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Background: B cells play many roles in health and disease. However, little is known about the mechanisms that drive B cell responses in the airways, especially in humans. Chronic rhinosinusitis (CRS) is an inflammatory disease of the upper airways that affects 10% of Europeans and Americans. A subset of CRS patients develop nasal polyps (NPs), which are characterized by type 2 inflammation, eosinophils and group 2 innate lymphoid cells (ILC2s). We have reported that NP contain elevated levels of B cells and antibodies, making NP an ideal system for studying B cells in the airways., Objective: We sought to determine the mechanisms that drive B cell activation and antibody production during chronic airway inflammation., Methods: We analysed B cells from NP or tonsil, or after ILC2 coculture, by flow cytometry. Antibody production from tissue was measured using Luminex assays and the frequency of antibody-secreting cells by ELISpot. Formation of B cell clusters was assessed using immunohistochemistry. Expression of genes associated with B cell activation and class switch recombination was measured by qRT-PCR., Results: NP contained significantly elevated frequencies of plasmablasts, especially those that expressed the extrafollicular marker Epstein-Barr virus-induced protein 2 (EBI2), but significantly fewer germinal centre (GC) B cells compared with tonsil. Antibody production and the frequency of antibody-secreting cells were significantly elevated in NP, and there was evidence for local class switch recombination in NP. Finally, ILC2s directly induced EBI2 expression on B cells in vitro., Conclusions and Clinical Relevance: Our data suggest there is a unique B cell activation environment within NP that is distinct from classic GC-mediated mechanisms. We show for the first time that ILC2s directly induce EBI2 expression on B cells, indicating that ILC2s may play an important role in B cell responses. B cell-targeted therapies may provide new treatment options for CRSwNP., (© 2016 John Wiley & Sons Ltd.)

Background: A foreign body (FB) penetrating intracranially after passing transorbitally or transnasally is a rare occurrence. However, otolaryngologists are increasingly being asked to participate in the care of these patients for both endoscopic removal of the object and repair of any skull base defects., Objective: To assess the presentation, workup, and management of transnasal or transorbital penetrating FB injury., Methods: Systematic review of the presentation, workup, and management of transnasal or transorbital penetrating FB injury; plus, a case report of a 53-year-old woman with a transorbital penetrating rose bush branch. We searched medical literature data bases, which resulted in 215 total titles, which were then narrowed based on inclusion and exclusion criteria., Results: Thirty-five cases of transorbital or transnasal low-velocity trauma that involved the paranasal sinuses were reviewed from 33 articles. The average age was 30 years, 40% of the objects were made of wood. Fifty-seven percent of the cases were transorbital, whereas 43% were transnasal. Forty-six percent of the surgical interventions were completed endoscopically or with endoscopic assistance. Complications of injury were common, with 66% of patients experiencing cerebrospinal fluid leaks; 23%, permanent blindness; 17%, meningitis; 14%, ophthalmoplegia; 9%, decreased visual acuity; and 3%, brain abscess. Our patient presented with a traumatic cerebrospinal fluid leak, and recovered well after transorbital and endoscopic removal of the branch, skull base repair, and a prolonged course of antibiotics and antifungal medications., Conclusions: Transnasal and transorbital penetrating FB injuries are a relatively uncommon occurrence but when they do occur require rapid workup and interdisciplinary management to prevent acute and delayed complications.

Background: The objective of this study was to describe the first US-based study to use the European Position Paper on Rhinosinusitis (EPOS) criteria to study the prevalence of chronic rhinosinusitis (CRS) in a general-population sample., Methods: A CRS symptom questionnaire was mailed to 23 700 primary care patients from Geisinger Clinic, a health system serving 45 counties in Pennsylvania. CRS cases were categorized into four unique subgroups based on EPOS symptoms: obstruction and discharge with no smell loss or pain/pressure; smell loss without pain/pressure; facial pain and/or pressure without smell loss; and both smell loss and pain/pressure. All cases were required to have nasal obstruction or discharge. Logistic regression was used to evaluate potential factors associated with CRS subgroups., Results: We found that 11.9% of patients met criteria for CRS. Prevalence peaked at 15.9% between ages 50 and 59 years and then dropped to 6.8% after age 69. The odds of CRS was higher among patients who were white, younger, smokers, had a history of Medical Assistance, and had other diseases. When CRS subgroups were modeled separately, these associations were no longer significant for some CRS subgroups. Comorbid diseases were most strongly associated with CRS cases who reported smell loss and facial pain and/or pressure and had the weakest associations with CRS cases who did not report these symptoms., Conclusions: CRS is a highly prevalent and heterogeneous condition. Differences in risk factors and health outcomes across symptom subgroups may be indicative of differences in etiology that have implications for disease management., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Responsiveness, or sensitivity to clinical change, is important when selecting patient-reported outcome measures (PROMs) for research and clinical applications. This study compares responsiveness of PROMs used in chronic rhinosinusitis (CRS) to inform the future development of a highly responsive instrument that accurately portrays CRS patients' symptom experiences., Methods: Adult CRS patients initiating medical therapy (MT; n = 143) or undergoing endoscopic sinus surgery after failing MT (ESS; n = 123) completed the 22-item Sino-Nasal Outcome Test (SNOT-22), European Position Statement on Rhinosinusitis (EPOS) visual analog scale (VAS), and 29-item Patient-Reported Outcomes Measurement Information System (PROMIS-29) at baseline and 3 months after treatment. Cohen's d and paired t statistics were used to evaluate the responsiveness of each measure., Results: Fifty-two (36.4%) subjects and 42 (34.1%) subjects in the MT and ESS groups, respectively, completed baseline and 3-month questionnaires. Subjects with and without 3-month data were similar with respect to baseline demographics, VAS scores, and SNOT-22 scores (p > 0.05). In MT patients, CRS-specific measures, like VAS (d = -0.58, p < 0.01; t = -1.81, p > 0.05) and SNOT-22 (d = -0.70, p < 0.01; t = -3.29, p < 0.05) scores, were more responsive than PROMIS-29 general health domains (p > 0.05 for Cohen's d). In ESS patients, VAS (d = -1.97; t = -9.63, both p < 0.01) and SNOT-22 (d = -1.56; t = -9.99, both p < 0.01) scores were similarly more responsive, although changes in PROMIS-29 domains of Fatigue (d = -0.82, p = 0.01; t = -4.63, p < 0.01), Sleep Disturbance (d = -0.83; t = -3.77, both p < 0.01), and Pain Intensity (d = -1.0; t = -5.67, both p < 0.01) were significant. All 22 individual SNOT-22 items differed significantly after surgery, whereas only 8 items were consistently responsive after MT., Conclusions: For both MT and ESS patients, CRS-specific PROMs are more responsive to posttreatment clinical changes than general health measures. Still, the SNOT-22 contains items that likely decrease its overall responsiveness. Our findings also indicate that existing PROMs had a greater response to ESS than MT., (© 2016 ARS-AAOA, LLC.)

