Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary Fibrosis.

BACKGROUND: Phosphodiesterase 4 (PDE4) inhibition is associated with antiinflammatory and antifibrotic effects that may be beneficial in patients with idiopathic pulmonary fibrosis. METHODS: In this phase 2, double-blind, placebo-controlled trial, we investigated the efficacy and safety of BI 1015550, an oral preferential inhibitor of the PDE4B subtype, in patients with idiopathic pulmonary fibrosis. Patients were randomly assigned in a 2:1 ratio to receive BI 1015550 at a dose of 18 mg twice daily or placebo. The primary end point was the change from baseline in the forced vital capacity (FVC) at 12 weeks, which we analyzed with a Bayesian approach separately according to background nonuse or use of an antifibrotic agent. RESULTS: A total of 147 patients were randomly assigned to receive BI 1015550 or placebo. Among patients without background antifibrotic use, the median change in the FVC was 5.7 ml (95% credible interval, -39.1 to 50.5) in the BI 1015550 group and -81.7 ml (95% credible interval, -133.5 to -44.8) in the placebo group (median difference, 88.4 ml; 95% credible interval, 29.5 to 154.2; probability that BI 1015550 was superior to placebo, 0.998). Among patients with background antifibrotic use, the median change in the FVC was 2.7 ml (95% credible interval, -32.8 to 38.2) in the BI 1015550 group and -59.2 ml (95% credible interval, -111.8 to -17.9) in the placebo group (median difference, 62.4 ml; 95% credible interval, 6.3 to 125.5; probability that BI 1015550 was superior to placebo, 0.986). A mixed model with repeated measures analysis provided results that were consistent with those of the Bayesian analysis. The most frequent adverse event was diarrhea. A total of 13 patients discontinued BI 1015550 treatment owing to adverse events. The percentages of patients with serious adverse events or severe adverse events were similar in the two trial groups. CONCLUSIONS: In this placebo-controlled trial, treatment with BI 1015550, either alone or with background use of an antifibrotic agent, prevented a decrease in lung function in patients with idiopathic pulmonary fibrosis. (Funded by Boehringer Ingelheim; 1305-0013 ClinicalTrials.gov number, NCT04419506.).

Sex Differences in Amyotrophic Lateral Sclerosis Survival and Progression: A Multidimensional Analysis.

OBJECTIVE: To investigate sex-related differences in amyotrophic lateral sclerosis (ALS) prognosis and their contributing factors. METHODS: Our primary cohort was the Piemonte and Aosta Register for ALS (PARALS); the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) and the Answer ALS databases were used for validation. Survival analyses were conducted accounting for age and onset site. The roles of forced vital capacity and weight decline were explored through a causal mediation analysis. Survival and disease progression rates were also evaluated after propensity score matching. RESULTS: The PARALS cohort included 1,890 individuals (44.8% women). Men showed shorter survival when stratified by onset site (spinal onset HR 1.20, 95% CI 1.00-1.44, p = 0.0439; bulbar onset HR 1.36, 95% CI 1.09-1.70, p = 0.006917), although women had a steeper functional decline (+0.10 ALSFRS-R points/month, 95% CI 0.07-0.15, p < 0.00001) regardless of onset site. Instead, men showed worse respiratory decline (-4.2 forced vital capacity%/month, 95% CI -6.3 to -2.2, p < 0.0001) and faster weight loss (-0.15 kg/month, 95% CI -0.25 to -0.05, p = 0.0030). Causal mediation analysis showed that respiratory function and weight loss were pivotal in sex-related survival differences. Analysis of patients from PRO-ACT (n = 1,394, 40.9% women) and Answer ALS (n = 849, 37.2% women) confirmed these trends. INTERPRETATION: The shorter survival in men is linked to worse respiratory function and weight loss rather than a faster disease progression. These findings emphasize the importance of considering sex-specific factors in understanding ALS pathophysiology and designing tailored therapeutic strategies. ANN NEUROL 2024;96:159-169.

Application of Global Lung Function Initiative Global Spirometry Reference Equations across a Large, Multicenter Pulmonary Function Lab Population.

