Pulmonary vascular structure and function are related to exercise capacity in health and COPD.

BACKGROUND: Although it is generally accepted that aerobic exercise training does not change lung structure or function, some work suggests that greater pulmonary vascular structure and function is associated with higher exercise capacity (VO2peak). RESEARCH QUESTION: Is there a cross-sectional association between the pulmonary vasculature and VO2peak? We hypothesized that those with higher computed tomography (CT) blood vessel volumes, and pulmonary diffusing capacity for carbon monoxide (DLCO) would have higher VO2peak, independent of airflow limitation. STUDY DESIGN AND METHODS: Participants from the CanCOLD study were categorized as: never-smokers with normal spirometry (n=263); ever-smokers with normal spirometry (n=407); and chronic obstructive pulmonary disease (COPD): individuals with spirometric airflow obstruction (n=334). Total vessel volume (TVV), the volume for all vessels with a cross-sectional area ≤5 mm2 (BV5), and between 5-10 mm2 (BV5-10) were generated from CT scans and used as indices of pulmonary vascular structure. DLCO was used as an index of pulmonary microvascular function. VO2peak was evaluated via incremental cardiopulmonary exercise testing. RESULTS: General linear regression models revealed that even after controlling for FEV1, emphysema severity and body morphology, DLCO, TVV, BV5 and BV5-10, were independently associated with VO2peak. Interaction effects were observed between COPD and TVV, BV5, and BV5-10 indicating a weaker association between pulmonary vascular volumes and VO2peak in COPD. INTERPRETATION: Our results suggest that pulmonary vascular structure and DLCO is independently associated with VO2peak, regardless of severity of airflow limitation and emphysema, suggesting that these associations are not limited to COPD.

Disparities in outcomes by race and ethnicity in the Canadian cystic fibrosis population.

BACKGROUND: Cystic Fibrosis has historically been described as a disease that affects people of European ancestry. Consequently, much of what we know about CF is based on evidence generated from data collected in white individuals. This may lead to systematic bias in how non-white people with CF are diagnosed and treated. In this study we compared clinical outcomes between the white and non-white people with CF in Canada. METHODS: Canadian CF Registry data collected between 2000 and 2019 were used in this population-based cohort study. Demographic characteristics and clinical outcomes of people with CF identified as white and those identified as non-white were compared. Analyses were adjusted for cohort effects but not socioeconomic status. RESULTS: Between 2000 and 2019, 5516 people with CF in the Registry were identified as white and 323 were identified as non-white. At diagnosis, the white and non-white groups were similar with respect to sex at birth, age at diagnosis, prevalence of pancreatic insufficiency, and meconium ileus. The non-white group had similar rates of CF-related complications and bacterial infections compared to the white, but worse lung function, worse nutritional status, lower treatment rates, and higher rate of hospitalizations. During the 20-year study period, the non-white group had a 1.85 higher risk of death compared to the white group (HR 95 %CI 1.39; 2.47). INTERPRETATION: There is an urgent need understand why outcomes for Canadians with CF differ between white and non-white individuals, including the role of socioeconomic circumstances.

Same-Day Repeatability and 28-Day Reproducibility of Xenon MRI Ventilation in Children With Cystic Fibrosis in a Multi-Site Trial.

