Reduce Asthma Exacerbations Research Articles

Inhaled Reliever Therapies for Asthma

The optimal inhaled reliever therapy for asthma remains unclear. To compare short-acting β agonists (SABA) alone with SABA combined with inhaled corticosteroids (ICS) and with the fast-onset, long-acting β agonist formoterol combined with ICS for asthma. The MEDLINE, Embase, and CENTRAL databases were searched from January 1, 2020, to September 27, 2024, without language restrictions. Pairs of reviewers independently selected randomized clinical trials evaluating (1) SABA alone, (2) ICS with formoterol, and (3) ICS with SABA (combined or separate inhalers). Two reviewers independently extracted data and assessed risk of bias. Random-effects meta-analyses synthesized outcomes. GRADE (Grading of Recommendations Assessment, Development, and Evaluation) was used to evaluate the certainty of evidence. Asthma symptom control (5-item Asthma Control Questionnaire; range, 0-6, lower scores indicate better asthma control; minimum important difference [MID], 0.5 points), asthma-related quality of life (Asthma Quality of Life Questionnaire; range, 1-7, higher scores indicate better quality of life; MID, 0.5 points), risk of severe exacerbations, and risk of serious adverse events. A total of 27 randomized clinical trials (N = 50 496 adult and pediatric patients; mean age, 41.0 years; 20 288 male [40%]) were included. Compared with SABA alone, both ICS-containing relievers were associated with fewer severe exacerbations (ICS-formoterol risk ratio [RR], 0.65 [95% CI, 0.60-0.72]; risk difference [RD], -10.3% [95% CI, -11.8% to -8.3%]; ICS-SABA RR, 0.84 [95% CI, 0.73-0.95]; RD, -4.7% [95% CI, -8.0% to -1.5%]) with high certainty. Compared with SABA alone, both ICS-containing relievers were associated with improved asthma control (ICS-formoterol RR improvement [MID] in total score, 1.07 [95% CI, 1.04-1.10]; RD, 4.1% [95% CI, 2.3%-5.9%]; ICS-SABA RR, 1.09 [95% CI, 1.03-1.15]; RD, 5.4% [95% CI, 1.8%-8.5%]) with high certainty. In an indirect comparison with ICS-SABA, ICS-formoterol was associated with fewer severe exacerbations (RR, 0.78 [95% CI, 0.66-0.92]; RD, -5.5% [95% CI, -8.4% to -2.0%]) with moderate certainty. Compared with SABA alone, ICS-formoterol (RD, -0.6% [95% CI, -1.3% to 0%]) was not associated with increased risk of serious adverse events (high certainty) and ICS-SABA (RD, 0% [95% CI, -1.1% to 1.2%]) was not associated with increased risk of serious adverse events (moderate certainty). In this network meta-analysis of patients with asthma, ICS combined with formoterol and ICS combined with SABA were each associated with reduced asthma exacerbations and improved asthma control compared with SABA alone.

Vitamin D supplementation decrease asthma exacerbations in children: a systematic review and meta-analysis of randomized controlled trials

Background Observational studies have linked low vitamin D (VD) levels to increased asthma attacks in children. Subsequent meta-analyses of adults and children revealed that VD treatment might benefit asthmatic patients by reducing the incidence of exacerbations. Therefore, this review aims to analyze the effects of VD supplementation in reducing asthma exacerbations in children. Methods Published reports from PubMed, Cochrane, and Google Scholar were systematically searched until April 2023. The study protocol was registered in the PROSPERO database CRD42023411796. Randomized controlled trial studies were included in this review. Meta-analysis was performed using Cochrane RevMan 5.1 and presented with 95% confidence intervals (CIs). Results Ten relevant studies enrolled 1243 asthmatic children (631 children receiving vitamin D3 supplementation, 612 children receiving placebo) were included in this review. Our pooled analysis found that VD supplementation had a significant effect on lowering the total number of asthma exacerbations (RR 0.62; 95% CI: 0.44, 0.87; p = 0.01). Subgroup analysis revealed that a daily dose of VD given based on standard daily dose recommendation had a significant improvement on asthma exacerbations [(RR 0.41; 95% CI: 0,18, 0,92; p = 0.03). Conclusions Vitamin D supplementation can lower the occurrence of exacerbations in children with asthma, along with the improvement of FEV1.

