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Aspirin-exacerbated respiratory disease (AERD) is associated with overproduction of proinflammatory cysteinyl leukotrienes (CysLTs), defective generation of anti-inflammatory prostaglandin E 2 (PGE 2 ), and reduced expression of the EP2 receptor for PGE 2 . Reduced PGE 2 synthesis results from the downregulation of inducible COX-2. Because PGE 2 signaling via EP2 inhibits the 5-lipoxygenase/leukotriene C 4 synthase-dependent pathway, the deficient levels of both PGE 2 and EP2 likely contribute to the excessive baseline production of cysteinyl leukotrienes in patients with AERD compared with in patients with aspirin-tolerant asthma. The COX-2 pathway is regulated by an autocrine metabolic loop involving IL-1β, IL-1 receptor type I, EP2, COX-2, membrane-bound PGE 2 prostaglandin E 2 synthase-1, and PGE 2 . Previous studies reported that this metabolic loop is dysregulated in patients with AERD. When the downexpressed EP2 receptor is normalized, the entire loop returns to its normal function. Cotreatment of airway cells from healthy subjects with IL-4 and IFN-γ induces alterations in the metabolic loop similar to those seen in patients with AERD. In these patients, IL-4, which is produced in excess in airways of patients with AERD, likely contributes to the alteration of normal functioning of the autocrine metabolic loop involving IL-1β, IL-1 receptor type I, EP2, COX-2, membrane-bound PGE 2 prostaglandin E 2 synthase-1, and PGE 2 . We hypothesized that by blocking IL-4 action, dupilumab normalizes EP2 expression and restores the normal functioning of the COX-2 pathway autocrine metabolic loop, thereby normalizing the synthesis of PGE 2 and restoring aspirin tolerance., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) frequently remains uncontrolled despite maximal medical therapy and sinonasal surgery, presenting several unmet needs and challenges. Omalizumab previously demonstrated efficacy in CRSwNP in duplicate phase 3, randomized, placebo-controlled trials (POLYP 1, POLYP 2)., Objective: This open-label extension evaluated the continued efficacy, safety, and durability of response of omalizumab in adults with CRSwNP who completed POLYP 1 or 2., Methods: After 24 weeks of omalizumab or placebo in POLYP 1 and 2, patients (n = 249) received open-label omalizumab plus background nasal mometasone therapy for 28 weeks and were subsequently followed for 24 weeks after omalizumab discontinuation. Efficacy end points assessed change from baseline for the coprimary end points, Nasal Polyp Score and Nasal Congestion Score, and the secondary end points of Sino-Nasal Outcome Test 22, Total Nasal Symptom Score and its components, and University of Pennsylvania Smell Identification Test scores. Safety objectives included incidence of adverse events and adverse events leading to omalizumab discontinuation., Results: Patients who continued omalizumab experienced further improvements across coprimary end points and secondary end points through 52 weeks. Patients who switched from placebo to omalizumab experienced favorable responses across end points through week 52 that were similar to POLYP 1 and 2 at week 24. After omalizumab discontinuation, scores gradually worsened over the 24-week follow-up, but remained improved from pretreatment levels for both groups. The safety profile was similar to previous reports., Conclusions: The efficacy and safety profile from this study supports extended omalizumab treatment up to 1 year for CRSwNP with inadequate response to nasal corticosteroids., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) is the most bothersome phenotype of chronic rhinosinusitis; it is typically characterized by a type 2 inflammatory reaction and by comorbidities, including asthma, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease, and allergies. Here, the European Forum for Research and Education in Allergy and Airway Diseases proposes structured definitions to enable communication between clinicians and provides a practical algorithm to define type 2 inflammation in CRSwNP in daily clinical practice. A rational approach for the treatment of uncontrolled severe CRSwNP is discussed; it consists of evaluating the perspective and risks of surgery and efficacy and adverse events of biologics on the basis of currently available data. Further, possible combinations of surgery and biologics are discussed, and a rationale is provided. Here, it is of importance to adequately counsel the patient about both approaches to enable a decision-making process with an informed patient. Criteria for the selection of a biologic drug are provided, as several biologics for uncontrolled severe CRSwNP will be available in many countries within a short time. Further, suggestions for monitoring of the drug effects that support recognition of responders to the therapy and, subsequently, the decision regarding continuation or discontinuation of the biologic are proposed., (Copyright © 2020. Published by Elsevier Inc.)

