Chilblain-like lesions and COVID-19 infection: A prospective observational study at Spain's ground zero
Authors: Marta Feito-Rodríguez, Ander Mayor-Ibarguren, Carmen Cámara-Hijón, Dolores Montero-Vega, Guillermo Servera-Negre, Elena Ruiz-Bravo, Pilar Nozal, José Luis Rodríguez-Peralto, Ana Belén Enguita, Luz Yadira Bravo-Gallego, Marí Granados-Fernández, Celia Fernández-Alcalde, Álvaro Fernández-Heredero, Marina Alonso-Riaño, Víctor Jiménez-Yuste, Almudena Nuño-González, Raúl De Lucas-Laguna, Eduardo López-Granados, Pedro Herranz-Pinto
Journal: Journal of the American Academy of Dermatology (2020)

To the Editor: Chilblain-like lesions (CBLL) have been related to severe acute respiratory coronavirus 2 (SARS-CoV-2) infection,1Colmenero 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: 729-737Crossref PubMed Scopus (332) Google Scholar although solid microbiological confirmation is still lacking. We present a prospective cohort study of 37 patients (median age, 14 years) presenting new-onset CBLL during the COVID-19 outbreak in Spain that included (1) SARS-CoV-2 testing (nasopharyngeal polymerase chain reaction [PCR] and serologies) and immunologic profiles for all patients, (2) custom recall antigen experiments and intracellular cytokine production evaluation in selected cases, and (3) skin biopsy for histopathology and immunochemistry (11 samples) and SARS-CoV-2 PCR and electron microscopy (3 cases) (Supplemental Tables I-IV; available via Mendeley at https://doi.org/10.17632/vgvxtcb82c.1). CBLL mainly affected the toes (Table I), with other features including dusky erythematoedematous changes on the dorsal surfaces of the toes and fingers (24.32%), purpuric macules (37.83%), and blisters (10.81%). Two patients presented with more obvious signs of distal skin ischemia (Supplemental Figs 1-3; available via Mendeley at https://doi.org/10.17632/vgvxtcb82c.1). In most cases, the lesions fully/partially remitted with topical therapy or no therapy. Only 1 patient presented with signs of retinal vasculitis. Vascular pulses and Doppler ultrasonography showed normal blood flows in the entire series. All biopsy specimens were consistent with pernio, and 54.5% showed complement C3d and C4d deposition around small vessels (Supplemental Fig 4; available via Mendeley at https://doi.org/10.17632/vgvxtcb82c.1). Nasopharyngeal PCR had positive results in 8.1%, and SARS-CoV-2 serology results were positive in just 8.1% of patients. Recall antigen assays showed positive responses in the 3 patients who underwent them (2 with negative SARS-CoV-2 serologies). Five of the 37 patients presented mild anticardiolipin titer elevation. Interferon (IFN) alfa levels were increased in only 1 of 24 tested patients, whereas the rest of the cytokines remained within normal or undetectable levels. No virus was detected on electron microscopy or PCR testing in skin samples.Table ISummary of demographic and clinical features of the patients presenting chilblain-like lesions (N = 37)Sex, n (%) Female20 (54.05) Male17 (45.95)Mean age, y, mean ± SD22.08 ± 15.46Median age, y14Latency between systemic symptoms and skin lesions, days21.76 ± 23.01Affected areas, n (%) Toes only15 (40.55) Fingers only10 (27.03) Toes and sides of feet7 (18.92) Toes and heels2 (5.40) Toes and fingers2 (5.40) Toes, fingers, and sides of feet1 (2.70)Associated signs and symptoms, n (%) Purpuric macules14 (37.83) Erythema6 (16.21) Pruritus5 (13.51) Cold skin5 (13.51) Blisters4 (10.81) Pain3 (8.10) Edema3 (8.10) Ulceration and/or necrosis2 (5.40)History of systemic symptoms, n (%)17 (45.95)Evolution of the lesions (+2 weeks), n (%) Complete resolution16 (43.24) Partial resolution14 (37.84) Persistence4 (10.81) Worsening3 (8.11)Prescribed therapy, n (%) None24 (64.86) Topical corticosteroids8 (21.63) Oral corticosteroids1 (2.70) Pentoxifylline4 (10.81)SD, Standard deviation. Open table in a new tab SD, Standard deviation. Our patients presented with CBLL in striking parallel to the rise and fall of the COVID-19 pandemic in Madrid, but approximately 2 weeks later (Fig 1). The low proportion of positive SARS-CoV-2 serology test results would argue against the idea of a causal relationship between CBLL and SARS-CoV-2 infection. Lack of serologic test accuracy and a more prominent innate immune response might explain this discrepancy.2Netea M.G. Joosten L.A.B. Trained immunity and local innate immune memory in the lung.Cell. 2018; 175: 1463-1465Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar However, our preliminary results with SARS-CoV-2 assays suggest that patients could have been exposed to SARS-CoV-2 despite negative routine serologic test results. These patients might have had mild SARS-CoV-2 infection, although the upregulation of the type I IFN pathway could have resulted in the onset of CBLL in genetically predisposed patients. The lower rate of measured IFN alfa could be due to the fact that we measured it in a late phase of infection, according to PCR test results. The exact role of SARS-CoV-2 in the development of CBLL, if any, remains unclear.3Kanitakis J. Lesort C. Danset M. Jullien D. Chilblain-like acral lesions during the COVID-19 pandemic ("COVID toes"): histologic, immunofluorescence and immunohistochemical study of 17 cases.J Am Acad Dermatol. 2020; 83: 870-875Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar We were unable to detect the virus in skin samples; however, the SARS-CoV-2 spike protein has been shown in the endothelial and epithelial cells of eccrine glands.4Torrelo A. Andina D. Santonja C. et al.Erythema multiforme-like lesions in children and COVID-19.Pediatr Dermatol. 2020; 37: 442-446Crossref PubMed Scopus (94) Google Scholar Additionally, immune complex deposition can lead to tissue injury through various mechanisms, including complement activation, which could contribute to their pathogenesis.5Rojko J.L. Evans M.G. Price S.A. et al.Formation, clearance, deposition, pathogenicity, and identification of biopharmaceutical-related immune complexes: review and case studies.Toxicol Pathol. 2014; 42: 725-764Crossref PubMed Scopus (121) Google Scholar In conclusion, if CBLL were secondary to SARS-CoV-2, absence of a more evident humoral response would be highlighted. Recall antigen assays could help clarify this association.