[Home Respiratory Therapies: SEPAR Technical Document for Institutional Decision Support]. / Terapias respiratorias domiciliarias: documento técnico de la Sociedad Española de Neumología y Cirugía Torácica (SEPAR) de apoyo institucional a la toma de decisiones.

Home Respiratory Therapies (HRT) encompass a variety of treatments for patients with chronic respiratory diseases, administered at home over extended periods. The Service Providers of HRT (SPHRT) collaborate with hospital resources to address chronic respiratory diseases, acting as strategic partners. The contracting of HRT in the public health system involves contests where the SPHRT present technical and economic offers. The purpose of this document is to provide a technical basis that can assist professionals, SPHRT, and the administration in making decisions when calling for, evaluating, and deciding on such contests.

Home noninvasive ventilation in severe COPD: in whom does it work and how?

Background: Not all hypercapnic COPD patients benefit from home noninvasive ventilation (NIV), and mechanisms through which NIV improves clinical outcomes remain uncertain. We aimed to identify "responders" to home NIV, denoted by a beneficial effect of NIV on arterial partial pressure of carbon dioxide (PaCO2), health-related quality of life (HRQoL) and survival, and investigated whether NIV achieves its beneficial effect through an improved PaCO2. Methods: We used individual patient data from previous published trials collated for a systematic review. Linear mixed-effect models were conducted to compare the effect of NIV on PaCO2, HRQoL and survival, within subgroups defined by patient and treatment characteristics. Secondly, we conducted a causal mediation analysis to investigate whether the effect of NIV is mediated by a change in PaCO2. Findings: Data of 1142 participants from 16 studies were used. Participants treated with lower pressure support (<14 versus ≥14 cmH2O) and with lower adherence (<5 versus ≥5 h·day-1) had less improvement in PaCO2 (mean difference (MD) -0.30 kPa, p<0.001 and -0.29 kPa, p<0.001, respectively) and HRQoL (standardised MD 0.10, p=0.002 and 0.11, p=0.02, respectively), but this effect did not persist to survival. PaCO2 improved more in patients with severe dyspnoea (MD -0.30, p=0.02), and HRQoL improved only in participants with fewer than three exacerbations (standardised MD 0.52, p=0.03). The results of the mediation analysis showed that the effect on HRQoL is mediated partially (23%) by a change in PaCO2. Interpretation: With greater pressure support and better daily NIV usage, a larger improvement in PaCO2 and HRQoL is achieved. Importantly, we demonstrated that the beneficial effect of home NIV on HRQoL is only partially mediated through a reduction in diurnal PaCO2.

[Results of the Implementation of a Case-Finding Program for Alpha-1 Antitrypsin Deficiency in COPD Patients]. / Resultados de la implementación de un programa de detección de casos de déficit de alfa-1 antitripsina en pacientes con EPOC.

Objectives: Currently, the identification of new cases of alpha-1 antitrypsin deficiency (AATD) continues to be one of the great challenges facing the disease. The present study aims to perform an analysis of the results of the implementation of a systematic case detection program of AATD for patients with chronic obstructive pulmonary disease. Material and methods: Cross-sectional observational study in which the results of AAT screening until December 2022 were analyzed. The cases studied were divided into three periods: (1) no systematic case detection until 2013; (2) systematic case detection of S and Z alleles for cases with AAT < 90 mg/dL until 2018, and (3) systematic case detection of 14 mutations for cases with AAT < 120 mg/dL since 2018. Results: A total of 471 cases were studied, of which 306 (65.0%) were carriers of some mutation related to HAD. The number of detected cases of all mutations with their percentage against those studied in each period was respectively: 6 (100%), 48 (88.8%) and 253 (61.5%). If we limit to severe mutations (AAT < 57.2 mg/dL), the distribution by periods was respectively: 3 (50.0), 10 (18.5%) and 17 (4.1%). Conclusions: The present study describes the changes in the detection of patients carrying DAAT-related alleles with three different case identification policies. The data support the use of systematic case detection system in the COPD patient population.

Metallomic Signatures of Lung Cancer and Chronic Obstructive Pulmonary Disease.

