A, Patient 15 had erythematous macules as well as bullous lesions on the second and fourth toes of the left foot. B, Patient 20 had purplish erythematous macules located in the periungual area of all toes and some erythematous macules on the backs of the feet, at the root of some toes. C, Patient 18 had purplish erythematous macules on all toes, vesicular in places, with some additional lesions on the backs of the feet. D, Patient 10 had discrete periungual, annular erythematous lesions, vesicular at the center, on the second and third toes. E, Patient 13 had purplish erythematous macular periungual lesions. F, Patient 1 had annular erythematous macules on the fourth and fifth fingers.
A. The epidermis shows scattered necrotic keratinocytes and focal vacuolar alteration of the basal layer (hematoxylin-eosin, original magnification ×20). B, In some samples, full-thickness epidermal necrosis is seen with subepidermal cleavage (hematoxylin-eosin, original magnification ×10). C, All biopsy specimens reveal heavy perivascular lymphocytic infiltrates in the superficial and deep dermis; eccrine extension of the infiltrates is often present (hematoxylin-eosin, original magnification ×5). D, Some specimens show lymphocytic vasculitis (mural and perivascular infiltrates of lymphocytes) (hematoxylin-eosin, original magnification ×20).
eAppendix. Detailed Methods for PCR, Serologic, Histologic, and Immunofluorescence Testing
eTable. Laboratory Results of 31 Patients With Chilblains
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Herman A, Peeters C, Verroken A, et al. Evaluation of Chilblains as a Manifestation of the COVID-19 Pandemic. JAMA Dermatol. Published online June 25, 2020. doi:10.1001/jamadermatol.2020.2368
Is there an association between chilblains and coronavirus disease 2019 (COVID-19)?
In this case series of 31 patients who had recently developed chilblains, none of the patients tested positive for COVID-19 on nasopharyngeal swabs, nor were blood immunoglobulin (Ig) M or IgG antibodies detected.
These ischemic, acral cutaneous lesions appeared not to be directly associated with COVID-19.
During the coronavirus disease 2019 (COVID-19) pandemic, several cases of chilblains have been reported.
To determine if chilblains are associated with COVID-19.
Design, Setting, and Participants
This monocentric case series was conducted at the Department of Dermatology at Cliniques universitaires Saint-Luc, a tertiary care hospital in Brussels, Belgium, between April 10 and April 17, 2020. We evaluated a total of 31 referred patients who had recently developed chilblains.
Main Outcomes and Measures
Real-time reverse transcriptase–polymerase chain reaction (RT-PCR) was used to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA on nasopharyngeal swabs for all patients and in skin biopsy specimens for 22 patients. Blood samples from all patients were tested for specific anti–SARS-CoV-2 immunoglobulin (Ig) M and IgG antibodies. All patients had extended blood analyses. Histologic (22 patients) and immunofluorescence examinations (15 patients) were performed on the skin biopsy specimens.
The 31 patients were generally in good health; most were teenagers or young adults, and 19 were women. Histopathologic analysis of skin biopsy specimens (22 patients) confirmed the diagnosis of chilblains and showed occasional lymphocytic or microthrombotic phenomena. Immunofluorescence analyses showed vasculitis of small-diameter vessels in 7 patients. In all patients, SARS-CoV-2 RNA remained undetected by RT-PCR on nasopharyngeal swabs and in biopsy samples of the skin lesions. The IgM and IgG antibody titers were negative for SARS-CoV-2 in all patients (<1.0 arbitrary unit/mL). No significant abnormalities in blood test results were suggestive of systemic disease. Antinuclear antibody titers were low in 7 patients and higher in 1 patient.
Conclusions and Relevance
Chilblains appeared not to be directly associated with COVID-19 in this case series. Lifestyle changes associated with community containment and lockdown measures are a possible explanation for these lesions.
Coronavirus disease 2019 (COVID-19) is mainly characterized by fever and respiratory symptoms.1 During this pandemic, several cases of unusual purplish red lesions on the feet and/or hands, mimicking chilblains, have been reported in the literature and on social media. Some researchers have suspected that these lesions are associated with asymptomatic or mildly symptomatic COVID-19.2-7 However, to our knowledge, no study has proved a pathologic link between these skin lesions and COVID-19. This observational prospective case series aimed to investigate the possible association between chilblains and COVID-19.
Between April 10 and April 17, 2020, we enrolled 31 patients who visited the Department of Dermatology at Cliniques universitaires Saint-Luc, Brussels, Belgium. All patients had purplish red chilblain lesions on toes and/or fingers, which had appeared between 1 and 30 days before consultation. The data from all study participants are summarized in the Table.
The study and data collection were approved by the institutional review boards of Cliniques universitaires Saint-Luc and Université Catholique de Louvain. Written informed consent was obtained from all study participants.
