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Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality and morbidity worldwide, with high and growing prevalence. Its underdiagnosis and hence under-treatment is a general feature across all countries. This is particularly true for the mild or early stages of the disease, when symptoms do not yet interfere with daily living activities and both patients and doctors are likely to underestimate the presence of the disease. A diagnosis of COPD requires spirometry in subjects with a history of exposure to known risk factors and symptoms. Postbronchodilator forced expiratory volume in 1 second (FEV )/forced vital capacity <0.7 or less than the lower limit of normal confirms the presence of airflow limitation, the severity of which can be measured by FEV % predicted: stage 1 defines COPD with mild airflow limitation, which means postbronchodilator FEV ≥80% predicted. In recent years, an elegant series of studies has shown that \"exclusive reliance on spirometry, in patients with mild airflow limitation, may result in underestimation of clinically important physiologic impairment\". In fact, exercise tolerance, diffusing capacity, and gas exchange can be impaired in subjects at a mild stage of airflow limitation. Furthermore, growing evidence indicates that smokers without overt abnormal spirometry have respiratory symptoms and undergo therapy. This is an essential issue in COPD. In fact, on one hand, airflow limitation, even mild, can unduly limit the patient's physical activity, with deleterious consequences on quality of life and even survival; on the other hand, particularly in younger subjects, mild airflow limitation might coincide with the early stage of the disease. Therefore, we thought that it was worthwhile to analyze further and discuss this stage of \"mild COPD\". To this end, representatives of scientific societies from five European countries have met and developed this document to stimulate the attention of the scientific community on COPD with \"mild\" airflow limitation. The aim of this document is to highlight some key features of this important concept and help the practicing physician to understand better what is behind \"mild\" COPD. Future research should address two major issues: first, whether mild airflow limitation represents an early stage of COPD and what the mechanisms underlying the evolution to more severe stages of the disease are; and second, not far removed from the first, whether regular treatment should be considered for COPD patients with mild airflow limitation, either to prevent progression of the disease or to encourage and improve physical activity or both.

Inhaled therapy is central in the management of asthma and chronic obstructive pulmonary disease, with inhaler device selection significantly influencing treatment efficacy and patient adherence. NEXThaler is a breath-actuated dry powder inhaler (DPI) designed to deliver extrafine formulations of inhaled corticosteroids (ICS) and bronchodilators, ensuring consistent drug deposition across both central and peripheral airways. This review provides a clinically oriented overview of inhaler technologies, focusing on the design features and clinical performance of this breath-actuated DPI. Notably, this narrative review is based on a comprehensive analysis of peer-reviewed clinical and preclinical studies on the NEXThaler DPI. Most evidence presented is derived from non-comparative studies, modeling approaches, or sponsor-supported trials. Key features of the NEXThaler DPI include a breath-actuated mechanism, flow-independent dosing, a dose counter and a triple feedback system that enhances correct usage, and a simplified open-inhale-close mechanism. The delivery of extrafine particles (<2 µm) facilitates deeper lung penetration, improving small airway targeting and potentially allowing for lower ICS doses with maintained efficacy. Lung deposition studies demonstrate superior peripheral distribution and consistent dosing across varying inspiratory flow rates. Clinical trials and real-world studies confirm the efficacy and safety of bronchodilators and ICS combinations delivered via the NEXThaler DPI in both asthma and chronic obstructive pulmonary disease populations, showing noninferiority to pressurized metered-dose inhalers and improved outcomes in lung function, symptom control, and adherence. The device's usability and patient satisfaction further support its role in respiratory care. Additionally, its propellant-free design contributes to reducing the environmental impact of inhaler therapy. Overall, thanks to its technological innovations, the NEXThaler DPI represents a clinically validated and patient-friendly option for the delivery of inhaled therapies in chronic respiratory diseases.

