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Purpose: Asthma is a clinical syndrome with various underlying pathomechanisms and clinical phenotypes. Genetic, ethnic, and geographic factors may influence the differences in clinical presentation, severity, and prognosis. We compared the characteristics of asthma based on the geographical background by analyzing representative cohorts from the United States, Europe, South America, and Asia using the Severe Asthma Research Program (SARP), Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED), Program for Control of Asthma in Bahia (ProAR), and Cohort for Reality and Evolution of Adult Asthma in Korea (COREA), respectively., Methods: The clinical characteristics and medications for the SARP (n = 669), U-BIOPRED (n = 509), ProAR (n = 996), and COREA (n = 3,748) were analyzed. Subgroup analysis was performed for severe asthma., Results: The mean age was highest and lowest in the COREA and SARP, respectively. The asthma onset age was lowest in the ProAR. The mean body mass index was highest and lowest in the SARP and COREA, respectively. Baseline pulmonary function was lowest and highest in the U-BIOPRED and COREA, respectively. The number of patients with acute exacerbation in the previous year was highest in U-BIOPRED. The mean blood eosinophil count was highest in COREA. The total immunoglobulin E was highest in the ProAR. The frequency of atopy was highest in the SARP. The principal component analysis plot revealed differences among all cohorts., Conclusions: The cohorts from 4 different continents exhibited different clinical and physiological characteristics, probably resulting from the interplay between genetic susceptibility and geographical factors., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2024 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Competing Interests: Declaration of competing interest ZD: received consultancy fees/lecture fees/fees for attending advisory boards from ALK, Antabio, Foresee Pharmaceuticals, GlaxoSmithKline, Hippo-Dx, QPS-Netherlands, Sanofi-Genzyme; she served as Director Respiratory & Allergy at QPS-NL and this CRO received research grants for clinical trials from HAL Allergy, Janssen Research & Development LLC, Patara pharma, Cerbios, Merck Sharp & Dohme, Novartis, Foresee Pharmaceuticals and ERA4TB (IMI-project). MJ: ALK, Stallergenes-Greer, Chiesi, GSK, Pfizer, Novartis, AstraZeneca and SANOFI. NH: Received honoraria for serving as advisor or consultant for GSK, AstraZeneca, Sanofi, Regeneron, Amgen, Genentech, Novartis and Teva. His institution received research grant support of his behalf from GSK, Genentech, Sanofi, Teva, Novartis, and AstraZeneca. LH: Has received grant funding, participated in advisory boards and given lectures at meetings supported by Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Hoffmann la Roche, GlaxoSmithKline, Novartis, Theravance, Evelo Biosciences, Sanofi, and Teva; he has received grants from MedImmune, Novartis UK, Roche/ Genentech Inc, and Glaxo Smith Kline, Amgen, Genentech/Hoffman la Roche, Astra Zeneca, MedImmune, Glaxo Smith Kline, Aerocrine and Vitalograph; he has received sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK and Napp Pharmaceuticals; he has also taken part in asthma clinical trials sponsored by AstraZeneca, Boehringer Ingelheim, Hoffmann la Roche, and GlaxoSmithKline for which his institution received remuneration; he is the Academic Lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma which involves industrial partnerships with a number of pharmaceutical companies including Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann la Roche, and Janssen. RD: Declares consulting fees from Synairgen, Sanofi and Galapagos, lecture fees from GSK, AZ and Airways Vista and he holds shares from Synairgen. DR: No COIs related to this work. SQ: ALK, Allergy Therapeutics, AstraZeneca, Chiesi, GSK, Leti, Mundipharma, Novartis, Sanofi-Genzyme, Teva. VB: Has worked as advisor, supervisor, investigator of pharmaceutical studies, unrestricted grants, and others with: AstraZeneca, GSK, MSD & Shering Plough, ALK-Abello; Chiesi,Novartis, Pharmaxis, Pfizer, Boehringer Ingelheim, Aerocrine, Teva, Sanofi, Birk NPC as. MG: No COIs related to this work. IP: In the last 5 years IDP has received speaker’s honoraria for speaking at sponsored meetings from Astra Zeneca, Boehringer Ingelheim, Aerocrine, Almirall, Novartis, Teva, Chiesi, Sanofi/Regeneron, Menarini and GSK and payments for organising educational events from AZ, GSK, Sanofi/Regeneron and Teva. He has received honoraria for attending advisory panels with Genentech, Sanofi/ Regeneron, Astra Zeneca, Boehringer Ingelheim, GSK, Novartis, Teva, Merck, Circassia, Chiesi and Knopp and payments to support FDA approval meetings from GSK. He has received sponsorship to attend international scientific meetings from Boehringer Ingelheim, GSK, AstraZeneca, Teva and Chiesi. He has received a grant from Chiesi to support a phase 2 clinical trial in Oxford. DAA: Has received honoraria as grants/contracts from Sociedad Española de Alergología e Inmunología Clínica (SEAIC), as consulting fees from ALK-Abelló, AstraZeneca, Chiesi and Gebro, as speaker from AstraZeneca, Chiesi, Gebro, GSK, Leti Pharma, Mundipharma, Novartis, Roxall, Sanofi. AS: GSK support for an asthma biologic clinical trial 2021-ongoing. PB: Has received honoraria for presentations and consultancy fees from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN, GSK, Menarini, Novartis, Sanofi, and Gilead. AB: Takeda, Novartis, Viatris, ALK, Zentiva, MERCK, Stallergenes Greer, Ewopharma, Astra Zeneca, Chiesi, S&D Pharma, Mundipharma, Berlin Chemie. WB: GlaxoSmithKline, Sanofi, Regeneron. JK: Grants and/or personal fees from ALK, Chiesi, GSK, Novartis, AstraZeneca, Sanofi, Boerhinger, Teva, Viatris, Stallergen, Abbot, all outside the submitted work. SL: Honorarium AstraZeneka, GSK, Chiesi Hellas, Sanofi, Elpen, Menarini, Guidoti. MVM: No COIs related to this work. PP: ALK, AstraZeneca, Stallergenes. HP: No COIs related to this work. AS: Reports lecture fees and/or consultancies from AstraZeneca, Chiesi, B.I., GSK, Merck, Novartis, Zambon, Sanofi. HS: No COIs related to this work. IS: No COIs related to this work. BT: No COIs related to this work. MKV: GlaxoSmithKline, AstraZeneca. Diego Conti: No COIs related to this work. WF: The department of Otorhinolaryngology of the Amsterdam University Medical centre, location AMC received grants for research in Rhinology from: ALK, AllergyTherapeutics, Novartis, EU, GSK, MYLAN, Sanofi-Aventis, and Zon-MW; personal COIs: for consultation and/or speaker fees from Dianosic, GSK, Novartis and Sanofi-Aventis/Regeneron. SL: Advisory Board Sanof-Aventis, GSK and Leo-Pharma. Honoraria by DBV Technologies, Allergopharma, Leti, Nutricia, Sanofi-Aventis. GKS: Honoraria for articles, speaker and advisory boards: ALK, AstraZeneca, Capnia, Church & Dwight, Circassia, Noucor, GSK, Meda/Mylan/Viatris, Merck, Sanofi- Regeneron, Stallergenes. Scientific Chief Editor, Rhinology Section, Frontiers in Allergy. Board Member, Lead for Allergic Rhinitis, EUFOREA. Chair of Data Monitoring Board for Paediatric AR trials of HDM SLIT. EVS: No COIs related to this work. PH: Recipient of research grants, honoraria and/or lecture fees of Sanofi, Regeneron, Viatris, GSK, and Novartis. LB: No COIs related to this work.

