Introduction
Bronchiectasis is a heterogeneous disease characterized by the presence of irreversible abnormal bronchial wall thickening and dilation of the bronchus on lung images, accompanied by productive sputum, cough, and recurrent respiratory infections [1]. Traditionally, bronchiectasis has been considered an obstructive ventilatory defect (OVD) disease [2]. However, recent studies have shown that the distribution of obstructive and restrictive components in bronchiectasis seems to be distinct according to race and region, and up to 28.5% of patients with bronchiectasis have restrictive ventilatory defects (RVD) among non-western populations. This is probably due to increased parenchymal destruction caused by tuberculosis and other infections [3-8].
Acute exacerbation (AE) of bronchiectasis is a serious event that patients with bronchiectasis can experience that is not only associated with aggravated respiratory symptoms and decreased quality of life but also with hospitalization, which can lead to death [9-12]. Decreased forced expiratory volume in 1 second (FEV1) in bronchiectasis patients with the presence of obstructive components or other obstructive lung diseases such as asthma or chronic obstructive pulmonary disease (COPD) is associated with an increased risk of AE or hospitalization [13,14]. However, little is known about whether spirometry-defined restrictive components (decreased forced vital capacity [FVC]; RVD and mixed ventilatory defects [MVD]) are associated with an increased AE risk in patients with bronchiectasis. Most models for assessing the severity of bronchiectasis include FEV1 as a covariate. However, considering that FVC reflects prognosis better than FEV1 in restrictive lung disease, it remains unclear whether FEV1 or FVC is the more appropriate parameter for assessing patients with bronchiectasis with ventilatory patterns other than OVD.
Herein, we investigated the association between ventilatory defects and AE risk for patients with bronchiectasis using the Korean Multicenter Bronchiectasis Audit and Research Collaboration (KMBARC) cohort [15], in which spirometry-defined restrictive components are relatively common, and aimed to determine if spirometry-defined restrictive components are linked to AE risk for patients with bronchiectasis.
Materials and Methods
1. Study design and participants
This study included patients with bronchiectasis enrolled in KMBARC cohort between August 2018 and April 2021 [15]. The KMBARC cohort is a multicenter, prospective, observational, non-interventional cohort with bronchiectasis in the Republic of Korea. The study population included patients at least 18 years old with stable bronchiectasis diagnosed by distinct chest computed tomography findings. Among the enrolled patients, we selected those with records related to their AE history during the first year after enrollment.
Based on the study protocol [15], the exclusion criteria were: (1) bronchiectasis caused by cystic fibrosis; (2) interstitial lung disease-related traction bronchiectasis; (3) actively treated lung infectious diseases, including pneumonia, pulmonary tuberculosis, or non-tuberculous mycobacterial pulmonary disease; (4) pregnancy; and (5) withdrawal of informed consent.
The detailed registry protocol has been previously published [15]. Detailed information on the study protocol and baseline characteristics of the participants has been described previously [15,16].
As shown in Figure 1, 938 patients with bronchiectasis who were followed up for at least 1 year were included. We excluded 319 patients who did not have spirometry data at the time of recruitment and 127 patients with missing AE history data during the first year after enrollment. Therefore, this study included 492 participants.
2. Ethics approval
This study was approved by the Institutional Review Board (IRB) of the Asan Medical Center (IRB No. 2018-0691) and each participating institution. According to their local regulations, all institutions approved the use of the required data for this study. All participants provided informed consent to participate in the study.
3. Exposures: ventilatory defect pattern
The eligible participants were classified into four groups: normal, OVD, RVD, and MVD groups. Although total lung capacity (TLC) is the gold standard for evaluating restrictive components [17], measurements were performed on only a small number of patients in this study. Therefore, we replaced TLC with FVC to investigate the spirometry-defined restrictive components [17].