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is often characterized by tissue eosinophilia that is associated with poor prognosis. Recent findings that proton pump inhibitors (PPIs) directly modulate the expression of eotaxin-3, an eosinophil chemoattractant, in patients with eosinophilic diseases suggest therapeutic potential for PPIs in those with CRSwNP., Objective: We assessed the effect of type 2 mediators, particularly IL-13 and eotaxin-3, on tissue eosinophilia and disease severity in patients with chronic rhinosinusitis (CRS). Further investigation focused on PPI suppression of eotaxin-3 expression in vivo and in vitro, with exploration of underlying mechanisms., Methods: Type 2 mediator levels in nasal tissues and secretions were measured by using a multiplex immunoassay. Eotaxin-3 and other chemokines expressed in IL-13-stimulated human sinonasal epithelial cells (HNECs) and BEAS-2B cells with or without PPIs were assessed by using ELISA, Western blotting, real-time PCR, and intracellular pH imaging., Results: Nasal tissues and secretions from patients with CRSwNP had increased IL-13, eotaxin-2, and eotaxin-3 levels, and these were positively correlated with tissue eosinophil cationic protein levels and radiographic scores in patients with CRS (P < .05). IL-13 stimulation of HNECs and BEAS-2B cells dominantly induced eotaxin-3 expression, which was significantly inhibited by PPIs (P < .05). Patients with CRS taking PPIs also showed lower in vivo eotaxin-3 levels compared with those without PPIs (P < .05). Using intracellular pH imaging and altering extracellular K + , we found that IL-13 enhanced H + ,K + -exchange, which was blocked by PPIs and the mechanistically unrelated H,K-ATPase inhibitor, SCH-28080. Furthermore, knockdown of ATP12A (gene for the nongastric H,K-ATPase) significantly attenuated IL-13-induced eotaxin-3 expression in HNECs. PPIs also had effects on accelerating IL-13-induced eotaxin-3 mRNA decay., Conclusion: Our results demonstrated that PPIs reduce IL-13-induced eotaxin-3 expression by airway epithelial cells. Furthermore, mechanistic studies suggest that the nongastric H,K-ATPase is necessary for IL-13-mediated epithelial responses, and its inhibitors, including PPIs, might be of therapeutic value in patients with CRSwNP by reducing epithelial production of eotaxin-3., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The advent of endoscopic sinus surgery has created an exciting interface between rhinology and ophthalmology in the area of orbital and optic nerve decompression Objectives: (1) To study the utilization of open versus endoscopic medial orbital decompression based on geography and indication, (2) to describe the demographics of the patient populations who underwent these different techniques, and (3) to compare outcomes, including mean charges and operating room (OR) times Methods: Cases identified by Current Procedural and Terminology codes were extracted from the California, Florida, Maryland, and New York State Ambulatory Surgery Databases from 2009 to 2011. Patient demographics, diagnoses, mean charge, and OR time were compared., Results: A total of 1009 patients underwent orbital decompression; 93.0% of cases involved the medial wall only; 22.9% of medial decompressions were performed endoscopically, 74.5% were open, and 2.6% were via combined approach. Eighty percent of patients had thyroid eye disease. Analyses adjusted for sex, age, race, state, and diagnosis found that surgeries for infection (N = 47) were more likely to be performed endoscopically compared with procedures for other diagnoses (N = 962) (odds ratio 5.27 [2.67-10.40], p < 0.001). Patients in Florida were more likely to undergo endoscopic decompression compared with patients in California (odds ratio 2.35 [1.42-3.62]). The difference in median charge for endoscopic ($13,119) versus open ($11,291; p = 0.085) procedures was not significant on bivariate analysis but was significant on multivariate analysis (p = 0.04). The median OR time for open procedures was, on average, 33 minutes shorter (endoscopic, 132 minutes; open, 98 minutes; p ≤ 0.001) on bivariate analysis but was not significantly different when controlling for covariables (p = 0.08)., Conclusion: In the study sample, endoscopic orbital decompression was performed in 22.9% of patients, with significant variation in surgical technique based on geography and indication. Procedures that used endoscopic compared with open decompression techniques had no significant difference in charge on bivariate analysis. The OR time for open procedures was shorter on bivariate but not on multivariate analysis. Further research is required regarding the relative effectiveness of open versus endoscopic surgical techniques for various indications.

Background: Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory condition of the sinonasal mucosa consisting of poorly defined subtypes and characterized by variable clinical manifestations, responses to therapy, and underlying pathophysiologies. In the related disorder of asthma, progress has been made in defining disease subtypes on both clinical and pathophysiologic levels, facilitating the development of targeted biologic pharmacotherapy. The potential role of these drugs for the management of CRS will be reviewed. The objective of this work is to highlight the emerging therapeutic targets in CRS in light of evolving treatment options for asthma and enhanced understandings of the clinical manifestations and pathophysiology of CRS., Methods: This article is a review of recent studies regarding current and future advances in biomarker-directed therapies in the medical treatment of CRS., Results: Various biologic therapies used in the management of asthma have demonstrated clinical promise for CRS, particularly within the CRS with nasal polyposis (CRSwNP) phenotype. Several randomized, double-blind, placebo-controlled studies increasingly support the targeting of immunoglobulin E (IgE) and interleukin (IL)-5 pathways to improve outcome measures in CRSwNP patients. The IL-4/IL-13 pathway and other type 2 inflammatory pathways have also shown potential as targets for CRSwNP, but all pathways require further investigation., Conclusion: Recalcitrant CRS in the United States and Europe is most commonly associated with nasal polyposis and a type 2 cytokine skewing in the tissue, resulting in tissue infiltration of eosinophils, mast cells, and basophils. Targeting biomarkers of the associated type 2 pathways may be a practical treatment option for recalcitrant CRSwNP in the future., Competing Interests: None, (© 2016 ARS-AAOA, LLC.)

Chronic rhinosinusitis with nasal polyps (CRSwNP) is an important clinical entity diagnosed by the presence of both subjective and objective evidence of chronic sinonasal inflammation. Symptoms include anterior or posterior rhinorrhea, nasal congestion, hyposmia, and/or facial pressure or pain that last for a duration of more than 12 weeks. Nasal polyps are inflammatory lesions that project into the nasal airway, are typically bilateral, and originate from the ethmoid sinus. Males are more likely to be affected than females, but no specific genetic or environmental factors have been strongly linked to the development of this disorder to date. CRSwNP is frequently associated with asthma and allergic rhinitis, but the cellular and molecular mechanisms that contribute to the clinical symptoms are not fully understood. Defects in the sinonasal epithelial cell barrier, increased exposure to pathogenic and colonized bacteria, and dysregulation of the host immune system are all thought to play prominent roles in disease pathogenesis. Additional studies are needed to further explore the clinical and pathophysiological features of CRSwNP so that biomarkers can be identified and novel advances can be made to improve the treatment and management of this disease., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Chronic rhinosinusitis (CRS) is likely a biologically heterogeneous disease process. Current guidelines propose subclassification using polyp status while others propose using mucosal eosinophilia. We hypothesized that appropriate CRS subclassification would increase homogeneity of baseline symptoms, and identify characteristic symptoms of each subtype., Methods: A total of 57 CRS patients undergoing surgery prospectively completed a preoperative battery of 73 questions relating to symptoms including the 22-item Sino-Nasal Outcome Test (SNOT-22) and 29-item Patient-Reported Outcomes Measurement Information System (PROMIS-29) general quality of life (QOL) measures. Eosinophilic cationic protein (ECP) levels were determined from ethmoid, uncinate, and polyp tissue homogenates using enzyme-linked immunosorbent assay (ELISA) and normalized to total protein. Patients were classified as eosinophilic (eCRS) or non-eosinophilic (neCRS) using a 95th percentile threshold established from control tissue from 82 patients without CRS. Separate pairwise comparisons were performed on patient-reported symptoms using polyp and eosinophilic status., Results: Of the 57 patients, 28 had CRS with nasal polyps (CRSwNP); 27 of 57 patients had eCRS (CRSwNP, n = 21; CRS without nasal polyps [CRSsNP], n = 6). CRSwNP patients had increased need to blow nose, frequency of nasal congestion, more severe difficulty breathing through nose, more severe nasal discharge, but less cough (p < 0.05). eCRS patients had more bothersome loss of taste/smell, ear pain, sneezing, severe difficulty breathing through nose, and severe nasal congestion compared to neCRS patients (p < 0.05)., Conclusion: Subclassifying CRS with symptoms alone is difficult with neither polyp status nor eosinophilia giving a distinctive clinical symptom profile. However, certain symptoms may help otolaryngologists identify CRS subtypes, which may help guide future treatments. Further validation and evaluation of prognosis following treatment is required to evaluate appropriate means of subclassifying CRS., (© 2015 ARS-AAOA, LLC.)