Background: Many patients with asthma experience loss of lung function over time, and in certain patients this can lead to progressive obstructive patterns similar to COPD. Patients with severe asthma may experience accelerated lung function decline (LFD). However, characteristics and risk factors for LFD in asthma have not been well described. Dupilumab may prevent or slow the rate of LFD in patients with uncontrolled, moderate-to-severe asthma. ATLAS trial is designed to evaluate the role of dupilumab in preventing/slowing LFD over a period of 3 years versus standard-of-care therapy., Methods: ATLAS (clinicaltrials.gov identifier NCT05097287) is a randomised, double-blind, placebo-controlled, multicentre study that will include adult patients with uncontrolled moderate-to-severe asthma. ∼1828 patients will be randomised (2:1) to dupilumab 300 mg or placebo in combination with maintenance therapy every 2 weeks for 3 years. The primary objective is to assess the effect of dupilumab on preventing or slowing LFD by year 1 in the exhaled nitric oxide fraction ( F eNO ) population (patients with F eNO ≥35 ppb). The effect of dupilumab in slowing the rate of LFD by year 2 and year 3 in both F eNO and total populations, exacerbations, asthma control, quality of life, biomarker changes and utility of F eNO as a biomarker of LFD will also be evaluated., Discussion: ATLAS is the first trial assessing the effect of a biologic on LFD, designed to establish the role of dupilumab in prevention of long-term loss of lung function and its potential effect on disease modification, which may provide unique insights into asthma pathophysiology, including predictive and prognostic factors of LFD., Competing Interests: Conflict of interest: L. De Prado Gomez, M. Zhang, J. Xing, J.A. Jacob-Nara and P.J. Rowe are employees of Sanofi, and may hold stock and/or stock options in the company. I. Pavord has received speaker fees from Aerocrine, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Sanofi/Regeneron and Teva; payments for organising educational events from AstraZeneca, GSK, Sanofi/Regeneron and Teva; consultancy fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Genentech, GSK, Knopp Biosciences, Merck, Novartis, Sanofi/Regeneron and Teva; international scientific meeting sponsorship from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK and Teva; a research grant from Chiesi; and payments to support Food and Drug Administration approval meetings from GSK; payments for use of the Leicester Cough Questionnaire (of which he is a co-patent holder of the rights) in clinical trials from Bayer, Insmed and Merck. He served as an expert witness for a patent dispute involving AstraZeneca and Teva. W. Busse has received consultancy and speaker fees from GlaxoSmithKline, Novartis, Sanofi and Teva. C.E. Brightling has received grants and consultancy fees from GSK, AstraZeneca, Novartis, Chiesi, BI, Genentech, Roche, Sanofi, Regeneron, Mologic and 4DPharma, paid to his institution. M.E. Wechsler has received consulting fees and honoraria from AstraZeneca, Amgen, GlaxoSmithKline, Sanofi, Regeneron, Boehringer Ingelheim, Novartis, Genentech, Pulmatrix, Teva, Equillium, Cytoreason, Restorbio, Cohero Health, Cerecor, Incyte, Sound Biologics and Kinaset. K.F. Rabe has received consultancy and speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, Sanofi and Teva., (Copyright ©The authors 2023.)

Asthma and brain interactions have long been appreciated and initially centered on increased anxiety and depression. Epidemiology studies have shown that early life stressors and situational disadvantages are risk factors for asthma. Conversely, the presence of asthma is a risk for mood and anxiety disorders, thus indicating a bidirectional effect between asthma and brain-related health. To substantiate asthma-brain interactions, validated instruments indicate and elucidate that communication likely exists between asthma and the brain. For example, provocation of an asthmatic response with an allergen challenge modulates how the brain responds to emotion-laden information. As detected by imaging studies, emotion-related brain activation is associated with generating airway inflammation. However, the specific mediators and processes mediating airway communication with the brain have yet to be established.Systemic inflammation is also associated with asthma and can affect other organ systems such as the cardiovascular system and the brain. Epidemiology studies have shown that asthma is a risk factor for dementia and Alzheimer's disease. In support of the importance of asthma as a risk factor for impaired cognitive function, imaging studies have shown changes to the white matter of the brain in asthma patients that resemble neuroinflammation changes seen in Alzheimer's disease and other neurodegenerative diseases. Therefore, bidirectional links between asthma and the brain exist with an important next research step to define asthma-brain interactions linked to neurodegeneration and dementia and explore whether treatments directed toward asthma-related inflammation can prevent the deleterious effects of asthma on brain health., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background: Although asthma does not appear to be a risk factor for severe coronavirus disease 2019 (COVID-19), outcomes could vary for patients with different asthma subtypes. The objective of this analysis was to compare COVID-19 outcomes in real-world cohorts in the United States among patients with asthma, with or without evidence of allergy., Methods: In a retrospective analysis of the COVID-19 Optum electronic health record dataset (February 20, 2020-January 28, 2021), patients diagnosed with COVID-19 with a history of moderate-to-severe asthma were divided into 2 cohorts: those with evidence of allergic asthma and those without (nonallergic asthma). After 1:1 propensity score matching, in which covariates were balanced and potential bias was removed, COVID-19 outcomes were compared between cohorts., Results: From a COVID-19 population of 591,198 patients, 1595 patients with allergic asthma and 8204 patients with nonallergic asthma were identified. After propensity score matching (n = 1578 per cohort), risk of death from any cause after COVID-19 diagnosis was significantly lower for patients with allergic vs nonallergic asthma (hazard ratio, 0.48; 95% CI 0.28-0.83; P = 0.0087), and a smaller proportion of patients with allergic vs nonallergic asthma was hospitalized within - 7 to + 30 days of COVID-19 diagnosis (13.8% [n = 217] vs 18.3% [n = 289]; P = 0.0005). Among hospitalized patients, there were no significant differences between patients with allergic or nonallergic asthma in need for intensive care unit admission, respiratory support, or COVID-19 treatment., Conclusions: Asthma subtype may influence outcomes after COVID-19; patients with allergic asthma are at lower risk for hospitalization/death than those with nonallergic asthma., (© 2022. The Author(s).)

Background: Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry., Methods: We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American-specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults., Results: Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma., Conclusions: Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases., (© 2022. The Author(s).)

Rationale: Androgens are potentially beneficial in asthma, but AR (androgen receptor) has not been studied in human airways. Objectives: To measure whether AR and its ligands are associated with human asthma outcomes. Methods: We compared the effects of AR expression on lung function, symptom scores, and fractional exhaled nitric oxide (Fe NO ) in adults enrolled in SARP (Severe Asthma Research Program). The impact of sex and of androgens on asthma outcomes was also evaluated in the SARP with validation studies in the Cleveland Clinic Health System and the NHANES (U.S. National Health and Nutrition Examination Survey). Measurements and Main Results: In SARP ( n  = 128), AR gene expression from bronchoscopic epithelial brushings was positively associated with both FEV 1 /FVC ratio ( R 2  = 0.135, P  = 0.0002) and the total Asthma Quality of Life Questionnaire score ( R 2  = 0.056, P  = 0.016) and was negatively associated with Fe NO ( R 2  = 0.178, P  = 9.8 × 10 -6 ) and NOS2 (nitric oxide synthase gene) expression ( R 2  = 0.281, P  = 1.2 × 10 -10 ). In SARP ( n  = 1,659), the Cleveland Clinic Health System ( n  = 32,527), and the NHANES ( n  = 2,629), women had more asthma exacerbations and emergency department visits than men. The levels of the AR ligand precursor dehydroepiandrosterone sulfate correlated positively with the FEV 1 in both women and men. Conclusions: Higher bronchial AR expression and higher androgen levels are associated with better lung function, fewer symptoms, and a lower Fe NO in human asthma. The role of androgens should be considered in asthma management.

