Improved pathogen identification in sepsis or septic shock by clinical metagenomic sequencing - 12/09/25

Doi : 10.1016/j.jinf.2025.106565

Thorsten Brenner ^a,^b,^⁎ , Sebastian O. Decker ^a, Yevhen Vainshtein ^c, Silke Grumaz ^c,^ab, Mehdi Manoochehri ^c, Manuel Feißt ^d, Andrea Seidel-Glätzer ^e, Mathias W. Pletz ^f, Hendrik Bracht ^g,^ac, Marc M. Berger ^b, Kristina Fuest ^h, Manfred Blobner ^g,^h, Friedhelm Bach ⁱ, Onnen Moerer ^j, Timo Brandenburger ^k, Thomas Dimski ^k, Klaudiusz Suchodolski ^l, Ulrike Jäkel ^m, Jana Zischkau ^m, Helene Häberle ⁿ, Peter Rosenberger ⁿ, Tobias Schürholz ^o,^p, Simone Lindau ^q, Stefan J. Schaller ^h,^r,^ad, Christian Putensen ^s, Fabian Dusse ^t, Sirak Petros ^u, Max Gaasch ^v, Christian Nusshag ^w, Markus A. Weigand ^a, Kai Sohn ^c,^⁎
for the German Society of Anaesthesiology and Intensive Care (GSAIC) Trials Group
Karolina Glanz ^x, Eberhard Barth ^y, Martin S. Winkler ^z, Hans-Jörg Gillmann ^aa
^x Fraunhofer IGB, Nobelstr. 12, 70569 Stuttgart, Germany
^y University Ulm, Faculty of Medicine, Department of Anaesthesiology & Intensive Care Medicine, Ulm, Germany
^z Department of Anesthesiology, University Medical Center Göttingen (UMG), Medical University of Göttingen, Göttingen, Germany
^aa Klinik für Anästhesiologie und Intensivmedizin, Medizinische Hochschule Hannover, Hannover, Germany

^a Heidelberg University, Medical Faculty Heidelberg, Department of Anesthesiology, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
^b Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
^c Fraunhofer IGB, Nobelstr. 12, 70569 Stuttgart, Germany
^d Insitute of Medical Biometry, University of Heidelberg, Im Neuenheimer Feld 130.3, 69120 Heidelberg, Germany
^e Coordination Centre for Clinical Trials (KKS), Ruprecht-Karls-University, Berliner Straße 10, 69120 Heidelberg, Germany
^f Institute of Infectious Diseases and Infection Control, Jena University Hospital, Erlanger Allee 101, 07740 Jena, Germany
^g University Ulm, Faculty of Medicine, Department of Anaesthesiology & Intensive Care Medicine, Ulm, Germany
^h Technical University of Munich, School of Medicine and Health, Department of Anaesthesiology and Intensive Care Medicine, Munich, Germany
ⁱ Abteilung Klinische Infektiologie, Evangelisches Klinikum Bethel, Universitätsklinikum OWL der Universität Bielefeld, Campus Bielefeld Bethel, Bielefeld, Germany
^j Department of Anesthesiology, University Medical Center Göttingen (UMG), Medical University of Göttingen, Göttingen, Germany
^k Department of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany
^l Klinik für Anästhesiologie und Intensivmedizin, Medizinische Hochschule Hannover, Hannover, Germany
^m Anästhesie und Intensivmedizin, Evangelisches Krankenhaus Luckau, Luckau, Germany
ⁿ Department of Anesthesiology and Intensive Care Medicine, University Hospital Tuebingen, Eberhard-Karls-University, Hoppe-Seyler-Strasse 3, 72076 Tuebingen, Germany
^o Department of Anesthesia and Intensive Care, Rostock University Medical Center, Rostock, Germany
^p Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Aachen, Germany
^q Goethe University Frankfurt, Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, 60590 Frankfurt, Germany
^r Charité - Universitätsmedizin Berlin, corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine (CCM/CVK), Berlin, Germany
^s Department of Anesthesiology and Surgical Intensive Care Medicine, Division of Intensive Care Medicine, Universitätsklinikum Bonn, Bonn, Germany
^t Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Kerpener Straße 62, 50937 Cologne, Germany
^u Medical ICU, University Hospital Leipzig, Leipzig, Germany
^v Department of Anaesthesiology and Intensive Care Medicine, General Hospital of Heidenheim, Heidenheim, Germany
^w Department of Nephrology, Heidelberg University Hospital, Im Neuenheimer Feld 162, Heidelberg, Germany
^ab Noscendo GmbH, Duisburg, Germany
^ac Department of Anesthesiology, Intensive Care, Emergency Medicine, Transfusion Medicine, and Pain Therapy, University Hospital of Bielefeld, Campus Bielefeld-Bethel, Bielefeld, Germany
^ad Medical University of Vienna, Department of Anaesthesia Intensive Care Medicine and Pain Medicine, Clinical Division of General Anaesthesia and Intensive Care Medicine, Vienna, Austria

