Abstract

INTRODUCTION

Tuberculosis (TB) is an infectious disease caused by the bacillus Mycobacterium tuberculosis. It typically affects the lungs but can affect other sites. TB is one of the leading causes of mortality and morbidity worldwide. In 2010, there were 8.8 million cases of TB, 1.1 million deaths from TB among human immunodeficiency virus (HIV)-negative people, and an additional 0.35 million deaths from HIV-associated TB [1]. Despite rapid economic development in South Korea, TB remains an important health issue in the country. Nationwide, 33,167 TB cases were reported in 2010. The prevalence and annual incidence of TB in South Korea are currently estimated to be 151/100,000 and 97/100,000, respectively [1].

Indoor air pollution is a well-known risk factor for TB development. The association between indoor air pollution and TB was suggested as early as 1911. Observations between 1858 and 1902 in Paris that TB mortality was inversely associated with the number of windows per household were the first suggestion of a connection [2]. Since then, many studies showing an association between indoor air pollution and TB have been published. For example, among residents of Mexico City, cooking with a biomass stove was associated with a 2.4-times higher odds of developing TB [3]. One recent meta-analysis showed that indoor air pollution increased the incidence of pulmonary TB, with a relative risk (RR) of 1.95 [4].

Despite the well-established relationship between indoor air pollution and TB, the impact of outdoor air pollution on the development of TB has not been examined sufficiently. We assessed the impact of major air pollutants on TB development in the Seoul metropolitan area, South Korea, an intermediate TB burden country.

METHODS

RESULTS

Air pollutant concentrations

Descriptive statistics for the air-quality variables are presented in Table 1. The average concentrations were 63.5 µg/m³ particulate matter (PM₁₀), 16.0 ppb ozone (O₃), 77.4 ppb carbon monoxide (CO), 34.4 ppb nitrogen dioxide (NO₂), and 6.1 ppb sulfur dioxide (SO₂). Of these, the annual averages of PM₁₀ and NO₂ were higher than the Korean national standard (PM₁₀ ≤ 50 µg/m³ and NO₂ ≤ 0.03 ppm) [11].

Table 1

Annual air pollutant concentrations from January 1, 1997 through December 2, 2006, in Seoul

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National standards for each pollutant set by the Ministry of the Environment [11].

PM₁₀ ≤ 50 µg/m³ (annual), O₃ ≤ 0.6 ppm (over 8 hours), CO ≤ 9 ppm (over 8 hours), NO₂ ≤ 0.03 ppm (annual), SO₂ ≤ 0.02 ppm (annual). SD, standard deviation; Min, minimum; Max, maximum; IQR, interquartile range; PM₁₀, particulate matter with an aerodynamic diameter ≤ 10 µm.

Numbers and characteristics of TB cases

Between January 1, 2002 and December 31, 2006, in Seoul, a total of 41,185 TB cases were reported to the Korean Institute of Tuberculosis. Of these, 24,952 (60.6%) were males. The mean age of the male patients was 44.2 years, and that of the female patients was 41.9 years. Of the male patients, 21,048 (84.4%) were new cases with no past history of TB treatment. Of the females, 14,547 (89.6%) were new cases. The proportion of smear-positive TB was 36.8% in males and 29.6% in females (Table 2).

Table 2

Demographic and clinical characteristics of reported tuberculosis cases 2002 to 2006, in Seoul

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Values are presented as mean ± SD or number (%).

TB, tuberculosis.

^aRespiratory TB includes pulmonary TB and TB pleuritis.

The mean male population of each township in 2005 was 9,714 and the mean female population was 9,755. The mean incidence of TB among males in each township was 47.8 and that of females was 31.1. Average SIRs of 522 Seoul metropolitan area towns were calculated as 1.03 for males and 1.02 for females (Table 3).

Table 3

Summary statistics of the distribution of the numbers and unsmoothed standardized incidence ratios of tuberculosis in males and females in Seoul from January 1, 2002 to December 31, 2006

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SD, standard deviation; Min, minimum; Max, maximum; TB, tuberculosis; SIRs, standardized incidence ratios.

Impact of air pollutant concentration on TB incidence

PM₁₀, O₃, CO, and NO₂ concentrations were not associated with the incidence of TB in males or females. However, the interquartile increase in SO₂ concentration was associated with a 7% increase in TB incidence (RR, 1.07; 95% CrI, 1.03 to 1.12) in males but not females (RR, 1.02; 95% CrI, 0.98 to 1.07) (Table 4).

Table 4

Impact of an interquartile increase in pollutant concentration on the incidence of tuberculosis

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RR, relative risk; CrI, credible interval; PM₁₀, particulate matter with an aerodynamic diameter ≤ 10 µm.

^aRRs were adjusted for the quintiles of the Carstairs index as an indicator variable.

