Refining the Clinical Utility of Plasma Microbial Cell-Free DNA Sequencing in High-Risk Population of Infection: A Narrative Review.

Plasma microbial cell-free DNA sequencing (mcfDNA-seq) has emerged as a promising diagnostic and prognostic tool for infectious diseases, with early enthusiasm driven by its potential to outperform conventional microbiological assays in detection sensitivity. However, its anticipated clinical superiority has not consistently translated into transformative improvements in infection management, particularly in high-risk populations. Since its inception in 2015, key controversies have persisted regarding the optimal timing of mcfDNA-seq testing, clinical utility of longitudinal quantification, preferred testing modality (plasma mcfDNA-seq vs blood cell DNA sequencing), and integrative analysis of mcfDNA-seq data incorporating host immune biomarkers and antimicrobial resistance (AMR) gene profiling to enhance diagnostic precision. To address these unresolved questions, this review synthesizes the current evidence on the clinical applications of plasma mcfDNA-seq, critically evaluates its performance across diverse infectious disease contexts, and concludes by delineating future challenges and opportunities to optimize its translational utility for clinical practice.