Lack of association of impaired upper airway sensation with the presence or absence of obstructive sleep apnoea or chronic rhinosinusitis in World Trade Center responders.

OBJECTIVE: Examine sensory function of the upper airway in four groups of subjects recruited from the World Trade Centre General Responder Cohort (WTCGRC), with/without obstructive sleep apnoea (OSA), and with/without chronic rhinosinusitis (CRS). METHODS: Upper airway sensory function was determined using 2-point discrimination (2-PD) and vibration threshold (VT) in 163 WTCGRC subjects with both OSA and CRS (cases), OSA or CRS alone and without OSA or CRS (controls). Presence of OSA was determined from clinical sleep studies or home sleep testing. Presence of CRS was determined by nasal symptom questionnaire. The relationship between the presence of OSA and CRS and upper airway sensory impairment was assessed using linear regression analysis with each of 2PD and VT sensory threshold values as the dependent variable; OSA, CRS and their interaction were the independent variables. Age, gender and body mass index were covariates in the statistical model. The primary analysis was comparison of OSA+CRS versus controls (no OSA and no CRS) evaluated by linear contrasts. RESULTS: There were no differences in 2-PD or VT in those with OSA+CRS, OSA and CRS alone or controls. However, both 2-PD and VT were significantly higher in the WTCGRC controls compared with values seen in historical controls using the same methodology (median 2-PD 13.0; CI (11.0 to 13.5) vs 10.5; CI (8 to 11); VT: mean±SEM (9.3±0.6 vs 2.2±0.1)). CONCLUSION: While no differences were found in upper airway sensation between cases of OSA and CRS versus controls in the WTGRC population, there was evidence of impaired upper airway sensation in the WTGRC overall.

A new surgical technique to increase airflow in the olfactory cleft: superior turbinate lateralization procedure.

BACKGROUND: The olfactory cleft (OC) is the most important anatomical site for the maintenance of olfactory function. Obstruction of airflow in the OC by various conditions, such as inflammation, leads to poor olfactory function. Therefore, it is important to increase OC airflow while performing endoscopic sinus surgery (ESS). However, no technique to increase airflow has yet been established. METHODS: We designed a superior turbinate lateralization (STL) procedure that displaces the entire ST bone laterally by eliminating the connection between the posterior ST and the anterior wall of the sphenoid sinus. The effect of the STL procedure was investigated in terms of anatomy and olfactory function. RESULTS: ESS with the STL procedure was performed on seven patients with chronic rhinosinusitis and nasal polyps. The cross-sectional area of the OC at 3 months postoperatively was significantly larger than that before ESS. In addition, the Open Essence test and questionnaires revealed significantly improvements in sense of smell. Airflow in the OC was significantly higher in STL procedure group than in the non-STL procedure group. CONCLUSION: The STL procedure enlarges the bony framework of the OC, and by increasing OC airflow, facilitates the transport of odorants to the olfactory epithelium, thereby improving olfactory perception.

Overall symptom severity as a patient-reported outcome measure for chronic rhinosinusitis: what it reflects and how to measure it.

BACKGROUND: The objective of this study was to identify how - and to what extent - overall symptom severity (OSS) score reflects individual chronic rhinosinusitis (CRS) symptoms and whether it can be measured using alternatives to the standard visual analog scale (VAS). METHODS: CRS patients from four sites across three continents rated their OSS scores, severities of nasal obstruction, nasal drainage, decreased sense of smell, facial pain/pressure and sleep disturbance using a standard VAS, VAS with labeled tick marks at every 1 centimeter, and by writing down their OSS on a scale of 0 - 100 (which was divided by 10), all of which lead to severity scores ranging from 0 - 10 in 0.1 intervals. Quality of life was measured using the SNOT-22 and EQ-5D VAS. RESULTS: In 311 CRS patients, OSS score was significantly correlated with SNOT-22 and EQ-5D VAS. OSS score was most greatly associated with the mean of all individual symptom severity scores. From individual CRS symptoms, OSS was most greatly associated with nasal obstruction followed by nasal drainage and facial pain/pressure severities. These results held true for participants with and without nasal polyps. Measurement of OSS and individual symptom severity scores using a standard VAS, tick-marked VAS, and write-in option had near-perfect consistency. CONCLUSIONS: We demonstrate for the first time that OSS largely reflects the mean of individual CRS symptom severities, although OSS is=== most weighted by nasal obstruction severity. OSS and individual symptom severity scores can be measured using a standard VAS, tick-marked VAS or write-in prompt with near-perfect consistency.

