Microbial lung-to-blood translocation associates with systemic inflammation in severe pneumonia: evidence from paired plasma and lower respiratory tract metagenomics

<h4>Background</h4>Biological heterogeneity in host inflammatory responses to severe pneumonia predicts clinical outcomes and may influence the effectiveness of immunomodulatory therapy. The upstream drivers of this heterogeneity remain poorly defined. We hypothesized that microbial translocation from the lungs to the bloodstream, detectable via multi-compartment metagenomic analysis, contributes to divergent host responses in pneumonia.<h4>Methods</h4>In this nested case-control study of mechanically ventilated patients with severe pneumonia, we collected paired plasma and endotracheal aspirate samples at baseline. Plasma samples underwent microbial cell-free DNA (mcfDNA) sequencing, and endotracheal aspirates were analyzed by Nanopore metagenomic sequencing. Host-response biomarkers were measured in both plasma and endotracheal aspirate samples. Microbial translocation of pulmonary origin was defined by the genus-level concordance of detectable taxa between matched endotracheal aspirate and plasma samples.<h4>Results</h4>Among 98 patients (76 pneumonia, 22 controls), plasma mcfDNA was markedly higher in microbiologically confirmed pneumonia compared with culture-negative pneumonia (median 4015 vs. 210 molecules/μL, p = 0.0006). Pulmonary microbial translocation was identified in 31 (41%) pneumonia patients and correlated significantly with plasma soluble ST2 levels, independent of clinical severity. Patients classified into the prognostically adverse hyperinflammatory subphenotype exhibited greater translocating microbial DNA levels compared to hypoinflammatory patients (p = 0.04), further linking translocation to host-response heterogeneity.<h4>Conclusions</h4>Microbial lung-to-blood translocation is a measurable biological process associated with systemic inflammatory heterogeneity in severe pneumonia. This pathway may represent a novel mechanistic target for precision therapeutic strategies aimed at mitigating immune dysregulation.