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Background: Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP), and aspirin-exacerbated respiratory disease (AERD) have varying levels of inflammation and disease severity. Solitary chemosensory cells (SCCs) are enriched in nasal polyps, are the primary source of interleukin 25 (IL-25) in upper airways, leading to type 2 inflammation, and are activated by bitter-tasting denatonium benzoate (DB). Thus, we sought to evaluate DB taste perception at a range of concentrations in order to identify 1 that most differentiates CRS subgroups from controls., Methods: CRSsNP (n = 25), CRSwNP (n = 26), and AERD (n = 27) patients as well as controls (n = 25) tasted 6 DB concentrations in a fixed, random order, rating on a category scale of 0 (no intensity) to 12 (extremely intense). Sinonasal epithelial cultures were treated with and without denatonium and analyzed for IL-25 via flow cytometry., Results: CRSsNP patients rated DB as significantly less intense than did controls at all concentrations: 5.62 × 10 -9 M, 1.00 × 10 -8 M, 1.78 × 10 -8 M, 3.16 × 10 -8 M, 5.62 × 10 -8 M, and 1.00 × 10 -7 M (all p < 0.0083). CRSwNP patients did not show significant differences from controls. AERD patients rated DB as significantly more intense than did controls at concentrations of 1.00 × 10 -8 M and 3.16 × 10 -8 M (p < 0.0083). In vitro data demonstrated significant increase in IL-25-positive cells after denatonium stimulation (n = 5), compared to control (n = 5) (p = 0.012)., Conclusion: Our findings link in vitro DB stimulation of sinonasal tissue with increased IL-25 and show differential DB taste perception in CRS subgroups relative to the control group, with CRSsNP being hyposensitive and AERD being hypersensitive. We propose a concentration of 3.16 × 10 -8 M for future study of clinical utility., (© 2020 ARS-AAOA, LLC.)

Background: Bitter and sweet taste receptors are present in the human upper airway, where they have roles in innate immunity. Previous studies have shown that 1 of the 25 bitter receptors, TAS2R38, responds to specific bacterial signaling molecules and evokes 1 type of a defense response in the upper airway, whereas ligands of sweet receptors suppress other types of defense responses., Methods: We examined whether other bitter taste receptors might also be involved in innate immunity by using sensory responses to bitter compounds that are not ligands of TAS2R38 (quinine and denatonium benzoate) to assess the sensitivity of other bitter receptors in chronic rhinosinusitis (CRS) patients. CRS patients with (n = 426) and without (n = 226) nasal polyps and controls (n = 356) rated the intensity of quinine, denatonium benzoate, phenylthiocarbamide (PTC; a ligand for TAS2R38), sucrose, and salt., Results: CRS patients rated the bitter compounds denatonium benzoate and quinine as less intense and sucrose as more intense than did controls (false discovery rate [FDR] <0.05) and CRS patients and controls did not differ in their ratings of salt (FDR >0.05). PTC bitter taste intensity differed between patient and control groups but were less marked than those previously reported. Though differences were statistically significant, overall effect sizes were small., Conclusion: CRS patients report bitter stimuli as less intense but sweet stimuli as more intense than do control subjects. We speculate that taste responses may reflect the competence of sinonasal innate immunity mediated by taste receptor function, and thus a taste test may have potential for clinical utility in CRS patients., (© 2020 ARS-AAOA, LLC.)

Background: Bitter (T2R) and sweet (T1R) taste receptors in the airway are important in innate immune defense, and variations in taste receptor functionality in one T2R (T2R38) correlate with disease status and disease severity in chronic rhinosinusitis (CRS). Quinine is a bitter compound that is an agonist for several T2Rs also expressed on sinonasal cells, but not for T2R38. Because of this property, quinine may stimulate innate immune defense mechanisms in the airway, and functional differences in quinine perception may be reflective of disease status in CRS., Methods: Demographic and taste intensity data were collected prospectively from CRS patients and non-CRS control subjects. Sinonasal tissue from patients undergoing rhinologic surgery was also collected and grown at an air-liquid interface (ALI). Nitric oxide (NO) production and dynamic regulation of ciliary beat frequency in response to quinine stimulation were assessed in vitro ., Results: Quinine reliably increased ciliary beat frequency and NO production in ALI cultures in a manner consistent with T2R activation ( p  < 0.01). Quinine taste intensity rating was performed in 328 CRS patients and 287 control subjects demonstrating that CRS with nasal polyps (CRSwNP) patients rated quinine as significantly less intense than did control subjects., Conclusion: Quinine stimulates airway innate immune defenses by increasing ciliary beat frequency and stimulating NO production in a manner fitting with T2R activation. Patient variability in quinine sensitivity is observed in taste intensity ratings, and gustatory quinine "insensitivity" is associated with CRSwNP status. Thus, taste tests for quinine may be a biomarker for CRSwNP, and topical quinine has therapeutic potential as a stimulant of innate defenses.

