BMJ Open Respiratory Research最新文献

Introduction: Preschool wheeze and asthma are associated with substantial morbidity and impaired future lung function. Yet, wheeze is unreliably reported with high disagreement (>50%) between parental and physician observations. Objectively defining wheeze and its reversibility could enable an earlier asthma diagnosis and improve preschool wheeze management.Our primary aim is to determine in preschool children (aged 0.5-6 years) suspected of asthma whether adding WheezeScan to routine clinical assessment (vs assessment without WheezeScan) improves the diagnosis of asthma. Our primary hypothesis is that using WheezeScan in preschool children suspected of asthma is associated with increased definitive asthma diagnoses in this age group. Our secondary aims are to (a) examine the effect of using WheezeScan on patient-reported outcomes (PROs) and (b) healthcare costs. Our secondary hypothesis is that using WheezeScan in preschool children suspected of asthma is associated with improved quality of life without incurring additional healthcare costs.

Methods and analysis: Our multicentre prospective cohort study involves recruiting 102 preschool children suspected of asthma. WheezeScan, a user-friendly digital device, incorporates artificial intelligence to objectively define wheeze and its response to bronchodilators. Over 6 weeks, parents/caregivers use the WheezeScan two times per day and whenever wheezing is suspected. If wheeze is detected, an inhaled short-acting β₂-agonist is administered and WheezeScan determines if wheeze resolves thereafter.Our primary endpoint is the proportion of children with a definitive asthma diagnosis, compared with baseline, based on the treating clinician's assessment using WheezeScan data. Our secondary outcomes are PROs, reflecting generic health-related quality-of-life and cough-specific (if chronic cough present) outcomes and health costs.

Ethics and dissemination: The Children's Health Queensland Human Research Ethics Committee (HREC/23/QCHQ/100691) and the Queensland University of Technology Office of Research Ethics and Integrity approved the study. We will publish and share results with the academic and healthcare communities and relevant patient organisations.

Trial registration number: Australian New Zealand Clinical Trials Registry ACTRN12623000904673.

Background: Pulmonary non-tuberculous mycobacterial (NTM) disease is a respiratory infection with an increasing incidence worldwide, including Japan. Host factors may also be involved in the establishment of pulmonary NTM disease. Cystic fibrosis transmembrane conductance regulator (CFTR) variants are associated with pulmonary NTM disease and bronchiectasis. However, data on CFTR variants in the Japanese population remain limited.

Objectives: We aimed to determine the frequency of CFTR variants and the impact on the clinical features of pulmonary NTM disease and bronchiectasis in the Japanese population.

Methods: We analysed 458 patients with either pulmonary NTM disease, non-cystic fibrosis bronchiectasis or both at Keio University Hospital from February 2016 to March 2019. CFTR variants were identified using exome sequencing, Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). These variants were determined to be deleterious using CFTR2 and in silico tools. Clinical characteristics of patients with and without CFTR variants were compared in a 1:8 age-matched and sex-matched ratio. Additionally, exome sequencing was performed for the family of a patient with a family history of pulmonary NTM disease.

Results: Deleterious CFTR variants were identified in 16 patients (3.5%). One variant was identified by MLPA, and 15 by Sanger sequencing. All patients harboured a CFTR variant in one allele. Compared with matched controls, these patients had lower sputum culture conversion rates and higher rates of macrolide resistance. In one family cluster, members with pulmonary NTM disease were found to carry the same CFTR variant.

Conclusions: We defined the frequency and clinical characteristics of CFTR variants among the Japanese population with either pulmonary NTM disease, non-cystic fibrosis bronchiectasis or both and found that patients with CFTR variants may be refractory to pulmonary Mycobacterium avium complex disease. Further comprehensive research is needed to assess the impact of CFTR variants on pulmonary NTM disease and bronchiectasis in non-European populations.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease. Prospective study of fibrosis in the lung endpoints (PROFILE) was a prospective, observational cohort study designed to better define the natural history of IPF, understand disease biology and identify biomarkers to support disease management and enhance clinical trial design.

