{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:58:54Z","timestamp":1753891134325,"version":"3.41.2"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"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>The coronavirus disease 19 (COVID-19) is a disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that invades lung epithelial cells and can lead to severe respiratory failure. In this study, we evaluated whether Clara cell 16 kDa protein (CC16), a serum marker of lung alveolar cell damage, is predictive for disease severity. Patients suspected of SARS-CoV-2 infection were included in this study. Serum levels of Clara cell 16 kDa protein (CC16), soluble Fas Ligand, cytochrome C, thymus- and activation regulated chemokine (TARC) and of oxidate stress related proteins were analyzed. Clinical patient data were extracted from the Utrecht Patient Oriented Database. COVID-19 positive patients were divided in two groups according to disease severity. The mean day difference between COVID-19 diagnosis date and sampling date was +11 days. Concentrations of TARC were lower in COVID-19 positive versus COVID-19 negative patients (unpaired t-test, <jats:italic>p<\/jats:italic>=0.002). In addition, CC16 serum levels were significantly elevated in sera taken from patients that were admitted at the intensive care unit (ICU) (<jats:italic>p<\/jats:italic>=0.0082). In a matched cohort, sera taken prior to ICU admission (-3 days) contained higher CC16 levels (paired t-test, <jats:italic>p<\/jats:italic>=0.0072). Multivariable analyses adjusted for known risk factors (age, gender, blood counts, lactate dehydrogenase, c-reactive protein, underlying disease) showed that CC16 levels were independently associated to COVID-19 severity (interquartile-range, odds ratio 1.53, <jats:italic>p<\/jats:italic>=0.0102). In conclusion, our findings highlight CC16 as a promising biomarker for early identification of severe COVID19 cases, which could improve patient management and resource allocation.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1527377","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T06:41:56Z","timestamp":1743489716000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Clara cell 16 kDa protein: an important marker for COVID-19 severity"],"prefix":"10.3389","volume":"16","author":[{"given":"Tineke","family":"Kardol-Hoefnagel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bart","family":"Luijk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leon","family":"Reteig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saskia","family":"Haitjema","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen L.","family":"Leavis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henny G.","family":"Otten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1080\/17512433.2021.1902303","article-title":"Epidemiology, pathogenesis, clinical presentations, diagnosis and treatment of COVID-19: a review of current evidence","volume":"14","author":"Rahman","year":"2021","journal-title":"Expert Rev Clin Pharmacol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tmaid.2020.101623","article-title":"Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis","volume":"34","author":"Rodriguez-Morales","year":"2020","journal-title":"Travel Med Infect Dis"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.25822","article-title":"Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2: A systematic review and meta-analysis","volume":"92","author":"Cao","year":"2020","journal-title":"J Med Virol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/rmv.2146","article-title":"Predictors of COVID-19 severity: A literature review","volume":"31","author":"Gallo Marin","year":"2021","journal-title":"Rev Med Virol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1080\/10408363.2020.1770685","article-title":"Biomarkers associated with COVID-19 disease progression","volume":"57","author":"Ponti","year":"2020","journal-title":"Crit Rev Clin Lab Sci"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.857573","article-title":"Laboratory biomarkers for diagnosis and prognosis in COVID-19","volume":"13","author":"Battaglini","year":"2022","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-042921-123443","article-title":"Club cell secretory protein in lung disease: emerging concepts and potential therapeutics","volume":"74","author":"Martinu","year":"2023","journal-title":"Annu Rev Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.2016.1139084","article-title":"Club cell protein 16 (CC16) augmentation: A potential disease-modifying approach for chronic obstructive pulmonary disease (COPD)","volume":"20","author":"Laucho-Contreras","year":"2016","journal-title":"Expert Opin Ther Targets"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0168552","article-title":"Increased expression of CC16 in patients with idiopathic pulmonary fibrosis","volume":"11","author":"Buend\u00eda-Rold\u00e1n","year":"2016","journal-title":"PloS One"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/jcla.22262","article-title":"Diagnostic and prognostic values of Club cell protein 16 (CC16) in critical care patients with acute respiratory distress syndrome","volume":"32","author":"Lin","year":"2018","journal-title":"J Clin Lab Anal"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1037115","article-title":"Brief Research Report: Serum clara cell 16 kDa protein levels are increased in patients hospitalized for severe SARS-CoV-2 or sepsis infection","volume":"13","author":"Rohmann","year":"2022","journal-title":"Front Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2021.761299","article-title":"SP-D and CC-16 pneumoproteins\u2019 Kinetics and their predictive role during SARS-CoV-2 infection","volume":"8","author":"Tiezzi","year":"2021","journal-title":"Front Med (Lausanne)"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1643","DOI":"10.3390\/diagnostics11091643","article-title":"The potential of lung epithelium specific proteins as biomarkers for COVID-19-associated lung injury","volume":"11","author":"Almuntashiri","year":"2021","journal-title":"Diagnostics (Basel)"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2020.145145","article-title":"Serum CCL17 level becomes a predictive marker to distinguish between mild\/moderate and severe\/critical disease in patients with COVID-19","volume":"766","author":"Sugiyama","year":"2021","journal-title":"Gene"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1134\/s0006297920120068","article-title":"COVID-19 and oxidative