Rationale: Rhinovirus (RV) C can cause asymptomatic infection and respiratory illnesses ranging from the common cold to severe wheezing. Objectives: To identify how age and other individual-level factors are associated with susceptibility to RV-C illnesses. Methods: Longitudinal data from the COAST (Childhood Origins of Asthma) birth cohort study were analyzed to determine relationships between age and RV-C infections. Neutralizing antibodies specific for RV-A and RV-C (three types each) were determined using a novel PCR-based assay. Data were pooled from 14 study cohorts in the United States, Finland, and Australia, and mixed-effects logistic regression was used to identify factors related to the proportion of RV-C versus RV-A detection. Measurements and Main Results: In COAST, RV-A and RV-C infections were similarly common in infancy, whereas RV-C was detected much less often than RV-A during both respiratory illnesses and scheduled surveillance visits ( P  < 0.001, χ 2 ) in older children. The prevalence of neutralizing antibodies to RV-A or RV-C types was low (5-27%) at the age of 2 years, but by the age of 16 years, RV-C seropositivity was more prevalent (78% vs. 18% for RV-A; P  < 0.0001). In the pooled analysis, the RV-C to RV-A detection ratio during illnesses was significantly related to age ( P  < 0.0001), CDHR3 genotype ( P  < 0.05), and wheezing illnesses ( P  < 0.05). Furthermore, certain RV types (e.g., C2, C11, A78, and A12) were consistently more virulent and prevalent over time. Conclusions: Knowledge of prevalent RV types, antibody responses, and populations at risk based on age and genetics may guide the development of vaccines or other novel therapies against this important respiratory pathogen.

There has been extensive progress in understanding the cellular and molecular mechanisms of inflammation and immune regulation in allergic diseases of the skin and lungs during the last few years. Asthma and atopic dermatitis (AD) are typical diseases of type 2 immune responses. interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin are essential cytokines of epithelial cells that are activated by allergens, pollutants, viruses, bacteria, and toxins that derive type 2 responses. Th2 cells and innate lymphoid cells (ILC) produce and secrete type 2 cytokines such as IL-4, IL-5, IL-9, and IL-13. IL-4 and IL-13 activate B cells to class-switch to IgE and also play a role in T-cell and eosinophil migration to allergic inflammatory tissues. IL-13 contributes to maturation, activation, nitric oxide production and differentiation of epithelia, production of mucus as well as smooth muscle contraction, and extracellular matrix generation. IL-4 and IL-13 open tight junction barrier and cause barrier leakiness in the skin and lungs. IL-5 acts on activation, recruitment, and survival of eosinophils. IL-9 contributes to general allergic phenotype by enhancing all of the aspects, such as IgE and eosinophilia. Type 2 ILC contribute to inflammation in AD and asthma by enhancing the activity of Th2 cells, eosinophils, and their cytokines. Currently, five biologics are licensed to suppress type 2 inflammation via IgE, IL-5 and its receptor, and IL-4 receptor alpha. Some patients with severe atopic disease have little evidence of type 2 hyperactivity and do not respond to biologics which target this pathway. Studies in responder and nonresponder patients demonstrate the complexity of these diseases. In addition, primary immune deficiency diseases related to T-cell maturation, regulatory T-cell development, and T-cell signaling, such as Omenn syndrome, severe combined immune deficiencies, immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, and DOCK8, STAT3, and CARD11 deficiencies, help in our understanding of the importance and redundancy of various type 2 immune components. The present review aims to highlight recent advances in type 2 immunity and discuss the cellular sources, targets, and roles of type 2 mechanisms in asthma and AD., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: In 2004, the landmark Gaining Optimal Asthma Control (GOAL) study demonstrated that most patients can achieve asthma control through sustained treatment and that adding a long-acting β 2 -adrenoreceptor agonist to an inhaled corticosteroid (ICS) is more effective than ICS alone in this regard. Definitions of asthma control have since evolved, and the consequent implications for the GOAL study findings are unclear., Objective: To evaluate the efficacy of fluticasone propionate and salmeterol and fluticasone propionate alone in achieving and maintaining asthma control, as derived from the Global Initiative for Asthma (GINA) 2016 report., Methods: In total, 3416 patients were stratified by prior medication (ICS-naive [stratum 1], low-dose ICS [stratum 2], or medium-dose ICS [stratum 3]) and randomized to receive fluticasone propionate and salmeterol or fluticasone propionate. The primary end point was the proportion of patients achieving well-controlled or partly controlled asthma; secondary end points included the proportion of patients achieving well-controlled asthma. Control was evaluated during the last 4 weeks of each dose titration., Results: In all strata, more patients achieved well-controlled or partly controlled asthma with fluticasone propionate and salmeterol vs fluticasone propionate alone (stratum 1: 91% vs 85%; P = .003; stratum 2: 86% vs 82%; P = .07; and stratum 3: 76% vs 66%; P < .001), as well as patients with well-controlled asthma (stratum 1: 64% vs 56%; P = .005; stratum 2: 59% vs 41%; P < .001; and stratum 3: 40% vs 22%; P < .001)., Conclusion: A markedly higher proportion of patients with uncontrolled asthma in each stratum achieved control according to GINA 2016 criteria compared with the original study criteria. The proportion of patients achieving control remained greater with fluticasone propionate and salmeterol than with fluticasone propionate alone., (Copyright © 2019. Published by Elsevier Inc.)

Background: Three anti-IL-5 pathway-directed therapies are approved for use in patients with severe eosinophilic asthma (SEA); however, no head-to-head comparison data are available., Objective: We sought to compare the efficacy of licensed doses of mepolizumab, benralizumab, and reslizumab in patients with SEA, according to baseline blood eosinophil counts., Methods: This indirect treatment comparison (ITC) used data from a Cochrane review and independent searches. Eligible studies were randomized controlled trials in patients aged 12 years or greater with SEA. End points included annualized rate of clinically significant exacerbations and change from baseline in Asthma Control Questionnaire score and FEV 1 . An ITC was performed in patients with Asthma Control Questionnaire scores of 1.5 or greater and stratified by baseline blood eosinophil count., Results: Eleven studies were included. All treatments significantly reduced the rate of clinically significant exacerbations and improved asthma control versus placebo in all blood eosinophil count subgroups. Mepolizumab reduced clinically significant exacerbations by 34% to 45% versus benralizumab across subgroups (rate ratio ≥400 cells/μL: 0.55 [95% CI, 0.35-0.87]; ≥300 cells/μL: 0.61 [95% CI, 0.37-0.99]; and ≥150 cells/μL: 0.66 [95% CI, 0.49-0.89]; all P < .05) and by 45% versus reslizumab in the 400 cells/μL or greater subgroup (rate ratio, 0.55 [95% CI, 0.36-0.85]; P = .007). Asthma control was significantly improved with mepolizumab versus benralizumab (all subgroups: P < .05) and versus reslizumab in the 400 cells/μL or greater subgroup (P = .004). Benralizumab significantly improved lung function versus reslizumab in the 400 cells/μL or greater subgroup (P = .025)., Conclusions: This ITC of the licensed doses suggests that mepolizumab was associated with significantly greater improvements in clinically significant exacerbations and asthma control compared with reslizumab or benralizumab in patients with similar blood eosinophil counts., (Copyright © 2018 GlaxoSmithKline. Published by Elsevier Inc. All rights reserved.)

