International Journal of Chronic Obstructive Pulmonary Disease Dovepress open access to scientific and medical research Open Access Full Text Article PERSPECTIVES A Proposed Approach to Chronic Airway Disease International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ on 17-Oct-2023 (CAD) Using Therapeutic Goals and Treatable Traits: A Look to the Future This article was published in the following Dove Press journal: International Journal of Chronic Obstructive Pulmonary Disease Luis Pérez de Llano, 1 Marc Abstract: Chronic airflow obstruction affects a wide range of airway diseases, the most Miravitlles, 2 Rafael Golpe,1 Francisco frequent of which are asthma, COPD, and bronchiectasis; they are clearly identifiable in their Javier Alvarez-Gutiérrez, 3 Carolina extremes, but quite frequently overlap in some of their pathophysiological and clinical Cisneros,4 Carlos Almonacid, 5 Eva Martinez-Moragon,6 Francisco-Javier characteristics. This has generated the description of new mixed or overlapping disease For personal use only. Gonzalez-Barcala, 7 David Ramos- phenotypes with no clear biological grounds. In this special article, a group of experts Barbón, 8 Vicente Plaza, 8 Jose Luis provides their perspective and proposes approaching the treatment of chronic airway disease Lopez-Campos, 3 Juan Pablo de-Torres,9 (CAD) through the identification of a series of therapeutic goals (TG) linked to treatable Ciro Casanova,10 Juan Luis Garcia Rivero,11 traits (TT) – understood as clinical, physiological, or biological characteristics that are Juan Rodriguez Hermosa, 12 Myriam Calle Rubio, 12 Juan Jose Soler-Cataluña,13 quantifiable using biomarkers. This therapeutic approach needs validating in a clinical trial Borja G Cosio 14 with the strategy of identification of TG and treatment according to TT for each patient 1 independently of their prior diagnosis. Pneumology Service, University Hospital Lucus Augusti, Lugo, EOXI Cervo, Lugo, Monforte, Spain; Keywords: airflow obstruction, biomarker, personalised medicine, COPD asthma overlap 2 Pneumology Service, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, CIBERES, Barcelona, Spain; 3Pneumology Service, Hospital Universitario Virgen del Rocio, Seville, Spain; 4Pneumology Service, La Princesa University Introduction Hospital, Madrid, Research Institute La Princesa IIP, Current definitions identify the classical patterns (clinical and biological) of asthma Madrid, Spain; 5Pneumology Service, Ramón y Cajal Hospital (Ramon y Cajal Health Research Institute, and COPD unequivocally. However, the heterogeneous nature of both processes IRYCIS), Madrid, Spain; 6Pneumology Service, and their overlap in some cases has given rise to intense research in order to define Hospital Universitario Dr Peset, Valencia, Spain; 7 Faculty of Medicine at the University of Santiago more homogeneous groups of patients on the basis of phenotypes or endotypes. de Compostela, Pneumology Service of the University Clinical Hospital of Santiago de This problem is not new and was pointed out as far back as 1987 by Burrows et al, Compostela, CIBERES, Santiago de Compostela, Spain; 8Pneumology Service, Hospital de la Santa who described a group of patients (with what they called “asthmatiform bronchi­ Creu i Sant Pau, Barcelona, Spain; 9Division of tis”) who had a clinical evolution and prognosis that lay between asthma and Respirology and Sleep Medicine, Queen's University, Canada, ON, Canada; 10Pneumology COPD1 supporting the view of a common origin of asthma and COPD, the so- Service, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz De Tenerife, Spain; called Dutch hypothesis.2 Recent studies of lung function trajectories in COPD also support the influence of early childhood asthma in early lung development.3 This is 11 Pneumology Service, Hospital de Laredo, Laredo, Spain; 12Pneumology Service and Faculty of Medicine, Hospital Clínico San Carlos, now known as asthma-COPD overlap (ACO).4 ACO is a theoretical construct with Complutense University of Madrid, Madrid, Spain; 13 Pneumology Service, Hospital Arnau de Vilanova, no clear biological grounds and with an imprecise definition that encompasses both Valencia, Spain; 14Pneumology Service, Son Espases long-standing asthmatics who smoke and develop chronic airflow obstruction, and University Hospital, IdISBa, CIBERES, Clínica Quirón-Rotger, Palma, Spain patients with COPD who have blood eosinophilia or greater reversibility after Correspondence: Borja G Cosio a bronchodilator test,5 even though they have been shown to be very different Pneumology Service, Hospital Universitario Son Espases, IdISBa, CIBERES, Clínica Quirón-Rotger, from each other.6 Ctra. de Valldemossa 79, Palma de Mallorca 07010, Spain Some authors