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Background Severe asthma is associated with a broad range of phenotypes and clinical characteristics. This analysis assessed whether select baseline patient characteristics could prognosticate mepolizumab efficacy in severe eosinophilic asthma. Methods This was a post hoc meta-analysis of data from the Phase III MENSA (NCT01691521/MEA115588) and MUSCA (NCT02281318/200862) studies. Patients aged ≥ 12 years with severe eosinophilic asthma and a history of exacerbations were randomised to receive placebo (MENSA/MUSCA), mepolizumab 75 mg intravenously (MENSA) or 100 mg subcutaneously (SC) (MENSA/MUSCA) every 4 weeks for 32 (MENSA) or 24 (MUSCA) weeks. The primary endpoint was the annual rate of clinically significant exacerbations; other outcomes included the proportion of patients with no exacerbations and changes from baseline in pre-bronchodilator forced expiratory volume in 1 s (FEV1), St George’s Respiratory Questionnaire (SGRQ) total score and Asthma Control Questionnaire (ACQ)-5 score. Analyses were performed by baseline age of asthma onset (1 ≤ 60; 60–80; > 80); airway reversibility (reversible [≥ 12% change in FEV1]; non-reversible [1]); perennial and/or seasonal allergen sensitivity (yes/no); asthma control (uncontrolled [ACQ-5 score ≥ 1.5]; partial/complete control [ACQ-5 score Results Overall, 936 patients received mepolizumab 100 mg SC or placebo. Across age at asthma onset, lung function and airway reversibility subgroups, mepolizumab reduced the rate of clinically significant exacerbations by 49–63% versus placebo. Improvements in lung function, SGRQ total score and ACQ-5 score were also seen with mepolizumab versus placebo across most age and lung function subgroups. Clinically significant exacerbations were reduced with mepolizumab versus placebo irrespective of season or allergen sensitivity; SGRQ total and ACQ-5 scores were generally improved across seasons. Conclusions Mepolizumab efficacy was consistent for patients with varying age at asthma onset, lung function, airway reversibility and allergen sensitivities at baseline. Our results indicate that mepolizumab is likely to be beneficial for patients with severe eosinophilic asthma with a broad range of baseline clinical characteristics; large-scale real-world studies are needed to confirm the external validity of these findings. Trial registration Post hoc meta-analysis of data from MENSA (NCT01691521/MEA115588) and MUSCA (NCT02281318/200862)

Introduction: Cathelicidin is a vitamin D-regulated, antimicrobial peptide involved in the innate immune response of the airways. Reduced plasma cathelicidin concentrations are independently associated with worse pulmonary outcomes in current and former smokers. This study aimed to determine whether oral vitamin D supplementation in vitamin D-deficient current smokers increases plasma and bronchoalveolar lavage (BAL) cathelicidin levels. Methods: Vitamin D-deficient (25-hydroxy vitamin D [25-OH vitamin D]

Background Little is known about the concordance of atopy with asthma COPD overlap. Among individuals with COPD, a better understanding of the phenotypes characterized by asthma overlap and atopy is needed to better target therapies. Research Question What is the overlap between atopy and asthma status among individuals with COPD, and how are categories defined by the presence of atopy and asthma status associated with clinical and radiologic phenotypes and outcomes in the Genetic Epidemiology of COPD Study (COPDGene) and Subpopulation and Intermediate Outcome Measures in COPD Study (SPIROMICS)? Study Design and Methods Four hundred three individuals with COPD from SPIROMICS and 696 individuals from COPDGene with data about specific IgEs to 10 common allergens and mixes (simultaneous assessment of combination of allergens in similar category) were included. Comparison groups were defined by atopic and asthma status (neither, atopy alone, atopic asthma, nonatopic asthma, with atopy defined as any positive specific IgE (≥0.35 KU/L) to any of the 10 allergens or mixes and asthma defined as self-report of doctor-diagnosed current asthma). Multivariable regression analyses (linear, logistic, and zero inflated negative binomial where appropriate) adjusted for age, sex, race, lung function, smoking status, pack-years smoked, and use of inhaled corticosteroids were used to determine characteristics of groups and relationship with outcomes (exacerbations, clinical outcomes, CT metrics) separately in COPDGene and SPIROMICS, and then adjusted results were combined using meta-analysis. Results The prevalence of atopy was 35% and 36% in COPD subjects from SPIROMICS and COPDGene, respectively, and less than 50% overlap was seen between atopic status with asthma in both cohorts. In meta-analysis, individuals with nonatopic asthma had the most impaired symptom scores (effect size for St. George's Respiratory Questionnaire total score, 4.2; 95% CI, 0.4-7.9; effect size for COPD Assessment Test score, 2.8; 95% CI, 0.089-5.4), highest risk for exacerbations (incidence rate ratio, 1.41; 95% CI, 1.05-1.88) compared with the group without atopy or asthma. Those with atopy and atopic asthma were not at increased risk for adverse outcomes. Interpretation Asthma and atopy had incomplete overlap among former and current smokers with COPD in COPDGene and SPIROMICS. Nonatopic asthma was associated with adverse outcomes and exacerbation risk in COPD, whereas groups having atopy alone and atopic asthma had less risk.

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. Acurrent challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

Asthma worsening and symptom control are clinically important health outcomes in patients with severe eosinophilic asthma. This analysis of COMET evaluated whether stopping versus continuing long-term mepolizumab therapy impacted these outcomes. Patients with severe eosinophilic asthma with ≥3 years continuous mepolizumab treatment (via COLUMBA (NCT01691859) or COSMEX (NCT02135692) open-label studies) were eligible to enter COMET (NCT02555371), a randomised, double-blind, placebo-controlled study. Patients were randomised 1:1 to continue mepolizumab 100 mg subcutaneous every 4 weeks or to stop mepolizumab, plus standard of care asthma treatment. Patients could switch to open-label mepolizumab following an exacerbation. Health outcome endpoints included time to first asthma worsening (composite endpoint: rescue use, symptoms, awakening at night and morning peak expiratory flow (PEF)), patient and clinician assessed global rating of asthma severity and overall perception of response to therapy, and unscheduled healthcare resource utilisation. Patients who stopped mepolizumab showed increased risk of and shorter time to first asthma worsening compared with those who continued mepolizumab (hazard ratio (HR) 1.71; 95% CI 1.17–2.52; p=0.006), including reduced asthma control (increased risk of first worsening in rescue use (HR 1.36; 95% CI 1.00–1.84; p=0.047) and morning PEF (HR 1.77; 95% CI 1.21–2.59; p=0.003). There was a higher probability of any unscheduled healthcare resource use (HR 1.81; 95% CI 1.31–2.49; p, The COMET study investigated whether stopping long-term mepolizumab had an impact on health outcomes in patients with severe eosinophilic asthma; data suggest those who continue long-term mepolizumab treatment sustain clinically important improvements https://bit.ly/3A0bvwu