^∗Corresponding author at: Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany.Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University Duisburg-EssenHufelandstr. 55Essen45147Germany^∗∗Correspondence to: Innovation Field of In Vitro Diagnostics, Fraunhofer IGB, Nobelstr. 12, 70569 Stuttgart, Germany.Innovation Field of In Vitro Diagnostics, Fraunhofer IGBNobelstr. 12Stuttgart70569Germany

Summary

Objectives

Despite limited sensitivity and specificity, blood cultures (BCs) still represent the gold standard of diagnostic care in septic patients. We aimed to overcome current diagnostic limitations by unbiased next-generation sequencing (NGS) of circulating microbial cell-free DNA (mcfDNA) in plasma samples.

Methods

We performed a prospective, observational, non-interventional, multicenter study (Next GeneSiS-Trial) to compare positivity rates for NGS-based identification of causative pathogens with BCs in patients suffering from sepsis or septic shock. An independent expert panel (n=3) retrospectively evaluated the plausibility of NGS-based findings and the potential for anti-infective treatment adaptations based on NGS results.

Results

The positivity rate of NGS-based diagnostics (NGS+) for 491 septic patients was 70.5% compared to positive BCs (BC+) with 19.4% within the first three days after sepsis onset. NGS+ results were evaluated as plausible in 98.6% of cases by the expert panel. Based on the experts´ recommendations, additional knowledge of NGS-based pathogen findings would have resulted in anti-infective treatment adaptations in 32.6% of all patients. Potentially inadequately treated NGS+/blood culture negative (BC-) patients showed worse outcomes.

Conclusion

The integration of NGS-based pathogen diagnostics in sepsis has the potential to improve patients´ outcomes as compared to a treatment strategy based on standard-of-care microbiological diagnostics alone.

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Graphical Abstract

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Highlights

•	Sepsis represents a major global health threat with up to 11 million deaths per year.
•	Blood cultures still represent the gold standard of diagnostic care in sepsis.
•	NextGeneSiS-Trial benchmarks clinical metagenomic pathogen diagnostics in sepsis.
•	Clinical metagenomics provides higher detection rates and plausibilities.
•	Next-generation sequencing has the potential to improve patients’ outcomes.

Le texte complet de cet article est disponible en PDF.

Keywords : Critical care, Bacteremia, Blood culture, Next-generation sequencing, NGS, Microbial cell-free DNA, Molecular diagnostics, Outcome, Clinical metagenomics

Plan

Introduction

Pathophysiology and epidemiology of sepsis

Guideline-compliant sepsis care

Recent challenges in sepsis care

Metagenomic next-generation sequencing (NGS) for pathogen identification in sepsis

Materials and methods

Study design

Sample collection and standard-of-care microbiological analyses

NGS-based workflow

Outcome analyses by expert panel evaluation

Statistical methods

Results

Study cohort and state-of-the-art microbiological diagnostics

Performance characteristics of BC and NGS-diagnostics

Clinical value of the NGS-based approach

Discussion

Funding

Author contributions

Export

Vol 91 - N° 3

Article 106565- septembre 2025 Retour au numéro

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Improved pathogen identification in sepsis or septic shock by clinical metagenomic sequencing - 12/09/25

Summary

Objectives

Methods

Results

Conclusion

Graphical Abstract

Highlights

Plan

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