Abstract
Sepsis remains a major cause of morbidity and mortality in both low- and high-income countries. Antibiotic therapy and supportive care have significantly improved survival following sepsis in the twentieth century, but further progress has been challenging. Immunotherapy trials for sepsis, mainly aimed at suppressing the immune response, from the 1990s and 2000s, have largely failed, in part owing to unresolved patient heterogeneity in the underlying immune disbalance. The past decade has brought the promise to break this blockade through technological developments based on omics-based technologies and systems medicine that can provide a much larger data space to describe in greater detail the immune endotypes in sepsis. Patient stratification opens new avenues towards precision medicine approaches that aim to apply immunotherapies to sepsis, on the basis of precise biomarkers and molecular mechanisms defining specific immune endotypes. This approach has the potential to lead to the establishment of immunotherapy as a successful pillar in the treatment of sepsis for future generations.
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Acknowledgements
The authors are partly supported by the ImmunoSep grant (no. 847422) and HDM-FUN grant from the Horizon 2020 program of the European Union. M.G.N. was partly supported by an ERC Advanced Grant (no. 833247) and a Spinoza Grant of the Netherlands Organization for Scientific Research. A.C.A., J.L.S. and M.G.N. are members of the excellence cluster ImmunoSensation (EXC 2151), funded by the German Research Foundation (DFG) under grant agreement no. 390873048. S.W. is currently funded by the Deutsche Forschungsgemeinschaft, DFG, project no. WE 4971/6-1, the Excellence Cluster Balance of the Microverse (EXC 2051; 390713860) and the Federal Ministry of Education and Research (BMBF) project no. 01EN2001.
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E.J.G.-B., M.B., C.B., T.C., I.G.-V., E.K., M.L., G.M., J.L.S., A.C.A., T.v.d.P, P.P., F.L.v.d.V., A.P.J.V., S.W., W.J.W., M.G.N. designed the manuscript, wrote the manuscript and corrected subsequent versions.
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E.J.G.-B. has received honoraria from Abbott, bioMérieux, Brahms, GSK, InflaRx, Sobi and XBiotech, and independent educational grants from Abbott, AxisShield, bioMérieux, InflaRx, Johnson & Johnson, MSD, Sobi and XBiotech. A.V. receives consulting fees from Inflarx paid to Amsterdam UMC. M.B. is cofounder and holds shares of SmartDyeLivery, Jena. M.G.N. is a scientific founder and holds shares of TTxD, BioTRIP and Lemba. All other authors have no conflicts of interest.
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Giamarellos-Bourboulis, E.J., Aschenbrenner, A.C., Bauer, M. et al. The pathophysiology of sepsis and precision-medicine-based immunotherapy. Nat Immunol 25, 19–28 (2024). https://doi.org/10.1038/s41590-023-01660-5
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DOI: https://doi.org/10.1038/s41590-023-01660-5