Assessing the environmental justice implications of decarbonizing the US electric grid: estimating changes in asthma exacerbation by race and income

Abstract This paper examines how air quality improvements due to the 100% decarbonization of the US power sector in 2040 can reduce asthma exacerbation among children disaggregated by poverty status, race, and geography. Using spatial datasets that differentiate asthma prevalence by income, race, and state, we find that children living in households with income below the poverty line receive a disproportionate share of the benefits. To obtain these results, we employ several different federally administered datasets: American Community Survey, Behavioral Risk Factor Surveillance System (BRFSS), and Poverty Thresholds as provided by the US Census. We find that Black children and poor children, on average, have higher reductions in exposure to PM2.5. Nationally, close to 235 372 asthma exacerbation cases will be averted in 2040 under the decarbonization policy compared with Business-as-Usual. States with significant gains in asthma cases averted per 100 000 are Indiana, Kentucky, Ohio, Missouri, Pennsylvania, Texas, and Wisconsin. Furthermore, since the asthma portion of the BRFSS is not conducted in South Carolina, Colorado, Arkansas, and South Dakota, these states were omitted from the analysis. Across all states with significant gains, children living below the poverty line have larger health benefits than children above the poverty line. Households with child poverty have 50% larger reductions in asthma exacerbations than households without childhood poverty. Black children below the poverty line experience 33% higher health gains compared to Black children per 100 000 above the poverty line, 50% higher health gains compared to White children below the poverty line, and 159% higher than White children above the poverty line. We also provide general methodological insights for quantifying the environmental justice impacts of regulatory policies. We demonstrate why using race and poverty status-based prevalence rates is critical for understanding the distribution of health improvements and evaluating whether policies contribute to environmental justice goals.

Reducing asthma attacks in disadvantaged school children with asthma: study protocol for a type 2 hybrid implementation-effectiveness trial (Better Asthma Control for Kids, BACK)

BackgroundAsthma is a leading cause of children’s hospitalizations, emergency department visits, and missed school days. Our school-based asthma intervention has reduced asthma exacerbations for children experiencing health disparities in the Denver Metropolitan Area, due partly to addressing care coordination for asthma and social determinants of health (SDOH), such as access to healthcare and medications. Limited dissemination of school-based asthma programs has occurred in other metropolitan and rural areas of Colorado. We formed and engaged community advisory boards in socioeconomically diverse regions of Colorado to develop two implementation strategy packages for delivering our school-based asthma intervention — now termed “Better Asthma Control for Kids (BACK)" — with tailoring to regional priorities, needs and resources.MethodsIn this proposed type 2 hybrid implementation-effectiveness trial, where the primary goal is equitable reach to families to reduce asthma disparities, we will compare two different packages of implementation strategies to deliver BACK across four Colorado regions. The two implementation packages to be compared are: 1) standard set of implementation strategies including Tailor and Adapt to context, Facilitation and Training termed, BACK-Standard (BACK-S); 2) BACK-S plus an enhanced implementation strategy, that incorporates network weaving with community partners and consumer engagement with school families, termed BACK-Enhanced (BACK-E). Our evaluation will be guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework, including its Pragmatic Robust Implementation Sustainability Model (PRISM) determinants of implementation outcomes. Our central hypothesis is that our BACK-E implementation strategy will have significantly greater reach to eligible children/families than BACK-S (primary outcome) and that both BACK-E and BACK-S groups will have significantly reduced asthma exacerbation rates (“attacks”) and improved asthma control as compared to usual care.DiscussionWe expect both the BACK-S and BACK-E strategy packages will accelerate dissemination of our BACK program across the state – the comparative impact of BACK-S vs. BACK-E on reach and other RE-AIM outcomes may inform strategy selection for scaling BACK and other effective school-based programs to address chronic illness disparities.Trial registrationClinicaltrials.gov identifier: NCT06003569, registered on August 22, 2023, https://classic.clinicaltrials.gov/ct2/show/NCT06003569.

Therapeutic relevance of eosinophilic inflammation and airway viral interactions in severe asthma.

The role of eosinophils in airway inflammation and asthma pathogenesis is well established, with raised eosinophil counts in blood and sputum associated with increased disease severity and risk of asthma exacerbation. Conversely, there is also preliminary evidence suggesting antiviral properties of eosinophils in the airways. These dual roles for eosinophils are particularly pertinent as respiratory virus infections contribute to asthma exacerbations. Biologic therapies targeting key molecules implicated in eosinophil-associated pathologies have been approved in patients with severe asthma and, therefore, the effects of depleting eosinophils in a clinical setting are of considerable interest. This review discusses the pathological and antiviral roles of eosinophils in asthma and exacerbations. We also highlight the significant reduction in asthma exacerbations seen with biologic therapies, even at the height of the respiratory virus season. Furthermore, we discuss the implications of these findings in relation to the role of eosinophils in inflammation and antiviral responses to respiratory virus infection in asthma.

