Chilblains and COVID-19—An Update on the Complexities of Interpreting Antibody Test Results, the Role of Interferon α, and COVID-19 Vaccines

To the Editor We applaud McCleskey and colleagues¹ for their contribution to the evolving literature on pernio/chilblains during the COVID-19 pandemic. The authors found a weak correlation between COVID-19 incidence and chilblains among 1319 northern California patients.¹ This finding, combined with high rates of negative SARS-CoV-2 polymerase chain reaction testing results and low antibody seropositivity, led the authors to postulate that the lesions represented an epiphenomenon.¹

The study’s main finding, a weak correlation (ρ = 0.18; P = .01) between chilblains incidence and COVID-19 infection, should be interpreted within a broader context.¹ Potential effect modifiers should be considered. For example, COVID-19 severity is associated with pernio incidence but was not considered.^1,2 Most chilblains occur in asymptomatic/mild COVID-19, but rarely in moderate or severe disease, because among the former, there is a substantially more robust interferon-α activation, which is associated with rapid viral clearance and pernio.² This antiviral response may explain the low rate of SARS-CoV-2 confirmation among patients with chilblains. Further evidence of a direct association between COVID-19 and pernio was found in increasing reports of pernio shortly after SARS-CoV-2 vaccination. In 1 such report of pernio after COVID-19 vaccination, the patient was negative for prior chilblains, rheumatoid disorders, cold exposure, and COVID-19 polymerase chain reaction tests but exhibited a positive interferon signature.³ This finding suggests that these lesions are not idiopathic, but rather represent an immunologic reaction to SARS-CoV-2.³

The ability to detect prior infection also depends on the assay and timing of testing.⁴ Among those with mild infection, sensitivities of commercial antibody assays are as low as 33% depending on the time of testing.⁴ Furthermore, the authors reported 1% antibody positivity, but only 97 of 780 patients with chilblains (12%) received testing and only immunoglobulin (Ig) G was measured.¹ Had serial testing been available, SARS-CoV-2 seropositivity would be more easily detected because antibody responses are transient.⁴ The IgG and IgM serologies may not be the most accurate method for COVID-19 confirmation in patients with asymptomatic/mildly symptomatic SARS-CoV-2 and chilblains, as IgA is more frequently positive in these patients.⁵ It has even been hypothesized that the IgA strong mucosal response could impair the triggering of IgG.⁵

Lastly, further investigation is necessary before attributing these lesions to an epiphenomenon. The authors reported that only 6% wore shoes at home during the pandemic, but a control group for comparison is needed to establish causation. Ultimately, the study’s findings should not be reflexively interpreted as evidence against an association between chilblains and COVID-19.

Corresponding Author: Esther E. Freeman, MD, PhD, Department of Dermatology, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114 (efreeman@mgh.harvard.edu).

Published Online: December 22, 2021. doi:10.1001/jamadermatol.2021.5172

Conflict of Interest Disclosures: Dr Freeman reported grants from the International League of Dermatologic Societies for the COVID-19 Dermatology Registry and honoraria from UpToDate. No other disclosures were reported.