Post-Acute COVID-19 syndrome (PACS) is heterogeneous in phenotype and functional state. This prospective, observational study studied adults six months after acute COVID-19. We defined clinical phenotypes and profiled plasma mediators grouped into functional pathways (IL-1, IL-17, IFNγ/IFNγ-related cytokines, pro−/anti-inflammatory clusters). A subset underwent RNA-seq and ChIP-seq experiments. Three cohorts were analyzed (Exploratory n = 46; Discovery n = 591; Validation Cohort n = 289). PACS compatible symptoms were identified in 69.6 %; 59.2 % and 54.7 % respectively. Five phenotypes emerged. IL-1 cytokines (OR: 3.17, 95 % CIs: 1.94–5.19, p: 4.5 × 10−6), IL-17 cytokines (OR: 2.45, 95 % CIs: 1.47–4.07 p: 5.88 × 10−4) and the anti-inflammatory biomarkers (OR: 2.15, 95 % CIs: 1.34–3.45, p: 1.5 × 10−3) were upregulated in PACS patients. Respiratory phenotype was correlated with IL-1 upregulation (OR 4.23; 95 % CIs, 1.69–10.8, p = 0.0025). Transcriptomic and epigenomic changes were observed. Distinct phenotypes of PACS are driven by different immunological mechanisms at the DNA, transcriptomic, and protein levels.
Long-term immune and epigenetic dysregulation following COVID-19 / C. Sidiropoulou, G. Poulakou, E. Kyriazopoulou, E. Tasouli, E. Giannitsioti, A. Strikou, M. Tsilika, E. Christaki, V. Rapti, V. Evangelopoulou, N. Rovina, N. Iannotti, E. Nicastri, E. Taddei, H. Florou, A. Angheben, M. Bassetti, L. Dagna, A. Torres, S. Foutadakis, G. Adamis, E. Stylianakis, G. Vatsellas, G. Damoraki, L. Efstratiou, C. Damoulari, K. Leventogiannis, A. Laskaratos, P. Koufargyris, N. Charalampaki, P. Chra, A. Galanopoulou, D. Thanos, P. Panagopoulos, K. Syrigos, A. Ziogas, R. Ter Horst, J.W.M. Van Der Meer, K. Iliopoulou, F.S. Serino, M. Pavlaki, P. Del Vecchio, L. Scorzolini, A. Bandera, A. Bakakos, S. Sympardi, H. Milionis, M.G. Netea, E.J. Giamarellos-Bourboulis. - In: CLINICAL IMMUNOLOGY. - ISSN 1521-7035. - 283:(2026 Feb), pp. 110656.1-110656.11. [10.1016/j.clim.2025.110656]
Long-term immune and epigenetic dysregulation following COVID-19
N. Iannotti;A. Bandera;
2026
Abstract
Post-Acute COVID-19 syndrome (PACS) is heterogeneous in phenotype and functional state. This prospective, observational study studied adults six months after acute COVID-19. We defined clinical phenotypes and profiled plasma mediators grouped into functional pathways (IL-1, IL-17, IFNγ/IFNγ-related cytokines, pro−/anti-inflammatory clusters). A subset underwent RNA-seq and ChIP-seq experiments. Three cohorts were analyzed (Exploratory n = 46; Discovery n = 591; Validation Cohort n = 289). PACS compatible symptoms were identified in 69.6 %; 59.2 % and 54.7 % respectively. Five phenotypes emerged. IL-1 cytokines (OR: 3.17, 95 % CIs: 1.94–5.19, p: 4.5 × 10−6), IL-17 cytokines (OR: 2.45, 95 % CIs: 1.47–4.07 p: 5.88 × 10−4) and the anti-inflammatory biomarkers (OR: 2.15, 95 % CIs: 1.34–3.45, p: 1.5 × 10−3) were upregulated in PACS patients. Respiratory phenotype was correlated with IL-1 upregulation (OR 4.23; 95 % CIs, 1.69–10.8, p = 0.0025). Transcriptomic and epigenomic changes were observed. Distinct phenotypes of PACS are driven by different immunological mechanisms at the DNA, transcriptomic, and protein levels.
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