Rationale: Global Lung Function Initiative (GLI) Global spirometry reference equations were recently derived to offer a "race-neutral" interpretation option. The impact of transitioning from the race-specific GLI-2012 to the GLI Global reference equations is unknown. Objectives: Describe the direction and magnitude of changes in predicted lung function measurements in a population of diverse race and ethnicity using GLI Global in place of GLI-2012 reference equations. Methods: In this multicenter cross-sectional study using a large pulmonary function laboratory database, 109,447 spirometry tests were reanalyzed using GLI Global reference equations and compared with the existing GLI-2012 standard, stratified by self-reported race and ethnicity. Measurements and Main Results: Mean FEV1 and FVC percent predicted increased in the White and Northeast Asian groups and decreased in the Black, Southeast Asian, and mixed/other race groups. The prevalence of obstruction increased by 9.7% in the White group, and prevalences of possible restriction increased by 51.1% and 37.1% in the Black and Southeast Asian groups, respectively. Using GLI Global in a population with equal representation of all five race and ethnicity groups altered the interpretation category for 10.2% of spirometry tests. Subjects who self-identified as Black were the only group with a relative increase in the frequency of abnormal spirometry test results (32.9%). Conclusions: The use of GLI Global reference equations will significantly impact spirometry interpretation. Although GLI Global offers an innovative approach to transition from race-specific reference equations, it is important to recognize the continued need to place these data within an appropriate clinical context.

Meaningful Endpoints for Idiopathic Pulmonary Fibrosis (IPF) Clinical Trials: Emphasis on 'Feels, Functions, Survives'. Report of a Collaborative Discussion in a Symposium with Direct Engagement from Representatives of Patients, Investigators, the National Institutes of Health, a Patient Advocacy Organization, and a Regulatory Agency.

Background: Idiopathic pulmonary fibrosis (IPF) carries significant mortality and unpredictable progression, with limited therapeutic options. Designing trials with patient-meaningful endpoints, enhancing the reliability and interpretability of results, and streamlining the regulatory approval process are of critical importance to advancing clinical care in IPF. Methods: A landmark in-person symposium in June 2023 assembled 43 participants from the US and internationally, including patients with IPF, investigators, and regulatory representatives, to discuss the immediate future of IPF clinical trial endpoints. Patient advocates were central to discussions, which evaluated endpoints according to regulatory standards and the FDA's 'feels, functions, survives' criteria. Results: Three themes emerged: 1) consensus on endpoints mirroring the lived experiences of patients with IPF; 2) consideration of replacing forced vital capacity (FVC) as the primary endpoint, potentially by composite endpoints that include 'feels, functions, survives' measures or FVC as components; 3) support for simplified, user-friendly patient-reported outcomes (PROs) as either components of primary composite endpoints or key secondary endpoints, supplemented by functional tests as secondary endpoints and novel biomarkers as supportive measures (FDA Guidance for Industry (Multiple Endpoints in Clinical Trials) available at: https://www.fda.gov/media/162416/download). Conclusions: This report, detailing the proceedings of this pivotal symposium, suggests a potential turning point in designing future IPF clinical trials more attuned to outcomes meaningful to patients, and documents the collective agreement across multidisciplinary stakeholders on the importance of anchoring IPF trial endpoints on real patient experiences-namely, how they feel, function, and survive. There is considerable optimism that clinical care in IPF will progress through trials focused on patient-centric insights, ultimately guiding transformative treatment strategies to enhance patients' quality of life and survival.

Prevalence, Diagnostic Utility and Associated Characteristics of Bronchodilator Responsiveness.

