Activin/Follistatin-axis deregulation is independently associated with COVID-19 in-hospital mortality

Abstract

Rationale: Activins are inflammatory and tissue-repair-related members of the TGFβ-superfamily that have been implicated in the pathogenesis of several immuno-inflammatory disorders including sepsis/acute respiratory distress syndrome (ARDS). We hypothesized that they might be of particular relevance to COVID-19 pathophysiology. Objectives: To assess the involvement of the Activin-Follistatin-axis in COVID-19 pathophysiology. Methods: Levels of Activins -A, -B and their physiological inhibitor Follistatin, were retrospectively analyzed in 314 serum samples from 117 COVID-19 patients derived from two 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. Main Results: The Activin/Follistatin-axis was significantly deregulated during the course of COVID-19 and was independently associated with severity and in-hospital mortality. FACT-CLINYCoD, a novel disease scoring system, adding one point for each of Follistatin >6235 pg/ml, Activin-A >591 pg/ml, Activin-B >249 pg/ml, CRP >10.3 mg/dL, LDH >427 U/L, Intensive Care Unit (ICU) admission, Neutrophil/Lymphocyte-Ratio >5.6, Years of Age >61, Comorbidities >1 and D-dimers >1097 ng/ml, efficiently predicted and monitored fatal outcome independently of multiplicity and timing of sampling (AUC: 0.951±0.032, p<10-6). Validation in 35 samples derived from a third hospital indicated comparable AUC (0.958±0.086, p=0.032). Conclusion: This study unravels the link between Activin/Folistatin-axis and COVID-19 mortality and introduces FACT-CLINYCoD, a novel pathophysiology-based tool that copes with the dynamic and heterogeneous nature of COCVID-19, predicts disease outcome and supports clinical decision making. Prospective large-scale validation of this calculator, as well as investigation of the mechanisms linking Activin/Folistatin-axis to COVID-19 pathogenesis is warranted.

Activin A levels are raised during human tuberculosis and blockade of the activin signaling axis influences murine responses to M. tuberculosis infection

“…Indeed, neutrophil levels are high in patients with active TB and decrease following successful TB treatment ( 53 ). Recently, it was shown that the activin signaling axis is upregulated during COVID-19, in which neutrophils infiltrate the lungs and correlate with severity and mortality ( 17 , 18 ). IL-1α and TNF-α, which are also induced by Mtb infection ( 54 , 55 ), induced activin A in human bronchial/tracheal smooth muscle cells and lung fibroblasts via the IKK/NF-κB pathway.…”

“…The expression of activin A is increased during asthma and acute respiratory distress syndrome (ARDS) ( 14 – 16 ). Recently, it was shown that activin A levels are increased during COVID-19 and are associated with the severity of the disease ( 17 , 18 ). Like TGF-β, activin A is a multi-faceted molecule with both pro- and anti-inflammatory effects ( 2 , 3 ).…”