A randomized 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 (PExs) 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 second (ppFEV1) in CF PExs not responding to antibiotic therapy. METHODS: This was a randomized, double-blind, placebo-controlled trial in pwCF treated with intravenous (IV) antibiotics for a PEx. At Day 7, those who had not returned to >90% baseline ppFEV1 were randomized to adjuvant prednisone 1 mg·kg-1 twice daily (max 60 mg/day) or placebo for 7 days. The primary outcome was the difference in proportion of subjects who recovered >90% baseline ppFEV1 at Day 14 of IV antibiotic therapy. RESULTS: 173 subjects were enrolled, with 76 randomized. 50% of subjects in the prednisone group recovered baseline FEV1 on Day 14 compared to 39% of subjects in the placebo group for a difference of 11% (95% CI -11, 34%, p=0.34). The mean (sd) change in ppFEV1 from Day 7 to Day 14 was 6.8% predicted (8.8) in the prednisone group and 4.6% (6.9) 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 (HR 0.83, 95% CI 0.45, 1.53; p=0.54). CONCLUSIONS: This study failed to detect a difference in ppFEV1 recovery between adjuvant oral prednisone and placebo treatment in pwCF not responding at day 7 of IV antibiotic therapy for PExs.

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.

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.

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.

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.

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.

Lung function decline is mitigated following liver transplantation in people with cystic fibrosis: A retrospective cohort study.

There is paucity of literature on the health outcomes following liver transplantation (LT) in people with cystic fibrosis (pwCF). We aim to evaluate changes in lung function following LT in pwCF. We performed a retrospective cohort study of pwCF who underwent LT between 1987 and 2019 in the United States and Canada. Simultaneous lung-liver transplants and individuals who had lung transplant prior to LT were excluded. We analyzed pre-LT and post-LT percent predicted forced expiratory volume in 1 second, body mass index, rates of pulmonary exacerbation, and post-LT overall survival. A total of 402 LT recipients were included. The median age of transplant was 14.9 years and 69.7% of the transplants were performed in children less than 18 years old. The rate of decline in percent predicted forced expiratory volume in 1 second was attenuated after LT from -2.2% to -0.7% predicted per year with a difference of 1.5% predicted per year (95% CI, 0.8, 2.2; p < 0.001). Following LT, the rate of decline in body mass index was reduced, and there were fewer pulmonary exacerbations (0.6 pre vs. 0.4 post; rate ratio 0.7, p < 0.01). The median survival time post-transplant was 13.9 years and the overall probability of survival at 5 years was 77.6%. Those with higher lung function pre-LT had a lower risk of death post-LT, and those with genotypes other than F508 deletion had worse survival. LT in pwCF occurs most often in children and adolescents and is associated with a slower rate of decline in lung function and nutritional status, and a reduction in pulmonary exacerbations.

Building a better model: abandon kitchen sink regression.

This paper critically examines 'kitchen sink regression', a practice characterised by the manual or automated selection of variables for a multivariable regression model based on p values or model-based information criteria. We highlight the pitfalls of this method, using examples from perinatal/neonatal medicine, and propose more robust alternatives. The concept of directed acyclic graphs (DAGs) is introduced as a tool for describing and analysing causal relationships. We highlight five key issues with 'kitchen sink regression': (1) the disregard for the directionality of variable relationships, (2) the lack of a meaningful causal interpretation of effect estimates from these models, (3) the inflated alpha error rate due to multiple testing, (4) the risk of overfitting and model instability and (5) the disregard for content expertise in model building. We advocate for the use of DAGs to guide variable selection for models that aim to examine associations between a putative risk factor and an outcome and emphasise the need for a more thoughtful and informed use of regression models in medical research.

Measuring the burden of cystic fibrosis: A scoping review.

BACKGROUND: Cystic fibrosis (CF) contributes a significant economic burden on individuals, healthcare systems, and society. Understanding the economic impact of CF is crucial for planning resource allocation. METHODS: We conducted a scoping review of literature published between 1990 and 2022 that reported the cost of illness, and/or economic burden of CF. Costs were adjusted for inflation and reported as United States dollars. RESULTS: A total of 39 studies were included. Direct healthcare costs (e.g., medications, inpatient and outpatient care) were the most frequently reported. Most studies estimated the cost of CF using a prevalence-based (n = 18, 46.2 %), bottom-up approach (n = 23, 59 %). Direct non-healthcare costs and indirect costs were seldom included. The most frequently reported direct cost components were medications (n = 34, 87.2 %), inpatient care (n = 33, 84.6 %), and outpatient care (n = 31, 79.5 %). Twenty-eight percent (n = 11) of studies reported the burden of CF from all three perspectives (healthcare system (payer), individual, and society). Indirect costs of CF were reported in approximately 20 % of studies (n = 8). The reported total cost of CF varied widely, ranging from $451 to $160,000 per person per year (2022 US$). The total cost depended on the number of domains and perspectives included in each study. CONCLUSIONS: Most studies only reported costs to the healthcare system (i.e., hospitalizations and healthcare encounters) which likely underestimates the total costs of CF. The wide range of costs reported highlights the importance of standardizing perspectives, domains and costs when estimating the economic burden of CF.

Cystic fibrosis survival outcomes following second lung transplant: The north American experience.

