LABA Research Articles

Effect of Primary Care on Reducing Rates of Hospitalization Among Chronic Obstructive Pulmonary Disease Patients

The normal course of Chronic obstructive pulmonary disease (COPD) includes a progressive reduction in lung function, exacerbations that necessitate primary care intervention or hospital admission, a steady decline in quality of life, and a shorter life expectancy. COPD is one of the ambulatory or primary care-sensitive illnesses for which it is hypothesized that efficient primary care management will lower the probability of hospital admission. Long-acting beta-agonist and inhaler steroid combination therapy improves spirometric results and overall health while lowering the annual risk of COPD exacerbations. Use of two or more treatment modules based on models designed specifically for chronic care delivery in developed countries have proven successful in lowering hospitalizations as well. Access to other therapies, such as pulmonary rehabilitation, acute exacerbation evaluation programs, and community or hospital-based respiratory specialists, may also be important. The goal of interventions to lessen the prevalence of COPD in underserved areas has to focus on locally driven integrated solutions, such as media campaigns to raise awareness and persuade at-risk individuals to get tested, as well as training for primary care workers on the significance and advantages of earlier detection and effective operation of chronic obstructive pulmonary disease. Importantly, uptake of influenza vaccination has demonstrated a link with hospital admission rates at the practice level. Proposed solutions for lowering hospitalization and reducing exacerbations among patients with COPD include greater access to pulmonary rehabilitative care, more rigorous implementation of smoking cessation programs and availability of modern long-acting medications.

Triple versus LAMA/LABA combination therapy for Japanese patients with COPD: A systematic review and meta-analysis.

In symptomatic COPD patients with a history of exacerbations, additional treatment with inhaled corticosteroid (ICS) to long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist (LABA) combination therapy is recommended based on the evidence of low incidence of exacerbations but with a caution for pneumonia. However, ethnic differences may affect the response to drugs. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of this treatment in the Japanese population (PROSPERO: CRD42020191978). We searched relevant randomized control trials and analyzed the exacerbations, quality of life, lung function, and adverse events including pneumonia and mortality as the outcomes of interest. We identified a total of three RCTs (N=632). Treatment with ICS/LAMA/LABA triple therapy significantly decreased the exacerbations (rate ratio, 0.56; 95% CI, 0.38 to 0.85) and improved the trough FEV1 (mean difference, 0.04; 95% CI, 0.01 to 0.07) compared to LAMA/LABA therapy. However, triple therapy showed a significantly higher incidence of pneumonia compared to LAMA/LABA (odds ratio, 3.38; 95% CI, 1.58 to 7.22). Concerning other adverse events including mortality, there were no significant difference between these therapies. In the current meta-analysis of the Japanese population, we confirmed that triple therapy causes a higher incidence of pneumonia than LAMA/LABA treatment but is a more preferable treatment since it showed a lower incidence of exacerbations and higher trough FEV1 in patients with symptomatic moderate to severe COPD. However, since the sample sizes were not statistically large enough, further trials involving Japanese patients are needed.

Treatment patterns and cost of exacerbations in patients with chronic obstructive pulmonary disease using multiple inhaler triple therapy in South Korea

BackgroundMultiple inhaler triple therapy (MITT), comprising inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA), has been used as an escalation treatment for patients with chronic obstructive pulmonary disease (COPD). However, real-world use of MITT has not been investigated in Asia, including South Korea. This study reports baseline characteristics of patients with COPD initiated on MITT in South Korea, and their treatment patterns. Healthcare resource utilization (HRU) and costs associated with COPD exacerbations following MITT initiation were also assessed.MethodsThis was a retrospective cohort study using the South Korea National Health Insurance database (2014–2018). Included patients were ≥ 40 years, had a COPD diagnosis, were newly initiated on MITT and had ≥ 12 months’ data both before (baseline) and after index date (the first day with overlapping supply of all MITT components). Treatment immediately before initiation and immediately following discontinuation of MITT were identified, and proportion of days covered (PDC) by MITT was calculated. HRU and costs (per person per year [PPPY]) associated with exacerbations were identified following MITT initiation; costs were calculated using the average 2020 exchange rate (0.0008 USD/KRW).ResultsAmong 37,400 patients, the mean age was 69 (SD 10) years and 73% were males; 56% had ≥ 1 COPD exacerbation during the baseline period, with a mean of 2 (SD 5) events/year. ICS/LABA was the most frequent regimen prescribed immediately before initiation (37%) and immediately following discontinuation (41% of 34,264 patients) of MITT. At 3, 6, and 12 months from treatment initiation, mean PDC was 81%, 63% and 49%, respectively; median treatment duration was 102 days. The mean (95% confidence interval [CI]) number of total visits for severe COPD exacerbations was 0.77 PPPY (0.75–0.78); mean PPPY total healthcare costs were 2093 USD.ConclusionsPatients with COPD in South Korea experienced frequent exacerbations prior to MITT, and PDC by MITT was low. Patients may benefit from early optimization of COPD therapy, and greater emphasis on adherence to inhaled COPD therapy. Severe exacerbations were found to incur substantial costs; treatment alternatives that can reduce the rate of severe exacerbations are likely to minimize healthcare costs.

