Integrated host-microbe plasma metagenomics for sepsis diagnosis in a prospective cohort of critically ill adultsKatrina L. Kalantar, Lucile Neyton, Mazin Abdelghany, Eran Mick, Alejandra Jauregui, Saharai Caldera, Paula Hayakawa Serpa, Rajani Ghale, Jack Albright, Aartik Sarma, Alexandra Tsitsiklis, Aleksandra Leligdowicz, Stephanie A. Christenson, Kathleen Liu, Kirsten N. Kangelaris, Carolyn Hendrickson, Pratik Sinha, Antonio Gomez, Norma Neff, Angela Pisco, Sarah B. Doernberg, Joseph L. Derisi, Michael A. Matthay, Carolyn S. Calfee & Charles R. Langelier
Nature Microbiology, 2022Abstract: 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.