Background: Sinonasal biofilms have been demonstrated in specimens collected from chronic rhinosinusitis (CRS) patients. Mounting evidence suggests that biofilms contribute to therapeutically recalcitrant CRS. Recently, the bitter taste receptor T2R38 has been implicated in the regulation of the sinonasal mucosal innate immune response. TAS2R38 gene polymorphisms affect receptor functionality and contribute to variations seen in sinonasal innate defense as well as taste perception reflected in gustatory sensitivity to the bitter compound phenylthiocarbamide (PTC). In a population of CRS patients with active infection or inflammation, we sought to determine if a correlation between T2R38 phenotype and in vitro biofilm formation existed., Methods: Endoscopically guided sinonasal swabs were obtained prospectively from CRS (±polyp) patients with evidence of persistent inflammation or mucopurulence. In vitro biofilm formation was assessed with a modified Calgary Biofilm Detection Assay. Patients' phenotypic (functional) expression of the bitter taste receptor T2R38 was evaluated with a taste test including the compound PTC. Linear regression was used to determine the level of significance between mean in vitro biofilm formation levels and mean PTC taste test intensity ratings across CRS patients., Results: Sinonasal swabs were obtained from 59 patients, with 42 of the 59 samples demonstrating in vitro biofilm formation. Analysis revealed an inverse linear association between in vitro biofilm formation and PTC taste intensity ratings (p = 0.019) for all patients. This association was exclusively driven by nonpolypoid CRS patients (p = 0.0026)., Conclusion: In vitro biofilm formation from sinonasal clinical isolates is inversely correlated with PTC taste sensitivity in nonpolypoid CRS patients., (© 2016 ARS-AAOA, LLC.)

Background: Over 550,000 sinus surgeries are performed annually in the United States on patients with chronic rhinosinusitis (CRS). Although the results of sinus surgery vary widely, no known genetic factor has been identified to predict surgical outcomes. The bitter taste receptor T2R38 has recently been demonstrated to regulate upper airway innate defense and may affect patient responses to therapy. Our goal was to determine whether TAS2R38 genetics predicts outcomes in CRS patients following sinus surgery., Methods: A prospective study of patients undergoing sinus surgery evaluating postoperative outcomes through the 22-item Sino-Nasal Outcome Test (SNOT-22). Patients were genotyped for TAS2R38., Results: A total of 123 patients with CRS were initially analyzed; 82 patients showed nasal polyps (CRSwNP) and 41 patients were without nasal polyps (CRSsNP). Six months after surgery, the overall SNOT-22 improvement was 25 ± 23 points. The TAS2R38 genotype was found to significantly correlate with surgical outcomes in patients without polyps; homozygotes for the functional receptor had a mean improvement of 38 ± 21, whereas heterozygotes or homozygotes for the nonfunctional receptor had a mean improvement of 12 ± 22 (p = 0.006). This result was confirmed with a multivariate regression that incorporated further patients with 1-month and 3-month scores (n = 207)., Conclusion: In patients undergoing sinus surgery for CRS, we have identified a genetic polymorphism that predicts variability in quality of life improvement following surgery at 6 months in nonpolypoid CRS. This is the first genetic polymorphism identified that has demonstrated to predict surgical outcome for a select group of CRS patients., (© 2015 ARS-AAOA, LLC.)

