Triple Therapy and Clinical Control in B+ COPD Patients: A Pragmatic, Prospective, Randomized Trial.

INTRODUCTION: Treatment with LABA/LAMA is recommended in GOLD B patients. We hypothesized that triple therapy (LABA/LAMA/ICS) will be superior to LABA/LAMA in achieving and maintaining clinical control (CC), a composite outcome that considers both impact and disease stability in a subgroup of GOLD B patients (here termed GOLD B+ patients) characterized by: (1) remaining symptomatic (CAT≥10) despite regular LABA/LAMA therapy; (2) having suffered one moderate exacerbation in the previous year; and (3) having blood eosinophil counts (BEC) ≥150cells/µL. METHODS: The ANTES B+ study is a prospective, multicenter, open label, randomized, pragmatic, controlled trial designed to test this hypothesis. It will randomize 1028 B+ patients to continue with their usual LABA/LAMA combination prescribed by their attending physician or to begin fluticasone furoate (FF) 92µg/umeclidinium (UMEC) 55µg/vilanterol (VI) 22µg in a single inhaler q.d. for 12 months. The primary efficacy outcome will be the level of CC achieved. Secondary outcomes include the clinical important deterioration index (CID), annual rate of exacerbations, and FEV1. Exploratory objectives include the interaction of BEC and smoking status, all-cause mortality and proportion of patients on LABA/LAMA arm that switch therapy arms. Safety analysis include adverse events and incidence of pneumonia. RESULTS: The first patient was recruited on February 29, 2024; results are expected in the first quarter of 2026. CONCLUSIONS: The ANTES B+ study is the first to: (1) explore the efficacy and safety of triple therapy in a population of B+ COPD patients and (2) use a composite index (CC) as the primary result of a COPD trial.

Pulmonary vascular reactivity in growth restricted fetuses using computational modelling and machine learning analysis of fetal Doppler waveforms.

The aim of this study was to investigate the pulmonary vasculature in baseline conditions and after maternal hyperoxygenation in growth restricted fetuses (FGR). A prospective cohort study of singleton pregnancies including 97 FGR and 111 normally grown fetuses was carried out. Ultrasound Doppler of the pulmonary vessels was obtained at 24-37 weeks of gestation and data were acquired before and after oxygen administration. After, Machine Learning (ML) and a computational model were used on the Doppler waveforms to classify individuals and estimate pulmonary vascular resistance (PVR). Our results showed lower mean velocity time integral (VTI) in the main pulmonary and intrapulmonary arteries in baseline conditions in FGR individuals. Delta changes of the main pulmonary artery VTI and intrapulmonary artery pulsatility index before and after hyperoxygenation were significantly greater in FGR when compared with controls. Also, ML identified two clusters: A (including 66% controls and 34% FGR) with similar Doppler traces over time and B (including 33% controls and 67% FGR) with changes after hyperoxygenation. The computational model estimated the ratio of PVR before and after maternal hyperoxygenation which was closer to 1 in cluster A (cluster A 0.98 ± 0.33 vs cluster B 0.78 ± 0.28, p = 0.0156). Doppler ultrasound allows the detection of significant changes in pulmonary vasculature in most FGR at baseline, and distinct responses to hyperoxygenation. Future studies are warranted to assess its potential applicability in the clinical management of FGR.

Clinical relevance of lung function trajectory clusters in middle-aged and older adults.

