Annual Exacerbation Rate Research Articles

Dupilumab for chronic obstructive pulmonary disease with type 2 inflammation: a pooled analysis of two phase 3, randomised, double-blind, placebo-controlled trials.

Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for IL-4 and IL-13, which are key drivers of type 2 inflammation. We aimed to characterise the efficacy and safety of dupilumab in patients with COPD and type 2 inflammation. For this pooled analysis, we pooled and analysed data from all patients in the intention-to-treat populations of the phase 3, randomised, double-blind, placebo-controlled BOREAS and NOTUS trials, which comprised 206 hospitals and clinics in BOREAS and 217 in NOTUS in 38 countries across Europe, Asia, North America, South America, Africa, and Australia. Eligible patients were current or former smokers with 10 pack-years or more of smoking history, were aged 40-85 years, had physician-diagnosed COPD for at least 12 months before randomisation, had a post-bronchodilator FEV1/forced vital capacity (FVC) ratio of less than 0·7, had a post-bronchodilator percentage predicted FEV1 of 30-70%, had documented evidence of two moderate or one severe exacerbations of COPD in the previous year (at least one exacerbation had to have occurred on triple therapy), and had blood eosinophil counts 300 cells per μL or more during screening. Patients had to have symptomatic COPD and a reported chronic productive cough for at least 3 months in the previous year. Key exclusion criteria were history of asthma, pulmonary disease other than COPD, or other diagnosed pulmonary or systemic disease associated with elevated blood eosinophil. In both trials, eligible patients were randomly assigned (1:1) via block randomisation with block size 4 to receive subcutaneous dupilumab 300 mg or matching placebo once every 2 weeks for 52 weeks, alongside established background therapy with inhaled corticosteroids, a long-acting β2-agonist, and a long-acting muscarinic antagonist. The primary endpoint was the annualised rate of moderate or severe exacerbations over 52 weeks. 1874 patients were randomly assigned in BOREAS and NOTUS from May 9, 2019, to May 23, 2023; 938 (50·1%) were randomly assigned to the dupilumab groups and 936 (49·9%) were randomly assigned to the placebo groups. Mean age across both groups was 65·1 years (SD 8·2). 622 (33·2%) of 1874 patients were female and 1252 (66·8%) were male. 1628 (86·9%) patients were White, 719 (38·4%) were from Eastern Europe, and 1316 (70·2%) were former smokers. During the 52-week treatment period, 559 moderate or severe exacerbations were reported in 338 (36·0%) of 938 patients in the dupilumab group and 774 exacerbations were reported in 394 (42·1%) of 936 patients in the placebo group. There was a reduction in the annualised rate of moderate or severe exacerbations compared with placebo (annualised exacerbation rate 0·794 in the dupilumab group and 1·156 in the placebo group; incidence rate ratio 0·687, 95% CI 0·595-0·793; p<0·0001). In the dupilumab group, the time to first severe exacerbation was longer than in the placebo group (0·611, 0·409-0·912; p=0·016). However, there was no reduction in the annualised rate of severe exacerbations (annualised exacerbation rate 0·084 in the dupilumab group and 0·124 in the placebo group; 0·674, 0·438-1·037; p=0·073). Treatment-emergent adverse events, serious adverse events, adverse events that led to permanent treatment discontinuation, and adverse events that led to death were similar between the two groups. Dupilumab, as an add-on to standard triple therapy, reduced the annualised rate of moderate or severe exacerbations compared with placebo, highlighting its potential for personalised treatment approaches in patients with COPD with specific clinical endotypes. Sanofi and Regeneron Pharmaceuticals.

Retrospective Cohort Study of Elderly Users of Single- or Multiple-Inhaler Triple Therapy for the Treatment of Asthma in the USA.

Escalation to single- or multiple-inhaler triple therapy (SITT; MITT) is a recommended option for patients with asthma who remain uncontrolled by medium-dose inhaled corticosteroid/long-acting β2-agonist; however, characterization of elderly users of triple therapy is limited. This real-world cohort study describes demographics and clinical characteristics of elderly patients with asthma with and without comorbid chronic obstructive pulmonary disease (COPD) who are new users of triple therapy, and asthma treatment patterns preceding triple therapy initiation. This retrospective cohort study used administrative claims data from the Optum Clinformatics Data Mart database. Eligible patients were ≥ 65years of age with asthma or with asthma and comorbid COPD who initiated either triple therapy with single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI; 100/62.5/25μg) or MITT between September 18, 2017 and September 30, 2020. Demographics, clinical characteristics, healthcare resource utilization, healthcare costs, and asthma treatment patterns were described in the 12-month period before triple therapy initiation (baseline period). In total, 15,557 patients were included. Among FF/UMEC/VI initiators with asthma (N = 635) mean age was 73.3years and 66.6% were female. During the baseline period, > 75% of patients used controller therapy, > 92% used rescue medications, 27.9% experienced ≥ 1 asthma-related exacerbation, with mean annual exacerbation rate of 0.42, and mean all-cause healthcare costs were $23,407. Patients with asthma initiating MITT and patients with asthma and comorbid COPD initiating FF/UMEC/VI or MITT had similar characteristics, healthcare resource utilization, healthcare costs, and asthma treatment patterns to FF/UMEC/VI initiators with asthma. Triple therapy is often initiated following use of other asthma controller medications in real-world practice. Substantial rescue medication use and high disease and economic burden among this elderly patient population suggest that their asthma was not adequately controlled prior to triple therapy initiation. This retrospective study provides an early profile of elderly patients with asthma in the USA.

