The EXACERBANTES Study (Exacerbation of Chronic Obstructive Pulmonary Disease According to the ANTES Proposal): Rationale, Goals and Design

Abstract

Introduction

COPD exacerbations (ECOPD) are complex events that demand a personalized approach. A novel patient-centered approach focuses on the identification of treatable traits (TTs) has recently been proposed.

Objectives

The primary goal of the EXACERBANTES study is to systematically describe the distribution of TTs in patients with ECOPD attending primary care (PC) and hospital-based emergency care (HC). Secondary goals include: (1) assessing the relationship between individual TTs and relevant clinical outcomes; (2) developing a predictive risk score based on TTs; (3) comparing the performance of different severity classifications; (4) validating these scores against the DECAF (Dyspnea, Eosinopenia, Consolidation, Acidosis, Atrial Fibrillation) index in hospitalized patients; (5) evaluating the feasibility of measuring FEV₁ during exacerbations using handheld microspirometers; and (6) comparing lung function during the acute phase with measurements taken 90 days later.

Material and methods

Prospective, multicenter, observational study involving patients diagnosed with ECOPD in PC and HC. The PC cohort will undergo routine and advanced testing including ECG, microspirometry, and capillary C-reactive protein (CRP). The HC cohort will undergo additional assessments such as blood tests, arterial blood gases, chest-X-test, and biomarkers (CRP, troponin T, NT-proBNP, D-dimer). Patients will be re-evaluated 90 days after the index event. The estimated sample size for the primary objective is 397 patients. The first patient was recruited on December 13, 2024; results are expected in the first quarter of 2026.

Conclusions

The EXACERBANTES study offers a framework to explore TTs in ECOPD and to develop a personalized, outcome-oriented treatment strategy.

Resumen

Introducción

Las agudizaciones de la EPOC (AEPOC) son eventos complejos que requieren un abordaje personalizado. Recientemente se ha propuesto un enfoque innovador centrado en el paciente, basado en la identificación de rasgos tratables (RT).

Objetivos

El objetivo principal del estudio EXACERBANTES es describir de forma sistemática la distribución de los RT en pacientes con AEPOC atendidos en Atención Primaria (AP) y en los servicios hospitalarios de urgencias (AH). Los objetivos secundarios incluyen: (1) evaluar la relación entre los RT individuales y los principales desenlaces clínicos; (2) desarrollar una puntuación predictiva de riesgo basada en RT; (3) comparar el rendimiento de diferentes clasificaciones de gravedad; (4) validar estas puntuaciones frente al índice DECAF (disnea, eosinopenia, consolidación, acidosis y fibrilación auricular) en pacientes hospitalizados; (5) evaluar la viabilidad de la medición del FEV₁ durante la agudización mediante microespirómetros portátiles; y (6) comparar la función pulmonar en fase aguda con las mediciones realizadas a los 90 días.

Material y métodos

Estudio observacional, prospectivo y multicéntrico que incluye pacientes diagnosticados de AEPOC en AP y en el ámbito hospitalario. La cohorte de AP se someterá a pruebas rutinarias y avanzadas que incluyen electrocardiograma, microespirometría y determinación capilar de proteína C reactiva (PCR). La cohorte hospitalaria será evaluada adicionalmente mediante analítica sanguínea, gasometría arterial, radiografía de tórax y determinación de biomarcadores (PCR, troponina T, NT-proBNP y dímero D). Los pacientes serán reevaluados a los 90 días del evento índice. El tamaño muestral estimado para el objetivo principal es de 397 pacientes. El primer paciente fue reclutado el 13 de diciembre de 2024 y se espera disponer de los resultados en el primer trimestre de 2026.

Conclusiones

El estudio EXACERBANTES proporciona un marco para explorar los RT en las AEPOC y para desarrollar estrategias terapéuticas personalizadas orientadas a resultados clínicos.

