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Background: Orbital, intracranial, and osseous extra-sinus complications can arise from bacterial or fungal sinusitis. Odontogenic sinusitis (ODS) can cause extra-sinus complications, but its prevalence remains poorly characterized. Objective: To determine the frequency of ODS as a cause of operative extra-sinus infectious complications and describe clinical features of all complicated sinusitis cases. Methods: A multi-institutional retrospective review was performed on all operative sinusitis-related extra-sinus complications from 2011 to 2020. ODS was diagnosed by sinus computed tomography (CT) and dental evaluations when available. Demographics, complication types, sinusitis etiologies, and various clinical features were analyzed. Results: Forty-five patients were included (mean age 55.5 years, 56% male). Of the extra-sinus complications, 40% were orbital only, 22% intracranial only, 13% osseous only, and 25% involved combined complications. The 2 most common causes of extra-sinus complications were ODS (40%) and mucopyocele (27%). When invasive fungal etiologies were excluded, and only unilateral maxillary opacification on CT was considered, nearly 60% of extra-sinus complications were due to ODS. Unilateral maxillary sinus opacification on CT was present in 100% of complicated ODS compared to 44% of nonodontogenic cases, and oral anaerobes were only identified in ODS cases. No complicated ODS patients underwent dental interventions during hospitalization. Conclusion: ODS was the most common cause of operative extra-sinus infectious complications. Clinicians should consider ODS high on the differential diagnosis of all patients presenting with complicated sinusitis, especially when sinusitis is unilateral and invasive fungal infection is not suspected. [ABSTRACT FROM AUTHOR]

Bitter taste receptors (T2Rs) are G protein-coupled receptors (GPCRs) expressed in various cell types including ciliated airway epithelial cells and macrophages. T2Rs in these two innate immune cell types are activated by bitter products, including those secreted by Pseudomonas aeruginosa, leading to Ca2+-dependent activation of endothelial nitric oxide (NO) synthase (eNOS). NO enhances mucociliary clearance and has direct antibacterial effects in ciliated epithelial cells. NO also increases phagocytosis by macrophages. Using biochemistry and live-cell imaging, we explored the role of heat shock protein 90 (HSP90) in regulating T2R-dependent NO pathways in primary sinonasal epithelial cells, primary monocyte-derived macrophages, and a human bronchiolar cell line (H441). Immunofluorescence showed that H441 cells express eNOS and T2Rs and that the bitter agonist denatonium benzoate activates NO production in a Ca2+- and HSP90-dependent manner in cells grown either as submerged cultures or at the air–liquid interface. In primary sinonasal epithelial cells, we determined that HSP90 inhibition reduces T2R-stimulated NO production and ciliary beating, which likely limits pathogen clearance. In primary monocyte-derived macrophages, we found that HSP-90 is integral to T2R-stimulated NO production and phagocytosis of FITC-labeled Escherichia coli and pHrodo-Staphylococcus aureus. Our study demonstrates that HSP90 serves as an innate immune modulator by regulating NO production downstream of T2R signaling by augmenting eNOS activation without impairing upstream Ca2+ signaling. These findings suggest that HSP90 plays an important role in airway antibacterial innate immunity and may be an important target in airway diseases such as chronic rhinosinusitis, asthma, or cystic fibrosis. [ABSTRACT FROM AUTHOR]

Background: Sinonasal posttransplant lymphoproliferative disorder (PTLD) is a serious but uncommon complication of solid organ and hematopoietic stem cell transplantation that can overlap in many features with invasive fungal sinusitis (IFS).Objective: To identify clinical, laboratory, and radiographic features that may help to differentiate sinonasal IFS and PTLD in the posttransplant population.Methods: We performed a retrospective chart review of patients with posttransplant sinonasal PTLD and IFS to evaluate for clinical, laboratory, and imaging characteristics.Results: A total of 4 patients with sinonasal PTLD and 10 posttransplant IFS patients were evaluated. A total of 2 of 4 PTLD patients presented with a symptom duration of greater than 3 months compared to none in the IFS group (p = 0.07). Mean absolute neutrophil count (ANC) was 2,976 per mm3 (range 2,488-3,462) in the PTLD group compared to 773 per mm3 (range 0.0-2,744) in the IFS group (p = 0.01). Both PTLD lesions with available diffusion-weighted imaging demonstrated diffusion restriction on magnetic resonance im-aging (MRI) compared to zero of the IFS lesions (p = 0.10). No PTLD lesions demonstrated mucosal infarcts compared to three of seven IFS lesions (p = 0.23).Conclusion: IFS was associated with a significantly lower ANC at the time of diagnosis compared to PTLD. Additionally, three other measures trend towards association with their respective pathology. PTLD typically has a more chronic time course than IFS, diffusion restriction on MRI is predominantly associated with PTLD patients, and mucosal infarct on MRI is more suggestive of IFS. Additionally, all cases of sinonasal PTLD arose following solid organ transplantation. These factors may assist clinicians during diagnosis. [ABSTRACT FROM AUTHOR]

Background: Chronic rhinosinusitis (CRS) is believed to create a substantial population-level disease burden in the United States due to its high prevalence and significant disease morbidity, but many studies of CRS epidemiology are based on administrative or historical record sources rather than primary population sources. Objective: To characterize CRS symptoms, burden, and patient characteristics by using a primary U.S. population-based representative sample. Methods: A demographically and geographically representative sample of 10,336 U.S. adults recruited from a general panel of 4.3 million were obtained by using three-stage randomization. Data collected included a range of respondent-reported CRS symptoms, symptom impact and severity, symptom duration, and treatment. Results: Approximately 11.5% of the respondents (n = 1189) reported defining symptom and duration criteria for CRS. A previous diagnosis of nasal polyps was reported by --10% of this population. The remaining respondents reported severe (7.3%) or moderate (3.1%) symptom severity. The most frequently reported defining symptoms were nasal congestion and/or obstruction (94-97%) and drainage (89-92%). CRS participants reported a high average degree of symptom burden (e.g., on a 0-10 scale, 8.2 for CRS with nasal polyps, 8.4 for CRS without nasal polyps with severe symptoms, and 6.4 for CRS without nasal polyps with moderate symptoms). The participants with CRS reported high health-care use for CRS, adverse effects of CRS symptoms on multiple areas of daily life, and high dissatisfaction with currently available treatments. Conclusion: More than 10% of the general U.S. adult population have CRS symptoms. Most report severe symptoms, lack of satisfaction with current treatment options, and a substantial adverse impact on daily functioning. [ABSTRACT FROM AUTHOR]

