The human glucocorticoid receptor (GR) is a member of the nuclear transcription fac­tor receptor superfamily. GR binds to its ligand (glucocorticoids) in the cell’s cyto­plasm, and the ligand-bound GR is translocated from the cytosol to the nucleus, regulating gene expression by (1) directly binding glucocorticoid response elements (GREs) in the enhancers and promoters of target genes, (2) physically interacting with (an)other transcription factor(s) (“tethering”), or (3) composite binding of the GR to a GRE and (an)other transcription factor(s) [28, 29]. Genomic activity of the GR modu­lates the expression of up to 20% of the genes in the human genome [30]. Glucocorticoids can also exert more rapid (i.e., in seconds to minutes) but poorly understood, nonge­nomic effects [28, 29]. Glucocorticoids are involved in a number of important physio­logical processes, including glucose metabolism, growth, development, reproduction, and immune response. The anti-inammatory actions of glucocorticoids are multifac­eted and include the downregulation of proinammatory cytokines (e.g., IL-1, IL-6, TNF), decreased expression of adhesion molecules (e.g., SELE, VLA4) on the vascular endothelium and circulating leukocytes, and decreased chemokine production [28]. The specic mechanisms regarding glucocorticoids in CRS treatment remain incom­pletely characterized. However, studies have shown that glucocorticoid treatment is signicantly associated with the reduced expression of the mucin gene MUC4 [31], the eosinophil chemokine eotaxin-2 [32], and the endothelial adhesion molecule P-selectin [33], as well as reduced numbers of eosinophils, CD4+ T cells, and cells expressing the type 2 cytokines IL-4 and IL-13 [33] in nasal polyp tissue.

There are several blinded, randomized, placebo-controlled studies examining the impact of steroid irrigations on symptom severity (Table22.1) [34–40]. Some of these studies are limited by smaller patient populations with heterogeneity among the presenting symptoms. However, most of these studies demonstrate a statistically signicant improvement in subjective and objective outcomes with regard to CRS treatment. The most recent RCT examined adult patients with budesonide irriga­tions (n=33) versus isotonic saline irrigations (n=22) in the postoperative period twice daily for 3months and found that the SNOT-22 at 2weeks was signicantly lower in the budesonide irrigation group at 2weeks and 3months postoperatively with a signicant difference in the Lund-Kennedy Endoscopic Score [34]. In con­trast, studies by Rawal etal. and Rotenberg etal. have found no signicant differ­ences in outcomes between budesonide and saline irrigation [39, 40].

43, 45], and oral steroid use [43] in CRS patients following treatment with steroid

placebo-controlled randomized studies, as saline irrigations (the vehicle for pla­cebo) are an active intervention (e.g., by removal of biolms) and an important part of CRS management [1, 2, 4–8, 47]. Variability in surgical extent, irrigation tech­nique, and/or perioperative management is another common problem in examining the literature on steroid irrigations, potentially contributing to the many negative studies. Ultimately, the randomized controlled literature on intranasal steroid irriga­tions in CRS treatment is challenging to interpret due to the wide variability in study population, steroid type and dose, and irrigation device, frequency, volume, and duration.

Patient adherence with steroid irrigation is 90–100% in blinded randomized con­trolled studies [36–40]. However, tolerance of and adherence to intranasal irriga­tions is a major issue in clinical practice. Gutierrez et al. (2024) reported that patients undergoing treatment with intranasal steroid irrigations showed a mean medication possession ratio (MPR) of 0.44 (i.e., patients possessed steroid