Host and Microbe Blood Metagenomics Reveals Key Pathways Characterizing Critical Illness Phenotypes.

Rationale: Two molecular phenotypes of sepsis and acute respiratory distress syndrome, termed hyperinflammatory and hypoinflammatory, have been consistently identified by latent class analysis in numerous cohorts, with widely divergent clinical outcomes and differential responses to some treatments; however, the key biological differences between these phenotypes remain poorly understood. Objectives: We used host and microbe metagenomic sequencing data from blood to deepen our understanding of biological differences between latent class analysis-derived phenotypes and to assess concordance between the latent class analysis-derived phenotypes and phenotypes reported by other investigative groups (e.g., Sepsis Response Signature [SRS1-2], molecular diagnosis and risk stratification of sepsis [MARS1-4], reactive and uninflamed). Methods: We analyzed data from 113 patients with hypoinflammatory sepsis and 76 patients with hyperinflammatory sepsis enrolled in a two-hospital prospective cohort study. Molecular phenotypes had been previously assigned using latent class analysis. Measurements and Main Results: The hyperinflammatory and hypoinflammatory phenotypes of sepsis had distinct gene expression signatures, with 5,755 genes (31%) differentially expressed. The hyperinflammatory phenotype was associated with elevated expression of innate immune response genes, whereas the hypoinflammatory phenotype was associated with elevated expression of adaptive immune response genes and, notably, T cell response genes. Plasma metagenomic analysis identified differences in prevalence of bacteremia, bacterial DNA abundance, and composition between the phenotypes, with an increased presence and abundance of Enterobacteriaceae in the hyperinflammatory phenotype. Significant overlap was observed between these phenotypes and previously identified transcriptional subtypes of acute respiratory distress syndrome (reactive and uninflamed) and sepsis (SRS1-2). Analysis of data from the VANISH trial indicated that corticosteroids might have a detrimental effect in patients with the hypoinflammatory phenotype. Conclusions: The hyperinflammatory and hypoinflammatory phenotypes have distinct transcriptional and metagenomic features that could be leveraged for precision treatment strategies.