Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by persistent airflow limitation and chronic respiratory symptoms. As a chronic disease, COPD interventions aim to reduce the risk of acute exacerbation and relieve symptoms in overt, advanced disease. Cigarette smoke inhalation is the main risk factor for developing COPD; other factors include poor lung growth and subsequently low maximal forced expiratory volume in 1s (FEV1), biomass exposure, and air pollution, especially in those who are at risk. Several recent studies have focused on patients with early disease; those with symptoms or physiological or radiological abnormalities are more likely to progress to COPD. To aid early identification and preventive measures, the Global Initiative for COPD (GOLD) suggested several definitions of early COPD.1,2 COPD is recognized as a condition that progresses from upstream to downstream, and attention has focused on elucidating prodromal conditions preceding disease progression.

Preserved ratio impaired spirometry (PRISm) is defined as a FEV1<80% of the predicted value without airflow limitation, i.e., with a normal FEV1/forced vital capacity (FVC) ratio.3 This was previously defined as restrictive pulmonary function,4,5 GOLD-unclassifiable,6 or even nonspecific findings.7,8 PRISm is associated with more severe respiratory symptoms4,5,9 and a higher risk of all-cause and respiratory mortality.9–13 It is regarded as a transitional state, either progressing to overt airflow obstruction (AFO) or reverting to normal spirometry in longitudinal studies6,10 in a significant proportion of individuals.14

Studies have found associations between respiratory symptoms, such as chronic mucus production,15–17 and abnormalities on chest images.18 The concept of pre-COPD encompasses not only symptoms but also structural abnormalities compatible with those found in COPD (e.g., emphysema). Formerly referred to as GOLD 0, the most recent GOLD document labeled these symptoms and abnormalities pre-COPD.2 Although it is associated with a higher risk of developing COPD, pre-COPD can transition to other airway disease statuses, including normal spirometry.19,20

While these airway diseases are acknowledged as precursors to COPD, not all patients progress to COPD. Indeed, many patients transition to normal lung function, as alluded to above. We examined the outcomes of individuals at risk of developing COPD by analyzing data collected prospectively from the general population. This well-constructed longitudinal cohort enables us to identify lung function trends over time and factors related to the development of airflow limitation.

This prospective cohort study sought to classify a substantial sample of the general population into airway groups based on lung function, respiratory symptoms, and radiological abnormalities. Group transitions were identified by analyzing follow-up data. Indicators of AFO, such as FEV1, the FEV1/FVC ratio, and FEF25–75, declined more rapidly in the pre-COPD group than in the PRISm group. Moreover, while transitions to normal status or COPD occurred in both the pre-COPD and PRISm groups, more transitions occurred in the PRISm group. Although the risk of developing COPD was much higher in the PRISm group than in the other groups, the risk was nevertheless significantly higher in both the pre-COPD and PRISm groups compared to the normal group.

This study found that the rates of decline in FEV1, the FEV1/FVC ratio, and FEF25–75 were notably higher in the pre-COPD group compared to the normal group, and the decline in FEV1 and FEF25–75 was slower in the PRISm group compared to the normal group. Moreover, there were significantly more status transitions in the pre-COPD and PRISm groups compared to the other groups. During the initial follow-up period, approximately half of the individuals in both the pre-COPD and PRISm groups transitioned to normal status. In the pre-COPD group, a similar pattern was seen during the second follow-up period, with approximately 55% of patients transitioning to normal status. However, in the PRISm group, a distinct trend emerged, with 51% of patients classified as “persistently PRISm” and >10% progressing to COPD during both the first and second follow-up periods. Other cohort studies have reported frequent transitions between PRISm and other lung function groups,5,6,10 and the reported occurrence of AFO in patients with PRISm progressing to COPD is in the range of 15–40%. In our study, however, the proportion of patients transiting from PRISm to COPD was only approximately 13%, which is lower than that reported elsewhere. Since our study included relatively young subjects (average age of 50 years) and many never-smokers compared to other studies, which often included mainly elderly patients and smokers with >10 pack-years of smoking, it is plausible to attribute these differences to age-related variation in pulmonary function and the influence of cigarette smoking.5,6,8

Given the recent interest in the earlier stages of COPD, the GOLD classified individuals with a high likelihood of developing COPD into pre-COPD and PRISm groups.23 Recently, Miguel et al.24 analyzed risk factors for the progression from pre-COPD to COPD within a cohort of smokers, identifying a low FEV1/FVC ratio, ≥30 pack-years of smoking, BMI<25kg/m2, and a history of chronic bronchitis as risk factors. Our study similarly identified smoking, low BMI, and impaired lung function as risk factors for COPD progression, and the pre-COPD and PRISm patients had higher risks of progression to COPD. However, it is noteworthy that all groups in this study had a mean BMI<25, possibly reflecting ethnic variation.

