2023 JRS指南：哮喘和慢性阻塞性肺疾病重叠的诊断和治疗（第2版）-概要

Summary of the Japanese Respiratory Society guidelines for the diagnosis and treatment of asthma and chronic obstructive pulmonary disease overlap 2023 (2nd edition) $\star$

Shigeo Muro $^{a}$, $^{*}$, $^{*}$, Kazuya Tanimura $^{a}$, Mitsuhiro Yamada $^{b}$, Shuichiro Maruoka $^{c}$, Hisatoshi Sugiura $^{b}$, Yasuhiro Gon $^{c}$, On behalf of the members of the Japanese Respiratory Society Guidelines for the Diagnosis and Treatment of Asthma and COPD Overlap 2023 Editing Committee

a Department of Respiratory Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan b Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryocho, Aoba-ku, Sendai, Miyagi, 980-8574, Japan c Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, 30-1 Oyaguchi Kami-cho, Itabashi-ku, Tokyo, 173-8610, Japan

ARTICLE INFO

Keywords: Asthma and COPD overlap Japanese guideline Diagnosis Treatment Management

Treatment Management

Treatment Management

ABSTRACT

Many patients have overlapping features of asthma and chronic obstructive pulmonary disease (COPD), but not all of them receive appropriate treatment for both conditions. The Japanese Respiratory Society published the guidelines on the diagnosis and treatment of asthma and COPD overlap (ACO) to promote its awareness. This English summary of the revised edition highlights the concepts, definitions, clinical features, diagnosis, and management of ACO based on recent evidence from observational studies. It also discusses the updates to the evaluation of ACO severity, workflow of management, and pharmacological treatment strategy. ACO is characterized by chronic airflow limitation with features of both asthma and COPD, and its diagnostic algorithm based on the clinical features and multidimensional evaluation, including imaging and functional tests, is provided. The classification of ACO severity based on exacerbations and symptoms is also advocated. There is no consensus on the treatment strategy for ACO, but the guidelines propose a pharmacotherapy strategy based on this classification to prevent under- or over-treatment. ACO requires a comprehensive approach that includes tailored pharmacological and non-pharmacological therapies. These guidelines will contribute to advancing research on the characteristics and pathophysiology of ACO and facilitate discussions on its management.

1. Introduction

Bronchial asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent respiratory disorders. A considerable proportion of patients with chronic airway symptoms have been identified to have features of both asthma and COPD in recent years, but they are often excluded from intervention and observational studies targeting either of these conditions. The mainstay treatments for these two diseases overlap to some extent. However, clear therapeutic guidelines for patients with overlapping features are lacking, and clinical guidelines rarely provide explicit diagnostic and therapeutic recommendations for

such cases.

The Global Initiative for Asthma (GINA) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) jointly published a document, entitled "Diagnosis of Diseases of Chronic Airflow Limitation: Asthma, COPD, and Asthma-COPD Overlap Syndrome," in 2014, which popularized the term ACOS [1]. However, concerns were subsequently raised that the term "syndrome" might imply that ACOS is a distinct disease entity separate from asthma and COPD and lead to misunderstanding. Accordingly, the 2017 GINA guidelines removed the term "syndrome" and proposed the use of "Asthma and COPD Overlap" (ACO) [2].

GOLD made a statement in 2020 that could be interpreted as a declaration of separation from ACO: "We no longer refer to ACO.

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|Abbreviations|LAA%|the percentage of low attenuation area| |---|---|---| |ACO|asthma and COPD overlap|LABA long-acting beta agonist| |ACOS|asthma-COPD overlap syndrome|LABD long-acting bronchodilator| |ACP|advance care planning|LAMA long-acting muscarinic antagonist| |ACQ|asthma control questionnaire|LTRA leukotriene receptor antagonist| |ACT|asthma control test|MITT multiple-inhaler triple therapy| |AERD|aspirin-exacerbated respiratory disease|mMRC modified Medical Research Council Dyspnea Scale| |CAT|COPD assessment test|PaCO2 partial pressure of arterial carbon dioxide| |CCQ|Clinical COPD Questionnaire|PaO2| |COPD|chronic obstructive pulmonary disease|PEF peak expiratory flow| |CT|computed tomography|PRO patient-reported outcome| |$DL_{CO}$|diffusing capacity of the lungs for carbon monoxide|QOL; quality of life| |FeNO|fractional exhaled nitric oxide|Rrs respiratory resistance| |$FEV_{1}$|forced expiratory volume in 1 s|RSV respiratory syncytial virus| |%$FEV_{1}$|percent predicted forced expiratory volume in 1 s|SABD short-acting beta agonist| |FVC|forced vital capacity|SAMA short-acting muscarinic antagonist| |GERD|gastroesophageal reflux disease|SARS-CoV-2 severe deucere respiratory syndrome coronavirus 2| |GINA|the Global Initiative for Asthma|SITT single-inhaler triple therapy| |GOLD|the Global Initiative for Chronic Obstructive Lung Disease|SpO2 transcutaneous arterial oxygen saturation| |ICS|inhaled corticosteroid|VA alveolar volume| |IgE|immunoglobulin E|Xrs respiratory reactance| |JRS|the Japanese Respiratory Society|6MWT the 6-min walk test|

Instead, we emphasize that asthma and COPD are different disorders, although they may share some common treatable traits and clinical features.” This stance has been maintained in the most recent edition [3]. The intent of this change was to caution against the overuse of inhaled corticosteroids (ICS) and other treatments by indiscriminately grouping asthma and COPD together [3]. In contrast, GINA still includes a dedicated chapter on ACO in the 2022 edition [4]. Therefore, expert consensus on the term ACO remains inconsistent. However, epidemiological studies have consistently demonstrated that many patients have features of both asthma and COPD. Therefore, it is imperative to provide clinicians with clear diagnostic and therapeutic guidelines for such clinical presentations.

