{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T01:53:51Z","timestamp":1777946031240,"version":"3.51.4"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T00:00:00Z","timestamp":1626998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004391","name":"China Medical University Hospital","doi-asserted-by":"publisher","award":["DMR-110-021"],"award-info":[{"award-number":["DMR-110-021"]}],"id":[{"id":"10.13039\/501100004391","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012544","name":"China Medical University, Taiwan","doi-asserted-by":"publisher","award":["1095310A"],"award-info":[{"award-number":["1095310A"]}],"id":[{"id":"10.13039\/501100012544","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 107-2314-B-039-053-MY3"],"award-info":[{"award-number":["MOST 107-2314-B-039-053-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Hyperinflammation with dysregulated production of galectins and cytokines may develop in COVID-19 or adult-onset Still\u2019s disease (AOSD). Given the similar clinical features in both diseases, it is necessary to identify biomarkers that can differentiate COVID-19 from AOSD. However, the related data remain scarce currently.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this cross-sectional study, plasma levels of galectin-3, galectin-9, and soluble TIM-3 (sTIM-3) were determined by ELISA in 55 COVID-19 patients (31 non-severe and 24 severe), 23 active AOSD patients, and 31 healthy controls (HC). The seropositivity for SARS-CoV-2 was examined using an immunochromatographic assay, and cytokine profiles were determined with the MULTIPLEX platform.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Significantly higher levels of galectin-3, galectin-9, IL-1\u03b2, IL-1Ra, IL-10, IFN-\u03b12, IL-6, IL-18, and TNF-\u03b1 were observed in severe COVID-19 and active AOSD patients compared with HC (all p&amp;lt;0.001). AOSD, but not COVID-19, showed significantly higher IFN-\u03b3 and IL-17A compared with HC (both p&amp;lt;0.01). Moreover, active AOSD patients had 68-fold higher IL-18 levels and 5-fold higher ferritin levels than severe COVID-19 patients (both p&amp;lt;0.001). IL-18 levels at the cut-off value 190.5pg\/mL had the highest discriminative power for active AOSD and severe COVID-19, with AUC 0.948, sensitivity 91.3%, specificity 95.8%, and accuracy of 91.5% (p&amp;lt;0.005). Multivariate regression analysis revealed IL-18 as a significant predictor of active AOSD (p&amp;lt;0.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Active AOSD patients share features of hyperinflammation and cytokine storm with severe COVID-19 patients but possess a distinct cytokine profile, including elevated IL-18, IL-6, IFN-\u03b3, and IL-17A. IL-18 is a potential discriminator between AOSD and COVID-19 and may significantly predict active AOSD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.719544","type":"journal-article","created":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T12:55:13Z","timestamp":1627044913000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":35,"title":["Interleukin-18 Is a Potential Biomarker to Discriminate Active Adult-Onset Still\u2019s Disease From COVID-19"],"prefix":"10.3389","volume":"12","author":[{"given":"Po-Ku","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joung-Liang","family":"Lan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Po-Hao","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jye-Lin","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ching-Kun","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ni","family":"Tien","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui-Ju","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Der-Yuan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","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":"Huang","year":"2020","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/CM9.0000000000000824","article-title":"Clinical Characteristics of Coronavirus Disease 2019 in China","volume":"382","author":"Guan","year":"2020","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01648","article-title":"Cytokine Storm in COVID-19-Immunopathological Mechanisms, Clinical Considerations, and Therapeutic Approaches: The Reprogram Consortium Position Paper","volume":"11","author":"Bhaskar","year":"2020","journal-title":"Front Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01708","article-title":"Cytokine