Airway proteomics reveals broad residual anti-inflammatory effects of prednisolone in mepolizumab-treated asthma

BackgroundMepolizumab is an anti-interleukin-5 monoclonal antibody treatment for severe eosinophilic asthma (SEA) that reduces asthma exacerbations. Residual airway inflammation on mepolizumab may lead to persistent exacerbations. Oral corticosteroids remain the main treatment for these residual exacerbations. ObjectiveOur study aimed to explore the corticosteroid-responsiveness of airway inflammation after mepolizumab treatment to find potentially treatable inflammatory mechanisms beyond the IL-5 pathway. MethodThe MAPLE trial was a multi-centre, randomized, double-blind, placebo-controlled, crossover study of 2 weeks of high-dose oral prednisolone treatment at stable state in 27 patients treated with mepolizumab for SEA. We analysed paired sputum (n=16) and plasma (n=25) samples from the MAPLE trial using high-throughput Olink® proteomics. We also analysed additional sputum proteins using ELISA. ResultsIn patients receiving mepolizumab, prednisolone significantly downregulated sputum proteins related to type-2 inflammation and chemotaxis including IL-4, IL-5, IL-13, CCL24, CCL26, EDN, CCL17, CCL22, OX40 receptor, FCER2, and the ST2 receptor. Prednisolone also downregulated cell adhesion molecules, prostaglandin synthases, mast cell tryptases, MMP1, MMP12, and neuroimmune mediators. Neutrophilic pathways were upregulated.Type-2 proteins were also downregulated in plasma, combined with IL-12, IFN-γ, and IP-10. IL-10 and amphiregulin were upregulated. ConclusionAt stable state, prednisolone has broad anti-inflammatory effects on top of mepolizumab. These effects are heterogeneous and may be clinically relevant in residual exacerbations.

Glucagon-like Peptide 1 Receptor Agonists and Asthma Exacerbations: Which Patients Benefit Most?

While recent evidence suggested glucagon-like peptide 1 receptor agonists (GLP1RA) may reduce the risk of asthma exacerbations, it remains unclear which subpopulations might derive the most benefit from GLP1RA treatment. To identify characteristics of patients with asthma that predict who might benefit the most from GLP1RA treatment using real-world data. We implemented an active-comparator, new-user design analysis using commercially insured patients ages 18-65 from Marketscan data 2007-2019 and identified two cohorts: GLP1RA vs thiazolidinediones and GLP1RA vs sulfonylureas. The outcome was acute exacerbation of asthma (hospital admission or emergency department (ED) visit for asthma) within 180 days after initiation. We applied iterative causal forest (iCF), a novel causal machine learning subgrouping algorithm, to assess HTE. In identified subgroups, we predicted propensity score, conducted propensity score trimming, and then estimated adjusted risk differences (aRD) for the effect of GLP1RA relative to comparators on asthma exacerbation using inverse probability treatment weighting in propensity score trimmed subpopulation. Among 10,989 patients initiating GLP1RA or thiazolidinediones and 17,088 patients initiating GLP1RA vs sulfonylurea, GLP1RA initiators had fewer exacerbations with an aRD of -0.5% (95% CI -1.1% to 0.1%) and -1.6% (95% CI -2.2% to -1.1%), respectively. In the GLP1RAvsSUcohort where we observed beneficial effect, our iCF analysis identified 5 subgroups with different treatment effects, defined by number of ED visits, number of prescriptions of short-acting beta2-agonsit (SABA), number of prescriptions of inhaled steroid (ICS) and long-acting beta-agonists (LABA) (either combination therapy or concurrent use), and aged 50+. Among these, patients with 2+ ED visits during 12-month baseline period had the largest absolute exacerbation risk reduction, with a decrease of 2.8% for GLP1RA (95% CI: -4.8% to -0.9%). GLP1RA demonstrated beneficial effect on reducing asthma exacerbation relative to sulfonylureas. Asthma patients with 2+ ED visits (a proxy for disease severity) benefit most from GLP1RA. ED visit frequency, and number of maintenance and reliever inhalers, and age may help individualize prediction of the short-term benefit from GLP1RA on asthma exacerbation.