International documents recommend providing both asthma and COPD treatments as appropriate for each case. However, the recommendations are often perceived to lack specificity for practical clinical use. The detection and diagnosis rates of COPD in Japan are lower than those of asthma. Consequently, some patients diagnosed with asthma may have ACO, which can lead to under-treatment [5]. This underscores the need for increased awareness and education about ACO. The Japanese Respiratory Society (JRS) published the ACO Guidelines in 2017 to provide more concrete therapeutic recommendations [6,7]. In the 2023 revised edition [8], the guidelines have been updated to reflect the findings of observational studies conducted since the first edition and highlight the role of newly available treatments for ACO. These updates aim to provide more specific clinical guidance.

This document summarizes the concepts, definitions, clinical features, diagnosis, and management of ACO based on the revised Japanese guidelines [8].

2. Disease concepts and definitions

2.1. Asthma

Asthma is defined in the Japanese guidelines as a disease characterized by chronic airway inflammation and clinical symptoms such as wheezing, dyspnea, chest tightness, and cough secondary to variable airway narrowing. International guidelines provide similar definitions [4]. The hallmark of asthma symptoms is their variable severity during the day: they tend to worsen at night or in the early morning [4,9]. They

are also often triggered by respiratory infections, exercise, allergen exposure, weather changes, laughter, air pollution, cold air, and strong odors (Table 1).

2.2. COPD

COPD is defined as a pulmonary disease caused by long-term inhalational exposure to noxious substances, primarily tobacco smoke, and characterized by airflow limitation on pulmonary function testing [3, 10]. The airflow limitation results from the complex interplay of peripheral airway lesions and emphysematous changes in varying

Table 1

Comparative features of asthma and chronic obstructive pulmonary disease (COPD) (translated and represented from Ref. [8]).

|Feature|Asthma|COPD| |---|---|---| |Age of onset|All age groups|Middle-aged and older adults| |Etiology|Allergy, infection|Smoking, air pollution| |Allergic history|Frequently present|Variable| |Family history|Sometimes present|Usually absent| |Airway inflammatory cells|Eosinophils, CD4+ T lymphocytes, mast cells|Neutrophils, CD8+ T lymphocytes, macrophages| |Symptoms (cough, sputum, dyspnea)|Diurnal variation, paroxysmal|Slow progressive, persistent, exertional| |Airflow obstruction/Structural changes|None in principle, airway remodeling|Emphysema, bronchiolar wall fibrosis| |Reversibility of airflow obstruction|Usually present|Absent to sometimes present| |Airway hyperresponsiveness|Present|Absent to sometimes present| |Diffusing capacity of the lung (DLCO)|Normal to increased|Decreased| |Low attenuation areas on chest Computed tomography (CT) sputum cell composition|Usually absent|Frequently present| |Sputum cell composition|Predominantly eosinophils|Predominantly neutrophils| |Peripheral blood eosinophils|Increased|Usually normal| |Fractional exhaled nitric oxide (FeNO)|Elevated|Normal| |Response to corticosteroids|Usually good|Present in some cases|

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proportions. Most cases of COPD are attributable to long-term exposure to tobacco smoke, an exogenous risk factor, and it is estimated that 15–20 % of smokers will develop COPD [3,10]. Symptoms, including exertional dyspnea, become apparent as the disease progresses (Table 1).

2.3. ACO

In Japan, the JRS guidelines define ACO as a condition characterized by chronic airflow limitation with features of both asthma and COPD.

Prior to the publication of these guidelines, numerous epidemiological studies on ACO had been conducted both domestically and internationally. However, the absence of standardized definitions and diagnostic criteria, combined with differences in study population characteristics, resulted in highly variable reported prevalence rates ranging from a few percent to over 50% [11]. The diagnostic criteria were similarly inconsistent, with various combinations of indicators being employed, including age, smoking history, history of allergy (such as atopy or allergic rhinitis), symptoms (subjective and objective), diagnosis of asthma (by physician or self-report), post-bronchodilator forced expiratory volume in 1 s (FEV$_1$/forced vital capacity (FVC), airway reversibility testing and its cut-off values, sputum eosinophil count, blood eosinophil count or percentage, serum immunoglobulin E (IgE) concentration, fractional exhaled nitric oxide (FeNO) concentration, and diffusing capacity of the lungs for carbon monoxide (DL$_{CO}$) [12].

Recognizing that meaningful progress in ACO research and clinical practice could not be achieved without standardized definitions and diagnostic criteria, the JRS determined that establishing unified definitions and perspectives was essential for advancing discussions on ACO in Japan. Consequently, the JRS published the Guidelines for the Diagnosis and Treatment of Asthma and COPD Overlap 2018, which proposed the definition mentioned above [6,7]. This definition has been maintained in the current revised edition as it remains appropriate and relevant.

3. Epidemiology of ACO

3.1. Prevalence

The prevalence of ACO varies considerably internationally and in Japan. This is largely attributable to differences in the diagnostic criteria for asthma (there are no universally established diagnostic criteria for bronchial asthma). The prevalence of ACO in the general population has been reported to range from 0.9 % to 11.1 % [13–25]. However, it has been reported to be 0.9 % among Japanese adults aged 40 years and older [26]. The prevalence of ACO among patients with asthma ranges from 13.3 % to 61.0 % [16,23,24,27–33]. Age-stratified analyses in a study revealed increasing prevalence with age: 16.0, 30.0%, and 61.0 % with aged 20–44, 45–64, and 65–84 years, respectively [16]. A study conducted in Japan reported an ACO prevalence of 27.1 % among patients previously diagnosed with asthma [27]. Studies on the prevalence of ACO among patients with COPD have reported a range of 12.1–66.0 % [18,23,24,34–43]. The prevalence of ACO in patients with COPD who have had exacerbations within the past year is high (66.0 %) [35]. Japanese studies have reported ACO prevalence ranging from 4.2 % to 49.7 % among patients with COPD [6,44–46]. Using the diagnostic criteria from the previous edition of these guidelines, a study reported an ACO prevalence of 25.5 % among Japanese patients with COPD who were aged 40 years and older [6].

