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Fractional exhaled nitric oxide (FeNO) has potential as a prognostic biomarker in asthma, but its prognostic value among other recognised indicators is unclear. We assessed the added prognostic value of baseline FeNO to blood eosinophil count and prior severe asthma exacerbations for subsequent exacerbations.In this post-hoc analysis of the 52-week, double-blind, phase 3 LIBERTY ASTHMA QUEST study, we identified 620 patients with moderate-to-severe asthma who were randomly assigned to placebo; had uncontrolled asthma with inhaled glucocorticoids plus up to two controllers; one or more exacerbations in the previous year; FEVPatients with baseline FeNO of 50 ppb or higher (n=144) had a 1·54-times higher exacerbation rate than patients with FeNO of less than 25 ppb (n=291; relative risk 1·54 [95% CI 1·11-2·14]; p=0·0097). Patients with baseline FeNO of 25 to50 ppb (n=185) had a 1·33-times higher exacerbation rate than patients with FeNO of less than 25 ppb (1·33 [0·99-1·78]; p=0·0572). Patients with baseline FeNO of 25 ppb or higher, a blood eosinophil count of 150 cells per μL or higher, and two or more prior exacerbations (n=157) had an exacerbation rate 3·62-times higher than patients with FeNO of less than 25 ppb, a blood eosinophil count of less than 150 cells per μL, and one prior exacerbation (n=116; 3·62 [1·67-7·81]; p=0·0011).In uncontrolled, moderate-to-severe asthma, higher baseline FeNO levels were associated with greater risk of severe asthma exacerbations, particularly in combination with elevated eosinophil count and prior exacerbations, supporting the added value of FeNO as a prognostic biomarker. Further research is needed to confirm FeNO as an independent predictor for asthma exacerbations.Sanofi and Regeneron Pharmaceuticals.

Despite advances in treatment, asthma remains uncontrolled in many patients, with increased risk of exacerbation and associated healthcare resource utilization (HCRU). We describe patient characteristics, exacerbations, asthma control, and HCRU using GINA treatment step (GS) as a proxy for asthma severity. .Using a large, US, health-claims database, 4 longitudinal cohorts of 517,738 patients in GS2-5, including a subgroup of patients with baseline eosinophil (EOS) counts, were analyzed retrospectively (study period 2010 - 2016). Index for each cohort was patients' first time entering the GS, determined by first claim of first regimen. Uncontrolled asthma was defined according to published criteria as a multi-dimensional measure that includes number of exacerbations. Key variables including, baseline characteristics, post-index exacerbations, and HCRU (all-cause and asthma-specific events) are summarized by descriptive statistics.Uncontrolled asthma was reported in 19.8% patients in GS2, 44.8% in GS3, 49.3% in GS4, and 58.6% in GS5. Annualized mean (SD) rates of exacerbation 12 months post-index generally increased across GS2-5 (0.26 [0.86], 0.32 [0.79], 0.36 [0.83], 0.29 [0.86], respectively). HCRU also increased with increasing GS, with higher HCRU among the uncontrolled cohort within each GS. In patients with EOS ≥300 cells/µL, uncontrolled asthma also increased with increasing GS (21.8%, 43.9%, 50.5%, 67.2% for GS2-5, respectively).This large database study provides real-world evidence of the substantial degree of uncontrolled asthma in US clinical practice across GS, supporting calls for better asthma management. Healthcare burden tends to increase with lack of control in all groups, highlighting the need for improved patient education, adherence, access, and treatment optimization.Supplemental data for this article can be accessed at publisher's website.

Background Frequent exacerbations are associated with greater FEV1 decline in patients with asthma. The effect of omalizumab versus placebo on lung function in patients experiencing asthma exacerbations has not been previously examined. Objective To evaluate the relationship between postbaseline (treatment phase) exacerbation status and lung function decline in children, adolescents, and adults treated with omalizumab versus placebo using data from 3 pediatric and adolescent/adult studies. Methods Changes in percent predicted FEV1 (ppFEV1) and FEV1 by treatment (omalizumab/placebo) and postbaseline exacerbation status (exacerbators/nonexacerbators) were assessed in patients aged 6 to 11 years (IA05, n = 576) and 12 to 75 years (EXTRA/INNOVATE pooled, n = 1202). Pediatric patients were examined at treatment weeks 12, 24, 28, 40, and 52, and adolescent/adult data at weeks 4, 12, 20, and 28. Results Omalizumab-treated patients experienced larger increases in ppFEV1 and FEV1 compared with placebo-treated patients in the pediatric and pooled adolescent/adult populations. The response was observed in pediatric exacerbators, with significantly larger increases in ppFEV1 and FEV1 at week 12 (mean difference [95% CI], 4.11% [0.93%-7.30%], P = .011 for ppFEV1; 80 [10-140] mL, P = .017 for FEV1) and week 28 (mean difference [95% CI], 3.65% [0.11%-7.19%], P = .043 for ppFEV1; 100 [30-170] mL, P = .007 for FEV1). In the adolescent/adult population, both exacerbators and nonexacerbators derived similar benefit with omalizumab compared with placebo. Conclusions Findings from this post hoc analysis suggest that omalizumab may confer some protection against lung function decline among patients who experienced exacerbations during treatment.

