Long-term immune and epigenetic dysregulation following COVID-19
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<sup>-6</sup>), IL-17 cytokines (OR: 2.45, 95 % CIs: 1.47-4.07 p: 5.88 × 10<sup>-4</sup>) and the anti-inflammatory biomarkers (OR: 2.15, 95 % CIs: 1.34-3.45, p: 1.5 × 10<sup>-3</sup>) 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.
Authors
- Periklis Panagopoulos (ORCID: https://orcid.org/0000-0003-0643-1090)
- Garyphallia Poulakou (ORCID: https://orcid.org/0000-0003-0778-0006)
- Eleonora Taddei (ORCID: https://orcid.org/0000-0002-5983-4291)
- Agamemnon Bakakos (ORCID: https://orcid.org/0000-0001-8933-6800)
- J.W.M. van der Meer (ORCID: https://orcid.org/0000-0001-5120-3690)
- Emmanouil Stylianakis (ORCID: https://orcid.org/0000-0003-2581-5727)
- Evangelos J. Giamarellos‐Bourboulis (ORCID: https://orcid.org/0000-0003-4713-3911)
- Panagiotis Koufargyris (ORCID: https://orcid.org/0000-0001-7800-3306)
- Spyros Foutadakis (ORCID: https://orcid.org/0000-0001-9161-1605)
- Elisavet Tasouli
- Eirini Christaki (ORCID: https://orcid.org/0000-0002-8152-6367)
- Rob ter Horst (ORCID: https://orcid.org/0000-0003-0576-5873)
- Nathalie Iannotti
- Konstantina Iliopoulou
- Konstantinos Leventogiannis
- Lorenzo Dagna (ORCID: https://orcid.org/0000-0002-7428-315X)
- Mihai Gheorghe Netea (ORCID: https://orcid.org/0000-0003-2421-6052)
- Leda Efstratiou
- Dimitris Thanos (ORCID: https://orcid.org/0000-0003-4288-3027)
- Vassiliki Evangelopoulou
- Νikoletta Ρovina (ORCID: https://orcid.org/0000-0003-0138-5582)
- Paraskevi Chra (ORCID: https://orcid.org/0000-0003-0861-9249)
- Evdoxia Kyriazopoulou (ORCID: https://orcid.org/0000-0002-9585-517X)
- Matteo Bassetti (ORCID: https://orcid.org/0000-0002-0145-9740)
- Styliani Sympardi
- Francesco Saverio Serino
- Emanuele Nicastri (ORCID: https://orcid.org/0000-0002-5606-8712)
- Aglaia Galanopoulou
- Efthymia Giannitsioti (ORCID: https://orcid.org/0000-0003-2715-7457)
- Haralampos J Milionis (ORCID: https://orcid.org/0000-0003-3958-2266)
- Christina Damoulari (ORCID: https://orcid.org/0000-0003-1523-1146)
- Giannis Vatsellas (ORCID: https://orcid.org/0000-0002-1631-1060)
- Achilleas Laskaratos (ORCID: https://orcid.org/0000-0002-2456-5781)
- Alessandra Bandera (ORCID: https://orcid.org/0000-0001-9440-4601)
- George Adamis
- Andrea Angheben (ORCID: https://orcid.org/0000-0003-4545-8034)
- Μαρία Τσιλικά (ORCID: https://orcid.org/0000-0002-8751-4711)
- Nikoletta Charalampaki
- Chrysanthi Sidiropoulou
- Anna Strikou
- Georgia Damoraki (ORCID: https://orcid.org/0000-0001-7986-7720)
- Vassiliki Rapti
- Pierluigi Del Vecchio (ORCID: https://orcid.org/0000-0003-4421-912X)
- Antoní Torres (ORCID: https://orcid.org/0000-0002-8643-2167)
- Konstantinos Syrigos
- Athanasios Ziogas
- Laura Scorzolini
- Helena Florou
- Maria Paulaki
Institutions
- Radboud University Nijmegen (NL)
- University of Ioannina (GR)
- Agostino Gemelli University Polyclinic (IT)
- Biomedical Research Foundation of the Academy of Athens (GR)
- Ospedale Sacro Cuore Don Calabria (IT)
- General Hospital of Athens G. Genimatas (GR)
- Ospedale Policlinico San Martino (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Universitat de Barcelona (ES)
- University of Genoa (IT)
Publication Details
- Journal
- Clinical Immunology
- Published
- 2025-12-13
- DOI
- https://doi.org/10.1016/j.clim.2025.110656
- Primary Topic
- Long-Term Effects of COVID-19
- Type
- article
- Field-Weighted Citation Impact
- 0.00