Background: Inadequate efficacy of current intranasal steroids in chronic rhinosinusitis (CRS) is attributable to ineffective and/or inconsistent drug delivery to target anatomic sites. A new exhalation delivery system with fluticasone (EDS‐FLU) may improve outcomes by significantly increasing superior/posterior corticosteroid delivery. A study was conducted to assess the long‐term efficacy and safety outcomes of EDS‐FLU in individuals with CRS. Methods: This was a 12‐month, multicenter, single‐arm study evaluating the safety and efficacy of EDS‐FLU 372 μg twice daily in CRS patients (with [n = 34] or without [n = 189] nasal polyps [NP]). Efficacy assessments by serial nasal endoscopy and patient report included: 22‐item Sino‐Nasal Outcome Test (SNOT‐22), NP grade, standardized surgical indicator assessment, Lund‐Kennedy score, and Patient Global Impression of Change. Adverse event (AE) evaluations included nasal endoscopy. Additional safety and efficacy outcomes were assessed. Results: Of 223 patients who received EDS‐FLU, 96% reported prior corticosteroid use and 29% prior sinus surgery. The EDS‐FLU AE profile was similar to conventional intranasal steroids studied in similar populations. Most patients (87%) reported symptom improvement. Through 12 months, mean SNOT‐22 scores improved by −21.5 and −21.1 for CRS with and without NP, respectively. Among patients with NP, 54.2% had polyp elimination in at least 1 nostril and 83.3% had ≥1‐point improvement in polyp grade. Conclusion: Over 1 year of treatment in CRS with and without NP, EDS‐FLU 372 μg twice daily was well tolerated and produced improvements across a broad range of objective and subjective measures. EDS‐FLU may be a desirable new option for patients with this condition. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: Topical sinus irrigations play a critical role in the management of sinonasal disease, and the improvement in irrigant penetration into the sinuses postoperatively greatly contributes to the success of endoscopic sinus surgery. Prior investigations on postoperative sinus irrigations have been mostly limited to cadaver studies, which are labor intensive and do not capture the full dynamics of the flows. A pilot study was conducted to investigate the impact of surgery on sinus irrigation through computational fluid dynamics (CFD) simulations.Study Design: Retrospective computational study.Methods: Pre- and postoperative computed tomography (CT) scans were obtained on a patient who underwent standard endoscopic surgeries for all sinuses, including a Draf III frontal sinusotomy. CT-based pre- and postoperative CFD models then simulated irrigations of 120 mL saline per nostril at 12 mL/s (typical of Sinugator) and 60 mL/s (SinusRinse Bottle), in two head positions: face parallel and at a 45° angle to the ground.Results: Overall, surgery most significantly improved frontal sinus irrigation, but surprisingly resulted in less maxillary and ethmoid sinuses penetration. This may due to the partial removal of the septum during the Draf III, causing most fluid to exit prematurely across the resected septum. Higher flow rate slightly improved ethmoid sinus irrigation, but resulted in less preoperative contralateral maxillary sinus penetration.Conclusions: CFD modeling of sinonasal irrigations is a novel technique for evaluating irrigant penetration of individual sinus cavities. It may prove useful in determining the optimal degree of surgery or the ideal irrigation strategy to allow for maximal and targeted sinus irrigant penetration.Level Of Evidence: NA Laryngoscope, 126:E90-E96, 2016. [ABSTRACT FROM AUTHOR]

Purpose: Concha bullosa (CB) alters the intranasal anatomy and may influence the buffering of inhalant allergens and the inflammatory microenvironment central to chronic rhinosinusitis (CRS). By investigating the link between allergies and CB, we can examine this theoretical benefit, which has implications on the extent of resection in endoscopic sinus surgery.Methods: Forty-three adults treated between 2010 and March 2014 with chronic sinonasal symptoms were retrospectively analyzed by skin prick allergy testing, maxillofacial computed tomography scan, and Lund-Mackay score. x03C7;2 analysis and t tests were employed to determine statistical significance.Results: Subjects were divided into 30 positive cases and 13 pan-negative allergy controls. No difference in CB prevalence was observed between those with positive (70%) and those with negative (69.2%) allergy tests (p = 0.93). Furthermore, no association between CB and Lund-Mackay score was identified (p = 0.69). Overall, 83.3% of CB were located in the middle turbinate, 16.7% in the superior turbinate, and 20% occurred in the middle turbinate bilaterally.Conclusions: Although an enlarged, pneumatized turbinate could function as a physical barrier to inhalant allergens, documented allergies demonstrate no association with CB formation. Furthermore, this study finds no correlation between CB and radiographic evidence of CRS. [ABSTRACT FROM AUTHOR]

The American Academy of Otolaryngology—Head and Neck Surgery Foundation has published a supplement to this issue featuring the updated “Clinical Practice Guideline: Adult Sinusitis” as a supplement to Otolaryngology–Head and Neck Surgery. To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 14 developed recommendations address diagnostic accuracy for adult rhinosinusitis, the appropriate use of ancillary tests to confirm diagnosis and guide management (including radiography, nasal endoscopy, computed tomography, and testing for allergy and immune function), and the judicious use of systemic and topical therapy. Emphasis was also placed on identifying multiple chronic conditions that would modify management of rhinosinusitis, including asthma, cystic fibrosis, immunocompromised state, and ciliary dyskinesia. An updated guideline is needed as a result of new clinical trials, new systematic reviews, and the lack of consumer participation in the initial guideline development group. [ABSTRACT FROM PUBLISHER]

Background Despite their widespread use, antibiotics have not been shown to improve chronic rhinosinusitis (CRS) outcomes. We aimed to determine whether culture-inappropriate postoperative antibiotic therapy was associated with less quality-of-life (QOL) improvement following functional endoscopic sinus surgery (FESS). Methods This retrospective cohort study recruited 376 adult CRS patients undergoing FESS between October 1, 2007 to December 31, 2011. Patient demographics, comorbidities and medications were collected at baseline. Trimethoprim-sulfamethoxazole and clindamycin were administered for 2 weeks postoperatively. The antibiotic appropriateness was determined based on bacterial resistance profile of organisms identified during intraoperative culture. The QOL outcome was defined as change of 22-item Sinonasal Outcome Test scores from preoperative visit to 1-month, 3-month, and 6-month post-FESS. Clinically significant difference was defined as at least 0.5 standard deviations (SD) of baseline QOL score in the reference group. Mixed-effects regression models were performed. Results Seven percent of patients (n = 27) had culture-inappropriate antibiotic therapy, and additional 5% (n = 19) had culture-specific antibiotic adjustment. Compared to patients with culture-appropriate antibiotics, patients with culture-inappropriate antibiotics had significantly less improvement of QOL from baseline to postoperative 1-month and 3-month follow-up where the difference became clinically significant; patients with antibiotic adjustment had more QOL improvement from baseline to 1-month follow-up, but their QOL worsened at 3-month follow-up, and these changes were not clinically significant. However, all effects washed out at 6-month follow-up with no significant differences. Conclusion Culture-inappropriate postoperative antibiotic therapy decreased short-term QOL improvement to a clinically meaningful level after FESS. Culture guided selection of antibiotics may improve short-term FESS outcome. [ABSTRACT FROM AUTHOR]

Background: Surfactants are a class of amphiphilic surface active compounds that show several unique physical properties at liquid-liquid or liquid-solid surface interfaces including the ability to increase the solubility of substances, lower the surface tension of a liquid, and decrease friction between two mediums. Because of these unique physical properties several in vitro, ex vivo, and human trials have examined the role of surfactants as stand-alone or adjunct therapy in recalcitrant chronic rhinosinusitis (CRS). Methods: A review of the literature was performed. Results: The data from three different surfactants have been examined in this review: citric acid zwitterionic surfactant (CAZS; Medtronic ENT, Jacksonville FL), Johnson's Baby Shampoo (Johnson & Johnson, New Brunswick NJ), and SinuSurf (NeilMed Pharmaceuticals, Santa Rosa, CA). Dilute surfactant therapy shows in vitro antimicrobial effects with modest inhibition of bacterial biofilm formation. In patients with CRS, surfactants may improve symptoms, most likely through its mucolytic effects. In addition, surfactants have several distinct potential benefits including their ability to improve an irrigant's penetration of the nonoperated sinus and their synergistic effects with antibiotics. However, surfactants potential for nasal irritation and possible transient ciliotoxicity may limit their use. Conclusion: Recent data suggest a possible therapeutic role of surfactants in treating rhinopathologies associated with mucostasis. Further investigation, including a standardization of surfactant formulations, is warranted to further elucidate the potential benefits and drawbacks of this therapy. [ABSTRACT FROM AUTHOR]

The article focuses on the development of consensus statement on the use of computed tomography (CT) for paranasal sinus disease. It mentions the use of Delphi method that was modified to refined the expert opinion gathered and for the panel to reach consensus. It states that the CT is consider as an essential diagnostic tool for patients with sinusitis and skull base pathology. It mentions the negative effect of CT imaging such as significant costs, radiation exposure, and overuse concerns.

