{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T04:46:06Z","timestamp":1782708366973,"version":"3.54.5"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"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:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Early diagnosis of sepsis remains a major clinical challenge due to the dynamic interplay between infection and host immune response. Conventional biomarkers often fail to capture the dynamic nature of immune activation. Neutrophil-derived reactive oxygen species (ROS), central to antimicrobial defense and tissue injury, may offer early insight into immune dysregulation. The Leukocyte ImmunoTest (LIT) is a rapid, bedside assay that quantifies neutrophil ROS production within minutes, providing a functional snapshot of innate immunity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This prospective observational study was conducted in intensive care and internal medicine wards of a university hospital. Participants were categorized\n                      <jats:italic>post hoc<\/jats:italic>\n                      into three groups: inpatient controls (n=29), infection (n=47), and sepsis (n=106). LIT was performed on whole blood samples, expressed as relative light units (RLU), and compared with C-reactive protein (CRP), procalcitonin (PCT), white blood cell count (WBC), and neutrophil count (PMNL). Diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis, and longitudinal LIT trends were assessed in relation to survival.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Median LIT values increased across diagnostic groups: 470 RLU in controls, 882 in infection, and 2466 in sepsis (adjusted p &amp;lt; 0.05). LIT demonstrated good diagnostic performance in identifying infection (AUC: 0.94, 95% CI: 0.911\u20130.968) and sepsis (AUC: 0.86, 95% CI: 0.795\u20130.915), with performance comparable to CRP and PCT, respectively. In a joint model, higher LIT values were independently associated with increased mortality (HR:1.6, 95% CI:1.2\u20132.2; p=0.005).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>LIT is a rapid bedside immune assay capturing the dynamic nature of neutrophil activation, demonstrating diagnostic and prognostic performance comparable to established biomarkers such as CRP and PCT in infection and sepsis. These findings suggest that LIT may have potential as a complementary biomarker in sepsis management. Multicenter studies are needed to confirm its integration into sepsis protocols and to further clarify its role in early recognition, risk stratification, and individualized care.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1829226","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T04:27:04Z","timestamp":1782707224000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Neutrophil-derived ROS as a rapid functional biomarker: diagnostic and prognostic performance of the Leukocyte ImmunoTest in infection and sepsis"],"prefix":"10.3389","volume":"17","author":[{"given":"Nazl\u0131han","family":"Boyac\u0131 D\u00fcndar","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Intensive Care Medicine, Gazi University Faculty of Medicine","place":["Ankara, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Sarphie","sequence":"additional","affiliation":[{"name":"Seroxo Limited","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenan","family":"Y\u00fcce","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology, Division of Virology, Gazi University Faculty of Medicine","place":["Ankara, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fclbin","family":"Aygencel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Intensive Care Medicine, Gazi University Faculty of Medicine","place":["Ankara, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melda","family":"T\u00fcrko\u011flu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Intensive Care Medicine, Gazi University Faculty of Medicine","place":["Ankara, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rubina","family":"Mian","sequence":"additional","affiliation":[{"name":"Seroxo Limited","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Moss","sequence":"additional","affiliation":[{"name":"Institute of Immunology and Immuno-therapy, University of Birmingham","place":["Birmingham, United Kingdom"]},{"name":"University Hospitals Birmingham NHS Foundation Trust","place":["Birmingham, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa Necmi","family":"\u0130lhan","sequence":"additional","affiliation":[{"name":"Department of Public Health, Faculty of Medicine, Gazi University","place":["Ankara, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fclendam","family":"Bozday\u0131","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology, Division of Virology, Gazi University Faculty of Medicine","place":["Ankara, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.0287","article-title":"The third international consensus definitions for sepsis and septic shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/bs.acc.2024.02.003","article-title":"Advances in sepsis biomarkers","volume":"119","author":"Marin","year":"2024","journal-title":"Adv Clin Chem"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/cells13050439","article-title":"Advances and challenges in sepsis management: modern tools and future directions","volume":"13","author":"Santacroce","year":"2024","journal-title":"Cells"},{"key":"B5","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1186\/s13054-023-04367-z","article-title":"Host response biomarkers for sepsis in the emergency room","volume":"27","author":"Turgman","year":"2023","journal-title":"Crit Care"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nature01326","article-title":"The immunopathogenesis of sepsis","volume":"420","author":"Cohen","year":"2002","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1631\/jzus.b2101075","article-title":"Roles of neutrophil reactive oxygen species (ROS) generation in organ function impairment in sepsis","volume":"23","author":"Lu","year":"2022","journal-title":"J Zhejiang Univ-Sci