Methods: Individuals with an incident diagnosis of IPF were recruited between 2010 and 2017 across two co-ordinating centres in the UK. Demographics, clinical measurements and blood samples were obtained at baseline, and 1, 3, 6, 12, 24 and 36 months. Disease progression events were defined as death or relative forced vital capacity (FVC) decline >10% at 12 months. Survival estimates were modelled using Cox proportional hazards; longitudinal lung function decline was estimated using mixed effect models, specified with restricted cubic splines, a random intercept for participant and random effect for study visit. All models were adjusted for baseline age, sex and continuous baseline percent predicted FVC (ppFVC).

Results: A total of 632 participants were recruited, 77.1% were male, and mean age at enrolment was 70.4 years (SD 8.4). Mean baseline ppFVC was 79.5% (SD 19.2), and mean percent predicted DL_CO (ppDL_CO) was 45.7% (SD 15.1). A total of 304 (48.1%) participants met disease progression criteria at 1 year. Median survival was 3.7 years (95%CI 3.3 to 4.0). More severe baseline physiology, 12-month relative lung function decline ≥10%, older age and short telomeres were independent risk factors for mortality. Twelve-month estimated change in ppFVC was -5.28% (95% CI -6.34 to -4.22) with an average FVC decline of 186.9 mL (95% CI -225.4 to -148.5); 12-month estimated change in ppDL_CO was -3.35% (95% CI -4.30 to -2.40).

Conclusion: The PROFILE cohort confirms that untreated IPF is inexorably progressive and inevitably fatal with a poor median survival from diagnosis.

Introduction: A patient pathway is an evidence-based tool that details the phases of care with the aim of increasing the effectiveness and efficiency of patient care. We describe diagnostic and treatment pathways and related overall survival (OS) of non-small cell lung cancer patients.

Methods: This was a longitudinal, historical descriptive cohort study based on administrative claim data, spanning from 2017 to 2022. The index date was determined by the first bronchoscopy with lung biopsy (BX) followed by histopathological (HP) examination, alongside the presence of the International Classification of Diseases 10th revision diagnosis code C34. Incident patients aged ≥18 without prior malignancy. Pharmacotherapies (PHT), including chemotherapy (PHT_CT), precision therapy (PHT_IOTT), as well as surgery (SX) and radiotherapy (RT), were investigated associated with OS. A presence of multidisciplinary team (MDT) and treatment at a Complex Oncological Center (COC) with high-load experience was considered.

Results: We analysed 5819 patient pathways. Less than half (45.6%) of patients had MDT reported within a median of 20 days. Of the 4417 patients treated, 30% underwent more than one BX, 47.7% received PHT_CT, 25.9% underwent SX, 16.4% underwent RT and 9.08% PHT_IOTT. Early initiation of treatment within 4 weeks from BX was identified in 21% of SX patients, 30% of patients treated with PHT_CT and 23% of RT patients. The centralisation of care in COCs primarily concerned SX and PHT_IOTT, while 33% of patients indicated to PHT_CT were treated elsewhere. The median OS reached approximately 16 months in the overall population, 21 months in the verified treated cohort and 13 months in patients treated with PHT_CT, while it was not reached in patients treated with SX. We observed a positive association between patient prognosis and treatment centralisation in COCs.

Conclusions: This methodology can be implemented as a technical infrastructure to fulfil the organisation and quality evaluation routines in cancer care, largely based on administrative data.

