The Activin/Follistatin Axis Is Severely Deregulated in COVID-19 and Independently Associated With In-Hospital Mortality

Abstract

Background Activins are members of the TGFβ-superfamily implicated in the pathogenesis of several immuno-inflammatory disorders. Based on our previous studies demonstrating that over-expression of Activin-A in murine lung causes pathology sharing key features of COVID-19, we hypothesized that Activins and their natural inhibitor Follistatin might be particularly relevant to COVID-19 pathophysiology. Methods Activin-A, Activin-B and Follistatin levels were retrospectively analyzed in 574 serum samples from 263 COVID-19 patients hospitalized in three independent centers, and compared with common demographic, clinical and laboratory parameters. Optimal-scaling with ridge-regression was used to screen variables and establish a prediction model. Result The Activin/Follistatin-axis was significantly deregulated during the course of COVID-19, correlated with severity and independently associated with mortality. FACT-CLINYCoD, a novel disease scoring system, adding one point for each of Follistatin>6235pg/ml, Activin-A>591pg/ml, Activin-B>249pg/ml, CRP>10.3mg/dL, LDH>427U/L, Intensive Care Unit (ICU) admission, Neutrophil/Lymphocyte-Ratio>5.6, Age>61, Comorbidities>1 and D-dimers>1097ng/ml, efficiently predicted fatal outcome in an initial cohort (AUC: 0.951; 95%CI: 0.919-0.983, p<10 -6). Two independent cohorts that were used for validation indicated similar AUC values. Conclusions This study unravels strong link between Activin/Follistatin-axis and COVID-19 mortality and introduces FACT-CLINYCoD, a novel pathophysiology-based tool that allows dynamic prediction of disease outcome, supporting clinical decision making.

Prognostic Role of Neutrophil to Lymphocyte Ratio in COVID-19 Patients: Still Valid in Patients That Had Started Therapy?

“…A study limitation is represented by the relatively small number of patients of I st wave in comparison to II nd wave. Further studies need to confirm our findings as a recent work documents NLR predictive value on both I st and II nd waves ( 21 ). However, at the state of the art, there is not a clear consensus on the role of such drugs, frequently used friendly without medical supervision ( 22 ) and on their impact on COVID-19 patients.…”

Social and Clinical Impact of COVID-19 on Patients with Fibrodysplasia Ossificans Progressiva

“…A study looking at serum samples of patients with severe, active COVID-19 infections found that Activin A, Activin B, and follistatin were all upregulated during the time when COVID-19 patients tended to deteriorate [21]. In a COVID-19 study de ning Acute Respiratory Distress Syndrome (ARDS), cytokine storms were observed in patients with severe COVID-19 symptoms [22].…”

The Activin/FLRG Pathway Associates with Poor COVID-19 Outcomes in Hospitalized Patients

“…While we were preparing our manuscript, another manuscript appeared similarly demonstrating activin A was disregulated in COVID-19 patients ( 11 ). The findings in the present manuscript are in agreement with that paper.…”

“…We evaluated sera from these patients after randomization and prior to therapy, to determine baseline activin A, activin B, FLRG, and PAI-1 levels, and correlated these to baseline clinical and laboratory variables and important disease outcomes. While we were preparing the manuscript, another manuscript appeared demonstrating activin A and activin B are elevated in COVID-19 patients ( 11 ). Our paper is consistent with findings in that manuscript, and goes further in demonstrating mechanism, additional clinical correlations, and providing a preclinical intervention study that helps to derisk this potential treatment approach.…”