Background: Omalizumab has demonstrated efficacy in clinical trials of patients with asthma, but real-world data are needed., Objective: To assess outcomes after omalizumab initiation in patients with asthma in a real-world setting., Methods: Patients aged 12 years and older with allergic asthma who were candidates for omalizumab on the basis of physician-assessed need were enrolled in a US-based, prospective, single-arm, 48-week multicenter study, the Prospective Observational Study to Evaluate Predictors of Clinical Effectiveness in Response to Omalizumab. Monthly assessments included exacerbations, health care utilization, asthma control test (ACT), and adverse events. At baseline, 6 months, and end of study, biomarkers (blood eosinophils and fractional exhaled nitric oxide) were collected and spirometry performed., Results: Of 806 enrollees, 801 (99.4%) received omalizumab and 622 (77.2%) completed the study. The exacerbation rate significantly improved from a mean of 3.00 ± 3.28 in the 12 months before baseline to 0.78 ± 1.37 through month 12 (P < .001) and was similar in adults and adolescents; there was a reduction of 81.9% in the percentage of patients with 1 or more hospitalizations. Lung function remained generally unchanged. A mean improvement of 4.4 ± 4.9 in ACT scores was observed. Eighty-seven percent of patients were responders on the basis of clinical improvement in exacerbations, lung function, or ACT scores. Baseline biomarker status was associated with ACT scores and lung function improvement, but the magnitude of this improvement was not clinically relevant. No new safety signals emerged., Conclusions: Omalizumab initiation in patients with asthma resulted in improved exacerbation rates, reduced hospitalizations, and improved ACT scores compared with pretreatment values, regardless of biomarker status., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Despite currently available treatments, many asthma patients remain inadequately controlled, but identifying distinct patient populations (phenotypes/endotypes) may optimize their management. This review discusses some of the controversies and opportunities for improved disease control in severe asthma., Recent Findings: Currently approved anti-immunoglobulin E and anti-interleukin 5 biologics, which target specific pathways instead of using a 'one size fits all' strategy, are efficacious and well tolerated therapies for severe asthma. The appropriate use of these biologics, and of those in development (e.g., benralizumab and dupilumab), should be aided by further understanding of asthma phenotypes and endotypes, utilizing appropriate biomarkers.Oral corticosteroids are often added as maintenance therapy for patients with severe uncontrolled asthma, but their use is associated with significant adverse effects and should be considered a last option. The true cost of this therapy, including the cost of morbidities associated with its use, remains to be determined.Severe asthma in pediatrics poses a unique opportunity for possible prevention strategies and the potential for primary prevention. Although several avenues for primary prevention are being explored and are out of the scope of this review, we focus our discussion on the use of omalizumab, which has been recently explored in clinical trials., Summary: Appropriate use of biologics in severe asthma should be supported by further understanding of biomarkers predicting response to targeted therapy. Because of their association with significant adverse effects, add-on oral corticosteroids should be considered a last treatment option for patients with uncontrolled severe asthma. Finally, severe asthma in pediatrics poses a unique opportunity for potential prevention strategies.

Background: Few data are available to assist clinicians with decisions regarding long-term use of asthma therapies, including omalizumab., Objective: We sought to evaluate the benefit and persistence of response in subjects continuing or withdrawing from long-term omalizumab treatment., Methods: Evaluating the Xolair Persistency Of Response After Long-Term Therapy (XPORT) was a randomized, double-blind, placebo-controlled withdrawal study that included subjects with moderate-to-severe persistent asthma receiving long-term omalizumab. Subjects were randomized by using a hierarchical dynamic randomization scheme to continue their same dose of omalizumab or withdraw to placebo and were then followed every 4 weeks for 1 year. The primary outcome was any protocol-defined severe asthma exacerbation. The secondary outcome was time to first protocol-defined severe asthma exacerbation. Exploratory outcomes included changes in Asthma Control Questionnaire and Asthma Control Test scores., Results: Significantly more subjects in the omalizumab group (67%) had no protocol-defined exacerbation than in the placebo group (47.7%); an absolute difference of 19.3% (95% CI, 5.0%, 33.6%) represents a 40.1% relative difference. Time to first protocol-defined exacerbation analysis revealed a significantly different between-group exacerbation pattern that was consistent with the primary analysis. Subjects continuing omalizumab had significantly better asthma control (mean [SD] change from baseline to week 52: Asthma Control Test score, -1.16 [4.14] vs placebo, -2.88 [5.38], P = .0188; Asthma Control Questionnaire score, 0.22 [0.66] vs placebo, 0.63 [1.13], P = .0039). Discontinuation of omalizumab was associated with an increase in free IgE levels and an increase in basophil expression of the high-affinity IgE receptor. No safety concerns were noted., Conclusion: Continuation of omalizumab after long-term treatment results in continued benefit, as evidenced by improved symptom control and reduced exacerbation risk., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: To analyse the efficacy of fluticasone propionate (FP) alone and combined with salmeterol (SAL) in achieving guideline-defined asthma control in Asian patients., Methods: A post hoc analysis of the GOAL study in which patients were stratified by prior-medication use into inhaled corticosteroid (ICS)-naïve (Stratum [S] 1), low-dose ICS (S2), and medium-dose ICS (S3), and randomised to receive FP/SAL or FP. Doses were stepped-up every 12 weeks until Totally Controlled asthma or maximum dose was reached (PhI) and then maintained until study end (PhII). The primary endpoint was the proportion of patients achieving Well-Controlled asthma during PhI. Additional endpoints included Total Control and adverse events. Asian and non-Asian patients were analysed separately., Results: In Asian patients in PhI, 74% (n = 87/118) in S1 achieved Well-Controlled asthma with FP/SAL versus 74% (n = 89/121) with FP alone (p = 0.839); corresponding values were 76% (n = 81/107) versus 60% (n = 62/104; p = 0.005) in S2, and 58% (n = 59/102) versus 43% (n = 41/95; p = 0.015) in S3. More patients in all three strata achieved Totally Controlled asthma with FP/SAL versus FP alone. Control was achieved more rapidly and with lower ICS doses with FP/SAL versus FP. A high proportion of patients who achieved control during PhI maintained control during PhII. Similar trends were found in non-Asian patients. No new safety concerns were identified., Conclusions: A greater proportion of Asian patients (S2 and S3, for Well-Controlled; all strata, for Totally Controlled) achieved guideline-defined asthma control with FP/SAL versus FP alone. High proportions of Asian patients in S1 achieved Well-Controlled asthma in both treatment groups.

The central role of IgE in the pathogenesis of allergic asthma has been well established; recent research has brought to light further interesting findings regarding the effects of IgE and anti-IgE therapy. This symposium explored these recent revelations and provided new insights into the importance of IgE in allergic asthma., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

S-Nitrosoglutathione is an endogenous airway smooth muscle relaxant. Increased airway S-nitrosoglutathione breakdown occurs in some asthma patients. We asked whether patients with increased airway catabolism of this molecule had clinical features that distinguished them from other asthma patients. We measured S-nitrosoglutathione reductase expression and activity in bronchoscopy samples taken from 66 subjects in the Severe Asthma Research Program. We also analysed phenotype and genotype data taken from the program as a whole. Airway S-nitrosoglutathione reductase activity was increased in asthma patients (p=0.032). However, only a subpopulation was affected and this subpopulation was not defined by a "severe asthma" diagnosis. Subjects with increased activity were younger, had higher IgE and an earlier onset of symptoms. Consistent with a link between S-nitrosoglutathione biochemistry and atopy: 1) interleukin 13 increased S-nitrosoglutathione reductase expression and 2) subjects with an S-nitrosoglutathione reductase single nucleotide polymorphism previously associated with asthma had higher IgE than those without this single nucleotide polymorphism. Expression was higher in airway epithelium than in smooth muscle and was increased in regions of the asthmatic lung with decreased airflow. An early-onset, allergic phenotype characterises the asthma population with increased S-nitrosoglutathione reductase activity., (Copyright ©ERS 2015.)