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by IgE hyperproduction and eosinophilic inflammation. The anti-IgE antibody, omalizumab, has demonstrated efficacy in patients with CRSwNP and comorbid asthma previously., Objective: Our aim was to determine omalizumab safety and efficacy in CRSwNP in phase 3 trials (POLYP 1 and POLYP 2)., Methods: Adults with CRSwNP with inadequate response to intranasal corticosteroids were randomized (1:1) to omalizumab or placebo and intranasal mometasone for 24 weeks. Coprimary end points included change from baseline to week 24 in Nasal Polyp Score (NPS) and Nasal Congestion Score. Secondary end points included change from baseline to week 24 in Sino-Nasal Outcome Test-22 (SNOT-22) score, University of Pennsylvania Smell Identification Test, sense of smell, postnasal drip, runny nose, and adverse events., Results: Patients in POLYP 1 (n = 138) and POLYP 2 (n = 127) exhibited severe CRSwNP and substantial quality of life impairment evidenced by a mean NPS higher than 6 and SNOT-22 score of approximately 60. Both studies met both the coprimary end points. SNOT-22 score, University of Pennsylvania Smell Identification Test score, sense of smell, postnasal drip, and runny nose were also significantly improved for omalizumab versus placebo. In POLYP 1 and POLYP 2, the mean changes from baseline at week 24 for omalizumab versus placebo were as follows: NPS, -1.08 versus 0.06 (P < .0001) and -0.90 versus -0.31 (P = .0140); Nasal Congestion Score, -0.89 versus -0.35 (P = .0004) and -0.70 versus -0.20 (P = .0017); and SNOT-22 score, -24.7 versus -8.6 (P < .0001) and -21.6 versus -6.6 (P < .0001). Adverse events were similar between groups., Conclusion: Omalizumab significantly improved endoscopic, clinical, and patient-reported outcomes in severe CRSwNP with inadequate response to intranasal corticosteroids, and it was well tolerated., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The selection of pharmacotherapy for patients with allergic rhinitis aims to control the disease and depends on many factors. Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines have considerably improved the treatment of allergic rhinitis. However, there is an increasing trend toward use of real-world evidence to inform clinical practice, especially because randomized controlled trials are often limited with regard to the applicability of results. The Contre les Maladies Chroniques pour un Vieillissement Actif (MACVIA) algorithm has proposed an allergic rhinitis treatment by a consensus group. This simple algorithm can be used to step up or step down allergic rhinitis treatment. Next-generation guidelines for the pharmacologic treatment of allergic rhinitis were developed by using existing GRADE-based guidelines for the disease, real-world evidence provided by mobile technology, and additive studies (allergen chamber studies) to refine the MACVIA algorithm., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: Mobile health can be used to generate innovative insights into optimizing treatment to improve allergic rhinitis (AR) control., Objectives: A cross-sectional real-world observational study was undertaken in 22 countries to complement a pilot study and provide novel information on medication use, disease control, and work productivity in the everyday life of patients with AR., Methods: A mobile phone app (Allergy Diary, which is freely available on Google Play and Apple stores) was used to collect the data of daily visual analogue scale (VAS) scores for (1) overall allergic symptoms; (2) nasal, ocular, and asthma symptoms; (3) work; and (4) medication use by using a treatment scroll list including all allergy medications (prescribed and over-the-counter) customized for 22 countries. The 4 most common intranasal medications containing intranasal corticosteroids and 8 oral H 1 -antihistamines were studied., Results: Nine thousand one hundred twenty-two users filled in 112,054 days of VASs in 2016 and 2017. Assessment of days was informative. Control of days with rhinitis differed between no (best control), single (good control for intranasal corticosteroid-treated days), or multiple (worst control) treatments. Users with the worst control increased the range of treatments being used. The same trend was found for asthma, eye symptoms, and work productivity. Differences between oral H 1 -antihistamines were found., Conclusions: This study confirms the usefulness of the Allergy Diary in accessing and assessing behavior in patients with AR. This observational study using a very simple assessment tool (VAS) on a mobile phone had the potential to answer questions previously thought infeasible., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline by using the best approach to integrated care pathways using mobile technology in patients with allergic rhinitis (AR) and asthma multimorbidity. The proposed next phase of ARIA is change management, with the aim of providing an active and healthy life to patients with rhinitis and to those with asthma multimorbidity across the lifecycle irrespective of their sex or socioeconomic status to reduce health and social inequities incurred by the disease. ARIA has followed the 8-step model of Kotter to assess and implement the effect of rhinitis on asthma multimorbidity and to propose multimorbid guidelines. A second change management strategy is proposed by ARIA Phase 4 to increase self-medication and shared decision making in rhinitis and asthma multimorbidity. An innovation of ARIA has been the development and validation of information technology