Background Mepolizumab and omalizumab are treatments for distinct but overlapping severe asthma phenotypes. Objective To assess if patients eligible for both biologics but not optimally controlled with omalizumab experience improved asthma control when switched directly to mepolizumab. Methods OSMO was a multicenter, open‐label, single‐arm, 32‐week trial in patients with ≥2 asthma exacerbations in the year prior to enrollment, despite receiving high‐dose inhaled corticosteroids and other controller(s), plus omalizumab (≥4 months). At baseline, patients with blood eosinophil counts ≥150 cells/µL (or ≥300 cells/µL in the prior year) and an Asthma Control Questionnaire (ACQ)‐5 score ≥1.5 discontinued omalizumab and immediately commenced mepolizumab 100 mg subcutaneously every 4 weeks. Endpoints included change from baseline in ACQ‐5 score (primary), St George's Respiratory Questionnaire (SGRQ) score and the proportions of ACQ‐5 and SGRQ responders, all at Week 32, and the annualized exacerbation rate over the study period. Results At Week 32 (intent‐to‐treat population [n = 145]), the least squares (LS) mean changes (standard error [SE]) in ACQ‐5 and SGRQ total scores were −1.45 (0.107) and −19.0 (1.64) points; with 77% and 79% of patients achieving the minimum clinically important differences (ACQ‐5: ≥0.5 points; SGRQ: ≥4 points), respectively. The annualized rate of clinically significant exacerbations was 1.18 events/year, a 64% reduction from 3.26 events/year during the previous year. Safety and immunogenicity profiles were consistent with previous trials. Conclusion After directly switching from omalizumab to mepolizumab, patients with uncontrolled severe eosinophilic asthma experienced clinically significant improvements in asthma control, health status, and exacerbation rate, with no tolerability issues reported., Minimal clinically important difference for improvement in asthma control questionnaire‐5 and St. George's Respiratory Questionnaire total scores was achieved by 77% and 79% of patients, respectively. Annualized rate of clinically significant exacerbations was reduced from 3.26 to 1.18 events/year. Safety and immunogenicity profiles of mepolizumab were consistent with previous placebo‐controlled trials in severe eosinophilic asthma.

Effective treatment of inflammatory diseases is often challenging owing to their heterogeneous pathophysiology. Understanding of the underlying disease mechanisms is improving and it is now clear that eosinophils play a complex pathophysiological role in a broad range of type 2 inflammatory diseases. Standard of care for these conditions often still includes oral corticosteroids (OCS) and/or cytotoxic immune therapies, which are associated with debilitating side effects. Selective, biological eosinophil-reducing agents provide treatment options that improve clinical symptoms associated with eosinophilic inflammation and reduce OCS use. Mepolizumab is a humanized monoclonal antibody that binds to and neutralizes interleukin-5, the major cytokine involved in eosinophil proliferation, activation, and survival. Mepolizumab is approved for the treatment of severe eosinophilic asthma, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. Additionally, the efficacy of add-on mepolizumab has been observed in patients with severe chronic rhinosinusitis with nasal polyposis and chronic obstructive pulmonary disease with an eosinophilic phenotype. Here, we review the development, approval, and real-world effectiveness of mepolizumab for the treatment of patients with severe eosinophilic asthma, from the DREAM to REALITI-A studies, and describe how knowledge from this journey extended to the use of mepolizumab and other biologics across a broad spectrum of eosinophilic diseases.

Background The long-term efficacy and safety of mepolizumab for treatment of severe eosinophilic asthma are well established. Here, we examine the clinical impact of stopping mepolizumab after long-term use. Methods COMET (NCT02555371) was a randomised, double-blind, placebo-controlled, parallel-group, multicentre study. Patients who had completed COLUMBA (NCT01691859) or COSMEX (NCT02135692) and received continuous mepolizumab treatment for ≥3 years were randomised 1:1 to stop (switch to placebo) or continue subcutaneous mepolizumab 100 mg every 4 weeks for 52 weeks. Primary end-point: time to first clinically significant exacerbation; secondary end-points: time to first exacerbation requiring hospitalisation/emergency department visit, time to decrease in asthma control (≥0.5-point increase in Asthma Control Questionnaire-5 score from COMET baseline) and blood eosinophil count ratio to COMET baseline. Safety was assessed. Results Patients stopping (n=151) versus continuing (n=144) mepolizumab had significantly shorter times to first clinically significant exacerbation (hazard ratio 1.61, 95% CI 1.17–2.22; p=0.004) and decrease in asthma control (hazard ratio 1.52, 95% CI 1.13–2.02; p=0.005), and higher blood eosinophil counts at week 52 (270 versus 40 cells·µL−1; ratio (stopping versus continuing) 6.19, 95% CI 4.89–7.83; p, This randomised study demonstrates increased exacerbation risk and a decrease in asthma control in patients with severe eosinophilic asthma who stop mepolizumab treatment after long-term use, when compared with those who continue treatment. https://bit.ly/3fsxGV2

Introduction and Objectives In the phase 2b PATHWAY study (NCT02054130), tezepelumab reduced annualized asthma exacerbation rates (AAER) by up to 71% versus placebo in adults with severe, uncontrolled asthma. We evaluated the effect of tezepelumab on exacerbations in patients from PATHWAY with low and high bronchodilator reversibility. Methods Adults with severe, uncontrolled asthma were randomized to receive tezepelumab (70 mg every 4 weeks [Q4W], 210 mg Q4W or 280 mg every 2 weeks) or placebo for 52 weeks. AAER and the rate of exacerbations resulting in hospitalization or emergency room (ER) visits were estimated for patients with low ( Results Of 550 randomized patients, 299 and 251 had low and high FEV1 reversibility, respectively. Tezepelumab 210 mg (phase 3 dose) reduced AAER over 52 weeks by 70% (95% confidence interval [CI]: 41, 85) and 72% (95% CI: 32, 88) versus placebo in patients with low and high FEV1 reversibility, respectively. For pooled tezepelumab doses, AAER was reduced by 69% (95% CI: 50, 81) and 60% (95% CI: 26, 78) in the low and high groups, respectively. Data were similar for 70 and 280 mg. Exacerbations resulting in hospitalizations or ER visits were reduced by 85% (95% CI: 21, 97) and 78% (95% CI: −32, 96) versus placebo in patients with low and high FEV1 reversibility, respectively, for tezepelumab 210 mg, and by 84% (95% CI: 51, 94) and 64% (95% CI: −18, 89) in the pooled tezepelumab group, respectively. Conclusions Tezepelumab treatment reduced AAER irrespective of baseline bronchodilator reversibility, further supporting its potential benefits in a broad population of patients with severe asthma.

