https://orcid.org/0000-0001-7786-5051
Abstract
This study aimed to evaluate the prevalence, trends, and risk factors of early chronic obstructive pulmonary disease (COPD) by using a nationally representative sample. The datasets of the Korea National Health and Nutrition Examination Survey 2010–2019 were used, where 80,860 individuals were identified; of these, 9,045 participants aged 40–49 years who underwent spirometry with no missing data were analyzed. Early COPD was defined as forced expiratory volume in 1 s /forced vital capacity ratio < the lower limit of normal (2.5th percentile) in individuals aged <50 years without a history of asthma, inhaler therapy, or persistent respiratory symptoms. The prevalence and trend of early COPD were estimated according to features such as smoking status and pack-years. Joinpoint regression analysis was used to analyze the significant annual change in the trend according to sex, smoking status, and pack-years. A complex sample multivariable-adjusted regression model was used to identify factors affecting early COPD. The estimated population size during 2010–2019 was 82,326,178. Early COPD was present in 4.5% of patients (6.5% of men and 2.3% of women). It was present in 7.7% of current smokers, followed by former and never smokers. Among smokers with ≥ 10 pack-years, early COPD was present in 8.2%, whereas it was present in 2.6% of smokers with < 10 pack-years. Joinpoint regression analyses found a recent decrease in the trend of prevalence in males who were former and current smokers. The multivariable-adjusted logistic regression model showed that being male, lower educational level, smoking status, and pack-years were factors that affected the presence of early COPD. Continued surveillance of this pre-disease condition is required, and further research are warrant.
Introduction
With the population aging, estimating the exact prevalence and risk factors of chronic obstructive pulmonary disease (COPD) is important for guiding further public health policy interventions. COPD is one of the leading causes of mortality, disability, and morbidity worldwide, and its prevalence is increasing [Citation1]. The high economic burden related to COPD is also associated with both the aging process and delayed diagnosis [Citation2]. Several approaches to identifying COPD at an early age before the onset of clinical manifestations have led to the introduction of an operational definition of early COPD [Citation3]. Early COPD was defined in individuals aged <50 years with a lifetime smoking amount ≥10 pack-years with one or more abnormalities in pulmonary function testing (PFT), computed tomographic (CT) examination, and evidence of accelerated lung function decline [Citation4]. Establishing the concept of early COPD has gained attention because early intervention may preclude or reverse COPD progression.
Several commentaries have introduced early COPD; however, clinical data related to this time point during the natural course of COPD are lacking. In the Copenhagen General Population Study (CGPS), where early COPD was defined using the age and results from PFT lower than lower limit of normal (LLN), the status was linked to the high probability of the development of clinical COPD [Citation5]. Approximately, a quarter of individuals with early COPD progressed to clinical COPD after a follow-up period of 10 years. Although the degree of progression to clinical COPD differed depending on smoking status and amount, early COPD smokers with more than 10 pack-years showed an odds ratio (OR) of about eightfold compared to individuals without early COPD. In another study in South Korea, the prevalence of early COPD was 2.4% among the middle-aged population and 8.2% in individuals with ≥10 pack-years of smoking [Citation6].
In this regard, estimating and tracing the trend in the prevalence of early COPD would be valuable. Predicting the future prevalence of this pre-disease status would also have implications on the establishment of public health policies. Discovering the clinical factors related to early COPD would aid in reducing its future disease burden. Therefore, the present study aimed to evaluate the prevalence, trends, and risk factors of early COPD using a nationally representative sample in South Korea.
Materials and methods
Datasets and study participants
The present study used data from the 2010–2019 Korea National Health and Nutrition Examination Survey (KNHANES). The survey was conducted annually by the Korean Centers for Disease Control and Prevention. The KNHANES collects nationally representative data of noninstitutionalized Korean citizens, which comprises health interviews, health examinations, and nutrition surveys. It provides information on the socioeconomic status, health-related behaviors, anthropometric indices, and biochemical and clinical profiles of noncommunicable diseases. Each survey year included a new sample of randomly enrolled participants. The detailed procedures of the KNHANES have been previously described [Citation7].
