International Journal of Chronic Obstructive Pulmonary Disease Dovepress open access to scientific and medical research Open Access Full Text Article PERSPECTIVES International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 158.109.88.164 on 18-Feb-2021 Time To Revise COPD Treatment Algorithm This article was published in the following Dove Press journal: International Journal of Chronic Obstructive Pulmonary Disease 1 Abstract: In 2017, a new two-step algorithm for the treatment of COPD was proposed. This Kazuto Matsunaga Keiji Oishi 2 algorithm was based on the severity of symptoms and phenotypes or treatable traits, and Marc Miravitlles 3 patient-specialised assessment targeting eosinophilic inflammation, chronic bronchitis, and Antonio Anzueto 4,5 frequent infections is recommended after exacerbation occurs despite maximal bronchodila- tion therapy. However, recent studies have revealed the clinical characteristics of patients 1 Department of Respiratory Medicine who should have second controllers added, such as ICS. We again realized that treatable and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube, traits should be assessed and intervened for as early as possible. Moreover, the treatment Yamaguchi, Japan; 2Department of algorithm is necessary to be adapted to the situation of clinical practice, taking into account Medicine and Clinical Science, Graduate the characteristics of the patients. The time to revise COPD treatment algorithm has come For personal use only. School of Medicine, Yamaguchi University, Ube, Yamaguchi, Japan; and we propose a new 3-step parallel approach for initial COPD treatment. After the 3 Department of Pneumology, Hospital diagnosis of COPD, the first assessment is to divide into two categories based on the usual Universitari Vall d’Hebron/Vall d’Hebron Research Institute (VHIR), Centro de clinical characteristics for patients with COPD and the specific clinical characteristics for Investigación Biomédica en Red each patient with concomitant disease. In the former, the assessment should be based on the Enfermedades Respiratorias (CIBERES), level of dyspnea and the frequency of exacerbations. After the assessment, mono- or dual Barcelona, Spain; 4Division of Pulmonary Diseases and Critical Care Medicine, bronchodilator should be selected. In the latter, the assessment should be based on asthma School of Medicine, The University of characteristics, chronic bronchitis, and chronic heart failure. After the assessment, patients Texas Health Science Center, San Antonio, TX, USA; 5Pulmonary Diseases with asthmatic characteristics may consider treatment with ICS, while patients with chronic Section, Audie L. Murphy Memorial VA bronchitis may consider treatment with roflumilast and/or macrolide, while patients with Hospital, South Texas Veterans Health chronic heart failure may consider treatment with selective β1-blocker. The 3-step parallel Care System, San Antonio, TX, USA approach is completed by adding an additional therapy for patients with concomitant disease to essential therapy for patients with COPD. In addition, it is important to review the response around 4 weeks after the initial therapy. This COPD management proposal might be considered as an approach based on patients’ clinical characteristics and on personalized therapy. Keywords: parallel approach, treatable traits, ICS, personalized therapy Introduction In 2017, a new two-step algorithm for the treatment of chronic obstructive pul- monary disease (COPD) was proposed.1 This treatment algorithm was based on the severity of symptoms and history of exacerbations. It can be argued that these are treatable traits. The algorithm underlies the importance to identify what are the COPD exacerbation’s precipitating factors, in order to provide patients’ with Correspondence: Kazuto Matsunaga appropriate prevention therapy. In this algorithm, patient-specialised assessment Department of Respiratory Medicine and Infectious Disease, Graduate School of targeting eosinophilic inflammation, chronic bronchitis, and frequent infections is Medicine, Yamaguchi University, 1-1-1 recommended after exacerbation occurs despite maximal bronchodilation therapy. Minami-kogushi, Ube, Yamaguchi 755-8505, Japan However, even just one severe exacerbation appears to accelerate the decline in Tel +81 836 85 3123 lung function, inducing physical inactivity, poorer quality of life, and an increased Fax +81 836 85 3124 Email kazmatsu@yamaguchi-u.ac.jp risk of death.2 Recent studies have revealed the clinical characteristics of patients submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 2229–2234 2229 DovePress © 2019 Matsunaga 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/ terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing http://doi.org/10.2147/COPD.S219051 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). Powered by TCPDF (www.tcpdf.org) Matsunaga et al Dovepress who should be added second controllers such as inhaled COPD are dyspnea, exacerbation, smoking, airflow