BMJ Open Respiratory Research最新文献

Introduction: Bexotegrast is an oral, once-daily, dual-selective inhibitor of integrins α_vβ₆ and α_vβ₁ in development for idiopathic pulmonary fibrosis (IPF). In the phase 2a study INTEGRIS-IPF study (NCT04396756), bexotegrast was well tolerated and showed antifibrotic activity.

Methods and analysis: BEACON-IPF (NCT06097260) is a randomised, double-blind, placebo-controlled, dose-finding, operationally seamless, adaptive phase 2b/3 study evaluating the efficacy and safety of bexotegrast over 52 weeks in participants with IPF. The phase 2b dose selection cohort will enrol 360 participants randomised 1:1:1 to once-daily bexotegrast 160 mg, 320 mg or placebo. After enrolling the last participant in the phase 2b cohort and while conduct is ongoing, the phase 3 cohort will immediately begin enrolment with a 'seamless group' using the same 1:1:1 randomisation. Once the phase 2b cohort has completed and a dose has been selected, the remainder of the phase 3 cohort will be enrolled. Participants in the phase 2b cohort receiving the non-selected dose will be eligible for an open-label study at the selected phase 3 dose. Background therapy with pirfenidone or nintedanib is permitted in ≤70% of the study population. Participants must be adults (≥40 years), have an IPF diagnosis ≤7 years per 2018 international guidelines, per cent predicted forced vital capacity (FVCpp) ≥45% and diffusing capacity for carbon monoxide (haemoglobin adjusted) ≥30%. The primary endpoint is change from baseline in absolute FVC at week 52. Additional endpoints include safety and tolerability, time to disease progression, participant-reported symptom assessments and quantitative lung fibrosis extent.

Ethics and dissemination: This study was approved by Advarra institutional review board (IRB; OHRP and Food and Drug Administration registration 00000971) and at each participating site by IRBs and local ethics review committees. Participants will provide written informed consent before taking part. Study results will be disseminated in peer-reviewed journals and international conferences targeted to medical, academic and patient communities.

Trial registration number: NCT06097260.

Introduction: COVID-19 has challenged traditional models of respiratory failure, and several studies have suggested that gas exchange impairment in COVID-19 pneumonia may involve mechanisms beyond anatomical shunt. This has renewed interest in non-invasive physiological tools to explore gas exchange abnormalities, including the evaluation of shunt, dead space and ventilation/perfusion mismatch.

Material and methods: This prospective cross-sectional study was conducted between October 2020 and January 2021 at Papa Giovanni XXIII Hospital (Bergamo, Italy), enrolling adults with acute respiratory failure due to COVID-19 or other pneumonias. Pulmonary shunt fraction was estimated non-invasively via the BEACON system using peripheral oxigen saturation (SpO₂)/fraction of inspired oxygen responses during incremental oxygen steps. Chest CT scans were quantitatively analysed for pathological patterns. The primary outcome was the comparison of BEACON-estimated shunt fraction between COVID-19 and non-COVID-19 groups; the secondary outcome included correlations with CT findings.

Results: A total of 51 patients were enrolled, including 36 with COVID-19 and 15 with non-COVID-19 pneumonia. COVID-19 patients showed significantly higher pulmonary shunt fractions (18.2% vs 12.5%, p=0.022). In non-COVID-19 cases, shunt fraction correlated positively with the extent of CT consolidations (ρ=0.567, p=0.035) and negatively with ground-glass opacities (ρ =-0.565, p=0.035). No significant correlations between shunt and CT findings were observed in COVID-19 patients.

Conclusions: Our findings demonstrate increased estimated shunt in COVID-19 pneumonia despite comparable radiological severity to non-COVID-19 pneumonias, reinforcing the concept of distinct gas exchange pathophysiology across different pneumonia aetiologies.

Introduction: Ventilator-associated pneumonia (VAP) is the most frequent healthcare-associated infection in intensive care units and is associated with high morbidity and mortality. Current diagnostic criteria lack specificity, leading to misclassification and unnecessary antibiotic use. Identifying patient subgroups with a common pathophysiological basis (pneumoclusters) may distinguish true VAP of varying aetiology and severity from non-infectious mimics, enabling more targeted therapy and improved antimicrobial stewardship.