evidence-based tools (Mobile Airways Sentinel Network [MASK]) that can inform patient decisions on the basis of a self-care plan proposed by the health care professional., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: To assess olfactory function in children and to create and validate an odor identification test to diagnose olfactory dysfunction in children, which we called the Universal Sniff (U-Sniff) test., Study Design: This is a multicenter study involving 19 countries. The U-Sniff test was developed in 3 phases including 1760 children age 5-7 years. Phase 1: identification of potentially recognizable odors; phase 2: selection of odorants for the odor identification test; and phase 3: evaluation of the test and acquisition of normative data. Test-retest reliability was evaluated in a subgroup of children (n = 27), and the test was validated using children with congenital anosmia (n = 14)., Results: Twelve odors were familiar to children and, therefore, included in the U-Sniff test. Children scored a mean ± SD of 9.88 ± 1.80 points out of 12. Normative data was obtained and reported for each country. The U-Sniff test demonstrated a high test-retest reliability (r 27  = 0.83, P < .001) and enabled discrimination between normosmia and children with congenital anosmia with a sensitivity of 100% and specificity of 86%., Conclusions: The U-Sniff is a valid and reliable method of testing olfaction in children and can be used internationally., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Allergic rhinitis (AR) affects 10% to 40% of the population. It reduces quality of life and school and work performance and is a frequent reason for office visits in general practice. Medical costs are large, but avoidable costs associated with lost work productivity are even larger than those incurred by asthma. New evidence has accumulated since the last revision of the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines in 2010, prompting its update., Objective: We sought to provide a targeted update of the ARIA guidelines., Methods: The ARIA guideline panel identified new clinical questions and selected questions requiring an update. We performed systematic reviews of health effects and the evidence about patients' values and preferences and resource requirements (up to June 2016). We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence-to-decision frameworks to develop recommendations., Results: The 2016 revision of the ARIA guidelines provides both updated and new recommendations about the pharmacologic treatment of AR. Specifically, it addresses the relative merits of using oral H 1 -antihistamines, intranasal H 1 -antihistamines, intranasal corticosteroids, and leukotriene receptor antagonists either alone or in combination. The ARIA guideline panel provides specific recommendations for the choice of treatment and the rationale for the choice and discusses specific considerations that clinicians and patients might want to review to choose the management most appropriate for an individual patient., Conclusions: Appropriate treatment of AR might improve patients' quality of life and school and work productivity. ARIA recommendations support patients, their caregivers, and health care providers in choosing the optimal treatment., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

The selection of pharmacotherapy for patients with allergic rhinitis (AR) depends on several factors, including age, prominent symptoms, symptom severity, control of AR, patient preferences, and cost. Allergen exposure and the resulting symptoms vary, and treatment adjustment is required. Clinical decision support systems (CDSSs) might be beneficial for the assessment of disease control. CDSSs should be based on the best evidence and algorithms to aid patients and health care professionals to jointly determine treatment and its step-up or step-down strategy depending on AR control. Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR [fighting chronic diseases for active and healthy ageing]), one of the reference sites of the European Innovation Partnership on Active and Healthy Ageing, has initiated an allergy sentinel network (the MACVIA-ARIA Sentinel Network). A CDSS is currently being developed to optimize AR control. An algorithm developed by consensus is presented in this article. This algorithm should be confirmed by appropriate trials., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Current phenotyping of chronic rhinosinusitis (CRS) into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP) might not adequately reflect the pathophysiologic diversity within patients with CRS., Objective: We sought to identify inflammatory endotypes of CRS. Therefore we aimed to cluster patients with CRS based solely on immune markers in a phenotype-free approach. Secondarily, we aimed to match clusters to phenotypes., Methods: In this multicenter case-control study patients with CRS and control subjects underwent surgery, and tissue was analyzed for IL-5, IFN-γ, IL-17A, TNF-α, IL-22, IL-1β, IL-6, IL-8, eosinophilic cationic protein, myeloperoxidase, TGF-β1, IgE, Staphylococcus aureus enterotoxin-specific IgE, and albumin. We used partition-based clustering., Results: Clustering of 173 cases resulted in 10 clusters, of which 4 clusters with low or undetectable IL-5, eosinophilic cationic protein, IgE, and albumin concentrations, and 6 clusters with high concentrations of those markers. The group of IL-5-negative clusters, 3 clusters clinically resembled a predominant chronic rhinosinusitis without nasal polyps (CRSsNP) phenotype