Impact of Ventilatory Disorders on Respiratory Symptoms, Physical Activity, and Quality of Life in Post-Tuberculosis Subjects: A National Database Study in Korea

Background Tuberculosis (TB) survivors experience post-TB lung damage and ventilatory function disorders. However, the proportions of obstructive and restrictive ventilatory disorders as well as normal ventilation among post-TB subjects are unknown. In addition, the impacts of ventilatory disorder and its severity on respiratory symptoms, physical activity limitations, and the quality of life in post-TB subjects remain unclear. Subjects were enrolled in this study. We evaluated the impact of each ventilatory disorder and its severity on respiratory symptoms, physical activity limitations, and quality of life (measured by the EuroQoL ve dimensions questionnaire [EQ-5D] index values) in post-TB subjects.

Despite the improved survival rate, approximately 50% of TB survivors experience post-TB lung damage and ventilatory disorders. [3][4][5] Depending on the severity of post-TB lung damage, post-TB subjects show various clinical courses, including no respiratory symptoms, dyspnea, or impaired quality of life (QoL). [6,7] The ventilatory disorders of post-TB subjects comprise obstructive and restrictive patterns.
[8] Obstructive ventilatory disorder, which is air ow limitation on pulmonary function tests, is the most well-known form of lung damage after TB treatment. [5,8] Post-TB lung damage, including cavity, bronchiectasis, or distorted airway, can cause obstructive ventilatory disorder, which can lead to dyspnea, chronic obstructive pulmonary disease (COPD), and reduced exercise capacity. [9,10] Although obstructive disorder has been recognized as post-TB lung damage, restrictive ventilatory disorder also is found in post-TB subjects and can lead to dyspnea or chest pain. [11] The restrictive pattern has been suggested to be a consequence of excessive brosis, brotic bands, or bronchovascular distortion in the process of post-TB lung repair. [12] The proportions of obstructive and restrictive ventilatory disorders as well as normal ventilation among post-TB subjects are unknown. Additionally, the impacts of ventilatory defects and severity of defects on respiratory symptoms, physical limitations, and QoL in post-TB subjects have not been investigated.
This study aimed to elucidate the composition of ventilatory defects among post-TB survivors using a nationally representative database in South Korea. Furthermore, this study investigated the impact of each ventilatory disorder and its severity on respiratory symptoms, physical activity limitations, and QoL Welfare. Health-related questionnaires, health examinations, and spirometry results were used in this study. Previous pulmonary TB was de ned based on formal reading of a chest X-ray or a history of physician diagnosed pulmonary TB. We classi ed post-TB subjects into three groups according to spirometric pattern (Fig. 1). The study protocol was approved by the Institutional Review Board of Chungbuk National University Hospital (application no. 2021-01-041).

Measurements
Data on age, sex, body mass index (BMI), smoking history, physical activity limitations, occupation, EuroQoL ve dimensions questionnaire (EQ-5D) index value, and spirometric results were obtained from the Korea NHANES database. The EQ-5D index, which is used to measure QoL, ranges between 0 (worst imaginable health state) and 1 (best imaginable health state). Spirometry was performed according to the recommendations of the American Thoracic Society and European Respiratory Society. [13] Absolute values of forced expiratory volume in 1 second (FEV 1 ) and forced vital capacity (FVC) were obtained, and the percentage of predicted values (% predicted) for FEV 1 and FVC were calculated using the reference equation obtained on analysis of a representative Korean sample. [14] Comorbidities of asthma, diabetes mellitus, hypertension, dyslipidemia, cardiovascular disease, osteoporosis, osteoarthritis or rheumatoid arthritis, and depression were self-reported based on previous physician diagnosis. [15] De nitions of ventilatory disorder Normal ventilation was de ned as pre-bronchodilator FEV 1 /FVC ≥ 0.70 and FVC ≥ 80%predicted.
[16] For cases with obstructive ventilatory disorder, FEV 1 ≥ 80%predicted, FEV 1 of 50-79 %predicted, and FEV 1 < 50 %predicted were classi ed as mild, moderate, and severe, respectively. Restrictive ventilatory disorder was de ned as FEV 1 /FVC ≥ 0.7 and FVC < 80%predicted. For cases with restrictive ventilatory disorder, FVC ≥ 70 %predicted, FVC of 60-69 %predicted, and FVC < 60 %predicted were classi ed as mild, moderate, and severe, respectively. [17,18] Outcomes We compared respiratory symptoms, physical activity limitations due to respiratory diseases (hereafter physical activity limitations), and QoL (measured by EQ-5D index) between post-TB subjects with different ventilatory disorders. We also analyzed the impacts of the severity of the ventilatory disorder on respiratory symptoms, physical activity limitations, and QoL in post-TB subjects.