Methods and analysis: ClusterVAP is an exploratory, observational, prospective, multicentre cross-sectional study conducted in intensive care units across Sweden, France, Portugal, Denmark and the UK. Mechanically ventilated patients aged 18 years or older with newly developed clinical signs of lower respiratory tract infection will undergo bronchoalveolar lavage (BAL) or mini BAL sampling on clinical indication. Proteomic profiling using liquid chromatography tandem mass spectrometry will be performed on BAL supernatants. Unsupervised consensus clustering will define pneumoclusters, which will be characterised using clinical, microbiological and radiological data. 30-day outcomes, including mortality, ventilator-free days, antibiotic-free days, intensive care unit-free days and hospital-free days, will be compared across clusters to describe clinical trajectories. Candidate protein biomarkers for pragmatic cluster assignment will be derived using differential expression analysis.

Ethics and dissemination: Ethical approval will be obtained at all participating sites. Deferred consent will be used where permitted, with subsequent patient or proxy consent according to local regulations. Results will be disseminated through peer-reviewed publications and scientific conferences.

Trial registration number: NCT07245888.

Introduction: Asthma among adolescents (aged 12-<18 years) is a common condition with high disease burden. Many are undertreated, at risk of adverse outcomes and exhibit poor adherence to maintenance medication. As-needed albuterol-budesonide 180/160 µg reduced the risk of severe exacerbations by 27% compared with as-needed albuterol 180 µg in patients aged ≥12 years, with moderate-to-severe asthma receiving inhaled corticosteroid (ICS) maintenance therapy in the MANDALA trial. A small number of adolescents were included in MANDALA, but data were inconclusive. The randomised, double-blind, multicentre, phase IIIb ACADIA trial is evaluating as-needed albuterol-budesonide versus as-needed albuterol in adolescents with asthma.

Methods and analysis: A planned 440 adolescents (aged 12-<18 years) with asthma using as-needed albuterol with low- to high-dose ICS-containing maintenance medications (with or without other controllers) and who had ≥1 severe exacerbation in the previous 12 months are randomised to as-needed albuterol-budesonide 180/160 µg or as-needed albuterol 180 µg for 52 weeks while continuing their own maintenance therapy. The primary endpoint is the annualised rate of severe asthma exacerbations. Secondary endpoints are the time to first severe asthma exacerbation and annualised total systemic corticosteroid exposure for asthma per participant. To minimise the number of adolescents exposed to study medications, the treatment effect will be estimated by partially extrapolating results from the patient population in the MANDALA trial using a Bayesian dynamic borrowing approach.

Ethics and dissemination: Ethical approval was obtained from the investigators' institutional review boards. Enrolment began in May 2024. Results will be presented at respiratory congresses and published in peer-reviewed journals.

Trial registration number: NCT06307665.

Introduction: Asthma is a heterogeneous condition and affected individuals show variable responses to available medications. An unmet need exists for add-on therapies that target novel molecular pathways, before patients escalate to biologics. Janus kinase 1 (JAK1) is implicated in multiple inflammatory cytokine pathways critical for the pathogenesis of asthma. Londamocitinib (AZD4604) is a highly specific, inhaled, JAK1 inhibitor with high potency to block multiple JAK1-dependent signalling pathways. AJAX is a phase 2a, randomised, double-blind, partially decentralised placebo-controlled study assessing the efficacy, safety and pharmacokinetics (PK) of londamocitinib in adults with moderate-to-severe asthma uncontrolled on medium-to-high-dose inhaled corticosteroid/long-acting β₂-agonist.

Methods and analysis: The primary endpoint is time to first CompEx Asthma event. Secondary endpoints include change from baseline in prebronchodilator forced expiratory volume in 1 s, chronic airways assessment test, six-item asthma control questionnaire, daily asthma symptom score, and morning and evening peak expiratory flow at weeks 4 and 12. In addition, assessment of the effect of londamocitinib on airway inflammation as measured by the fractional exhaled nitric oxide test; cough severity assessment; and the PK of londamocitinib in all participants after 4 and 12 weeks will also be evaluated.

