Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025 Apr;51(4):756-768.
doi: 10.1007/s00134-025-07873-6. Epub 2025 Mar 31.

Sepsis subphenotypes, theragnostics and personalized sepsis care

David B Antcliffe  1   2 , Aidan Burrell  3 , Andrew J Boyle  4   5 , Anthony C Gordon  6 , Daniel F McAuley  4   5 , Jon Silversides  4   5
Affiliations
Review

Sepsis subphenotypes, theragnostics and personalized sepsis care

David B Antcliffe et al. Intensive Care Med. 2025 Apr.

Abstract

Heterogeneity between critically ill patients with sepsis is a major barrier to the discovery of effective therapies. The use of machine learning techniques, coupled with improved understanding of sepsis biology, has led to the identification of patient subphenotypes. This exciting development may help overcome the problem of patient heterogeneity and lead to the identification of patient subgroups with treatable traits. Re-analyses of completed clinical trials have demonstrated that patients with different subphenotypes may respond differently to treatments. This suggests that future clinical trials that take a precision medicine approach will have a higher likelihood of identifying effective therapeutics for patients based on their subphenotype. In this review, we describe the emerging subphenotypes identified in the critically ill and outline the promising immune modulation therapies which could have a beneficial treatment effect within some of these subphenotypes. Furthermore, we will also highlight how bringing subphenotype identification to the bedside could enable a new generation of precision-medicine clinical trials.

Keywords: Critical illness; Heterogeneity of treatment effect; Phenotype; Precision medicine; Sepsis; Sub-phenotype.

PubMed Disclaimer

Conflict of interest statement

Declarations. Conflicts of interest: ACG reports that outside of this work he has received grant funding from the National Institute for Health and Care Research. AB reports grant funding from the NHMRC. AJB reports grant funding from the Belfast Health and Social Care Trust Charity and support from ViroGates. ACG reports that outside of this work he has received consulting fees from AstraZeneca, Beckman Coulter, and VVB Bio, speaker fees from Fresenius Kabi and grant support from the NIHR HTA programme. ACG is the director of the NIHR National Research Collaboration Programme. Outside the submitted work, DFM reports personal fees for consultancy from Bayer, GSK, Boehringer Ingelheim, Eli Lilly, Novartis and SOBI and for being a member of the data monitoring and ethics committee for Vir Biotechnology and Faron studies and as an educational seminar speaker for GSK. DFM has received funding to his institution from the NIHR, MRC, Wellcome Trust, Innovate UK, Northern Ireland Health and Social Care Research and Development Office, Novavax and Randox. In addition, DFM is a named inventor on a patent US8962032 covering the use of sialic acid-bearing nanoparticles as anti-inflammatory agents issued to his institution. DFM was a Director of Research for the Intensive Care Society and is the Director for the MRC/NIHR EME Programme and is the Scientific Director for NIHR Programmes. All other authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
Representation of how knowledge of subphenotypes of sepsis and critical illness could lead to targeted therapeutics
Fig. 2
Fig. 2
Future potential therapeutic approaches by gene-expression and protein based critical illness subphenotypes. Ang, Angiopoietin; IL, interleukin; PEEP, positive end expiratory pressure; SRS, sepsis response signature; sTNFR1, soluble tumour necrosis factor receptor 1
See this image and copyright information in PMC

References

    1. Singer M, Deutschman CS, Seymour CW et al (2016) The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315:801–810. 10.1001/jama.2016.0287 - PMC - PubMed
    1. Rudd KE, Johnson SC, Agesa KM et al (2020) Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet 395:200–211. 10.1016/S0140-6736(19)32989-7 - PMC - PubMed
    1. Marshall JC (2014) Why have clinical trials in sepsis failed? Trends Mol Med 20:195–203. 10.1016/j.molmed.2014.01.007 - PubMed
    1. Shankar-Hari M, Calandra T, Soares MP et al (2024) Reframing sepsis immunobiology for translation: towards informative subtyping and targeted immunomodulatory therapies. Lancet Respir Med 12:323. 10.1016/S2213-2600(23)00468-X - PMC - PubMed
    1. Coopersmith CM, De Backer D, Deutschman CS et al (2018) Surviving sepsis campaign: research priorities for sepsis and septic shock. Intensive Care Med 44:1400–1426. 10.1007/s00134-018-5175-z - PMC - PubMed

LinkOut - more resources