The Global Otolaryngology-Head and Neck Surgery Workforce.

Importance: A core component of delivering care of head and neck diseases is an adequate workforce. The World Health Organization report, Multi-Country Assessment of National Capacity to Provide Hearing Care, captured primary workforce estimates from 68 member states in 2012, noting that response rates were a limitation and that updated more comprehensive data are needed. Objective: To establish comprehensive workforce metrics for global otolaryngology-head and neck surgery (OHNS) with updated data from more countries/territories. Design, Setting, and Participants: A cross-sectional electronic survey characterizing the OHNS workforce was disseminated from February 10 to June 22, 2022, to professional society leaders, medical licensing boards, public health officials, and practicing OHNS clinicians. Main Outcome: The OHNS workforce per capita, stratified by income and region. Results: Responses were collected from 121 of 195 countries/territories (62%). Survey responses specifically reported on OHNS workforce from 114 countries/territories representing 84% of the world's population. The global OHNS clinician density was 2.19 (range, 0-61.7) OHNS clinicians per 100 000 population. The OHNS clinician density varied by World Bank income group with higher-income countries associated with a higher density of clinicians. Regionally, Europe had the highest clinician density (5.70 clinicians per 100 000 population) whereas Africa (0.18 clinicians per 100 000 population) and Southeast Asia (1.12 clinicians per 100 000 population) had the lowest. The OHNS clinicians deliver most of the surgical management of ear diseases and hearing care, rhinologic and sinus diseases, laryngeal disorders, and upper aerodigestive mucosal cancer globally. Conclusion and Relevance: This cross-sectional survey study provides a comprehensive assessment of the global OHNS workforce. These results can guide focused investment in training and policy development to address disparities in the availability of OHNS clinicians.

Flipping the Otolaryngology Didactics Curriculum: Results of a Novel Resident Course Structure.

OBJECTIVE: To assess the impact of a novel flipped-classroom (FC) otolaryngology resident didactic curriculum on resident learning. METHODS: Based on the preferences elicited in a survey of preferred learning styles of residents, a hybrid web-based and in-person FC otolaryngology didactic curriculum was implemented over a 6-month period in 2020-2021. Resident reactions to the new curriculum were assessed via a second survey. Kruskal Wallis tests were used to compare mean stanine scores on the Otolaryngology Training Examination (OTE) exam for topics taught in the new format with topics delivered in the old format. RESULTS: After instituting the curriculum reform, engagement in at least a moderate amount of the pre-didactic work and synchronous case discussions was reported by 67% and 88% of the residents, respectively. After the curriculum change, residents in years PGY2 and above reported statistically significant increases in self-reported ability to retain information from didactics, to feel prepared for the OTE, and to feel confident in fund of knowledge (p < 0.001, p = 0.004, and p = 0.004, respectively). Compared to the prior year, mean stanine increased on OTE scores for residents in years PGY2-PGY5 to a statistically significant degree (5.45 vs. 4.41, p = 0.001) for the topics delivered in the new format compared to topics delivered in the traditional format (5.13 vs. 4.70, p = 0.07). CONCLUSION: By organizing a didactic curriculum through online modules that incorporate pre-recorded lectures and external resources, residents reported and demonstrated improved knowledge retention. LEVEL OF EVIDENCE: NA Laryngoscope, 133:2129-2134, 2023.

Divergent bitter and sweet taste perception intensity in chronic rhinosinusitis patients.

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.

Denatonium benzoate bitter taste perception in chronic rhinosinusitis subgroups.

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.

Adenocarcinoma of the Sinonasal Tract: A Review of the National Cancer Database.