Ethics and dissemination: The study has received ethical approval from the appropriate ethic committee and will be conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and all applicable regulatory requirements. All participants will provide written informed consent prior to enrolment, with procedures in place to ensure comprehension and voluntary participation. Findings will be disseminated through peer‑reviewed publications and/or presentations at scientific conferences. Summary results will be posted on the trial registry and shared with participants and relevant patient groups in lay summaries.

Introduction: The recent rollout of nirsevimab across multiple countries represents an important advancement in respiratory syncytial virus (RSV) prevention. However, real-world evidence on how its effectiveness varies with infant age and time since administration, and on the characteristics of breakthrough infections, remains limited.

Methods and analysis: In this study, we aimed to conduct an international collaborative study to assess the real-world effectiveness of nirsevimab by monthly interval of chronological age and time since administration and to understand the characteristics of breakthrough infections. Both individual-participant-level data (IPD) and aggregated data will be collected from international collaborators identified by systematic review, existing collaborative network and academic conferences. The effectiveness of nirsevimab will be assessed by a test-negative study design, and a two-stage IPD meta-analysis will be conducted for data synthesis; a one-stage IPD meta-analysis will also be conducted among a subset of IPD data with sufficient sample size as an exploratory analysis. We will also describe the epidemiological, clinical and molecular features of breakthrough infections and compare them with infants and young children who were either unvaccinated and infected or vaccinated but not infected. The study will provide detailed insights into the dynamic effectiveness of nirsevimab and the characteristics of breakthrough cases.

Ethics and dissemination: The study protocol has been approved by the Ethics Committee of Nanjing Medical University (2025-179). Ethical approval for the contributing studies is expected to be obtained independently by local investigators from their respective ethics committees. Findings will be presented at international conferences and submitted to peer-reviewed journals for publication.

Background: Pleural infection remains a major cause of morbidity and mortality, with a significant healthcare burden. Despite growing research and guideline recommendations, real-world management continues to vary widely.

Methods: An anonymous cross-sectional survey evaluating current practice was conducted among respiratory physicians across all public hospitals in Singapore. The survey examined key aspects of management, including pleural fluid diagnostics, chest drain management, surgical referral and intrapleural fibrinolytic therapy (IPFT).

Results: 95 respondents (58% response rate) completed the survey. Only 36.8% routinely inoculate pleural fluid into both plain specimen bottles and blood culture bottles, and up to 22% used plain tubes for pH analysis. Opinions on pH-guided chest drain insertion were divided: 50.6% would always consider pH, while 43.1% did not find it useful. IPFT was regarded as first line treatment following failure of standard care (antibiotics and chest drainage) by 63.2%, while 30.5% would only administer IPFT when surgery was deemed unsuitable. Most respondents (81.0%) had used a reduced dose of tissue plasminogen activator, with 12.6% doing so for all patients. The most common reduced dose was 5 mg (73.7%), largely driven by perceived reduction in bleeding risk (64.2%). Once-daily IPFT dosing was reported by 35.8%, primarily due to logistical constraints and safety concerns related to after-hours administration. Management practices, including pleural fluid sampling for microbiology and pH, indication and timing of surgery or IPFT, and IPFT dose adjustment, varied substantially between hospitals and between individual physicians within the same hospital, with no clear association with respondent seniority. Overall key challenges cited included variation in practice (48.4%), limited after-office hours expertise (44.2%) and limited surgical support (37.9%).

Conclusions: Significant variation exists in pleural infection management across Singapore. Strengthening multidisciplinary collaboration, establishing dedicated pleural services and high-quality trials are needed to optimise care pathways.Cite Now.

Introduction: Sexual life is important for many people and may be limited by breathlessness. We evaluated associations between breathlessness and individuals' perceived satisfaction with sexual lives and explored mediating factors in this relationship.

Methods: A cross-sectional, online, population-based survey of Australian adults with key demographics (age, sex, rurality, state/territory) reflected the 2016 national census. Assessments included: demographics, breathlessness (modified Medical Research Council (mMRC) scale); satisfaction with overall sexual life; whether breathlessness had affected overall sexual life and physical, social and emotional functioning. Binomial and ordinal logistic regression evaluated associations; a structural equation model evaluated direct, indirect and total associations.