B"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2016.03.004","article-title":"Human neutrophils in auto-immunity","volume":"28","author":"Thieblemont","year":"2016","journal-title":"Semin Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/149185","article-title":"Chronic inflammation and cytokines in the tumor microenvironment","volume":"2014","author":"Landskron","year":"2014","journal-title":"J Immunol Res"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2006.09.030","article-title":"Reactive oxygen and nitrogen species as signaling molecules regulating neutrophil function","volume":"42","author":"Fialkow","year":"2007","journal-title":"Free Radic Biol Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.2741\/4423","article-title":"Pathophysiology of neutrophil-mediated extracellular redox reactions","volume":"21","author":"Jaganjac","year":"2016","journal-title":"Front Biosci (Landmark Ed)"},{"key":"B12","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1186\/s13054-021-03576-8","article-title":"Serial measurement of pancreatic stone protein for the early detection of sepsis in intensive care unit patients: a prospective multicentric study","volume":"25","author":"Pugin","year":"2021","journal-title":"Crit Care"},{"key":"B13","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s13613-017-0238-9","article-title":"Superior accuracy of mid-regional proadrenomedullin for mortality prediction in sepsis with varying levels of illness severity","volume":"7","author":"Andaluz-Ojeda","year":"2017","journal-title":"Ann Intensive Care"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.meegid.2021.105074","article-title":"Diagnostic and prognostic predictive values of circulating sTREM-1 in sepsis: a meta-analysis","volume":"96","author":"Qin","year":"2021","journal-title":"Infect Genet Evol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajem.2019.158361","article-title":"Interleukin-6 improves infection identification when added to physician judgment during evaluation of potentially septic patients","volume":"38","author":"Henning","year":"2020","journal-title":"Am J Emerg Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2018.09.013","article-title":"Comparison of accuracy of presepsin and procalcitonin concentrations in diagnosing sepsis in patients with and without acute kidney injury","volume":"490","author":"Nakamura","year":"2019","journal-title":"Clin Chim Acta"},{"key":"B17","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1186\/s13054-020-02993-5","article-title":"Biomarkers of sepsis: time for a reappraisal","volume":"24","author":"Pierrakos","year":"2020","journal-title":"Crit Care"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3390\/jcm11041085","article-title":"Pancreatic stone protein: review of a new biomarker in sepsis","volume":"11","author":"Fidalgo","year":"2022","journal-title":"J Clin Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1186\/cc11406","article-title":"Pancreatic stone protein as an early biomarker predicting mortality in a prospective cohort of patients with sepsis requiring ICU management","volume":"16","author":"Que","year":"2012","journal-title":"Crit Care"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1530","DOI":"10.1038\/s41467-023-37200-w","article-title":"Integrative omics identifies conserved and pathogen-specific responses of sepsis-causing bacteria","volume":"14","author":"Mu","year":"2023","journal-title":"Nat Commun"},{"key":"B21","doi-asserted-by":"publisher","first-page":"111","DOI":"10.3390\/healthcare6030111","article-title":"Sepsis: personalized medicine utilizing 'omic' technologies-a paradigm shift","volume":"6","author":"Itenov","year":"2018","journal-title":"Healthcare (Basel)"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1113\/eph8802571","article-title":"Leukocyte coping capacity: a novel technique for measuring the stress response in vertebrates","volume":"88","author":"McLaren","year":"2003","journal-title":"Exp Physiol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1186\/s40635-023-00554-y","article-title":"Assessing neutrophil-derived ROS production at the bedside: a potential prognostic tool in severe COVID-19 cases","volume":"11","author":"D\u00fcndar","year":"2023","journal-title":"Intensive Care Med Exp"},{"key":"B24","doi-asserted-by":"publisher","first-page":"10484","DOI":"10.1038\/s41598-022-13825-7","article-title":"High generation of reactive oxygen species from neutrophils in patients with severe COVID-19","volume":"12","author":"Veenith","year":"2022","journal-title":"Sci Rep"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1503\/cmaj.170149","article-title":"Clinical implications of the third international consensus definitions for sepsis and septic shock (Sepsis-3)","volume":"190","author":"Fernando","year":"2018","journal-title":"CMAJ"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1378\/chest.101.6.1644","article-title":"Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis","volume":"101","author":"Bone","year":"1992","journal-title":"Chest"},{"key":"B27","article-title":"Repurposing the oxford mediStress leukocyte coping capacity\u2122 Assay as a novel point-of-care biomarker of neutrophil function","volume-title":"Presentation at British Pharmacological Society","author":"Fullerton","year":"2019"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20122220","article-title":"Diverse novel functions of neutrophils in immunity, inflammation, and beyond","volume":"210","author":"M\u00f3csai","year":"2013","journal-title":"J Exp Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nri3423","article-title":"Beyond oxidative stress: an immunologist's guide to reactive oxygen species","volume":"13","author":"Nathan","year":"2013","journal-title":"Nat Rev Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.14740\/jocmr4240","article-title":"Use of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in COVID-19","volume":"12","author":"Chan","year":"2020","journal-title":"J Clin Med Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.25819","article-title":"Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive protein ratio in patients with severe coronavirus disease 2019 (COVID-19): a meta-analysis","volume":"92","author":"Lagunas-Rangel","year":"2020","journal-title":"J Med Virol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0148142","article-title":"Neutrophil extracellular traps induce organ damage during experimental and clinical sepsis","volume":"11","author":"Czaikoski","year":"2016","journal-title":"PloS One"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciab437","article-title":"Increased peripheral blood neutrophil activation phenotypes and neutrophil extracellular trap formation in critically ill coronavirus disease 2019 (COVID-19) patients: a case series and review of the literature","volume":"74","author":"Masso-Silva","year":"2022","journal-title":"Clin Infect Dis"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20122220","article-title":"How to use biomarkers of infection or sepsis at the bedside: guide to clinicians","volume":"49","author":"P\u00f3voa","year":"2023","journal-title":"Intensive Care Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/s1473-3099(07)70052-x","article-title":"Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systematic review and meta-analysis","volume":"7","author":"Tang","year":"2007","journal-title":"Lancet Infect Dis"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/s1473-3099(12)70323-7","article-title":"Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis","volume":"13","author":"Wacker","year":"2013","journal-title":"Lancet Infect Dis"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2025.120640","article-title":"Sepsis diagnosis and monitoring: frontiers in innovative technology","volume":"579","author":"Mirmotahari","year":"2026","journal-title":"Clin Chim Acta"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofy313","article-title":"Sepsis in intensive care unit patients: worldwide data from the Intensive Care over Nations Audit","volume":"5","author":"Sakr","year":"2018","journal-title":"Open Forum Infect Dis"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0120276","article-title":"Pancreatic stone protein predicts postoperative infection in cardiac surgery patients irrespective of cardiopulmonary bypass or surgical technique","volume":"10","author":"Klein","year":"2015","journal-title":"PloS One"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-018-5228-3","article-title":"Circulating biomarkers may be unable to detect infection at the early phase of sepsis in ICU patients: the CAPTAIN prospective multicenter cohort study","volume":"44","author":"Parlato","year":"2018","journal-title":"Intensive Care Med"},{"key":"B41","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1111\/eci.12732","article-title":"Pancreatic stone protein and soluble CD25 for infection and sepsis in an emergency department","volume":"47","author":"Garc\u00eda de Guadiana-Romualdo","year":"2017","journal-title":"Eur J Clin Invest"},{"key":"B42","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1186\/s13054-021-03576-8","article-title":"Serial measurement of pancreatic stone protein for the early detection of sepsis in intensive care unit patients: a prospective multicentric study","volume":"25","author":"Pugin","year":"2021","journal-title":"Crit Care"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-009-1402-y","article-title":"Is C-reactive protein a good prognostic marker in septic patients","volume":"35","author":"Silvestre","year":"2009","journal-title":"Intensive Care Med"},{"key":"B44","doi-asserted-by":"publisher","first-page":"6579","DOI":"10.1038\/s41598-019-42972-7","article-title":"The usefulness of C-reactive protein and procalcitonin to predict prognosis in septic shock patients: a multicenter prospective registry-based observational study","volume":"9","author":"Ryoo","year":"2019","journal-title":"Sci Rep"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1097\/01.ccm.0000217961.75225.e9","article-title":"Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock","volume":"34","author":"Kumar","year":"2006","journal-title":"Crit Care Med"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1086\/421997","article-title":"Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis","volume":"39","author":"Simon","year":"2004","journal-title":"Clin Infect Dis"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofv098","article-title":"Acute phase reactants in infections: evidence-based review and a guide for clinicians","volume":"2","author":"Markanday","year":"2015","journal-title":"Open Forum Infect Dis"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1007\/s11845-023-03385-8","article-title":"C-reactive protein and procalcitonin during course of sepsis and septic shock","volume":"193","author":"Schupp","year":"2024","journal-title":"Ir J Med Sci"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1590\/s0100-879x2006005000143","article-title":"Neutrophil function and metabolism in individuals with diabetes mellitus","volume":"40","author":"Alba-Loureiro","year":"2007","journal-title":"Braz J Med Biol Res"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.678771","article-title":"A bittersweet response to infection in diabetes; targeting neutrophils to modify inflammation and improve host immunity","volume":"12","author":"Dowey","year":"2021","journal-title":"Front Immunol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.897968","article-title":"Predictive value of Leukocyte ImmunoTest (LIT\u2122) in cancer patients: a prospective cohort study","volume":"12","author":"Li","year":"2022","journal-title":"Front Oncol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1829226\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T04:27:05Z","timestamp":1782707225000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1829226\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,29]]},"references-count":51,"alternative-id":["10.3389\/fimmu.2026.1829226"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1829226","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,29]]},"article-number":"1829226"}}