Our purpose was to evaluate the effect of the mechanical force of a sneeze on sinonasal cilia function and determine the molecular mechanism responsible for eliciting the ciliary response to a sneeze. A novel model was developed to deliver a stimulation simulating a sneeze (55 mmHg for 50 ms) at 26°C to the apical surface of mouse and human nasal epithelial cells. Ciliary beating was visualized, and changes in ciliary beat frequency (CBF) were determined. To interrogate the molecular cascades driving sneeze-induced changes of CBF, pharmacologic manipulation of intra- and extracellular calcium, purinergic, PKA, and nitric oxide (NO) signaling were performed. CBF rapidly increases by ≥150% in response to a sneeze, which is dependent on the release of adenosine triphosphate (ATP), calcium influx, and PKA activation. Furthermore, apical release of ATP is independent of calcium influx, but calcium influx and subsequent increase in CBF are dependent on the ATP release. Lastly, we observed a blunted ciliary response in surgical specimens derived from patients with chronic rhinosinusitis compared to control patients. Apical ATP release with subsequent calcium mobilization and PKA activation are involved in sinonasal ciliary response to sneezing, which is blunted in patients with upper-airway disease. [ABSTRACT FROM AUTHOR]

Background: Sinonasal mucosal biofilms are recognized as contributors to the pathogenesis of chronic rhinosinusitis (CRS). Attachment of bacteria to the sinonasal surface is an initial step in biofilm formation. A critical defense against this occurrence is mucociliary clearance (MCC). To ascertain whether the ciliary component of MCC is uniform throughout the airway we compared ciliary beat frequency (CBF) in the murine nasal septum and trachea at baseline and after challenge with Pseudomonas aeruginosa, a common pathogen of CRS. Methods: Murine septal and tracheal air-liquid interface cultures were evaluated for basal and stimulated CBF after exposure to control or conditioned media from Pseudomonas. Additionally, the attachment of Pseudomonas to nasal and tracheal cultures was assessed after pretreatment with control or conditioned media. Results: Basal CBF is significantly slower in primary nasal airway cultures compared with tracheal airway cultures. Tracheal airway cultures show resistance to Pseudomonas secreted ciliotoxins not evident in nasal septal cultures. Furthermore, after challenge with viable Pseudomonas, significantly more bacteria attach to the nasal cultures compared with the tracheal cultures. Conclusion: Using primary murine nasal and tracheal airway cultures we show inherent differences in cilia function and increased susceptibility of the upper airway to attachment by Pseudomonas. Understanding the differences between upper and subglottic airway mucociliary clearance should lead to novel approaches in the management of upper airway infection. [ABSTRACT FROM AUTHOR]

Cigarette smokers and those exposed to second hand smoke are more susceptible to life threatening infection than nonsmokers. While much is known about the devastating effect tobacco exposure has on the human body, less is known about the effect of tobacco smoke on the commensal and commonly found pathogenic bacteria of the human respiratory tract, or human respiratory tract microbiome. Chronic rhinosinusitis (CRS) is a common medical complaint, affecting 16% of the US population with an estimated aggregated cost of $6 billion annually. Epidemiologic studies demonstrate a correlation between tobacco smoke exposure and rhinosinusitis. Although a common cause of CRS has not been defined, bacterial presence within the nasal and paranasal sinuses is assumed to be contributory. Here we demonstrate that repetitive tobacco smoke exposure induces biofilm formation in a diverse set of bacteria isolated from the sinonasal cavities of patients with CRS. Additionally, bacteria isolated from patients with tobacco smoke exposure demonstrate robust in vitro biofilm formation when challenged with tobacco smoke compared to those isolated from smoke naïve patients. Lastly, bacteria from smoke exposed patients can revert to a non-biofilm phenotype when grown in the absence of tobacco smoke. These observations support the hypothesis that tobacco exposure induces sinonasal biofilm formation, thereby contributing to the conversion of a transient and medically treatable infection to a persistent and therapeutically recalcitrant condition. [ABSTRACT FROM AUTHOR]

Abstract: This study compared the pharmacokinetics of azithromycin (AZI) following administration of extended-release (ER) and immediate-release (IR) formulations in plasma and sinus mucosa in patients with chronic rhinosinusitis. Patients (n =71) were randomised 1:1 to receive a single dose of AZI-ER 2g or up to three doses of AZI-IR 500mg daily. Paired plasma and sinus tissue samples were taken during endoscopic sinus surgery at 2–168h (four patients per time point) after the first dose. Samples were measured by a validated liquid chromatography/mass spectrometry assay. Pharmacokinetics were determined using composite concentration–time profiles. Comparison between formulations showed that within the first 24h, the AZI area under the plasma concentration–time curve (AUC24) for ER was 5.2- and 7.0-fold higher than IR in plasma and sinus tissue, respectively. Comparison between matrices showed that the AUC24 and AUC168 in sinus tissue were 28.2- and 62.2-fold higher than in plasma for the ER formulation, whilst the AUC24 in sinus tissue was 21.1-fold higher than in plasma for IR formulation. These results indicated that AZI has good penetration into sinus tissue regardless of formulation; however, dosing of AZI-ER (2g) increased AZI exposure within the first 24h compared with the Day 1 dose of 500mg IR regimen. [Copyright &y& Elsevier]

Background: Bacterial biofilms consist of a complex, organized community of bacteria that anchor to both biotic and abiotic surfaces. They are composed of layers of embedded, live bacteria within extruded exopolymeric matrix. This configuration allows for evasion of host defenses and decreased susceptibility to antibiotic therapy while maintaining the ability to deliberately release planktonic bacteria, resulting in recurrent acute infections. Thus, bacterial biofilms were hypothesized to contribute to the progression and persistence of chronic rhinosinusitis. Methods: This review summarizes several of the seminal papers supporting this hypothesis. Results: Multiple reports using various imaging modalities have demonstrated the presence of biofilms in sinonasal mucosa of patients with chronic rhinosinusitis. More recently, several studies have correlated the presence of biofilms with poor clinical outcomes in the disease process. Early therapeutic interventions have generated mixed results. Conclusions: Bacterial biofilms appear to contribute to the progression of chronic rhinosinusitis in a subset of patients, although substantial effort toward therapeutic intervention is still necessary. [ABSTRACT FROM AUTHOR]