have already proposed leaving behind the approach based on Tel +34 871 206714 Ext 76714 phenotypes or endotypes in order to adopt a pragmatic view through the identifica­ Fax +34 871 909724 Email borja.cosio@ssib.es tion of “treatable traits” (TT) for each particular patient.7,8 However, this novel submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2020:15 2091–2100 2091 DovePress © 2020 Pérez de Llano et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/ http://doi.org/10.2147/COPD.S263430 terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Pérez de Llano et al Dovepress approach contains a few inaccuracies as there is some Operational Definition of Chronic confusion as to what TT really are, and which ones should Airway Disease (CAD) be taken into account. The article published by The proposal is to group patients who have Chronic McDonald et al9 defines them as “therapeutic targets iden­ Airflow Obstruction under the common denomination of tified by the phenotype or endotype through validated Chronic Airway Disease (CAD) – defined as an obstruc­ biomarkers”. This publication puts forwards lists with tive spirometry pattern with post-bronchodilator FEV1 different TT that leave out cardinal symptoms such as /FVC below 0.70 – independently of the underlying etio­ dyspnoea while including others such as “smooth muscle pathogenic mechanism; and to adapt their treatment based contraction” or “oedema of the bronchial mucosa”, which on TG and TT that have been previously identified using are of doubtful clinical significance. What is more, contra­ biomarkers or specific diagnostic tests (Figure 1). dictorily, blood or sputum eosinophilia is considered a TT, whereas at the same time it is claimed not to be a TT, but Therapeutic Goals and Treatable rather a “TT biomarker”. Traits in CAD With the present document, a group of authors in the We argue that it is reasonable to separate clinical needs – areas of asthma and COPD from the Spanish Society of what we want to improve in each patient (TG) – from the Pneumology and Thoracic Surgery (SEPAR) aims to pro­ characteristics (TT) upon which action may be taken in order vide their insight with regard to the therapeutic approach to achieve this improvement. The definitions proposed for based on TT, by overcoming some inaccuracies so that this TG and TT are summarised in Table 1. We acknowledge that may be applicable in clinical practice, and be able to serve scientific evidence is still scarce in some cases, but we as a basis for a clinical trial in order to prove its effective­ believe this approach offers practical advantages when it ness. Further, we argue that the therapeutic goals (TG) set comes to deciding on therapeutic interventions for specific for each patient must be considered separately from the TT patients. In this article, we will discuss the TG and TT in upon which action can be taken in order to achieve them. CAD, and we will show that the different diseases making it Figure 1 Conceptual approach to treatment of CAD. Abbreviations: Eos, eosinophils; OCS, oral corticosteroids; PCR, polymerase chain reaction; FEV1, Forced expiratory volume in 1 second; COHb, carboxyhemoglobin; TAI, test of the adherence to inhalers; pO2, partial pressure of oxygen; pCO2, partial pressure of carbon dioxide; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting muscarinic antagonists; NRT, nicotine replacement therapy; NIV, non-invasive ventilation. 2092 submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2020:15 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Pérez de Llano et al Table 1 Definition and Characteristics of Therapeutic Goals and Treatable Traits Definition Characteristics Therapeutic goals These are the clinical needs of patients (symptoms, -These are not therapeutic targets, but rather clinical exacerbations, quality of life, physical activity) or aspects of problems that must be eliminated or improved the disease upon which action must be taken to improve -Most patients have several TG their prognosis (progression of the disease, mortality) -It is possible to improve different TG with a single therapeutic intervention Treatable traits These are the clinical, physiological, or biological -They must themselves have an impact on one of the TG characteristics present in each individual patient, and they are (that is, there must be a clear relationship between the value quantifiable through biomarkers or specific diagnostic tests. the characteristic takes and that of the objective in question; They must have effective treatment to improve the value of eg: more eosinophils, more exacerbations) the variable -Treatment, through the improvement of the value of the treatable trait must, as a result, improve one or more TG