Emerging Evidence of the Direct Association Between COVID-19 and Chilblains | JAMA Dermatology | JAMA Network
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Comment & Response
December 23, 2020

Emerging Evidence of the Direct Association Between COVID-19 and Chilblains

Author Affiliations
  • 1Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston
  • 2Medical Practice Evaluation Center, Mongan Institute, Massachusetts General Hospital, Harvard Medical School, Boston
  • 3Department of Dermatology, University of California San Francisco, San Francisco
JAMA Dermatol. 2021;157(2):238-239. doi:10.1001/jamadermatol.2020.4937

To the Editor Herman et al1 reported 31 patients with chilblains/pernio who had negative results for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) testing and antibodies, a phenomenon noted by several articles in JAMA Dermatology. The authors hypothesize that pernio during the coronavirus disease 2019 (COVID-19) pandemic “may be caused by lifestyle changes brought on by containment.”1

As our understanding of COVID-19 evolves, we need to explore why people may test negative by PCR and antibodies. Several factors in this study may account for negative serologic testing results. First, patients had antibody testing early in the disease course, between 3 to 30 days after chilblains developed, with most (22 of 31 [71%]) evaluated less than 15 days after pernio onset. The authors deny that “testing was done too soon” because a few of the patients had chilblains for more than 15 days. However, during COVID-19, delayed antibody development is common.2 Patients with COVID-19 who develop chilblains have relatively mild clinical courses,3 and like other asymptomatic/mildly symptomatic individuals, may not mount substantial antibody responses.4 Furthermore, given that chilblains are often a later manifestation of COVID-19, it is unsurprising that patients had negative PCR results.3 Polymerase chain reaction and antibody results highly depend on when in the disease course testing is performed and have imperfect sensitivities and specificities.2 Finally, we suggest this series should not have included 9 patients with a history of chilblains, as these are presumably not associated with SARS-CoV-2.

While we agree that not all cases of pernio are associated with COVID-19, there is a growing body of literature demonstrating a direct association between SARS-CoV-2 and pernio-like lesions.5 In a series of 7 pediatric patients with chilblains who had negative PCR results for SARS-CoV-2, authors used immunohistochemistry to demonstrate SARS-CoV-2 in endothelial cells and eccrine glands, as well as coronavirus-like particles on electron microscopy.5 Additionally, 40 consecutive patients in France with chilblains were PCR negative, with 30% antibody positive for SARS-CoV-2 (7 IgA, 3 IgG, 1 IgM/IgG, and 1 IgA/IgG), whereas the general population antibody positivity was 3.4%.4 In an international registry of COVID-19 manifestations, even when relatively few of 422 patients with pernio/chilblains were able to access timely testing early in the epidemic, 16 had positive PCR results and 11 were antibody positive.3

We need studies focusing on innate and adaptive immune responses to SARS-CoV-2, antibody generation with repeated serosurveys over time, and direct effects of viral infection on skin. Clinicians should understand that a negative swab or antibody test at one point in time does not necessarily rule out SARS-CoV-2 as a causative agent.

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Article Information

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

Published Online: December 23, 2020. doi:10.1001/jamadermatol.2020.4937

Conflict of Interest Disclosures: Drs Freeman and Fox are part of the American Academy of Dermatology COVID-19 Ad Hoc Task Force. They have also collaborated administratively with the American Academy of Dermatology and the International League of Dermatological Societies on the COVID-19 Dermatology Registry. No other disclosures were reported.

References
1.
Herman  A, Peeters  C, Verroken  A,  et al.  Evaluation of chilblains as a manifestation of the COVID-19 pandemic.   JAMA Dermatol. 2020;156(9):998-1003. doi:10.1001/jamadermatol.2020.2368PubMedGoogle ScholarCrossref
2.
Sethuraman  N, Jeremiah  SS, Ryo  A.  Interpreting diagnostic tests for SARS-CoV-2.   JAMA. 2020;323(22):2249-2251. doi:10.1001/jama.2020.8259PubMedGoogle ScholarCrossref
3.
Freeman  EE, McMahon  DE, Lipoff  JB,  et al.  The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries.   J Am Acad Dermatol. 2020;83(4):1118-1129. doi:10.1016/j.jaad.2020.06.1016PubMedGoogle ScholarCrossref
4.
Hubiche  T, Le Duff  F, Chiaverini  C, Giordanengo  V, Passeron  T.  Negative SARS-CoV-2 PCR in patients with chilblain-like lesions.   Lancet Infect Dis. 2020;S1473-3099(20)30518-1. doi:10.1016/S1473-3099(20)30518-1PubMedGoogle Scholar
5.
Colmenero  I, Santonja  C, Alonso-Riaño  M,  et al.  SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases.   Br J Dermatol. 2020;183(4):729-737. doi:10.1111/bjd.19327PubMedGoogle ScholarCrossref
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