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. Alarge proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.

BackgroundLittle is known about the concordance of atopy with asthma COPD overlap. Among individuals with COPD, a better understanding of the phenotypes characterized by asthma overlap and atopy is needed to better target therapies.Research questionWhat is the overlap between atopy and asthma status among individuals with COPD, and how are categories defined by the presence of atopy and asthma status associated with clinical and radiologic phenotypes and outcomes in the Genetic Epidemiology of COPD Study (COPDGene) and Subpopulation and Intermediate Outcome Measures in COPD Study (SPIROMICS)?Study design and methodsFour hundred three individuals with COPD from SPIROMICS and 696 individuals from COPDGene with data about specific IgEs to 10 common allergens and mixes (simultaneous assessment of combination of allergens in similar category) were included. Comparison groups were defined by atopic and asthma status (neither, atopy alone, atopic asthma, nonatopic asthma, with atopy defined as any positive specific IgE (≥0.35 KU/L) to any of the 10 allergens or mixes and asthma defined as self-report of doctor-diagnosed current asthma). Multivariable regression analyses (linear, logistic, and zero inflated negative binomial where appropriate) adjusted for age, sex, race, lung function, smoking status, pack-years smoked, and use of inhaled corticosteroids were used to determine characteristics of groups and relationship with outcomes (exacerbations, clinical outcomes, CT metrics) separately in COPDGene and SPIROMICS, and then adjusted results were combined using meta-analysis.ResultsThe prevalence of atopy was 35%and 36%in COPD subjects from SPIROMICS and COPDGene, respectively, and less than 50%overlap was seen between atopic status with asthma in both cohorts. In meta-analysis, individuals with nonatopic asthma had the most impaired symptom scores (effect size for St. George's Respiratory Questionnaire total score, 4.2; 95%CI, 0.4-7.9; effect size for COPD Assessment Test score, 2.8; 95%CI, 0.089-5.4), highest risk for exacerbations (incidence rate ratio, 1.41; 95%CI, 1.05-1.88) compared with the group without atopy or asthma. Those with atopy and atopic asthma were not at increased risk for adverse outcomes.InterpretationAsthma and atopy had incomplete overlap among former and current smokers with COPD in COPDGene and SPIROMICS. Nonatopic asthma was associated with adverse outcomes and exacerbation risk in COPD, whereas groups having atopy alone and atopic asthma had less risk.

The Precision Interventions for Severe and/or Exacerbation-prone Asthma (PrecISE) study is an adaptive platform trial designed to investigate novel interventions to severe asthma. The study is conducted under a master protocol and utilizes a crossover design with each participant receiving up to five interventions and at least one placebo. Treatment assignments are based on the patients’ biomarker profiles and precision health methods are incorporated into the interim and final analyses. We describe key elements of the PrecISE study including the multistage adaptive enrichment strategy, early stopping of an intervention for futility, power calculations, and the primary analysis strategy.

Background: In the phase 2b PATHWAY study (NCT02054130), tezepelumab reduced annualized asthma exacerbation rates (AAER) by up to 71% versus placebo in adults with severe, uncontrolled asthma. We evaluated the effect of tezepelumab on exacerbations in patients from PATHWAY with low and high bronchodilator reversibility. Methods: Adults with severe, uncontrolled asthma were randomized to receive tezepelumab (70mg every 4 weeks [Q4W], 210mg Q4W or 280mg every 2 weeks) or placebo for 52 weeks. AAER and the rate of exacerbations resulting in hospitalization or emergency room (ER) visits were estimated for patients with low ( Results: Of 550 randomized patients, 299 and 251 had low and high FEV1 reversibility, respectively. Tezepelumab 210mg (phase 3 dose) reduced AAER over 52 weeks by 70% (95% confidence interval [CI]: 41, 85) and 72% (95% CI: 32, 88) versus placebo in patients with low and high FEV1 reversibility, respectively. For pooled tezepelumab doses, AAER was reduced by 69% (95% CI: 50, 81) and 60% (95% CI: 26, 78) in the low and high groups, respectively. Data were similar for 70 and 280mg. Exacerbations resulting in hospitalizations or ER visits were reduced by 85% (95% CI: 21, 97) and 78% (95% CI: −32, 96) versus placebo in patients with low and high FEV1 reversibility, respectively, for tezepelumab 210mg, and by 84% (95% CI: 51, 94) and 64% (95% CI: −18, 89) in the pooled tezepelumab group, respectively. Conclusions: Tezepelumab treatment reduced AAER irrespective of baseline bronchodilator reversibility, further supporting its potential benefits in a broad population of patients with severe asthma.

Allergic asthma affects more women than men. It is mediated partially by IL-4/IL-13-driven polarization of monocyte-derived macrophages in the lung. We tested whether sex differences in asthma are due to differential IL-4 responsiveness and/or chemokine receptor expression in monocytes and monocyte-derived macrophages from healthy and allergic asthmatic men and women. We found female cells expressed M2 genes more robustly following IL-4 stimulation than male cells, as did cells from asthmatics than those from healthy controls. This likely resulted from increased expression of γC, part of the type I IL-4 receptor, and reduced IL-4–induced SOCS1, a negative regulator of IL-4 signaling, in asthmatic compared to healthy macrophages. Monocytes from asthmatic women expressed more CX3CR1, which enhances macrophage survival. Our findings highlight how sex differences in IL-4 responsiveness and chemokine receptor expression may affect monocyte recruitment and macrophage polarization in asthma, potentially leading to new sex-specific therapies to manage the disease.