Rationale: The prevalence and diagnostic utility of bronchodilator responsiveness (BDR) in a real-life setting is unclear. Objective: To explore this uncertainty in patients aged ⩾12 years with physician-assigned diagnoses of asthma, asthma and chronic obstructive pulmonary disease (COPD), or COPD in NOVELTY, a prospective cohort study in primary and secondary care in 18 countries. Methods: The proportion of patients with a positive BDR test in each diagnostic category was calculated using 2005 (ΔFEV1 or ΔFVC ⩾12% and ⩾200 ml) and 2021 (ΔFEV1 or ΔFVC >10% predicted) European Respiratory Society/American Thoracic Society criteria. Measurements and Main Results: We studied 3,519 patients with a physician-assigned diagnosis of asthma, 833 with a diagnosis of asthma + COPD, and 2,436 with a diagnosis of COPD. The prevalence of BDR was 19.7% (asthma), 29.6% (asthma + COPD), and 24.7% (COPD) using 2005 criteria and 18.1%, 23.3%, and 18.0%, respectively, using 2021 criteria. Using 2021 criteria in patients diagnosed with asthma, BDR was associated with higher fractional exhaled nitric oxide; lower lung function; higher symptom burden; more frequent hospital admissions; and greater use of triple therapy, oral corticosteroids, or biologics. In patients diagnosed with COPD, BDR (2021) was associated with lower lung function and higher symptom burden. Conclusions: BDR prevalence in patients with chronic airway diseases receiving treatment ranges from 18% to 30%, being modestly lower with the 2021 than with the 2005 European Respiratory Society/American Thoracic Society criteria, and it is associated with lower lung function and greater symptom burden. These observations question the validity of BDR as a key diagnostic tool for asthma managed in clinical practice or as a standard inclusion criterion for clinical trials of asthma and instead suggest that BDR be considered a treatable trait for chronic airway disease.

Zinpentraxin Alfa for Idiopathic Pulmonary Fibrosis: The Randomized Phase III STARSCAPE Trial.

Rationale: A phase II trial reported clinical benefit over 28 weeks in patients with idiopathic pulmonary fibrosis (IPF) who received zinpentraxin alfa. Objectives: To investigate the efficacy and safety of zinpentraxin alfa in patients with IPF in a phase III trial. Methods: This 52-week phase III, double-blind, placebo-controlled, pivotal trial was conducted at 275 sites in 29 countries. Patients with IPF were randomized 1:1 to intravenous placebo or zinpentraxin alfa 10 mg/kg every 4 weeks. The primary endpoint was absolute change from baseline to Week 52 in FVC. Secondary endpoints included absolute change from baseline to Week 52 in percent predicted FVC and 6-minute walk distance. Safety was monitored via adverse events. Post hoc analysis of the phase II and phase III data explored changes in FVC and their impact on the efficacy results. Measurements and Main Results: Of 664 randomized patients, 333 were assigned to placebo and 331 to zinpentraxin alfa. Four of the 664 randomized patients were never administered study drug. The trial was terminated early after a prespecified futility analysis that demonstrated no treatment benefit of zinpentraxin alfa over placebo. In the final analysis, absolute change from baseline to Week 52 in FVC was similar between placebo and zinpentraxin alfa (-214.89 ml and -235.72 ml; P = 0.5420); there were no apparent treatment effects on secondary endpoints. Overall, 72.3% and 74.6% of patients receiving placebo and zinpentraxin alfa, respectively, experienced one or more adverse events. Post hoc analysis revealed that extreme FVC decline in two placebo-treated patients resulted in the clinical benefit of zinpentraxin alfa reported by phase II. Conclusions: Zinpentraxin alfa treatment did not benefit patients with IPF over placebo. Learnings from this program may help improve decision making around trials in IPF. Clinical trial registered with www.clinicaltrials.gov (NCT04552899).

Can We Use Lung Function Thresholds and Respiratory Symptoms to Identify Pre-Chronic Obstructive Pulmonary Disease? A Prospective, Population-based Cohort Study.

Rationale: The term "pre-chronic obstructive pulmonary disease" ("pre-COPD") refers to individuals at high risk of developing COPD who do not meet conventional spirometric criteria for airflow obstruction. New approaches to identifying these individuals are needed, particularly in younger populations. Objectives: To determine whether lung function thresholds and respiratory symptoms can be used to identify individuals at risk of developing COPD. Methods: The Tasmanian Longitudinal Health Study comprises a population-based cohort first studied in 1968 (at age 7 yr). Respiratory symptoms, pre- and post-bronchodilator (BD) spirometry, diffusing capacity, and static lung volumes were measured in a subgroup at age 45, and the incidence of COPD was assessed at age 53. For each lung function measure, z-scores were calculated using Global Lung Function Initiative references. The optimal threshold for best discrimination of COPD incidence was determined by the unweighted Youden index. Measurements and Main Results: Among 801 participants who did not have COPD at age 45, the optimal threshold for COPD incidence by age 53 was pre-BD FEV1/FVC z-score less than -1.264, corresponding to the lowest 10th percentile. Those below this threshold had a 36-fold increased risk of developing COPD over an 8-year follow-up period (risk ratio, 35.8; 95% confidence interval, 8.88 to 144), corresponding to a risk difference of 16.4% (95% confidence interval, 3.7 to 67.4). The sensitivity was 88%, and the specificity was 87%. Positive and negative likelihood ratios were 6.79 and 0.14, respectively. Respiratory symptoms, post-BD spirometry, diffusing capacity, and static lung volumes did not improve on the classification achieved by pre-BD FEV1/FVC alone. Conclusions: This is the first study, to our knowledge, to evaluate the discriminatory accuracy of spirometry, diffusing capacity, and static lung volume thresholds for COPD incidence in middle-aged adults. Our findings support the inclusion of pre-BD spirometry in the physiological definition of pre-COPD and indicate that pre-BD FEV1/FVC at the 10th percentile accurately identifies individuals at high risk of developing COPD in community-based settings.

