Investigating the Link Between ‘COVID Toes’ and the Virus

The project, Interferon Responses in “COVID toes,” The Link to SARS-CoV2 Infection, is funded with a $125,000 strategic COVID-19 Response Grant from the Wisconsin Partnership Program at the UW School of Medicine and Public Health. It is led by Lisa Arkin, MD, assistant professor, dermatology and pediatrics; director of Pediatric Dermatology, and Anne Marie Singh, MD, associate professor, pediatrics; director, Food Allergy Research and Education Center of Excellence. The researchers will investigate how a critical immune response involved in COVID toes may protect against severe manifestations of COVID-19.

The phenomenon of COVID toes was recognized shortly after the initial peak of COVID-19 infection in Madison, Wisconsin, when dozens of healthy young patients presented with tender, purple toes, clinically identical to a skin condition known as chilblains. Importantly, chilblains are rare; when seen in children they are a prototypical sign of a genetic disorder characterized by early-onset chilblains, systemic inflammation and elevated levels of type I interferon. The interferons comprise a family of proteins which constitute the first major line of defense against viral infection and are critical in containing the SARS-CoV-2 virus. They activate a powerful antiviral defense program that interferes with every step of viral replication. In severe COVID-19, type I interferon production is both attenuated and delayed, leading to rapid viral replication and later induction of a pathologic host immune response with pro-inflammatory cytokines. Older adults are more likely to produce lower levels of type I interferon, which may explain the increasing severity of COVID-19 with age. Because low levels of type I interferon correlate with severe disease, investigators are now investigating commercially available interferons in the treatment of COVID-19.

While the precise link between this phenomenon and SARS-CoV-2 remains unknown, the research team hypothesizes that COVID toes represent a visible manifestation of a robust interferon response to initial SARS-CoV-2 exposure, which rapidly eradicates the virus, and that the surge in COVID toes observed locally, nationally and internationally is a manifestation of this protective response. By studying children with “COVID toes,” the mildest manifestation of SARS-CoV-2 infection, the researchers aim to investigate a crucial immune response in children who may be protected from severe manifestations of SARS-CoV-2 infection.

The project will establish a registry and biobank to track the progression of patients COVID toes through the course of the evolving pandemic, to confirm the association with this virus through specialized immune studies, and to identify the systemic immune signature in affected patients. The knowledge gained from the project will help clarify the precise link between COVID toes and COVID-19.

If as the investigators anticipate, patients with COVID toes represent visible outliers – individuals who are naturally resistant to severe manifestations of SARS-CoV-2 infection – then their immune signature may catalyze the development of potential therapeutics to prevent severe disease in vulnerable populations. This would complement ongoing vaccine efforts by providing the rationale for a therapeutic intervention to reduce disease severity in vulnerable patients.

The researchers have developed partnerships and outreach throughout the state via telemedicine, and the team will share data in near real-time through open research channels to make its findings publicly available.

Co-investigators include:

• Beth Drolet, MD, UW Dermatology
• Anna Huttenlocher, MD, UW Pediatric Rheumatology, Department of Microbiology
• Greg Demuri, MD, UW Pediatric Infectious Disease
• Sheryl Henderson, MD, PhD, UW Pediatric Infectious Disease
• James Conway, MD, UW Pediatric Infectious Disease
• David O’Connor, PhD UW Department of Pathology
• Kristen Holland, MD, Medical College of Wisconsin, Dermatology
• Valerie Carlberg, MD, Medical College of Wisconsin, Dermatology