{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T15:24:23Z","timestamp":1774625063186,"version":"3.50.1"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2021,7,2]],"date-time":"2021-07-02T00:00:00Z","timestamp":1625184000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003621","name":"Ministry of Science, ICT and Future Planning","doi-asserted-by":"publisher","award":["2019R1C1C1006417"],"award-info":[{"award-number":["2019R1C1C1006417"]}],"id":[{"id":"10.13039\/501100003621","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Dexamethasone provides benefits in patients with coronavirus disease 2019 (COVID-19), although data regarding immunological profiles and viral clearance are limited. This study aimed to evaluate for differences in biomarkers among patients with severe COVID-19 who did and did not receive dexamethasone. We measured plasma biomarkers of lung epithelial\/endothelial injury and inflammation in 31 patients with severe COVID-19 and in 13 controls. Changes in biomarkers and clinical parameters were compared during the 7-day period among COVID-19 patients, and also according to dexamethasone use. Thirty-two patients with severe COVID-19 who received mechanical ventilation (n = 6), high-flow nasal cannula (n = 11), and supplemental oxygen (n = 15) were analyzed. Relative to controls, patients with severe COVID-19 had significantly higher concentrations of biomarkers related to glycocalyx shedding (endocan and syndecan-1), endothelial injury (von Willebrand factor), and inflammation (soluble receptor for advanced glycation end-products [sRAGE] and interleukin-6). The 7-day decreases in biomarkers of endothelial injury (angiopoietin-2 [Ang-2] and intercellular adhesion molecule-1 [ICAM-1]) and sRAGE, but not in the biomarker of lung epithelial injury (surfactant protein D), were correlated with decreases in C-reactive protein and radiologic score at day 7. Twenty patients (63%) received dexamethasone, and the dexamethasone and non-dexamethasone groups differed in terms of disease severity. However, dexamethasone was associated marginally with increased SpO<jats:sub>2<\/jats:sub>\/FiO<jats:sub>2<\/jats:sub> and significantly with decreases in C-reactive protein and radiologic score after adjusting for baseline imbalances. Furthermore, the dexamethasone group exhibited a significant decrease in the concentrations of Ang-2, ICAM-1, soluble form of the Tie2 receptor (a biomarker of glycocalyx shedding), and sRAGE. Both groups exhibited a clinically insignificant increase in the cycle threshold value. Severe COVID-19 may be characterized by more severe endothelial injury and inflammation, and less severe lung epithelial injury. There is a possibility that dexamethasone improved severe COVID-19 and related endothelial injury without delaying viral clearance.<\/jats:p>","DOI":"10.1371\/journal.pone.0254167","type":"journal-article","created":{"date-parts":[[2021,7,2]],"date-time":"2021-07-02T18:12:54Z","timestamp":1625249574000},"page":"e0254167","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":49,"title":["Dexamethasone may improve severe COVID-19 via ameliorating endothelial injury and inflammation: A preliminary pilot study"],"prefix":"10.1371","volume":"16","author":[{"given":"Won-Young","family":"Kim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oh Joo","family":"Kweon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min Jae","family":"Cha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moon Seong","family":"Baek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8108-2412","authenticated-orcid":true,"given":"Seong-Ho","family":"Choi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,7,2]]},"reference":[{"key":"pone.0254167.ref001","unstructured":"World Health Organization. Coronavirus disease (COVID-19) pandemic. [cited 10 February 2021]. Available from: https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019."},{"issue":"10223","key":"pone.0254167.ref002","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"C Huang","year":"2020","journal-title":"Lancet"},{"issue":"13","key":"pone.0254167.ref003","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1056\/NEJMoa2001316","article-title":"Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia","volume":"382","author":"Q Li","year":"2020","journal-title":"N Engl J Med"},{"issue":"7821","key":"pone.0254167.ref004","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/s41586-020-2588-y","article-title":"Longitudinal analyses reveal immunological misfiring in severe COVID-19","volume":"584","author":"C Lucas","year":"2020","journal-title":"Nature"},{"issue":"6504","key":"pone.0254167.ref005","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1126\/science.abc6027","article-title":"Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients","volume":"369","author":"J Hadjadj","year":"2020","journal-title":"Science"},{"key":"pone.0254167.ref006","doi-asserted-by":"crossref","unstructured":"Sarma A, Christenson S, Mick E, Deiss T, DeVoe C, Pisco A, et al. COVID-19 ARDS is characterized by a dysregulated host response that differs from cytokine storm and is modified by dexamethasone. Res Sq: rs.3.rs-141578 [Preprint]. 2021 [cited 2021 Feb 10]. 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Angus","year":"2020","journal-title":"JAMA"},{"issue":"3","key":"pone.0254167.ref012","doi-asserted-by":"crossref","first-page":"2000045","DOI":"10.2807\/1560-7917.ES.2020.25.3.2000045","article-title":"Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR","volume":"25","author":"VM Corman","year":"2020","journal-title":"Euro Surveill"},{"issue":"5","key":"pone.0254167.ref013","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1007\/s00134-020-06022-5","article-title":"Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19)","volume":"46","author":"W Alhazzani","year":"2020","journal-title":"Intensive Care Med"},{"key":"pone.0254167.ref014","article-title":"Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19","author":"A Bhimraj","year":"2020","journal-title":"Clin Infect 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Force","year":"2012","journal-title":"JAMA"},{"issue":"2","key":"pone.0254167.ref021","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1378\/chest.07-0617","article-title":"Comparison of the SpO2\/FIO2 ratio and the PaO2\/FIO2 ratio in patients with acute lung injury or ARDS","volume":"132","author":"TW Rice","year":"2007","journal-title":"Chest"},{"issue":"9","key":"pone.0254167.ref022","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1136\/thoraxjnl-2017-211280","article-title":"Severity scoring of lung oedema on the chest radiograph is associated with clinical outcomes in ARDS","volume":"73","author":"MA Warren","year":"2018","journal-title":"Thorax"},{"issue":"7","key":"pone.0254167.ref023","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1093\/aje\/kwj063","article-title":"The inconsistency of \"optimal\" cutpoints obtained using two criteria based on the receiver operating characteristic curve","volume":"163","author":"NJ Perkins","year":"2006","journal-title":"Am J Epidemiol"},{"key":"pone.0254167.ref024","doi-asserted-by":"crossref","first-page":"119251","DOI":"10.1016\/j.lfs.2021.119251","article-title":"Targeting RAGE to prevent SARS-CoV-2-mediated multiple organ failure: Hypotheses and perspectives","volume":"272","author":"S Chiappalupi","year":"2021","journal-title":"Life Sci"},{"issue":"16","key":"pone.0254167.ref025","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1001\/jama.2013.278477","article-title":"Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial","volume":"310","author":"A Morelli","year":"2013","journal-title":"JAMA"},{"issue":"5","key":"pone.0254167.ref026","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1038\/s41591-020-0869-5","article-title":"Temporal dynamics in viral shedding and transmissibility of COVID-19","volume":"26","author":"X He","year":"2020","journal-title":"Nat 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