{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:27:30Z","timestamp":1780446450430,"version":"3.54.1"},"reference-count":51,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T00:00:00Z","timestamp":1768694400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Procalcitonin (PCT), presepsin (PSEP), interferon-\u03bb3 (IFN-\u03bb3), and bioactive adrenomedullin (bio-ADM) are promising sepsis biomarkers. We explored the clinical utility of a multi-marker approach using these four biomarkers in patients with suspected sepsis. Materials and Methods: In a total of 248 patients, the biomarkers were evaluated with the sequential organ failure assessment (SOFA) score. Receiver operating characteristic curves with area under the curve (AUC) were analyzed to diagnose sepsis and predict in-hospital mortality. Survival and reclassification analyses were also used to predict in-hospital mortality. Results: The four biomarkers showed comparable diagnostic performance (AUC = 0.61\u20130.95, p &lt; 0.001\u20130.003), and sepsis proportion increased significantly as the number of biomarkers used in the multi-marker approach increased (7.7\u201391.7%, p &lt; 0.001). The proportion of biomarker quartiles (Q1\u2013Q4) differed significantly according to SOFA score (p &lt; 0.001). The four biomarkers predicted in-hospital mortality (AUC = 0.63\u20130.84, p &lt; 0.001\u20130.004). The multi-marker approach performed better than the SOFA score (mortality rate, 58.3% vs. 31.3%; adjusted hazard ratio [HR], 14.7 vs. 4.6), and the addition of biomarkers to the SOFA score increased the performance. The multi-marker approach resulted in a higher HR in patients aged \u226575 years than in the overall population (9.2 vs. 4.2). Conclusions: Each biomarker showed clinical utility in patients with suspected sepsis. The multi-marker approach showed complementary clinical utility in addition to the SOFA score and better prognostic performance in patients aged \u226575 years. The use of biomarkers, alone or in combination, would be a valuable tool in combination with the SOFA score.<\/jats:p>","DOI":"10.3390\/medicina62010201","type":"journal-article","created":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T08:23:56Z","timestamp":1768811036000},"page":"201","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Multi-Marker Approach in Sepsis: A Clinical Role Beyond SOFA Score"],"prefix":"10.3390","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9278-4572","authenticated-orcid":false,"given":"Gun Hyuk","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3266-638X","authenticated-orcid":false,"given":"Hanah","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Konkuk University School of Medicine, Seoul 05030, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9509-6073","authenticated-orcid":false,"given":"Hee-Won","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Konkuk University School of Medicine, Seoul 05030, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeo-Min","family":"Yun","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Konkuk University School of Medicine, Seoul 05030, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7069-267X","authenticated-orcid":false,"given":"Seungho","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine, College of Medicine, Dong-A University, Busan 49201, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4429-9978","authenticated-orcid":false,"given":"Mina","family":"Hur","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Konkuk University School of Medicine, Seoul 05030, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990\u20132017: Analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1186\/s13054-020-02950-2","article-title":"Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019\u2014Results from a systematic review and meta-analysis","volume":"24","author":"Bauer","year":"2020","journal-title":"Crit. Care"},{"key":"ref_3","unstructured":"Center for Disease Control and Prevention (CDC) (2023, March 23). Sepsis-Related Mortality Among Adults Aged 65 and over: United States, 2019, Available online: https:\/\/www.cdc.gov\/nchs\/products\/databriefs\/db422.htm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"23","DOI":"10.5492\/wjccm.v1.i1.23","article-title":"Severe sepsis and septic shock in the elderly: An overview","volume":"1","author":"Nasa","year":"2012","journal-title":"World