We reviewed the data of KNHANES from 2010 to 2019, where of total 103,465 study participants 80,860 (78.2%) individuals responded to the survey. PFT were only performed in adults aged ≥40 years and were not conducted in 2020 because of the risk of transmission of severe acute respiratory syndrome coronavirus 2. Therefore, 47,885 participants without PFT data were excluded from the study. In addition, adults aged ≥50 years were excluded because the operational definition of early COPD classifies the preclinical stage of disease in individuals aged <50 years [Citation3]. Then, we also excluded individuals with a history of asthma or who had experienced persistent cough or sputum for more than three months (n = 274). Therefore, 8,766 individuals aged 40–49 years with PFT information were included in the analysis.
Data measurements
PFT was performed using dry rolling seal spirometers (Model 2130; SensorMedics, Yorba Linda, CA, USA) in 2010 to 2015 and Vyntus Spiro (CareFusion, San Diego, CA, USA) from 2016 to 2019. Calibration and quality control followed the standardization criteria of the American Thoracic Society (ATS) and European Respiratory Society (ERS) [Citation8]. Forced expiratory volume in 1 s (FEV1, L), forced vital capacity (FVC, L), and the ratio of FEV1/FVC (%) were obtained from the prebronchodilator test. Meanwhile, postbronchodilator testing was not performed in the KNHANES.
Early COPD was defined based on the practical definitions by Martinez et al. [Citation3] and Çolak et al. in the CGPS [Citation5]. In these studies, individuals aged <50 years with FEV1/FVC less than the 5th percentile LLN were classified as having early COPD. However, because our study used the screening dataset of a healthy noninstitutionalized population, a more conservative level of 2.5% was adopted to reduce the number of false positives; this was in accordance with the 2021 ERS/ATS technical standard for interpretive strategies [Citation9]. The LLN value was calculated according to the 2012 Global Lung Function Initiative reference equations [Citation10]. Given that the prevalence of early COPD differs according to the smoking amount [Citation5], we further classified the individuals according to pack-years: smoking exposure <10 pack-years or ≥10 pack-years. However, because the age at which smoking began among current smokers was not evaluated in the survey during 2013–2014, calculation of pack-years was unfeasible during that period, and analyses related to pack-years were performed except for that period.
Other variables included age (years), sex (male and female), residence (rural and urban), educational level (high school or lower and college or higher), household income at quantile levels, smoking status (never, former, and current), alcohol consumption level, and body mass index (BMI, kg/m2). Smoking status was categorized based on the National Health Interview Survey of the United States [Citation11]. Current smokers were defined as individuals who smoked more than 100 cigarettes in their lifetime and who currently smoked. Former smokers were defined as individuals who smoked more than 100 cigarettes in their lifetime but had stopped smoking for more than 1 year. High-risk alcohol consumption was defined as more than seven drinks in men and more than five drinks in women on a single occasion.
Statistical analysis
The KNHANES was designed to represent noninstitutionalized South Korean citizens. A stratified multistage probability sampling method was used to design KNHANES data. Therefore, all statistical analyses in this study were conducted using the complex sample analysis in SPSS, considering the sampling weights, stratification, and clustering of the KNHANES. Categorical variables in the descriptive analysis were presented as percentages with standard errors and compared using chi-squared test.
The prevalence of early COPD was estimated and shown with its standard error. A complex sample logistic regression analysis was used to calculate the OR and 95% confidence intervals for the factors affecting early COPD. For multivariable analysis, sex, residence, educational level, household income, smoking, pack-years, high-risk alcohol consumption, and BMI were considered together, smoking status and pack-years were added to separate the models because of multicollinearity. Subgroup analyses for the estimation of the prevalence of early COPD were performed according to smoking status and pack-years.
