A dangerous combination: tuberculosis and chronic obstructive pulmonary disease

Both chronic obstructive pulmonary disease (COPD) and pulmonary tuberculosis are leading causes of morbidity and mortality, and therefore the most important challenges to public health in China. A large, populationbased survey showed that the prevalence of COPD was 8.2% (men, 12.4%; women, 5.1%) in adults 40 years of age or older,1 and even higher in Chinese rural areas where biomass fuels are the main sources of energy for cooking, heating, and other household needs in poorly ventilated dwellings.2 Under-diagnosis and under-treatment of COPD in these areas was another serious concern.2 It is also notable that pulmonary tuberculosis is highly prevalent in rural areas, which may share common risk factors with COPD. A systemic review by Lin et al3 showed that smoking was also an independent risk factor for tuberculosis and suggested a positive association between indoor air pollution and the disease. Cigarette smoking is the leading risk factor for COPD, but the prevalence of COPD in non-smokers is as high as 6.6%, and it is estimated that 25%-45% COPD patients are neversmokers.4 Biomass fuel and occupational exposure are two major risk factors in never-smokers, and accumulating evidence suggests that tuberculosis is another significant risk factor for COPD. Facing the colliding epidemics of tuberculosis, tobacco smoking and COPD in developing countries,5 it is of urgent need to address the impact of tuberculosis on COPD, as well as the risk of tuberculosis in COPD patients. Tuberculosis as a cause for diffuse obstructive lung disease was reported around 1950s. It was reported that in some sanatoriums more patients died from obstructive pulmonary emphysema than from progressive tuberculosis.6 But not until recently has convincing evidence for tuberculosis as a major risk factor for COPD emerged when results of large population-based studies were reported. In 2007, the PLATINO (Latin American Project for the Investigation of Obstructive Lung Disease) study revealed that history of tuberculosis was associated with airflow obstruction in Latin American middle-aged and older adults.7 This population-based, multicenter study enrolled 5571 subjects aged ≥40 years living in five Latin American metropolitan areas. The overall prevalence of airflow obstruction (forced expiratory volume in one second/forced vital capacity (FEV1/FVC) <0.7) was 30.7% among those with a history of tuberculosis, compared with 13.9% among those without a history. Males with a medical history of tuberculosis were four times more likely to have airflow obstruction than those without such a diagnosis. This remained unchanged after adjustment for confounding factors such as age, sex, smoking, exposure to dust and smoke, among others. In females, the unadjusted and adjusted odds ratios were 2.3 and 1.7, respectively.7 Later, a large cohort study comprised of older adults living in Guangzhou, a metropolitan city in Southern China, confirmed that prior tuberculosis was an independent risk factor for airflow obstruction in Chinese people.8 In this study, all participants underwent spirometry and chest radiography. Prior tuberculosis was defined as the presence of radiological evidence suggestive of inactive tuberculosis. The result showed that the prevalence of prior tuberculosis in this cohort (n=8066, mean age 61.9 years) was 24.2%, and prior tuberculosis was independently associated with an increased risk of airflow obstruction after adjustment of sex, age and smoking exposure.8 The authors conclude that high prevalence of tuberculosis may partly explain the higher prevalence of COPD in China. Clinicians should be aware of this long-term risk in individuals with prior tuberculosis, irrespective of smoking status.8 An epidemiologic study in a local rural area of Shandong, China, also provided data supporting the association of old tuberculosis (by chest radiography) with increased risk of airflow obstruction (OR 2.547) in residents aged ≥40 years, and the risk was higher in women.9 More recently, a cohort study using health insurance databases of Taiwan found that history of pulmonary tuberculosis was an independent risk factor, among others, for COPD.10 The impact of tuberculosis persisted for six years after its diagnosis and was significant in women and subjects aged >70 years. Interestingly, among patients with tuberculosis, delay in anti-tuberculous therapy had a dose-response relationship with the risk of developing COPD. The authors concluded that controlling tuberculosis epidemic, early tuberculosis diagnosis and prompt initiation of appropriate anti-tuberculous treatment may prevent some cases of COPD.10 On the other hand, COPD per se is associated with a higher risk of developing tuberculosis, as evidenced by a number of studies. More recently, a population-based cohort study from Sweden demonstrated that COPD patients had a three-fold increased hazard ratio of developing active tuberculosis that was mainly dependent on an increased risk of pulmonary tuberculosis.11 The study also showed that COPD patients who developed active tuberculosis had a two-fold increased risk of death from all causes within first year after diagnosis of tuberculosis compared to the general population control subjects with tuberculosis. These results raise concerns that the increasing global burden of COPD will increase the incidence of active tuberculosis.11 As mentioned earlier, the prevalence of COPD in China is around 8% in people aged ≥40 years. Currently, 40% of the Chinese population is aged ≥40 years (530 million people). By 2030, more than one-half of the entire Chinese population will be aged ≥40 years.12 Because the prevalence of COPD begins to increase exponentially beyond this age threshold, the future burden of COPD will be enormous.12 It seems, therefore, imperative to evaluate the impact of COPD epidemic on tuberculosis incidence in China. Another concern over the combination of COPD and tuberculosis is whether long-term inhaled corticosteroid (ICS) therapy is associated with increased risk of tuberculosis, and hence, if it is necessary to screen tuberculosis (active, inactive or sequelae ) by chest X-ray before initiating ICS in COPD patients. Several recent studies give the answer “yes”. A populationbased cohort study in patients with airways disease from Canada demonstrated that exposure to ICS was associated with increased tuberculosis risk in nonusers of oral corticosteroids.13 A study from Taiwan proved that the use of high doses of ICS, prednisolone ≥10 mg/d, and prior pulmonary tuberculosis were independent risk factors for developing active pulmonary tuberculosis in COPD patients,14 and the authors suggest that before starting ICS therapy, chest X-ray, sputum smear and/or culture for M. tuberculosis should be considered.14 Most recently, a study from Korea again confirmed that ICS use increased the risk of pulmonary tuberculosis in patients with COPD and the risk was greater in patients who had radiological sequelae of prior tuberculosis.15 Currently, high-dose ICS (usually in combination with long-acting bronchodilators) is recommended for severe to very severe COPD (FEV1/FVC <50%) with frequent exacerbations,16 although it is often used for less severe disease in clinical practice. The association of ICS, alone or in combination with long-acting bronchodilators, with increased risk of pneumonia has been demonstrated by randomized controlled clinical trials, but it is still unclear if ICS has any impact (and to what extent) on the development of active tuberculosis in COPD patients in China where both the burdens of COPD and tuberculosis are enormous. It is therefore of great clinical significance to carry out prospective and/or observational studies to explore the long-term safety of ICS therapy relating to tuberculosis in the largest population of COPD in the world.

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