**5. Conclusions and the Way Forward**

The goal of telemedicine is the early identification and diagnosis of AECOPDs and timely access to appropriate treatment in order to improve patient outcomes. An important issue for the effective application of telemonitoring in COPD is the parameters monitored in terms of reliable prediction of an AECOPD (e.g., FEV1, symptoms, pulse oximetry). When an algorithm is used, the design is even more crucial regarding the satisfactory sensitivity and specificity of the method. Moreover, the effort that was required from the patients was not associated with the outcomes of the studies; however, it is likely that patients would be more compliant to interventions that would require minimal effort on their end. The results of the negative studies regarding exacerbations, hospital admissions, ED visits, and total GP calls could be attributed to the short telemonitoring period and the fact that in most of them, healthcare utilization and exacerbations were not the primary endpoints. Importantly, the small number of participants may have led to negative results and may have additionally precluded the extraction of safe conclusions. Additionally, the short follow-up periods of many studies were not long enough to capture the natural history of AECOPD, and in our opinion a minimum of 12 months would be required. Moreover, adherence to inhaled medication, which is enhanced during RCTs, may additionally lead to reduced AECOPDs and hospital admissions in both intervention and usual care groups, thereby resulting in non-significant differences. The commitment and appropriate training of the study team involved in such programs is crucial for successful telehealth services, while the interruption of monitoring during weekends by healthcare interventions may have affected the results in some cases, although prevention of exacerbations was reported without active intervention by the study team, which was attributed to better disease awareness and self-management. Finally, it is unknown which patients will benefit more from telemedicine, and larger RCTs are needed with subgroup analysis to define the most appropriate population for telemonitoring interventions. These studies would need to be of a proper length and size, and following a multifactorial evaluation would need to involve the appropriate participants who will adopt these telemonitoring interventions, which ideally will require minimal patient effort, in order to maximize the engagement and potential benefits. The proposed characteristics of future studies are summarized in Table 3.

**Table 3.** Proposed characteristics of future studies.


**Author Contributions:** Conceptualization, A.K., A.G., C.K., K.I.G. and K.K.; methodology, C.K., A.G. and A.K.; software, C.K., G.N., N.G. and A.G. validation, C.K.,A.G., A.K. and K.K.; formal analysis, C.K., A.G. and G.N.; investigation, C.K. and A.G.; resources, A.K. and K.K.; data curation, C.K., A.G., A.K. and K.K.; writing—original draft preparation, C.K., A.G., G.N., N.G. and K.I.G.; writing review and editing, A.K. and K.K.; visualization, A.G.; supervision, A.K.; project administration, K.K.; funding acquisition, A.K. All authors have read and agreed to the published version of the manuscript.

**Funding:** The present study was partly funded by the project entitled 'PRECURSOR: PREventing COPD URgent States Of Relapse', co-financed by the European Union and Greek national funds through the Operational Program for Research and Innovation Smart Specialization Strategy (RIS3) of Ipeiros (Project Code: HΠ1AB-0028176).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** All data generated or analyzed during this study are included in this published article. Anonymized data will be shared uponrequest from any qualified investigator.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **Abbreviations**


### **References**


**Shih-Lung Cheng 1,2,\* and Ching-Hsiung Lin 3,4,5**


**Abstract:** Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease that is associated with significant morbidity and mortality, giving rise to an enormous social and economic burden. The Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (GOLD) report is one of the most frequently used documents for managing COPD patients worldwide. A survey was conducted across country-level members of Asia-Pacific Society of Respiratory (APSR) for collecting an updated version of local COPD guidelines, which were implemented in each country. This is the first report to summarize the similarities and differences among the COPD guidelines across the Asia-Pacific region. The degree of airflow limitation, assessment of COPD severity, management, and pharmacologic therapy of stable COPD will be reviewed in this report.

**Keywords:** COPD guideline; Asia

**Citation:** Cheng, S.-L.; Lin, C.-H. COPD Guidelines in the Asia-Pacific Regions: Similarities and Differences. *Diagnostics* **2021**, *11*, 1153. https:// doi.org/10.3390/diagnostics11071153

Academic Editor: Koichi Nishimura

Received: 1 June 2021 Accepted: 21 June 2021 Published: 24 June 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **1. Introduction**

Although chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease, it is associated with significant morbidity and mortality, giving rise to an enormous social and economic burden. The results from the Epidemiology and Impact of COPD (EPIC) Asia population-based survey suggest a high prevalence of COPD in the participating Asia-Pacific territories [1] and indicate a substantial socioeconomic burden of the disease in this region. Individuals with the disease reported substantial limitations in their daily activities and loss in work productivity. To address this situation and influence the behavior of healthcare providers and health policy makers and payers, numerous organizations have developed clinical practice guidelines (CPG) to assist in the diagnosis and treatment of COPD. In such an environment, CPG development often relies upon expert opinion. Conflicting interpretations of the literature regarding COPD management may result in disparities across guidelines. Local factors, such as the availability of certain health care services or the cost impact of an intervention, may also influence how local experts view and apply the published literature during guideline development.

The Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (GOLD) report is one of the most frequently used documents for managing COPD patients worldwide [2,3]. It was developed by using an evidencebased methodology and expert opinion consensus and is considered the most up-to-date, comprehensive reference for COPD diagnosis and management. However, a major gap is that its focus is only in the application of the recommended GOLD strategies for pharmacological treatment of COPD based on the A, B, C, and D groups. Here, our focus of

this survey is to determine the degree of consensus in the Asian Pacific region's practice guidelines for COPD regarding the diagnosis and management of COPD.

#### *Estimated Prevalence*

The prevalence of COPD in the Asia-Pacific countries is estimated at 14.5% in Australia [4], 4.4% to 16.7% in China [5–7], and 5.6% in Indonesia [1]; the prevalence of Air Flow Limitation (FEV1/FVC < 70%) was reported at 10.9% and COPD (after excluding asthmatics) was 8.6% in Japan [8], 13.4% in Korea [9], 4.7% in Malaysia [1], 5.4% to 6.1% in Taiwan [1,10], 3.7% to 6.8% in Thailand [11], 3.5% to 20.8% in Philippines [1,12], and 6.7% in Vietnam [1], respectively (Table 1).

**Table 1.** Publication year of current and last version of Asia Pacific (APAC) guidelines, and COPD prevalence in the reviewed APAC countries.


\* Stepwise management table of COPD was published in 2017; Concise Guide for Primary Care (COPD-X plan) was published in 2017.

#### **2. Method**

A survey was conducted across country-level members of the Asia-Pacific Society of Respiratory (APSR) for collecting an updated version of COPD guidelines which were implemented in each country. The APSR sent a questionnaire to members, who were asked to provide the current local guideline and comparative review of the collected guidelines. Ten guidelines were reviewed, including those of Australia/New Zealand, China, Indonesia, Japan, Korea, Malaysia, Taiwan, Thailand, Philippines, and Vietnam, in either English or national language. The key disease management graphs, flowcharts, and algorithms were translated into English language for review. Detailed information was completely collected, including the definition, the approach to diagnosis, severity classification of staging, pharmacotherapy for stable COPD, and other recommendations. In the Asia-Pacific available COPD guidelines, Australia, Japan, Korea, Taiwan, and China have revised and updated guidelines during the period of 2013 to 2020 (Table 1). Guidelines in the other countries were not revised in the recent three years. We compared the similarities and differences between these guidelines.

The different methods used to estimate disease prevalence including expert opinion, patient-reported diagnosis, and symptom-based or spirometry-based methods may affect the results. In the People's Republic of China, COPD is one of the most common chronic diseases in the population older than 40 years of age, with a prevalence of 8.2% in 2007 and increased to 13.6% in 2015 using spirometry-based survey. [5,7] Comparatively higher prevalence with 13.7% to 13.4% was noted in Korea using spirometry-based survey [9,13]. Another study in the Asia-Pacific region, EPIC Asia population-based survey [1] based on face-to-face or fixed-line telephone interviews, revealed that the prevalence of COPD is between 6.2% and 19.1%. Regarding the estimated prevalence rate of COPD in each country, there is no appropriate method to do this in current status.

#### **3. Results**

COPD diagnosis, classification, and treatment recommendation from Taiwan and China were similar to the GOLD guidelines. The degree of airflow limitation, assessment of COPD severity, management, and pharmacologic therapy of stable COPD were based on the GOLD principles. Australia, Japan, and Korea guidelines display some differences regarding classification and management strategy of stable COPD compared with the GOLD (Table 2). Besides, Taiwan guidelines have been written based on GRADE (Grading of Recommendations, Assessment, Development and Evaluations)'s recommendation, which is the most widely adopted tool for grading the quality of evidence and for making recommendations.


