Daily Respiratory Research Analysis
Analyzed 143 papers and selected 3 impactful papers.
Summary
Two large randomized trials show that targeting the IL-33/ST2 pathway with astegolimab reduces COPD exacerbations, while a phase 3 trial demonstrates tezepelumab enables meaningful oral corticosteroid reduction in severe asthma. A systematic review links higher mechanical power during invasive ventilation with increased mortality, reinforcing ergotrauma as a clinically relevant target.
Research Themes
- Biologics for COPD beyond eosinophil-defined subgroups
- Steroid-sparing strategies in severe asthma via TSLP blockade
- Ventilator-induced lung injury quantified by mechanical power
Selected Articles
1. Safety and efficacy of astegolimab for COPD with frequent exacerbations regardless of baseline blood eosinophil counts (ALIENTO and ARNASA): randomised, double-blind, placebo-controlled, phase 2b and 3 trials.
Across two randomized, double-blind trials, astegolimab reduced annualized moderate/severe COPD exacerbations versus placebo, achieving statistical significance in ALIENTO (Q2W) and ARNASA (Q4W). Safety profiles were balanced, with similar adverse events and mortality across groups, supporting the clinical viability of ST2/IL-33 pathway blockade.
Impact: This is among the first large, eosinophil-agnostic biologic programs in COPD showing exacerbation reduction, suggesting a new immunologic target for patients beyond current inhaled therapies.
Clinical Implications: Astegolimab may be considered for COPD patients with frequent exacerbations regardless of blood eosinophils, pending regulatory approval, as an add-on to optimized inhaled therapy to reduce exacerbation burden.
Key Findings
- ALIENTO: Astegolimab Q2W reduced annualized moderate/severe exacerbations vs placebo (rate ratio 0.85; 95% CI 0.72–1.00; p=0.049).
- ARNASA: Astegolimab Q4W reduced exacerbations vs placebo (rate ratio 0.82; 95% CI 0.70–0.98; p=0.024).
- Adverse events were common but balanced across groups (ALIENTO 84.0%, ARNASA 85.5% with ≥1 AE).
- All-cause mortality ~3% and similar between groups; investigator-related deaths were extremely rare (0.1%).
Methodological Strengths
- Two large, multicenter, randomized, double-blind, placebo-controlled trials with prespecified endpoints
- Stratified randomization and consistent background optimized inhaled therapy over 52 weeks
Limitations
- One dosing schedule in each trial did not reach statistical significance, yielding mixed signals across regimens
- Event-driven differences modest; longer-term outcomes and responder subgroups require clarification
Future Directions: Define biomarkers of response (e.g., IL-33 axis activity, epithelial alarmin signatures), refine dosing schedules, and evaluate long-term outcomes including health-related quality of life and cost-effectiveness.
BACKGROUND: Interleukin-33 and its receptor, ST2, are implicated in neutrophilic and eosinophilic inflammation during chronic obstructive pulmonary disease (COPD) exacerbations. We aimed to assess the efficacy and safety of astegolimab, an anti-ST2 human IgG2 monoclonal antibody, which were evaluated in two COPD pivotal trials. METHODS: In two randomised, double-blind, placebo-controlled trials (phase 2b ALIENTO and phase 3 ARNASA), current or former smokers with COPD and a history of frequent exacerbations, irrespective of baseline blood eosinophils, were randomly assigned (1:1:1; stratification by smoking status and region) to receive subcutaneous astegolimab 476 mg every 2 weeks, every 4 weeks, or placebo, alongside optimised inhaled maintenance therapy over 52 weeks. The primary endpoint (analysed in participants receiving one or more doses) was annualised rate of moderate or severe exacerbations. Missing data were considered similar to data from other participants in the same treatment group with the same baseline characteristics. The trials were registered with ClinicalTrials.gov (NCT05037929 and NCT05595642). FINDINGS: In ALIENTO, 1301 participants (astegolimab every 2 weeks, n=433; astegolimab every 4 weeks, n=437; and placebo, n=431) initiated treatment between Oct 5, 2021, and Feb 19, 2024. In ARNASA, 1375 participants (astegolimab every 2 weeks, n=459; astegolimab every 4 weeks, n=459; and placebo, n=457) initiated treatment between Jan 9, 2023, and June 25, 2024. Adjusted rate ratios versus placebo for the primary endpoint were 0·85 (95% CI 0·72-1·00; p=0·049) for astegolimab every 2 weeks and 0·93 (0·79-1·10; p=0·38) for astegolimab every 4 weeks in ALIENTO, and 0·85 (0·72-1·01; p=0·068) for astegolimab every 2 weeks and 0·82 (0·70-0·98; p=0·024) for astegolimab every 4 weeks in ARNASA. Adverse events were balanced between treatments, with most participants experiencing one or more adverse events (1093 [84·0%] of 1301 participants in ALIENTO and 1176 [85·5%] of 1375 in ARNASA). The most common non-COPD adverse event was nasopharyngitis in ALIENTO and upper respiratory chest infection in ARNASA. Deaths occurred in 40 (3·1%) of 1301 participants in ALIENTO and in 44 (3·2%) of 1375 participants in ARNASA, and were balanced across treatment groups. Across both trials, a total of three deaths (0·1%) were considered to be related to treatment by investigators. INTERPRETATION: In ALIENTO, astegolimab every 2 weeks was associated with a lower annual rate of exacerbations versus placebo in patients with COPD and a history of frequent exacerbations. In ARNASA, these findings did not meet statistical significance. Together, these findings suggest a role for targeting the ST2/IL-33 pathway to reduce the frequency of COPD exacerbations in patients with limited treatment options.