Background: Cigarette smoke exposure is considered an important negative prognostic factor for chronic rhinosinusitis (CRS) patients. However, there is no clear mechanistic evidence implicating cigarette smoke exposure in the poor clinical evolution of the disease or in the maintenance of the inflammatory state characterizing CRS. This study aimed to evaluate the effects of cigarette smoke exposure on respiratory cilia differentiation. Methods: Mouse nasal septal epithelium cultures grown at an air-liquid interface were used as a model of respiratory epithelium. After 5 days of cell growth, cultures were exposed to air on the apical surface. Additionally, cigarette smoke condensate (CSC; the particulate phase of tobacco smoke) or cigarette smoke extract (CSE; the volatile phase) were diluted in the basolateral compartment in different concentrations. After 15 days of continuous exposure, scanning electron microscopy and immunofluorescence for type IV tubulin were used to determine presence and maturation of cilia. Transepithelial resistance was also recorded to evaluate confluence and physiological barrier integrity. Results: CSC and CSE impair ciliogenesis in a dose-dependent manner with notable effects in concentrations higher than 30 μg/mL, yielding >70% nonciliation and shorter cilia compared with control. No statistical difference on transepithelial resistance was evident. Conclusion: CSC and CSE exposure negatively impacts ciliogenesis of respiratory cells at concentrations not effecting transepithelial resistance. The impairment on ciliogenesis reduces the mucociliary clearance apparatus after injury and/or infection and may explain the poor response to therapy for CRS patients exposed to tobacco smoke. [ABSTRACT FROM AUTHOR]

Background: Chitosan is a polysaccharide derived from chitin deacetylation, which can form a biodegradable matrix capable of reversibly binding dexamethasone. The purpose of this study was to optimize the chitosan formulation to produce a pliable sheet, to assess the innate longevity and inflammatory potential of the polymer, and to study the in vivo rate of dexamethasone release over time. Methods: Chitosan glycerophosphate (CGP) sheets were produced with varying degrees of deacetylation (70-100%) and analyzed for structural integrity. Two-squared centimeter sheets of 91.7% deacetylated CGP were mixed with dexamethasone and implanted in 12 rabbit maxillary sinuses. Nasal lavage and peripheral blood samples were tested for dexamethasone levels by enzyme-linked immunosorbent assay (ELISA) over 15 days. Sinuses were examined histologically on postoperative days 3, 7, and 15 for persistence of the stent and degree of inflammation when compared with CGP alone. Results: The 91.7% deacetylated CGP formulation was found to have optimal mechanical properties and remained present with moderate degradation and negligible inflammation through postoperative day 15. Dexamethasone levels were detectable in nasal lavage and blood samples through postoperative day 15 and decayed over time (lavage: day 0, 7.70 ± 0.97 ng/mL, and day 15, 2.53 ± 1.71 ng/mL; blood: day 3, 2.51 ± 0.14 ng/mL, and day 15, 1.70 ± 0.36 ng/mL). Conclusion: CGP may be used to create a semirigid sheet that is malleable, inert, and capable of eluting steroid over 15 days when implanted intranasally. This material may be used to create a pharmacologically active stent that spontaneously degrades over time. [ABSTRACT FROM AUTHOR]

Bitter taste receptors (T2Rs) are G-protein-coupled receptors (GPCRs) expressed on the tongue but also in various locations throughout the body, including on motile cilia within the upper and lower airways. Within the nasal airway, T2Rs detect secreted bacterial ligands and initiate bactericidal nitric oxide (NO) responses, which also increase ciliary beat frequency (CBF) and mucociliary clearance of pathogens. Various neuropeptides, including neuropeptide tyrosine (neuropeptide Y or NPY), control physiological processes in the airway including cytokine release, fluid secretion, and ciliary beating. NPY levels and/or density of NPYergic neurons may be increased in some sinonasal diseases. We hypothesized that NPY modulates cilia-localized T2R responses in nasal epithelia. Using primary sinonasal epithelial cells cultured at air–liquid interface (ALI), we demonstrate that NPY reduces CBF through NPY2R activation of protein kinase C (PKC) and attenuates responses to T2R14 agonist apigenin. We find that NPY does not alter T2R-induced calcium elevation but does reduce T2R-stimulated NO production via a PKC-dependent process. This study extends our understanding of how T2R responses are modulated within the inflammatory environment of sinonasal diseases, which may improve our ability to effectively treat these disorders. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Endoscopic sinus surgery (ESS) maximized for topical steroid irrigations is highly effective for polyp disease. As extent and completeness of ESS varies widely by situation and practitioner, it is important to understand when revision surgery is appropriate, particularly in the era of biologic treatments.A Completion of Surgery Index (CoSI) was developed to assess operative changes in polyp patients using pre‐ and postoperative computed tomography scans. The CoSI was then applied and tested in a cohort of consecutive chronic rhinosinusitis with nasal polyps (CRSwNP) patients, and examined within the context of quality‐of‐life improvements.The CoSI assesses surgical extent on a scale of 0–100, with 100 representing the highest possible degree of surgical completeness. Among 100 consecutive CRSwNP patients undergoing ESS in 2021 with postoperative topical steroid irrigations, including 75 revision surgeries, SNOT‐22 scores improved at 6 months postoperatively, with durable and consistent improvement at 24 months (p < 0.001). Preoperative CoSI scores in revision surgery patients were 49.4 ± 26.0, improving to 91.0 ± 8.1 postoperatively. SNOT‐22 scores for primary ESS patients and patients with a preoperative CoSI score of less than 70 improved by 26.4 and 28.1 points, respectively, in contrast to patients with a preoperative CoSI of 70 or greater (14.1 points, p = 0.029).It is important to define extent of surgery in CRSwNP to stratify postsurgical patients based on likelihood to benefit from revision surgery or alternative medications. The CoSI can be utilized to identify patients who are likely to improve significantly with revision surgical intervention. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion The inability of topical medications to reach sinus cavities is a potential reason for lack of efficacy in chronic rhinosinusitis (CRS). One purpose of endoscopic sinus surgery (ESS) is to enable delivery of medications into the sinus cavities. The exhalation delivery system with fluticasone (EDS‐FLU; XHANCE) creates unique biomechanics that enable deposition of intranasal corticosteroid into sinuses and sinus drainage pathways but may have differing efficacy in operated versus unoperated sinuses. Two 24‐week randomized trials (ReOpen1/2) evaluated EDS‐FLU versus EDS‐placebo in patients with CRS, stratified by surgical status.Surgery‐naive (n = 332) and prior‐surgery (n = 215) patient groups were analyzed as pooled data from ReOpen1/2. Outcome measures (least‐squares mean change from baseline) included combined symptom score (CSS) and congestion score at weeks 4, 8, and 12 and average of percentages of opacified volume (APOV) of ethmoid/maxillary sinuses on CT and Sinonasal Outcome Test 22 (SNOT‐22) total score at week 24.Baseline scores suggested moderate–severe disease: mean CSS = 5.8; APOV = 67.2%. EDS‐FLU produced significant improvement versus placebo (p < 0.05): CSS (surgery‐naive, −0.68 vs. −1.42; prior ESS, −0.70 vs. −1.87); congestion (surgery‐naive, −0.24 vs. −0.59; prior ESS, −0.24 vs. −0.69); and SNOT‐22 (surgery‐naive, −7.56 vs. −18.30; prior ESS, −10.72 vs. −18.74). Similar results were observed for APOV (p < 0.05). No statistically significant difference was observed between surgery subgroups with either EDS‐FLU dose.EDS‐FLU improved symptoms, sinus opacification, and quality of life in patients with CRS with or without prior ESS, suggesting a role for EDS‐FLU in both populations. [ABSTRACT FROM AUTHOR]