Objective nasal airflow measures in relation to subjective nasal obstruction, trigeminal function, and olfaction in patients with chronic rhinosinusitis.

BACKGROUND: This study aimed to determine how nasal airflow measures and trigeminal function vary among patients with chronic rhinosinusitis (CRS) versus healthy controls and whether these measures are correlated with subjective nasal obstruction (SNO), olfactory function, and CRS control. METHODOLOGY: Participants included CRS patients and healthy controls. After a structured medical history, nasal airflow (peak nasal inspiratory flow [PNIF]; active anterior rhinomanometry [AAR]), trigeminal function (trigeminal lateralization test, CO2 sensitivity), and olfactory "Sniffin's Sticks" odor identification test) tests were performed. SNO ratings were also obtained. RESULTS: Sixty-nine participants were included (37 men, 32 women, mean age 51 years). There was no significant difference for objective nasal airflow between patients and controls, but CRS patients had worse SNO, trigeminal function, and olfaction compared to controls. SNO, but not objective nasal airflow tests, was negatively correlated with CO2 sensitivity and odor identification. CONCLUSION: The perception of nasal obstruction does not only depend on nasal airflow, but may also be modulated by trigeminal function and other factors. Thus, the role of objective nasal airflow measures as a sole method of functional nasal obstruction assessment in CRS remains limited.

Clinical outcomes of functional endoscopic sinus surgery in cystic fibrosis patients - a single centre experience.

BACKGROUND: Endoscopic sinus surgery (ESS) is an established surgical option for cystic fibrosis (CF) patients with chronic rhinosinusitis that is refractory to conventional medical management. Objective and subjective evidence of benefit of ESS in this cohort of patients is currently conflicting in the literature. METHODOLOGY: A single center retrospective study was undertaken of all CF patients (transplanted and non-transplanted) over the age of 16 who underwent an ESS over a six-year period from 2015 to 2021. Patients on triple-therapy CFTR modulators were excluded. Data was collected on demographics, clinical management, and outcome measures. The objective outcome measures were lung function (%predicted FEV1), pulmonary exacerbations (total number of days of IV antibiotics- both ambulatory and in hospital). The subjective outcome measure was SNOT-22 scores pre and 6 months post-operatively. A minimally clinical important difference (MCID) in SNOT-22 scores of 9 points was used. RESULTS: 55 patients were included in our study, with a median age of 31 and 53% females. Median Lund-Mackay scores for the cohort was 13 (3-24). There was a significant improvement in lung function at 1-year post-surgery, and a significant MCID reduction in SNOT-22 scores at 6 months post-surgery across the cohort. Sub-group analysis revealed a sustained MCID reduction in SNOT-22 scores in both lung-transplanted and native lung groups, and in patients with primary ESS or previous ESS. However, there was no post-operative pulmonary function improvement in lung transplanted patients and patients with previous ESS. There was no impact on the rate of pulmonary exacerbations across the cohort. 2 patients in the cohort died secondary to pulmonary disease. CONCLUSIONS: There was a demonstrated clinical and symptomatic benefit of ESS in CF patients in this study. Stricter guidelines for indications for ESS need to be established with regards to CF patients who will undergo ESS in the future.

Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161.

Innate lymphoid cells (ILCs) are emerging as a family of effectors and regulators of innate immunity and tissue remodeling. Interleukin 22 (IL-22)- and IL-17-producing ILCs, which depend on the transcription factor RORγt, express CD127 (IL-7 receptor α-chain) and the natural killer cell marker CD161. Here we describe another lineage-negative CD127(+)CD161(+) ILC population found in humans that expressed the chemoattractant receptor CRTH2. These cells responded in vitro to IL-2 plus IL-25 and IL-33 by producing IL-13. CRTH2(+) ILCs were present in fetal and adult lung and gut. In fetal gut, these cells expressed IL-13 but not IL-17 or IL-22. There was enrichment for CRTH2(+) ILCs in nasal polyps of chronic rhinosinusitis, a typical type 2 inflammatory disease. Our data identify a unique type of human ILC that provides an innate source of T helper type 2 (T(H)2) cytokines.