The proof of the pudding is in the eating: real-life intra- and extrapulmonary impact of elexacaftor/tezacaftor/ivacaftor.

Elexacaftor/tezacaftor/ivacaftor (ETI) has shown significant improvements in pulmonary and nutritional status in persons with cystic fibrosis (pwCF). Less is known about the extrapulmonary impact of ETI and effects on airway microbiology, lung clearance index (LCI) and fraction of exhaled nitric oxide (FeNO). A multicentre prospective observational trial, including 79 pwCF ≥ 18 years eligible for ETI. Assessments were done at the initiation of, and 3 and 6 months into treatment with ETI. Outcomes included forced expiratory volume in 1 second (FEV1), LCI, FeNO, sputum or cough swab culture, body mass index (BMI), cystic fibrosis questionnaire-revised respiratory domain (CFQ-R RD), sinonasal outcome test-22 (SNOT-22), general anxiety disorder-7 (GAD-7), patient health questionnaire-9 (PHQ-9), fecal elastase-1 (FE-1), adherence to baseline therapies, exacerbation rate and adverse events. Our cohort included 79 pwCF (31±11(SD) years) with a baseline ppFEV1 of 68±23. Forty-two (53%) pwCF were previously treated with a CFTR modulator. In the entire study group, there were significant improvements from baseline in ppFEV1, LCI, FeNO, annualized exacerbation rate, BMI, CFQ-R RD and SNOT-22 (p<0.05 for all). Airway culture positivity for methicillin-susceptible Staphylococcus aureus and Pseudomonas aeruginosa also decreased during the study period. There was no significant change in FE-1, GAD-7 or PHQ-9. Adherence to dornase alfa and hypertonic saline decreased. ETI treatment led to significant improvements in respiratory and nutritional status, alongside a decrease in adherence to chronic supportive therapies. We did not observe any significant changes in exocrine pancreas function or in questionnaire scores for depression and anxiety.

Biologic therapies targeting type 2 cytokines are effective at improving asthma symptoms and control - a systematic review and meta-analysis

BackgroundAllergic asthma is a highly prevalent chronic inflammatory disease driven by aeroallergen exposure. In severe asthma, the current standard of care does not fully control disease symptoms, indicating an unmet clinical need. Biologic therapies targeting cytokines IL-4, IL-5, and IL-13 have been shown to provide benefits to asthmatics over currently existing asthma treatments. ObjectiveTo review the effects of recently developed biologic therapies for asthma treatment. MethodsIn this meta-analysis, the impact of IL-5 and IL-4/IL-13 biologic inhibitors was critically appraised considering overall lung function, symptom control, and oral corticosteroid use in asthmatic patients. Trials were identified using PubMed, Web of Science, Scopus, and clinicaltrials.gov. Clinical trials assessing participants with severe asthma over the age of 12 were included. ResultsThe meta-analysis included 6,600 participants from 14 trials published in 2013-2020. For IL-5 inhibitors, improvements in FEV1 (MD = 0.11, 95% Cl: 0.11-0.12), ACQ scores (MD = -0.4, 95% Cl: -0.41- -0.38), annual exacerbation rates (MD = -0.46, 95% Cl: -0.48 - -0.45), and OCS use (MD = -50, 95% Cl: -52.58 - -47.42) favored biologic treatment. Significant improvements in FEV1 (MD = 0.11, 95% Cl: 0.10-0.11), ACQ scores (MD = -0.20, 95% Cl: -0.22 - -0.18), and annual exacerbation rates (MD = -0.15, 95% Cl: -0.16 - -0.14) were also seen with anti-IL4/IL-13 biologic therapies. However, anti-IL-4/IL-13 inhibitors were associated with more adverse events than placebo (MD = 1.13, 95% Cl: 0.97-1.3). ConclusionBiologic inhibitors targeting Th2 cytokines are beneficial for improving overall asthma control.

