BACKGROUND: Change in 6-min walk distance (6MWD) over time serves as a measure of change in functional exercise performance. We analysed a large cohort of current or former tobacco smokers over a 5-year period to identif...BACKGROUND: Change in 6-min walk distance (6MWD) over time serves as a measure of change in functional exercise performance. We analysed a large cohort of current or former tobacco smokers over a 5-year period to identify correlates of 6MWD decline. METHODS: A total of 4734 participants with normal spirometry or spirometric evidence of chronic obstructive pulmonary disease (COPD) who completed a 5-year follow-up in the COPDGene study were included. Baseline and 5-year assessments included 6MWD, spirometry, St. George's Respiratory Questionnaire (SGRQ), gender, race and CT measures of emphysema, gas trapping and airway wall thickness. 6MWD decline correlates relative to baseline and 5-year changes were examined using univariate and multivariate linear regression. RESULTS: At baseline, 2573 had normal spirometry; 487 were classified as GOLD1, 1044 as GOLD2, 514 as GOLD3 and 116 as GOLD4. Average 5-year decline in 6MWD was 35.6±101.7 (SD) metres (p<0.001). COPD participants experienced greater 6MWD decline (44.1±101.9 m, p<0.001) compared with those with normal spirometry (28.5±101.0 m, p<0.001). Only baseline 6MWD and study site accounted for appreciable fractions of 6MWD decline variance (R=12.1% and 9.1%, respectively). 5 year change in variables assessed (including FEV and SGRQ) explained only small fractions of 6MWD decline variance (each R≤5%). CONCLUSION: 6MWD declined significantly, but with high variability; spirometry, CT, health status, demographic and anthropometric measures accounted for only small portions of this variance. Our findings suggest that a meaningful decline in 6MWD observed over 5 years in COPD patients is in large part related to factors other than decline in pulmonary structure or function.
Houchen-Wolloff L, Hong A, Alqahtani K
… +10 more, Gerlis C, Gardiner N, Barradell A, Nolan CM, Man W, Richardson M, Khan A, Gumber A, Szczepura A, Singh SJ
INTRODUCTION: The benefits of pulmonary rehabilitation (PR) decline after 6-12 months. Previous studies of maintenance in the literature have been labour-intensive and concentrated on secondary care healthcare utilisatio...INTRODUCTION: The benefits of pulmonary rehabilitation (PR) decline after 6-12 months. Previous studies of maintenance in the literature have been labour-intensive and concentrated on secondary care healthcare utilisation only. We aimed to investigate whether Self-management Programme of Activity, Coping and Education (SPACE) for chronic obstructive pulmonary disease (COPD), a light-touch self-management programme, was clinically and cost-effective following PR. METHODS: We conducted a prospective, multicentre, assessor-blind randomised controlled trial. Patients with COPD were randomised 1:1 to usual care (control) or SPACE. The intervention included a home-based manual and four facilitated group sessions, delivered over 12 months. PRIMARY OUTCOME: Endurance Shuttle Walking Test at 12 months. SECONDARY OUTCOMES: maximal exercise capacity, mood, patient activation, physical activity, healthcare costs and health-related quality-of-life (HRQoL). RESULTS: 116 participants were recruited (October 2019-June 2022). Baseline characteristics: SPACE (65% male, aged 71.8 years, median Medical Research Council (MRC) 3, mean pack years 41.1, mean body mass index (BMI) 29.1), control (51% male, aged 71.8 years, median MRC 3, mean pack years 44.5, mean BMI 28.3). SPACE completion rate=83% and intervention fidelity (assessed via checklist) was excellent. No statistically significant differences at 12 months for primary and secondary outcomes. Economic analysis at 12 months shows a positive HRQoL difference between groups of 0.0871 quality adjusted life years (QALY) and reduced National Health Service (NHS) costs of £139 per participant, driven primarily by a reduction in general practitioner visits in favour of SPACE. CONCLUSIONS: Endurance exercise tolerance was maintained in both groups. The programme improved HRQoL at 12 months in the intervention group (above control) and was cost-effective, driven by reduced primary care costs.
