A Pilot Study on Proteomic Predictors of Mortality in Stable COPD.

Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of global mortality. Despite clinical predictors (age, severity, comorbidities, etc.) being established, proteomics offers comprehensive biological profiling to obtain deeper insights into COPD pathophysiology and survival prognoses. This pilot study aimed to identify proteomic footprints that could be potentially useful in predicting mortality in stable COPD patients. Plasma samples from 40 patients were subjected to both blind (liquid chromatography-mass spectrometry) and hypothesis-driven (multiplex immunoassays) proteomic analyses supported by artificial intelligence (AI) before a 4-year clinical follow-up. Among the 34 patients whose survival status was confirmed (mean age 69 ± 9 years, 29.5% women, FEV1 42 ± 15.3% ref.), 32% were dead in the fourth year. The analysis identified 363 proteins/peptides, with 31 showing significant differences between the survivors and non-survivors. These proteins predominantly belonged to different aspects of the immune response (12 proteins), hemostasis (9), and proinflammatory cytokines (5). The predictive modeling achieved excellent accuracy for mortality (90%) but a weaker performance for days of survival (Q2 0.18), improving mildly with AI-mediated blind selection of proteins (accuracy of 95%, Q2 of 0.52). Further stratification by protein groups highlighted the predictive value for mortality of either hemostasis or pro-inflammatory markers alone (accuracies of 95 and 89%, respectively). Therefore, stable COPD patients' proteomic footprints can effectively forecast 4-year mortality, emphasizing the role of inflammatory, immune, and cardiovascular events. Future applications may enhance the prognostic precision and guide preventive interventions.

Relationship between Respiratory Microbiome and Systemic Inflammatory Markers in COPD: A Pilot Study.

The respiratory microbiome may influence the development and progression of COPD by modulating local immune and inflammatory events. We aimed to investigate whether relative changes in respiratory bacterial abundance are also associated with systemic inflammation, and explore their relationship with the main clinical COPD phenotypes. Multiplex analysis of inflammatory markers and transcript eosinophil-related markers were analyzed on peripheral blood in a cohort of stable COPD patients (n = 72). Respiratory microbiome composition was analyzed by 16S rRNA microbial sequencing on spontaneous sputum. Spearman correlations were applied to test the relationship between the microbiome composition and systemic inflammation. The concentration of the plasma IL-8 showed an inverted correlation with the relative abundance of 17 bacterial genera in the whole COPD cohort. COPD patients categorized as eosinophilic showed positive relationships with blood eosinophil markers and inversely correlated with the degree of airway obstruction and the number of exacerbations during the previous year. COPD patients categorized as frequent exacerbators were enriched with the bacterial genera Pseudomonas which, in turn, was positively associated with the severity of airflow limitation and the prior year's exacerbation history. The associative relationships of the sputum microbiome with the severity of the disease emphasize the relevance of the interaction between the respiratory microbiota and systemic inflammation.

Exploring the Interplay between Cellular Senescence, Immunity, and Fibrosing Interstitial Lung Diseases: Challenges and Opportunities.

Fibrosing interstitial lung diseases (ILDs) are characterized by the gradual and irreversible accumulation of scar tissue in the lung parenchyma. The role of the immune response in the pathogenesis of pulmonary fibrosis remains unclear. In recent years, substantial advancements have been made in our comprehension of the pathobiology driving fibrosing ILDs, particularly concerning various age-related cellular disturbances and immune mechanisms believed to contribute to an inadequate response to stress and increased susceptibility to lung fibrosis. Emerging studies emphasize cellular senescence as a key mechanism implicated in the pathobiology of age-related diseases, including pulmonary fibrosis. Cellular senescence, marked by antagonistic pleiotropy, and the complex interplay with immunity, are pivotal in comprehending many aspects of lung fibrosis. Here, we review progress in novel concepts in cellular senescence, its association with the dysregulation of the immune response, and the evidence underlining its detrimental role in fibrosing ILDs.

Limited Use and Potential Implementation Hurdles of Telemedicine Tools for the Remote Management of Patients With Chronic Obstructive Pulmonary Disease Among Members of SEPAR.

