Longitudinal changes in forced expiratory volume in 1 s in patients with eosinophilic chronic obstructive pulmonary disease

Background Data on changes in lung function in eosinophilic chronic obstructive pulmonary disease (COPD) are limited. We investigated the longitudinal changes in forced expiratory volume in 1 s (FEV1) and effects of inhaled corticosteroid (ICS) in Korean COPD patients. Methods Stable COPD patients in the Korean COPD subgroup study (KOCOSS) cohort, aged 40 years or older, were included and classified as eosinophilic and non-eosinophilic COPD based on blood counts of eosinophils (greater or lesser than 300 cells/μL). FEV1 changes were analyzed over a 3-year follow-up period. Results Of 627 patients who underwent spirometry at least twice during the follow up, 150 and 477 patients were classified as eosinophilic and non-eosinophilic, respectively. ICS-containing inhalers were prescribed to 40% of the patients in each group. Exacerbations were more frequent in the eosinophilic group (adjusted odds ratio: 1.49; 95% confidence interval: 1.10–2.03). An accelerated FEV1 decline was observed in the non-eosinophilic group (adjusted annual rate of FEV1 change: − 12.2 mL/y and − 19.4 mL/y for eosinophilic and non-eosinophilic groups, respectively). In eosinophilic COPD, the adjusted rate of annual FEV1 decline was not significant regardless of ICS therapy, but the decline rate was greater in ICS users (− 19.2 mL/y and − 4.5 mL/y, with and without ICS therapy, respectively). Conclusions The annual rate of decline in FEV1 was favorable in eosinophilic COPD compared to non-eosinophilic COPD, and ICS therapy had no beneficial effects on changes in FEV1. Supplementary Information The online version contains supplementary material available at 10.1186/s12890-022-01873-8.


Background
Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory airway disease characterized by reduced airflow, and is a leading cause of mortality worldwide [1].
COPD is regarded as heterogeneous condition and chronic airway inflammation in COPD is thought to be driven by neutrophils and lymphocytes [2]. This type of airway inflammation is a prominent feature in most COPD patients unlike in asthmatic patients, and related to the degree of airflow limitation [3].
Airway inflammation in asthma is mediated by type-2 T helper (Th2) cells and eosinophils, associated with an exacerbation risk and poor disease control following inhaled corticosteroid (ICS) withdrawal [4,5]. The presence of eosinophils has been reported in the blood or sputum of 30-40% COPD patients [6]. Excluding patients with clinical features suggestive of asthma, such as bronchial hyperresponsiveness, history of asthma, atopy, and reversible airflow limitation, a subset of COPD patients demonstrates eosinophilic airway inflammation and responds to corticosteroid therapy [7][8][9].
Several studies have reported a greater risk for COPD exacerbation with higher blood counts of eosinophils, although the relationship remains controversial. In the general population, spirometry-based COPD patients experience more exacerbations with high blood eosinophil counts [10,11]. Although higher eosinophil levels increase the risk for COPD exacerbation, they are also associated with a greater risk reduction after the use of ICS [12][13][14].
However, few studies have investigated the effects of blood levels of eosinophils on lung function. In this study, we evaluated longitudinal changes in forced expiratory volume in 1 s (FEV 1 ) in patients with eosinophilic COPD, and analyzed the effects of ICS on this parameter.

Study population
Data were obtained from the Korean COPD Subgroup Study (KOCOSS; 2012-2019), an ongoing prospective multicenter observational cohort, which has recruited COPD patients from 48 referral hospitals in the Republic of Korea [15]. The inclusion criteria were (1) age ≥ 40 years; and (2) COPD diagnosed by pulmonologists based on respiratory symptoms and spirometryconfirmed fixed airflow limitation (post-bronchodilator FEV 1 /forced vital capacity (FVC) < 0.70). Only patients with blood eosinophil count data at baseline enrollment during stable state and followed up at least 3 years from enrollment were included in the analyses.

Clinical data
KOCOSS cohort contained detailed information regarding sociodemographics (including age, sex, smoking history, and education level), symptoms (chronic cough or persistent phlegm ˃ 3 months), dyspnea severity based on the Modified Medical Research Council Dyspnea Scale (mMRC), and quality of life based on the COPD assessment test (CAT) and the St George's Respiratory Questionnaire (SGRQ). Data on comorbidities, including cardiovascular disease, tuberculosis, and asthma, were also collected. The treatment of the subjects depended on their attending pulmonologist.
The KOCOSS cohort patients were followed-up at least every 6 months, and moderate and severe exacerbations were recorded at each visit. Moderate exacerbation was defined as an exacerbation leading to an outpatient-clinic visit earlier than scheduled and prescribed systemic steroids and/or antibiotics, whereas severe exacerbation was defined as leading to an emergency department visit or hospitalization.

