Skip to main content
NCBI home page
Springer Nature - PMC COVID-19 Collection logoLink to Springer Nature - PMC COVID-19 Collection
. 2022 Nov 12;32(3):377–383. doi: 10.1684/ejd.2022.4260

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

Axel De Greef 1,#, Mathilde Choteau 2,#, Anne Herman 1,3, Caroline Bouzin 4, Liliane Marot 1,5, Claire Dachelet 5, Julie Lelotte 5, Delphine Hoton 5, Laure Dumoutier 2, Marie Baeck 1,3,✉
PMCID: PMC9660172  PMID: 36065533

Abstract

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.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at 10.1684/ejd.2022.4260.

Key words: Chilblains, COVID toes, COVID-19, immunostaining, SARS-CoV-2, Type 1 interferon

Acknowledgements

We thank Dr. Mariana Andrade who provided editorial assistance. We would like to thank all interns (Anne-Laure Fouarge, M.D., Laura Mengeot, M.D., Marie Cuvelier M.D., Alexia Kervyn, M.D., Charlotte-Eglantine Roquet-Gravy, M.D., Evelyne Harkemanne M.D., Alexia Degraeuwe, M.D., Héloïse Moens, M.D., and Antoine Willemart, M.D.) of the Department of Dermatology, Cliniques universitaires Saint-Luc, Brussels, Belgium for their contribution. We thank Michèle De Beukelaer (2IP imaging platform, IREC, Brussels, Belgium) for technical support regarding tissue staining. The patients in this manuscript have given written informed consent to publication of their case details.

Supplementary data

Supplementary material (780.1KB, pdf)

Footnotes

Supplementary data

Supplementary data associated with this article can be found, in the online version, at doi: 10.1684/ejd.2022.4260. Table S1. Demographic data of 43 patients with chilblainlike lesions.

Figure S1. Immunohistochemistry for SARS-CoV-2 spike protein showing: diffuse weak non-specific staining of keratinocytes and sebaceous glands of healthy skin (A); diffuse non-specific staining of eccrine glands and endothelial cells as well as a lymphocyte infiltrate in a CL (B) and a pre-pandemic idiopathic chilblain (C); diffuse non-specific staining of bronchial epithelium, pneumocytes and endothelial cells of healthy lung (D); non-specific staining of pneumocytes, endothelial cells and lymphocytes of SARS-CoV-2-positive lung (E) and pre-pandemic ARDS lung (F); and diffuse staining of synciotiotrophoblasts and endothelial cells of healthy at-term pre-pandemic placenta (G) and placenta of a SARS-CoV-2-positive patient (H) (haematoxylin and eosin; magnification: x20 for all images).

Figure S2. Immunohistochemistry for SARS-CoV-2 nucleocapsid protein showing negative staining of healthy skin (note the scarce, non-specific, positive staining of the basal layer of the epidermis) (A); negative staining of a CL (B) and a pre-pandemic idiopathic chilblain (C); negative staining of healthy lung (D), COVID-19 lung (E) and prepandemic ARDS lung (F); and negative staining of healthy at-term pre-pandemic placenta (G). H) Strong and clear granular positivity of syncitiotrophoblasts of the placenta of a SARS-CoV-2 positive patient, with respect to endothelial cells (haematoxylin and eosin; magnification: x20 for all images).

Figure S3. Immunohistochemistry for angiotensinconverting enzyme 2. A) Positive staining of eccrine glands in healthy skin. Eccrine glands and the endothelium of a CL (B) and a pre-pandemic idiopathic chilblain (C) remain strictly negative, and some rare pneumocytes in healthy lung stain positive (D), however, staining is slightly stronger in pneumocytes, endothelial cells and lymphocytes of SARS-CoV-2-infected lung (E) and pre-pandemic ARDS lung (F). G) Positive staining of syncitiotrophoblasts of healthy at-term pre-pandemic placenta which is stronger in the placenta of a SARS-CoV-2-positive patient (H) (haematoxylin and eosin; magnification: x20 for all images).

Financial support

none.

Conflict of interest

none.

