Despite thousands of reported patients with pandemic-associated pernio, low rates of seroconversion and PCR positivity have defied causative linkage to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pernio in uninfected children is associated with monogenic disorders of excessive IFN-1 immunity, whereas severe COVID-19 pneumonia can result from insufficient IFN-1. Moreover, SARS-CoV-2 spike protein and robust IFN-1 response are seen in the skin of patients with pandemic-associated pernio, suggesting an excessive innate immune skin response to SARS-CoV-2. Understanding the pathophysiology of this phenomenon may elucidate the host mechanisms that drive a resilient immune response to SARS-CoV-2 and could produce relevant therapeutic targets.

Comparative Immunology School of Biochemistry and Immunology Trinity College Dublin Dublin Ireland

Department of Dermatology School of Medicine and Public Health University of Wisconsin Madison Madison Wisconsin USA

Department of Pediatrics School of Medicine and Public Health University of Wisconsin Madison Madison Wisconsin USA

Dermatology branch National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institute of Health Bethesda Maryland USA

Division of Genetics Department of Medicine Brigham and Women's Hospital Boston Massachusetts USA

Oral Immunobiology Unit National Institute of Dental and Craniofacial Research National Institutes of Health Bethesda Maryland USA

St Giles Laboratory of Human Genetics of Infectious Diseases The Rockefeller University New York New York USA; Howard Hughes Medical Institute The Rockefeller University New York New York USA

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