Integrated Host-Microbe Signatures Differentiate Respiratory Infection from Incidental Pathogen Carriage

Accurately distinguishing lower respiratory tract infection (LRTI) from incidental pathogen carriage (IPC) is clinically challenging. The host immunologic and microbial factors that define the states of LRTI and IPC are poorly understood. We performed host-microbe metatranscriptomic profiling of tracheal aspirate from 326 mechanically ventilated children with clinically adjudicated LRTI (n=207), IPC (n=70), or non-infectious acute respiratory illnesses (n=49). In the airway microbiome, LRTI was characterized by reduced alpha diversity and taxonomic richness, while IPC was characterized greater total bacterial abundance, enrichment in respiratory anaerobes and increased metabolic activity. In terms of host response, patients with LRTI exhibited a distinct lower airway transcriptional signature of innate and adaptive immune activation compared to those with IPC, who had similar transcriptional profiles as uninfected controls. Mediation analyses suggested that the airway microbiome influences the host response to pathogens. An integrated host-microbe metatranscriptomic classifier discriminated LRTI from IPC and controls with an AUC=0.89 (95% confidence interval (CI) 0.85-0.92). The single gene FABP4, when combined with alpha diversity, performed similarly, and FABP4 protein alone achieved an AUC=0.88 (95% CI 0.82-0.93). Together, our findings reveal distinct ecological and immunologic archetypes that define LRTI and IPC, and support data-driven, biology-informed LRTI diagnostics that incorporate host and microbe.