Rationale

The clinical course of chronic obstructive pulmonary disease (COPD) is often punctuated by acute episodes of increased symptoms, commonly referred to as exacerbations of the disease (ECOPD). These episodes worsen the health status of the patient, influence disease progression and clinical control, increase the risk of mortality, and generate a substantial demand of healthcare resources, with significant socioeconomic consequences.^1–4 Therefore, the prevention and appropriate management of ECOPD represent a key priority in COPD guidelines.^5,6

ECOPD are complex and heterogeneous events. Potential triggering factors (etiotypes), underlying biological mechanisms (endotypes), and clinical manifestations (phenotypes) vary across patients,^7,8 underscoring the need for a personalized approach. Yet, current therapeutic strategies are based almost universally on (more) bronchodilators, systemic corticosteroids, and antibiotics.^5,6 This non-precise management strategy leads to suboptimal outcomes.^4,9–11

To improve this scenario, three novel definitions of ECOPD have been recently proposed.^12–14 The Rome proposal¹² defines an ECOPD as “an event occurring in a patients with COPD characterized by worsening dyspnea and/or cough and sputum within ≤14 days, which may be accompanied by tachypnoea and/or tachycardia, and is often associated with increased local and systemic inflammation due to airway infection, pollution, or other airway insult.” This definition sets a temporal boundary, incorporates pathophysiological mechanisms (inflammation), and identifies major triggering factors. Furthermore, it includes a novel severity classification that considers multiple clinical variables and biomarkers.¹²

The 2021 edition of the Spanish COPD Guideline (GesEPOC) proposed a new definition based on a syndromic approach.¹³ The COPD Exacerbation Syndrome (CES) is defined as “a clinical instability episode occurring in a patient with COPD as a consequence of worsening expiratory airflow limitation or the underlying inflammatory process and characterized by an acute worsening of respiratory symptoms compared to the patient's baseline condition”. GesEPOC acknowledges that, from a pathophysiological perspective, the CES is a complex and heterogeneous event involving a range of distinct abnormalities that, either in isolation or more commonly in combination, manifest with a similar clinical presentation in patients with COPD. Essentially, like the Rome proposal, this definition emphasizes the underlying pathophysiology but differs from it in adopting a syndromic framework that allows the inclusion of various concomitant diseases. GesEPOC complements this new definition with a proposed severity classification that incorporates variables related to the underlying disease and additional parameters reflecting the intensity of the acute episode.¹³

In contrast to these two disease-centered approaches (Rome and GesEPOC), in which the disease itself is considered to decompensate, a patient-centered framework has also been proposed. This approach assumes that is the patient with COPD – rather than COPD itself – who decompensates as a result of multiple, often concurrent contributing factors.¹⁴ This novel personalized approach to care, termed ANTES proposal, is the result of expert consensus following a Delphi methodology within the ANTES (“earlier” in Spanish) program, a multicenter research initiative, supported by GlaxoSmithKline and led by a Scientific Committee of academic COPD experts in Spain that aims at anticipating the diagnosis and treatment of COPD to reduce or eliminate the very significant health-care burden of the disease.^15,16 The ANTES proposal for COPD exacerbations acknowledges that a wide range of etiopathogenic mechanisms may lead to clinical deterioration alone or in combination. Hence, the proposed management approach is based on the identification of distinct treatable traits (TTs)¹⁷ in three domains (respiratory, cardiovascular, and behavioral/educational/social). Treating specifically each of the TTs identified can promote a more personalized and precise management strategy that can lead to better outcomes. Yet, this proposal requires investigation and validation in clinical practice. Specifically, the distribution of TTs in patients with ECOPD seen in primary care (PC) or hospital setting care (HC) is likely to be different, potential associations or clusters of TTs are unknown, and their association with the severity of the episode and, most importantly, with relevant clinical outcomes requires research. In this manuscript we describe the methodology of the EXACERBANTES (Exacerbation of COPD according to the ANTES proposal) study designed to address these questions.

