Persistent Activation of Chronic Inflammatory Pathways in Long Covid

Abstract Long Covid, or Post-Acute Sequelae of COVID-19 (PASC), involves a spectrum of chronic symptoms following resolution of acute SARS-CoV-2 infection. Current hypotheses for the pathogenesis of Long Covid include persistent SARS-CoV-2, activation of other viruses, tissue damage, autoimmunity, endocrine insufficiency, immune dysfunction, and complement activation. We evaluated 142 participants, including uninfected controls (N=35), acutely infected individuals (N=54), convalescent controls (N=25), and Long Covid patients (N=28), by comprehensive immunologic, virologic, transcriptomic, and proteomic analyses. Long Covid was characterized by persistent inflammatory pathways compared with convalescent controls and uninfected controls, including upregulation of IL-6 and JAK-STAT pathways as well as activation of coagulation, complement, metabolism, and T cell exhaustion pathways. Moreover, robust activation of these pathways during acute COVID-19 infection correlated with the subsequent development of Long Covid. In an independent validation cohort (N=47), Long Covid patients had higher levels of plasma IL-6R compared with convalescent controls and uninfected controls. These data demonstrate that Long Covid is characterized by persistent activation of chronic inflammatory pathways, suggesting novel therapeutic targets and biomarkers of disease.