{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T00:57:01Z","timestamp":1792198621808,"version":"4.4.0"},"reference-count":24,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Introduction: Patients with extremely elevated IL-6 levels remain poorly characterized, and no specific plasma concentration has been established to reliably predict mortality or guide immunomodulatory interventions. We hypothesized that extreme hypercytokinemia is associated with increased mortality in sepsis. The primary objective was to identify, in patients with hyperinflammatory endotype, an IL-6 threshold associated with a significantly elevated risk of death. Methods: We conducted a retrospective, single-center observational study based on a historical cohort of adult patients with consecutive activation of the in-hospital sepsis code, a prospective and standardized institutional care pathway, at Vall d\u2019Hebron University Hospital between July 2018 and December 2024. Patients fulfilling Sepsis-2 diagnostic criteria and criteria for severe sepsis or septic shock were eligible. Plasma interleukin-6 (IL-6) levels were routinely determined in all patients. The analysis included patients with complete clinical and laboratory data available in the study database. To identify the IL-6 threshold associated with critical risk of death, a cumulative conditional relative frequency analysis was performed. A quantile-based analysis was conducted using predefined intervals of 1000 pg\/mL and 15,000 pg\/mL. A multivariable logistic regression analysis was conducted to identify clinical and laboratory parameters independently associated with IL-6 &gt; 15,000 pg\/mL and outcome. Results are presented as odds ratios (ORs). Survival differences were assessed using Kaplan\u2013Meier analysis. Results: Overall mortality was 31% in the 1669 patients analyzed. Median IL-6 concentration was 772 pg\/mL (IQR: 164\u20138750 pg\/mL) with significantly higher levels in non-survivors (2137 pg\/mL, IQR: 267\u201334,758). A critical IL-6 cutoff of 14,930 pg\/mL was identified, which was rounded to 15,000 pg\/mL for clinical applicability. IL-6 &gt; 15,000 pg\/mL was associated with increased mortality (OR 2.22, 95% CI: 1.12\u20135.36). Kaplan\u2013Meier analysis revealed significantly reduced survival in patients above this IL-6 threshold (p &lt; 0.0001). Conclusions: In this cohort of patients with severe sepsis or septic shock, plasma IL-6 levels &gt; 15,000 pg\/mL defined a critical threshold beyond which mortality risk exceeded survival probability. Critical hypercytokinemia may serve as a clinically relevant biomarker to identify patients with sepsis and multiorgan dysfunction who could benefit from precision immunomodulatory therapies.<\/jats:p>","DOI":"10.3390\/jcm15031057","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T17:40:22Z","timestamp":1769622022000},"page":"1057","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Critical Hypercytokinemia in Sepsis and Septic Shock: Identifying Interleukin-6 Thresholds Beyond Which Mortality Risk Exceeded Survival Probability"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7392-8617","authenticated-orcid":false,"given":"Juan Carlos","family":"Ruiz-Rodr\u00edguez","sequence":"first","affiliation":[{"name":"Intensive Care Department, Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain"},{"name":"Shock, Organ Dysfunction and Resuscitation Research Group, Vall d\u2019Hebron Research Institute (VHIR), Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0037-0610","authenticated-orcid":false,"given":"Luis","family":"Chiscano-Cam\u00f3n","sequence":"additional","affiliation":[{"name":"Intensive Care Department, Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain"},{"name":"Shock, Organ Dysfunction and Resuscitation Research Group, Vall d\u2019Hebron Research Institute (VHIR), Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adolf","family":"Ruiz-Sanmartin","sequence":"additional","affiliation":[{"name":"Intensive Care Department, Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain"},{"name":"Shock, Organ Dysfunction and Resuscitation Research Group, Vall d\u2019Hebron Research Institute (VHIR), Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3799-9877","authenticated-orcid":false,"given":"Natalia","family":"Costa-Allu\u00e9","sequence":"additional","affiliation":[{"name":"Intensive Care Department, Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain"},{"name":"Shock, Organ Dysfunction and Resuscitation Research Group, Vall d\u2019Hebron Research Institute (VHIR), Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Baja\u00f1a","sequence":"additional","affiliation":[{"name":"Intensive Care Department, Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain"},{"name":"Shock, Organ Dysfunction and Resuscitation Research Group, Vall d\u2019Hebron Research Institute (VHIR), Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3560-829X","authenticated-orcid":false,"given":"Pablo","family":"Nicolas-Morales","sequence":"additional","affiliation":[{"name":"Intensive Care Department, Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain"},{"name":"Shock, Organ Dysfunction and Resuscitation Research Group, Vall d\u2019Hebron Research Institute (VHIR), Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana","family":"Bastidas","sequence":"additional","affiliation":[{"name":"Intensive Care Department, Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain"},{"name":"Shock, Organ Dysfunction and Resuscitation Research Group, Vall d\u2019Hebron Research Institute (VHIR), Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6054-1069","authenticated-orcid":false,"given":"Sergi","family":"Cantenys-Molina","sequence":"additional","affiliation":[{"name":"Immunology Department, Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Hern\u00e1ndez-Gonzalez","sequence":"additional","affiliation":[{"name":"Immunology Department, Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nieves","family":"Larrosa","sequence":"additional","affiliation":[{"name":"Microbiology Department, Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2419-5909","authenticated-orcid":false,"given":"Juan Jose","family":"Gonz\u00e1lez-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Microbiology Department, Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7266-6106","authenticated-orcid":false,"given":"Vicent","family":"Ribas","sequence":"additional","affiliation":[{"name":"EHealth Unit, Eurecat, Centre Tecnol\u00f2gic de Catalunya, 08005 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4859-4747","authenticated-orcid":false,"given":"Ricard","family":"Ferrer","sequence":"additional","affiliation":[{"name":"Intensive Care Department, Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain"},{"name":"Shock, Organ Dysfunction and Resuscitation Research Group, Vall d\u2019Hebron Research Institute (VHIR), Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, 08035 Barcelona, 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Intensiv. (Engl. Ed.)"