An Updated Reappraisal of Dupilumab in Children and Adolescents with Severe Asthma.

Severe asthma (SA) is still a demanding challenge in clinical practice. Type 2 inflammation is the most common phenotype in children and adolescents with SA. As a result, anti-inflammatory drugs, mainly corticosteroids (CSs), represent the first choice to reduce type 2 inflammation. However, SA patients may require high inhaled and oral CS doses to achieve and maintain asthma control. Some SA patients, despite the highest CS dosages, can even display uncontrolled asthma. Therefore, the biological era constituted a breakthrough in managing this condition. Dupilumab is a monoclonal antibody directed against the IL-4 receptor α-subunit (IL-4Rα), antagonizing against both IL-4 and IL-13, and has been approved for pediatric severe type 2 asthma. This review presents and discusses the most recent published studies on dupilumab in children and adolescents with SA. There is convincing evidence that dupilumab is a safe and effective option in managing SA as it can reduce asthma exacerbations, reduce CS use, and improve lung function, asthma control, and quality of life, also for caregivers. However, a thorough diagnostic pathway is mandatory, mainly concerning phenotyping. In fact, the ideal eligible candidate is a child or adolescent with a type 2 allergic phenotype.

Long-term use of omalizumab in patients with allergic bronchopulmonary aspergillosis: a tertiary-level care center experience

Introduction Allergic bronchopulmonary aspergillosis (ABPA) is a lung disease caused by a hypersensitivity reaction to antigens of Aspergillus fumigatus. Objective The aim of this study was to evaluate the long-term clinical outcomes of omalizumab use in patients with ABPA. Methods In this retrospective study, 12 patients diagnosed with ABPA and receiving omalizumab for at least 2 years, and 32 patients diagnosed with severe allergic asthma and receiving omalizumab for at least 2 years (control group) were evaluated. Results Evaluation was made of a total of 44 participants, comprising 11 (25%) males and 33 (75%) females, who received omalizumab for at least 2 years with the diagnosis of the control group (n = 32) and ABPA (n = 12). The increase in asthma control test (ACT) score after omalizumab was significant at 12 months and at 24 months in patients with ABPA. After omalizumab, the use of oral corticosteroid (OCS), the annual number of asthma attacks and hospitalizations were significantly decreased at 12 months and at 24 months in patients with ABPA. The increase in forced expiratory volume in 1 s (FEV1) (%) and ACT score after omalizumab were significant at 12 months and at 24 months in the control group. After omalizumab, the use of OCS, annual number of asthma attacks and hospitalizations were significantly decreased at 12 months and at 24 months in the control group. Conclusion Long-term omalizumab use in patients with ABPA seems to be an effective treatment for improving pulmonary function and reducing asthma exacerbations and hospitalizations.

Efficacy of Tezepelumab in Patients with Severe, Uncontrolled Asthma Across Multiple Clinically Relevant Subgroups in the NAVIGATOR Study.

Many patients with severe asthma continue to experience symptoms and exacerbations despite treatment with standard-of-care therapy. In the phase 3 NAVIGATOR study, tezepelumab significantly reduced exacerbations over 52weeks compared with placebo in patients with severe, uncontrolled asthma. This analysis assessed the efficacy of tezepelumab in reducing asthma exacerbations in various clinically relevant subgroups of patients in NAVIGATOR. NAVIGATOR was a phase 3, multicentre, randomized, double-blind, placebo-controlled study. Participants (12-80years old) with severe, uncontrolled asthma were randomized 1:1 to receive tezepelumab 210mg or placebo subcutaneously every 4weeks for 52weeks. Pre-specified and post hoc analyses were performed to evaluate the annualized asthma exacerbation rate (AAER) over 52weeks in clinically relevant subgroups of patients defined by baseline patient characteristics, medical history, exacerbation triggers, medication eligibility and medication use before and during the study. Tezepelumab reduced the AAER over 52weeks compared with placebo across a wide range of patient subgroups assessed. Reductions in exacerbations were similar across subgroups defined by baseline patient characteristics, ranging from 48% (95% confidence interval [CI]: 21, 65) to 60% (95% CI: 44, 71) in subgroups analysed by sex, smoking history and body mass index. Among the asthma-related comorbidity subgroups investigated, patients with aspirin or NSAID sensitivity had the greatest reductions in AAER with tezepelumab compared with placebo (83%; 95% CI: 66, 91). In patients eligible to receive dupilumab, tezepelumab reduced exacerbations compared with placebo by 64% (95% CI: 54, 71). Reductions in the AAER with tezepelumab compared with placebo were also observed irrespective of exacerbation trigger category and the number of asthma controller medications patients were receiving at baseline. These findings further support the benefits of tezepelumab in patients with severe, uncontrolled asthma and can help to inform healthcare providers' treatment decisions. NAVIGATOR (NCT03347279).