Study hypothesis and goals

The study's hypothesis of the EXACERBANTES study is based on four key conceptual pillars: (1) a systematic description of potential TTs during ECOPD is essential to address the complexity and heterogeneity of this condition; (2) the distribution and severity of TTs may differ between patients managed in PC or HC (emergency departments or day hospitals); (3) some TTs may be associated with clinically relevant outcomes; and (4) it may be feasible to develop a risk prediction model based on the presence of specific TTs.

Accordingly, the primary goal of the EXACERBANTES study is to systematically collect and describe the distribution of different TTs in patients presenting with ECOPD in PC and HC. Secondary goals are to: (1) evaluate the association between different TTs and various clinically relevant outcomes; (2) develop a novel risk stratification tool based on the identified TTs; (3) compare the predictive performance of this new tool with existing severity classifications, including the Rome and GesEPOC proposals^12,13; (4) compare the new risk scale with the DECAF score (Dyspnea, Eosinopenia, Consolidation, Acidosis, and Atrial Fibrillation),¹⁸ in the subgroup of patients attended in HC; (5) to assess the feasibility of determining the forced expiratory volume in the first second (FEV₁) using a micro spirometer during an ECOPD episode; and (6) comparing lung function during the acute phase with measurements taken 90 days later.

Methods

The EXACERBANTES study is a multicenter investigation, conducted within the framework of the Integrated Research Programs on COPD of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR). The study is also part of the ANTES initiative (clinicaltrials.gov ID: NCT06147206).^15,16

Study design

EXACERBANTES is an observational, prospective, multicenter study conducted in a cohort of patients attended for ECOPD in both PC and hospital settings (emergency departments or day hospitals). Patients will be reassessed 90 days after the index episode. The study involves 18 sites across Spain (listed in the online supplement), including both PC and HC sites. The first patient was enrolled on December 12, 2023, and results are expected in the first quarter of 2026 (Fig. 1).

Fig. 1.

Study design diagram. *Biomarkers to be tested, according to availability in different health care settings (primary care vs. hospital care). For further explanations, see text. ECOPD: COPD exacerbations; CAT: COPD assessment test; SaO₂: arterial oxygen saturation; ECG: electrocardiogram; CRP: C-reactive protein; NT-proBNP: N-terminal prohormone of brain natriuretic peptide; PE: pulmonary embolism; MACE: mayor adverse cardiovascular event.

Study population

Eligible participants include men and women aged ≥40 years presenting to emergency services (either PC or HC) for acute worsening of respiratory symptoms, regardless of the underlying cause. Additional inclusion criteria are current or former smoking history of ≥10 pack-years and evidence of expiratory airflow limitation, demonstrated by one of the following: (1) Post-bronchodilator FEV₁/forced vital capacity (FVC) < 0.7 on a previous spirometry; or (2) FEV1/FEV6 < 0.73 measured by microspirometry during the acute event. Exclusion criteria include active malignancy within the past 3 years, massive pleural effusion, pneumothorax, thoracic trauma, or inability to ensure follow-up after discharge.

Measurements

To identify the different TTs, all patients will undergo a set of core diagnostic tests. In patients managed in HC, an extended panel of investigations will also be performed (Table 1). The operational definition of the treatable traits evaluated in the study, including their diagnostic criteria and measurement methods, is summarized in Supplementary Table S1.

Table 1.

Battery of tests to be performed both in primary care and in hospital setting in the EXACERBANTES study.

	V0 (Exacerbation)	VEND (90 days, stability)
In all patients (primary care and hospital setting)
Complementary tests:
• CRP	X	X
• ECG	X
• COPD-6 (FEV1, FEV6, FEV1/FEV6)	X	X
Only in hospital setting
Extended complementary tests:
• Complete blood count and biochemistry.	X	X
• Biomarkers
̊ CRP	X	X
̊ NT-proBNP	X	X
̊ T troponin	X	X
̊ D dimer	X
• Chest X-ray	X
• Arterial blood gases	X
• Angio-CT (when PE is suspected)	X
• Forced spirometry and COPD-6	X	X

CRP: C-reactive protein; CT: computed tomography; NT-proBNP: N-terminal pro-B-type natriuretic peptide; PE: pulmonary embolism.

