Clinical Characteristics of Individuals with Chronic Obstructive Pulmonary Disease (COPD), Pre-COPD, Smokers with Normal Lung Function in Korea: Updated Analysis of the Korea COPD Subgroup Study Cohort
Article information
Abstract
Background
Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung disease characterized by persistent airflow limitation and is a leading cause of mortality worldwide. Pre-COPD refers to a pre-disease state associated with an increased risk of COPD development. This study aims to evaluate the clinical characteristics of individuals with COPD, pre-COPD, and smokers with normal lung function in South Korea, and to provide an updated analysis of the Korea COPD subgroup study (KOCOSS) cohort data.
Methods
We analyzed data from 4,502 participants in the KOCOSS database collected between 2012 and 2025, including 4,197 with COPD, 126 with pre-COPD, and 179 smokers with normal lung function. Baseline characteristics were compared across these groups.
Results
Patients with COPD were more likely to be male, older, and had a lower body mass index than those with pre-COPD and smokers with normal lung function. Symptom burden, as assessed by the COPD Assessment Test and modified Medical Research Council dyspnea scale, was highest in patients with COPD, followed by pre- COPD and smokers with normal lung function. Patients with COPD had the highest overall use of respiratory medications (89.3%), including inhalers and other treatments, followed by pre-COPD individuals (61.5%) and smokers with normal lung function (47.4%). Hypertension was the most common comorbidity across all groups, with no significant differences in the prevalence of comorbidities.
Conclusion
This analysis of the KOCOSS cohort highlights the distinct clinical characteristics of individuals with COPD, pre-COPD, and smokers with normal lung function. Notably, individuals without spirometric COPD still showed substantial symptom burden and inhaler use.
Introduction
Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition characterized by persistent airflow limitation and respiratory symptoms, including dyspnea, cough, and sputum production [1,2] . It is a leading cause of morbidity and mortality worldwide, ranking as the fourth most common cause of death globally [3]. A recent nationwide study in South Korea reported an overall COPD prevalence of 12.9% between 2015 and 2019, with a higher prevalence of 30.4% in individuals aged ≥70 years [2]. Moreover, chronic respiratory disease, mainly COPD, was the 8th leading cause of death among males in South Korea in 2020 [4]. COPD plays a significant burden on patients, caregivers and health care systems, contributing to increased medical costs and reduced work productivity [5,6].
The Korea COPD subgroup study (KOCOSS) was initiated in 2012 to address the high prevalence and risk of COPD in South Korea. Its aim is to facilitate the early diagnosis and effective treatment of COPD by evaluating its clinical characteristics, natural course, treatment, and outcome. Since its first publication in 2016 [7], KOCOSS has continuously provided valuable insights into the clinical profiles of Korean patients with COPD [8-13]. Recently, the importance of early identification, treatment, and management of pre-COPD, which refers to individuals not yet diagnosed with COPD but at risk of disease progression [14,15], has been increasingly recognised [14,16,17]. To facilitate early identification and prevention of COPD, KOCOSS expanded its enrollment criteria in 2021 to include patients with pre-COPD and smokers with normal lung function. Accordingly, an updated analysis of the KOCOSS cohort is necessary to reflect the evolving characteristics of the cohort. Therefore, this study aimed to describe the sociodemographic and clinical characteristics of individuals with COPD, pre-COPD, and smokers with normal lung function, and to provide an updated analysis of the KOCOSS cohort data.
Materials and Methods
1. Study design and population
KOCOSS is an ongoing, multicenter, prospective, non-interventional, observational cohort study initiated in 2012. It enrolls consecutive patients diagnosed with COPD from 55 referral hospitals in South Korea (Figure 1). Following a baseline visit, the participants were followed up every 6 months. All participants continued to take their prescribed medications without restrictions.
Geographic distribution of participating hospitals in the Korea COPD subgroup study (KOCOSS) cohort in Korea. COPD: chronic obstructive pulmonary disease.
