New insights in COVID-19–associated chilblains: A comparative study with chilblain lupus erythematosus
Authors: Gilles Battesti, Jihane El Khalifa, Nour Abdelhedi, Valentine Ferre, Fabrice Bouscarat, Catherine Picard-Dahan, Florence Brunet-Possenti, Gilles Collin, Justine Lavaud, Patrick Le Bozec, Marion Rousselot, Amélie Tournier, Coralie Lheure, Anne Couvelard, Salima Hacein-Bey-Abina, Amine M. Abina, Charlotte Charpentier, Sabine Mignot, Pascale Nicaise, Diane Descamps, Lydia Deschamps, Vincent Descamps
Journal: Journal of the American Academy of Dermatology (2020)

To the Editor: An unexpected outbreak of chilblains has been reported in association with COVID-19.1de Masson A. Bouaziz J.-D. Sulimovic L. et al.Chilblains are a common cutaneous finding during the COVID-19 pandemic: a retrospective nationwide study from France.J Am Acad Dermatol. 2020; 83: 667-670Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been shown in a few documented cases of chilblains. Chilblains may also be observed in acquired lupus and rarely as a manifestation of a familial disorder related to interferonopathies. To enhance understanding of these epidemic chilblains (EC) cases and their relevance to SARS-CoV-2 infection, we studied clinical, hematoimmunologic, histopathologic, immunohistochemical, and virologic characteristics of 7 EC cases and compared them with 11 previous cases of chilblain lupus erythematosus (CLE). Patients with EC were included between February and April 2020 and were suspected of COVID-19 because they presented with COVID-19 symptoms or were in close contact with patients with presumed/confirmed COVID-19. Exclusion criteria were patients with previous chilblains episode, cold exposure preceding chilblains occurrence, and history of known autoimmune disorder. For each patient, we collected demographic data and clinical and laboratory test results, including exhaustive hematoimmunologic screening, cutaneous histology (including immunostaining for CD123, a plasmocytoid dendritic cell marker, and MxA, a type I interferon [IFN-I]–induced protein), and virologic studies. The clinicobiological findings of EC and CLE cases are summarized in Table I. Hands, ears, or nose localization were more frequently observed in the CLE group (82% vs 0%). Antinuclear antibodies were detected only in the CLE group (91% vs 0%). Age at onset of chilblains, sex, pre-existing Raynaud phenomenon, and other immunologic abnormalities did not differ between groups. Antineutrophil cytoplasmic antibodies (ANCAs) and lupus-type circulating anticoagulant were found in 2 and 1 patients with EC, respectively, without any clinical manifestation of ANCA vasculitis or thrombosis. No patient with EC had cryoprotein, cold agglutinin, or anticardiolipin antibodies.Table IClinical and biological findings in EC and CLEVariableEC (N = 7)CLE (N = 11)P valueFemale, n (%)4 (57)7 (64)>.99Age, y, mean (SD)42 (10)49 (15).27Previous Raynaud phenomenon, n (%)4 (57)4 (36).63Previous other cutaneous symptoms, n (%)3∗Two patients had acrocyanosis, and 1 patient had photosensitivity. (43)8 (73).33Localized to feet, n (%)7 (100)2 (18)<.01COVID-19 symptoms, n (%)5 (71)NA—Potential SARS-CoV-2 contact, n (%)4 (57)NA—Positive antinuclear antibodies, n (%)0 (0)10 (91)<.01Presence of other immunologic abnormalities, n (%)3†Two patients had antineutrophil cytoplasmic antibodies, and 1 patient had lupus-type circulating anticoagulant. (43)9 (82).14CLE, Chilblain lupus erythematosus; EC, epidemic chilblains; NA, not applicable; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SD, standard deviation.∗ Two patients had acrocyanosis, and 1 patient had photosensitivity.† Two patients had antineutrophil cytoplasmic antibodies, and 1 patient had lupus-type circulating anticoagulant. Open table in a new tab CLE, Chilblain lupus erythematosus; EC, epidemic chilblains; NA, not applicable; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SD, standard deviation. Our 7 EC cases were histologically similar to CLE. High expression of CD123 and MxA were observed in both groups (Table II).Table IIHistologic and immunohistochemical comparison between EC and CLEVariableEC (N = 7)CLE (N = 11)P valueEpidermis, n (%) Lymphocyte exocytosis3 (43)7 (64).63 Confluent necrosis1 (14)0 (0).39 Apoptotic keratinocytes2 (29)4 (36)>.99 Vacuolized basement membrane zone1 (14)8 (73).049Papillary dermis Edema, n (%)4 (57)2 (18).14 Lymphocyte infiltrate intensity score,∗Intensity was scored as follow: 0, absence; 1, rare; 2, moderated; 3, intense. median (range)2 (1-3)2 (1-3).34 Lymphocyte infiltrate localization, n (%)Perivascular localization7 (100)11 (100)>.99Interstitial localization3 (43)8 (73).33 Other