{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T20:19:28Z","timestamp":1793305168956,"version":"4.5.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["20fk0108404h0001"],"award-info":[{"award-number":["20fk0108404h0001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004398","name":"Mitsubishi Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004398","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012016","name":"Nipponham Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012016","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010795","name":"Chugai Pharmaceutical","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010795","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Although an increase in neutrophil count has been observed in patients with coronavirus disease 2019 (COVID-19), the relationship between the systemic neutrophil transcriptome and clinical course of COVID-19 remains unclear. Hence, we examined the relationship between the clinical course and RNA sequencing analysis results in COVID-19 patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Peripheral blood samples were obtained from 28 patients with COVID-19-associated ARDS and 16 healthy controls. Bulk RNA sequencing was\u00a0performed, and clustering analysis was used to explore relationships between gene expression and clinical characteristics. In a separate cohort, neutrophils were isolated from the peripheral blood of five COVID-19 patients with ARDS for single-cell RNA sequencing to further characterize the neutrophil subpopulations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In bulk RNA sequencing analysis, COVID-19 patients with ARDS had elevated gene expression associated with neutrophils compared with healthy controls.Clustering analysis revealed no differences in the clinical characteristics of COVID-19 patients with ARDS. In the single-cell RNA sequencing analysis, clustering analysis showed that the patients were divided into two groups: those who could be weaned from the ventilator within 28 days and those who could not be weaned.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings indicate that differences in neutrophil gene expression may have important clinical implications. This study may support the exploratory identification of genomic factors, such as neutrophil gene expression, that are relevant to clinical parameters.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1620745","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T05:29:16Z","timestamp":1762406956000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Neutrophil gene expression in COVID-19 patients with acute respiratory distress syndrome"],"prefix":"10.3389","volume":"16","author":[{"given":"Hiroshi","family":"Ito","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masakazu","family":"Ishikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jumpei","family":"Yoshimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhei","family":"Sakakibara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuminori","family":"Sugihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisatake","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruhiko","family":"Hirata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Ogura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Oda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Okuzaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-020-0695-z","article-title":"The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2","volume":"5","author":"Gorbalenya","year":"2020","journal-title":"Nat Microbiol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2001017","article-title":"A novel coronavirus from patients with pneumonia in China, 2019","volume":"382","author":"Zhu","year":"2020","journal-title":"N Engl J Med"},{"key":"B3","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":"B4","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1007\/s00134-020-06294-x","article-title":"Clinical characteristics and day-90 outcomes of 4244 critically ill adults with COVID-19: a prospective cohort study","volume":"47","author":"Schmidt","year":"2021","journal-title":"Intensive Care Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.bj.2020.09.001","article-title":"Understanding the role of neutrophils in acute respiratory distress syndrome","volume":"44","author":"Yang","year":"2021","journal-title":"BioMed J"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01778","article-title":"Neutrophils: orchestrators of the Malignant phenotype","volume":"11","author":"Hsu","year":"2020","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1608077","article-title":"Acute respiratory distress syndrome","volume":"377","author":"Thompson","year":"2017","journal-title":"N Engl J Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.155055","article-title":"Atypical response to bacterial coinfection and persistent neutrophilic bronchoalveolar inflammation distinguish critical COVID-19 from influenza","volume":"7","author":"Cambier","year":"2022","journal-title":"JCI Insight"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3390\/cells9112374","article-title":"Single-cell transcriptome analysis highlights a role for neutrophils and inflammatory macrophages in the pathogenesis of severe COVID-19","volume":"9","author":"Shaath","year":"2020","journal-title":"Cells"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.resinv.2020.06.001","article-title":"COVID-19: role of neutrophil extracellular traps in acute lung injury","volume":"58","author":"Yaqinuddin","year":"2020","journal-title":"Respir Investig"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2588-y","article-title":"Longitudinal analyses reveal immunological misfiring in severe COVID-19","volume":"584","author":"Lucas","year":"2020","journal-title":"Nature"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-020-00823-5","article-title":"Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients","volume":"13","author":"Aschenbrenner","year":"2021","journal-title":"Genome Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3390\/cells11050847","article-title":"Severe COVID-19 shares a common neutrophil activation signature with other acute inflammatory states","volume":"11","author":"Schimke","year":"2022","journal-title":"Cells"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s00063-012-0126-x","article-title":"The Berlin definition: novel criteria and