INTRODUCTION: Re-transplant is an option for those who develop end-stage lung disease due to rejection; however, little data exist following re-transplantation in cystic fibrosis (CF). METHODS: Data from the Canadian CF Registry and US CF Foundation Patient Registry supplemented with data from United Network for Organ Sharing were used. Individuals who underwent a 2nd lung transplant between 2005 and 2019 were included. The Kaplan-Meier method was used to estimate the probability of survival post-second transplant at 1, 3, and 5-years. RESULTS: Of those people who were waitlisted for a second transplant (N = 818), a total of 254 (31%) died waiting, 395 (48%) were transplanted and 169 (21%) people were alive on the waitlist. Median survival time after 2nd lung transplant was 3.3 years (95% CI: 2.8-4.1). The 1-, 3- and 5-year survival rates were 77.4% (95% CI: 73.1-82%), 52% (95% CI: 46.7-58%) and 39.4% (95% CI: 34.1-45.6%). CONCLUSIONS: Survival following second lung transplant in CF patients is lower than estimates following the first transplant. Over half of subjects who are potentially eligible for a second transplant die without receiving a second organ. This warrants further investigation.

Real-world effectiveness of airway clearance techniques in children with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is commonly characterised by thick respiratory mucus. From diagnosis, people with CF are prescribed daily physiotherapy, including airway clearance techniques (ACTs). ACTs consume a large proportion of treatment time, yet the efficacy and effectiveness of ACTs are poorly understood. This study aimed to evaluate associations between the quality and quantity of ACTs and lung function in children and young people with CF. METHODS: Project Fizzyo, a longitudinal observational cohort study in the UK, used remote monitoring with electronic pressure sensors attached to four different commercial ACT devices to record real-time, breath-by-breath pressure data during usual ACTs undertaken at home over 16 months in 145 children. ACTs were categorised either as conformant or not with current ACT recommendations based on breath pressure and length measurements, or as missed treatments if not recorded. Daily, weekly and monthly associations between ACT category and lung function were investigated using linear mixed effects regression models adjusting for clinical confounders. RESULTS: After exclusions, 45 224 ACT treatments (135 individuals) and 21 069 days without treatments (141 individuals) were analysed. The mean±sd age of participants was 10.2±2.9 years. Conformant ACTs (21%) had significantly higher forced expiratory volume in 1 s (FEV1) (mean effect size 0.23 (95% CI 0.19-0.27) FEV1 % pred per treatment) than non-conformant (79%) or missed treatments. There was no benefit from non-conformant or missed treatments and no significant difference in FEV1 between them (mean effect size 0.02 (95% CI -0.01-0.05) FEV1 % pred per treatment). CONCLUSIONS: ACTs are beneficial when performed as recommended, but most people use techniques that do not improve lung function. Work is needed to monitor and improve ACT quality and to increase the proportion of people doing effective airway clearance at home.

Global, Race-Neutral Reference Equations and Pulmonary Function Test Interpretation.

Importance: Race and ethnicity are routinely used to inform pulmonary function test (PFT) interpretation. However, there is no biological justification for such use, and it may reinforce health disparities. Objective: To compare the PFT interpretations produced with race-neutral and race-specific equations. Design, Setting, and Participants: In this cross-sectional study, race-neutral reference equations recently developed by the Global Lung Function Initiative (GLI) were used to interpret PFTs performed at an academic medical center between January 2010 and December 2020. The interpretations produced with these race-neutral reference equations were compared with those produced using the race and ethnicity-specific reference equations produced by GLI in 2012. The analysis was conducted from April to October 2022. Main Outcomes and Measures: The primary outcomes were differences in the percentage of obstructive, restrictive, mixed, and nonspecific lung function impairments identified using the 2 sets of reference equations. Secondary outcomes were differences in severity of these impairments. Results: PFTs were interpreted from 2722 Black (686 men [25.4%]; mean [SD] age, 51.8 [13.9] years) and 5709 White (2654 men [46.5%]; mean [SD] age, 56.4 [14.3] years) individuals. Among Black individuals, replacing the race-specific reference equations with the race-neutral reference equations was associated with an increase in the prevalence of restriction from 26.8% (95% CI, 25.2%-28.5%) to 37.5% (95% CI, 35.7%-39.3%) and of a nonspecific pattern of impairment from 3.2% (95% CI, 2.5%- 3.8%) to 6.5% (95% CI, 5.6%-7.4%) and no significant change in the prevalence of obstruction (19.9% [95% CI, 18.4%-21.4%] vs 19.5% [95% CI, 18.0%-21.0%]). Among White individuals, replacing the race-specific reference equations with the race-neutral reference equations was associated with a decrease in the prevalence of restriction from 22.6% (95% CI, 21.5%-23.6%) to 18.0% (95% CI, 17.0%-19.0%), a decrease in the prevalence of a nonspecific pattern of impairment from 8.7% (95% CI, 7.9%-9.4%) to 4.0% (95% CI, 3.5%-4.5%), and no significant change in the percentage with obstruction from 23.9% (95% CI, 22.8%-25.1%) to 25.1% (95% CI, 23.9%- 26.2%). The race-neutral reference equations were associated with an increase in severity in 22.8% (95% CI, 21.2%-24.4%) of Black individuals and a decrease in severity in 19.3% (95% CI, 18.2%-20.3%) of White individuals vs the race-specific reference equations. Conclusions and Relevance: In this cross-sectional study, the use of race-neutral reference equations to interpret PFTs resulted in a significant increase in the number of Black individuals with respiratory impairments along with a significant increase in the severity of the identified impairments. More work is needed to quantify the effect these reference equations would have on diagnosis, referral, and treatment patterns.