up (asthma, COPD, bronchiectasis . . .) basically coincide in these events worsen the quality of life of patients and their these. Table 2 summarises the TG and TT in CAD. prognosis.15,16 Lastly, it is of vital importance to avoid the iatrogeny associated with the treatment, which is espe­ Therapeutic Goals cially evident in the case of systemic corticosteroids.17 Two types of TG can be considered: symptomatic improve­ Control of symptoms, particularly dyspnoea, is an ment, and reduction of the risks involved in the disease and indisputable TG in CAD, taking into account its relation­ its treatment. The main TG is a reduction in mortality, some­ ship to the quality of life of patients. Besides, in the case thing that has already been achieved in asthma with the use of of asthma, poor symptomatic control represents a greater inhaled corticosteroids (ICS);10 however, even in developed risk of exacerbations,18 and in COPD it is independently countries, deaths are still recorded, but they are nearly always associated with mortality.19 associated to poor social conditions.11 COPD is a disease with a high mortality rate, although to date few strategies Treatable Traits have been proven to be effective in reducing it (for instance, * Therapeutic non-adherence (TN). It is well established that giving up smoking). TN in asthma is a risk factor for exacerbations.20 However, Exacerbations have a high impact on the quality of life different reminder systems (e-mails, telephone . . .) have been of asthmatics,12 as they are risk factors for mortality,13 and shown to improve adherence21 and, although some doubts also for loss of lung function.14 In COPD and bronchiec­ still persist concerning their impact on asthma control22 it tasis, control of exacerbations is also an evident TG, as seems reasonable to detect and reduce TN. Patients with poor Table 2 Therapeutic Goals and Treatable Traits in CAD Therapeutic Goals Treatable Traits Biomarker Associated to Therapeutic Trait Reduction of symptoms: - Bronchial obstruction -FEV1 -Dyspnoea -Non-adherence -Questionnaires -Night awakenings -Aggravating factors (allergens, environmental pollution, etc.) -Environmental levels -Health-related quality of life -Smoking -CO-oximetry Reduction of risk: -Comorbidities -Variable in each case -Reduce mortality -Eosinophilia -Eosinophils in blood or airways -Reduce progression of the disease - Chronic infection -Germ isolation -Prevent exacerbations - Chronic bronchitis - Chronic bronchitis -Reduce adverse effects of - Chronic hypoxemia -PaO2/SaO2 medication - Chronic hypercapnia -PaCO2 -Deficit of alfa1-AT -AAT levels -Lung hyperinflation - Inspiratory capacity submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2020:15 2093 DovePress Powered by TCPDF (www.tcpdf.org) Pérez de Llano et al Dovepress adherence to the treatments used in COPD are at greater risk treatment of severe eosinophilic asthma has been perfectly of being hospitalised and even passing away.23,24 Some established.44 interventions may improve therapeutic adherence in this Eosinophilia, measured in induced sputum or in per­ disease.24 ipheral blood, is a good marker of the therapeutic response * Tobacco use. Smoking worsens asthma control in to ICS also in COPD. Due to the difficulty in using sputum a dose-dependent way.25 However, giving up the habit eosinophilia as a biomarker in usual clinical practice, improves both the lung function and symptoms of blood eosinophilia is emerging as the most useful TT asthmatics.26 Carrying on smoking bears a strong relation­ biomarker in order to decide about the use of ICS as ship to morbidity and mortality in COPD, whereas giving it maintenance treatment in COPD.45–50 up is associated to clear improvements in survival rates.27 * Chronic bronchial infection. The isolation of poten­ * Comorbidities. The presence of certain comorbidities tially pathogenic microorganisms (PPMs) in bronchial associated with asthma are linked to poorer control of the secretions of patients with COPD is considered to be disease28 and specific treatment for any of them improves a chronic infection, instead of a colonization.51 it, as occurs for instance with polyposis and obstructive Colonization implies no harm to the host, and, by defini­ apnoea syndrome during sleep.29,30 Patients with COPD tion, it would not require any type of treatment, but PPMs and bronchiectasis suffer from numerous comorbidities in stable COPD are associated with increased inflamma­ that aggravate their prognosis.31–34 Nevertheless, these tion, increased frequency and severity of exacerbations must be considered independent diseases that require spe­ and faster decline in pulmonary function; therefore, the term colonization is no longer considered adequate.52 