ORIGINAL RESEARCH article
Front. Immunol.
Sec. Microbial Immunology
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1601316
This article is part of the Research TopicAdvancing Understanding of Neonatal Bacterial InfectionsView all 8 articles
Transcriptomic Mortality Signature Defines High-Risk Neonatal Sepsis Endotype
Provisionally accepted
- 1The Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
- 2College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States
- 3Department of Biomedical Informatics, School of Medicine, Emory University, Atlanta, Georgia, United States
- 4Division of Neonatology, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida, United States
- 5Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, North Carolina, United States
- 6Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
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Introduction: Neonatal sepsis remains a leading cause of global childhood mortality, yet treatment options are limited. Clinical and biological heterogeneity hinders the development of targeted therapies. Gene-expression profiling offers a potential strategy to identify neonatal sepsis subtypes and guide targeted intervention. Methods: We performed secondary analyses of publicly available gene-expression datasets. Differential gene expression analysis and T-distributed Stochastic Neighbor Embedding (t-SNE) identified biologically relevant patient clusters. Mortality and organ dysfunction were compared across clusters to determine clinical relevance. Results: We identified three endotypes of neonatal sepsis based on the 100 gene expression mortality signature, distinguishing five non-survivors from 72 survivors across datasets. Compared with other endotypes, Endotype A was associated with high mortality (22% vs. 0%, p=0.003) and cardiac dysfunction (61% vs. 31%, p=0.025). Pathobiology among endotype A patients was primarily driven by neutrophil progenitors. Conclusions: Gene-expression profiling can be used to disentangle neonatal sepsis heterogeneity. Dysregulated hyperinflammatory response with emergency granulopoiesis was pathognomonic of high-risk endotype A. Pending further validation, gene-expression-based subclassification may be used to identify at-risk neonates and inform the selection of targeted sepsis therapies.
Keywords: Neonatal sepsis, Mortality, gene-expression profiling, Endotypes, Neutrophils
Received: 27 Mar 2025; Accepted: 11 Jun 2025.
Copyright: © 2025 Al Gharaibeh, Huang, Wynn, Kamaleswaran and ATREYA. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Faris Al Gharaibeh, The Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
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