BACKGROUND: Fibrotic interstitial lung diseases (fILDs) are chronic lung diseases with rising incidence and prevalence. Patients affected become increasingly breathless, dependent on supplementary oxygen and generally di...BACKGROUND: Fibrotic interstitial lung diseases (fILDs) are chronic lung diseases with rising incidence and prevalence. Patients affected become increasingly breathless, dependent on supplementary oxygen and generally die from respiratory failure. Despite the availability of antifibrotic therapies, treatment options that can positively impact the quality of life of patients with fILD remain limited. OBJECTIVE: To review the current clinical trial landscape in fILD, and explore emerging strategies to accelerate the development of therapies that improve outcomes that are meaningful to patients. DISCUSSION: There is growing recognition that advances in clinical trial design and endpoint selection are needed to better and more quickly evaluate investigational therapies to improve outcomes for patients with this often-devastating disease. There is increasing interest in incorporating endpoints that reflect on how the patient feels, functions and survives rather than a singular focus on forced vital capacity changes, which currently is a widely accepted endpoint for clinical trials for fILD. To accelerate the development of more effective therapies for these patients, innovative approaches to fILD clinical trial designs are needed. Approaches such as biomarker-based cohort enrichment, incorporation of alternative endpoints, use of adaptive and/or platform trial designs and decentralisation of studies can enhance the efficiency of clinical trials. Furthermore, engaging and aligning key stakeholders, most importantly patients, is crucial to ensure that outcomes important to the patients are addressed in the trial design. This review examines the current status of clinical trials in fILD, highlights the limitations of traditional clinical trial design approaches and explores potential strategies to accelerate the path towards improved treatments and outcomes for patients living with fILD.
RATIONALE: Obstructive sleep apnoea (OSA) is a prevalent disorder with major health consequences for which there is no approved pharmacological therapy targeting upper airway muscle pathophysiology. A combination of a no...RATIONALE: Obstructive sleep apnoea (OSA) is a prevalent disorder with major health consequences for which there is no approved pharmacological therapy targeting upper airway muscle pathophysiology. A combination of a noradrenergic (atomoxetine) and antimuscarinic (oxybutynin) (AtoOxy) may meaningfully reduce apnoea-hypopnoea index (AHI), but further repeated-dose intervention data are needed. METHODS: 58 participants with moderate-to-severe OSA were randomised to receive AtoOxy (80/5 mg) and placebo in a 1-month cross-over study. Primary analysis quantified the effect of AtoOxy versus placebo on AHI (percent change from baseline). Individual pathophysiology was characterised at baseline in a stand-alone gold-standard physiology study to determine whether OSA traits (collapsibility per 'Pcrit'; arousal threshold and muscle effectiveness per intraoesophageal catheter; loop gain) modified AtoOxy effectiveness. RESULTS: AHI was lowered by -23.8 (-35.2, -10.6)% (estimate (95% CI)) with AtoOxy versus by -11.7 (-24.3, 2.9)% with placebo; the treatment difference of -12.1 (-22.4, -0.5)% was significant (p=0.041). Only arousal threshold was a significant modifier of response: AtoOxy treatment effect was greater in high versus low arousal threshold (-25 vs +3 % treatment difference from placebo). Point-estimate treatment differences were observed within low but not high muscle effectiveness (-20 vs -4 %) and mild but not severe collapsibility (-17 vs -7 %). Sensitivity analysis suggested a twofold greater treatment difference using AHI (4% hypopnoea criteria). CONCLUSIONS: AtoOxy reduced AHI over 1 month; although the average response was not clinically meaningful, greater improvements were observed in participants with a higher arousal threshold, lower muscle effectiveness and milder collapsibility, which could enable targeted pharmacological intervention.
BACKGROUND: Currently available pharmacotherapies for interstitial lung disease (ILD) are limited to systemic glucocorticoids, steroid-sparing immunosuppressive medications and antifibrotic medications. Each of these tre...BACKGROUND: Currently available pharmacotherapies for interstitial lung disease (ILD) are limited to systemic glucocorticoids, steroid-sparing immunosuppressive medications and antifibrotic medications. Each of these treatments target major components of ILD biology. OBJECTIVE: This review presents the relevant evidence to the pharmacological management of ILD that is based on a treatable traits approach. We further highlight major knowledge gaps that should be the focus of future research that moves patient care toward a more precision-medicine approach. SUMMARY OF REVIEW: The previous treatment paradigm for the pharmacotherapy of ILD is based on the integration of several clinical, laboratory, radiological and pathological features to an underlying biology that is more likely to respond to a given medication strategy. Patients with more acute presentations and suggestion of significant inflammation are typically treated with systemic glucocorticoid therapy, with the route and initial dose decided primarily based on the severity of disease. Patients with ILD who have chronic disease with suggestion of inflammatory features are typically treated with long-term steroid-sparing immunosuppression. Patients with ILD who have chronic disease with progressive fibrotic features are typically treated with antifibrotic medication. Emerging therapies include nerandomilast, a phosphodiesterase 4B inhibitor with antifibrotic and immunomodulatory effects that has recently been approved in the USA. A major goal is future integration of molecular endotypes to support a transition towards precision-based management of ILD. CONCLUSIONS: Pharmacotherapy of ILD has previously focused on a morphology-based treatable traits approach that uses various clinical, laboratory, radiological and pathological clues to suggest a preferred treatment. We describe this approach and highlight specific questions that need to be addressed in future studies as we move toward a precision-based approach to patient management.
