Abstract
Rationale 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 five-fold increase in 30-day mortality.
Objectives To describe immune-pathways and gene-networks altered following major-abdominal surgery and identify transcriptomic patterns associated with postoperative pneumonia.
Methods and Measurements From a prospective consecutive cohort (n=150) undergoing major-abdominal surgery whole-blood RNA was collected preoperatively and at three time-points postoperatively (2-6, 24 and 48hrs). Twelve patients diagnosed with postoperative pneumonia and 27 matched patients remaining infection-free were identified for analysis with RNA-sequencing.
Main Results Compared to preoperative sampling, 3,639 genes were upregulated and 5,043 downregulated at 2-6hrs. Pathway-analysis demonstrated innate-immune activation with neutrophil-degranulation and Toll-like-receptor signalling upregulation alongside adaptiveimmune 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 48hrs 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.
Competing Interest Statement
Professor Rupert M Pearse declares research grants and/or honoraria from Edwards Lifesciences, Intersurgical and GlaxoSmithkline and Professor Anthony C Gordon declares consulting fees from AstraZeneca, both unrelated to this project. All other authors report no conflict of interest.
Funding Statement
This study was supported in part from the National Institute for Health Research, the National Institute of Academic Anaesthesia, the Medical Research Council, the Wellcome Trust, and the Chinese Academy of Medical Sciences Innovation Fund for Medical Science.
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East Midlands Nottingham 2 Research Ethics Committee gave ethical approval for this work.
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Footnotes
↵† Senior authors
Data Availability
All data produced in the present study are available upon reasonable request to the authors