Вплив поліморфізму C79G (rs1072714) та A46G (rs1042713) гена ADRB2 на клінічний перебіг ХОЗЛ

Аbstract. Chronic obstructive pulmonary disease (COPD) is a prevalent disease, that can be prevented and treated. Genetic factors play an important role in the COPD development. The aim of our study was to found ADRB2 gene polymorphism prevalence among patients with COPD, and assessment of its relation with the COPD development and clinical course. Materials and methods. 100 patients with COPD were included into the study. Source documentation, clinical and historical data were collected during study visits. Blood samples for ADRB2 gene testing were taken in all patients. All patients were treated according to GOLD guidelines, which included a combination of long-acting beta-2 agonists and long-acting anticholinergic drugs. According to the genetic analysis all patients were divided into 3 groups C79C/G46G (Haplotype 1) — 23 patients (23 %), C79G/A46G (Haplotype 2) — 26 patients (26 %), G79G/A46A (Haplotype 3) — 26 patients (26 %). Results. In correlation analysis there was a weak negative correlation between Haplotype 1 and total amount of exacerbations (r = -0.245, p = 0.032) and hospitalizations (r = -0.248, p = 0.032), and haplotype 3 had weak positive correlation with the amount of out-patient exacerbations (r = 0.263, p = 0.023). An average amount of antibiotic courses in group 1 was (1.09 ± 0.2), in group 2 — (1.69 ± 0.18), in group 3 — (2.00 ± 0.22), this difference was statistically significant (р = 0.005). There also was a significant difference in the duration of antibiotic treatment, which was (8.61 ± 1.55) in group 1, (12.88 ± 1.62) days in group 2 and (14.42 ± 1.68) days in group 3 (р = 0.036). Conclusions. ADRB2 gene polymorphism affects clinical course of COPD, which manifest in the different need in the administration of antibiotics in study groups, and also in the tendency towards different amount of exacerbations and rate of glucocorticoid use. Key words: COPD, gene ADRB2, exacerbations, antibiotics.

The role of interleukin-33 in the pathogenesis, and treatment of severe asthma

Interleukin-33 (IL-33) belongs to the IL-1 family of cytokines, which has 11 members, including IL-1α, IL-1β, IL-1Ra, IL-18, IL-36α, IL-36β, and IL-37. Unlike its family members, IL-33 mediates T helper type-2 (Th2) immune responses, and promotes eosinophilic inflammation, similar to the other epithelial-derived cytokines, such as IL-25, and thymic stromal lymphopoietin (TSLP). Epithelial injury due to viral, and bacterial infections, allergens, chemical irritants, and trauma lead to secretion of alarmin cytokines, including IL-25, IL-33, and TSLP. IL-33 plays an important role in activating Th2 lymphocytes, group 2 innate lymphoid cells, dendritic cells, mast cells, basophils, and eosinophils, which result in secretion of cytokines, such as IL-4, IL-13, and IL-5; chemokines, including CCL2, and CXCL8, and adhesion molecules. The inflammatory mediators promote eosinophilic airway inflammation, airway hyperresponsiveness, and remodeling. IL-33 signaling is via a complex heterodimeric receptor comprising of IL-1 receptor-like 1 (IL-1RL1), and IL-1 receptor accessory protein. Downstream signaling cascade leads to the transcription of multiple cytokines and chemokines, which orchestrate eosinophilic asthma. Treatment of severe eosinophilic asthma include long-acting beta2-agonists, and inhaled corticosteroids, and addition of biologics at GINA step 4/5, such as omalizumab, mepolizumab, dupilumab, and tezepelumab. Currently, there are no anti-IL-33 biologics which have been approved for the treatment of eosinophilic asthma. Etokimab is a first-in-class IgG1 monoclonal antibody which blocks the activity of IL-33, thereby, inhibiting its biological effects. Phase 2a proof-of-concept clinical trial in 25 patient with severe eosinophilic asthma, showed that a single intravenous dose of etokimab (330 mg) resulted in a rapid and sustained improvement in lung function, and reduction in the asthma control questionnaire-5 scores throughout the study period of 64 days. Recently, itepekimab has been shown to improve asthma control, lung function, and quality of life, although the effects of itepekimab were slightly lesser than those observed for dupilumab. The dual therapy of itepekimab plus dupilumab did not achieve optimal outcomes, moreover, treatment with the doublet resulted in minimal change in pre-bronchodilator FEV1 compared with placebo. Dual blockade of interleukins incriminated in the pathogenesis of eosinophilic asthma need further careful studies, because of the immunological consequences in the era of SARS-CoV-2.