cific treatment which, on most occasions, does not depend Regarding the treatment of chronic bronchial infection in on their association with chronic airway disease. chronic airway diseases, there is limited experience in Gastroesophageal reflux is associated with a greater risk asthma and COPD. The isolation of Pseudomonas aerugi­ of exacerbations, but there is no definitive evidence that its nosa has been shown to be associated to a greater risk of treatment reduces its incidence.35 exacerbation in asthma, and the AMAZES study evi­ * Bronchial obstruction. In asthma, FEV1 below 80% denced that azithromycin at a dose of 500 mg 3 times of the theoretical value is an independent predictor of a week, as a treatment added to the usual medication, is exacerbations36 and poor lung function is related (albeit capable of reducing severe exacerbations and improving imperfectly) to symptoms of the disease.37 Further, several the quality of life of poorly controlled asthmatics despite clinical trials have demonstrated that tiotropium added to a combination of ICS/LABA.53 Several studies have a combination of inhaled corticosteroids and long-acting demonstrated that long-term treatment with macrolides β-2 agonists (ICS/LABA) in poorly controlled asthmatics reduces exacerbations in COPD.54–56 with bronchial obstruction achieves significant functional Clinical trials of intermittent treatment with quinolones improvement (approximately 100 mL), resulting in a 21% in patients with chronic bronchial infection have been reduction of exacerbations,38 accompanied by sympto­ shown to decrease exacerbations.57 However, this treat­ matic improvement independently of blood eosinophils.39 ment is not currently recommended due to the risk of In COPD, bronchial obstruction is associated with greater inducing resistance against a first-line drug in the manage­ mortality, more symptoms, and more exacerbations.40 ment of exacerbations. Other measurements of airflow obstruction such as air The greatest experience is in bronchiectasis and, there­ trapping or lung hyperinflation would need to be explored. fore, we consider that treatment must follow the recom­ * T2 Inflammation. The presence of T2 inflammation, mendations of antibiotic treatment of chronic bronchial measured by the presence of eosinophils, both local and infection in bronchiectasis.58 According to the pathogen, peripheral is associated with poorer asthma control and the antimicrobial resistance pattern and the clinical mani­ more exacerbations.41 Besides, it has been proven that eosi­ festations, treatment may consist of a course of antibiotics, nophilia is a good predictor of the response to the long-term use of macrolides or inhaled antibiotics. corticosteroids,42 and that adjusting the treatment of severe * Chronic bronchitis. Patients with COPD and chronic asthma on the basis of sputum eosinophilia reduces bronchitis suffer more exacerbations, have a poorer quality exacerbations.43 The role of the monoclonal antibodies anti- of life, and experience greater loss of lung function than interleuquina-5 (anti-IL-5) and anti-IL4 and 13 in the subjects without a production of sputum.59 Mucolytics 2094 submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2020:15 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Pérez de Llano et al could also have a beneficial effect in patients with emphy­ out, not even in expert consultations. The AMPUL study72 sema owing to their antioxidising action, but another drug demonstrated that adjusting medication on the basis of used to reduce exacerbations, roflumilast, is indicated only methacholine test results could improve lung function in patients with chronic bronchitis.60 and reduce exacerbations (mild ones), but a single study In patients with asthma, mucous hypersecretion is asso­ does not seem to be enough to justify considering ciated with more symptoms, more obstruction, and more BHR a TT. exacerbations.61 Furthermore, in this case, roflumilast has In COPD, BHR appears to be a biomarker that is able revealed improvement of symptoms and lung function in to identify subgroups of patients with greater risk of dis­ asthmatics when added to montelukast, in comparison to ease progression and mortality.73 These subjects could, this drug used in monotherapy.62 hypothetically, be the best target group for treatment with * Respiratory insufficiency. Severe chronic hypoxemia ICS, which would confer this variable the character of TT. is a factor associated with a rise in mortality in COPD, and However, using this trait to indicate treatment with corti­ its correction is one of the few interventions known to costeroids has not yet been demonstrated to produce clini­ increase survival in the disease, wherefore it constitutes