Whole Blood Transcriptomic Response to Perioperative Dexamethasone in Total Knee Arthroplasty: A Targeted Panel Analysis.

Abstract

Changes in the transcriptome of immune cells are predictive of clinical outcomes. These effects may be surgery-specific and possibly modulated by glucocorticoids. We investigated the immune response and the impact of dexamethasone on the response in patients undergoing total knee arthroplasty (TKA). The transcript levels (n = 579) in whole blood of 63 patients undergoing TKA and receiving either dexamethasone (DXM, n = 46) or placebo (n = 17) perioperatively were characterised by the Nanostring nCounter platform and the Immunology V2 panel. Samples were collected before surgery and on the first postoperative day (POD1). Dexamethasone induced differential expression of 113 genes (|log2 fold change| > 0.5, adjusted p-value [p-adj] < 0.05). Pathway enrichment analysis using an Over-Representation Analysis (ORA) indicated an up-regulation of IL6/JAK-STAT3-signalling (p-adj 0.016) and down-regulation of a pathway related to allograft-rejection (p-adj 0.032). The immune response itself induced differential expression of 169 genes and ORA only found an allograft rejection pathway significant (p-adj 0.016). Cell type deconvolution indicated that dexamethasone increased the granulocyte fraction (69.6% vs. 73.6%, p-adj = 0.005) and reduced B- and Plasma-cell fraction (10.1% vs. 8.4%, p-adj = 0.016). The granulocyte fraction on POD1 was significantly different between dexamethasone and placebo-treated patients (73.6% vs. 70.1%, p-adj = 0.048). Perioperative dexamethasone in TKA induced differential expression of genes related to IL6-JAK/STAT3-signalling as estimated by the Immunology V2 panel. This, however, is not supported by the literature or a rank-based interpretation of the most differentially expressed genes and was most likely due to technical reasons. Future studies should focus on broader panels, different techniques or measures leading to fewer exclusions of genes during quality control when seeking to characterise the immune response to TKA and dexamethasone. This transcriptomic sub‑study shows that perioperative dexamethasone does not simply suppress, but distinctly reshapes, the early whole‑blood immune response to total knee arthroplasty. However, the study investigated an early postoperative snapshot after a single perioperative dose only. Thus, longitudinal linkage to circulating biomarkers of inflammation and injury as well as clinical outcomes could not be assessed. This study therefore should be regarded as hypothesis‑generating, urging for extended, multi‑modal and outcome‑oriented studies before concluding on the broader clinical effects of perioperative dexamethasone.