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Background Patients with alpha-1 antitrypsin defciency (AATD), commonly categorized as a rare disease, have been afected by the changes in healthcare management brought about by COVID-19. This study’s aim was to identify the changes that have taken place in AATD patient care as a result of the COVID-19 pandemic in Spain and to propose experts’ recommendations aimed at ensuring humanized and quality care for people with AATD in the post-pan‑ demic situation. Methods A qualitative descriptive case study with a holistic single-case design was conducted, using focus groups with experts in AATD clinical management, including 15 health professionals with ties to the Spanish health system (12 pneumologists and 2 hospital pharmacists from 11 diferent hospitals in Spain) and 1 patient representative. Results COVID-19 has had a major impact on numerous aspects of AATD clinical patient management in Spain, including diagnostic, treatment, and follow-up phases. The experts concluded that there is a need to strengthen coor‑ dination between Primary Care and Hospital Care and improve the coordination processes across all the organizations and actors involved in the healthcare system. Regarding telemedicine and telecare, experts have concluded that it is necessary to promote this methodology and to develop protocols and training programs. Experts have recom‑ mended developing personalized and precision medicine, and patient participation in decision-making, promoting self-care and patient autonomy to optimize their healthcare and improve their quality of life. The possibility of moni‑ toring and treating AATD patients from home has also been proposed by experts. Another result of the study was the recommendation of the need to ensure that plasma donations are made on a regular basis by a sufcient number of healthy individuals. Conclusion The study advances knowledge by highlighting the challenges faced by health professionals and changes in AATD patient management in the context o

Objetivos. El presente proyecto parte de la hipótesis de que un programa docente basado en la enseñanza integrada y en el aprendizaje basado en problemas constituye una forma innovadora de docencia que alcanza una mayor satisfacción en el alumnado sin disminuir el rendimiento académico. Método. Durante el curso académico 2018-19, los alumnos de cuarto curso de medicina del Campus Virgen del Rocío participaron en una implementación de una docencia integrada basada en resolución de problemas integrando tres asignaturas complementarias: patología médica de sistemas, patología quirúrgica de sistemas y diagnóstico por la imagen. Los alumnos se dividieron en dos grupos, uno sin intervención como grupo control. Tras la finalización de la asignatura, la satisfacción del alumnado fue evaluada mediante una encuesta, junto con el análisis de las calificaciones finales entre ambos grupos. Resultados. El plan docente se implementó sin grandes incidencias. La encuesta de satisfacción mostró que esta satisfacción fue elevada con un 76% de los alumnos que estaban bastante o muy satisfechos. Sin embargo, no había una aceptación uniforme para impartir la docencia exclusivamente en este formato. No hubo diferencias en las calificaciones finales entre los grupos de intervención y control Conclusiones. Los resultados avalan el uso de la enseñanza basada en resolución de problemas como método complementario la docencia tradicional sin detrimento de las calificaciones finales, Objectives. The present project is based on the hypothesis that a teaching program based on integrated teaching and problem-based learning constitutes an innovative form of teaching that achieves greater student satisfaction without reducing academic performance. Method. During the 2018-19 academic year, fourth-year medical students at the Virgen del Rocío Campus participated in an implementation of integrated teaching based on problem-solving integrating three complementary subjects: systems medical pathology, systems surgical pathology, and diagnostic imaging. The students were divided into two groups, one without intervention as a control group. After completion of the course, student satisfaction was evaluated by means of a survey, together with the analysis of final grades between the two groups. Results. The teaching plan was implemented without major incidents. The satisfaction survey showed that satisfaction was high with 76% of the students being fairly or very satisfied. However, there was no uniform acceptance for teaching exclusively in this format. There were no differences in the final ratings between the intervention and control groups. Conclusions. The results support the use of problem-based teaching as a complementary method to traditional teaching without detriment to final grades.

Microbes play an important role in the pathogenesis of chronic lung diseases, such as chronic obstructive pulmonary disease, cystic fibrosis, non-cystic fibrosis bronchiectasis, and asthma. While the role of bacterial pathogens has been extensively studied, the contribution of fungal species to the pathogenesis of chronic lung diseases is much less understood. The recent introduction of next generation sequencing techniques has revealed the existence of complex microbial lung communities in healthy individuals and patients with chronic respiratory disorders, with fungi being an important part of these communities’ structure (mycobiome). There is growing evidence that the components of the lung mycobiome influence the clinical course of chronic respiratory diseases, not only by direct pathogenesis but also by interacting with bacterial species and with the host’s physiology. In this article, we review the current knowledge on the role of fungi in chronic respiratory diseases, which was obtained by conventional culture and next-generation sequencing, highlighting the limitations of both techniques and exploring future research areas.

