Abstract
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Treatments that influence this dysregulated host response are sparse. The immunopathophysiology of sepsis entails overzealous inflammation causing acute organ dysfunction, as well as a profound and/or persistent anti-inflammatory response that increases susceptibility to secondary infection. The immune response in sepsis is under the influence of various endogenous and exogenous factors, including genetic makeup, age, sex, comorbidities, metabolism, prior microbial exposure and medications. The consequent heterogeneity of the syndrome hampers immunomodulatory treatment strategies that rely on a ‘one-size-fits-all’ approach. A precision medicine approach is therefore warranted. Balanced application of prognostic- and predictive-enrichment strategies is instrumental to achieve precision medicine. Phenotyping of patients using clinical, physiological, microbiological and/or molecular (‘omics’) data enables the identification of more homogeneous patient subgroups. Several studies suggest that such approaches can be used to tailor adjunctive immunomodulatory therapies in patients with sepsis. As well as repurposing existing drugs to treat sepsis, new drugs aimed at restoring immune homeostasis are under investigation. New clinical trial methodologies, including flexible platform trials, Bayesian statistics and embedding trials in health care systems are increasingly being used to keep pace with rapid developments in the field of sepsis immunobiology and ultimately to improve clinical outcomes.
Key points
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Sepsis is a highly heterogenous syndrome resulting from a dysregulated immune response that is characterized by varying degrees of inflammation and immune suppression.
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Immunomodulatory treatment strategies that use a ‘one-size-fits-all approach’ have consistently failed to attenuate organ dysfunction or reduce mortality in sepsis, underscoring the need for a better understanding of the host response and theragnostic biomarkers to guide appropriate therapeutic interventions.
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Harnessing concepts such as disease tolerance, resilience, resolution and trained immunity may shed new perspectives on the dysregulated host response in sepsis, moving away from the simplified hyperinflammatory versus immunosuppressive paradigm.
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Unsupervised clustering methods and machine learning can assign patients with sepsis into distinct subgroups on the basis of various demographic, clinical, physiological and/or molecular data, with the ultimate goal of enabling precision medicine — appropriate treatment for individual patients, at the right dose and at the optimal time.
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Several retrospective analyses indicate that precision medicine may be feasible and effective in sepsis, but prospective studies are required to demonstrate clinical benefit.
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Overcoming the limitations of traditional trial designs and adopting innovative approaches such as flexible platform trials, Bayesian methods and embedded trials could help to advance the delivery of effective, timely treatments to improve the outcomes of patients with sepsis.
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All authors researched data for the article, contributed substantially to discussion of the content and wrote the article. M.K. and P.P. reviewed and/or edited the manuscript before submission.
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M.K. has received institutional funding (full institutional disclosure) from Reumafonds, Medisieve, Comentis, Abionic, CytoSorbents, Adrenomed, Inflammatix, SurvivX and 4TEEN4, as well as travel reimbursements and consulting fees from ARTCLINE, Atriva, AOP pharma, Inflammatix, SurvivX and 4TEEN4 outside the submitted work. M.B. has received travel reimbursements and consulting fees from ARTCLINE, BAYER, BRAHMS/ Thermo Fisher, Volition and research grants from DFG (German Research Council) and BMBF (Federal Ministry of Education and Research). L.D.J.B. has consulted for Aptarion, AstraZeneca, Bayer, CSL, Novartis, Volition and Bayer. He received an unrestricted grant from Volition. Consultancy fees and grants were paid to the institution. H.B. has received institutional funding from Becton Dickinson, Inflammatix, Octapharma, OSAsense, MeMed, Dutch Kidney Foundation, Dutch Research Council (NWO). T.C. reports grants from the Swiss Academy of Medical, Swiss Federal Institute of Technology Zurich and Horizon 2020 from the European Community; consulting, speaker’s bureau and data-safety-monitoring boards from Basilea, Cidara, Gilead Sciences, A. Menarini Pharma, MSD Merck Sharp & Dohme, Moderna, Novartis, Pfizer and Shionogi, all paid to his institution; and sponsorship to the International Sepsis Forum (ISF) by BD, Cytosorbents, Deepull, Gentian, Inflammatix, Inotrem, MeMed, Oxford Nanopore, RevImmune, Thermo Fisher Scientific and Volition. C.S.C. has consulted for Vasomune, Gen1e Life Sciences, Arrowhead, Cellenkos, Calcimedical, EnliTisa, Novartis, Aerogen, Fisher and Paykel, and Boehringer. She received grant funding from NIH, Roche Genentech and Quantum Leap Healthcare Collaborative (paid to the institution), all outside the submitted work other than NIH grant R35HL140026. B.G.C. received speaker fees from Baxter and was a member of an advisory board for Roche Diagnostics. L.P.G.D. reports institutional grants from HORIZON-Health (2021-2026) (ECRAID-Base, Grant agreement ID: 965313) and ZonMw (Immune Modulation Platform for Influenza Treatment (IMPRINT) project number 10140252210024 and NCOH Pandemic Preparedness Research Kickstarter project number 10710022210003). E.J.G.