Chilblains observed during the COVID-19 pandemic cannot be distinguished from classic, cold-related chilblains

Background: Type 1 interferon (IFN-I) response induced by SARS-CoV-2 has been hypothesized to explain the association between chilblain lesions (CL) and SARS-CoV-2 infection. Objective: To explore direct cytopathogenicity of SARS-CoV-2 in CL and to focus on IFN-I expression in patients with chilblains. Materials & Methods: A monocentric cohort of 43 patients presenting with CL from April 2020 to May 2021 were included. During this period, all CL were, a priori, considered to be SARS-CoV-2-related. RT-qPCR on nasopharyngeal swabs and measurements of anti-SARS-CoV-2 antibodies were performed. Anti-SARS-CoV-2 immunostainings as well as SARS-CoV-2 RT-qPCR were performed on biopsy specimens of CL and controls. Expression of MX1 and IRF7 was analysed on patients' biopsy specimens and/or PBMC and compared with controls and/or chilblains observed before the pandemic. Serum IFN-α was also measured. Results: RT-qPCR was negative in all patients and serological tests were positive in 11 patients. Immunostaining targeting viral proteins confirmed the lack of specificity. SARS-CoV-2 RNA remained undetected in all CL specimens. MX1 immunostaining was positive in CL and in pre-pandemic chilblains compared to controls. MX1 and IRF7 expression was significantly increased in CL specimens but not in PBMC. Serum IFN-α was undetected in CL patients. Conclusion: CL observed during the pandemic do not appear to be directly related to SARS-CoV-2 infection, either based on viral cytopathogenicity or high IFN-I response induced by the virus.

Pandemic chilblains: Are they SARS-CoV-2-related or not?

The exact etiopathology of chilblains observed during the Coronavirus Disease 2019 (COVID-19) pandemic is still unclear. Initially, SARS-CoV-2 appeared as the obvious causing agent, but two years of various investigations have failed to convincingly support its direct implication. Most affected individuals have no detectable virus, no anti-SARS-CoV-2 antibodies and no symptoms of COVID-19. Analyses of skin biopsies similarly failed to unambiguously demonstrate presence of the virus or its genome. In a recent hypothesis, SARS-CoV-2 would cause the lesions before being promptly eliminated by unusually strong type I interferon responses. With others, we feel that environmental factors have not been sufficiently considered, in particular cold exposure related to unprecedented containment measures. The cause of pandemic chilblains remains a stimulating puzzle which warrants further investigation.

COVID toes: where do we stand with the current evidence?

BACKGROUND: Numerous of cases of chilblains have been observed, mainly in young subjects with no or mild symptoms compatible with COVID-19. The pathophysiology of these lesions is still widely debated and an association with SARS-CoV-2 infection remains unconfirmed. OBJECTIVES: This paper focus on the unresolved issues about these COVID toes and in particular whether or not they are associated with COVID-19. ARGUMENTS: The temporal link between the outbreak of chilblains and the COVID-19 pandemic is a first suggests a link between the two events. Positive anti-SARS-CoV/SARS-CoV-2 immunostaining on skin biopsy of chilblains seem to confirm the presence of the virus in the lesions, but lack specificity and must be interpreted with caution. Conversely, RT-PCR and anti-SARS-CoV-2 serology were negative in the majority of patients with chilblains. Therefore, SARS-CoV-2 infection can be excluded, with relative certainty, even after accounting for possible lower immunization in mild/asymptomatic patients and for some differences in sensitivity/specificity between the tests used. Some authors hypothesize that chilblains could be the cutaneous expression of a strong type I interferon (IFN-I) response. High production of IFN-I is suggested to be associated with early viral control and may suppress antibody response. However, the absence of other cutaneous or extracutaneous symptoms as observed in other interferonopathies raises unanswered questions. To date, a direct link between chilblains and COVID-19 still seems impossible to confirm. A more indirect association due to lifestyle changes induced by lockdown is a possible explanation. Improvement of chilblains when protective measures were adopted and after lifting of lockdown, support this hypothesis. CONCLUSION: Conflicting current evidence highlights the need for systematic and repeated testing of larger numbers of patients and the need for valid follow-up data that take into consideration epidemic curves and evolution of lockdown measures.

Evaluation of Chilblains as a Manifestation of the COVID-19 Pandemic.

Importance: During the coronavirus disease 2019 (COVID-19) pandemic, several cases of chilblains have been reported. Objective: To determine if chilblains are associated with COVID-19. Design, Setting, and Participants: This monocentric case series was conducted at the Department of Dermatology at Cliniques universitaires Saint-Luc, a tertiary care hospital in Brussels, Belgium, between April 10 and April 17, 2020. We evaluated a total of 31 referred patients who had recently developed chilblains. Main Outcomes and Measures: Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was used to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA on nasopharyngeal swabs for all patients and in skin biopsy specimens for 22 patients. Blood samples from all patients were tested for specific anti-SARS-CoV-2 immunoglobulin (Ig) M and IgG antibodies. All patients had extended blood analyses. Histologic (22 patients) and immunofluorescence examinations (15 patients) were performed on the skin biopsy specimens. Results: The 31 patients were generally in good health; most were teenagers or young adults, and 19 were women. Histopathologic analysis of skin biopsy specimens (22 patients) confirmed the diagnosis of chilblains and showed occasional lymphocytic or microthrombotic phenomena. Immunofluorescence analyses showed vasculitis of small-diameter vessels in 7 patients. In all patients, SARS-CoV-2 RNA remained undetected by RT-PCR on nasopharyngeal swabs and in biopsy samples of the skin lesions. The IgM and IgG antibody titers were negative for SARS-CoV-2 in all patients (<1.0 arbitrary unit/mL). No significant abnormalities in blood test results were suggestive of systemic disease. Antinuclear antibody titers were low in 7 patients and higher in 1 patient. Conclusions and Relevance: Chilblains appeared not to be directly associated with COVID-19 in this case series. Lifestyle changes associated with community containment and lockdown measures are a possible explanation for these lesions.