without increased asthma prevalence, and 1 cluster had a TH17 profile and had mixed CRSsNP/CRSwNP. The IL-5-positive clusters were divided into a group with moderate IL-5 concentrations, a mixed CRSsNP/CRSwNP and increased asthma phenotype, and a group with high IL-5 levels, an almost exclusive nasal polyp phenotype with strongly increased asthma prevalence. In the latter group, 2 clusters demonstrated the highest concentrations of IgE and asthma prevalence, with all samples expressing Staphylococcus aureus enterotoxin-specific IgE., Conclusion: Distinct CRS clusters with diverse inflammatory mechanisms largely correlated with phenotypes and further differentiated them and provided a more accurate description of the inflammatory mechanisms involved than phenotype information only., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: We hypothesized that the 2 reported alterations in aspirin-exacerbated respiratory disease (AERD), reduced expression/production of COX-2/prostaglandin (PG) E2 and diminished expression of E-prostanoid (EP) 2 receptor, are closely linked., Objective: We sought to determine the mechanisms involved in the altered regulation of the COX pathway in patients with AERD., Methods: Fibroblasts were obtained from nasal mucosa; samples of control subjects (NM-C, n = 8) and from nasal polyps from patients with aspirin-exacerbated respiratory disease (NP-AERD, n = 8). Expression of the autocrine loop components regulating PGE2 production and signaling, namely IL-1 type I receptor (IL-1RI), COX-2, microsomal prostaglandin E synthase 1 (mPGES-1), and EP receptors, was assessed at baseline and after stimulation with IL-1β, PGE2, and specific EP receptor agonists., Results: Compared with NM-C fibroblasts, basal expression levels of IL-1RI and EP2 receptor were lower in NP-AERD fibroblasts. IL-1β-induced IL-1RI, COX-2, and mPGES-1 expression levels were also lower in these cells. Levels of IL-1RI positively correlated with COX-2 and mPGES-1 expression in both NM-C and NP-AERD fibroblasts. Incubation with either exogenous PGE2 or selective EP2 agonist significantly increased expression of IL-1RI in NM-C fibroblasts and had hardly any effect on NP-AERD fibroblasts. Alterations in IL-1RI, COX-2, and mPGES-1 expression that were found in NP-AERD fibroblasts were corrected when EP2 receptor expression was normalized by transfection of NP-AERD fibroblasts., Conclusion: Altered expression of EP2 in patients with AERD contributes to deficient induction of IL-1RI, reducing the capacity of IL-1β to increase COX-2 and mPGES-1 expression, which results in low PGE2 production. This impairment in the generation of PGE2 subsequently reduces its ability to induce IL-1RI., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Allergic rhinitis (AR) and asthma represent global health problems for all age groups. Asthma and rhinitis frequently coexist in the same subjects. Allergic Rhinitis and its Impact on Asthma (ARIA) was initiated during a World Health Organization workshop in 1999 (published in 2001). ARIA has reclassified AR as mild/moderate-severe and intermittent/persistent. This classification closely reflects patients' needs and underlines the close relationship between rhinitis and asthma. Patients, clinicians, and other health care professionals are confronted with various treatment choices for the management of AR. This contributes to considerable variation in clinical practice, and worldwide, patients, clinicians, and other health care professionals are faced with uncertainty about the relative merits and downsides of the various treatment options. In its 2010 Revision, ARIA developed clinical practice guidelines for the management of AR and asthma comorbidities based on the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system. ARIA is disseminated and implemented in more than 50 countries of the world. Ten years after the publication of the ARIA World Health Organization workshop report, it is important to make a summary of its achievements and identify the still unmet clinical, research, and implementation needs to strengthen the 2011 European Union Priority on allergy and asthma in children., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Local allergic rhinitis (LAR) is a localized nasal allergic response in the absence of systemic atopy characterized by local production of specific IgE (sIgE) antibodies, a T(H)2 pattern of mucosal cell infiltration during natural exposure to aeroallergens, and a positive nasal allergen provocation test response with release of inflammatory mediators (tryptase and eosinophil cationic protein). Although the prevalence remains to be established, a number of patients previously given a diagnosis of nonallergic rhinitis or idiopathic rhinitis are now being classified as having LAR. Culprit allergens responsible include house dust mite, grass and olive pollens, and many others. For the diagnosis of LAR, neither skin prick testing nor determination of the presence of serum sIgE antibodies is useful, and a nasal allergen provocation test is needed to identify the culprit allergen or allergens. In a certain proportion of cases, local sIgE can be detected, and conjunctivitis, asthma, or both can be associated. Whether patients with LAR will have systemic atopy in the future is a matter of debate. Further studies are needed for examine the prevalence of this phenomenon in different areas, to improve the diagnostic methods to better identify these patients, and to develop therapeutic approaches, including the use of immunotherapy., (Published by Mosby, Inc.)