Initially, only patients with COPD were enrolled, based on the spirometric criteria defined by the Global Initiative for Chronic Obstructive Lung Disease (post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity [FVC] <0.7) [2]. Since 2021, the KOCOSS cohort has included individuals with pre-COPD and smokers with normal lung function. The pre-COPD group included patients with emphysema and preserved ratio impaired spirometry (PRISm). Emphysema was defined based on either visual assessment of chest computed tomography (CT) scans by respiratory specialists or radiologic reports indicating the presence of emphysema at each participating site, in individuals with normal lung function (FEV1 >80% and FEV1/FVC >0.7). PRISm was defined as post-bronchodilator FEV1/FVC >0.7 and FEV1 <80%. Smokers with normal lung function were defined as individuals aged >40 years, with a smoking history of ≥100 cigarettes, and normal lung function (FEV1 >80% and FEV1/FVC >0.7).
Patients were excluded from the study if they met any of the following criteria: (1) current diagnosis of bronchial asthma; (2) inability to perform pulmonary function tests or communicate effectively; (3) history of myocardial infarction or stroke within the past 3 months; (4) pregnancy; (5) refusal to provide informed consent; (6) presence of rheumatoid diseases; (7) diagnosis of active malignancy, including metastatic solid tumors, leukemia, or lymphoma; (8) inflammatory bowel disease; or (9) recent use of systemic steroids within the past 1 month for conditions other than COPD.
2. Data collection and assessment
Baseline data were collected at the time of enrollment. Sociodemographic variables, such as age, sex, level of education, residential area, smoking status, body mass index (BMI), and biomass exposure were collected. Education level was categorized into three groups: middle school or less, high school, and college or more. The area of residence was classified as large city, middle or small city, or rural area. A ‘large city’ referred to metropolitan or special cities (e.g., Seoul, Busan, Daegu, Incheon); a ‘middle or small city’ included all other urban areas excluding large cities and rural areas; and a ‘rural area’ referred to agricultural and fishing regions, specifically areas designated administratively as eup , myeon , or ri . The smoking status was categorized as a non-smoker, ex-smoker, and current smoker. A current smoker was defined as an individual who had smoked >100 cigarettes in their lifetime and was actively smoking at the time of enrollment. An ex-smoker was defined as an individual who had smoked >100 cigarettes in their lifetime but had quit smoking at the time of study enrollment. An individual who had smoked 100 cigarettes or fewer was classified as a non-smoker. BMI was calculated as weight (kg)/height squared (m2) and classified according to the Asia-Pacific standards: underweight (<18.5 kg/m2), normal weight (18.5–22.9 kg/m2), overweight (23.0–24.9 kg/m2), and obese (≥25.0 kg/m2). Biomass exposure was assessed using baseline questionnaires. Participants were asked whether they had personally used firewood or briquettes for cooking or heating for at least 1 year during their lifetime. For those who answered ‘yes,’ the duration of use (in years) was also recorded.
To assess symptoms and quality of life, the modified Medical Research Council (mMRC) dyspnea scale, the COPD Assessment Test (CAT), and the COPD-specific version of St. George’s Respiratory Questionnaire (SGRQ-C) were used and reassessed every 6 months during follow-up visits. Depression and anxiety were evaluated using the Beck anxiety inventory (BAI) and Beck Depression Inventory (BDI). A history of exacerbations in the previous year was also collected. Exacerbation was defined consistently across all groups as an acute worsening of respiratory symptoms (e.g., dyspnea, increased sputum volume or purulence) beyond daily variation and a need for additional treatment. A moderate exacerbation was defined as one requiring treatment with antibiotics or systemic corticosteroids in an outpatient setting, whereas a severe exacerbation was defined as one requiring an emergency department visit or hospitalization [2,15]. To minimize potential recall bias, we further validated exacerbation history using data from the Health Insurance Review and Assessment Service (HIRA) for patients whose national identification numbers were available. This linkage and analysis were conducted only for participants who had provided written consent for data linkage at the time of cohort enrollment.
Although not analyzed in the present study, mortality data are included in the KOCOSS database. They were obtained either through direct reports from participating hospitals during follow-up or via linkage with national death records from Statistics Korea for participants who had consented to data linkage.