Lung cancer (LC) is the leading cause of cancer deaths, and chronic obstructive pulmonary disease (COPD) can increase LC risk. Metallomics may provide insights into both of these tobacco-related diseases and their shared etiology. We conducted an observational study of 191 human serum samples, including those of healthy controls, LC patients, COPD patients, and patients with both COPD and LC. We found 18 elements (V, Al, As, Mn, Co, Cu, Zn, Cd, Se, W, Mo, Sb, Pb, Tl, Cr, Mg, Ni, and U) in these samples. In addition, we evaluated the elemental profiles of COPD cases of varying severity. The ratios and associations between the elements were also studied as possible signatures of the diseases. COPD severity and LC have a significant impact on the elemental composition of human serum. The severity of COPD was found to reduce the serum concentrations of As, Cd, and Tl and increased the serum concentrations of Mn and Sb compared with healthy control samples, while LC was found to increase Al, As, Mn, and Pb concentrations. This study provides new insights into the effects of LC and COPD on the human serum elemental profile that will pave the way for the potential use of elements as biomarkers for diagnosis and prognosis. It also sheds light on the potential link between the two diseases, i.e., the evolution of COPD to LC.

Pulmonologists' Opinion on the Use of Inhaled Corticosteroids in Chronic Obstructive Pulmonary Disease Patients in Spain: A Cross-Sectional Survey.

Introduction: Identifying the variables that guide decision-making in relation to the use of inhaled corticosteroids (ICS) can contribute to the appropriate use of these drugs. The objective of this study was to identify the clinical variables that physicians consider most relevant for prescribing or withdrawing ICS in COPD. Methods: A cross-sectional survey was conducted in Spain from November 2020 to May 2021. Therapeutic decisions on the use of ICS in 11 hypothetical COPD patient profiles were collected using an online survey answered by specialists with experience in the management of patients with COPD. Mixed-effects logistic regression was used to analyze the impact of patients' characteristics in the therapeutic decision for prescribing ICS or proceeding to its withdrawal. Results: A total of 74 pulmonologists agreed to collaborate in the survey and answered the questionnaire. The results showed great variability, with only 2 profiles achieving consensus for starting or withdrawing the treatment. The frequency and severity of exacerbations influenced the decision to prescribe ICS in a dose-response fashion (1 exacerbation odds ratio (OR) = 1.86, 95% confidence interval (CI) 1.02 to 3.43, two exacerbations OR = 11.6, 95% CI: 4.47 to 30.2 and three OR = 123, 95% CI: 25 to 601). Similarly, increasing blood eosinophils and history of asthma were associated with ICS use. On the other hand, pneumonia reduced the probability of initiating treatment with ICS (OR = 0.54 [0.29 to 0.98]). Lung function and dyspnea degree did not influence the clinician's therapeutic decision. The results for withdrawal of ICS were similar but in the opposite direction. Conclusion: In accordance with guidelines, exacerbations, blood eosinophils and history of asthma or pneumonia are the factors considered by pulmonologist for the indication or withdrawal of ICS. However, the agreement in prescription or withdrawal of ICS when confronted with hypothetical cases is very low, suggesting a great variability in clinical practice.

Inflammatory response in human lung cells stimulated with plasma from COPD patients.

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 culture 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 epithelial 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.

FIDEPOC: Consensus on Inspiratory Flow and Lung Deposition as Key Decision Factors in COPD Inhaled Therapy.

Purpose: The pharmacological treatment of chronic obstructive pulmonary disease (COPD) is largely based on inhaled bronchodilators. Inspiratory flow and lung deposition are key parameters to be considered in inhaled therapy; however, the relationship between these two parameters, the patient specificities, and the suitability of the inhaler type for COPD management has not been fully addressed. The present study follows a Delphi Panel methodology to find expert consensus on the role of inspiratory flow and lung deposition as key decision factors in COPD inhaled therapy. Methods: A two-round Delphi Panel, consisting of 38 statements (items) and completed by 57 Spanish pulmonologists, was carried out to measure the experts' consensus degree with each item. Results: A high degree of consensus was reached on most of the items consulted, among these inspiratory flow or inspiratory capacity should be periodically considered when choosing an inhalation device and to ensure the suitability of the inhaler used; the outflow velocity and particle size of the different devices should be considered to ensure adequate lung deposition; an active device (pressurized metered-dose inhalers (pMDI) or soft mist inhalers (SMI)) should be used in patients with low inspiratory flow to achieve adequate lung deposition; and, the use of dry powder inhalers (DPI) should be re-evaluated in patients with severe obstruction and severe exacerbations. Conclusion: This study shows the relevance of inspiratory flow and the degree of particle deposition in the lung in the choice of an inhalation device for COPD management, as well as the convenience of an SMI type device in cases of low inspiratory flow. Moreover, it highlights the scarcity of information on the specific features of inhalation devices in COPD guidelines.