No difference in omalizumab efficacy in patients with asthma by number of asthma-related and allergic comorbidities.

BACKGROUND: Comorbidities are common in asthma and may complicate treatment response. OBJECTIVE: To examine response to omalizumab in patients with moderate-to-severe allergic asthma by asthma-related and allergic comorbidities. METHODS: Patients aged 12 years or more from placebo-controlled 008/009 (n = 1071), EXTRA (n = 848), and INNOVATE (n = 419), and single-armed PROSPERO (n = 801) omalizumab studies were included. Poisson regression/analysis of covariance models were used to estimate adjusted exacerbation rates and forced expiratory volume in 1 second (FEV1) change from baseline after omalizumab initiation for subgroups by number of comorbidities (0, 1 [008/009]; 0, 1, ≥2 [EXTRA and INNOVATE]; 0, 1, 2, ≥3 [PROSPERO]). Self-reported comorbidities included allergic rhinoconjunctivitis, chronic rhinosinusitis, recurrent acute sinusitis, nasal polyps, atopic and contact dermatitis, urticaria, food allergy, anaphylaxis, other allergies, gastroesophageal reflux disease, eosinophilic esophagitis, and eosinophilic granulomatosis with polyangiitis. RESULTS: In the EXTRA and INNOVATE studies, no consistent pattern was observed for placebo-corrected relative rate reduction in normalized asthma exacerbations among omalizumab-treated comorbidity subgroups. In PROSPERO, on-study exacerbation rates in the comorbidity subgroups were similar (0, 0.68; 1, 0.70; 2, 0.77; ≥3, 0.80). FEV1 improvements were observed throughout the study for omalizumab vs placebo for all comorbidity subgroups. There were no consistent differences in FEV1 improvements among comorbidity subgroups in 008/009, EXTRA, or INNOVATE. Similarly, no among-group differences were observed for FEV1 change from baseline at month 12 in PROSPERO (0, 0.05 L; 1, 0.08 L; 2, 0.00 L; ≥3, 0.04 L). The 95% confidence intervals overlapped substantially in all instances. CONCLUSION: In these analyses of placebo-controlled/single-armed studies, on-study exacerbation rates and FEV1 improvements with omalizumab treatment were similar irrespective of comorbidity burden. TRIAL REGISTRATION: ClinicalTrials.gov identifiers are as follows: EXTRA, NCT00314574 (https://clinicaltrials.gov/ct2/show/NCT00314574); INNOVATE, NCT00046748 (https://clinicaltrials.gov/ct2/show/NCT00046748); and PROSPERO, NCT01922037 (https://clinicaltrials.gov/ct2/show/NCT01922037).

The Functional Diversity of Nitric Oxide Synthase Isoforms in Human Nose and Paranasal Sinuses: Contrasting Pathophysiological Aspects in Nasal Allergy and Chronic Rhinosinusitis.

The human paranasal sinuses are the major source of intrinsic nitric oxide (NO) production in the human airway. NO plays several roles in the maintenance of physiological homeostasis and the regulation of airway inflammation through the expression of three NO synthase (NOS) isoforms. Measuring NO levels can contribute to the diagnosis and assessment of allergic rhinitis (AR) and chronic rhinosinusitis (CRS). In symptomatic AR patients, pro-inflammatory cytokines upregulate the expression of inducible NOS (iNOS) in the inferior turbinate. Excessive amounts of NO cause oxidative damage to cellular components, leading to the deposition of cytotoxic substances. CRS phenotype and endotype classifications have provided insights into modern treatment strategies. Analyses of the production of sinus NO and its metabolites revealed pathobiological diversity that can be exploited for useful biomarkers. Measuring nasal NO based on different NOS activities is a potent tool for specific interventions targeting molecular pathways underlying CRS endotype-specific inflammation. We provide a comprehensive review of the functional diversity of NOS isoforms in the human sinonasal system in relation to these two major nasal disorders' pathologies. The regulatory mechanisms of NOS expression associated with the substrate bioavailability indicate the involvement of both type 1 and type 2 immune responses.

