Persistent SARS-CoV-2 Spike Protein in Vasculitic Skin Lesions after Infection or mRNA Vaccination: A Retrospective Case control Immunofluorescence Study
DOI:
https://doi.org/10.2340/actadv.v106.adv-2025-0308Keywords:
vasculitis, long COVID, SARS-CoV-2, spikeAbstract
Vasculitic skin lesions have been reported in association with both SARS-CoV-2 infection and vaccination. Whether viral proteins persist in lesional vessels beyond the acute phase remains unclear. The aim of this study was to investigate the presence of SARS-CoV-2 spike protein in persistent or delayed-onset cutaneous vasculitis temporally associated with COVID-19 infection or vaccination. This retrospective case–control study includes 9 patients with persistent or delayed-onset vasculitic skin lesions following COVID-19 infection (n=4) or mRNA vaccination (n=5). Skin biopsies were analysed using immunofluorescence for SARS-CoV-2 spike protein. Prepandemic leukocytoclastic vasculitis (n=3) and healthy postinfection/postvaccination skin (n=3) served as controls. Spike protein was detected in vascular endothelial cells of all 9 patients with COVID-19- or vaccine-associated vasculitis. Staining was absent in all prepandemic vasculitis and healthy control samples. Histopathology showed typical features of leukocytoclastic vasculitis without evidence of viral cytopathic changes. We found that SARS-CoV-2 spike protein can persist in endothelial cells of vasculitic skin lesions weeks to months after COVID-19 infection or mRNA vaccination. These findings suggest that retained viral proteins may contribute to prolonged or delayed-onset vasculitic skin manifestations. Further studies are needed to clarify the mechanisms underlying spike persistence and its clinical significance.
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Galván Casas C, Català A, Carretero Hernández G, Rodríguez-Jiménez P, Fernández-Nieto D, Rodríguez-Villa Lario A, 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. DOI: https://doi.org/10.1111/bjd.19163
Català A, Muñoz-Santos C, Galván-Casas C, Roncero Riesco M, Revilla Nebreda D, Solá-Truyols A, et al. Cutaneous reactions after SARS-CoV-2 vaccination: a cross-sectional Spanish nationwide study of 405 cases. Br J Dermatol 2022; 186: 142–152. DOI: https://doi.org/10.1111/bjd.20639
Kofler L, Forchhammer S. Delayed local reaction with subcutaneous infiltration after vaccination with mRNA-1273-a previously undescribed reaction pattern of COVID arm. Hautarzt 2022; 73: 488–490. DOI: https://doi.org/10.1007/s00105-022-04986-7
Llamas-Velasco M, Fraga J, Rodríguez-Villa Lario A, Catalá A, Pérez-González YC, Galván C, et al. A series of 69 COVID-related dermatoses with biopsy, immunohistochemistry with anti-spike 3, in situ hybridization and PCR: a critical reappraisal of viral involvement in COVID-19 skin lesions. Actas Dermosifiliogr 2023; 114: 747–754. DOI: https://doi.org/10.1016/j.ad.2023.05.024
Gawaz A, Schindler M, Hagelauer E, Blanchard G, Riel S, Vollert A, et al. SARS-CoV-2-induced vasculitic skin lesions are associated with massive spike protein depositions in autophagosomes. J Invest Dermatol 2024; 144: 369–377. DOI: https://doi.org/10.1016/j.jid.2023.07.018
Almehdi AM, Khoder G, Alchakee AS, Alsayyid AT, Sarg NH, Soliman SSM. SARS-CoV-2 spike protein: pathogenesis, vaccines, and potential therapies. Infection 2021; 49: 855–876. DOI: https://doi.org/10.1007/s15010-021-01677-8
Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N Engl J Med 2020; 383: 2603–2615. DOI: https://doi.org/10.1056/NEJMoa2034577
Corbett KS, Edwards DK, Leist SR, Abiona OM, Boyoglu-Barnum S, Gillespie RA, et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 2020; 586: 567–571. DOI: https://doi.org/10.1038/s41586-020-2622-0
Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med 2021; 384: 403–416. DOI: https://doi.org/10.1056/NEJMoa2035389
Walsh EE, Frenck RW Jr, Falsey AR, Kitchin N, Absalon J, Gurtman A, et al. Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates. N Engl J Med 2020; 383: 2439–2450. DOI: https://doi.org/10.1056/NEJMoa2027906
Gambichler T, Boms S, Susok L, Dickel H, Finis C, Abu Rached N, et al. Cutaneous findings following COVID-19 vaccination: review of world literature and own experience. J Eur Acad Dermatol Venereol 2022; 36: 172–180. DOI: https://doi.org/10.1111/jdv.17744
Sano H, Kase M, Aoyama Y, Sano S. A case of persistent, confluent maculopapular erythema following a COVID-19 mRNA vaccination is possibly associated with the intralesional spike protein expressed by vascular endothelial cells and eccrine glands in the deep dermis. J Dermatol 2023; 50: 1208–1212. DOI: https://doi.org/10.1111/1346-8138.16816
World Health Organization. A clinical case definition of post COVID-19 condition by A Delphi consensus. 2021. [cited 2021 October 6].
McMahon DE, Gallman AE, Hruza GJ, Rosenbach M, Lipoff JB, Desai SR, et al. Long COVID in the skin: a registry analysis of COVID-19 dermatological duration. Lancet Infect Dis 2021; 21: 313–314. DOI: https://doi.org/10.1016/S1473-3099(20)30986-5
Carlson JA. The histological assessment of cutaneous vasculitis. Histopathology 2010; 56: 3–23. DOI: https://doi.org/10.1111/j.1365-2559.2009.03443.x
Dittmayer C, Meinhardt J, Radbruch H, Radke J, Heppner BI, Heppner FL, et al. Why misinterpretation of electron micrographs in SARS-CoV-2-infected tissue goes viral. Lancet 2020; 396: e64–e65. DOI: https://doi.org/10.1016/S0140-6736(20)32079-1
Patterson BK, Francisco EB, Yogendra R, Long E, Pise A, Rodrigues H, et al. Persistence of SARS-CoV-2 S1 protein in CD16+ monocytes in post-acute sequelae of COVID-19 (PASC) up to 15 months post-infection. Front Immunol 2021; 12: 746021. DOI: https://doi.org/10.3389/fimmu.2021.746021
Swank Z, Senussi Y, Manickas-Hill Z, Yu XG, Li JZ, Alter G, et al. Persistent circulating severe acute respiratory syndrome coronavirus 2 spike is associated with post-acute coronavirus disease 2019 sequelae. Clin Infect Dis 2023; 76: e487–e490.. DOI: https://doi.org/10.1093/cid/ciac722
Rong Z, Mai H, Ebert G, Kapoor S, Puelles VG, Czogalla J, et al. Persistence of spike protein at the skull-meninges-brain axis may contribute to the neurological sequelae of COVID-19. Cell Host Microbe 2024; 32: 2112–2130. DOI: https://doi.org/10.1016/j.chom.2024.11.007
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