Dupilumab Efficacy and Safety in Children With Moderate-to-Severe Asthma and High Blood Eosinophils: A Post Hoc Analysis of VOYAGE

Elevated blood or tissue eosinophils are considered to characterize type 2 inflammation in children with asthma and are associated with increased exacerbation rates and worse asthma control. Dupilumab, a human monoclonal antibody that blocks type 2 inflammatory drivers IL-4 and IL-13, reduced severe exacerbation rates and improved lung function vs placebo in children aged 6-11 years with uncontrolled moderate-to-severe asthma in the phase 3 LIBERTY ASTHMA VOYAGE study (NCT02948959). This post hoc analysis assessed dupilumab efficacy and safety in children from VOYAGE with moderate-to-severe asthma and ≥500 and <1500 blood eosinophils/μL at baseline. Children received add-on dupilumab (100/200 mg by body weight) or matched placebo every 2 weeks for 52 weeks. We assessed annualized severe exacerbation rates, least squares mean (LSM) change from baseline in pre-bronchodilator percent predicted forced expiratory volume in 1 second (ppFEV1), and incidence of treatment-emergent adverse events. In children with elevated baseline eosinophils (N = 174), dupilumab vs placebo significantly reduced annualized exacerbation rates by 67% (95% CI: 38-82%; P < .001) and improved pre-bronchodilator ppFEV1 from baseline at Weeks 24 and 52 (LSM difference [95% CI] 7.58 percentage points [2.85-12.31]; P = .002; 7.98 percentage points [2.17-13.78]; P = .007, respectively). The incidence of treatment emergent adverse events was similar with dupilumab and placebo. Dupilumab significantly reduced severe exacerbations and improved lung function in children with moderate-to-severe asthma and baseline blood eosinophil counts ≥500 and <1500 cells/μL, with a safety profile comparable with the overall study population.

Long-Term High-Flow Nasal Therapy in Patients with Bronchiectasis of Different Severity: A Retrospective Cohort Study.

Background/Objectives: High-flow nasal therapy (HFNT) has been shown to reduce exacerbations of COPD and some evidence displays benefits in non-cystic fibrosis bronchiectasis (NCFB) patients. The present study aimed to compare the effectiveness of 12 months of home HFNT on the annual exacerbation rate between mild/moderate and severe NCFB patients, classified by the bronchiectasis severity index (BSI). Secondary outcomes were the evaluation of the dyspnea, pulmonary function, and sputum cultures in both groups. Methods: The study population included NCFB adult patients, with at least one severe exacerbation in the previous year on optimized therapy. NCFB exacerbations, dyspnea (mMRC score), pulmonary function test, and sputum cultures were assessed at baseline and after 12 months of HFNT. Results: A total of 86 NCFB patients were enrolled: 36 in the mild/moderate (BSI < 9) and 50 in the severe (BSI ≥ 9) group. A significant improvement in the annual exacerbation rate was found in both BSI ≥ 9 (p < 0.0001) and BSI < 9 cohorts (p < 0.0001), with a between-group difference of -1 (95% CI: -2 to 0) exacerbations per year (p = 0.0209). The change in the annual exacerbation rate was significantly correlated with BSI (ρ = -0.26, p = 0.0151) and with HFNT daily use (ρ = -0.22, p = 0.0460). The mMRC score significantly improved by -2 points (95% CI: -2 to -1) after treatment in both groups (p < 0.0001). The percentage of patients with P. aeruginosa colonization decreased from 34.9% to 27.9%. Conclusions: Long-term HFNT reduces the annual exacerbation rate in NCFB patients and its effectiveness increases alongside disease severity and daily use of HFNT.

Effect of high-dose N-acetylcysteine on exacerbations and lung function in patients with mild-to-moderate COPD: a double-blind, parallel group, multicentre randomised clinical trial.

Evidence for the treatment of patients with mild-to-moderate chronic obstructive pulmonary disease (COPD) is limited. The efficacy of N-acetylcysteine (an antioxidant and mucolytic agent) for patients with mild-to-moderate COPD is uncertain. In this multicentre, randomised, double-blind, placebo-controlled trial, we randomly assigned 968 patients with mild-to-moderate COPD to treatment with N-acetylcysteine (600 mg, twice daily) or matched placebo for two years. Eligible participants were 40-80 years of age and had mild-to-moderate COPD (forced expiratory volume in 1 second [FEV1] to forced vital capacity ratio <0.70 and an FEV1 ≥ 50% predicted value after bronchodilator use). The coprimary outcomes were the annual rate of total exacerbations and the between-group difference in the change from baseline to 24 months in FEV1 before bronchodilator use. COPD exacerbation was defined as the appearance or worsening of at least two major symptoms (cough, expectoration, purulent sputum, wheezing, or dyspnoea) persisting for at least 48 hours. Assessment of exacerbations was conducted every three months, and lung function was performed annually after enrolment. The difference between the N-acetylcysteine group and the placebo group in the annual rate of total exacerbation were not significant (0.65 vs. 0.72 per patient-year; relative risk [RR], 0.90; 95% confidence interval [CI], 0.80-1.02; P = 0.10). There was no significant difference in FEV1 before bronchodilator use at 24 months. Long-term treatment with high-dose N-acetylcysteine neither significantly reduced the annual rate of total exacerbations nor improved lung function in patients with mild-to-moderate COPD. Chinese Clinical Trial Registration: ChiCTR-IIR-17012604.