Circulating biomarkers of airflow limitation across the life span.

BACKGROUND: Airflow limitation is a hallmark of chronic obstructive pulmonary disease, which can develop through different lung function trajectories across the life span. There is a need for longitudinal studies aimed at identifying circulating biomarkers of airflow limitation across different stages of life. OBJECTIVES: This study sought to identify a signature of serum proteins associated with airflow limitation and evaluate their relation to lung function longitudinally in adults and children. METHODS: This study used data from 3 adult cohorts (TESAOD [Tucson Epidemiological Study of Airway Obstructive Disease], SAPALDIA [Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults], LSC [Lovelace Smoker Cohort]) and 1 birth cohort (TCRS [Tucson Children's Respiratory Study]) (N = 1940). In TESAOD, among 46 circulating proteins, we identified those associated with FEV1/forced vital capacity (FVC) percent (%) predicted levels and generated a score based on the sum of their z-scores. Cross-sectional analyses were used to test the score for association with concomitant lung function. Longitudinal analyses were used to test the score for association with subsequent lung function growth in childhood and decline in adult life. RESULTS: After false discovery rate adjustment, serum levels of 5 proteins (HP, carcinoembryonic antigen, ICAM1, CRP, TIMP1) were associated with percent predicted levels of FEV1/FVC and FEV1 in TESAOD. In cross-sectional multivariate analyses the 5-biomarker score was associated with FEV1 % predicted in all adult cohorts (meta-analyzed FEV1 decrease for 1-SD score increase: -2.9%; 95% CI: -3.9%, -1.9%; P = 2.4 × 10-16). In multivariate longitudinal analyses, the biomarker score at 6 years of age was inversely associated with FEV1 and FEV1/FVC levels attained by young adult life (P = .02 and .005, respectively). In adults, persistently high levels of the biomarker score were associated with subsequent accelerated decline of FEV1 and FEV1/FVC (P = .01 and .001). CONCLUSIONS: A signature of 5 circulating biomarkers of airflow limitation was associated with both impaired lung function growth in childhood and accelerated lung function decline in adult life, indicating that these proteins may be involved in multiple lung function trajectories leading to chronic obstructive pulmonary disease.

Lung Function Trajectories in Mild COVID-19 With 2-year Follow-up.

BACKGROUND: The long-term pulmonary sequelae of mild coronavirus disease 2019 (COVID-19) remains unknown. In this study, we aimed to characterize lung function trajectories in individuals with mild COVID-19 from preinfection to 2 years postinfection. METHODS: We reinvited participants 2 years after infection from our matched cohort study of the Copenhagen General Population who had initially been examined 5.4 months after infection. We repeated lung tests and questionnaires. Linear mixed models were used to estimate dynamics in lung volumes in individuals with COVID-19 patients versus uninfected controls over two intervals: from pre-infection to 6 months postinfection and 6 months postinfection to 2 years postinfection. RESULTS: 52 individuals (48.6%) attended the 2-year examination at median 1.9 years (interquartile range, 1.8-2.4) after COVID-19, all with mild infection. Individuals with COVID-19 had an adjusted excess decline in forced expiratory volume in 1 second (FEV1) of 13.0 mL per year (95% confidence interval [CI], -23.5 to -2.5; P = .02) from before infection to 6 months after infection compared to uninfected controls. From 6 to 24 months after infection, they had an excess decline of 7.5 mL per year (95% CI, -25.6-9.6; P = .40). A similar pattern was observed for forced vital capacity (FVC). Participants had a mean increase in diffusing capacity for carbon monoxide (DLco) of 3.33 (SD 7.97) between the 6- and 24-month examination. CONCLUSIONS: Our results indicate that mild COVID-19 infection affects lung function at the time of infection with limited recovery 2 years after infection.

