We explored the clinical features of COPD patients according to BDR positivity, as defined by the ATS/ERS definition. We divided COPD patients into those with FEV1 responsiveness (i.e., BDR-FEV1) and those with FVC responsiveness (i.e., BDR-FVC), then compared the clinical characteristics of these patients with BDR-FEV1 and BDR-FVC negative patients, respectively. BDR positive patients were more likely to be ever-smokers and to have severe symptoms and worse lung function compared to BDR negative patients. BDR positive patients had been more frequently diagnosed with ACO and prescribed ICS compared to BDR negative patients. However, Th2 inflammatory biomarkers did not differ significantly between the groups. In addition, there were no significant differences in the risk for exacerbation or decline in lung function according to BDR, BDR-FEV1, or BDR-FVC.
BDR positive COPD patients have lower FEV1 and FEV1/FVC than BDR negative patients [22–24]. However, the results differ between BDR-FEV1 and BDR-FVC patients. Although BDR-FVC positive patients have lower FEV1 compared to BDR-FVC negative patients, BDR-FEV1 positive patients may have better  or worse  lung function than BDR-FEV1 negative patients. Our study found lower FEV1 in BDR-FVC positive patients and higher FEV1 in BDR-FEV1 positive patients. This is consistent with previous results that showed that BDR-FEV1 positive patients more often had mild to moderate COPD, whereas BDR-FVC positive patients more often had severe COPD . This may be because FEV1 is mainly affected by airflow limitation at high lung volumes, whereas FVC is mainly affected by airflow at low lung volumes [7, 15]. Numerous studies have shown that BDR positive patients have a rapid decline in lung function [25, 26]. However, the difference between BDR positive and negative patients is not statistically significant after baseline FEV1 is adjusted for [8, 18, 27]. Our study found similar results: After we adjusted for baseline lung function, there were no significant differences in 3-year changes in FEV1 between the BDR groups.
Although BDR is associated with worse control of disease and frequent use of reliever medications in asthmatic patients [5, 6], it is not associated with the risk for COPD exacerbations [7, 8, 10, 11, 13]. In the ECLIPSE study, although the exacerbation rate was significantly higher in patients with less reversible than more reversible airway restriction, the results may have been affected by the lack of adjustment for baseline FEV1 [8, 26]. By contrast, many studies have shown that BDR is associated with poor control of COPD symptoms, similar to asthma [12, 25, 28, 29]. However, some studies have reported negative results . It is important to note that BDR-FEV1 is associated with wheezing and BDR-FVC with breathlessness [28, 29]. In our study, only BDR-FVC was associated with high mMRC and CAT scores, which may be because BDR-FVC was more frequently present at higher GOLD stages compared to BDR-FEV1.
ACO is characterized by overlapping clinical manifestations of both COPD and asthma. Identifying ACO in COPD patients is important because such patients benefit from the use of ICS . Although there is no consensus on the definition of ACO, most studies include BDR in the diagnostic criteria . However, in Jo et al.’s analysis of several factors, including history of asthma, history of atopy, history of allergic rhinitis, BDR, and blood eosinophil and IgE, only blood eosinophil count (≥ 300 cell/µL) was associated with a positive response of exacerbations to ICS . Our study showed similar results: There were no associations of ICS use or BDR with exacerbation rate. Furthermore, there were no differences in Th2 inflammatory markers (e.g., blood eosinophil count or IgE and FeNO) between BDR positive and negative patients. BDR may also be present in COPD patients without asthma [3, 31], which suggests that BDR may not be appropriate for diagnosing ACO. In the present study, BDR positive patients were often diagnosed with ACO and prescribed ICS; therefore, other factors, in particular blood eosinophil count, should be considered when deciding whether to prescribe ICS.
Although BDR positive patients have distinct features, such as poor symptom control and lung function, there are several limitations to considering BDR a phenotype. Most important is that BDR varies significantly over time, and reversibility decreases as the disease progresses [2, 19]. Moreover, previous studies have shown that BDR varies with baseline lung function. Patients with lower FEV1 may easily meet the BDR percentage criterion but are unlikely to meet the BDR absolute volume criterion . In addition, patients with poor lung function have a low probability of having BDR [7, 10, 18].
Our study has several limitations. First, this study included patients recruited since 2012, and those enrolled before 2016 were prescribed ICS based on a history of frequent exacerbations and poor lung function, as recommended by the previous GOLD guidelines. This may have introduced bias into the study results, because patients with frequent exacerbations were more likely to have received ICS at baseline, which makes the analyses of the effectiveness of ICS unreliable. To overcome this limitation, we included history of exacerbations as a covariate in the regression model. Second, because the KOCOSS cohort includes patients that presented to tertiary hospitals, the study participants may be representative of the general COPD population and sufficient patients with mild COPD may not have been included.
Despite these limitations, our study has several strengths. First, the study included a large number of patients enrolled in a nationwide multicenter cohort study for 8 years. We performed comprehensive analyses of the clinical characteristics of patients with BDR, BDR-FEV1, and BDR-FVC. We also performed prospective analyses of disease exacerbations and decline in lung function, which are the most important clinical parameters of COPD. Second, although it is frequently done in clinical practice, diagnosing ACO and ICS use according to BDR is unreliable. To the best of our knowledge, few studies have reported results similar to ours; the results of these studies are important for establishing diagnostic criteria for ACO and developing treatment guidelines.