Pulmonary function tests included spirometry (pre-and post-bronchodilator), diffusing capacity of the lung for carbon monoxide (DLCO), body plethysmography, and fractional exhaled nitric oxide. Pulmonary function tests were followed up at least once a year. The 6-minute walk test (6MWT) was performed according to the modified American Thoracic Society guidelines, and the results were used to assess exercise capacity. Blood samples were collected at the designed centers, and exhaled breath condensate was obtained at the selected centers.
Prescribed medications included inhalers (inhaled corticosteroid [ICS], long-acting β₂-agonist [LABA], long-acting muscarinic antagonist [LAMA], ICS/LABA, LABA/LAMA, ICS/LABA/LAMA), and other medications (roflumilast, mucoactive agents, etc.).
All data were obtained from case report forms completed by a physician or trained nurse.
3. Statistical analysis
Descriptive statistics were used to summarize the baseline characteristics. Continuous variables are presented as means±standard deviations and were compared using one-way analysis of variance (ANOVA) for three-group comparisons. Categorical variables are expressed as numbers (percentages) and were analyzed using chi-square tests or Fisher’s exact tests. A p<0.05 was considered statistically significant. All statistical analyses were performed using R version 4.2.1 (R Foundation for Statistical Computing, Vienna, Austria).
4. Ethical statement
The study protocol was reviewed and approved by the Institutional Review Board of the Konkuk University Medical Center (approval No. KUMC2022-07-009) and the Institutional Review Board of each participating center, and written informed consent was obtained from all participants.
Results
1. Demographic characteristics
Between 2012 and February 2025, a total of 4,502 patients were included in this analysis: 4,197 patients with COPD, 126 patients with pre-COPD, and 179 smokers with normal lung function. The baseline demographic characteristics of the study participants are summarized in Table 1.
Baseline sociodemographic characteristics of study participants
Most participants were male, with 91.0% in the COPD group, 69.1% in the pre-COPD group, and 96.1% in smokers with normal lung function (p<0.001). The mean age was significantly higher in patients with COPD (68.7±8.2 years) compared to those of individuals with pre-COPD (63.0±10.5 years) and smokers with normal lung function (63.2±11.1 years; p<0.001). Smoking history differed significantly among the three groups (p<0.001), with current and former smokers accounting for 26.5% and 62.7% in the COPD group, 20.8% and 43.2% in the pre-COPD group, and 46.9% and 53.1% in the smokers with normal lung function group. Patients with COPD had a lower mean BMI (23.1±3.4 kg/m²) than those with pre-COPD (24.3±4.1 kg/m²) and smokers with normal lung function (24.3±3.3 kg/m², p<0.001). Education level was also significantly lower in COPD group, with 50.0% having completed middle school or lower, compared to 35.5% in pre-COPD group and 24.5% in smokers with normal lung function group (p<0.001). COPD patients also had a higher rate of biomass smoke exposure (42.8%) compared to those with pre-COPD (15.2%) and smokers with normal lung function (19.3%, p=0.032).
2. Clinical characteristics
The mMRC dyspnea score, CAT score, and SGRQ-C were the highest in patients with COPD, followed by individuals with pre-COPD and smokers with normal lung function (p<0.001) (Table 2 and Figure 2). A history of moderate exacerbations in the previous year was reported in 15.7% of patients with COPD, whereas only 8.1% of those with pre-COPD and 7.6% of smokers with normal lung function did so (p<0.001). Similarly, severe exacerbations requiring hospitalization occurred in 7.2% of patients with COPD, whereas only 5.2% of those with pre-COPD and 1.3% of smokers with normal lung function experienced severe exacerbations (p<0.001).
Baseline clinical characteristics of study participants
Symptom burden and health-related quality of life across chronic obstructive pulmonary disease (COPD), pre- COPD, and smokers with normal lung function. (A) Modified Medical Research Council (mMRC) dyspnea scale, (B) COPD Assessment Test (CAT), and (C) St. George’s Respiratory Questionnaire for COPD (SGRQ-C) patients.