Proteomic Evolution from Acute to Post-COVID-19 Conditions.

Many COVID-19 survivors have post-COVID-19 conditions, and females are at a higher risk. We sought to determine (1) how protein levels change from acute to post-COVID-19 conditions, (2) whether females have a plasma protein signature different from that of males, and (3) which biological pathways are associated with COVID-19 when compared to restrictive lung disease. We measured protein levels in 74 patients on the day of admission and at 3 and 6 months after diagnosis. We determined protein concentrations by multiple reaction monitoring (MRM) using a panel of 269 heavy-labeled peptides. The predicted forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) were measured by routine pulmonary function testing. Proteins associated with six key lipid-related pathways increased from admission to 3 and 6 months; conversely, proteins related to innate immune responses and vasoconstriction-related proteins decreased. Multiple biological functions were regulated differentially between females and males. Concentrations of eight proteins were associated with FVC, %, and they together had c-statistics of 0.751 (CI:0.732-0.779); similarly, concentrations of five proteins had c-statistics of 0.707 (CI:0.676-0.737) for DLCO, %. Lipid biology may drive evolution from acute to post-COVID-19 conditions, while activation of innate immunity and vascular regulation pathways decreased over that period. (ProteomeXchange identifiers: PXD041762, PXD029437).

Body composition and respiratory outcomes in children: a population-based prospective cohort study.

BACKGROUND: Body composition might influence lung function and asthma in children, but its longitudinal relations are unclear. We aimed to identify critical periods for body composition changes during childhood and adolescence in relation to respiratory outcomes in adolescents. METHODS: In a population-based prospective cohort study, we measured body mass index, fat mass index (FMI), lean mass index (LMI) and the ratio of android fat mass divided by gynoid fat mass (A/G ratio) by dual-energy X-ray absorptiometry at 6, 10 and 13 years. At 13 years, lung function was measured by spirometry, and current asthma was assessed by questionnaire. RESULTS: Most prominently and consistently, higher FMI and A/G ratio at age 13 years were associated with lower forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and forced expiratory flow after exhaling 75% of FVC (FEF75) (range Z-score difference -0.13 (95% CI -0.16 to -0.10) to -0.08 (95% CI -0.11 to -0.05) per SD score increase), and higher LMI at all ages was associated with higher FEF75 (range Z-score difference 0.05 (95% CI 0.01 to 0.08) to 0.09 (95% CI 0.06 to 0.13)). Between the ages of 6 and 13 years, normal to high FMI and A/G ratio were associated with lower FEV1/FVC and FEF75 (range Z-score difference -0.20 (95% CI -0.30 to -0.10) to -0.17 (95% CI -0.28 to -0.06)) and high to high LMI with higher FEF75 (range Z-score difference0.32 (95% CI 0.23 to 0.41)). Body composition changes were not associated with asthma. CONCLUSION: Adolescents with higher total and abdominal fat indices may have impaired lung function, while those with a higher lean mass during childhood and adolescence may have better small airway function. Public health measures should focus on a healthy body composition in adolescents to minimise respiratory morbidity.

Spirometric patterns in young and middle-aged adults: a 20-year European study.

BACKGROUND: Understanding the natural history of abnormal spirometric patterns at different stages of life is critical to identify and optimise preventive strategies. We aimed to describe characteristics and risk factors of restrictive and obstructive spirometric patterns occurring before 40 years (young onset) and between 40 and 61 years (mid-adult onset). METHODS: We used data from the population-based cohort of the European Community Respiratory Health Survey (ECRHS). Prebronchodilator forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were assessed longitudinally at baseline (ECRHS1, 1993-1994) and again 20 years later (ECRHS3, 2010-2013). Spirometry patterns were defined as: restrictive if FEV1/FVC≥LLN and FVC<10th percentile, obstructive if FEV1/FVC

Distinct trajectories of lung function from childhood to mid-adulthood.