**Table 2.** Comparison of GOLD 2015 and APAC guidelines with current version updated after 2011.

#### *3.1. Combined COPD Assessment*

The Korean COPD guideline categorizes severity into three groups, Group ga (GOLD Group A), Group na (GOLD Group B), and Group da (GOLD Group C and D) [13] (Figure 1). The spirometric cutoff point of FEV1 is 60% predicted to distinct Group ga, na from Group da. They further divide Group da into two groups with FEV1 < 60% predicted, but >=50% predicted, or FEV1 < 50% predicted. [14]. Assessment of symptoms and exacerbation is similar as described in GOLD. In Australia, COPD-X concise guide [15] for primary care categorizes the severity of COPD into mild (FEV1: 60–80% of predicted), moderate (FEV1: 40–59% of predicted), and severe (FEV1: <40% of predicted) accompanied with typical symptoms of varying degree of dyspnea, cough, and limitation of daily activity (Figure 2) [16]. The rationale was that regular treatment with inhaled corticosteroid (ICS) can improve symptoms, lung function, quality of life, and reduce the frequency of exacerbation for patients with FEV1 < 50% predicted and a history of frequent exacerbations, observed in several clinical studies [16–18].

**Figure 2.** Stepwise management of stable COPD guidelines in Australia and New Zealand.

## *3.2. Pharmacologic Management of Stable Disease*

In the GOLD guideline, the initial pharmacological management of COPD is according to patient group which has different recommended treatments. In the guidelines of Australia, Japan, and Korea (Figure 2 [15], Figure 3 [19], and Figure 4 [14]), a stepwise approach of optimized pharmacotherapy for stable COPD is used which recommends a gradual increase of bronchodilators, inhaled corticosteroids, or other drugs based on a comprehensive evaluation of symptoms, airflow obstruction, and exacerbation. In Japan's 2018 guideline, ICS positioning for COPD treatment had been revised from the previous criteria of FEV1 < 50% of predicted, frequent exacerbation, and concomitant asthma to only the concomitant asthma (ACO) criterion.

### *3.3. Non-Pharmacologic Management*

Most guidelines had emphasized the importance of pulmonary rehabilitation, longterm oxygen therapy, and self-management plan including smoking cessation and vaccination. Particularly, Japan's guideline (fifth edition) discussed the nutrition management including nutritional impairment, evaluation, therapy, and diet education [19]. COPD patients whose BMI is less than 90% are suspected to have a nutrition disorder and nutrition therapy may be indicated. Nutritionists, physician, and nurses should form a team to provide nutritional guidance.


**Figure 4.** Algorithm of pharmacologic treatment in patients with stable COPD in Korea.

#### *3.4. Coexisting Asthma and COPD*

Coexisting asthma and COPD are only defined and described in Australia and Japan guidelines. This Australia guideline recommends that an FEV1 increase over 12% and 200 mL constitutes a positive bronchodilator response. An FEV1 increase >400 mL strongly suggests underlying asthma or coexisting asthma and COPD diagnosis. Besides, the diagnosis of asthma–COPD overlap (ACO) has both characteristics of COPD and asthma (Figure 5).

### *3.5. End-of-Life ISSUES*

GOLD 2013, for the first time, proposed that palliative care may be applied in advanced severe COPD patients. Among these guidelines in the Asia-Pacific region, Taiwan, Japan, China [20], and Australia [15] may already have their policies about end-of-life care. Improving quality of life, optimizing function, helping with decision- making about endof-life care, and providing emotional and spiritual support to patients and family are the main goals. In Taiwan, the National Health Insurance Administration Ministry of Health and Welfare had programmed hospice-care plans in 2011 and provided in-hospital critical care facilities for patients with advanced diseases and poor response to regular treatments instead of home or hospice ward care.


**Figure 5.** Diagnostic criteria of asthma–COPD overlap in Japanese ACO guideline 2018.

#### **4. Discussion**

There are several studies evaluating and validating the new GOLD assessment system; however, uneven distribution of COPD patients and limited data on the clinical outcomes are noticed under these combined assessments. [21–24] The degree of the COPD Assessment Test (CAT) score of ≥10 might not be equivalent to that of the mMRC score of ≥2 for categorizing patients' symptoms. [25–28] Neither the 2007 GOLD nor the 2011 classification scheme has sufficient discriminatory power to be used clinically for risk classification to predict total mortality at the individual level. [29] Accordingly, some countries have developed COPD guidelines to build up appropriate strategies for diagnosis, assessment, pharmacotherapy, and prediction of acute exacerbation and mortality based on evidence and real-world clinical practice.

The Korean and Australia guidelines stratified the lung function severity and exacerbation risk with FEV1 < 60% or ≥ 60% of predicted value. From the validation study in Korea, it was found that there were many patients (15.3% to 16%) who experienced exacerbation with FEV1 between 50% and 60% of predicted value. [14] The cutoff point of an FEV1 50% predicted does not address the heterogeneity in the GOLD Stage II (50%–80% predicted). Patients with limited airflow around FEV1 50% to 60% predicted had a more rapid decline in lung function than patients with FEV1 < 50% in the TORCH study [30,31]. A recent study showed that parameters related to volume, diffusing capacity, and reactance showed break-points around 65% of FEV1 which may have an impact on patients' management plan.

