A consensus immune dysregulation framework for sepsis and critical illnesses

Andrew R Moore^{1

2

3}, Hong Zheng^{2

3}, Ananthakrishnan Ganesan^{2

3}, Yehudit Hasin-Brumshtein⁴, Manoj V Maddali^{1

3}, Joseph E Levitt¹, Tom van der Poll^{5

6}, Jingyi Lu^{7

8}, Hjalmar R Bouma^{7

8

9}, Brendon P Scicluna¹⁰, Evangelos J Giamarellos-Bourboulis^{11

12}, Antigone Kotsaki^{11

12}, Ignacio Martin-Loeches^{13

14}, Alexis Garduno¹³, Jeremiah Hinson¹⁵, Richard E Rothman¹⁵, Jonathan Sevransky¹⁶, David W Wright¹⁷, Mihir R Atreya¹⁸, Lyle L Moldawer¹⁹, Philip A Efron¹⁹, Marcela Kralovcova²⁰, Thomas Karvunidis²⁰, Heather M Giannini²¹, Nuala J Meyer²¹, Timothy E Sweeney⁴, Angela J Rogers¹, Purvesh Khatri^{22

23}

Affiliations

¹ Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, CA, USA.
² Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA.
³ Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA, USA.
⁴ Inflammatix Inc., Sunnyvale, CA, USA.
⁵ Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
⁶ Division of Infectious Diseases, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
⁷ Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁸ Department of Acute Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁹ Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹⁰ Department of Applied Biomedical Science, Faculty of Health Sciences, and Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta.
¹¹ 4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
¹² Hellenic Institute for the Study of Sepsis, Athens, Greece.
¹³ Department of Intensive Care Medicine, Multidisciplinary Intensive Care Research Organization (MICRO), St James's Hospital, Dublin, Ireland.
¹⁴ Hospital Clinic, Universitat de Barcelona, IDIBAPS, CIBERES, Barcelona, Spain.
¹⁵ Department of Emergency Medicine, The Johns Hopkins University, Baltimore, MD, USA.
¹⁶ Division of Pulmonary, Allergy, Critical Care and Sleep and Emory Critical Care Center, Emory University, Atlanta, GA, USA.
¹⁷ Department of Emergency Medicine, Emory University, Atlanta, GA, USA.
¹⁸ Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
¹⁹ Sepsis and Critical Illness Research Center and the SPIES Consortium, University of Florida College of Medicine, Gainesville, FL, USA.
²⁰ 1st Department of Internal Medicine, Faculty of Medicine, Teaching Hospital and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic.
²¹ Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
²² Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA. pkhatri@stanford.edu.
²³ Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA, USA. pkhatri@stanford.edu.

PMID: 41028543
DOI: 10.1038/s41591-025-03956-5

A consensus immune dysregulation framework for sepsis and critical illnesses

Andrew R Moore et al. Nat Med. 2025.

. 2025 Sep 30.

doi: 10.1038/s41591-025-03956-5. Online ahead of print.

Authors

Affiliations

¹ Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, CA, USA.
² Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA.
³ Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA, USA.
⁴ Inflammatix Inc., Sunnyvale, CA, USA.
⁵ Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
⁶ Division of Infectious Diseases, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
⁷ Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁸ Department of Acute Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁹ Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹⁰ Department of Applied Biomedical Science, Faculty of Health Sciences, and Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta.
¹¹ 4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
¹² Hellenic Institute for the Study of Sepsis, Athens, Greece.
¹³ Department of Intensive Care Medicine, Multidisciplinary Intensive Care Research Organization (MICRO), St James's Hospital, Dublin, Ireland.
¹⁴ Hospital Clinic, Universitat de Barcelona, IDIBAPS, CIBERES, Barcelona, Spain.
¹⁵ Department of Emergency Medicine, The Johns Hopkins University, Baltimore, MD, USA.
¹⁶ Division of Pulmonary, Allergy, Critical Care and Sleep and Emory Critical Care Center, Emory University, Atlanta, GA, USA.
¹⁷ Department of Emergency Medicine, Emory University, Atlanta, GA, USA.
¹⁸ Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
¹⁹ Sepsis and Critical Illness Research Center and the SPIES Consortium, University of Florida College of Medicine, Gainesville, FL, USA.
²⁰ 1st Department of Internal Medicine, Faculty of Medicine, Teaching Hospital and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic.
²¹ Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
²² Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA. pkhatri@stanford.edu.
²³ Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA, USA. pkhatri@stanford.edu.

PMID: 41028543
DOI: 10.1038/s41591-025-03956-5

Erratum in

Author Correction: A consensus immune dysregulation framework for sepsis and critical illnesses.
Moore AR, Zheng H, Ganesan A, Hasin-Brumshtein Y, Maddali MV, Levitt JE, van der Poll T, Lu J, Bouma HR, Scicluna BP, Giamarellos-Bourboulis EJ, Kotsaki A, Martin-Loeches I, Garduno A, Hinson J, Rothman RE, Sevransky J, Wright DW, Atreya MR, Moldawer LL, Efron PA, Kralovcova M, Karvunidis T, Giannini HM, Meyer NJ, Sweeney TE, Rogers AJ, Khatri P. Moore AR, et al. Nat Med. 2025 Oct 27. doi: 10.1038/s41591-025-04066-y. Online ahead of print. Nat Med. 2025. PMID: 41145793 No abstract available.