RATIONALE: Life course trajectories of lung function development and decline influence the risk for lung disease but are poorly documented. OBJECTIVE: To document lung function trajectories from childhood to mid-adult life. METHODS: We modelled forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC at ages 9, 11, 13, 15, 18, 21, 26, 32, 38 and 45 years from a population-based cohort using latent profile analysis to identify distinct subgroups of participants with similar lung function trajectories. Regression analyses were used to assess associations between the trajectories, early life factors and postbronchodilator airflow obstruction at age 45. RESULTS: Among 865 participants with ≥6 measures of lung function, we identified 10 distinct FEV1 trajectories. Most were approximately parallel except for a childhood airway hyper-responsiveness-related persistently low trajectory (3% of study population); two accelerated-decline trajectories, one of which (8%) was associated with smoking and higher adult body mass index (BMI) and a catch-up trajectory (8%). Findings for FEV1/FVC trajectories were similar. Nine trajectories were identified for FVC: most were also approximately parallel except for a higher BMI-related accelerated-decline trajectory. The three FEV1 trajectories leading to the lowest FEV1 values comprised 19% of the cohort but contributed 55% of airflow obstruction at age 45. CONCLUSIONS: Lung function trajectories to mid-adult life are largely established before adolescence, with a few exceptions: a childhood airway hyper-responsiveness-related persistently low trajectory, which starts low and gets worse with age, and accelerated adult decline trajectories associated with smoking and obesity. Adverse trajectories are associated with a high risk of airflow obstruction in mid-adult life.

Physical activity and body mass related to catch-up lung function growth in childhood: a population-based accelerated cohort study.

OBJECTIVE: The existence of catch-up lung function growth and its predictors is uncertain. We aimed to identify lung function trajectories and their predictors in a population-based birth cohort. METHODS: We applied group-based trajectory modelling to z-scores of forced expiratory volume in 1 second (zFEV1) and z-scores of forced vital capacity (zFVC) from 1151 children assessed at around 4, 7, 9, 10, 11, 14 and 18 years. Multinomial logistic regression models were used to test whether potential prenatal and postnatal predictors were associated with lung function trajectories. RESULTS: We identified four lung function trajectories: a low (19% and 19% of the sample for zFEV1 and zFVC, respectively), normal (62% and 63%), and high trajectory (16% and 13%) running in parallel, and a catch-up trajectory (2% and 5%) with catch-up occurring between 4 and 10 years. Fewer child allergic diseases and higher body mass index z-score (zBMI) at 4 years were associated with the high and normal compared with the low trajectories, both for zFEV1 and zFVC. Increased children's physical activity during early childhood and higher zBMI at 4 years were associated with the catch-up compared with the low zFEV1 trajectory (relative risk ratios: 1.59 per physical activity category (1.03-2.46) and 1.47 per zBMI (0.97-2.23), respectively). No predictors were identified for zFVC catch-up growth. CONCLUSION: We found three parallel-running and one catch-up zFEV1 and zFVC trajectories, and identified physical activity and body mass at 4 years as predictors of zFEV1 but not zFVC catch-up growth.

Comprehensive analysis of environmental exposure to hazardous trace elements and lung function: a national cross-sectional study.

BACKGROUND: There is growing interest in the joint effects of hazardous trace elements (HTEs) on lung function deficits, but the data are limited. This is a critical research gap given increased global industrialisation. METHODS: A national cross-sectional study including spirometry was performed among 2112 adults across 11 provinces in China between 2020 and 2021. A total of 27 HTEs were quantified from urine samples. Generalised linear models and quantile-based g-computation were used to explore the individual and joint effects of urinary HTEs on lung function, respectively. RESULTS: Overall, there were negative associations between forced expiratory volume in 1 s (FEV1) and urinary arsenic (As) (z-score coefficient, -0.150; 95% CI, -0.262 to -0.038 per 1 ln-unit increase), barium (Ba) (-0.148, 95% CI: -0.258 to -0.039), cadmium (Cd) (-0.132, 95% CI: -0.236 to -0.028), thallium (Tl) (-0.137, 95% CI: -0.257 to -0.018), strontium (Sr) (-0.147, 95% CI: -0.273 to -0.022) and lead (Pb) (-0.121, 95% CI: -0.219 to -0.023). Similar results were observed for forced vital capacity (FVC) with urinary As, Ba and Pb and FEV1/FVC with titanium (Ti), As, Sr, Cd, Tl and Pb. We found borderline associations between the ln-quartile of joint HTEs and decreased FEV1 (-20 mL, 95% CI: -48 to +8) and FVC (-14 mL, 95% CI: -49 to+2). Ba and Ti were assigned the largest negative weights for FEV1 and FVC within the model, respectively. CONCLUSION: Our study investigating a wide range of HTEs in a highly polluted setting suggests that higher urinary HTE concentrations are associated with lower lung function, especially for emerging Ti and Ba, which need to be monitored or regulated to improve lung health.