Purpose of Review: The review presents some information on known options for treatment of nonallergic rhinitis (NAR) with introduction to new therapies. The merits and limitations of recent advancements in pharmacotherapy of this common problem are briefly discussed as well., Recent Findings: Intranasal corticosteroids are first-line therapy for NAR. Fluticasone propionate and beclomethasone remain the only topical corticosteroids approved for NAR. The use of azelastine - another first-line option - has also been found to be effective even though NAR is a nonallergic entity by definition. Combination of fluticasone propionate and azelastine is a promising option in achieving better symptom reduction. Coadministration of intranasal corticosteroid and topical decongestants is an attractive topic that requires additional safety studies before recommending treatment. Although promising, no scientifically valid recommendation can be made for treatment of NAR with capsaicin. Surgical options in patients with refractory NAR are limited. New studies demonstrate a lack of correlation between objective outcome of radiofrequency ablation of the inferior turbinate and subjective patient symptoms., Summary: The heterogeneity in clinical presentation makes NAR treatment a daily challenge for otolaryngologists. The diversity of clinical studies with use of unique outcome measures limit systematic reviews which may be instrumental in providing strong recommendations.

Objectives/hypothesis: To provide the final results from the REMODEL (randomized evaluation of maxillary antrostomy versus ostial dilation efficacy through long-term follow-up) full-study cohorts and perform meta-analyses of standalone balloon sinus dilation studies to explore long-term outcomes in a large patient sample., Study Design: Randomized controlled trial and meta-analysis., Methods: Final outcomes from the REMODEL randomized trial, including a larger cohort of 135 patients treated with functional endoscopic sinus surgery (FESS) or in-office balloon dilation, were evaluated. One hundred thirty patients had 12-month data, 66 had 18-month data, and 25 had 24-month data. In addition, a meta-analysis evaluated outcomes from six studies including 358 standalone balloon dilation patients with up to 24 months follow-up., Results: Outcomes out to 2 years from the REMODEL full-study cohort are consistent with 6-month and 12-month outcomes. In the meta-analysis of standalone balloon dilation studies, technical success is 97.5%, and mean 20-item Sino-Nasal Outcomes Test scores are significantly and clinically improved at all time points (P < .0001). There are significant reductions (P < .0001) in work/school days missed, homebound days, physician/nurse visits, acute infections, and antibiotic prescriptions. Mean recovery time is 1.4 days. Comparison of 12-month symptom improvements and revision rates between the REMODEL FESS arm (n = 59), REMODEL balloon dilation arm (n = 71), and pooled single-arm standalone balloon dilation studies (n = 243) demonstrated no statistical difference., Conclusions: All outcomes are comparable between FESS and balloon dilation at all time points from 6 months to 24 months. Balloon dilation produces faster recovery, less postoperative pain, and fewer debridements than FESS. There is significant, durable benefit in a large series of 358 patients undergoing standalone balloon dilation., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Chronic rhinosinusitis (CRS) is a multifactorial disease of unknown cause characterized by sinonasal inflammation, increased mucus production, and defective mucociliary clearance. Expression of Pendrin, an epithelial anion transporter, is increased in asthma and chronic obstructive pulmonary disease. Pendrin increases mucus production and regulates mucociliary clearance., Objectives: We sought to investigate the expression of pendrin and the mucus-related protein Muc5AC in sinonasal tissues of control subjects and patients with CRS and to evaluate the regulation of pendrin expression in nasal epithelial cells (NECs) in vitro., Methods: The expression and distribution of pendrin in sinonasal tissues was analyzed by using real-time PCR, immunoblot analysis, and immunohistochemistry. Differentiated NECs were used to study the regulation of pendrin expression., Results: Increased pendrin expression was observed in nasal polyp (NP) tissue of patients with CRS. Immunohistochemistry analysis revealed that pendrin was largely restricted to the epithelial layer. Pendrin expression significantly correlated with inflammatory cell markers, suggesting that the factors made by these cells might induce pendrin expression. Furthermore, both pendrin and periostin levels (a biomarker in asthma) correlated with IL-13 levels, suggesting that pendrin can be induced by this cytokine in sinonasal tissues. Expression of the mucus component protein Muc5AC correlated weakly with pendrin expression, indicating that pendrin might modulate mucus production in NPs. In cultured NECs pendrin expression was induced by TH2 cytokines and induced synergistically when TH2 cytokines were combined with IL-17A. Interestingly, human rhinovirus had a potentiating effect on IL-13-induced pendrin expression. Dexamethasone suppressed pendrin expression, suggesting that the therapeutic benefit of dexamethasone in asthmatic patients and those with CRS might involve regulation of pendrin expression., Conclusions: TH2-mediated pendrin expression is increased in NPs of patients with CRS and might lead to increased inflammation, mucus production, and decreased mucociliary clearance., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Chronic rhinosinusitis (CRS) has a broad range of comorbidities. Due to a lack of longitudinal studies, it is not known whether these comorbidities cause CRS, are promoted by CRS, or share a systemic disease process with CRS., Objective: The objective of this study was to determine the risk of incident disease within 5 years after a new diagnosis of CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP)., Methods: We conducted a case-control study nested within the longitudinal cohort of primary care patients in the Geisinger Clinic using electronic health record data. We evaluated incident disease over 5 years in newly diagnosed CRSwNP and CRSsNP cases compared to controls using multivariable Cox regression models., Results: CRSsNP (n = 3612) cases were at greater risk (HR, 95% confidence interval) than controls for incidence of: upper airway diseases, including adenotonsillitis (3.29, 2.41-4.50); lower aerodigestive tract diseases, including asthma (2.69, 2.14-3.38); epithelial conditions, including atopic dermatitis (2.75, 1.23-6.16); and hypertension (1.38, 1.19-1.61). CRSwNP (n = 241) cases were at greater risk for obesity than controls (1.74, 1.08-2.80), but CRSwNP was not associated with other diseases., Conclusion: The risk of other diseases associated with CRS adds to the burden of an already highly burdensome condition, and suggests either that CRS promotes onset of other diseases or is an indicator of systemic disease processes. Different patterns of association with diseases by CRS phenotype may be due to CRSwNP sample size limitations or reflect a different pattern of disease onset by phenotype. These findings have implications for screening guidelines and care of CRS patients., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Chronic rhinosinusitis (CRS) is a prevalent and disabling paranasal sinus disease, with a likely multifactorial etiology potentially including hazardous occupational and environmental exposures. We completed a systematic review of the occupational and environmental literature to evaluate the quality of evidence of the role that hazardous exposures might play in CRS., Methods: We searched PubMed for studies of CRS and following exposure categories: occupation, employment, work, industry, air pollution, agriculture, farming, environment, chemicals, roadways, disaster, and traffic. We abstracted information from the final set of articles across 6 primary domains: study design; population; exposures evaluated; exposure assessment; CRS definition; and results., Results: We identified 41 articles from 1080 manuscripts: 37 occupational risk papers, 1 environmental risk paper, and 3 papers studying both categories of exposures. None of the 41 studies used a CRS definition consistent with current diagnostic guidelines. Exposure assessment was generally dependent on self-report or binary measurements of exposure based on industry of employment. Only grain, dairy, and swine operations among farmers were evaluated by more than 1 study using a common approach to defining CRS, but employment in these settings was not consistently associated with CRS. The multiple other exposures did not meet quality standards for reporting associations or were not evaluated by more than 1 study., Conclusion: The current state of the literature allows us to make very few conclusions about the role of hazardous occupational or environmental exposures in CRS, leaving a critical knowledge gap regarding potentially modifiable risk factors for disease onset and progression., (© 2015 ARS-AAOA, LLC.)