Since the beginning of the COVID-19 SARS-CoV-2 pandemic, numerous papers have been published on strategic planning and the positioning of different medical societies in the prevention and management of chronic obstructive pulmonary disease (COPD).1, 2, 3, 4, 5, 6 However, the reality is far from perfect. Although much was learned during the darkest hours of the pandemic, many aspects of the diagnosis, treatment, and follow-up of these patients remain controversial and raise concerns among health professionals.7 Therefore, in order to determine the opinion of COPD experts, we drew up a Delphi-based consensus statement8 on certain issues surrounding disease management during the COVID-19 pandemic. (extract)

Purpose Acute phase reactants (APRs) play a critical role in inflammation. The difference in their physiological functions or the different dynamic ranges of these proteins in plasma makes it difficult to detect them simultaneously and to use several of these proteins as a tool in clinical practice. Experimental Design A novel multiplex assay has been designed and optimized to carry out a high-throughput and simultaneous screening of APRs, allowing the detection of each of them at the same time and in their corresponding dynamic range. Results Using Sars-CoV-2 infection as a model, it has been possible to profile different patterns of acute phase proteins that vary significantly between healthy and infected patients. In addition, severity profiles (acute respiratory distress syndrome and sepsis) have been established. Conclusions and Clinical Relevance Differential profiles in acute phase proteins can serve as a diagnostic and prognostic tool, among patient stratification. The design of this new platform for their simultaneous detection paves the way for them to be more extensive use in clinical practice.

Background: The fundamentals of the infectivity and immune evasion of the SARS-CoV-2 Omicron variant are not yet fully understood. Here, we carried out an in-silico study analyzing the spike protein, the protein electrostatic potential, and the potential immune evasion. Methods: The analysis was based on the structure of the spike protein from two SARS-CoV-2 variants, the original Wuhan and the Botswana (Omicron). The full-length genome sequences and protein sequences were obtained from databanks. The interaction of the spike proteins with the human Angiotensin Converting Enzyme 2 (ACE2) receptor was evaluated through the open-source software. The Immune Epitope Database was used to analyze the potential immune evasion of the viruses. Results: Our data show that the Omicron spike protein resulted in 37 amino acid changes. The physicochemical properties of the spike had changed, and the electrostatic potentials differed between both variants. This resulted in a decrease in protein interactions, which does not establish a greater interaction with the ACE2 receptor. These changes compromise key receptor-binding motif residues in the SARS-CoV-2 spike protein that interact with neutralizing antibodies and ACE2. Conclusions: These mutations appear to confer enhanced properties of infectivity. The Omicron variant appears to be more effective at evading immune responses.

The definition of exacerbation of COPD as a syndrome, as proposed by the Spanish COPD guidelines (GesEPOC) 2021 update, and the consequences that this implies, have direct implications on patient care. This review analyzes this novel vision of the COPD exacerbation syndrome, its rationale, and its clinical implications, as opposed to the traditional symptoms-based or event-based definitions. An exacerbation conceived as a syndrome provides us with an umbrella term to include a set of diverse alterations, which, either in isolation or more frequently in combination, are clinically expressed in a similar way in patients with COPD. In patients with COPD, this occurs as a consequence of worsening expiratory airflow limitation or the underlying inflammatory process, producing a worsening in symptoms with respect to the baseline situation. This definition therefore assumes a worsening in at least one of the two key physiopathological markers, lung function and inflammation. The main features of this new physiopathological proposal include a syndromic approach with narrower differential diagnosis, the use of several biomarkers, treatable traits to better guide treatment, and a new severity classification. Further research is needed to examine the role of eosinophils in this context, but currently, the early results are promising. The evaluation of severity is key in the multidimensional characterization of exacerbation and the GesEPOC 2021 proposes new approaches and also recommends the use of multidisciplinary scores for severity categorization in patients. Finally, another innovation in the GesEPOC 2021 refers to the recurrence of exacerbations, which has implications for disease prognosis or long-term clinical impact which need to be elucidated in further studies.

Introduction: Currently, strategies for improving alpha1 antitrypsin defciency (AATD) diagnosis are needed. Here we report the performance of a multinational multiplex-based genotyping test on dried blood spots and buccal swabs sent by post or courier and with web registration for subjects with suspected AATD in Argentina, Brazil, Chile, Colom‑ bia, Spain, and Turkey. Methods: This was an observational, cross-sectional analysis of samples from patients with suspected AATD from March 2018 to January 2022. Samples were coded on a web platform and sent by post or courier to the central laboratory in Northern Spain. Allele-specifc genotyping for the 14 most common mutations was carried out with the A1AT Genotyping Test (Progenika-Grifols, Spain). SERPINA1 gene sequencing was performed if none of the muta‑ tions were found or one variant was detected in heterozygous status and the AAT serum level was<60 mg/dl, or if requested by the clinician in charge. Results: The study included 30,827 samples: 30,458 (94.7%) with fnal results after direct genotyping and 369 (1.1%) with additional gene sequencing. Only 0.3% of the samples were not processed due to their poor quality. The preva‑ lence of the most frequent allele combinations was MS 14.7%, MZ 8.6%, SS 1.9%, SZ 1.9%, and ZZ 0.9%. Additionally, 70 cases with new mutations were identifed. Family screening was conducted in 2.5% of the samples. Samples from patients with respiratory diseases other than COPD, including poorly controlled asthma or bronchiectasis, also pre‑ sented AATD mutations. Conclusions: Our results confrm the viability of this diagnostic system for genotyping AATD conducted simultane‑ ously in diferent countries. The system has proved satisfactory and can improve the timely diagnosis of AATD.

