Role of the complement system in Long COVID

Long COVID, or Post-Acute COVID Syndrome (PACS), may develop following SARS-CoV-2 infection, posing a substantial burden to society. Recently, PACS has been linked to a persistent activation of the complement system (CS), offering hope for both a diagnostic tool and targeted therapy. However, our findings indicate that, after adjusting proteomics data for age, body mass index and sex imbalances, the evidence of complement system activation disappears. Furthermore, proteomic analysis of two orthogonal cohorts—one addressing PACS following severe acute phase and another after a mild acute phase—fails to support the notion of persistent CS activation. Instead, we identify a proteomic signature indicative of either ongoing infections or sustained immune activation similar to that observed in acute COVID-19, particularly within the mild-PACS cohort.