Complement inhibition in severe COVID-19 - Blocking C5a seems to be key.

With great interest we read the report by Annane and colleagues describing the effect of blocking complement factor C5 with the antibody eculizumab in patients with severe COVID-19 [1]. Results of this non-controlled study show an important proof of principle of complement inhibition therapy in patients with severe COVID-19. Increasing evidence point towards a critical role of the proinflammatory anaphylatoxin C5a in the pathogenesis of severe COVID-19 [2], [3], [4]. A previous study showed that controlling the anaphylatoxin C5a in disease requires a specifically targeted inhibition [5].

The authors mention that frequency and dosage of eculizumab had to be increased during the study to achieve complete and sustained complement inhibition [1]. Concentrations of C5a during the study of patients treated with or without high or higher dose eculizumab may provide important information about the potential of complement inhibition in COVID-19. Alternatively, selective approaches blocking C5a could be preferred. We recently published results of a phase 2 trial, showing that selective C5a inhibition with vilobelimab is safe in patients with severe COVID-19, with secondary outcome results in favour of vilobelimab [4]. Because blockade of an upstream component in the complement pathways will inevitably affect the formation of the membrane attack complex, such upstream intervention might put patients with COVID-19 at risk of secondary bacterial infections. The authors could provide more insight in this issue by presenting C5a concentrations of patients treated with eculizumab, with a breakdown for initial and high dose of eculizumab.

Declaration of Competing Interest

Dr. Vlaar reports personal fees from InflaRx, outside the submitted work. All other authors declare no competing interests.