A transcriptomic approach to understand patient susceptibility to pneumonia after abdominal surgery

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 adaptive-immune suppression. Cell-type deconvolution of preoperative RNA-sequencing revealed elevated S100A8/9-high neutrophils alongside reduced naive 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.

Early dynamic changes to monocytes following major surgery are associated with subsequent infections

“…Several studies have investigated the change in immunophenotype of patients following surgery ( 4 , 5 , 13 – 15 , 23 , 24 ). However, few studies have investigated the effect on the dynamic immune response to a subsequent in vitro challenge before and after surgery and how this differs between patients who develop post-operative infections and those who do not.…”

“…An unsupervised analysis of a wider panel of markers may reveal other druggable targets. Several studies have assessed the transcriptomic profile of immune cells in the perioperative period, although transcriptional changes may not be reflected in cell surface proteins/receptor expression, and bulk transcriptomics do not directly assess the phenotype of specific cell subsets ( 4 , 24 ).…”

“…Patients who developed an infection had a longer hospital length of stay (p = 0.0001) although there were no differences in unplanned ICU readmission or mortality (Table 1). Antibiotic duration was a median of 5 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12) days for treatment of post-operative infections. Continuous data were analyzed using Mann-Whitney U-test for comparison of two groups, whereas chi-squared test was used for analysis of categorical data.…”

“…This response is influenced by a myriad of factors including patient age, medical conditions (e.g., cancer), and medications. A number of immune responses following surgery are associated with subsequent infections ( 4 , 5 ). Two well-characterized changes associated with post-operative infections are a reduction in monocyte HLA-DR (human leukocyte antigen–DR isotype) and persistent lymphopenia ( 6 , 7 ).…”

High-throughput mass spectrometry maps the sepsis plasma proteome and differences in patient response

“…This was an observational study designed to understand the sepsis proteomic response and individual heterogeneity by assaying the plasma proteome of multiple sepsis and nonsepsis comparator cohorts and integrating with paired leukocyte transcriptomic data. Study cohorts included UK GAinS (10,25) [patients admitted to ICU with sepsis (49) due to CAP or FP (50)(51)(52)], VANISH (53) (clinical trial cohort of all-cause sepsis requiring vasopressors), HVs from the Oxford BioBank (54), elective surgery patients [X-MINS (55) and BIONIC (56)], and noninfected ICU patients [MOTION (57), MONOGRAM, and TACE (58)] with cohorts described in the Supplementary Materials (numbers of individuals and samples given in data file S1). Our processed timsTOF sepsis proteomics data were split into two nonoverlapping cohorts for some analyses.…”