Background: The determinants and health outcomes of lung function trajectories in adults among the general population are poorly understood. We aimed to identify and characterise clusters of lung function trajectories in adults aged ≥45 years. Methods: Gaussian finite-mixture modelling was applied to baseline and annualised change of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio z-scores in participants of the Rotterdam Study, a prospective population-based cohort study, with repeated spirometry (n=3884; mean±sd age 64.7±8.9 years). Longitudinal outcomes were all-cause mortality, respiratory outcomes (symptoms, COPD (FEV1/FVC <0.7 in absence of asthma), preserved ratio impaired spirometry (PRISm; FEV1/FVC ≥0.7 and FEV1 or FVC <80%)), smoking cessation and weight changes. Independent risk factors, including genetics, were identified by multiple logistic regression. Results: We identified eight trajectory clusters, with the reference group having persistently normal spirometry (prevalence 42.8%). Three clusters showed higher mortality, adjusted for confounders: 1) the persistently low FEV1 cluster (prevalence 6.8%, hazard ratio (HR) 1.71, 95% CI 1.37-2.13); 2) rapid FEV1 decliners (prevalence 4.6%, HR 1.48, 95% CI 1.10-1.99); and 3) FVC decliners (prevalence 3.7%, HR 1.49, 95% CI 1.09-2.03). In contrast, FVC improvers (prevalence 6.7%, HR 0.61, 95% CI 0.41-0.90) and persistently high FEV1 (prevalence 29.2%, HR 0.82, 95% CI 0.69-0.98) were protective trajectory clusters. Clusters were characterised by differences in genetic predisposition (polygenic scores of FEV1 and FEV1/FVC), demographics, cigarette smoking, respiratory symptoms (chronic cough, wheezing and dyspnoea), cardiovascular factors (body mass index, hypertension and heart failure) and serum C-reactive protein levels. Frailty, weight changes and the development of respiratory symptoms, COPD and PRISm were significantly associated with trajectory clusters. Conclusions: This study reveals clinically relevant lung function trajectory clusters in older adults of the general population.

Iron accumulation drives fibrosis, senescence and the senescence-associated secretory phenotype.

Fibrogenesis is part of a normal protective response to tissue injury that can become irreversible and progressive, leading to fatal diseases. Senescent cells are a main driver of fibrotic diseases through their secretome, known as senescence-associated secretory phenotype (SASP). Here, we report that cellular senescence, and multiple types of fibrotic diseases in mice and humans are characterized by the accumulation of iron. We show that vascular and hemolytic injuries are efficient in triggering iron accumulation, which in turn can cause senescence and promote fibrosis. Notably, we find that senescent cells persistently accumulate iron, even when the surge of extracellular iron has subdued. Indeed, under normal conditions of extracellular iron, cells exposed to different types of senescence-inducing insults accumulate abundant ferritin-bound iron, mostly within lysosomes, and present high levels of labile iron, which fuels the generation of reactive oxygen species and the SASP. Finally, we demonstrate that detection of iron by magnetic resonance imaging might allow non-invasive assessment of fibrotic burden in the kidneys of mice and in patients with renal fibrosis. Our findings suggest that iron accumulation plays a central role in senescence and fibrosis, even when the initiating events may be independent of iron, and identify iron metabolism as a potential therapeutic target for senescence-associated diseases.

Blood Immunophenotypes of Idiopathic Pulmonary Fibrosis: Relationship with Disease Severity and Progression.

(1) The role of the immune response in the pathogenesis of idiopathic pulmonary fibrosis (IPF) remains controversial. We hypothesized that peripheral blood immune phenotypes will be different in IPF patients and may relate to the disease severity and progression. (2) Whole blood flow cytometry staining was performed at diagnosis in 32 IPF patients, and in 32 age- and smoking-matched healthy controls. Thirty-one IPF patients were followed up for one year and categorized as stable or progressors based on lung function, deterioration and/or death. At 18-60 months, immunophenotypes were characterized again. (3) The main results showed that: (1) compared to matched controls, at diagnosis, patients with IPF showed more neutrophils, CD8+HLA-DR+ and CD8+CD28- T cells, and fewer B lymphocytes and naïve T cells; (2) in IPF, circulating neutrophils, eosinophils and naïve T cells were associated with lung function abnormalities; (3) patients whose disease progressed during the 12 months of follow-up showed evidence of cytotoxic dysregulation, with increased CD8+CD28- T cells, decreased naïve T cells and an inverted CD4/CD8 ratio at baseline; and (4) blood cell alterations were stable over time in survivors. (4) IPF is associated with abnormalities in circulating immune cells, particularly in the cytotoxic cell domain. Patients with progressive IPF, despite antifibrotic therapy, present an over-activated and exhausted immunophenotype at diagnosis, which is maintained over time.