Background: Chronic obstructive pulmonary disease (COPD) is a condition resulting from a persistent inflammatory state in the airways even after smoking cessation. Intriguingly, the reasons behind this persistence of the inflammatory influx without smoking exposure have not been fully unraveled. We aimed to explore the hypothesis that systemic inflammation in COPD patients influences lung cell inflammatory response. Methods: We cultured human lung fibroblast and human airway epithelial cell lines with plasma from COPD patients (four emphysematous-COPD, four asthma-COPD overlap, four chronic bronchitis-COPD, and four bronchiectasis COPD), and four smokers or ex-smokers without COPD as controls. Non-stimulated cells were used as controls. We measured Interleukine-8 (IL-8), C-reactive protein (CRP) and matrix metalloproteinase-9 (MMP-9) in plasma and cul ture supernatants by ELISA. Results: Cells stimulated with plasma from COPD patients and non-COPD smoker subjects produced higher CRP, IL 8 and MMP-9 levels, an increase for COPD in CRP (p=0.029) in epithelial cells and IL-8 (p=0.039) in fibroblasts and decrease for MMP-9 (p=0.039) in fibroblasts, compared with non-stimulated cells. The response was higher in epithe lial cells for IL-8 (p=0.003) and in fibroblasts for MMP-9 (p=0.063). The plasma from chronic bronchitis and bronchiectasis phenotypes induced higher IL-8 in fibroblasts. Conclusions: Plasma from COPD patients increases the inflammatory response in lung epithelial cells and lung fibroblasts, with a different response depending on the cell type and clinical phenotype.

Chronic obstructive pulmonary disease (COPD) patients constitute a heterogeneous population in terms of treatment response. Our objective was to identify possible predictive factors of response to treatment with single bronchodilation monotherapy in patients diagnosed with COPD. The Time-based Register and Analysis of COPD Endpoints (TRACE; clinicaltrials.gov NCT03485690) is a prospective cohort of COPD patients who have been attending annual visits since 2012. Patients who were kept on a single bronchodilator during the first year of follow-up were selected. The responders were defined according to all of the following variables: any improvement in morning post-dose forced expiratory volume in 1 s or deterioration <100 mL, no change or improvement in dyspnea score, and no occurrence of exacerbations. Significant and plausible variables were analyzed using a proportional hazard Cox regression for single bronchodilator responders. We analyzed 764 cases, of whom 128 (16.8%) were receiving monotherapy with one bronchodilator. Of these, 85 patients (66.4%) were responders. Factors affecting responder status were: female gender (hazard ratio (HR) 0.276; 95% confidence interval (CI) 0.089–0.858), dyslipidemia (HR 0.436; 95%CI 0.202–0.939), not performing regular exercise (HR 0.523; 95%CI 0.254–1.076), active smoking (HR 0.413; 95%CI 0.186–0.920), and treatment adherence (HR 2.527; 95%CI 1.271–5.027). The factors associated with a single bronchodilation response are mainly non-pharmacological interventions and comorbidities.

This is the first case of a patient taking aprepitant for a post-acute COVID-19 syndrome. This case may encourage researchers to look for the evidence for the efficacy and safety of a neurokinin 1 receptor antagonist in this frequent syndrome

Background: The global prevalence of chronic obstructive pulmonary disease (COPD) has increased markedly in recent decades. Given the scarcity of resources available to address global health challenges and respiratory medicine being relatively under-invested in, it is important to define research priorities for COPD globally. In this paper, we aim to identify a ranked set of COPD research priorities that need to be addressed in the next 10 years to substantially reduce the global impact of COPD. Methods: We adapted the Child Health and Nutrition Research Initiative (CHNRI) methodology to identify global COPD research priorities. Results: 62 experts contributed 230 research ideas, which were scored by 34 researchers according to six pre-defined criteria: answerability, effectiveness, feasibility, deliverability, burden reduction, and equity. The top-ranked research priority was the need for new effective strategies to support smoking cessation. Of the top 20 overall research priorities, six were focused on feasible and cost-effective pulmonary rehabilitation delivery and access, particularly in primary/community care and low-resource settings. Three of the top 10 overall priorities called for research on improved screening and accurate diagnostic methods for COPD in low-resource primary care settings. Further ideas that drew support involved a better understanding of risk factors for COPD, development of effective training programmes for health workers and physicians in low resource settings, and evaluation of novel interventions to encourage physical activity. Conclusions: The experts agreed that the most pressing feasible research questions to address in the next decade for COPD reduction were on prevention, diagnosis and rehabilitation of COPD, especially in low resource settings. The largest gains should be expected in low- and middle-income countries (LMIC) settings, as the large majority of COPD deaths occur in those settings. Research priorities identified by