Storm in COVID-19: The Current Evidence and Treatment Strategies","volume":"11","author":"Tang","year":"2020","journal-title":"Front Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.668507","article-title":"Interleukin-6, CXCL10 and Infiltrating Macrophages in COVID-19-related Cytokine Storm: Not One for All But All for One","volume":"12","author":"Coperchini","year":"2021","journal-title":"Front Immunol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"e20201707","DOI":"10.1084\/jem.20201707","article-title":"Inflammasomes Are Activated in Response to SARS-CoV-2 Infection and Are Associated With COVID-19 Severity in Patients","volume":"218","author":"Rodrigues","year":"2021","journal-title":"J Exp Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.7150\/thno.49713","article-title":"Immunopathogenesis and Treatment of Cytokines Storm in COVID-19","volume":"11","author":"Kim","year":"2021","journal-title":"Theranostics"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.26232","article-title":"The Cytokine Storm and COVID-19","volume":"93","author":"Hu","year":"2021","journal-title":"J Med Virol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.589095","article-title":"Cytokine Storm: The Primary Determinant for the Pathophysiological Evolution of COVID-19 Deterioration","volume":"12","author":"Chen","year":"2021","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.666223","article-title":"Profile of Circulatory Cytokines and Chemokines in Human Coronaviruses: A Systemic Review and Meta-Analysis","volume":"12","author":"Zawawi","year":"2021","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2015.01.007","article-title":"Swizing the Clinical Presentation in Adult Onset Still\u2019s Disease. An Extensive Literature Reviews","volume":"14","author":"Narula","year":"2015","journal-title":"Autoimmun Rev"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3109\/07853890.2014.971052","article-title":"Adult-Onset Still\u2019s Disease-Pathogenesis, Clinical Manifestations, and New Treatment Options","volume":"22","author":"Kadavath","year":"2015","journal-title":"Ann Med"},{"key":"B13","article-title":"Clinical Features and Current Treatments of Adult-Onset Still\u2019s Disease: A Multicenter Survey of 517 Patients in China","author":"Hu","year":"2019","journal-title":"Clin Exp Rheumatol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2015.11.002","article-title":"Macrophage Activation Syndrome Complicating Adult Onset Still\u2019s Disease: A Single Center Case Series and Comparison With Literature","volume":"45","author":"Lenert","year":"2016","journal-title":"Semin Arthritis Rheumatol"},{"key":"B15","article-title":"Serum Cytokine Profiles in Patients With Adult Onset Still\u2019s Disease","volume":"30","author":"Choi","year":"2003","journal-title":"J Rheumatol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200107)44:7<1716::AID-ART298>3.0.CO;2-I","article-title":"Interleukin-18 as a Novel Diagnostic Marker and Indicator of Disease Severity in Adult-Onset Still\u2019s Disease","volume":"44","author":"Kawaguchi","year":"2001","journal-title":"Arthritis Rheumatol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keq284","article-title":"Potential Role of Th17 Cells in the Pathogenesis of Adult-Onset Still\u2019s Disease","volume":"49","author":"Chen","year":"2010","journal-title":"Rheumatol (Oxford)"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-018-0081-x","article-title":"Mechanisms, Biomarkers and Targets for Adult-Onset Still\u2019s Disease","volume":"14","author":"Feist","year":"2018","journal-title":"Nat Rev Rheumatol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.161354","article-title":"Elevated Expression of the NLRP3 Inflammasome and Its Correlation With Disease Activity in Adult-Onset Still Disease","volume":"44","author":"Hsieh","year":"2017","journal-title":"J Rheumatol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.111549","article-title":"Beneficial Effect of Interleukin 1 Inhibition With Anakinra in Adult-Onset Still\u2019s Disease. An Open, Randomized, Multicenter Study","volume":"39","author":"Nordstr\u00f6m","year":"2012","journal-title":"J Rheumatol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/art.38398","article-title":"Efficacy of Tocilizumab in Conventional Treatment-Refractory Adult-Onset Still\u2019s Disease: Multicenter Retrospective Open-Label Study