{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T01:56:55Z","timestamp":1793066215627,"version":"4.5.0"},"reference-count":29,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T00:00:00Z","timestamp":1630627200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["FO 354\/14\u20101"],"award-info":[{"award-number":["FO 354\/14\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Infection with the novel coronavirus SARS\u2013CoV\u20102 triggers severe illness with high mortality in a subgroup of patients. Such a critical course of COVID\u201019 is thought to be associated with the development of cytokine storm, a condition seen in macrophage activation syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (HLH). However, specific data demonstrating a clear association of cytokine storm with severe COVID\u201019 are still lacking. The aim of this study was to directly address whether immune activation in COVID\u201019 does indeed mimic the conditions found in these classic cytokine storm syndromes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Levels of 22 biomarkers were quantified in serum samples from patients with COVID\u201019 (n = 30 patients, n = 83 longitudinal samples in total), patients with secondary HLH\/MAS (n = 50), and healthy controls (n = 9). Measurements were performed using bead array assays and single\u2010marker enzyme\u2010linked immunosorbent assay. Serum biomarker levels were assessed for correlations with disease outcome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In patients with secondary HLH\/MAS, we observed pronounced activation of the interleukin\u201018 (IL\u201018)\u2013interferon\u2010\u03b3 axis, increased serum levels of IL\u20101 receptor antagonist, intercellular adhesion molecule 1, and IL\u20108, and strongly reduced levels of soluble Fas ligand in the course of SARS\u2013CoV\u20102 infection. These observations appeared to discriminate immune dysregulation in critical COVID\u201019 from the well\u2010recognized characteristics of other cytokine storm syndromes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Serum biomarker profiles clearly separate COVID\u201019 from MAS or secondary HLH in terms of distinguishing the severe systemic hyperinflammation that occurs following SARS\u2013CoV\u20102 infection. These findings could be useful in determining the efficacy of drugs targeting key molecules and pathways specifically associated with systemic cytokine storm conditions in the treatment of COVID\u201019.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41763","type":"journal-article","created":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T18:09:28Z","timestamp":1619028568000},"page":"1791-1799","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Discrimination of COVID\u201019 From Inflammation\u2010Induced Cytokine Storm Syndromes Using Disease\u2010Related Blood Biomarkers"],"prefix":"10.1002","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0638-2949","authenticated-orcid":false,"given":"Christoph","family":"Kessel","sequence":"first","affiliation":[{"name":"Department of Pediatric Rheumatology and Immunology University Children's Hospital Muenster  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Vollenberg","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology, Endocrinology and Clinical Infectiology University Hospital Muenster  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Masjosthusmann","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics University Children's Hospital Muenster  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9247-4729","authenticated-orcid":false,"given":"Claas","family":"Hinze","sequence":"additional","affiliation":[{"name":"Department of Pediatric Rheumatology and Immunology University Children's Hospital Muenster  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helmut","family":"Wittkowski","sequence":"additional","affiliation":[{"name":"Department of Pediatric Rheumatology and Immunology University Children's Hospital Muenster  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"France","family":"Debaugnies","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Research, Centre Hospitalier Universitaire Brugmann Universit\u00e9 Libre de Bruxelles, Brussels, Belgium and Medical Biology Department, Laboratoire National de Sant\u00e9  Dudelange Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole","family":"Nagant","sequence":"additional","affiliation":[{"name":"Immunology Department, LHUB\u2010ULB Universit\u00e9 Libre de Bruxelles  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Corazza","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Research Centre Hospitalier Universitaire Brugmann and Immunology Department LHUB\u2010ULB, Universit\u00e9 Libre de Bruxelles  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"V\u00e9ly","sequence":"additional","affiliation":[{"name":"Aix Marseille Universit\u00e9 CNRS INSERM CIML and Assistance Publique des H\u00f4pitaux de Marseille H\u00f4pital de la Timone, Immunology, Marseille Immunopole  Marseilles France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Kaplanski","sequence":"additional","affiliation":[{"name":"Assistance Publique\u2010H\u00f4pitaux de Marseille Centre Hospitalier Universitaire Conception Service de M\u00e9decine Interne et Immunologie Clinique Aix\u2010Marseille Universit\u00f4 and Center for Cardiovascular Research and Nutrition Aix\u2010Marseille Universit\u00e9, INSERM UMRS1263  Marseilles France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Girard\u2010Guyonvarc\u2019h","sequence":"additional","affiliation":[{"name":"Division of Rheumatology Department of Medicine, University Hospital of GenevaDepartment of Medicine, University Hospital of Geneva University of Geneva  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cem","family":"Gabay","sequence":"additional","affiliation":[{"name":"Division of Rheumatology Department of Medicine, University Hospital of GenevaDepartment of Medicine, University Hospital of Geneva University of Geneva  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hartmut","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology, Endocrinology and Clinical Infectiology University Hospital Muenster  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1946-3916","authenticated-orcid":false,"given":"Dirk","family":"Foell","sequence":"additional","affiliation":[{"name":"Department of Pediatric Rheumatology and Immunology University Children's Hospital Muenster  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2757-4755","authenticated-orcid":false,"given":"Phil\u2010Robin","family":"Tepasse","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology, Endocrinology and Clinical Infectiology University Hospital Muenster  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,9,3]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30628-0"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00119"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41285"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2020.3313"},{"key":"e_1_2_6_6_1","first-page":"2526","article-title":"Acute respiratory distress syndrome: the Berlin Definition","volume":"307","author":"Force AD","year":"2012","journal-title":"JAMA"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019003664"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-020-00950-z"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kew300"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.021908.132612"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-209020"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2020-219448"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1051-9"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc6027"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.144455"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.140329"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.11.5860"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-020-00454-7"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.154.3.8810593"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(20)30404-5"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1911326"},{"issue":"4","key":"e_1_2_6_22_1","article-title":"Emapalumab (anti\u2010interferon\u2010gamma monoclonal antibody) in patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA)","volume":"72","author":"De Benedetti F","year":"2020","journal-title":"Arthritis Rheumatol"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(20)30556-7"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-020-03364-w"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40498"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2009017117"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(20)30127-2"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.05.002"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2020.102726"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.17021"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.41763","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/art.41763","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.41763","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T11:46:44Z","timestamp":1759924004000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.41763"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,3]]},"references-count":29,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2021,10]]}},"alternative-id":["10.1002\/art.41763"],"URL":"https:\/\/doi.org\/10.1002\/art.41763","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,3]]},"assertion":[{"value":"2020-11-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-04-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-09-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}