The participants were categorized in four groups according to their spirometry results compared with those of the healthy population as follows: (1) normal group, FEV1/FVC ratio ≥ lower limit of normal (LLN) and FVC% of predicted normal value ≥ LLN; (2) OVD group, FEV1/FVC ratio < LLN and FVC% of predicted normal value ≥ LLN; (3) RVD group, FEV1/FVC ratio ≥ LLN and FVC% of predicted normal value < LLN; and (4) MVD group FEV1/FVC ratio < LLN and FVC% of predicted normal value < LLN [18]. The spirometry-defined restrictive component was defined as the presence of FVC < LLN regardless of the FEV1/FVC ratio (MVD+RVD). Spirometry was performed according to the standard protocol established by the American Thoracic Society/European Respiratory Society [19]. The equation used to estimate the LLN is presented in Supplementary Table S1 [20,21].
4. Study outcomes: AE
The study outcome was the number of any AE or severe AEs during the first year after enrollment in the KMBARC cohort. Any AE and severe AEs were identified based on interviews annually conducted after enrollment in the KMBARC cohort, as well as medical records documented after each visit at hospitals or admissions. Bronchiectasis AE was defined as the aggravation of at least three of the following symptoms for at least 48 hours: (1) cough; (2) sputum volume increase and/or consistent change; (3) sputum purulence; (4) dyspnea and/or exercise intolerance; (5) fatigue and/or malaise; and (6) hemoptysis [10]. Severe AE was defined as an event requiring emergency room visits or hospitalization [22].
5. Covariables
We investigated the baseline characteristics, including age, sex, body mass index, smoking history, and comorbidities, based on the reported information. We collected information related to bronchiectasis, including the exacerbation history in the previous year, the modified Medical Research Council (mMRC) scale scores, Reiff scores, FACED scores, the bronchiectasis severity index (BSI), and Pseudomonas colonization. Additionally, FEV1 (L and % of predicted normal value), FVC (L and % of predicted normal value), and the diffusing capacity of the lungs for carbon monoxide (DLCO, mL/min/mmHg, and % of predicted normal value) were evaluated.
6. Statistical analyses
All data are presented as numbers and percentages for categorical variables and as means and standard deviations for continuous variables. We compared the four groups using the chi-square test or Fisher’s exact test for the categorical variables and the analysis of variance (ANOVA) or the Kruskal-Wallis test for the continuous variables. To determine the relationship between ventilatory defect pattern and AE rate, we used both univariate and multivariable negative binomial regression models and present the annual any AE and severe AE rates per person-year. We also estimated the incidence rate ratio (IRR) relative to that of the normal group, as a reference group. In the multivariable model, we included independent variables, such as demographics, and the most important risk factor for subsequent exacerbations. In the final regression model, IRRs were adjusted for age, sex, body mass index, Pseudomonas colonization, the number of AEs in the preceding year, use of inhaled corticosteroid, and any bronchodilators. Missing values of the variables included in the multivariable analysis were filled by multiple imputations using the Markov chain Monte Carlo method. Four patients had missing data for both the Reiff and BSI scores, whereas all other variables were complete. Among these, three patients were in the RVD group and one in the normal group. The IRR trend by the ventilatory defect pattern was assessed using p for the trend. To determine whether the effect of FEV1 or FVC on the annual exacerbation rate was modified by the presence of a spirometry-defined restrictive component, p for interaction and its significance was calculated from the negative binomial regression analysis for the interaction term between the presence of a spirometry-defined restrictive component and FEV1 or FVC% of predicted normal value.
Significance was set at two-sided p-values of <0.05. All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA) and R version 3.6.1 (www.r-project.org).
Results
1. Baseline characteristics
The baseline characteristics of the study population are summarized in Table 1. Of the 492 eligible patients, 62 (12.6%), 59 (12.0%), 148 (30.1%), and 223 patients (45.3%) belonged to the normal, OVD, RVD, and MVD groups, respectively. The proportion of patients with asthma and cardiovascular disease was the highest in the MVD group and lowest in the normal group. The proportion of other comorbidities and the number of AEs in the previous year did not differ significantly among the four groups. The MVD group had the highest number of severe AEs in the previous year and highest severity index and mMRC scores, followed by the RVD, OVD, and normal groups. Pseudomonas colonization was most frequently observed in the MVD group (30.9%), followed by the RVD (27.7%), OVD (18.6%), and normal groups (12.9%). Inhaled corticosteroids and bronchodilators were most frequently prescribed for the MVD group, followed by the OVD, RVD, and normal groups.
