- •Population: individuals of any age and sex with CLL coinciding with the SARS-CoV-2 pandemic.
- •Intervention: any intervention including patients who were not treated and observed only.
- •Comparator: any other treatment received; studies which reported on patients without a comparator group were also included.
- •Outcomes: clinical characteristics of CLL, presence and characteristics of ECS, SARS-CoV-2 testing information, and clinical outcomes.
- •Study design: any study design with primary data.
Literature Search and Screening
COVID Testing Results
|Clinical Characteristics and Outcomes||Cases, % (n/N)|
|Patient Characteristics (n=4982)|
|Sex||Men||45% (n = 2001/4472)|
|Women||55% (n = 2471/4472)|
|Age, years||Mean||25 (n = 2326/4982)|
|Range||0 to 95 years|
|Feet||90% (n = 2195/2429)|
|Hands||18% (n = 431/2429)|
|Other||1% (n = 20/2429)|
|Extracutaneous Symptoms (ECS)|
|Presence of ECS||Yes||37% (n = 987/2636)|
|No (asymptomatic)||63% (n = 1649/2636)|
|Timing of CLL|
|After ECS||81% (n = 544/670)|
|Mean, days (range)||13 (1 to 270)|
|Concomitant with ECS||13% (n = 84/670)|
|Before ECS||6% (n = 42/670)|
|Mean, days (range)||7 (1 to 19)|
|SARS-CoV-2 Infection Information|
|Positive SARS-CoV-2 Test||19% (347/1838)|
|Negative SARS-CoV-2 Test||81% (1491/1838)|
|Positivity by Type of Test|
|PCR||9% (n = 132/1503)|
|Serological test (IgG, IgM)||10% (n = 95/925)|
|IgA||15% (n = 30/204)|
|PCR on biopsy||1% (n = 1/75)|
|IgG against spike protein||29% (n = 19/65)|
|Resolved||80% (n = 979/1224)|
|Mean response time||16 days|
|Range||1 to 252 days|
|No treatment||47% (n = 204/432)|
|Treated||53% (n = 228/432)|
|Systemic corticosteroids||8% (n = 10/126)|
|Topical corticosteroids||45% (n = 57/126)|
|Oral analgesia||55% (n = 69/126)|
|Oral antihistamines||19% (n = 24/126)|
|Systemic antimicrobials||6% (n = 7/126)|
|Topical antimirobials||24% (n = 30/126)|
|Chloroquine, hydroxychloroquine||5% (n = 6/126)|
|Unresolved||7% (n = 91/1224)|
|Mean follow up time||64 days|
|Range||9 to 495 days|
|Recurrent||13% (n = 154/1224)|
|Mean time to recurrence||71 days|
|Range||5 to 196 days|
|Clinical Characteristics and Outcomes||Cases, % (n/N)|
|Patient Characteristics (n=188)|
|Sex||Men||50% (n = 56/111)|
|Women||50% (n = 55/111)|
|Age, years||Mean||30 (n = 114/188)|
|Range||7 to 80 years|
|Feet||86% (n = 83/96)|
|Hands||23% (n = 22/96)|
|Other||4% (n= 4/96)|
|Extracutaneous Symptoms (ECS)|
|Presence of ECS||Yes||72% (n = 90/125)|
|No (asymptomatic)||28% (n = 35/125)|
|Timing of CLL|
|CLL occurred after ECS||71% (n = 55/77)|
|Mean days after ECS||55 days|
|Range||2 to 270 days|
|Concomitant with ECS||23% (n = 18/77)|
|CLL occurred before ECS||5% (n = 4/77)|
|Mean days before ECS||4 days|
|Range||3 to 6 days|
|Resolution||93% (n = 114/123)|
|Mean response time||17 days|
|Range||3 to 84 days|
|Did not receive treatment||63% (n = 60/95)|
|Treated||37% (n = 35/95)|
|Unresolved||4 % (n = 5/123)|
|Mean follow up time||186 days|
|Range||79 to 452 days|
Characteristics of CLL
SARS-CoV-2 Positive Test Rate
- 1Wu F, Zhao S, Yu B, et al. A new coronavirus associated with human respiratory disease in China. Nature. 2020;579(7798):265-269.
- 2Grant MC, Geoghegan L, Arbyn M, et al. The prevalence of symptoms in 24,410 adults infected by the novel coronavirus (SARS-CoV-2; COVID-19): A systematic review and meta-analysis of 148 studies from 9 countries. PLoS One. 2020;15(6):e0234765.