Lung immune signatures define two groups of end-stage IPF patients.

BACKGROUND: The role of the immune system in the pathobiology of Idiopathic Pulmonary Fibrosis (IPF) is controversial. METHODS: To investigate it, we calculated immune signatures with Gene Set Variation Analysis (GSVA) and applied them to the lung transcriptome followed by unbiased cluster analysis of GSVA immune-enrichment scores, in 109 IPF patients from the Lung Tissue Research Consortium (LTRC). Results were validated experimentally using cell-based methods (flow cytometry) in lung tissue of IPF patients from the University of Pittsburgh (n = 26). Finally, differential gene expression and hypergeometric test were used to explore non-immune differences between clusters. RESULTS: We identified two clusters (C#1 and C#2) of IPF patients of similar size in the LTRC dataset. C#1 included 58 patients (53%) with enrichment in GSVA immune signatures, particularly cytotoxic and memory T cells signatures, whereas C#2 included 51 patients (47%) with an overall lower expression of GSVA immune signatures (results were validated by flow cytometry with similar unbiased clustering generation). Differential gene expression between clusters identified differences in cilium, epithelial and secretory cell genes, all of them showing an inverse correlation with the immune response signatures. Notably, both clusters showed distinct features despite clinical similarities. CONCLUSIONS: In end-stage IPF lung tissue, we identified two clusters of patients with very different levels of immune signatures and gene expression but with similar clinical characteristics. Weather these immune clusters differentiate diverse disease trajectories remains unexplored.

Phenotyping asthma with airflow obstruction in middle-aged and older adults: a CADSET clinical research collaboration.

BACKGROUND: The prevalence and clinical profile of asthma with airflow obstruction (AO) remain uncertain. We aimed to phenotype AO in population- and clinic-based cohorts. METHODS: This cross-sectional multicohort study included adults ≥50 years from nine CADSET cohorts with spirometry data (N=69 789). AO was defined as ever diagnosed asthma with pre-BD or post-BD FEV1/FVC <0.7 in population-based and clinic-based cohorts, respectively. Clinical characteristics and comorbidities of AO were compared with asthma without airflow obstruction (asthma-only) and chronic obstructive pulmonary disease (COPD) without asthma history (COPD-only). ORs for comorbidities adjusted for age, sex, smoking status and body mass index (BMI) were meta-analysed using a random effects model. RESULTS: The prevalence of AO was 2.1% (95% CI 2.0% to 2.2%) in population-based, 21.1% (95% CI 18.6% to 23.8%) in asthma-based and 16.9% (95% CI 15.8% to 17.9%) in COPD-based cohorts. AO patients had more often clinically relevant dyspnoea (modified Medical Research Council score ≥2) than asthma-only (+14.4 and +14.7 percentage points) and COPD-only (+24.0 and +5.0 percentage points) in population-based and clinic-based cohorts, respectively. AO patients had more often elevated blood eosinophil counts (>300 cells/µL), although only significant in population-based cohorts. Compared with asthma-only, AO patients were more often men, current smokers, with a lower BMI, had less often obesity and had more often chronic bronchitis. Compared with COPD-only, AO patients were younger, less often current smokers and had less pack-years. In the general population, AO patients had a higher risk of coronary artery disease than asthma-only and COPD-only (OR=2.09 (95% CI 1.26 to 3.47) and OR=1.89 (95% CI 1.10 to 3.24), respectively) and of depression (OR=1.41 (95% CI 1.19 to 1.67)), osteoporosis (OR=2.30 (95% CI 1.43 to 3.72)) and gastro-oesophageal reflux disease (OR=1.68 (95% CI 1.06 to 2.68)) than COPD-only, independent of age, sex, smoking status and BMI. CONCLUSIONS: AO is a relatively prevalent respiratory phenotype associated with more dyspnoea and a higher risk of coronary artery disease and elevated blood eosinophil counts in the general population compared with both asthma-only and COPD-only.

