Long-term immune and epigenetic dysregulation following COVID-19, 2026, Sidiropoulou et al.

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Long-term immune and epigenetic dysregulation following COVID-19

Spoiler: Authors

Sidiropoulou; Poulakou; Kyriazopoulou; Tasouli; Giannitsioti; Strikou; Tsilika; Christaki; Rapti; Evangelopoulou; Rovina; Iannotti; Nicastri; Taddei; Florou; Angheben; Bassetti; Dagna; Torres; Foutadakis; Giamarellos-Bourboulis

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.

HIGHLIGHTS
• Five different clinical phenotypes have been identified in PACS patients 6 months after acute infection.

• IL-1, IL-17 and anti-inflammatory groups of cytokines were upregulated in PACS patients.

• Respiratory phenotype was associated with IL-1 activation (OR 4.23; 95% CIs, 1.69–10.8, p = 0.0025).

• Transcriptomic and epigenetic analysis support phenotype-related immune pathways.

Web | DOI | Clinical Immunology | Open Access

 

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This is a prospective, observational study conducted in outpatient post COVID units in Greece (five sites), Italy (eight sites) and Spain (one site).

Patients were divided into three cohorts. The Exploratory Cohort was recruited from one study site, between September and October 2020 and included 46 patients; they were compared with 25 sex- and age-matched controls without a history of COVID-19 infection and negative antiSARS-CoV-2 antibodies. Patients who were recruited from June 2021 to August 2023 were randomly 2:1 split into two cohorts; the Discovery Cohort and the Validation Cohort. Healthy asymptomatic vaccinated comparators were also enrolled.

PACS was defined according to the WHO consensus definition 1 as symptoms that lasted for at least 2 months which could not be explained by an alternative diagnosis and occured within 3 months after the acute COVID-19 infection. The discrimination of specific clinical phenotypes was accomplished using an electronic 16-symptoms questionnaire to be answered as either Yes or No.

five clusters were identified: a) patients with predominantly neurological symptoms (i.e. brain fog, memory problems); b) patients with predominant fatigue; c) patients with mixed fatigue and neurological symptoms; d) patients with mixed respiratory and neurological symptoms; and e) patients with mixed respiratory, neurological and fatigue symptoms

 

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PACS patients exhibited consistent upregulation of the IL-1 cytokines group (OR: 3.17, 95 % CIs: 1.94–5.19, p = 4.5 × 10 − 6 ), the IL-17 cytokines group (OR: 2.45, 95 % CIs: 1.47–4.07, p = 5.88 × 10 − 4 ) and the anti-inflammatory biomarkers group (OR: 2.15, 95 % CIs: 1.34–3.45, p = 1.5 × 10− 3 ) concomitant with downregulation of the pro-inflammatory biomarkers group (OR:1.92, 95 % CIs: 1.21–3.05, p = 5.2 × 10−3)

Abnormal pulmonary function tests were considered the gold-standard for the diagnosis of predominant respiratory phenotype. For patients missing pulmonary function tests, clinical answers to the questionnaires reported by patients with abnormal pulmonary function tests were used to extrapolate classification into respiratory PACS.

in accordance with the cytokines analysis, we found that responses to IL-1 and type-II interferons are enriched in patients with the respiratory phenotype compared to those with non-respiratory phenotypes.

Six differentially expressed genes (DEGs) were found (LOC388588, AQP1, BAK1, COTL1, GRINA and TRPM2) and were all up-regulated in patients with respiratory phenotype.

The expressions of COTL1, TRPM2, BAK1 and AQP1 were upregulated among patients with respiratory PACS. These genes encode for proteins associated with the maturation of IL-1 across different cellular environments and experimental models. This is compatible with the over-activation of the IL-1 cytokine group in patients with respiratory PACS.

The seemingly contradictory combination of anti-inflammatory upregulation and pro-inflammatory down-regulation of immune biomarkers in our results is compatible with a chronically adjusted, tolerance-like immune profile after severe viral infection. Although it is anticipated that pro-inflammation should prevail in PACS because of the high incidence of fatigue, previous research in patients with chronic fatigue syndrome before the pandemic suggests similar dissociation between immune patterns. In a randomized clinical trial, treatment patients with chronic fatigue conditions with the IL-1 blocker anakinra did not result in reduction of fatigue severity [31], suggesting that chronic fatigue is not a pro-inflammatory condition.

[31] is Cytokine Inhibition in Patients With Chronic Fatigue Syndrome (2017, Annals of Internal Medicine) | Sci-Hub