Table 2 presents the spirometry results for each group. The normal group had the highest mean values for FEV1 (2.5±0.6 L, 91.8%±9.1% of predicted normal value) and DLCO (17.5±4.4 mL/min/mmHg, 89.6%±14.8% of predicted normal value), followed by the OVD, RVD, and MVD groups. The mean FVC values for the RVD (2.3±0.7 L, 65.7%±11.7% of predicted normal value) and MVD (2.4±0.7 L, 64.8%±11.7% of predicted normal value) groups were lower than those of the normal (3.2±0.8 L, 91.9%±7.8% of predicted normal value) and OVD (3.3±0.8 L, 92.9%±9.0% of predicted normal value) groups.
2. Annual AE rates during the 1-year follow-up
Table 3 and Supplementary Figure S1 present the number and annual rates of any AE and severe AE during the 1-year follow-up. The annual rates of any AE and severe AE for the KMBARC cohort were 0.84 (95% confidence interval [CI], 0.70 to 1.00) and 0.20 (95% CI, 0.15 to 0.28), respectively. All patients who experienced any AE, including severe AE, were prescribed antibiotics at each AE event. We performed negative binomial regression analysis to investigate the IRRs for any AE and severe AE during the 1-year follow-up compared to normal group, as a reference group. The unadjusted IRRs for annual any AE compared to the normal group increased in the order of the OVD, RVD, and MVD groups (p for trend=0.049). However, the multivariable analysis did not reveal a significant trend (p for trend=0.153). The IRRs for annual severe AE relative to the normal group significantly increased in the order of OVD, RVD, and MVD in for both the univariate (p for trend=0.001), and multivariable analyses (p for trend=0.051). The unadjusted and adjusted IRRs of other covariates used in the univariate and multivariable analyses are listed in Supplementary Table S2. After excluding patients with malignancy, the results were consistent with the data in Table 3 (Supplementary Table S3).
3. Modification effect of the spirometry-defined restrictive component on the association of FVC with the annual AE rate
Figure 2 illustrates the relationships between the annual rates of any AE and severe AE and the FEV1 and FVC % of predicted normal value by the spirometry-defined restrictive component. Table 4 presents the results of the interaction analysis. The annual rates of any AE and severe AE were increased by a lower FVC % of predicted normal value in patients with spirometry-defined restrictive components (RVD and MVD), although not in patients without spirometry-defined restrictive components (OVD and normal group). The relationship between FVC and any AE (p for interaction=0.021 in the multivariable analysis) and severe AE rates (p for interaction=0.044 in the multivariable analysis) were different for the patients with bronchiectasis with and those without spirometry-defined restrictive components. However, the spirometry-defined restrictive component did not affect the relationship between FEV1 and annual any AE (p for interaction=0.611 in multivariable analysis) or severe AE rates (p for interaction=0.164 in multivariable analysis). FACED and BSI repeated the relationship in annual any AE and severe AE rates with FEV1 based on the spirometry-defined restrictive component. The results of Table 4 were repeated for the study population, except for patients with malignancy (Supplementary Table S4).
4. Annual AE rates based on TLC-defined ventilatory defect
We additionally investigated the annual AE rates based on the TLC-defined ventilatory defect. We defined the TLC-defined ventilatory defect using the FEV1/FVC ratio and TLC % of predicted normal value with the LLN as the reference. A total of 129 patients were classified by TLC-defined ventilatory defect: normal group (n=28, 21.7%), OVD (n=64, 49.6%), RVD (n=14, 10.9%), and MVD (n=23, 17.8%). The differences in the ventilatory defect pattern defined by TLC or FVC are listed in Supplementary Table S5. Supplementary Tables S6, S7 present the baseline characteristics and spirometry results. Annual any AE rates were higher in the groups with TLC-defined restrictive components (2.50; 95% CI, 0.96 to 6.52 in RVD group; and 1.09; 95% CI, 0.49 to 2.43 in MVD group) than in those without TLC-defined restrictive component (0.67; 95% CI, 0.40 to 1.13 in OVD group; and 0.61; 95% CI, 0.27 to 1.34 in normal group). Similar trends were also observed in the annual severe AE rates (0.21; 95% CI, 0.05 to 0.95 in the RVD group; 0.17; 95% CI, 0.05 to 0.60 in the MVD group; 0.09; 95% CI, 0.04 to 0.24 in OVD group; with no severe AE in the normal group). The results of the negative binomial regression analysis for any AE during the 1-year follow-up are presented in Supplementary Table S8 and were in line with the annual any AE rates.
