Brar, Tripti

Purpose of review Increasing evidence suggests that epigenetic regulation plays a central role in chronic rhinosinusitis pathogenesis, heterogeneity, and treatment response. This review summarizes current knowledge of epigenetics in CRS pathogenesis, their role in endotype differentiation, and potential as diagnostic and therapeutic targets. Recent findings Distinct epigenetic signatures have been identified across CRS subtypes. Hypermethylation of TSLP and differential regulation of FZD5, IL8, and EMT-related genes distinguish eosinophilic CRSwNP from other phenotypes. Specific microRNAs (miR-941, miR-21, miR-125b, miR-155) correlate with disease severity, tissue eosinophilia, and corticosteroid responsiveness, highlighting their utility as noninvasive biomarkers. Experimental data suggest that targeting DNMTs or HDACs may reverse pathogenic remodeling. Emerging therapeutic approaches – such as biologics modulating epigenetically controlled cytokines (e.g. tezepelumab) and engineered extracellular vesicle-based miRNA delivery – illustrate translational promise. Summary Epigenetic mechanisms critically influence CRS pathogenesis and clinical variability. Their modulation offers novel opportunities for biomarker discovery, disease stratification, and personalized therapy. Future research should focus on standardizing epigenetic profiling methodologies, validating candidate biomarkers in diverse populations, and integrating multiomics and single-cell approaches to uncover cell-specific regulatory networks. These advances may enable precision medicine in CRS, bridging the gap between molecular mechanisms and targeted clinical management.

Key Points Combined endoscopic sinus surgery and nasal septal perforation repair is technically feasible. NOSE‐Perf is a recently developed patient‐reported outcome measure for nasal septal perforation. The decision to perform combined ESS and NSP repair should be made on a case‐by‐case basis.

Background Epigenetics studies mechanisms such as DNA methylation, histone modifications, non-coding RNAs, and alternative polyadenylation that can modify gene activity without changing the underlying DNA nucleotide base-pair structure. Because these changes are reversible, they have potential in developing novel therapeutics. Currently, seven pharmaceutical agents targeting epigenetic changes are FDA approved and commercially available for treatment of certain cancers. However, studies investigating epigenetics in chronic rhinosinusitis (CRS) have not been undertaken previously in the United States. Objectives The goal of this study was to investigate sinonasal DNA methylation patterns in CRS versus controls, to discern environmentally-induced epigenetic changes impacting CRS subjects. Methods and Results Ethmoidal samples from CRS and inferior turbinate mucosal tissue samples from controls without CRS were studied. DNA methylation was studied by Reduced Representation Bisulfite Sequencing. RADMeth® biostatistical package was used to identify differentially methylated regions (DMRs) between CRS and controls. Ingenuity Pathway analysis of DMRs was performed to identify top upstream regulators and canonical pathways. Ninety-three samples from 64 CRS subjects (36 CRSwNP; 28 CRSsNP) and 29 controls were studied. CRS and control samples differed in 13 662 CpGs sites and 1381 DMRs. Top upstream regulators identified included: 1. CRS versus controls: TGFB1, TNF, TP53, DGCR8, and beta-estradiol. 2. CRSwNP versus controls: TGFB1, CTNNB1, lipopolysaccharide, ID2, and TCF7L2. 3. CRSsNP versus controls: MYOD1, acetone, ID2, ST8SIA4, and LEPR. Conclusions Differential patterns of methylation were identified between controls and CRS, CRSwNP, and CRSsNP. Epigenetic, environmentally-induced changes related to novel, inflammatory, immunologic, and remodeling pathways appear to affect epithelial integrity, cell proliferation, homeostasis, vascular permeability, and other yet uncharacterized pathways and genes.

Background Mometasone-eluting poly-L-lactide-coglycolide (MPLG) is available commercially for frontal sinus ostium (FSO) stenting. An alternative chitosan polymer-based drug delivery microsponge is also available at a lower cost per unit. Objective To compare the outcomes of MPLG stents versus triamcinolone-impregnated chitosan polymer (TICP) microsponge in frontal sinus surgery. Methods Patients who underwent endoscopic sinus surgery from December 2018 to February 2022 were reviewed to identify those with the intraoperative placement of TICP microsponge or MPLG stent in the FSO. FSO patency was evaluated by endoscopy at follow-up. Twenty-two-item sinonasal outcome test (SNOT-22) was also recorded, and complications were noted. Results A total of 68 subjects and 96 FSOs were treated. TICP was first used in August 2021 and MPLG in December 2018. MPLG placement in a Draf 3 cavity was excluded since TICP had not been used during Draf 3 procedure. Both cohorts (TICP 20 subjects, 35 FSOs; MPLG 26 subjects, 39 FSOs) had similar clinical characteristics. At a mean total follow-up of 249.2 days for TICP and 490.4 days for MPLG, FSO patency was 82.9% and 87.1%, respectively ( P = .265). At an equivalent follow-up of 130.6 days in TICP and 154.0 days in MPLG, patency was 94.3% and 89.7%, respectively ( P = .475). Both groups showed significant reductions in SNOT-22 ( P < .001). MPLG demonstrated crusting within the FSO at 1 month (none in TICP). Conclusion FSO patency for both stents was similar, although TICP had significantly lower costs per unit. Additional comparative trials may be helpful for guiding clinicians on the appropriate clinical situations for the use of these devices.

