Background:The body of knowledge regarding rhinosinusitis (RS) continues to expand, with rapid growth in number of publications, yet substantial variability in the quality of those presentations. In an effort to both consolidate and critically appraise this information, rhinologic experts from around the world have produced the International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR:RS). Methods:Evidence-based reviews with recommendations (EBRRs) were developed for scores of topics, using previously reported methodology. Where existing evidence was insufficient for an EBRR, an evidence-based review (EBR) was produced. The sections were then synthesized and the entire manuscript was then reviewed by all authors for consensus. Results:The resulting ICAR:RS document addresses multiple topics in RS, including acute RS (ARS), chronic RS (CRS) with and without nasal polyps (CRSwNP and CRSsNP), recurrent acute RS (RARS), acute exacerbation of CRS (AE-CRS), and pediatric RS. Conclusion:As a critical review of the RS literature, ICAR:RS provides a thorough review of pathophysiology and evidence-based recommendations for medical and surgical treatment. It also demonstrates the significant gaps in our understanding of the pathophysiology and optimal management of RS. Too o en the foundation upon which these recommendations are based is comprised of lowerlevel evidence. It is our hope that this summary of the evidence in RS will point out where additional research efforts may be directed. C 2016 ARS-AAOA, LLC. Key Words:rhinosinusitis; chronic rhinosinusitis; acute rhinosinusitis; recurrent acute rhinosinusitis; evidence-based medicine; systematic review; endoscopic sinus surgery List of Abbreviations Used

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.

Background Chronic rhinosinusitis (CRS) is a prevalent condition with underexplored risk factors. Objectives To determine CRS incidence and evaluate associations with a range of pre-morbid medical conditions for CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP) using real-world clinical practice data. Methods Electronic health record (EHR) data from 446,480 Geisinger Clinic primary care patients was used for a retrospective longitudinal cohort study for data from 2001–2010. Using logistic regression, newly diagnosed CRS cases between 2007-2009 were compared to frequency-matched controls on pre-morbid factors in the immediate (0-6 months), intermediate (7-24 months) and entire observed timeframes prior to diagnosis. Results : The average incidence of CRS was 83 (±13) CRSwNP cases per 100,000 person-years and 1048 (±78) CRSsNP cases per 100,000 person-years. Between 2007-2009, 595 patients with incident CRSwNP and 7523 patients with incident CRSsNP were identified and compared to 8118 controls. Compared to controls and CRSsNP, CRSwNP patients were older and more likely to be male. Prior to diagnosis, CRS patients had a higher prevalence of acute rhinosinusitis, allergic rhinitis, chronic rhinitis, asthma, gastroesophageal reflux disease (GERD), adenotonsillitis, sleep apnea, anxiety and headaches (all p < 0.001). CRSsNP had a higher pre-morbid prevalence of infections of the upper and lower airway, skin/soft tissue and urinary tract (all p < 0.001). In the immediate and intermediate timeframes analyzed, patients who developed CRS had more outpatient encounters and antibiotic prescriptions (p < 0.001) but guideline-recommended diagnostic testing was performed in a minority of cases. Conclusions Patients who are diagnosed with CRS have a higher pre-morbid prevalence of anxiety, headaches, GERD, sleep apnea and infections of the respiratory system and some non-respiratory sites that results in higher antibiotic, corticosteroid and health care utilization. The use of guideline-recommended diagnostic testing for confirmation of CRS remains poor.

Rationale: Nasal polyps (NPs) are characterized by intense edema or formation of pseudocysts filled with plasma proteins, mainly albumin. However, the mechanisms underlying NP retention of plasma proteins in their submucosa remain unclear. Objectives: We hypothesized that formation of a fibrin mesh retains plasma proteins in NPs. We assessed the fibrin deposition and expression of the components of the fibrinolytic system in patients with chronic rhinosinusitis (CRS). Methods:We assessed fibrin deposition in nasal tissue from patients with CRS and control subjects by means of immunofluorescence. Fibrinolytic components, d-dimer, and plasminogen activators were measured using ELISA, real-time PCR, and immunohistochemistry. We also performed gene expression and protein quantification analysis in cultured airway epithelial cells. Measurements and Main Results: Immunofluorescence data showed profound fibrin deposition in NP compared with uncinate tissue (UT) from patients with CRS and control subjects. Levels of the cross-linked fibrin cleavage product protein, d-dimer, were significantly decreased in NP compared with UT from patients with CRS and control subjects, suggesting reduced fibrinolysis (P , 0.05). Expression levels of tissue plasminogen activator (t-PA) mRNA and protein were significantly decreased in NP compared with UT from patients with CRS and control subjects (P , 0.01). Immunohistochemistry demonstrated clear reduction of t-PA in NP, primarily in the epithelium and glands. Th2 cytokine-stimulated cultured airway epithelial cells showed down-regulation of t-PA, suggesting a potential Th2 mechanism in NP. Conclusions: A Th2-mediated reduction of t-PA might lead to excessive fibrin deposition in the submucosa of NP, which might contribute to the tissue remodeling and pathogenesis of CRS with nasal polyps.