Pulmonary function test
Spirometry was performed based on American Thoracic Society and European Respiratory Society guidelines [16]. Absolute FEV 1 values were obtained, and the predicted percentage values (% pred) for FEV 1 were calculated using an equation developed for the Korean population [17]. Positive bronchodilator response (BDR) was defined as post-bronchodilator FEV 1 increase in 12% or more, and 200 mL from baseline. Subjects were followed-up at least every 6 months, and spirometry was performed annually.

Statistical analysis
Baseline characteristics were expressed as means ± standard deviations and absolute numbers with percentages. Continuous and categorical variables were compared using t-test and chi-square test, respectively.
In this study, we assess the longitudinal changes in post-bronchodilator FEV 1 (mL). To exclude the immediate effects of bronchodilator treatment, lung function data used for longitudinal analysis were collected one year after enrollment.
Although variability on serial blood eosinophil counts may be concernable, over 300 cells/µL is regarded as threshold for predicting increased risk of exacerbation and high likelihood of benefit with ICS [18,19]. We compared the longitudinal FEV 1 change between eosinophilic (blood eosinophil count ≥ 300 cells/μL) and non-eosinophilic (blood eosinophil count < 300 cells/μL) COPD, using a linear mixed-effects model with random intercepts and slopes. We analyzed mean annual rates of FEV 1 change based on multiple covariates: age, sex, smoking (pack-years), and body mass index (BMI). Then, we analyzed FEV 1 changes based on ICS usage.
All tests were two-sided and a p-value less than.05 was considered statistically significant. Statistical analyses were performed using Stata (v. 16; StataCorp, College Station, TX, USA).

Study subjects
A total of 2,181 COPD patients were enrolled between January 2012 and December 2019. FEV 1 change analysis based on blood counts of eosinophils was available for 627 patients (Fig. 1). Comparison of clinical features between eosinophilic and non-eosinophilic COPD is shown in Table 1. Eosinophilic COPD was more prevalent in males (98.7% and 91.2%, for eosinophilic and non-eosinophilic groups, respectively). There were no significant differences in age, smoking status, symptoms, and quality of life. Past exacerbations were more common in eosinophilic COPD group, compared to noneaosinophilic group (25.3% and 18.5%, respectively), but the difference was not statistically significant.
Baseline pulmonary function test results are shown in Table 2. More than 60% of the patients in both groups were GOLD stage 1 or 2 (FEV 1 ≥ 50% of predicted value), and there were no significant differences in the severity of airflow limitation and exercise capacity. Mean blood counts of eosinophils were higher in the eosinophilic COPD group (546.1 vs. 141.8 cells/μL).
ICS therapy, either alone or in combination with longacting β2-agonists (LABA) and/or long-acting muscarinic antagonists (LAMA), was prescribed in 41.1% and 40.7% in non-eosinophilic and eosinophilic groups, respectively.

Longitudinal FEV 1 change
A greater FEV 1 decline rate was observed in the noneosinophilic group, compared to the eosinophilic group (− 19.6 mL/y and − 12.9 mL/y, respectively) (Fig. 2). The adjusted annual FEV 1 declined significantly in the noneosinophilic COPD group (− 19.4 mL/y). Although the adjusted annual FEV 1 also decreased in the eosinophilic COPD group, the rate of decline was not significant (− 12.2 mL/y) ( Table 4). In the eosinophilic COPD group, the adjusted annual FEV 1 decline rate was not significant regardless of ICS therapy, but the decline rate was greater in ICS users (− 19.2 mL/y and − 4.5 mL/y, with and without ICS therapy, respectively) ( Table 5). The exact values of FEV 1 changes during two years of follow-up between eosinophilic and non-eosinophilic COPD are shown in Additional file 1: Figure S1.

