Type I Interferon Response and Vascular Alteration in Chilblain-like Lesions During the COVID-19 Outbreak

L. Frumholtz; J.-D. Bouaziz; M. Battistella; J. Hadjadj; R. Chocron; D. Bengoufa; H. Le Buanec; L. Barnabei; S. Meynier; O. Schwartz; L. Grzelak; N. Smith; B. Charbit; D. Duffy; N. Yatim; A. Calugareanu; A. Philippe; C.L. Guerin; B. Joly; V. Siguret; L. Jaume; H. Bachelez; M. Bagot; F. Rieux-Laucat; S. Maylin; J. Legoff; C. Delaugerre; N. Gendron; D.M. Smadja; C. Cassius


The British Journal of Dermatology. 2021;185(6):1176-1185. 

In This Article

Abstract and Introduction


Background: The outbreak of chilblain-like lesions (CLL) during the COVID-19 pandemic has been reported extensively, potentially related to SARS-CoV-2 infection, yet its underlying pathophysiology is unclear.

Objectives: To study skin and blood endothelial and immune system activation in CLL in comparison with healthy controls and seasonal chilblains (SC), defined as cold-induced sporadic chilblains occurring during 2015 and 2019 with exclusion of chilblain lupus.

Methods: This observational study was conducted during 9–16 April 2020 at Saint-Louis Hospital, Paris, France. All patients referred with CLL seen during this period of the COVID-19 pandemic were included in this study. We excluded patients with a history of chilblains or chilblain lupus. Fifty patients were included.

Results: Histological patterns were similar and transcriptomic signatures overlapped in both the CLL and SC groups, with type I interferon polarization and a cytotoxic–natural killer gene signature. CLL were characterized by higher IgA tissue deposition and more significant transcriptomic activation of complement and angiogenesis factors compared with SC. We observed in CLL a systemic immune response associated with IgA antineutrophil cytoplasmic antibodies in 73% of patients, and elevated type I interferon blood signature in comparison with healthy controls. Finally, using blood biomarkers related to endothelial dysfunction and activation, and to angiogenesis or endothelial progenitor cell mobilization, we confirmed endothelial dysfunction in CLL.

Conclusions: Our findings support an activation loop in the skin in CLL associated with endothelial alteration and immune infiltration of cytotoxic and type I IFN-polarized cells leading to clinical manifestations.


A range of cutaneous manifestations have been described in association with SARS-CoV-2 infection during the COVID-19 pandemic.[1] Among them, chilblain-like lesions (CLL) have been occurring more frequently than expected. However, the link between SARS-CoV-2 infection and CLL is not well established.[2,3] Chilblains are cutaneous inflammatory erythematous papules mainly involving fingers and toes, which are thought to be triggered by cold. Most of them are idiopathic, and therefore called seasonal chilblains (SC), but they can be associated with connective tissue disease such as lupus erythematous, or monogenic diseases such as STING-associated vasculopathy with onset in infancy (SAVI).[4]

SARS-CoV-2 infection strongly triggers the expression of type I interferon (IFN)-stimulated genes, which assist in the host's antiviral protection.[5] Diseases mediated by type I IFN, such as monogenic autoinflammatory interferonopathies or lupus erythematosus, are characterized by microangiopathy leading to clinical chilblains.[6]

SARS-CoV-2 infection seems to be associated with vascular skin symptoms[7] and has been shown to damage capillary endothelium and disrupt the thrombo-protective state of endothelial cells,[8] likely contributing to microvascular thrombosis.[9–11] Moreover, the histopathological features of COVID-19-associated CLL include endothelial damage and features of microangiopathic damage.[12]

The aim of this study was to analyse deeply the immunological and vascular pathophysiology of CLL during the COVID-19 outbreak compared with SC.