- 3Mirza FN, Malik AA, Omer SB, Sethi A. Dermatologic manifestations of COVID-19: a comprehensive systematic review. Int J Dermatol. 2021;60:418-450.
- 4Rocha KO, Zanuncio VV, Freitas BAC de, Lima LM. “COVID toes”: A meta-analysis of case and observational studies on clinical, histopathological, and laboratory findings. Pediatr Dermatol. 2021;38:1143-1149.
- 5Kashetsky N, Mukovozov IM, Bergman J. Chilblain-Like Lesions (CLL) Associated With COVID-19 (“COVID Toes”): A Systematic Review. J Cutan Med Surg. 2021;25(6):627-633.
- 6Sánchez-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. Published online September 21, 2021. doi:10.1111/jdv.17672
- 7OCEBM Levels of Evidence Working Group. The Oxford 2011 Levels of Evidence. Centre for Evidence-Based Medicine. Accessed April 3, 2022. https://www.cebm.net/wp-content/uploads/2014/06/CEBM-Levels-of-Evidence-2.1.pdf
- 8Docampo-Simón A, Sánchez-Pujol MJ, Gimeno-Gascon A, et al. No SARS-CoV-2 antibody response in 25 patients with pseudo-chilblains. Dermatol Ther. 2020;33:e14332.
- 9Poizeau F, Barbarot S, Le Corre Y, et al. Long-term Outcome of Chilblains Associated with SARS-CoV-2. Acta Derm Venereol. Published online September 13, 2021. doi:10.2340/00015555-3930
- 10Hubiche T, Le Duff F, Fontas E, Rapp J, Chiaverini C, Passeron T. Relapse of chilblain-like lesions during the second wave of the COVID-19 pandemic: a cohort follow-up. Br J Dermatol. 2021;185:858-859.
- 11Recalcati 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(5):e315-e316.
- 12Ko CJ, Harigopal M, Gehlhausen JR, Bosenberg M, McNiff JM, Damsky W. Discordant anti-SARS-CoV-2 spike protein and RNA staining in cutaneous perniotic lesions suggests endothelial deposition of cleaved spike protein. J Cutan Pathol. 2021;48:47-52.
- 13Baeck M, Peeters C, Herman A. Chilblains and COVID-19: further evidence against a causal association. J Eur Acad Dermatol Venereol. 2021;35:e2-e3.
- 14Piccolo V, Bassi A, Russo T, et al. Chilblain-like lesions and COVID-19: second wave, second outbreak. J Eur Acad Dermatol Venereol. 2021;35:e316-e318.
- 15Wu J, Scarabel F, McCarthy Z, Xiao Y, Ogden NH. A window of opportunity for intensifying testing and tracing efforts to prevent new COVID-19 outbreaks due to more transmissible variants. Can Commun Dis Rep. 2021;47:329-338.
- 16Bascuas-Arribas M, Andina-Martinez D, Añon-Hidalgo J, et al. Evolution of incidence of chilblain-like lesions in children during the first year of COVID-19 pandemic. Pediatr Dermatol. 2022;39:243-249.
- 17Kluger 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-e101.
- 18Tokgöz Akyil F, Saygili E, Arikan H, Akyil M, Karadogan D. Country-based analysis of COVID-19 publications in the first few months of the pandemic. Popul Med. 2021;3(June). doi:10.18332/popmed/136032
- 19Kantor J. May 2021: Heterogeneity in reported skin manifestations of COVID-19 and vaccines. J Am Acad Dermatol. 2021;84:1251.
- 20Tan SW, Tam YC, Oh CC. Skin manifestations of COVID-19: A worldwide review. JAAD Int. 2021;2:119-133.
- 21Daneshjou R, Rana J, Dickman M, Yost JM, Chiou A, Ko J. Pernio-like eruption associated with COVID-19 in skin of color. JAAD Case Rep. 2020;6:892-897.
- 22Magro C, Nuovo G, Mulvey JJ, Laurence J, Harp J, Crowson AN. The skin as a critical window in unveiling the pathophysiologic principles of COVID-19. Clin Dermatol. 2021;39:934-965.
- 23Rizzoli L, Collini L, Magnano M, et al. Chilblain-like lesions during the COVID-19 pandemic: a serological study on a case series. Br J Dermatol. 2020;183:782-784.