Effects of Wnt signaling on epithelial to mesenchymal transition in chronic rhinosinusitis with nasal polyp.

BACKGROUND: Epithelial to mesenchymal transition (EMT) is associated with the pathophysiology of chronic rhinosinusitis with nasal polyp (CRSwNP). Wnt signaling is causative for EMT, whereas the mechanism in CRSwNP is not fully understood. OBJECTIVE: We sought to evaluate the role of Wnt signaling in EMT of CRSwNP using a murine nasal polyp (NP) model and human tissues. METHODS: Inflammatory markers and EMT-related molecules were evaluated in NP models using adenomatosis polyposis coli (Apc)Min/+ mice with activated Wnt signaling and NP models treated with Wnt signaling inhibitor, indocyanine green-001 (ICG-001). EMT markers and Wnt signaling-associated mediators were analysed using human sinonasal tissues from control subjects and CRSwNP patients. RESULTS: ApcMin/+ mice-induced NPs exhibited more frequent polypoid lesions and upregulation of Wnt-related molecules, including nuclear ß-catenin, WNT3A and cyclin D1. Markers of EMT were significantly overexpressed in the ApcMin/+ NP mice (p<0.001 for E-cadherin and α-smooth muscle actin), and interleukin (IL)-17A+ cells and neutrophilic infiltration were increased in ApcMin/+ NP mice (p<0.001). Inhibition of Wnt signaling via ICG-001 resulted in significantly decreased nasal polypoid lesions (p<0.001), EMT-related markers (p=0.019 for E-cadherin and p=0.002 for vimentin) and the mRNA levels of IL-4 (p<0.001) and IL-17A (p=0.004) compared with the positive control group. Finally, nuclear ß-catenin (p=0.042) was significantly increased compared with the control, and the expression levels of Wnt ligands and receptors were upregulated in human NP tissues (p=0.045 for WNT3A and p=0.042 for FZD2), suggesting increased Wnt signaling and EMT in CRSwNP. CONCLUSION: Wnt signaling may contribute to the pathogenesis of NPs through EMT. Therefore, inhibition of Wnt signaling may be a potential therapeutic strategy for patients with CRSwNP.

Impaired small airway function in non-asthmatic chronic rhinosinusitis with nasal polyps.

BACKGROUND: There is clinical evidence for impaired lung function in chronic rhinosinusitis with nasal polyps (CRSwNP) patients, which may be due to a high incidence of asthma comorbidity. The lung function characteristics of non-asthmatic CRSwNP patients are not known. Small airway dysfunction (SAD) is involved in the pathogenesis of asthma. However, whether SAD is detected in non-asthmatic patients with CRSwNPs remains unclear. OBJECTIVE: This study analysed the lung function of non-asthmatic patients with CRSwNPs and evaluated its clinical relevance in CRSwNPs. METHODS: The clinical data for 191 consecutive CRSwNP patients (73 asthmatic and 118 non-asthmatic) and 30 control subjects were prospectively collected. The patients were followed up for at least 3 years (mean [standard deviation], 42.47 ± 8.38 months). Serum and tissue total IgE levels were measured in 95 and 93 patients, respectively. Tissue eosinophil counts were documented in 63 patients. RESULTS: Non-asthmatic CRSwNP patients had decreased forced expiratory flow at 75% of the FVC (FEF75 ) and FEF50 compared to the control subjects, and this difference was related to the severity of CRSwNP. The risk factors for impaired lung function in asthmatic and non-asthmatic patients were duration of asthma and smoking. A multivariate logistic analysis showed that decreased FEF50 was associated with the recurrence of non-asthmatic CRSwNPs. The lung function of CRSwNP patients negatively correlated with the degree of type-2 inflammation, which was defined by the levels of Eos and IgE in polyp tissues and blood. The SAD of non-asthmatic CRSwNP patients was related to serum IgE levels. CONCLUSIONS AND CLINICAL RELEVANCE: This study provides evidence that non-asthmatic CRSwNP patients may have SAD, which correlated with the severity and recurrence of CRSwNP. The decreased lung function of patients with CRSwNP was related to the degree of type-2 inflammation.

Chronic invasive fungal rhinosinusitis vs sinonasal squamous cell carcinoma: the differentiating value of MRI.

