The Risk of Obstructive Lung Disease by Previous Pulmonary Tuberculosis in a Country with Intermediate Burden of Tuberculosis

Tuberculosis (TB) and chronic obstructive pulmonary disease (COPD) are major public health problems worldwide. Despite intensive global efforts, the total number of new TB cases is still increasing, with 9.27 million new cases and 1.78 million deaths in 2006 (1). The mortality rate of COPD is also increasing, and more than three million people worldwide were estimated to die from COPD in 2005 (2). About 80 million people worldwide are estimated to have moderate-to-severe COPD. Several previous reports have suggested an association between these two diseases. There is a high and increasing prevalence of obstructive lung disease in patients who are being treated for pulmonary TB (3). A previous epidemiological study found that the prevalence of COPD may be different in subjects with and those without a history of TB (4). Another population-based study found that a history of TB is closely associated with airflow obstruction (5).

Although some previous studies have shown an association of TB and obstructive lung disease, most of these studies had small sample sizes and did not totally exclude the effect of smoking, a potential and strong confounding factor. Smoking is a major cause of COPD (6) and also increases the risk of developing TB (7). In most studies, a medical history of TB is based on self-reporting, a method limited by recall bias. Patients with spontaneously healed TB will not report a history of TB, and that can be the cause of underestimation on the presence of TB (8). Therefore, a previous TB should be also evaluated by chest imaging.

In the present study, we evaluated the risk attributable to pulmonary TB on the development of obstructive lung disease. We performed nationwide representative sampling in Korea, a country with an intermediate TB burden. We also evaluated the risk in patients with minimal TB lesions, and in patients who have never smoked.

In this study, based on a nationwide representative sampling of Korean subjects, we found that previous TB was a risk factor for obstructive lung disease and even a minimal TB lesion was an also strong risk factor in never smokers. The proportions of subjects with previous TB lesion increased as the severity of obstructive lung disease, suggesting previous TB is an important contributing factor for obstructive lung disease among never smokers.

Previous studies have suggested that pulmonary TB is associated with obstructive lung disease. Patients with previous pulmonary TB were more likely to suffer from acute exacerbation of COPD than those who did not have pulmonary TB (15). In silicosis patients, history of TB is an independent predictor of airflow obstruction (16). The bronchodilator response of patients with a tuberculous-destroyed lung is lower than that of patients with COPD (17). Airflow impairment is related to the radiological extent of TB (3) and to the number of TB episodes. However, most of these studies had small sample sizes, were not population-based, or did not fully adjust for smoking history. A smoking history could potentially have biased the estimated effect of TB on loss of lung function. A previous study found that smoking history is associated with an increased risk of TB for a cohort of white gold miners, and smoking is known to increase lung function loss (18). Recently, a population-based study of Latin American middle-aged and older adults found that previous medical diagnosis of TB was associated with airflow obstruction (5). A cohort study showed that radiologic evidence of inactive TB was associated with increased risk of airflow obstruction, although it was not population-based (8).

A history of TB may affect lung function by pleural change, bronchial stenosis, or parenchymal scarring. TB increases the activity of the matrix metalloproteinases, thus contributing to pulmonary damage (19). Extensive TB lesions may produce restrictive changes, with reduced transfer of carbon monoxide in the lung (20). However, we found that the presence of minimal lesions was also an independent risk factor for airflow obstruction. In these patients, airway fibrosis and inflammation may play important roles. TB infection is associated with airway fibrosis and the immune response to mycobacteria could cause airway inflammation, a characteristic of obstructive lung disease (21).

Smoking is a well-established major risk factor for COPD (22) and much COPD research has focused on smokers (23). However, recent evidence suggests that other risk factors are also important in causing obstructive lung disease, especially in developing countries. These factors include air pollutants, dust and fumes, history of repeated lower respiratory tract infections during childhood, chronic asthma, intrauterine growth retardation, poor nourishment, and poor socioeconomic status. Several questionnaire studies have also suggested that a history of TB is a risk factor for airflow obstruction (24, 25). In our study, 22.7% (25/110) of never smokers with airflow obstruction had TB lesions, and the proportion increased for subjects with FEV₁ < 80% of predicted value. This suggests that previous TB can be an important cause of obstructive lung disease among never smokers.

In this study, we defined airflow obstruction as FEV₁/FVC less than 0.70 or LLN. Although a fixed ratio of 0.70 is simple and widely used, it is criticized due to over-diagnosis of both the presence and severity of COPD in the elderly (26). TB lesion on CXR was still associated with airflow obstruction (adjusted OR = 2.66, 95% CI 1.99-3.55, P < 0.001) and it is consistent in never smokers (adjusted OR = 4.02, 95% CI 2.54-6.36, P < 0.001), when we defined obstructive lung disease by LLN. We enrolled subjects with two or more acceptable spirometry performances for practical consideration of a large-scale examination survey. ATS and European Respiratory Society (ERS) recommendations was published after this survey, requiring three or more acceptable curves for an adequate test with the differance in the two largest values of FVC or FEV₁ < 0.150 L (27). When we adopted this recommendation (n = 2,533), TB lesion on CXR was still associated with airflow obstruction (FEV₁/FVC < 0.70) with adjusted OR = 2.20, 95% CI 1.44-3.35, P < 0.001) and it was also consistent in never smokers (adjusted OR = 3.38, 95% CI 1.75-6.55, P = 0.001).

This study has some limitations. First, airflow obstruction was defined by FEV₁/FVC rather than post-bronchodilator FEV₁/FVC. This might lead to an overestimate of the prevalence of obstructive lung disease. However, our estimates are similar to those of previous studies. Second, previous TB was only evaluated by CXR and clinical history was not examined. From a specificity point of view, a lesion that seems to be TB-related on CXR could be a sequela of other diseases such as pneumonia. From a view of sensitivity, CXR could miss some parenchymal TB lesions, which can only be identified by computed tomography (CT) analysis (28, 29). In addition, some TB patients might have had complete healing without any evidence on the CXR. Although CXR has limitations in confirming previous TB, in the present study 3 qualified radiologists interpreted the CXRs to reduce this limitation and interpretation on CXRs of radiologists showed almost perfect agreement. Third, there was relatively large number of subjects with TB lesion on CXR (8.0%), compared with the number of TB reports in Korea (30). In other study, the prevalence of prior TB based on self-reports (2.9%) was also significantly lower than that defined by CXR (24.2%) (8). Considering this discrepancy between radiologic evidence and self-report of TB and continuously decreasing annual incidence in Korea, our interpretations of TB lesion on CXR do not seem to go beyond reasonable level. Fourth, there were only four subjects with advanced TB lesion. In this survey, subjects should visit a car with special equipment to undergo spirometry. Therefore, the possibility of selection bias, to enroll relatively healthy subjects mainly, cannot be excluded.

In conclusion, previous TB was an independent risk factor for obstructive lung disease, even if the lesions are minimal. TB could be also an important cause of airflow obstruction in subjects who had never smoked. The results of this population-based study indicated that appropriate management and control of TB is as important as smoking quitting for reducing obstructive lung disease.