- 24Khalili M, Iranmanesh B, Mohammadi S, Aflatoonian M. Cutaneous and histopathological features of coronavirus disease 2019 in pediatrics: A review article. Dermatol Ther. 2021;34:e14554.
- 25Cassius C, Merandet M, Frumholtz L, et al. Analysis of T-cell responses directed against the spike and/or membrane and/or nucleocapsid proteins in patients with chilblain-like lesions during the COVID-19 pandemic. Br J Dermatol. Published online July 14, 2021. doi:10.1111/bjd.20647
- 26Aschoff 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.
- 27Herman A, Peeters C, Verroken A, et al. Evaluation of Chilblains as a Manifestation of the COVID-19 Pandemic. JAMA Dermatol. 2020;156:998-1003.
- 28Cuenca Saez MA, Gomez-Biedma SL. Immunoglobulin A antiphospholipid antibodies in patients with chilblain-like lesions during the COVID-19 pandemic. Actas Dermosifiliogr. 2021;112:290-292.
- 29Kluckow E, Krieser DM, Slaa M. COVID toes in stay-at-home adolescents: An epiphenomenon? Emerg Med Australas. 2020;32:1088-1090.
- 30McCleskey PE, Zimmerman B, Lieberman A, et al. Epidemiologic Analysis of Chilblains Cohorts Before and During the COVID-19 Pandemic. JAMA Dermatol. 2021;157:947-953.
- 31Le Cleach L, Dousset L, Assier H, et al. Most chilblains observed during the COVID-19 outbreak occur in patients who are negative for COVID-19 on polymerase chain reaction and serology testing. Br J Dermatol. 2020;183:866-874.
- 32Magro 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;184:141-150.
- 33Kolivras A, Thompson C, Pastushenko I, et al. A clinicopathological description of COVID-19-induced chilblains (COVID-toes) correlated with a published literature review. J Cutan Pathol. 2022;49:17-28.
- 34Moghadam P, Frumholtz L, Jaume L, et al. Frequency of relapse and persistent cutaneous symptoms after a first episode of chilblain-like lesion during the COVID-19 pandemic. J Eur Acad Dermatol Venereol. 2021;35:e566-e568.
- 35Akuffo-Addo E, Nicholas MN, Joseph M. COVID-19 Skin Manifestations in Skin of Colour. J Cutan Med Surg. Published online October 19, 2021:12034754211053310.
- 36Deutsch A, Blasiak R, Keyes A, et al. COVID toes: Phenomenon or epiphenomenon? J Am Acad Dermatol. 2020;83:e347-e348.
- 37Castelo-Soccio L, Lara-Corrales I, Paller AS, et al. Acral Changes in pediatric patients during COVID 19 pandemic: Registry report from the COVID 19 response task force of the society of pediatric dermatology (SPD) and pediatric dermatology research alliance (PeDRA). Pediatr Dermatol. 2021;38:364-370.
- 38Visconti A, Bataille V, Rossi N, et al. Diagnostic value of cutaneous manifestation of SARS-CoV-2 infection. Br J Dermatol. 2021;184:880-887.
- 39Poizeau F, Oger E, Barbarot S, et al. Chilblains during lockdown are associated with household exposure to SARS-CoV-2: a multicentre case-control study. Clin Microbiol Infect. Published online October 4, 2021. doi:10.1016/j.cmi.2021.09.032
- 40Recalcati S, Gianotti R, Fantini F. COVID-19: The experience from Italy. Clin Dermatol. 2021;39:12-22.
- 41Galván Casas C, Català A, Carretero Hernández G, et al. Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases. Br J Dermatol. 2020;183:71-77.
- 42Mascitti H, Jourdain P, Bleibtreu A, et al. Prognosis of rash and chilblain-like lesions among outpatients with COVID-19: a large cohort study. Eur J Clin Microbiol Infect Dis. 2021;40:2243-2248.
- 43Marzano AV, Genovese G, Moltrasio C, et al. The clinical spectrum of COVID-19-associated cutaneous manifestations: An Italian multicenter study of 200 adult patients. J Am Acad Dermatol. 2021;84:1356-1363.
Appendix. Supplementary materials
Publication stageIn Press Accepted Manuscript
Edited by Franco Rongioletti, MD and Leonard J. Hoenig, MD
Declarations of Interest: None
Funding sources: None