{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:25:01Z","timestamp":1790745901256,"version":"4.1.0"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T00:00:00Z","timestamp":1659052800000},"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:p>Uncontrolled release of damage-associated molecular patterns (DAMPs) is suggested to be a major trigger for the dysregulated host immune response that leads to severe COVID-19. Cold-inducible RNA-binding protein (CIRP), is a newly identified DAMP that aggravates inflammation and tissue injury, and induces respiratory failure in sepsis. Whether CIRP contributes to the pathogenesis of respiratory failure in COVID-19 has not yet been explored.<\/jats:p><jats:sec><jats:title>Aim<\/jats:title><jats:p>To investigate if the concentration of extracellular CIRP (eCIRP) in serum associates with respiratory failure and lung involvement by chest computed tomography (CT) in COVID-19.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Herein we report a prospective observational study of\u00a0patients with COVID-19 included at two University Hospitals in Sweden between April 2020 and May 2021. Serum from hospitalized patients in \u00d6rebro (N=97) were used to assess the association between eCIRP and the level of respiratory support and its correlation with pulmonary involvement on chest CT and inflammatory biomarkers. A cohort of hospitalized and non-hospitalized patients from Ume\u00e5 (N=78) was used as an external validation cohort. The severity of disease was defined according to the highest degree of respiratory support; mild disease (no oxygen), non-severe hypoxemia (conventional oxygen or high-flow nasal oxygen, HFNO &amp;lt;50% FiO2), and severe hypoxemia (HFNO \u226550% FiO2, mechanical ventilation). Unadjusted and adjusted linear regression was used to evaluate peak eCIRP day 0-4 in respect to severity, age, sex, Charlson comorbidity score, symptom duration, and BMI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Peak eCIRP concentrations were higher in patients with severe hypoxemia and were independently associated with the degree of respiratory support in both cohorts (\u00d6rebro; <jats:italic>p<\/jats:italic>=0.01, Ume\u00e5; <jats:italic>p<\/jats:italic>&amp;lt;0.01).\u00a0The degree of pulmonary involvement measured by CT correlated with eCIRP, r<jats:sub>s<\/jats:sub>=0.30, <jats:italic>p<\/jats:italic>&amp;lt;0.01 (n=97).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>High serum levels of eCIRP are associated with acute respiratory failure in COVID-19. Experimental studies are needed to determine if treatments targeting eCIRP reduces the risk of acute respiratory failure in COVID-19.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.945603","type":"journal-article","created":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T14:35:05Z","timestamp":1659105305000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Serum concentration of extracellular cold-inducible RNA-binding protein is associated with respiratory failure in COVID-19"],"prefix":"10.3389","volume":"13","author":[{"given":"Felix","family":"Schagatay","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klara","family":"Diamant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mats","family":"Lid\u00e9n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Edin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Athlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olof","family":"Hultgren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clas","family":"Ahlm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattias N. E.","family":"Forsell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Savilampi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Normark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Lange","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Cajander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,29]]},"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":"10.1001\/jama.2020.2648","article-title":"Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72314 cases from the Chinese center for disease control and prevention","volume":"323","author":"Wu","year":"2020","journal-title":"JAMA"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2521-4","article-title":"Factors associated with COVID-19-related death using OpenSAFELY","volume":"584","author":"Williamson","year":"2020","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","first-page":"19","DOI":"10.15585\/mmwr.mm7101a4","article-title":"Risk factors for severe COVID-19 outcomes among persons aged \u226518 years who completed a primary COVID-19 vaccination series - 465 health care facilities, united states, December 2020-October 2021","volume":"71","author":"Yek","year":"2022","journal-title":"MMWR Morb Mortal Wkly Rep"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2200121","DOI":"10.2807\/1560-7917.ES.2022.27.9.2200121","article-title":"Risk of severe COVID-19 from the delta and omicron variants in relation to vaccination status, sex, age and comorbidities \u2013 surveillance results from southern Sweden, July 2021 to January 2022","volume":"27","author":"Kahn","year":"2022","journal-title":"Eurosurveillance"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0247461","article-title":"Population risk factors for severe disease and mortality in COVID-19: A global systematic review and meta-analysis","volume":"16","author":"Booth","year":"2021","journal-title":"PLoS One"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(21)00218-6","article-title":"The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity","volume":"9","author":"Osuchowski","year":"2021","journal-title":"Lancet Respir Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"114847","DOI":"10.1016\/j.bcp.2021.114847","article-title":"The impact of DAMP-mediated inflammation in severe COVID-19 and related disorders","volume":"195","author":"Parthasarathy","year":"2022","journal-title":"Biochem Pharmacol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.619221","article-title":"Extracellular RNA as a versatile DAMP and alarm signal that influences leukocyte recruitment in inflammation and