OBJECTIVES: To investigate MRI features in discriminating chronic invasive fungal rhinosinusitis (CIFRS) from sinonasal squamous cell carcinomas (SNSCC). METHODS: MRI findings of 33 patients with CIFRS and 47 patients with SNSCC were retrospectively reviewed and compared. Multivariate logistic regression analysis was performed to identify significant imaging features in distinguishing between CIFRS and SNSCC. The ROC curves and the AUC were used to evaluate diagnostic performance. RESULTS: There were significant differences in cavernous sinus involvement (p < 0.001), sphenoid sinus involvement (p < 0.001), meningeal involvement (p = 0.024), T2 signal intensity (p = 0.006), and enhancement pattern (p < 0.001) between CIFRS and SNSCC. Multivariate logistic regression analysis identified cavernous sinus involvement (odds ratio [OR] = 0.06, 95% confidence interval [95% CI] = 0.02-0.20) and sphenoid sinus involvement (OR = 0.14, 95% CI = 0.05-0.45) as significant indicators for CIFRS and T2 isointensity to gray matter (OR = 4.44, 95% CI = 1.22-16.22) was a significant indicator for SNSCC. ROC curve analysis showed the AUC from a combination of three imaging features was 0.95 in differentiating CIFRS and SNSCC. CONCLUSIONS: MRI showed significant differences between CIFRS and SNSCC features. In immunocompromised patients, a sinonasal hypointense mass on T2WI with septal enhancement or loss of contrast enhancement, and involvement of cavernous sinus, sphenoid sinus, and meninges strongly suggest CIFRS. KEY POINTS: • Chronic invasive fungal rhinosinusitis (CIFRS) is often difficult to distinguish from sinonasal squamous cell carcinomas (SNSCC) in clinical practice. • Cavernous sinus and sphenoid sinus involvement appear to be significant indicators for CIFRS. T2 isointensity to gray matter appears to be a significant indicator for SNSCC. • Loss of contrast enhancement and septal enhancement can be used to distinguish CIFRS from SNSCC with a high degree of specificity.

Janus looks both ways: How do the upper and lower airways interact?

Our understanding of the relationship between the upper and lower airways has greatly increased as a consequence of epidemiologic and pharmacologic studies. A consistent body of scientific evidence supports the concept that rhinitis, rhinosinusitis and asthma may be the expression of a common inflammatory process, which manifests at different sites of the respiratory tract, at different times. This paradigm states that allergic reactions may begin at the local mucosa, but tend to propagate along the airway. Central to the allergic diathesis is the eosinophil and its interaction with the airway epithelium. The implications of the interplay between upper and lower airway are not only academic, but also important for diagnostic and therapeutic reasons. Furthermore, there is significant overlap in symptomatology and pathophysiology for childhood sleep disordered breathing (SDB) and asthma. Recent evidence supports an association between these two conditions, but causality has not been demonstrated. Regardless, it is important to recognize the overlap and evaluate for the other condition when one is present. In children with poorly controlled asthma, the presence of SDB may significantly contribute to asthma morbidity and, as such, should be actively excluded. On the other hand, clinical evaluation for asthma should be considered in children with SDB. Future robust longitudinal research is needed to explore the association between upper and lower airway diseases using objective measures in children.

Differences in self-reported symptoms in patients with chronic odontogenic and non-odontogenic rhinosinusitis.

PURPOSE: To evaluate the possible differences in self-reported symptoms between patients with chronic odontogenic rhinosinusitis (CORS) and patients with chronic non-odontogenic rhinosinusitis (CnORS). MATERIALS AND METHODS: The study included 64 patients diagnosed with chronic rhinosinusitis according to EPOS guidelines. 32 patients had CORS, and the control group were 32 patients with CnORS. Patients were matched according to gender and age. All the patients underwent a CT scan evaluated by a radiologist, and were evaluated by an oral surgeon and otorhinolaryngologist before being assigned to one of the groups. The severity of the symptoms was assessed through questioners SNOT-22 (sino-nasal outcome test) and VAS (visual analogue scale) symptom score. Kolmogorov-Smirnov's, Fisher's and Mann-Whitney U test were used in the statistical analysis of the data. RESULTS: People with CORS show similar symptomatology on SNOT-22 score to patients with CnORS, with no significant statistical difference between any of the SNOT-22 symptoms. VAS symptom score showed that odontogenic group had a significantly higher score for fever (p = .004) and halitosis (p = .003). CONCLUSION: Halitosis and fever might be the most important symptoms in differentiating between CORS and CnORS symptomatology. Better diagnostic tools, such as VAS symptom score might help medical professionals to be quicker at recognizing CORS specific symptomatology, and help them treat the disease as early and adequately as possible.