of Thirty-Four Patients","volume":"66","author":"Ortiz-Sanju\u00e1n","year":"2014","journal-title":"Arthritis Rheumatol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2017-212608","article-title":"Open-Label, Multicentre, Dose-Escalating, Phase II Clinical Trial on the Safety and Efficacy of Tadekining Alfa (IL-18BP) in Adult-Onset Still\u2019s Disease","volume":"77","author":"Gabay","year":"2018","journal-title":"Ann Rheum Dis"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2020.102573","article-title":"Covid-19 Gone Bad: A New Character in the Spectrum of the Hyperferritinemic Syndrome","volume":"19","author":"Colafrancesco","year":"2020","journal-title":"Autoimmun Rev"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2008.11.009","article-title":"The Immunological Potential of Galectin-1 and -3","volume":"8","author":"Dhirapong","year":"2009","journal-title":"Autoimmun Rev"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2009.00794.x","article-title":"The Regulation of Inflammation by Galectin-3","volume":"230","author":"Henderson","year":"2009","journal-title":"Immunol Rev"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2009.00790.x","article-title":"Galectins in Innate Immunity: Dual Functions of Host Soluble Beta-Galactoside-Binding Lectins as Damage-Associated Molecular Patterns (Damps) and as Receptors for Pathogen-Associated Molecular Patterns (Pamps)","volume":"230","author":"Sato","year":"2009","journal-title":"Immunol Rev"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1078","DOI":"10.12688\/f1000research.25979.2","article-title":"Immunopathology of galectin-3: An Increasingly Promising Target in COVID-19","volume":"9","author":"Caniglia","year":"2020","journal-title":"F1000Res"},{"key":"B28","doi-asserted-by":"publisher","first-page":"3434","DOI":"10.1038\/s41467-020-17292-4","article-title":"Marked T Cell Activation, Senescence, Exhaustion and Skewing Towards TH17 in Patients With COVID19 Pneumonia","volume":"11","author":"De Biasi","year":"2020","journal-title":"Nat Commun"},{"key":"B29","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1002\/JLB.3COVR0520-272R","article-title":"Cytokine Storm and Leukocyte Changes in Mild Versus Severe SARS-CoV-2 Infection: Review of 3939 COVID-19 Patients in China and Emerging Pathogenesis and Therapy Concepts","volume":"108","author":"Wang","year":"2020","journal-title":"J Leukoc Biol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-020-04946-3","article-title":"Elevated Plasma Galectin-3 Levels and Their Correlation With Disease Activity in Adult-Onset Still\u2019s Disease","volume":"39","author":"Chen","year":"2020","journal-title":"Clin Rheumatol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.clim.2008.01.006","article-title":"Galectin-9 Suppresses the Generation of Th17, Promotes the Induction of Regulatory T Cells, and Regulates Experimental Autoimmune Arthritis","volume":"127","author":"Seki","year":"2008","journal-title":"Clin Immunol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/82_2010_84","article-title":"TIM-3 and Its Regulatory Role in Immune Responses","volume":"350","author":"Zhu","year":"2011","journal-title":"Curr Top Microbiol Immunol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1186\/s13075-020-02263-3","article-title":"Elevated Serum Levels of Checkpoint Molecules in Patients With Asult Still\u2019s Disease","volume":"22","author":"Fujita","year":"2020","journal-title":"Arthritis Res Thera"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-020-00571-1","article-title":"Immune Cartography of Macrophage Activation Syndrome in the COVID-19 Era","volume":"17","author":"McGonagle","year":"2021","journal-title":"Nat Rev Rheumatol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.603389","article-title":"Cytokine Storm in Coronavirus Disease 2019 and Adult-Onset Still\u2019s Disease: Similarities and Differencies","volume":"11","author":"Meng","year":"2021","journal-title":"Front Immunol"},{"key":"B36","unstructured":"Press Releases2021"},{"key":"B37","unstructured":"Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (Covid-19)2020"},{"key":"B38","article-title":"Preliminary Criteria for Classification of Adult Still\u2019s Disease","volume":"19","author":"Yamaguchi","year":"1992","journal-title":"J\u00a0Rheumatol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.100247","article-title":"Clinical Manifestations But Not