Post-bronchodilator FEV₁% predicted was lowest in patients with COPD (60.0±18.7), followed by pre-COPD (72.1±13.1) and smokers with normal lung function (94.5±14.0, p<0.001). The FEV₁/FVC ratio was markedly lower in patients with COPD (52.9±12.8) compared to pre-COPD (76.2±7.0) and smokers with normal lung function (76.2±9.4, p<0.001). Similarly, the predicted DLCO% was lowest in patients with COPD (65.3±21.0) compared to pre-COPD patients (78.0±16.4) and smokers with normal lung function (82.2±18.4). 6MWT, BDI, and BAI scores did not significantly differ among groups (p=0.572, p=0.594, and p=0.622) (Table 2).
3. Prescribed medications
The overall medication use rate was the highest in the COPD group (89.3%), followed by pre-COPD (61.5%) and smokers with normal lung function (47.4%) (p<0.001) (Table 3). The LABA/LAMA combination was commonly used across all groups, with the highest rate in pre-COPD (41.8%), followed by COPD (35.8%) and smokers with normal lung function (34.1%) (p=0.35). ICS/LABA was the second most common treatment for patients with COPD (29.3%) but was rarely used in pre-COPD (4.9%) and smokers with normal lung function (5.2%) (p<0.001). Triple therapy (ICS/LABA/LAMA) was predominantly used by patients with COPD (19.2%), with significantly lower rates in pre-COPD individuals (0.8%) and smokers with normal lung function (2.9%) (p<0.001).
Treatment patterns and comorbidities
4. Comorbidities
The most common comorbidities across groups were hypertension (39.0% for COPD, 37.2% for pre-COPD, 41.8% for smokers with normal lung function), followed by diabetes (17.9% for COPD, 19.8% for pre-COPD, 18.1% for smokers with normal lung function), and hyperlipidemia (15.5% for COPD, 37.2% for pre-COPD, 41.8% for smokers with normal lung function) (Table 3). Most comorbidities, including myocardial infarction, heart failure, peripheral vascular disease, diabetes, hypertension, osteoporosis, and gastroesophageal reflux disease (GERD), did not show significant differences among groups.
Discussion
KOCOSS represents the largest prospective cohort study on COPD in South Korea. This study provides an updated analysis of the KOCOSS cohort, highlighting key differences in demographic and clinical characteristics among patients with COPD, individuals with pre-COPD, and smokers with normal lung function.
Our findings demonstrate that, compared to individuals with pre-COPD, patients with COPD were more likely to be male, older, had a history of smoking and lower BMI, and report higher biomass exposure. Patients with COPD exhibited the highest symptom burden and the lowest FEV1, followed by individuals with pre-COPD and smokers with normal lung function. Hypertension was the most prevalent comorbid condition across all groups. However, there was no significant in the prevalence of comorbidities among groups, except for dyslipidemia.
Emphysema and PRISm are representative of pre-COPD conditions [14]. Therefore, we included both as subgroups within the pre-COPD group in the KOCOSS cohort. Based on our inclusion criteria, approximately 20% of individuals in this group had emphysema, while 80% had PRISm. As our pre-COPD group included both conditions, it exhibited characteristics of each. PRISm is associated with the female sex and high BMI [18], whereas emphysema is typically linked to male sex and lower BMI [19,20]. Notably, the proportion of males in our pre-COPD group was approximately 70%, which is higher than previously reported in PRISm studies [15-17]. Similarly, while obesity was more common in patients with PRISm than in those with COPD, the proportion of underweight individuals was comparable between the two groups. Nevertheless, given that PRISm comprises most of our pre-COPD group, the overall trends observed in this study are generally consistent with previous PRISm studies. We plan to conduct separate analyses for PRISm and emphysema subgroups once the number of participants with pre-COPD in KOCOSS cohort increases sufficiently.
A key characteristic of patients with COPD in KOCOSS is the high proportion of male patients, which may be largely attributed to gender differences in smoking behavior. Smoking is the most significant risk factor for COPD development [2,21], and South Korea exhibits a pronounced gender difference in this regard. In 2022, the smoking rate in South Korea was 30.0% among males and 5.0% among females [22]. In contrast, the smoking prevalence in the same year in the United States was more balanced, 13.2% for males and 10.0% for females [23]. This substantial gender difference in South Korea may explain why approximately 90% of patients with COPD enrolled in the KOCOSS cohort were male. In comparison, other large COPD cohorts that exclusively enrolled smokers, such as COPDGene and the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), reported male proportions of 55.6% and 58.7%, respectively [15,17]. South Korea still has a relatively high smoking rate, comparable to the average among countries in the Organization for Economic Co-operation and Development (OECD) [22]. Given that smoking is also associated with the development of both PRISm and emphysema, and that individuals with these conditions have an increased risk of progression to COPD [16,24,25], smoking cessation remains a critical intervention for current smokers with PRISm or emphysema.
