“…They speculated that the direct infection of endothelial cells may be sufficient to induce local type I IFN induction and CLL. 7 This finding has been recently supported by Hubiche et al 6 , who demonstrated an increased IFN-alfa response in CLL patients as compared to non-CLL patients with acute COVID-19 infection. The hypothesis of a pathogenetic role of IFNs in the development of CLL is further supported by the observation that patients with chronic type I IFN activation due to rare genetic type I interferonopathies frequently develop chilblain lesions.…”

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“…Reports of delayed onset chilblain-like lesions predominantly affecting the lower extremities have increased during the pandemic, but strong conclusions about its etiology cannot be made due to inconsistent clinical and laboratory evidence of prior SARS-CoV-2 infection. While the younger age of these patients make asymptomatic or mild COVID-19 more likely, and may therefore reduce the sensitivity of SARS-CoV-2 testing, no study has proven a pathologic link between SARS-CoV-2 and chilblains [69]. Results of a recent study suggest that chilblains may be a manifestation of a post-viral type I interferonopathy [69].…”

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“…We did not perform correlation analyses with the number of COVID-19–related deaths. Indeed, chilblain-like lesions are associated with mild or asymptomatic SARS-CoV-2 infection [ 40 , 41 ], thus undermining correlation analyses with the number of COVID-19–related deaths, and correlations with the number of detected COVID-19 cases are unreliable owing to the limited number of tests performed at the beginning of the pandemic in many countries. Therefore, caution must be exercised when performing correlation analyses between GT data on chilblain-like symptoms and COVID-19 progression.…”