We report that S100 proteins were reduced in patients with chronic rhinosinusitis (CRS). S100A8/9, which is important in epithelial barrier function, was particularly decreased in elderly patients with CRS. Epithelial expression of S100A8/9 is partly regulated by the IL-6 trans-signaling pathway. The goal of this study was to investigate whether or not age-related reduction of S100A8/9 in CRS is associated with blunting of IL-6 trans-signaling. The levels of IL-6, soluble IL-6 receptor (sIL-6R), soluble gp130 (sgp130), and S100A8/9 from control subjects (n = 10), and patients with CRS without nasal polyps (n = 13) and those with CRS with nasal polyps (CRSwNP) (n = 14), were measured by ELISA. Age-related differences in the level of each protein were investigated. Normal human bronchial epithelial cells were cultured in air-liquid interface and stimulated with IL-6/sIL-6R and tumor necrosis factor (TNF)-α with or without the addition of sgp130, a natural inhibitor of IL-6 trans-signaling. There was a significant age-related decline in S100A8/9 and an increase in sgp130 in nasal tissue samples from patients with CRSwNP, although there was no age-related difference in IL-6/sIL-6R production. Additionally, expression of the S100A8/9 gene and protein was increased significantly by IL-6/sIL-6R plus TNF-α in normal human bronchial epithelial cells. This increase was blocked by sgp130. These results suggest that increased sgp130 in older patients may inhibit IL-6 trans-signaling, impair barrier function, and decrease S1008/9 production in elderly patients with CRSwNP. Restoration of barrier function by targeting sgp130 may be a novel treatment strategy.

Background: Chronic rhinosinusitis (CRS) is a common condition encountered in primary care medicine and is estimated to affect 12.5% of the United States population. This study aims to compare methods of assessing health utility in CRS., Methods: A cross-sectional sample of CRS patients (n = 137) were interviewed using direct health utility assessment measures: the visual analogue scale (VAS), time trade-off (TTO), and standard gamble (SG). General quality of life (QOL) scores were obtained via the 36-item Short Form Health Survey (SF-36) and converted to SF-6D health utility values using a Bayesian algorithm. Disease-specific QOL was measured with the 22-item Sino-Nasal Outcome Test (SNOT-22). A selected subgroup of patients (n = 51) not initiating surgery or new treatment for CRS were re-interviewed within 3 weeks., Results: The mean ± SD health utilities were VAS 0.69 ± 0.19; TTO 0.80 ± 0.27; SG 0.93 ± 0.11; and SF-6D 0.72 ± 0.12; they differed significantly (p < 0.001). Only VAS scores differed based on disease state classification or the presence of nasal polyposis. Correlations between methods of determining health utility were weak, but significant. VAS, TTO, and SF-6D scores were significantly associated with SNOT-22 (p < 0.001 for all); however, SG and SNOT-22 were poorly correlated (Spearman correlation = -0.33). The test-retest reliability of TTO (Spearman correlation = 0.71) and SG (0.73) was strong., Conclusion: CRS patients show significant impairment in QOL, with health utility values similar to those of patients with acquired immune deficiency syndrome (AIDS) or intermittent claudication using similar methods. The method of ascertainment significantly affects measured health utility, but the degree of impairment warrants improved recognition and appropriate treatment of the condition., (© 2015 ARS-AAOA, LLC.)

Objective: To describe current levels and trends of funding for the National Institutes of Health (NIH) in obstructive sleep apnea (OSA) and to recognize the current status of otolaryngologists in OSA research., Study Design: Scientometric analysis., Methods: The NIH RePORTER database was queried for the search term "obstructive sleep apnea" for all available years. Sex, degree, academic department, NIH funding source, geography, funding totals and years, and h-index of principal investigators (PIs) were collected and summarized., Results: A total of 397 projects spanning 1242 total funding years were funded. Of the 273 individual PIs, 33.3% (91/273) were female. Regarding credentials, 52.4% of PIs (143/273) were MD or MD/PhD, and 41.0% (112/273) were PhD alone. Academic departments of PIs were most often medicine (34.1%), pediatrics (12.1%), cell biology/physiology (10.6%), and psychiatry (7.7%). Seven otolaryngology faculty members had received NIH funding for OSA research (2.6% of total PIs) since 2000. They accounted for 8 grants (0.25% of total grants) and $7,235,729 (1.5% of total dollars) of research funding., Conclusion: Despite studies showing increasing levels of OSA surgery being performed and major areas of research and clinical opportunity, otolaryngologists represent a small minority of OSA research funding. This information may help direct our specialty when setting priorities regarding research funding, as research into the basic science and clinical management of OSA represents a broad and interdisciplinary pursuit., (© American Academy of Otolaryngology-Head and Neck Surgery Foundation 2015.)

Olfactory dysfunction is a common complaint for patients with chronic rhinosinusitis, because smell loss decreases a patient's quality of life. Smell loss is caused by obstruction from polyps, nasal discharge, and mucosal edema, as well as inflammatory changes within the olfactory epithelium. Addressing olfaction before endoscopic sinus and skull base surgery is important in order to set postoperative expectations, because an improvement in smell is difficult to predict. Several commercially available olfactory testing measures are available and can easily be administered in clinic. During surgery, careful dissection within the olfactory cleft is recommended in order to optimize postoperative olfactory function., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Rationale: The mechanisms that underlie the pathogenesis of chronic rhinosinusitis without nasal polyps (CRSsNP), chronic rhinosinusitis with nasal polyps (CRSwNP), and aspirin-exacerbated respiratory disease (AERD) are not clear., Objectives: To first evaluate the inflammatory profiles of CRSsNP and CRSwNP tissues and then to investigate whether clinical differences observed between CRSwNP and AERD are in part secondary to differences in inflammatory mediator expression within nasal polyp (NP) tissues., Methods: Expression levels of numerous inflammatory mediators were determined by quantitative real-time polymerase chain reaction, ELISA, and multiplex immunoassay., Measurements and Main Results: CRSwNP NP had increased levels of type 2 mediators, including IL-5 (P < 0.001), IL-13 (P < 0.001), eotaxin-2 (P < 0.001), and monocyte chemoattractant protein (MCP)-4 (P < 0.01), compared with sinonasal tissue from subjects with CRSsNP and control subjects. Expression of IFN-γ messenger RNA or protein was low and not different among the chronic rhinosinusitis subtypes examined. Compared with CRSwNP, AERD NP had elevated protein levels of eosinophil cationic protein (ECP) (P < 0.001), granulocyte-macrophage colony-stimulating factor (GM-CSF) (P < 0.01), and MCP-1 (P = 0.01), as well as decreased gene expression of tissue plasminogen activator (tPA) (P = 0.02). Despite the higher eosinophilia in AERD, there was no associated increase in type 2 mediator protein levels observed., Conclusions: CRSwNP was characterized by a predominant type 2 inflammatory environment, whereas CRSsNP did not reflect a classic type 1 milieu, as has been suggested previously. AERD can be distinguished from CRSwNP by elevated ECP levels, but this enhanced eosinophilia is not associated with elevations in traditional type 2 inflammatory mediators associated with eosinophil proliferation and recruitment. However, other factors, including GM-CSF, MCP-1, and tPA, may be important contributors to AERD pathogenesis.