Core assessment in all participants (PC and HC)

Demographics, smoking history, and comorbidities, including calculation of the Charlson Comorbidity Index,¹⁹ will be collected for all patients. Patients will also be categorized by risk level and clinical phenotype according to GesEPOC,⁶ baseline GOLD classification,⁵ and treatment prior to the ECOPD event. Social or functional dependency will also be evaluated using five binary (yes/no) questions: Does the patient live alone?;Does the patient interact with relatives or neighbors other than the primary caregiver?;Does the patient need assistance for personal hygiene?;Does the patient require help climbing stairs?;Does the patient require help using public transportation?.

Besides, symptoms (cough, sputum production, sputum color, dyspnea, level of consciousness) and vital signs (temperature, respiratory and heart rates, blood pressure) will also be assessed and the COPD Assessment Test (CAT) will be administered.²⁰ Dyspnea will be evaluated using both the modified Medical Research Council (mMRC) scale²¹) and a Visual Analogue Scale (VAS) ranging from 0 to 10. A 12-lead electrocardiogram will be recorded and microspirometry will be performed using the COPD-6 Screener device (Vitalograph Ltd, Ireland) before the treatment of exacerbation will be administered. The following parameters will be recorded: FEV₁, FEV₆, and the FEV₁/FEV₆ ratio. In addition, C-reactive protein (CRP) levels will be measured in all cases; in primary care, this will be determined via capillary blood sampling.²² Finally, both the treatment administered during the acute episode and the treatment prescribed at discharge will be recorded, as per physician discretion. The Rome and GesEPOC severity classification^12,13 will be applied to all patients.

Extended assessment (HC only)

In patients managed in hospital settings (emergency room or day hospital), additional investigations will include: Blood tests, including eosinophil count and the neutrophil-to-lymphocyte ratio (NLR). Biomarkers as CRP, N-terminal pro-B-type natriuretic peptide (NT-proBNP), troponin T (TnT), and D-dimer. Chest radiography and arterial blood gas analysis will be performed in cases with oxygen saturation (SaO₂) ≤ 92%. In patients with suspected pulmonary embolism, contrast-enhanced computed tomography (CT pulmonary angiography) will be performed. In the subgroup of patients managed in HS, the DECAF score¹⁸ will also be calculated in addition to Rome and GesEPOC severity classification.^12,13 All these tests will be performed before receiving treatment or in the first few hours of the exacerbation.

Follow-up

A second visit will be conducted at least 90 days after the index exacerbation to assess vital status, relapse, recurrence, readmission, and major adverse cardiovascular events (MACE). Relapse is defined as a new worsening of respiratory symptoms occurring within 4 weeks of completing treatment for the index exacerbation. Recurrence refers to symptom worsening occurring beyond 4 weeks after completion of treatment. MACE is defined as the occurrence of at least one of the following cardiovascular events: acute myocardial infarction, unstable angina, coronary revascularization, heart failure, stroke, or cardiovascular death. All these outcomes will be reviewed and assigned by the investigator at each center according to standardized definitions. There is no centralized committee. During this follow-up visit, in addition to clinical evaluation, blood testing will be repeated to measure CRP, troponin, and NT-proBNP in all patients. Pulmonary function will also be re-assessed using both the COPD-6 device and standard spirometry according to international recommendations.²³

Outcomes

To assess the association between different TTs and clinically relevant outcomes, we evaluate a composite endpoint including relapse, recurrence, hospital readmission, MACE, or all-cause mortality. Each of these outcomes will also be analyzed individually.

Statistical analysis plan

Sample size calculation

The primary objective of the EXACERBANTES study is to assess the distribution of TTs in patients with ECOPD. As the prevalence of individual TTS in this clinical scenario remains largely unknown, a conservative prevalence estimate of 50% was assumed. Under this assumption, a random sample of 397 patients would allow the estimation of a population proportion of 50% with a 95% confidence level and a precision of ±5.5%. A replacement rate of 20% has been anticipated to account for potential losses to follow up.