Discussion
There is limited data regarding the effects of ICS on FEV 1 change in COPD. We hypothesized that the rate of FEV 1 change differed based on the baseline blood eosinophil  counts and ICS therapy. The adjusted annual rate of FEV 1 change declined significantly in the low-blood-eosinophil group, compared to the high-blood-eosinophil group, although the difference was not statistically significant. Analyses of ICS effects on FEV 1 change in high-blood eosinophil group showed no statistically significant differences.
It is widely accepted that COPD develops because of a genetic susceptibility for progressive airway inflammation, triggered by complex environmental factors over time, such as smoking, pollutants, and allergens, which leads to irreversible damage and airflow obstruction [3,20]. Typically, airways of COPD patients exhibit increased CD8 + T cells and neutrophils. Although Th2  inflammatory pathway is considered a feature of asthma rather than COPD, 30-40% of COPD patients demonstrated eosinophilic-inflammation [6]. These heterogeneity of disease are now accepted as various clinical phenotypes with different pathophysiologies and endotypes. Therefore, response to therapies might also be variable. The ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End points) cohort study reported that 37.4% of COPD patients had persistently high (≥ 2%), 13.6% had persistently low (< 2%), and 49% had variable eosinophil counts over a 3-year follow-up period [6]. A subset of COPD patients demonstrate eosinophilic inflammation either in stable period  or during acute exacerbations. Blood eosinophilia was associated with increased exacerbation risk, and this phenotype could benefit from corticosteroid therapy directed against eosinophilic inflammation [13,14,[21][22][23]. A recent trial targeted eosinophilic inflammation (IL-5) to reduce exacerbation risk in eosinophilic COPD patients, suggesting that selectively eosinophilic-pathway blockers may be effective for such patients [24]. Elevated peripheral blood eosinophil counts in COPD may be used to identify patients who are expected to have favorable response to ICS therapy or biologics targeting Th2 inflammatory pathway. Conversely, ICS withdrawal in eosinophilic COPD leads to increases exacerbation risk [25]. Following ICS withdrawal, trough FEV 1 decreased and exacerbation risk increased only in the high eosinophil group [26].
Most trials assess the impact of ICS on COPD using exacerbation risk as the outcome, therefore data regarding ICS effects on FEV 1 change is limited. A post hoc study reported favorable effects of extrafine beclomethasone dipropionate and formoterol fumarate, compared to formoterol fumarate alone, on FEV 1 change in the highest blood eosinophil quartile (≥ 279.8 cells/μL). In this trial, severe COPD patients with FEV 1 of 30-50% of predicted value, and at least one exacerbation in the previous year were included [27].
A study on effects of ICS monotherapy on disease progression in moderate to severe COPD reported no differences in the rate of decline of post-bronchodilator FEV 1 between fluticasone propionate and placebo over 3 years. However, when analyzed using baseline blood eosinophil levels, the rate of FEV 1 decline was significantly lower in the fluticasone propionate group compared to placebo in the ≥ 2% eosinophil group (− 40.6 mL/y and − 74.5 mL/y, respectively; p = 0.003) [22].
In the present study, annual rate of FEV 1 change declined significantly in the lower blood eosinophil group. Analyses of ICS effects on longitudinal FEV 1 change in high-blood-eosinophil group revealed a greater decline rate in ICS users. Although we demonstrated increased exacerbation risk in the eosinophilic COPD group, consistent with previous studies [10][11][12], the annual FEV 1 decline rate was low in eosinophilic COPD compared to non-eosinophilic COPD, and ICS provided no benefits. Unlike previous trials [22,27], only 20% of subjects had previous exacerbations and approximately 66% had mild to moderate FEV 1 severities in the KOCOSS cohort. Different airflow obstruction severities and previous exacerbation history may have caused the differences in FEV 1 change.
In this study, we used blood eosinophil count as a marker of treatment response to ICS in COPD cohort.
In consideration of patients with asthma-COPD overlap (ACO) high probability, we defined ACO by eosinophil count of cells/μL and/or extreme BDR criteria (> 15% and 400 mL). More than 98% were classified according to the eosinophil criteria. Absence of unified diagnostic criteria for ACO resulted in inconsistent clinical manifestations and outcomes. Moreover, in our previous study, we showed that blood eosinophil was the single most important biomarker to predict the decrease of exacerbation by ICS [28]. Recently, interests in precision medicine according to the subtype of COPD, rather than ACO is increasing. Blood eosinophil count is considered as the reliable biomarker in identifying subtype that might be benefitted by ICS. Although we did not find meaningful relation between FEV 1 change and ICS use in eosinophilic COPD in real world data, additional prospective studies will be needed.
There were several limitations in this study. First, we analyzed subsequent 2 years of FEV 1 data, which is a relatively short follow-up period. Second, we defined eosinophilic COPD using blood eosinophil counts at a stable period, and variation over time were not reflected. Third, COPD patients in our study were enrolled irrespective of treatment-naïve status. Whether blood eosinophil count less than or over 300cell/μL, the prescription rate for ICS containing inhalers was similar, which implies considerable numbers of subjects who have already been exposed to ICS are included, and this might be related to attenuation of ICS effects on eosinophilic COPD. Fourth, this was not a randomized clinical trial. Although the prescription rate for ICS containing inhalers was similar in both groups (41.1% and 40.7% in non-eosinophilic and eosinophilic groups, respectively.), ICS containing inhalers was not randomly assigned. ICS prescription was decided by pulmonologists. Thus, there can be a bias for the prescription of ICS. Caution is needed to interpret the impact of ICS on eosinophilic COPD. Fifth, changes in FEV 1 according to GOLD classification could not be performed because approximately 90% of subjects were in GOLD group A or B. Lastly, we aimed to assess the rate of decline of FEV 1 according to blood eosinophil count and whether FEV 1 decline differs between eosinophilic COPD with and without ICS. Whittaker et al. [29] reported ICS use is associated with slower rates of FEV 1 decline in COPD regardless of blood eosinophil level in a cohort of 26,675 COPD patients. On the other hand, Celli et al. [30] reported ICS plus LABA combination or the component, reduces the rate of decline of FEV 1 in moderate to severe COPD. This study included more than 1,000 patients in each of subgroups. However, our study is underpowered to address intended questions about rate of decline of FEV 1 due to small number of subjects.