an cally relevant results. evident TT.63,64 Chronic hypercapnic respiratory insuffi­ - Left ventricular diastolic dysfunction associated with ciency is associated with greater risk of mortality,65 which lung hyperinflation. Some patients could present an altera­ could be modified through the use of non-invasive ventila­ tion in filling of the left ventricle produced specifically by tion (even though there are some discordant studies in this the hyperinflation associated with COPD. Bronchodilator regard),66–68 in which case it could also be considered treatment has been shown to be able to improve left ventri­ a treatable trait. cular telediastolic volume in these cases.71 Thus, it is con­ * In contrast, we do not consider the following to be ceivable that in the future it will emerge as a new TT in TT at this time, due to a lack of clear evidence in some of COPD; however, for the time being, information is limited the fundamental aspects (although this is something that to a single study, and its relationship with dyspnoea, mor­ could change in the future): tality, and other clinical outcomes has not yet been proven, - Exhaled nitric oxide fraction (FeNO). Despite the fact whereby it is still premature to consider it as such. that this is widely used clinically, there is ongoing con­ troversy as to whether adjusting treatment on the basis of its values improves asthma control, and neither is there Unified Treatment of CAD and a well-established cut-off point separating what is normal Controversial Points from pathological; consequently, a recent review in the Figure 1 shows a unified conceptual approach to the treat­ Cochrane database advises against this indication (except, ment of CAD – independently of the “classical” diagno­ perhaps, in patients with frequent exacerbations).69 In sis – based on TG and TT using their biomarkers or COPD, something similar happens: its persistent high specific diagnostic tests. This conceptual approach poses levels seem to be associated to a greater risk of exacerba­ a series of problems in clinical practice: tion of COPD,70,71 but a therapeutic strategy based on this The definition of “high T2”: It seems evident that biomarker has not yet been demonstrated to have an blood eosinophils must be included in this definition. impact on clinical results, and neither has the best cut-off Ideally, eosinophilia should be measured in airways, but points been established as yet. this is not feasible from a practical point of view at this -Allergy. Immunotherapy is not indicated in severe time. According to the literature, the reasonable cut-off asthma, which usually presents with non-reversible bron­ point appears to be 300 cells/µL. It must be taken into chial obstruction, and allergic avoidance is not well estab­ account that eosinophil count is affected by treatment with lished in this context. oral corticosteroids (OCS), high doses of inhaled corticos­ - Bronchial hyperresponsiveness (BHR). Asthma con­ teroids (ICS), and biological drugs, so historical values trol and degree of BHR do not show a close relationship should be taken into consideration. and a large percentage of patients with good control of the The question also arises as to whether FeNO ought to disease exhibit ongoing BHR. Further, bronchoprovoca­ be considered a marker of “high T2”, since high values tion tests are contraindicated with FEV1 < 65% and their can be recorded in patients with rhinitis or respiratory relative complexity means they are not routinely carried infection. Besides, there is no clear cut-off point to submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2020:15 2095 DovePress Powered by TCPDF (www.tcpdf.org) Pérez de Llano et al Dovepress separate what is normal from abnormal, and each device previous diagnosis, and with a significant clinical impact offers different values of FeNO. Therefore, although its (measured by 2 exacerbations requiring oral corticoster­ use is widespread in routine clinical practice and it may be oids or antibiotics in the previous year and ACT<19 or useful in some situations, it does not seem advisable at the CAT>10) would be recruited and randomized. At one arm, current time to classify it as a TT. patients would be classified according to their prior diag­ Meanwhile, neither is the definition of “low T2” clear nosis (asthma, COPD or bronchiectasis) and would be enough to make it possible to claim that a patient will not treated in accordance with the recommendations in inter­ benefit from anti-inflammatory treatment with corticoster­ national guidelines (GINA, GOLD, or ERS bronchiectasis oids or biological therapy working on T2 inflammation. In guidelines).81 In the other, patients would be treated in COPD there are already data that