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. Here, we analyse 184 endotracheal aspirates (ETAs) collected in 94 intubated critically ill patients enrolled in a clinical trial (NCT04793568). Combining viral-metagenomics with metatranscriptomics analyses, we identify a high-risk functional pneumotype observed before the onset of hospital-acquired pneumonia and associated with lung inflammation and mortality. This unfavourable pneumotype is 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 define two-viral- and four-bacterial-factor signatures predicting unfavourable pneumotype (AUC 0.8 and 0.7, respectively). Validation in an independent cohort (NCT02003196) of 117 ICU patients (239 ETAs) demonstrates the robustness of the association of these signatures with the risk of mortality. Causal inference identifies virulent bacteriophages associated with Streptococcus and host genes including IL18R1, ADM and PTX3, as key regulators of severe lung dysbiosis linked to mortality in critically ill patients. Here, the authors identify high-risk viral-bacterial functional pneumotypes associated with all-cause mortality in critically ill patients, which are characterized by expansion of virulent bacteriophages, depletion of health-associated bacteria, and lung inflammation.