Lung function trajectories from school age to adulthood and their relationship with markers of cardiovascular disease risk.

RATIONALE: Lung function in early adulthood is associated with subsequent adverse health outcomes. OBJECTIVES: To ascertain whether stable and reproducible lung function trajectories can be derived in different populations and investigate their association with objective measures of cardiovascular structure and function. METHODS: Using latent profile modelling, we studied three population-based birth cohorts with repeat spirometry data from childhood into early adulthood to identify trajectories of forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC). We used multinomial logistic regression models to investigate early-life predictors of the derived trajectories. We then ascertained the extent of the association between the derived FEV1/FVC trajectories and blood pressure and echocardiographic markers of increased cardiovascular risk and stroke in ~3200 participants at age 24 years in one of our cohorts. RESULTS: We identified four FEV1/FVC trajectories with strikingly similar latent profiles across cohorts (pooled N=6377): above average (49.5%); average (38.3%); below average (10.6%); and persistently low (1.7%). Male sex, wheeze, asthma diagnosis/medication and allergic sensitisation were associated with trajectories with diminished lung function in all cohorts. We found evidence of an increase in cardiovascular risk markers ascertained by echocardiography (including left ventricular mass indexed to height and carotid intima-media thickness) with decreasing FEV1/FVC (with p values for the mean crude effects per-trajectory ranging from 0.10 to p<0.001). In this analysis, we considered trajectories as a pseudo-continuous variable; we confirmed the assumption of linearity in all the regression models. CONCLUSIONS: Childhood lung function trajectories may serve as predictors in the development of not only future lung disease, but also the cardiovascular disease and multimorbidity in adulthood.

Effects of testosterone and sex hormone binding globulin on lung function in males and females: a multivariable Mendelian Randomisation study.

BACKGROUND: Observational studies suggest that total testosterone (TT) and sex hormone-binding globulin (SHBG) may have beneficial effects on lung function, but these findings might be spurious due to confounding and reverse causation. We addressed these limitations by using multivariable Mendelian randomisation (MVMR) to investigate the independent causal effects of TT and SHBG on lung function. METHODS: We first identified genetic instruments by performing genome-wide association analyses of TT and SHBG in the large UK Biobank, separately in males and females. We then assessed the independent effects of TT and SHBG on forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC using one-sample MVMR. We addressed pleiotropy, which could bias MVMR, using several methods that account for it. We performed subgroup MVMR analyses by obesity, physical activity and menopausal status, and assessed associations between TT and SHBG with lung function decline. Finally, we compared the MVMR results with those of observational analyses in the UK Biobank. FINDINGS: In the MVMR analyses, there was evidence of pleiotropy, but results were consistent when accounting for it. We found a strong beneficial effect of TT on FVC and FEV1 in both males and females, but a moderate detrimental effect of SHBG on FEV1 and FEV1/FVC in males only. Subgroup analyses suggested stronger effects of TT among obese and older males. The observational analyses, in line with previous studies, agreed with MRMV for TT, but not for SHBG. INTERPRETATION: These findings suggest that testosterone improves lung function in males and females, while SHBG has an opposite independent effect in males.

Definition of diaphragmatic sleep disordered breathing and clinical meaning in Duchenne muscular dystrophy.