BACKGROUND: MRI with xenon-129 gas (Xe MRI) can assess airflow obstruction and heterogeneity in lung diseases. Specifically, Xe MRI may represent a sensitive modality for future therapeutic trials of cystic fibrosis (CF) therapies. The reproducibility of Xe MRI has not yet been assessed in the context of a multi-site study. PURPOSE: To determine the same-day repeatability and 28-day reproducibility of Xe MRI in children with CF. STUDY TYPE: Four-center prospective, longitudinal. POPULATION: Thirty-eight children (18 females, 47%), median interquartile range (IQR) age 12 (9-14) years old, with mild CF (forced expiratory volume in 1 second (FEV1) ≥85% predicted). FIELD STRENGTH/SEQUENCE: 3-T, two-dimensional (2D) gradient-echo (GRE) sequence. ASSESSMENT: Xe MRI, FEV1, and nitrogen multiple-breath wash-out for lung-clearance index (LCI2.5) were performed. To assess same-day reproducibility, Xe MRI was performed twice within the first visit, and procedures were repeated at 28 days. Xe hypoventilation was quantified using ventilation-defect percentage (VDP) and reader-defect volume (RDV). For VDP, hypoventilated voxels from segmented images were identified using a threshold of <60% mean whole-lung signal and expressed as a percentage of the lung volume. For RDV, hypoventilation was identified by two trained readers and expressed as a percentage. STATISTICAL TESTS: Inter-site comparisons were conducted using Kruskal-Wallis nonparametric tests with Dunn's multiple-comparisons tests. Differences for individuals were assessed using Wilcoxon matched-pairs tests. Bland-Altman tests were used to evaluate same-day repeatability, 28-day reproducibility, and inter-reader agreement. A P-value ≤0.05 was considered significant. RESULTS: Median FEV1 %-predicted was 96.8% (86%-106%), and median LCI2.5 was 6.6 (6.3-7.4). Xe MRI had high same-day reproducibility (mean VDP difference 0.12%, 95% limits of agreement [-3.2, 3.4]; mean RDV difference 0.42% [-2.5, 3.3]). At 28 days, 26/31 participants (84%) fell within the same-day 95% limits of agreement. DATA CONCLUSION: Xe MRI may offer excellent same-day and short-term reproducibility. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Longitudinal Changes in Bone Mineral Density in Adults with Cystic Fibrosis.

BACKGROUND: Improved survival in people with cystic fibrosis (pwCF) presents new complexities of care, including CF-related bone disease, a common complication in older pwCF. The trajectory of bone loss with age in this population remains unclear. The objective of this study was to estimate the average rate of change in bone mineral density (BMD) in adults with CF. METHODS: This retrospective study included adults with CF, aged 25-48 years, followed between January 2000 and December 2021. Subjects with at least one dual-energy X-ray absorptiometry (DXA) scan were included. Scans obtained post-transplantation, after the initiation of bisphosphonates or cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy were excluded. The primary outcome was BMD (g/cm2) at the lumbar spine (LS) and femoral neck (FN). A linear mixed-effects model with both random intercept and random slope terms was used to estimate the average annual change in BMD. RESULTS: A total of 1502 DXA scans in 500 adults (average age 28.4y) were included. There was a statistically significant annual decline in BMD of -0.008 gm/cm2/year (95% CI -0.009, -0.007) at the FN and -0.006 gm/cm2/year (95% CI -0.007, -0.004) at the LS. Relative to BMD at age 25, there was a -18.8% decline at the FN by age 48 years and a -11% decline at the LS. Pancreatic insufficient (PI) subjects had a faster rate of decline in BMD compared to pancreatic sufficient (PS) subjects. After adjusting for markers of disease severity, the annual rate of decline remained significant. CONCLUSIONS: Individuals with CF experience bone loss at an age when it is not anticipated, thereby entering early adulthood, where further bone loss is inevitable especially with the decrease in estrogen during menopause, with suboptimal BMD. As the CF population ages, it will become very important to consider interventions to maximize bone health.

Improved survival in people with cystic fibrosis (pwCF) presents new complexities of care, including CF-related bone disease, a common complication in older pwCF. The objective of this study was to estimate how bone mineral density (BMD) changes over time in adults with CF. The study included 500 adults with CF, aged 25-48 years, followed between January 2000 and December 2021 who underwent a scan to assess BMD. On average, BMD decreased over time both at the spine and the hip. People who have pancreatic insufficiency had a faster rate of decline in BMD than people with pancreatic sufficiency. Individuals with CF experience bone loss at an age when bone density is expected to be stable. As the CF population ages, interventions to maximize bone health should be emphasized to prevent fractures in the future.

ERS technical standard: Global Lung Function Initiative reference values for multiple breath washout indices.

