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..
References
Ackermann, Verleden, Kuehnel, Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19, N Engl J Med
Apostolou, Stavropoulos, Sountoulidis, Activin-A overexpression in the murine lung causes pathology that simulates acute respiratory distress syndrome, Am J Respir Crit Care Med
Berlin, Gulick, Martinez, Severe Covid-19, N Engl J Med
Bösmüller, Traxler, Bitzer, The evolution of pulmonary pathology in fatal COVID-19 disease: an autopsy study with clinical correlation, Virchows Arch
Cherian, Chandra, Tung, Vuylsteke, COVID-19 conundrum: Clinical phenotyping based on pathophysiology as a promising approach to guide therapy in a novel illness, Eur Respir J
Collins, Reitsma, Altman, Moons, Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD): The TRIPOD Statement, Annals of Internal Medicine,
doi:10.7326/M14-0697Collins, Reitsma, Altman, Moons, Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD): The TRIPOD Statement, Annals of Internal Medicine,
doi:10.7326/M14-0697De Kretser, Bensley, Pettilä, Serum activin A and B levels predict outcome in patients with acute respiratory failure: a prospective cohort study, Crit Care
De Kretser, Hehir, Hardy, Hedger, The roles of activin A and its binding protein, follistatin, in inflammation and tissue repair, Mol Cell Endocrinol
George, Wells, Jenkins, Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy, Lancet Respir Med
Gupta, Madhavan, Sehgal, Extrapulmonary manifestations of COVID-19, Nat Med
Hadjadj, Yatim, Barnabei, Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients, Science
Hadjadj, Yatim, Barnabei, Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients, Science
Hedger, De Kretser, The activins and their binding protein, follistatin-Diagnostic and therapeutic targets in inflammatory disease and fibrosis, Cytokine Growth Factor Rev
Hue, Beldi-Ferchiou, Bendib, Uncontrolled Innate and Impaired Adaptive Immune Responses in Patients with COVID-19 ARDS, Am J Respir Crit Care Med
Iaccarino, Grassi, Borghi, Age and Multimorbidity Predict Death Among COVID-19 Patients: Results of the SARS-RAS Study of the Italian Society of Hypertension, Hypertension
Jones, De Kretser, Patella, Phillips, Activin A and follistatin in systemic inflammation, Mol Cell Endocrinol
Jones, Mansell, Patella, Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia, Proc Natl Acad Sci
Khinda, Janjua, Cheng, Van Den Heuvel, Bhatti et al., Association between markers of immune response at hospital admission and COVID-19 disease severity and mortality: A meta-analysis and meta-regression, J Med Virol
Liang, Liang, Ou, Development and Validation of a Clinical Risk Score to Predict the Occurrence of Critical Illness in Hospitalized Patients With COVID-19, JAMA Intern Med
Linko, Hedger, Pettilä, Serum activin A and B, and follistatin in critically ill patients with influenza A(H1N1) infection, BMC Infect Dis
Mehta, Mcauley, Brown, COVID-19: consider cytokine storm syndromes and immunosuppression, Lancet
Meizlish, Pine, Goshua, Circulating Markers of Angiogenesis and Endotheliopathy in COVID-19, medRxiv
Namwanje, Brown, Activins and Inhibins: Roles in Development, Physiology, and Disease, Cold Spring Harb Perspect Biol
Palin, Savikko, Pasternack, Activin inhibition limits early innate immune response in rat kidney allografts-a pilot study, Transpl Int
Panagiotou, Papakonstantinou, Vagionas, Polyzos, Mantzoros, Serum Levels of Activins, Follistatins, and Growth Factors in Neoplasms of the Breast: A Case-Control Study, J ClinEndocrinolMetab
Richardson, Hirsch, Narasimhan, Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area, JAMA
Rocio, Paloma, Interleukin-6-based mortality risk model for hospitalised COVID-19 patients, J Allergy Clin Immunol
Schulte-Schrepping, Reusch, Paclik, Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment, Cell
Shang, Liu, Wei, Scoring systems for predicting mortality for severe patients with COVID-19, EClinicalMedicine
Sideras, Apostolou, Stavropoulos, Activin, neutrophils, and inflammation: just coincidence?, Semin Immunopathol
Skendros, Mitsios, Chrysanthopoulou, Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis, J Clin Invest
Tang, Bai, Chen, Gong, Li et al., Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy, J Thromb Haemost
Thompson, Lerch, Cook, Woodruff, Jardetzky, The structure of the follistatin:activin complex reveals antagonism of both type I and type II receptor binding, Dev Cell
Tuuri, Erämaa, Hildén, Ritvos, The tissue distribution of activin beta Aand beta B-subunit and follistatin messenger ribonucleic acids suggests multiple sites of action for the activin-follistatin system during human development, J Clin Endocrinol Metab
Valle, Kim-Schulze, Huang, An inflammatory cytokine signature predicts COVID-19 severity and survival, Nat Med
Wacker, Sachs, Knaup, Key role for activin B in cellular transformation after loss of the von Hippel-Lindau tumor suppressor, Mol Cell Biol
Wynants, Van Calster, Collins, Prediction models for diagnosis and prognosis of covid-19 infection: systematic review and critical appraisal, BMJ
Yan, Zhang, Goncalves, An interpretable mortality prediction model for COVID-19 patients, Nature Machine Intelligence
Yoshioka, Funada, Luo, The inherent problems with the generalizability of the CALL score: towards reliable clinical prediction models for COVID-19, Clin Infect Dis Available,
doi:10.1093/cid/ciaa1564/5925185Yoshioka, Funada, Luo, The inherent problems with the generalizability of the CALL score: towards reliable clinical prediction models for COVID-19, Clin Infect Dis Available,
doi:10.1093/cid/ciaa1564/5925185Zhou, Yu, Du, Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study, Lancet