Statistical analysis
All analysis was performed using survey commands in STATA 15.1 version (StataCorp LP, College Station, TX, USA) to account for the complex sampling design and survey weights. For each variable, we calculated prevalence and 95% con dence interval (CI) by group.
The associations between ventilatory disorders and respiratory symptoms (cough, sputum, or dyspnea) and physical activity limitations were analyzed using logistic regression analysis: Model 1 was adjusted for age (categorized as ≥ 65 years or not), sex, and BMI; Model 2 was additionally adjusted for education level (categorized as high school or less vs. college or above) and family income (categorized as low vs. high). A linear regression analysis was performed to assess the association between ventilatory disorders and the EQ-5D index scores: Model 1 and Model 2 were adjusted for covariates as mentioned above. We used trend tests to evaluate whether there was a trend between severity of ventilator disorder and study outcome.
All tests were two-sided, and p-values < 0.05 were considered to indicate statistically signi cant differences.

Baseline characteristics
As shown in Table 1, the post-TB patient group included 1,466 patients (54.9%) with normal ventilation, 783 patients (29.3%) with obstructive ventilatory disorders, and 420 patients (15.8%) with restrictive ventilatory disorders. The mean ages of subjects with normal ventilation, obstructive ventilatory disorders, and restrictive ventilatory disorders were 53.4, 64.4, and 59.6 years, respectively (P < 0.001). The proportion of males was highest in subjects with obstructive ventilatory disorders, followed by those with restrictive ventilatory disorders and those with normal ventilation (76.2%, 52.0%, and 49.5%, respectively, P < 0.001). Subjects with obstructive ventilatory disorders had lower BMI than those with normal ventilation or restrictive ventilatory disorders (22.8 kg/m 2 , 23.7 kg/m 2 , and 23.8 kg/m 2 , respectively, P < 0.001). The proportion of subjects with low family income was highest in subjects with obstructive ventilatory disorders, followed by those with restrictive ventilatory disorders and those with normal ventilation (68.3%, 55.9%, and 43.0%, respectively, P < 0.001). The subjects with obstructive ventilatory disorders had the highest prevalence of asthma (10.9%), diabetes mellitus (19.1%), and hypertension (50.8%) among post-TB subjects, while subjects with restrictive ventilatory disorders had the highest prevalence of dyslipidemia (48.7%) and osteoporosis (11.9%) among the study population.
The EQ-5D index values, denoting QoL, were lower among subjects with obstructive ventilatory disorders and restrictive ventilatory disorders than in those with normal ventilation (0.91, 0.91, and 0.94, respectively, P = 0.002). Regarding the individual EQ-5D component arm, subjects with obstructive ventilatory disorders had the highest rates of di culty in mobility (24.1%, P < 0.001) and limitation in selfcare (7.7%, P = 0.005) among post-TB subjects; however, those with restrictive ventilatory disorders had the highest rates of di culty in usual activity (19.1%, P < 0.001) and pain/discomfort (36.3%, P = 0.015) among post-TB subjects ( Table 2).
The impact of obstructive ventilatory disorder and its severity on respiratory symptoms, physical activity limitations, and EQ-5D index in post-TB subjects.
As shown in Table 3  Data are presented as a ratio (95% con dence interval) or a difference estimate (95% con dence interval). * Age, sex, education (categorized as > high school or ≤ high school), and family income (categorized as low or high) were adjusted.
The impact of restrictive ventilatory disorder and its severity on respiratory symptoms, physical activity limitations, and EQ-5D index value in post-TB subjects Restrictive ventilatory disorder was not signi cantly associated with increased respiratory symptoms (cough, sputum, or dyspnea), physical activity limitations, and EQ-5D index value compared with normal ventilation in adjusted models (Table 4).  Data are presented as a ratio (95% con dence interval) or a difference estimate (95% con dence interval). * Adjusted for age, sex, BMI, education (categorized as > high school or ≤ high school), and family income (categorized as low or high).