Our study confirmed that individuals with pre-COPD experienced a high symptom burden and lower quality of life. This finding is consistent with the previous COPDGene study, which reported that approximately 50% of patients with PRISm had a CAT score ≥10 [17]. Additionally, PRISm patients with higher CAT scores were more likely to experience acute respiratory exacerbation [15]. In a United Kingdom (UK) study, 17.7% of patients with PRISm experienced dyspnea when walking on level ground [24], which is consistent with our findings in patients with pre-COPD (mMRC grade ≥2, 19.2%). Smokers with normal lung function also exhibited a considerable symptom burden and impaired quality of life in our study. In the COPDGene cohort, 23.5% of smokers with normal spirometry reported breathlessness (mMRC score ≥2), and 12.6% met the criteria for chronic bronchitis [26]. Although these individuals do not meet the spirometry criteria for COPD or PRISm, many experience dyspnea and other respiratory symptoms. These findings highlight the importance of clinical attention to this population.
In terms of treatment patterns, 61.5% of patients with pre-COPD were prescribed medication, with LABA/LAMA (42%) being the most used therapy. This finding aligns with the results from the SPIROMICS study, which reported that 42% of symptomatic smokers (current or former) with preserved lung function used an inhaled bronchodilator [15]. In our study, inhaler use among smokers with normal lung function was also notably high, with 47.4% receiving COPD-related medications, including LABA/LAMA (34.1%), ICS/LABA (5.2%), and triple therapy (1.8%). This represents a marked difference from the COPDGene study, in which only 9.7% of individuals with a smoking history and normal spirometry were prescribed inhaled medications [27]. This discrepancy may be attributed to differences in healthcare access and prescribing practices between countries. In South Korea, inhaled medications are relatively inexpensive and broadly reimbursed under the national insurance system, which may lead to more proactive prescribing even for individuals without spirometric-defined COPD. Supporting this interpretation, the COPDGene study reported that many of these individuals had respiratory symptoms (20.1% had an mMRC score ≥2 and 45.0% experienced wheezing), yet inhaler use remained low despite the symptom burden. Although many individuals with pre-COPD and smokers with normal lung function exhibited significant symptoms and frequently received inhaled medications, there was limited evidence regarding whether these therapies improve symptoms and quality of life or reduce the risk of acute respiratory exacerbations in this population. Given the current lack of evidence, clinicians should be cautious in prescribing inhalers in routine clinical practice. Additional studies are necessary to assess the effectiveness of inhaler therapy in individuals with pre-COPD and smokers with normal lung function. We aim to address this issue through long-term follow-up of the extended KOCOSS cohort.
Comorbid conditions, such as cardiovascular disease, hypertension, osteoporosis, and GERD, are frequently associated with COPD [2]. Similarly, pre-COPD is often linked to chronic health conditions, such as hypertension, cardiovascular disease, diabetes, and hyperlipidemia [17,24,28]. The COPDGene study reported a higher prevalence of diabetes among patients with PRISm (21.6%) compared to those with COPD (13.1%); in contrast, the prevalence of coronary artery disease (13.5% vs. 16.5%) and GERD (25.9% vs. 30.3%) was lower in patients with PRISm [17]. A UK study found hypertension (33.4%) and diabetes (8.7%) to be common comorbidities in patients with PRISm [24]. In comparison to UK and United States studies, our findings revealed a relatively high prevalence of diabetes (19.8%) in patients with pre-COPD, and a comparable prevalence of hypertension (37.2%). A recent meta-analysis of 52 studies reported that diabetes is associated with incident PRISm, which in turn is linked to increase all-cause and cardiovascular mortaltity [29]. These findings underscore the necessity of a comprehensive management approach for patients with pre-COPD, including the evaluation and treatment of associated comorbidities.