Type 1/type 2 inflammatory cytokines correlate with olfactory function in patients with chronic rhinosinusitis.

BACKGROUND: Olfactory dysfunction secondary to chronic rhinosinusitis (CRS) has been highly associated with impaired quality of life. Asian CRS patients showed a distinct inflammatory profile, with less type 2 endotype compared with European and North American. This study aimed to explore the pattern of the inflammatory cytokines in CRS patients from China and their association with olfactory function. METHODS: Institutional review board-approved prospective study in which the olfactory function of 71 CRS patients was assessed with Sniffin' Sticks before the nasal endoscopic surgery. A set of cytokines and inflammatory mediators including type 1 and type 2 inflammatory cytokines were measured in nasal mucus by using a multiplex flow cytometric bead assay (CBA). Baseline characteristics in CRS patients were collected and the Spearman r statistic was performed to assess the association of olfactory function with cytokines and inflammatory mediators. RESULTS: A total of 71 nasal mucus samples of CRS patients, including 25 chronic rhinosinusitis without nasal polyposis (CRSsNP) patients and 46 chronic rhinosinusitis with nasal polyposis (CRSwNP) patients, were evaluated in this study. The nasal mucus levels of type 1 inflammatory cytokine IFN-γ (interferon-γ), type 2 inflammatory cytokines including IL-4, IL-5 and GM-CSF (granulocyte-macrophage colony-stimulating factor) and anti-inflammatory cytokine IL-10 were significantly and inversely correlated with olfactory function in total patients with CRS (r = -0.308, p = 0.009; r = -0.250, p = 0.036; r = -0.399, p = 0.001; r = -0.269, p = 0.023; r = -0.273, p = 0.021, respectively). In CRSsNP, the olfactory function was inversely correlated with levels of type 1 inflammatory cytokine TNF-α (tumor necrosis factor-α) (r = -0.637, p = 0.001) and IL-10 (r = -0.468, p = 0.018). Nevertheless, the olfactory function in CRSwNP was inversely correlated with type 2 inflammatory cytokines including IL-4 (r = -0.303, p = 0.041) and IL-5 (r = -0.383, p = 0.009). CONCLUSION: Both type 1 and type 2 inflammatory cytokines may contribute to the pathogenesis of CRS-associated olfactory dysfunction in the Chinese population.

Is there "hidden hearing loss" in patients with chronic rhinosinusitis?

Objective: This study was to investigate whether there is impairment of auditory function in chronic rhinosinusitis (CRS).Study sample: A total of 85 patients were allocated into either the CRS group (n = 65) or a simple deviated nasal septum group (n = 20). Both groups without other risk factors for sensorineural hearing loss exhibited normal thresholds at standard audiometric frequencies. Another group (n = 30) of healthy subjects without CRS or a deviated nasal septum were gender and age matched.Design: Analyse the results of audiology test including pure tone audiometry, an acoustic impedance test, distortion product otoacoustic emissions (DPOAE) and the auditory brainstem response (ABR) for each subject analyse the test results of for each object.Results: The group differences were statistically significant for each high-frequency pure tone (p < 0.05). The ABR showed a difference between groups in amplitude. The DPOAE pass rate of the CRS group was lower than that of the control group.Conclusions: This study showed a significant correlation between CRS and auditory impairment. CRS might impair cochlear functions by damaging inner ear hair cells and/or, outer hair cells (OHCs), consequently altering the activity of the entire auditory pathway originating in the ventral cochlear nucleus (VCN) to the inferior colliculus.

NAVIGATE II: Randomized, double-blind trial of the exhalation delivery system with fluticasone for nasal polyposis.