BACKGROUND: Allergic inflammation is a common feature of asthma and may contribute to both development and perpetuation of disease. The interaction of antigen presenting cells (APC) with sensitized helper T lymphocytes (TC) producing Th2 cytokines may determine the inflammatory response. Recruitment of APC and TC to the lung during allergic responses has been demonstrated, but functional studies in humans have been limited. OBJECTIVE: This study examined the function of APC and TC accumulating at sites of inflammation after segmental allergen challenge (SAC). METHODS: 15 allergic patients underwent SAC, and cells from bronchoalveolar lavage (BAL) were collected after 24 hours. APC and TC from the blood and BAL were purified based on expression of the monocyte marker, CD14; the plasmacytoid dendritic cell (pDC) marker, BDCA4, identifying neuropilin 1 (NRP1); and the helper T cell marker, CD4. Functional activity was assessed using allergen-induced T cell proliferation. Flow-cytometry identified cells expressing CD14 and NRP1. RESULTS: SAC resulted in a 12-fold increase of mononuclear cells having the morphologic appearance of blood monocytes. Most of these cells co-expressed CD14 and NRP1. After saline challenge, BAL mononuclear cells demonstrated little APC function Following SAC, BAL mononuclear cells showed function equal to pDC from blood and greater than blood monocytes. Purified NRP1(+) cells from BAL had even greater function than pDC cells from blood (p = .008). Using consistent sources of APC, enhanced proliferation of TC from lung compared to blood was also demonstrated (p = .002). CONCLUSIONS: The marked increase in APC function for allergen-specific TC proliferation during allergic inflammation is largely due to the recruitment of monocytes and dendritic cells. There is also an enhanced response in the lung TC population, consistent with recruitment of allergen-specific T cells. Interactions between recruited APC and TC may occur as an early event promoting allergic airway inflammation.

Introduction Dans l’etude OSMO (Switch de l’Omalizumab au Mepolizumab), des patients non controles de maniere optimale malgre l’administration de fortes doses de corticosteroides inhales et d’un ou plusieurs traitements du fond plus l’omalizumab, ont ete passes a mepolizumab. Cette analyse post hoc a evalue les changements dans les resultats cliniques apres changement de traitement, stratifie selon les quartiles de poids ( Methodes Il s’agissait d’une analyse post-hoc de l’etude OSMO multicentrique, en ouvert, a un seul bras (204471 ; NCT02654145 ). Les patients atteints d’asthme severe a eosinophiles (ASE) non controle traites par l’omalizumab (≥ 4 mois) ont ete passes directement sous mepolizumab 100 mg sous-cutane toutes les 4 semaines pendant 32 semaines. Les criteres d’evaluation incluaient les changements par rapport a l’inclusion du score du questionnaire de controle de l’asthme (ACQ-5) (critere primaire), du score total au questionnaire respiratoire de St George (SGRQ), du volume expiratoire maximal en 1 seconde (VEMS) pre-bronchodilatateur et du taux d’exacerbation. Resultats A la semaine 32 (n = 145 [population en intention de traiter] ; âge moyen : 53,6 ans ; 59 % de femmes), quel que soit le poids ou l’IMC du patient a l’inclusion, ont ete observees des ameliorations marquees du score ACQ-5 (difference minimale cliniquement importante (DMCI) 0,5 ; −1,17 a −1,69), du SGRQ (DMCI 4 ; −11,9 a −23,1) du taux d’exacerbation (rapport de taux [traitement/periode de pretraitement] de 0,23 a 0,56). Les ameliorations moyennes du VEMS pre-bronchodilatateur ont varie parmi les quartiles de poids et d’IMC (DMCI 100 ml ; plage intervalle de −51 a 316 ml et de 66 a 270 ml respectivement), avec la plus petite modification chez ceux Conclusion Globalement, le poids et l’IMC n’ont pas impacte l’efficacite clinique en termes de controle de l’asthme, de l’etat de sante et des taux d’exacerbations suite au switch direct a mepolizumab chez les patients atteints d’ASE non controle par l’omalizumab.

Background Patients with severe asthma can present with overlapping eosinophilic and allergic phenotypes, which makes it challenging when deciding which biologic therapy is most appropriate to reduce exacerbations and help achieve asthma control. Objective This post hoc meta-analysis evaluated the efficacy of the licensed dose of mepolizumab (100 mg administered subcutaneously [SC]) versus placebo in patients with severe eosinophilic asthma (SEA), according to omalizumab eligibility and associated allergic characteristics. Methods Data from two Phase 3 studies (MENSA [MEA115588/NCT01691521]; MUSCA [200862/NCT02281318]) were analyzed. Patients ≥12 years of age with SEA who experienced ≥2 exacerbations in the previous year received placebo, mepolizumab 100 mg SC or 75 mg intravenously, plus standard of care (high-dose inhaled corticosteroids and other controllers), every 4 weeks. Data from patients who received ≥1 dose placebo or mepolizumab 100 mg SC were used for this analysis. The primary endpoint was the rate of clinically significant exacerbations; other outcomes included forced expiratory volume in 1 s (FEV1), Asthma Control Questionnaire (ACQ-5) score and quality of life measured using St George's Respiratory Questionnaire (SGRQ). Results Rate reductions in clinically significant exacerbations with mepolizumab versus placebo were similar in omalizumab eligible and ineligible patients (57% vs 55%). FEV1, ACQ-5 and SGRQ scores improved with mepolizumab versus placebo regardless of omalizumab eligibility, Immunoglobulin E levels, or atopic status. Conclusion This analysis indicated that mepolizumab 100 mg SC has clinical benefit in patients with blood eosinophil counts ≥150 cells/μL (or history of ≥300 cells/μL), regardless of allergic characteristics or omalizumab eligibility.

BackgroundThe long-term efficacy and safety of mepolizumab for treatment of severe eosinophilic asthma are well established. Here, we examine the clinical impact of stopping mepolizumab after long-term use.MethodsCOMET (NCT02555371) was a randomised, double-blind, placebo-controlled, parallel-group, multicentre study. Patients who had completed COLUMBA (NCT01691859) or COSMEX (NCT02135692) and received continuous mepolizumab treatment for ≥3 years were randomised 1:1 to stop (switch to placebo) or continue subcutaneous mepolizumab 100 mg every 4 weeks for 52 weeks. Primary end-point: time to first clinically significant exacerbation; secondary end-points: time to first exacerbation requiring hospitalisation/emergency department visit, time to decrease in asthma control (≥0.5-point increase in Asthma Control Questionnaire-5 score from COMET baseline) and blood eosinophil count ratio to COMET baseline. Safety was assessed.ResultsPatients stopping (n=151) versus continuing (n=144) mepolizumab had significantly shorter times to first clinically significant exacerbation (hazard ratio 1.61, 95% CI 1.17–2.22; p=0.004) and decrease in asthma control (hazard ratio 1.52, 95% CI 1.13–2.02; p=0.005), and higher blood eosinophil counts at week 52 (270 versus 40 cells·µL−1; ratio (stopping versus continuing) 6.19, 95% CI 4.89–7.83; pConclusionPatients who stopped mepolizumab had an increase in exacerbations and reduced asthma control versus those who continued.