2. Efficacy and safety of tezepelumab versus placebo in reducing oral corticosteroid use in adults with severe, oral corticosteroid-dependent asthma (SUNRISE): a multicentre, placebo-controlled, double-blind, phase 3 trial.
Tezepelumab significantly increased the odds of achieving greater categorized reductions in maintenance oral corticosteroids versus placebo over 28 weeks while maintaining asthma control. Exacerbations and adverse events were numerically lower with tezepelumab, and no treatment-related safety signals emerged despite early study termination.
Impact: Demonstrates clinically meaningful steroid-sparing with TSLP blockade in severe OCS-dependent asthma, addressing a major unmet need to reduce steroid toxicity without loss of control.
Clinical Implications: For severe, OCS-dependent asthma, tezepelumab can be considered to achieve OCS reduction while preserving control, potentially mitigating long-term steroid adverse effects.
Key Findings
- Primary endpoint met: higher odds of greater OCS dose reduction with tezepelumab vs placebo (OR 2.93; 95% CI 1.43–6.03; p=0.0034).
- Fewer patients experienced ≥1 exacerbation with tezepelumab (30%) vs placebo (59%) over 28 weeks.
- Adverse events and serious adverse events were numerically lower with tezepelumab; no treatment-related deaths were identified.
Methodological Strengths
- Multicenter, double-blind, placebo-controlled phase 3 design with stratification by region and eosinophils
- Clear, clinically relevant primary endpoint (categorized OCS reduction with maintained control)
Limitations
- Early termination led to reduced sample size (122/207 planned), potentially limiting power and precision
- Follow-up limited to 28 weeks; long-term OCS-sparing durability and safety need confirmation
Future Directions: Confirm durability of OCS-sparing, characterize patient subgroups most likely to benefit, and quantify long-term reduction in steroid-related morbidity and healthcare utilization.
BACKGROUND: Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. This study aimed to evaluate the oral corticosteroid-sparing effect of tezepelumab in adults with severe, oral corticosteroid-dependent asthma. METHODS: SUNRISE was a phase 3, double-blind, placebo-controlled trial conducted across 63 sites in 12 countries. After oral corticosteroid optimisation, participants aged 18-80 years with physician-diagnosed asthma who were receiving medium-dose or high-dose inhaled corticosteroids for at least 12 months before screening were randomly assigned (2:1) to receive tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 28 weeks. Participants were stratified by region and blood eosinophil count. Participants, investigators, and site staff were masked to treatment assignment. The primary outcome was the categorised percentage reduction from baseline in the daily maintenance oral corticosteroid dose at week 28 while maintaining asthma control. The primary outcome and safety outcomes were evaluated in all randomly assigned participants who received at least one dose of tezepelumab or placebo (ie, the full analysis set). This study is registered with ClinicalTrials.gov (NCT05398263). FINDINGS: Between Aug 9, 2022, and March 24, 2025, when the study was terminated, 122 of 207 planned participants received tezepelumab (n=83) or placebo (n=39). 90 (74%) participants completed treatment. Of 122 participants, 25 (20%) did not complete the study owing to early study termination due to recruitment challenges. The odds of reaching a category of greater percentage oral corticosteroid reduction at week 28 were significantly higher with tezepelumab than placebo (odds ratio 2·93 [95% CI 1·43-6·03]; p=0·0034). Overall, 25 (30%) participants in the tezepelumab group and 23 (59%) participants in the placebo group had at least one asthma exacerbation over 28 weeks. Adverse events occurred in 47 (57%) participants in the tezepelumab group and 28 (72%) participants in the placebo group. Serious adverse events occurred in seven (8%) participants in the tezepelumab group and five (13%) participants in the placebo group. Three deaths occurred (two in the tezepelumab group during the post-treatment period and one in the placebo group during the treatment period); none were considered causally related to study treatment based on investigator assessment. INTERPRETATION: In this study, tezepelumab treatment led to greater reductions from baseline in daily oral corticosteroid dose than placebo at week 28 despite early study termination. No safety concerns were identified for tezepelumab. These findings show that patients receiving tezepelumab can reduce maintenance oral corticosteroid use while maintaining asthma control and without compromising efficacy.