Asthma treatments have evolved from bronchodilators to interventions directed toward the regulation of airway inflammation. From these advances has come greater disease control and reduced morbidity. The addition of biologics directed toward specific pathways of inflammation has advanced the efficacy of asthma control. With these treatment advances, a renewed interest in achieving a remission in asthma has arisen. Although asthma remission has been considered to reflect a "cure," new evaluations of this concept have proposed criteria for remission while on treatment. These criteria reflect a high level of disease control including absence of symptoms, optimization and stabilization of lung function, and absence of the use of systemic corticosteroids and have been proposed to indicate a remission of disease activity. Given the added efficacy found with biologics in asthma treatment for patients with moderate to severe disease, the question has arisen as to whether the use of biologics meets criteria for remission and may this change a component of underlying disease and risks. Biologics are highly effective in reducing exacerbations, diminishing symptoms, and improving lung function in well-defined asthma populations. At present, however, biologics achieve some, but in most cases not all criteria for a remission on treatment. However, the concept of promoting treatment efforts to achieve disease remission in asthma is important, potentially achievable, and merits consideration for future guideline-directed care approaches.

Objective The use of biologics in severe asthma has made substantial strides in disease management and fostered a personalized medicine approach; however, how, when, and which biologic to choose are unresolved issues, which form the focus of this review. Data Sources The data sources were published literature, including current guidelines, available through PubMed searches and online resources. Study Selections Studies and randomized controlled trials pertaining to the use of biologics in various phenotypes and/or endotypes of asthma and comparative analyses between biologics in asthma were included. Results Inflammatory constructs in asthma are complex and translate differentially into clinical practice for both disease severity and treatment responsiveness. The utilization of biologics, which target selected components of inflammation, has begun to dramatically improve the course of management for many patients with severe asthma. A retuning of our approach into selecting appropriate patient cohorts or phenotypes for studies and selection of clinically relevant outcomes, which are reflected by existing and novel emerging biomarkers, is enabling a paradigm shift in asthma management. Comparing the efficacy of the available biologics for asthma is challenging as no direct head-to-head studies are available, and indirect comparisons to this query provide varying results. Conclusion Significant progress has been achieved in the management of severe asthma with treatment of target-specific biologics. Sophisticated algorithms and trial designs, using a combination of available biomarker profiles and clinical characteristics to stratify patient populations into more precise subphenotypes and endotypes to guide our choice of a biologic or therapy, are critically needed but currently not formulated.

Significance Although resistance to glucocorticoids is a major clinical problem, the underlying mechanisms are unknown. It is known that glucocorticoid use can suppress adrenal androgen production. In population studies, animal models, and cell culture experiments, androgens are associated with several benefits in asthma, but neither androgen use in glucocorticoid-resistant asthma nor the genetic determinants of androgen responsiveness have been studied in humans. A missense-encoding variant in HSD3B1 is known to regulate conversion from adrenal precursors to potent androgens and clinical outcomes in prostate cancer. This is the first genetic evidence to our knowledge that implicates an androgen synthesis variant in resistance to glucocorticoids for asthma or any other inflammatory disease. Furthermore, this study demonstrates an adverse consequence of adrenal androgen suppression with glucocorticoid therapy., Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. HSD3B1 encodes for 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive HSD3B1(1245A) allele limits conversion, whereas the adrenal permissive HSD3B1(1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEV1PP). HSD3B1(1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEV1PP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined (n = 318). Validation was performed in a second cohort (SARP I&II; n = 184). DHEA-sulfate is associated with FEV1PP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEV1PP compared with noGC patients (54.3% vs. 75.1%; P < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEV1PP difference in GC vs. noGC patients (73.4% vs. 78.9%; P = 0.39). Results were independently confirmed: FEV1PP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 (P < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 (P = 0.92). The adrenal restrictive HSD3B1(1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3β-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.

Background: This analysis from the 6-month AUSTRI study (GSK115359, n=11,679) explored the rate and heterogeneity of severe exacerbations with fluticasone propionate (FP) alone compared with FP plus salmeterol (FSC) in patients aged ≥12 years with persistent asthma and a 1-year history of exacerbations. Methods: Primary cause of severe exacerbation was grouped as: environmental, allergic, infective and other. Patient characteristics according to exacerbation (yes/no), primary cause, and period before and after events (Day -14 to +14) vs a corresponding 29-day period in non-exacerbating patients, were analysed post-hoc. Results: 1077 (9.2%) patients reported ≥1 severe exacerbation during study. Exacerbation cause was recorded as environmental for 14.3% of exacerbations, allergic for 8.4%, and infective for 45.3%. Rate of asthma exacerbations was significantly reduced by 21.8% (Ratio: 0.782; 95% CI: 0.691-0.886) for FSC vs FP patients. In patients with exacerbation, mean rescue use (puffs/day) increased from 1.5 (Day -14) to 3.2 (Day 1) and back to 1.5 (Day +14), compared with mean 0.8 puffs/day in non-exacerbating patients (Fig. 1). Conclusions: In patients with a history of severe asthma exacerbations, regular twice-daily dosing with FSC was associated with a lower rate of asthma exacerbations compared with FP. Rescue medication use was higher pre- and post-exacerbation than the average for non-exacerbating patients. Funding: GSK (ID 213505)

Background Benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody. Treatment with benralizumab significantly reduces exacerbations and improves lung function after 1 year for patients with severe, uncontrolled eosinophilic asthma. Objective We explored whether benralizumab efficacy was sustained after an additional year of treatment while maintaining an acceptable safety profile. Methods Data from the pivotal 48-week SIROCCO and 56-week CALIMA studies were integrated with data from the predefined 56-week adult phase of the BORA extension study to provide a 2-year integrated efficacy and safety analysis of benralizumab. BORA enrolled patients who had completed SIROCCO or CALIMA. Patients receiving benralizumab 30 mg subcutaneously, either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses Q4W), were assessed. Efficacy was evaluated based on baseline blood eosinophil counts from the pivotal studies (≥300 and