Human senescent fibroblasts trigger progressive lung fibrosis in mice.

Cell senescence has recently emerged as a potentially relevant pathogenic mechanism in fibrosing interstitial lung diseases (f-ILDs), particularly in idiopathic pulmonary fibrosis. We hypothesized that senescent human fibroblasts may suffice to trigger a progressive fibrogenic reaction in the lung. To address this, senescent human lung fibroblasts, or their secretome (SASP), were instilled into the lungs of immunodeficient mice. We found that: (1) human senescent fibroblasts engraft in the lungs of immunodeficient mice and trigger progressive lung fibrosis associated to increasing levels of mouse senescent cells, whereas non-senescent fibroblasts do not trigger fibrosis; (2) the SASP of human senescent fibroblasts is pro-senescence and pro-fibrotic both in vitro when added to mouse recipient cells and in vivo when delivered into the lungs of mice, whereas the conditioned medium (CM) from non-senescent fibroblasts lacks these activities; and, (3) navitoclax, nintedanib and pirfenidone ameliorate lung fibrosis induced by senescent human fibroblasts in mice, albeit only navitoclax displayed senolytic activity. We conclude that human senescent fibroblasts, through their bioactive secretome, trigger a progressive fibrogenic reaction in the lungs of immunodeficient mice that includes the induction of paracrine senescence in the cells of the host, supporting the concept that senescent cells actively contribute to disease progression in patients with f-ILDs.

Supranormal lung function: Prevalence, associated factors and clinical manifestations across the lifespan.

BACKGROUND AND OBJECTIVE: It is now well established that there are different life-long lung function trajectories in the general population, and that some are associated with better or worse health outcomes. Yet, the prevalence, clinical characteristics and risk factors of individuals with supranormal FEV1 or FVC values (above the upper-limit of normal [ULN]) in different age-bins through the lifetime in the general population are poorly understood. METHOD: To address these questions, we investigated the prevalence of supranormal FEV1 and FVC values in the LEAD (Lung, hEart, sociAl and boDy) study, a general population cohort in Austria that includes participants from 6 to 82 years of age. RESULTS: We found that: (1) the prevalence of supranormal pre-bronchodilator FEV1 and FVC values was 3.4% and 3.1%, respectively, and that these figures remained relatively stable through different age-bins except for participants >60 years., in whom they increased (5.0% and 4.2%, respectively). Approximately 50% of supranormal individuals had both increased FEV1 and FVC values; (2) supranormal spirometric values were consistently accompanied by higher static lung volumes and lower specific airway resistance through the lifespan, indicating better overall lung function; and (3) multivariate regression analysis identified that female sex, higher muscle mass (FFMI), less diabetes and fewer respiratory symptoms were consistently associated with supranormal FEV1 and FVC values. CONCLUSION: Supranormal FEV1 and/or FVC values occur in about 3% of the general population in different age bins and are associated with better health markers.

Pathophysiology of Chronic Bronchial Infection in Bronchiectasis.

Bronchiectasis is a complex and heterogeneous disease. Its pathophysiology is poorly understood, but chronic bronchial infection plays an important role in its natural history, and is associated with poor quality of life, more exacerbations and increased mortality. Pseudomonas aeruginosa, Haemophilus influenzae and Staphylococcus aureus are the most common bacteria related to chronic bronchial infection. Non-tuberculous mycobacteria, fungi and respiratory viruses are also present during clinical stability, and may increase the risk of acute exacerbation. Chronic inflammation is present in bronchiectasis, especially neutrophilic inflammation. However, macrophages and eosinophils also play a key role in the disease. Finally, airway epithelium has innate mechanisms such as mucociliary clearance and antibacterial molecules like mucins and antimicrobial peptides that protect the airways from pathogens. This review addresses how the persistence of microorganisms in the airways and the imbalance of the immune system contribute to the development of chronic bronchial infection in bronchiectasis.

