Search

Jonathan Corren,1 David J Jackson,2,3 Thomas B Casale,4 Larry Borish,5,6 Klaus F Rabe,7,8 William W Busse,9 Jorge F Maspero,10 Daniel J Jackson,11 Nadia Daizadeh,12 Arman Altincatal,12 Amr Radwan,13 Angela Khodzhayev,13 Michel Djandji,12 Juby A Jacob-Nara,12,14 Paul J Rowe,14 Yamo Deniz13 1David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 2King’s College London, London, UK; 3Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 4Division of Allergy and Immunology, University of South Florida, Tampa, FL, USA; 5Asthma and Allergic Disease Center, University of Virginia Health System, Charlottesville, VA, USA; 6Carter Immunology Center, University of Virginia Health System, Charlottesville, VA, USA; 7LungenClinic Grosshansdorf (Member of the German Center for Lung Research [DZL]), Airway Research Center North (ARCN), Grosshansdorf, Germany; 8Christian-Albrechts University (Member of the German Center for Lung Research [DZL]), Airway Research Center North (ARCN), Kiel, Germany; 9UW Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 10Fundación CIDEA, Buenos Aires, Argentina; 11University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 12Sanofi, Cambridge, MA, USA; 13Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 14Sanofi, Bridgewater, NJ, USACorrespondence: Jonathan Corren, David Geffen School of Medicine at UCLA, 10780 Santa Monica Blvd., Suite 280, Los Angeles, CA, 90025, USA, Email jcorren@ucla.eduPurpose: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukins-4/-13, key and central drivers of type 2 (T2) inflammation in multiple diseases. In phase 3 QUEST (NCT02414854), dupilumab vs placebo significantly reduced asthma exacerbation rates (AER) and improved pre-bronchodilator forced expiratory volume in 1 second (FEV1) in patients with uncontrolled, moderate-to-severe asthma, with greater effects in patients with elevated T2 biomarkers (≥ 150 eosinophils/μL or fractional exhaled nitric oxide [FeNO] ≥ 25 parts per billion). Overall safety was consistent with the known dupilumab safety profile. This post hoc analysis assessed dupilumab efficacy in QUEST patients with T2 asthma with evidence of an allergic phenotype (baseline serum IgE ≥ 30 IU/mL and aeroallergen-specific IgE ≥ 0.35 IU/mL) by number of aeroallergen sensitizations: 1, 2, 3, or ≥ 4. Non-sensitized patients (serum total IgE < 30 IU/mL without evidence of allergic phenotype) were also assessed.Patients and Methods: Endpoints were annualized AER, change from baseline in pre-bronchodilator FEV1 and asthma control (5-item Asthma Control Questionnaire [ACQ-5]), and FeNO and serum total IgE levels over the 52-week treatment period.Results: In all subgroups by number of allergens sensitized, dupilumab vs placebo reduced AER by 35– 67% and improved both pre-bronchodilator FEV1 at Week 12 (least squares mean differences: 0.10– 0.26 L across subgroups) and ACQ-5 score at Week 52 (– 0.26 to – 0.43). Dupilumab significantly reduced FeNO and total IgE levels at Week 52 compared with placebo. Similar results were observed in non-sensitized patients.Conclusion: Dupilumab improved clinical outcomes and reduced biomarker levels in patients with uncontrolled, moderate-to-severe T2 asthma irrespective of allergen sensitization status or number.Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02414854.Keywords: dupilumab, allergic asthma, type 2 asthma, perennial aeroallergen

Management of asthma in adults has advanced in the past 10 years. Central to these advances has been further clarification of type (T) 2 mechanisms of airway inflammation and utilization of T2 biomarkers, that is, eosinophils and fractional exhaled nitric oxide. In addition, epithelial cells are emerging as significant contributors to inflammation through generation of alarmins to initiate local injury as well as downstream pathways. Five new biologics, mepolizumab, benralizumab, reslizumab, dupilumab, and tezepelumab, were approved to join omalizumab and revolutionize severe asthma treatment. These biologics significantly prevent exacerbations to spare systemic corticosteroids use and their side effects. Guidelines attest to the effectiveness of inhaled corticosteroids/long-acting β-agonists (formoterol) for both maintenance and rescue therapy. Focused updates to the Expert Panel Report addressed limited but specific questions relevant to asthma control. Future guidelines should include phenotype/endotype-directed therapeutics to gain more precision-directed treatment.

