Risk of new onset diabetes mellitus in patients with asthma or COPD taking inhaled corticosteroids

SummaryBackgroundA recent case-controlled study reported an increased risk of diabetes mellitus in patients treated with inhaled corticosteroids for asthma or COPD, versus age-matched controls.ObjectiveThe purpose of the current study was to evaluate whether there was an increased risk of new onset diabetes mellitus or hyperglycaemia among patients with asthma or COPD treated with inhaled corticosteroids.MethodsA retrospective analysis evaluated all double-blind, placebo-controlled, trials in patients ≥4 years of age involving budesonide or budesonide/formoterol in asthma (26 trials; budesonide: n = 9067; placebo: n = 5926), and in COPD (8 trials; budesonide: n = 4616; non-ICS: n = 3643). A secondary dataset evaluated all double-blind, controlled trials in asthma involving the use of inhaled corticosteroids (60 trials; budesonide: n = 33,496; fluticasone: n = 2773).ResultsIn the primary asthma dataset, the occurrence of diabetes mellitus/hyperglycaemia adverse events (AEs) was 0.13% for budesonide and 0.13% for placebo (HR 0.98 [95% CI: 0.38–2.50], p = 0.96) and serious adverse events (SAEs) was 0% for budesonide and 0.05% for placebo. In the secondary dataset, the occurrence of diabetes/hyperglycaemia as AE and SAE was 0.19% and 0.03%, respectively. In the COPD dataset, the occurrence of diabetes mellitus/hyperglycaemia AEs was 1.3% for budesonide and 1.2% for non-ICS (HR 0.99 [95% CI: 0.67–1.46], p = 0.96) and SAEs was 0.1% for budesonide and 0.03% for non-ICS.Conclusion and clinical relevanceTreatment with inhaled corticosteroids in patients with asthma or COPD was not associated with increased risk of new onset diabetes mellitus or hyperglycaemia

The natural history of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in the USA, and it remains one of the few diseases that continues to increase its numbers. The development and progression of COPD can vary dramatically between individuals. A low level of lung function remains the cornerstone of COPD diagnosis and is a key predictor of prognosis. Lung function, however, is not the only factor in determining morbidity and mortality related to COPD, with factors such as body mass index, exercise capability and comorbid disease being important predictors of poor outcomes. Exacerbations of COPD are additional important indicators of both quality of life and outcomes in COPD patients. Definitions of exacerbations can vary, ranging from an increase in symptoms to COPD-related hospitalisations and death. COPD exacerbations are more common in patients with lower levels of lung function and may lead to more rapid declines in lung function. Better understanding of the natural history of COPD may lead to better definitions of specific COPD phenotypes, better interventions and improved outcomes

Exploring mechanisms of lipid nanoparticle-mucus interactions in healthy and cystic fibrosis conditions

Mucus forms the first defense line of human lungs, and as such hampers the efficient delivery of therapeutics to the underlying epithelium. This holds particularly true for genetic cargo such as CRISPR-based gene editing tools which cannot readily surmount the mucosal barrier. While lipid nanoparticles (LNPs) emerge as versatile non-viral gene delivery systems that can help overcome the delivery challenge, many knowledge gaps remain, especially for diseased states such as cystic fibrosis (CF). This study provides fundamental insights into Cas9 mRNA or ribonucleoprotein-loaded LNP-mucus interactions in healthy and diseased states by assessing the impact of the genetic cargo, mucin sialylation, mucin concentration, ionic strength, pH, and polyethylene glycol (PEG) concentration and nature on LNP diffusivity leveraging experimental approaches and Brownian dynamics (BD) simulations. Taken together, this study identifies key mucus and LNP characteristics that are critical to enabling a rational LNP design for transmucosal delivery

American thoracic society/national heart, lung, and blood institute asthma-chronic obstructive pulmonary disease overlap workshop report

Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent chronic obstructive lung diseases with an associated high burden of disease. Asthma, which is often allergic in origin, frequently begins in infancy or childhood with variable airflow obstruction and intermittent wheezing, cough, and dyspnea. Patients with COPD, in contrast, are usually current or former smokers who present after the age of 40 years with symptoms (often persistent) including dyspnea and a productive cough. On the basis of age and smoking history, it is often easy to distinguish between asthma andCOPD. However, some patients have features compatible with both diseases. Because clinical studies typically exclude these patients, their underlying disease mechanisms and appropriate treatment remain largely uncertain. To explore the status of and opportunities for research in this area, the NHLBI, in partnership with the American Thoracic Society, convened a workshop of investigators in San Francisco, California on May 14, 2016. At the workshop, current understanding of asthma-COPD overlap was discussed among clinicians, pathologists, radiologists, epidemiologists, and investigators with expertise in asthma and COPD. They considered knowledge gaps in our understanding of asthma-COPD overlap and identified strategies and research priorities that will advance its understanding. This report summarizes those discussions

Mortality prediction in chronic obstructive pulmonary disease comparing the GOLD 2015 and GOLD 2019 staging: a pooled analysis of individual patient data

In 2019, The Global Initiative for Chronic Obstructive Lung Disease (GOLD) modified the grading system for patients with COPD, creating 16 subgroups (1A-4D). As part of the COPD Cohorts Collaborative International Assessment (3CIA) initiative, we aim to compare the mortality prediction of the 2015 and 2019 COPD GOLD staging systems. We studied 17 139 COPD patients from the 3CIA study, selecting those with complete data. Patients were classified by the 2015 and 2019 GOLD ABCD systems, and we compared the predictive ability for 5-year mortality of both classifications. In total, 17139 patients with COPD were enrolled in 22 cohorts from 11 countries between 2003 and 2017; 8823 of them had complete data and were analysed. Mean +/- SD age was 63.9 +/- 9.8 years and 62.9% were male. GOLD 2019 classified the patients in milder degrees of COPD. For both classifications, group D had higher mortality. 5-year mortality did not differ between groups B and C in GOLD 2015; in GOLD 2019, mortality was greater for group B than C. Patients classified as group A and B had better sensitivity and positive predictive value with the GOLD 2019 classification than GOLD 2015. GOLD 2015 had better sensitivity for group C and D than GOLD 2019. The area under the curve values for 5-year mortality were only 0.67 (95% CI 0.66-0.68) for GOLD 2015 and 0.65 (95% CI 0.63-0.66) for GOLD 2019. The new GOLD 2019 classification does not predict mortality better than the previous GOLD 2015 system

Sex differences between women and men with COPD: A new analysis of the 3CIA study

Background: There is partial evidence that COPD is expressed differently in women than in men, namely on symptoms, pulmonary function, exacerbations, comorbidities or prognosis. There is a need to improve the characterization of COPD in females. Methods: We obtained and pooled data of 17 139 patients from 22 COPD cohorts and analysed the clinical differences by sex, establishing the relationship between these characteristics in women and the prognosis and severity of the disease. Comparisons were established with standard statistics and survival analysis, including crude and multivariate Cox-regression analysis. Results: Overall, 5355 (31.2%) women were compared with men with COPD. Women were younger, had lower pack-years, greater FEV1%, lower BMI and a greater number of exacerbations (all p < 0.05). On symptoms, women reported more dyspnea, equal cough but less expectoration (p < 0.001). There were no differences in the BODE index score in women (2.4) versus men (2.4) (p = 0.5), but the distribution of all BODE components was highly variable by sex within different thresholds of BODE. On prognosis, 5-year survival was higher in COPD females (86.9%) than in males (76.3%), p < 0.001, in all patients and within each of the specific comorbidities that we assessed. The crude and adjusted RR and 95% C.I. for death in males was 1.82 (1.69–1.96) and 1.73 (1.50–2.00), respectively. Conclusions: COPD in women has some characteristic traits expressed differently than compared to men, mainly with more dyspnea and COPD exacerbations and less phlegm, among others, although long-term survival appears better in female COPD patients