BACKGROUND: Multi-center randomized controlled trials (RCTs) for asthma management that incorporate usual care regimens could benefit from standardized application of evidence-based guidelines. OBJECTIVE: To evaluate performance of a computerized decision support tool, Asthma Control Evaluation and Treatment (ACET) Program, to standardize usual care regimens for asthma management in RCTs. METHODS: Children and adolescents with persistent, uncontrolled asthma, living in urban census tracts were recruited into 3 multi-center RCTs (each with a usual care arm) between 2004 and 2014. A computerized decision support tool scored asthma control and assigned an appropriate treatment step based on published guidelines. Control level determinants (symptoms, rescue medication use, pulmonary function measure, adherence estimates) were collected at visits and entered into the ACET Program. Changes in control level and treatment steps were examined during the trials. RESULTS: At screening, over half the participants were rated as not or poorly controlled. The proportion of participants who gained good control between screening and randomization increased significantly in all three trials. Between 51% and 70% were well-controlled by randomization. The proportion of well-controlled participants remained constant or improved slightly from randomization until the last post-treatment visit. Night symptoms were the most common control level determinant; there were few (

RATIONALE: ACE2, a critical SARS-CoV-2 entry receptor, has reduced expression in those with allergic sensitizations. Consequently, SARS-CoV-2 infections may impact patients with allergic asthma (AA) or no evidence of allergic asthma (NEAA) differently. We explore demographics of SARS-CoV-2-infected AA and NEAA patients. METHODS: Retrospective data were obtained from the US-representative COVID-19 Optum Electronic Health Record dataset through 10/15/2020. Index was the earliest date of presumed diagnosis or laboratory-confirmed SARS-CoV-2 infection (CDC guidelines) from 02/20/2020, defined as (1) diagnosis code of U07.1/U07.2, or (2) positive diagnostic test for SARS-CoV-2, (3) diagnosis code of B97.29 without a negative molecular SARS-CoV-2 test within a 14-day window (+/-7 days). Patients SARS-CoV-2-positive with evidence of moderate-to-severe asthma at any time (ICD-10 J45.4X or J45.5X) were included. AA was defined as positive specific IgE (≥0.35 kU/L) serum test or skin prick test (code 95004) ordered by a specialist (eg, allergist, pulmonologist, dermatologist) or omalizumab use. NEAA was defined as failing to meet the AA definition and patients with allergic comorbidities were excluded. Baseline demographic and clinical characteristics were obtained 6-12 months before COVID-19 diagnosis. RESULTS: The database included 242,280 SARS-CoV-2-positive patients;569 (0.2%) had evidence of comorbid AA and 3137 (1.3%) had asthma and NEAA. For AA patients, mean (SD) age at index was 48.2 (18.2) years;70.3% were female, with 54.3% White, 26.4% Black, and 12.5% Hispanic (Table 1). Most AA patients were from the US Midwest and Northeast (80.5%). NEAA patients had similar demographics: mean (SD) age at index was 50.7 (19.5) years;67.6% female;with 60.0% White, 21.5% Black, and 13.0% Hispanic;and 81.5% were from the US Midwest and Northeast. A greater proportion of patients had severe asthma in AA versus NEAA groups (220/569 [38.7%] versus 457/3137 [14.6%]). More patients with AA versus NEAA used asthma biologic treatment (62/569 [10.9%] vs 27/3137 [0.9%]). Comorbid conditions (hypertension, diabetes, pregnancy, chronic obstructive pulmonary disease, and Charlson Comorbidity Index), body mass index, and smoking history were comparable between groups. A higher proportion of NEAA patients were current smokers. CONCLUSIONS: A smaller proportion of patients with SARS-CoV-2 infection in this retrospective analysis had comorbid AA versus NEAA, whereas patient demographics and comorbidities were generally comparable between groups. Differences included the proportion of patients with severe asthma and biologic treatment use (greater in AA), and current smoking (lower in AA). The observed lower prevalence of AA versus NEAA in SARS-CoV-2-positive patients warrants further investigation.

Background Nasal allergen challenge (NAC) could be a means to assess indication and/or an outcome of allergen-specific therapies, particularly for perennial allergens. NACs are not commonly conducted in children with asthma and cockroach NACs are not well established. This study's objective was to identify a range of German cockroach extract doses that induce nasal symptoms and to assess the safety of cockroach NAC in children with asthma. Methods Ten adults (18-37 years) followed by 25 children (8-14 years) with well-controlled, persistent asthma and cockroach sensitization underwent NAC with diluent followed by up to 8 escalating doses of cockroach extract (0.00381 -11.9 mcg/mL Bla g 1). NAC outcome was determined by Total Nasal Symptom Score (TNSS) and/or sneeze score. Cockroach allergen-induced T cell activation and IL-5 production were measured in peripheral blood mononuclear cells. Results 67% (6/9) of adults and 68% (17/25) of children had a positive NAC at a median response dose of 0.120 mcg/mL [IQR 0.0380-0.379 mcg/mL] of Bla g 1. Additionally, three children responded to diluent alone, and did not receive any cockroach extract. Overall, 32% (11/34) were positive with sneezes alone, 15% (5/34) with TNSS alone, and 21% (7/34) with both criteria. At baseline, NAC responders had higher cockroach-specific IgE (p=0.03), lower cockroach-specific IgG/IgE ratios (children, p=0.002), and increased cockroach-specific IL-5-producing T lymphocytes (p=0.045). The NAC was well tolerated. Conclusion We report the methodology of NAC development for children with persistent asthma and cockroach sensitization. This NAC could be considered a tool to confirm clinically relevant sensitization and to assess responses in therapeutic studies.

