Genetic and T2 biomarkers linked to the efficacy of HDM sublingual immunotherapy in asthma.

BACKGROUND: Hypersensitivity to house dust mite (HDM) allergens is a common cause of allergic asthma symptoms and can be effectively treated with allergy immunotherapy (AIT). OBJECTIVE: To investigate whether genetic and type 2 (T2) inflammatory biomarkers correlate with disease severity in subjects with allergic asthma, and whether this can be modified by AIT. METHODS: MITRA (NCT01433523) was a phase III, randomised, double-blind, placebo-controlled trial of HDM sublingual immunotherapy (SLIT)-tablets in adults with HDM allergic asthma. Post hoc analyses of the study population (N=742) evaluated associations between T2 inflammatory (blood eosinophils, eosinophil cationic protein (ECP), total IgE and tryptase) and genetic (single-nucleotide polymorphisms, SNP) biomarkers (n=582) for the primary study endpoint (time to first moderate/severe asthma exacerbation). SNP associations were verified in HDM-positive subgroup from an independent 3-year Severe Asthma Research Programme (SARP3) subject cohort. RESULTS: An increased asthma exacerbation risk in subjects homozygous for SNP rs7216389 (chromosomal locus 17q12-21) was reduced (p=0.037) by treatment with HDM SLIT (HR=0.37 (95% CI 0.22 to 0.64), p<0.001). The associations between exacerbation risk and 17q12-21 SNPs were replicated in the SARP3 HDM-positive subgroup. High levels of T2 biomarkers were associated with increased risk of asthma exacerbations in the placebo group. HDM SLIT-tablet treatment reduced this risk (blood eosinophils: HR=0.50 (95% CI 0.30 to 0.85); ECP: HR=0.45 (95% CI 0.29 to 0.87); tryptase: HR=0.45 (95% CI 0.25 to 0.80)). The treatment effect was higher (p=0.006) for subjects with a higher number of elevated T2 biomarkers. CONCLUSIONS: HDM SLIT-tablet AIT is efficacious in HDM-sensitised asthma subjects with a genetic asthma predisposition and/or an underlying T2 endotype. TRIAL REGISTRATION NUMBER: NCT01433523.

Dupilumab Is Effective in Patients With Moderate-to-Severe Uncontrolled GINA-Defined Type 2 Asthma Irrespective of an Allergic Asthma Phenotype.

BACKGROUND: 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. OBJECTIVE: To assess dupilumab efficacy in patients with a type 2 phenotype in the presence or absence of allergic asthma phenotype. METHODS: 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 FEV1 were evaluated in patients with allergic and nonallergic phenotype with baseline blood eosinophils greater than or equal to 150 cells/µL and/or Feno greater than or equal to 20 parts per billion. RESULTS: Of 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 FEV1 in patients with elevated type 2 biomarkers, irrespective of whether they showed evidence of an allergic asthma phenotype. CONCLUSIONS: In 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.

Global Initiative for Asthma Strategy 2021. Executive Summary and Rationale for Key Changes.

The Global Initiative for Asthma (GINA) Strategy Report provides clinicians with an annually updated evidence-based strategy for asthma management and prevention, which can be adapted for local circumstances (e.g., medication availability). This article summarizes key recommendations from GINA 2021, and the evidence underpinning recent changes. GINA recommends that asthma in adults and adolescents should not be treated solely with short-acting ß2-agonist (SABA), because of the risks of SABA-only treatment and SABA overuse, and evidence for benefit of inhaled corticosteroids (ICS). Large trials show that as-needed combination ICS-formoterol reduces severe exacerbations by ≥60% in mild asthma compared with SABA alone, with similar exacerbation, symptom, lung function, and inflammatory outcomes as daily ICS plus as-needed SABA. Key changes in GINA 2021 include division of the treatment figure for adults and adolescents into two tracks. Track 1 (preferred) has low-dose ICS-formoterol as the reliever at all steps: as needed only in Steps 1-2 (mild asthma), and with daily maintenance ICS-formoterol (maintenance-and-reliever therapy, "MART") in Steps 3-5. Track 2 (alternative) has as-needed SABA across all steps, plus regular ICS (Step 2) or ICS-long-acting ß2-agonist (Steps 3-5). For adults with moderate-to-severe asthma, GINA makes additional recommendations in Step 5 for add-on long-acting muscarinic antagonists and azithromycin, with add-on biologic therapies for severe asthma. For children 6-11 years, new treatment options are added at Steps 3-4. Across all age groups and levels of severity, regular personalized assessment, treatment of modifiable risk factors, self-management education, skills training, appropriate medication adjustment, and review remain essential to optimize asthma outcomes.