SMART therapy in adolescent and adults patients with moderate persistent asthma: a cost-utility analysis

Background Recent asthma guidelines, recommends for persistent asthma as first alternative low dose inhaled budesonide-formoterol maintenance and reliever over fixed combination of low doses inhaled corticosteroids - long-acting beta-agonist, or fixed-dose inhaled corticosteroids. Concerns arise as to which of the proposed alternatives has the best possible cost-effectiveness profile. This study aimed to assess the health and economic consequences of SMART, fixed combination, and fixed-dose inhaled corticosteroids in patients with moderate-severe persistent asthma. Methods A probabilistic Markov model was created to estimate the cost and quality-adjusted life-years (QALYs) of patients with persistent asthma. Total costs and QALYs of SMART, fixed combination, and fixed-dose inhaled corticosteroids were calculated over a lifetime horizon. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at a willingness-to-pay value of $19,000. Results The model suggests a potential gain of 1.27 and 1.34 QALYs per patient per year on SMART respect to fixed combination and fixed-dose ICS respectively. We observed a reduction of US$4 in total discounted cost per person-year on SMART with respect to fixed combination and US$0.1 respect to fixed-dose ICS. In the deterministic and probabilistic sensitivity analyses, our base-case results were robust to variations of all assumptions and parameters Conclusion SMART therapy was found to be cost-effective regarding fixed combination and fixed-dose inhaled corticosteroids. This evidence supports the use of SMART therapy in Colombia and must to be replicated in others middle-income countries.

The ELSA trial: single versus combinatory effects of non-prohibited beta-2 agonists on skeletal muscle metabolism, cardio-pulmonary function and endurance performance\u2014study protocol for a randomized 4-way balanced cross-over trial

BackgroundAsthma and/or airway hyper-responsiveness (AHR) are common in elite endurance athletes with a high prevalence rate of beta-2 adrenoreceptor (beta-2) agonists use. Nevertheless, there are data on dose-dependent ergogenic effects of beta-2 agonists suggesting increased muscle strength, endurance and neuromuscular performance. Therefore, most beta-2 agonists belong to the World Anti Doping Agency (WADA) list of prohibited substances and it is tempting to speculate that illegitimate use of beta-2 agonists might be a common practice to boost performance in competitive sports. It is currently unknown whether or not inhaled beta-2 agonists enhance performance by stimulatory effects in skeletal and cardiac muscle.MethodsThe ELSA trial is a double-blinded, placebo-controlled, randomized, balanced, four-way cross-over study. Study participants (n=24, 12 ♀, 12 ♂) complete four study arms (i.e. periods with treatment A, placebo; B, salbutamol; C, formoterol; D, formoterol + salbutamol) in random order after an initial preliminary testing session. Participants inhale the study medication 20 min before the 10-min time trial (TT; exercise performance test), where participants cycle 10 min at the highest possible workload. Cardiac output is measured continuously. A skeletal muscle biopsy is collected 3 h after the TT. Study endpoints include measures of skeletal muscle expression of nuclear receptors, hormones and cytokine levels, urinary and plasma concentrations of salbutamol and formoterol, circulating cardiac markers, cardiopulmonary function and exercise performance (average power and peak power during the TT). Blood and urine are collected and respiratory testing is performed 24 h post TT.Summary/conclusionsThis clinical trial evaluates the potential performance-enhancing effects of non-prohibited, not medically indicated inhaled short- and long-acting beta-2 agonists on skeletal muscle gene expression, endocrine regulation, cardiac biomarkers, cardiopulmonary function and acute endurance exercise performance. These data will be used by WADA to adapt the annually published list of prohibited substances (WADA 2021) and will be published in scientific journals.Trial registrationThe trial is registered at the European Clinical Trials Database (Eudra CT) with the number: 2015-005598-19 as well as at the German register for clinical studies (DRKS number 00010574).