BACKGROUND: Chronic rhinosinusitis is common and sometimes complicated by nasal polyps (NPs). Corticosteroid nasal sprays are often unsatisfactory because they are ineffective at delivering medication to high/deep sites of inflammation. OBJECTIVE: We sought to assess whether an exhalation delivery system with fluticasone (EDS-FLU) capable of high/deep drug deposition improves outcomes. METHODS: Patients (n = 323) 18 years and older with moderate-to-severe congestion and NPs were randomized to twice-daily EDS-FLU (93, 186, or 372 µg) or exhalation delivery system (EDS)-placebo for 24 weeks (16 double-blind plus 8 open-label when all received 372 µg). Coprimary end points were change in nasal congestion/obstruction at 4 weeks and summed bilateral polyp grade at 16 weeks. Secondary end points included symptoms, polyp elimination, and functioning. RESULTS: EDS-FLU was superior on both coprimary end points (P < .001 vs EDS-placebo, all doses). Mean polyp grade improved continuously through week 24 (P < .009, all comparisons), with polyps eliminated on at least 1 side in approximately 25% of patients at week 24 versus 8.7% with EDS-placebo (P ≤ .014, all comparisons). Sino-Nasal Outcomes Test scores also improved significantly versus those in patients receiving EDS-placebo (-21.1 to -21.4 vs -11.7 at week 16, P < .05 all doses). At the end of the double-blind period, EDS-FLU (all doses) significantly improved all 4 defining disease symptoms. In most patients (68%), those receiving EDS-FLU reported "much" or "very much" improvement. The number of patients eligible for surgery decreased by 62%-67%. The safety profile was similar to that reported in prior trials evaluating conventional corticosteroid nasal sprays in comparable populations. CONCLUSION: EDS-FLU produces clinically and statistically significant improvement in all 4 diagnostically defining disease symptoms, polyp grade, and quality of life in patients with chronic rhinosinusitis with NPs.

Development and Modification of an Outcome Measure to Follow Symptoms of Children with Sinusitis.

OBJECTIVE: To develop a parent-reported Pediatric Rhinosinusitis Symptom Scale (PRSS) that could be used to monitor symptoms of young children with acute sinusitis in response to therapy. STUDY DESIGN: We developed an 8-item symptom severity scale and evaluated its internal reliability, construct validity, and responsiveness in children 2-12 years of age with acute sinusitis. Parents of 258 children with acute sinusitis completed the PRSS at the time of diagnosis, as a diary at home, and at the follow-up visit at days 10-12. Based on psychometric results and additional parent feedback, we revised the scale. We evaluated the revised version in 185 children with acute sinusitis. RESULTS: Correlations between the scale and reference measures on the day of enrollment were in the expected direction and of the expected magnitude. PRSS scores at the time of presentation correlated with radiographic findings (P < .001), functional status (P < .001), and parental assessment of overall symptom severity (P < .001). Responsiveness (standardized response mean) and test-retest reliability of the revised scale were good (2.17 and 0.75, respectively). CONCLUSIONS: We have developed an outcome measure to track the symptoms of acute sinusitis. Data presented here support the use of the PRSS as a measure of change in symptom burden in clinical trials of children with acute sinusitis.

Type 2/Th2-driven inflammation impairs olfactory sensory neurogenesis in mouse chronic rhinosinusitis model.

BACKGROUND: Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is a chronic inflammatory disease often accompanied by impairment of sense of smell. This symptom has been somewhat overlooked, and its relationship to inflammatory cytokines, tissue compression, neuronal loss, and neurogenesis is still unclear. METHODS: In order to elucidate potential mechanisms leading to CRS in humans, we have established a type 2/T helper type 2 cell (Th2)-mediated allergic CRS mouse model, based on house dust mite (HDM) and Staphylococcus aureus enterotoxin B (SEB) sensitization. The inflammatory status of the olfactory epithelium (OE) was assessed using histology, biochemistry, and transcriptomics. The sense of smell was evaluated by studying olfactory behavior and recording electro-olfactograms (EOGs). RESULTS: After 22 weeks, a typical type 2/Th2-mediated inflammatory profile was obtained, as demonstrated by increased interleukin (IL)-4, IL-5, and IL-13 in the OE. The number of mast cells and eosinophils was increased, and infiltration of these cells into the olfactory mucosa was also observed. In parallel, transcriptomic and histology analyses indicated a decreased number of immature olfactory neurons, possibly due to decreased renewal. However, the number of mature sensory neurons was not affected and neither the EOG nor olfactory behavior was impaired. CONCLUSION: Our mouse model of CRS displayed an allergic response to HDM + SEB administration, including the type 2/Th2 inflammatory profile characteristic of human eosinophilic CRSwNP. Although the sense of smell did not appear to be altered in these conditions, the data reveal the influence of chronic inflammation on olfactory neurogenesis, suggesting that factors unique to humans may be involved in CRSwNP-associated anosmia.