Discussion
This study evaluated the association between ventilatory defects and the risk of AE in patients with bronchiectasis from the KMBARC cohort, a prospective bronchiectasis cohort in the Republic of Korea. Traditionally, bronchiectasis has been classified as an OVD. However, approximately three-fourths of the participants with bronchiectasis had spirometry-defined restrictive components in this study. Regarding ventilatory defects and AEs, the spirometry-defined restrictive component was associated with an increased AE risk, and the severe AE rates during the 1-year follow-up were higher for the participants with spirometry-defined restrictive components (RVD and MVD) than for those without spirometry-defined restrictive components (OVD and normal). Additionally, the spirometry-defined restrictive component significantly affected the relationship between FVC and the rates of annual any AE and severe AE, but not the relationship between FEV1 and the rates of annual any AE and severe AE. To our knowledge, this was the first study to demonstrate an association between spirometry-defined restrictive components and AE in patients with bronchiectasis.
In our study, MVD and RVD (45.3% and 30.1%, respectively) were more common ventilatory defects in the patients with bronchiectasis than in those in the normal and OVD groups (12.6% and 12.0%, respectively). This result differs from those reported by other studies, especially those from Western countries, which have reported that the proportion of restrictive components without obstructive components ranges from 6.6% to 25.8% [23-25]. The prevalence of bronchiectasis with restrictive components without obstructive components is higher in Asian countries (26.7% to 28.5%), similar to the results reported in this study (30.1%) [3,7]. This may be due to regional differences in the etiology of bronchiectasis [6,8]. Bronchiectasis may be caused by various underlying causes, including post-infection, tuberculosis, non-tuberculous mycobacterial infection, connective tissue disease, asthma, and COPD [1,8,23]. Furthermore, several studies have reported that the etiology of bronchiectasis presents with different ventilatory defect patterns [3,26].
In this study, the annual rates of any and severe AE showed a trend: highest for patients with MVD, followed by those with RVD and OVD, and the lowest for the normal group. These results imply that the accompanying spirometry-defined restrictive component was associated with a higher risk of AE. Habesoglu et al. [27] reported that bronchiectasis with restrictive components is caused by atelectasis, pleural disease, parenchymal scarring, and peribronchial fibrosis. These features of bronchiectasis with restrictive components could increase the risk of bronchiectasis AE. When restrictive components were defined by TLC, a similar trend was also repeated. However, despite its importance, limited studies have illustrated the clinical features of spirometry-defined restrictive components in patients with bronchiectasis [13,28]. Accordingly, more studies are required to obtain clear evidence regarding the role of AE-related restrictive components in bronchiectasis.
FEV1 is a critical clinical parameter used to predict the clinical outcomes of obstructive lung diseases, including bronchiectasis. It is considered an essential component of the BSI and FACED-E scores [18,29,30], the most well-known models for predicting AE in bronchiectasis. However, FEV1 was not significantly associated with AE events in a study of an Indian registry of bronchiectasis [7]. This might have been due to difference in etiology and ventilatory defect bronchiectasis. In contrast, FVC has traditionally been used to evaluate RVD severity [31]. The results of this study suggest that FVC is a good indicator of disease severity and prognosis in patients with bronchiectasis with restrictive components. However, to our knowledge, no studies have addressed this topic. Additionally, an important finding of this study was that the relationship between FVC and any AE and severe AE rates significantly differed with the spirometry-defined restrictive component. However, there was no difference in the relationship between FEV1 and any AE or severe AE rates in the patients with bronchiectasis with and those without the spirometry-defined restrictive component. FACED and BSI showed similar results with FEV1 in this study. Decreased FVC significantly correlated with increased annual any AE and severe AE rates only in patients with bronchiectasis with spirometry-defined restrictive components (Figure 2). However, changes in FVC were not significantly related to the risk of any AE or severe AE in patients with bronchiectasis without spirometry-defined restrictive components. Therefore, FVC may be a good indicator of AE events in bronchiectasis patients with spirometry-defined restrictive components and may help predict the risk of AE in this ventilatory phenotype.
