Hospitalised older adults with community-acquired pneumonia and sepsis have dysregulated neutrophil function but preserved glycolysis

Background Community acquired pneumonia (CAP) is a leading cause of hospitalisation in older adults and is associated with greater likelihood of adverse outcomes. Given the ageing population and lack of therapeutic advances in CAP, new strategies to manage the burden of this disease are needed. Neutrophil dysfunction has been widely demonstrated in CAP and is associated with poor outcomes. Neutrophil functions such as migration, phagocytosis and NETosis require glycolysis for effective pathogen control. There is a scarcity of literature addressing neutrophil immunometabolism, especially in disease states. We hypothesised that dysfunctional neutrophil responses in older adults with CAP were due to aberrant glycolytic metabolism.

Methods Prospective observational single site recruiting adults ≥65 years of age with hospitalised but non-intensive care unit CAP, age and frailty matched controls and healthy young adults. Neutrophil functions (chemotaxis to Interleukin 8, respiratory burst, degranulation and cell surface expression) were assessed ex-vivo. Glycolysis was assessed using extracellular flux and RNA sequencing.

Results 25 CAP donors and 32 age matched controls were recruited. CAP participants had severe CAP with median CURB65 score 3 (IQR 3–4) and 30-day mortality was 36%. Ex vivo neutrophils from CAP donors displayed inaccurate migration, impaired respiratory burst in response to PMA and increased spontaneous degranulation compared to age matched controls. Glycolysis was not altered between age matched groups; however, basal rates of neutrophil glycolysis are significantly higher in CAP patients and older adult controls compared to healthy young adults. Also, stimulated glycolysis was significantly higher in young adults compared to older adults with and without CAP (figure 1). RNA sequencing confirmed that expression of glycolytic enzymes were not altered, and glycolytic pathways were not significantly different. Together these data demonstrate that the altered neutrophil function seen in older adults with CAP is not related to glycolysis. Further work to explore the underlying mechanisms is needed.