BACKGROUND: Multiple breath washout is a lung function test based on tidal breathing that assesses lung volume and ventilation distribution. The aim of this analysis was to use the Global Lung Function Initiative methodology to develop all-age reference equations for the multiple breath washout indices lung clearance index (LCI) and functional residual capacity (FRC). METHODS: Multiple breath washout data from healthy individuals were collated from sites. Data were re-analysed using the latest software versions. Reference equations were derived using the lambda-mu-sigma (LMS) method using the generalised additive models of location shape and scale programme in R. The impact of equipment type, inert tracer gas, and equipment dead space volume on the derived reference ranges were investigated. RESULTS: Data from 23 sites (n=3647 test occasions) were submitted. Reference equations were derived from 1581 unique observations from participants between the ages of 2 and 81 years. Equipment type, inert tracer gas, and equipment dead space volume did not significantly affect the prediction equations for either LCI or FRC. Reference equations for LCI include age as the only predictor, whereas sex-specific reference equations for FRC included height and age. CONCLUSIONS: Global Lung Function Initiative reference equations for multiple breath washout variables provide a standard for reporting and interpretation of LCI and FRC.

Variability in forced expiratory volume in 1 s in children with symptomatically well-controlled asthma.

AIMS: Spirometry is used by many clinicians to monitor asthma in children but relatively little is understood about its variability over time. The aim of this study was to determine the variability of forced expiratory volume in 1 s (FEV1) in children with symptomatically well-controlled asthma by applying three different methods of expressing change in FEV1 over 3-month intervals. METHODS: Data from five longitudinal studies of children with asthma which measured FEV1 at 3-month intervals over 6 or 12 months were used. We analysed paired FEV1 measurements when asthma symptoms were controlled. The variability of FEV1% predicted (FEV1%), FEV1 z-score (FEV1z) and conditional z score for change (Zc) in FEV1 was expressed as limits of agreement. RESULTS: A total of 881 children had 3338 FEV1 measurements on occasions when asthma was controlled; 5184 pairs of FEV1 measurements made at 3-month intervals were available. Each unit change in FEV1 z score was equivalent to a Zc 1.45 and an absolute change in FEV1% of 11.6%. The limits of agreement for change in FEV1% were -20 and +21, absolute change in FEV1 z were -1.7 and +1.7 and Zc were -2.6 and +2.1. Regression to the mean and increased variability in younger children were present for change in FEV1% and FEV1z comparisons, but not Zc. CONCLUSION: Given the wide limits of agreement of paired FEV1 measurements in symptomatically well-controlled children, asthma treatment should primarily be guided by symptoms and not by a change in spirometry.

Development of a Canadian Guidance for Reporting Real-world Evidence for Regulatory and Health-Technology Assessment (HTA) Decision Making.

Real-world evidence (RWE) can complement and fill knowledge gaps from randomized controlled trials to assist in health-technology assessment (HTA) for regulatory decision-making. However, the generation of RWE is an intricate process with many sequential decision points, and different methods and approaches may impact the quality and reliability of evidence. Standardization and transparency in reporting these decisions is imperative to appraise RWE and incorporate it into HTA decision-making. A partnership between Canadian health system stakeholders, namely Health Canada and Canada's Drug Agency (formerly the Canadian Agency for Drugs and Technologies in Health (CADTH)), was established to develop a guidance for standardization of reporting of RWE for regulatory and HTA decision-making in Canada. In this article, we describe the methods to develop the Guidance for Reporting Real-World Evidence document and checklist for reporting RWE for regulatory and HTA decision-making in Canada. This guidance can be adapted for other jurisdictions and will have future extensions to incorporate emerging issues with RWE and HTA decision-making.

Socioeconomic burden of cystic fibrosis in Canada.