This study has several limitations. First, we could not evaluate the causal relationship between ventilatory defect patterns and annual AE rates owing to the observational nature of the study. Despite the inclusion of multiple covariates in the multivariable analysis, the potential influence of residual or unmeasured confounding factors on the occurrence of AE cannot be entirely excluded. Given that AE of various chronic respiratory diseases may manifest with clinical features that closely resemble those of AE in bronchiectasis, further investigations are warranted to control for the potential confounding effects of coexisting respiratory conditions. Second, we defined the restrictive component based on FVC and not TLC due to a lack of information. Although FVC has been substituted for TLC to define restrictive components in many studies [5,7,28], we additionally investigated the annual AE rate in patients with TLC results and found an increased annual AE rate in patients with TLC-defined restrictive components. Because only limited patients were included in the additional analysis, further studies with TLC information are required to concisely classify the ventilatory defect pattern in patients with bronchiectasis and confirm the results of this study. However, our findings suggest that bronchiectasis accompanied by reduced FVC, regardless of TLC results, may represent a distinct phenotype associated with worse clinical outcomes. In a sensitivity analysis conducted among patients with available lung volume measurements (n=130), those with TLC-defined MVD and RVD groups exhibited a higher annual any AE rate compared to the TLC-defined OVD and normal groups. Although this difference did not reach significance due to the limited sample size, the results indicate that the presence of a restrictive component, whether defined by TLC or FVC, may contribute to an increased risk of AE in bronchiectasis. Given the practical limitations of routine TLC measurement in real-world clinical settings, our findings highlight the potential clinical utility of assessing a spirometry-defined restrictive component. Nevertheless, since spirometry-based definitions are not considered the gold standard for restrictive lung disease, further studies incorporating TLC measurements are needed to enhance generalizability and validate these findings. Third, we cannot fully exclude the contributions of other factors to the spirometry-defined restrictive component [32]. Patients with interstitial lung disease, a representative lung disease with restrictive components, were initially excluded from the KMBARC cohort [15]. Cardiovascular comorbidities were more prevalent in RVD and MVD at the time of enrollment. Although a causal relationship could not be determined in this study, FVC reduction in patients with bronchiectasis may be a phenotype with a worse clinical outcome, and it may reflect pulmonary congestion, right ventricle enlargement, or cardiomegaly not detected in initial chest images with restrictive or obstructive lung disease. In addition, we did not assess the prevalence of COPD in this study because OVD and MVD were defined based on the pre-bronchodilator FEV₁/FVC ratio, and including COPD as a covariate could have resulted in an issue of overfitting. However, since a definitive diagnosis of COPD should be based on the post-bronchodilator FEV₁/FVC ratio, our analysis may have been limited in adequately accounting for the impact of COPD. Finally, since this study was conducted using a Korean population, our results may lack generalizability. Therefore, further studies are warranted.
This study determined that MVD was the most common ventilatory defect in the KMBARC cohort, followed by RVD, OVD, and a normal pattern. The annual rates of any AE and severe AE were higher in the groups with spirometry-defined restrictive components than those in the other groups. The presence of a spirometry-defined restrictive component affected the FVC effect on the risk for any AE and severe AE; however, it did not affect the FEV1 effect on the risk for any AE or severe AE. Consequently, FVC may help assess the AE risk for patients with bronchiectasis with spirometry-defined restrictive components.
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