Background: The delivery of topical intranasal corticosteroid sprays has traditionally been the primary method of treating recurrent nasal polyposis. An emerging treatment for polyposis is budesonide nasal irrigations. Delivered at concentrations nearly 100 times greater than found in prescription nasal sprays, there have been little studies on the effects of budesonide irrigation on the adrenal axis. Therefore, we investigated whether irrigation with budesonide solution was associated with any increase in serum cortisol and 24-hour urinary cortisol levels. Methods: Patients who previously had undergone endoscopic sinus surgery and were not taking prednisone for 3 months were prospectively enrolled in this study. Patients irrigated twice daily with 0.5 mg/2 mL of budesonide mixed with 240 mL of saline solution. Serum cortisol and 24-hour urinary cortisol were collected before drug administration and 6 weeks after continuous use. Results: Ten patients completed this study. The average serum cortisol and 24-hour urinary cortisol before drug administration were 9.8 ± 5.4 μg/dL and 28.1 ± 15.1 μg/24 hours, respectively. After 6-week follow-up, the average serum cortisol and 24-hour urinary cortisol were 12.8 ± 3.5 μg/dL and 16.5 ± 5.6 μg/24 hours, respectively. Normal ranges for serum cortisol and 24-hour urinary cortisol are 5-25 μg/dL and 4-50 μg/24 hours, respectively. Conclusions: Irrigation with budesonide, 0.5 mg/2 mL, in 250 mL of saline solution does not result in decreases of serum cortisol and 24-hour urinary cortisol levels. Based on this, we feel irrigation with budesonide solution is safe to perform in patients as an alternative to traditional aerosolized steroid sprays or systemic corticosteroids. [ABSTRACT FROM AUTHOR]

Key points: We created a LangChain/OpenAI API‐powered chatbot based solely on International Consensus Statement of Allergy and Rhinology: Rhinosinusitis (ICAR‐RS).The ICAR‐RS chatbot is able to provide direct and actionable recommendations.Utilization of consensus statements provides an opportunity for AI applications in healthcare. [ABSTRACT FROM AUTHOR]

METHODS Patient selection Institutional review board approval was obtained from the University of Pennsylvania for a retrospective chart review of patients receiving dupilumab for CRSwNP at a tertiary rhinology/allergy clinic between November 2018 and February 2022. Reasons for discontinuation All patients had undergone prior sinus surgery and were receiving dupilumab for CRSwNP with or without asthma treatment. DISCUSSION Although there was a recent database-based publication on adverse events of dupilumab,[7] our study is the first to report on a large real-world case series of patients who were treated with dupilumab for CRSwNP and experienced AEs significant enough to discontinue the medication. [Extracted from the article]

Background Sinonasal mucosa in patients with chronic rhinosinusitis (CRS) is often devoid of motile cilia. This defect is presumed to result from prolonged inflammation, infection, or both. However, the mechanism underlying this observation is unknown. Recently, centrosomal protein 110 (Cp110) was shown to prevent the terminal step in ciliary maturation (ie, elongation), suggesting that Cp110 might be involved in pathological states in which ciliation is abnormal. Objectives First, we sought to investigate the expression of Cp110 in sinonasal mucosa from patients with CRS and control subjects. Second, we sought to determine the extent that inflammatory cytokines modulate Cp110 expression and ciliary maturation in vitro . Methods Sinonasal mucosal specimens from patients with and without CRS were analyzed for Cp110 mRNA and protein expression. Furthermore, human and murine nasal respiratory epithelial cultures were used to investigate Cp110 expression under normal growth conditions and in the presence of exogenous proinflammatory cytokines. Results Increased Cp110 mRNA and protein expression was found in sinonasal mucosal specimens from patients with CRS compared with that seen in control specimens. During ciliogenesis in vitro , the expression of Cp110 gradually decreased in cultures derived from patients without CRS but remained increased in cultures derived from patients with CRS. Furthermore, cultures grown in the presence of proinflammatory cytokines demonstrated increased levels of Cp110 expression with concomitant inhibition of ciliogenesis. Conclusion Increased Cp110 expression in mucosa from patients with CRS might contribute to the poor ciliation observed in patients with CRS. Exogenous cytokine exposure maintains increased levels of Cp110 expression. Regulation of Cp110 expression by inflammation warrants additional investigation because it might offer a novel target in the management of respiratory tract diseases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background The bitter taste receptor T2R38, expressed in the tongue and nasal epithelium, has been shown to trigger sinonasal innate immunity contributing to the prevention of gram-negative upper airway bacterial infections. Common polymorphisms of the T2R38 gene, correlating with bitter taste sensitivity to phenylthiocarbamide (PTC), have been linked to differences in sinonasal innate immune response, with specific genotypes significantly more common in medically recalcitrant chronic rhinosinusitis patients. The purpose of this study was to examine this association between T2R38 function and sinonasal infection or symptoms in a healthy population. Methods A survey of the frequency of sinus infections, as well as other nasal symptoms such as colds, allergies, and overall nasal quality of life (nQOL), was administered to healthy adult participants. nQOL was measured using a 0 to 3 scale of worsening symptoms. A PTC compound taste strip was administered with T2R38 taste sensitivity classified as extremely, somewhat, or not sensitive. Results Among 217 participants (55% female, 70% Caucasian, 42% age 21 to 25 years), 30% did not detect bitterness (nontasters), 34% were moderate tasters, and 36% were 'supertasters,' experiencing a strong, unpalatable bitterness. Supertasters were associated with less frequent sinus infections ( p = 0.04), and PTC sensitivity was predictive of nasal symptoms: Supertasters had the best nQOL scores, followed by moderate tasters and nontasters (means: 0.65, 0.81, 1.00, respectively; p = 0.014 for trend). There were no significant associations with other variables. Conclusion This study provides evidence that T2R38 functionality in the tongue correlates with nasal symptoms in healthy individuals. [ABSTRACT FROM AUTHOR]

Background The bitter taste receptor T2R38 was recently described to play a role in upper airway innate mucosal defense. When activated by bacterial quorum-sensing molecules, T2R38 stimulates the ciliated epithelial cells to produce nitric oxide (NO), resulting in bactericidal activity and an increase in mucociliary clearance (MCC). Polymorphisms within the T2R38 gene ( TAS2R38) confer variability in activation of the receptor yielding dramatic differences in upper airway defensive responses (NO production and accelerated MCC) to microbial stimulation based on genotype. Our objective was to determine whether the nonprotective TAS2R38 polymorphisms, which render the receptor inactive, correlate with medically recalcitrant chronic rhinosinusitis (CRS) necessitating surgical intervention in the context of known risk factors, and thus identify whether the TAS2R38 genotype is an independent risk factor for patients undergoing functional endoscopic sinus surgery (FESS). Methods CRS patients undergoing primary FESS were prospectively genotyped for TAS2R38. Chi-square analysis was performed on the genotype distribution with respect to other risk factors, including allergies, asthma, nasal polyposis, aspirin sensitivity, diabetes, and smoking exposure. Results Seventy primary FESS patients were genotyped demonstrating a statistically significant skewing from the expected distribution of the general population ( p < 0.0383). CRS patients with a particular polymorphism seemed less likely to have allergies, asthma, nasal polyposis, aspirin sensitivity, and diabetes, but this did not demonstrate statistical significance. Conclusion Our investigation suggests that TAS2R38 genotype is an independent risk factor for patients failing medical therapy, necessitating surgical intervention. [ABSTRACT FROM AUTHOR]