Several reports have indicated that patients with ACO are older than those with asthma [13–15,19,27,47,48]. However, the findings are inconsistent when patients with ACO are compared with those with COPD. Some studies have reported that patients with ACO are younger [13–15,19,26,38,41,42,45,47,49], whereas others have reported no significant age differences [36,39,46,50–54]. International reports on

sex differences are also inconsistent. Some have reported a male predominance [13,20,35,36,40,41], whereas others have reported a female predominance [14,15,19,21,38,39,42,50]. All the Japanese reports indicate a male predominance [6,26,27,44-47,49,51-54], which reflects the significant role of smoking in the development of COPD in Japan.

3.2. Exacerbations and long-term prognosis

Several cross-sectional studies conducted outside Japan have reported higher frequencies of exacerbation in patients with ACO than in those with COPD [15,38,39,41,55]. However, one study reported no significant difference [40]. The findings of cohort studies on the rates of exacerbation in patients with ACO are contradictory. Some studies have reported higher rates than those for asthma and COPD [13], some have reported no difference from those for COPD [36], and others have reported lower rates [35]. Few studies have examined the exacerbation frequency in Japan, but cross-sectional and cohort studies have reported no differences between ACO and COPD [45,46,49]. The definitions of exacerbation vary among these reports.

Few cohort studies conducted in Japan and internationally have compared the long-term prognosis of ACO (including mortality, decline in quality of life and annual decline in FEV₁) with those of asthma and COPD. Some reports indicate a poorer prognosis for ACO [14], while others indicate no difference [50] or even a better prognosis [36,46,47]. The lack of consensus on the frequency of exacerbations and their prognostic implications is likely attributable not only to differences in definitions and diagnostic criteria but also to variability in treatment regimens. This underscores the urgent need for additional large-scale prospective studies.

4. Pathophysiology of ACO

Asthma and COPD are not single diseases with uniform pathophysiology. They are syndromes shaped by diverse underlying mechanisms and have overlapping pathophysiological features [32]. The pathophysiology of ACO can be categorized into (1) mechanisms primarily associated with asthma, (2) mechanisms primarily associated with COPD, and (3) mechanisms common to both asthma and COPD (Table 2).

The development of asthma and COPD involves several fundamental pathophysiological processes. These processes contribute in varying proportions in individual patients and interact to determine the phenotype. The clinical phenotypes are highly heterogeneous. For example, some patients have coexisting type 2 airway inflammation and neutrophilic inflammation. This has led to the identification of a significant subset of patients with overlapping features of asthma and COPD.

The contribution of each pathophysiological component may vary within the same patient depending on the life stage, seasonal factors, or treatment regimen. Understanding the molecular pathophysiology of individual patients is critical to overcoming disease heterogeneity, enabling personalized treatment, reducing the disease burden (including drug-related adverse effects), and improving prognosis [56]. This approach goes beyond clinical labels such as asthma, COPD, or overlap.

5. Diagnosis of ACO

5.1. Diagnostic guidelines

ACO is characterized by persistent airflow limitation (post-bron-chodilator FEV₁/FVC <70 %) in individuals aged 40 years or older with clinical features of both asthma and COPD [2]. The symptoms of ACO include cough, sputum, wheezing, shortness of breath, and dyspnea. These symptoms are common in chronic airway diseases. However, they are more severe and frequent in patients with ACO than in those with

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Table 2

Pathophysiological features of asthma and chronic obstructive pulmonary disease overlap (translated and reprinted from Ref. [8]).

|Mainly associated with asthma| |---| |1. Type 2 airway inflammation| |2. Airway hyperresponsiveness| |3. Susceptibility to viral infections| |Mainly associated with COPD| |1. Neutrophilic airway inflammation| |2. Smoking| |3. Aging| |Common to asthma and COPD| |1. Impaired lung development| |2. Childhood asthma| |3. Airway remodeling| |4. Impaired airway epithelial barrier function and mucosal defense mechanisms| |5. Gastroesophageal reflux disease (GERD)|

COPD or asthma alone. The symptoms of ACO are characteristic of both asthma and COPD. Therefore, ACO should be suspected in patients diagnosed with asthma who have a history of smoking, chronic cough, and sputum symptoms during non-exertional periods and progressive or worsening dyspnea every year. Conversely, ACO should be suspected in patients with chronic dyspnea on exertion (which is typical of COPD) with significant fluctuations and marked symptom relief following treatment (Table 3). Therefore, ACO should be suspected in patients with asthma or COPD who have symptoms of COPD or asthma, respectively [1].