Background: Epithelial barrier dysfunction is thought to play a role in many mucosal diseases, including asthma, chronic rhinosinusitis (CRS), and eosinophilic esophagitis., Objective: The objective of this study was to investigate the role of oncostatin M (OSM) in epithelial barrier dysfunction in human mucosal disease., Methods: OSM expression was measured in tissue extracts, nasal secretions, and bronchoalveolar lavage fluid. The effects of OSM stimulation on barrier function of normal human bronchial epithelial cells and nasal epithelial cells cultured at the air-liquid interface were assessed by using transepithelial electrical resistance and fluorescein isothiocyanate-dextran flux. Dual-color immunofluorescence was used to evaluate the integrity of tight junction structures in cultured epithelial cells., Results: Analysis of samples from patients with CRS showed that OSM mRNA and protein levels were highly increased in nasal polyps compared with those seen in control uncinate tissue (P < .05). OSM levels were also increased in bronchoalveolar lavage fluid of allergic asthmatic patients after segmental allergen challenge and in esophageal biopsy specimens from patients with eosinophilic esophagitis. OSM stimulation of air-liquid interface cultures resulted in reduced barrier function, as measured by decreased transepithelial electrical resistance and increased fluorescein isothiocyanate-dextran flux (P < .05). Alterations in barrier function by OSM were reversible, and the viability of epithelial cells was unaffected. OSM levels in lysates of nasal polyps and uncinate tissue positively correlated with levels of α2-macroglobulin, a marker of epithelial leak, in localized nasal secretions (r = 0.4855, P < .05)., Conclusions: These results suggest that OSM might play a role in epithelial barrier dysfunction in patients with CRS and other mucosal diseases., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Chronic rhinosinusitis (CRS) is a broad clinical syndrome that is characterized by prolonged mucosal inflammation of the nose and paranasal sinuses, and is typically divided into two subtypes based on the presence or absence of nasal polyps. The etiology and pathogenesis of both forms remain areas of active research. Over the last 15 years, a number of hypotheses have been proposed to explain all or part of the clinical CRS spectrum. These hypotheses reflect the concept that CRS results from a dysfunctional interplay between individual host characteristics and factors exogenous to the host. Six broad theories on CRS etiology and pathogenesis are discussed as follows: (1) the "fungal hypothesis," (2) the "superantigen hypothesis," (3) the "biofilm hypothesis," and (4) the "microbiome hypothesis," all of which emphasize key environmental factors, and (5) the "eicosanoid hypothesis" and (6) the "immune barrier hypothesis," which describe specific host factors. These theories are reviewed, and the evidence supporting them is critically appraised.

Objectives/hypothesis: The objective of this study was to report patients' knowledge and comfort level with computed tomography (CT) imaging for sinus disease and evaluate patient willingness to undergo empiric medical therapy (EMT) versus CT-directed therapy (CTDT)., Study Design: Prospective survey study., Methods: A 22-item survey was administered to patients with nasal/sinus symptoms in a tertiary care rhinology clinic. Questions elicited patient demographics, imaging history, and knowledge/comfort regarding imaging-related radiation exposure. Patients were presented with the theoretical choice of EMT versus CTDT, given the expected positive predictive value, in chronic rhinosinusitis (CRS) management., Results: Two hundred patients (52% female, age range 18-83 years) participated. Of these, 85% had symptoms for over 3 months. Only 91 patients (45.5%) were aware that CT imaging involved radiation exposure. Prior CT experience and past sinus surgery (P < .05), but not sex or education level, were associated with increased comfort with CT imaging. Most patients (78%) preferred CTDT over EMT. If a CT sinus was recommended, 77 patients (38.5%) had concerns, of which 26% identified radiation exposure as the leading concern. The majority (70%) were unsure about the relative radiation dose of a conventional CT., Conclusions: Patients with CRS symptoms prefer CTDT over EMT if a diagnosis cannot be established definitively using exam findings. Although most patients deferred to the physician regarding the decision to utilize CT imaging, there is low awareness of CT-related radiation exposure, and a significant minority of patients have radiation-related concerns with regard to medical imaging for nasal and sinus symptoms., (© 2014 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: To describe national trends in retropharyngeal abscess (RPA) complicating peritonsillar abscess (PTA) and to determine factors associated with RPA in patients with PTA., Study Design: Cross-sectional analysis., Setting: Nationwide Inpatient Sample, 2003-2010., Subjects and Methods: PTA patients ≥18 years old, with or without RPA, were extracted according to ICD-9-CM codes. The cohort was analyzed with descriptive statistics and multivariate regression modeling to identify factors associated with RPA., Results: Of the 91,647 (95% CI: 86,433-95,449) patients identified with PTA, 885 (1.0%) also had a concurrently coded RPA. The annual rate of concomitant RPA increased from 0.5% (95% CI: 0.3%-0.8%) to 1.4% (95% CI: 1.0%-2.0%) between 2003 and 2010 (P < .001). PTA patients with RPA more frequently underwent tonsillectomy (23.5% vs 11.1%), endotracheal intubation (7.1% vs 1.5%), and mechanical ventilation (13.2% vs 2.0%) than those without RPA (all P < .001). PTA patients with RPA were significantly older (41 vs 34 years old), had a longer hospital stay (6.4 vs 2.5 days), and had more procedures (2.5 vs 0.9) when compared to patients without RPA (all P < .001). Upon multivariate regression analysis, factors associated with RPA included the age groups of 40 to 64 years (odds ratio, 2.256; P < .001) and 65 and older (odds ratio, 2.086; P = .045). Median total charges for PTA inpatients with concomitant RPA were approximately $8700 greater (P < .001) when compared to patients with PTA alone., Conclusions: The incidence of RPA among adult inpatients with PTA is increasing, and patients with RPA have higher in-hospital resource utilization. Further studies may help validate factors predictive of RPA to enable prevention or earlier identification., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.)