Discussion
To the best of our knowledge, this is the rst study to evaluate respiratory symptoms, physical activity limitations, and QoL according to type of ventilatory disorder and its severity in post-TB subjects. Among post-TB subjects, approximately 29% and 16% developed obstructive and restrictive ventilatory disorders, respectively. Severe obstructive ventilatory disorders were associated with more respiratory symptoms, more physical activity limitations, and poorer quality of life. Severe restrictive ventilatory disorder was associated with more physical activity limitations.
TB survivors frequently experience structural and functional lung sequelae that vary in severity. [7] For example, approximately 24-35% of TB survivors have been shown to experience obstructive ventilatory disorders. [19][20][21] In agreement with previous reports, 29% of the post-TB subjects in this study had obstructive ventilatory disorders. Thus, development of obstructive ventilatory disorders can cause important health-related burden in TB survivors. Post-TB subjects also can experience restrictive ventilatory disorders. Post-TB survivors often show a brotic pattern on chest imaging due to the sequelae of pulmonary TB including destruction of lung parenchyma. [22] Restrictive ventilatory disorders occur in post-TB subjects due to volume loss, lung scarring with reduction of pulmonary compliance, and an increase in elastic retraction pressure. [23,24] In contrast to the literature on obstructive ventilatory disorders, only a few studies have described restrictive ventilatory disorders, and the prevalence was reported as 31-42% among TB survivors. [25,26] The small number of patients in these studies (n = 107 and n = 33) limits the study ndings. [25,26] Thus, our study has the advantage of con rming these ndings with the largest number of subjects using a nationwide database.
As shown in previous studies, [19,27] clinical factors associated with poorer QoL (e.g., old age, male sex, smoking history, lower BMI, and lower education level) were more common in post-TB subjects with obstructive ventilatory disorders than in those with normal ventilation. Approximately 72% of post-TB subjects with obstructive ventilatory disorders in this study were current or ex-smokers. In line with this nding, smoking is a well-established factor associated with obstructive ventilatory disorder in post-TB subjects. [19] However, little is known as to whether development of obstructive ventilatory disorder is associated with higher symptomatic burdens in post-TB survivors, as most previous studies focused on the presence of obstructive ventilatory disorders and their severity after TB treatment. [5,11,28] From this perspective, our study is meaningful in elucidating that development of severe obstructive ventilatory disorders was associated with more respiratory symptoms, more physical activity limitations, and poorer QoL compared to patients with normal ventilation; however, the ndings were not signi cant in patients with mild-to-moderate obstructive ventilatory disorders. These results indicate that regular health checkup with pulmonary function measurement after completing TB treatment is necessary to detect obstructive ventilatory disorders early and provide appropriate treatment to prevent further lung function impairment. Recent studies also support this suggestion in showing clinical improvement after bronchodilator treatment in TB-destroyed lung patients with obstructive ventilatory disorder. [29,30] Despite the prevalence of restrictive ventilatory disorders after TB, to the best of our knowledge, no studies have evaluated the association between restrictive ventilatory disorder and respiratory symptoms, physical activity limitations, and QoL in TB survivors. Our study revealed that respiratory symptoms and QoL were not signi cantly impaired in post-TB subjects with restrictive ventilatory disorders, while physical activity limitations were signi cant in post-TB subjects with moderate-to-severe restrictive ventilatory disorders. Restrictive ventilatory disorders might be an underappreciated cause of functional impairments and respiratory symptoms. [31,32] One study showed that 35.4% of subjects with restrictive ventilatory disorders reported at least one chronic respiratory symptom. [32] One reason why our study results are contrary to previous ndings might be that most subjects with restrictive ventilatory disorders in our study had a mild degree of restrictive abnormality; thus, the number of subjects with moderate-tosevere restrictive ventilatory was relatively small to exert statistical signi cance. Accumulating evidence has shown that restrictive ventilatory disorders are related to physical activity limitations, which is in line with our study results. [33,34] The signi cant association of moderate-to-severe restrictive ventilatory disorders with physical activity limitations, but not with respiratory symptoms, suggests that restrictive ventilatory disorders in uence physical activity limitations through mechanisms that are at least partly independent of respiratory symptoms. The decreased lung or chest wall compliance and increased elastic work of breathing might be a mechanism underlying the physical activity limitations in patients with advanced restrictive ventilatory disorders. [35] This study has several limitations. First, this study was performed in a representative sample of Korea.
Thus, our data might not be generalizable to other ethnic groups or populations. Second, obstructive ventilatory disorders were de ned by pre-bronchodilator spirometric results. This might lead to an overestimate of the prevalence of obstructive ventilatory disorders. However, our estimates were similar with those of previous studies. [19] Third, the relatively small number of post-TB subjects with moderateto-severe restrictive ventilatory disorders might lead to statistical nonsigni cance when analyzing the impact of ventilatory disorder severity on respiratory symptoms or QoL.
In conclusion, among the TB survivors, 29% had obstructive ventilatory disorders and 16% had restrictive ventilatory disorders. Severe obstructive ventilatory disorders were associated with increased healthrelated burden, including more respiratory symptoms, more physical activity limitations, and poorer QoL, while severe restrictive ventilatory disorder was associated with more physical activity limitations. More research is needed to establish strategies for early diagnosis and adequate treatment of ventilatory disorders in TB survivors.