Background Sinonasal adenocarcinoma (SNAC) is a rare malignancy arising from mucus-secreting glandular tissue. Limited large-scale studies are available due to its rarity. We evaluated SNAC in the National Cancer Database (NCDB), a source that affords multi-institutional, population studies of rare cancers and their outcomes. Methods The NCDB was queried for adenocarcinoma in the sinonasal tract. Multivariate analyses were performed to evaluate for factors contributing to overall survival (OS). Results A total of 553 patients were identified. The cohort was composed of 59.3% males. The nasal cavity was the most common primary site, representing 44.1% of cases. About 5.7% of patients presented with nodal disease, while 3.3% had distant metastases. About 40.6% of cases presented with stage IV disease. About 73.5% of patients underwent surgery, 54.2% received radiation therapy, and 27.7% had chemotherapy. Median OS was 71.7 months, while OS at 1, 2, and 5 years was 82, 73.0, and 52%, respectively. On multivariate analysis, advanced age (hazard ratio [HR]: 1.04; 95% confidence interval [CI]: 1.02-1.05), Charlson-Deyo score of 1 (HR: 1.99; 95% CI: 1.20-3.30), advanced tumor grade (HR: 2.73; 95% CI: 1.39-5.34), and advanced tumor stage (HR: 2.71; 95% CI: 1.33-5.50) were associated with worse OS, whereas surgery (HR: 0.34; 95% CI: 0.20-0.60) and radiation therapy (HR: 0.55; 95% CI: 0.33-0.91), but not chemotherapy (HR: 1.16; 95% CI: 0.66-2.05), predicted improved OS. Conclusions SNAC is a rare malignancy with 5-year survival approximating 50%. Surgery and radiation therapy, but not chemotherapy, are associated with improved survival, and likely play a critical role in the interdisciplinary management of SNAC.

Extraprimary Local Recurrence of Esthesioneuroblastoma: Case Series and Literature Review.

OBJECTIVES: Esthesioneuroblastoma (ENB) is a rare sinonasal malignancy arising from olfactory neuroepithelium. Recurrence typically occurs locoregionally at the primary site or in the form of cervical metastasis. Delayed local recurrence away from the initial primary site is exceedingly rare. METHODS: Retrospective review of 4 patients with histologically confirmed extraprimary local recurrence of ENB was performed with review of the literature. RESULTS: All cases initially presented with ENB isolated to the cribriform plate(s) treated with primary surgical resection and adjuvant radiotherapy. The first patient had ENB recurrence 8 years posttreatment involving the right orbit. She later developed metastases to the spine, neck, and mandible requiring composite resection and 4 courses of radiotherapy. The second patient had ENB recurrence of the dorsal septum 9 years posttreatment with cervical metastases requiring septectomy, bilateral neck dissection, and radiotherapy. The third patient had ENB recurrence 7 years posttreatment in the posterior nasopharynx requiring endonasal nasopharyngectomy. Finally, the fourth patient had ENB recurrence 12 years posttreatment in the sphenopalatine foramen, which was endoscopically resected. At the time of this review, all 4 patients were disease free at 32, 21, 4, and 24 months posttreatment follow-ups, respectively. CONCLUSIONS: This case series describes the rare phenomenon of delayed extraprimary local recurrence of histologically confirmed ENB. Treatment of extraprimary recurrences, analogous to other forms of ENB, should include primary surgical resection with adjuvant radiotherapy for generally favorable outcomes. Long-term close follow-up based on symptoms, endoscopy, and imaging is essential because of the risk of delayed recurrence.

Incidence, risk factors, and outcomes of endoscopic sinus surgery after endoscopic skull-base surgery.

BACKGROUND: Patients undergoing endoscopic resection of neoplasms with both sinonasal and skull base involvement can develop chronic rhinosinusitis (CRS) after treatment and may occasionally benefit from additional endoscopic sinus surgery (ESS). We investigate risk factors and outcomes associated with revision ESS (rESS) after endoscopic skull-base surgery (SBS) for neoplasms with combined sinonasal and skull base involvement. METHODS: A retrospective review of patients with neoplasms with both sinonasal and skull base involvement who underwent endoscopic resection at a single tertiary care academic institution from 2004 through 2017 was performed. Eighty-three patients were included. Main outcome measures included incidence and timing of revision surgery, Lund-Mackay (LM) scores, and 22-item Sino-Nasal Outcome Test (SNOT-22) scores. RESULTS: rESS was performed in 21 (25%) cases, 15 (18%) of which were due to CRS. Time between initial resection and rESS was an average of 42 months (range, 6 to 142 months). Pre-SBS and post-SBS LM scores were not significantly different (5.0 vs 4.7, p = 0.640), although pre-SBS and post-SBS SNOT-22 scores showed significant improvement (32.6 vs 24.5, p = 0.030). Malignant pathology correlated with need for rESS (odds ratio [OR] 5.07, p = 0.04), as well as treatment including chemotherapy (OR 5.10, p = 0.003) and radiation (OR 4.15, p = 0.013). CONCLUSION: A significant proportion of patients develop clinically significant sinusitis after endoscopic SBS for neoplasms with combined sinonasal and skull base involvement and may benefit from rESS. Intervention occurred, on average, 3.5 years after initial tumor resection. Malignant pathology, radiation therapy, and chemotherapy correlate with need for rESS.

In vitro safety of ketotifen as a topical nasal rinse.