Inhaled colistimethate sodium in patients with bronchiectasis and Pseudomonas aeruginosa infection: results of PROMIS-I and PROMIS-II, two randomised, double-blind, placebo-controlled phase 3 trials assessing safety and efficacy over 12 months

Chronic lung infection with Pseudomonas aeruginosa is associated with increased exacerbations and mortality in people with bronchiectasis. The PROMIS-I and PROMIS-II trials investigated the efficacy and safety of 12-months of inhaled colistimethate sodium delivered via the I-neb. Two randomised, double-blind, placebo-controlled trials of twice per day colistimethate sodium versus placebo were conducted in patients with bronchiectasis with P aeruginosa and a history of at least two exacerbations requiring oral antibiotics or one requiring intravenous antibiotics in the previous year in hospitals in Argentina, Australia, Belgium, Canada, France, Germany, Greece, Israel, Italy, Netherlands, New Zealand, Poland, Portugal, Spain, Switzerland, the UK, and the USA. Randomisation was conducted through an interactive web response system and stratified by site and long term use of macrolides. Masking was achieved by providing colistimethate sodium and placebo in identical vials. After random assignment, study visits were scheduled for 1, 3, 6, 9, and 12 months (the end of the treatment period); and telephone calls were scheduled for 7 days after random assignment and 2 weeks after the end of treatment. The primary endpoint was the mean annual exacerbation rate. These trials are registered with EudraCT: number 2015-002743-33 (for PROMIS-I) and 2016-004558-13 (for PROMIS-II), and are now completed. 377 patients were randomly assigned in PROMIS-I (177 to colistimethate sodium and 200 to placebo; in the modified intention-to-treat population, 176 were in the colistimethate sodium group and 197 were in the placebo group) between June 6, 2017, and April 8, 2020. The annual exacerbation rate was 0·58 in the colistimethate sodium group versus 0·95 in the placebo group (rate ratio 0·61; 95% CI 0·46-0·82; p=0·0010). 287 patients were randomly assigned in PROMIS-II (152 were assigned to colistimethate sodium and 135 were assigned to placebo, in the modified intention-to-treat population), between Feb 12, 2018, and Oct 22, 2021. PROMIS-II was then prematurely terminated due to the effect of the COVID-19 pandemic. No significant difference was observed in the annual exacerbation rate between the colistimethate sodium and placebo groups (0·89 vs 0·89; rate ratio 1·00; 95% CI 0·75-1·35; p=0·98). No major safety issues were identified. The overall frequency of adverse events was 142 (81%) patients in the colistimethate sodium group versus 159 (81%) patients in the placebo group in PROMIS-I, and 123 (81%) patients versus 104 (77%) patients in PROMIS-II. There were no deaths related to study treatment. The data from PROMIS-I suggest a clinically important benefit of colistimethate sodium delivered via the I-neb adaptive aerosol delivery system in patients with bronchiectasis and P aeruginosa infection. These results were not replicated in PROMIS-II, which was affected by the COVID-19 pandemic and prematurely terminated. Zambon.

A comparison of the impact of anti-IL5/5r therapies in allergic versus non-allergic patients with severe eosinophilic asthma in a real-life setting

Objective This study aimed to compare the clinical characteristics and treatment outcomes of allergic patients (AP) and non-allergic patients (NAP) with severe eosinophilic asthma (SEA) treated with anti-IL5/IL5R biologic agents (mepolizumab, benralizumab, or reslizumab) over one year. Sub-analyses assessed treatment response variations between AP and NAP based on the biological used and compared outcomes among AP with and without fungal allergy. Methods Observational retrospective analysis. Clinical characteristics, laboratory findings, pulmonary function tests, Asthma Control Test (ACT) scores, oral corticosteroid (OCS) usage, and exacerbation frequency were assessed at the initiation of biological treatment and after one year. Results Sixty-five patients with SEA were included, 41 AP and 24 NAP. 55.4% were treated with mepolizumab, 33.8% with benralizumab, and 10.8% with reslizumab. Before anti-IL5/5R treatment, AP had worse baseline outcomes but there were no differences in pulmonary function. Mean annual exacerbation rate and percentage of patients requiring OCS and dose of prednisone were higher in AP than NAP. AP had significantly higher total IgE values. After one year of treatment, more AP discontinued OCS than NAP (p = 0.025). Both experienced a significant reduction in exacerbation frequency (p = 0.001) and improved respiratory function. 70.7% of AP and 60% of NAP improved ACT ≥3 points. There was no significant difference between AP and NAP using mepolizumab (p = 0.145) or benralizumab (p = 0.174) in reducing OCS. Conclusions Anti-IL5/IL5R reduced the need for OCS and improved asthma control, regardless of allergic status. Fungal allergy led to lower ACT scores and higher exacerbations than other allergens; both groups improved with anti-IL5/ILR.