-B. reports honoraria and consultation fees from Abbott Products Operations, bioMérieux, Brahms GmbH, GSK and Sobi (granted to the National and Kapodistrian University of Athens); independent educational grants from AbbVie, InCyte, Novartis and UCB (granted to the National and Kapodistrian University of Athens) and from Abbott Products Operations, bioMérieux Inc, Johnson & Johnson, MSD and Swedish Orphan Biovitrum AB (granted to the Hellenic Institute for the Study of Sepsis); and funding from the Horizon 2020 European Grants ImmunoSep and RISCinCOVID and the Horizon Health grants EPIC-CROWN-2, POINT and Homi-Lung (granted to the Hellenic Institute for the Study of Sepsis). H.G. has received consulting fees from Trilinear Bioventures, Talphera, Novartis, speaker fees from bioMérieux and research grants from bioMérieux, Baxter, TES Pharma, the National Institutes of Health and the Department of Defense of the United States of America. M.G.N. is a Scientific Founder of Biotrip, Lemba, TTxD and Salvina Therapeutics. He is chairman of the Scientific Board of TTxD. He performed consultancy for Curevac and Primmune. M.O. has received research funding from Baxter and BioMérieux and consulted for AM-Pharma (paid to the institution). T.v.d.P. received funding from EU (FAIR) and the Dutch Ministry of Economic Affairs & Health Holland, and consultancy fees from Matisse, all paid to the institution. B.P.S. received funds from the European Society of Intensive Care Medicine (ESICM), Xjenza Malta Research Excellence Program (REP-2023-049; REP-2024-062) and a University of Malta Research Excellence Award 2023. All grants were paid to the institution. C.S. has consulted for Beckman Coulter, Edwards, Deepull, Inflammatix and Octapharma. He received grant funding from NIH and the Moore Foundation (paid to the institution). M.S.-H. declares that he is a Director of Research for the Intensive Care Society, Member of the MRC/NIHR EME Programme, Chair of the EME-NIHR Advanced Fellowship Committee, Council of International Sepsis Forum, receives funding for studies from the NIHR, Wellcome Trust, Medical Research Council, and has done advisory board activity either directly or indirectly through International Sepsis Forum for Biotest, Endpoint Health, Janssen, Pfizer, Aurobac, GSK and Santersus, with payments going into the unrestricted institutional research funds. M.S.-H. also acknowledges the programme grant named Time critical precision medicine for acute critical illness using treatable trait principles: TRAITS Programme (PMAS/21/08) from the Chief Scientist’s Office, Scotland. N.S. received grant funding from Bluejay Diagnostics, Inflammatix, CDC and NIH. He or his institution receives fees for lectures, presentations, speaker bureaus, manuscript writing or educational events from Lumos diagnostics. Stock options were offered to him from Prenosis. M.S. received grant funding from the Medical Research Council, UK National Institute for Health and Care Research (NIHR), Rosetrees Trust, UCL Therapeutic Acceleration Support Fund, Gentian, DSTL and the European Society of Intensive Care Medicine. He or his institution receives fees for consulting, advisory boards, data safety monitoring boards and speaking/chairing from AOP Pharma, Aptarion, BioMérieux, Biotest, Deltex Medical, deePull, Hemotune, Matisse, Roche Diagnostics, Safeguard Biosystems, Sanofi, Volition. He is past-president of the International Sepsis Forum (ISF) and current Sepsis Topic Advisor for NICE. F.V. has received travel reimbursement fees from Astra-Zeneca. A.P.J.V. received consultant fees from AM-Pharma, InflaRx and CSL Behring paid to the institution. L.A.v.V. was supported by the Netherlands Organisation for Health Research and Development ZonMW (Nederlandse Organisatie voor Wetenschappelijk Onderzoek NWO) VENI grant 09150161910033. S.W., is currently funded by the Deutsche Forschungsgemeinschaft, DFG, project number WE 4971/6-1, WE 4971/9-1 and the Federal Ministry of Education and Research (BMBF) project number 01EN2001. W.J.W. receives funding from EU (Eurostars) and Netherlands Organisation for Health Research and Development (ZonMw) in addition to consultancy fees from AstraZeneca and Shionogi outside the submitted work (all fees paid to the host institution). P.P. has received travel reimbursements and consulting fees from AM-Pharma, Adrenomed, EBI, Paion, Sphingotec and 4Teen4 outside the submitted work.
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Glossary
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Trial designs that use Bayesian inference to integrate prior knowledge with accumulating trial data, enabling adaptive decision making and real-time updates to probabilities of treatment efficacy or other outcomes.
- Jarisch–Herxheimer reaction
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An acute, systemic inflammatory response that can occur after the initiation of antibiotic treatment.
- Quorum sensing
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A cell-to-cell communication process used by bacteria to coordinate collective behaviours based on population density.
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Kox, M., Bauer, M., Bos, L.D.J. et al. The immunology of sepsis: translating new insights into clinical practice. Nat Rev Nephrol (2025). https://doi.org/10.1038/s41581-025-01004-6
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DOI: https://doi.org/10.1038/s41581-025-01004-6