Background: This study evaluated 1-year outcomes in patients with chronic rhinosinusitis (CRS) who were considered surgical candidates by study criteria and elected either medical management or endoscopic sinus surgery (ESS). In addition, some patients initially enrolled in the medical treatment arm crossed over to the surgery arm during the study period and their respective outcomes are evaluated. Methods: Adult subjects with CRS who failed initial medical therapy were prospectively enrolled into a nonrandomized, multi-institutional cohort. Subjects were included in 1 of 3 cohorts: medically managed, surgically managed, or crossover (from medical to surgical). The primary outcome measure was disease-specific quality-of-life (QOL). Bivariate and multivariate analyses compared QOL improvement between cohort groups. Results: Baseline comorbidity, QOL, and other disease severity measures were not different between the 3 cohorts. With 1-year follow up, surgical patients (n = 65) reported significantly more improvement than medically managed patients (n = 33; Rhinosinusitis Disability Index (RSDI), p = 0.039; Chronic Sinusitis Survey (CSS), p = 0.018). Seventeen subjects who had initially elected medical management crossed over to surgery during the follow-up period. QOL in the crossover cohort was initially stagnant or worsening followed by improvement after ESS (RSDI, p = 0.035; CSS, p = 0.070). At 1-year follow-up, higher frequency of improvement was found in the surgical cohort vs medical cohort for several outcomes (total CSS: 70.8% vs 45.5%; odds ratio [OR], 3.37; 95% confidence interval [CI], 1.27-8.90; p = 0.014). Conclusion: With 1 year of follow-up, patients electing ESS experienced significantly higher levels of improvement in outcomes compared to patients managed by medication alone. In addition, a crossover cohort who initially elected medical management experienced improvement in several outcomes after crossing over to ESS. © 2013 ARS-AAOA, LLC. [ABSTRACT FROM AUTHOR]

Background: Chronic rhinosinusitis (CRS) is a multifactorial disease with a high co‐occurrence with asthma. In this multicohort study, we tested whether single nucleotide polymorphisms (SNPs) associated with childhood asthma and rhinovirus (RV)‐associated disease are related to an increased susceptibility to adult CRS in a multicohort retrospective case‐control study. Methods: Participants at two tertiary academic rhinology centers, University of Arizona (UofA) and University of Pennsylvania (UPenn) were recruited. Cases were defined as those with physician diagnosed CRS (UofA, n = 149; UPenn, n = 250), and healthy controls were those without CRS (UofA, n = 66; UPenn, n = 275). Genomic DNA was screened for the GSDMB rs7216389 SNP and CDHR3 rs6967330 SNP. Gene dosage, or the number of combined risk alleles in a single subject was calculated. Meta‐analysis of the association between GSDMB or CDHR3 genotypes and CRS was performed and additive gene dosage effect for each population calculated using p for trend. Results: A meta‐analysis revealed a combined increased risk for CRS in subjects with the GSDMB rs7216389 SNP (odds ratio [OR] 1.40; 95% confidence interval [CI], 1.16–1.76; p = 0.004). Both the UofA (OR 1.73; 95% CI, 1.23–2.43; p = 0.002) and UPenn (OR 1.27; 95% CI, 1.02–1.58; p = 0.035) populations showed a significant positive association between the number of combined risk alleles of GSDMB rs7216389 SNP and CDHR3 rs6967330 SNP and risk for CRS. Conclusion: Carriers of the GSDMB rs7216389 SNP and CDHR3 rs6967330 SNP are at increased susceptibility for CRS. These data suggest that therapeutic approaches to target aberrant responses to RV infection may play a role in the treatment of unified airway disease. [ABSTRACT FROM AUTHOR]

Keywords: chronic rhinosinusitis; human leukocyte antigen; rhinosinusitis; sinusitis EN chronic rhinosinusitis human leukocyte antigen rhinosinusitis sinusitis 1075 1077 3 07/27/22 20220801 NES 220801 INTRODUCTION Chronic rhinosinusitis (CRS), an extremely common chronic condition, is defined as symptomatic and objective inflammation of the sinonasal mucosa lasting more than 12 weeks.1,2 Treatment for CRS remains a challenge despite our evolving understanding of the underlying mechanisms. RESULTS The 550 patients comprised 317 CRS patients (208 CRSwNP, 109 CRSsNP) and 233 controls (Table 1), all self-identified as white/Caucasian and middle-aged. In summary, we have determined that heterozygous carriers of the rs1391371 T allele are at significantly increased risk for developing CRSwNP, which further supports the potential contribution of this HLA region to CRS. [Extracted from the article]

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 × 10–9M, 1.00 × 10–8M, 1.78 × 10–8M, 3.16 × 10–8M, 5.62 × 10–8M, and 1.00 × 10–7M (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 × 10–8M and 3.16 × 10–8M (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 × 10–8M for future study of clinical utility. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of inverted papilloma (IP) has not been fully elucidated. However, chronic paranasal sinus inflammation has been anecdotally observed in sites distant from tumor obstruction in IP patients, suggesting an association between inflammation and IP tumorigenesis. This study assesses the association between sinonasal inflammation found in IP and compares this to the level of inflammation observed in other sinonasal tumors. Methods: A retrospective chart review was performed identifying patients with unilateral IP. Pertinent clinical data was obtained and comparative analysis of preoperative computed tomography (CT) imaging and histopathology was performed. A sample of unilateral, sinonasal, non‐IP and non–squamous cell tumors was used as the control. The Lund‐Mackay scoring system was used to assess radiologic sinonasal inflammation both ipsilateral and contralateral to the tumor. Results: Seventy‐one patients were included; 58.9% of patients with IP had evidence of contralateral sinusitis at the time of presentation. In the control group, 26.7% had evidence of contralateral inflammation. When comparing contralateral sinus inflammation between the 2 study groups, the IP patients had significantly higher Lund‐Mackay scores than the control group (1.9 vs 0.26, p < 0.001). When comparing ipsilateral sinus inflammation, no significant difference was found in Lund‐Mackay scores (5.44 vs 4.00, p < 0.184). Conclusion: In this study, unilateral IPs were associated with a higher level of contralateral sinonasal inflammation when compared to control. This suggests that IP may be associated with inflammation that is independent of obstruction by the tumor. Further studies are needed to better understand the temporal relationship between chronic inflammation and tumorigenesis. [ABSTRACT FROM AUTHOR]

