Receptor-binding autoantibodies are not associated with post-COVID fatigue

Persistent fatigue is a common symptom following SARS-CoV-2 infection, but its underlying mechanisms remain incompletely understood. Autoantibodies targeting G-protein coupled receptors and other neurotransmitter-related receptors have been proposed as potential biomarkers or mediators of post-COVID symptoms. However, their association with post-COVID fatigue remains unclear. Therefore, in the current study, we investigated receptor-binding autoantibodies against 13 neurotransmitter-related receptors in 206 participants with prior infection with SARS-CoV-2. Three groups of patients were enrolled: controls with no persistent fatigue, patients experiencing new-onset post-infection fatigue, and a group of patients who already suffered from fatigue before their infection with SARS-CoV-2. Fatigue was assessed using a standardized self-reported fatigue questionnaire. We found no significant differences in the concentrations of the measured receptor-binding autoantibodies between participants with new-onset fatigue, pre-existing fatigue, and controls without persistent fatigue. In multivariable analyses, none of the individual antibody concentrations was significantly associated with new-onset fatigue after adjustment for age, sex, and time since infection and correction for multiple testing. Individual antibody concentrations were also not associated with fatigue severity. The proportion of participants exceeding manufacturer-defined reference values did not differ significantly between the study groups. Similarly, cumulative antibody positivity was not associated with fatigue severity. In conclusion, in this cohort of SARS-CoV-2-infected participants, we found no evidence that concentrations of the measured receptor-binding autoantibodies are associated with post-COVID fatigue or fatigue severity. These findings do not support the use of these antibodies as stand-alone biomarkers of post-COVID fatigue. Because all participants had previously experienced SARS-CoV-2 infection, the study cannot determine whether infection itself alters antibody concentrations. Furthermore, the binding assays do not establish whether the detected antibodies have functional receptor activity. These findings underscore the urgent need for longitudinal studies with comprehensive clinical phenotyping and functional antibody assays are needed to further investigate the potential role of receptor-binding autoantibodies in post-COVID symptoms.