limita- corticosteroids (ICS).3–6 Based on these evidence, we tion and physical inactivity, while specific clinical charac- again realized that treatable traits should be assessed and teristics for patients with concomitant disease are chronic International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 158.109.88.164 on 18-Feb-2021 intervened as early as possible. Moreover, the treatment bronchitis, cardiovascular disease, anxiety, depression and algorithm must be adapted to the situation of clinical other concomitant medical conditions.11 It is our firm belief practice, taking into account the characteristics of the that the approach of considering the specific concomitant patients. The time to revise COPD treatment algorithm disease in parallel with the usual clinical characteristics is has come and we propose a new 3-step parallel approach extremely important. We newly advocate a parallel for initial COPD treatment. approach for the management of COPD (Figure 1). In accordance with a concept of parallel approach for State Of The Art the management of COPD, we propose a new 3-step According to the latest 2019 update of the Global Initiative parallel approach for initial COPD treatment based on for Chronic Obstructive Lung Disease (GOLD) report, the evidence of recent studies (Figure 2). pharmacological treatment was divided into two algo- Once the diagnosis of COPD has been confirmed by rithms, “initial treatment” and “follow-up treatment”.7 spirometry, the first assessment is to divide into two cate- Initial pharmacological treatment has been recommended gories based on the usual clinical characteristics for by the ABCD grouping based on symptom burden and risk patients with COPD and the specific clinical characteris- of exacerbation after the initial diagnosis of COPD. In tics for each patient with concomitant disease. For personal use only. initial pharmacological management, use of ICS is recom- In usual clinical characteristics for patients with COPD, mended only for Group D patients with blood eosinophil the assessment (Step 1: assessment) should be based on the counts ≥ 300/μL or a history of asthma. If there is no level of dyspnea (as measured by the modified Medical response to the initial treatment, GOLD 2019 report pro- Research Council dyspnea scale, mMRC) and the fre- poses considering the predominant treatable trait to target quency of exacerbations. After the assessment, patients (dyspnea or exacerbations). The dyspnea algorithm path- with a mMRC score of 0 or 1 or no more than one exacer- way recommends escalation using additional long-acting bation during the previous year may start treatment with a bronchodilator (LABD) treatment for breathlessness. For mono-bronchodilator [a long-acting muscarinic antagonist patients with breathlessness who are already treated with a (LAMA) or a long-acting β-agonist (LABA)] whereas dual bronchodilator or dual bronchodilator and ICS com- patients with either a mMRC score higher than 1 or with bination, it is recommended to switch molecules or inhaler more than one exacerbation in the previous year should start device and to investigate other possible causes of dyspnea with a dual bronchodilator (LABA/LAMA) (Step 2: drug such as heart failure and pulmonary hypertension. The selection). For patients with persistent breathlessness on a exacerbation algorithm pathway recommends escalation monotherapy of LABDs, there might be room to consider a using additional LABD or ICS. If the above-mentioned combination therapy of LABDs. Our proposal based on the steps do not work, addition of roflumilast or macrolide was level of dyspnea and the frequency of exacerbations is recommended. similar to the algorithm published by Miravitlles and Anzueto in 2017.1 Additionally, for patients with COPD, Algorithm it goes without saying that smoking cessation, pulmonary GOLD 2019 report and many other algorithms recommend rehabilitation (or regular exercise) and vaccination are that the use of drugs other than LABDs should be after important as a treatment other than bronchodilator, and exacerbation occurs. However, considering the burden of they should be included under general recommendations exacerbations,8,9 it is very important to preemptive treat- to all patients.7 ment tailored to the treatable trait at the initial treatment. In specific clinical characteristics for patients with con- There are various risk factors and triggers for comitant disease, the assessment (Step 1: assessment) exacerbations,10 while risk factors and triggers can be should be based on the asthma characteristics, chronic roughly divided into two categories. It is the usual clinical bronchitis,12 and chronic heart failure.13 Most importantly, characteristics for patients with COPD and the specific our approach differs from many other algorithms in that clinical characteristics for patients with concomitant dis- the use of ICS has priority for the patients with asthma ease. The usual clinical characteristics for