Controller Medication Use and Exacerbations for Children and Adults With Asthma in High-Deductible Health Plans

To examine the association between enrollment in high-deductible health plans (HDHPs) and asthma controller medication use and exacerbations.A longitudinal cohort of children (4–17 years old) and adults (18–64 years old) on employer-sponsored insurance, who had at least 24 months of continuous insurance enrollment.Identified from a national administrative claims database in the United States, patients with persistent asthma were selected, and their insurance was categorized as a HDHP, defined as an annual individual deductible of ≥$1000, or a traditional plan, with deductibles of $0–500. Enrollees in a HDHP were only those who switched from a traditional plan after 12 months to a HDHP for the following 12 months. A differences-in-differences analyses design was used to compare outcomes between patients who switched to a HDHP to that of controls, who remained in a traditional plan for the 24 months. Outcomes included controller medication fills, adherence, and asthma exacerbations.The study sample included 7275 children and 17 614 adults with HDHPs. In the differences-in-differences analyses among children, there were no differences in controller medical fill rates, except for a significant reduction in fills for inhaled corticosteroid (ICS) and long-acting beta-agonist (LABA) (−0.04; 95% confidence interval: −0.07 to −0.01). There were also no significant changes in the proportion of days covered by a controller medication (ie, adherence measure), steroid bursts, or asthma-related ED visits, comparing children with HDHPs to controls. Among adults with HDHPs, there were also no significant differences in outcomes.The findings are consistent with previous adult studies that revealed that enrollment in HDHPs have minimal to no decrease in medication use and without significant changes in health outcomes. The authors think this is partly due to HDHPs exempting medications, like asthma controller medications, from deductibles. These medications are instead paid in a copayment arrangement.This insurance policy approach reveals that HDHPs can be designed to support affordable coverage but also preserve necessary asthma care for patients.

Cost-utility of triple versus dual inhaler therapy in moderate to severe asthma

BackgroundAn important proportion of asthma patients remain uncontrolled despite using inhaled corticosteroids and long-acting beta-agonists. Clinical guidelines recommend, in these patients, using add-on long-acting muscarinic antagonists (triple therapy) to treatment with high doses of inhaled corticosteroids-long-acting beta2-agonist (dual therapy). The purpose of this study was to assess the cost-effectiveness of triple therapy versus dual therapy for patients with severe asthma.MethodsA probabilistic Markov model was created to estimate the cost and quality-adjusted life-years (QALYs) of patients with severe asthma in Colombia. Total costs and QALYS of dual and triple therapy were calculated over a lifetime horizon. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at a willingness-to-pay value of $19,000.ResultsThe model suggests a potential gain of 1.55 QALYs per patient per year on triple therapy with respect to dual therapy. We observed a difference of US$304 in discounted cost per person-year on triple therapy with respect to dual therapy. The incremental cost-effectiveness ratio was US$196 in the probabilistic model. In the sensitivity analysis, our base‐case results were robust to variations in all assumptions and parameters.ConclusionIn conclusion, triple therapy in patients with moderate-severe asthma was cost-effective. Using triple therapy emerges with our results as an alternative before using oral corticosteroids or biologics, especially in resource-limited settings.

Bronchial Thermoplasty Global Registry (BTGR): 2-year results

ObjectivesBronchial thermoplasty (BT) is a device-based treatment for subjects ≥18 years with severe asthma not well controlled with inhaled corticosteroids and long-acting beta-agonists. The Bronchial Thermoplasty Global Registry (BTGR) collected...

Efficacy and safety of salmeterol/fluticasone compared with montelukast alone (or add-on therapy to fluticasone) in the treatment of bronchial asthma in children and adolescents: a systematic review and meta-analysis.

Background:Despite the recommendation of inhaled corticosteroids (ICSs) plus long-acting beta 2-agonist (LABA) and leukotriene receptor antagonist (LTRA) or ICS/LTRA as stepwise approaches in asthmatic children, there is a lack of published systematic review comparing the efficacy and safety of the two therapies in children and adolescents aged 4 to 18 years. This study aimed to compare the safety and efficacy of salmeterol/fluticasone (SFC) vs. montelukast (MON), or combination of montelukast and fluticasone (MFC) in children and adolescents aged 4 to 18 years with bronchial asthma.Methods:A systematic search was conducted in MEDLINE, EMBASE, the Cochrane Library, China BioMedical Literature Database, Chinese National Knowledge Infrastructure, VIP Database for Chinese Technical Periodical, and Wanfang for randomized controlled trials (RCTs) published from inception to May 24, 2021. Interventions are as follows: SFC vs. MON, or combination of MFC, with no limitation of dosage or duration. Primary and secondary outcome measures were as follows: the primary outcome of interest was the risk of asthma exacerbation. Secondary outcomes included risk of hospitalization, pulmonary function, asthma control level, quality of life, and adverse events (AEs). A random-effects (I2 ≥ 50%) or fixed-effects model (I2 < 50%) was used to calculate pooled effect estimates, comparing the outcomes between the intervention and control groups where feasible.Results:Of the 1006 articles identified, 21 studies met the inclusion criteria with 2643 individuals; two were at low risk of bias. As no primary outcomes were similar after an identical treatment duration in the included studies, meta-analysis could not be performed. However, more studies favored SFC, instead of MON, owing to a lower risk of asthma exacerbation in the SFC group. As for secondary outcome, SFC showed a significant improvement of peak expiratory flow (PEF)%pred after 4 weeks compared with MFC (mean difference [MD]: 5.45; 95% confidence interval [CI]: 1.57–9.34; I2 = 95%; P = 0.006). As for asthma control level, SFC also showed a higher full-controlled level (risk ratio [RR]: 1.51; 95% CI: 1.24–1.85; I2 = 0; P < 0.001) and higher childhood asthma control test score after 4 weeks of treatment (MD: 2.30; 95% CI: 1.39–3.21; I2 = 72%; P < 0.001) compared with MFC.Conclusions:SFC may be more effective than MFC for the treatment of asthma in children and adolescents, especially in improving asthma control level. However, there is insufficient evidence to make firm conclusive statements on the use of SFC or MON in children and adolescents aged 4 to 18 years with asthma. Further research is needed, particularly a combination of good-quality long-term prospective studies and well-designed RCTs.PROSPERO registration number:CRD42019133156.