Descriptive statistics

A descriptive analysis of the study sample will be performed. Continuous variables will be expressed as mean ± standard deviation (SD) or median and interquartile range (IQR), depending on their distribution. Categorical variables will be presented as absolute numbers and percentages. Comparisons between groups will be performed using Student's t-test or analysis of variance (ANOVA) for continuous variables and the Chi-square test or Fisher's exact test for categorical variables, as appropriate. A two-sided p value < 0.05 will be considered statistically significant.

Network analysis

To explore the relationship among treatable traits, a network analysis will be conducted. In this model, the node size will represent the prevalence of each TT, and the edges (connections between nodes) will reflect the strength of the bivariate correlation between traits. Pearson's correlation will be used for continuous variables, and Spearman's rank-order correlation matrix will be used for ordinal or categorical variables.

Multivariate analysis and risk score development

A multivariable logistic regression will be performed to identify independent predictors of adverse clinical outcomes. The dependent variable will be the occurrence of a composite endpoint including relapse, recurrence, hospital readmission, MACE, or all-cause mortality during the follow-up.

Candidate predictors will include the TTs identified during the index exacerbation. Variables showing a statistically significant association in univariate analysis and those considered clinically relevant will be considered for inclusion in the multivariable model. Model selection will be performed using a stepwise approach while taking clinical plausibility into account.

All TTs showing statistically significant associations in the prior bivariate analysis will be included as independent variables. Based on the resulting independent predictors and their odds ratios, a new risk prediction score will be constructed.

To minimize the risk of model overfitting, internal validation will be performed using bootstrap resampling techniques. Model discrimination will be assessed using the area under the receiver operating characteristic curve (C-statistic), and calibration will be evaluated using appropriate goodness-of-fit measures.

Machine learning analysis

In addition to regression-based modeling, exploratory machine learning approaches will be applied to assess potential non-linear relationships and interactions among variables. Decision tree models will be developed to identify potential patients subgroups with distinct risk profiles. These analyses will be considered exploratory and hypothesis-generating.

Cluster analysis

Cluster analysis will be conducted to explore the existence of potential phenotypic subgroups among patients with ECOPD based on the distribution of treatable traits. Both hierarchical clustering and partitioning methods (K-means and K-medoids) will be explored. Cluster solutions will be evaluated according to internal validity metrics and clinical interpretability.

Handling of missing data

Missing data will be explored to determine their pattern and potential mechanism. When appropriate, multiple imputation techniques will be applied to reduce potential bias associated with missing information.

Discussion

The concept of treatable traits represents a paradigm shift in the diagnosis and management of COPD.¹⁷ Moving away from the traditional diagnostic label approach, the TT-based strategy advocates for a multidimensional assessment of each patient's phenotypic and endotypic characteristics that are clinically relevant, measurable, and modifiable by appropriate treatment. This strategy aligns with the principles of precision medicine, aiming to personalize therapeutic interventions to improve clinical outcomes.¹⁷

Emerging evidence supports the effectiveness of this approach in identifying patients and guiding targeted therapies in asthma and COPD.^17,24 However, data on patients with ECOPD are very limited, restricted to observational studies in hospitalized populations.^25,26 In a recent multicenter, prospective cohort study²⁵ conducted in 475 patients hospitalized for ECOPD, authors analyzed a total of 28 TTs. An average of 9.1 ± 2.4 TTs per patient was identified, of which 5.7 ± 1.7 were pulmonary, 2.0 ± 1.1 extrapulmonary, and 1.4 ± 1.0 related to behavioral or risk factors. The total number of TTs was significantly associated with health status. During follow-up, 43% of patients experienced at least one moderate-to-severe exacerbation. Each additional TT was associated with a 14.2% increase in the risk of readmission (HR: 1.142, 95% CI: 1.056–1.237). In addition, the authors identified five core traits that independently predicted readmission: a history of frequent exacerbations, exercise-induced oxygen desaturation, eosinophilic airway inflammation, airway pathogen colonization, and gastroesophageal reflux.²⁵

This study illustrates the high prevalence of TTs in patients with ECOPD, encompassing pulmonary, extrapulmonary, and behavioral dimensions. It also suggests that risk models for future complications can be developed based on the presence and combination of TTs. However, these findings were derived from a Chinese cohort of hospitalized patients, requiring external validation in different clinical settings and diverse populations. TTs were selected based on prior literature and the information available in their database, potentially omitting traits of clinical relevance. Moreover, comorbidities were self-reported in some cases, which may have led to under- or overestimation.