Background: Balanced activation and inhibition of the immune system ensures pathogen clearance while avoiding hyperinflammation. Siglecs, sialic acid-binding proteins found on subsets of immune cells, often inhibit inflammation: Siglec-8 on eosinophils and Siglec-9 on neutrophils engage sialoglycan ligands on airways to diminish ongoing inflammation. The identities of human siglec ligands and their expression during inflammation are largely unknown., Objective: The histologic distribution, expression, and molecular characteristics of siglec ligands were explored in healthy and inflamed human upper airways and in a cellular model of airway inflammation., Methods: Normal and chronically inflamed upper airway tissues were stained for siglec ligands. The ligands were extracted from normal and inflamed tissues and from human Calu-3 cells for quantitative analysis by means of siglec blotting and isolation by means of siglec capture., Results: Siglec-8 ligands were expressed on a subpopulation of submucosal gland cells of human inferior turbinate, whereas Siglec-9 ligands were expressed more broadly (submucosal glands, epithelium, and connective tissue); both were significantly upregulated in patients with chronic rhinosinusitis. Human airway (Calu-3) cells expressed Siglec-9 ligands on mucin 5B (MUC5B) under inflammatory control through the nuclear factor κB pathway, and MUC5B carried sialoglycan ligands of Siglec-9 on human upper airway tissue., Conclusion: Inflammation results in upregulation of immune-inhibitory Siglec-8 and Siglec-9 sialoglycan ligands on human airways. Siglec-9 ligands are upregulated through the nuclear factor κB pathway, resulting in their enhanced expression on MUC5B. Siglec sialoglycan ligand expression in inflamed cells and tissues may contribute to the control of airway inflammation., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Up to 50% of patients with chronic rhinosinusitis (CRS) have comorbid asthma, and we have reported that a subset of CRS patients who have nasal polyps (CRSwNP) have elevated autoantigen-specific antibodies within their nasal polyps (NP). While increases in the prevalence and/or severity of both asthma and autoimmunity in women are well characterized, it is not known whether CRSwNP is more severe or frequent in women than men. We sought to determine whether CRSwNP demonstrated sex-specific differences in frequency and/or severity. Using a retrospectively collected database of tertiary care patients (n = 1393), we evaluated the distribution of sex in patients with CRSwNP with or without comorbid asthma or aspirin hypersensitivity. We further compared the severity of sinus disease between men and women with CRSwNP. Although women comprised 55% of CRS patients without NP (CRSsNP), a significantly smaller proportion of CRSwNP patients were female (38%, P < 0.001). Interestingly, women with CRSwNP were significantly more likely than men to have comorbid asthma (P < 0.001), and 61% of patients with the most severe form of disease (aspirin-exacerbated respiratory disease (CRSwNP plus asthma plus aspirin sensitivity)) were women (P < 0.05). Women with CRSwNP were significantly more likely to have taken oral steroids, and were more likely to have a history of revision surgeries (P < 0.05) compared to men. These data suggest that women with CRSwNP have more severe disease than men in a tertiary care setting. Future studies are needed to elucidate the mechanisms that drive disease severity in men and women, paving the way for the development of personalized treatment strategies for CRSwNP based on sex.

Background: Specific antibody deficiency (SAD) involves a deficient response to a polysaccharide vaccine in the setting of normal immunoglobulin G (IgG) levels and chronic infections. Patients with chronic rhinosinusitis (CRS) are often evaluated for SAD. There are limited data that describe patients with CRS and SAD., Objective: The objective of this study was to better characterize the role of SAD in CRS., Methods: We reviewed electronic records of adults with CRS who were evaluated for immunodeficiency with quantitative Ig levels and pre- and postantibody titers to a pneumococcal polysaccharide vaccine (PPV)., Results: Fourteen pneumococcal serotypes were determined in 239 subjects from 2002 to 2009. Of these subjects, 64 had adequate protective titers of 1.3 μg/mL or higher in 7 or more serotypes of the 14 serotypes checked; 56 (23%) had less than 7 protective titers post-PPV and were diagnosed with SAD; and 119 had an adequate response to the vaccine with 7 or more serotypes being higher than 1.3 μg/mL (>50% response) and were characterized as "responders." Subjects with SAD received more antibiotic courses relative to responders in the 2 years after immunization (3.19 ± 2.64 vs 2.19 ± 2.24, P < .05). Of 56 subjects with SAD, 10 (17.9%) received Ig replacement therapy. Subjects who received Ig had fewer numbers of protective pneumococcal titers post-PPV and had more pneumonia (40.0%) versus subjects with SAD who did not receive Ig (10.9%)., Conclusions: Of the 239 patients with CRS with normal IgG levels evaluated for immunodeficiency, 56 (23.4%) had SAD. A majority of patients with SAD may not need Ig replacement; however, a subset of patients with SAD benefit from Ig replacement., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objectives/hypothesis: Nasal irrigations are commonly employed to promote nasal hygiene in the treatment of various sinonasal conditions. Few studies have evaluated how the ionic composition of irrigation solutions affects olfactory performance. The purpose of this study was to determine the dose responsiveness of human olfactory thresholds for each of the following ions: potassium, sodium, and calcium., Study Design: Prospective translational study., Methods: Irrigation solutions with variable potassium, sodium, and calcium were tested in 25 healthy human participants. Six potassium concentrations (range, 2-10 mM), six sodium concentrations (range, 73.7-113.7 mM), and three calcium concentrations (range, 0.44-0.64 mM) were used. Before and immediately following irrigations, olfactory thresholds were determined using the Sniffin' Sticks test. Differences in olfactory threshold scores before and after irrigations were compared to assess the effect of ionic composition on olfactory sensitivity., Results: Physiologic concentrations of potassium, sodium, and calcium at 5.7, 89.5, and 0.54 mM, respectively, did not significantly change olfactory thresholds. Variations in both potassium and sodium concentrations demonstrated statistically significant dose-dependent elevations in olfactory thresholds (P < .05). Only the calcium concentration that was lower than the physiologic level led to significant elevations in olfactory thresholds., Conclusions: Different potassium and sodium concentrations in irrigation solutions provide distinctive dose-dependent shifts in olfactory thresholds. Calcium concentrations also elevate olfactory thresholds, but calcium plays a less significant role than potassium and sodium in modulating olfactory thresholds. These results highlight the importance of the intranasal ionic microenvironment in olfactory physiology and suggest that optimal ionic concentrations in irrigation solutions exist to preserve olfactory function., Level of Evidence: NA., (© 2014 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Although chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by Th2 inflammation, the mechanism underlying the onset and amplification of this inflammation has not been fully elucidated. Dendritic cells (DCs) are major antigen-presenting cells, central inducers of adaptive immunity and critical regulators of many inflammatory diseases. However, the presence of DCs in CRS, especially in nasal polyps (NPs), has not been extensively studied., Objective: The objective of this study was to characterize DC subsets in CRS., Methods: We used real-time PCR to assess the expression of mRNA for markers of myeloid DCs (mDCs; CD1c), plasmacytoid DCs (pDCs; CD303) and Langerhans cells (LCs; CD1a, CD207) in uncinate tissue (UT) from controls and patients with CRS as well as in NP. We assayed the presence of DCs by immunohistochemistry and flow cytometry., Results: Compared to UT from control subjects (n = 15) and patients with CRS without NP (CRSsNP) (n = 16) and CRSwNP (n = 17), mRNAs for CD1a and CD1c were significantly elevated in NPs (n = 29). In contrast, CD207 mRNA was not elevated in NPs. Immunohistochemistry showed that CD1c(+) cells but not CD303(+) cells were significantly elevated in NPs compared to control subjects or patients with CRSsNP. Flow cytometric analysis showed that CD1a(+) cells in NPs might be a subset of mDC1s and that CD45(+) CD19(-) CD1c(+) CD11c(+) CD141(-) CD303(-) HLA-DR(+) mDC1s and CD45(+) CD19(-) CD11c(+) CD1c(-) CD141(high) HLA-DR(+) mDC2s were significantly elevated in NPs compared to UT from controls and CRSsNP, but CD45(+) CD11c(-) CD303(+) HLA-DR(+) pDCs were only elevated in NPs compared to control UT., Conclusion and Clinical Relevance: Myeloid DCs are elevated in CRSwNP, especially in NPs. Myeloid DCs thus may indirectly contribute to the inflammation observed in CRSwNP., (© 2014 John Wiley & Sons Ltd.)