INTRODUCTION: Lung-function outcomes among preterm-born children referred for pulmonology care are highly heterogeneous, and early determinants remain incompletely defined. We aimed to identify early-life factors associa...INTRODUCTION: Lung-function outcomes among preterm-born children referred for pulmonology care are highly heterogeneous, and early determinants remain incompletely defined. We aimed to identify early-life factors associated with school-age lung function after preterm birth and to examine whether school-age spirometry patterns relate to subsequent lung-function trajectories. METHODS: Early-life analyses (n=511) examined predictors of forced expiratory volume in 1 s (FEV) and forced vital capacity (FVC) z-scores at ages 6-8 years using multivariable regression. Spirometry-based phenotypes included prematurity-associated preserved-ratio impaired spirometry (pPRISm), prematurity-associated obstructive lung disease (POLD) and prematurity-associated dysanapsis. Longitudinal mixed-effects models assessed lung-function trajectories from ages 8 to 21 years. Parallel analyses were conducted in the National Health and Nutrition Examination Survey (NHANES). RESULTS: Lower weight-for-height at 4 years was non-linearly associated with both FEV and FVC at school age. Invasive ventilation in the first year of life was associated with lower FEV (β -0.62, 95% CI -0.96 to -0.28) and FVC (β -0.54, 95% CI -0.92 to -0.18). In exploratory analyses, pPRISm was inversely associated with neighbourhood income (risk ratio (RR) 0.63 per SD increase, 95% CI 0.46 to 0.88), and POLD was associated with invasive ventilation (RR 8.07, 95% CI 3.33 to 19.5). Similar subtypes and associations were observed in NHANES. School-age pPRISm was associated with progressive FEV z-score decline (age x pPRISm β -0.08 SD/year, 95% CI -0.15 to -0.02), while POLD was associated with improving FVC z-score (age x POLD β 0.13 SD/year, 95% CI 0.07 to 0.20). DISCUSSION: Early-childhood growth, neonatal respiratory exposures and school-age spirometry patterns help stratify long-term pulmonary risk among preterm-born children referred for pulmonary care.
Eriksson Ström J, Pesonen I, Liv P
… +22 more, Andersson A, Bossios A, Egesten A, Ekström M, Engvall J, Good E, Hammarsten O, Holm J, Janson C, Johnsson Å, Lind L, Lindberg E, Lindén A, Malinovschi A, Moberg A, Nilsson U, Palmqvist E, Skold M, Sundh J, Tanash HA, Zaigham S, Blomberg A
Elevated troponin I (TnI) has been reported in patients with chronic obstructive pulmonary disease (COPD) without cardiovascular disease (CVD), suggesting non-ischaemic mechanisms. We assessed this association in a popul...Elevated troponin I (TnI) has been reported in patients with chronic obstructive pulmonary disease (COPD) without cardiovascular disease (CVD), suggesting non-ischaemic mechanisms. We assessed this association in a population-based cohort of 22 526 individuals without known CVD or significant coronary artery calcification. TnI showed no association with COPD (adjusted OR 0.87, 95% CI 0.60 to 1.26; highest category vs below limit of detection) or with forced expiratory volume in 1 s/forced vital capacity (adjusted difference 0.002, 95% CI -0.001 to 0.004). Median TnI was 2.2 ng/L in both obstructive and non-obstructive groups. These findings do not support a pulmonary source of TnI elevation in mild to moderate, stable COPD and suggest that TnI elevations should prompt cardiovascular evaluation rather than being attributed to pulmonary disease alone.