Asthma management in low and middle income countries: case for change.

Asthma is the most common noncommunicable disease in children, and among the most common in adults. The great majority of people with asthma live in low and middle income countries (LMICs), which have disproportionately high asthma-related morbidity and mortality. Essential inhaled medications, particularly those containing inhaled corticosteroids (ICS), are often unavailable or unaffordable, and this explains much of the global burden of preventable asthma morbidity and mortality. Guidelines developed for LMICs are generally based on the outdated assumption that patients with asthma symptoms <1-3 times per week do not need (or benefit from) ICS. Even when ICS are prescribed, many patients manage their asthma with oral or inhaled short-acting ß2-agonists (SABA) alone, owing to issues of availability and affordability. A single ICS-formoterol inhaler-based approach to asthma management for all severities of asthma, from mild to severe, starting at diagnosis, might overcome SABA overuse/over-reliance and reduce the burden of symptoms and severe exacerbations. However, ICS-formoterol inhalers are currently very poorly available or unaffordable in LMICs. There is a pressing need for pragmatic clinical trial evidence of the feasibility and cost-effectiveness of this and other strategies to improve asthma care in these countries. The global health inequality in asthma care that deprives so many children, adolescents and adults of healthy lives and puts them at increased risk of death, despite the availability of highly effective therapeutic approaches, is unacceptable. A World Health Assembly Resolution on universal access to affordable and effective asthma care is needed to focus attention and investment on addressing this need.

Pairwise indirect treatment comparison of dupilumab versus other biologics in patients with uncontrolled persistent asthma.

BACKGROUND: Currently, five biologic treatment options are available for use in patients with uncontrolled persistent asthma: three interleukin (IL)-5 antagonists, which either bind to the anti-IL-5 ligand (mepolizumab, reslizumab) or to the IL-5 receptor (benralizumab); one anti-immunoglobulin E (anti-IgE) therapy (omalizumab); and one anti-IL-4/IL-13 therapy (dupilumab). To date, no comparative data from head-to-head clinical trials are available for these biologics. OBJECTIVE: An indirect treatment comparison (ITC) of dupilumab versus each of the anti-IL-5 and anti-IgE therapies using the endpoints of annualized severe asthma exacerbation rates and change in pre-bronchodilator forced expiratory volume in 1 s (FEV1). METHODS: Embase®, MEDLINE®, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for studies published between January 1, 1980 and March 25, 2019. Eligible articles included randomized controlled trials (RCTs) in patients aged ≥ 12 years with persistent/uncontrolled asthma using at least medium-to-high dose inhaled corticosteroid plus long-acting ß2-agonist with add-on biologic therapy. Bucher ITCs were performed to compare subgroups of dupilumab patients with the anti-IL-5s and anti-IgE trial populations. RESULTS: Fourteen RCTs were included in the analyses. The matched dupilumab subgroups were associated with greater reductions in annualized severe exacerbation rates compared with benralizumab, mepolizumab, reslizumab, and omalizumab (54%, 28%, 38%, and 26% greater reduction, respectively). A greater improvement in FEV1 was also observed for dupilumab at week 12 and/or week 24/52 than for the other biologics (0.06-0.14 L). CONCLUSION: In this ITC, dupilumab was associated with lower severe asthma exacerbation rates and greater improvements in lung function than anti-IL-5s and omalizumab.

A Practical Guide to Implementing SMART in Asthma Management.

The use of a single inhaler containing the combination of an inhaled corticosteroid (ICS) and formoterol, a specific long-acting bronchodilator, for both maintenance and quick relief therapy (single maintenance and reliever therapy [SMART or MART]) is recommended by both the Global Initiative for Asthma and the National Asthma Education and Prevention Program Coordinating Committee in steps 3 and 4 of asthma management. This article provides practical advice about implementing SMART in clinical practice based on evidence and clinical experience. Fundamental to SMART is that ICS-formoterol provides quick relief of asthma symptoms similar to that of short-acting ß2-agonists such as albuterol, while reducing the risk for severe asthma exacerbations and at an overall lower ICS exposure. Most SMART clinical trials were in adults and adolescents (aged ≥12 years), using budesonide-formoterol 160/4.5 µg (delivered dose), one inhalation once or twice daily (step 3) and two inhalations twice daily (step 4). For both steps 3 and 4, patients take additional inhalations of budesonide-formoterol 160/4.5 µg, one inhalation whenever needed for symptom relief, up to a maximum for adults and adolescents of 12 total inhalations in any single day (delivering 54 µg formoterol). The efficacy and safety of SMART with budesonide-formoterol and beclometasone-formoterol have been confirmed, but other ICS-long-acting bronchodilator combinations have not been studied. The SMART regimen should be introduced with a careful explanation of its role in self-management, preferably with a customized written asthma action plan. The cost to patients and the availability of SMART treatment will depend on the prescribed dose and national or local payer agreements.