La Sociedad Espanola de Neumología y Cirugía Torácica (SEPAR) ha elaborado este documento de reco mendaciones sobre la vacuna para la COVID-19 en las enfermedades respiratorias, con el objetivo de ayudar al personal sanitario en la toma de decisiones sobre cómo actuar en la vacunación de estos pacientes. Las recomendaciones han sido elaboradas por un grupo de expertos en la materia, tras la revisión de la literatura recopilada hasta el 7 de marzo del 2021, y de la información aportada por distintas sociedades científicas, agencias del medicamento y estrategias de organismos gubernamentales hasta esa fecha. Podemos concluir que las vacunas para la COVID-19 no solo son seguras y eficaces, sino que, en aquellos pacientes vulnerables con enfermedades respiratorias crónicas, son prioritarias. Además, la implicación activa de los profesionales sanitarios que manejan estas patologías en la estrategia de vacunación es clave para lograr una buena adherencia y coberturas vacunales elevadas., The Spanish Society of Pneumonology and Thoracic Surgery (SEPAR) has elaborated this document of recommendations for COVID-19 vaccination in patients with respiratory diseases aimed to help healthcare personnel make decisions about how to act in case of COVID-19 vaccination in these patients. The recommendations have been developed by a group of experts in this field after reviewing the materials published up to March 7, 2021, the information provided by different scientific societies, drug agencies and the strategies of the governmental bodies up to this date. We can conclude that COVID-19 vaccines are not only safe and effective, but also prior in vulnerable patients with chronic respiratory diseases. In addition, an active involvement of healthcare professionals, who manage these diseases, in the vaccination strategy is the key to achieve good adherence and high vaccination coverage.

Recent advances in inhaled drugs and a clearer definition of the disease have made the task of managing COPD more complex. Different proposals have been put forward which combine all the available treatments and the different clinical presentations in an effort to select the best therapeutic options for each clinical context. As COPD is a chronic progressive disease, the escalation of therapy has traditionally been considered the most natural way to tackle it. However, the notion of COPD as a constantly progressing disease has recently been challenged and, in specific areas, this points to the possibility of a de escalation in treatment. In this context, the clinician requires simple, specific recommenda tions to guide these changes in treatment in their daily clinical practice. To accomplish this, the first step must be a correct evaluation and an accurate initial preliminary diagnosis of the patient’s condition. Thereafter, the first escalation in therapy must be introduced with caution as the disease progresses, since clinical trials are not designed with clinical decision-making in mind. During this escalation, three possibilities are open to change the current treatment for a different one within the same family, to increase non-pharmacological interventions or to increase the pharmacological therapies. Beyond that point, a patient with persistent symptoms represents a complex clinical scenario which requires a specialized approach, including the evaluation of different respiratory and non-respiratory comorbidities. Unfortunately, there are few de-escalation studies available, and these are mainly observa tional in nature. The debate on de-escalation in pharmacological treatment, therefore, involves two main discussion points: the withdrawal of bronchodilators and the withdrawal of inhaled steroids. Altogether, the scheme for modifying treatment must be more persona lized than just adding molecules, and the therapeutic response and its conditioning factors shou

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 admis- sions 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 ana- lyzed. 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 (FEV1 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. © 2021 Cosio et al.

The study of the interaction between the SARS-CoV-2 spike protein and the angiotensin-converting enzyme 2 (ACE2) receptor is key to understanding binding affinity and stability. In the present report, we sought to investigate the differences between two already sequenced genome variants (Spanish and British) of SARS-CoV-2. Methods: In silico model evaluating the homology, identity and similarity in the genome sequence and the structure and alignment of the predictive spike by computational docking methods. Results: The identity results between the Spanish and British variants of the Spike protein were 28.67%. This close correspondence in the results between the Spanish and British SARS-CoV-2 variants shows that they are very similar (99.99%). The alignment obtained results in four deletions. There were 23 nucleotide substitutions also predicted which could affect the functionality of the proteins produced from this sequence. The interaction between the binding receptor domain from the spike protein and the ACE2 receptor produces some of the mutations found and, therefore, the energy of this ligand varies. However, the estimated antigenicity of the British variant is higher than its Spanish counterpart. Conclusions: Our results indicate that minimal mutations could interfere in the infectivity of the virus due to changes in the fitness between host cell recognition and interaction proteins. In particular, the N501Y substitution, situated in the RBD of the spike of the British variant, might be the reason for its extraordinary infective potential.

Background: The study of hematic concentrations of alpha1 antitrypsin (AAT) is currently one step in the diagnosis of AAT deficiency. To try to clarify the relevance of the laboratory techniques, we carried out a systematic review of the literature. Methods: Studies evaluating the quantification of AAT in peripheral blood were searched in PubMed in July 2021. The selection criteria included (1) any type of study design that included a quantification of AAT in peripheral blood; (2) studies written in English or Spanish; (3) studies evaluating human beings; and (4) studies involving adults. Results: Out of 207 studies, the most frequently used techniques were nephelometry (43.9%), followed by ELISA (19.8%) and turbidimetry (13.5%). Altogether, 182 (87.9%) cases expressed their results in units of gram, while 16 (7.7%) articles expressed them in units of mole. Only 2.9% articles referred to the standard used, 43.5% articles indicated the commercial kit used, and 36.2% indicated the analyzer used. Conclusions: The technical aspects of these determinations are not always reported in the literature. Journals should be attentive to these technical requirements and ensure that they are included in the works in which AAT is determined in order to ensure a correct interpretation of the study findings.