Background The effect of comorbid conditions such as asthma and atopy on the severity of chronic rhinosinusitis (CRS) and the presence of nasal polyps (NPs) remains an area of investigation. We sought to elucidate the relationship among these entities. Methods The study population included 106 consecutive patients who were referred to a multidisciplinary, university-based allergy and sinus clinic that underwent computed tomography (CT) scan, skin-prick testing, and had CRS. Data were analyzed to determine Lund-MacKay score (LMS), presence of NPs, asthma status, and sensitivity to seven classes of aeroallergens. Results Skin tests were positive in 52 cases and negative in 54 cases. Although, there was no statistical relationship between LMS and atopic status in the entire group, among the asthmatic subgroup, mean LMS was greater in nona topic asthmatic patients than in atopic asthmatic patients. Asthmatic patients had a higher LMS than nonasthmatic patients (p < 0.0001). Asthmatic patients were more likely than nonasthmatic patients to have NPs (57.6% versus 25%; p = 0.0015), regardless of atopic status. Mean LMS was higher in NP patients compared with nonpolyp patients (p < 0.0001), independent of atopic status. Mean LMS was not affected by sensitivity to any particular allergen, with the exception of cockroach-allergic patients who were more likely to have an LMS of >10 (p = 0.0236) and had more severe maxillary sinus involvement (p = 0.0391). Conclusion These data indicate a strong relationship between CRS severity, as measured by LMS, and chronic airway inflammatory diseases, asthma, and NPs. The association between LMS and atopic status appears weak. The present study suggests that CRS is an inflammatory disease that occurs independently of systemic IgE-mediated pathways.

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 elevated levels of TSLP mRNA have been found in nasal polyps (NPs), expression of TSLP protein and its function in CRS have not been fully explored. Objectives The objective of this study was to investigate the role of TSLP in CRS. Methods We investigated the presence and stability of TSLP protein in NPs by ELISA and western blot, and the function of TSLP in nasal tissue extracts with a bioassay based upon activation of human mast cells. Results Although TSLP mRNA was significantly increased in NP tissue from patients with CRSwNP compared to uncinate tissue from patients with CRS or control subjects, TSLP protein was significantly decreased in NP tissue as detected by 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 NP contain biologically relevant levels of TSLP activity. Conclusion TSLP and its metabolic products may play an important role in the inflammation in CRSwNP.

Objective Olfactory loss is a challenging clinical problem with few proven therapeutic options. Early experimental results with olfactory training (OT) suggest that this novel therapy may be an effective intervention for olfactory dysfunction of multiple etiologies. The aim of this study was to systematically review currently available studies that assess the efficacy and outcomes of OT in patients with olfactory loss. Methods A comprehensive systematic literature review was performed with the assistance of a reference librarian using the Medline, PsycInfo, Google Scholar, EMBASE, and Proquest databases. Eligible studies were extracted based on defined inclusion criteria and the effect of OT on objective olfactory function was evaluated qualitatively and by meta-analysis. Results A total of ten studies with 639 patients were identified and systematically reviewed. Sufficient data for meta-analysis was available for 3 studies. Patients receiving OT experienced a statistically significant improvement in the TDI (Threshold, Discrimination, Identification) score compared to control patients (mean difference [MD] 3.77; 95% CI 2.28–5.26). Improvement in olfactory function was observed in discrimination ([MD] 1.92; 95% CI 1.13–2.71) and identification ([MD] 1.61; 95% CI 0.55–2.68), but not in olfactory thresholds ([MD] −0.01; 95% CI −0.42–0.39). Conclusion Olfactory training is a promising modality for the treatment of olfactory dysfunction. Results of this systematic review and meta-analysis suggest that it may be an effective treatment for olfactory dysfunction due to multiple etiologies. Additional high quality studies are needed to define indications, outcomes, and duration of therapy for this novel therapy.

Background There is a clinical association between asthma and chronic rhinosinusitis (CRS). This study was designed to determine whether severity of coexistent asthma affects the clinical presentation of CRS. Methods Cross-sectional analysis was performed of prospectively collected data in 187 patients with CRS who were evaluated in a large, tertiary academic nasal and sinus center. Patients were stratified into three groups based on asthma status using National Institutes of Health criteria: (1) nonasthmatic, (2) intermittent/mild asthma, (3) or moderate/severe asthma. Results Mean Lund-Mackay scores were 9.7, 11.6, and 15.6, respectively. ANOVA testing with post-hoc Tukey analysis revealed that Lund-MacKay scores were significantly greater in group 3 than either group 1 (p < 0.05) or group 2 (p < 0.01). The prevalence of allergic sensitization was 72.4, 82.8, and 100% in groups 1, 2, and 3, respectively (p < 0.03). The prevalence of nasal polyposis was 31.4% in group 1, 48.3% in group 2, and 94.4% in group 3 (p < 0.0001). No differences were observed regarding demographic factors or the incidence of the triad of aspirin sensitivity, asthma, and nasal polyposis among those with different severities of asthma. Conclusion Increasing severity of asthma is associated with advancing radiological severity of CRS and a greater prevalence of allergic sensitization and nasal polyposis. This large adult series shows that asthma severity may have a significant correlation with the presentation of CRS. This study adds to the growing support for the unified airway theory.