Abstract
BACKGROUND: Immune response dysregulation has been implicated in the development of intensive care unit (ICU)-acquired pneumonia. We aimed to determine differences in the longitudinal blood transcriptional response between patients who develop ICU-acquired pneumonia (cases) and those who do not (controls). METHODS: We performed a case-cohort study in mechanically ventilated trauma and surgery patients with ICU stays >2 days, enrolled in 30 hospitals across Europe. We collected blood for RNA sequencing at baseline, day 7 and (in cases) the day of pneumonia diagnosis. We performed gene set enrichment analysis and analysed longitudinal gene expression changes using linear mixed models. External validation was performed using an independent trauma cohort. RESULTS: We enrolled 113 cases and 115 controls, with similar baseline characteristics. At baseline (median 2 days after ICU admission), cases showed upregulated gene pathways relating to innate immunity, haemostasis and metabolism, and downregulated adaptive immune pathways. These changes persisted at the day of pneumonia diagnosis (median 6 days, compared to day 7 in controls). In the longitudinal comparison, cases exhibited enhanced upregulation of innate immunity, adaptive immunity and haemostasis pathways, along with enhanced downregulation of metabolism pathways, relative to controls (all p<0.00001, except haemostasis p<0.05). These findings were largely externally validated. Cases had higher quantitative sepsis response signature scores (p<0.001), reflective of immune dysregulation. CONCLUSION: Patients developing ICU-acquired pneumonia exhibit distinct blood transcriptional responses shortly after ICU admission and in the subsequent path to pneumonia, suggestive of broad immune dysfunction with both immunosuppressive and inflammatory features.