In recent years, numerous pathways were explored in the pathogenesis of COPD in the quest for new potential therapeutic targets for more personalised medical care. In this context, the study of the cystic fibrosis transmembrane conductance regulator (CFTR) began to gain importance, especially since the advent of the new CFTR modulators which had the potential to correct this protein’s dysfunction in COPD. The CFTR is an ion transporter that regulates the hydration and viscosity of mucous secretions in the airway. Therefore, its abnormal function favours the accumulation of thicker and more viscous secretions, reduces the periciliary layer and mucociliary clearance, and produces inflammation in the airway, as a consequence of a bronchial infection by both bacteria and viruses. Identifying CFTR dysfunction in the context of COPD pathogenesis is key to fully understanding its role in the complex pathophysiology of COPD and the potential of the different therapeutic approaches proposed to overcome this dysfunction. In particular, the potential of the rehydration of mucus and the role of antioxidants and phosphodiesterase inhibitors should be discussed. Additionally, the modulatory drugs which enhance or restore decreased levels of the protein CFTR were recently described. In particular, two CFTR potentiators, ivacaftor and icenticaftor, were explored in COPD. The present review updated the pathophysiology of the complex role of CFTR in COPD and the therapeutic options which could be explored.

Despite recent notable innovations in the management of chronic obstructive pulmonary disease (COPD), no major advances in patient-centered medicine have been achieved. Current guidelines base their proposals on the average results from clinical trials, leading to what could be termed ‘means-based’ medical practice. However, the therapeutic response is variable at the patient level. Additionally, the variability of the clinical presentation interacts with comorbidities to form a complex clinical scenario for clinicians to deal with. Consequently, no consensus has been reached over a practical approach for combining comorbidities and disease presentation markers in the therapeutic algorithm. In this context, from the patients’ first visit, the clinician faces four major dilemmas: (1) establishing the correct diagnosis of COPD as opposed to other airway diseases, such as bronchial asthma; (2) deciding on the initial therapeutic approach based on the clinical characteristics of each case; (3) setting up a study strategy for non-responding patients; (4) pursuing a follow-up strategy with two well-defined periods according to whether close or long-term follow-up is required. Here, we will address these major dilemmas in the search for a patient-centered approach to COPD management and suggest how to combine them all in a single easy-to-use strategy.

Ever since the first studies, restoring proteinase imbalance in the lung has traditionally been considered as the main goal of alpha1 antitrypsin (AAT) replacement therapy. This strategy was therefore based on ensuring biochemical efficacy, identifying a protection threshold, and evaluating different dosage regimens. Subsequently, the publication of the results of the main clinical trials showing a decrease in the progression of pulmonary emphysema has led to a debate over a possible change in the main objective of treatment, from biochemical efficacy to clinical efficacy in terms of lung densitometry deterioration prevention. This new paradigm has produced a series controversies and unanswered questions which face clinicians managing AAT deficiency. In this review, the concepts that led to the approval of AAT replacement therapy are reviewed and discussed under a new prism of achieving clinical efficacy, with the reduction of lung deterioration as the main objective. Here, we propose the use of current knowledge and clinical experience to face existing challenges in different clinical scenarios, in order to help clinicians in decision-making, increase interest in the disease, and stimulate research in this field.

La enfermedad pulmonar obstructiva crónica (EPOC) es una enfermedad común, prevenible y tratable, que se caracteriza por la presencia de síntomas respiratorios persistentes y una limitación al flujo aéreo que se debe a anomalías en las vías aéreas y/o en los alveolos, generalmente causado por una exposición significativa a partículas nocivas o gases. La inflamación sistémica en la EPOC se define como un aumento de los niveles de marcadores inflamatorios de diferentes vías biológicas. La presente Tesis Doctoral se enmarca en el estudio de la EPOC como enfermedad con repercusión sistémica. Para ello hemos tratado de comparar la expresión génica de RFA tanto a nivel local, en el parénquima pulmonar y tejido vascular de arteria pulmonar, como a nivel sistémico, en células sanguíneas y plasma, de pacientes con EPOC y fumadores sin la enfermedad. Posteriormente comparamos la síntesis de estos mediadores inflamatorios en células pulmonares con respecto a nivel hepático, principal síntesis en humanos, con objeto de determinar la contribución de cada uno a la inflamación sistémica. Los objetivos principales de esta tesis son 1) Comparar la expresión génica de PCR y AAS en el parénquima pulmonar, en tejido vascular de arteria pulmonar y sangre periférica de pacientes con EPOC frente a fumadores sanos. Estudiar la relación entre la expresión tisular y la concentración sérica de las proteínas. 2) Evaluar la producción de RFA en células epiteliales bronquiales, fibroblastos pulmonares y hepatocitos humanos, comparando la producción pulmonar frente a la hepática. Dado que la inflamación juega un papel crítico en el desarrollo, curso y la gravedad de la EPOC, los hallazgos del presente trabajo contribuirán a un mayor conocimiento de la patogenia de la enfermedad y sus repercusiones sistémicas que podrían culminar en mejorar los enfoques actuales de diagnóstico, pronóstico y detección de nuevas dianas terapéuticas en un futuro.

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. The new GOLD 2019 classification does not predict mortality better than the previous GOLD 2015 system.