These authors contributed equally

References

  • 1.Cappel MA, Cappel JA, Wetter DA. Pernio (Chilblains), SARS-CoV-2 and COVID toes unified through cutaneous and systemic mechanisms. Mayo Clin Proc. 2021;96:989–1005. doi: 10.1016/j.mayocp.2021.01.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Freeman EE, McMahon DE, Fox LP. Emerging evidence of the direct association between COVID-19 and chilblains. JAMA Dermatol. 2021;157:238–9. doi: 10.1001/jamadermatol.2020.4937. [DOI] [PubMed] [Google Scholar]
  • 3.Balestri R, Magnano M, Rizzoli L, Rech G. Do we have serological evidences that chilblain-like lesions are related to SARS-CoV-2? A review of the literature. Dermatol Ther. 2020;33:e14229. doi: 10.1111/dth.14229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Sánchez-García V, Hernández-Quiles R, de-Miguel-Balsa E, Docampo-Simón A, Belinchón-Romero I, Ramos-Rincón JM. Are the chilblain-like lesions observed during the COVID-19 pandemic due to severe acute respiratory syndrome coronavirus 2? Systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2022;36:24–38. doi: 10.1111/jdv.17672. [DOI] [PMC free article] [PubMed] [Google 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;183:729–37. doi: 10.1111/bjd.19327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Recalcati S, Barbagallo T, Tonolo S, Milani M, Fantini F. Relapse of chilblain-like lesions during the second wave of coronavirus disease 19. J Eur Acad Dermatol Venereol. 2021;35:e315–6. doi: 10.1111/jdv.17168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Lipsker D. A chilblain epidemic during the COVID-19 pandemic. A sign of natural resistance to SARS-CoV-2? Med Hypotheses. 2020;144:109959. doi: 10.1016/j.mehy.2020.109959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.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;157:202–6. doi: 10.1001/jamadermatol.2020.4324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Damsky W, Peterson D, King B. When interferon tiptoes through COVID-19: Pernio-like lesions and their prognostic implications during SARS-CoV-2 infection. J Am Acad Dermatol. 2020;83:e269–70. doi: 10.1016/j.jaad.2020.06.052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Battesti G, El Khalifa J, Abdelhedi N, et al. New insights in COVID-19-associated chilblains: a comparative study with chilblain lupus erythematosus. J Am Acad Dermatol. 2020;83:1219–22. doi: 10.1016/j.jaad.2020.06.1018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Aschoff R, Zimmermann N, Beissert S, Günther C. Type I interferon signature in chilblain-like lesions associated with the COVID-19 pandemic. Dermatopathology (Basel) 2020;7:57–63. doi: 10.3390/dermatopathology7030010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Bessis D. Impaired type I interferon response in SARS-CoV-2 infection: looking through the cutaneous window. Br J Dermatol. 2021;184:11–2. doi: 10.1111/bjd.19596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Bastard P, Rosen LB, Zhang Q, et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020;370:eabd4585. doi: 10.1126/science.abd4585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Zhang Q, Bastard P, Liu Z, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020;370:eabd4570. doi: 10.1126/science.abd4570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Santonja C, Heras F, Núñez L, Requena L. COVID-19 chilblainlike lesion: immunohistochemical demonstration of SARS-CoV-2 spike protein in blood vessel endothelium and sweat gland epithelium in a polymerase chain reaction-negative patient. Br J Dermatol. 2020;183:778–80. doi: 10.1111/bjd.19338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Magro CM, Mulvey JJ, Laurence J, et al. The differing pathophysiologies that underlie COVID-19-associated perniosis and thrombotic retiform purpura: a case series. Br J Dermatol. 2021;184:141–50. doi: 10.1111/bjd.19415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Baeck M, Hoton D, Marot L, Herman A. Chilblains and COVID-19: why SARS-CoV-2 endothelial infection is questioned. Br J Dermatol. 2020;183:1152–3. doi: 10.1111/bjd.19489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.von Stillfried S, Boor P. Nachweismethoden von SARS-CoV-2 in Gewebe [Methods of SARS-CoV-2 detection in tissue] Pathologe. 2021;42:208–15. doi: 10.1007/s00292-021-00919-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Herman A, Peeters C, Verroken A, et al. Evaluation of chilblains as a manifestation of the COVID-19 Pandemic. JAMA Dermatol. 2020;156:998–1003. doi: 10.1001/jamadermatol.2020.2368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Data from Sciensano, the Belgian institute for health responsible for the epidemiological follow-up of the COVID-19 epidemic (https://epistat.wiv-isp.be/covid/).