Long-Term Clinical Efficacy of Elexacaftor-Tezacaftor-Ivacaftor in People With Cystic Fibrosis and Preexisting Advanced Lung Disease at Treatment Initiation

BackgroundElexacaftor-tezacaftor-ivacaftor (ETI) is associated with increased forced expiratory volume in the first second (FEV1), decreased exacerbation frequency, and increased body mass index (BMI) in people with Cystic Fibrosis (pwCF) [1, 2]. Landmark clinical trials excluded patients with advanced lung disease (ALD) as defined by FEV1<40%. We have previously reported an improvement in ppFEV1 of 7.9% after 3 months of ETI in people with CF and ALD (ACFLD)[3]. The long-term effects of ETI on this cohort are unknown. This study reports the efficacy of ETI following 24 months of treatment in people with ACFLD. Study DesignWe conducted a retrospective cohort study of adult patients with FEV1<40% and/or other high-risk features defined by the 2019 CFF lung transplant guidelines who were started on ETI between September 2019 and February 2020. Response to therapy was assessed with repeat spirometry measured at 12 and 24 months. All measurements were taken outside of an acute exacerbation. Demographics and clinical data including BMI and pulmonary exacerbation frequency were extracted from the medical record. Results57 of 64 people with ACFLD showed improved lung function with a mean change in ppFEV1 of 6.74% (p = <0.001, 95% CI 4.25 – 9.23%) between baseline and 24 months of treatment. BMI increased by a mean change of 1.55 kg/m2 (p = <0.001, 95% CI 0.93 – 2.18 kg/m2) during this interval. The annual exacerbation rate between the year before ETI and 24 months on ETI declined with a median of 1 fewer per year (p = 0.0007). InterpretationPeople with ACFLD experienced a significant increase in lung function at 24 months on ETI, although less than those with higher baseline lung function compared to prior studies [1, 2]. They also had an increase in BMI and a decline in the rate of annual pulmonary exacerbations.

Brensocatib in patients with bronchiectasis: subgroup analyses from the WILLOW trial.

Bronchiectasis is a chronic inflammatory airway disease. Brensocatib, an oral, reversible inhibitor of dipeptidyl peptidase 1 (DPP1), reduces pulmonary inflammation by preventing the activation of neutrophil serine proteases. In the phase II WILLOW trial, brensocatib prolonged time to first exacerbation in patients with bronchiectasis. In this post hoc analysis we compare clinical outcomes in patients from WILLOW according to baseline disease characteristics. Adults with bronchiectasis treated with brensocatib (10 or 25 mg) or placebo once daily were analysed by baseline Bronchiectasis Severity Index (BSI) score (≤4 (mild), 5-8 (moderate), or ≥9 (severe)), exacerbation history (2 or ≥3 in the previous year), blood eosinophil count (<300 cells per µL or ≥300 cells per µL), long-term macrolide use (≥6 months; no or yes) and Pseudomonas aeruginosa culture at screening (negative or positive). End-points were time to first exacerbation, annualised exacerbation rate, change in lung function from baseline, and safety. All patients who received brensocatib were pooled and compared with placebo. Treatment with brensocatib versus placebo was associated with a longer time to first exacerbation (hazard ratio (95% confidence interval), BSI: ≤4, 0.28 (0.08-0.96); 5-8, 0.75 (0.35-1.60); ≥9, 0.61 (0.35-1.04); prior exacerbations: 2, 0.56 (0.34-0.90); ≥3, 0.71 (0.32-1.59); blood eosinophils per µL: <300, 0.66 (0.42-1.06); ≥300, 0.49 (0.20-1.20); long-term macrolide use: no, 0.60 (0.38-0.94); yes, 0.60 (0.25-1.45); P. aeruginosa culture: negative, 0.54 (0.32-0.92); positive, 0.68 (0.37-1.27)). Safety results were similar across subgroups. Patients treated with brensocatib had a numerically longer time to first exacerbation and reduced annualised rate of exacerbation versus placebo across all key baseline disease characteristics.