Background: Clinical audits have reported considerable variability in COPD medical care and frequent inconsistencies with recommendations. The objectives of this study were to identify factors associated with a better adherence to clinical practice guidelines and to explore determinants of this variability at the the hospital level. Methods: EPOCONSUL is a Spanish nationwide clinical audit that evaluates the outpatient management of COPD. Multilevel logistic regression with two levels was performed to assess the relationships between individual and disease-related factors, as well as hospital characteristics. Results: A total of 4508 clinical records of COPD patients from 59 Spanish hospitals were evaluated. High variability was observed among hospitals in terms of medical care. Some of the patient’s characteristics (airflow obstruction, degree of dyspnea, exacerbation risk, presence of comorbidities), the hospital factors (size and respiratory nurses available) and treatment at a specialized COPD outpatient clinic were identified as factors associated with a better adherence to recommendations, although this only explains a small proportion of the total variance. Conclusion: To be treated at a specialized COPD outpatient clinic and some intrinsic patient characteristics were factors associated with a better adherence to guideline recommendations, although these variables were only explaining part of the high variability observed among hospitals in terms of COPD medical care.

La enfermedad pulmonar obstructiva crónica (EPOC) es una enfermedad pulmonar común, prevenible y tratable que se caracteriza por síntomas respiratorios persistentes y limitación del flujo de aire que se debe anomalías alveolares y/o de las vías respiratorias generalmente causadas por una exposición significativa a partículas o gases nocivos, con un alto impacto sanitario en morbilidad, mortalidad y que genera una importante repercusión en el sistema sanitario. Estas connotaciones la hacen ser considerada como una enfermedad de primera magnitud en la que la calidad asistencial debe ser primordial para garantizar la correcta utilización de los recursos que consigan mejorar la situación clínica de los pacientes. En la actualidad disponemos de diversas herramientas para valorar la calidad asistencial que reciben nuestros pacientes y el cumplimiento de las guías de práctica clínica por parte de los profesionales sanitarios. Dentro de estas herramientas disponemos de las auditorías clínicas las cuales pueden definirse como el análisis crítico y sistemático de la calidad de la asistencia médica, incluyendo procedimientos diagnósticos y terapéuticos, el uso de recursos y los resultados de los mismos en cuanto a desenlaces clínicos y la calidad de vida del paciente. A pesar de la relevancia clínica de la enfermedad y su importancia epidemiológica, hasta hace unos años, en España no existía un programa de auditorías clínicas específico para la EPOC. Hasta el momento ningún proyecto español ha aportado información sobre la calidad asistencial y la adecuación a guías de práctica clínica en el paciente con EPOC en el ámbito especializado ambulatorio de Neumología. La presente Tesis Doctoral se enmarca por tanto en este proceso de mejora continua de la atención sanitaria centrándose en la evaluación de la calidad asistencial de la EPOC en consultas externas de Neumología. Los objetivos principales de esta Tesis Doctoral son 1) Evaluar los recursos sanitarios disponibles para la a

El cáncer de pulmón es la mayor causa de muerte relacionada con el cáncer en mujeres. Existen claras diferencias en la biología, historia natural y respuesta al tratamiento entre hombres y mujeres con esta enfermedad. Una literatura emergente está proporcionando una base biológica para apoyar estas diferencias. Teniendo en cuenta estos antecedentes, la presente Tesis Doctoral pretende profundizar en el conocimiento del cáncer de pulmón en las mujeres, con la hipótesis de que el tiempo de demora que se genera en los diferentes niveles de todo el proceso clínico-diagnóstico-terapéutico del cáncer de pulmón tiene una influencia definitiva sobre el pronóstico final y, por tanto, en la supervivencia. Para ello, se estudió la supervivencia de las mujeres con diagnóstico de cáncer de pulmón, se determinaron los tiempos medios de espera en los diferentes niveles de atención en nuestro hospital para esta patología y su evolución en el tiempo, y se analizó la relación entre la demora en el diagnóstico y el tratamiento y la mortalidad por cáncer de pulmón en mujeres. Se ha realizado un estudio retrospectivo, mediante cohortes históricas, recogiéndose 240 casos de cáncer de pulmón en mujeres en 15 años desde 1994, estableciéndose los tiempos de estudio como: Tiempo desde la fecha de inicio de los síntomas hasta la primera consulta con un médico (demora atribuible a la paciente); Tiempo desde esa primera consulta hasta la fecha de la prueba que estableciera la base diagnóstica (demora diagnóstica); Tiempo desde la fecha de la prueba base diagnóstica hasta el inicio del primer tratamiento, ya fuera cirugía, quimioterapia (QT) o radioterapia (RT), (demora terapéutica); y Supervivencia: tiempo desde la fecha de la prueba tomada como base diagnóstica hasta la fecha de éxitus/última consulta. Entre los principales resultados, la supervivencia media fue de 40,3 meses, pero no hemos encontrado un aumento de la misma a lo largo del tiempo. Con respecto a las variables de tiempo, no supu

Rationale The Spanish guideline for COPD (GesEPOC) recommends COPD treatment according to four clinical phenotypes: non-exacerbator phenotype with either chronic bronchitis or emphy- sema (NE), asthma-COPD overlap syndrome (ACOS), frequent exacerbator phenotype with emphysema (FEE) or frequent exacerbator phenotype with chronic bronchitis (FECB). How- ever, little is known on the distribution and outcomes of the four suggested phenotypes. Objective We aimed to determine the distribution of these COPD phenotypes, and their relation with one-year clinical outcomes. Methods 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. Results 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, FEV 1 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 exacer- bations 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. Conclusions There is an uneven distribution of COPD phenotypes in stable COPD patients, with signifi- cant differences in demographics, patient-centered outcomes and health care resources use.

