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Metagenomic RNA and DNA next generation sequencing can pinpoint sepsis patients from those with non-infectious systemic inflammatory conditions. From whole-blood gene expression data, patients with sepsis were distinguished from those with non-infectious systemic inflammatory conditions using a trained bagged support vector machine (bSVM) classifier.

Pathogen detection of plasma mNGS varied on the basis of pathogen and site of infection. To improve detection of virus, the group developed a secondary transcriptomic classifier. They combined host and microbial features to develop an integrated sepsis diagnostic model that identified 99% of microbiologically confirmed sepsis cases, and predicted sepsis in 74% of suspected and 89% of indeterminate sepsis cases.

The work was led by researchers at the Chan Zuckerberg Biohub and was published in Nature Microbiology.

Sepsis causes 20% of all deaths globally and contributes to 20–50% of hospital deaths in the United States alone. Early detection is crucial, but in over 30% of cases the underlying microbial pathogens are never identified. As a result, antibiotic treatment is typically not pathogen-targeted, with clinical decision-making based on epidemiological information rather than individual patient data. Similarly, clinicians often continue antimicrobial treatment despite negative microbiologic testing.

“Both scenarios,” the authors write, “lead to antimicrobial overuse and misuse, which contributes to treatment failures, opportunistic infections such as C. difficile colitis and the emergence of drug-resistant organisms.”

With the introduction of culture-independent methods such as metagenomic next generation sequencing (mNGS), limitations in sepsis diagnostics may be overcome. Recent advancements in plasma cell-free DNA sequencing have expanded the scope of metagenomic diagnostics by enabling minimally invasive detection of circulating pathogen nucleic acid originating from diverse anatomical sites of infection.

This team carried out integrated host and pathogen metagenomic RNA and DNA (mNGS) of whole blood and plasma from critically ill patients following hospital admission. They assigned patients into sepsis groups on the basis of clinical and microbiological criteria. Plasma RNA also yielded a transcriptional signature of sepsis with several genes previously reported as sepsis biomarkers, and a bSVM sepsis diagnostic.

As the authors write: “Patients were categorized into five subgroups on the basis of sepsis status. These included patients with: (1) clinically adjudicated sepsis and a microbiologically confirmed bacterial bloodstream infection (Sepsis), (2) clinically adjudicated sepsis and a microbiologically confirmed non-bloodstream infection (Sepsis), (3) suspected sepsis with negative clinical microbiologic testing (Sepsis), (4) patients with no evidence of sepsis and a clear alternative explanation for their critical illness (No-sepsis) or (5) patients of indeterminate status (Indeterm).”

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