Interferon Responses in “COVID Toes,” Footprints from SARS-CoV2 Infection

At a Glance

After the initial peak of the COVID-19 pandemic in April 2020, physicians noted a surge of red to purple bruise-like bumps on the toes of otherwise healthy patients. This symptom, popularly referred to as “COVID toes,” is clinically identical to a skin condition known as chilblains. Rarely, chilblains can be a cutaneous manifestation of the type 1 interferonopathies, genetic disorders associated with elevated levels of type 1 interferons. Type 1 interferons are proteins produced in response to viral infections and are critical in the host response to the SARS-CoV-2 infection. However, the precise link between COVID toes and the SARS-CoV-2 virus remained unknown. Because patients with COVID toes often reported close contacts with COVID-19 infection but consistently tested negative for infection in their blood and nasopharynx, researchers hypothesized that COVID toes could be a manifestation of resiliency to the SARS-CoV-2 virus via a robust and early type 1 interferon response, which remained visible in the toes.

Researchers found evidence of local activation of the type I interferon in COVID toe biopsies that was significantly higher than in normal skin from patients without COVID. Researchers also identified the presence of viral RNA in patients’ toes, suggesting that SARS-CoV-2 infection could be a possible trigger for COVID toes. Finally, a golden hamster animal model was employed to evaluate whether SARS-CoV-2 viral RNA could reach the toes. In this model, after low-dose exposure of SARS-CoV-2 through the nasopharynx, viral RNA was found both in the lungs and indeed in the toes of infected hamsters. The hamsters mounted a robust type I interferon response in their lungs and their toes, and this response closely correlated with the presence of SARS-CoV-2 viral RNA. Previous studies in humans with COVID toes found a very early type 1 interferon response in the peripheral blood, which waned within days. This study found a durable type 1 interferon response in skin but not in the peripheral blood, which could explain why most patients with COVID toes felt systemically well aside despite their skin findings.

The Challenge

After the initial peak of the COVID-19 pandemic in April 2020, physicians noted a surge of red to purple bruise-like bumps on the toes of otherwise healthy patients. This symptom, popularly referred to as “COVID toes,” is clinically identical to a skin condition known as chilblains. Chilblains can rarely be a cutaneous manifestation of the type 1 interferonopathies, genetic disorders that lead to elevated levels of type 1 interferons in the peripheral blood. Interferons are proteins that are produced in response to viral infections and are critical in the host response to the SARS-CoV-2 virus. Because most patients with COVID toes reported exposure to close contacts with COVID-19 infection and yet tested negative for the virus in their nasopharynx and blood, researchers hypothesized that this cutaneous manifestation might identify a population with resiliency to the virus.

Project Goals

The overarching goals of this project were to determine if there is any association between chilblains during the pandemic and SARS-CoV-2 infection, and to investigate the systemic and local immune response in these patients.

These goals were approached through two specific aims. First, researchers aimed to establish a registry and biobank from patients across Wisconsin with the diagnosis of pandemic-associated-chilblains to track the progression of the dermatologic disease and to determine clinical and immunologic phenotypes in relation to SARS-CoV2. Second, the researchers worked to determine the local and systemic immune response in 60 patients with COVID toes compared to healthy controls.

Results

The researchers enrolled 111 subjects with COVID toes in their registry. Twelve subjects consented to skin biopsies.  Patients had blood collected a total of four times within the study period. The initial draw was within two weeks of presentation, and the final draw was four to six months after they presented with COVID toes. Only 4% of patients had a positive PCR test for COVID-19 or mounted an adaptive response to the virus via seroconversion. No patients had detectable SARS-CoV-2 specific T cell responses.  This is consistent with what has been previously shown in patients with COVID toes. Interestingly, researchers found that cases of COVID toes aligned with the COVID-19 incidence in Wisconsin, and they were inversely correlated with temperature, meaning that cases of COVID toes rose only during months with lower temperatures.

Immune studies revealed evidence of local activation of the type I interferon in COVID toe biopsies that was significantly higher than normal skin from patients without COVID. Further, the predominant cell type found in COVID toes was plasmocytic dendritic cells, which secrete high levels of type I interferon. Utilizing RNAscope, a technique to identify a sequence of RNA within a sample, the research team found sparse SARS-CoV-2 viral RNA in the toes of 20 percent of patients from the Wisconsin cohort and found RNA in 33% of patients from a second validation cohort form Switzerland. The presence of viral RNA in some patients suggests that SARS-CoV-2 could be a possible trigger for COVID toes but may not be the only trigger. There was limited interferon response in the patients’ blood, which could represent the timing of the blood draw as other studies have demonstrated the type 1 interferon response wanes within days of exposure.

The researchers also employed an animal model utilizing the golden hamster, which has a similar response to COVID-19 as humans, to evaluate whether SARS-CoV-2 viral RNA could reach the toes. In hamsters infected with low-inoculum of SARS-CoV-2 through the nasopharynx, the research team found viral RNA, but not infectious virus, in both the lungs and the toes. These findings were associated with an early type 1 interferon response at both sites, which paralleled the presence and clearance of viral RNA. Previous studies have demonstrated that patients with COVID toes mount a very early type 1 interferon response in the blood which wanes within days. In this study, researchers found a durable type 1 interferon response in the skin but not the blood, which could explain why most patients with COVID toes fell systematically well. This evidence supports the relationship between SARS-CoV-2 and COVID toes, at least in some cases, but does not provide mechanistic proof of resiliency to the infection.  Ongoing work to disentangle the genetic landscape of those affected might provide more mechanistic insight in COVID toes.

Looking to the Future

This work could serve as a launching point to investigate other autoimmune disorders including dermatomyositis and lupus, which share a type 1 interferon signature and have been presumed to have a viral trigger.