  • 21.Fischer B, Lindenkamp C, Lichtenberg C, Birschmann I, Knabbe C, Hendig D. Evidence of long-lasting humoral and cellular immunity against SARS-CoV-2 even in elderly COVID-19 convalescents showing a mild to moderate disease progression. Life (Basel) 2021;11:805. doi: 10.3390/life11080805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Vono M, Huttner A, Lemeille S, et al. Robust innate responses to SARS-CoV-2 in children resolve faster than in adults without compromising adaptive immunity. Cell Rep. 2021;37:109773. doi: 10.1016/j.celrep.2021.109773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203:631–7. doi: 10.1002/path.1570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Potdar AA, Dube S, Naito T, et al. Altered intestinal ACE2 levels are associated with inflammation, severe disease and response to anti-cytokine therapy in inflammatory bowel disease. Gastroenterology. 2021;160:809–22.e7. doi: 10.1053/j.gastro.2020.10.041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Verstockt B, Verstockt S, Abdu Rahiman S, et al. Intestinal receptor of SARS-CoV-2 in inflamed IBD tissue seems downregulated by HNF4A in ileum and upregulated by interferon regulating factors in colon. J Crohns Colitis. 2021;15:485–98. doi: 10.1093/ecco-jcc/jjaa185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Freeman EE, McMahon DE, Hruza GJ, et al. Timing of PCR and antibody testing in patients with COVID-19-associated dermatologic manifestations. J Am Acad Dermatol. 2021;84:505–7. doi: 10.1016/j.jaad.2020.09.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Rodero MP, Crow YJ. Type I interferon-mediated monogenic autoinflammation: The type I interferonopathies, a conceptual overview. J Exp Med. 2016;213:2527–38. doi: 10.1084/jem.20161596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Papa R, Volpi S, Gattorno M. Monogenetic causes of chilblains, panniculitis and vasculopathy: the Type I interferonopathies. G Ital Dermatol Venereol. 2020;155:590–8. doi: 10.23736/S0392-0488.20.06709-7. [DOI] [PubMed] [Google Scholar]
  • 29.Nyssen A, Benhadou F, Magnée M, André J, Koopmansch C, Wautrecht JC. Chilblains. Vasa. 2020;49:133–40. doi: 10.1024/0301-1526/a000838. [DOI] [PubMed] [Google Scholar]
  • 30.Roca-Ginés J, Torres-Navarro I, Sánchez-Arráez J, et al. Assessment of acute acral lesions in a case series of children and adolescents during the COVID-19 pandemic. JAMA Dermatol. 2020;156:992–7. doi: 10.1001/jamadermatol.2020.2340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Neri I, Virdi A, Corsini I, et al. Major cluster of paediatric ‘true’ primary chilblains during the COVID-19 pandemic: a consequence of lifestyle changes due to lockdown. J Eur Acad Dermatol Venereol. 2020;34:2630–5. doi: 10.1111/jdv.16751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Rouanet J, Lang E, Beltzung F, et al. Recent outbreak of chilblainlike lesions is not directly related to SARS-CoV-2 infection. J Eur Acad Dermatol Venereol. 2020;34:e689–92. doi: 10.1111/jdv.16776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Kluger N. Why are chilblains underreported in Nordic countries during the COVID-19 pandemic? An analysis of Google Trends. J Eur Acad Dermatol Venereol. 2021;35:e100–1. doi: 10.1111/jdv.16974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.McCleskey PE, Zimmerman B, Lieberman A, et al. Epidemiologic analysis of chilblains cohorts before and during the COVID-19 pandemic. JAMA Dermatol. 2021;157:947–53. doi: 10.1001/jamadermatol.2021.2120. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from European Journal of Dermatology are provided here courtesy of Nature Publishing Group

RESOURCES