AbstractBackgroundBiological sex is increasingly recognized as a critical variable in health care. The authors reviewed the current literature regarding sex‐based differences in rhinology to summarize the data and identify critical knowledge gaps.MethodsA scoping review was conducted. Publications reporting sex‐based differences in anatomy, physiology, and pathology focusing on disease prevalence, disease burden, and outcomes in rhinology were identified.ResultsSeventy‐five relevant manuscripts were identified. While paranasal sinuses are of similar size at birth, they become larger in males leading to differences in ostium location. Females outperform males in olfactory identification but only in the 18‐ to 50‐year age group. Estrogen and progesterone administration can impact muscarinic and α1‐adrenergic nasal mucosa receptor density. Chronic rhinosinusitis (CRS) and CRS without nasal polyps are more prevalent in females while CRS with nasal polyps is more prevalent in males. CRS symptom burden is higher in females before and after endoscopic sinus surgery; however, no difference in endoscopic sinus surgery utilization was found based on sex. Allergic rhinitis is more common in males before puberty and in females after puberty. Epistaxis is more prevalent in males and postmenopausal females compared with premenopausal females, perhaps from differences in sex‐hormonal and hypertension status. In nasopharyngeal carcinoma, the incidence of sinus abnormalities was higher in males than females.ConclusionsAlthough many sex‐based differences exist in rhinology, further research is necessary to offer evidence‐based treatment guidelines. Gonadal hormones should be studied as a therapeutic in rhinologic pathology as baseline physiologic differences exist such as those found in nasal mucosa receptor density.

ObjectiveRNA sequencing (transcriptomics) is used to study biological pathways. However, the yield of data depends on comparing well‐characterized cohorts. We compared tissue eosinophilia versus nasal polyp (NP) status as the metric to characterize transcriptomic mechanisms at play in eosinophilic and non‐eosinophilic chronic rhinosinusitis (CRS) versus controls.MethodsRNA sequencing was conducted on sinonasal tissue samples of CRS and controls. Analyses were conducted based on polyp status [with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP)] as well as tissue eosinophil levels per high power field (eos/hpf)[non‐eosinophilic (<10 eos/hpf, neCRS) or eosinophilic (≥10 eos/hpf, eCRS)]. The yield of differentially expressed genes (DEGs) and biological pathways through Ingenuity Pathway Analysis (IPA) were compared.ResultsCRS tissue differed from controls by 736 statistically significant DEGs. Both NP status and tissue eosinophilia were effective in differentiating CRS from controls and into two distinct subgroups. Statistically significant DEGs identified when comparing CRS by NP status were 60, whereas 110 DEGs were identified using eosinophil cutoff ≥10 and <10 eos/hpf. Additionally, heatmaps showed greater homogeneity within each CRS subgroup when analyzed by tissue eosinophilia versus NP status. On IPA, the IL‐17 signaling pathway was significantly different only by tissue eosinophilia status, not NP status, being higher in CRS <10 eos/hpf.ConclusionTissue eosinophilia is superior to an analysis by NP status for the study of CRS transcriptome by RNA sequencing in identifying DEGs. Classification of CRS samples by eosinophil counts agnostic of NP status may offer advantageous insights into CRS pathogenetic mechanisms.Level of Evidence3 Laryngoscope, 133:2480–2489, 2023

AbstractBackgroundThe role of microbes in chronic rhinosinusitis (CRS) is poorly understood. We hypothesize that analyzing prior microbial exposures via assessing microbial protein serological reactivity in CRS versus controls may offer insights for CRS etiopathogenesis.MethodsWe profiled IgG and IgA antibodies to individual microbial proteins in serum samples of CRS patients and controls using a novel high‐throughput microarray protein technology, Nucleic Acid Programmable Protein Array (NAPPA). The study was conducted on 118 subjects (39 CRS, 79 controls). A CRS‐focused NAPPA array, with 1557 potentially sero‐reactive microbial proteins elected from a pre‐screening of 6500 genes of interest was constructed. It included membrane‐associated proteins from 47 bacterial species and all proteins from 43 viral strains. Differences between CRS and controls were compared across individual antimicrobial antibodies and the species.ResultsChronic rhinosinusitis patients had significantly elevated antimicrobial antibodies compared with controls. One bacterium (Staphylococcus aureus) and three viral strains (human metapneumovirus, human herpesvirus 5, and human herpesvirus 4) were identified as sources of the proteins that showed significantly elevated sero‐reactivity in CRS patients. Within CRS, patients with polyps had elevated antibodies against S. aureus, influenza A virus (H1N1, H3N2), and rhinovirus B14. CRS patients without polyps showed more antibodies against human herpesvirus 1 and vaccinia virus WR.ConclusionsCompared with healthy controls, CRS patients’ serum samples showed significantly increased sero‐reactivity to both bacterial and viral proteins, reflecting recent or current infection or active colonization. Significantly higher antibodies against S. aureus, human metapneumovirus, human herpesvirus 5, and human herpesvirus 4 in CRS need further study.