patients with characteristics. There is now more evidence that patients submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 2230 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Matsunaga et al International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 158.109.88.164 on 18-Feb-2021 For personal use only. Figure 1 A concept of parallel approach for the management of chronic obstructive pulmonary disease (COPD). with COPD and characteristics of asthma [asthma-COPD assessment, patients with asthmatic characteristics may overlap (ACO)] are recognized in several national and consider treatment with ICS (Step 2: drug selection). international guidelines.14–16 Because the definitive defini- From the viewpoint of the effectiveness and the risk of tion and diagnostic criteria have not been established, the side effects such as pneumonia, osteoporosis and myco- prevalence of ACO among patients previously diagnosed bacterial infection, there is a need to identify which as COPD has varied widely in studies: from 15% to patients will benefit from ICS. 55%.14 To manage COPD patients with asthma character- Patients with chronic bronchitis may consider treatment istics effectively, it is important to make the diagnosis.17 It with roflumilast and/or macrolide (Step 2: drug selection). is inaccurate to distinguish based on clinical characteristics Although gastrointestinal adverse effects and weight loss because no significant difference was observed in baseline were common, pooled analysis of recently completed two characteristics between patients with ACO and non- phase IV clinical studies confirmed the benefit of the phos- ACO.18 Therefore, ACO patients without history of phodiesterase (PDE) 4 inhibitor roflumilast in preventing asthma are easily overlooked. There is a COPD subgroup exacerbations in patients with prior hospitalization for characterized by asthma-like gene expression signatures of exacerbation and higher exacerbation frequency.21 The type 2 inflammation associated with airway eosinophilia mechanisms for the helpful therapeutic effects of macrolide and ICS responsiveness.19 In clinical practice, the desig- can go beyond their direct anti-infective effect because nation of the type 2 signature is commonly used in the latest data presented that they exert multiple effects on the presence of atopy and/or eosinophilic inflammation, iden- structure and composition of the lower airway microbiota tified on the basis of blood eosinophilia (≥ 300/μL) and with increased production of bacterial metabolites with anti- high level of fraction of exhaled nitric oxide (FeNO) (≥ 35 inflammatory properties.22,23 Mucolytic therapy such as ppb). Although FeNO has variability in patients with N-acetylcysteine, ambroxol or carbocisteine can also be COPD,20 these persistently elevated type 2 biomarkers considered for patients with chronic bronchitis. The ERS/ may reflect eosinophilic airway inflammation and predict ATS task force on the management of COPD exacerbations ICS responsiveness in patients with COPD.3–6 After the has reported the beneficial effect of the high-dose mucolytic submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 2231 DovePress Powered by TCPDF (www.tcpdf.org) Matsunaga et al Dovepress International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 158.109.88.164 on 18-Feb-2021 For personal use only. Figure 2 A new 3-step parallel approach for initial chronic obstructive pulmonary disease (COPD) treatment. Abbreviations: mMRC, modified Medical Research Council dyspnoea scale; LABA, long-acting β-agonist; LAMA, long-acting muscarinic antagonist; ICS, inhaled corticosteroids; FeNO, fraction of exhaled nitric oxide. agent in patients with frequent exacerbation despite optimal We now recognize that COPD patients also have other inhaled therapy.24 concomitant conditions which include anxiety/depression, Patients with chronic heart failure may consider treatment skeletal muscle dysfunction, osteoporosis, gastroesopha- with selective β1-blocker (Step 2: drug selection). The pre- geal reflux (GERD), bronchiectasis, metabolic syndrome, valence of heart failure patients combined with COPD is one- and lung cancer. COPD patients had a higher prevalence of third.25 β-Blockers were thought to be potentially unsafe to anxiety/depression, and anxiety/depression are associated COPD patients. However, a reduction in COPD-related mor- with poorer quality of life and survival.27 In contrast, there tality of 31% with usage of new selective β1-blocker was remain unanswered questions about adequate treatment pointed out in a systematic review and meta-analysis of retro- strategies of comorbid anxiety/depression in patients with spective cohort studies.26 Despite increasing evidence that COPD. Skeletal muscle dysfunction affects both ventila- selective β1-blocker is safe and beneficial in patients with tory and nonventilatory muscle groups, leading to poor COPD, they are often underused in this group worldwide. quality of life and increasing