Airway inflammation in asthma involves complex, interactive, and redundant cascades mediated by an array of proinflammatory cytokines, including a type 2 (T2) pattern of injury. T2 inflammation is characterized by elevations in absolute peripheral or sputum eosinophil counts and levels of IgE (total and allergen-specific) and fractional exhaled nitric oxide, which serve as biomarkers for the presence of this type of inflammation. T2 inflammation is mediated by key "downstream" cytokines, particularly IL-4, IL-5, and IL-13, which act at the effector cell level, as well as upstream cytokines, or "alarmins," such as thymic stromal lymphopoietin, IL-25, and IL-33 generated by epithelial cells. The relevance of these pathways has led to the development of biologic therapies targeting these T2 cytokines, which have not only resulted in modifying these biomarker signatures for inflammation but have also reduced the disease burden associated with asthma exacerbations, systemic corticosteroid use, and lung function compromises. This review will summarize experiences with anticytokine biologics to highlight which specific asthma outcomes they affect and how these effects reflect inflammatory pathways modified by biologics and may relate to pathophysiologic features of asthma.

BACKGROUND: Patients with asthma and/or chronic rhinosinusitis with nasal polyps (CRSwNP) experience recurrent respiratory tract infections. Dupilumab targets type 2 inflammation, a common underlying pathophysiology of both conditions, with proven efficacy. OBJECTIVE: To examine investigator-reported respiratory infection adverse events and anti-infective medication use with dupilumab versus placebo in patients with moderate-to-severe asthma or severe CRSwNP. METHODS: We performed a post hoc analysis of the pivotal phase 3 trials LIBERTY ASTHMA QUEST (NCT02414854) and LIBERTY NP SINUS-52 (NCT02898454) in moderate-to-severe asthma and severe CRSwNP, respectively. RESULTS: Investigator-reported respiratory infection events occurred at a significantly lower incidence in patients treated with dupilumab versus placebo, in both asthma (22% lower; P < .0001; 95% CI 0.71-0.85) and CRSwNP (38% lower; P

Patients with atopic dermatitis (AD) are more likely than the general population to have other type 2 associated conditions, for example, asthma, allergic rhinitis (AR) and food allergy (FA).1,2 Classically, the atopic march is thought to begin with AD and progresses to FA, asthma and AR,1,2 but this may be an oversimplification. This study aimed to describe the epidemiology of type 2 associated conditions included in the atopic march among patients newly diagnosed with AD in a large healthcare provider database in Israel. This retrospective cohort study was performed using the Maccabi Healthcare Services database in Israel, which includes over 2.5 million members. Based on the International Classification of Diseases, 9th revision (ICD-9) diagnosis codes, patients with diagnosed AD during 2000–2019 were identified. The earliest AD diagnosis was defined as the index date and patients had to have been enrolled for ≥12 months pre-index to exclude prevalent AD. Diagnosis data were obtained during 1998–2020 to describe the cumulative prevalence of asthma, AR and FA pre- and post-AD diagnosis (−1, 0, 1, 5, 10 and 20 years) using Kaplan–Meier analysis among patients aged

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.