Cytokine Profiles Differentiate Adult-Onset Still\u2019s Disease and Sepsis","volume":"37","author":"Rau","year":"2010","journal-title":"J Rheumatol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.181058","article-title":"Neutrophil Extracellular Traps may Contribute to the Pathogenesis in Adult-Onset Still\u2019s Disease","volume":"46","author":"Ahn","year":"2019","journal-title":"J Rheumatol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2020.102473","article-title":"Characteristics and Prognostic Factors of Disease Severity in Patients With COVID-19: The Beijing Experience","volume":"112","author":"Sun","year":"2020","journal-title":"J Autoimmun"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s10096-013-1919-4","article-title":"Circulating Galectin-3 in Infections and Noninfectious Inflammatory Diseases","volume":"32","author":"Ten Oever","year":"2013","journal-title":"Eur J Clin Microbiol Infect Dis"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(20)30127-2","article-title":"Interleukin-1 Blockade With High-Dose Anakinra in Patients With COVID-19, Acute Respiratory Distress Syndrome, and Hyperinflammation: A Retrospective Cohort Study","volume":"2","author":"Cavalli","year":"2020","journal-title":"Lancet Rheumatol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"e139834","DOI":"10.1172\/jci.insight.139834","article-title":"Longitudinal COVID-19 Profiling Associates IL-1RA and IL-10 With Disease Severity and RANTES With Mild Disease","volume":"5","author":"Zhao","year":"2020","journal-title":"JCI Insight"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2020.102568","article-title":"Tocilizumab for the Treatment of Severe COVID-19 Pneumonia With Hyperinflammatory Syndrome and Acute Respiratory Failure: A Single Center Study of 100 Patients in Brescia, Italy","volume":"19","author":"Toniati","year":"2020","journal-title":"Autoimmun Rev"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1080\/14397595.2017.1416924","article-title":"Efficacy and Safety of Tocilizumab With Inhibition of Interleukin-6 in Adult-Onset Still\u2019s Disease: A Meta-Analysis","volume":"28","author":"Ma","year":"2018","journal-title":"Mod Rheumatol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD013881","article-title":"Interleukin-6 Blocking Agents for Treating COVID-19: A Living Systemic Review","volume":"3","author":"Ghosn","year":"2021","journal-title":"Cochrane Database Syst Rev"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1186\/s41927-019-0053-z","article-title":"Comparative Study of Interleukin-18 (Il-18) Serum Levels in Adult Onset Still\u2019s Disease (AOSD) and Systemic Onset Juvenile Idiopathic Arthritis (sJIA) and Its Use as a Biomarker for Diagnosis and Evaluation of Disease Activity","volume":"3","author":"Kudela","year":"2019","journal-title":"BMC Rheumatol"},{"key":"B49","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1186\/s13075-020-02200-4","article-title":"Interleukin-18 and Fibroblast Growth Factor 2 in Combination Is a Useful Diagnostic Biomarker to Distinguish Adult-Onset Still\u2019s Disease From Sepsis","volume":"22","author":"Koga","year":"2020","journal-title":"Arthritis Res Thera"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1111\/cei.13069","article-title":"Ferritin Is Essential in Modulating Inflammation","volume":"191","author":"Sharif","year":"2018","journal-title":"Clin Exp Immunol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2020-217618","article-title":"Severe COVID-19 and Related Hyperferritinaemia: More Than an Innocent Bystander","volume":"79","author":"Ruscitti","year":"2020","journal-title":"Ann Rheum Dis"},{"key":"B52","doi-asserted-by":"publisher","first-page":"e1005973","DOI":"10.1371\/journal.ppat.1005973","article-title":"Il-1\u03b2\/Il-6\/CRP and IL-18\/ferritin: Distinct Inflammatory Programss in Infections","volume":"12","author":"Slaats","year":"2016","journal-title":"PloS Pathog"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.719544\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T12:55:20Z","timestamp":1627044920000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.719544\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,23]]},"references-count":52,"alternative-id":["10.3389\/fimmu.2021.719544"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.719544","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,23]]},"article-number":"719544"}}