Geographic distribution of air pollutants and incidence of TB

Fig. 1 provides a map of the Seoul metropolitan area and the SO₂ krigged values between January 1, 1997 and December 31, 2006, using 27 monitoring stations, categorized by deciles. The predicted SO₂ concentrations of the central and northern townships were higher than those of other areas. Fig. 2 shows the unsmoothed and smoothed geographical distribution of the incidence of TB in males and females for the period January 1, 2002 to December 31, 2006. There was no spatial cluster of TB incidence; however, the incidence in the southern townships was generally higher than that in other areas.

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Figure 1

Estimated SO₂ levels using air-monitoring data and kriging between January 1, 1997 and December 31, 2006, in the Seoul metropolitan area.

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Figure 2

Unsmoothed (A) and smoothed (B) map of the standardized incidence ratios of tuberculosis in the Seoul metropolitan area between January 1, 2002 and December 31, 2006 (smoothing of risk estimates were calculated based on Bayesian inference methods).

DISCUSSION

Despite the established relationship between indoor air pollution and TB, the impact of outdoor air pollution on the development of TB has not been determined. In this study, by analyzing air pollutant data and formally reported TB cases, we found that annual SO₂ level is associated with an increased risk of TB in males in the Seoul metropolitan area, South Korea, a country with an intermediate TB burden.

The group of air pollutants collectively termed "sulfur oxides" comprises both gaseous and particulate chemical species. Four gas-phase compounds of sulfur oxide exist (SO, SO₂, SO₃, and S₂O). Among them, only SO₂ is present at sufficient concentrations in ambient air to be a public health concern [12]. Because of its high water solubility, SO₂ can be readily scrubbed from inhaled air in the upper airways [13]. Penetration is more efficient during oral, rather than nasal, breathing and during physical activity. Upon contacting airway-covering fluid, SO₂ dissolves quickly into the aqueous phase. Subsequently, it readily dissociates into bisulfite and sulfite ions, which can be transferred into the systemic circulation [12,13].

SO₂ can affect various aspects of the pulmonary defenses, including alveolar macrophage function, mucociliary transport, and alveolar clearance. In a previous study, in vitro exposure to 12.5 ppm SO₂ for 30 minutes induced the death of 62% of alveolar macrophages and caused a 63% decrease in the release of reactive oxygen species [14], which probably play a significant role in intracellular inhibition/killing of mycobacteria [15]. Another study indicated that in vitro exposure to SO₂ decreased production or release of tumor necrosis factor-α (TNF-α) and interleukin-1 [16]. TNF-α is crucial for host defenses against M. tuberculosis because it plays a central role in the containment of tuberculous bacilli through granuloma formation [17]. Frequent reactivation of latent TB in patients using a TNF-neutralizing agent underscores the importance of TNF-α in defenses against M. tuberculosis [18]. Thus, the association between SO₂ exposure and the development of active TB in our study may have been mediated by the negative effect of SO₂ on reactive oxygen intermediate and TNF-α.

In this study, an association between SO₂ exposure and TB was observed only in males. This may be due to gender differences in susceptibilities to air pollutants as well as to TB. Indeed, epidemiological studies on the effects of air pollutants on respiratory health have shown significant gender differences [19]. For example, SO₂ and PM_2.5 had a greater effect on forced expiratory volume in 1 second in males (199 mL) than females (87 mL) [20]. In addition, the association between SO₂ exposure and evening peak expiratory flow rate was observed only in boys with asthma [21]. Hypotheses explaining these differences include anatomical/physiological differences in the airway [22], gender-linked hormonal status [23], and other factors (more household tasks performed by females may result in increased exposure to viral infection, indoor allergens, combustion exhaust, cleaning solvents, and aeroallergens) [24].

Furthermore, males seem to be more affected by TB than females, with a male/female ratio of 1.9 ± 0.6 for the worldwide case notification rate. In some countries, this ratio may reach values as high as 3 [25]. The possibility of under-notification of females [26] and poor quality of sputum samples collected from females [27] have been suggested to explain this. However, smoking, alcohol consumption, drug use, exposure to indoor dusts, sex steroid hormones, and the genetic makeup of the sex chromosomes may render males more susceptible to pulmonary TB than females [25]. The results of our study indicate that different susceptibility to outdoor air pollution, especially SO₂, may also contribute to gender inequality in TB.

Given the greater prevalence of smoking in males compared to females in South Korea (47.3% vs. 3.1% in 2010) [28], our observation suggests the presence of synergistic effects between SO₂ exposure and smoking, which is a risk factor for TB development [29]. In fact, such a synergistic effect on lung function has been reported in a Chinese population [30]. Impaired respiratory defense mechanisms that clear inhaled pollutants [31,32] and changes in respiratory responses [33] caused by smoking may increase the risk of TB development after inhaling M. tuberculosis. However, we could not prove the presence of synergy between SO₂ exposure and smoking on the development of TB because of a lack of information on the smoking status of individual TB patients. This is a limitation of our study.

In conclusion, this study provides evidence of an association between outdoor air pollution and an increased risk of TB. Long-term exposure to ambient SO₂ increases the risk of TB in males.

KEY MESSAGE

Acknowledgments

Footnotes

References