Background: Researchers have debated whether regulation of the COX enzymes (COX-1 and COX-2), which mediate production of prostaglandins (PGs), affects the pathogenesis of nasal polyps (NPs) and aspirin-intolerant asthma (AIA)., Objective: We investigated the roles of PGE(2), COX-1 and COX-2, and PGE(2) receptors in the development of NPs and AIA by measuring their expression in fibroblasts derived from nasal mucosa (NM) and NPs., Methods: Fibroblasts were isolated from the NM of subjects without asthma who had septal deviation, turbinate hypertrophy, or both (control subjects, n = 7); NPs of aspirin-tolerant nonasthmatic patients (n = 7); and NPs of patients with asthma who were intolerant of aspirin (n = 7). Polyp samples were collected during endoscopic surgery. Cultures were stimulated with IL-1β (10 ng/mL) for 72 hours. We used ELISA, immunoblotting, and immunofluorescence analyses to measure secretion of PGE(2), expression of COX-1 and COX-2, and expression of the PGE(2) receptors EP1 to EP4., Results: Compared with NM from control subjects, PGE(2) concentrations were significantly lower in IL-1β-stimulated fibroblasts from patients with NPs who were tolerant to aspirin and even lower in polyps from patients with AIA. Similarly, IL-1β exposure induced the expression of COX-1 and COX-2 in fibroblasts from NM of control subjects, had only moderate effects on fibroblasts from NPs of aspirin-tolerant nonasthmatic patients, and almost no effect on fibroblasts from NPs of patients with AIA. IL-1β also induced expression of EP2 in fibroblasts from control NM but not in fibroblasts from NPs of aspirin-tolerant nonasthmatic patients or those with AIA., Conclusion: Alterations in the COX pathway (ie, reduced production of PGE(2) and lack of upregulation of COX-1, COX-2, and EP2 under conditions of inflammation) are associated with NPs in patients with or without AIA., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Allergic Rhinitis and its Impact on Asthma (ARIA) differentiates mild from moderate/severe patients on the basis of 4 severity items. The high prevalence of moderate/severe patients suggests the need to differentiate between them., Objectives: To identify the categorization that maximizes discrimination between moderate and severe allergic rhinitis (AR) by using ARIA guidelines., Methods: Observational, cross-sectional study. Clinical characteristics, nasal symptoms (Total Symptom Score 4), and health-related quality of life (HRQL; Rhinoconjunctivitis Quality of Life Questionnaire and Short Form 12) were assessed. The association of severity items (sleep, daily activities/sport, work/school, and troublesome symptoms) with symptoms and HRQL was analyzed using linear regression models. ANOVA and effect sizes were used to assess differences in symptoms and HRQL among groups defined by the number of affected ARIA items., Results: Nontreated patients (N = 141) with moderate/severe AR were studied. All severity items showed a similar independent association with symptoms and HRQL scores, and there were no interaction effects, indicating that categorization of patients into moderate and severe could be based only on the number of items affected. Effect sizes were highest between patients with 4 affected ARIA items and those with 3, 2, or 1 affected item (effect sizes greater than 0.8 in all comparisons using Rhinoconjunctivitis Quality of Life Questionnaire and Short Form 12 Physical Composite Summary, and greater than 0.5 using the Total Symptom Score 4; P < .001)., Conclusion: Using ARIA severity items, the criterion that best discriminates AR severity is considering moderate those with 1 to 3 affected items and severe those with 4., Clinical Implications: Discrimination between patients with moderate and severe AR should help to obtain homogeneous populations for both research and clinical purposes.

Background: Chronic rhinosinusitis (CRS) is one of the most common chronic diseases. Recently, it has been suggested that an exaggerated immune response to fungi is crucial in the pathogenesis of the disease. On the basis of this hypothesis, intranasal treatment with amphotericin B should benefit patients with CRS. Data from 2 uncontrolled and 2 controlled trials are conflicting, however., Objective: To clarify the role of intranasal antifungal drugs in the treatment of CRS, we conducted a large, double-blind, placebo-controlled, multicenter study comparing the effectiveness of amphotericin B nasal lavages with placebo., Methods: A total of 116 randomly selected patients with CRS were instructed to instill 25 mL amphotericin B (100 microg/mL) or placebo to each nostril twice daily for 3 months. Primary outcomes included a reduction in total visual analog scale (VAS) score and nasal endoscopy score. Secondary outcome measures included peak nasal inspiratory flow, polyp score, quality of life (Short Form-36, Rhinosinusitis Outcome Measure-31), and individual VAS scores., Results: Analysis was based on intention to treat and involved all patients randomly assigned. Mean VAS scores, Short Form-36 and Rhinosinusitis Outcome Measure-31 data, peak nasal inspiratory flow values, nasal endoscopy scores, and polyp scores were similar in both treatment groups at the time of randomization, and no significant differences were observed after 13 weeks of treatment., Conclusion: Amphotericin B nasal lavages in the described dosing and time schedule do not reduce clinical signs and symptoms in patients with CRS., Clinical Implications: Amphotericin B nasal lavages in the described dosing and time schedule are ineffective and therefore not advised in the treatment of patients with CRS.

Background: Only dynamic studies can elucidate the discrepancies concerning the expression of the inducible COX-2 gene in inflammatory airway diseases., Objectives: To quantify the expression and spontaneous regulation of COX-1 and COX-2 mRNAs in nasal polyps and nasal mucosa by real-time PCR., Methods: Nasal polyps were obtained from 16 aspirin-tolerant patients with asthma/rhinitis (ATAR) and 18 aspirin-intolerant patients with asthma/rhinitis (AIAR) undergoing nasal polypectomy. Nasal mucosa was obtained from 12 subjects undergoing nasal corrective surgery. All specimens were cut into 3 pieces. One was immediately snap-frozen in liquid nitrogen, and the remaining 2 were left at room temperature for 30 or 60 minutes before freezing. Data are presented as medians and 25th to 75th percentiles of 10 6 cDNA molecules/microg total RNA., Results: Baseline COX-2 mRNA levels were significantly lower in both ATAR (0.45; 0.13-1.20; P <.05) and AIAR (0.24; 0.12-0.41; P <.001) nasal polyps than in nasal mucosa (1.35; 0.52-3.90). COX-2 mRNA expression did not change over time in nasal mucosa but increased significantly in ATAR nasal polyps ( P <.05), reaching similar levels to nasal mucosa after 60 minutes. In contrast, COX-2 mRNA showed no significant change over time in AIAR nasal polyps. COX-1 mRNA was higher in nasal polyps than in nasal mucosa, and its expression was not modified over time in any group of patients., Conclusion: These results suggest differential kinetics of COX-2 mRNA between nasal mucosa and nasal polyps. AIAR nasal polyps appear to have a greater abnormality of the COX-2 pathway than ATAR.

