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Lancet Respir Med2026;14(4):327-340.April 1, 2026Journal Article

Quantifying immune dysregulation in pneumonia and sepsis with a parsimonious machine-learning model: a multicohort analysis across care settings and reanalysis of a hydrocortisone randomised controlled trial.

Erik H A Michels1, Pierre-François Dequin2, Joe M Butler3, Antoine Guillon2, Bruno Evrard4, Fleur P Paling5, Tom D Y Reijnders3, Alex R Schuurman3, Tjitske S R van Engelen3, Xanthe Brands3, Bastiaan W Haak3, Lieuwe D J Bos6, Carolyn Leroux7, Evangelos J Giamarellos-Bourboulis8, Jaap Stoker9, Jan M Prins10, Daniël R Faber11, Renée A Douma12, Timothy E Sweeney13, Surbhi Malhotra-Kumar14, Jan A J W Kluytmans15, Brendon P Scicluna16, Olaf L Cremer17, Michael Matthay7, Carolyn Calfee7, W Joost Wiersinga18, Hessel Peters-Sengers19, Tom van der Poll18
1Center for Infection and Molecular Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands. Electronic address: e.h.michels@amsterdamumc.nl.
2Department of Critical Care, University Hospital Center of Tours, Inserm UMR 1100, University of Tours, Tours, France.
3Center for Infection and Molecular Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands.
4Inserm CIC 1435, Dupuytren University Hospital, Limoges, France; Medical-Surgical ICU, Dupuytren University Hospital, Limoges, France.
5Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
6Department of Intensive Care, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands.
7Departments of Medicine and Anesthesia, Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, CA, USA.
84th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
9Department of Radiology and Nuclear Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands.
10Department of Internal Medicine, Division of Infectious Disease, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands.
11Department of Internal Medicine, BovenIJ Hospital, Amsterdam, Netherlands.
12Department of Internal Medicine, Flevo Hospital, Almere, Netherlands.
13Inflammatix, Sunnyvale, CA, USA.
14Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
15Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
16Department of Applied Biomedical Science, University of Malta, Msida, Malta; Center for Molecular Medicine and Biobanking, University of Malta, Msida, Malta.
17Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
18Center for Infection and Molecular Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Internal Medicine, Division of Infectious Disease, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands.
19Center for Infection and Molecular Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Epidemiology and Data Science, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
PubMed DOI

Abstract

BACKGROUND: Sepsis is a dysregulated host response to infection resulting in life-threatening organ failure. Although immune dysregulation is central to the sepsis definition, immunomodulation trials enrol participants based on clinical severity, not the extent of dysregulation, which could contribute to treatment heterogeneity. A pragmatic way to quantify immune dysregulation could improve progno…

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