stress","volume":"85","author":"Chernyak","year":"2020","journal-title":"Biochem (Mosc)"},{"key":"B16","doi-asserted-by":"publisher","first-page":"2177","DOI":"10.3390\/ijms22042177","article-title":"sFasL-the key to a riddle: immune responses in aging lung and disease","volume":"22","author":"Wallach-Dayan","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.947401","article-title":"Serum soluble Fas ligand is a severity and mortality prognostic marker for COVID-19 patients","volume":"13","author":"Saleki","year":"2022","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/cti2.1357","article-title":"Blunted sFasL signalling exacerbates TNF-driven neutrophil necroptosis in critically ill COVID-19 patients","volume":"10","author":"Schweizer","year":"2021","journal-title":"Clin Transl Immunol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/s12014-023-09394-0","article-title":"Mitochondria and cytochrome components released into the plasma of severe COVID-19 and ICU acute respiratory distress syndrome patients","volume":"20","author":"Chen","year":"2023","journal-title":"Clin Proteomics"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1515\/cclm.2007.009","article-title":"Linking laboratory and medication data: new opportunities for pharmacoepidemiological research","volume":"45","author":"ten Berg","year":"2007","journal-title":"Clin Chem Lab Med"},{"key":"B21","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-4757-3462-1","volume-title":"Regression modeling strategies: with applications to linear models, logistic regression, and survival analysis","author":"Harrell","year":"2001"},{"key":"B22","doi-asserted-by":"publisher","first-page":"00690-2020","DOI":"10.1183\/23120541.00690-2020","article-title":"Analysis of pathological changes in the epithelium in COVID-19 patient airways","volume":"7","author":"Yin","year":"2021","journal-title":"ERJ Open Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00713-0","article-title":"SARS-coV-2 pathogenesis","volume":"20","author":"Lamers","year":"2022","journal-title":"Nat Rev Microbiol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-02156-9","article-title":"Comorbidities, multimorbidity and COVID-19","volume":"29","author":"Russell","year":"2023","journal-title":"Nat Med"},{"key":"B25","doi-asserted-by":"publisher","first-page":"6078","DOI":"10.1038\/s41467-020-19967-4","article-title":"Cellular events of acute, resolving or progressive COVID-19 in SARS-CoV-2 infected non-human primates","volume":"11","author":"Fahlberg","year":"2020","journal-title":"Nat Commun"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2020-0011OC","article-title":"Rhinovirus-induced CCL17 and CCL22 in asthma exacerbations and differential regulation by STAT6","volume":"64","author":"Williams","year":"2021","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.3.1648","article-title":"Respiratory syncytial virus synergizes with Th2 cytokines to induce optimal levels of TARC\/CCL17","volume":"179","author":"Monick","year":"2007","journal-title":"J Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2003.12.007","article-title":"Serum thymus and activation-regulated chemokine (TARC) and cutaneous T cell- attracting chemokine (CTACK) levels in allergic diseases: TARC and CTACK are disease-specific markers for atopic dermatitis","volume":"113","author":"Hijnen","year":"2004","journal-title":"J Allergy Clin Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2016.11.038","article-title":"Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients","volume":"140","author":"Silkoff","year":"2017","journal-title":"J Allergy Clin Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.trim.2021.101495","article-title":"T helper type (Th1\/Th2) responses to SARS-CoV-2 and influenza A (H1N1) virus: From cytokines produced to immune responses","volume":"70","author":"Aleebrahim-Dehkordi","year":"2022","journal-title":"Transpl Immunol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"L14","DOI":"10.1152\/ajplung.00049.2022","article-title":"Chemokines, soluble PD-L1, and immune cell hyporesponsiveness are distinct features of SARS-CoV-2 critical illness","volume":"323","author":"Morrell","year":"2022","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.14336\/ad.2021.0709","article-title":"Regulatory T cells in COVID-19","volume":"12","author":"Wang","year":"2021","journal-title":"Aging Dis"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1515\/revneuro-2021-0047","article-title":"Triangle of cytokine storm, central nervous system involvement, and viral infection in COVID-19: the role of sFasL and neuropilin-1","volume":"33","author":"Saleki","year":"2022","journal-title":"Rev Neurosci"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2003.09.015","article-title":"Soluble form of Fas and Fas ligand in serum and bronchoalveolar lavage fluid of individuals infected with human T-lymphotropic virus type 1","volume":"98","author":"Sakamoto","year":"2004","journal-title":"Respir Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-022-00936-x","article-title":"T cell apoptosis characterizes severe Covid-19 disease","volume":"29","author":"Andr\u00e9","year":"2022","journal-title":"Cell Death Differ"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciad294","article-title":"Preexisting autoimmunity is associated with increased severity of coronavirus disease 2019: A retrospective cohort study using data from the national COVID cohort collaborative (N3C)","volume":"77","author":"Yadaw","year":"2023","journal-title":"Clin Infect Dis"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2022.10.013","article-title":"(SP-D) as a biomarker of SARS-CoV-2 infection","volume":"537","author":"Salvioni","year":"2022","journal-title":"Clin Chim Acta"},{"key":"B38","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1186\/s13054-024-05149-x","article-title":"A narrative review on lung injury: mechanisms, biomarkers, and monitoring","volume":"28","author":"Fan","year":"2024","journal-title":"Crit Care"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1527377\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T06:41:58Z","timestamp":1743489718000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1527377\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,1]]},"references-count":38,"alternative-id":["10.3389\/fimmu.2025.1527377"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1527377","relation":{},"ISSN":["1664-3224"],"issn-type":[{"type":"electronic","value":"1664-3224"}],"subject":[],"published":{"date-parts":[[2025,4,1]]},"article-number":"1527377"}}