Objective: To examine the existing evidence on gender differences in the prevalence, treatment, and quality of life of patients with chronic rhinosinusitis (CRS)., Methods: Review of the literature and expert opinion., Results: From a sociologic standpoint, women have historically been considered more likely to report symptoms, seek medical care, and give poorer self-evaluation of health, which may bias data toward increased prevalence and a greater effect of CRS on quality of life in women. However, the influence of gender seems to be restricted primarily to the evaluation of general quality of life, whereas the disease-specific health-related quality of life is not different between genders. Furthermore, migraine headaches, which are more common among women, may be misdiagnosed as CRS, which contributes to gender differences in the prevalence of CRS. The degree to which reported differences in prevalence and health utilization represent biologic or physiologic differences between genders is not known; however, differences in anatomic size, tobacco susceptibility, and hormonal factors have been speculated to increase the overall susceptibility to CRS in women compared with men., Conclusions: Focused research that examines the effect of gender on the development, treatment, and outcomes of CRS is warranted.

Objectives/hypothesis: To systematically assess the prevalence of bacterial infection in adults with acute rhinosinusitis (ARS)., Methods: Electronic databases were systematically searched for relevant studies published up to June 2012., Results: Twenty-nine articles, evaluating a total of 9,595 patients with a clinical diagnosis of ARS, were included in the study. Of these, 14 (48%) studies required radiographic confirmation of sinusitis, one study (3%) required evidence of purulence, 10 studies (35%) required both for inclusion in the study population, and four studies (14%) required neither. The random effects model estimate of prevalence of bacterial growth on all cultures was 53.7% (CI 48.4%-59.0%), ranging from 52.5% (CI 46.7%-58.3%) in studies requiring radiographic confirmation of sinusitis to 61.1% (CI 54.0%-68.1%) in studies requiring neither radiographic evidence nor purulence on exam. Studies that obtained cultures from antral swab had a prevalence of bacterial growth of 61.0% (CI 54.7%-67.2%), whereas those utilizing endoscopic meatal sampling had a prevalence of 32.9% (CI 19.0%-46.8%)., Conclusions: Few studies evaluate the recovery of bacteria via culture in adults with a diagnosis of ABRS or ARS based on clinical criteria alone. With radiographic and/or endoscopic confirmation, antral puncture and endoscopically guided cultures produce positive bacterial cultures in approximately one-half of patients. Opportunities exist to improve diagnostic accuracy for bacterial infection in ARS., (© 2014 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Patients with recurrent sinonasal polyposis after endoscopic sinus surgery (ESS) have limited treatment options. This study evaluated the safety and efficacy of a bioabsorbable steroid-eluting implant with 1350 μg of mometasone furoate for its ability to dilate obstructed ethmoid sinuses, reduce polyposis, and reestablish sinus patency., Methods: This was a randomized, controlled, blinded study including 100 patients chronic rhinosinusitis with nasal polyposis (CRSwNP) refractory to medical therapy and considered candidates for revision ESS. Follow-up included endoscopic grading by investigators and patient-reported outcomes., Results: Treated patients (n = 53; age as mean ± standard deviation [SD] 47.8 ± 12.6 years; 55% male) underwent in-office bilateral placement. Control patients (n = 47; age 51.6 ± 13.1 years; 66% male) underwent a sham procedure. At 3 months, treated patients experienced a significant reduction in bilateral polyp grade (p = 0.0269) and ethmoid sinus obstruction (p = 0.0001) compared to controls. Treated patients also experienced a 2-fold improvement in the mean nasal obstruction/congestion score (-1.33 ± 1.47 vs -0.67 ± 1.45; p = 0.1365). This improvement reached statistical significance (p = 0.025) in patients with greater polyp burden (grade ≥2 bilaterally; n = 74). At 3 months, 53% of treated patients compared to only 23% of controls were no longer indicated for repeat ESS. There was no serious adverse event or clinically significant increases in intraocular pressure or cataract formation., Conclusion: The symptomatic improvement and statistically significant reduction in polyp grade and ethmoid sinus obstruction supported the efficacy of the steroid-eluting implant for in-office treatment of CRS patient with recurrent polyposis after ESS. The study results demonstrated that the steroid-eluting implant represents a safe and effective alternative to current management for this patient population., (© 2014 ARS-AAOA, LLC.)

Chronic rhinosinusitis (CRS) has a significant impact not only on individuals who are afflicted but also on society as a whole. An increasing emphasis is being placed on incorporating the best available evidence into the care of patients, in association with an individual clinician's expertise and the patient's values. Recent evidence-based reviews with recommendations (EBRRs) have distilled our knowledge of CRS treatment options and have also pointed out continued gaps in this knowledge. This review synthesizes the findings of 8 EBRRs regarding CRS published in the International Forum of Allergy and Rhinology between 2011 and 2014. The recommendations in this review are based on the best available evidence and are meant to be incorporated into each patient's individual care, along with the practitioner's expertise and the individual patient's values and expectations. It is hoped that the EBRRs, and the process that spawned them, can provide the foundation for future guidelines in the diagnosis and management of CRS., (© 2014 ARS-AAOA, LLC.)

Objectives/hypothesis: To diagnose chronic rhinosinusitis (CRS), current guidelines require either endoscopic or computed tomography (CT) findings of sinus disease. To a primary care physician, this means a referral to an otolaryngologist or obtaining a CT scan. Unfortunately, the sensitivity of endoscopy for detecting CRS is low, and examination by the Otolaryngologist may not yield a definitive diagnosis. This leaves CT scanning. However, this is contradicted by recommendations to limit CT scanning for only preoperative planning purposes due to cost concerns. This study aims to provide an evidence-based cost-efficient recommendation for primary care practice., Study Design: Health care economics-based decision analysis model., Methods: A cost-based decision analysis based on literature-reported probabilities and Medicare costs was constructed for two scenarios: 1) primary care physicians who are comfortable initiating first-line treatment for chronic rhinosinusitis, rhinitis, and atypical facial pain; and 2) primary care physicians who are less comfortable with medical management of these conditions., Results: Under both scenarios and the extremes of sensitivity analysis, upfront CT scanning provides cost-efficient diagnosis over presuming a diagnosis of chronic rhinosinusitis. Primary care physicians who attempt first-line treatment can expect $503 (range = $296-$761) saved per patient. Meanwhile, primary care physicians who prefer to refer may expect $326 (range = $299-$353) saved per patient., Conclusions: In all scenarios, confirming diagnosis with CT scanning prior to treatment or referral is more cost-efficient than presuming a diagnosis of CRS based on symptoms alone., (© 2013 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Current symptom criteria poorly predict a diagnosis of chronic rhinosinusitis (CRS) resulting in excessive treatment of patients with presumed CRS. The objective of this study was analyze the positive predictive value of individual symptoms, or symptoms in combination, in patients with CRS symptoms and examine the costs of the subsequent diagnostic algorithm using a decision tree-based cost analysis., Methods: We analyzed previously collected patient-reported symptoms from a cross-sectional study of patients who had received a computed tomography (CT) scan of their sinuses at a tertiary care otolaryngology clinic for evaluation of CRS symptoms to calculate the positive predictive value of individual symptoms. Classification and regression tree (CART) analysis then optimized combinations of symptoms and thresholds to identify CRS patients. The calculated positive predictive values were applied to a previously developed decision tree that compared an upfront CT (uCT) algorithm against an empiric medical therapy (EMT) algorithm with further analysis that considered the availability of point of care (POC) imaging., Results: The positive predictive value of individual symptoms ranged from 0.21 for patients reporting forehead pain and to 0.69 for patients reporting hyposmia. The CART model constructed a dichotomous model based on forehead pain, maxillary pain, hyposmia, nasal discharge, and facial pain (C-statistic 0.83). If POC CT were available, median costs ($64-$415) favored using the upfront CT for all individual symptoms. If POC CT was unavailable, median costs favored uCT for most symptoms except intercanthal pain (-$15), hyposmia (-$100), and discolored nasal discharge (-$24), although these symptoms became equivocal on cost sensitivity analysis. The three-tiered CART model could subcategorize patients into tiers where uCT was always favorable (median costs: $332-$504) and others for which EMT was always favorable (median costs -$121 to -$275). The uCT algorithm was always more costly if the nasal endoscopy was positive., Conclusion: Among patients with classic CRS symptoms, the frequency of individual symptoms varied the likelihood of a CRS diagnosis marginally. Only hyposmia, the absence of facial pain, and discolored discharge sufficiently increased the likelihood of diagnosis to potentially make EMT less costly. The development of an evidence-based, multisymptom-based risk stratification model could substantially affect the management costs of the subsequent diagnostic algorithm., (© 2013 ARS-AAOA, LLC.)

