Journal Article

Integrated host-microbe plasma metagenomics for sepsis diagnosis in a prospective cohort of critically ill adults

Derisi, Joseph L., Neff, Norma, Christenson, Stephanie A., Caldera, Saharai, Abdelghany, Mazin, Sinha, Pratik, Kalantar, Katrina L., Albright, Jack, Langelier, Charles R., Tsitsiklis, Alexandra, Hendrickson, Carolyn, Mick, Eran, Gomez, Antonio, Leligdowicz, Aleksandra, Neyton, Lucile, Liu, Kathleen, Doernberg, Sarah B., Ghale, Rajani, Sarma, Aartik, Pisco, Angela, Calfee, Carolyn S., Matthay, Michael A., Serpa, Paula Hayakawa, Kangelaris, Kirsten N., Jauregui, Alejandra

2022

Overview

We carried out integrated host and pathogen metagenomic RNA and DNA next generation sequencing (mNGS) of whole blood ( n  = 221) and plasma ( n  = 138) from critically ill patients following hospital admission. We assigned patients into sepsis groups on the basis of clinical and microbiological criteria. From whole-blood gene expression data, we distinguished patients with sepsis from patients with non-infectious systemic inflammatory conditions using a trained bagged support vector machine (bSVM) classifier (area under the receiver operating characteristic curve (AUC) = 0.81 in the training set; AUC = 0.82 in a held-out validation set). Plasma RNA also yielded a transcriptional signature of sepsis with several genes previously reported as sepsis biomarkers, and a bSVM sepsis diagnostic classifier (AUC = 0.97 training set; AUC = 0.77 validation set). Pathogen detection performance of plasma mNGS varied on the basis of pathogen and site of infection. To improve detection of virus, we developed a secondary transcriptomic classifier (AUC = 0.94 training set; AUC = 0.96 validation set). We 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. In summary, we suggest that integrating host transcriptional profiling and broad-range metagenomic pathogen detection from nucleic acid is a promising tool for sepsis diagnosis. Combined host transcriptional profiling and metagenomic pathogen detection of whole blood and plasma samples from critically ill patients enables the generation of classifiers for reliable prediction of sepsis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38 / 38/23 / 38/90 / 38/91 / 631/326/2521 / 631/61/514/2254 / 692/4017 / 692/53/2421 / 692/699/255 / Adult / Biomedical and Life Sciences / Blood / Cohort Studies / Critical Illness / Diagnosis / DNA sequencing / Gene expression / Humans / Infectious Diseases / Inflammation / Life Sciences / Medical Microbiology / Metagenomics / Microbiology / Next-generation sequencing / Parasitology / Pathogens / Patients / Plasma / Prospective Studies / RNA / Sepsis / Sepsis - diagnosis / Transcription / Transcriptomics / Virology