IgE is central to the pathophysiology of allergic asthma. Omalizumab, a humanized anti-IgE mAb, specifically binds free IgE and interrupts the allergic cascade by preventing binding of IgE with its high-affinity FcεRI receptors on mast cells, antigen-presenting cells, and other inflammatory cells. The clinical efficacy of omalizumab has been well documented in a number of clinical trials that involve adults, adolescents, and children with moderate-to-severe and severe allergic asthma. In these studies, omalizumab reduced exacerbations, asthma symptoms, inhaled corticosteroid and rescue medication use, and improved quality of life relative to placebo or best standard of care. Similar benefits have been reported in observational studies in "real-world" populations of patients. Results from recent pooled data from randomized clinical trials and from a large prospective cohort study provide reassurance about the long-term safety of omalizumab. Omalizumab dosing is individualized according to body weight and serum-IgE level, and recent adjustments to the dosing algorithm in Europe have enabled more patients to be eligible for treatment. Ongoing and future research is investigating the optimal duration of therapy, accurate predictors of response to treatment, and efficacy in nonatopic asthma as well as other IgE-mediated conditions., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Rationale and Objectives: Previous cross-sectional studies have demonstrated that airway wall thickness and air trapping are greater in subjects with severe asthma than in those with mild-to-moderate asthma. However, a better understanding of how airway remodeling and lung density change over time is needed. This study aimed to evaluate predictors of airway wall remodeling and change in lung function and lung density over time in severe asthma., Materials and Methods: Phenotypic characterization and quantitative multidetector-row computed tomography (MDCT) of the chest were performed at baseline and ∼2.6 years later in 38 participants with asthma (severe n = 24 and mild-to-moderate n = 14) and nine normal controls from the Severe Asthma Research Program., Results: Subjects with severe asthma had a significant decline in postbronchodilator forced expiratory volume in 1 second percent (FEV1%) predicted over time (P < .001). Airway wall thickness measured by MDCT was increased at multiple airway generations in severe asthma compared to mild-to-moderate asthma (wall area percent [WA%]: P < .05) and normals (P < .05) at baseline and year 2. Over time, there was an increase in WA% and wall thickness percent (WT%) in all subjects (P = .030 and .009, respectively) with no change in emphysema-like lung or air trapping. Baseline prebronchodilator FEV1% inversely correlated with WA% and WT% (both P < .05). In a multivariable regression model, baseline WA%, race, and health care utilization were predictors of subsequent airway remodeling., Conclusions: Severe asthma subjects have a greater decline in lung function over time than normal subjects or those with mild-to-moderate asthma. MDCT provides a noninvasive measure of airway wall thickness that may predict subsequent airway remodeling., (Copyright © 2014 AUR. Published by Elsevier Inc. All rights reserved.)

Glucocorticoids remain a cornerstone of guideline-based management of persistent asthma and allergic diseases. Glucocorticoid-induced osteoporosis (GIO) is the most common iatrogenic cause of secondary osteoporosis and an issue of concern for physicians treating patients with inhaled or oral glucocorticoids either continuously or intermittently. Patients with GIO experience fragility fractures at better dual-energy x-ray absorptiometry T-scores than those with postmenopausal or age-related osteoporosis. This might be explained, at least in part, by the effects of glucocorticoids not only on osteoclasts but also on osteoblasts and osteocytes. Effective options to detect and manage GIO exist, and a management algorithm has been published by the American College of Rheumatology to provide treatment guidance for clinicians. This review will summarize GIO epidemiology and pathophysiology and assess the role of inhaled and oral glucocorticoids in asthmatic adults and children, with particular emphasis on the effect of such therapies on bone health. Lastly, we will review the American College of Rheumatology GIO guidelines and discuss diagnostic and therapeutic strategies to mitigate the risk of GIO and fragility fractures., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Decreased 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with an increased prevalence and severity of asthma and a lower response to inhaled corticosteroids., Objective: The objective was to determine the association between serum 25(OH)D concentrations and asthma prevalence, severity, and response to asthma treatment., Design: Secondary analyses were conducted in 2 samples of adolescents 12-20 y of age: 1) NHANES 2001-2006 (n = 6487), a cross-sectional nationally representative sample of the US population, and 2) a cohort of inner-city adolescents with asthma managed prospectively for 46 wk with guidelines-based therapy in the Asthma Control Evaluation (ACE; n = 226) trial., Results: Mean (±SD) serum 25(OH)D concentrations in the NHANES and ACE samples were lower in African Americans than in non-African Americans (NHANES: 14.9 ± 6.5 compared with 23.0 ± 8.4 ng/mL, P < 0.0001; ACE: 11.2 ± 6.9 compared with 15.8 ± 7.1 ng/mL, P < 0.0001). In the NHANES sample, mean concentrations did not differ between participants without and with asthma (African Americans: 14.9 ± 6.4 compared with 15.0 ± 6.6 ng/mL, respectively, P = 0.87; non-African Americans: 23.0 ± 8.5 compared with 23.6 ± 8.2 ng/mL, respectively, P = 0.16). In the ACE models that used either a predefined cutoff (<20 ng/mL) or linear regression, 25(OH)D concentrations showed either no relation or minor contradictory correlations with indicators of asthma severity, treatment requirements, spirometry, or atopy/inflammation., Conclusion: In 2 samples of adolescents, overall serum 25(OH)D concentrations were low and were not consistently associated with the presence of asthma, multiple asthma characteristics, asthma morbidity, or response to treatment. The ACE trial was registered at clinicaltrials.gov as NCT0011441.

Rationale: For many patients with asthma, allergic airway inflammation is primarily a Th2-weighted process; however, heterogeneity in patterns of inflammation suggests phenotypic distinctions exist that influence disease presentation and treatment effects., Objectives: To assess the potential of fractional exhaled nitric oxide (FE(NO)), peripheral blood eosinophil count, and serum periostin as biomarkers of Th2 inflammation and predictors of treatment effects of omalizumab., Methods: The EXTRA omalizumab study enrolled patients (aged 12-75 yr) with uncontrolled severe persistent allergic asthma. Analyses were performed evaluating treatment effects in relation to FE(NO), blood eosinophils, and serum periostin at baseline. Patients were divided into low- and high-biomarker subgroups. Treatment effects were evaluated as number of protocol-defined asthma exacerbations during the 48-week treatment period (primary endpoint)., Measurements and Main Results: A total of 850 patients were enrolled. Data were available from 394 (46.4%), 797 (93.8%), and 534 (62.8%) patients for FE(NO), blood eosinophils, and serum periostin, respectively. After 48 weeks of omalizumab, reductions in protocol-defined exacerbations were greater in high versus low subgroups for all three biomarkers: FE(NO), 53% (95% confidence interval [CI], 37-70; P = 0.001) versus 16% (95% CI, -32 to 46; P = 0.45); eosinophils, 32% (95% CI, 11-48; P = 0.005) versus 9% (95% CI, -24 to 34; P = 0.54); and periostin, 30% (95% CI, -2 to 51; P = 0.07) versus 3% (95% CI, -43 to 32; P = 0.94)., Conclusions: The difference in exacerbation frequency between omalizumab and placebo was greatest in the three high-biomarker subgroups, probably associated with the greater risk for exacerbations in high subgroups. Additional studies are required to explore the value of these biomarkers in clinical practice. Clinical trial registered with www.clinicaltrials.gov (NCT00314574).

Purpose: The effect of sleep quality on asthma control independent from common comorbidities like gastroesophageal reflux disease (GERD) and obstructive sleep apnea (OSA) is unknown. This study examined the association between sleep quality and asthma control and quality of life after accounting for OSA and GERD in non-severe (NSA) and severe (SA) asthma., Methods: Cross-sectional data from 60 normal controls, 143 with NSA, and 79 with SA participating in the Severe Asthma Research Program was examined. Those who reported using positive airway pressure therapy or were at high risk for OSA were excluded., Results: Both SA and NSA had poorer sleep quality than controls, with SA reporting the worst sleep quality. All asthmatics with GERD and 92% of those without GERD had poor sleep quality (p = 0.02). The majority (88-100%) of NSA and SA participants who did not report nighttime asthma disturbances still reported having poor sleep quality. In both NSA and SA, poor sleep quality was associated with worse asthma control and quality of life after controlling for GERD and other covariates., Conclusions: These results suggest that poor sleep quality is associated with poor asthma control and quality of life among asthmatics and cannot be explained by comorbid GERD and nighttime asthma disturbances.