The KOCOSS cohort is a large, representative cohort in South Korea and has several strengths. First, in contrast to COPDGene and SPIROMICS, which enrolled only smokers with or without COPD, our cohort enrolled participants regardless of their smoking history. This provides a significant advantage in analyzing COPD characteristics arising from various causes [30]. However, despite the inclusive enrollment criteria, most participants were male smokers, reflecting the epidemiological characteristics of COPD in South Korea, which is strongly associated with smoking and more prevalent in men. With continued enrollment, we expect to expand the cohort over time to include COPD patients with more diverse etiologies. Second, KOCOSS includes a wide range of COPD subgroups, including chronic bronchitis, emphysema, asthma-COPD overlap syndrome, COPD with bronchiectasis, COPD in young people (<50 years old), PRISm, and emphysema with normal lung function. Third, KOCOSS collects comprehensive data across multiple variables, including sociodemographic and clinical information, lung function assessments (spirometry, body plethysmography, and impulse oscillometry), blood and respiratory samples, and radiological data. Recently, kernel conversion was performed to standardize CT images acquired using different protocols across multiple centers, improving the correlation between CT imaging and clinical parameters in COPD [31]. Lastly, KOCOSS has been ongoing cohort (enrollment started in 2012) with a planned 10-year follow-up for participants enrolled since 2016. As the prevalence and characteristics of COPD evolve, our cohort provides a valuable opportunity to investigate long-term outcomes and emerging trends in COPD.
Our study has several limitations. First, due to its cross-sectional and observational design, causal relationships could not be established. Moreover, the generalizability of our findings may be limited, as participants were recruited from 55 tertiary and university hospitals in South Korea. Patients with more severe symptoms or multiple comorbidities are more likely to be referred to such centers, potentially introducing a selection bias. Accordingly, the clinical characteristics described in this study reflect the KOCOSS cohort and may not be representative of the general population. Second, the definition of pre-COPD varies across studies. In this study, we defined pre-COPD as including individuals with PRISm and those with emphysema without airflow limitation. This definition may limit the direct comparability of our findings with other studies that use different criteria. Third, we did not perform matched comparisons between groups, which may reduce the ability to clearly identify group-specific differences in clinical characteristics and outcomes. As the number of participants in the pre-COPD and smokers with normal lung function increases with continued cohort enrollment, such matched analyses will be considered in future studies. Fourth, the presence of emphysema was determined based on either radiologic reports or visual assessment by physicians at each participating site, which may have introduced variability in the identification of emphysema across centers. Lastly, comorbidities were evaluated using electronic medical records or patient reports, which may introduce potential misclassification or reporting bias.
Despite these limitations, this study provides valuable insights into the clinical characteristics of individuals with COPD, pre-COPD, and smokers with normal lung function in South Korea, and highlights the need for early identification and management in these populations.
In conclusion, this 10-year analysis of the KOCOSS cohort summarized the characteristics of Korean patients with COPD and highlighted the differential characteristics among individuals with COPD, pre-COPD, and smokers with normal lung function. Notably, not only patients with COPD but also individuals with pre-COPD and smokers with normal lung function exhibited a high symptom burden and used inhaled bronchodilators. Further, longitudinal studies are needed to assess disease progression and optimize therapeutic interventions for COPD and pre-COPD.
Notes
Authors’ Contributions
Conceptualization: Yoo KH. Methodology: Jang JG, Kim Y, Lee JK. Formal analysis: Kim Y. Data curation: Jang JG, Kim Y. Funding acquisition: Yoo KH. Writing - original draft preparation: Jang JG, Kim Y. Writing - review and editing: all authors. Approval of final manuscript: all authors.
Conflicts of Interest
Dong Il Park is an editor and Seung Won Ra is an associate editor of the journal, but they were not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
Funding
This work was supported by the Research Program funded by the Korea National Institutes of Health (Fund CODE 2016ER670100, 2016ER670101, 2016ER670102, 2018ER67100, 2018ER67101, 2018ER67102, 2021ER120500, 2021ER120501, 2021ER120502 and 2024ER120100). This work was supported by the Yeungnam University Research Grant (2024).