Background Conflicting data exist on the role of pulmonary dendritic cells (DCs) and their maturation in patients with chronic obstructive pulmonary disease (COPD). Herein, we investigated whether disease severity and smoking status could affect the distribution and maturation of DCs in lung tissues of patients undergoing elective pneumectomy or lobectomy for suspected primary lung cancer. Materials and Methods A total of 75 consecutive patients were included. Spirometry testing was used to identify COPD. Lung parenchyma sections anatomically distant from the primary lesion were examined. We used flow cytometry to identify different DCs subtypes—including BDCA1-positive myeloid DCs (mDCs), BDCA3-positive mDCs, and plasmacytoid DCs (pDCs)—and determine their maturation markers (CD40, CD80, CD83, and CD86) in all participants. We also identified follicular DCs (fDCs), Langerhans DCs (LDCs), and pDCs in 42 patients by immunohistochemistry. Results COPD was diagnosed in 43 patients (16 current smokers and 27 former smokers), whereas the remaining 32 subjects were classified as non-COPD (11 current smokers, 13 former smokers, and 8 never smokers). The number and maturation of DCs did not differ significantly between COPD and non-COPD patients. However, the results of flow cytometry indicated that maturation markers CD40 and CD83 of BDCA1-positive mDCs were significantly decreased in smokers than in non-smokers (P = 0.023 and 0.013, respectively). Immunohistochemistry also revealed a lower number of LDCs in COPD patients than in non-COPD subjects. Conclusions Cigarette smoke, rather than airflow limitation, is the main determinant of impaired DCs maturation in the lung.

Los reactantes de fase aguda (RFA) mayores, proteína C reactiva (PCR) y amiloide A sérico (AAS), tiene un papel relevante durante la reacción aguda del organismo ante diversos estímulos nocivos. La inducción de la expresión de estas moléculas (PCR y AAS), cuya concentración se multiplica por 1000 durante una agresión aguda, se realiza principalmente a nivel hepático a través de un complejo sistema de interacción mediado por diversas citoquinas entre las que tienen un papel crucial la interleucina-1, interleucina-6 y factor de necrosis tumoral alfa (1). El papel de ambos RFA mayores en la respuesta aguda está parcialmente estudiado y entre sus principales efectos figuran: acción inmunomoduladora (2), efectos sobre el genoma (3) y efectos sobre el metabolismo lipídico (4). Sin embargo, además de su función durante una lesión aguda, los RFA también han demostrado tener un papel en enfermedades crónicas como consecuencia de una estimulación constante de su expresión. La enfermedad pulmonar obstructiva crónica (EPOC) es una enfermedad crónica inflamatoria del aparato respiratorio producida como consecuencia de la inhalación repetida del humo del tabaco. La implicación de la inflamación local en la EPOC se ha demostrado en diversos trabajos concluyendo resumidamente que esta inflamación está presente desde momentos iniciales de la enfermedad (5), una vez establecida es independiente del consumo de tabaco (6) y aumenta durante los periodos de exacerbación de la enfermedad (7). Por otro lado, recientemente se ha demostrado que la EPOC, lejos de ser una enfermedad con una repercusión exclusivamente pulmonar, tiene una serie de importantes repercusiones sistémicas que son consideradas como parte de la misma (8), entre las que caben destacar alteraciones nutricionales, disfunción muscular periférica y efectos cardiovasculares, entre otros (9). La patogenia de estas manifestaciones sistémicas está aún poco clara, pero se ha demostrado que los RFA y otras moléculas inflamatorias

Purpose: Health utilities are widely used in health economics as a measurement of an individual’s preference and show the value placed on different health states over a specific period. Thus, health utilities are used as a measure of the benefits of health interventions in terms of quality-adjusted life years. This study aimed to determine the demographic and clinical variables significantly associated with health utilities for chronic obstructive pulmonary disease (COPD) patients. Patients and methods: This was a multicenter, observational, cross-sectional study conducted between October 2012 and April 2013. Patients were aged 40 years, with spirometrically confirmed COPD. Utility values were derived from the preference-based generic questionnaire EQ-5D-3L applying weighted Spanish societal preferences. Demographic and clinical variables associated with utilities were assessed by univariate and multivariate linear regression models. Results: Three hundred and forty-six patients were included, of whom 85.5% were male. The mean age was 67.9 (standard deviation [SD] =9.7) years and the mean forced expiratory volume in 1 second (%) was 46.2% (SD =15.5%); 80.3% were former smokers, and the mean smoking history was 54.2 (SD =33.2) pack-years. Median utilities (interquartile range) were 0.81 (0.26) with a mean value of 0.73 (SD =0.29); 22% of patients had a utility value of 1 (ceiling effect) and 3.2% had a utility value lower than 0. The factors associated with utilities in the multivariate analysis were sex (beta =-0.084, 95% confidence interval [CI]: -0.154; -0.013 for females), number of exacerbations the previous year (-0.027, 95% CI: -0.044; -0.010), and modified Medical Research Council Dyspnea Scale (mMRC) score (-0.123 [95% CI: -0.185; -0.061], -0.231 [95% CI: -0.301; -0.161], and -0.559 [95% CI: -0.660; -0.458] for mMRC scores 2, 3, and 4 versus 1), all P0.05. Conclusion: Multivariate analysis showed that female sex, frequent exacerbations, and an increased le

