{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T08:45:05Z","timestamp":1792226705492,"version":"4.4.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T00:00:00Z","timestamp":1624406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and has evoked a pandemic that challenges public health-care systems worldwide. Endothelial cell dysfunction plays a key role in pathophysiology, and simple prognosticators may help to optimize allocation of limited resources. Endothelial activation and stress index (EASIX) is a validated predictor of endothelial complications and outcome after allogeneic stem cell transplantation. Aim of this study was to test if EASIX could predict life-threatening complications in patients with COVID-19.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>SARS-CoV-2-positive, hospitalized patients were enrolled onto a prospective non-interventional register study (n=100). Biomarkers were assessed at hospital admission. Primary endpoint was severe course of disease (mechanical ventilation and\/or death, V\/D). Results were validated in 126 patients treated in two independent institutions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>EASIX at admission was a strong predictor of severe course of the disease (odds ratio for a two-fold change 3.4, 95%CI 1.8-6.3, p&amp;lt;0.001), time to V\/D (hazard ratio (HR) for a two-fold change 2.0, 95%CI 1.5-2.6, p&amp;lt;0.001) as well as survival (HR for a two-fold change 1.7, 95%CI 1.2-2.5, p=0.006). The effect was retained in multivariable analysis adjusting for age, gender, and comorbidities and could be validated in the independent cohort. At hospital admission EASIX correlated with increased suppressor of tumorigenicity-2, soluble thrombomodulin, angiopoietin-2, CXCL8, CXCL9 and interleukin-18, but not interferon-alpha.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>EASIX is a validated predictor of COVID19 outcome and an easy-to-access tool to segregate patients in need for intensive surveillance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2021.634416","type":"journal-article","created":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T02:38:20Z","timestamp":1624415900000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":66,"title":["EASIX for Prediction of Outcome in Hospitalized SARS-CoV-2 Infected Patients"],"prefix":"10.3389","volume":"12","author":[{"given":"Thomas","family":"Luft","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens-Martin","family":"Wendtner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florentina","family":"Kosely","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandar","family":"Radujkovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Benner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Korell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Kihm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias F.","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Dreger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uta","family":"Merle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.7326\/M20-0504","article-title":"The Incubation Period of Coronavirus Disease 2019 (Covid-19) From Publicly Reported Confirmed Cases: Estimation and Application","volume":"172","author":"Lauer","year":"2020","journal-title":"Ann Intern Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.1585","article-title":"Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China","volume":"323","author":"Wang","year":"2020","journal-title":"JAMA"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvaa106","article-title":"Covid-19 and the Cardiovascular System: Implications for Risk Assessment, Diagnosis, and Treatment Options","volume":"116","author":"Guzik","year":"2020","journal-title":"Cardiovasc Res"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2020.0950","article-title":"Association of Cardiac Injury With Mortality in Hospitalized Patients With Covid-19 in Wuhan, China","volume":"5","author":"Shi","year":"2020","journal-title":"JAMA Cardiol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijid.2020.03.017","article-title":"Prevalence of Comorbidities and Its Effects in Coronavirus Disease 2019 Patients: A Systematic Review and Meta-Analysis","volume":"94","author":"Yang","year":"2020","journal-title":"Int J Infect Dis"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30566-3","article-title":"Clinical Course and Risk Factors for Mortality of Adult Inpatients With COVID-19 in Wuhan, China: A Retrospective Cohort Study","volume":"395","author":"Zhou","year":"2020","journal-title":"Lancet"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)31103-X","article-title":"An Outbreak of Severe Kawasaki-Like Disease at the Italian Epicentre of the SARS-CoV-2 Epidemic: An Observational Cohort Study","volume":"395","author":"Verdoni","year":"2020","journal-title":"Lancet"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)31129-6","article-title":"Kawasaki-Like Disease: Emerging Complication During the COVID-19 Pandemic","volume":"395","author":"Viner","year":"2020","journal-title":"Lancet"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2020.04.031","article-title":"Covid-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review","volume":"75","author":"Bikdeli","year":"2020","journal-title":"J Am Coll Cardiol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.thromres.2020.04.014","article-title":"Severe COVID-19 Infection Associated With Endothelial Activation","volume":"190","author":"Escher","year":"2020","journal-title":"Thromb Res"},{"key":"B11","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1002\/jmv.25915","article-title":"Central Nervous System Involvement