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

Background: Five clinical clusters (early-onset increasing severity clusters 1, 2, and 4, late-onset severe cluster 3, and late-onset severe obstructed cluster 5) have been identified in the SARP cross-sectional cohort (n=726; Moore 2010). This approach demonstrated asthma heterogeneity and showed differential responses to biologic therapy (Bleecker 2019 ERS). Objective: Investigate longitudinal phenotypes of clinical clusters in the SARP longitudinal cohort. Methods: Subjects in longitudinal cohort (n=594) with 3-year (n=461) and 5-year (n=272) were assigned to clinical clusters using an 11-variable discriminant function. Phenotypes were compared using Kruskal-Wallis test. Results: Baseline clinical characteristics of five clusters in the longitudinal cohort were similar to the cross-sectional cohort. From baseline to Year 5, 2/3 of subjects remained in the same cluster and 1/6 each changed to more severe or milder clusters. Cluster 5 had consistently higher numbers of asthma exacerbations than clusters 1-4. Responses to a corticosteroid evoked phenotype (before and after 40 mg intramuscular triamcinolone): severe asthma clusters 3-5 had greater % increase in FEV1 than non-severe clusters (p Conclusions: SARP clinical clusters are reproducible in the longitudinal cohort. Severe clusters have better responses to corticosteroid. Cluster 5 has consistently greater asthma exacerbations over time. Longitudinal changes in FEV1 primarily determine cluster progression.

Background: Comorbid perennial allergic rhinitis (PAR) or year-round aeroallergen sensitivity substantially contributes to disease burden in patients with asthma. Dupilumab blocks the shared receptor for interleukin (IL) 4 and IL-13, key drivers of type 2 inflammation that play important roles in asthma and PAR. In the LIBERTY ASTHMA QUEST trial (NCT02414854), dupilumab reduced severe asthma exacerbations and improved forced expiratory volume in 1 second (FEV1) in patients with uncontrolled, moderate-to-severe asthma, with greater efficacy observed in patients with elevated type 2 inflammatory biomarkers at baseline (blood eosinophils and fractional exhaled nitric oxide). Objective: To assess dupilumab efficacy in LIBERTY ASTHMA QUEST patients with comorbid PAR. Methods: Severe asthma exacerbation rates, FEV1, asthma control (5-item Asthma Control Questionnaire), rhinoconjunctivitis-specific health-related quality of life (Standardized Rhinoconjunctivitis Quality of Life Questionnaire +12 scores), and type 2 inflammatory biomarkers during the 52-week treatment period were assessed. Results: A total of 814 of the 1902 patients (42.8%) had comorbid PAR (defined as an allergic rhinitis history and >= 1 perennial aeroallergen specific immunoglobulin E (IgE) level >= 0.35 kU/L at baseline). Dupilumab, 200 and 300 mg every 2 weeks, vs placebo reduced severe exacerbations rates by 32.2% and 34.6% (P = 300 cells/mL) and fractional exhaled nitric oxide. Dupilumab treatment also numerically improved the 5-item Asthma Control Questionnaire and Standardized Rhinoconjunctivitis Quality of Life Questionnaire +12 scores and suppressed type 2 inflammatory biomarkers. Conclusion: Dupilumab improved key asthma-related outcomes, asthma control, and rhinoconjunctivitisspecific health-related quality of life while suppressing type 2 inflammatory biomarkers and perennial allergen-specific IgE in patients with moderate-to-severe asthma and comorbid PAR, highlighting its dual inhibitory effects on IL-4 and IL-13 and its role in managing asthma and PAR. (C) 2020 American College of Allergy, Asthma & Immunology.

McDonald and colleagues are the first to demonstrate in a clinical trial that treatment of treatable traits in severe asthma improved disease control compared to guideline-directed carehttp://bit.ly/2QXZG6v

For patients with severe asthma, disease control is not achieved resulting in persistent morbidity and risks for exacerbations. The advent of biologics is providing a new form of treatment for many with severe asthma.Four mAb biologics are approved for clinical use: omalizumab (anti-IgE) and three antieosinophilic interventions (mepolizumab, reslizumab, and benralizumab). These four biologics target components of the type 2-inflammatory pathway which is reflected by biomarkers: peripheral blood eosinophils and exhaled nitric oxide. In severe asthma, biologics have reduced asthma exacerbations. The antieosinophilic biologics have also improved lung function. The safety profile of these biologics has been good.For patients with severe asthma and biomarkers indicating a type 2 inflammatory pathway, the addition of biologics has proven to be an effective approach to achieve disease control and is an appropriate next step treatment.