Treatable traits in the NOVELTY study.

BACKGROUND AND OBJECTIVE: Asthma and chronic obstructive pulmonary disease (COPD) are two prevalent and complex diseases that require personalized management. Although a strategy based on treatable traits (TTs) has been proposed, the prevalence and relationship of TTs to the diagnostic label and disease severity established by the attending physician in a real-world setting are unknown. We assessed how the presence/absence of specific TTs relate to the diagnosis and severity of 'asthma', 'COPD' or 'asthma + COPD'. METHODS: The authors selected 30 frequently occurring TTs from the NOVELTY study cohort (NOVEL observational longiTudinal studY; NCT02760329), a large (n = 11,226), global study that systematically collects data in a real-world setting, both in primary care clinics and specialized centres, for patients with 'asthma' (n = 5932, 52.8%), 'COPD' (n = 3898, 34.7%) or both ('asthma + COPD'; n = 1396, 12.4%). RESULTS: The results indicate that (1) the prevalence of the 30 TTs evaluated varied widely, with a mean ± SD of 4.6 ± 2.6, 5.4 ± 2.6 and 6.4 ± 2.8 TTs/patient in those with 'asthma', 'COPD' and 'asthma + COPD', respectively (p < 0.0001); (2) there were no large global geographical variations, but the prevalence of TTs was different in primary versus specialized clinics; (3) several TTs were specific to the diagnosis and severity of disease, but many were not; and (4) both the presence and absence of TTs formed a pattern that is recognized by clinicians to establish a diagnosis and grade its severity. CONCLUSION: These results provide the largest and most granular characterization of TTs in patients with airway diseases in a real-world setting to date.

Chronic Bronchial Infection Is Associated with More Rapid Lung Function Decline in Chronic Obstructive Pulmonary Disease.

Rationale: Some patients with chronic obstructive pulmonary disease (COPD) suffer accelerated lung function (forced expiratory volume in 1 second [FEV1]) decline over time. Objectives: To investigate the relationship between chronic bronchial infection (CBI) and, in particular, the isolation of Pseudomonas aeruginosa (PA), and FEV1 decline in COPD. Methods: Post-hoc analysis of a prospective cohort of 201 patients with COPD followed up every 3-6 months for 84 months. CBI was defined as ⩾3 sputum positive cultures of the same pathogenic micro-organism (PPM) over 1 year. Patients were stratified according to the presence of CBI by any PPM, as well by a single or multiple isolation of PA during follow-up. An adjusted mixed-effects linear regression model was used to investigate the independent effects of CBI and PA isolation on FEV1 decline over time. Results: During follow-up, PPMs were never isolated in 43.3% of patients, in 23.9% of them PPMs were isolated once, and CBI by any PPM was confirmed in 32.8% of participants. FEV1 decline in the entire cohort was 33.7 (95% confidence interval [CI], 21.4-46.1) ml/year. This was significantly increased in patients with CBI by any PPM (57.1 [95% CI, 28.5-79.3] ml/year) and in those in whom PA was isolated at least once (48.5 [95% CI, 27.3-88.2] ml/year). Multivariable analysis showed that the presence of both CBI by any PPM, and at least one PA isolation, were independent factors associated with faster FEV1 decline adjusted by baseline FEV1, presence of bronchiectasis, body mass index, age, exacerbations, smoking status, symptoms, baseline treatment, and comorbidities. Conclusions: The presence of CBI by any PPM, and one or more PA isolation, were independently associated with FEV1 decline in patients with COPD.

Pathogenesis of chronic obstructive pulmonary disease: understanding the contributions of gene-environment interactions across the lifespan.

