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 × 10-6), 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.