A history of smoking (>10 pack-years) and evaluation of the low attenuation area percentage (LAA%) on computed tomography (CT) are recommended for COPD. The LAA% is closely associated with alveolar wall destruction [57]. DLCO and DLCO/alveolar volume (V.A) evaluations through respiratory function tests also helpful for assessing the degree of peripheral airway involvement and alveolar capillary bed destruction characteristic of COPD [58]. The diagnosis of asthma requires confirmation of the respiratory symptoms with diurnal or seasonal variations, atopic predisposition, and allergic rhinitis (a complication in more than 60% of patients with asthma in Japan) [59]. The measurement of FeNO (which correlates well with eosinophilic inflammation of the airways), assessment of airway reversibility (improvement in FEV₁ of >12% and >200 mL), determination of peripheral blood eosinophil count (>5% or 300/µL), and detection of high IgE concentrations aid in the diagnosis of ACO [60]. Elevated FeNO concentrations in patients with COPD are useful for diagnosis and treatment decision-making because they indicate a complication of

asthma and a marked response to treatment with ICSs [61]. Oscillometry reveals greater airflow obstruction and worse uneven ventilation, expiratory airflow limitation, and emphysema in ACO than in asthma and COPD [62]. The sputum eosinophil ratio is highly correlated with asthma pathology and is useful for predicting the response to ICS. The peripheral blood eosinophil count (>300/µL) is also an important indicator for treatment choice for the diagnosis of ACO [63].

The diagnosis of ACO should be based on multiple factors, including clinical features of asthma and COPD, biomarkers, chest imaging findings, respiratory function test results, and comorbidities.

5.2. Diagnostic algorithm for ACO

The diagnostic algorithm for ACO is provided in Fig. 1. Imaging and functional tests should be performed as much as possible for patients with a history of smoking because middle-aged and older patients tend to underestimate symptoms such as cough, sputum, and shortness of breath due to aging. Further, assessments such as CT, lung diffusion capacity testing, and FeNO measurement should be actively performed. Symptoms and signs characteristic of asthma and COPD that were not initially apparent often become apparent over time. Therefore, it is essential to follow the course of ACO over time rather than rely on a single assessment.

5.2.1. The first-time patient

5.2.1.1. Step 1. Patients older than 40 years with chronic respiratory symptoms (cough, sputum, dyspnea, or wheezing) or an FEV₁/FVC ratio of <70 % should undergo evaluation of their FEV₁/FVC ratio after bronchodilator administration. This should be done after excluding differential diagnoses, including diffuse panbronchiolitis, congenital sinobronchial syndrome, bronchiolitis obliterans, bronchiectasis, pulmonary tuberculosis, pneumoconiosis, lymphangioleomyomatosis, congestive heart failure, interstitial lung disease, and lung cancer. Chest X-ray radiography is essential for differentiation, and chest CT imaging is performed if necessary.

5.2.1.2. Step 2. An interview should be conducted to obtain detailed information on the characteristics of COPD and asthma. The symptoms of asthma vary diurnally, daily, and seasonally. However, those of COPD are chronic and persistent. Dyspnea in COPD is chronic and gradually worsens on exertion. Detailed imaging, respiratory function tests, FeNO measurement, assessment of airway reversibility, and determination of peripheral blood eosinophil count and IgE (total IgE or specific IgE for inhaled antigens) are performed as needed.

Table 3

Typical symptoms of asthma, chronic obstructive pulmonary disease (COPD), and asthma and COPD overlap (ACO) (translated and reprinted from Ref. [8]).

|Symptoms suggestive of asthma| |---| |Symptoms vary over time (daily, weekly, or seasonally) and can differ annually.Symptoms typically worsen at night or in the early morning� Common triggers include exercise, emotions, infections, and exposure to smoke or allergens.Symptoms often improve spontaneously or with treatment.Symptoms do not typically worsen progressively over the years.| |Symptoms suggestive of COPD| |Chronic dyspnea and respiratory discomfort, especially during physical exertion.The symptoms persist, but their severity varies.Chronic cough and sputum production.There is usually no clear trigger.Symptoms generally progress slowly over the years despite treatment.| |Symptoms of ACO| |Features of asthma and COPD�istent respiratory symptoms during exertion with marked variability.Symptoms can improve with treatment, but they may gradually progress or worsen over the years.|

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![graph TD\n A1[40 years or older with respiratory symptoms such as cough, sputum, shortness of breath, or an FEV1/FVC ratio less than 70%] --> A2[Exclude other diseases by chest X-ray and other relevant tests]\n A2 --> A3[Post-bronchodilator FEV1/FVC ratio less than 70%]\n A3 --> A4[[COPD Characteristics]\n A3 --> A5[Asthma Characteristics]\n A4 --> A6[ACO]\n A5 --> A6\n A6 --> A7[At least one of the following 1, 2, or 3:\n 1. Smoking history ≥10 pack-years) or equivalent exposure to significant air pollution\n 2. Presence of low attenuation areas suggestive of emphysema on chest CT\n 3. Impaired pulmonary diffusing capacity (%DLCO <80% or %DLCO/VA <80%)]\n A6 --> A8[Either two or more from item 4:\n 4.1 Variable (diurnal, daily, seasonal) or episodic respiratory symptoms (dyspnea, wheezing, chest tightness, cough)\n 4.2 History of asthma before age 40\n 4.3 Fractional exhaled nitric oxide (FeNO) >35 ppb\n 4.4 Comorbid allergic rhinitis\n 4.5 Bronchodilator reversibility (FEV1 improvement ≥12% and ≥200 mL)\n 4.6 Blood eosinophils >3% or >300 cells/µL\n 4.7 Elevated IgE (total IgE or specific IgE to common inhalant allergens)]\n](1/parseimages/figureec31cacf8c3e4c848031f68ab68db451_0_2.png) The post-bronchodilator FEV₁ should be determined for patients with respiratory symptoms or an FEV₁/FVC ratio of less than 70 % on spirometry. This should be done after excluding conditions requiring differentiation (such as diffuse panbronchiolitis, allergic bronchopulmonary aspergillosis, bronchiolitis obliterans, bronchiectasis, pulmonary tuberculosis, pleural effusion, lymphangioiomyomatosis, congestive heart failure, and pulmonary thromboembolism).