Additional management options, and better use of current options, are needed to help support a large proportion of patients with asthma whose symptoms remain uncontrolled on inhaled corticosteroids (ICS). Here, we aim to review the safety and efficacy of adding tiotropium to ICS compared with adding a long-acting β2-agonist (LABA) for adults whose asthma is not well controlled on ICS alone. Adding tiotropium to a background of ICS provides beneficial effects that are comparable with addition of a LABA in terms of lung function measures, exacerbations, asthma control and other endpoints. In addition, tiotropium and LABAs are both well tolerated. Some patients respond to either tiotropium or LABA treatment, but not both, suggesting that there are groups of patients that may respond better to one of these drugs. Currently, tiotropium is recommended as an add-on therapy in patients with severe asthma (Global Initiative for Asthma Steps 4 and 5) whose asthma is uncontrolled despite treatment with ICS/LABA. Tiotropium is also effective in patients with less severe disease and may benefit patients who experience adverse events from LABA treatment or where LABAs are ineffective. Tiotropium is therefore an important therapeutic option in asthma, not only as recommended as an add-on treatment with ICS/LABA, but also as an alternative to the addition of LABA to maintenance therapy with an ICS.

BACKGROUND: Safety concerns regarding long-acting β2-agonists (LABAs) in asthma management were initially identified in a large postmarketing trial in which the risk of death was increased. In 2010, the Food and Drug Administration (FDA) mandated that the four companies marketing LABAs for asthma perform prospective, randomized, controlled trials comparing the safety of combination therapy with a LABA plus an inhaled glucocorticoid with that of an inhaled glucocorticoid alone in adolescents (12 to 17 years of age) and adults. In conjunction with the FDA, the manufacturers harmonized their trial methods to allow an independent joint oversight committee to provide a final combined analysis of the four trials.METHODS: As members of the joint oversight committee, we performed a combined analysis of the four trials comparing an inhaled glucocorticoid plus a LABA (combination therapy) with an inhaled glucocorticoid alone. The primary outcome was a composite of asthma-related intubation or death. Post hoc secondary outcomes included serious asthma-related events and asthma exacerbations.RESULTS: Among the 36,010 patients in the intention-to-treat study, there were three asthma-related intubations (two in the inhaled-glucocorticoid group and one in the combination-therapy group) and two asthma-related deaths (both in the combination-therapy group) in 4 patients. In the secondary analysis of serious asthma-related events (a composite of hospitalization, intubation, or death), 108 of 18,006 patients (0.60%) in the inhaled-glucocorticoid group and 119 of 18,004 patients (0.66%) in the combination-therapy group had at least one composite event (relative risk in the combination-therapy group, 1.09; 95% confidence interval [CI], 0.83 to 1.43; P=0.55); 2100 patients in the inhaled-glucocorticoid group (11.7%) and 1768 in the combination-therapy group (9.8%) had at least one asthma exacerbation (relative risk, 0.83; 95% CI, 0.78 to 0.89; PCONCLUSIONS: Combination therapy with a LABA plus an inhaled glucocorticoid did not result in a significantly higher risk of serious asthma-related events than treatment with an inhaled glucocorticoid alone but resulted in significantly fewer asthma exacerbations.

Introduction Dupilumab, a fully human anti-IL-4Rα monoclonal antibody, inhibits signaling of both interleukin (IL)-4 and IL-13, which are key drivers of type 2-mediated inflammation. Dupilumab is approved in the EU, USA, and other countries for the treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis. Following positive phase 2 results in asthma, the phase 3 Liberty Asthma QUEST trial was initiated to provide further evidence for dupilumab efficacy and safety in patients with uncontrolled, moderate-to-severe asthma. Methods Liberty Asthma QUEST is a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (NCT02414854) in patients with persistent asthma who are receiving continuous treatment with inhaled corticosteroids (ICS) plus one or two other asthma controller medicines. A total of 1902 patients (aged ≥ 12 years) were randomized in a 2:2:1:1 ratio to receive 52 weeks of add-on therapy with subcutaneously administered dupilumab 200 or 300 mg every 2 weeks or matched placebo. The study consisted of a 4 ± 1-week screening period, 52-week randomized treatment period, and 12-week post-treatment follow-up period. All patients continued to receive their prescribed ICS plus up to two additional controller medications. The primary efficacy endpoints were annualized rate of severe exacerbation events during the 52-week treatment period and absolute change from baseline in pre-bronchodilator FEV1 at week 12. Conclusion Uncontrolled asthma patients with persistent symptoms represent a population of significant unmet need, for whom new treatments are required. Patients with severe asthma are at high risk of asthma exacerbations, and face an accelerated decline in lung function and impaired quality of life. QUEST examines the efficacy of dupilumab in this at-risk patient population; it is the largest placebo-controlled study in uncontrolled, moderate-to-severe asthma with a biologic agent to date, and the only phase 3 study of a biologic therapy of asthma that enrolled patients irrespective of baseline type 2 inflammatory biomarker levels. Funding Sanofi and Regeneron Pharmaceuticals, Inc. Clinical Trials.gov Identifier NCT02414854.

