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.

The authors have declared no competing interest.

This work was supported by the Ministry of Education and Research (BMBF), as part of the National Research Initiative - Mass Spectrometry in Systems Medicine - (MSCoreSys), under grant agreement number 01EP2201 (to MR) and 16LW0239K (to MM), under Grant 01EP2201 (to CS) as well as the. Weidenhammer-Zoebele Foundation, and the Berlin University Alliance (BUA Link Lab, 501_Massenspektrometrie, 501_Linklab).

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The PA-COVID-19 study is a prospective observational study registered with German clinical trials registry (DRKS 00021688) aiming to provide a platform for clinical characterisation of acute and post-acute COVID-19. The study was approved by the ethics committee of Charite - Universitaetsmedizin Berlin (EA2/066/20) and conducted in accordance with the declaration of Helsinki.

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