Global Initiative for Asthma Strategy 2021: Executive Summary and Rationale for Key Changes.

The Global Initiative for Asthma (GINA) Strategy Report provides clinicians with an annually updated evidence-based strategy for asthma management and prevention, which can be adapted for local circumstances (e.g., medication availability). This article summarizes key recommendations from GINA 2021, and the evidence underpinning recent changes. GINA recommends that asthma in adults and adolescents should not be treated solely with short-acting ß2 -agonist (SABA), because of the risks of SABA-only treatment and SABA overuse, and evidence for benefit of inhaled corticosteroids (ICS). Large trials show that as-needed combination ICS-formoterol reduces severe exacerbations by ≥60% in mild asthma compared with SABA alone, with similar exacerbation, symptom, lung function, and inflammatory outcomes as daily ICS plus as-needed SABA. Key changes in GINA 2021 include division of the treatment figure for adults and adolescents into two tracks. Track 1 (preferred) has low-dose ICS-formoterol as the reliever at all steps: as needed only in Steps 1-2 (mild asthma), and with daily maintenance ICS-formoterol (maintenance-and-reliever therapy, "MART") in Steps 3-5. Track 2 (alternative) has as-needed SABA across all steps, plus regular ICS (Step 2) or ICS-long-acting ß2 -agonist (Steps 3-5). For adults with moderate-to-severe asthma, GINA makes additional recommendations in Step 5 for add-on long-acting muscarinic antagonists and azithromycin, with add-on biologic therapies for severe asthma. For children 6-11 years, new treatment options are added at Steps 3-4. Across all age groups and levels of severity, regular personalized assessment, treatment of modifiable risk factors, self-management education, skills training, appropriate medication adjustment, and review remain essential to optimize asthma outcomes.

Short-acting ß2-agonist prescriptions are associated with poor clinical outcomes of asthma: the multi-country, cross-sectional SABINA III study.

BACKGROUND: To gain a global perspective on short-acting ß2-agonist (SABA) prescriptions and associated asthma-related clinical outcomes in patients with asthma, we assessed primary health data across 24 countries in five continents. METHODS: SABINA III was a cross-sectional study that employed electronic case report forms at a study visit (in primary or specialist care) to record prescribed medication(s), over-the-counter (OTC) SABA purchases and clinical outcomes in asthma patients (≥12 years old) during the past 12 months. In patients with ≥1 SABA prescriptions, associations of SABA with asthma symptom control and severe exacerbations were analysed using multivariable regression models. RESULTS: Of 8351 patients recruited (n=6872, specialists; n=1440, primary care), 76.5% had moderate-to-severe asthma and 45.4% experienced ≥1 severe exacerbations in the past 12 months. 38% of patients were prescribed ≥3 SABA canisters; 18.0% purchased OTC SABA, of whom 76.8% also received SABA prescriptions. Prescriptions of 3-5, 6-9, 10-12 and ≥13 SABA canisters (versus 1-2) were associated with increasingly lower odds of controlled or partly controlled asthma (adjusted OR 0.64 (95% CI 0.53-0.78), 0.49 (95% CI 0.39-0.61), 0.42 (95% CI 0.34-0.51) and 0.33 (95% CI 0.25-0.45), respectively; n=4597) and higher severe exacerbation rates (adjusted incidence rate ratio 1.40 (95% CI 1.24-1.58), 1.52 (95% CI 1.33-1.74), 1.78 (95% CI 1.57-2.02) and 1.92 (95% CI 1.61-2.29), respectively; n=4612). CONCLUSIONS: This study indicates an association between high SABA prescriptions and poor clinical outcomes across a broad range of countries, healthcare settings and asthma severities, providing support for initiatives to improve asthma morbidity by reducing SABA overreliance.

Global Initiative for Asthma Strategy 2021: Executive Summary and Rationale for Key Changes.