Abstract

Critical care syndromes such as sepsis, acute respiratory distress syndrome (ARDS) and trauma continue to have unacceptably high morbidity and mortality, with progress limited by the inherent heterogeneity within syndromic illnesses. Although numerous immune endotypes have been proposed for sepsis and critical care, the similarities and differences between these endotypes remain unclear, hindering clinical translation. The SUBSPACE consortium is an international consortium that aims to advance precision medicine in critical care through the sharing of transcriptomic data. Here, evaluating the overlap of existing immune endotypes in sepsis across >7,074 samples from 37 independent cohorts, we developed cell-type-specific gene expression signatures to quantify dysregulation within immune compartments. Myeloid and lymphoid dysregulation were associated with disease severity and mortality across all cohorts. Importantly, this dysregulation was also observed in patients with ARDS, trauma and burns, suggesting a conserved mechanism across various critical illness syndromes. Moreover, analysis of randomized controlled trial data revealed that myeloid and lymphoid dysregulation are associated with differential mortality in patients treated with anakinra in the SAVE-MORE trial (n = 452) and corticosteroids in the VICTAS (n = 89) and VANISH (n = 117) trials, underscoring their prognostic and therapeutic implications. In conclusion, our proposed immunology-based framework for quantifying cellular compartment dysregulation offers a potentially valuable tool for understanding immune dysregulation in critical illness with prognostic and therapeutic significance.

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Conflict of interest statement

Competing interests: Y.H.-B. is employed by Inflammatix, Inc. P.K. is co-founder of and consultant to Inflammatix, Inc. T.E.S. is co-founder and CEO of Inflammatix, Inc. Gene expression sequencing was funded by Inflammatix, Inc.; however Inflammatix employees were not involved in the analytical plan, performance or supervision of analyses. N.J.M. reports consulting fees from Novartis, Inc., AstraZeneca, Inc. and Endpoint Health, Inc. (>2 years ago). E.J.G. has received honoraria from Abbott Products Operations AG, bioMérieux, Brahms GmbH, GSK, InflaRx GmbH, Sobi and Xbiotech Inc.; independent educational grants from Abbott Products Operations, bioMérieux Inc, InflaRx GmbH, Johnson & Johnson, MSD, UCB and Swedish Orphan Biovitrum AB; and funding from the Horizon 2020 European Grants ImmunoSep and RISCinCOVID and the Horizon Health grant EPIC-CROWN-2, Homi-LUNG and POINT (granted to the Hellenic Institute for the Study of Sepsis or to the National and Kapodistrian University of Athens). H.R.B. has received unrestricted institutional funding from Becton Dickinson, Inflammatix, Octapharma, OSAsense and MeMed. J.H. is employed by Danaher Diagnostics. Danaher Diagnostics played no role in the study. The other authors declare no competing interests.

Update of

International multi-cohort analysis identifies novel framework for quantifying immune dysregulation in critical illness: results of the SUBSPACE consortium.
Moore AR, Zheng H, Ganesan A, Hasin-Brumshtein Y, Maddali MV, Levitt JE, van der Poll T, Scicluna BP, Giamarellos-Bourboulis EJ, Kotsaki A, Martin-Loeches I, Garduno A, Rothman RE, Sevransky J, Wright DW, Atreya MR, Moldawer LL, Efron PA, Marcela K, Karvunidis T, Giannini HM, Meyer NJ, Sweeney TE, Rogers AJ, Khatri P. Moore AR, et al. bioRxiv [Preprint]. 2024 Nov 15:2024.11.12.623298. doi: 10.1101/2024.11.12.623298. bioRxiv. 2024. Update in: Nat Med. 2025 Sep 30. doi: 10.1038/s41591-025-03956-5. PMID: 39605502 Free PMC article. Updated. Preprint.

References

1. Berthelsen, P. G. & Cronqvist, M. The first intensive care unit in the world: Copenhagen 1953. Acta Anaesthesiol. Scand. 47, 1190–1195 (2003). - PubMed - DOI
1. Zimmerman, J. E., Kramer, A. A. & Knaus, W. A. Changes in hospital mortality for United States intensive care unit admissions from 1988 to 2012. Crit. Care 17, R81 (2013). - PubMed - PMC - DOI
1. Maslove, D. M. et al. Redefining critical illness. Nat. Med. 28, 1141–1148 (2022). - PubMed - DOI
1. Marshall, J. C. Why have clinical trials in sepsis failed? Trends Mol. Med. 20, 195–203 (2014). - PubMed - DOI
1. Antcliffe, D. B. et al. Transcriptomic signatures in sepsis and a differential response to steroids. From the VANISH randomized trial. Am. J. Respir. Crit. Care Med. 199, 980–986 (2019). - PubMed - PMC - DOI

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A consensus immune dysregulation framework for sepsis and critical illnesses

Affiliations

A consensus immune dysregulation framework for sepsis and critical illnesses

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Update of

References

Grants and funding

LinkOut - more resources

Full Text Sources