Adoption and implementation of maintenance and reliever therapy for adults with moderate-to-severe asthma

BackgroundThe use of single-combination inhaled corticosteroid and long-acting bronchodilator for maintenance and relief therapy (MART) significantly reduces asthma exacerbations and has been incorporated into asthma guidelines since December 2020, but there are limited data regarding the implementation of this approach to asthma management. ObjectiveTo determine the frequency at which MART was recommended to patients with moderate-to-severe asthma being seen at subspecialty pulmonary and allergy practices at an academic healthcare system, and the patient and clinician characteristics associated with the use of MART. MethodsWe conducted a retrospective cross-sectional study of the electronic medical records of an academic healthcare system in the Northeastern United States between January 2021 and October 2023. Patient demographic and clinician data were collected, and MART recommendation was confirmed by chart review. We assessed the relationships among patient demographics, clinician characteristics, and MART recommendation. ResultsOf 2016 patients reviewed, 293 (14.5%) were recommended MART, with 255 (87%) concurrently prescribed short-acting bronchodilators. Patients on inhaled corticosteroid-formoterol at baseline were significantly more likely to be recommended MART, whereas older patients and those on Medicare were significantly less likely to be recommended MART; 22 of 50 clinicians (44%) did not recommend MART ever, and only 3 clinicians recommended MART to 30% to 60% of their patients. Clinicians who were part of the asthma group were significantly more likely to recommend MART. ConclusionAmong academic subspecialty clinicians, there has been limited implementation of MART, with a small number of clinicians adopting MART routinely and more than 40% of clinicians not recommending it.

Biomarkers and clinical outcomes after tezepelumab cessation: Extended follow-up from the 2-year DESTINATION study

BackgroundLong-term tezepelumab treatment in the DESTINATION study (NCT03706079) resulted in reduced asthma exacerbations, reduced biomarker levels, and improved lung function and symptom control in patients with severe, uncontrolled asthma. ObjectiveTo explore the time course of changes in biomarkers and clinical manifestations after treatment cessation after 2 years of tezepelumab treatment. MethodsDESTINATION was a 2-year, phase 3, multicenter, randomized, placebo-controlled, double-blind study of tezepelumab treatment in patients (12-80 years old) with severe asthma. Patients received their last treatment doses at week 100 and could enroll in an extended follow-up period from weeks 104 to 140. Change over time in key biomarkers and clinical outcomes were assessed in tezepelumab vs placebo recipients for 40 weeks after stopping treatment. ResultsOf 569 patients enrolled in the extended follow-up period, 426 were included in the analysis (289 received tezepelumab and 137 placebo). In the 40-week period after the last tezepelumab dose, blood eosinophil counts, fractional exhaled nitric oxide levels, and Asthma Control Questionnaire-6 scores gradually increased from weeks 4 to 10, with a gradual reduction in pre-bronchodilator forced expiratory volume in 1 second such that blood eosinophil counts, fractional exhaled nitric oxide levels, and clinical outcomes returned to placebo levels; however, none of these outcomes returned to baseline levels. Total IgE levels increased later from week 28 and remained well below placebo and baseline levels during the 40-week period after the last tezepelumab dose. ConclusionThis analysis reveals the benefits of continued tezepelumab treatment in the management of patients with severe, uncontrolled asthma, compared with stopping treatment after 2 years. Trial RegistrationClinicalTrials.gov Identifier: NCT03706079.

Mepolizumab and benralizumab in patients with severe asthma and a history of eosinophilic granulomatosis with polyangiitis.