BACKGROUND: Cost of illness studies are important tools to summarise the burden of disease for individuals, the healthcare system and society. The lack of standardised methods for reporting costs for cystic fibrosis (CF) makes it difficult to quantify the total socioeconomic burden. In this study, we aimed to comprehensively report the socioeconomic burden of CF in Canada. METHODS: The total cost of CF in Canada was calculated by triangulating information from three sources (Canadian CF Registry, customised Burden of Disease survey and publicly available information). A prevalence-based, bottom-up, human capital approach was applied, and costs were categorised into four perspectives (ie, healthcare system, individual/caregiver, variable (ie, medicines) and society) and three domains (ie, direct, indirect and intangible). All costs were converted into 2021 Canadian dollars (CAD) and adjusted for inflation. The cost of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies was excluded. RESULTS: The total socioeconomic burden of CF in Canada in 2021 across the four perspectives was $C414 million. Direct costs accounted for two-thirds of the total costs, with medications comprising half of all direct costs. Out-of-pocket costs to individuals and caregivers represented 18.7% of all direct costs. Indirect costs representing absenteeism accounted for one-third of the total cost. CONCLUSION: This comprehensive cost of illness study for CF represents a community-oriented approach describing the socioeconomic burden of living with CF and serves as a benchmark for future studies.

A randomised trial of oral prednisone for cystic fibrosis pulmonary exacerbation treatment.

BACKGROUND: Elevated markers of systemic and pulmonary inflammation are associated with failure to recover lung function following pulmonary exacerbations in people with cystic fibrosis (pwCF). Our aim was to determine whether adjuvant oral prednisone treatment would improve recovery of forced expiratory volume in 1 s (FEV1) % pred in CF pulmonary exacerbations not responding to antibiotic therapy. METHODS: This was a randomised, double-blind, placebo-controlled trial in pwCF treated with intravenous antibiotics for a pulmonary exacerbation. At day 7, those who had not returned to >90% baseline FEV1 % pred were randomised to adjuvant prednisone 1 mg·kg-1 twice daily (maximum 60 mg·day-1) or placebo for 7 days. The primary outcome was the difference in proportion of subjects who recovered >90% baseline FEV1 % pred at day 14 of i.v. antibiotic therapy. RESULTS: 173 subjects were enrolled, with 76 randomised. 50% of subjects in the prednisone group recovered baseline FEV1 on day 14 compared with 39% of subjects in the placebo group (difference of 11%, 95% CI -11-34%; p=0.34). The mean±sd change in FEV1 % pred from day 7 to day 14 was 6.8±8.8% predicted in the prednisone group and 4.6±6.9% predicted in the placebo group (mean difference 2.2% predicted, 95% CI -1.5-5.9%; p=0.24). Time to subsequent exacerbation was not prolonged in prednisone-treated subjects (hazard ratio 0.83, 95% CI 0.45-1.53; p=0.54). CONCLUSIONS: This study failed to detect a difference in FEV1 % pred recovery between adjuvant oral prednisone and placebo treatment in pwCF not responding at day 7 of i.v. antibiotic therapy for pulmonary exacerbations.

Incorporating equity, diversity, and inclusion into the epidemiology and biostatistics curriculum: A workshop report and implementation strategies recommendations.

There is an obligation among those teaching epidemiology to incorporate principles of equity, diversity, and inclusion (EDI) into the curriculum. While there is a well-established literature related to teaching epidemiology, this literature rarely addresses critical aspects of EDI. To our knowledge, there is no working group or central point of discussion and learning for incorporating EDI into epidemiology teaching in Canada. To address this gap, we convened a workshop entitled "Incorporating EDI into the epidemiology and biostatistics curriculum and classroom." The workshop discussed nine strategies to incorporate EDI in the epidemiology curriculum: positionality (or reflexivity) statements; opportunities for feedback; land acknowledgements; clarifying the purpose of collecting data on race and ethnicity, sex and gender, Indigeneity; acknowledging that race/ethnicity is a social construct, not a biological variable; describing incidence and prevalence of disease; demonstrating explicit bias using directed acyclic graphs (DAGs); critical appraisal of study population diversity; and admission criteria and considerations. Key take-aways from the workshop were the need to be more intentional when determining the validity of evidence, particularly with respect to historical context and the need to recognize that there is no single solution that will address EDI.