The strategy for stable COPD management was based on lung function severity before GOLD 2011. A refinement of the ABCD assessment tool had been separated from spirometric grade from "ABCD" groups in GOLD 2020. A stepwise approach policy is currently presented in the Japan and Australia guidelines. The management strategy is similar in the Korea and GOLD guidelines including for symptoms severity and exacerbation frequency. Moreover, a phenotype-guided treatment policy has been shown in the Spanish and Czech guidelines. [32,33] Which strategies are optimal in clinical practice guidelines for COPD management? There were several strategies including lung function-guided, stepwise approach-guided, GOLD A–D-guided, and phenotype-guided strategies. The optimal treatment of COPD patients requires an individualized, multidisciplinary approach to the

lung function severity, patient's symptoms, clinical phenotypes, biomarkers, comorbidity evaluation, and needs.

The treatment of patients with COPD in a more personalized way must address diverse aspects not only related with the disease, but also with its comorbidities, and current schemes do not offer such personalized medical treatment. Comorbidity evaluation and management were all mentioned in each Asia country CPG. In the JRS guideline l19], the comorbidities included systemic inflammation, osteoporosis, musculoskeletal defect, cardiovascular disorders, gastro-intestinal dysfunction, depression, metabolic disorders, and obstructive sleep apnea. Additionally, the variability of the clinical presentation interacts with comorbidities to form a complex clinical scenario for clinicians. Different comorbidities have different evaluation and management policies. Consequently, the CPG or consensus should be reached over a practical approach for combining comorbidities and disease presentation markers in the therapeutic algorithm, in order to improve the quality of clinical care.

In a previous study, the increased total health expenditure was shown as share GDP ≥ 7% in Korea, Japan, and Australia in 2007. [34] In Japan, major reforms are needed to reduce waste and enhance cost-effectiveness. Moreover, a national system to accredit training programs, including for general practice, has been introduced. [35] The challenges of the healthcare system in Korea include over-consumption and excessively high frequency of specialist consultation, which are major problems for the medical system. The government and the primary care group seek to strengthen primary care, but this is opposed by the medical society governed by the specialist group. [35] In Australia, some provider payment methods were performed such as case payment, diagnostic-related groups, etc. [34]. We think that guideline differences are driven by the disparities in diagnosis modalities or by the treatment variations in different healthcare systems and the socioeconomic burden in each country.

Additionally, diagnosis tools and management of COPD were among the lower guideline-recommended levels in most of the regions investigated among primary care physicians or general practitioners (GPs). [36] The survey demonstrated that the GPs' understanding of COPD was variable and large numbers of GPs have very limited knowledge of COPD and its management in Asia countries. The percentage for COPD management by guideline is as follows: Australia 64%, Japan 74%, Korea 54%, and Taiwan 70%. In China, only 50% of patients with COPD have ever had spirometry tests in tertiary hospitals, and only 18% had in primary or secondary hospitals. [37] Therefore, from the education system, clinical practice, and medical impact, there appears to be an optimal strategy developed to simplify the guidelines for daily practice in each country.

Research evidence has raised concerns that hospital death may be preceded by potentially burdensome and inappropriate hospital admission and aggressive treatments shortly before death, which could be a threat to better end-of-life care and death. [38–41] On the other hand, enabling people to have end-of-life care at home compared with end-of-life care in hospital may incur a potential cost saving. [42,43] The concepts of palliative and hospice care should be established gradually in regards to diseases with an advanced stage.

#### *APSR Recommendations for COPD Diagnosis and Treatment*


#### **5. Conclusions**

This is the first report to summarize the similarities and differences among the COPD guidelines across the Asia-Pacific region. The guideline developed in each country would be based on clinical evidence, experts' consensus, healthcare insurance, reality of clinical practice, and the best interests of patients. We hope, through collaboration of research, that the guidelines will evolve positively and that differences or gaps will diminish with time.

**Author Contributions:** S.-L.C. and C.-H.L.; methodology, validation, and formal analysis; S.-L.C.; writing—original draft preparation, S.-L.C.; writing—review and editing, C.-H.L. Both authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** Thanks to the professors for finishing this work including: Kazuto Matsunaga (Japan); Chin Kook Rhee (Korea); Diahn-Warng Perng (Taiwan).

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