Bronchial Thermoplasty in Patients With Severe Asthma at 5 Years: The Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma Study

Bronchial thermoplasty is a device-based treatment for subjects≥ 18 years of age with severe asthma poorly controlled with inhaled corticosteroids and long-acting beta-agonists. The Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) study collected data on patients with severe asthma undergoing this procedure. What are the 5-year efficacy and safety results in patients with severe asthma who have undergone bronchial thermoplasty? This was a prospective, open-label, observational, multicenter study conducted in the United States and Canada. Subjects 18 to 65 years of age who were taking inhaled corticosteroids≥ 1,000 μg/d (beclomethasone or equivalent) and long-acting beta-agonists≥ 80 μg/d (salmeterol or equivalent) were included. Severe exacerbations, hospitalization, ED visits, and medication usage were evaluated for the 12months prior to and at years 1 through 5 posttreatment. Spirometry was evaluated at baseline and at years 1 through 5 posttreatment. A total of 284 subjects were enrolled at 27 centers; 227 subjects (80%) completed 5 years of follow-up. By year 5 posttreatment, the proportion of subjects with severe exacerbations, ED visits, and hospitalizations was 42.7%, 7.9%, and 4.8%, respectively, compared with 77.8%, 29.4%, and 16.1%in the 12months prior to treatment. The proportion of subjects on maintenance oral corticosteroids decreased from 19.4%at baseline to 9.7%at 5 years. Analyses of subgroups based on baseline clinical and biomarker characteristics revealed a statistically significant clinical improvement among all subgroups. Five years after treatment, subjects experienced decreases in severe exacerbations, hospitalizations, ED visits, and corticosteroid exposure. All subgroups demonstrated clinically significant improvement, suggesting that bronchial thermoplasty improves asthma control in different asthma phenotypes. ClinicalTrials.gov; No.: NCT01350336; URL: www. gov.

The Role of Inhaled Corticosteroids (ICS) in Critically Ill Patients With COVID-19: A Multicenter, Cohort Study.

Background: Severe coronavirus disease 2019 (COVID-19) can boost the systematic inflammatory response in critically ill patients, causing a systemic hyperinflammatory state leading to multiple complications. In COVID-19 patients, the use of inhaled corticosteroids (ICS) is surrounded by controversy regarding their impacts on viral infections. This study aims to evaluate the safety and efficacy of ICS in critically ill patients with COVID-19 and its clinical outcomes. Method: A multicenter, noninterventional, cohort study for critically ill patients with COVID-19 who received ICS. All patients aged ≥ 18 years old with confirmed COVID-19 and admitted to intensive care units (ICUs) between March 1, 2020 and March 31, 2021 were screened. Eligible patients were classified into two groups based on the use of ICS ± long-acting beta-agonists (LABA) during ICU stay. Propensity score (PS)-matched was used based on patient's Acute Physiology and Chronic Health Evaluation II (APACHE II) score, Sequential Organ Failure Assessment (SOFA) score, systemic corticosteroids use, and acute kidney injury (AKI) within 24 h of ICU admission. We considered a P-value of < 0.05 statistically significant. Results: A total of 954 patients were eligible; 130 patients were included after PS matching (1:1 ratio). The 30-day mortality (hazard ratio [HR] [95% confidence interval [CI]]: 0.53 [0.31, 0.93], P-value = 0.03) was statistically significant lower in patients who received ICS. Conversely, the in-hospital mortality, ventilator-free days (VFDs), ICU length of stay (LOS), and hospital LOS were not statistically significant between the two groups. Conclusion: The use of ICS ± LABA in COVID-19 patients may have survival benefits at 30 days. However, it was not associated with in-hospital mortality benefits nor VFDs.