Asthma associated with eosinophilic granulomatosis with polyangiitis (EGPA) is often severe and corticosteroid-dependent, leading to significant morbidity. Mepolizumab and benralizumab are humanized monoclonal antibodies targeting interleukin 5 (IL-5) and its receptor, respectively. They have been shown to be effective in steroid-sparing in patients with severe eosinophilic asthma. Our aim was to evaluate the efficacy and safety of mepolizumab and benralizumab prescribed for severe asthma in patients with EGPA under "real-world" conditions. This was a retrospective analysis of patients with EGPA and persistent asthma who received either mepolizumab 100 or 300 mg administered every 4 weeks, or benralizumab 30 mg administered every 4 weeks for the initial 3 injections and followed by an injection every 8 weeks thereafter, whilst combined with oral glucocorticoids. The follow-up every 6 ± 3 months included an assessment of clinical manifestations, pulmonary function tests and eosinophil cell count. The primary outcome was the proportion of patients at 12 months receiving a daily oral dose of prednisone or equivalent of 4 mg or less with a BVAS of 0. Twenty-six patients were included. After 12 months of treatment with mepolizumab or benralizumab, 32% of patients met the primary outcome and were receiving less than 4 mg of prednisone per day with a BVAS of 0. The median dose of prednisone was 10 mg per day at baseline, 9 mg at 6 months, and 5 mg at 12 months (p ≤ 0.01). At 12 months, 23% of patients were weaned off corticosteroids, while an increase or no change in dose was observed in 27% of patients. The median eosinophil count was significantly reduced from 365 cells/mm3 to 55 cells/mm3 at 6 months and 70 cells/mm3 at 12 months, respectively. No significant change was observed in FEV1. After 12 months of treatment, 14% of patients had had an average of 1 exacerbation of asthma, compared with 52% of patients before baseline. The tolerability profile was favorable. In this real-world study in patients with severe asthma and a history of EGPA asthma, mepolizumab and benralizumab had a significant steroid-sparing effect and reduced asthma exacerbation, but no significant effect on lung function.

Real-World Effectiveness of Mepolizumab in Patients with Allergic and Non-Allergic Asthma.

Real-world data on mepolizumab in patients with severe asthma and allergic and non-allergic phenotypes are limited. This study investigated the effectiveness of mepolizumab treatment in patients with severe asthma with allergic and non-allergic phenotypes. This retrospective cohort study (GSK ID: 214148) used administrative claims data from the Optum Research Database. Eligible patients were ≥6 years of age with asthma and had ≥2 mepolizumab claims post-index. Index date was the first mepolizumab claim/administration (January 2016-December 2018). Patients were divided into two cohorts: allergic and non-allergic asthma, based on diagnosis codes, medication use and lab test results. Outcomes included the rate of asthma-related exacerbations and oral corticosteroid (OCS) use during the 12 months before (baseline period) and 12 months after (follow-up period) mepolizumab initiation. Study ended in December 2019. Overall, 240 (44.6%) and 298 (55.4%) patients were included in the allergic and non-allergic asthma cohorts, respectively. Mean (standard deviation [SD]) counts of asthma-related exacerbations were significantly reduced from baseline to follow-up in both the allergic and non-allergic asthma cohorts (3.2 [2.5] to 2.1 [2.1], p < 0.001 and 2.5 [2.2] to 1.7 [1.9], p < 0.001, respectively). The mean number of OCS pharmacy claims was significantly decreased by 33.3% and 41.4% from baseline to follow-up in the allergic and non-allergic cohorts, respectively (p < 0.001); mean daily OCS dose significantly decreased by 30.6% and 45.4%, respectively (p < 0.001) as well as the mean number of OCS bursts, which decreased by 44.9% and 41.8%, respectively (p < 0.001). No significant differences were observed between cohorts in reductions in asthma exacerbations, counts of OCS pharmacy claims or OCS bursts (baseline to follow-up). Mepolizumab significantly reduced asthma exacerbations and OCS use in patients with allergic and non-allergic asthma, suggesting that mepolizumab provides real-world benefit in severe asthma irrespective of whether a patient has an allergic phenotype.