BACKGROUND: Ketotifen is a second-generation noncompetitive H1-antihistamine and mast-cell stabilizer. It is commonly used to treat or prevent allergic conjunctivitis, asthma, chronic urticaria, anaphylaxis, mast-cell, and other allergic-type disorders. However, it has never been studied in aspirin-exacerbated respiratory disease (AERD), an aggressive phenotype of chronic rhinosinusitis with nasal polyps, where the mast cell plays a prominent role its pathogenesis. METHODS: Human sinonasal epithelial cells were grown at an air-liquid interface (ALI). Ketotifen powder was dissolved in saline to make 4 test solutions at 1.04, 2.08, 10.4, and 20.8 µg/mL. Control (saline) or ketotifen solution was added apically to ALI cultures from tissue of 5 unique patients, and ciliary beat frequency (CBF) changes were recorded. Lactate dehydrogenase was measured at 24 and 48 hours to estimate long-term cellular toxicity. RESULTS: Apical application of ketotifen at all concentrations was neither ciliotoxic nor ciliostimulatory, with no change in CBF over a period of 15 minutes after application. Cellular toxicity for all concentrations at 24 and 48 hours after application was <3% and <7%, respectively, that of lysed cultures. CONCLUSION: Topical application of ketotifen to an in vitro model of sinonasal epithelium is safe, as evaluated by CBF and lactate dehydrogenase. Ketotifen is neither ciliotoxic nor ciliostimulatory, and no long-term cellular toxicity was observed. Ketotifen may have promise as a topical nasal rinse in the treatment of AERD.

Clinical Implications of Carcinoma In Situ in Sinonasal Inverted Papilloma.

OBJECTIVE: Sinonasal inverted papilloma (IP) is a typically benign sinonasal tumor with a tendency to recur and the potential for malignant transformation. Varying degrees of dysplasia may be present, of which carcinoma in situ (CIS) is most advanced. We hereby describe the biological and clinical behavior of IP with CIS (IPwCIS). STUDY DESIGN: Retrospective cohort. SETTING: Tertiary academic referral center. SUBJECTS AND METHODS: Patients who underwent surgical resection for IP between 2002 and 2017. Pertinent clinical data were obtained, and all IPwCIS cases were histologically confirmed. RESULTS: In total, 37 of 215 cases (17.2%) were identified with IPwCIS. Mean age was 57 years and 86.5% of patients were male. Median follow-up was 82 months, and the recurrence rate was 27%. The maxillary sinus was the most common primary site (37.8%) and 14 tumors (37.8%) demonstrated multifocal attachment, which was associated with recurrence (odds ratio [OR], 9.7; 95% confidence interval [CI], 1.4-112.8; P = .028). IPwCIS was also associated with multiple recurrences (OR, 2.71; 95% CI, 1.246-5.814; P = .021). Most patients were treated with surgery alone (89.1%) and 4 patients received adjuvant radiotherapy (8.1%). Only 1 patient (2.7%) demonstrated malignant transformation after definitive surgery. CONCLUSIONS: IPwCIS represents the most severe degree of dysplasia prior to malignant transformation and is associated with higher recurrence rate and multifocal involvement but low rate of conversion to invasive carcinoma. The need for adjuvant therapy remains controversial, and further research into the etiology of the disease is warranted.

Sinonasal mucoepidermoid carcinoma: a review of the National Cancer Database.

BACKGROUND: Primary sinonasal mucoepidermoid carcinoma (SN-MEC) is a malignancy arising from seromucinous glands of the nasal cavity and paranasal sinuses. Given its rarity, few large-scale studies have been performed. In this study we describe the incidence and determinants of survival of patients with SN-MEC leveraging the National Cancer Database (NCDB). METHODS: This was a retrospective, population-based cohort study of patients diagnosed with SN-MEC between 2004 and 2012 within the NCDB. The main outcome measure was overall survival (OS). RESULTS: A total of 164 patients were identified. The cohort was composed of 47.6% males. Mean age at diagnosis was 59.7 years. The maxillary sinus was the most common primary site, accounting for 45.7% of cases. Eleven percent of patients presented with nodal disease, whereas 2.1% had distant metastases. Stage IV disease was seen in 30.4% of cases. A total of 79.8% of the patients underwent surgery, 61.0% received radiation therapy, and 15.1% had chemotherapy. OS at 1, 2, and 5 years was 83%, 77.0%, and 57%, respectively. On multivariate analysis, Medicaid insurance status (hazard ratio [HR], 7.29; 95% confidence interval [CI], 1.74-30.57), advanced tumor size (HR, 4.94; 95% CI, 1.19-20.5), and advanced nodal disease (N1: HR, 9.48; 95% CI, 1.66-54.23; N2B: HR, 19.3; 95% CI, 1.07-350.64) were associated with worse OS. CONCLUSION: Mucoepidermoid carcinoma is the most common salivary gland malignancy but a rare sinonasal malignancy, with 5-year survival for SN-MEC approximating 50%. A significant proportion of patients present with advanced disease. Both socioeconomic factors and tumor characteristics are associated with survival.