Longitudinal Changes in Maximal Forced Inspiratory Flow and Clinical Outcomes in Patients With COPD

BackgroundChronic obstructive pulmonary disease (COPD) primarily impairs expiratory flow due to progressive airflow obstruction and reduced lung elasticity. Increasing evidence underlines the importance of inspiratory flow as a biomarker for selecting inhaler devices and providing ancillary aerodynamic information. Research QuestionDoes the longitudinal changes in maximum forced inspiratory flow (FIFmax) influence acute exacerbations and lung function decline in COPD patients? Study Design and MethodsThis longitudinal study observed FIFmax in COPD patients over a 7-year period from 2004 to 2020. Eligible patients were categorized into two groups based on FIFmax trajectory: the increased FIFmax group and the decreased FIFmax group. Our study assessed the annual rate of acute exacerbations and the annual decline rate of forced expiratory volume in 1 second (FEV1). Subgroup analyses were conducted based on treatment status, with a focus on inhaled therapy and inhaler device usage. ResultsAmong the eligible 956 COPD patients, 56.5% belonged to the increased FIFmax group. After propensity score matching, the increased FIFmax group experienced lower rates of severe exacerbations (0.16/yr vs. 0.25/yr, P-value=0.017) and a slower decline in FEV1 (0 [interquartile range (IQR), -51–71] vs. -43 [IQR, -119–6] ml/yr, P-value<0.001) compared to the decreased FIFmax group. These associations were particularly prominent in patients using specific inhaler therapies, such as DPI therapies. InterpretationOur study revealed that the longitudinal changes in FIFmax are associated with clinical outcomes in COPD patients. Patients with increased FIFmax experienced a lower rate of severe exacerbations and a slower decline in lung function. These findings suggest the potential benefits of optimizing inspiratory flow in COPD management, though further studies are needed to confirm these observations due to potential confounding factors.

Real-Life Response to Biologics in Severe Asthma with Nasal Polyposis: Insights from the Belgian Severe Asthma Registry.

Nasal polyposis (NP) is a comorbidity of type 2 severe asthma (SA) which could influence response to SA biologics. We evaluated (super-) response in SA patients with (NP +) and without NP (NP-) enrolled in the Belgian Severe Asthma Registry (BSAR). 914 patients, of whom 31% NP + , were included. At enrollment, NP + patients had higher annual exacerbation rates, higher number of emergency room visits and more elevated type 2 biomarkers. In the longitudinal subanalysis of 104 patients, both groups had significant and similar asthma responses to asthma biologics, except for a greater increase in FEV1 in the NP + group. Super-response was achieved in 33 patients (32%), irrespective of NP status or type of biologic. In conclusion, both NP + and NP - patients had positive treatment responses, with some able to achieve super-response. In SA patients with NP, a greater FEV1 improvement as compared to SA patients without NP was observed.

A Simulation Study of the Effect of Clinical Characteristics and Treatment Choice on Reliever Medication Use, Symptom Control and Exacerbation Risk in Moderate-Severe Asthma.

The relationship between immediate symptom control, reliever medication use and exacerbation risk on treatment response and factors that modify it have not been assessed in an integrated manner. Here we apply simulation scenarios to evaluate the effect of individual baseline characteristics on treatment response in patients with moderate-severe asthma on regular maintenance dosing monotherapy with fluticasone propionate (FP) or combination therapy with fluticasone propionate/salmeterol (FP/SAL) or budesonide/formoterol (BUD/FOR). Reduction in reliever medication use (puffs/24h), change in symptom control scores (ACQ-5), and annualised exacerbation rate over 12months were simulated in a cohort of patients with different baseline characteristics (e.g. time since diagnosis, asthma control questionnaire (ACQ-5) symptom score, smoking status, body mass index (BMI) and sex) using drug-disease models derived from large phaseIII/IV clinical studies. Simulation scenarios show that being a smoker, having higher baseline ACQ-5 and BMI, and long asthma history is associated with increased reliever medication use (p < 0.01). This increase correlates with a higher exacerbation risk and higher ACQ-5 scores over the course of treatment, irrespective of the underlying maintenance therapy. Switching non-responders to ICS monotherapy to combination therapy after 3months resulted in immediate reduction in reliever medication use (i.e. 1.3 vs. 1.0 puffs/24h for FP/SAL and BUD/FOR, respectively). In addition, switching patients with ACQ-5 > 1.5 at baseline to FP/SAL resulted in 34% less exacerbations than those receiving regular dosing BUD/FOR (p < 0.01). We have identified baseline characteristics of patients with moderate to severe asthma that are associated with greater reliever medication use, poor symptom control and higher exacerbation risk. Moreover, the effects of different inhaled corticosteroid (ICS)/long-acting beta agonist (LABA) combinations vary significantly when considering long-term treatment performance. These factors should be considered in clinical practice as a basis for personalised management of patients with moderate-severe asthma symptoms.

Real-world biologics response and super-response in the International Severe Asthma Registry cohort.