Accuracy of Signs and Symptoms for the Diagnosis of Acute Rhinosinusitis and Acute Bacterial Rhinosinusitis.

PURPOSE: To evaluate the accuracy of signs and symptoms for the diagnosis of acute rhinosinusitis (ARS). METHODS: We searched Medline to identify studies of outpatients with clinically suspected ARS and sufficient data reported to calculate the sensitivity and specificity. Of 1,649 studies initially identified, 17 met our inclusion criteria. Acute rhinosinusitis was diagnosed by any valid reference standard, whereas acute bacterial rhinosinusitis (ABRS) was diagnosed by purulence on antral puncture or positive bacterial culture. We used bivariate meta-analysis to calculate summary estimates of test accuracy. RESULTS: Among patients with clinically suspected ARS, the prevalence of imaging confirmed ARS is 51% and ABRS is 31%. Clinical findings that best rule in ARS are purulent secretions in the middle meatus (positive likelihood ratio [LR+] 3.2) and the overall clinical impression (LR+ 3.0). The findings that best rule out ARS are the overall clinical impression (negative likelihood ratio [LR-] 0.37), normal transillumination (LR- 0.55), the absence of preceding respiratory tract infection (LR- 0.48), any nasal discharge (LR- 0.49), and purulent nasal discharge (LR- 0.54). Based on limited data, the overall clinical impression (LR+ 3.8, LR- 0.34), cacosmia (fetid odor on the breath) (LR+ 4.3, LR- 0.86) and pain in the teeth (LR+ 2.0, LR- 0.77) are the best predictors of ABRS. While several clinical decision rules have been proposed, none have been prospectively validated. CONCLUSIONS: Among patients with clinically suspected ARS, only about one-third have ABRS. The overall clinical impression, cacosmia, and pain in the teeth are the best predictors of ABRS. Clinical decision rules, including those incorporating C-reactive protein, and use of urine dipsticks are promising, but require prospective validation.

Pathophysiologic mechanisms of chronic rhinosinusitis and their roles in emerging disease endotypes.

OBJECTIVE: Chronic rhinosinusitis (CRS) is a heterogeneous disorder with distinct pathophysiologic mechanisms. Based on transcription factor expression and cytokine production patterns in different innate lymphoid cell (ILC) types, in parallel with those of adaptive CD4+ T-helper (TH) cells and CD8+ cytotoxic T (Tc) cells, new perspectives on endotypes of patients are emerging for the immune response deviation into type 1 (orchestrated by ILC1s and Tc1, and TH1 cells), type 2 (characterized by ILC2s and Tc2 and TH2 cells), and type 3 (mediated by ILC3s and Tc17 and TH17 cells). In addition, cluster analysis has been applied to endotyping of CRS in recent years, which has provided additional novel insights into CRS pathogenesis. This review assessed pathologic mechanisms of CRS based on type 1, 2, and 3 immune responses and how they inform us to begin to understand CRS endotypes. This review also assessed recent cluster analysis studies of CRS endotypes. The impact of endotype on therapeutic management of CRS also is summarized. DATA SOURCES: Review of published literature. STUDY SELECTIONS: Relevant literature concerning CRS endotypes and possible underlying mechanisms was obtained from a PubMed search and summarized. RESULTS AND CONCLUSION: CRS with and without nasal polyps are composed of distinct endotypes with distinct deviated immune responses, pathogenic mechanisms, and different responses to medical and surgical treatment. An endotype of CRS with prominent type 2 immune responses is the best-studied endotype and generally can benefit from treatment with steroids and specific type 2 disrupting biologics.