Background: Allergic Rhinitis and its Impact on Asthma in collaboration with the World Health Organization initiative reclassified allergic rhinitis, like asthma, by duration and severity. The Xyzal in Persistent Rhinitis Trial is the first large, long-term clinical trial studying patients with persistent rhinitis as defined by Allergic Rhinitis and its Impact on Asthma., Objectives: Two primary objectives were defined: comparison of the Rhinoconjunctivitis Quality of Life Questionnaire overall score and Total 5 Symptoms Score (rhinorrhea, sneezing, nasal congestion, and nasal and ocular pruritus) over a period of 4 weeks between levocetirizine 5 mg and placebo. Secondary endpoints included similar evaluations at 1 week and 3, 4.5, and 6 months, summary scores for a general health status questionnaire (Medical Outcomes Survey Short Form 36), a pharmacoeconomic assessment, comorbidities, and a safety evaluation., Methods: The Xyzal in Persistent Rhinitis Trial was a 6-month double-blind, placebo-controlled, multicenter, multinational trial in 551 patients. Adults with persistent rhinitis sensitized to both grass pollen and house dust mite were randomized to receive levocetirizine 5 mg/d or placebo., Results: A total of 421 patients completed the full study. Levocetirizine significantly improved both the Rhinoconjunctivitis Quality of Life Questionnaire overall score and the Total 5 Symptoms Score from week 1 to 6 months (all P values <.001). Medical Outcomes Survey Short Form 36 summary scores were also improved in the levocetirizine group compared with the placebo group. Treatment cessation because of lack of effect, comorbidities, and overall costs of disease, and comorbidities per working patient per month (160.27 vs 108.18) were lower in the levocetirizine group., Conclusion: Levocetirizine was shown to improve quality of life and symptoms and to decrease the overall costs of the disease over the 6-month treatment period.

Background: There is evidence that impairment of prostanoid metabolism might be involved in the pathogenesis of nasal polyps (NPs). Prostanoids are synthesized by 2 cyclooxygenase (Cox) enzymes, one constitutive (Cox-1) and another inducible (Cox-2)., Objective: The aim of these studies was to investigate Cox-1 and Cox-2 regulation in NPs of aspirin-tolerant human patients compared with that seen in nasal mucosa (NM)., Methods: Cultured explants from human NPs and healthy mucosa from patients undergoing polypectomy and corrective nasal surgery, respectively, were examined for Cox-1 and Cox-2 expression by means of semiquantitative competitive PCR and Western blotting., Results: Cox-1 mRNA was spontaneously upregulated in cultured NM but not in NPs. A spontaneous but delayed upregulation of Cox-2 mRNA was found in NPs (24 hours) compared with that seen in NM (6 hours). After cytokine stimulation (IFN-gamma, IL-1beta, and TNF-alpha), the induction of Cox-2 mRNA and protein was also faster in NM (1 hour) than in NPs (4 hours)., Conclusion: These data showing an abnormal regulation of Cox-1 and Cox-2 in NPs from aspirin-tolerant patients reinforce the concept that prostanoid metabolism might be important in the pathogenesis of inflammatory nasal diseases and suggest a potential role for this alteration in the formation of NPs.