Biologic asthma therapies reduce exacerbations and long-term oral corticosteroids (LTOCS) use in randomized controlled trials (RCTs); however, there are limited data on outcomes among patients ineligible for RCTs. Hence, we investigated responsiveness to biologics in a real-world population of adults with severe asthma. Adults in the International Severe Asthma Registry (ISAR) with ≥24 weeks of follow-up were grouped into those who did, or did not, initiate biologics (anti-IgE, anti-IL5/IL5R, anti-IL4/13). Treatment responses were examined across four domains: forced expiratory volume in 1 second (FEV1) increase by ≥100 mL, improved asthma control, annualized exacerbation rate (AER) reduction ≥50%, and any LTOCS dose reduction. Super-response criteria were: FEV1 increase by ≥500 mL, new well-controlled asthma, no exacerbations, and LTOCS cessation or tapering to ≤5 mg/day. 5.3% of ISAR patients met basic RCT inclusion criteria; 2116/8451 started biologics. Biologic initiators had worse baseline impairment than non-initiators, despite having similar biomarker levels. Half or more of initiators had treatment responses: 59% AER reduction, 54% FEV1 increase, 49% improved control, 49% reduced LTOCS, of which 32%, 19%, 30%, and 39%, respectively, were super-responses. Responses/super-responses were more frequent in biologic initiators than in non-initiators; nevertheless, ~40-50% of initiators did not meet response criteria. Most patients with severe asthma are ineligible for RCTs of biologic therapies. Biologics are initiated in patients who have worse baseline impairments than non-initiators despite similar biomarker levels. Although biologic initiators exhibited clinical responses and super-responses in all outcome domains, 40-50% did not meet the response criteria.

Real-World Data on Tezepelumab in Patients With Severe Asthma in Germany

Tezepelumab is a novel biologic blocking thymic stromal lymphopoetin, approved for severe asthma irrespective of biomarker levels or phenotype. To characterize a real-world tezepelumab patient cohort and the efficacy among various asthma phenotypes. We performed a retrospective, multicenter study on patients with severe asthma initiating tezepelumab. Clinical response was evaluated at 3 and 6 months. We included 129 patients with an average age of 52.5 ± 13.1 years, 59.7% were female. The majority (86.0%) had increased type 2 (T2) biomarkers, 68.2% an allergic and 31.8% an eosinophilic phenotype. 23.3% of patients were biologic-naive. 22 (18.2%) patients discontinued tezepelumab therapy owing to suspected side effects or insufficient efficacy. At 6 months' follow-up, median reduction in annualized exacerbation rate was-1 [25th percentile; 75% percentile {-2.9; 0.0}], the reduction of oral corticosteroid dose among patients with long-term oral corticosteroid therapy was -5 mg [-10; 0] and the Asthma Control Test (ACT) improved by 2 [0; 5] points. A treatment response according to Biologic Asthma Response Score of 80.8% was demonstrated. There were no significant differences in treatment response between T2-high versus T2-low, early- versus adult-onset and eosinophilic versus non-eosinophilic asthma. Prior treatment with other biologics was associated with inferior treatment response. In this real-life cohort, including a large proportion of patients with history of previous biologic use and encompassing various subgroups, the majority responded to tezepelumab. Our data further suggest a steroid-sparing effect of tezepelumab.

Ratio of plasma IL-13/TNF- ∝ and CXCL10/CCL17 predicts mepolizumab and omalizumab response in asthma better than eosinophil count or immunoglobulin E level

To date, most studies to identify biomarkers associated with response to the anti-interleukin 5 agent, mepolizumab, and to the anti-immunoglobulin E agent, omalizumab have focused on clinically available biomarkers, such as the peripheral blood eosinophil counts (BEC) and total immunoglobulin E (IgE). However, these biomarkers often have low predictive accuracy, with many patients with eosinophilic or allergic asthma failing to demonstrate clinical response to mepolizumab or omalizumab respectively. In this study, we evaluated the association of baseline pre-biologic plasma levels of 26 cytokines and chemokines, including T-helper 1 (Th1)-, Th2-, Th17-related cytokines, and their ratios with subsequent clinical response to mepolizumab or omalizumab. We defined clinical response as a reduction in the baseline annual exacerbation rate by half or more over the one-year period following initiation of the biologic. Baseline levels of plasma IL-13 were differentially elevated in responders versus non-responders to mepolizumab and plasma CXCL10 levels were differentially elevated in responders to omalizumab. The ratio of IL-13/TNF-α had the best sensitivity and specificity in predicting response to mepolizumab and CXCL10/CCL17 to omalizumab, and these performed better as predictive biomarkers of response than BEC and IgE. Cytokines and chemokines associated with airway eosinophilia, allergic inflammation, or Th2 inflammation, such as IL-13 and CXCL10, may be better predictors of clinical response to mepolizumab and omalizumab, than IL-5 or IgE, the targets of mepolizumab and omalizumab.