Deconstructing Phenotypes in COPD: an Analysis of the TRACE Cohort. / Deconstruyendo los fenotipos en la EPOC: un análisis de la cohorte TRACE.

OBJECTIVES: In a clinical phenotype-based management strategy for COPD, it would be preferable to at least assign all patients to a phenotype, but to a single phenotype only. The aim of this study was to evaluate whether all patients are assigned to one and only one phenotype using the Spanish COPD guidelines (GesEPOC) and to evaluate the criteria that define these categories. METHOD: The Time-based Register and Analysis of COPD Endpoints study (TRACE; clinicaltrials.gov NCT03485690) is a prospective cohort of COPD patients attending annual visits since 2012, which collects GesEPOC phenotypes. Although the GesEPOC recommends that patients considered to be at low risk are not phenotyped, an analysis of the criteria for identifying high- and low-risk phenotypes was performed, comparing the distribution of phenotypes and the criteria applied between these 2 groups. RESULTS: The cohort included 970 patients with a confirmed diagnosis of COPD, divided into 427 (44.02%) low-risk and 543 (55.9%) high-risk patients. The most frequent phenotype was the non-exacerbator (44.9% of high-risk patients). Overall, 20.6% of low-risk patients met criteria for asthma-COPD overlap syndrome, while 9.2% of the cohort did not meet the diagnostic criteria for any phenotype, and 19.1% met the criteria for 2 phenotypes, with no differences between risk groups. CONCLUSIONS: Our data highlight some of the weaknesses of the current clinical phenotype strategy, revealing overlapping categories in some cases, and patients to whom no phenotype was assigned.

Predictors of Single Bronchodilation Treatment Response for COPD: An Observational Study with the Trace Database Cohort.

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.

Lung Deposition and Inspiratory Flow Rate in Patients with Chronic Obstructive Pulmonary Disease Using Different Inhalation Devices: A Systematic Literature Review and Expert Opinion.

BACKGROUND: Our aim was to describe: 1) lung deposition and inspiratory flow rate; 2) main characteristics of inhaler devices in chronic obstructive pulmonary disease (COPD). METHODS: A systematic literature review (SLR) was conducted to analyze the features and results of inhaler devices in COPD patients. These devices included pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs), and a soft mist inhaler (SMI). Inclusion and exclusion criteria were established, as well as search strategies (Medline, Embase, and the Cochrane Library up to April 2019). In vitro and in vivo studies were included. Two reviewers selected articles, collected and analyzed data independently. Narrative searches complemented the SLR. We discussed the results of the reviews in a nominal group meeting and agreed on various general principles and recommendations. RESULTS: The SLR included 71 articles, some were of low-moderate quality, and there was great variability regarding populations and outcomes. Lung deposition rates varied across devices: 8%-53% for pMDIs, 7%-69% for DPIs, and 39%-67% for the SMI. The aerosol exit velocity was high with pMDIs (more than 3 m/s), while it is much slower (0.84-0.72 m/s) with the SMI. In general, pMDIs produce large-sized particles (1.22-8 µm), DPIs produce medium-sized particles (1.8-4.8 µm), and 60% of the particles reach an aerodynamic diameter <5 µm with the SMI. All inhalation devices reach central and peripheral lung regions, but the SMI distribution pattern might be better compared with pMDIs. DPIs' intrinsic resistance is higher than that of pMDIs and SMI, which are relatively similar and low. Depending on the DPI, the minimum flow inspiratory rate required was 30 L/min. pMDIs and SMI did not require a high inspiratory flow rate. CONCLUSION: Lung deposition and inspiratory flow rate are key factors when selecting an inhalation device in COPD patients.

Effects of genetics and altitude on lung function.

