Evidence of cytokine activation in patients with post-acute COVID-19 syndrome with- and without postural orthostatic tachycardia syndrome

FUNDING ACKNOWLEDGEMENTS: Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swedish Research Council Swedish Heart- and Lungfoundation INTRODUCTION: Post-acute COVID-19 syndrome (PACS) affects approximately 10% of non-hospitalized COVID-19 patients with mild primary infection and constitutes an increasing burden for society and healthcare systems. We have previously reported that a proportion of PACS patients develop postural orthostatic tachycardia syndrome (POTS). The pathophysiological mechanisms behind PACS and associated POTS remain largely unknown but cytokine activation and inflammation have been proposed. PURPOSE: To test the hypothesis that PACS and POTS-specific phenotype are associated with cytokine activation. METHODS: We recruited 20 patients with PACS and POTS verified by head-up TILT test (95% female, 39±11 years, 18±3 months after acute SARS-CoV-2 infection) and 22 patients with PACS without POTS (100% female, 44±11years, 19±3 months after acute SARS-CoV-2 infection). Age- and sex matched healthy volunteers (n=21; 95% female, 43±6 years) without- (n=16) and with (n=5) a history of SARS-Cov-2 infection but without symptoms served as control group. Peripheral blood samples were collected and analyzed for concentrations of 45 cytokines and inflammatory markers using Proximity Extension Assay. Protein-protein interactions and signaling pathway analysis were assessed using String database, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). RESULTS: Several cytokines and inflammatory biomarkers were overexpressed in patients with PACS compared to healthy controls irrespective of the presence of POTS (Figure 1). Protein-protein interaction analysis revealed a cluster including IL-7, CXCL12, CXCL11, CCL8 and CCL13. Cytokine-receptor activation, viral protein – cytokine receptor interaction and chemokine signaling were the most significantly upregulated KEGG pathways. Cytokine-mediated signaling, and cell- and leukocyte migration and chemotaxis were the most significantly upregulated GO biological processes. CONCLUSION: PACS is associated with increased levels of circulating cytokines regardless of concomitant POTS up to 18 months after a mild primary SARS-CoV-2 infection. This suggests that PACS-associated POTS exist on a background of cytokine activation but other specific pathophysiological mechanisms for PACS induced POTS needs to be established. Whether the cytokine profile of PACS is associated with persistent viral load or prolonged activation of the innate immune system and chronic inflammation, constituting a potential treatment target should be explored in future studies. [Figure: see text]