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.thromres.2016.11.007","article-title":"Coagulation and sepsis","volume":"149","author":"Levi","year":"2017","journal-title":"Thromb. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/nri.2017.36","article-title":"The immunopathology of sepsis and potential therapeutic targets","volume":"17","author":"Scicluna","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Beltr\u00e1n-Garc\u00eda, J., Osca-Verdegal, R., J\u00e1vega, B., Herrera, G., O\u2019Connor, J.E., Garc\u00eda-L\u00f3pez, E., Casab\u00f3-Vall\u00e9s, G., Rodriguez-Gimillo, M., Ferreres, J., and Carbonell, N. (2022). Characterization of Early Peripheral Immune Responses in Patients with Sepsis and Septic Shock. Biomedicines, 10.","DOI":"10.3390\/biomedicines10030525"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e253","DOI":"10.1097\/CCM.0000000000006032","article-title":"Identification of Clinically Significant Cytokine Signature Clusters in Patients with Septic Shock","volume":"51","author":"Zhao","year":"2023","journal-title":"Crit. Care Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"13995","DOI":"10.1038\/s41598-018-32275-8","article-title":"The clinical importance of a cytokine network in the acute phase of sepsis","volume":"8","author":"Matsumoto","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1093\/infdis\/171.2.472","article-title":"Interleukin-10 and the monocyte\/macrophage-induced inflammatory response in septic shock","volume":"171","author":"Sauri","year":"1995","journal-title":"J. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"R49","DOI":"10.1186\/cc5783","article-title":"Cytokine profiles as markers of disease severity in sepsis: A multiplex analysis","volume":"11","author":"Bozza","year":"2007","journal-title":"Crit. Care"},{"key":"ref_11","first-page":"1","article-title":"Precision medicine in sepsis and septic shock: From omics to clinical tools","volume":"11","author":"Palmada","year":"2022","journal-title":"World J. Crit. Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Chiscano-Cam\u00f3n, L., Ruiz-Sanmartin, A., Baja\u00f1a, I., Bastidas, J., Lopez-Martinez, R., Franco-Jarava, C., Gonzalez, J.J., Larrosa, N., Riera, J., and Nuvials-Casals, X. (2024). Current perspectives in the management of sepsis and septic shock. Front. Med., 11.","DOI":"10.3389\/fmed.2024.1431791"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1097\/00003246-198510000-00009","article-title":"APACHE II: A severity of disease classification system","volume":"13","author":"Knaus","year":"1985","journal-title":"Crit. Care Med."},{"key":"ref_14","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_15","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1097\/01.CCM.0000050454.01978.3B","article-title":"2001 SCCM\/ESICM\/ACCP\/ATS\/SIS International Sepsis Definitions Conference","volume":"31","author":"Levy","year":"2003","journal-title":"Crit. Care Med."},{"key":"ref_16","first-page":"2526","article-title":"Acute respiratory distress syndrome: The Berlin Definition","volume":"307","author":"Ranieri","year":"2012","journal-title":"JAMA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"c179","DOI":"10.1159\/000339789","article-title":"KDIGO clinical practice guidelines for acute kidney injury","volume":"120","author":"Khwaja","year":"2012","journal-title":"Nephron Clin. Pract."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Vandenbroucke, J.P., von Elm, E., Altman, D.G., G\u00f8tzsche, P.C., Mulrow, C.D., Pocock, S.J., Poole, C., Schlesselman, J.J., Egger, M., and STROBE Initiative (2007). Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): Explanation and elaboration. PLoS Med., 4.","DOI":"10.1371\/journal.pmed.0040297"},{"key":"ref_19","unstructured":"(2016). General Data Protection Regulation (GDPR) (Standard No. Regulation (EU) 2016\/679)."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1001\/archinte.167.15.1655","article-title":"Understanding the inflammatory cytokine response in pneumonia and sepsis: Results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study","volume":"167","author":"Kellum","year":"2007","journal-title":"Arch. Intern. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"R15","DOI":"10.1186\/cc8872","article-title":"Sepsis biomarkers: A review","volume":"14","author":"Pierrakos","year":"2010","journal-title":"Crit. Care"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s41512-023-00152-2","article-title":"Basal procalcitonin, C-reactive protein, interleukin-6, and presepsin for prediction of mortality in critically ill septic patients: A systematic review and meta-analysis","volume":"7","author":"Muriel","year":"2023","journal-title":"Diagn. Progn. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00281-017-0639-8","article-title":"Cytokine storm and sepsis disease pathogenesis","volume":"39","author":"Chousterman","year":"2017","journal-title":"Semin. Immunopathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1159\/000111568","article-title":"Direct hemoperfusion with a cytokine-adsorbing device for the treatment of persistent or severe hypercytokinemia: A pilot study","volume":"25","author":"Kobe","year":"2007","journal-title":"Blood Purif."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/3\/1057\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T17:48:56Z","timestamp":1769622536000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/3\/1057"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,28]]},"references-count":24,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["jcm15031057"],"URL":"https:\/\/doi.org\/10.3390\/jcm15031057","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,28]]}}}