The Spanish guideline for COPD (GesEPOC) recommends COPD treatment according to four clinical phenotypes: non-exacerbator phenotype with either chronic bronchitis or emphysema (NE), asthma-COPD overlap syndrome (ACOS), frequent exacerbator phenotype with emphysema (FEE) or frequent exacerbator phenotype with chronic bronchitis (FECB). However, little is known on the distribution and outcomes of the four suggested phenotypes. We aimed to determine the distribution of these COPD phenotypes, and their relation with one-year clinical outcomes. We followed a cohort of well-characterized patients with COPD up to one-year. Baseline characteristics, health status (CAT), BODE index, rate of exacerbations and mortality up to one year of follow-up were compared between the four phenotypes. Overall, 831 stable COPD patients were evaluated. They were distributed as NE, 550 (66.2%); ACOS, 125 (15.0%); FEE, 38 (4.6%); and FECB, 99 (11.9%); additionally 19 (2.3%) COPD patients with frequent exacerbations did not fulfill the criteria for neither FEE nor FECB. At baseline, there were significant differences in symptoms, FEV1 and BODE index (all p<0.05). The FECB phenotype had the highest CAT score (17.1±8.2, p<0.05 compared to the other phenotypes). Frequent exacerbator groups (FEE and FECB) were receiving more pharmacological treatment at baseline, and also experienced more exacerbations the year after (all p<0.05) with no differences in one-year mortality. Most of NE (93%) and half of exacerbators were stable after one year. There is an uneven distribution of COPD phenotypes in stable COPD patients, with significant differences in demographics, patient-centered outcomes and health care resources use.

The use of inhaled corticosteroids (ICS) in combination with bronchodilators in patients with COPD has been shown to decrease the rate of disease exacerbations and to improve the lung function and patients' quality of life. However, their use has also been associated with an increased risk of pneumonia. We have reviewed existing clinical evidence on the risks and benefits of ICS in COPD, including large randomized clinical trials, meta-analyses, and clinical reviews. A large body of evidence supports the clinical benefits of ICS in patients with COPD in terms of exacerbations, symptoms, lung function, and quality of life. The incidence of adverse events related to ICS, including pneumonia, varies strongly among the studies and seems to be dose dependent, with recent well-designed, large studies on low-dose ICS reporting similar safety profiles in ICS and non-ICS groups. The benefits of ICS in COPD continue to outweigh the risks, especially when lower ICS doses are employed. Given that the data on ICS withdrawal in COPD are scarce and conflicting, we argue that using reduced doses of ICS could be an optimal strategy to manage patients with COPD.

Abstract Rationale Patients with chronic obstructive pulmonary disease (COPD) have increased pulmonary lymphoid follicle (LF) counts. B cell–activating factor of tumor necrosis factor family (BAFF) regulates B cells in health, but its role in COPD pathogenesis is unclear. Objectives To determine whether BAFF expression in pulmonary LFs correlates with COPD severity, LF size or number, and/or readouts of B-cell function in LFs. Methods We correlated BAFF immunostaining in LFs in lung explants or biopsies from nonsmoking control subjects (NSC), smokers without COPD (SC), and patients with COPD with the number and size of LFs, and LF B-cell apoptosis, activation, and proliferation. We analyzed serum BAFF levels and BAFF expression in B cells in blood and bronchoalveolar lavage samples from the same subject groups. We assessed whether: (1) cigarette smoke extract (CSE) increases B-cell BAFF expression and (2) recombinant BAFF (rBAFF) rescues B cells from CSE-induced apoptosis by inhibiting activation of nuclear factor-κB (NF-κB). Measurements and Main Results Patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage IV COPD had increased numbers and larger pulmonary LFs than patients with GOLD stages I–II COPD and SC. We identified two main types of pulmonary LFs: (1) type A, the predominant type in GOLD stages I–II COPD and SC, characterized by abundant apoptotic but few BAFF-positive cells (mostly B cells); and (2) type B, the main type in GOLD stage IV COPD, characterized by abundant BAFF-positive cells but few apoptotic cells (mostly B cells). BAFF levels were also higher in blood and bronchoalveolar lavage B cells in patients with COPD versus NSC and SC. Surprisingly, rBAFF blocked CSE-induced B-cell apoptosis by inhibiting CSE-induced NF-κB activation. Conclusions Our data support the hypothesis that B-cell BAFF expression creates a self-perpetuating loop contributing to COPD progression by promoting pulmonary B-cell survival and LF expansion.