Results: Of 10 033 respondents (52% women; mean age 45.4 (SD 18.6)), 4245/10 033 (42%) reported mMRC ≥1, 1214/10 033 (12%) reported being very dissatisfied with their overall sexual life and 943/10 033 (9%) reported that breathlessness had impacted their overall sexual life. Compared with mMRC 0, there was an unadjusted association between mMRC 1 and satisfaction with overall sexual life which remained after adjusting for age, sex and body mass index (adjusted OR (aOR): 1.50; 95% CI 1.29 to 1.74).Breathlessness severity was associated with worse unadjusted and adjusted impact on overall sexual life: mMRC 0 versus mMRC 1 (aOR: 1.84; 95% CI 1.36 to 2.47). The associations increased stepwise for each higher mMRC level. There may be moderation of the effect of breathlessness on satisfaction with sexual life through emotional functioning.

Conclusions: Increasing breathlessness severity increases the likelihood of a person's overall sexual life being impacted negatively, potentially mediated partly through emotional functioning.

Introduction: Severe asthma incurs a financial burden on both patients and societies. However, little is known about the long-term financial burden and impact of biologic therapy.

Methods: All Danish adults initiating biologic therapy for severe asthma between 2016 and 2020 were included and followed retrospectively between 2002 and 2022, both prior to and during biologic therapy. Excess healthcare costs, foregone income and welfare transfers were calculated on an annual basis using a level of education-adjusted, zero-inflated generalised linear model with a gamma distribution and a log-link compared with age, sex, residence and civil status matched comparators.

Results: In total, 562 patients and 2207 comparators (median age 56 years, 51% female) were included. Excess healthcare costs during the year prior to biologic therapy were €10 590 and foregone income was €5389 per patient. The excess welfare transfers for patients aged 18-64 were €3335.Prior to biologic therapy, pooling of crude annual costs resulted in an accumulation of €59 364 and €44 155 in excess healthcare costs and foregone income per patient, respectively. Patients aged 18-64 had accumulated €32 021 in excess welfare transfers.Biologic therapy was associated with an increase in excess outpatient care costs (€25 938,+398.6%) compared with the year prior to biologic therapy. Outpatient care costs declined to (€14 486,+78.5%) during treatment year 4. Furthermore, at year 4, reductions in hospitalisations (€-2270, -67.7%) and patient-facing medication costs (€-557, -29.7%) compared with the year prior to biologic therapy were observed. Welfare transfers and foregone income were unaffected.

Conclusions: In the present study, patients with severe asthma initiating biologic therapy accumulated a substantial financial burden for both healthcare and welfare institutions, as well as a significant loss of personal income over time. Biologic therapy was associated with increased healthcare costs overall, but did not affect welfare transfers or foregone income.

Background: Bronchiectasis is a respiratory disease structurally characterised by irreversible airway dilatation. Functional impairments are also implicated in bronchiectasis, but the detailed changes in pulmonary function and the impact of clinical factors are yet to be examined. We analysed pulmonary function in patients with bronchiectasis based on their clinical features.

Methods: Two study cohorts-a multicentre bronchiectasis registry and health check-up examinees-were analysed. Airflow limitation was defined as forced expiratory volume in 1 s (FEV₁)/forced vital capacity (FVC) <0.7, and bronchiectasis severity was categorised using the number of involved lobes.

Results: Among 13 589 health check-up examinees, 606 (4.5%) had bronchiectasis; airflow limitation was more prevalent in those with bronchiectasis than in those without (17.3% vs 8.1%, p<0.001). Ever-smokers with bronchiectasis had the lowest FEV₁, FEV₁/FVC and FVC values, and the highest prevalence of airflow limitation. In the bronchiectasis registry (n=768), lung function parameters were worse in those with more involved lobes and Pseudomonas colonisation. Multivariable logistic regression analysis showed that bronchiectasis was independently associated with airflow limitation (OR 2.22 (95% CI 1.75 to 2.82)).

Conclusions: Bronchiectasis is an independent risk factor for airflow limitation, and disease severity, smoking and Pseudomonas colonisation were each associated with worsening in pulmonary function.