BACKGROUND: Airway neutrophils are abundant in some children with severe asthma, but their functions are poorly understood. OBJECTIVE: We hypothesized that the inflammatory airway environment of children with neutrophil-predominant severe asthma promotes neutrophil survival and disrupts neutrophil-associated innate immune defenses. METHODS: Sixty seven children with severe asthma refractory to high-dose inhaled corticosteroid (ICS) treatment undergoing bronchoscopy with bronchoalveolar lavage (BAL) for clinical indications were stratified into neutrophil “high” versus “low” groups based on BAL differential counts. Neutrophil activation markers, functional assays and phenotyping studies were performed as well as airway macrophage functional assays. Results were compared to those from children with moderate asthma treated with ICS. RESULTS: Children with neutrophil-predominant severe asthma had increased markers of neutrophil activation/degranulation and a greater magnitude of airway pro-inflammatory cytokine and chemokine release. Primary neutrophils exposed to BAL of these children exhibited greater phagocytic capability and greater neutrophil extracellular trap formation, but a more impaired respiratory burst. Despite greater abundance of airway TGF-β1 the neutrophils were not more apoptotic. Instead, neutrophils had a highly pro-inflammatory phenotype associated with a number of surface markers that regulate neutrophil activation, recruitment/migration and granule release. Airway macrophages from children with neutrophil-predominant severe asthma were also more pro-inflammatory with impaired phagocytosis and increased apoptosis. CONCLUSIONS: Children with neutrophil-predominant severe asthma have pro-inflammatory neutrophils with enhanced survival. Airway macrophages are also pro-inflammatory and dysfunctional and may contribute to global innate immune impairment. Therapies that target neutrophils and related inflammation may be warranted in this subset of children.

Background Adults and adolescents with severe asthma who completed the 48-week SIROCCO and 56-week CALIMA phase III benralizumab trials entered the safety extension study BORA (NCT02258542). The continued safety and efficacy of benralizumab in the first year of BORA (year 2 of treatment) have been reported. Objective We sought to report outcomes for adolescents during years 2 and 3 of treatment in BORA. Methods Patients on benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W) in SIROCCO/CALIMA continued their regimens in BORA (Q4W/Q4W and Q8W/Q8W, respectively), whereas placebo patients were rerandomized 1:1 to benralizumab (placebo/Q4W and placebo/Q8W, respectively) for 108 weeks. The primary outcome was safety; secondary outcomes included reduction in annual asthma exacerbation rate and change from baseline in prebronchodilator FEV1. Results Adolescents (N = 86) were treated with benralizumab Q8W (n = 61) or Q4W (n = 25); 69 completed treatment (Q8W: n = 51; Q4W: n = 18). For Q4W and Q8W regimens, rates of treatment-emergent adverse events were 68% (17 of 25) and 74% (45 of 61), respectively, rates of treatment-emergent adverse events (TEAEs) were 68% (17/25) and 74% (45/61), TEAEs leading to discontinuation were 4% (1/25) and 0%, serious AEs were 8% (2/25) and 7% (4/61), and no deaths occurred. In efficacy analyses, 69% (42 of 61) Q8W patients were exacerbation-free (placebo/Q8W: 62% [18 of 29], Q8W/Q8W: 75% [24 of 32]). Mean ± SD change in FEV1 at week 108 versus BORA baseline was 0.327 ± 0.452 L (placebo/Q8W) and 0.323 ± 0.558 L (Q8W/Q8W). Conclusions Safety and efficacy profiles in this 2-year extension study (up to 3 years of benralizumab treatment in adolescents) were consistent with previous findings.

Asthma is frequently undertreated, resulting in a relatively high prevalence of patients with uncontrolled disease, characterized by the presence of symptoms and risk of adverse outcomes. Patients with uncontrolled asthma have a higher risk of morbidity and mortality, underscoring the importance of identifying uncontrolled disease and modifying management plans to improve control. Several assessment tools exist to evaluate control with various cutoff points and measures, but these tools do not reliably correlate with physiological measures and should be considered a supplement to physiological tests. When attempting to improve control in patients, nonpharmacological interventions should always be attempted before changing or adding pharmacotherapies. Among patients with severe, uncontrolled asthma, individualized treatment based on asthma phenotype and eosinophil presence should be considered. The efficacy of the anti-IgE antibody omalizumab has been well established for patients with allergic asthma, and novel biologic agents targeting IL-5, IL-13, IL-4, and other allergic pathways have been investigated for patients with allergic or eosinophilic asthma. Fevipiprant (a CRTH2 [chemokine receptor homologous molecule expressed on Th2 cells] antagonist) and imatinib (a tyrosine kinase inhibition) are examples of nonbiologic therapies that may be useful for patients with severe, uncontrolled asthma. Incorporation of new and emerging treatment into therapeutic strategies for patients with severe asthma may improve outcomes for this patient population.

Guideline-based management of asthma focuses on disease severity and choosing the appropriate medical therapy to control symptoms and reduce the risk of exacerbations. However, irrespective of asthma severity and often despite optimal medical therapy, patients may experience acute exacerbations of symptoms and a loss of disease control. Asthma exacerbations are most commonly triggered by viral respiratory infections, particularly with human rhinovirus (RV). Given the importance of these events to asthma morbidity and healthcare costs, we will review common inciting factors for asthma exacerbations and approaches to prevent and treat these events.

Asthma is one of the most common chronic diseases of childhood. Allergen sensitization and high frequencies of comorbid allergic diseases are characteristic of severe asthma in children. Omalizumab, an anti-IgE mAb, is the first targeted biologic therapeutic approved for the treatment of moderate-to-severe persistent allergic asthma (AA) that remains uncontrolled despite high-dose inhaled corticosteroids plus other controller medications. Since its initial licensing for use in adults and adolescents 12 years of age and older, the clinical efficacy, safety, and tolerability of omalizumab have been demonstrated in several published clinical trials in children aged 6 to less than 12 years with moderate-to-severe AA. These studies supported the approval of the pediatric indication (use in children aged ≥6 years) by the European Medicines Agency in 2009 and the US Food and Drug Administration in 2016. After this most recent change in licensing, we review the outcomes from clinical trials in children with persistent AA receiving omalizumab therapy and observational studies from the past 7 years of clinical experience in Europe. Data sources were identified by using PubMed in 2016. Guidelines and management recommendations and materials from the recent US Food and Drug Administration's Pediatric Advisory Committee meeting are also reviewed.