Introduction: Telemedicine (TM) can help in the management of chronic obstructive pulmonary disease (COPD). This study examines knowledge, current use and potential limitations for practical implementation of TM for the remoted management of COPD patients among members of the COPD area of SEPAR (n = 3118). Methods: An electronic survey was circulated three times to these 3118 health-care professionals. Their knowledge, current use and potential limitations for implementation of different forms of TM, including tele-monitoring, tele-education and self-care, tele-rehabilitation and mobile health, for the remote management of COPD patients were tabulated and described. Results: Only 120 health-care professionals responded to the survey (3.9%). The rate of response varied greatly across different Autonomous Communities (AACC); 99.2% of responders declared being aware of TM, but only 60.5% knew about the different TM alternatives investigated here, and only 40.3% actually used some form of TM for their current management of patients with COPD. Of those using TM, 47.1% referred being satisfied with its use. Main identified barriers for implementation of TM in their institutions were technological limitations and data security. Conclusions: The potential of TM for the clinical management of COPD is well known among interviewed health-care professionals, but only less than half used it currently. The potential for growth is therefore clear. We propose that SEPAR analyze critically this potential and promotes measures to achieve it for the benefit of COPD patients.

Introducción: La telemedicina (TM) puede ayudar en el tratamiento de la enfermedad pulmonar obstructiva crónica (EPOC). Este estudio examina el conocimiento, el uso actual y las posibles limitaciones para la implementación práctica de la TM para el tratamiento remoto de pacientes con EPOC entre los miembros del área de EPOC de la SEPAR (n = 3.118). Métodos: Se distribuyó 3 veces una encuesta electrónica entre estos 3.118 profesionales de la salud. Se tabularon y describieron sus conocimientos, el uso actual y las limitaciones potenciales para la implementación de diferentes formas de la TM, incluida la telemonitorización, la teleeducación y el autocuidado, la telerrehabilitación y la salud móvil, para el tratamiento remoto de los pacientes con EPOC. Resultados: Solo 120 profesionales sanitarios respondieron a la encuesta (3,9%). La tasa de respuesta varió mucho entre las distintas comunidades autónomas (CC. AA.); el 99,2% de los encuestados declaró conocer la TM, pero solo el 60,5% conocía las diferentes alternativas de la TM investigadas aquí, y solo el 40,3% realmente utilizó alguna forma de TM para el manejo actual de los pacientes con EPOC. De quienes utilizan la TM, el 47,1% refirió estar satisfecho con su uso. Las principales barreras identificadas para la implementación de la TM en sus instituciones fueron las limitaciones tecnológicas y la seguridad de los datos. Conclusiones: El potencial de la TM para el tratamiento clínico de la EPOC es bien conocido entre los profesionales sanitarios entrevistados, pero solo menos de la mitad la utiliza actualmente. Por tanto, el potencial de crecimiento es claro. Proponemos que la SEPAR analice críticamente este potencial y promueva medidas para alcanzarlo en beneficio de los pacientes con EPOC.

Change is in the air: key questions on the 'Treatable Traits' model for chronic airway diseases in primary care.

Despite great advancements in the treatment of chronic airway diseases, improvements in morbidity and mortality have stalled in recent years. Asthma and chronic obstructive pulmonary disease are complex and heterogeneous diseases that require tailored management based on individual patient characteristics and needs. The Treatable Traits (TTs) approach aims to personalise and improve patient care through the identification and targeting of clinically relevant and modifiable pulmonary, extra-pulmonary and behavioural traits. In this article, we outline the rationale for TTs-based management and provide practical guidance for its application in primary care. To aid implementation, seven potential 'prime' traits are proposed: airflow obstruction, eosinophilic inflammation, adherence, inhaler technique, smoking, low body mass index/obesity and anxiety and depression-selected for their prevalence, recognisability and feasibility of use. Some of the key questions among healthcare professionals, that may be roadblocks to widespread application of a TTs model of care, are also addressed.

Systemic Inflammation Differences in Brain-vs. Circulatory-Dead Donors: Impact on Lung Transplant Recipients.