infection","volume":"8","author":"Preissner","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"41363","DOI":"10.1038\/srep41363","article-title":"Cold-inducible RNA-binding protein (CIRP) causes sepsis-associated acute lung injury via induction of endoplasmic reticulum stress","volume":"7","author":"Khan","year":"2017","journal-title":"Sci Rep"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0266163","article-title":"The role of eCIRP in bleomycin-induced pulmonary fibrosis in mice","volume":"17","author":"Bolourani","year":"2022","journal-title":"PloS One"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3368","article-title":"Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis","volume":"19","author":"Qiang","year":"2013","journal-title":"Nat Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1083\/jcb.137.4.899","article-title":"A glycine-rich RNA-binding protein mediating cold-inducible suppression of mammalian cell growth","volume":"137","author":"Nishiyama","year":"1997","journal-title":"J Cell Biol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.01026","article-title":"Oxygen-regulated expression of the RNA-binding proteins RBM3 and CIRP by a HIF-1-independent mechanism","volume":"117","author":"Wellmann","year":"2004","journal-title":"J Cell Sci"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.3MIR1118-443R","article-title":"Extracellular CIRP (eCIRP) and inflammation","volume":"106","author":"Aziz","year":"2019","journal-title":"J Leukoc Biol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0137721","article-title":"The cold-inducible RNA-binding protein (CIRP) level in peripheral blood predicts sepsis outcome","volume":"10","author":"Zhou","year":"2015","journal-title":"PLoS One"},{"key":"B17","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1186\/s12931-020-01457-2","article-title":"Cold-inducible RNA-binding protein might determine the severity and the presences of major\/minor criteria for severe community-acquired pneumonia and best predicted mortality","volume":"21","author":"Guo","year":"2020","journal-title":"Respir Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2017.06.002","article-title":"Increased admission serum cold-inducible RNA-binding protein concentration is associated with prognosis of severe acute pancreatitis","volume":"471","author":"Gong","year":"2017","journal-title":"Clin Chim Acta"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/1756-185X.12892","article-title":"Serum and synovial fluid concentrations of cold-inducible RNA-binding protein in patients with rheumatoid arthritis","volume":"21","author":"Yoo","year":"2018","journal-title":"Int J Rheum Dis"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-0471","article-title":"Stress response protein cirp links inflammation and tumorigenesis in colitis-associated cancer","volume":"74","author":"Sakurai","year":"2014","journal-title":"Cancer Res"},{"key":"B21","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1097\/SHK.0000000000000251","article-title":"Blocking cold-inducible RNA-binding protein protects liver from ischemia-reperfusion injury","volume":"43","author":"Godwin","year":"2015","journal-title":"Shock"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1080\/23744235.2021.1910727","article-title":"Visual scoring of chest CT at hospital admission predicts hospitalization time and intensive care admission in covid-19","volume":"53","author":"Ahlstrand","year":"2021","journal-title":"Infect Dis (Lond)"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1097\/01.ID9.0000733572.40970.6c","article-title":"Changes of damage associated molecular patterns in COVID-19 patients","volume":"1","author":"Fan","year":"2021","journal-title":"Infect Dis Immunity"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.17800","article-title":"Cold inducible RNA binding protein is involved in chronic hypoxia induced neuron apoptosis by down-regulating HIF-1alpha expression and regulated by microRNA-23a","volume":"13","author":"Chen","year":"2017","journal-title":"Int J Biol Sci"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s00330-020-07033-y","article-title":"Chest CT score in COVID-19 patients: correlation with disease severity and short-term prognosis","volume":"30","author":"Francone","year":"2020","journal-title":"Eur Radiol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"26571","DOI":"10.1038\/srep26571","article-title":"Cold-inducible RNA-binding protein causes endothelial dysfunction via activation of Nlrp3 inflammasome","volume":"6","author":"Yang","year":"2016","journal-title":"Sci Rep"},{"key":"B27","doi-asserted-by":"publisher","first-page":"6252","DOI":"10.1038\/s41598-019-42762-1","article-title":"Cold-inducible RNA-binding protein induces neutrophil extracellular traps in the lungs during sepsis","volume":"9","author":"Ode","year":"2019","journal-title":"Sci Rep"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2101004","article-title":"Active release of eCIRP via gasdermin d channels to induce inflammation in sepsis","volume":"208","author":"Tan","year":"2022","journal-title":"J Immunol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/s41420-021-00428-w","article-title":"SARS-CoV-2 engages inflammasome and pyroptosis in human primary monocytes","volume":"7","author":"Ferreira","year":"2021","journal-title":"Cell Death Discovery"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.721970","article-title":"Extracellular CIRP induces an inflammatory phenotype in pulmonary fibroblasts via TLR4","volume":"12","author":"Bolourani","year":"2021","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.579157","article-title":"Extracellular CIRP induces inflammation in alveolar type II cells via TREM-1","volume":"8","author":"Tan","year":"2020","journal-title":"Front Cell Dev Biol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.945603\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T14:35:08Z","timestamp":1659105308000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.945603\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,29]]},"references-count":31,"alternative-id":["10.3389\/fimmu.2022.945603"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.945603","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,29]]},"article-number":"945603"}}