Asthma exacerbations are major contributors to disease morbidity in patients of all ages. To develop strategies that reduce the disease burden from exacerbations, it is helpful to review current concepts about the risk factors for asthma attacks and current approaches for prevention and treatment. Multiple factors contribute as risks and to the development of asthma exacerbations, including allergic and infectious processes. Viral respiratory infections, primarily from rhinoviruses, are the dominant exacerbating cause for most asthma patients. Allergic sensitization and allergen exposure contribute directly and enhance susceptibility for respiratory viral infections. Respiratory viruses infect airway epithelium to promote underlying type 2 inflammation with eosinophils, the predominant cellular component of increased inflammation. Deficiencies of antiviral interferon responses and generation have been identified that increase susceptibility to viral infections in asthma. Exacerbation treatment focuses on reducing airflow obstruction and suppressing inflammation, followed by improving long-term asthma control. Increasing concern exists regarding the side effects associated with frequent systemic corticosteroid use. A major advance has been the selective use of biologics to prevent exacerbations, primarily in patients with existing type 2 inflammation. Future research to prevent exacerbations is being directed toward antiviral activity and a more encompassing regulation of underlying airway inflammation.

Taking a novel approach, this narrative review collates knowledge about nasal polyposis and the biological functions of IgE in several diseases (allergic rhinitis, allergic asthma, nonsteroidal anti-inflammatory drugs-exacerbated respiratory disease, and chronic spontaneous urticaria) to consider which IgE-mediated mechanisms are relevant to nasal polyposis pathology. A type 2 eosinophil-dominated inflammatory signature is typical in nasal polyp tissue of European patients with nasal polyposis, with a shift toward this endotype observed in Asian populations in recent years. Elevated polyclonal IgE is present in the nasal tissue of patients with and without allergy. It is derived from many different B-cell clones and, importantly, is functional (proinflammatory). Staphylococcus aureus enterotoxins are thought to act as superantigens, inducing production of polyclonal IgE via B-cell and T-cell activation, and triggering release of inflammatory mediators. In some patients, exposure to antigens/triggers leads to production of high levels of antigen-specific IgE, which mediates cross-linking of the high-affinity IgE receptor on various cells, causing release of inflammatory mediators. The efficacy of omalizumab confirms IgE as an important inflammatory mediator in nasal polyposis. By blocking IgE, omalizumab targets the T2 inflammation in nasal polyposis, reduces nasal polyp score and improves symptoms.

Fractional exhaled nitric oxide (FeNO) may have a role both as a prognostic and predictive biomarker, in combination with eosinophils, for assessing responsiveness to some biological therapies.We evaluated the value of baseline FeNO, adjusted for baseline blood eosinophil levels and other clinical characteristics, as an independent predictor of treatment response to dupilumab in patients with uncontrolled, moderate-to-severe asthma.We performed a post-hoc analysis of LIBERTY ASTHMA QUEST (NCT02414854), a phase 3, double-blind study in patients aged ≥ 12 years with uncontrolled moderate-to-severe asthma who received dupilumab 200/300 mg, or placebo every 2 weeks up to 52 weeks. Annualized event rate (AER) of severe exacerbations and least squares mean change from baseline in pre-bronchodilator forced expiratory volume in 1 s (FEVAER increased with increasing baseline FeNO in placebo, and decreased in dupilumab groups. The relative risk of severe exacerbations was 22·7%, 58·3%, and 69·3% lower for dupilumab vs placebo for the FeNO25, 25 to50, and ≥ 50 ppb subgroups. The magnitude of FEVIncreased baseline FeNO was associated with greater clinical effects in dupilumab vs placebo, independent of eosinophil levels and other clinical characteristics.

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.

Asthma exacerbations significantly impact millions of patients worldwide to pose large disease burdens on affected patients, families, and health-care systems. Although numerous environmental factors cause asthma exacerbations, viral respiratory infections are the principal triggers. Advances in the pathophysiology of asthma have elucidated dysregulated protective immune responses and upregulated inflammation that create susceptibility and risks for exacerbation. Biologics for the treatment of severe asthma reduce rates of exacerbations and identify specific pathways of inflammation that contribute to altered pathophysiology, novel therapeutic targets, and informative biomarkers. Major steps to prevent exacerbations include the identification of molecular pathways whose blockage will prevent asthma attacks safely, predictably, and effectively.