Triple Therapy and Clinical Control in B+ COPD Patients: A Pragmatic, Prospective, Randomized Trial

IntroductionTreatment with LABA/LAMA is recommended in GOLD B patients. We hypothesized that triple therapy (LABA/LAMA/ICS) will be superior to LABA/LAMA in achieving and maintaining clinical control (CC), a composite outcome that considers both impact and disease stability in a subgroup of GOLD B patients (here termed GOLD B+ patients) characterized by: (1) remaining symptomatic (CAT≥10) despite regular LABA/LAMA therapy; (2) having suffered one moderate exacerbation in the previous year; and (3) having blood eosinophil counts (BEC) ≥150cells/μL. MethodsThe ANTES B+ study is a prospective, multicenter, open label, randomized, pragmatic, controlled trial designed to test this hypothesis. It will randomize 1028 B+ patients to continue with their usual LABA/LAMA combination prescribed by their attending physician or to begin fluticasone furoate (FF) 92μg/umeclidinium (UMEC) 55μg/vilanterol (VI) 22μg in a single inhaler q.d. for 12 months. The primary efficacy outcome will be the level of CC achieved. Secondary outcomes include the clinical important deterioration index (CID), annual rate of exacerbations, and FEV1. Exploratory objectives include the interaction of BEC and smoking status, all-cause mortality and proportion of patients on LABA/LAMA arm that switch therapy arms. Safety analysis include adverse events and incidence of pneumonia. ResultsThe first patient was recruited on February 29, 2024; results are expected in the first quarter of 2026. ConclusionsThe ANTES B+ study is the first to: (1) explore the efficacy and safety of triple therapy in a population of B+ COPD patients and (2) use a composite index (CC) as the primary result of a COPD trial.

Radiographic Outcomes in Pediatric Bronchiectasis and Factors Associated with Reversibility.

Rationale: Conventionally considered irreversible, bronchiectasis has been demonstrated to be reversible in children in small studies. However, the factors associated with radiographic reversibility of bronchiectasis have yet to be defined. Objectives: In a large cohort of children with bronchiectasis, we aimed to determine: 1) if and to what extent bronchiectasis is reversible and 2) factors associated with radiographic chest high-resolution computed tomography (cHRCT) resolution. Methods: We identified children with bronchiectasis who had a repeat multidetector cHRCT scan between 2010 and 2021. We excluded those with cystic fibrosis, surgical pulmonary resection, traction bronchiectasis only, or lobar opacification. Measurements and Main Results: cHRCT scans were scored using the modified Reiff score (MRS) with a pediatric correction. Resolution was defined as an absence of abnormal bronchoarterial ratio (>0.8) on the second cHRCT scan. We included 142 children (median age, 5 years; IQR, 2.6-7.4). Inter- and intrarater agreement in MRSs was excellent (weighted κ = 0.83-0.86 and 0.95, respectively). There was radiographic resolution in 57 of 142 patients (40.1%), improvement in 56 of 142 (39.4%), and no change or worsening in 29 of 142 (20.4%). Pseudomonas aeruginosa (PsA) was absolutely associated with a lack of resolution. On multivariable regression, in those without PsA cultured, younger age at the time of diagnosis (risk ratio [RR], 0.94; 95% confidence interval [CI], 0.88-0.99), lower MRS (RR, 0.89; 95% CI, 0.82-0.97), and lower annual rate of exacerbations requiring intravenous antibiotic therapy (RR, 0.60; 95% CI, 0.37-0.98) increased the likelihood of radiographic resolution. Conclusions: This first large cohort confirms that bronchiectasis in children is often reversible with appropriate management. Younger children and those with lesser radiographic severity at diagnosis were most likely to exhibit radiographic reversibility, whereas those with PsA infection were least likely.

Benralizumab in severe eosinophilic asthma by previous biologic use and key clinical subgroups: real-world XALOC-1 programme.

Pivotal phase 3 trials and real-world studies have demonstrated benralizumab's overall efficacy and safety in severe eosinophilic asthma (SEA). Additional large-cohort data are needed to confirm its real-world effectiveness in SEA according to previous biologic use and key baseline characteristics important for treatment selection. XALOC-1 is a large, multinational, retrospective, observational, real-world study programme of benralizumab in adults with SEA. This 48-week integrated analysis assessed annualised exacerbation rate (AER), maintenance oral corticosteroid (mOCS) use, asthma symptom control and lung function during a 12-month baseline period and up to 48 weeks after benralizumab initiation. Subgroup analyses were based on previous biologic use and key baseline clinical characteristics (mOCS use, blood eosinophil count, exacerbation history, age at asthma diagnosis, fractional exhaled nitric oxide level and presence of atopy and chronic rhinosinusitis with nasal polyps). Out of 1002 patients analysed, 380 were biologic-experienced. At week 48, 71.3% were exacerbation-free (versus 17.2% at baseline); relative reduction in AER was 82.7% overall and 72.9% in biologic-experienced patients; rates were maintained across all key clinical characteristic subgroups. Of patients using mOCS at baseline (n=274), 47.4% (130 out of 274) eliminated their use by week 48; the mean reduction from baseline in daily dose was 51.2% and, notably, 34.9% in biologic-experienced patients (n=115). Clinically significant improvements in asthma symptom control and lung function were observed. In this large, real-world programme, SEA patients treated with benralizumab had substantial improvements in clinical outcomes irrespective of previous biologic use and key clinical characteristics important to therapeutic decision-making in clinical practice.