J. Crit. Care Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"801","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":"ref_6","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s13054-017-1609-1","article-title":"SOFA and mortality endpoints in randomized controlled trials: A systematic review and meta-regression analysis","volume":"21","author":"Geenen","year":"2017","journal-title":"Crit. Care"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1186\/s13054-019-2663-7","article-title":"The SOFA score-development, utility and challenges of accurate assessment in clinical trials","volume":"23","author":"Lambden","year":"2019","journal-title":"Crit. Care"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1007\/BF01709751","article-title":"The SOFA (Sepsis-related organ failure assessment) score to describe organ dysfunction\/failure. On behalf of the working group on sepsis-related problems of the European Society of Intensive Care Medicine","volume":"22","author":"Vincent","year":"1996","journal-title":"Intensive Care Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.chest.2017.12.015","article-title":"A comparison of the quick-SOFA and systemic inflammatory response syndrome criteria for the diagnosis of sepsis and prediction of mortality: A systematic review and meta-analysis","volume":"153","author":"Serafim","year":"2018","journal-title":"Chest"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s13049-018-0527-9","article-title":"Head-to-head comparison of qSOFA and SIRS criteria in predicting the mortality of infected patients in the emergency department: A meta-analysis","volume":"26","author":"Jiang","year":"2018","journal-title":"Scand. J. Trauma Resusc. Emerg. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1007\/s11739-018-1965-0","article-title":"SIRS or qSOFA? Is that the question? Clinical and methodological observations from a meta-analysis and critical review on the prognostication of patients with suspected sepsis outside the ICU","volume":"14","author":"Franchini","year":"2019","journal-title":"Intern. Emerg. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1515\/cclm-2018-1181","article-title":"Procalcitonin (PCT)-guided antibiotic stewardship: An international experts consensus on optimized clinical use","volume":"57","author":"Schuetz","year":"2019","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.cca.2019.06.010","article-title":"Procalcitonin: Between evidence and critical issues","volume":"496","author":"Aloisio","year":"2019","journal-title":"Clin. Chim. Acta"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"332","DOI":"10.7150\/ijms.39367","article-title":"Procalcitonin: A promising tool or just another overhyped test?","volume":"17","author":"Paudel","year":"2020","journal-title":"Int. J. Med. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"S5","DOI":"10.21037\/jtd.2019.11.63","article-title":"Role of procalcitonin use in the management of sepsis","volume":"12","author":"Gregoriano","year":"2020","journal-title":"J. Thorac. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.cca.2015.06.026","article-title":"Presepsin (sCD14-ST), an innate immune response marker in sepsis","volume":"450","author":"Borderie","year":"2015","journal-title":"Clin. Chim. Acta"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Yang, H.S., Hur, M., Yi, A., Kim, H., Lee, S., and Kim, S.N. (2018). Prognostic value of presepsin in adult patients with sepsis: Systematic review and meta-analysis. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0191486"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3903","DOI":"10.1080\/14767058.2018.1475643","article-title":"Comparison between presepsin and procalcitonin in early diagnosis of neonatal sepsis","volume":"32","author":"Iskandar","year":"2019","journal-title":"J. Matern.-Fetal Neonatal Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s40560-019-0374-4","article-title":"Diagnostic value of procalcitonin and presepsin for sepsis in critically ill adult patients: A systematic review and meta-analysis","volume":"7","author":"Kondo","year":"2019","journal-title":"J. Intensive Care"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1001\/jamapediatrics.2022.1647","article-title":"Presepsin for the diagnosis of neonatal early-onset sepsis: A systematic review and meta-analysis","volume":"176","author":"Poggi","year":"2022","journal-title":"JAMA Pediatr."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Syedbasha, M., and Egli, A. (2017). Interferon lambda: Modulating immunity in infectious diseases. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.00119"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e20190295","DOI":"10.1084\/jem.20190295","article-title":"Type III interferons: Balancing tissue tolerance and resistance to pathogen invasion","volume":"217","author":"Broggi","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"155959","DOI":"10.1016\/j.cyto.2022.155959","article-title":"Assessment of serum interleukin-28 as a biomarker to predict mortality in traumatic patients with sepsis","volume":"157","author":"Yang","year":"2022","journal-title":"Cytokine"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lee, G.H., Park, M., Hur, M., Kim, H., Lee, S., Moon, H.W., and Yun, Y.-M. (2023). Utility of presepsin and interferon-\u03bb3 for predicting disease severity and clinical outcomes in COVID-19 patients. Diagnostics, 13.","DOI":"10.3390\/diagnostics13142372"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s13613-016-0229-2","article-title":"Adrenomedullin: A marker of impaired hemodynamics, organ dysfunction, and poor prognosis in cardiogenic shock","volume":"7","author":"Tolppanen","year":"2017","journal-title":"Ann. Intensive Care"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1002\/ejhf.1437","article-title":"Bio-adrenomedullin as a marker of congestion in patients with new-onset and worsening heart failure","volume":"21","author":"Kremer","year":"2019","journal-title":"Eur. J. Heart Fail."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1111\/joim.13220","article-title":"Promotion of vascular integrity in sepsis through modulation of bioactive adrenomedullin and dipeptidyl peptidase 3","volume":"289","author":"Kox","year":"2021","journal-title":"J. Intern. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"454","DOI":"10.3343\/alm.2019.39.5.454","article-title":"Circulating biologically active adrenomedullin predicts organ failure and mortality in sepsis","volume":"39","author":"Kim","year":"2019","journal-title":"Ann. Lab. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1186\/s13054-020-03351-1","article-title":"Circulating bioactive adrenomedullin as a marker of sepsis, septic shock and critical illness","volume":"24","author":"Lundberg","year":"2020","journal-title":"Crit. Care"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Hur, M., Kim, H., Lee, S., Cristofano, F., Magrini, L., Marino, R., Gori, C.S., Bongiovanni, C., Zancla, B., and Cardelli, P. (2014). Diagnostic and prognostic utilities of multimarkers approach using procalcitonin, B-type natriuretic peptide, and neutrophil gelatinase-associated lipocalin in critically ill patients with suspected sepsis. BMC Infect. Dis., 14.","DOI":"10.1186\/1471-2334-14-224"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s13017-018-0202-5","article-title":"A combination of SOFA score and biomarkers gives a better prediction of septic AKI and in-hospital mortality in critically ill surgical patients: A pilot study","volume":"13","author":"Lee","year":"2018","journal-title":"World J. Emerg. Surg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e20495","DOI":"10.1097\/MD.0000000000020495","article-title":"Biomarker combination and SOFA score for the prediction of mortality in sepsis and septic shock: A prospective observational study according to the Sepsis-3 definitions","volume":"99","author":"Song","year":"2020","journal-title":"Medicine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s13054-021-03862-5","article-title":"Biomarkers for sepsis: More than just fever and leukocytosis-a narrative review","volume":"26","author":"Barichello","year":"2022","journal-title":"Crit. Care"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Lee, G.H., Kim, H., Moon, H.W., Yun, Y.M., Park, M., Lee, S., and Hur, M. (2024). Diagnostic and prognostic utilities of pancreatic stone protein in patients with suspected sepsis. Diagnostics, 14.","DOI":"10.3390\/diagnostics14182076"},{"key":"ref_35","unstructured":"National Institute for Health and Care Excellence (NICE) (2025, July 07). QuikRead Go for C-Reactive Protein Testing in Primary Care 2019. Available online: https:\/\/www.nice.org.uk\/advice\/mib78."},{"key":"ref_36","unstructured":"National Institute for Health and Care Excellence (NICE) (2025, July 07). Sepsis: Recognition, Diagnosis and Early Management. Available online: https:\/\/www.nice.org.uk\/guidance\/ng51."