The EXACERBANTES study aims to identify key TTs associated with ECOPD, explore their interrelationships, and assess their potential predictive value for short-term complications, with the goal of proposing a new risk stratification score. In contrast to the work by Meng et al.,²⁵ the EXACERBATES study will offer a broader perspective by encompassing the full spectrum of COPD exacerbations, including those requiring hospital admission, those managed in emergency departments, and those evaluated in primary care settings. Potential sources of selection bias should also be acknowledged. Patients managed in primary care are likely to represent milder exacerbations and may differ from those evaluated in hospital setting in terms of disease severity, comorbidity burden, and clinical presentation. These differences may influence the distribution of treatable traits and clinical outcomes, and should therefore be considered when interpreting the study findings.

Particular attention has been given to the analysis of certain potentially relevant TTs. One of the central pathophysiological features of ECOPD is the worsening of airflow limitation, which leads to gas trapping and lung hyperinflation.²⁷ However, the severity of airflow limitation—or the increase in static lung volumes—is rarely, if ever, assessed at the point of care. In our study, we will measure FEV₁ using the COPD-6 microspirometer. The use of handheld microspirometry during acute exacerbations may have several limitations. The COPD-6 device measures FEV₁ and FEV₆ instead of the conventional FEV₁/FVC ratio, which may introduce some variability in the estimation of airflow limitation. In addition, measurements obtained during the acute phase may be influenced by patient effort, dyspnea, and dynamic hyperinflation, potentially affecting reproducibility. Finally, although this device has been validated as a screening tool for COPD in stable patients, its performance in the context of exacerbations has been less extensively studied.²⁸ Despite these limitations, handheld microspirometry may represent a practical and feasible approach to approximate lung function during acute exacerbations.

In addition, the EXACERBANTES study will also evaluate educational and social determinants, both of which have been linked to an increased risk of hospitalization and mortality following COPD exacerbations.^29,30 Educational level is crucial for ensuring the correct use of inhaler devices and maintaining therapeutic adherence—factors consistently associated with improved health status, fewer hospital admissions, reduced healthcare utilization, and lower mortality rates.³¹ Likewise, social support programs have been shown to mitigate stress, enhance immune function, promote adherence to treatment, and ultimately lower the risk of future exacerbations.³²

Among the secondary objectives of the EXACERBANTES study is the development of a predictive risk model based on the most clinically relevant TTs. Traditionally, exacerbation severity has been classified according to healthcare resource utilization as mild if self-managed, moderate if treated with oral steroids and/or antibiotics in the outpatient setting, and severe if the patient was hospitalized. However, both the Rome proposal and the GesEPOC guidelines advocate for a more pathophysiological approach. The Rome classification, in particular, has been evaluated in various cohorts—especially in hospitalized patients, who are conventionally considered as having severe exacerbations based on resource-use criteria. When this new classification is applied, a significant proportion of patients are reclassified as moderate (ranging from 40% to 56%) or even mild (ranging from 14.3% to 41.9%).^33–37

However, the predictive capacity of Rome classification for adverse outcomes is not consistent across studies. Although the classification appears to better discriminate between mild and severe events, it shows limitations in distinguishing mortality risk between moderate and severe cases.^33–37 Notably, most of these studies do not adequately account for outpatient-managed exacerbations and are predominantly retrospective in nature. Consequently, important clinical variables—such as dyspnea assessment using the visual analog scale or measurement of respiratory rate—are frequently missed. The prospective design of our cohort, the broad range of care settings included, and the incorporation of core variables proposed in previous classifications will enable a more robust validation of the predictive capacity of each model. This approach will allow the direct comparison between existing proposals and may even support the development of a novel risk prediction model.