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.

Black and Hispanic children living in urban environments in the USA have an excess burden of morbidity and mortality from asthma. Therapies directed at the eosinophilic phenotype reduce asthma exacerbations in adults, but few data are available in children and diverse populations. Furthermore, the molecular mechanisms that underlie exacerbations either being prevented by, or persisting despite, immune-based therapies are not well understood. We aimed to determine whether mepolizumab, added to guidelines-based care, reduced the number of asthma exacerbations during a 52-week period compared with guidelines-based care alone.This is a randomised, double-blind, placebo-controlled, parallel-group trial done at nine urban medical centres in the USA. Children and adolescents aged 6-17 years, who lived in socioeconomically disadvantaged neighbourhoods and had exacerbation-prone asthma (defined as ≥two exacerbations in the previous year) and blood eosinophils of at least 150 cells per μL were randomly assigned 1:1 to mepolizumab (6-11 years: 40 mg; 12-17 years: 100 mg) or placebo injections once every 4 weeks, plus guideline-based care, for 52 weeks. Randomisation was done using a validated automated system. Participants, investigators, and the research staff who collected outcome measures remained masked to group assignments. The primary outcome was the number of asthma exacerbations that were treated with systemic corticosteroids during 52 weeks in the intention-to-treat population. The mechanisms of treatment response were assessed by study investigators using nasal transcriptomic modular analysis. Safety was assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03292588.Between Nov 1, 2017, and Mar 12, 2020, we recruited 585 children and adolescents. We screened 390 individuals, of whom 335 met the inclusion criteria and were enrolled. 290 met the randomisation criteria, were randomly assigned to mepolizumab (n=146) or placebo (n=144), and were included in the intention-to-treat analysis. 248 completed the study. The mean number of asthma exacerbations within the 52-week study period was 0·96 (95% CI 0·78-1·17) with mepolizumab and 1·30 (1·08-1·57) with placebo (rate ratio 0·73; 0·56-0·96; p=0·027). Treatment-emergent adverse events occurred in 42 (29%) of 146 participants in the mepolizumab group versus 16 (11%) of 144 participants in the placebo group. No deaths were attributed to mepolizumab.Phenotype-directed therapy with mepolizumab in urban children with exacerbation-prone eosinophilic asthma reduced the number of exacerbations.US National Institute of Allergy and Infectious Diseases and GlaxoSmithKline.

Asthma prevalence and severity have markedly increased with urbanisation, and children in low-income urban centres have among the greatest asthma morbidity. Outdoor air pollution has been associated with adverse respiratory effects in children with asthma. However, the mechanisms by which air pollution exposure exacerbates asthma, and how these mechanisms compare with exacerbations induced by respiratory viruses, are poorly understood. We aimed to investigate the associations between regional air pollutant concentrations, respiratory illnesses, lung function, and upper airway transcriptional signatures in children with asthma, with particular focus on asthma exacerbations occurring in the absence of respiratory virus.We performed a retrospective analysis of data from the MUPPITS1 cohort and validated our findings in the ICATA cohort. The MUPPITS1 cohort recruited 208 children aged 6-17 years living in urban areas across nine US cities with exacerbation-prone asthma between Oct 7, 2015, and Oct 18, 2016, and monitored them during reported respiratory illnesses. The last MUPPITS1 study visit occurred on Jan 6, 2017. The ICATA cohort recruited 419 participants aged 6-20 years with persistent allergic asthma living in urban sites across eight US cities between Oct 23, 2006, and March 25, 2008, and the last study visit occurred on Dec 30, 2009. We included participants from the MUPPITS1 cohort who reported a respiratory illness at some point during the follow-up and participants from the ICATA cohort who had nasal samples collected during respiratory illness or at a scheduled visit. We used air quality index values and air pollutant concentrations for PMOf the 208 participants from the MUPPITS1 cohort and 419 participants from the ICATA cohort, 168 participants in the MUPPITS1 cohort (98 male participants and 70 female participants) and 189 participants in the ICATA cohort (115 male participants and 74 female participants) were included in our analysis. We identified that increased air quality index values, driven predominantly by increased PMOur findings suggest that air pollution is an important independent risk factor for asthma exacerbations in children living in urban areas and is potentially linked to exacerbations through specific inflammatory pathways in the airway. Further investigation of these potential mechanistic pathways could inform asthma prevention and management approaches.National Institutes of Health, National Institute of Allergy and Infectious Diseases.

