Long Term Immune and Epigenetic Dysregulation Following COVID-19: The Impact of Anti-IL-1 Treatment in the Post-Acute COVID Syndrome

We studied whether progression of severe pneumonia into post-acute COVID-19 syndrome (PACS) is associated with long-term immune dysregulation. Patients with known history of COVID-19 pneumonia during two different time periods and matched comparators were divided into a discovery cohort (n=46, September-October 2020) and a validation cohort (n=484, June-August 2021). Peripheral blood mononuclear cells (PBMCs) were stimulated for cytokine production, patient-reported questionnaires and lung function tests (LFTs) were analyzed. Increased production of interleukin (IL)-1β (p<0.001) and IL-6 (p<0.001) was found in post-COVID-19 patients from both study periods. Anti-inflammatory Th2 responses and Th17 responses were attenuated compared to controls. PACS was present in 22%: fatigue was associated with predominance of Th2 responses; abnormal LFTs with overproduction of IL-1β and IL-6. Epigenetic markers of chromatin accessibility such as H3K27Ac were associated with these changes. Importantly, anti-IL-1 treatment with anakinra during the acute phase of disease reduced the chance of developing PACS by 40%.Funding Information: The study was sponsored and funded by the Hellenic Institute for the Study of Sepsis (HISS), which was also responsible for the design, conduct, analysis and interpretation of data and the decision to publish.Declaration of Interests: E. J. Giamarellos-Bourboulis has received honoraria from Abbott CH, bioMérieux, Brahms GmbH, GSK, InflaRx GmbH, Sobi and XBiotech Inc; independent educational grants from Abbott CH, AbbVie, bioMérieux Inc, InflaRx GmbH, Johnson & Johnson, MSD, Novartis, Sobi, UCB and XBiotech Inc.; and funding from the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), the Horizon 2020 European Grants ImmunoSep and RISKinCOVID (granted to the Hellenic Institute for the Study of Sepsis) and from the Horizon Europe project EPIC-CROWN-2 (granted to the Hellenic Institute for the Study of Sepsis). G. Poulakou has received independent educational grants from Pfizer, MSD, Angelini, and Biorad. H. Milionis reports receiving honoraria, consulting fees and non-financial support from healthcare companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer, and Servier. M. G. Netea is supported by an ERC Advanced Grant (#833247) and a Spinoza grant of the Netherlands Organization for Scientific Research. He has also received independent educational grants from TTxD, GSK and ViiV HealthCare. P. Panagopoulos has received honoraria from GILEAD Sciences, Janssen, and MSD. G. N. Dalekos is an advisor or lecturer for Ipsen, Pfizer, Genkyotex, Novartis, Sobi, received research grants from Abbvie, Gilead and has served as PI in studies for Abbvie, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics Inc, Tiziana Life Sciences, Bayer, Astellas, Pfizer, Amyndas Pharmaceuticals, CymaBay Therapeutics Inc., Sobi and Intercept Pharmaceuticals. S. Foutadakis and G. Vatsellas were supported by a grant to DT for the General Secreteriat for Research and Innovation (Emblematic Action on COVID-19). E. Giannitsioti has received honoraria from Pfizer Hellas, Norma Hellas and from Advisory Board in bioMerieux France. The other authors do not have any competing interest to declare.Ethics Approval Statement: The protocol was approved by the Ethics Committee of the participating hospitals (Attikon University Hospital 1-11/1/2022 and General Hospital of Piraeus Tzaneio 16-14/5/2021). All patients or their legal representatives provided written informed consent before enrollment.