The Activin/FLRG pathway associates with poor COVID-19 outcomes in hospitalized patients.

A subset of hospitalized COVID-19 patients, particularly the aged and those with co-morbidities, develop the most severe form of the disease, characterized by Acute Respiratory Disease Syndrome (ARDS), coincident with experiencing a "cytokine storm." Here, we demonstrate that cytokines which activate the NF-kappaB pathway can induce Activin A. Patients with elevated Activin A, Activin B, and FLRG at hospital admission were associated with the most severe outcomes of COVID-19, including the requirement for mechanical ventilation, and all-cause mortality. A prior study showed that Activin A could decrease viral load, which indicated there might be a risk to giving COVID-19 patients an inhibitor of Activin. To evaluate this, the role for Activin A was examined in a hamster model of SARS-CoV2 infection, via blockade of Activin A signaling. The hamster model demonstrated that use of an anti-ActivinA antibody did not worsen the disease and there was no evidence for increase in lung viral load and pathology. The study indicates blockade of Activin signaling may be beneficial in treating COVID-19 patients experiencing ARDS.