OBJECTIVES: The aim of this work is to present a review on the impact of genetics and altitude on lung function from classic and recent studies. DATA SOURCE: A systematic search has been carried out in different databases of scientific studies, using keywords related to lung volumes, spirometry, altitude and genetics. RESULTS: The results of this work have been structured into three parts. First, the relationship between genes and lung function. Next, a review of the genetic predispositions related to respiratory adaptation of people who inhabit high-altitude regions for millennia. Finally, temporary effects and long-term acclimatisation on respiratory physiology at high altitude are presented. CONCLUSIONS: The works focused on the influence of genetics and altitude on lung function are currently of interest in terms of studying the interactions between genetic, epigenetic and environmental factors in the configuration of the pathophysiological adaptation patterns.

Triple therapy for COPD: a crude analysis from a systematic review of the evidence.

We systematically reviewed the current knowledge on fixed-dose triple therapies for the treatment of chronic obstructive pulmonary disease (COPD), with a specific focus on its efficacy versus single bronchodilation, double fixed dose combinations, and open triple therapies. Articles were retrieved from PubMed, Embase, and Scopus up to 3 August 2018. We selected articles with randomized controlled or crossover design conducted in patients with COPD and published as full-length articles or scientific letters, evaluating triple therapy combinations in a single or different inhaler, and with efficacy data versus monocomponents, double combinations, or open triple therapies. Our systematic search reported 108 articles, of which 24 trials were finally selected for the analysis. A total of 7 studies with fixed dose triple therapy combinations, and 17 studies with open triple therapies combinations. Triple therapy showed improvements in lung function [trough forced expiratory volume (FEV1) ranging from not significant (NS) to 147 ml], health status using the St. George's Respiratory Questionnaire [(SGRQ) from NS to 8.8 points], and exacerbations [risk ratio (RR) from NS to 0.59 for all exacerbations] versus single or double therapies with a variability in the response, depending the specific combination, and the comparison group. The proportion of adverse effects was similar between study groups, the exception being the increase in pneumonia for some inhaled corticosteroid (ICS) containing groups. The reviews of this paper are available via the supplementary material section.

The BIOMEPOC Project: Personalized Biomarkers and Clinical Profiles in Chronic Obstructive Pulmonary Disease. / Proyecto de biomarcadores y perfiles clínicos personalizados en la enfermedad pulmonar obstructiva crónica (proyecto BIOMEPOC).

Chronic obstructive pulmonary disease (COPD) is an entity with a heterogeneous presentation. For this reason, attempts have been made to characterize different phenotypes and endotypes to enable a more individualized approach. The aim of the Biomarkers in COPD (BIOMEPOC) project is to identify useful biomarkers in blood to improve the characterization of patients. Clinical data and blood samples from a group of patients and healthy controls will be analyzed. The project will consist of an exploration phase and a validation phase. Analytical parameters in blood will be determined using standard techniques and certain 'omics' (transcriptomics, proteomics, and metabolomics). The former will be hypothesis-driven, whereas the latter will be exploratory. Finally, a multilevel analysis will be conducted. Currently, 269 patients and 83 controls have been recruited, and sample processing is beginning. Our hope is to use the results to identify new biomarkers that, alone or combined, will allow a better characterization of patients.

Smart Vest for Respiratory Rate Monitoring of COPD Patients Based on Non-Contact Capacitive Sensing.

In this paper, a first approach to the design of a portable device for non-contact monitoring of respiratory rate by capacitive sensing is presented. The sensing system is integrated into a smart vest for an untethered, low-cost and comfortable breathing monitoring of Chronic Obstructive Pulmonary Disease (COPD) patients during the rest period between respiratory rehabilitation exercises at home. To provide an extensible solution to the remote monitoring using this sensor and other devices, the design and preliminary development of an e-Health platform based on the Internet of Medical Things (IoMT) paradigm is also presented. In order to validate the proposed solution, two quasi-experimental studies have been developed, comparing the estimations with respect to the golden standard. In a first study with healthy subjects, the mean value of the respiratory rate error, the standard deviation of the error and the correlation coefficient were 0.01 breaths per minute (bpm), 0.97 bpm and 0.995 (p < 0.00001), respectively. In a second study with COPD patients, the values were −0.14 bpm, 0.28 bpm and 0.9988 (p < 0.0000001), respectively. The results for the rest period show the technical and functional feasibility of the prototype and serve as a preliminary validation of the device for respiratory rate monitoring of patients with COPD.

Factors Affecting Lung Function: A Review of the Literature. / Factores que afectan a la función pulmonar: una revisión bibliográfica.

