Introduction: Morbidity and mortality in patients hospitalised with lower respiratory tract infection (LRTI) remains high and emerging anti-inflammatory therapies may improve patient outcomes.

Aim: Characterise the systemic immune response in LRTI to determine therapeutic potential.

Methods: Patients with non-COVID LRTI (n=78) and matched controls (n=55) were enrolled within 96h of admission to Ninewells Hospital, Dundee (May2020?May2021) and blood sampling performed. Peripheral blood leukocytes were analysed by mRNAseq and 45 serum cytokines measured by immunoassay.

Results: LRTI patients were aged 66.1±15.8 (mean±SD), 46(59%) were male, 55.1% and 38.5% had unilobar or bilateral pneumonia, respectively. The 29-day mortality rate was 7.7%.

Serum IL6 (ROC analysis; AUC(95%CI); 0.75(0.66-0.84)) and OSM (0.70(0.60-0.81))(p?0.0001) were discriminating for LRTI vs. controls. IL6 (0.80(0.67-0.92)) and also IFN-inducible IL15 (0.76(0.64-0.87))(p?0.0001) were the most predictive markers of 29-day mortality. Changes in IFN signalling genes were observed by mRNAseq in non-survivors and in lymphopenic patients (<0.5x10⁹ cells/L).

Serum TRAIL was also discriminating between LRTI and controls (0.79(0.69-0.88)) but was conversely lower in LRTI patients (p?0.0001); those with the lowest levels had higher blood neutrophil counts(p=0.005) and mRNAseq demonstrated alterations in complement, proteolysis and B cell activation pathways. In those with unilateral vs. bilateral pneumonia there were 391 significant differentially expressed genes, including changes in extracellular matrix organisation pathways.

Conclusion: Systemic immune responses are associated with clinical and radiological features of LRTI.