RéSUMé: Les personnes qui enseignent l'épidémiologie ont l'obligation d'intégrer les principes d'équité, de diversité et d'inclusion (EDI) dans le programme d'études. Bien qu'il existe une littérature bien établie sur l'enseignement de l'épidémiologie, cette littérature aborde rarement les aspects critiques de l'EDI. À notre connaissance, il n'existe pas de groupe de travail ou de point central de discussion et d'apprentissage pour l'intégration de l'EDI dans l'enseignement de l'épidémiologie au Canada. Pour combler cette lacune, nous avons organisé un atelier intitulé « Incorporer l'EDI dans le programme d'enseignement de l'épidémiologie et de la biostatistique et dans la salle de classe ¼. L'atelier a examiné neuf stratégies visant à intégrer l'EDI dans le programme d'enseignement de l'épidémiologie : déclarations de positionnement (ou de réflexivité); occasions pour partager de la rétroaction; reconnaissances territoriales; clarification de l'objectif derrière la collecte de données sur la race et l'ethnicité, le sexe et le genre et l'indigénéité; reconnaissance du fait que la race/l'ethnicité est une construction sociale et non une variable biologique; description de l'incidence et de la prévalence des maladies; démonstration de parti pris explicites à l'aide de graphe orienté acyclique (DAG); évaluation critique de la diversité de l'échantillon étudié; et critères et considérations d'admission. Les principaux enseignements tirés de l'atelier sont la nécessité d'être plus intentionnel dans la détermination de la validité des données probantes, en particulier en ce qui concerne le contexte historique, et la nécessité de reconnaître qu'il n'existe pas de solution unique pour prendre en compte les principes de l'EDI.

Lung-function trajectories: relevance and implementation in clinical practice.

Lung development starts in utero and continues during childhood through to adolescence, reaching its peak in early adulthood. This growth is followed by gradual decline due to physiological lung ageing. Lung-function development can be altered by several host and environmental factors during the life course. As a result, a range of lung-function trajectories exist in the population. Below average trajectories are associated with respiratory, cardiovascular, metabolic, and mental health comorbidities, as well as with premature death. This Review presents progressive research into lung-function trajectories and assists the implementation of this knowledge in clinical practice as an innovative approach to detect poor lung health early, monitor respiratory disease progression, and promote lung health. Specifically, we propose that, similar to paediatric height and weight charts used globally to monitor children's growth, lung-function charts could be used for both children and adults to monitor lung health status across the life course. To achieve this proposal, we introduce our free online Lung Function Tracker tool. Finally, we discuss challenges and opportunities for effective implementation of the trajectory concept at population level and outline an agenda for crucial research needed to support such implementation.

The total-breath method yields higher values of DLCO and TLC than the conventional method.

BACKGROUND: The 2017 ATS/ERS technical standard for measuring the single-breath diffusing capacity (DLCO) proposed the "rapid-gas-analyzer" (RGA) or, equivalently, "total-breath" (TB) method for the determination of total lung capacity (TLC). In this study, we compared DLCO and TLC values estimated using the TB and conventional method, and how estimated TLC using these two methods compared to that determined by body plethysmography. METHOD: A total of 95 people with COPD (GOLD grades 1-4) and 23 healthy subjects were studied using the EasyOne Pro (ndd Medical Technologies, Switzerland) and Master Screen Body (Vyaire Medical, Höchberg, Germany). RESULTS: On average the TB method resulted in higher values of DLCO (mean ± SD Δ = 0.469 ± 0.267; 95%CI: 0.420; 0.517 mmol*min-1*kPa-1) and TLC (Δ = 0.495 ± 0.371; 95%CI: 0.427; 0.562 L) compared with the conventional method. In healthy subjects the ratio between TB and conventional DLCO was close to one. TLC estimated using both methods was lower than that determined by plethysmography. The difference was smaller for the TB method (Δ = 1.064 ± 0.740; 95%CI: 0.929; 1.199 L) compared with the conventional method (Δ = 1.558 ± 0.940; 95%CI: 1.387; 1.739 L). TLC from body plethysmography could be estimated as a function of TB TLC and FEV1 Z-Score with an accuracy (normalized root mean square difference) of 9.1%. CONCLUSION: The total-breath method yielded higher values of DLCO and TLC than the conventional analysis, especially in subjects with COPD. TLC from the total-breath method can also be used to estimate plethysmographic TLC with better accuracy than the conventional method. The study is registered under clinicaltrial.gov NCT04531293.

FEV1Q: a race-neutral approach to assessing lung function.