Introduction L’efficacite et la tolerance du mepolizumab dans ASE etant bien etablies, COMET a examine les resultats apres la poursuite ou l’arret du mepolizumab a long terme. Methodes COMET etait une etude multicentrique, randomisee, en double aveugle, controle par placebo. Les patients eligibles avaient complete COLUMBA/COSMEX, recu un traitement continu par mepolizumab pendant au moins 3 ans. Les patients ont ete randomises 1 :1 pour continuer mepolizumab 100 mg par voie SC toutes les 4 semaines pendant 52 semaines ou pour arreter mepolizumab. Les patients pouvaient revenir au traitement par mepolizumab en ouvert a la suite d’une exacerbation. Le critere primaire etait la duree jusqu’a la premiere exacerbation cliniquement significative. Les criteres secondaires etaient : la duree jusqu’a la diminution du controle de l’asthme ; la reduction de taux d’eosinophiles sanguins. Les criteres ont ete analyses en utilisant le modele des risques proportionnels de Cox et des modeles repetes de modele mixte ajustes pour les covariables. Resultats Cent quarante-quatre patients ont recu mepolizumab et 151 placebo. Quarante-six pour cent (66/144) patients ayant continue mepolizumab versus 59 % (89/151) patients ayant arrete mepolizumab ont eu une exacerbation. Les patients ayant continue versus ceux ayant arrete mepolizumab ont eu une duree plus longue jusqu’a la premiere exacerbation (HR : 0,62 [(IC)95 % : 0,45 ; 0,86] ; p = 0,004) et une duree significativement plus longue jusqu’a la diminution du controle de l’asthme (HR : 0,66 [0,49 ; 0,88] ; p =0,005), sans difference entre les traitements pour la duree jusqu’a la premiere exacerbation necessitant une venue aux urgences ou une consultation (HR : 1,33 [0,50 ; 3,51]). Les patients continuant mepolizumab ont maintenu leur taux d’eosinophiles entre 40 et 60 cellules/μL, les taux d’eosinophiles ont augmente jusqu’a 270 cellules/μL a la semaine 12 pour les patients ayant arrete mepolizumab (ratio : 0,19 [0,15 ; 0,24] ; p Conclusion Les patients ayant arrete mepolizumab ont presente une augmentation du taux d’eosinophiles sanguins, une augmentation des exacerbations, une duree plus courte jusqu’a la premiere exacerbation, et une reduction du controle de l’asthme compare a ceux ayant continue mepolizumab. Ces resultats montrent que le traitement continu par mepolizumab a des benefices cliniques durables chez la plupart des patients avec ASE.

Introduction Le mepolizumab reduit le taux d’exacerbations cliniquement pertinentes chez les patients atteints d’asthme severe eosinophilique (ASE). L’effet du mepolizumab dans un sous-groupe des patients atopiques presente un interet clinique. Les donnees presentees proviennent d’une meta-analyse post-hoc des etudes MENSA et MUSCA, chez les groupes du traitement stratifies par le taux d’immunoglobuline E (IgE), le statut atopique et le score du test radioallergosorbent (RAST). Methodes Les etudes MENSA (MEA115588/ NCT01691521 ) et MUSCA (200862/ NCT02281318 ) sont des etudes de phase 3 multicentriques, controlees vs placebo, randomisees, en double-aveugle, en groupes paralleles. Les patients ASE avec des antecedents ≥ 2 exacerbations dans l’annee precedente, malgre l’utilisation reguliere de fortes doses de CSI et d’un autre traitement de fond, ont recu le mepolizumab 100 mg en SC ou le placebo, toutes les 4 semaines pendant 32 (MENSA) ou 24 semaines (MUSCA). Les patients ayant recu ≥ 1 dose et qui avaient a l’inclusion des IgE mesurees ont ete inclus. Les criteres d’evaluation incluaient le taux annuel d’exacerbations cliniquement pertinentes. Les resultats ont ete stratifies par les quartiles de niveau total d’IgE (≤ 60, 60–170, > 170–450, > 450 UI/mL), le statut atopique (positif/negatif base sur ≥ 1 score du test RAST ≥ 3), et le nombre d’allergenes (acariens, squames de chien, de chat, alternaria, cafard) avec un score RAST ≥ 3 (0, 1 ou ≥ 2) a l’inclusion. Les criteres d’evaluation ont ete analyses par une meta-analyse a effets fixes ponderes par la variance inverse. Resultats Neuf cent neuf patients ont ete inclus dans la meta-analyse (moyenne d’âge : 50,6 ans ; 59 % femmes). Les taux d’exacerbations cliniquement pertinentes ont ete reduits de 49–62 % avec le mepolizumab par rapport au placebo dans tous les quartiles des taux d’IgE (≤ 60 IU/mL : ratio de taux [RR] 0,51 [95 % CI : 0,34 ;0,76] n = 230 ; 60–170 UI/mL : 0,38 [95 % CI : 0,24 ;0,59] n = 218 ; > 170–450 UI/mL : 0,40 [95 % CI : 0,26 ;0,62] n = 233 ; > 450 UI/mL : 0,43 [95 % CI :0,27 ;0,68] n = 228). Les taux de reductions d’exacerbations pour le mepolizumab par rapport au placebo ont ete similaires chez les patients avec un statut atopique positif ou negatif (56 % et 57 %, respectivement) et sur l’ensemble des scores RAST ≥ 3 (57–67 %). Conclusion Mepolizumab reduit les exacerbations chez les patients avec differents niveaux d’IgE, de statut atopique et des scores RAST, suggerant que mepolizumab apporte des benefices cliniques constants chez les patients ASE avec ou sans maladie atopique.