[Step 2]

Evaluate the presence of COPD and asthma based on respiratory symptoms such as cough, sputum, and dyspnea. Confirm the variability (daily, diurnal, and seasonal), episodic nature, and persistence of asthma symptoms through clinical evaluation.

[Step 3]

Diagnose ACO if the patient has at least one COPD characteristic and two or more asthma characteristics from items 1–3 or one characteristic from items 1–3 and two or more from item 4. Diagnose COPD if only COPD characteristics are present. Diagnose asthma if only asthma characteristics (including airway remodeling) are present.

Abbreviations: ACO, asthma and COPD overlap; COPD, chronic obstructive pulmonary disease; CT, computed tomography; DLCO, diffusing capacity of the lungs for carbon monoxide; FeNO, fractional exhaled nitric oxide; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; IgE, immunoglobulin E; VA, alveolar volume.

5.2.1.3. Step 3. A comprehensive judgment is based on the results above. Asthma is diagnosed if the FEV₁/FVC ratio is greater than 70 % and any of the features of asthma, such as elevated FeNO, blood eosinophil count, total IgE, or inhaled antigen, are present. ACO is diagnosed if one of the features of COPD and two of the asthma features 1, 2, or 3) are present or if one of the asthma features 1, 2, and 3 and two or more of the remaining features (4) are present.

5.2.2. Patients undergoing examination

5.2.2.1. Diagnosis of ACO in patients with asthma. The diagnosis of COPD in patients with asthma requires (1) a history of long-term inhalation exposure to noxious substances, primarily tobacco smoke, and (2) evidence of airflow obstruction secondary to peripheral airway or emphysematous lesions. A history of smoking, emphysematous changes on CT imaging, lower diffusing capacity on respiratory function tests, and progressive dyspnea are important for diagnosing ACO in patients with asthma.

5.2.2.2. Diagnosis of ACO in patients with COPD. It is important to check for paroxysmal or fluctuating symptom changes, type 2 inflammation based on laboratory findings, and a history of previous asthma.

5.3. Evaluation, severity, and classification of ACO

The severity of ACO is comprehensively evaluated and classified into grades 1–4 based on the severity of asthma and COPD stage, as reported

in the previous edition of the ACO guidelines. ACO is considered advanced if the severity of asthma and the stage of COPD are discordant [6,7]. The current version of the ACO guidelines recommends a type classification (1A, 1B, 2A, 2B, 3, 4) based on exacerbations and symptoms (patient-reported outcomes [PROs]) (Table 4). This classification aims to improve the underuse and overuse of ICS for ACOs from the COPD perspective and the underuse of bronchodilators (mainly long-acting muscarinic antagonists [LAMAs]) from the asthma perspective.

5.4. Comorbidities of ACO

ACO is associated with more comorbidities, such as cardiovascular disease, osteoporosis, gastroesophageal reflux disease (GERD), and depression, than asthma or COPD alone. Appropriate treatment interventions for comorbidities have been reported to improve the prognosis of ACO [25,42,64].

6. Management goals and treatment

6.1. Management goals of ACO

There is currently no consensus on the treatment strategy for ACO based. This is attributable to the exclusion of patients with a history of smoking and older adults from asthma clinical trials and those with asthma from COPD studies. As a result, large-scale clinical studies involving patients with ACO are lacking. The diagnostic criteria and

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Table 4

Asthma and COPD overlap phenotype classification (2023 revised edition) (translated and reprinted from Ref. [8]).

Table 4 and COPD Overlap Phenotype Classification (2023 Revised Edition) (translated and reprinted from Ref. [8]).

|Asthma Severity COPD $Severity^{*1}$|Mild intermittent|Mild persistent|Moderate persistent|Severe persistent- Very severe persistent||| |---|---|---|---|---|---|---| |Basic treatment|PRO|mMRC 0-1 CAT<10|Type 1A|Type 2A|Type 3|Type 4| |Basic treatment|PRO|mMRC ≥ 2 CAT ≥ 10|Type 1B|Type 2B|Type 3|Type 4|

*1: COPD exacerbations are considered equivalent to asthma exacerbations.

Abbreviations: CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; mMRC, modified Medical Research Council

Dyspnea Scale; PRO, patient-reported outcome.

severity classifications for patients with ACO are diverse and have not yet been standardized internationally.

The fundamental principle of ACO treatment is to provide balanced and adequate treatment for the asthma and COPD components present in each individual. The management goals for ACO are based on the objectives outlined in the Asthma Prevention and Management Guidelines 2021 [9] and the JRS Guideline for the Management of COPD 2022 [10] (Table 5).

6.2. Long-term management during stable periods

Appropriate long-term management during the stable phases of both asthma and COPD is crucial. ACO also requires a comprehensive approach that includes tailored pharmacological and non-pharmacological therapies. The treatment policy and evaluation process are outlined in Fig. 2.

6.2.1. Pharmacological therapy

The pharmacological treatment for ACO is based on the type and involves inhalation therapy (Table 6). Patients with ACO have higher exacerbation rates [15,65,66], faster decline in respiratory function [5],

Table 5

Management goals of patients with asthma and COPD overlap (translated and reprinted from Ref. [8]).

1. Improvement of symptoms and quality of life

2. Improvement of respiratory dysfunction and control of airway inflammation

3. Improvement and maintenance of exercise tolerance and physical activity

4. Suppression of age-related decline in respiratory function and disease progression

5. Prevention of exacerbation

6. Prevention and treatment of comorbidities

7. Improvement of life prognosis and extension of healthy life expectancy

8. Avoiding adverse effects of medications

and lower QOL [67] than those with asthma or COPD alone. These findings indicate clinical fragility. Therefore, early and adequate treatment is essential. Individual symptoms and disease evaluations, such as assessing residual type 2 inflammation, are necessary when considering additional treatment.

