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The underlying immunological disturbances of LC are poorly understood. Multiple explanatory mechanisms, such as persisting SARS-CoV-2 reservoirs, reactivation of latent viruses, endothelial dysfunction, auto-antibodies, tissue damage, and immune abnormalities, have been proposed but remain incompletely characterized, particularly in younger populations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The present study included 12 to 25-year-old females with and without mild SARS-CoV-2 infection, who were prospectively followed for six months after infection and assessed according to the WHO definition of post COVID-19 condition, resulting in four groups (\u201cLong COVID\u201d (LC), recovered convalescents (RC), fatigued controls (FC), healthy controls (HC)). Peripheral blood mononuclear cells were either stimulated with Phorbol-12-myristate-13-acetate\/ionomycin or left unstimulated, and analyzed using a 41-antibody CyTOF panel, unsupervised clustering with FlowSOM, dimensionality reduction via UMAP, polyfunctionality assessment with COMPASS, and machine learning for identifying correlates of LC and fatigue. All participants were female with a median age of 18.5 years.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Higher frequencies of Terminal NK cells were associated with LC and FC, showing enhanced polyfunctional responses upon stimulation. Increased CD4\u2009+\u2009T cell activation and exhaustion were observed in both LC and FC, with elevated effector memory and effector T cells expressing PD-1, alongside decreased marginal zone B cells and transitional B cells. Machine learning analysis revealed terminal NK cells as the most important feature for predicting fatigue. Importantly, no unique LC-specific immune changes were detected.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our results point to a shared underlying pathophysiology in LC and other forms of fatigue. The absence of unique LC-related immune changes supports the notion that LC represents a specific example of post-infective fatigue syndrome triggered by SARS-CoV-2 in susceptible individuals. Innate and adaptive immune dysregulation, particularly higher levels of hyperresponsive terminal NK cells, is most striking and could serve as a general fatigue marker rather than an LC-specific biomarker. These findings highlight the need for further studies to correlate immune perturbations with symptom clusters and inform diagnostic and treatment strategies for fatigue states.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-08149-3","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T03:10:02Z","timestamp":1776827402000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Long COVID: Deep single-cell immunophenotyping and machine learning reveal a general signature for fatigue"],"prefix":"10.1186","volume":"24","author":[{"given":"Silke Lauren","family":"Sommen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunniva","family":"Segtnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel","family":"Selvakumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lise Beier","family":"Havdal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tonje","family":"Stiansen-Sonerud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Gjerstad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siri","family":"Mjaaland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Unni Cecilie","family":"Nygaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vegard Bruun Bratholm","family":"Wyller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4874-4493","authenticated-orcid":false,"given":"Ratnadeep","family":"Mukherjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lise Lund","family":"Berven","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"issue":"4","key":"8149_CR1","doi-asserted-by":"publisher","first-page":"e102","DOI":"10.1016\/S1473-3099(21)00703-9","volume":"22","author":"JB Soriano","year":"2022","unstructured":"Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV. 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