A joinpoint regression analysis was performed to identify any changes in the trend of prevalence of early COPD. The number of joinpoint within the years 2010–2019 was selected as one based on the Grid Search Method. Thus, the regression coefficients of the slope were separately calculated before and after the joinpoint year, and the significance level was also obtained.
All statistical analyses were performed using SPSS (version 24 for Windows, Chicago, USA) and Joinpoint Regression Program version 4.9.1.0 (Statistical Research and Applications Branch, National Cancer Institute, USA). For all analyses, p value <0.05 was considered statistically significant.
Ethical approval
The study and protocol were approved by the Institutional Review Board of Armed Forces Medical Command (no. 202212-HR-065-01). This study was conducted in accordance with the Declaration of Helsinki. All procedures were performed in accordance with the relevant guidelines and regulations.
Results
The estimated population size of KNHANES 2010–2019 was 82,326,178 (). Of all study participants, 50.6% were men, and the mean age was 44.7 years. Most of the study participants (85.3%) lived in urban areas, 52.2% graduated from college or higher, household income in the 3rd and 4th quartiles was about 70%, 54.6% were never smokers, smokers with pack-years of more than 10 were 26.8%, high-risk alcohol consumption less than once a week in 69.3%, and obese individuals were 37.0%.
Table 1. Characteristics of study participants aged 40–49 years by survey year.
The prevalence of early COPD in all the study participants aged 40–49 years was 4.5% (). Male participants had significantly higher rates of early COPD than female participants, and the trend of prevalence is shown in . Individuals with a lower educational level, current smoking exposure, pack-years ≥10, and frequent high-risk alcohol consumption were shown to have higher rates of early COPD. The prevalence of early COPD in current smokers was 7.7%, followed by former smokers (5.0%), and never smokers (2.5%). The prevalence trends are presented in . Early COPD was present in 8.2% of the individuals with ≥10 pack-years and 2.6% with <10 pack-years. The prevalence trends are shown in .
Figure 1. Prevalence of early COPD in individuals aged 40–49 years according to sex by year. COPD, chronic obstructive pulmonary disease.
Figure 2. Prevalence of early COPD in individuals aged 40–49 years according to sex and smoking status by year. COPD, chronic obstructive pulmonary disease.
Figure 3. Prevalence of early COPD in individuals aged 40–49 years according to sex and smoking pack-years by year. COPD, chronic obstructive pulmonary disease.
Table 2. Estimated percentage prevalence (SE) of early chronic obstructive pulmonary disease in aged 40–49 years according to features.
In the univariable model, male sex, educational level of high school or lower, lower household income level, current smoking, pack-years ≥10, and high-risk alcohol consumption ≥1/week were associated with increased OR of early COPD (). A multivariable-adjusted analysis revealed that male sex, lower educational level, smoking status, pack-years, and alcohol consumption level were related to the presence of early COPD.
Table 3. Estimated odds ratio of factors associated with early chronic obstructive pulmonary disease.
Subgroup analyses according to sex and smoking status are shown in . Among men, early COPD was present in 8.2% of the current smokers, 5.3% former smokers, and 3.8% never smokers, with a p value of <0.001. Individuals with pack-years > 10 years had significantly higher rates of early COPD (8.3%) than those with pack-years <10 (3.2%). Meanwhile, the significance level was not reached in women according to their smoking status. Females with current smoking or pack-years ≥10 had numerically larger rates of early COPD.
Table 4. Estimated percentage prevalence (SE) of early chronic obstructive pulmonary disease among 40–49 years according to sex, smoking status, and smoking amount by year.