Background: Besides sensorineural factors, conductive impediments likely contribute to olfactory losses in chronic rhinosinusitis (CRS) patients, yet no conclusive evidence exists. We aimed to examine possible conductive factors using computational fluid dynamics (CFD) models., Methods: A total of 29 CRS patients were assessed via odorant detection thresholds (ODTs), rhinomanometry (nasal resistance [NR]), acoustic rhinometry (minimum-cross-sectional area [MCA]) and computed tomography (CT) staging. CFD simulations of nasal airflow and odorant absorption to olfactory region were carried out based on individual CTs. Biopsies of olfactory epithelium (OE) were collected, cryosectioned, stained, and scored for erosion., Results: Significant correlations to ODTs were found for 3 variables: odor absorption in the olfactory region (r = -0.60, p < 0.01), MCA (r = -0.40, p < 0.05), and CT staging (r = 0.42, p < 0.05). However, significant findings were limited to ODTs of the highly soluble l-carvone. Multiple regression analysis revealed that these variables combined, with the addition of NR, can account for 65% of the total variance in ODTs. CT staging correlated significantly with OE erosion (r = 0.77, p < 0.01) and can replace the latter in the regression with comparable outcomes. Partial correlations suggest the contributions of both conductive and sensorineural variables are more prominent if adjusted for the effects of the other. Olfactory loss and inflammatory factors have strong bilateral involvement, whereas conductive factors are independent between sides. As validation, CFD-simulated NRs significantly correlated with rhinomanometrically assessed NRs (r = 0.60, p < 0.01)., Conclusion: Both conductive and sensorineural mechanisms can contribute to olfactory losses in CRS. CFD modeling provides critical guidance in understanding the role of conductive impediments in olfactory dysfunction in CRS., (© 2014 ARS-AAOA, LLC.)

Background: Chronic rhinosinusitis (CRS) is a complex heterogeneous inflammatory disease that affects the nasal cavity, but the pathological examination of the olfactory mucosa (OM) in this disease has been limited., Methods: Nasal biopsy specimens were obtained from 20 control subjects and 50 CRS patients in conjunction with clinical assessments. Histopathology of these nasal biopsy specimens was performed and immunohistochemistry was used to characterize nonneuronal, neuronal, and inflammatory cells in the OM. These OM characteristics were then evaluated to determine the degree to which pathological features may be related to smell loss in CRS., Results: Histopathological examination of control and CRS OM revealed changes in the normal pseudostratified olfactory epithelium (OE): intermixing of goblet cells, metaplasia to squamous-like cells, and erosion of the OE. Lower percentages of normal epithelium and olfactory sensory neurons were found in CRS OE compared with controls. Relative to other CRS patients, those with anosmia had the greatest amount of OE erosion, the highest density of eosinophils infiltrating the OE, and exhibited the most extensive abnormalities on CT and endoscopic examination, including being significantly more likely to exhibit nasal polyposis., Conclusion: Our results suggest that OM pathology observed in nasal biopsy specimens can assist in understanding the degree of epithelial change and sensorineural damage in CRS and the potential for olfactory loss.

Few studies have examined the induction of squamous metaplasia in human olfactory nasal tissue caused by tobacco use and the implications it may have for olfaction, particularly when there are pre-existing insults, such as chronic rhinosinusitis (CRS). Quantitative histopathological analyses were performed on Alcian blue- and H&E-stained sections of nasal biopsies taken from the upper aspect of the middle turbinate of CRS patients. Chronic rhinosinusitis patients who were current smokers had a predominance of squamous metaplasia in the olfactory sensory epithelium, whereas CRS patients who were nonsmokers and were not exposed to secondhand cigarette smoke had a prevalence of goblet cell hyperplasia. In spite of this difference, the groups did not differ significantly in olfactory threshold sensitivity. The impact of primary cigarette smoke on olfaction and a possible role of squamous metaplasia in preserving olfactory neurogenesis are discussed.

The impact of chronic rhinosinusitis (CRS) on the olfactory mucosa (OM) is dramatic. Cellular profiles and epithelial integrity in OM biopsies were evaluated using histological and immunohistochemical methods to define a strategy for future histological studies of CRS. We have examined nasal biopsies of 54 CRS patients (18-63 years old) and have defined specific histopathological patterns of the OM: normal pseudostratified, goblet cell hyperplasia, squamous metaplasia, and erosion. Goblet cell hyperplasia was most similar to a normal pseudostratified OM pattern but with goblet cells intermixed in the apical layers. Squamous metaplasia exhibited an absence of olfactory supporting cells and had olfactory sensory neurons that were morphologically abnormal. It is unknown if these neurons would be functional in this type of tissue transformation. The pattern of erosion exhibited a severe loss of epithelial layers and a higher prevalence of infiltrating inflammatory cells within the olfactory epithelium when compared to the other OM patterns. Although it is not known if the OM patterns we have noted correspond to specific stages or distinct pathways of the disease, the template proposed here can be used in further studies to understand how the histopathological progression of CRS relates to olfactory loss and the response to treatment.