Comparative Impact of Asthma Biologics: A Nationwide US Claim-Based Analysis

BackgroundBiologic modifiers targeting type-2 (T2) airway inflammation are effective in reducing asthma exacerbation, however real-world and comparative effectiveness studies remain limited.Objective: to examine and compare the real-world impact of anti-T2 asthma biologics MethodsIn this retrospective new user cohort study, we used the MarketScan, a Commercial Claims and Encounters Database, to identify adult patients with asthma who were started on an anti-T2 biologic agent (anti-IL-5s, dupilumab or omalizumab). We examined the influence of the biologic class on asthma exacerbation by comparing the average number of asthma exacerbation 1-year pre- and post-biologic initiation. We conducted multivariable regression analyses to compare the effectiveness of these asthma biologics on reducing the incidence of asthma exacerbations within 18-month of initial administration of biologics while controlling for demographic variables, comorbidities, and asthma severity. ResultsWe identified 5,538 asthma patients who were initiated on an anti-T2 biologic [mean age (±SD); 45.6 (12.78) years; % females, 65.8%). Asthma biologics reduced asthma exacerbation by 11-47%, particularly among patients with 2+ asthma exacerbations in the year preceding biologic initiation (31-65% reduction). Biologics were especially effective in reducing asthma-related hospitalizations (44.6-60%). After adjusting for baseline demographics, asthma medication, and co-morbidities, dupilumab was associated with a lower estimated mean number of asthma exacerbation per year and lower adjusted OR for developing asthma exacerbation relative to other biologics (50-80% less likely). ConclusionAnti-T2 asthma biologics reduced asthma exacerbation in real-word settings. Evidence supports growing literature that dupilumab might have a more favorable impact on asthma exacerbation relative to other asthma biologics.

Lebrikizumab in Uncontrolled Asthma: Reanalysis in a Well-Defined Type 2 Population

LAVOLTA (L)I, LII, and ACOUSTICS were randomized, placebo-controlled, Phase 3 trials of lebrikizumab, a monoclonal antibody targeting IL-13 in patients with uncontrolled asthma. Failure to demonstrate efficacy may have been related to patient selection in those trials. To assess the efficacy in a well-defined subpopulation of patients with elevated blood eosinophil counts and a minimum number of prior asthma exacerbations. We performed an additional analysis in a subpopulation of patients with elevated FeNO and prior exacerbations. Adult (LI and LII) and adolescent patients (aged 12-17 years weighing ≥40 kg, ACOUSTICS) with uncontrolled asthma received lebrikizumab (125 mg, n= 832; or 37.5 mg, n= 829) or placebo (n= 833) subcutaneously every 4 weeks. Post hoc analysis of the annualized adjusted exacerbation rate (AER) was performed in a subpopulation of patients with baseline blood eosinophils of 300 cells/μL or greater and history of one or more exacerbations. In this subpopulation, there were 227 patients in the placebo group, 222 in the lebrikizumab 37.5-mg group, and 217 in the lebrikizumab 125-mg group. We summarized safety in patients who received at least one dose of lebrikizumab using adverse events. Lebrikizumab significantly reduced AER compared with placebo in adults (AER reduction: 125 mg [38%]; and 37.5 mg [41%]) and adolescents (AER reduction:125 mg [59%]; 37.5 mg [64%]) with baseline blood eosinophils of 300 cells/μL or greater and one or more exacerbations. Most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. Lebrikizumab significantly reduced asthma exacerbations in a subpopulation of patients with elevated blood eosinophils, elevated FeNO, and a history of asthma exacerbation.

Real-world outcomes of mepolizumab for the treatment of severe eosinophilic asthma in Canada: an observational study

BackgroundMepolizumab, the first widely available anti-interleukin 5 biologic, targets eosinophilic inflammation and has been shown in clinical trials to reduce exacerbations, oral corticosteroid dependence, and healthcare utilization in patients with severe asthma. The impact of mepolizumab in a real-world, publicly funded healthcare setting is unknown. The objective of this study was to describe the demographics and clinical characteristics of real-world patients receiving mepolizumab, and to compare asthma-related outcomes and associated asthma-related costs before and during mepolizumab use.MethodsThis retrospective, observational study in Ontario, Canada, included patients initiating mepolizumab between February 2016 and March 2019. Patients were identified using the mepolizumab patient support program and linked to the Institute for Clinical Evaluative Sciences database of publicly accessed healthcare. Patient outcomes were obtained for 12 months pre- and post-mepolizumab initiation and compared.ResultsA total of 275 patients were enrolled in the overall patient support program cohort (mean [standard deviation] age 57.6 [13.5] years, mean [standard deviation] of the median per-patient eosinophil count 540.4 [491.9] cells/μL). Mepolizumab was associated with reductions in asthma exacerbations (46.1%, P < 0.001) and in the number of asthma-related visits to general practitioners (40.2%, P < 0.001), specialists (27.2%, P < 0.001), and emergency departments (52.1%, P < 0.001). Associated costs were significantly lower post- versus pre-mepolizumab for asthma-related general practitioner and specialist visits, and for all-cause emergency department visits and hospital admissions.ConclusionsIn a real-world population of Canadian patients with severe asthma with an eosinophilic phenotype, the use of mepolizumab within a patient support program reduced asthma exacerbations and decreased asthma-related healthcare resource utilization and associated costs.