by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-Cov-2)","volume":"92","author":"Paniz-Mondolfi","year":"2020","journal-title":"J Med Virol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0343-0","article-title":"Covid-19: The Vasculature Unleashed","volume":"20","author":"Teuwen","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30937-5","article-title":"Endothelial Cell Infection and Endotheliitis in COVID-19","volume":"35","author":"Varga","year":"2020","journal-title":"Lancet"},{"key":"B14","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-Cov-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"B15","first-page":"284","article-title":"Microvascular COVID-19 Lung Vessels Obstructive Thromboinflammatory Syndrome (MicroCLOTS): An Atypical Acute Respiratory Distress Syndrome Working Hypothesis","volume":"22","author":"Ciceri","year":"2020","journal-title":"Crit Care Resusc"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-020-09730-0","article-title":"Angiopoietin-2 as a Marker of Endothelial Activation Is a Good Predictor Factor for Intensive Care Unit Admission of COVID-19 Patients","volume":"23","author":"Smadja","year":"2020","journal-title":"Angiogenesis"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.047419","article-title":"Will Complement Inhibition be the New Target in Treating Covid-19 Related Systemic Thrombosis","author":"Campbell","year":"2020","journal-title":"Circulation"},{"key":"B18","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1161\/CIRCULATIONAHA.120.047549","article-title":"The Science Underlying COVID-19: Implications for the Cardiovascular System","volume":"142","author":"Liu","year":"2020","journal-title":"Circulation"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-02-334821","article-title":"Steroid-Refractory GVHD: T-Cell Attack Within a Vulnerable Endothelial System","volume":"118","author":"Luft","year":"2011","journal-title":"Blood"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/bmt.2017.119","article-title":"Transplant-Associated Thrombotic Microangiopathy Is an Endothelial Complication Associated With Refractoriness of Acute GvHD","volume":"52","author":"Zeisbrich","year":"2017","journal-title":"Bone Marrow Transplant"},{"key":"B21","doi-asserted-by":"publisher","first-page":"95","DOI":"10.3324\/haematol.10699","article-title":"Diagnostic Criteria for Hematopoietic Stem Cell Transplant-Associated Microangiopathy: Results of a Consensus Process by an International Working Group","volume":"92","author":"Ruutu","year":"2007","journal-title":"Haematologica"},{"key":"B22","first-page":"95","article-title":"Predicting Sinusoidal Obstruction Syndrome After Allogeneic Stem Cell Transplantation With the EASIX Biomarker Panel","volume":"92","author":"Jiang","year":"2020","journal-title":"Haematologica"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(17)30108-4","article-title":"EASIX in Patients With Acute Graft-Versus-Host Disease: A Retrospective Cohort Analysis","volume":"4","author":"Luft","year":"2017","journal-title":"Lancet Haematol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41409-019-0703-1","article-title":"EASIX and Mortality After Allogeneic Stem Cell Transplantation","volume":"55","author":"Luft","year":"2020","journal-title":"Bone Marrow Transplant"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019032268","article-title":"External Validation and Comparison of Multiple Prognostic Scores in Allogeneic Hematopoietic Stem Cell Transplantation","volume":"3","author":"Shouval","year":"2019","journal-title":"Blood Adv"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2020.01.028","article-title":"Endothelial Activation and Stress Index (EASIX) at Admission Predicts Fluid Overload in Recipients of Allogeneic Stem Cell Transplantation","volume":"3","author":"Varma","year":"2020","journal-title":"Biol Blood Marrow Transplant"},{"key":"B27","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1038\/s41408-019-0247-z","article-title":"EASIX for Prediction of Survival in Lower-Risk Myelodysplastic Syndromes","volume":"9","author":"Merz","year":"2019","journal-title":"Blood Cancer J"},{"key":"B28","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1186\/s12885-020-07317-y","article-title":"Endothelial Activation and Stress Index (EASIX) Is a Reliable Predictor for Overall Survival in Patients With Multiple Myeloma","volume":"20","author":"Song","year":"2020","journal-title":"BMC Cancer"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2012.09.018","article-title":"Endothelial Vulnerability and Endothelial Damage Are Associated With Risk of Graft-Versus-Host Disease and Response to Steroid Treatment","volume":"19","author":"Dietrich","year":"2013","journal-title":"Biol Blood Marrow Transplant"},{"key":"B30","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1038\/s41408-021-00434-2","article-title":"Polymorphisms in CXCR3 Ligands Predict Early CXCL9 Recovery and Severe Chronic GVHD","volume":"11","author":"Dai","year":"2021","journal-title":"Blood Cancer J"},{"key":"B31","doi-asserted-by":"publisher","first-page":"2789","DOI":"10.3390\/cancers12102789","article-title":"Interleukin-18 and Hematopoietic Recovery After Allogeneic Stem Cell Transplantation","volume":"12","author":"Radujkovic","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.10.024","article-title":"Interleukin-18 and Outcome After Allogeneic Stem Cell Transplantation: A Retrospective Cohort Study","volume":"49","author":"Radujkovic","year":"2019","journal-title":"EBioMedicine"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.648004","article-title":"Blood Interferon-Alpha Levels and Severity, Outcomes, and Inflammatory Profiles in Hospitalized Covid-19 Patients","volume":"12","author":"Contoli","year":"2021","journal-title":"Front