suggest that an eosino­ accordance with the TG/TT strategy, independently of phil count below 100 cells/µL enables a poor response to their original diagnosis. Patients should be stratified ICS to be predicted;74 and in asthma, data from the according to their level of airflow obstruction severity (to SIENNA study point in the same direction in patients avoid differences between the two groups) in the initial with a low sputum eosinophil count.75 visit. The follow-up period would be 12 months, and - According to this approach, patients classically diag­ adjustments in medication could be made depending on nosed as COPD and “high T2” would be treated with ICS, their evolution. The main response variable ought to be the whereas patients with the diagnosis of asthma and “low burden the disease represents for the patient, by grouping T2” would not receive them. There is a good number of specific aspects such as severe exacerbations and health published reports to support the former statement,45–50 but status. The main objective would be to demonstrate that the evidence to underpin the latter is more limited. the strategy based on TG/TT achieves a greater proportion Nevertheless, it has been shown that both sputum and of controlled patients (without severe exacerbations, and blood eosinophilia predict significant response to corticos­ with ACT ≥ 20 and CAT ≤10). Variables for secondary teroids in asthma patients.76–78 Bearing in mind that objectives would be exacerbations, pneumonias, quality of induced sputum is technically demanding, the number of life, and burden of corticosteroid treatment in both arms. eosinophils in blood and sputum can be influenced by As secondary analysis, other variables are to be explored treatment (particularly systemic and inhaled corticoster­ such as FeNO, BHR, sputum eosinophils and microbiota oids) and the predictive value of these two biomarkers is or lung hyperinflation. far from perfect, it seems risky to leave a patient with bronchial obstruction – a clinical presentation compatible Conclusions with asthma and a low blood eosinophil count – without Asthma, COPD, and other obstructive bronchial processes ICS. Although blood eosinophil count is universally avail­ can have similar TG and TT, which enables them to be able, it is an imperfect surrogate for airway eosinophilia encompassed in a broader concept: chronic airways dis­ and a significant proportion of patients in real life have ease (CAD). It is possible to develop a therapeutic algo­ eosinophil counts between 100 and 300 cells/µL, in which rithm that is valid for CAD, based on TG and TT, although case it would be necessary to draw up a therapeutic the one put forward herein lacks prospective validation approach based on other TT (obstruction, infection, etc.) (we propose launching a clinical trial) and relies on bio­ and/or carry out a therapeutic trial with anti-inflammatory markers with some limitations in identifying the under­ drugs. While novel omics-based signatures have emerged, lying inflammatory process. We have absolutely no doubt they have hardly ever been evaluated clinically, although that in the near future we will be able to have more precise a limited number of investigations have observed that tools available in order to decide the treatment for each a given gene expression signature in respiratory samples patient, without the most relevant being the classical clin­ can predict response to corticosteroids.79,80 ical diagnosis. Clinical Trial Proposal Disclosure Evidently, this conceptual approach must be validated in Luis Perez de Llano declares to have received grants and/ a clinical trial. We propose launching a prospective, multi- or fees for consultancy or speeches from Novartis, Astra- centre, open-label, double-arm clinical trial. Patients with Zeneca, GSK, Teva, Boehringer-Ingelheim, Chiesi, Sanofi, post-bronchodilator FEV1/FVC<0,70 regardless of the Menarini, Mundipharma, and Esteve, and reports grants, 2096 submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2020:15 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Pérez de Llano et al personal fees, and non-financial support from TEVA, Menarini, Chiesi and Mundipharma, and personal AstraZeneca, TEVA, and Chiesi, personal fees and non- fees from ALK, outside the submitted work. Carlos financial support from GSK, Novartis, Mundipharma and Almonacid declares to have received funding in the last 5 Boehringer, personal fees from Sanofi, other from years from Astra-zeneca, GSK, Novartis, Chiesi, Menarini, and personal fees from Esteve, BIAL, Mundipharma, Menarini, and TEVA, by way of aid to attend TECHDOW PHARMA, MSD, and ROVI S.A., outside congresses, or as speaking or consulting fees, and reports the submitted work; grants