Pharmacogenetic studies of long-acting beta agonist and inhaled corticosteroid responsiveness in randomised controlled trials of individuals of African descent with asthma

Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent. We did ancestry-based pharmacogenetic studies of children (aged 5-11 years) and adolescents and adults (aged 12-69 years) from the Best African Response to Drug (BARD) trials, in which participants with asthma uncontrolled with low-dose ICS (fluticasone propionate 50 μg in children, 100 μg in adolescents and adults) received different step-up combination therapies. The hierarchal composite outcome of pairwise superior responsiveness in BARD was based on asthma exacerbations, a 31-day difference in annualised asthma-control days, or a 5% difference in percentage predicted FEV1. We did whole-genome admixture mapping of 15 159 ancestral segments within 312 independent regions, stratified by the two age groups. The two co-primary outcome comparisons were the step up from low-dose ICS to the quintuple dose of ICS (5 × ICS: 250 μg twice daily in children and 500 μg twice daily in adolescents and adults) versus double dose (2-2·5 × ICS: 100 μg twice daily in children, 250 μg twice daily in adolescents and adults), and 5 × ICS versus 100 μg fluticasone plus a LABA (salmeterol 50 μg twice daily). We used a genome-wide significance threshold of p<1·6 × 10-4, and tested for replication using independent cohorts of individuals of African descent with asthma. We included 249 unrelated children and 267 unrelated adolescents and adults in the BARD pharmacogenetic analysis. In children, we identified a significant admixture mapping peak for superior responsiveness to 5 × ICS versus 100 μg fluticasone plus salmeterol on chromosome 12 (odds ratio [ORlocal African] 3·95, 95% CI 2·02-7·72, p=6·1 × 10-5) fine mapped to a locus adjacent to RNFT2 and NOS1 (rs73399224, ORallele dose 0·17, 95% CI 0·07-0·42, p=8·4 × 10-5). In adolescents and adults, we identified a peak for superior responsiveness to 5 × ICS versus 2·5 × ICS on chromosome 22 (ORlocal African 3·35, 1·98-5·67, p=6·8 × 10-6) containing a locus adjacent to TPST2 (rs5752429, ORallele dose 0·21, 0·09-0·52, p=5·7 × 10-4). We replicated rs5752429 and nominally replicated rs73399224 in independent African American cohorts. BARD is the first genome-wide pharmacogenetic study of LABA and ICS response in clinical trials of individuals of African descent to detect and replicate genome-wide significant loci. Admixture mapping of the composite BARD trial outcome enabled the identification of novel pharmacogenetic variation accounting for differential therapeutic responses in people of African descent with asthma. National Institutes of Health, National Heart, Lung, and Blood Institute.

Keeping Pace with Adolescent Asthma: A Practical Approach to Optimizing Care.

Known for their pre-occupation with body image, self-identity creation, peer acceptance, and risk-taking behaviors, adolescents with asthma face unique challenges. Asthma is a heterogeneous disease and accurate diagnosis requires assessment through detailed clinical history, examination, and objective tests. Diagnostic challenges exist as many adolescents can present with asthma-like symptoms but do not respond to asthma treatment and risk being mis-diagnosed. Under-recognition of asthma symptoms and denial of disease severity must also be addressed. The over-reliance on short-acting beta-agonists in the absence of anti-inflammatory therapy for asthma is now deemed unsafe. Adolescents with mild asthma benefit from symptom-driven treatment with combination inhaled corticosteroids (ICS) and long-acting beta-agonist (LABA) on an as-required basis. For those with moderate-to-persistent asthma requiring daily controller therapy, maintenance and reliever therapy using the same ICS-LABA controller simplifies treatment regimes, while serving to reduce exacerbation risk. A developmentally staged approach based on factors affecting asthma control in early, middle, and late adolescence enables better understanding of the individual’s therapeutic needs. Biological, psychological, and social factors help formulate a risk assessment profile in adolescents with difficult-to-treat and severe asthma. Smoking increases risks of developing asthma symptoms, lung function deterioration, and asthma exacerbations. Morbidity associated with e-cigarettes or vaping calls for robust efforts towards smoking and vaping cessation and abstinence. As adolescents progress from child-centered to adult-oriented care, coordination and planning are required to improve their self-efficacy to ready them for transition. Frequent flare-ups of asthma can delay academic attainment and adversely affect social and physical development. In tandem with healthcare providers, community and schools can link up to help shoulder this burden, optimizing care for adolescents with asthma.

Effect of Adding Inhaled Corticosteroid to Long-Acting Muscarinic Antagonist/Long-Acting Beta-Agonist Therapy Among Patients With Chronic Obstructive Pulmonary Disease.

