Identification of functional bacterial-viral pneumotypes associated with airway inflammation and all-cause mortality in critically ill patients

Alterations in lung virome and bacteriome compositions have been associated with hospital-acquired pneumonia in critically ill patients, but data on lung microbiome functions underlying progression to severe complications remain unclear. Combining viral-metagenomics with metatranscriptomics analyses of 184 endotracheal aspirates (ETAs) collected in 94 intubated critically ill patients, we identified a high-risk functional pneumotype associated with lung inflammation and mortality. This unfavourable pneumotype was characterised by enrichment in virulent Streptococcus- bacteriophages and temperate Klebsiella- bacteriophages, decreased transcriptional activity of commensal taxa such as Streptococcus and Alloprevotella , and increased transcriptional activity of Klebsiella pneumoniae . Machine-learning models defined two-viral- and four-bacterial-factor signatures predicting unfavourable pneumotype (AUC 0.9 and 0.8, respectively). Validation in an independent cohort of 117 ICU patients (239 ETAs) demonstrated the robustness of the association of these signatures with the risk of mortality. Causal inference identified virulent bacteriophages associated with Streptococcus and Alloprevotella and host genes including CCL2 , PLGRKT and PTX3 , as key regulators of severe lung dysbiosis linked to mortality in critically ill patients.