Hyperinflammatory ARDS is characterized by interferon-stimulated gene expression, T-cell activation, and an altered metatranscriptome in tracheal aspirates

Two molecular phenotypes of the acute respiratory distress syndrome (ARDS) with substantially different clinical trajectories have been identified. Classification as "hyperinflammatory" or "hypoinflammatory" depends on systemic biomarker profiling. Differences in the biology underlying these phenotypes at the site of injury, the lung, are unknown. We analyze tracheal aspirate transcriptomes from 46 mechanically ventilated subjects to assess differences in lung inflammation and repair between ARDS phenotypes. We then integrate these results with metatranscriptomic sequencing, single cell RNA sequencing, and plasma proteomics to identify distinct features of each ARDS phenotype. We also compare phenotype-specific differences in gene expression to experimental models of acute lung injury and use an in silico analysis to identify candidate treatments for each phenotype. We find that hyperinflammatory ARDS is associated with increased integrated stress response and interferon gamma signaling, distinct immune cell polarization, and differences in microbial community composition in TA. These findings demonstrate that each phenotype has distinct respiratory tract biology that may be relevant to developing effective therapies for ARDS.