Inverted papilloma with multifocal attachment is associated with increased recurrence.

BACKGROUND: Inverted papilloma (IP) is a benign sinonasal tumor with a well-known propensity to recur, especially at its bony attachment site. Anecdotal evidence suggests lower rate of recurrence in primary resection. We also aimed to evaluate the effect of multifocal vs single focus of attachment in disease control. METHODS: This work is a retrospective review of 535 IP resections performed during the period from 2006 to 2016 at a tertiary-care center. Demographic data, tumor location and attachment sites, and follow-up duration data were obtained. RESULTS: Two hundred ten patients were eligible for analysis. The mean age was 57 years, with an average postoperative surveillance of 36.4 months. Patients who had a previous procedure at an outside institution have a recurrence rate of 22.3%, compared with 12.4% for patients who had primary surgery at our institution. The most common site of attachment was maxillary sinus (47.6%), followed by ethmoid sinus (39%). Individual tumor review showed 50% of the patients to have multifocal attachment disease, of which there is a higher prevalence in secondary cases when compared with primary cases (53.7% vs 44.9%). Multiple tumor attachment sites had a significant effect on recurrence (odds ratio, 3.5; 95% confidence interval, 1.6-7.6; p = 0.002). CONCLUSION: Primary resection and single-focus attachment of inverted papilloma are associated with lower recurrence rates at 3-year follow-up.

Fungal extracts stimulate solitary chemosensory cell expansion in noninvasive fungal rhinosinusitis.

BACKGROUND: Solitary chemosensory cells (SCCs) are rare epithelial cells enriched in nasal polyps and are the primary source of interleukin-25 (IL-25), an innate cytokine eliciting T-helper 2 (Th2) immune response. Although it is proposed that SCCs are stimulated by antigens released by upper airway pathogens, the exogenous triggers of human SCCs remain elusive. We studied patients with noninvasive fungal rhinosinusitis to determine whether extracts of Aspergillus fumigatus and Alternaria alternata stimulate SCC proliferation as an early event in type 2 inflammation. METHODS: Multicolor flow cytometry, immunofluorescence, and enzyme-linked immunoassay were used to interrogate mucosa from patients with mycetomas and allergic fungal rhinosinusitis (AFRS) for SCCs and IL-25. Primary sinonasal epithelial cells from AFRS patients and noninflamed inferior turbinates were stimulated with fungal extracts for 72 hours, and SCC population frequency as well as mitotic activity were quantified using flow cytometry. RESULTS: SCCs producing IL-25 are enriched in inflamed mucosa compared with intrapatient noninflamed control tissue (38.6% vs 6.5%, p = 0.029). In cultured sinonasal epithelial cells from AFRS nasal polyps, Aspergillus fumigatus and Alternaria alternata stimulated higher SCC frequency compared with controls (27.4% vs 10.6%, p = 0.002; 18.1% vs 10.6%, p = 0.046), which led to increased IL-25 secretion in culture media (75.5 vs 3.3 pg/mL, p < 0.001; 32.3 vs 3.3 pg/mL, p = 0.007). Ki-67 expression was higher in SCCs grown in fungal stimulation conditions compared with controls. CONCLUSION: Although fungal antigens are known to potentiate immune response through innate cytokines, including IL-25, the early expansion of SCCs in the presence of fungus has not been described. This early event in the pathogenesis of noninvasive fungal rhinosinusitis may represent a target for intervention.

Asymptomatic radiographic sinonasal inflammation does not affect pituitary surgery outcomes.