BACKGROUND: Mold sensitization and exposure are associated with asthma severity, but the specific species that contribute to difficult-to-control (DTC) asthma are unknown. OBJECTIVE: To determine the association between overall and specific mold levels in the homes of urban children and DTC asthma. METHODS: The Asthma Phenotypes in the Inner-City (APIC) study recruited participants, 6 to 17 years of age, from eight US cities and classified each participant as having either DTC asthma or easy-to-control (ETC) asthma based on treatment step level. Dust samples had been collected in each participant’s home (n=485) and any dust remaining (n=265 samples), after other analyses, were frozen at −20°C. The dust samples (n=265) were analyzed using qPCR to determine the concentrations of the 36 molds in the Environmental Relative Moldiness Index (ERMI). Logistic regression was performed to discriminate specific mold content of dust from homes of children with DTC versus ETC asthma. RESULTS: Frozen-dust samples were available from 54% of homes of children with DTC (139/253) and ETC asthma (126/232). Only the average concentration of the mold Mucor was significantly (p

Severe asthma affects an estimated 5–10% of the total asthma patient population [1]. Various demographic factors, such as sex, age, obesity and age of onset, have been associated with asthma disease severity [2, 3], and the efficacy of asthma treatments has previously been found to vary depending on patient demographics [4, 5]., Dupilumab treatment versus placebo improved exacerbation rate and lung function outcomes in patients with uncontrolled moderate-to-severe asthma and high type 2 biomarkers at baseline, regardless of baseline characteristics in the phase 3 QUEST study https://bit.ly/3yR7MlD

Background Characterization of allergic responses to cockroach (CR), a common aeroallergen associated with asthma, has focused mainly on IgE reactivity, but little is known about T cell responses, particularly in children. We conducted a functional evaluation of CR allergen‐specific T cell reactivity in a cohort of CR allergic children with asthma. Methods Peripheral blood mononuclear cells (PBMCs) were obtained from 71 children, with mild‐to‐moderate asthma who were enrolled in a CR immunotherapy (IT) clinical trial, prior to treatment initiation. PBMC were stimulated with peptide pools derived from 11 CR allergens, and CD4+ T cell responses assessed by intracellular cytokine staining. Results Highly heterogeneous responses in T cell reactivity were observed among participants, both in terms of the magnitude of cytokine response and allergen immunodominance. Reactivity against Bla g 9 and Bla g 5 was most frequent. The phenotype of the T cell response was dominated by IL‐4 production and a Th2 polarized profile in 54.9% of participants, but IFNγ production and Th1 polarization was observed in 25.3% of the participants. The numbers of regulatory CD4+ T cells were also highly variable and the magnitude of effector responses and Th2 polarization were positively correlated with serum IgE levels specific to a clinical CR extract. Conclusions Our results demonstrate that in children with mild‐to‐moderate asthma, CR‐specific T cell responses display a wide range of magnitude, allergen dominance, and polarization. These results will enable examination of whether any of the variables measured are affected by IT and/or are predictive of clinical outcomes.