Brain death triggers a systemic inflammatory response. Whether systemic inflammation is different in lung donors after brain- (DBD) or circulatory-death (DCD) is unknown, but this may potentially increase the incidence of primary graft dysfunction (PGD) after lung transplantation. We compared the plasma levels of interleukin (IL)-6, IL-8, IL-10 and TNF-α in BDB and DCD and their respective recipients, as well as their relationship with PGD and mortality after LT. A prospective, observational, multicenter, comparative, cohort-nested study that included 40 DBD and 40 DCD lung donors matched and their respective recipients. Relevant clinical information and blood samples were collected before/during lung retrieval in donors and before/during/after (24, 48 and 72 h) LT in recipients. Incidence of PGD and short-term mortality after LT was recorded. Plasma levels of all determined cytokines were numerically higher in DBD than in DCD donors and reached statistical significance for IL-6, IL-10 and IL-8. In recipients with PGD the donor's plasma levels of TNF-α were higher. The post-operative mortality rate was very low and similar in both groups. DBD is associated with higher systemic inflammation than DCD donors, and higher TNF-α plasma levels in donors are associated with a higher incidence of PGD.

Treatable traits in pre-COPD: Time to extend the treatable traits paradigm beyond established disease.

To date, the treatable traits (TTs) approach has been applied in the context of managing diagnosed diseases. TTs are clinical characteristics and risk factors that can be identified clinically and/or biologically, and that merit treatment if present. There has been an exponential increase in the uptake of this approach by both researchers and clinicians. Realizing the potential of the TTs approach to pre-clinical disease, this expert review proposes that it is timely to consider acting on TTs present before a clinical diagnosis is made, which might help to prevent development of the full disease. Such an approach is ideal for diseases where there is a long pre-clinical phase, such as in chronic obstructive pulmonary disease (COPD). The term 'pre-COPD' has been recently proposed to identify patients with respiratory symptoms and/or structural or functional abnormalities without airflow limitation. They may eventually develop airflow limitation with time but patients with pre-COPD are likely to have traits that are already treatable. This review first outlines the contribution of recently generated knowledge into lifetime lung function trajectories and the conceptual framework of 'GETomics' to the field of pre-COPD. GETomics is a dynamic and cumulative model of interactions between genes and the environment throughout the lifetime that integrates information from multi-omics to understand aetiology and mechanisms of diseases. This review then discusses the current evidence on potential TTs in pre-COPD patients and makes recommendations for practice and future research. At a broader level, this review proposes that introducing the TTs in pre-COPD may help reenergize the preventive approaches to health and diseases.

Relationships between symptoms and lung function in asthma and/or chronic obstructive pulmonary disease in a real-life setting: the NOVEL observational longiTudinal studY.

BACKGROUND: The relationships between spirometric assessment of lung function and symptoms (including exacerbations) in patients with asthma and/or chronic obstructive pulmonary disease (COPD) in a real-life setting are uncertain. OBJECTIVES: To assess the relationships between baseline post-bronchodilator (post-BD) spirometry measures of lung function and symptoms and exacerbations in patients with a physician-assigned diagnosis of asthma and/or COPD. DESIGN: The NOVEL observational longiTudinal studY (NOVELTY) is a global, prospective, 3-year observational study. METHODS: Logistic regression analysis was used to evaluate relationships. Spirometry measures were assessed as percent predicted (%pred). Symptoms were assessed at baseline, and exacerbations were assessed at baseline and Year 1. RESULTS: A total of 11,181 patients in NOVELTY had spirometry data (asthma, n = 5903; COPD, n = 3881; asthma + COPD, n = 1397). A 10% lower post-BD %pred forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) - adjusted for age and sex - were significantly associated with dyspnea (modified Medical Research Council ⩾ grade 2), frequent breathlessness [St George's Respiratory Questionnaire (SGRQ)], frequent wheeze attacks (SGRQ), nocturnal awakening (Respiratory Symptoms Questionnaire; ⩾1 night/week), and frequent productive cough (SGRQ). Lower post-BD %pred FEV1 and, to a lesser extent, lower post-BD %pred FVC were significantly associated with ⩾1 physician-reported exacerbation at baseline or Year 1. This association was stronger in patients with COPD than in those with asthma. CONCLUSION: In a real-life setting, reduced lung function is consistently associated with symptoms in patients with asthma, COPD, or asthma + COPD. The relationship with exacerbations is stronger in COPD only than in asthma. TRAIL REGISTRATION: clinicaltrials.gov identifier: NCT02760329 (www.clinicaltrials.gov).

