A Transcriptomic Approach to Understand Patient Susceptibility to Pneumonia After Abdominal Surgery

Abstract

Objective: To describe immune pathways and gene networks altered following major abdominal surgery and to identify transcriptomic patterns associated with postoperative pneumonia. Background: Nosocomial infections are a major healthcare challenge, developing in over 20% of patients aged 45 or over undergoing major abdominal surgery, with postoperative pneumonia associated with an almost 5-fold increase in 30-day mortality. Methods: From a prospective consecutive cohort (n=150) undergoing major abdominal surgery, whole-blood RNA was collected preoperatively and at 3 time-points postoperatively (2–6, 24, and 48 h). Twelve patients diagnosed with postoperative pneumonia and 27 matched patients remaining infection-free were identified for analysis with RNA-sequencing. Results: Compared to preoperative sampling, 3639 genes were upregulated and 5043 downregulated at 2 to 6 hours. Pathway analysis demonstrated innate-immune activation with neutrophil degranulation and Toll-like-receptor signaling upregulation alongside adaptive-immune suppression. Cell-type deconvolution of preoperative RNA-sequencing revealed elevated S100A8/9-high neutrophils alongside reduced naïve CD4 T-cells in those later developing pneumonia. Preoperatively, a gene-signature characteristic of neutrophil degranulation was associated with postoperative pneumonia acquisition (P=0.00092). A previously reported Sepsis Response Signature (SRSq) score, reflecting neutrophil dysfunction and a more dysregulated host response, at 48 hours postoperatively, differed between patients subsequently developing pneumonia and those remaining infection-free (P=0.045). Analysis of the novel neutrophil gene-signature and SRSq scores in independent major abdominal surgery and polytrauma cohorts indicated good predictive performance in identifying patients suffering later infection. Conclusions: Major abdominal surgery acutely upregulates innate-immune pathways while simultaneously suppressing adaptive-immune pathways. This is more prominent in patients developing postoperative pneumonia. Preoperative transcriptomic signatures characteristic of neutrophil degranulation and postoperative SRSq scores may be useful predictors of subsequent pneumonia risk.