Improved pathogen identification in sepsis or septic shock by clinical metagenomic sequencing
- PMID: 40774415
- DOI: 10.1016/j.jinf.2025.106565
Improved pathogen identification in sepsis or septic shock by clinical metagenomic sequencing
Abstract
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.
Keywords: Bacteremia; Blood culture; Clinical metagenomics; Critical care; Microbial cell-free DNA; Molecular diagnostics; NGS; Next-generation sequencing; Outcome.
Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.
Conflict of interest statement
Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Thorsten Brenner received scientific grants from Deutsche Forschungsgemeinschaft (DFG), Innovation Fund of the Federal Joint Committee (G-BA), Dietmar Hopp Stiftung, Heidelberg Foundation of Surgery as well as Stiftung Universitätsmedizin Essen. Moreover, he received honoraria for lectures as well as advisory board participation from Baxter Deutschland GmbH, Schöchl medical education GmbH, Boehringer Ingelheim Pharma GmbH, CSL Behring GmbH, Astellas Pharma GmbH, B. Braun Melsungen AG, MSD Sharp & Dohme GmbH, BRAHMS GmbH, Lücke Kongresse GmbH, Georg Thieme Verlag GmbH as well as Akademie für Infektionsmedizin e.V. Sebastian Decker received scientific grants from Heidelberg Foundation of Surgery and B.Braun Foundation as well as research support from SphingoTec GmbH and Inflammatix, Inc. Silke Grumaz and Kai Sohn are co-founders of Noscendo GmbH, a diagnostic company dedicated for detection of pathogens based on Next-generation sequencing Moreover, Silke Grumaz and Kai Sohn are inventors of a patent in bioinformatics algorithms for relevance scoring of sequencing data. Onnen Moerer received scientific grants from Bundesministerium für Bildung und Forschung (BMBF). Furthermore, he received honoraria for lectures during workshops supported by Pulsion (Maquet Critical Care) and from CSL Behring GmbH. Tobias Schuerholz received consulting fees from UMR-V GmbH, Adrenomed AG and Clinomic Group GmbH and honoraria for lectures from Adrenomed AG. Moreover, he received honoraria for advisory board participation from University Hospital Eppendorf, Hamburg, Germany. Fabian Dusse received honoraria for lectures from Forum für Medizinische Fortbildung GmbH, bioMérieux SA, and The First Hospital of Lanzhou University, China. Manfred Blobner received research support from MSD (Haar, Germany), fees for consultancy or lectures from GE Healthcare (Helsinki, Finland), Grünenthal (Aachen, Germany), Senzime (Landshut, Germany), MIPM (Mammendorf, Germany), and Biosyn (Fellbach, Germany). Stefan J Schaller received grants and non-financial support from Reactive Robotics GmbH (Munich, Germany), ASP GmbH (Attendorn, Germany), STIMIT AG (Biel, Switzerland), ESICM (Geneva, Switzerland), grants, personal fees, and non-financial support from Fresenius Kabi Deutschland GmbH (Bad Homburg, Germany), grants from the Innovationsfond of The Federal Joint Committee (G-BA), personal fees from Springer Verlag GmbH (Vienna, Austria) for educational purposes and Advanz Pharma GmbH (Bielefeld, Germany), non-financial support from national and international societies (and their congress organizers) in the field of anesthesiology and intensive care medicine, outside the submitted work. Stefan J Schaller holds stocks in small amounts from Alphabeth Inc., Bayer AG, and Siemens AG; these holdings have not affected any decisions regarding his research or this study. Markus A. Weigand received grants from Köhler Chemie, DFG and BMBF, consulting fees from B. Braun, Gilead, Mundipharma and Boehringer Ingelheim, and payment or honoraria for lectures, presentations, or educational events from MSD, Gilead, Shionogi, Pfizer and Beckman Coulter. He is also a patent owner (EP17185036.5 and EP17198330.7), has participated on advisory boards for MSD, Gilead, Shionogi, Biotest, Pfizer, Eumedica, SOBI and Beckman Coulter, is the secretary general of the German Sepsis Society and member of the scientific advisory council of PEG, and is cofounder of Delta Theragnostics. Martin Winkler received scientific grants from Deutsche Forschungsgemeinschaft, Grifols SA and Sartorius AG. His projects were supported by Inflammatix Inc. and SphingoTec GmbH. He is in the advisory board of Gilead, Inc. and Amomed GmbH.
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