Background: Chronic rhinosinusitis (CRS) is a frequently observed condition in patients with immunodeficiency secondary to tumor necrosis factor alpha inhibitors (TNFαis). The histologic features of CRS caused by TNFαis have yet to be determined and may have important implications in understanding the pathophysiology of the disease process. Methods: A structured histopathology report was used to analyze sinus tissue removed during functional endoscopic sinus surgery (FESS). These structured histopathology variables were compared among patients with CRS on TNFαi (CRSαi), CRS without nasal polyps (CRSsNP) patients, and CRS with nasal polyps (CRSwNP) patients. Results: Eighteen CRSαi, 91 CRSwNP, and 113 CRSsNP patients undergoing FESS were analyzed. Compared to CRSsNP, CRSαi patients exhibited increased mucosal ulceration (16.7% vs 0.9%, p < 0.008), increased fibrosis (100% vs 34.5%, p < 0.001), and increased presence of Charcot‐Leiden crystals (16.7% vs 0%, p < 0.002). Compared to CRSwNP, CRSαi patients demonstrated increased fibrosis (100% vs 54.9%, p < 0.001), decreased presence of subepithelial edema (44.4% vs 69.2% p < 0.043), decreased eosinophil aggregates (22.2% vs 47.3% p < 0.042), and fewer eosinophils per high‐power field (44.4% vs 73.6%, p < 0.017). Conclusion: CRSαi exhibits structured histopathology more similar to CRSsNP. In the appropriate clinical context, it may be reasonable that the medical regimen for these patients be focused on a more antineutrophilic, macrolide‐based approach. This study provides insight into the inflammatory environment of patients with CRSαi and may have implications for disease management. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Aspirin‐exacerbated respiratory disease (AERD) is characterized by chronic eosinophilic rhinosinusitis, nasal polyps, asthma, and respiratory sensitivity to aspirin and nonsteroidal anti‐inflammatory drugs (NSAIDs). In addition to sensitivity to aspirin and NSAIDs, the majority of patients with AERD have been reported to have respiratory intolerance associated with the consumption of alcohol. Methods: A multicenter prospective cohort study was performed. Patients with AERD confirmed by aspirin challenge were eligible to participate. Those who described themselves as able to tolerate alcohol consumption were excluded. Patients underwent aspirin desensitization following endoscopic sinus surgery. A questionnaire was distributed to patients before and after desensitization to determine pre‐desensitization and post‐desensitization symptoms associated with alcohol ingestion. Results: Forty‐five patients were enrolled and 37 patients completed the study. The most common pre‐desensitization symptoms were nasal congestion (95.6%), rhinorrhea (46.7%), and wheezing (40%). Improvement in the ability to tolerate alcohol was noted in 86.5% of participants (95% confidence interval [CI], 75.5% to 97.5%) and 70.3% of participants (95% CI, 55.5% to 85.0%) described desensitization to be “very helpful” or “extremely helpful” for their ability to tolerate alcohol. Conclusion: The majority of patients with AERD who experience respiratory symptoms with alcohol consumption describe improvement in this domain following aspirin desensitization. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Bitter taste receptors (taste family 2 bitter receptor proteins; T2Rs), discovered in many tissues outside the tongue, have recently become potential therapeutic targets. We have shown previously that airway epithelial cells express several T2Rs that activate innate immune responses that may be important for treatment of airway diseases such as chronic rhinosinusitis. It is imperative to more clearly understand what compounds activate airway T2Rs as well as their full range of functions. T2R isoforms in airway motile cilia (T2R4, -14, -16, and -38) produce bactericidal levels of nitric oxide (NO) that also increase ciliary beating, promoting clearance of mucus and trapped pathogens. Bacterial quorum-sensing acyl-homoserine lactones activate T2Rs and stimulate these responses in primary airway cells. Quinolones are another type of quorum-sensing molecule used by Pseudomonas aeruginosa. To elucidate whether bacterial quinolones activate airway T2Rs, we analyzed calcium, cAMP, and NO dynamics using a combination of fluorescent indicator dyes and FRET-based protein biosensors. T2R-transfected HEK293T cells, several lung epithelial cell lines, and primary sinonasal cells grown and differentiated at the air--liquid interface were tested with 2-heptyl-3-hydroxy-4-quinolone (known as Pseudomonas quinolone signal; PQS), 2,4-dihydroxyquinolone, and 4-hydroxy-2-heptylquinolone (HHQ). In HEK293T cells, PQS activated T2R4, -16, and -38, whereas HHQ activated T2R14. 2,4-Dihydroxyquinolone had no effect. PQS and HHQ increased calcium and decreased both baseline and stimulated cAMP levels in cultured and primary airway cells. In primary cells, PQS and HHQ activated levels of NO synthesis previously shown to be bactericidal. This study suggests that airway T2R-mediated immune responses are activated by bacterial quinolones as well as acyl-homoserine lactones. [ABSTRACT FROM AUTHOR]

Background Off-label use of topical ophthalmologic formulations for treatment of rhinologic disease is cited in recent literature and is anecdotally prevalent among practicing otolaryngologists. Steroids, antibiotics, and other drugs designed for ocular use have subjective clinical efficacy in the nose and sinuses, but their specific effects on the ciliated epithelium are less well defined. This study examines 9 commercially available ophthalmologic drug formulations for effects on ciliary motility in sinonasal cultures, in an effort to characterize their utility as topical therapies for sinonasal diseases. Methods Ophthalmologic solutions were tested on human sinonasal cultures grown at an air-liquid interface. Baseline ciliary beat frequency (CBF) was recorded and compared with CBF changes in the 20 minutes after drug addition. Substances were categorized by degree of ciliostimulation or cilioinhibition. Results All ophthalmologic solutions tested had only moderate effects on CBF during the 20-minute experimental period, with no solutions causing overt ciliostasis. Azithromycin, neomycin, and olopatadine were slightly ciliostimulatory, whereas levofloxacin, tobramycin, dexamethasone, azelastine, and prednisolone acetate were cilioinhibitory. Ciprofloxacin elicited moderate cilioinhibition that progressed to ciliostimulation. Conclusion All solutions tested appear to have moderate effects on ciliated cell surfaces for a period of time typical of mucociliary clearance (10 to 20 minutes). Both active drugs and excipients can play a role in ciliary modulation, and specific formulations can show unique or unexpected properties. Any other individual ophthalmologic solutions to be used in a nasal drug delivery system should be tested in this manner to evaluate potential ciliary effects before clinical use. [ABSTRACT FROM AUTHOR]

Background Sinonasal bitter taste receptors (T2Rs) contribute to upper airway innate immunity and correlate with chronic rhinosinusitis (CRS) clinical outcomes. A subset of T2Rs expressed on sinonasal solitary chemosensory cells (SCCs) are activated by denatonium, resulting in a calcium-mediated secretion of bactericidal antimicrobial peptides (AMPs) in neighboring ciliated epithelial cells. We hypothesized that there is patient variability in the amount of bacterial killing induced by different concentrations of denatonium and that the differences correlate with CRS clinical outcomes. Methods Bacterial growth inhibition was quantified after mixing bacteria with airway surface liquid (ASL) collected from denatonium-stimulated sinonasal air-liquid interface (ALI) cultures. Patient ASL bacterial killing at 0.1 mM denatonium and baseline characteristics and sinus surgery outcomes were compared between these populations. Results There is variability in the degree of denatonium-induced bacterial killing between patients. In CRS with nasal polyps (CRSwNP), patients with increased bacterial killing after stimulation with low levels of denatonium undergo significantly more functional endoscopic sinus surgeries (FESSs) ( p = 0.037) and have worse 6-month post-FESS 22-item Sino-Nasal Outcome Test (SNOT-22) scores ( p = 0.012). Conclusion Bacterial killing after stimulation with low levels of denatonium correlates with number of prior FESS and postoperative SNOT-22 scores in CRSwNP. Some symptoms of CRS in patients with hyperresponsiveness to low levels of denatonium may be due to increased airway immune activity or inherent disease severity. [ABSTRACT FROM AUTHOR]