The Global Initiative for Asthma (GINA) Strategy Report provides clinicians with an annually updated evidence-based strategy for asthma management and prevention, which can be adapted for local circumstances (e.g., medication availability). This article summarizes key recommendations from GINA 2021, and the evidence underpinning recent changes. GINA recommends that asthma in adults and adolescents should not be treated solely with short-acting ß2-agonist (SABA), because of the risks of SABA-only treatment and SABA overuse, and evidence for benefit of inhaled corticosteroids (ICS). Large trials show that as-needed combination ICS-formoterol reduces severe exacerbations by ⩾60% in mild asthma compared with SABA alone, with similar exacerbation, symptom, lung function, and inflammatory outcomes as daily ICS plus as-needed SABA. Key changes in GINA 2021 include division of the treatment figure for adults and adolescents into two tracks. Track 1 (preferred) has low-dose ICS-formoterol as the reliever at all steps: as needed only in Steps 1-2 (mild asthma), and with daily maintenance ICS-formoterol (maintenance-and-reliever therapy, "MART") in Steps 3-5. Track 2 (alternative) has as-needed SABA across all steps, plus regular ICS (Step 2) or ICS-long-acting ß2-agonist (Steps 3-5). For adults with moderate-to-severe asthma, GINA makes additional recommendations in Step 5 for add-on long-acting muscarinic antagonists and azithromycin, with add-on biologic therapies for severe asthma. For children 6-11 years, new treatment options are added at Steps 3-4. Across all age groups and levels of severity, regular personalized assessment, treatment of modifiable risk factors, self-management education, skills training, appropriate medication adjustment, and review remain essential to optimize asthma outcomes.

Global Initiative for Asthma Strategy 2021: Executive Summary and Rationale for Key Changes.

The Global Initiative for Asthma (GINA) Strategy Report provides clinicians with an annually updated evidence-based strategy for asthma management and prevention, which can be adapted for local circumstances (e.g., medication availability). This article summarizes key recommendations from GINA 2021, and the evidence underpinning recent changes. GINA recommends that asthma in adults and adolescents should not be treated solely with short-acting ß2-agonist (SABA), because of the risks of SABA-only treatment and SABA overuse, and evidence for benefit of inhaled corticosteroids (ICS). Large trials show that as-needed combination ICS-formoterol reduces severe exacerbations by ≥60% in mild asthma compared with SABA alone, with similar exacerbation, symptom, lung function, and inflammatory outcomes as daily ICS plus as-needed SABA. Key changes in GINA 2021 include division of the treatment figure for adults and adolescents into two tracks. Track 1 (preferred) has low-dose ICS-formoterol as the reliever at all steps: as needed only in Steps 1-2 (mild asthma), and with daily maintenance ICS-formoterol (maintenance-and-reliever therapy, "MART") in Steps 3-5. Track 2 (alternative) has as-needed SABA across all steps, plus regular ICS (Step 2) or ICS-long-acting ß2-agonist (Steps 3-5). For adults with moderate-to-severe asthma, GINA makes additional recommendations in Step 5 for add-on long-acting muscarinic antagonists and azithromycin, with add-on biologic therapies for severe asthma. For children 6-11 years, new treatment options are added at Steps 3-4. Across all age groups and levels of severity, regular personalized assessment, treatment of modifiable risk factors, self-management education, skills training, appropriate medication adjustment, and review remain essential to optimize asthma outcomes.

Chronic airflow obstruction and ambient particulate air pollution.

Smoking is the most well-established cause of chronic airflow obstruction (CAO) but particulate air pollution and poverty have also been implicated. We regressed sex-specific prevalence of CAO from 41 Burden of Obstructive Lung Disease study sites against smoking prevalence from the same study, the gross national income per capita and the local annual mean level of ambient particulate matter (PM2.5) using negative binomial regression. The prevalence of CAO was not independently associated with PM2.5 but was strongly associated with smoking and was also associated with poverty. Strengthening tobacco control and improved understanding of the link between CAO and poverty should be prioritised.

Positioning As-needed Budesonide-Formoterol for Mild Asthma: Effect of Prestudy Treatment in Pooled Analysis of SYGMA 1 and 2.