BACKGROUND: Forced expiratory volume in 1 s quotient (FEV1Q) is a simple approach to spirometry interpretation that compares measured lung function to a lower boundary. This study evaluated how well FEV1Q predicts survival compared with current interpretation methods and whether race impacts FEV1Q. METHODS: White and Black adults with complete spirometry and mortality data from the National Health and Nutrition Examination Survey (NHANES) III and the United Network for Organ Sharing (UNOS) database for lung transplant referrals were included. FEV1Q was calculated as FEV1 divided by 0.4 L for females or 0.5 L for males. Cumulative distributions of FEV1 were compared across races. Cox proportional hazards models tested mortality risk from FEV1Q adjusting for age, sex, height, smoking, income and among UNOS individuals, referral diagnosis. Harrell's C-statistics were compared between absolute FEV1, FEV1Q, FEV1/height2, FEV1 z-scores and FEV1 % predicted. Analyses were stratified by race. RESULTS: Among 7182 individuals from NHANES III and 7149 from UNOS, 1907 (27%) and 991 (14%), respectively, were Black. The lower boundary FEV1 values did not differ between Black and White individuals in either population (FEV1 first percentile difference ≤0.01 L; p>0.05). Decreasing FEV1Q was associated with increasing hazard ratio (HR) for mortality (NHANES III HR 1.33 (95% CI 1.28-1.39) and UNOS HR 1.18 (95% CI 1.12-1.23)). The associations were not confounded nor modified by race. Discriminative power was highest for FEV1Q compared with alternative FEV1 approaches in both Black and White individuals. CONCLUSIONS: FEV1Q is an intuitive and simple race-neutral approach to interpreting FEV1 that predicts survival better than current alternative methods.

Unravelling the respiratory health path across the lifespan for survivors of preterm birth.

Many survivors of preterm birth will have abnormal lung development, reduced peak lung function and, potentially, an increased rate of physiological lung function decline, each of which places them at increased risk of chronic obstructive pulmonary disease across the lifespan. Current rates of preterm birth indicate that by the year 2040, around 50 years since the introduction of surfactant therapy, more than 700 million individuals will have been born prematurely-a number that will continue to increase by about 15 million annually. In this Personal View, we describe current understanding of the impact of preterm birth on lung function through the life course, with the aim of putting this emerging health crisis on the radar for the respiratory community. We detail the potential underlying mechanisms of prematurity-associated lung disease and review current approaches to prevention and management. Furthermore, we propose a novel way of considering lung disease after preterm birth, using a multidimensional model to determine individual phenotypes of lung disease-a first step towards optimising management approaches for prematurity-associated lung disease.

ERS technical standard: Global Lung Function Initiative reference values for exhaled nitric oxide fraction (F ENO50 ).

BACKGROUND: Elevated exhaled nitric oxide fraction at a flow rate of 50 mL·s-1 (F ENO50 ) is an important indicator of T-helper 2-driven airway inflammation and may aid clinicians in the diagnosis and monitoring of asthma. This study aimed to derive Global Lung Function Initiative reference equations and the upper limit of normal for F ENO50 . METHODS: Available individual F ENO50 data were collated and harmonised using consensus-derived variables and definitions. Data collected from individuals who met the harmonised definition of "healthy" were analysed using the generalised additive models of location, scale and shape (GAMLSS) technique. RESULTS: Data were retrospectively collated from 34 782 individuals from 34 sites in 15 countries, of whom 8022 met the definition of healthy (19 sites, 11 countries). Overall, height, age and sex only explained 12% of the between-subject variability of F ENO50 (R2=0.12). F ENO device was neccessary as a predictor of F ENO50 , such that the healthy range of values and the upper limit of normal varied depending on which device was used. The range of F ENO50 values observed in healthy individuals was also very wide, and the heterogeneity was partially explained by the device used. When analysing a subset of data in which F ENO50 was measured using the same device and a stricter definition of health (n=1027), between-site heterogeneity remained. CONCLUSION: Available F ENO50 data collected from different sites using different protocols and devices were too variable to develop a single all-age reference equation. Further standardisation of F ENO devices and measurement are required before population reference values might be derived.