BACKGROUND: Diaphragmatic sleep disordered breathing (dSDB) has been recently identified as sleep dysfunction secondary to diaphragmatic weakness in Duchenne muscular dystrophy (DMD). However, scoring criteria for the identification of dSDB are missing.This study aimed to define and validate dSDB scoring criteria and to evaluate whether dSDB severity correlates with respiratory progression in DMD. METHODS: Scoring criteria for diaphragmatic apnoea (dA) and hypopnoeas (dH) have been defined by the authors considering the pattern observed on cardiorespiratory polygraphy (CR) and the dSDB pathophysiology.10 sleep professionals (physiologists, consultants) blinded to each other were involved in a two-round Delphi survey to rate each item of the proposed dSDB criteria (Likert scale 1-5) and to recognise dSDB among other SDB. The scorers' accuracy was tested against the authors' panel.Finally, CR previously conducted in DMD in clinical setting were rescored and diaphragmatic Apnoea-Hypopnoea Index (dAHI) was derived. Pulmonary function (forced vital capacity per cent of predicted, FVC%pred), overnight oxygen saturation (SpO2) and transcutaneous carbon dioxide (tcCO2) were correlated with dAHI. RESULTS: After the second round of Delphi, raters deemed each item of dA and dH criteria as relevant as 4 or 5. The agreement with the panel in recognising dSDB was 81%, kappa 0.71, sensitivity 77% and specificity 85%.32 CRs from DMD patients were reviewed. dSDB was previously scored as obstructive. The dAHI negatively correlated with FVC%pred (r=-0.4; p<0.05). The total number of dA correlated with mean overnight tcCO2 (r 0.4; p<0.05). CONCLUSIONS: dSDB is a newly defined sleep disorder that correlates with DMD progression. A prospective study to evaluate dSDB as a respiratory measure for DMD in clinical and research settings is planned.

Clinical implications of airway obstruction with normal or low FEV1 in childhood and adolescence.

BACKGROUND: Airway obstruction is defined by spirometry as a low forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio. This impaired ratio may originate from a low FEV1 (classic) or a normal FEV1 in combination with a large FVC (dysanaptic). The clinical implications of dysanaptic obstruction during childhood and adolescence in the general population remain unclear. AIMS: To investigate the association between airway obstruction with a low or normal FEV1 in childhood and adolescence, and asthma, wheezing and bronchial hyperresponsiveness (BHR). METHODS: In the BAMSE (Barn/Child, Allergy, Milieu, Stockholm, Epidemiology; Sweden) and PIAMA (Prevention and Incidence of Asthma and Mite Allergy; the Netherlands) birth cohorts, obstruction (FEV1:FVC ratio less than the lower limit of normal, LLN) at ages 8, 12 (PIAMA only) or 16 years was classified as classic (FEV1

Impact of ambient air pollution on lung function in preterm-born school-aged children.

RATIONALE: Increased outdoor air pollution worsens lung function in children. However, these associations are less well studied in preterm-born individuals. OBJECTIVES: We assessed associations between ambient air pollutants and spirometry measures in preterm-born children. METHODS: The Respiratory Health Outcomes in Neonates study recruited preterm-born children aged 7-12 years who were born at ≤34 week's gestation. We associated four ambient air pollutants (particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5), PM10, nitrogen dioxide (NO2) and sulfur dioxide) at time of birth and spirometry assessment and averaged exposure between these two time points with spirometry measures, using linear regression analyses. Gestational age was banded into 23-28, 29-31 and 32-34 week's. Regression models estimated spirometry values against pollutant levels at birth and at the time of spirometry. MEASUREMENTS AND MAIN RESULTS: From 565 preterm-born children, 542 (96%) had satisfactory data. After adjustments for early and current life factors, significant detrimental associations were noted between PM10 at birth and per cent predicted forced vital capacity (%FVC) for the 23-28 and 29-31 week's gestation groups and between current PM2.5 and NO2 exposure and %FVC for the 23-28 week's gestation group. No associations with spirometry were noted for the averaged pollution exposure between birth and spirometry. Predictive models showed 5.9% and 7.4% differences in %FVC between the highest and lowest current pollution exposures for PM2.5 and NO2, respectively, in the 23-28 week group. CONCLUSIONS: Birth and current exposures to road-traffic-associated pollutants detrimentally affected %FVC in preterm-born school-aged children, who already have compromised lung function.