Rationale: Little is known about the longitudinal changes associated with using the 2013 update of the multidimensional GOLD strategy for chronic obstructive pulmonary disease (COPD). Objective: To determine the COPD patient distribution of the new GOLD proposal and evaluate how this classification changes over one year compared with the previous GOLD staging based on spirometry only. Methods: We analyzed data from the CHAIN study, a multicenter observational Spanish cohort of COPD patients who are monitored annually. Categories were defined according to the proposed GOLD: FEV1%, mMRC dyspnea, COPD Assessment Test (CAT), Clinical COPD Questionnaire (CCQ), and exacerbations-hospitalizations. One-year follow-up information was available for all variables except CCQ data. Results: At baseline, 828 stable COPD patients were evaluated. On the basis of mMRC dyspnea versus CAT, the patients were distributed as follows: 38.2% vs. 27.2% in group A, 17.6% vs. 28.3% in group B, 15.8% vs. 12.9% in group C, and 28.4% vs. 31.6% in group D. Information was available for 526 patients at one year: 64.2% of patients remained in the same group but groups C and D show different degrees of variability. The annual progression by group was mainly associated with one-year changes in CAT scores (RR, 1.138; 95%CI: 1.074-1.206) and BODE index values (RR, 2.012; 95%CI: 1.487-2.722). Conclusions: In the new GOLD grading classification, the type of tool used to determine the level of symptoms can substantially alter the group assignment. A change in category after one year was associated with longitudinal changes in the CAT and BODE index.

La presente Tesis Doctoral se enmarca en el estudio de la enfermedad pulmonar obstructiva crónica (EPOC) como enfermedad pulmonar con repercusión sistémica y se basa en el estudio de la expresión celular diferencial de marcadores inflamatorios inespecíficos haciendo un especial hincapié en la importancia de los reactantes de fase aguda. Con objeto de centrar la exposición de la metodología y poder valorar adecuadamente los resultados, iniciaremos el presente trabajo realizando una revisión de la situación actual del tema. En concreto, revisaremos los siguientes apartados: · EPOC. Concepto actual. Donde se revisarán los aspectos principales del concepto actual de la enfermedad, así como su estadificación funcional. · Conceptos básicos sobre su diagnóstico y detección en pacientes con factores de riesgo. · Epidemiología de la EPOC. Haciendo especial énfasis en la prevalencia, mortalidad y morbilidad. · Patogenia. Datos sobre la patogenia de la enfermedad, donde se discutirán los principales tipos celulares implicados en su génesis. · Importancia de la inflamación sistémica. Evaluación de la importancia de la inflamación sistémica dentro del nuevo marco conceptual de la EPOC como enfermedad sistémica. · Reactantes de fase aguda mayores. Importancia de los reactantes de fase aguda como parte de la inflamación sistémica y base de nuestro estudio. Existe producción de RFA por el tejido pulmonar siendo ésta diferente según el territorio y el tipo celular analizado y variando entre pacientes con EPOC frente a fumadores sanos, de manera que su síntesis se encuentra relacionada con la presencia de la enfermedad. Objetivos OBJETIVOS PRINCIPALES 1. Explorar la existencia de una expresión génica de RFA en sujetos sanos y comparala con los pacientes con EPOC. 2. Comparar la expresión génica de PCR y AAS en el tejido bronquial y en parénquima de pulmón humano. 3. Determinar la expresión de PCR y AAS en células epiteliales, macrófagos y fibroblastos pulmonares humanos. 4. Comparar

Aquaporin-1 (AQP1) is the main water channel responsible for water transport through many epithelia and endothelia. The latest evidence pointed toward an important role of this protein also in gas permeation, angiogenesis, cell proliferation and migration. In the present work we studied the expression of AQP1 by immunohistochemical staining of 92 lung biopsies from patients diagnosed with a pleuropulmonary tumor (71 lung and 21 pleural neoplasms). AQP1 expression was analyzed comparing the results among the different histological patterns and against 9 control cases (5 parenchyma and 4 healthy pleura). Clear staining of AQP1 was detected in 39 of the 92 tumors analyzed. In parenchyma, AQP1 was more frequently detected in primary lung denocarcinomas (55%,P<0.001); in contrast, small cell carcinomas were the least AQP1 expressive tumors studied (93% of negative staining, P<0.05). Carcinomas analyzed in pleura (mesotheliomas and metastatic adenocarcinomas) also revealed strong xpression of AQP1. High expression of this protein was detected in small capillaries in areas near or surrounding the tumor, and novel intense AQP1 immunostaining was detected over thicker alveolar walls in alveoli inside or next to the tumoral tissue regardless of the tumor type. An important role of AQP1 in tumor angiogenesis is sustained by the abundant expression of this protein in the endothelia of tumor capillaries. Further studies are necessary to elucidate the potential pathophysiological role of this protein in pleuropulmonary neoplasms.