inflammatory cell infiltrate, n (%)2 (29)3 (27)>.99 Lymphocytic vasculitis, n (%)5 (71)1 (9).01 Congestive vessels, n (%)2 (29)0 (0).13 Red blood cell extravasation, n (%)4 (57)1 (9).047Reticular and deep dermis Lymphocyte infiltrate intensity score,∗Intensity was scored as follow: 0, absence; 1, rare; 2, moderated; 3, intense. median (range)2 (1-3)2 (0-3).77 Lymphocyte infiltrate localization, n (%)Perivascular7 (100)10 (91)>.99Interstitial0 (0)0 (0)>.99Perieccrine6 (86)7/10 (70)†One CLE biopsy sample did not show the eccrine gland..60Perineural4 (57)7/9 (78)‡Two of CLE biopsy samples did not show the nerve..59 Other inflammatory cell infiltrate, n (%)2 (29)3 (27)>.99 Lymphocytic vasculitis, n (%)4 (57)7 (64)>.99 Leukocytoclastic vasculitis, n (%)1 (14)1 (9)>.99 Congestive vessels, n (%)3 (43)1 (9).24 Neural section, median (range)5 (2-9)3 (0-4).008Hypodermis§Hypodermis was observed in 2 biopsy samples in each groups. Perivascular lymphocyte infiltrate, n (%)2/2 (100)0/2 (0).33Immunohistochemical features Case with MxA+ cells, n (%)7 (100)10/10 (100)‖One CLE did not have immunohistochemistry analysis.>.99 MxA expression, median (range)180 (105-280)270 (120-300).28 Case with CD123+ cells, n (%)6 (86)9/10 (90)‖One CLE did not have immunohistochemistry analysis.>.99 CD123 expression, median (range)50 (0-60)15 (0-100).32Positive cutaneous DIF, n (%)0/3 (0)¶Three DIF analyses were performed in the EC group.1/2 (50)#Two DIF analyses were performed in the CLE group..4Bold values are statistically significant.CLE, Chilblain lupus erythematosus; DIF, direct immunofluorescence; EC, epidemic chilblains; MxA, myxovirus resistance protein A; SD, standard deviation.∗ Intensity was scored as follow: 0, absence; 1, rare; 2, moderated; 3, intense.† One CLE biopsy sample did not show the eccrine gland.‡ Two of CLE biopsy samples did not show the nerve.§ Hypodermis was observed in 2 biopsy samples in each groups.‖ One CLE did not have immunohistochemistry analysis.¶ Three DIF analyses were performed in the EC group.# Two DIF analyses were performed in the CLE group. Open table in a new tab Bold values are statistically significant. CLE, Chilblain lupus erythematosus; DIF, direct immunofluorescence; EC, epidemic chilblains; MxA, myxovirus resistance protein A; SD, standard deviation. SARS-CoV-2 RNA detection performed at a median delay of 23 days after symptom onset (range, 10-36 d) showed negative results in nasopharyngeal, skin biopsy, and plasma samples. Repeated SARS-CoV-2 immunoglobulin (Ig) G/IgA test results were negative for all patients, except for 1 who showed an isolated IgA positivity (time between first symptoms and serologic tests range, 21-51 d). Active human herpes virus types 6, 7, and 8 and Epstein-Barr virus infections were excluded by reliable tests (polymerase chain reaction). These results confirmed that chilblains may be considered as a manifestation of high production of IFN-I as observed in interferonopathies. These patients may exhibit only IFN-I associated symptoms or minor forms of COVID-19 infection. High level of IFN-I was associated with moderate cases of COVID-19.2Hadjadj J. Yatim N. Barnabei L. et al.Impaired type I interferon activity and exacerbated inflammatory responses in severe Covid-19 patients.MedRχiv. 2020; https://www.medrxiv.org/content/10.1101/2020.04.19.20068015v1Date accessed: May 14, 2020Google Scholar Interferon-induced proteins such as IFITM (interferon-induced trans-membrane) 1, 2, and 3 inhibit early replication of several enveloped RNA viruses, such as Middle East respiratory syndrome coronaviruses.3Wrensch F. Winkler M. Pöhlmann S. IFITM proteins inhibit entry driven by the MERS-coronavirus spike protein: evidence for cholesterol-independent mechanisms.Viruses. 2014; 6: 3683-3698Crossref PubMed Scopus (104) Google Scholar In addition, active viral replication may not be necessary to mount an efficient IFN response in SARS-CoV infection.4de Lang A. Baas T. Smits S.L. Katze M.G. Osterhaus A.D. Haagmans B.L. Unraveling the complexities of the interferon response during SARS-CoV infection.Future Virol. 2009; 4: 71-78Crossref PubMed Scopus (12) Google Scholar IFN-I may also suppress antibody responses, which might explain the negative serology test results in most patients with EC.5Fallet B. Narr K. Ertuna Y.I. et al.Interferon-driven deletion of antiviral B cells at the onset of chronic infection.Sci Immunol. 2016; 1: eaah6817PubMed Google Scholar SARS-Cov-2 infection may induce, in some predisposed patients, a high production of IFN-I responsible for a high innate immune protective response. This hypothesis provides additional arguments to propose early IFN treatment for infected high-risk patients.