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Comment & Response
December 22, 2021

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

Author Affiliations
  • 1Department of Internal Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 2Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston
JAMA Dermatol. 2022;158(2):217-218. doi:10.1001/jamadermatol.2021.5172

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.

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Article Information

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.

McCleskey  PE, Zimmerman  B, Lieberman  A,  et al.  Epidemiologic analysis of chilblains cohorts before and during the COVID-19 pandemic.   JAMA Dermatol. 2021;157(8):947-953. doi:10.1001/jamadermatol.2021.2120 PubMedGoogle ScholarCrossref
Hubiche  T, Cardot-Leccia  N, Le Duff  F,  et al.  Clinical, laboratory, and interferon-alpha response characteristics of patients with chilblain-like lesions during the COVID-19 pandemic.   JAMA Dermatol. 2021;157(2):202-206. doi:10.1001/jamadermatol.2020.4324 PubMedGoogle ScholarCrossref
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