6.2.1.1. Inhalation therapy. Combined therapy with ICS and long-acting bronchodilators (LABDs) is fundamental for patients with ACO because of their clinical fragility and the need for early intensive treatment. ICS is indispensable in treating ACO. However, no standardized dosing guidelines exist. Smokers generally have reduced responsiveness to ICSs [68]. The ICS dosage should be determined based on the severity of asthma. The COPD guidelines recommend ICS use for patients with overlapping asthma and those with frequent exacerbations and elevated peripheral eosinophil counts. Discontinuation of ICS is recommended for cases of pneumonia, severe adverse effects, or ineffectiveness [3,10]. This contrasts with the ACO principle, which emphasizes the necessity of continuing ICS. There is no consensus on whether a long-acting beta2 agonist (LABA) or LAMA is superior for ACO. ICS/LABA combinations are widely used. However, meta-analyses for asthma have reported the equivalence of LABA and LAMA [69]. LAMA has been reported to be more effective in preventing COPD exacerbations [70]. Both asthma and COPD guidelines recommend triple therapy (LAMA + LABA + ICS) for cases with severe symptoms or repeated exacerbations [10]. Triple therapy may also be considered as an initial treatment for ACO. Single-inhaler triple therapy is preferred over multiple-inhaler triple therapy because it is associated with better adherence and simpler administration [9,71].

Incorrect inhaler use is common [72]. Poor inhalation technique and adherence are associated with increased exacerbation frequency in COPD [73]. The factors affecting inhaler adherence in COPD include complex techniques, multiple devices, insufficient effects or adverse events, cost, advanced age, comorbidities, lack of understanding, and

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![graph TD\n A1[Patients with initial diagnosis of ACO with prior diagnosis of asthma or COPD] --> A2[1-3 months of treatment]\n A2 --> A3[Cough/phlegm Frequency of paroxysmal dyspnea Severity of dyspnea(mMRC)]\n A2 --> A4[Asthma-related PRO(ACT or ACQ) COPD-related PRO(CAT or CCQ)]\n A2 --> A5[Pulmonary function(FEV1, %FEV1, FEV1/FVC) FeNO Peripheral eosinophil count]\n A3 --> A6[Improvement]\n A4 --> A6\n A5 --> A6\n A6 --> A7[Good]\n A6 --> A8[Poor]\n A7 --> A9[Continuation of treatment]\n A8 --> A10[Dose escalation of ICS Addition of bronchodilators Addition of LTRA]\n A10 --> A11[Anti-IgE antibody Anti-IL-5 antibody Anti-IL-5Rα antibody Anti-IL-4Rα antibody Anti-TSLP antibody]\n A12[Non-pharmacological therapy] --> A13[Oxygen therapy Ventilatory support Surgical treatment Endoscopic treatment]\n A12 --> A14[Utilizing social resources and advance care planning]\n A12 --> A15[Instruction/support of inhalation technique and checking adherence]\n A12 --> A16[Management/treatment of pulmonary complications and systemic comorbidities]\n A12 --> A17[Improvement and maintenance of physical activity]\n A12 --> A18[Vaccination and infection prevention]\n A12 --> A19[Identification and evaluation of smoking cessation aid and aggravating factors(eg\n smokingcessationaidandaggravatingfactors(eg\n](1/parseimages/figuree91facda967c417bbb12b8c5781f49e6_0_2.png) Fig. 2. Algorithm for the management of stable asthma and copd overlap (translated and reprinted from Ref. [8]).

Abbreviations: ACO, asthma and COPD overlap; ACQ, asthma control questionnaire; ACT, asthma control test; CAT, COPD assessment test; CCQ, Clinical COPD Questionnaire; COPD, chronic obstructive pulmonary disease; FeNO, fractional exhaled nitric oxide; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; ICS, inhaled corticosteroid; LABA, long-acting beta2 agonist; LAMA, long-acting muscarinic antagonist; LTRA, leukotriene receptor antagonist; mMRC, modified Medical Research Council Dyspnea Scale; PRO, patient-reported outcome; %FEV₁, percent predicted forced expiratory volume in 1 s.

poor technique [10]. Drug selection should consider these factors because patients with ACO are often older adults. Appropriate inhalation support and education, including support from caregivers, are essential.

6.2.1.2. Biologic agents. Five biologics (omalizumab, mepolizumab, benralizumab, dupilumab, and dezepelumab) had been approved for the treatment of asthma in Japan. They all primarily target type 2 airway inflammation pathways. The efficacy of biologics in ACO has been reported in only a few studies. However, some observational studies have reported the effects of malizumab on the symptoms and exacerbations of ACO [74,75]. There is no evidence supporting the use of other biologics for ACO. However, biologics may be considered for patients with ACO who have poor disease control and frequent exacerbations despite conventional therapies because of their efficacy for treating asthma and COPD.

6.2.1.3. Expectorants. Chronic sputum symptoms are associated with poor disease control and frequent exacerbations in both asthma [76,77] and COPD [78-81]. Sputum and mucus hypersecretion are important targets in ACO. Expectorants may be considered for residual sputum symptoms in addition to ICS and bronchodilators. They are classified into mucolytics, mucus-repair agents, mucosal lubricants, and airway secretion normalizers based on their mechanisms of action [82]. Carbocisteine (a mucus-repair agent) and ambroxol (a mucosal lubricant) have been reported to reduce COPD exacerbations [83,84]. They are commonly used and may have benefits for ACO.