The aim of the study was to assess the microbial composition of bronchial secretions in chronic obstructive pulmonary disease (COPD), focusing on the impact of the exacerbation patterns on the common components of the respiratory flora and their relationship with inflammatory proteins. A total of 72 clinically stable COPD patients provided sputum and blood samples for 16S rRNA gene amplification and peripheral biomarkers. Beta-diversity analyses of the bronchial microbiome showed significant differences between infrequent and frequent (≥2) exacerbators (p = 0.001). Haemophilus was underrepresented in frequent exacerbators (relative abundance [RA] 0.07 [0.003–0.31] vs. 0.24 [0.06–2.36], p = 0.02) while the presence of Pseudomonas was increased (7.70 [0.66–11.68] vs. 1.11 [0.37–2.88], p = 0.01). Eight common taxa, Prevotella, Moryella, Atopobium, Megasphaera, Parvimonas, Veillonella, Bulleidia and Selenomonas, showed significant decreases in their RAs when exacerbations required hospitalization. RAs of Haemophilus and eight common taxa were positively correlated (p < 0.01). Among them, Porphyromonas, Leptotrichia and Selenomonas showed a negative correlation with blood interleukin-8 (IL-8) (p < 0.01) and an equivalent correlation was found for Haemophilus parainfluenzae. Frequent exacerbations cause a decrease in the RA of Haemophilus and have a more extensive impact when hospitalization is required. The RAs of common bronchial bacteria were closely related and some of them were inversely associated with blood IL-8 levels.

The natural history of chronic obstructive pulmonary disease (COPD) is still not well understood. Traditionally believed to be a self-inflicted disease by smoking, now we know that not all smokers develop COPD, that other inhaled pollutants different from cigarette smoke can also cause it, and that abnormal lung development can also lead to COPD in adulthood. Likewise, the inflammatory response that characterizes COPD varies significantly between patients, and not all of them perceive symptoms (mostly breathlessness) similarly. To investigate the variability and determinants of different \"individual natural histories\" of COPD, we developed a theoretical, multi-stage, computational model of COPD (EASI) that integrates dynamically and represents graphically the relationships between exposure (E) to inhaled particles and gases (smoking), the biological activity (inflammatory response) of the disease (A), the severity (S) of airflow limitation (FEV1) and the impact (I) of the disease (breathlessness) in different clinical scenarios. EASI shows that the relationships between E, A, S and I vary markedly within individuals (through life) and between individuals (at the same age). It also helps to delineate some potentially relevant, but often overlooked concepts, such as disease progression, susceptibility to COPD and issues related to symptom perception. In conclusion, EASI is an initial conceptual model to interpret the longitudinal and cross-sectional relationships between E, A, S and I in different clinical scenarios. Currently, it does not have any direct clinical application, thus it requires experimental validation and further mathematical development. However, it has the potential to open novel research and teaching alternatives.