Background: Since initial registration, the omalizumab clinical trial database has expanded considerably, with a doubling of patients exposed in the clinical trial environment. Previous pooled data (2003) from phase I to III studies of omalizumab showed a numeric imbalance in malignancies arising in omalizumab recipients (0.5%) compared with control subjects (0.2%). The previous analysis was based on limited available data, warranting further investigation., Objective: We sought to examine the incidence of malignancy using comprehensive pooled data from clinical trials of omalizumab-treated patients., Methods: This pooled analysis included data from 67 phase I to IV clinical trials. The prespecified primary analysis assessed the incidence of primary malignancy in 32 randomized, double-blind, placebo-controlled (RDBPC) trials., Results: There were 11,459 unique patients in all clinical trials (7,789 received omalizumab). The primary analysis identified malignancies in 25 patients (RDBPC trials): 14 in 4,254 omalizumab-treated patients and 11 in 3,178 placebo-treated patients. Incidence rates per 1,000 patient-years of observation time for omalizumab- and placebo-treated patients were 4.14 (95% CI, 2.26-6.94) and 4.45 (95% CI, 2.22-7.94), respectively; the corresponding rate ratio was 0.93 (95% CI, 0.39-2.27). Primary malignancies were of varying histologic type and occurred in a number of different organ systems; no cluster of histologies was identified., Conclusions: In this pooled analysis no association was observed between omalizumab treatment and risk of malignancy in RDBPC trials; the rate ratio was below unity. The data suggest that a causal relationship between omalizumab therapy and malignancy is unlikely., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Inhaled corticosteroids (ICS) and long-acting β(2)-agonists (LABAs) are recommended in patients with asthma that is not well-controlled; however, many patients continue to have inadequately controlled asthma despite this therapy., Objective: To evaluate the efficacy and safety of omalizumab in patients with inadequately controlled severe asthma who are receiving high-dose ICS and LABAs, with or without additional controller therapy., Design: Prospective, multicenter, randomized, parallel-group, double-blind, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00314575)., Setting: 193 investigational sites in the United States and 4 sites in Canada., Patients: 850 patients aged 12 to 75 years who had inadequately controlled asthma despite treatment with high-dose ICS plus LABAs, with or without other controllers., Intervention: Omalizumab (n = 427) or placebo (n = 423) was added to existing medication regimens for 48 weeks., Measurements: The primary end point was the rate of protocol-defined exacerbations over the study period. Secondary efficacy end points included the change from baseline to week 48 in mean daily number of puffs of albuterol, mean total asthma symptom score, and mean overall score on the standardized version of the Asthma Quality of Life Questionnaire (AQLQ[S]). Safety end points included the frequency and severity of treatment-emergent adverse events., Results: During 48 weeks, the rate of protocol-defined asthma exacerbations was significantly reduced for omalizumab compared with placebo (0.66 vs. 0.88 per patient; P = 0.006), representing a 25% relative reduction (incidence rate ratio, 0.75 [95% CI, 0.61 to 0.92]). Omalizumab improved mean AQLQ(S) scores (0.29 point [CI, 0.15 to 0.43]), reduced mean daily albuterol puffs (-0.27 puff/d [CI, -0.49 to -0.04 puff/d]), and decreased mean asthma symptom score (-0.26 [CI, -0.42 to -0.10]) compared with placebo during the 48-week study period. The incidence of adverse events (80.4% vs. 79.5%) and serious adverse events (9.3% vs. 10.5%) were similar in the omalizumab and placebo groups, respectively., Limitations: The results are limited by early patient discontinuation (20.8%). The study was not powered to detect rare safety events or the treatment effect in the oral corticosteroid subgroup., Conclusion: In this study, omalizumab provided additional clinical benefit for patients with severe allergic asthma that is inadequately controlled with high-dose ICS and LABA therapy., Primary Funding Source: Genentech and Novartis Pharmaceuticals.

Background: Biologic factors are known to contribute to asthma severity. It is unknown whether these factors differentially contribute to asthma severity in black compared with white subjects., Objective: We sought to assess the extent to which racial disparities between black and white subjects with severe asthma are attributable to physiologic, immunoinflammatory, and sociodemographic variables., Methods: Black and white asthmatic adults enrolled in a cross-sectional study focused on severe asthma were evaluated. Severe asthma was identified by using the American Thoracic Society definition. After initial univariable analyses, unconditional logistic regression models were used to estimate the probability of having severe asthma for black and white subjects., Results: Differences in severe asthma in black compared with white subjects were observed. In univariable analysis IgE level was not associated with severe asthma in black or white subjects, whereas in multivariable analysis IgE level was significantly associated with severe asthma for black subjects (P = .014) but not for white subjects. The odds of having severe asthma more than doubled for black subjects with 2 or more family members with asthma (P = .026), whereas the odds of severe asthma for white participants with a strong family history of asthma decreased by almost half (P = .05). Atopy was negatively associated with severe asthma in both races in univariable analysis but remained significant only in black subjects, whereas comorbidities were associated with severe asthma in white subjects., Conclusion: Biologic factors were distinctly associated with severe asthma only in black subjects. Studies that incorporate comprehensive evaluation of biologic factors associated with asthma might lead to the development of therapies that target biologic abnormalities in black subjects., (Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Rationale: Exhaled nitric oxide (Fe(NO)) is a biomarker of airway inflammation in mild to moderate asthma. However, whether Fe(NO) levels are informative regarding airway inflammation in patients with severe asthma, who are refractory to conventional treatment, is unknown. Here, we hypothesized that classification of severe asthma based on airway inflammation as defined by Fe(NO) levels would identify a more reactive, at-risk asthma phenotype., Methods: Fe(NO) and major features of asthma, including airway inflammation, airflow limitation, hyperinflation, hyperresponsiveness, and atopy, were determined in 446 individuals with various degrees of asthma severity (175 severe, 271 non-severe) and 49 healthy subjects enrolled in the Severe Asthma Research Program., Measurements and Main Results: Fe(NO) levels were similar among patients with severe and non-severe asthma. The proportion of individuals with high Fe(NO) levels (>35 ppb) was the same (40%) among groups despite greater corticosteroid therapy in severe asthma. All patients with asthma and high Fe(NO) had more airway reactivity (maximal reversal in response to bronchodilator administration and by methacholine challenge), more evidence of allergic airway inflammation (sputum eosinophils), more evidence of atopy (positive skin tests, higher serum IgE and blood eosinophils), and more hyperinflation, but decreased awareness of their symptoms. High Fe(NO) identified those patients with severe asthma characterized by the greatest airflow obstruction and hyperinflation and most frequent use of emergency care., Conclusions: Grouping of asthma by Fe(NO) provides an independent classification of asthma severity, and among patients with severe asthma identifies the most reactive and worrisome asthma phenotype.

Rationale: IL-4 and IL-13 share many biological functions important in the development of allergic airway inflammation and are implicated in the pathogenesis of asthma. AMG 317 is a fully human monoclonal antibody to IL-4Ralpha that blocks both IL-4 and IL-13 pathways., Objectives: To evaluate efficacy and safety of AMG 317 in patients with moderate to severe asthma., Methods: In this phase 2, randomized, double-blind, placebo-controlled study, patients received weekly subcutaneous injections of placebo or AMG 317 (75-300 mg) for 12 weeks, followed by a 4-week follow-up period. The primary endpoint was change from baseline at Week 12 in Asthma Control Questionnaire (ACQ) symptom score., Measurements and Main Results: Mean ACQ change (SE) was -0.49 (0.09) in placebo (n = 74), and -0.43 (0.11), -0.58 (0.12), and -0.70 (0.09) in the AMG 317 75 mg (n = 73), 150 mg (n = 73), and 300 mg (n = 74) groups, respectively (treatment effect P = 0.25). No statistically significant differences were observed in the secondary endpoints. Numerical decreases in number of and time to exacerbations were noted in patients receiving AMG 317 150 mg and 300 mg. Preplanned analyses by tertile of baseline ACQ revealed that patients with higher baseline ACQ scores (>or=2.86) were more likely to respond to AMG 317. Serious adverse events were reported in three patients, each noted as not related to study drug., Conclusions: AMG 317 did not demonstrate clinical efficacy across the overall group of patients. Clinically significant improvements were observed in several outcome measures in patients with higher baseline ACQ scores. AMG 317 was safe and well tolerated in this study population. Clinical trial registered with www.clinicaltrials.gov (NCT 00436670).