Joinpoint regression analysis was performed to find any statistically meaningful change in the trend of the prevalence of early COPD according to sex, pack-years, and smoking status (). An example of trend analysis is shown in . The graph shows the estimated trend of early COPD in male participants. The most meaningful joinpoint year was 2014. Before that year the estimated slope was 0.104 showing a trend for increasing prevalence (p = 0.134) but after 2014 the slope was –0.136 showing decreasing prevalence (p = 0.028). In the joinpoint regression analysis, significant decreases in the recent trend of prevalence of early COPD were observed in male individuals who were current and former smokers. Although a p value was below <0.05 in female participants with pack-years ≥10 and former smokers, many missing values in the rate of early COPD for each year were present, thereby the joinpoint was set at 0 and only 1 slope was estimated.
Figure 4. An example of joinpoint regression analysis for the estimation of the trend of prevalence of early COPD in males aged 40–49 years. COPD, chronic obstructive pulmonary disease.
Table 5. Joinpoint regression analysis for trend estimation of early chronic obstructive pulmonary disease.
Discussion
This study assessed the prevalence, 10-year trends, and risk factors of early COPD in South Korean citizens using a nationally representative survey sample. Early COPD, defined as FEV1/FVC less than LLN 2.5 percentile in individuals aged <50 years without the history of asthma and relevant respiratory symptoms, was present in 4.5% of all Korean adults aged 40–49 years (6.5% of men and 2.3% of women). The prevalence of early COPD was highest in current smokers (7.7%), followed by former smokers (5.0%), and never smokers (2.5%). The prevalence of early COPD among never smokers corresponded with the expected value when applying the specified threshold on healthy individuals. Consequently, it is solely the ex-smokers and current smokers who exhibit a higher prevalence of COPD than expected. Among smokers with ≥10 pack-years, 8.2% had early COPD, which was much more prevalent than among smokers with <10 pack-years (2.6%). A multivariable-adjusted model found that being male, lower educational level, current smokers, and having >10 pack-years were associated with an increased OR for early COPD. In addition, joinpoint regression analyses for the estimation of the trend of early COPD by sex, smoking status, and pack-years showed that the prevalence of early COPD was declining recently, particularly in former and current male smokers. This decline might be attributable to the decreasing rates of current smokers and smoking amount in South Korean men [Citation12]. Given that population-level studies on the clinical characteristics of early COPD are lacking, especially in Asian populations, the findings of our study may be informative and warrant future long-term cohort studies.
Our study had the strength of estimating the prevalence of early COPD according to several clinical features. Although a recent CGPS study showed the prevalence of early COPD in the general Danish population, sex-specific rates by smoking status and smoking amount were not measured [Citation4]. In the present study, smoking status and the amount of smoking exposure were related to higher rates of early COPD in both sexes. Although smoking status was not significantly associated with the prevalence of early COPD in women, current smokers had a higher rate of early COPD than both former and never smokers. Smoking is the leading cause of the development of COPD, but the difference in the prevalence of early COPD according to smoking status and amount was not considered in the previous CGPS, all of which make the observations from the current study noteworthy.
Considering that COPD remains a major public health problem, especially in low- and middle-income countries, it is necessary to elucidate the natural course of COPD, focus on the pathological changes before the development of clinically evident COPD, and prevent its progression in susceptible individuals [Citation13]. Although COPD is a common disease in older adults, its pathogenesis often begins much earlier. For example, early life exposure to smoking negatively affects lung function development during adolescence or early adulthood [Citation14]. Children with a history of severe asthma are more likely to develop COPD when they grow up [Citation15]. In this regard, several efforts have been made to investigate early changes in the lungs resulting in COPD in younger adults. In a multicohort analysis by Lange et al. the combination of low maximally attained lung function and rapid FEV1 decline led to an increased risk of developing COPD [Citation16].