Mortality prediction in chronic obstructive pulmonary disease comparing the GOLD 2015 and GOLD 2019 staging: a pooled analysis of individual patient data

In 2019, The Global Initiative for Chronic Obstructive Lung Disease (GOLD) modified the grading system for patients with COPD, creating 16 subgroups (1A–4D). As part of the COPD Cohorts Collaborative International Assessment (3CIA) initiative, we aim to compare the mortality prediction of the 2015 and 2019 COPD GOLD staging systems. We studied 17 139 COPD patients from the 3CIA study, selecting those with complete data. Patients were classified by the 2015 and 2019 GOLD ABCD systems, and we compared the predictive ability for 5-year mortality of both classifications. In total, 17 139 patients with COPD were enrolled in 22 cohorts from 11 countries between 2003 and 2017; 8823 of them had complete data and were analysed. Mean±sd age was 63.9±9.8 years and 62.9% were male. GOLD 2019 classified the patients in milder degrees of COPD. For both classifications, group D had higher mortality. 5-year mortality did not differ between groups B and C in GOLD 2015; in GOLD 2019, mortality was greater for group B than C. Patients classified as group A and B had better sensitivity and positive predictive value with the GOLD 2019 classification than GOLD 2015. GOLD 2015 had better sensitivity for group C and D than GOLD 2019. The area under the curve values for 5-year mortality were only 0.67 (95% CI 0.66–0.68) for GOLD 2015 and 0.65 (95% CI 0.63–0.66) for GOLD 2019

Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of l

Large-scale external validation and comparison of prognostic models: an application to chronic obstructive pulmonary disease

Background: External validations and comparisons of prognostic models or scores are a prerequisite for their use in routine clinical care but are lacking in most medical fields including chronic obstructive pulmonary disease (COPD). Our aim was to externally validate and concurrently compare prognostic scores for 3-year all-cause mortality in mostly multimorbid patients with COPD. Methods: We relied on 24 cohort studies of the COPD Cohorts Collaborative International Assessment consortium, corresponding to primary, secondary, and tertiary care in Europe, the Americas, and Japan. These studies include globally 15,762 patients with COPD (1871 deaths and 42,203 person years of follow-up). We used network meta-analysis adapted to multiple score comparison (MSC), following a frequentist two-stage approach; thus, we were able to compare all scores in a single analytical framework accounting for correlations among scores within cohorts. We assessed transitivity, heterogeneity, and inconsistency and provided a performance ranking of the prognostic scores. Results: Depending on data availability, between two and nine prognostic scores could be calculated for each cohort. The BODE score (body mass index, airflow obstruction, dyspnea, and exercise capacity) had a median area under the curve (AUC) of 0.679 [1st quartile-3rd quartile = 0.655-0.733] across cohorts. The ADO score (age, dyspnea, and airflow obstruction) showed the best performance for predicting mortality (difference AUC(ADO) - AUC(BODE) = 0.015 [95% confidence interval (CI) = - 0.002 to 0.032]; p = 0.08) followed by the updated BODE (AUCBODE updated - AUCBODE = 0.008 [95% CI = -0.005 to +0.022]; p = 0.23). The assumption of transitivity was not violated. Heterogeneity across direct comparisons was small, and we did not identify any local or global inconsistency. Conclusions: Our analyses showed best discriminatory performance for the ADO and updated BODE scores in patients with COPD. A limitation to be addressed in future studies is the extension of MSC network meta-analysis to measures of calibration. MSC network meta-analysis can be applied to prognostic scores in any medical field to identify the best scores, possibly paving the way for stratified medicine, public health, and research

Variants associated withHHIP expression have sex-differential effects on lung function

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P</p