Background: Although specific immunotherapy is a valuable treatment option for patients with allergic asthma, the potential for systemic allergic reactions has limited its use, especially for patients with symptomatic disease., Objective: To evaluate omalizumab's effect on the tolerability of specific immunotherapy in patients with symptomatic persistent asthma not adequately controlled with inhaled corticosteroids., Methods: This multicenter, double-blind, parallel-group study randomized patients to treatment with omalizumab or placebo, after which they received specific immunotherapy to at least 1 of 3 perennial aeroallergens (cat, dog, and house dust mite) according to a 4-week, 18-injection cluster regimen, followed by 7 weeks of maintenance therapy. The primary efficacy variable, a systemic allergic reaction after immunotherapy, was analyzed by using the Cochrane-Mantel-Haenszel test., Results: A total of 248 randomized patients (126 omalizumab, 122 placebo) received at least 1 dose of immunotherapy and were evaluated for efficacy. Patients receiving omalizumab experienced significantly fewer systemic allergic reactions to immunotherapy than those receiving placebo (17/126 [13.5%] vs 32/122 [26.2%]; P = .017; 95% CI, 2.91% to 22.56%) and had fewer respiratory-related (grade 3) systemic allergic reactions (6 vs 24, respectively). Grade 4 reactions were reported in 2 patients in each group. More omalizumab patients were able to reach the target maintenance immunotherapy dose (110 [87.3%] vs 88 [72.1%], respectively; P = .004)., Conclusion: Use of omalizumab in patients whose asthma was symptomatic despite use of inhaled corticosteroids was associated with fewer systemic allergic reactions to specific immunotherapy and enabled more patients to achieve the target immunotherapy maintenance dose., (Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Purpose of Review: The use of immunomodulators in asthma has been well established with omalizumab. Evidence is accumulating for other biologic agents. The following article presents an overview of current biologic therapies employed and under investigation in the treatment of asthma., Recent Findings: Anti-immunoglobulin E and anti-interleukin-5 are best supported by current evidence. However, new data are also available with other therapies, including cytokine inhibitors, oligonucleotides and CpG vaccines., Summary: Biologic therapies currently represent useful adjunctive treatments for asthma, especially in patients with more severe disease that is not responsive to conventional therapies alone. However, the varied responses now found suggest that specific phenotypes may need to be identified to see optimal effects from specific treatments. Further studies are required to access the efficacy and side effect profiles of these therapies.

Rationale: The treatment effect of golimumab, a human monoclonal antibody against tumor necrosis factor (TNF)-alpha, in severe persistent asthma is unknown., Objectives: To assess the safety and efficacy of golimumab in a large population of patients with uncontrolled, severe persistent asthma., Methods: From 2004 to 2006, 309 patients with severe and uncontrolled asthma, despite high-dose inhaled corticosteroids and long-acting beta(2) agonists, were randomized 1:1:1:1 to monthly subcutaneous injections of placebo or golimumab (50, 100, or 200 mg) through Week 52. Coprimary endpoints were the change from baseline through Week 24 in prebronchodilator percent-predicted FEV(1) and the number of severe asthma exacerbations through Week 24., Measurements and Main Results: No significant differences were observed for the change in percent-predicted FEV1 (least squares mean: placebo, 2.44 [95% confidence interval (CI) -0.574 to 5.461]; combined 100-mg and 200-mg, 2.91 [0.696-5.116]) or severe exacerbations (mean +/- SD: placebo, 0.5 +/- 1.07 vs. combined 100-mg and 200-mg 0.5 +/- 0.97) through week 24. Through Week 24, 2.6% of patients treated with placebo vs. 19.5% of those treated with golimumab discontinued the study agent, and 1.3% and 7.8% discontinued study participation, respectively. An unfavorable risk-benefit profile led to early discontinuation of study-agent administration after the Week-24 database lock. Through Week 76, 20.5% of patients treated with placebo and 30.3% of patients treated with golimumab experienced serious adverse events, with serious infections occurring more frequently in golimumab-treated patients. One death and all eight malignancies occurred in the active groups., Conclusions: Overall, treatment with golimumab did not demonstrate a favorable risk-benefit profile in this study population of patients with severe persistent asthma. Clinical trial registered with www.clinicaltrials.gov (NCT00207740).

Rationale: As the sole nitrogen donor in nitric oxide (NO) synthesis and key intermediate in the urea cycle, arginine and its metabolic pathways are integrally linked to cellular respiration, metabolism, and inflammation., Objectives: We hypothesized that arginine (Arg) bioavailability would be associated with airflow abnormalities and inflammation in subjects with asthma, and would be informative for asthma severity., Methods: Arg bioavailability was assessed in subjects with severe and nonsevere asthma and healthy control subjects by determination of plasma Arg relative to its metabolic products, ornithine and citrulline, and relative to methylarginine inhibitors of NO synthases, and by serum arginase activity. Inflammatory parameters, including fraction of exhaled NO (Fe(NO)), IgE, skin test positivity to allergens, bronchoalveolar lavage, and blood eosinophils, were also evaluated., Measurements and Main Results: Subjects with asthma had greater Arg bioavailability, but also increased Arg catabolism compared with healthy control subjects, as evidenced by higher levels of Fe(NO) and serum arginase activity. However, Arg bioavailability was positively associated with Fe(NO) only in healthy control subjects; Arg bioavailability was unrelated to Fe(NO) or other inflammatory parameters in severe or nonsevere asthma. Inflammatory parameters were related to airflow obstruction and reactivity in nonsevere asthma, but not in severe asthma. Conversely, Arg bioavailability was related to airflow obstruction in severe asthma, but not in nonsevere asthma. Modeling confirmed that measures of Arg bioavailabilty predict airflow obstruction only in severe asthma., Conclusions: Unlike Fe(NO), Arg bioavailability is not a surrogate measure of inflammation; however, Arg bioavailability is strongly associated with airflow abnormalities in severe asthma.

Rationale: Accumulation of eosinophils in the bronchial mucosa of individuals with asthma is considered to be a central event in the pathogenesis of asthma. In animal models, airway eosinophil recruitment and airway hyperresponsiveness in response to allergen challenge are reduced by specific targeting of interleukin-5. A previous small dose-finding study found that mepolizumab, a humanized anti-interleukin-5 monoclonal antibody, had no effect on allergen challenge in humans., Objectives: To investigate the effect of three intravenous infusions of mepolizumab, 250 or 750 mg at monthly intervals, on clinical outcome measures in 362 patients with asthma experiencing persistent symptoms despite inhaled corticosteroid therapy (400-1,000 mug of beclomethasone or equivalent)., Methods: Multicenter, randomized, double-blind, placebo-controlled study., Measurements and Main Results: Morning peak expiratory flow, forced expiratory volume in 1 second, daily beta(2)-agonist use, symptom scores, exacerbation rates, and quality of life measures. Sputum eosinophil levels were also measured in a subgroup of 37 individuals. Mepolizumab was associated with a significant reduction in blood and sputum eosinophils in both treatment groups (blood, P < 0.001 for both doses; sputum, P = 0.006 for 250 mg and P = 0.004 for 750 mg). There were no statistically significant changes in any of the clinical end points measured. There was a nonsignificant trend for decrease in exacerbation rates in the mepolizumab 750-mg treatment group (P = 0.065)., Conclusions: Mepolizumab treatment does not appear to add significant clinical benefit in patients with asthma with persistent symptoms despite inhaled corticosteroid therapy. Further studies are needed to investigate the effect of mepolizumab on exacerbation rates, using protocols specifically tailored to patients with asthma with persistent airway eosinophilia.