Impulse oscillometry system (IOS) is an effort-independent pulmonary function testing technique that assesses respiratory system mechanics during tidal breathing and has gained increasing interest as a complementary modality to traditional pulmonary function tests (PFTs), while its physiological relevance and clinical role alongside conventional tests remain incompletely defined. This narrative literature review synthesises evidence on the correlations between IOS parameters and traditional PFT indices, summarises clinical applications across major chronic respiratory diseases, and discusses emerging developments including artificial intelligence-based approaches; the review is based on studies published since 2010 that compare IOS with spirometry, body plethysmography, and diffusing capacity of the lung for carbon monoxide (DLCO) in chronic obstructive pulmonary disease (COPD), asthma, and interstitial lung disease (ILD). Correlation studies indicate that IOS resistance-related parameters are more closely associated with obstructive ventilatory impairment, particularly in COPD and asthma, whereas reactance-related parameters show stronger associations with restrictive ventilatory abnormalities, lung volumes, and diffusion impairment, especially in ILD. Across disease entities, R5-20 and resonant frequency consistently demonstrate higher sensitivity for detecting small airway dysfunction. Clinically, IOS provides value in assessing bronchodilator responsiveness, evaluating asthma control, detecting small airway involvement when spirometry is preserved, and monitoring exposure-related airway effects. Artificial intelligence-based models integrating multidimensional IOS data further highlight its potential in disease screening and classification. Overall, IOS provides complementary physiological and clinical information beyond traditional PFTs, and further large-scale, multicentre studies and methodological standardisation are needed to support its broader clinical implementation.

Background: Vitamin K, through its role in the vitamin K-dependent activation of matrix-GLA-protein, has been suggested to have a lung-protective effect, though the mechanism is unknown. Chronic obstructive pulmonary disease (COPD) patients treated with vitamin K antagonists (VKAs) may lose this protection, thereby increasing their risk of an acute exacerbation of COPD (AE-COPD) and death. We examined this hypothesis in a nationwide cohort of COPD patients treated with VKA. COPD patients treated with direct oral anticoagulant (DOAC) served as controls.

Objective: To assess the association between VKA treatment and the 1-year risk of AE-COPD-related hospitalisation and all-cause mortality in patients with COPD and atrial fibrillation or flutter.

Methods: This nationwide, observational, register-based cohort study applied Cox proportional hazard regression models, adjusting for established confounders. HRs with 95% CIs were reported. Sensitivity analyses included complete-case analysis and inverse probability of treatment weighting (IPTW).

Results: A total of 7091 COPD patients were included, of whom 3455 (48.7%) received VKA treatment. A total of 1955 patients reached the endpoint, including 820 in the VKA-treated group. In the primary analysis, VKA treatment was associated with a lower risk of AE-COPD hospitalisation or death (adjusted HR of 0.87 (95% CI 0.78 to 0.98), p=0.024). The association remained in the sensitivity analyses but lost statistical significance. Complete-case analysis: adjusted HR of 0.88 (CI 0.76 to 1.01), p=0.079. IPTW analysis: HR of 0.85 (CI 0.72 to 1.01), p=0.070.

Interpretation: VKA treatment was associated with a reduction in risk of AE-COPD hospitalisation and mortality compared to DOAC. Sensitivity analysis was consistent with the main analysis; however, it did not reach statistical significance.

Background: While delivery of supplemental oxygen is a life-saving therapy, exposure to high oxygen, called hyperoxia, leads to increased intensive care unit mortality. Hyperoxia induces oxidant-mediated acute lung injury (ALI) and pulmonary cell death, called hyperoxic ALI (HALI). Elucidating molecular mechanisms in HALI could identify therapeutic targets in ALI.

Methods: In the current study, we examined in vivo effects of HALI on Beclin-1 (BCN1), which regulates autophagy, and modulation of BCN1 by epidermal growth factor receptor (EGFR). Effects of HALI on BCN1 and autophagy were examined in mice with genetically decreased EGFR (EGFR^Wa5/+). Wildtype (WT) and EGFR^Wa5/+ mice were exposed to 100% oxygen for 24-72 hours along with normoxia controls (eight groups; n=4-6/group), and analysis of pulmonary BCN1 and autophagy was completed.