Background The D-prostanoid receptor and the chemoattractant receptor homologous molecule expressed on T H 2 cells (CRTH2) are implicated in asthma pathogenesis. AMG 853 is a potent, selective, orally bioavailable, small-molecule dual antagonist of human D-prostanoid and CRTH2. Objective We sought to determine the efficacy and safety of AMG 853 compared with placebo in patients with inadequately controlled asthma. Methods Adults with moderate-to-severe asthma were randomized to placebo; 5, 25, or 100 mg of oral AMG 853 twice daily; or 200 mg of AMG 853 once daily for 12 weeks. All patients continued their inhaled corticosteroids. Long-acting β-agonists were not allowed during the treatment period. Allowed concomitant medications included short-acting β-agonists and a systemic corticosteroid burst for asthma exacerbation. The primary end point was change in total Asthma Control Questionnaire score from baseline to week 12. Secondary and exploratory end points included FEV 1 , symptom scores, rescue short-acting β-agonist use, and exacerbations. Results Among treated patients, no effect over placebo (n = 79) was observed in mean changes in Asthma Control Questionnaire scores at 12 weeks (placebo, −0.492; range for AMG 853 groups [n = 317], −0.444 to −0.555). No significant differences between the active and placebo groups were observed for secondary end points. The most commonly reported adverse events were asthma, upper respiratory tract infection, and headache; 9 patients experienced serious adverse events, all of which were deemed unrelated to study treatment by the investigator. Conclusion AMG 853 as an add-on to inhaled corticosteroid therapy demonstrated no associated risks but was not effective at improving asthma symptoms or lung function in patients with inadequately controlled moderate-to-severe asthma.

Introduction Mepolizumab reduit les taux d’exacerbations dans les etudes cliniques chez des patients avec un asthme severe eosinophilique (ASE). La comprehension de l’efficacite du mepolizumab chez les patients eligibles ou precedemment traites par omalizumab constitue un interet clinique. Methodes Cette meta-analyse post-hoc provient de deux etudes phase 3, versus placebo, randomisees, en double insu, en groupe parallele, et multicentriques (MENSA [MEA115588/ NCT01691521 ] ; MUSCA [200862/ NCT02281318 ]). Les patients ASE avec ≥ 2 exacerbations dans l’annee precedant l’inclusion ont recu 100 mg de mepolizumab en SC ou placebo, avec un traitement de fond, toutes les 4 semaines pendant 32 (MENSA) ou 24 (MUSCA) semaines. Les patients recevant ≥ 1 dose ont ete inclus dans la meta-analyse. Les criteres d’evaluation incluaient le taux annuel d’exacerbations cliniquement pertinentes (principal) et les exacerbations necessitant une hospitalisation ou une visite aux urgences (secondaire). Les analyses ont ete effectuees chez les patients eligibles/non eligibles a l’omalizumab a l’inclusion (selon les criteres de prescription UE/Japon) et avec/sans omalizumab prealable. Les differences de traitement ont ete combinees a travers les etudes en utilisant une meta-analyses a effets fixes ponderes par la variance inverse. Resultats Parmi 936 patients inclus, 468 (50 %) ont recu mepolizumab et 468 (50 %) le placebo. Les caracteristiques d’inclusion etaient similaires entre les groupes de traitement (moyenne d’âge : 50,4/50,9 ans ; 57 %/60 % de femmes ; moyenne geometrique des eosinophiles sanguins 320/340 cellules/μL). Dans l’ensemble, 324 (35 %) patients etaient eligibles a l’omalizumab et 132 (14 %) avaient recu au prealable omalizumab. Compare au placebo, mepolizumab a genere des reductions similaires du taux annuel d’exacerbations chez les patients eligibles/non eligibles a l’omalizumab ([RR] [IC 95 %] : 0,45 [0,31 ; 0,65]/0,46 [0,35 ; 0,59], respectivement) et chez ceux avec/sans omalizumab au prealable (RR [IC 95 %] : 0,41 [0,27 ; 0,63]/0,46 [0,36 ; 0,59]) ; des reductions similaires du taux annuel d’exacerbations necessitant une hospitalisation/visite aux urgences ont ete observees chez les patients eligibles/non eligibles a l’omalizumab (RR [IC 95 %] : 0,54 [0,21 ; 1,36]/0,30 [0,13 ; 0,67]) et avec/sans omalizumab au prealable (RR [IC 95 %] : 0,37 [0,10 ; 1,40]/0,34 [0,17 ; 0,69]). Conclusion Chez les patients ASE, mepolizumab reduit le taux annuel d’exacerbations independamment de l’eligibilite ou du traitement prealable par omalizumab.

The purpose of this review is to discuss recent findings made during studies of the upper airways and sinuses of people with chronic rhinosinusitis (CRS) in the context of the literature. CRS is a chronic inflammatory disorder affecting nearly 30 million Americans and is generally resistant to therapy with antibiotics and glucocorticoids (Meltzer EO and coworkers, J Allergy Clin Immunol 2004;114:155–212). We have formed a collaboration that consists of otolaryngologists, allergists, and basic scientists to address the underlying immunologic and inflammatory processes that are occurring in, and possibly responsible for, this disease. The main emphasis of our work has been to focus on the roles that epithelium, in the sinuses and upper airways, plays as both a mediator and regulator of immune and inflammatory responses. It is not our intention here to provide a comprehensive review of the literature in this area, but we will try to put our work in the context of the findings of others (Kato A and Schleimer RP, Curr Opin Immunol 2007;19:711–720; Schleimer RP and coworkers, J Allergy Clin Immunol 2007;120:1279–1284). In particular, we discuss the evidence that epithelial cell responses are altered in CRS, including those relevant to regulation of dendritic cells, T cells, B cells, and barrier function.

Purpose Albuterol reduces lower esophageal sphincter (LES) pressure in normal volunteers, although the effects of albuterol on esophageal function in asthmatic patients are not known. The aim of this study was to evaluate the effects of nebulized albuterol on lower esophageal function in asthmatic patients. Symptoms and a methacholine challenge test were used to identify asthmatic patients who were then enrolled in a prospective, randomized, placebo-controlled, double-blinded, crossover trial. Changes in esophageal function in response to nebulized albuterol or placebo were evaluated over two sessions spaced 1 week apart. Results Albuterol induced a dose-dependent drop in lower esophageal sphincter basal pressure with a threshold dose as low as 2.5 mg. Albuterol did not affect the amplitude of esophageal contractions. Conclusions Nebulized albuterol induces a dose-dependent reduction in LES basal pressure in asthmatic patients. These effects raise the possibility that gastroesophageal reflux may occur after bronchodilator therapy.

