Reactivation of herpesvirus type-6 and IgA/IgM-mediated responses to activin-A underpin Long COVID, including affective symptoms and chronic fatigue syndrome

Abstract

AbstractBackgroundPersistent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), reactivation of dormant viruses, and immune-oxidative responses are involved in Long COVID.ObjectivesTo investigate whether Long COVID and depressive, anxiety and chronic fatigue syndrome (CFS) symptoms, are associated with IgA/IgM/IgG to SARS-CoV-2, human Herpesvirus type 6 (HHV-6), Epstein-Barr Virus (EBV), and immune-oxidative biomarkers.MethodsWe examined 90 Long COVID patients and 90 healthy controls. We measured serum IgA/IgM/IgG against HHV-6 and EBV and their deoxyuridine 5′-triphosphate nucleotidohydrolase (duTPase), SARS-CoV-2, and activin-A, C-reactive protein (CRP), advanced oxidation protein products (AOPP), and insulin resistance (HOMA2-IR).ResultsLong COVID patients showed significant elevations in IgG/IgM-SARS-CoV-2, IgG/IgM-HHV-6 and HHV-6-duTPase, IgA/IgM-activin-A, CRP, AOPP, and HOMA2-IR. Neural network analysis yielded a highly significant predictive accuracy of 80.6% for the Long COVID diagnosis (sensitivity: 78.9%, specificity: 81.8%, area under the ROC curve=0.876); the topmost predictors were: IGA-activin-A, IgG-HHV-6, IgM-HHV-6-duTPase, IgG-SARS-CoV-2, and IgM-HHV-6 (all positively) and a factor extracted from all IgA levels to all viral antigens (inversely). The top-5 predictors of affective symptoms due to Long COVID were: IgM-HHV-6-duTPase, IgG-HHV-6, CRP, education, IgA-activin-A (predictive accuracy of r=0.636). The top-5 predictors of CFS due to Long COVID were in descending order: CRP, IgG-HHV-6-duTPase, IgM-activin-A, IgM-SARS-CoV-2, and IgA-activin-A (predictive accuracy: r=0.709).ConclusionReactivation of HHV-6, SARS-CoV-2 persistence, and autoimmune reactions to activin-A combined with activated immune-oxidative pathways play a major role in the pathophysiology of Long COVID as well as the severity of affective symptoms and CFS due to Long COVID.