Relationships between symptoms and lung function in asthma and/or chronic obstructive pulmonary disease in a study performed in a real-life setting: the NOVELTY studyBackground: Asthma and chronic obstructive pulmonary disease (COPD) have many symptoms in common. To confirm diagnosis, doctors use spirometry, a test to measure the amount of air that can be breathed out from the lungs and how fast it can be blown out. The relationship between these measurements and symptoms in asthma and COPD is not well understood.Objectives: The aim of this research is to describe the characteristics, treatment, and impact of asthma and/or COPD in patients who are receiving their usual medical care.Methods: NOVELTY is a large study of around 12,000 patients across 19 countries. This analysis of NOVELTY looked at the relationships between two spirometry measurements and the symptoms of asthma and/or COPD experienced by patients. The spirometry measurements were: - forced expiratory volume in 1 second (FEV₁) ­ the amount of air that can be blown out of the lungs in 1 second- forced vital capacity (FVC) ­ the amount of air that can be forcibly breathed out from the lungs after taking the deepest breath possibleResults: The lower the FEV₁ and FVC, the more common the symptoms of breathlessness, wheeze attacks, night-time awakening, and coughing up of phlegm or mucus. These relationships were similar for FEV₁ and FVC. Lower FEV₁ was more strongly associated with worse symptoms in COPD than in asthma.Conclusion: These findings help to improve our understanding of the relationships between spirometry measures and symptoms in patients with asthma and/or COPD.

Association of Preserved Ratio Impaired Spirometry with Arterial Stiffness.

Rationale: Preserved ratio impaired spirometry (PRISm) is a recently recognized spirometric pattern defined by a ratio of forced expiratory volume in 1 second to forced vital capacity of at least 0.70 and a forced expiratory volume in 1 second <80% of reference. For unclear reasons, PRISm is associated with increased cardiovascular (CV) morbidity and mortality. Arterial stiffness is a major mechanism of CV disease, which can be measured by carotid-femoral pulse-wave velocity (cfPWV). Objectives: We explored the hypothesis that cfPWV would be increased in individuals with PRISm and airflow limitation (AL). Methods: We measured forced spirometry, lung volumes by body plethysmography, and cfPWV in 9,466 subjects recruited from the general population in the Austrian cross-sectional LEAD (Lung, Heart, Social, Body) study and tested the association of arterial stiffness with PRISm and AL by multivariable linear regression analysis. Individuals younger than 18 years were excluded from the study. Results: Individuals with PRISm (n = 431; 4.6%) were of similar age to those with normal spirometry (n = 8,136; 85.9%) and significantly younger than those with AL (n = 899; 9.5%). Arterial hypertension, diabetes mellitus, coronary artery disease, heart failure, and peripheral arterial occlusive disease were significantly more common in individuals with PRISm than in those with normal lung function and similar to those with AL. There was a significant association between PRISm and arterial stiffness on bivariate linear regression analysis (crude model, ß = 0.038; 95% confidence interval [CI], 0.016-0.058), which persisted after robust adjustment for clinical confounders upon multivariable analysis (final model, ß = 0.017; 95% CI, 0.001-0.032). cfPWV was significantly higher in individuals with PRISm irrespective of the presence of established CV disease or pulmonary restriction. AL also showed a significant association with arterial stiffness on multivariable linear regression analysis (final model, ß = 0.025; 95% CI, 0.009-0.042). Conclusions: Arterial stiffness measured by cfPWV is increased in individuals with PRISm independent of CV disease and risk factors. The pathobiological mechanisms underlying this association deserve further research.

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.