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Unterberg, M., Rahmel, T., Rump, K., Wolf, A., Haberl, H., von Busch, A., Bergmann, L., Bracht, T., Zarbock, A., and Ehrentraut, S.F. (2022). The impact of the COVID-19 pandemic on non-COVID induced sepsis survival. BMC Anesthesiol., 22.","DOI":"10.1186\/s12871-021-01547-8"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Szabo, B.G., Kiss, R., Lenart, K.S., Marosi, B., Vad, E., Lakatos, B., and Ostorhazi, E. (2019). Clinical and microbiological characteristics and outcomes of community-acquired sepsis among adults: A single center, 1-year retrospective observational cohort study from Hungary. BMC Infect. Dis., 19.","DOI":"10.1186\/s12879-019-4219-5"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1159\/000521288","article-title":"Charlson comorbidity index: A critical review of clinimetric properties","volume":"91","author":"Charlson","year":"2022","journal-title":"Psychother. Psychosom."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.jclinepi.2007.11.008","article-title":"The strengthening the reporting of observational studies in epidemiology (STROBE) statement: Guidelines for reporting observational studies","volume":"61","author":"Altman","year":"2008","journal-title":"J. Clin. Epidemiol."},{"key":"ref_41","unstructured":"(2025, July 07). Elecsys\u00ae BRAHMS PCT Assay. Available online: https:\/\/diagnostics.roche.com\/global\/en\/products\/lab\/elecsys-brahms-pct-cps-000496.html."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.1016\/j.cca.2011.07.024","article-title":"Development of a point-of-care assay system for measurement of presepsin (sCD14-ST)","volume":"412","author":"Okamura","year":"2011","journal-title":"Clin. Chim. Acta"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"145145","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":"ref_44","doi-asserted-by":"crossref","unstructured":"P\u00e9rez-Garc\u00eda, F., Jim\u00e9nez-Sousa, M., Soria, S., Jorge-Monjas, P., Fern\u00e1ndez-Rodr\u00edguez, A., G\u00f3mez-S\u00e1nchez, E., Heredia-Rodr\u00edguez, M., G\u00f3mez-Pesquera, E., Mart\u00ednez-Paz, P., and Tamayo, E. (2020). IFNL3 rs12980275 polymorphism predicts septic shock-related death in patients undergoing major surgery: A retrospective study. Front. Med., 7.","DOI":"10.3389\/fmed.2020.00186"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e24618","DOI":"10.1002\/jcla.24618","article-title":"Performance evaluation of presepsin using a Sysmex HISCL-5000 analyzer and determination of reference interval","volume":"36","author":"Kang","year":"2022","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1002\/pst.2090","article-title":"Sample size calculations for single-arm survival studies using transformations of the Kaplan-Meier estimator","volume":"20","author":"Nagashima","year":"2021","journal-title":"Pharm. Stat."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"263","DOI":"10.3343\/alm.2014.34.4.263","article-title":"Update on procalcitonin measurements","volume":"34","author":"Meisner","year":"2014","journal-title":"Ann. Lab. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.biopha.2018.12.124","article-title":"Presepsin: A promising biomarker for the detection of bacterial infections","volume":"111","author":"Memar","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1186\/s13054-019-2481-y","article-title":"Procalcitonin levels in candidemia versus bacteremia: A systematic review","volume":"23","author":"Cortegiani","year":"2019","journal-title":"Crit. Care"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1097\/MOP.0000000000000337","article-title":"Pediatric sepsis","volume":"28","author":"Mathias","year":"2016","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Xia, Y., Xia, C., Wu, L., Li, Z., Li, H., and Zhang, J. (2023). Systemic immune inflammation index (SII), system inflammation response index (SIRI) and risk of all-cause mortality and cardiovascular mortality: A 20-year follow-up cohort study of 42,875 US adults. J. Clin. Med., 12.","DOI":"10.3390\/jcm12031128"}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/1\/201\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T05:11:04Z","timestamp":1769058664000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/1\/201"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,18]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["medicina62010201"],"URL":"https:\/\/doi.org\/10.3390\/medicina62010201","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,18]]}}}