All patients underwent reverse transcriptase–polymerase chain reaction (RT-PCR) analysis by nasopharyngeal swab to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA when they presented for chilblains. In all patients, blood analyses included the following: liver function and renal function; tests for antinuclear antibodies, rheumatoid factor, CH50, C3, C4, antineutrophil cytoplasmic autoantibody, antistreptolysin O antibody, and cold agglutinins; prothrombin time and activate partial thromboplastin time; levels of D-dimer, anticardiolipin and anti–β2-glycoprotein antibodies, cryoglobulins, and C-reactive protein; protein electrophoresis; and in a subgroup of patients, tests for factor VIII, von Willebrand factor, and lupus anticoagulant in addition to haptoglobin level, bilirubin level, reticulocyte count, and schizocyte count. Serologic testing for specific anti–SARS-CoV-2 IgM and IgG antibodies was performed in all patients. For some patients, skin biopsy specimens were obtained for histologic (22 patients) and immunofluorescence analyses (15 patients), as well as for the RT-PCR detection of SARS-CoV-2 RNA (22 patients).
Detailed methods of PCR, serologic, histologic, and immunofluorescence testing are available in the eAppendix in the Supplement.
All demographic data and laboratory results are summarized in the Table as well as the eTable in the Supplement. Eleven patients were teenagers (<18 years), and 19 were female. Median (range) age was 22 (6-72) years. Median (range) body mass index (calculated as weight in kilograms divided by height in meters squared) was 19.13 (15.57–33.56), and 9 patients had a body mass index lower than 20.
Skin lesions were localized to the feet (29 patients) and/or hands (3 patients) and presented as erythematous or purplish erythematous macules, sometimes with central vesicular or bullous lesions or with necrotic areas (Figure 1). Patients complained of pain, burning, and/or itching. Of the 31 patients, 20 (64%) reported mild symptoms possibly correlated with COVID-19. Only 3 patients (10%) reported contact with a person considered COVID-19 positive.
Nine patients (29%) had a history of chilblains (perniosis) and 4 (13%) of Raynaud syndrome. In addition, 3 patients were receiving β-blocker treatment, 1 smoked, and some occasionally consumed recreational drugs, herbal teas, herbal medicines, alcohol, or energy drinks.
Histopathologic analysis of skin biopsy specimens (22 patients) confirmed the diagnosis of chilblains (Figure 2). Occasional signs of lymphocytic or microthrombotic phenomena were observed. Results of immunofluorescence analyses were negative in 7 cases and noncontributory for 1 patient. In 7 others, results showed vasculitis of small-diameter vessels: 1 patient with IgM, IgA, and C3 deposits, 3 with IgM and C3, and 3 with only C3; test results were negative for IgG and C1q.
The RT-PCR analysis failed to detect SARS-CoV-2 RNA on nasopharyngeal swabs from all patients and in the 22 biopsy samples from the skin lesions. Tests for IgM and IgG antibody titerswere negative for SARS-CoV-2 all patients (<1.0 arbitrary unit/mL). No significant biochemical, autoimmune, hematologic, or hemostatic abnormalities were found on blood test results. Eosinopenia, lymphopenia, and hyperferritinemia, often reported in patients with COVID-19, were not observed in this series. Low titers of antinuclear antibodies were detected in 7 patients, and higher titers were detected in 1 patient with a history of perniosis. The most relevant laboratory findings are reported in the eTable in the Supplement.
Since the beginning of the current pandemic, ischemic acral lesions have been observed both in adults with severe forms of COVID-198 and in younger, otherwise healthy patients. In patients with severe COVID-19, these lesions present as peripheral cyanotic lesions and appear to be secondary to systemic consequences of the disease, particularly thrombotic vasculopathy.9 However, chilblains observed in patients with no, or possibly mild, symptoms of COVID-19 have raised the possibility of a link between this type of lesion and COVID-19.2-7
Histopathologic examination of skin biopsy specimens revealed patterns consistent with typical chilblain lesions with, in some cases, vasculitic and microthrombotic phenomena.10 Results of some immunofluorescence analyses showed microvascular deposits of IgM and/or C3 consistent with vasculitis of small-diameter vessels.