OBJECTIVE: Chronic rhinosinusitis (CRS) is a proposed risk factor for meningitis and other intracranial complications following the endoscopic endonasal transsphenoidal approach (TSA). Some have recommended staging TSA following surgery for CRS; however, delaying TSA has important ramifications. The objective of this study is to determine whether asymptomatic sinonasal inflammation (RSNI) on preoperative computed tomography scans, without clinical CRS, is associated with postoperative complications following TSA. METHODS: All consecutive TSA cases performed at a single tertiary care institution from January 1, 2009, to December 31, 2017, were reviewed for patient demographics, prior surgery, presence of RSNI on preoperative computed tomography scan based on Lund-Mackay (LM) score, intraoperative cerebrospinal fluid (CSF) leak, and postoperative complications (postoperative CSF leak, bleeding, infection). The association between preoperative RSNI and postoperative complications was analyzed via multivariate logistic regression. RESULTS: One hundred seventy-one cases of TSA were included with mean patient age of 52.6 years, 42.7% males, 18.1% revision cases, and mean LM score of 1.9 ± 2.7. Complications were identified in 9.9% of patients at the following rates: 5.3% postoperative CSF leak, 2.9% bleeding, and 1.8% infection (all sinusitis, no episodes of meningitis). Neither total LM score nor LM score > 5 (representative of clinically significant radiographic CRS) were predictors of any postoperative complication (both P > 0.05). Age, sex, revision status, intraoperative CSF leak, and total LM score were not independent predictors of any postoperative complication on multivariate analysis (all P > 0.05). CONCLUSION: In asymptomatic patients, radiographic evidence of sinonasal inflammation is not associated with increased risk of complications following TSA. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:1545-1548, 2019.

Adenoid cystic carcinoma of the sinonasal tract: a review of the national cancer database.

BACKGROUND: Sinonasal adenoid cystic carcinoma (SNACC) is a rare malignancy with a propensity for distant metastasis. In this study we describe the incidence and determinants of survival among patients with SNACC between the years 2004 and 2012 using the National Cancer Database (NCDB). METHODS: This was a retrospective, population-based cohort study performed at a tertiary academic medical center. All participants were diagnosed with SNACC between 2004 and 2012 within the NCDB. The main outcome was overall survival (OS). RESULTS: A total of 793 patients were identified. The cohort was composed of 46.9% males. Mean age at diagnosis was 59.6 years. The maxillary sinus was the most common primary site (49.7%). Nodal disease was seen in 3.6% of the patients, whereas 3.7% had distant metastases. Stage IV disease was seen in 49.1% of cases. In total, 77.4% of patients underwent surgery, 68.2% received radiation therapy, and 16.4% had chemotherapy. Median OS was 78.5 months; OS at 1, 2, and 5 years was 91%, 83%, and 61%, respectively. On multivariate analysis, advanced age (p = 0.001), frontal sinus primary site (p < 0.001), positive margins (p < 0.001), Charlson comorbidity index >0 (p = 0.01), residing in an urban setting (p = 0.04), poorly differentiated or undifferentiated tumor grade (p = 0.003), and advanced tumor stage (p = 0.01) were associated with worse OS, whereas surgery (p < 0.001), but not radiation therapy (p = 0.52) or chemotherapy (p = 0.57), predicted improved OS. CONCLUSION: Predictors of survival in SNACC include age, comorbidity status, grade, and stage. Surgery is associated with improved survival and remains the mainstay of therapy, whereas the roles of radiation therapy and chemotherapy require future investigation.

Broncho-Vaxom® (OM-85 BV) soluble components stimulate sinonasal innate immunity.

BACKGROUND: Broncho-Vaxom® (OM-85 BV) is an extract of infectious respiratory bacteria that is used as an immunostimulant outside of the United States for the prevention and treatment of bronchitis and rhinosinusitis. Prior studies have shown that use of OM-85 BV is associated with reduction in frequency of respiratory infection and decreased duration of antibiotic usage. However, the effects of OM-85 BV on respiratory mucosal innate immunity are unknown. METHODS: Human sinonasal epithelial cells were grown at an air-liquid interface (ALI). Ciliary beat frequency (CBF) and nitric oxide (NO) production in response to stimulation with OM-85 BV was measured in vitro. Pharmacologic inhibitors of bitter taste receptor (T2R) signaling were used to determine if this pathway was taste-receptor-mediated. RESULTS: Apical application of OM-85 BV resulted in an NO-mediated increase in CBF (p < 0.05) and increased NO production (p < 0.0001) when compared to saline-stimulated control cultures. ALI pretreatment with taste receptor pathway inhibitors blocked OM-85 BV-induced increases in NO. CONCLUSION: OM-85 BV has ciliostimulatory and immunogenic properties that may be partially responsible for its observed efficacy as a respiratory therapeutic. These responses were NO-dependent and consistent with T2R activation. Further work is necessary to elucidate specific component-receptor signaling relationships.