The impact of outdoor pollution and extreme temperatures on asthma-related outcomes: A systematic review for the EAACI guidelines on environmental science for allergic diseases and asthma.

Air pollution is one of the biggest environmental threats for asthma. Its impact is augmented by climate change. To inform the recommendations of the EAACI Guidelines on the environmental science for allergic diseases and asthma, a systematic review (SR) evaluated the impact on asthma-related outcomes of short-term exposure to outdoor air pollutants (PM2.5, PM10, NO2, SO2, O3, and CO), heavy traffic, outdoor pesticides, and extreme temperatures. Additionally, the SR evaluated the impact of the efficacy of interventions reducing outdoor pollutants. The risk of bias was assessed using ROBINS-E tools and the certainty of the evidence by using GRADE. Short-term exposure to PM2.5, PM10, and NO2 probably increases the risk of asthma-related hospital admissions (HA) and emergency department (ED) visits (moderate certainty evidence). Exposure to heavy traffic may increase HA and deteriorate asthma control (low certainty evidence). Interventions reducing outdoor pollutants may reduce asthma exacerbations (low to very low certainty evidence). Exposure to fumigants may increase the risk of new-onset asthma in agricultural workers, while exposure to 1,3-dichloropropene may increase the risk of asthma-related ED visits (low certainty evidence). Heatwaves and cold spells may increase the risk of asthma-related ED visits and HA and asthma mortality (low certainty evidence).

The Use of Albuterol/Budesonide as Reliever Therapy to Reduce Asthma Exacerbations

Prevention of asthma exacerbations and reduction of systemic corticosteroid burden remain unmet needs in asthma. US asthma guidelines recommend concomitant short-acting β2-agonist (SABA) and inhaled corticosteroid (ICS) as alternative reliever at Step 2. The FDA approved a pressurized metered-dose inhaler containing albuterol and budesonide for as-needed treatment or prevention of bronchoconstriction and to reduce exacerbation risk in patients with asthma aged ≥18 years. This combination is approved for use as a reliever with or without maintenance therapy but it is not indicated for maintenance therapy (or for single maintenance and reliever therapy). Intervening with as-needed SABA–ICS during the window-of-opportunity to reduce inflammation during loss of asthma control can reduce exacerbation risk, by exerting both genomic and nongenomic anti-inflammatory effects. We propose that use of albuterol–budesonide rather than albuterol as reliever to manage episodic symptoms driven by acute bronchoconstriction and airway inflammation can improve outcomes. This combination approach, shown to decrease asthma exacerbations and oral corticosteroid burden in patients with moderate-to-severe asthma, represents a paradigm shift for asthma treatment in the US. Further safety and efficacy studies should provide evidence that this type of reliever should be standard of care.

When sequential use of mepolizumab and dupilumab in a severe atopic eosinophilic asthmatic questions the role of eosinophils in mediating the clinical expression of the disease: a case report

BackgroundThe advent of biologics has resulted in major progress in the treatment of severe T2 high asthmatics. There are currently several classes of biologics approved for severe asthma including anti-immunoglobulin E, anti-interleukin-5/interleukin 5R, anti-interleukin 4/interleukin 13R, and anti-thymic stromal lymphopoietin.Case presentationsHere we report the case of a 55-year-old Caucasian man with severe eosinophilic atopic asthma, who sequentially benefited from a treatment with mepolizumab, an anti-interleukin-5 monoclonal antibody, followed by treatment with dupilumab, an anti-interleukin-4/interleukin-13R antibody, the switch being justified by a flare-up of dermatitis while on mepolizumab. Overall, the patient has been followed for 72 months, including 42 months on mepolizumab and 30 months on dupilumab. Close monitoring of exacerbations, asthma control, lung function, asthma quality of life, and biomarkers shows that both biologics reduced asthma exacerbation and provided an improvement in asthma control and quality of life, with the patient achieving remission after 30 months on dupilumab. However, the effects of the two biologics on the biomarkers were very different, with mepolizumab controlling eosinophilic inflammation and dupilumab reducing serum immunoglobulin E and fractional exhaled nitric oxide levels.ConclusionThe originality of this case resides in the description of clinical status and biomarker evolution after a sequential use of mepolizumab and dupilumab in a severe atopic eosinophilic asthmatic. It shows that mepolizumab reduces exacerbation and improves asthma control by curbing eosinophilic inflammation whereas dupilumab provides asthma remission without controlling airway eosinophilic inflammation.