and personal fees from GSK and AstraZeneca, personal Marc Miravitlles has received speaking fees from fees from ALK, Novartis, Chiesy, and Mundipharma, and AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, non-financial support from Menarini, outside the submitted AstraZeneca, Menarini, Rovi, Bial, Zambon, CSL Behring, work. Eva Martinez-Moragon declares to have received fund­ Grifols, and Novartis; consulting fees from AstraZeneca, ing in the last 5 years from Astra-zeneca, GSK, ALK, Boehringer Ingelheim, Chiesi, Ferrer, GlaxoSmithKline, Novartis, Chiesi, Mundipharma, Menarini, and TEVA, by Bial, Gebro Pharma, CSL Behring, Laboratorios Esteve, way of aid to attend congresses, as speaking fees, or participa­ Ferrer, Mereo Biopharma, Verona Pharma, TEVA, pH tion in scientific consultancy. Francisco-Javier Gonzalez- Pharma, Novartis, and Grifols; and aid for research from Barcala has received speaking fees or research grants from GlaxoSmithKline and Grifols, and reports personal fees from ALK, AstraZeneca, Bial, Boehringer Ingelheim, Chiesi, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Gebro Pharma, GlaxoSmithKline, Laboratorios Esteve, Rovi, Bial, Sandoz, Zambon, CSL Behring, Novartis, Menarini, Mundipharma, Novartis, Rovi, Roxall, GlaxoSmithKline, Gebro Pharma, Kamada, Laboratorios Stallergenes-Greer, and Teva, and reports speaker fees, con­ Esteve, Ferrer, Mereo Biopharma, Verona Pharma, TEVA, sulting fees or research grants from ALK, Astra-Zeneca, Spin Therapeutics, pH Pharma, Sanofi and Grifols, and grants Bial, Boehringer Ingelheim, Chiesi, Gebro Pharma, from GlaxoSmithKline and Grifols, outside the submitted GlaxoSmithKline, Laboratorios Esteve, Menarini, work. Rafael Golpe declares that he has received speaking or Mundipharma, Novartis, Rovi, Roxall, Stallergenes-Greer advisory fees, or economic aid to attend congresses from and Teva. David Ramos-Barbón reports personal fees from Astra-Zeneca, GSK, Novartis, Chiesi, Mundipharma, GlaxoSmithKline, AstraZeneca, TEVA Pharmaceuticals, per­ Menarini, TEVA, Grifols, Ferrer, Boehringer-Ingelheim, sonal fees and non-financial support from Novartis and Chiesi, Rovi, and Gebro. Borja G Cosío declares he has received non-financial support from Boehringer-Ingelheim, and perso­ speaking or advisory fees, or economic aid to attend con­ nal fees from BIAL Pharmaceuticals, outside the submitted gresses from Astra-Zeneca, GSK, Novartis, Chiesi, work. Vicente Plaza declares to have received, in the last 3 Mundipharma, Menarini, TEVA, Boehringer-Ingelheim, and years, fees for participating as speaker at meetings sponsored Rovi and reports personal fees from AstraZeneca, by AstraZeneca, Chiesi, and Novartis, and as a consultant GlaxoSmithKline, Rovi, Boehringer-Ingelheim, Chiesi, from ALK, AstraZeneca, Bial, Boehringer, MundiPharma, Menarini, Rovi, Zambon, Grifols, Novartis, Ferrer, Gebro and Sanofi; he received economic aid to attend congresses Pharma, and Laboratorios Esteve, during the conduct of the from AZ, Chiesi, and Novartis; and he received subsidies for study. Francisco Javier Alvarez-Gutiérrez declares that in the research projects from AZ, Chiesi, and Menarini; and reports last 3 years he has received fees for advisory work, lectures, or grants and personal fees from AstraZeneca and Chiesi, grants subsidies to attend congresses and scientific meetings from from Menarini, and personal fees from Sanofi, Mundipharma, ALK, AstraZeneca, BIal, Boehringer-Ingelheim, Chiesi, GSK, Boehringer-Ingelheim, GlaxoSmithKline, and Merck, outside Menarini, Mundipharma, Novartis, and TEVA. Carolina the submitted work. Jose Luis López-Campos has received Cisneros has received speaking fees from AstraZeneca, fees, in the last 3 years, for giving lectures, scientific GSK, TEVA, Menarini, Mundipharma, and Novartis; aid to consultancy, participation in clinical studies, or writing papers attend congresses from Chiesi, TEVA, Menarini, and for (alphabetical order): AstraZeneca, Boehringer Mundipharma; and fees for advisory work from ALK, Ingelheim, Chiesi, CSL Behring, Esteve, Ferrer, Gebro, AstraZeneca, MundiPharma, TEVA, GSK, and Novartis, and GlaxoSmithKline, Grifols, Menarini, Novartis, Rovi, and reports grants, personal fees, and non-financial support from Teva, and reports personal fees and non-financial support AstraZeneca, grants and personal fees from GSK and from AstraZeneca, grants, personal fees, and non-financial Novartis, personal fees and non-financial support from support from Boehringer, Chiesi, GSK, Grifols, Menarini, submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2020:15 2097 DovePress Powered by TCPDF (www.tcpdf.org) Pérez de Llano et al Dovepress and Novartis, personal fees from CSL Behring, Esteve, and 4. Barnes PJ. Asthma-COPD Overlap. Chest. 