Summary Background Lysophosphatidic acid (LPA) is a biologically active lysophospholipid and a component of normal plasma. LPA binds to receptors expressed on circulating and structural lung cells and affects cell growth and activation. Whether LPA is present in the lung has not been previously reported. Objective To develop an assay to measure LPA in bronchoalveolar lavage (BAL) fluids, and to study the association between LPA and allergic airway inflammation. Methods Seventeen allergic subjects underwent bronchoscopy and segmental allergen challenge, followed 18 h later by BAL. Supernatants were analysed for LPA content using liquid chromatography and mass spectroscopy. Expression of LPA receptors on primary bronchial epithelial cells was analysed by immunolabelling, and the effects of LPA on epithelial cell barrier function was investigated by measuring transepithelial resistance. Results LPA was detectable in BAL from control lung segments, and significantly increased 18 h after allergen challenge. Polyunsaturated species of LPA were especially increased following segmental allergen challenge. LPA levels did not strongly correlate with the number or percentages of eosinophils, neutrophils of lymphocytes, whereas MIP-3α (CCL20) levels correlated significantly with the allergen-driven influx of lymphocytes. The levels of LPA from control sites correlated inversely with BAL protein content, suggesting that LPA promoted epithelial barrier integrity at baseline. Experiments using primary human bronchial epithelial cells confirmed that LPA tightened the epithelial cell barrier. Conclusion Lysophosphatidic acid is detectable in human BAL fluids at baseline and its expression increases during allergic inflammation. LPA does not appear to be a dominant chemoattractant for eosinophils or lymphocytes during allergic airway inflammation. In the absence of ongoing inflammation, LPA may promote epithelial barrier integrity.

Background Human rhinovirus (HRV) infections are associated with exacerbations of asthma, chronic obstructive pulmonary disease, and sinusitis. Nitric oxide (NO) might play an important role in host defense through its potent antiviral properties. Previous studies have shown that HRV infection in human subjects increased nasal epithelial expression of type 2 nitric oxide synthase (NOS2), an isoform of the enzyme that produces NO. Objective We sought to investigate whether increases in exhaled NO (eNO) would accompany the increased NOS2 expression and would be associated with clearance of the virus. Methods Six human subjects were infected with HRV-16 intranasally. eNO from nasal and lower airways was measured by means of direct measurement at multiple controlled flow rates. eNO was monitored at baseline (day 1) and on days 2 to 5, 8, 14, and 42 after infection. Nasal lavages were performed on days 1 to 5 and 8, and nasal scrapings were performed on days 1 to 4. NOS2 mRNA expression in nasal cells was measured by using quantitative real-time RT-PCR. Viral shedding in nasal lavage fluid was monitored by using real-time RT-PCR and bioassay. Results Peak HRV titers and symptom scores were correlated on day 3, and HRV persisted until day 5 (n=4) or day 8 (n=2). Infection was associated with transient but significant increases in lymphocytes and monocytes in nasal lavage fluid. Significant increases in both nasal and lower airway eNO concentrations accompanied HRV infection and were positively correlated. Increased nasal eNO concentrations on day 3 were associated with increased expression of NOS2 mRNA in nasal scrapings. Symptom scores on day 4 were inversely correlated with the increases in nasal eNO concentration. Conclusions We conclude that increased production of NO occurs as part of the host response to HRV infection and speculate that NO plays a beneficial role in viral clearance.

Background Segmental antigen bronchoprovocation has long been used as a model to study allergic pulmonary inflammatory responses. Among the characteristics of the resulting cellular infiltrate is the preferential recruitment of T H 2 lymphocytes. The mechanisms responsible for their selective recruitment remain unknown, but T H 2 cells preferentially express the chemokine receptors CCR4 and CCR8. Objectives We tested the hypothesis that the chemokines thymus- and activation-regulated chemokine (TARC) (CCL17) and macrophage-derived chemokine (MDC) (CCL22), whose receptor is CCR4, and I-309 (CCL1), whose receptor is CCR8, would be released at sites of segmental allergen challenge. Methods Segmental allergen challenge with saline or allergen was performed in 10 adult allergic subjects with asthma, who were off medications. Bronchoalveolar lavage (BAL) was performed at both the saline- and allergen-challenged sites 20 hours after challenge. BAL fluids were analyzed for total cell counts and differentials, and supernatants were assayed by ELISA for levels of TARC, MDC, and I-309. As a control, the BAL fluids were also analyzed for levels of interferon-inducible protein 10 (IP-10) (CXCL10), an IFN-γ—induced chemokine active on CXCR3, a chemokine receptor that is preferentially expressed on T H 1 lymphocytes. Results Allergen challenge led to an approximately 6-fold increase in total leukocytes, including lymphocytes, compared with those seen at saline-challenged sites. At antigen-challenged sites, eosinophils predominated. Chemokine levels at control, saline-challenged sites were either below the detectable limit or low, with the predominant chemokine detected being IP-10. At antigen-challenged sites, levels of MDC, TARC, and IP-10 were all significantly increased compared with saline sites, each with a median of 486 to 1130 pg/mL detected. On the basis of a comparison with serum values, BAL chemokine levels at most antigen-challenged sites could not be accounted for by transudation from plasma. In contrast, levels of I-309 were extremely low or undetectable in all BAL and serum samples tested. Finally, BAL levels of MDC significantly correlated with those for TARC, but no significant correlations were found between levels of chemokine and any cell type. Conclusions These data suggest that among the chemokines measured in this study, IP-10 is the predominant chemokine detected 20 hours after saline challenge, likely representing baseline production of a chemokine that favors T H 1 cell recruitment. At antigen-challenged sites, levels of both CCR4 and CXCR3 active chemokines, but not CCR8 active chemokines, are markedly increased and are produced at levels that are likely to have biologic significance. Given the preferential accumulation of T H 2 cells at these antigen-challenged sites, the increased production of CCR4-active chemokines might contribute to this response.