This study was conducted to assess the safety and efficacy of zileuton controlled release [CR] 1,200 mg BID added to usual care (UC) in 926 patients with moderate asthma (619 patients randomized to zileuton CR and 307 to placebo). Sustained improvements in AM and PM peak expiratory flow (PEF) were observed in the zileuton CR group compared to placebo. The adverse event profile was similar in the two treatment groups. Eleven patients (1.8%) receiving zileuton CR and 2 (0.7%) receiving placebo experienced elevations of alanine aminotransferase (ALT) >or= 3X the upper limit of normal (ULN). These elevations typically occurred (81.8%) during the first 3 months of exposure and most resolved within 21 days after discontinuation.

Background: Leukotriene modifiers have been shown to protect against exercise-induced bronchoconstriction (EIB) with repeated, chronic dosing., Objective: To study the onset and duration of protection against EIB after a single dose of montelukast, a leukotriene receptor antagonist., Methods: In this randomized, crossover, double-blind study, 51 adult asthma patients with EIB (> or = 20% postexercise decrease in forced expiratory volume in 1 second [FEV1]) received a single oral dose of montelukast (10 mg), or placebo followed by exercise challenge 2, 12, and 24 hours after dosing. The primary end point was maximum percentage decrease in FEV1 from preexercise baseline during 60 minutes after the 2-hour challenge., Results: At 2, 12, and 24 hours after dosing, the maximum decrease in FEV1 was 10.8% +/- 7.9%, 8.4% +/- 7.5%, and 8.3% +/- 7.3% for montelukast and 22.3% +/- 13.1%, 16.1% +/- 10.2%, and 16.9% +/- 11.7% for placebo, respectively (P < or = .001 at each time point). Postexercise recovery was quicker with montelukast than with placebo (P < or = .001); mean (95% confidence interval) differences were -26.8 minutes (-35.1 to -18.4 minutes), -16.0 minutes (-22.9 to -9.2 minutes), and -17.4 minutes (-24.9 to -9.9 minutes) at the 3 time points, respectively. At all time points, area under the curve for percentage decrease in FEV1 during 60 minutes after exercise was smaller after montelukast (P < or = .001); montelukast protected more patients against EIB (P < or = .001). Fewer patients required postexercise beta-agonist rescue at 2 hours after dosing with montelukast (P = .03)., Conclusion: Montelukast provided significant protection against EIB as soon as 2 hours after a single oral dose, with persistent benefit up to 24 hours.

Systemically bioavailable leukotriene receptor antagonists (LTRAs) can reduce the essential components of allergic inflammation in allergic rhinitis (AR) and asthma by blocking cysteinyl leukotriene (CysLT) activity, resulting in a wide range of clinical effects. CysLTs, mediators, and modulators in the pathophysiology of asthma and AR are a key target for therapy because they modulate production of hemopoietic progenitor cells, survival and recruitment of eosinophils to inflamed tissue, activity of cytokines and chemokines, quantity of exhaled NO, smooth-muscle contraction, and proliferation of fibroblasts. The mechanism of action of LTRAs leads to their effects on systemic allergic inflammatory processes.

Background: Inhaled beta(2)-agonists are widely used in asthma treatment. The design limitations of pressurized metered dose inhalers (pMDIs) have prompted the development of dry powder inhalers (DPIs) for the delivery of asthma medications., Objective: The goal of this study was to evaluate the efficacy, tolerability, and effect on asthma-related quality of life (QOL) of a long-acting beta(2)-adrenoreceptor agonist, formoterol, delivered via multidose DPI, compared with albuterol delivered via pMDI or placebo in adolescents and adults with persistent asthma., Methods: This multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study was conducted in outpatient clinics at 18 US centers. Adolescents and adults with persistent asthma received formoterol 10 pg BID via multidose DPI, albuterol 180 microg QID via pMDI, or placebo for 12 weeks. The primary efficacy variable was the 12-hour AUC of forced expiratory volume in 1 second (FEV(1)) after 12 weeks treatment. Secondary efficacy variables included asthma-related QOL, asthma symptom scores, rescue medication use, and other pulmonary function measures., Results: A total of 239 patients (147 females, 92 males; age range, 13-85 years) with persistent asthma were enrolled (formoterol, n = 80; albuterol, n = 79; placebo, n = 80). Formoterol delivered via the multidose DPI resulted in clinically relevant and statistically significant increases in 12-hour AUC of FEV(1) after 12 weeks of treatment compared with albuterol pMDI and placebo (P < 0.019 and P < 0.001, respectively). Asthma-related QOL (total score) was significantly improved with formoterol treatment compared with placebo (P < 0.015). Nocturnal asthma symptom scores significantly improved with formoterol compared with albuterol and placebo (P < 0.001 and P < 0.003, respectively) and rescue medication use was significantly less with formoterol compared with albuterol and placebo (P < 0.004 and P < 0.002, respectively). Treatment with formoterol was well tolerated., Conclusions: In this study of adolescents and adults with persistent asthma, 12 weeks of treatment with formoterol 10 microg BID delivered via a multidose DPI provided significantly greater 24-hour bronchodilation compared with albuterol and placebo and resulted in significant improvements in asthma-related QOL compared with placebo. Formoterol was well tolerated in these patients.

Over the last 20 years, the prevalence of asthma has nearly doubled and now affects 8-10% of the population in the United States. Asthma also remains a major illness in terms of morbidity and suffering, and is the leading cause of hospitalizations in children under 15 years of age. Because asthma poses a lifelong burden to patients and society, efforts to increase the understanding of its pathogenesis are a key factor leading to its control and cure. Consequently, the National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group of extramural experts, entitled "Future Research Directions in Asthma," on April 9-10, 2003, to identify research areas of greatest promise and opportunity in the field of asthma. The priority areas identified for research in asthma include: (1) innate immunity, adaptive immunity, and tolerance; (2) mechanisms and consequences of persistent asthma and asthma exacerbations; (3) airway remodeling: clinical consequences and reversibility (clinical relevance and resolution); (4) genetics/gene-environment interactions, pharmacogenetics; (5) intervention/prevention/therapeutics; and (6) vascular basis of asthma.

Background: Concurrent use of an inhaled corticosteroid (ICS) and an inhaled long-acting beta2-agonist provides better overall asthma control than the use of higher doses of ICS alone., Objective: The purpose of this investigation was to determine whether fluticasone propionate (FP) combined with salmeterol in the Diskus device can be used to reduce the dose of ICS in patients currently stable on medium-dose ICS while maintaining asthma control., Methods: This was a randomized, double-blind, parallel-group, 12- to 24-week trial consisting of a 3-part run-in period. The run-in period was designed to first establish FP 250 microg administered twice a day (bid) via Diskus as the minimum effective dose. During run-in period 1, patients received FP 220 microg bid or the equivalent for 10 to 14 days. Controlled patients moved to run-in period 2 (5-28 days), which assessed asthma stability on FP 100 microg bid administered via Diskus. Only patients who became unstable on FP 100 microg bid were eligible to enter run-in period 3 (26-30 days), during which they were placed on FP 250 microg bid and those regaining asthma control were eligible for randomization. The primary efficacy endpoint was the proportion of patients who remained in the study with no evidence of worsening asthma. Secondary efficacy measures included FEV1, morning peak expiratory flow, percent of symptom-free days, and daily albuterol use., Results: Only 5% of patients treated with FP100/salmeterol withdrew because of worsening asthma in the first 12 weeks; this compared with 7% in the FP250 group. All patients from a subset of sites continued in the study for an additional 12 weeks; only an additional 1% of patients treated with either FP100/salmeterol or FP250 withdrew because of worsening asthma. Secondary efficacy measures confirmed primary efficacy results., Conclusion: In patients requiring FP250 bid for asthma stability, FP100/salmeterol bid was steroid-sparing, allowing a 60% reduction in the FP dose while maintaining overall asthma control.