Background: Airway hypersecretion is a common finding in rhinitis and asthma in which proinflammatory cytokines are upregulated. The effect of inflammation on glandular secretion remains unclear., Objective: We sought to investigate the effect of proinflammatory cytokines and eosinophil products in in vitro lactoferrin glandular secretion from human nasal mucosa and the role of corticosteroids and IL-10 in modulating this effect., Methods: Nasal explants from patients undergoing turbinectomies were incubated in a controlled atmosphere (50% N(2), 5% CO(2), and 45% O(2)) at 37 degrees C. Nasal explants were incubated with or without IL-1beta, IL-4, IL-5, IL-8, eotaxin, GM-CSF, TNF-alpha, eosinophil cationic protein (ECP), IL-10, and budesonide in a time-course and dose-response fashion. Lactoferrin concentrations in culture supernatants were measured by means of ELISA., Results: ECP (up to 30%) caused a dose-related stimulation of lactoferrin secretion. TNF-alpha (20 ng/mL) induced a significant increase of lactoferrin release from 8 hours (27.7% +/- 17.8%, P <.05) to 24 hours (40.8% +/- 17.2%, P <.01) compared with that found in media-treated explants. At 24 hours, TNF-alpha caused a dose-related stimulation of lactoferrin secretion (up to 35%). IL-1beta (65.3% +/- 15.2%, P <.05) and GM-CSF (15.7% +/- 6.7%, P <.05), both at 20 ng/mL, exerted a stimulatory effect only at 24 hours, and IL-4, IL-5, IL-8, and eotaxin had no significant effect. Budesonide caused a dose-related inhibition of lactoferrin secretion induced by IL-1beta (down to -76%) and TNF-alpha (down to -70%), whereas IL-10 had no effect., Conclusions: ECP and some proinflammatory cytokines (IL-1beta, TNF-alpha, and GM-CSF) may contribute to glandular hypersecretion in the inflamed nose. Corticosteroids may reduce nasal hypersecretion by blocking the direct effect of proinflammatory cytokines on glandular output.

Background: Mucus hypersecretion is a hallmark of upper and lower airway diseases, such as rhinitis, asthma, and chronic obstructive pulmonary disease. Although topical glucocorticoids are widely used to treat mucosal inflammation, their effect on mucus hypersecretion remains uncertain., Objective: The aim of this study was to investigate the effect of budesonide and beclomethasone dipropionate on in vitro lactoferrin glandular secretion from both human nasal and bronchial mucosa and the potential mediating role of lipocortin 1., Methods: Nasal and bronchial explants obtained from patients undergoing surgery were cultured in a controlled atmosphere. Lactoferrin (ELISA) was measured in culture supernatants, and lipocortin 1 (Western blot) was analyzed in explant tissues., Results: Both budesonide and beclomethasone dipropionate (10(-6) mol/L) decreased spontaneous lactoferrin secretion in nasal and bronchial mucosa. The maximum effect of cortico-steroids (10(-6) mol/L) was obtained at day 3 in bronchial mucosa (budesonide: -56% +/- 9%, P <.05; beclomethasone dipropionate: -32% +/- 6%, P <.05) and at day 5 in nasal mucosa (budesonide: -34% +/- 10%, P <.05; beclomethasone dipropionate: -37% +/- 10%, P <.05). Methacholine (10(-4) mol/L) increased lactoferrin secretion in both bronchial (248% +/- 72%, P <.05) and nasal (107% +/- 28%, P <.05) explants, with this effect being completely abrogated by atropine. Budesonide caused a dose-related inhibitory effect on methacholine-induced lactoferrin secretion that was similar in both bronchial (down to -86% at 10(-6) mol/L) and nasal (down to -73% at 10(-6) mol/L) mucosa. Budesonide (10(-6) mol/L) did not show any effect on lipocortin 1 expression., Conclusions: These results suggest that glucocorticoid effects on airway inflammation may include a reduction of mucus hypersecretion in both nasal and bronchial mucosa.

Background: We evaluated the effect of furosemide on allergen-induced rhinitis in a double-blind, crossover, placebo-controlled experiment., Methods: Fourteen patients with rhinitis who were allergic to house dust were nebulized with an intranasal dose of 20 mg of furosemide or placebo before allergen challenge with an extract of Dermatophagoides pteronyssinus (100 BU). Clinical evaluation and nasal lavages with normal saline solution were performed at baseline; after placebo-furosemide nebulization, and at 10, 30, and 60 minutes after allergen challenge. Number of sneezes and a composite symptom score were recorded to evaluate clinical response. Prostaglandin E2 (PGE2), PGD2 peptide leukotrienes and 15-hydroxy, 5,8,11,13-eicosatetraenoic acid (15-HETE) were measured by radioimmunoassay in nasal lavages. Cells were counted and classified as epithelial cells, neutrophils, eosinophils, and others., Results: No differences in either clinical symptoms or cell influx after allergen challenge were found between furosemide and placebo groups. PGE2 levels did not change after provocation, and furosemide had no effect on its production. Ten minutes after antigen challenge there was a marked increase of PGD2 (p < 0.01), peptide leukotrienes (p < 0.01), and 15-HETE (not significant) on both study days. However, no significant differences in the release of eicosanoids were found between furosemide and placebo groups., Conclusions: Our observations in the nasal mucosa suggest that furosemide has no effect on the release of proinflammatory and bronchoconstrictor metabolites (PGD2, peptide leukotrienes, and 15-HETE). In contrast to bronchial asthma, allergen-induced rhinitis was not effectively prevented by furosemide.