Background We have previously shown that oncostatin M (OSM) levels are increased in nasal polyps (NPs) of patients with chronic rhinosinusitis (CRS), as well as in bronchoalveolar lavage fluid, after segmental allergen challenge in allergic asthmatic patients. We also showed in vitro that physiologic levels of OSM impair barrier function in differentiated airway epithelium. Objective We sought to determine which hematopoietic or resident cell type or types were the source of the OSM expressed in patients with mucosal airways disease. Methods Paraffin-embedded NP sections were stained with fluorescence-labeled specific antibodies against OSM, GM-CSF, and hematopoietic cell-specific markers. Live cells were isolated from NPs and matched blood samples for flow cytometric analysis. Neutrophils were isolated from whole blood and cultured with the known OSM inducers GM-CSF and follistatin-like 1, and OSM levels were measured in the supernatants. Bronchial biopsy sections from control subjects, patients with moderate asthma, and patients with severe asthma were stained for OSM and neutrophil elastase. Results OSM staining was observed in NPs, showed colocalization with neutrophil elastase (n = 10), and did not colocalize with markers for eosinophils, macrophages, T cells, or B cells (n = 3-5). Flow cytometric analysis of NPs (n = 9) showed that 5.1% ± 2% of CD45 + cells were OSM + , and of the OSM + cells, 56% ± 7% were CD16 + Siglec-8 − , indicating neutrophil lineage. Only 0.6 ± 0.4% of CD45 + events from matched blood samples (n = 5) were OSM + , suggesting that increased OSM levels in patients with CRS was locally stimulated and produced. A majority of OSM + neutrophils expressed arginase 1 (72.5% ± 12%), suggesting an N2 phenotype. GM-CSF levels were increased in NPs compared with those in control tissue and were sufficient to induce OSM production ( P in vitro . OSM + neutrophils were also observed at increased levels in biopsy specimens from patients with severe asthma. Additionally, OSM protein levels were increased in induced sputum from asthmatic patients compared with that from control subjects ( P Conclusions Neutrophils are a major source of OSM-producing cells in patients with CRS and severe asthma.

Epithelial barrier dysfunction is thought to play a role in many mucosal diseases, including asthma, chronic rhinosinusitis (CRS), and eosinophilic esophagitis.The objective of this study was to investigate the role of oncostatin M (OSM) in epithelial barrier dysfunction in human mucosal disease.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.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).These results suggest that OSM might play a role in epithelial barrier dysfunction in patients with CRS and other mucosal diseases.

Study objectives Albuterol, aβ 2-adrenergic agonist that is commonly used to treat asthma, reduces bronchial smooth muscle tone. The pharmacodynamics of inhaled albuterol on esophageal function were studied in healthy volunteers. Design A prospective, randomized, placebo-controlled, double-blind crossover design. Setting An academic medical center. Patients Nine healthy volunteers (five men, four women; age, 22 to 30 years). Interventions Albuterol (2.5 to 10 mg) or placebo was given via nebulizer. Volunteers were studied at two sessions, 1 week apart, using a 6-cm manometry assembly and a low-compliance pneumohydraulic pump. The percentage of lower esophageal sphincter (LES) relaxation, the frequency of transient LES relaxations (TLESRs), and the amplitude, duration, and propagation velocity of esophageal contractions were measured at 5 and 10 cm above the LES. Dependent measures were evaluated using two-way, repeated-measures analysis of variance. Measurements and results Albuterol therapy reduced LES basal tone in a dose-dependent manner (baseline, 17.0 ± 2.6 mm Hg; at 10 mg, 8.9 ± 2.1 mm Hg; p=0.01). The frequency of TLESRs was not different from placebo (not significant). Albuterol reduced the amplitude of esophageal contractions at 5 cm above the LES (baseline, 72.5 ± 18.6 mm Hg; at 10 mg, 48.8 ± 10.0 mm Hg; p Conclusions Inhaled albuterol reduced LES basal tone and contractile amplitudes in the smooth muscle esophageal body in a dose-dependent manner. Inhaled β2-agonists may increase the likelihood of acid reflux in a subset of patients who receive cumulative dosing.

Background: Human blood basophils secrete high levels of IL-4 following activation with specific allergen, yet their role as cytokine-producing cells in allergic lesions has not been described. Objective: Our objective was to investigate whether and under what conditions basophils infiltrating allergic lesions in the lung secrete IL-4 in vitro. Methods: Bronchoalveolar lavage (BAL) cells were recovered 20 hours after segmental allergen challenge. Basophils were enriched with Percoll using a protocol commonly used for blood basophils. IL-4 and histamine were measured in culture supernatants following activation with a variety of stimuli. Two-color flow cytometry was performed to detect intracellular IL-4. Results: IL-4 protein was detected in all basophil culture supernatants following a 4- to 5-hour incubation in medium alone; the levels obtained did not significantly increase with the addition of anti-IgE. BAL basophils failed to release histamine in response to specific allergen but showed nearly 60% histamine release with N-formyl-methionyl-leucyl-phenylalanine, suggesting that they were desensitized to IgE-mediated stimuli as a result of their activation in vivo. Using these same conditions, IL-4 was not detected in BAL cell fractions enriched for lymphocytes and eosinophils. Ionomycin induced IL-4 secretion by BAL basophils, and this response was reduced with the addition of phorbol myristate acetate. In contrast, phorbol myristate acetate promoted the secretion of IL-4 by BAL cells enriched for lymphocytes; both findings are identical to those reported for basophils and lymphocytes purified from blood. Flow cytometry confirmed the secretion of IL-4 by BAL basophils. Conclusions: These data suggest that basophils migrating to the lung following allergen challenge represent a major source of IL-4. (J Allergy Clin Immunol 2001;107:265-71.)

Chemokine-induced eosinophil chemotaxis is mediated primarily through the C-C chemokine receptor, CCR3. We have now detected CCR3 immunoreactivity on epithelial cells in biopsies of patients with asthma and other respiratory diseases. CCR3 mRNA was detected by Northern blot analysis after TNF-α stimulation of the human primary bronchial epithelial cells as well as the epithelial cell line, BEAS-2B; IFN-γ potentiated the TNF-α-induced expression. Western blots and flow cytometry confirmed the expression of CCR3 protein. This receptor is functional based on studies demonstrating eotaxin-induced intracellular Ca2+ flux and tyrosine phosphorylation of cellular proteins. The specificity of this functional response was confirmed by blocking these signaling events with anti-CCR3 mAb (7B11) or pertussis toxin. Furthermore, 125I-eotaxin binding assay confirmed that CCR3 expressed on epithelial cells have the expected ligand specificity. These studies indicate that airway epithelial cells express CCR3 and suggest that CCR3 ligands may influence epithelial cell functions.