Cytokine antagonists are monoclonal antibodies that offer new treatment options for refractory asthma but will also increase complexity because they are effective only for patients with certain asthma subtypes that remain to be more clearly defined. The clinical and inflammatory heterogeneity within refractory asthma makes it difficult to manage the disease and to determine which, if any, biologic therapy is suitable for a specific patient. The purpose of this article is to provide a data-driven discussion to clarify the use of biologic therapies in patients with refractory asthma. We first discuss the epidemiology and pathophysiology of refractory asthma. We then interpret current evidence for biomarkers of eosinophilic or type 2-high asthma so that clinicians can determine potential treatments for patients based on knowledge of their effectiveness in specific asthma phenotypes. We then assess clinical data on the efficacy, safety, and mechanisms of action of approved and pipeline biologic therapies. We conclude by discussing the potential of phenotyping or endotyping refractory asthma and how biologic therapies can play a role in treating patients with refractory asthma.

Background Low-dose inhaled corticosteroids (ICS) are highly effective for reducing asthma exacerbations and mortality. Conventionally, ICS treatment is recommended for patients with symptoms on more than 2 days per week, but this criterion has scant evidence. We aimed to assess the validity of the previous symptom-based cutoff for starting ICS by establishing whether there was a differential response to budesonide versus placebo for severe asthma exacerbations, lung function, and asthma symptom control across subgroups identified by baseline asthma symptom frequency. Methods We did a post-hoc analysis of the 3 year inhaled Steroid Treatment As Regular Therapy (START) study, done in 32 countries, with clinic visits every 3 months. Patients (aged 4–66 years) with mild asthma diagnosed within the previous 2 years and no previous regular corticosteroids were randomised to receive once daily, inhaled budesonide 400 μg (those aged 1 to ≤2 symptom days per week, 0·57 [0·41–0·79] >2 symptom days per week, pinteraction=0·94), and the decline in postbronchodilator lung function was less at 3 years' follow-up (pinteraction=0·32). For budesonide versus placebo, severe exacerbations requiring oral or systemic corticosteroids were reduced (rate ratio 0·48 [0·38–0·61] 0–1 symptom days per week, 0·56 [0·44–0·71] >1 to ≤2 symptom days per week, and 0·66 [0·55–0·80] >2 symptom days per week, pinteraction=0·11), prebronchodilator lung function was higher, and symptom-free days were more frequent (pinteraction=0·43; symptom-free days pinteraction=0·53). Similar results were noted when participants were classified by any guidelines criterion as so-called persistent versus so-called intermittent asthma. Interpretation In mild recent-onset asthma, once daily, low-dose budesonide decreases SARE risk, reduces lung function decline, and improves symptom control similarly across all symptom subgroups. The results do not support restriction of inhaled corticosteroids to patients with symptoms on more than 2 days per week and suggest that treatment recommendations for mild asthma should consider both risk reduction and symptoms. Funding AstraZeneca.

Introduction Dupilumab, a fully human VelocImmune®-derived monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4/IL-13, key drivers of type 2 inflammation in multiple diseases. In the phase 3 LIBERTY ASTHMA QUEST study (NCT02414854), add-on dupilumab 200 mg/300 mg every 2 weeks (q2w) vs placebo reduced severe exacerbations and improved pre-bronchodilator forced expiratory volume in 1 second (FEV1) in patients with uncontrolled, moderate-to-severe asthma. Treatment effects were greater in patients with elevated type 2 biomarkers at baseline. This post hoc analysis assessed dupilumab effect on severe asthma exacerbation rates by baseline disease characteristics in patients with baseline blood eosinophils ≥150 cells/µL or fractional exhaled nitric oxide (FeNO) ≥20 ppb. Methods Annualized severe exacerbation rates during the 52-week treatment period were assessed using negative binomial regression models. Results Dupilumab 200 mg/300 mg q2w vs placebo reduced the annualized rate of severe exacerbations during the 52-week treatment period in all subgroups of patients defined by controller medications at randomization, pre-bronchodilator FEV1 (≤1.75 L/>1.75 L), number of severe asthma exacerbations (≥1, ≥2, ≥3) in the previous year, smoking history (never smoked/former smoker), and age at asthma onset (≤40 years/>40 years) (figure 1). The effect of dupilumab was significant in all subgroups except for 2 subgroups with relatively fewer patients. Overall, the most frequent dupilumab 200 mg/300 mg vs matched placebo adverse event was injection-site reaction (15%/18% vs 5%/10%). Conclusions Dupilumab significantly reduced severe exacerbations across most baseline disease characteristics in patients with uncontrolled, moderate-to-severe asthma with evidence of type 2 inflammation at baseline. Dupilumab was generally well tolerated.