BackgroundThe role of inhaled corticosteroid (ICS) in chronic obstructive pulmonary disease (COPD) is unclear. Hence, this study aimed to evaluate the efficacy of ICS as an add-on to long-acting muscarinic antagonist (LAMA)/long-acting beta 2 agonist (LABA), which was assessed using the impulse oscillation system (IOS), in patients with COPD.MethodologyWe included patients with COPD whose treatment was changed from LAMA/LABA (≥four weeks) to ICS/LAMA/LABA between April 2019 and March 2021. To gain insight into the effect and safety of ICS-containing triple therapy for COPD, pulmonary function; Short-Form 36, St. George’s Respiratory Questionnaire, COPD Assessment Test, and modified Medical Research Council scores; and airway resistance assessed using the IOS from one week before LAMA/LABA was switched to ICS/LAMA/LABA therapy until more than eight but less than twelve weeks after switching were evaluated.ResultsIn total, 46 patients with COPD (mean age: 72.28 ± 7.81 years) were included in the study. None of the pulmonary function test parameters significantly changed from baseline values (mean difference in forced expiratory volume in one second [FEV1.0]: +0.032, P = 0.12; percentage FEV1.0 [FEV1.0%]/forced vital capacity [FVC]: −0.58, P = 0.42; and FVC: +0.087, P = 0.058). Meanwhile, the IOS showed that resonant frequency (mean difference from baseline: −2.12, P < 0.0001) and bodily pain scores in the St. George’s Respiratory Questionnaire (mean difference: −7.03, P = 0.031) significantly decreased.ConclusionsSwitching from LAMA/LABA to ICS/LAMA/LABA therapy reduces airway elasticity-to-inertial resistance ratios, which may lead to structural airway improvements in patients with COPD.

Pharmacotherapeutic strategy for COPD patients: focus on dual bronchodilators

For two decades, the GOLD Initiative has consistently identified the use of bronchodilators as a priority in the pharmacotherapeutic strategy for COPD. The authors of international and national clinical guidelines consider fixed combinations of long-acting beta2-agonists (LABAs) and long-acting muscarinic receptor antagonists (LAMAs) as “first-line” drugs in most patients with COPD. Numerous clinical studies have shown that fixed LABAs/LAMAs combinations provide optimal bronchodilation and play a paramount role in preventing exacerbations of COPD. Outperforming placebo and active controls, LABAs, LAMAs, inhaled glucocorticosteroids (ICS)/LABAs combination bronchodilators may differ in their therapeutic potential. The available evidence base currently does not allow to make an unambiguous choice in favor of one or another fixed LABAs/ LAMAs combination. With the appearance of “triple” combinations (ICS/LABAs/LAMAs) on the pharmaceutical market, the issue of their comparison with “dual” bronchodilators has become particularly acute. Currently available data suggest that the use of “triple” therapy is not considered as a starting treatment option for COPD and is appropriate only in a subgroup of patients with a higher baseline risk of exacerbations: in the presence of a history of exacerbations ≥ 1, which required prescription of systemic antibiotics and/or glucocorticosteroids, or necessitated hospitalization during the previous year. Thus, ICS-containing therapy is justified only in cases of recurrent exacerbations of moderate COPD or single episodes of severe exacerbations, despite the continued administration of LABAs/LAMAs, as well as in certain categories of patients whose inflammatory profile suggests a “response” to ICS.

Combined therapy with inhaled glucocorticosteroids and long-acting β2-agonists in patients with bronchial asthma: the problem of choice

Bronchial asthma remains one of the most common chronic respiratory diseases. The apparent heterogeneity of BA underlies the concept of phenotype-specific or patient-centered therapy. However, in real clinical practice, BA continues to be regarded as a rather homogeneous pathological condition and its treatment in the vast majority of cases retains an empirical approach, the basis of which are inhaled glucocorticosteroids, usually in combination with long-acting beta2-agonists. Since this group of drugs is very representative, the physician is faced with the question of choosing the optimal drug. The basis of evidence-based medicine is a hierarchical classification, where systematic reviews, meta-analyses, and randomized clinical trials are considered the highest level of evidence. Because randomized clinical trials are conducted in carefully selected highly selected patient populations, they have little relevance to patients encountered in everyday clinical practice. In contrast, pragmatic randomized clinical trials assess the clinical efficacy of the investigational agent in a large, unselected population in which patients with comorbidities are included. In this context, the Salford Lung Study (SLS) is of particular interest. It was conducted before the registration of a new combination drug containing the modern ICS fluticasone furoate and the long-acting beta2-agonist vilanterol. The SLS results indicated not only that the use of fluticasone furoate with vilanterol provides better control of BA compared to continued "conventional therapy" (ICS ± LABAs) in symptomatic patients, but also leads to a consistent improvement in the surrogate parameters of quality of life.

61 Adherence to Daily Medication Regimens in Pediatric Asthma: Do Socioeconomic Status and Daily Dose Frequency have an Impact?