Background Antimicrobial peptides (AMPs) produced by the epithelium are important for innate immune defense. In 2001, a novel AMP dermcidin (DCD) was described with no homology to other AMPs and an expression pattern restricted to eccrine sweat glands. In contrast to other AMPs, DCD expression has not been shown to be induced under inflammatory conditions in the skin. After identifying DCD by mass spectrometry in a protein sample isolated from human nasal secretions, we sought to determine the role of DCD in innate defense of the sinonasal airway. Methods After institutional review board approval, sinonasal mucosal tissue specimens were acquired from residual clinical material obtained during sinonasal surgery and used to grow cultures in an air-liquid interface environment. After stimulation of the cultures with various bitter compounds and phosphate-buffered saline, airway surface liquid was collected, and a DCD-specific enzyme-linked immunoassay was used to quantify DCD in each sample. To localize DCD expression, ALI cultures were fixed and immunofluorescence performed against DCD, β-tubulin IV, and Muc-5A. Results Enzyme-linked immunoassay showed DCD in air-surface liquid and in clinical nasal secretion samples at concentrations comparable to eccrine sweat. There was no evidence of inducible expression with any of the tested stimulants. Confocal microscopy revealed DCD expression in sinonasal mucosal goblet cells. Conclusion This is the first report of the presence of DCD in nasal mucosa and demonstration of DCD in clinical samples of human nasal secretions at clinically relevant concentrations, which may represent a novel arm of sinonasal airway innate defense. [ABSTRACT FROM AUTHOR]

Background Current guidelines have identified 10 to 12 weeks posttreatment as the ideal time-point for improved diagnostic accuracy of positron emission tomography/computed tomography (PET/CT) for deep tissue sites of the head and neck. After treatment, the sinonasal skull base is predisposed to prolonged inflammation that may render this time-point inappropriate for initial posttreatment imaging surveillance for sinonasal malignancies. The purpose of this study is to evaluate temporal trends in 18F-fluorodeoxyglucose (18FDG) sinonasal uptake after treatment for sinonasal malignancies to better elucidate the optimal time-point for initial PET/CT posttreatment evaluation in this patient population. Methods A retrospective analysis of all successfully treated and non-locally recurrent sinonasal malignancies over a 15-year study period (2000 to 2015) was performed at our institution. Posttreatment 18FDG PET/CT standardized uptake value data were collected and compared between various time-points (2 to 4 months, 5 to 12 months, 5 to 24 months, and 13 to 24 months) using an independent-samples t test. Results A statistically significant difference was noted between the posttreatment time windows 2 to 4 and 5 to 12 months ( p = 0.048) as well as 2 to 4 and 5 to 24 months ( p = 0.02). A trend toward significance was seen when comparing 2 to 4 and 13 to 24 months ( p = 0.083). Conclusion Our analysis of PET/CT in patients previously treated for sinonasal malignancy suggests that the posttreatment sinonasal skull base is characterized by a prolonged period of hypermetabolism that endures beyond the period previously described for deep tissue sites of the head and neck. These findings prompt a reevaluation of the previously described 10- to 12-week cutoff point for initial posttreatment PET/CT for head and neck squamous cell carcinoma as applied to sinonasal malignancies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Chronic rhinosinusitis (CRS) is very prevalent in the cystic fibrosis (CF) patient population, and leads to high morbidity and markedly decreased quality of life (QOL). Identification of genetic markers that contribute to CRS symptoms in these patients can allow for risk stratification and tailoring of medical and surgical treatments. T2R38 is a bitter taste receptor expressed in the sinonasal tract, and nonfunctional alleles of this receptor have been implicated in treatment-refractory CRS in non-CF patients. The purpose of this study is to investigate the significance of T2R38 genotype in the variability of sinonasal QOL and CRS disease severity in a sample of CF patients. Methods ΔF508 homozygous CF patients were recruited from the University of Pennsylvania Cystic Fibrosis Center and were genotyped for the TAS2R38 locus. To assess sinonasal symptom severity, a 22-item Sino-Nasal Outcome Test (SNOT-22) was collected from each patient. Additional demographic and medical history data was obtained at the time of patient enrollment. Results A total of 49 ΔF508 homozygous CF patients aged 18 to 32 years were included in the final SNOT-22 score analysis. Individuals with 2 functional T2R38 alleles (PAV/PAV) had significantly lower SNOT-22 scores (n = 49, p < 0.05). On further breakdown of SNOT-22 subcategories, rhinologic symptoms specifically were less severe in PAV/PAV patients than patients with other genotypes (n = 47, p < 0.05). Conclusion Our investigation indicates that T2R38 genotype correlates both with SNOT-22 scores and rhinologic-specific QOL in ΔF508 homozygous CF patients. [ABSTRACT FROM AUTHOR]

Background Nitric oxide (NO) is an important antibacterial defense molecule produced by upper airway (sinonasal) epithelial cells. We previously showed that a bitter taste receptor expressed in airway epithelium detects quorum-sensing molecules secreted by Gram-negative bacteria and subsequently triggers bactericidal NO production. We hypothesized that the upper airway epithelium may also be able to detect the Gram-positive aerobe Staphylococcus aureus and mount an NO response. Methods Human sinonasal air-liquid interface (ALI) cultures were treated with methicillin-resistant S. aureus (MRSA)-conditioned medium (CM), and NO production was measured using fluorescence imaging. Inhibitors of bitter taste receptor signaling were used to pharmacologically determine if this pathway was involved in the production of NO. Results A low-molecular-weight, heat, and protease-stabile product found in MRSA CM induced differential, NO synthase (NOS)-mediated NO production. This response varied markedly between individual patients. The MRSA-stimulated NO production was not dependent on 2 important components of bitter taste signaling: phospholipase C isoform β-2 or the transient receptor potential melastatin isoform 5 (TRPM5) ion channel. Conclusion This study shows that a S. aureus product elicits an NO-mediated innate defense response in human upper airway epithelium. The active bacterial product is likely a small, nonpeptide molecule that triggers a pathway independent of bitter taste receptors. Patient variation in the NO response to MRSA product(s), potentially due to genetic differences, might play a role in pathophysiology of Gram-positive upper respiratory infections and/or pathogenesis of chronic rhinosinusitis. [ABSTRACT FROM AUTHOR]

Background Staphylococcus aureus and Pseudomonas aeruginosa are common culture isolates in chronic rhinosinusitis (CRS). We aimed to determine whether they were associated with different clinical factors of CRS. Methods Adult CRS patients who underwent functional endoscopic sinus surgery (FESS) between October 1, 2007 and December 31, 2011 were recruited. Patient demographics, Lund-Mackay computed tomography (CT) scores, 22-item Sino-Nasal Outcome Test (SNOT-22) scores, disease characteristics, and medication use were collected prior to FESS. Intraoperative culture was obtained in a standard manner. We compared patients with isolates of S. aureus or P. aeruginosa to patients with other culture results and no bacterial growth, respectively. Multivariate logistic regression was performed. Results A total of 376 patients met criteria; 104 patients (28%) had S. aureus, 32 (9%) had P. aeruginosa, and 10 patients (3%) had no bacterial growth. After adjusting for all clinical factors, compared to patients with positive culture other than S. aureus, patients with S. aureus had 1.9 times increased odds of having nasal polyps (odds ratio [OR] = 1.9; 95% confidence interval [CI], 1.0 to 3.3; p = 0.036); when compared to patients with positive culture other than P. aeruginosa, patients with P. aeruginosa had 7.8 times increased odds of having prior FESS (OR = 7.8; 95% CI, 2.1 to 28.9; p = 0.002) (91% vs 58%; p < 0.001) and 3.6 times increased odds of having diabetes with marginal significance (OR = 3.6; 95% CI, 1.0 to 13.2; p = 0.053). The sample size in the no bacterial growth group was too small to draw firm conclusions. Conclusion S. aureus was more common in CRS patients with nasal polyps, whereas P. aeruginosa was more common in CRS patients with prior FESS history and possibly diabetes. [ABSTRACT FROM AUTHOR]