Conclusions

The EXACERBANTES study represents an opportunity to evaluate the distribution of TTs in a broad population of patients with ECOPD across varying levels of severity. Understanding the prevalence, interrelationships, and potential associations of TTs with relevant clinical outcomes may contribute to a more personalized approach to ECOPD management, ultimately aimed at improving patient outcomes.

Ethical considerations

The study protocol has been approved by the Ethics Committee of Hospital Arnau de Vilanova (Valencia, Spain) as reference center (meeting minutes 10_2023), and by all ethics committees of the participating centers. The study is conducted in accordance with the Declaration of Helsinki and the Spanish legislation on research with human beings and confidentiality and data protections.

Artificial intelligence involvement

No artificial intelligence was used at any stage of this study.

Informed consent

All patients will sign their written informed consent.

Funding

This study has been supported by GlaxoSmithKline (ANTES program).

Authors’ contributions

All authors participated in the conceptualization and design of the study and review manuscript writing. JJSC and AA contributed to manuscript writing.

Conflicts of interest

Juan José Soler-Cataluña has received grant research from GlaxoSmithKline, speaker fees from AstraZeneca, Bial, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini and Novartis, and consulting fees from Bial, Chiesi, GlaxoSmithKline and Novartis; Alberto Fernandez-Villar has received honoraria during the last 3 years for lecturing, scientific advice, participation in clinical studies or writing for publications for (alphabetical order): AstraZeneca, Bial, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Menarini and Novartis; José Luis Izquierdo reports personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, GSK, Grifols, Menarini, Novartis, Orion, Pfizer, Sandoz and Teva; Juan Luis García-Rivero has received speaker's fees from Gebro Pharma, Novartis, GlaxoSmithKline, Boehringer-Ingelheim, Astra-Zeneca, Chiesi, ALK, Teva, Menarini, Viso and Sanofi; and consulting fees from Novartis, GlaxoSmithKline, Astra-Zeneca, Teva, Boehringer-Ingelheim, ALK, Viso, Gebro Pharma and Sanofi, and research grants from Astra-Zeneca; Borja G Cosio has received grant research from Boehringer Ingelheim, Menarini and TEVA, speaker fees from AstraZeneca, Sanofi, Chiesi, GlaxoSmithKline, Menarini and Novartis, and consulting fees from Astrazeneca, Chiesi, TEVA, Sanofi, GlaxoSmithKline and Novartis; José Luis López-Campos has received honoraria during the last 3 years for lecturing, scientific advice, participation in clinical studies or writing for publications for (alphabetical order): AstraZeneca, Bial, Boehringer Ingelheim, Chiesi, CSL Behring, Ferrer, Gebro, GlaxoSmithKline, Grifols, Menarini, Megalabs, Novartis and Rovi; Marc Miravitlles has received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Glenmark Pharmaceuticals, Menarini, Kamada, Takeda, Zambon, Tabuk Pharmaceuticals, CSL Behring, Zambon, Specialty Therapeutics, Sanofi/Regeneron, Grifols and Novartis, consulting fees from AstraZeneca, Atriva Therapeutics, Boehringer Ingelheim, BEAM Therapeutics, GondolaBio, Chiesi, GlaxoSmithKline, CSL Behring, Ferrer, Korrobio, Menarini, Mereo Biopharma, Spin Therapeutics, Specialty Therapeutics, Palobiofarma SL, Takeda, Novartis, Novo Nordisk, Sanofi/Regeneron, Zambon, Zentiva and Grifols and research grants from Grifols; and Alvar Agustí has received grant research support from AstraZeneca, GlaxoSmithKline and Menarini, speaker fees from AstraZeneca, Chiesi, GlaxoSmithKline, Menarini and Zambon, and consulting fees from AstraZeneca, Chiesi, GlaxoSmithKline and Menarini.