The Efficacy and Safety of Triple Therapy in Obstructive Lung Disease (ETHOS) and Informing the Pathway of Chronic Obstructive Pulmonary Disease (COPD) Treatment (IMPACT) trials have been interpreted as showing a mortali...The Efficacy and Safety of Triple Therapy in Obstructive Lung Disease (ETHOS) and Informing the Pathway of Chronic Obstructive Pulmonary Disease (COPD) Treatment (IMPACT) trials have been interpreted as showing a mortality benefit from introducing triple therapy inhalers in patients with COPD. However, reanalysis of the trial data instead reveals an excess mortality arising from the withdrawal of maintenance inhaled corticosteroids from patients with COPD randomised to the dual therapy long-acting muscarinic antagonist-long-acting beta-agonist inhaler used as the comparator, as dictated by the trial protocols. The findings from this reanalysis are of direct relevance to guidelines and management of COPD.
BACKGROUND: Ventilator-free days (VFDs), a composite endpoint combining survival and mechanical ventilation duration, are increasingly used in acute respiratory distress syndrome (ARDS) trials to capture patient-centred...BACKGROUND: Ventilator-free days (VFDs), a composite endpoint combining survival and mechanical ventilation duration, are increasingly used in acute respiratory distress syndrome (ARDS) trials to capture patient-centred outcomes beyond mortality. However, its interpretation and analysis are challenged by methodological limitations of conventional statistical methods. This study aims to investigate the interpretability and statistical performance of the hierarchical VFDs compared with the conventional versions for ARDS-related trials. METHODS: We applied a hierarchical composite endpoint framework, incorporating mortality and ventilation duration prioritised in sequence, to reconstruct VFDs censored at 28 days. Using the win ratio method, we carried out a post hoc analysis based on data from 10 high-quality randomised controlled trials and conducted simulation studies to assess its statistical performance. RESULTS: Analysis revealed bimodal VFD distributions across trials, with peaks near zero and around 18-20 days. The win ratio method detected all the significant treatment effects that were identified by conventional analyses. Simulation studies suggested that the win ratio demonstrated greater statistical power, particularly when mortality was the primary driver of treatment effect, outperforming traditional methods. CONCLUSIONS: The hierarchical VFDs endpoint, analysed using win statistics, provides a more sensitive and interpretable approach by distinguishing the contribution of mortality and ventilation duration components to the overall treatment effect in ARDS trials compared to the conventional approach.
Gilchrist FJ, Solis-Trapala I, Aspey M
… +13 more, Baker Z, Bowler R, Brodlie M, Desai S, Harris C, Hinton E, Kulkarni H, Lea S, Ogbolosingha A, Sinha I, Stock J, Carroll W, CLASSIC PBB study group
BACKGROUND: Protracted bacterial bronchitis (PBB) is a leading cause of paediatric chronic wet cough. Identifying the causative pathogen promotes antibiotic stewardship, but bronchoalveolar lavage taken during flexible b...BACKGROUND: Protracted bacterial bronchitis (PBB) is a leading cause of paediatric chronic wet cough. Identifying the causative pathogen promotes antibiotic stewardship, but bronchoalveolar lavage taken during flexible bronchoscopy (FB-BAL) is the only validated sampling strategy. We prospectively investigated if cough swab (CS) or induced sputum (IS) was a viable alternative. METHODS: Children with PBB, referred for FB-BAL, provided a cough swab and induced sputum. Discordance in microbiological yield (failure to identify identical pathogens) between cough swab and BAL, and between induced sputum and BAL was assessed. This was performed for single-lobe (BAL1), two-lobe (BAL2) and six-lobe BAL (BAL6). RESULTS: 135 underwent FB-BAL, 134 produced a cough swab and 111 an induced sputum sample. 30 (22%) cough swab, 67 (60%) induced sputum and 101 (78%) BAL6 were pathogen positive. cough swab/BAL6 discordance was seen in 74% with a discordance OR (95% CI) for cough swabBAL6 versus cough swabBAL6 of 30.3 (9.6 to 95.8). induced sputum/BAL6 discordance was seen in 71% with a discordance OR (95% CI) for induced sputumBAL6 versus induced sputumBAL6 of 4.2 (2.4 to 7.4). The ability of each sampling strategy to identify all pathogens from cough swab, induced sputum and BAL6 was: cough swab 17%, induced sputum 38%, BAL1 40%, BAL2 53% and BAL6 78%. The false negative rates were: cough swab 67%, induced sputum 27%, BAL1 33%, BAL2 16% and BAL6 9%. CONCLUSIONS: The pathogen yield of both cough swab and induced sputum had high discordance with BAL6, meaning neither is a viable alternative to FB-BAL. However, the tolerability and relatively low false negative rate of induced sputum mean it can be part of early PBB assessment in children who do not warrant FB-BAL.