Interleukin (IL)-4 causes the dose limiting sensation of nasal congestion when administered systematically at doses of 3 micrograms/kg or higher thrice daily to humans. This side effect was observed in a group of patients treated as part of an immunotherapy protocol for cancer management. To determine the source of this congestion, nasal secretions were collected prospectively in a group of patients at baseline and after provocation with normal saline, methacholine (which stimulates glandular secretion), and histamine (which causes increased vascular permeability). Nasal lavages obtained at baseline and after provocation were analyzed for the presence of these glandular and vascular proteins and inflammatory mediators. Washings and provocations were performed before IL-4 administration, after 24 hours of IL-4 treatment, and after 3 days of treatment, at a time when nasal congestion was maximal. Compared with histamine challenge before IL-4 treatment, the secretion of the plasma proteins albumin and IgG were significantly decreased after 3 days of IL-4 treatment. IL-4 treatment had no apparent effect on methacholine-induced responses. Thus systemically administered IL-4 causes the subjective sensation of nasal congestion, increased histamine in nasal lavages, and the development of vascular unresponsiveness to histamine, without affecting parasympathetic responses to histamine. The relationships among increases in nasal lavage histamine, vascular unresponsiveness to histamine, and the sensation of nasal congestion are unclear.

Sixteen patients with allergic rhinitis were recruited into a double-blind crossover protocol studying the immediate effect of nedocromil sodium (NS) on the pattern of nasal symptoms and secretions after allergen challenge. After pretreatment with placebo or NS, allergen challenge resulted in pruritus, rhinorrhea, nasal congestion, and/or sneezing within 10 minutes in 12 of 16 subjects. Prostaglandin D2 (PGD2), a marker of mast cell degranulation, increased proportionately with symptom scores, remaining above the 95% confidence interval for 120 minutes after both pretreatments. No difference in PGD2 between the NS-treatment and placebo-treatment days was observed. Protein markers extravasated through the vasculature (albumin and IgG) or secreted by mucosal glands (lactoferrin) were assayed. Total protein, albumin, IgG, and lactoferrin all remained greater than 95% confidence interval for 100 minutes after allergen challenge in the placebo-pretreated group and 120 minutes in the NS-pretreated group. Although there appeared to be a trend for lower secretion of PGD2, albumin, and IgG in the NS-treated group, the overall differences did not achieve statistical significance. This protocol revealed that two topical 130 microliter doses of a 1% solution of NS failed to significantly reduce allergen-induced symptoms, PGD2 generation, or secretion of albumin, IgG, or lactoferrin when NS was compared with placebo. The anti-inflammatory and mast cell-stabilizing effects of NS may require more prolonged pretreatment before provocation to be effective.

The secretion of proteins from the human nasal mucosa induced by histamine, alpha-adrenergic, beta-adrenergic, and cholinergic agonists was studied in vivo and in vitro. Glandular secretion of lactoferrin, lysozyme (in vivo only), and respiratory glycoconjugates (RGCs) was measured. Vascular permeability was determined in vivo by albumin secretion in relationship to the other proteins. Muscarinic stimulation by methacholine induced significant glandular secretion (lactoferrin, lysozyme and/or RCGs) both in vivo and in vitro, confirming that muscarinic receptors are stimulated directly. Histamine induced predominantly vascular permeability in vivo but caused some glandular secretion as well. However, in vitro, histamine had no effect on glandular secretion, suggesting that histamine acts predominantly on the nasal vascular bed and only affects glandular secretion through reflex actions. Phenylephrine, an alpha-adrenergic agonist, selectively stimulated lysozyme release in vivo, and both RGCs and lactoferrin release in vitro. Thus, alpha-adrenergic stimulation has some direct, albeit minimal, capacity to stimulate mucosal glands. beta-Adrenergic agonists had no effect on glandular secretion or vascular permeability either in vivo or in vitro. Therefore, glandular secretion is directly stimulated by alpha-adrenergic and cholinergic agonists, but not by beta-adrenergic agonists. The stimulation of glandular secretion by histamine is indirect and mediated through the action of neural reflexes.

Possible roles of eosinophil (EO) products in modulating the release of mucus from airway explants were investigated. Cell- and membrane-free lysates from purified human EOs (1 to 20 x 10(5)) caused a dose-dependent release of respiratory glycoconjugates (RGC) from cultured feline tracheal explants. Crude extracts from isolated EO granules also stimulated RGC release, suggesting that a granular protein might be responsible. Three proteins derived from EO granules, EO-derived neurotoxin, EO cationic protein (ECP), and major basic protein (MBP) were separated by sequential sizing and affinity chromatography. ECP (0.025 to 25 micrograms/ml) caused a dose-dependent increase in RGC release from both feline and human airway explants and also stimulated the release of the serous cell-marker, lactoferrin, from human bronchial explants. EO-derived neurotoxin (0.025 to 50 micrograms/ml) failed to affect RGC release, whereas MBP (50 micrograms/ml) significantly inhibited RGC release from feline explants. Thus, ECP stimulates RGC and lactoferrin release from airway explants, whereas MBP inhibits RGC release.