Background The respiratory microbiome is altered in COPD patients but its relationship with core components of the disease, such as the severity of airflow limitation, the frequency of exacerbations or the circulating levels of eosinophils, is unclear. Methods Cross-sectional study comprising 72 clinically stable COPD patients (mean age 68 [SD 7.9] years; FEV1 48.7 [SD 20.1]% of reference) who provided spontaneous sputum samples for 16S rRNA gene amplification and sequencing. The microbiome composition was analysed with QIIME. Results We observed that: (1) more severe airflow limitation was associated with reduced relative abundance (RA) of Treponema and an increase in Pseudomonas ; (2) patients with ≥2 exacerbations the previous year showed a significantly different bacterial community with respect to non-exacerbators ( p  = 0.014), with changes in 13 genera, including an increase of Pseudomonas, and finally, (3) peripheral eosinophils levels ≥2% were associated with more diverse microbiome [Chao1 224.51 (74.88) vs 277.39 (78.92) p  = 0.006; Shannon 3.94 (1.05) vs 4.54 (1.06) p  = 0.020], and a significant increase in the RAs of 20 genera. Conclusion The respiratory microbiome in clinically stable COPD patients varies significantly according to the severity of airflow limitation, previous history of exacerbations and circulating eosinophils levels.

Purpose: Exacerbations of COPD (ECOPD) are a frequent cause of hospitalization that seemed to ameliorate during the COVID outbreak. We aimed to evaluate the clinical characteristics of COPD-related hospital admissions and mortality in relation to the presence of COVID-19. Patients and Methods: We conducted a case-control study of patients admitted in four teaching hospitals throughout Spain between March 15 and April 30, 2020. Hospital admissions of respiratory cause with and without PCR-proven SARS-CoV-2 infection in patients with COPD were evaluated. Baseline and episode-related clinical characteristics were analyzed. Logistic regression analysis was performed to evaluate the risk for mortality. Results: During the study period, 2101 patients were admitted for respiratory worsening, 1200 (57.1%) with COVID-19. A total of 228 (10.8%) were admitted due to COPD worsening, of whom 52 (22.8%) tested positive for COVID-19. COPD patients with COVID-19, when compared to those without COVID-19, were more frequently males with better lung function ([FEV.sub.1] postbronchodilator 71% vs 46% respectively, p<0.001) and had higher mortality (44.9% vs 13.6% respectively, p<0.001) despite similar age, comorbidities, total days of hospitalization and admission to intensive care unit. COVID-19 and eosinopenia were the strongest risk factors for mortality in the multivariate analysis in the overall COPD population. Inhaled corticosteroid use was not associated to mortality. Conclusion: Hospitalizations for ECOPD without COVID-19 were more frequent than COPD with COVID-19 during the first outbreak, but the latter were associated with higher mortality and low eosinophil counts that warrant further analysis. Keywords: COPD exacerbation, mortality, inhaled corticosteroids, hospitalization

Coronavirus disease 2019 (COVID-19) pneumonia is associated to systemic hyper-inflammation and abnormal coagulation profile. D-dimer elevation is particularly frequent, and values higher than 1μg/mL have been associated with disease severity and in-hospital mortality. Previous retrospective studies found a high pulmonary embolism (PE) prevalence, however, it should be highlighted that diagnoses were only completed when PE was clinically suspected. Single-center prospective cohort study. Between April 6th and April 17th 2020, consecutive confirmed cases of COVID-19 pneumonia with D-dimer >1 μg/mL underwent computed tomography pulmonary angiography (CTPA) to investigate the presence and magnitude of PE. Demographic and laboratory data, comorbidities, CTPA scores, administered treatments, and, clinical outcomes were analysed and compared between patients with and without PE. Thirty consecutive patients (11 women) were included. PE was diagnosed in 15 patients (50%). In patients with PE, emboli were located mainly in segmental arteries (86%) and bilaterally (60%). Patients with PE were significantly older (median age 67.0 (IQR 63.0-73.0) vs. 57.0 (IQR 48.0-69.0) years, p = .048) and did not differ in sex or risk factors for thromboembolic disease from the non-PE group. D-dimer, platelet count, and, C reactive protein values were significantly higher among PE patients. D-dimer values correlated with the radiologic magnitude of PE (p<0.001). Patients with COVID-19 pneumonia and D-dimer values higher than 1 μg/mL presented a high prevalence of PE, regardless of clinical suspicion. We consider that these findings could contribute to improve the prognosis of patients with COVID-19 pneumonia, by initiating anticoagulant therapy when a PE is found.