In this series, patients were predominantly teenagers or young adults with unremarkable medical histories and no known autoimmune diseases. No significant abnormalities were found in blood test results, including antiphospholipid antibodies or hypercoagulability status, as has been reported in patients with critical COVID-19 pneumonia with acro-ischemia.11
We did not detect SARS-CoV-2 RNA in the nasopharyngeal swabs of any patient, nor in the 21 skin biopsy samples analyzed. Negative RT-PCR findings could suggest that chilblains are a late manifestation of COVID-19, occurring outside the time frame of viral shedding in the nasopharynx.12 Therefore, serologic tests were carried out to detect IgM and IgG anti–SARS-CoV-2 antibodies; unexpectedly, these results were negative for all patients. The sensitivity and specificity of the serologic tests used13 was estimated to be 100% 15 days after the beginning of symptoms. Because some patients had experienced chilblains for more than 15 days (≤30 days) at the time of inclusion, we can reasonably exclude the possibility that serologic testing was done too soon. Given the negativity of RT-PCR and serologic test results in all patients, we can assume that these patients had not been infected with SARS-CoV-2.
The concomitant increase in reports of chilblains during spring, in conjunction with the COVID-19 pandemic, suggests that there may be an indirect link between these events. One hypothesis points to an indirect consequence of the COVID-19 pandemic due to imposed community containment and lockdown measures leading to lifestyle changes that are considered risk factors for developing chilblains.14 When subsequently questioned about their lifestyles, all patients reported that they had either been working from home or were home schooled since the beginning of containment measures in Belgium (March 11, 2020). Most of them (20/31 [64%]) reported decreased physical activity and considerably more time spent in sedentary positions. Some patients also reported a consumption of recreational drugs, herbal medicines, and/or energy drinks. Finally, most patients declared that they remained barefoot or in socks most of the day.
Median (range) body mass index of the patients was relatively low (19.13 [range, 15.57-33.56]), suggesting that thin people may be more at risk for developing chilblains. A few patients reported a history of Raynaud phenomenon or chilblains in winter, and some blood analyses revealed an isolated positive result for antinuclear antibodies.
Limitations of this study include a small sample size and a population that may not be representative. There was also no control group and no long-term follow-up.
We report several cases of chilblains occurring mainly in young people during the COVID-19 pandemic. The RT-PCR and serologic test results showed no signs of COVID-19 in all 31 patients. Other important risk factors for chilblains were also excluded. We hypothesize that these skin lesions may be caused by lifestyle changes brought on by containment and lockdown measures. Dermatologic lesions, even if increasingly observed during the current pandemic, should be carefully interpreted.
Accepted for Publication: May 15, 2020.
Corresponding Author: Anne Herman, MD, Department of Dermatology, Cliniques universitaires Saint-Luc, Université Catholique de Louvain, Avenue Hippocrate 10, B-1200, Brussels, Belgium (firstname.lastname@example.org).
Published Online: June 25, 2020. doi:10.1001/jamadermatol.2020.2368
Author Contributions: Dr Baeck had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Peeters and Verroken contributed equally.
Concept and design: Herman, Peeters, Tennstedt, Baeck.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Herman, Peeters, Tennstedt, Hermans, Baeck.
Critical revision of the manuscript for important intellectual content: Peeters, Verroken, Tromme, Marot, Dachelet, Gruson, Baeck.
Statistical analysis: Peeters.
Obtained funding: Baeck.
Administrative, technical, or material support: Peeters, Verroken, Tennstedt, Marot, Dachelet, Gruson, Baeck.
Supervision: Tennstedt, Hermans, Baeck.
Conflict of Interest Disclosures: Dr Herman has received personal fees from the Fondation Saint-Luc and personal fees and nonfinancial support from Bioderma. No other disclosures were reported.
Funding/Support: This study was supported by the Fondation Saint-Luc, which provided academic funding (to Dr Baeck) for this research.
Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank the patients and their families for granting permission to publish this information. We thank all interns (Marie Cuvelier, MD; Laetitia Fameree, MD; Evelyne Harkemanne, MD; Fanny Ickx, MD; Margaux Mairlot, MD; Marine Matthews, MD; Nina Nielens, MD; Laura Nobile, MD; and Romane Thirion, MD) and members (Laurence de Montjoye, MD; Diane Declaye, MD; Pierre-Dominique Ghislain, MD; Bernard Leroy, MD; and Alexia Vanden Daelen, MD) of the Department of Dermatology, Cliniques Universitaires Saint-Luc, for their contribution. We also thank Ines Zoungrana and Pascale Rosiere (medical clinical research coordinators, Department of Dermatology, Cliniques Universitaires Saint-Luc) for data encoding. Moreover, we thank Yves Horsmans, MD, PhD; Chantal Lefebvre, MD, PhD; Leila Belkhir, MD, PhD; Jean-Cyr Yombi, MD, PhD; and Julien De Greef, MD, of the Department of Internal Medicine, Cliniques Universitaires Saint-Luc, for their support. We thank all of the dermatologists, pediatricians, and general practitioners who referred patients to our department. Finally, we thank Mariana Andrade, MD, for editorial assistance. Compensation but no commercial funding was received for this work.
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