Plasma and Serum Metagenomic Sequencing of Microbial Cell-Free Nucleic Acids for Suspected Central Nervous System Infection: A Systematic Review

Background/Objectives: Untargeted metagenomic sequencing of microbial cell-free DNA or RNA in plasma or serum offers pathogen detection without lumbar puncture or biopsy, but its value in suspected central nervous system (CNS) infection is uncertain. We reviewed diagnostic yield, agreement with CNS-site testing, clinical impact, and failure modes.

Methods

PubMed/MEDLINE was searched with seven documented strings (inception to 2 September 2026), supplemented by citation and web searching. Eligible reports were primary human studies of untargeted plasma or serum metagenomic sequencing with a separable result in patients with suspected or confirmed infectious CNS syndromes. Selection, extraction, and design-specific risk-of-bias appraisal followed PRISMA 2020 and were performed independently by two authors with disagreements resolved by discussion; the search was restricted to PubMed/MEDLINE and no protocol was registered. Synthesis was narrative because designs and reference standards were incompatible.