Rationale: The SYGMA (Symbicort Given as Needed in Mild Asthma) studies evaluated the efficacy and safety of as-needed budesonide (BUD)-formoterol (FORM) in patients whose asthma was uncontrolled on as-needed inhaled short-acting bronchodilators (subgroup 1) or controlled on inhaled corticosteroids (ICS) or leukotriene receptor antagonists (subgroup 2). Objectives: To assess the influence of prestudy treatment in a post hoc analysis of the SYGMA studies. Methods: In the SYGMA 1 (NCT022149199) and SYGMA 2 (NCT02224157) 52-week, double-blind, randomized, parallel-group studies, 6,735 patients with mild asthma were randomized to as-needed BUD-FORM, low-dose BUD + as-needed terbutaline (BUD maintenance), or as-needed terbutaline (SYGMA 1 only). Exacerbation rates and changes in symptom control and lung function were compared among treatments for both subgroups. Results: In a pooled analysis of SYGMA 1 and 2, the annual severe exacerbation rate in subgroup 1 was significantly lower with as-needed BUD-FORM (0.08 [95% confidence interval (CI), 0.06-0.10]) than with BUD maintenance (0.10 [95% CI, 0.09-0.13]) (rate ratio [RR], 0.74 [95% CI, 0.56-0.98]; P = 0.03), and similar results were shown in subgroup 2 with BUD-FORM (0.12 [95% CI, 0.10-0.14]) and BUD maintenance (0.10 [95% CI, 0.09-0.13]) (RR, 1.10 [95% CI, 0.86-1.41]; P = 0.44). In SYGMA 1, the annual severe exacerbation rate in both subgroups was significantly lower with as-needed BUD-FORM than with as-needed terbutaline (subgroup 1: RR, 0.34 [95% CI, 0.20-0.58]; P < 0.001; subgroup 2: RR, 0.37 [95% CI, 0.25-0.54]; P < 0.001). The number needed to treat to prevent one severe exacerbation with as-needed BUD-FORM and BUD maintenance versus as-needed terbutaline were 20 and 34 in subgroup 1 and 13 and 12 in subgroup 2, respectively. Conclusions: These findings suggest that, for patients with mild asthma currently receiving short-acting ß2-agonists alone, as-needed low-dose ICS-FORM should be preferred over maintenance ICS as initial controller treatment. For patients whose asthma is controlled on maintenance low-dose ICS, as-needed BUD-FORM is an alternative to maintenance ICS without the need for daily treatment, and both of these options are safer than switching to short-acting ß2-agonist-only treatment.

Efficacy and Safety of As-Needed Budesonide-Formoterol in Adolescents with Mild Asthma.

BACKGROUND: Medication adherence is challenging for adolescents. In mild asthma, as-needed budesonide-formoterol (BUD-FORM) reduces severe exacerbations compared with as-needed short-acting beta2-agonists, similar to the reduction with maintenance budesonide. OBJECTIVE: This post hoc pooled analysis of Symbicort Given as-needed in Mild Asthma (SYGMA) 1 and 2 assessed the efficacy and safety of as-needed BUD-FORM in adolescents. METHODS: SYGMA 1 and 2 were 52-week, double-blind studies (NCT022149199; NCT02224157) in patients 12 years or older with mild asthma. Patients were randomized to twice-daily placebo + as-needed BUD-FORM 200/6 µg, twice-daily BUD 200 µg + as-needed terbutaline (BUD maintenance), or twice-daily placebo + as-needed terbutaline 0.5 mg (SYGMA 1 only). Annualized severe exacerbation rates, maintenance treatment adherence, and safety (including change in height) were compared between treatment groups in adolescents (aged ≥12 to <18 years). RESULTS: Severe exacerbation rate was similar with as-needed BUD-FORM and BUD maintenance (pooled analysis: 0.08 vs 0.07/y; P = .634), and was significantly lower with as-needed BUD-FORM versus as-needed terbutaline (SYGMA 1: 0.04 vs 0.17/y; P = .005). Median adherence was 73% in SYGMA 1 and 51% in SYGMA 2. Change in height from baseline in adolescents aged ≥12 years to <14 years was significantly greater with as-needed BUD-FORM (4.8 cm) versus BUD maintenance (3.9 cm) (pooled: P < .046), and was similar between as-needed BUD-FORM (4.5 cm) and as-needed terbutaline (4.1 cm) (SYGMA 1: P = .500). No new or unexpected safety concerns were identified. CONCLUSIONS: In adolescents with mild asthma, as-needed BUD-FORM was superior to as-needed terbutaline for severe exacerbation reduction, with similar efficacy to BUD maintenance. As-needed BUD-FORM provides an alternative treatment option for adolescents with mild asthma, without needing daily treatment.