6.2.2. Non-pharmacological therapy

6.2.2.1. Avoidance of risk factors such as tobacco smoke and allergens. Identifying and avoiding risk factors that contribute to exacerbations and disease progression are essential. Patients should avoid exposure to allergens, tobacco smoke, air pollutants, and infectious agents such as viruses and bacteria. Environmental improvements, such as indoor cleaning and the use of air purifiers, should also be considered. Triggers such as medications, stress, and overexertion should also be avoided. Smoking cessation is essential for all stages of ACO prevention (primary, secondary, and tertiary). Heated tobacco products and e-cigarettes are not recommended because their reduced harm relative to traditional cigarettes has not been established.

6.2.2.2. Vaccinations. Combined vaccination with the influenza and pneumococcal vaccines has been shown to more effectively reduce exacerbations due to infections in patients with COPD than influenza vaccination alone [85]. Therefore, both vaccines are recommended for patients with ACO. The benefits of infection prevention and reduction in disease severity outweigh the concerns about adverse events in patients with COPD. Therefore, SARS-CoV-2 vaccination is recommended for these patients [10].

6.2.2.3. Pulmonary rehabilitation. Pulmonary rehabilitation is effective in relieving dyspnea, improving exercise tolerance [10], and enhancing health-related QOL across all disease stages [86]. It is, therefore, recommended for ACO. The key components include exercise therapy,

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Table 6

Pharmacotherapy of asthma and COPD overlap based on type (translated and reprinted from Ref. [8]).

|COPD severity|COPD severity|COPD severity|Mild intermittent|Mild persistent|Moderate persistent|Severe persistent- Very severe persistent| |---|---|---|---|---|---|---| |Basic treatment|PRO|mMRC 0-1 CAT<10|ICS (low-dose)+LABA or ICS (low-dose)+LAMA|ICS (low to medium dose)+LABA or ICS (low to medium dose)+LAMA|LAMA+LABA+ICS (medium to high dose)*1|LAMA+LABA+ICS (medium to high dose)*1,6| |Basic treatment|PRO|mMRC ≥ 2 CAT ≥ 10|LAMA+LABA+ICS (low-dose)*1,2|LAMA+LABA+ICS (low to medium dose)*1,2|LAMA+LABA+ICS (medium to high dose)*1|LAMA+LABA+ICS (medium to high dose)*1,6|

|Additional treatment|Additional treatment|LTRA theophylline|In addition to the left, macrolides|In addition to the left, biologic agents*3| |---|---|---|---|---| |||mucolytic agents|(some biologic agents*3)|oral corticosteroids| |||allergen immunotherapy*4||| |For exacerbations For as-need use|Administration of SABD as needed*5||||

*1: Single-inhaler triple therapy (SITT) is preferable.

*2: Either LABA/ICS+LAMA or LAMA/LABA+ICS is acceptable for LAMA+LABA+ICS.

*3: Refer to the package insert, the Asthma Prevention and Management Guidelines 2021, and the Asthma Clinical Practice Guidelines 2023 for the indications for biologic agents.

*4: Consider for cases of mite allergy, especially those with allergic rhinitis and stable %FEV₁≥70%.

*5: SABA is usually used frequently, but SAMA has also been shown to be effective in alleviating symptoms in COPD.

*6: High-dose ICS is necessary for severe asthma. The ICS dose is medium to high for patients with dominant COPD because of the increased risk of pneumonia.

ICSs have been reported to increase the risk of airway infection in both bronchial asthma and COPD, and this risk is dose-dependent. The ICS dose may need to be increased or decreased.

Abbreviations: CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid; LABA, long-acting beta2 agonist; LAMA, long-acting muscarinic antagonist; LTRA, leukotriene receptor antagonist; mMRC, modified Medical Research Council Dyspnea Scale; PRO, patient-reported outcome; SABA, short-acting beta 2 agonist; SABD, short-acting bronchodilator; SAMA, short-acting muscarinic antagonist; %FEV₁, percent predicted forced expiratory volume in one second.

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nutritional therapy, and self-management education.

Exercise therapy aims to relieve dyspnea and maintain or improve exercise tolerance and physical activity. Advanced cases often involve nutritional deficiencies, and combined exercise and nutritional therapy are recommended. The goals of self-management education are to improve the understanding of patients about the disease, help them acquire self-management skills, and foster collaborative care between them and healthcare providers.

6.2.2.4. Management and treatment of systemic comorbidities and pulmonary complications can affect symptoms, quality of life, exacerbations, and prognosis. Their management is therefore essential. Patients with ACO have higher risks of comorbid GERD and osteoporosis but a lower risk of comorbid ischemic heart disease than those with COPD alone [42]. Patients with ACO have a higher risk of comorbid diabetes than those with COPD or asthma alone [87].

6.2.2.5. Utilization of social resources and advance care planning. Many patients with ACO are older adults and have limitations in daily life that extend beyond their disease. Respecting the wishes of patients and supporting their independence and quality of life often require home medical care. Active use of social support resources should be considered to reduce financial and caregiving burdens.

Advance care planning is important because of the high exacerbation frequency and rapid decline in pulmonary function associated with ACO. It involves providing appropriate information and supporting decision-making during stable phases to prepare for future health changes.

6.2.2.6. Oxygen therapy and ventilatory support. Long-term oxygen therapy for ≥15 h/day is recommended for patients with COPD with severe hypoxemia (partial pressure of arterial oxygen [PaO2] ≤ 55 Torr or transcutaneous arterial oxygen saturation [SpO₂] ≤ 88 %) [10]. Ventilatory support therapy should be considered for patients with stable COPD and chronic hypercapnic respiratory failure (partial pressure of arterial oxygen [PaCO₂] ≥ 55 Torr) or those with PaCO₂ < 55 Torr but repeated exacerbations due to nocturnal hypoventilation. The indications for these therapies in ACO should be assessed similarly to those for COPD.