Pre-COPD and PRISm contributed to an earlier time to first AFO Another interesting finding in the present study was that both pre-COPD and PRISm significantly shortened the time to first AFO, although this was not seen in the PRISm group when CVD was considered. CVD is thought to be a comorbid condition of COPD. However, a recent Danish study based on the Copenhagen City Heart study,25 which included 1160 individuals aged 20–40 years, found that incident PRISm could increase the risk of hospitalization for CVDs, such as ischemic heart disease or heart failure. Furthermore, PRISm was associated with obesity, smoking, cardiovascular comorbidities, and increased CVD-related morbidity and mortality.12,26 Not all individuals with pre-COPD or PRISm will necessarily develop fixed airflow limitation. Particularly in PRISm patients diagnosed solely based on pulmonary function tests, without concurrent respiratory symptoms or imaging findings suggestive of COPD, clinicians should consider the presence of pre-existing CVD.

Considering the socioeconomic impact of COPD, it is necessary to define early disease and examine the effects of early intervention on these patients. However, there are few randomized controlled trials (RCTs) have addressed the early detection and treatment of such individuals who are at-risk for development of COPD. Moreover, a recent RCT reported that the use of dual-bronchodilator inhaler treatment in the PRISm group did not reduce respiratory symptoms.27

This study had several limitations. First, the KoGES cohort did not include post-BD values, necessitating the classification of airway groups based on pre-bronchodilator (BD) values. However, numerous studies have used pre-BD values as an alternative to post-BD values for evaluation of patients with COPD in terms of diagnosis, clinical features and longitudinal outcomes.28–31 Recently, respiratory symptoms were found to be more severe in a post-BD PRISm group compared to a pre-BD PRISm group whose post-BD values were normalized.32 However, there are few comparative studies of pre-BD and post-BD, and the concept of PRISm includes patients capable of transitioning. Second, radiological abnormalities were ascertained using chest radiographs, not chest computed tomography (CT). Consequently, structural abnormalities indicative of COPD beyond emphysema and bullae, such as airway wall thickening, were not discernible. However, repeated CT examinations present challenges in terms of time, resources, and radiation exposure-related risks in the general population. Third, the diffusing capacity for carbon monoxide (DLCO) values was not known. Given that DLCO can help to identify individuals with an elevated risk of developing COPD among smokers without AFO, the unavailability of this metric may have resulted in underestimation of the risk of progression to COPD. Fourth, as this cohort did not focused primarily on airway and lung diseases, there were no indicators of airway disease-specific quality of life or the severity of symptoms. However, we addressed this deficiency by using the mMRC dyspnea scale and EQ-5D-5L, derived from multiple inquiries related to dyspnea and general quality of life. Lastly, we were unable to obtain mortality information, and some patients may have passed away during the follow-up period. We have presented the number of participants at each follow-up in Table S1. From Year 0 to Year 4, there were no missing data. By Year 12, 3352 out of 4762 patients were followed up.

In conclusion, in a large cohort drawn from the general population, we found that individuals with pre-COPD and those in the PRISm group exhibited comparable differences in the longitudinal changes of lung function parameters over time. Additionally, a significant proportions of individuals in both groups transitioned to other lung function groups over time. As well as age, male sex, lower BMI, and low lung function, pre-COPD and PRISm were identified as risk factors for progression to COPD. However, in PRISm patients, the concurrent presence of CVD should be considered.

Ethical approval was obtained from the Ethics Committee of Incheon St. Mary's Hospital, and the IRB number was OC23ZISI0033. The requirement for informed consent was waived by the Ethics Committee of Incheon St. Mary's Hospital.

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (grant number) (NRF-2022R1I1A1A01063654).

YSJ and JYC contributed to study concept/study design.

YSJ and JYC contributed to data acquisition and analysis.

All authors contributed to interpretation for the work.

YSJ and JYC contributed to drafting the work.

All authors contributed to critical revision for relevant intellectual content and final approval of this manuscript.

None.

The raw data involved in this study will be available by the corresponding author to any qualified researcher.

None.