Regrettably, there is no consensus on the definition of early COPD. Rennard and Drummond emphasized in 2015 the importance of distinguishing early from mild COPD and proposed that early COPD is an interval in time at the beginning of the disease. They suggested that subsequent longitudinal PFT, exercise performance testing, imaging, symptom assessment, and the development of biomarkers of disease progression together could help early identification of progression to COPD [Citation17]. Siafakas et al. defined early COPD in 2018 as a preclinical stage of COPD (stage 0) in individuals suffering from chronic cough and sputum without airflow obstruction [Citation18]. Martinez et al. proposed the early COPD in individuals younger than 50 years with smoking pack-years more than 10, satisfying at least one of the followings in 2018 [Citation3]: (i) FEV1/FVC less than LLN, (ii) abnormal findings on CT (emphysema, gas trapping, and thickening of the tracheal wall), and (iii) annual decline rate of FEV1 ≥ 60 mL. However, these proposals were not based on epidemiological evidence. Furthermore, given that a recent technical standard for the interpretation of spirometry highlighted the possibility of false positives when using the 5th percentile as the cutoff for LLN, this initial attempt to classify early COPD using the 2.5th percentile would be more informative [Citation9].
Findings from the previous CGPS provide important insights into the longitudinal effect of early COPD on the development of clinical COPD [Citation5]. Early COPD was defined as baseline FEV1/FVC less than LLN 5th percentile in individuals aged <50 years. The rate of developing clinical COPD after a 10-year follow-up was much higher in individuals with early COPD than in those without it. The risk of early COPD in the development of clinical COPD was independent of smoking status, but smoking amount was related to an increased risk of developing clinical COPD. Among smokers with ≥10 pack-years of smoking, 24% progressed to clinical COPD 10 years after early COPD. Early COPD was developed in 10% among smokers with <10 pack-years and 1% among never smokers, respectively.
Early COPD differs from “mild” COPD. It is very challenging to distinguish early from mild forms of COPD because there is confusion between earlier onset of the disease and the recent onset of the mild form [Citation19]. The natural history of COPD can be divided into preclinical and clinical stages. The clinical phase of COPD was defined based on chronic respiratory symptoms and postbronchodilator spirometry of FEV1/FVC <0.7, and the severity of clinical COPD was classified according to FEV1 by the Global Initiative for Chronic Obstructive Lung Disease. Mild COPD refers to postbronchodilator FEV1%, which is 80% of the predicted value or greater. However, there are patients with mild COPD with a gentle decline in lung function, while there are individuals with normal spirometry but rapid lung function decline, especially symptomatic individuals [Citation20]. Considering the heterogeneity in the pathogenesis of COPD, further longitudinal studies are necessary to clarify the different trajectories of mild vs. early COPD.
Although our study might provide important insights into the epidemiological characteristics of early COPD, several limitations should be noted. First, the KNHANES is an observational study; estimation of causality on the effect of several clinical factors on the development of COPD could be expanded in future longitudinal studies. Second, because of the nature of self-reported questionnaires, recall bias on smoking status, pack-years, and other health-related conditions might exist. Third, the KNHANES only assessed prebronchodilator PFT. However, the operational definition of early COPD in CGPS is based on prebronchodilator results. Fourth, clinical information regarding the diagnosis of COPD by physicians and inhaler therapy was unavailable during the study period. Although we excluded participants with asthma and persistent respiratory symptoms, the clinical information on COPD might have altered the observed findings. Fifth, because the study was conducted using data from the Korean population, generalizability could be limited. Sixth, given that occupational exposure is associated with COPD, the lack of information on this might have further affected the findings of this study. Considering the importance of understanding the holistic spectrum of COPD, especially in its early stages, our results might add to the big picture. Further prospective studies are needed to understand the impact of early COPD on the development of clinical COPD and to reverse the course of progression to COPD.
Conclusion
The prevalence and 10-year trend of early COPD, defined as FEV1/FVC less than LLN 2.5th percentile, in individuals aged <50 years were estimated. Although the recent annual change in the prevalence of early COPD has shifted in a decreasing direction among never- and former male smokers, continued attention in individuals of both sexes is needed to prevent further progression to clinical COPD. Future studies on early COPD should focus on establishing a universally accepted definition and determining the longitudinal effect of early COPD on the development of COPD and other chronic respiratory conditions.
Disclosure statement
Authors have no competing interests.
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