3. The Association Between Mechanical Power and Mortality in Critically Ill Patients Receiving Invasive Mechanical Ventilation: A Systematic Review and Meta-Analysis.
Across 34 studies, nonsurvivors had higher mechanical power, and each 1 J/min increase was independently associated with higher mortality. Findings support mechanical power as a pragmatic marker of ergotrauma, though interventional trials are needed to test whether targeting mechanical power improves outcomes.
Impact: Provides quantitative synthesis linking ventilator energy delivery to mortality, reinforcing a unifying metric to guide lung-protective strategies beyond single-parameter limits.
Clinical Implications: Incorporate mechanical power into bedside assessment to complement traditional lung-protective targets (tidal volume, driving pressure, respiratory rate), and consider strategies that reduce mechanical power exposure.
Key Findings
- Nonsurvivors had higher mechanical power than survivors (MD 1.91 J/min; 95% CI 1.30–2.51).
- Per 1 J/min increase in mechanical power, adjusted odds of death increased (AOR 1.04; 95% CI 1.03–1.06) and hazard increased (AHR 1.03; 95% CI 1.00–1.07).
- A threshold above ~17 J/min was associated with higher mortality (OR 1.60; 95% CI 1.34–1.91).
Methodological Strengths
- Comprehensive systematic search with random-effects meta-analyses and normalization analyses
- Separate synthesis of adjusted effect estimates (AOR/AHR) to address confounding
Limitations
- Predominantly observational data prone to residual confounding and heterogeneity
- Associative findings; interventional evidence for mechanical power targeting is lacking
Future Directions: Prospective trials testing ventilatory strategies that explicitly limit mechanical power and evaluating patient-centered outcomes; integration with automated ventilator control algorithms.
OBJECTIVES: To investigate the association between mechanical power and mortality in adult critically ill patients receiving invasive mechanical ventilation. DATA SOURCES: We conducted a systematic search of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials on August 12, 2025. STUDY SELECTION: We included studies comparing mechanical power between survivors and nonsurvivors or reporting adjusted mortality estimates in adult critically ill patients receiving invasive mechanical ventilation. DATA EXTRACTION: Two reviewers independently extracted study characteristics, ventilator variables, and mortality outcomes. DATA SYNTHESIS: Pooled mean differences (MDs) were calculated using inverse-variance random-effects models. Secondary analyses evaluated mechanical power normalized to predicted body weight and respiratory system compliance. Adjusted odds ratios (AORs) and adjusted hazard ratios (AHRs) for mortality per 1 J/min increase in mechanical power were synthesized separately using generic inverse-variance random-effects models. A total of 34 studies met inclusion criteria and were included in the meta-analyses. Mechanical power was higher in nonsurvivors than survivors (MD, 1.91 J/min; 95% CI, 1.30-2.51 J/min). Mechanical power normalized to predicted body weight (MD, 0.06 J/min/kg; 95% CI, 0.04-0.08 J/min/kg) and normalized to respiratory system compliance (MD, 0.28 J/min/mL/cm H2O; 95% CI, 0.10-0.45 J/min/mL/cm H2O) were also higher among nonsurvivors. Mechanical power was independently associated with mortality, with pooled AOR (1.04 per 1 J/min increase; 95% CI, 1.03-1.06 per 1 J/min increase) and pooled AHR (1.03; 95% CI, 1.00-1.07). A mechanical power threshold older than 17 J/min was associated with greater mortality (odds ratio, 1.60; 95% CI, 1.34-1.91). CONCLUSIONS: Higher mechanical power was consistently associated with increased mortality in invasively ventilated adults. Mechanical power may serve as a clinically relevant marker of ergotrauma; however, whether interventions that reduce mechanical power improve outcomes requires prospective investigation.