Sentinels at the wall: epithelial-derived cytokines serve as triggers of upper airway type 2 inflammation.

Recent evidence has demonstrated an expanding role of respiratory epithelial cells in immune surveillance and modulation. Studies have been focusing on the earliest events that link epithelial injury to downstream inflammatory responses. Cytokines produced by and released from respiratory epithelial cells are among these early trigger signals. Epithelial-derived cytokines, namely thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33, have come to the forefront of recent investigations. Each of these 3 cytokines has been implicated in chronic rhinosinusitis (CRS), asthma, and atopy. Herein we review studies elucidating the roles of epithelial-derived cytokines in the pathobiology of upper airway disease, with particular emphasis on type 2 inflammatory conditions.

The role of bitter and sweet taste receptors in upper airway innate immunity: Recent advances and future directions.

Bitter (T2R) and sweet (T1R) taste receptors have been implicated in sinonasal innate immunity and in the pathophysiology of chronic rhinosinusitis (CRS). Taste receptors are expressed on several sinonasal cell types including ciliated epithelial cells and solitary chemosensory cells. Bitter agonists released by pathogenic microbes elicit a T2R dependent signaling cascade which induces the release of bactericidal nitric oxide, increases mucociliary clearance, and promotes secretion of antimicrobial peptides. Genetic variation conferred by polymorphisms in T2R related genes is associated with differential CRS susceptibility, symptomatology and post-treatment outcomes. More recently, based on our understanding of T1R and T2R function, investigators have discovered novel potential therapeutics in T2R agonists and T1R antagonists. This review will discuss bitter and sweet taste receptor function in sinonasal immunity, explore the emerging diagnostic and therapeutic implications stemming from the most recent findings, and suggest directions for future research.

Taste Exam: A Brief and Validated Test.

The emerging importance of taste in medicine and biomedical research, and new knowledge about its genetic underpinnings, has motivated us to supplement classic taste-testing methods in two ways. First, we explain how to do a brief assessment of the mouth, including the tongue, to ensure that taste papillae are present and to note evidence of relevant disease. Second, we draw on genetics to validate taste test data by comparing reports of perceived bitterness intensity and inborn receptor genotypes. Discordance between objective measures of genotype and subjective reports of taste experience can identify data collection errors, distracted subjects or those who have not understood or followed instructions. Our expectation is that fast and valid taste tests may persuade researchers and clinicians to assess taste regularly, making taste testing as common as testing for hearing and vision. Finally, because many tissues of the body express taste receptors, taste responses may provide a proxy for tissue sensitivity elsewhere in the body and, thereby, serve as a rapid, point-of-care test to guide diagnosis and a research tool to evaluate taste receptor protein function.

Solitary chemosensory cells producing interleukin-25 and group-2 innate lymphoid cells are enriched in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is commonly characterized by type-2 inflammation. It is established that group-2 innate lymphoid cells (ILC2s) are a subset of immune cells important in orchestrating mucosal type-2 response. IL-25 is an epithelial-derived cytokine that is a critical activator of ILC2s. Recent evidence demonstrates that specialized taster epithelial cells, such as solitary chemosensory cells (SCCs), may be producers of IL-25. To elucidate the relationship between SCCs and ILC2s in CRSwNP, we sought to quantify ILC2s and SCCs to determine if these cell types are enriched in nasal polyps compared to healthy sinonasal mucosa. METHODS: We quantified SCCs and ILC2s using multicolor flow cytometry in nasal polyps and non-inflamed turbinate mucosa from seven patients and investigated the role of IL-13 and dexamethasone on SCC frequency using tissue explants of nasal polyps and turbinate mucosa. RESULTS: SCCs were found to be the primary source of IL-25. Nasal polyps demonstrated higher populations of SCCs (33.0% vs 5.6%, p < 0.001) and ILC2s (2.40% vs 0.19%, p = 0.008) compared to patient-matched nonpolypoid turbinates. In cultured polyp explants, exogenous IL-13 increased the proportion of epithelial SCCs (40.2% IL-13 condition vs 28.9% untreated, p = 0.012), and this effect was reversed by addition of dexamethasone (40.2% vs 8.9%, p < 0.0005). CONCLUSION: These data support SCC and ILC2 expansion as well as increased IL-25 production in nasal polyps and may represent early events in the pathogenesis of CRSwNP. IL-13 stimulates proliferation of SCC in a feed-forward loop, a process that is steroid-sensitive.