Background: Profound edema or formation of a pseudocyst containing plasma proteins is a prominent characteristic of nasal polyps (NP). However, the mechanisms underlying NP retention of plasma proteins in the submucosa remain unclear. Recently, we reported that impairment of fibrinolysis causes excessive fibrin deposition in NP and this might be involved in the retention of plasma proteins. Although the coagulation cascade plays a critical role in fibrin clot formation at extravascular sites, the expression and role of coagulation factors in NP remain unclear., Objective: The objective of this study was to investigate the expression of coagulation factors in patients with chronic rhinosinusitis (CRS)., Methods: Sinonasal tissues were collected from patients with CRS and control subjects. We assayed mRNA for factor XIII-A (FXIII-A) by using real-time PCR and measured FXIII-A protein by means of ELISA, immunohistochemistry, and immunofluorescence., Results: FXIII-A mRNA levels were significantly increased in NP tissue from patients with CRS with NP (P < .001) compared with uncinate tissue from patients with CRS or control subjects. Similarly, FXIII-A protein levels were increased in NP. Immunofluorescence analysis revealed that FXIII-A expression in inflammatory cells and FXIII-A(+) cell numbers were significantly increased in NP. Most FXIII-A staining was observed within CD68(+)/CD163(+) M2 macrophages in NP. Levels of FXIII-A correlated with markers of M2 macrophages, suggesting that M2 macrophages are major FXIIIA-producing cells in NP., Conclusion: Overproduction of FXIII-A by M2 macrophages might contribute to the excessive fibrin deposition in the submucosa of NP, which might contribute to the tissue remodeling and pathogenesis of CRS with NP., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Chronic rhinosinusitis (CRS) consists of a constellation of symptoms, including facial pressure/pain, hyposmia, rhinorrhea, and nasal congestion. On histopathological evaluation, the disease can be divided into pathophysiologically distinct subgroups. This study systematically reviews the literature regarding the unique histopathological findings of the various subtypes of CRS to determine the potential diagnostic value of performing tissue analysis of CRS specimens beyond routine hematoxylin and eosin (H&E) staining., Methods: A PubMed search was untaken to identify articles that evaluated the histopathological features of CRS. Six hundred fifty-four relevant articles were identified and after application of specific exclusion criteria, 71 articles were further reviewed in detail., Results: All articles included analysis of tissue samples from in-office biopsies or intraoperative specimens of patients who underwent sinus surgery. CRS was often further divided into subgroups and compared with each other and with a control group. The subgroups included CRS with and without nasal polyps, asthmatic and nonasthmatic patients, and with and without eosinophilia. Distinct inflammatory mediators were found for the different subgroups. Twenty-eight articles evaluated these inflammatory markers for their potential value as prognostic indicators., Conclusion: CRS is a heterogeneous disease based on its histopathological findings. Information that is obtainable from light microscopy, but typically goes unreported, can serve as valuable prognostic indictors. However, routine H&E staining is suboptimal in distinguishing among the various subgroups of CRS. Assessment of specific inflammatory mediators in sinus mucosa specimens may help provide prognostic information and guide more tailored treatment for the individual patient.

Objectives/hypothesis: Chronic Rhinosinusitis (CRS) is accompanied by evidence of a vigorous adaptive immune response, and emerging studies demonstrate that some nasal polyps manifest a polyclonal autoantibody response. We previously found that antibodies against BP180, a component of the hemidesmosome complex and the dominant epitope in autoimmune bullous pemphigoid, were found at elevated levels in nasal polyp tissue. Given the critical role of hemidesmosomes in maintaining epithelial integrity, we sought to investigate the distribution of BP180 in nasal tissue and evaluate for evidence of systemic autoimmunity against this antigen in CRS., Study Design: Case-control experimental study., Methods: The expression and distribution of BP180 in cultured nasal epithelial cells and normal nasal tissue were confirmed using real-time polymerase chain reaction (PCR), Western immunoblotting, immunofluorescence and immunohistochemistry. Sera were collected from three groups: control, CRSsNP, and CRSwNP. A commercially available ELISA was utilized to compare anti-BP180 autoantibody levels in sera., Results: BP180 is expressed in nasal epithelium, but is not confined to the basement membrane as it is in human skin. In cultured nasal epithelial cells, confocal immunofluorescence showed a punctate distribution of BP180 along the basal surface, consistent with its distribution in epithelial keratinocytes. There are significantly higher levels of circulating nonpathologic anti-BP180 autoantibodies in CRS patients compared with normal controls (P <0.05)., Conclusions: BP180 is more widely expressed in nasal epithelium versus skin, although it appears to play a similar role in the formation of hemidesmosomes along the basement membrane. Further investigations are ongoing to characterize the pathogenicity of the anti-epithelial antibody response in CRS.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with TH2-dominant inflammation. Thymic stromal lymphopoietin (TSLP) is a cytokine that triggers dendritic cell-mediated TH2 inflammatory responses and that enhances IL-1-dependent TH2 cytokine production in mast cells. Although increased TSLP mRNA levels have been found in nasal polyps (NPs), expression of TSLP protein and its function in patients with chronic rhinosinusitis (CRS) have not been fully explored., Objectives: The objective of this study was to investigate the role of TSLP in patients with CRS., Methods: We investigated the presence and stability of TSLP protein in NPs using ELISA and Western blotting and investigated the function of TSLP in nasal tissue extracts with a bioassay based on activation of human mast cells., Results: Although TSLP mRNA levels were significantly increased in NP tissue from patients with CRSwNP compared with uncinate tissue from patients with CRS or control subjects, TSLP protein was significantly decreased in NP tissue, as detected by using the commercial ELISA kit. We found that recombinant TSLP was time-dependently degraded by NP extracts, and this degradation was completely inhibited by a protease inhibitor cocktail, suggesting that TSLP is sensitive to tissue proteases. Interestingly, NP extract-treated TSLP had higher activity in mast cells, although the amount of full-length TSLP was reduced up to 85%. NP extracts significantly enhanced IL-1β-dependent IL-5 production in mast cells compared with uncinate tissue homogenates, and responses were significantly inhibited by anti-TSLP, suggesting that NPs contain biologically relevant levels of TSLP activity., Conclusion: TSLP and its metabolic products might play an important role in the inflammation seen in patients with CRSwNP., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)