Abstract Primary Subject area Respirology Background Children with asthma from lower socioeconomic status (SES), and those with poor adherence to controller medications have worse health outcomes, including higher rates of exacerbations and hospitalizations. Simpler medication regimens could potentially improve medication adherence and asthma control. Objectives We aimed to determine if: (1) medication adherence (proportion of prescribed days covered [PPDC]) and primary non-adherence (PPDC = 0%) varied by SES; and if (2) there was an interaction between SES and daily dose frequency on adherence. Design/Methods This retrospective cohort study included children 2-17 years old followed at the asthma clinic of a large Canadian pediatric hospital between 2011 and 2020. Patients were prescribed one of five medication regimens that included one or more of the following medication classes: inhaled corticosteroids (ICS), long-acting beta-agonists (LABA) and leukotriene receptor antagonists (LTRA). Primary outcome was medication adherence, using the PPDC: the number of days for which a medication was dispensed divided by the number of days for which it was prescribed. For regimens with two different medications, total PPDC was the average of the PPDCs for each medication. The main predictor was SES, measured by the Pampalon’s material deprivation index, a compounded index of income, employment, and education, based on postal codes. It is divided in quintiles, with quintile 1 being the least materially deprived. Comparison of PPDC between quintiles of SES was achieved by a Kruskal-Wallis test. Chi-square testing was used to assess the relationship between the proportion of patients with primary non-adherence (PPDC=0) and quintiles of SES. In the subset of patients who did not have primary non-adherence (n = 462), interaction between SES and daily dose frequency on log transformed PPDC was examined using linear regression models. Results Among 551 patients, mean age was 7.1 years (SD 3.8) (Table1), and there was a similar number of patients in each quintile of SES based on a chi-square goodness of fit test (p=0.61). For the overall sample, mean PPDC was 38.1% (SD 27.6). PPDC was not statistically different between quintiles of SES (p=0.57) (Figure 1). Distribution of primary non-adherence (PPDC = 0) in the cohort was independent of the quintiles of SES (p=0.57). Keeping SES constant, twice-daily dose frequency was associated with a 1.1% decrease in PPDC (p=0.85). The interaction between daily dose frequency and SES was not statistically significant (p=0.66). Conclusion Medication adherence (PPDC) and primary non-adherence (PPDC = 0) did not vary significantly by SES, but twice-daily dose frequency was associated with a small decrease in mean PPDC. Quebec’s mandatory medication insurance could potentially explain the absence of difference in medication adherence across SES quintiles.

Efficacy and Safety of Itepekimab in Patients with Moderate-to-Severe Asthma

BackgroundMonoclonal antibodies targeting IgE, interleukin-4 and -13, and interleukin-5 are effective in treating severe type 2 asthma, but new targets are needed. Itepekimab is a new monoclonal antibody against the upstream alarmin interleukin-33. The efficacy and safety of itepekimab as monotherapy, as well as in combination with dupilumab, in patients with asthma are unclear.MethodsIn a phase 2 trial, we randomly assigned, in a 1:1:1:1 ratio, adults with moderate-to-severe asthma receiving inhaled glucocorticoids plus long-acting beta-agonists (LABAs) to receive subcutaneous itepekimab (at a dose of 300 mg), itepekimab plus dupilumab (both at 300 mg; combination therapy), dupilumab (300 mg), or placebo every 2 weeks for 12 weeks. After randomization, LABA was discontinued at week 4, and inhaled glucocorticoids were tapered over weeks 6 through 9. The primary end point was an event indicating a loss of asthma control, assessed in the itepekimab group and the combination group, as compared with the placebo group. Secondary and other end points included lung function, asthma control, quality of life, type 2 biomarkers, and safety.ResultsA total of 296 patients underwent randomization. By 12 weeks, an event indicating a loss of asthma control occurred in 22% of the patients in the itepekimab group, 27% of those in the combination group, and 19% of those in the dupilumab group, as compared with 41% of those in the placebo group; the corresponding odds ratios as compared with placebo were as follows: in the itepekimab group, 0.42 (95% confidence interval [CI], 0.20 to 0.88; P=0.02); in the combination group, 0.52 (95% CI, 0.26 to 1.06; P=0.07); and in the dupilumab group, 0.33 (95% CI, 0.15 to 0.70). As compared with placebo, the forced expiratory volume in 1 second before bronchodilator use increased with the itepekimab and dupilumab monotherapies but not with the combination therapy. Itepekimab treatment improved asthma control and quality of life, as compared with placebo, and led to a greater reduction in the mean blood eosinophil count. The incidence of adverse events was similar in all four trial groups.ConclusionsInterleukin-33 blockade with itepekimab led to a lower incidence of events indicating a loss of asthma control than placebo and improved lung function in patients with moderate-to-severe asthma. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03387852.)