Host–microbiome archetypes differentiate infection from pathogen carriage in the human lower airway

Abstract Distinguishing lower respiratory tract infection (LRTI) from incidental pathogen carriage (IPC) is clinically challenging. The immunologic and microbial factors defining the states of LRTI and IPC are poorly understood. Here, we perform host-microbe metatranscriptomic profiling of tracheal aspirates from 326 mechanically ventilated children with clinically adjudicated LRTI ( n = 207), IPC ( n = 70), or non-infectious respiratory failure ( n = 49). In the airway microbiome, LRTI shows reduced alpha diversity and taxonomic richness, while IPC displays greater bacterial abundance, enrichment in respiratory anaerobes, and increased metabolic activity. At the host level, patients with LRTI exhibit a distinct lower airway transcriptional signature of innate and adaptive immune activation compared to those with IPC, who have similar transcriptional profiles to uninfected controls. Mediation analyses suggest the airway microbiome influences the host response to pathogens. An integrated host-microbe metatranscriptomic classifier accurately discriminates LRTI from IPC and controls (AUC = 0.89, 95% confidence interval (CI) 0.85–0.92). The single gene FABP4 , encoding a macrophage-associated lipid chaperone and recently described pneumonia biomarker, performs similarly when combined with alpha diversity; FABP4 protein alone achieves an AUC = 0.88 (95% CI 0.82–0.93). Together, our findings reveal distinct ecological and immunologic archetypes defining LRTI and IPC, and support data-driven, biology-informed LRTI diagnostics incorporating host and microbial features.