mortality.28 Muscle recovery The 3-step parallel approach is completed by adding actions combined with pulmonary rehabilitation and the additional therapy for patients with concomitant dis- optimized nutrition contribute to a better prognosis. ease to essential therapy for patients with COPD (Step 3: Osteoporosis in COPD are often underdiagnosed and initial therapy). In addition, it is important to review the undertreated.29 Although there is no evidence that osteo- response around 4 weeks after the initial therapy. The porosis treatment improves the prognosis of COPD evaluation factors are inhaler technique, adherence, symp- patients, it seems reasonable to treat osteoporosis accord- toms, exacerbations, side effects, patient satisfaction, lung ing to usual guidelines. GERD is known to be a risk factor function and eosinophilic inflammation. for frequent exacerbation.11 Although there is not enough submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 2232 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Matsunaga et al evidence in pharmacological treatment, proton pump inhi- Chest, Torii pharma, and GlaxoSmithKline, outside the bitors may be effective for COPD patients with GERD.30 submitted work. Keiji Oishi reports speaker fees from Bronchiectasis coexisting with COPD is often identified Boehringer Ingelheim, Astra-Zeneca, Meiji-Seika Pharma, International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 158.109.88.164 on 18-Feb-2021 with an increasing use of computed tomography (CT) in Novartis, Kyorin Pharma, outside the submitted work. Marc the assessment of COPD patients.31 It is associated with Miravitlles has received speaker fees from AstraZeneca, longer exacerbations and increased mortality.32,33 COPD Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, patients with bronchiectasis might be a potential popula- Bial, CSL Behring, Grifols and Novartis, consulting tion to benefit from macrolide and/or mucolytic therapy. fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Moreover, since there is significant evidence that the use GlaxoSmithKline, Bial, Gebro Pharma, CSL Behring, of ICS increases the risk of mycobacterium infection in Laboratorios Esteve, Ferrer, Mereo Biopharma, Verona patients with COPD,34 we should consider bronchiectasis Pharma, pH Pharma, Novartis and Grifols and research in the initial assessment. Lung cancer is common in COPD grants from GlaxoSmithKline and Grifols, outside the sub- patients and one of the main cause of death. Smoking mitted work. Antonio Anzueto has received consulting fees, cessation is very important not only for the treatment of lecture fees, and travel support from AstraZeneca, COPD but also for the prevention of lung cancer. Boehringer Ingelheim, Sunovion, GlaxoSmithKline, and It is fully known that the proposed algorithm will need Novartis, and grant support from GlaxoSmithKline, outside to be validated, particularly in the real world. Moreover, the submitted work. The authors report no other conflicts of there are some limitations to use this algorithm. Medical interest in this work. For personal use only. resources vary greatly from country to country. At the present time, roflumilast is not approved in many Asian countries. In some areas, there is difficult access to some References diagnosis tools, such as CT, echocardiography, and FeNO. 1. Miravitlles M, Anzueto A. A new two-step algorithm for the treat- ment of COPD. Eur Respir J. 2017;49(2):1602200. doi:10.1183/ Low utilization of these diagnostic techniques is a signifi- 13993003.02200-2016 cant barrier to adequate disease management. 2. Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary. Arch Bronconeumol. Conclusion 2017;53(3):128–149. doi:10.1016/j.arbres.2017.02.001 This perspective article proposes to identify treatable clin- 3. Lehtimaki L, Kankaanranta H, Saarelainen S, et al. Bronchial nitric oxide is related to symptom relief during fluticasone treatment in COPD. Eur ical features early and to treat usual and specific clinical Respir J. 2010;35(1):72–78. doi:10.1183/09031936.00177508 characteristics in parallel. The management of COPD 4. Akamatsu K, Matsunaga K, Sugiura H, et al. 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This journal is indexed on PubMed Central, MedLine journal of therapeutics and pharmacology focusing on concise rapid and CAS. The manuscript management system is completely online reporting of clinical studies and reviews in COPD. Special focus is and includes a very quick and fair peer-review system, which is given to the pathophysiological processes underlying the disease, inter- all easy to use. Visit http://www.dovepress.com/testimonials.php to vention programs, patient focused education, and self management read real quotes from published authors. Submit your manuscript here: https://www.dovepress.com/international-journal-of-chronic-obstructive-pulmonary-disease-journal submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 2234 DovePress Powered by TCPDF (www.tcpdf.org)