classification of ARDS","volume":"107","author":"Hecker","year":"2012","journal-title":"Med Klin Intensivmed Notfallmed"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199502093320601","article-title":"A comparison of four methods of weaning patients from mechanical ventilation","volume":"332","author":"Esteban","year":"1995","journal-title":"N Engl J Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1186\/s12985-022-01930-y","article-title":"Transcriptional differences between coronavirus disease 2019 and bacterial sepsis","volume":"19","author":"Ito","year":"2022","journal-title":"Virol J"},{"key":"B17","doi-asserted-by":"publisher","first-page":"R36","DOI":"10.1186\/gb-2013-14-4-r36","article-title":"TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions","volume":"14","author":"Kim","year":"2013","journal-title":"Genome Biol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: an efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: a Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"B20","doi-asserted-by":"publisher","first-page":"2847","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.998233","article-title":"Single-cell RNA-seq analysis identifies distinct myeloid cells in a case with encephalitis temporally associated with COVID-19 vaccination","volume":"14","author":"Ishikawa","year":"2023","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Hao","year":"2021","journal-title":"Cell"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1419","DOI":"10.1016\/j.cell.2020.08.001","article-title":"Severe COVID-19 is marked by a dysregulated myeloid cell compartment","volume":"182","author":"Schulte-Schrepping","year":"2020","journal-title":"Cell"},{"key":"B24","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1186\/s12859-019-3167-9","article-title":"SCOPIT: sample size calculations for single-cell sequencing experiments","volume":"20","author":"Davis","year":"2019","journal-title":"BMC Bioinf"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e6","DOI":"10.1016\/j.jinf.2020.04.002","article-title":"Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19","volume":"81","author":"Liu","year":"2020","journal-title":"J Infect"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e844","DOI":"10.1002\/hsr2.844","article-title":"Neutrophil-to-lymphocyte ratio as a predictor of clinical outcomes in critically ill COVID-19 patients: a retrospective observational study","volume":"5","author":"Ali","year":"2022","journal-title":"Health Sci Rep"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-00796-1","article-title":"Hypertension delays viral clearance and exacerbates airway hyperinflammation in patients with COVID-19","volume":"39","author":"Trump","year":"2021","journal-title":"Nat Biotechnol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"397","DOI":"10.4037\/15597768-2007-4008","article-title":"How to withdraw mechanical ventilation: a systematic review of the literature","volume":"18","author":"Campbell","year":"2007","journal-title":"AACN Adv Crit Care"},{"key":"B29","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.jcrc.2018.08.023","article-title":"Predictive factors of weaning from mechanical ventilation and extubation outcome: a systematic review","volume":"48","author":"Baptistella","year":"2018","journal-title":"J Crit Care"},{"key":"B30","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.thromres.2020.05.006","article-title":"The clinical implication of dynamic neutrophil to lymphocyte ratio and D-dimer in COVID-19: a retrospective study in Suzhou China","volume":"192","author":"Fu","year":"2020","journal-title":"Thromb Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.138999","article-title":"Neutrophil extracellular traps in COVID-19","volume":"5","author":"Zuo","year":"2020","journal-title":"JCI Insight"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202149680","article-title":"Alterations of blood monocyte subset distribution and surface phenotype are linked to infection severity in COVID-19 inpatients","volume":"52","author":"Haschka","year":"2022","journal-title":"Eur J Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2022.100779","article-title":"Longitudinal characterization of circulating neutrophils uncovers phenotypes associated with severity in hospitalized COVID-19 patients","volume":"3","author":"LaSalle","year":"2022","journal-title":"Cell Rep Med"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0141-8","article-title":"Heterogeneity of neutrophils","volume":"19","author":"Ng","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3390\/cells10010151","article-title":"Significance of NETs formation in COVID-19","volume":"10","author":"Janiuk","year":"2021","journal-title":"Cells"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/jlb.66.4.549","article-title":"S100A8: emerging functions and regulation","volume":"66","author":"Passey","year":"1999","journal-title":"J Leukoc Biol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3390\/cells11233944","article-title":"Role of S100A8\/A9 in platelet-neutrophil complex formation during acute inflammation","volume":"11","author":"Revenstorff","year":"2022","journal-title":"Cells"},{"key":"B38","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/j.chom.2020.12.016","article-title":"Induction of alarmin S100A8\/A9 mediates activation of aberrant neutrophils in the pathogenesis of COVID-19","volume":"29","author":"Guo","year":"2021","journal-title":"Cell Host Microbe"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.26.753","article-title":"Calprotectin (S100A8\/S100A9), an inflammatory protein complex from neutrophils with a broad apoptosis-inducing activity","volume":"26","author":"Yui","year":"2003","journal-title":"Biol Pharm Bull"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202101013","article-title":"S100A8 may govern hyper-inflammation in severe COVID-19","volume":"35","author":"Deguchi","year":"2021","journal-title":"FASEB J"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1620745\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T11:36:29Z","timestamp":1762428989000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1620745\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,6]]},"references-count":40,"alternative-id":["10.3389\/fimmu.2025.1620745"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1620745","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,6]]},"article-number":"1620745"}}