Treatment guidelines recommend triple therapy for patients with asthma who remain uncontrolled on inhaled corticosteroid/long-acting βTo compare adherence and persistence among adult patients with asthma receiving single-inhaler FF/UMEC/VI versus multiple-inhaler triple therapy (MITT) in the United States.This retrospective cohort study used IQVIA PharMetrics Plus data to evaluate patients with asthma who initiated once-daily FF/UMEC/VI 100/62.5/25 mcg or MITT between September 18, 2017, and September 30, 2019. Inverse probability weighting and multivariable regression adjusted for differences in characteristics between the FF/UMEC/VI and MITT cohorts. Adherence was assessed using proportion of days covered (PDC) and proportion of patients achieving PDC ≥0.8 and PDC ≥0.5. Non-persistence was identified as a45-day gap between fills.The study included 1396 FF/UMEC/VI and 5115 MITT initiators. Three months after initiation, FF/UMEC/VI users had significantly higher mean PDC versus MITT users (0.68 vs 0.59; P.001) and 31% more likely to be adherent (PDC ≥0.8; 40.6% vs 31.3%; adjusted risk ratio [95% confidence interval (CI)]: 1.31 [1.13-1.54]; P.001). Similar patterns were observed at 6 and 12 months post initiation. In addition, FF/UMEC/VI users were 49% more likely to persist at 12 months than MITT users (25.9% vs 15.1%, adjusted hazard ratio [95% CI]: 1.49 [1.39-1.60]; P.001).Patients with asthma initiating triple therapy with FF/UMEC/VI had significantly better adherence and persistence compared with MITT initiators.

The Global Initiative for Asthma report recommends consideration of add-on biologics for patients with type 2 inflammation (blood eosinophils ≥150 cells/μL, fractional exhaled nitric oxide [Feno] ≥20 parts per billion or allergic asthma) whose asthma cannot be controlled by high-dose inhaled corticosteroids. In QUEST (NCT02414854), add-on dupilumab versus placebo was efficacious in patients with uncontrolled, moderate to severe asthma, including those with eosinophils greater than or equal to 150 cells/μL and/or Feno greater than or equal to 25 parts per billion.To assess dupilumab efficacy in patients with a type 2 phenotype in the presence or absence of allergic asthma phenotype.Patients aged 12 years or older received add-on dupilumab 200/300 mg versus matched placebo every 2 weeks for 52 weeks. Allergic asthma phenotype was defined as baseline serum total IgE greater than or equal to 30 IU/mL and 1 or more perennial aeroallergen-specific IgE level greater than or equal to 0.35 kU/L. Annualized rate of severe asthma exacerbations and changes from study baseline in prebronchodilator and postbronchodilator FEVOf 1902 patients in QUEST, 83.3% had eosinophils and/or Feno above Global Initiative for Asthma thresholds; 56.9% had evidence for allergic asthma. Dupilumab significantly reduced the rate of severe asthma exacerbations in patients with (48.8%) and without (64.0%) evidence of allergic asthma and improved prebronchodilator and postbronchodilator FEVIn patients with type 2 biomarkers over Global Initiative for Asthma thresholds, dupilumab significantly reduced exacerbations and improved lung function. Efficacy was not impacted by allergic status.

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)

At present, there is no cure for asthma, and treatment typically involves therapies that prevent or reduce asthma symptoms, without modifying the underlying disease. A “disease-modifying” treatment can be classed as able to address the pathogenesis of a disease, preventing progression or leading to a long-term reduction in symptoms. Such therapies have been investigated and approved in other indications, e.g. rheumatoid arthritis and immunoglobulin E-mediated allergic disease. Asthma's heterogeneous nature has made the discovery of similar therapies in asthma more difficult, although novel therapies (e.g. biologics) may have the potential to exhibit disease-modifying properties. To investigate the disease-modifying potential of a treatment, study design considerations can be made, including: appropriate end-point selection, length of trial, age of study population (key differences between adults/children in physiology, pathology and drug metabolism) and comorbidities in the patient population. Potential future focus areas for disease-modifying treatments in asthma include early assessments (e.g. to detect patterns of remodelling) and interventions for patients genetically susceptible to asthma, interventions to prevent virally induced asthma and therapies to promote a healthy microbiome. This review explores the pathophysiology of asthma, the disease-modifying potential of current asthma therapies and the direction future research may take to achieve full disease remission or prevention.