2016;149(1):7–8. doi:10.1016/j.chest.2015.08.017 Ferrer, grants and personal fees from GebroPharma, and per­ 5. Miravitlles M, Alvarez-Gutierrez FJ, Calle M, et al. Algorithm for sonal fees from Rovi and Teva, outside the submitted work. identification of asthma-COPD overlap: consensus between the Ciro Casanova has received fees for giving lectures, scientific Spanish COPD and asthma guidelines. Eur Respir J. 2017;49 (5):1700068. doi:10.1183/13993003.00068-2017 consultancy, participation in clinical studies, or writing papers 6. Pérez-de-Llano L, Cosio BG. Asthma-COPD overlap is not for (alphabetical order): AstraZeneca, Bial, Boehringer a homogeneous disorder: further supporting data. Respir Res. 2017;18(1):183. doi:10.1186/s12931-017-0667-x Ingelheim, Chiesi, Esteve, Gebro, GlaxoSmithKline, 7. Agusti A, Bel E, Thomas M, et al. Treatable traits: toward precision Menarini, Novartis, Rovi, and Teva, and reports non- medicine of chronic airway diseases. Eur Respir J. 2016;47 financial support from Astra-Zeneca, personal fees from (2):410–419. doi:10.1183/13993003.01359-2015 8. Pavord ID, Beasley R, Agusti A, et al. After asthma: redefining Bial, Boehringer-Ingelheim, Chiesi, Esteve, and Novartis, airways diseases. Lancet. 2017;S0140-6736(17)30879–6. personal fees and non-financial support from GSK, and grants 9. McDonald VM, Fingleton J, Agusti A, et al. Treatable traits: a new paradigm for 21st century management of chronic airway diseases: and non-financial support from Menarini, outside the sub­ treatable traits down under international workshop report. Eur Respir mitted work. Juan Luis Rodriguez Hermosa has received J. 2019;53(5):1802058. doi:10.1183/13993003.02058-2018 speaking fees from Boehringer Ingelheim and Gebro Pharma 10. Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B. Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl and reports personal fees from Boehringer Ingelheim, Grifols, J Med. 2000;343(5):332–336. doi:10.1056/NEJM200008033430504 Gebro, and Glaxo, outside the submitted work. Myriam Calle 11. Gupta RP, Mukherjee M, Sheikh A, Strachan DP. Persistent varia­ tions in national asthma mortality, hospital admissions and preva­ Rubio has received speaking fees from Boehringer Ingelheim, lence by socioeconomic status and region in England. Thorax. AstraZeneca, GlaxoSmithKline, Menarini, and Novartis; and 2018;73(8):706–712. doi:10.1136/thoraxjnl-2017-210714 consulting fees from GlaxoSmith¬Kline, Gebro Pharma, and 12. Mroczek B, Kurpas D, Urban M, Sitko Z, Grodzki T. The influence of asthma exacerbations on health-related quality of life. Adv Exp Novartis, and reports personal fees from Boehringer Med Biol. 2015;873:65–77. Ingelheim, Menarini, Novartis, Gebro, Glaxo, and 13. McCoy L, Redelings M, Sorvillo F, Simon P. A multiple cause-of- death analysis of asthma mortality in the United States, 1990–2001. AstraZeneca, outside the submitted work. JJ Soler-Cataluña J Asthma. 2005;42(9):757–763. doi:10.1080/02770900500308189 declares to have received fees for giving lectures, scientific 14. O’Byrne PM, Pedersen S, Lamm CJ, Tan WC, Busse WW. START consultancy, or participation in clinical studies on behalf of Air investigators group. Severe exacerbations and decline in lung func­ tion in asthma. Am J Respir Crit Care Med. 2009;179(1):19–24. Liquide, AstraZeneca, Boehringer Ingelheim, Chiesi, Esteve, doi:10.1164/rccm.200807-1126OC Ferrer, GSK, Menarini, Mundipharma, Novartis, Rovi, 15. Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, Salcedo E, Navarro M, Ochando R. Severe acute exacerbations and Sandoz, and Teva and reports grants and personal fees from mortality in patients with chronic obstructive pulmonary disease. AstraZeneca, Chiesi, and GSK, grants, personal fees, and non- Thorax. 2005;60(11):925–931. doi:10.1136/thx.2005.040527 financial support from Boehringer-Ingelheim and Novartis, 16. Martínez-García MA, Athanazio R, Gramblicka G, Corso M, Cavalcanti Lundgre F. Prognostic value of frequent exacerbations in and personal fees from Bial, Ferrer, Rovi, and Teva, outside bronchiectasis: the relationship with disease severity. Arch the submitted work. Borja G Cosio reports grants and personal Bronconeumol. 2019;55(2):81–87. doi:10.1016/j.arbres.2018.07.002 fees from AstraZeneca, Chiesi, and GSK, personal fees from 17. Bloechliger M, Reinau D, Spoendlin J, et al. Adverse events profile of oral corticosteroids among asthma patients in the UK: cohort study Novartis, personal fees and non-financial support from with a nested case-control analysis. Respir Res. 2018;19(1):75. Mundipharma, and grants from Menarini, Teva, Boehringer- doi:10.1186/s12931-018-0742-y 18. Ko FW, Hui DS, Leung TF, et al. 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