Immunol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"2045894020966547","DOI":"10.1177\/2045894020966547","article-title":"Circulating Markers of Angiogenesis and Endotheliopathy in COVID-19","volume":"10","author":"Pine","year":"2020","journal-title":"Pulm Circ"},{"key":"B35","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1186\/s13054-020-2833-7","article-title":"Host Susceptibility to Severe COVID-19 and Establishment of a Host Risk Score: Findings of 487 Cases Outside Wuhan","volume":"24","author":"Shi","year":"2020","journal-title":"Crit Care"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/bimj.200810443","article-title":"The Performance of Risk Prediction Models","volume":"50","author":"Gerds","year":"2008","journal-title":"Biom J"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/bimj.200610301","article-title":"Consistent Estimation of the Expected Brier Score in General Survival Models With Right-Censored Event Times","volume":"48","author":"Gerds","year":"2006","journal-title":"Biom J"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1111\/j.0006-341X.2000.00337.x","article-title":"Time-Dependent ROC Curves for Censored Survival Data and a Diagnostic Marker","volume":"56","author":"Heagerty","year":"2000","journal-title":"Biometrics"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1111\/j.1541-0420.2008.00995.x","article-title":"Generalized Maximally Selected Statistics","volume":"64","author":"Hothorn","year":"2008","journal-title":"Biometrics"},{"key":"B40","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/s40001-020-00432-3","article-title":"Laboratory Features of Severe vs. Non-Severe COVID-19 Patients in Asian Populations: A Systematic Review and Meta-Analysis","volume":"25","author":"Ghahramani","year":"2020","journal-title":"Eur J Med Res"},{"key":"B41","doi-asserted-by":"publisher","first-page":"e175","DOI":"10.1017\/S095026882000179X","article-title":"Risk Factors of Severe Cases With COVID-19: A Meta-Analysis","volume":"148","author":"Ou","year":"2020","journal-title":"Epidemiol Infect"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1515\/cclm-2020-1062","article-title":"Lactate Dehydrogenase: An Old Enzyme Reborn as a COVID-19 Marker (and Not Only)","volume":"58","author":"Panteghini","year":"2020","journal-title":"Clin Chem Lab Med"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1080\/09537104.2020.1762852","article-title":"Platelet Functions and Activities as Potential Hematologic Parameters Related to Coronavirus Disease 2019 (Covid-19)","volume":"31","author":"Salamanna","year":"2020","journal-title":"Platelets"},{"key":"B44","doi-asserted-by":"crossref","first-page":"100449","DOI":"10.1016\/j.eclinm.2020.100449","article-title":"Prognostic Factors Associated With Mortality Risk and Disease Progression in 639 Critically Ill Patients With COVID-19 in Europe: Initial Report of the International RISC-19-ICU Prospective Observational Cohort","volume":"25","author":"Wendel Garcia","year":"2020","journal-title":"EClinicalMedicine"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1007\/s002770050364","article-title":"Endothelial Dysfunction After Bone Marrow Transplantation: Increase of Soluble Thrombomodulin and PAI-1 in Patients With Multiple Transplant-Related Complications","volume":"76","author":"Nurnberger","year":"1998","journal-title":"Ann Hematol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2008.09.027","article-title":"Nonmyocardial Production of ST2 Protein in Human Hypertrophy and Failure Is Related to Diastolic Load","volume":"52","author":"Bartunek","year":"2008","journal-title":"J Am Coll Cardiol"},{"key":"B47","doi-asserted-by":"publisher","first-page":"3B","DOI":"10.1016\/j.amjcard.2015.01.034","article-title":"The Biology of ST2: The International St2 Consensus Panel","volume":"115","author":"Pascual-Figal","year":"2015","journal-title":"Am J Cardiol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2011.061051","article-title":"Loss of Endothelial Thrombomodulin Predicts Response to Steroid Therapy and Survival in Acute Intestinal Graft-Versus-Host Disease","volume":"97","author":"Andrulis","year":"2012","journal-title":"Haematologica"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1213299","article-title":"ST2 as a Marker for Risk of Therapy-Resistant Graft-Versus-Host Disease and Death","volume":"369","author":"Vander Lugt","year":"2013","journal-title":"N Engl J Med"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiaa528","article-title":"Circulating Endothelial Cells as a Marker of Endothelial Injury in Severe Covid-19","volume":"222","author":"Guervilly","year":"2020","journal-title":"J Infect Dis"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1101\/2020.04.29.20085878","article-title":"Circulating Endothelial Progenitors are Increased in Covid-19 Patients and Correlate With SARS-CoV-2 RNA in Severe Cases","volume":"18","author":"Mancuso","year":"2020","journal-title":"J Thromb Haemost"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvaa230","article-title":"Endothelial Dysfunction in COVID-19: A Position Paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science","volume":"116","author":"Evans","year":"2020","journal-title":"Cardiovasc Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.634416\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T02:38:26Z","timestamp":1624415906000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.634416\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,23]]},"references-count":52,"alternative-id":["10.3389\/fimmu.2021.634416"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.634416","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,23]]},"article-number":"634416"}}