Results: In WT, HALI led to increased BCN1 (59% increased total BCN1/β-Actin; p<0.01) in lung and alveolar epithelium (484% increased H-score; p<0.001). HALI led to decreased microtubule-associated protein 1B-light chain (LC3B)-II/-I ratios (43% decrease; p<0.05) and increased p62 (93% increase; p<0.05), suggesting reduced autophagic flux. In human alveolar type-II cells derived from induced pluripotent stem cells (AT2s^iPSC), HALI caused increased LDH release (130% increase; p<0.0001) and decreased LC3B-II/-I ratios (32% decrease; p<0.05). We previously showed that EGFR^Wa5/+ mice are protected in HALI. In the current study, EGFR^Wa5/+ mice showed increased pulmonary BCN1 (122% increase; p<0.05), reduced phosphorylated-(p-)/total BCN1 (47% decrease; p<0.05) and decreased LC3B-II/-I ratios (70% decrease; p<0.01) in HALI compared with WT. In addition, wortmannin (1 mg/kg), which decreases BCN1-mediated autophagy, increased mortality in HALI compared with vehicle control (n=10/group; 18% decreased hours survived; p<0.001).

Conclusions: These data delineate a novel cell death pathway in HALI involving BCN1 and EGFR with therapeutic potential.

Background: The prognostic significance of systemic inflammation in pulmonary embolism (PE) remains unclear. This study aimed to evaluate the predictive value of a novel Inflammatory Burden Index (IBI) for long-term mortality in patients with acute PE.

Methods: A total of 1642 patients with acute PE were retrospectively analysed. The optimal cut-off for IBI was determined using maximally selected rank statistics. The association between high IBI and all-cause mortality was assessed using multivariable Cox proportional hazards models. The predictive performance of IBI and its individual components was compared using time-dependent receiver operating characteristic (ROC) curves. Variable importance for mortality prediction was further evaluated using random survival forest (RSF) analysis.

Results: During a median follow-up of 41.2 months, 262 patients (16.0%) died. High IBI was independently associated with increased risk of all-cause mortality (adjusted HR 2.33, 95% CI 1.78 to 3.04; p<0.001). Time-dependent ROC analysis demonstrated that IBI provided superior prognostic accuracy for mortality, with area under the curve (AUC) values of 0.73, 0.74 and 0.75 at 1, 3 and 5 years, respectively, which were higher than those of C-reactive protein, neutrophil count and lymphocyte count. Addition of IBI to the basic clinical model significantly improved the AUC at all time points. RSF analysis confirmed that IBI was the most important inflammatory predictor of long-term mortality.

Conclusions: The IBI is a robust and independent predictor of long-term mortality in patients with acute PE and offers incremental prognostic value beyond conventional risk factors. Incorporating IBI into clinical risk stratification may improve patient management and outcomes.

Objective: Patient-reported experience measures (PREMs) are a key component of healthcare accountability frameworks, health policy, integrated care board commissioning and integrated care partnerships generating data which are crucial markers of patient care quality. The Rheumatoid Arthritis Patient-Reported Experience Measure (RA-PREM) incorporates the eight core elements of NHS Patient Experience Framework and is validated in a range of rheumatic conditions. Our objective is to determine the acceptability and feasibility of the RA-PREM for an interstitial lung disease (ILD) population.

Design: A mixed-methods patient-centred approach incorporating an interdisciplinary research steering group with patient partners. Patient surveys evaluated the language and meaning of the RA-PREM 8 domains, 24 statements and response categories. A patient focus group examined contentious statements. A consensus group of expert patient-partners agreed statements for the modified RA-PREM. Focus group participants reviewed the modified instrument (ILD-PREM) for acceptability and face/content validity.

Setting: A single NHSE-commissioned, regional ILD service/UK.

Results: Thirteen patients (10 male) diagnosed with ILD participated in focus group discussions. Critical discussion of the RA-PREM resulted in nuanced modifications of four statements of three domains. Five patients (three male) and three healthcare researchers attained consensus on the face/content validity of statements. Seventy-three patients completed the ILD-PREM following outpatient contact.

Conclusion: The ILD-PREM retains 24 statements representing the eight domains of the RA-PREM. It meets face/content validity criteria and is acceptable to an ILD population. Longitudinal validation of the ILD-PREM across ILD services including further testing in global minority groups will establish criterion and construct validity and objective measures of reliability.