Lung function reference values are traditionally based on anthropometric factors, such as weight, height, sex, and age. FVC and FEV1 decline with age, while volumes and capacities, such as RV and FRC, increase. TLC, VC, RV, FVC and FEV1 are affected by height, since they are proportional to body size. This means that a tall individual will experience greater decrease in lung volumes as they get older. Some variables, such as FRC and ERV, decline exponentially with an increase in weight, to the extent that tidal volume in morbidly obese patients can be close to that of RV. Men have longer airways than women, causing greater specific resistance in the respiratory tract. The increased work of breathing to increase ventilation among women means that their consumption of oxygen is higher than men under similar conditions of physical intensity. Lung volumes are higher when the subject is standing than in other positions. DLCO is significantly higher in supine positions than in sitting or standing positions, but the difference between sitting and standing positions is not significant. Anthropometric characteristics are insufficient to explain differences in lung function between different ethnic groups, underlining the importance of considering other factors in addition to the conventional anthropometric measurements.

Understanding of COPD among final-year medical students.

Objective: Several previous studies have shown a suboptimal level of understanding of COPD among different population groups. Students in their final year of Medicine constitute a population that has yet to be explored. The evaluation of their understanding provides an opportunity to establish strategies to improve teaching processes. The objective of the present study is to determine the current level of understanding of COPD among said population. Methods: A cross-sectional observational study was done using digital surveys given to medical students in their final year at the Universidad de Sevilla. Those surveyed were asked about demographic data, smoking habits as well as the clinical manifestation, diagnosis and treatment of COPD. Results: Of the 338 students contacted, responses were collected from 211 of them (62.4%). Only 25.2% had an accurate idea about the concept of the disease. The study found that 24.0% of students were familiar with the three main symptoms of COPD. Tobacco use was not considered a main risk factor for COPD by 1.5% of students. Of those surveyed, 22.8% did not know how to spirometrically diagnose COPD. Inhaled corticosteroids were believed to be part of the main treatment for this disease among 51.0% of the students. Results show that 36.4% of respondents believed that home oxygen therapy does not help COPD patients live longer. Only 15.0% considered the Body-mass index, airflow Obstruction, Dyspnea, and Exercise (BODE) index to be an important parameter for measuring the severity of COPD. Giving up smoking was not believed to prevent worsening COPD among 3.4% of students surveyed. Almost half of students (47.1%) did not recommend that those suffering from COPD undertake exercise. Conclusion: The moderate level of understanding among the population of medical students in their final year shows some strengths and some shortcomings. Teaching intervention is required to reinforce solid knowledge among this population.

Double bronchodilation in chronic obstructive pulmonary disease: a crude analysis from a systematic review.

OBJECTIVE: The combination of a long-acting muscarinic antagonist (LAMA) and a long-acting ß2-agonist (LABA) in a single inhaler is a viable treatment option for patients with chronic obstructive pulmonary disease (COPD). Here, we systematically review the current knowledge on double bronchodilation for the treatment of COPD, with a specific focus on its efficacy versus placebo and/or monotherapy bronchodilation. METHODS: A systematic review of clinical trials investigating LABA/LAMA combination therapies was conducted. Articles were retrieved from PubMed, Embase, and Scopus on June 26, 2016. We specifically selected clinical trials with a randomized controlled or crossover design published in any scientific journal showing the following characteristics: 1) comparison of different LABA/LAMA combinations in a single inhaler for patients with COPD, 2) dose approved in Europe, and 3) focus on efficacy (versus placebo and/or bronchodilator monotherapy) in terms of lung function, respiratory symptoms, or exacerbations. RESULTS: We analyzed 26 clinical trials conducted on 24,338 patients. All LABA/LAMA combinations were consistently able to improve lung function compared with both placebo and bronchodilator monotherapy. Improvements in symptoms were also consistent versus placebo, showing some lack of correlation for some clinical end points and combinations versus monotherapy bronchodilation. Albeit being an exploratory end point, exacerbations showed an improvement with LABA/LAMA combinations over placebo in some trials; however, scarce information was available in comparison with bronchodilator monotherapy in most studies. CONCLUSION: Our data show consistent improvements for LABA/LAMA combinations, albeit with some variability (depending on the clinical end point, the specific combination, and the comparison group). Clinicians should be aware that these are average differences. All treatments should be tailored at the individual level to optimize clinical outcomes.