The traditional view of chronic obstructive pulmonary disease (COPD) as a self-inflicted disease caused by tobacco smoking in genetically susceptible individuals has been challenged by recent research findings. COPD can instead be understood as the potential end result of the accumulation of gene-environment interactions encountered by an individual over the life course. Integration of a time axis in pathogenic models of COPD is necessary because the biological responses to and clinical consequences of different exposures might vary according to both the age of an individual at which a given gene-environment interaction occurs and the cumulative history of previous gene-environment interactions. Future research should aim to understand the effects of dynamic interactions between genes (G) and the environment (E) by integrating information from basic omics (eg, genomics, epigenomics, proteomics) and clinical omics (eg, phenomics, physiomics, radiomics) with exposures (the exposome) over time (T)-an approach that we refer to as GETomics. In the context of this approach, we argue that COPD should be viewed not as a single disease, but as a clinical syndrome characterised by a recognisable pattern of chronic symptoms and structural or functional impairments due to gene-environment interactions across the lifespan that influence normal lung development and ageing.

Beyond the COPD-tobacco binomium: New opportunities for the prevention and early treatment of the disease. / Más alla del binomio EPOC-tabaco: nuevas oportunidades para la prevención y tratamiento precoz de la enfermedad.

Chronic obstructive pulmonary disease (COPD) has been traditionally understood as a self-inflicted disease cause by tobacco smoking occurring in individuals older than 50-60 years. This traditional paradigm has changed over the last decade because new scientific evidence showed that there are many genetic (G) and environmental (E) factors associated with reduced lung function, that vary, accumulate, and interact over time (T), even before birth (G×E×T). This new perspective opens novel windows of opportunity for the prevention, early diagnosis, and personalized treatment of COPD. This review presents the evidence that supports this proposal, as well as its practical implications, with particular emphasis on the need that clinical histories in patients with suspected COPD should investigate early life events and that spirometry should be used much more widely as a global health marker.

Elevated plasma levels of epithelial and endothelial cell markers in COVID-19 survivors with reduced lung diffusing capacity six months after hospital discharge.

BACKGROUND: Some COVID-19 survivors present lung function abnormalities during follow-up, particularly reduced carbon monoxide lung diffusing capacity (DLCO). To investigate risk factors and underlying pathophysiology, we compared the clinical characteristics and levels of circulating pulmonary epithelial and endothelial markers in COVID-19 survivors with normal or reduced DLCO 6 months after discharge. METHODS: Prospective, observational study. Clinical characteristics during hospitalization, and spirometry, DLCO and plasma levels of epithelial (surfactant protein (SP) A (SP-A), SP-D, Club cell secretory protein-16 (CC16) and secretory leukocyte protease inhibitor (SLPI)), and endothelial (soluble intercellular adhesion molecule 1 (sICAM-1), soluble E-selectin and Angiopoietin-2) 6 months after hospital discharge were determined in 215 COVID-19 survivors. RESULTS: DLCO was < 80% ref. in 125 (58%) of patients, who were older, more frequently smokers, had hypertension, suffered more severe COVID-19 during hospitalization and refer persistent dyspnoea 6 months after discharge. Multivariate regression analysis showed that age ≥ 60 years and severity score of the acute episode ≥ 6 were independent risk factors of reduced DLCO 6 months after discharge. Levels of epithelial (SP-A, SP-D and SLPI) and endothelial (sICAM-1 and angiopoietin-2) markers were higher in patients with reduced DLCO, particularly in those with DLCO ≤ 50% ref. Circulating SP-A levels were associated with the occurrence of acute respiratory distress syndrome (ARDS), organizing pneumonia and pulmonary embolisms during hospitalization. CONCLUSIONS: Reduced DLCO is common in COVID-19 survivors 6 months after hospital discharge, especially in those older than 60 years with very severe acute disease. In these individuals, elevated levels of epithelial and endothelial markers suggest persistent lung damage.