Activin/Follistatin-axis deregulation is independently associated with COVID-19 in-hospital mortality
Evgenia Synolaki, Vasileios Papadopoulos, Georgios Divolis, Efstratios Gavriilidis, Georgia Loli, Arianna Gavriil, Christina Tsigalou, Olga Tsahouridou, Eleni Sertaridou, Petros Rafailidis, Arja Pasternack, Dimitrios T Boumpas, Georgios Germanidis, Olli Ritvos, Simeon Metallidis, Panagiotis Skendros, Dr Paschalis Sideras
doi:10.1101/2020.09.05.20184655
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, Years of Age>61, Comorbidities>1 and D-dimers>1097ng/ml, efficiently predicted fatal outcome in an initial cohort (AUC: 0.951±0.032, p<10 -6 ). Two independent cohorts that were used for validation indicated comparable AUC (0.958, p=0.880 and 0.924, p=0.256, respectively). Conclusions: This study unravels strong link between Activin/Follistatin-axis and COVID-19 mortality and introduces FACT-CLINYCoD, a novel pathophysiology-based .
Supplementary Data Study criteria and disease status Inclusion criteria of the study were: a) adult patients (>18 years old), any gender; b) positive SARS-CoV-2 RT-PCR testing in nasopharyngeal swab or BAL; c) hospitalization due to COVID-19, any disease stage; d) Known final disease outcome. Patients without available sample obtained before the 21 st day-of-disease were excluded. Comorbidities considered were diabetes mellitus, arterial hypertension, dyslipidemia, obesity, atrial fibrillation, coronary disease, heart-failure, renal-failure, chronic obstructive pulmonary disease or asthma, immunosuppression (without a record of malignancy), autoimmunity and cancer. The disease-status (DS) of COVID-19 patients was classified based on the adaptation of the Sixth Revised Trial Version of the Novel Coronavirus Pneumonia Diagnosis and Treatment Guidance, as described previously by Hadjadj et al [1] . Specifically, mild cases (DS1) were defined as mild clinical symptoms (fever, myalgia, fatigue, diarrhea) and no sign of pneumonia on thoracic X-Ray or/and CT scan. Moderate cases (DS2) were defined as clinical symptoms associated with dyspnea and radiological findings of pneumonia on thoracic X-Ray or/and CT scan, and requiring a maximum of 3 L/min of oxygen. Severe cases (DS3) were defined as respiratory distress requiring more than 3 L/min of oxygen and no other organ failure. Critical cases (DS4) were defined as respiratory failure requiring mechanical ventilation, shock..
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"abstract": "<jats:title>Abstract</jats:title><jats:sec><jats:title>Rationale</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Objectives</jats:title><jats:p>To assess the involvement of the Activin-Follistatin-axis in COVID-19 pathophysiology.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Main Results</jats:title><jats:p>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<jats:sup>-6</jats:sup>). Validation in 35 samples derived from a third hospital indicated comparable AUC (0.958±0.086, p=0.032).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>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.</jats:p></jats:sec>",
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"URL": "http://medrxiv.org/lookup/doi/10.1101/2020.09.05.20184655"
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"title": "Activin/Follistatin-axis deregulation is independently associated with COVID-19 in-hospital mortality",
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