6.2.2.7. Surgical and endoscopic treatments. Surgical lung volume reduction may be considered for patients with COPD and severe dyspnea despite optimal medical therapy, especially those with upper lobed predominant emphysema. Endobronchial valve insertion is another option. Bronchial thermoplasty has been used for uncontrolled severe asthma. These interventions have not been evaluated in ACO-specific clinical trials. Therefore, their applicability to ACO should be carefully considered in light of the limited evidence on their safety and efficacy.

6.3. Evaluation of treatment effectiveness

The effectiveness of treatment should be comprehensively evaluated based on patient-reported outcomes, exacerbation frequency, clinical symptoms, and test findings. Improvement in severity and changes in type classification should also be confirmed before and after treatment.

FeNO, sputum eosinophil percentage, and peripheral blood eosinophil count and percentage are useful test indicators for inflammatory profiling (including Type 2 inflammation). Respiratory function tests such as FEV₁, %FEV₁, FEV₁/FVC, and peak expiratory flow (PEF) are commonly used. Arterial blood gas analysis and the 6-min walk test

(6MWT) may also be performed as needed. Further studies are required to validate the effectiveness assessment criteria.

6.4. Management and treatment during exacerbations

Clear guidelines for the management of ACO exacerbations are lacking. However, identifying the cause and evaluating the inflammatory profile (eosinophilic vs. neutrophilic) via sputum or blood tests are desirable. Treatment should follow the asthma and COPD guidelines [9, 10].

Infectious causes, especially viral and bacterial infections, are common in COPD exacerbations. Bacterial infection should be suspected if purulent sputum is present, and antibiotics are recommended [10]. Short-acting beta 2 agonist (SABA) inhalation is recommended for asthma and COPD and should be used similarly for ACO. The patient can continue using the budesonide/formoterol combination therapy during exacerbations.

The responsible component (asthma or COPD) should be determined for moderate or severe exacerbations requiring systemic corticosteroids. Intravenous corticosteroids are used for asthma exacerbations. Betathamasone (4-8 mg) or dexamethasone (6.6-9.9 mg) may be administered intravenously every 6 h. The initial dose of hydrocortisone desirable. Treatment should follow the asthma and COPD guidelines [9, 10].

7. Conclusions

We have summarized the diagnosis, clinical evaluation, and management goals of ACO based on the JRS ACO Guidelines 2023. We added new epidemiological data, including data from the ACO Japan Cohort Study, and proposed a new classification of disease severity based on exacerbations and symptoms. We have also proposed an updated pharmacological treatment strategy based on the newly defined disease severity classification to facilitate accurate treatment and avoid under- and overtreatment. Patients with ACO require early and adequate treatment through a comprehensive approach that includes pharmacological and non-pharmacological therapies tailored to the disease. We believe that the guideline will contribute to advancing research on the characteristics and pathophysiology of ACO and facilitate discussions on its management, including the appropriate use of biologics.

Author contributions

Shigeo Muro was the Chairman of the Japanese Respiratory Society Guidelines for the Diagnosis and Treatment of Asthma and COPD Overlap 2023 Editing Committee and responsible for the organization and coordination of the manuscript. Hisatoshi Sugiura and Yasuhiro Gon were the Vice-Chairmans of the Japanese Respiratory Society Guidelines for the Diagnosis and Treatment of Asthma and COPD Overlap 2023 Editing Committee. Shigeo Muro, Hisatoshi Sugiura, and Yasuhiro Gon contributed in Writing – Review & Editing.

Kazuya Tanimura, Mitsuhiro Yamada, and Shuichiro Maruoka contributed in English translation and Writing – Original Draft Preparation.

All authors have approved the submitted version of the manuscript and agreed to be accountable for any part of the work.

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Funding source

The Japanese Respiratory Society.

Declaration of competing interest

Shigeo Muro received lecture fees from AstraZeneca K.K., Sanofi K. K., Nippon Boehringer Ingelheim Co., Ltd, and GlaxoSmithKline K.K. and honoraria for scientific advisory boards from AstraZeneca K.K., GlaxoSmithKline K.K., and Sanofi K.K.

Kazuya Tanimura received lecture fees from GlaxoSmithKline K.K.

Mitsuhiro Yamada received lecture fees from AstraZeneca K.K. and Nippon Boehringer Ingelheim Co., Ltd.

Shuichiro Maruoka has no conflict of interest to declare.

Hisatoshi Sugiura received lecture fees from AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd, Sanofi K.K., KYORIN Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., and Novartis Pharma K.K. and honoraria for scientific advisory boards from AstraZeneca K.K., GlaxoSmithKline K.K., Sanofi K.K., and Nippon Boehringer Ingelheim Co., Ltd.

Yasuhiro Gon received lecture fees from AstraZeneca K.K., Sanofi K. K., KYORIN Pharmaceutical Co., Ltd., and GlaxoSmithKline K.K. and honoraria for scientific advisory boards from AstraZeneca K.K., GlaxoSmithKline K.K., and Sanofi K.K.

Acknowledgments

This article was supported by the Japanese Respiratory Society.

We thank Editage (www.editage.jp) for editing the English of this manuscript.

The list of members of the Japanese Respiratory Society Guidelines for the Diagnosis and Treatment of Asthma and COPD Overlap 2023 Editing Committee is provided in the supplemental file.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.resinv.2025.101360.

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