Lung Tissue Multi-Layer Network Analysis Uncovers the Molecular Heterogeneity of COPD.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous condition. We hypothesized that the unbiased integration of different COPD lung omics using a novel multi-layer approach may unravel mechanisms associated with clinical characteristics. METHODS: We profiled mRNA, miRNA and methylome in lung tissue samples from 135 former smokers with COPD. For each omic (layer) we built a patient network based on molecular similarity. The three networks were used to build a multi-layer network, and optimization of multiplex-modularity was employed to identify patient communities across the three distinct layers. Uncovered communities were related to clinical features. RESULTS: We identified five patient communities in the multi-layer network which were molecularly distinct and related to clinical characteristics, such as FEV1 and blood eosinophils. Two communities (C#3 and C#4) had both similarly low FEV1 values and emphysema, but were molecularly different: C#3, but not C#4, presented B and T cell signatures and a downregulation of secretory (SCGB1A1/SCGB3A1) and ciliated cells. A machine learning model was set up to discriminate C#3 and C#4 in our cohort, and to validate them in an independent cohort. Finally, using spatial transcriptomics we characterized the small airway differences between C#3 and C#4, identifying an upregulation of T/B cell homing chemokines, and bacterial response genes in C#3. CONCLUSIONS: A novel multi-layer network analysis is able to identify clinically relevant COPD patient communities. Patients with similarly low FEV1 and emphysema can have molecularly distinct small airways and immune response patterns, indicating that different endotypes can lead to similar clinical presentation.

COPD: systemic proteomic profiles in frequent and infrequent exacerbators.

Background: Some patients with COPD suffer frequent exacerbations (FE). We hypothesised that their systemic proteomic profile would be different from that of non-frequent exacerbators (NFE). The objective of the present study was to contrast the systemic proteomic profile in FE versus NFE. As a reference, we also determined the systemic proteomic profile of healthy controls (HC) and COPD patients during an actual episode of exacerbation (AE). Methods: In the analysis we included 40 clinically stable COPD patients (20 FE and 20 NFE), and 20 HC and 10 AE patients. Their plasma samples were analysed by combining two complementary proteomic approaches: label-free liquid chromatography-tandem mass spectrometry and multiplex immunoassays. Gene Ontology annotation, pathway enrichment and network analyses were used to investigate molecular pathways associated with differentially abundant proteins/peptides (DAPs). Results: Compared with HC, we identified 40 DAPs in FE, 10 in NFE and 63 in AE. Also compared to HC, pathway functional and protein-protein network analyses revealed dysregulation of inflammatory responses involving innate and antibody-mediated immunity in COPD, particularly in the FE group, as well as during an AE episode. Besides, we only identified alterations in the complement and coagulation cascades in AE. Conclusion: There are specific plasma proteome profiles associated with FE, which are partially shared with findings observed during AE, albeit others are uniquely present during the actual episode of AE.

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.

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.

Epigenome-Wide Association Studies of Chronic Obstructive Pulmonary Disease and Lung Function: A Systematic Review.

Rationale: Chronic obstructive pulmonary disease (COPD) results from gene-environment interactions over the lifetime. These interactions are captured by epigenetic changes, such as DNA methylation. Objectives: To systematically review the evidence form epigenome-wide association studies related to COPD and lung function. Methods: A systematic literature search performed on PubMed, Embase, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases identified 1,947 articles that investigated epigenetic changes associated with COPD and/or lung function; 17 of them met our eligibility criteria, from which data were manually extracted. Differentially methylated positions (DMPs) and/or annotated genes were considered replicated if identified by two or more studies with a P < 1 × 10-4. Measurements and Main Results: Ten studies profiled DNA methylation changes in blood and seven in respiratory samples, including surgically resected lung tissue (n = 3), small airway epithelial brushings (n = 2), BAL (n = 1), and sputum (n = 1). Main results showed: 1) high variability in study design, covariates, and effect sizes, which prevented a formal meta-analysis; 2) in blood samples, 51 DMPs were replicated in relation to lung function and 12 related to COPD; 3) in respiratory samples, 42 DMPs were replicated in relation to COPD but none in relation to lung function; and 4) in COPD versus control studies, 123 genes (2.6% of total) were shared between one or more blood and one or more respiratory samples and associated with chronic inflammation, ion transport, and coagulation. Conclusions: There is high heterogeneity across published COPD and/or lung function epigenome-wide association studies. A few genes (n = 123; 2.6%) were replicated in blood and respiratory samples, suggesting that blood can recapitulate some changes in respiratory tissues. These findings have implications for future research. Systematic Review [protocol] registered with Open Science Framework (OSF).