Introduction: Obesity is associated with increased asthma severity, poor asthma control, and poor response to inhaled corticosteroids. Dupilumab (DPL), a fully human monoclonal antibody blocks the shared receptor component for interleukin (IL)-4/IL-13, key drivers of type 2 inflammation. In the phase 3 QUEST trial (NCT02414854), add-on DPL 200/300 mg every 2 wks (q2w) vs placebo (PBO) reduced severe exacerbations and improved pre-bronchodilator (BD) FEV1 in patients (pts) with uncontrolled, moderate-to-severe asthma. Aim: To assess the effect of baseline (BL) body mass index (BMI) on DPL efficacy in uncontrolled, moderate-to-severe asthma pts. Methods: Annualized rate of severe exacerbations during the 52-wk treatment period and LS mean (LSM) change from BL at Wk 12 in pre-BD FEV1 were assessed by BL BMI subgroups ( Results: Across all BL BMI subgroups, both DPL 200 and 300 mg q2w vs PBO consistently reduced severe exacerbations (–35.1 to –51.4%; all P Conclusion: Dupilumab reduced severe exacerbations and improved FEV1 in pts with uncontrolled, moderate-to-severe asthma, regardless of BL BMI or DPL dose received.

Introduction: Dupilumab (DPL), a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4 and IL-13, key drivers of type 2 inflammation. In the phase 3 LIBERTY ASTHMA QUEST study (NCT02414854), add-on DPL 200/300mg every 2 weeks (q2w) vs placebo (PBO) reduced severe asthma exacerbations and improved pre-bronchodilator (BD) FEV1 in patients (pts) with uncontrolled, moderate-to-severe asthma. The new GINA report for difficult‑to‑treat and severe asthma proposes baseline (BL) blood eosinophils (Eos) ≥150cells/µL and/or BL FeNO ≥20ppb as cutoffs to define type 2 inflammatory asthma. Aim: This post hoc analysis assessed DPL efficacy in pts with BL Eos ≥150cells/µL and FeNO ≥20ppb and in the other quadrant subgroups. Methods: Annualized rate of severe exacerbations during the 52-week treatment period and LS mean change from BL in pre-BD FEV1 at Week 12 were assessed. Results: In pts with BL Eos ≥150cells/µL and FeNO ≥20ppb, DPL 200/300mg q2w vs PBO significantly reduced severe exacerbations by 66% and 63% and improved FEV1 by 0.26L and 0.22L, respectively (all P Conclusion: Dupilumab significantly reduced severe exacerbations and improved FEV1 in pts with type 2 inflammatory asthma.

Background Omalizumab improves clinical outcomes in patients with asthma. Several studies have shown lung function improvements with omalizumab; however, this has not been examined exclusively in adolescents. Objective To assess the effect of omalizumab on lung function and eosinophil counts in adolescents with uncontrolled moderate-to-severe allergic asthma. Methods In this post hoc analysis, data from adolescents aged 12 to 17 years from 8 randomized trials of omalizumab were pooled (studies 008, 009, and 011, and SOLAR, INNOVATE, ALTO, ETOPA, and EXTRA). Changes from baseline to end of study in forced expiratory volume in 1 second (FEV1), percent predicted FEV1 (ppFEV1), forced vital capacity (FVC), and blood eosinophil counts were assessed by fitting an analysis of covariance model and calculating least squares mean (LSM) difference for omalizumab vs placebo. Results A total of 340 adolescents were identified (omalizumab, n = 203 [59.7%]; placebo, n = 137 [40.3%]). Omalizumab increased all baseline lung function variables more than placebo by end of study: LSM treatment differences (95% confidence interval) were 3.0% (0.2%-5.7%; P = .035), 120.9 mL (30.6-211.2 mL; P = .009), and 101.5 mL (8.3-194.6 mL; P = .033) for ppFEV1, absolute FEV1, and FVC, respectively. The LSM difference demonstrated a greater reduction in eosinophil counts for omalizumab vs placebo: −85.9 cells/μL (−137.1 to −34.6 cells/μL; P = .001). Conclusion Omalizumab was associated with lung function improvements and circulating eosinophil counts reductions in adolescents with moderate-to-severe uncontrolled asthma. Findings emphasize the effect of omalizumab in young patients and the need to optimize treatment early in the disease course. https://clinicaltrials.gov/: NCT00314574, NCT00046748, NCT00401596

Serum IL-6 was associated with asthma exacerbation risk but not with symptoms or lung function in urban children; further studies to evaluate the role of IL-6 in the life course of asthma are needed.

With novel therapies in development, there is an opportunity to consider asthma remission as a treatment goal. In this Rostrum, we present a generalized framework for clinical and complete remission in asthma, on and off treatment, developed on the basis of medical literature and expert consensus. A modified Delphi survey approach was used to ascertain expert consensus on core components of asthma remission as a treatment target. Phase 1 identified other chronic inflammatory diseases with remission definitions. Phase 2 evaluated components of those definitions as well as published definitions of spontaneous asthma remission. Phase 3 evaluated a remission framework created using consensus findings. Clinical remission comprised 12 or more months with (1) absence of significant symptoms by validated instrument, (2) lung function optimization/stabilization, (3) patient/provider agreement regarding remission, and (4) no use of systemic corticosteroids. Complete remission was defined as clinical remission plus objective resolution of asthma-related inflammation and, if appropriate, negative bronchial hyperresponsiveness. Remission off treatment required no asthma treatment for 12 or more months. The proposed framework is a first step toward developing asthma remission as a treatment target and should be refined through future research, patient input, and clinical study.

Combination of IL-6 (non-Type 2 asthma) and FeNO or blood eosinophil count (Type 2 asthma) identified asthma endotypes related to asthma severity, exacerbations, and responsiveness to corticosteroids and potential for response to anti-Type 2 and anti-IL-6 treatment.