Associations between air pollutants and acute exacerbation of drug-resistant tuberculosis: evidence from a prospective cohort study

Tuberculosis (TB) is the main cause of death from infectious diseases worldwide, causing 1.4 million deaths in 2021 [1]. Eight countries accounted for more than two thirds of global TB cases, and China ranked the 3rd among these eight countries [1]. Drug-resistant tuberculosis (DR-TB) is a kind of TB that has developed resistance to one or more anti-TB drugs. Treating DR-TB patients require toxic and expensive second-line drugs and 40% cases are treated unsuccessfully [1].

A growing number of researches have investigated connections between short-term air pollution exposure and TB risk [2‐7]. For each 10-μg/m³ increase in SO₂ with a 3-day lag, the risk of an initial TB outpatient visit was reduced by 2.0% [2]. Research also showed that the higher the concentration of PM_2.5, PM₁₀ and NO₂, the higher the risk of tuberculosis [3‐6]. Air pollutants could contribute to airway inflammation activation, immune imbalance and higher prevalence of respiratory symptoms including sore throat, cough, sputum, wheeze and dyspnea [8‐10]. In clinical practice, the most visible sign of DR-TB aggravation is an escalation of respiratory symptoms like cough and sputum. Short-term exposure to air pollutants may trigger the symptoms of DR-TB by stimulating lung tissue, damaging tracheobronchial mucosa and the key anti-mycobacterium T cell immune function, and promoting the generation and secretion of inflammatory cytokines [11‐13].

When analyzing the relationship between the acute exacerbation of DR-TB and the concentration of air pollutants, considering the lag effect of pollutants, the concentration of air pollutants in the period before the case was used. We conducted this case-crossover study, wishing to (1) assess the connection between the risk of acute exacerbation of DR-TB and short-term exposure to PM₁₀, PM_2.5, SO₂, NO₂, O₃ and CO in Anhui Province, China; (2) investigate if there were any subpopulations particularly vulnerable to the impact of short-term air pollution exposure.

This study has observed three intriguing findings. First, short-term exposure to NO₂ was significantly related to an increased risk of acute exacerbation of DR-TB. Second, two subpopulations (those ≥ 65 years and high-risk DR-TB cases) appeared more vulnerable to the effect of SO₂. Third, DR-TB patients who first visited clinics in the warm season were more vulnerable to the effect of O₃.

To the best of our knowledge, this is the first study that examines the association between exacerbation of DR-TB symptoms and short-term air pollution exposure. A rising number of investigations have investigated the relationships between air pollutants and TB. Positive associations were found between exposure to PM_2.5 [5, 20‐23], PM₁₀ [6, 21‐24], NO₂ [3‐5, 22, 25], SO₂ [3, 21‐23, 26, 27], CO [22, 23] or O₃ [23] and the risk of TB. However, some studies also found a negative association between exposure to O₃ [22, 25], SO₂ [2, 5] and PM₁₀ [28] and the risk of TB. A cohort study also showed a significant positive relationship between O₃ exposure and the incidence of DR-TB [29]. Another study found that among patients with multidrug-resistant TB, greenness reduced air pollution-related mortality [30]. The two studies above suggested that environmental factors may determine the outcome of DR-TB patients. Several studies reported that NO₂ inhalation can trigger proinflammatory responses and promote pulmonary infections, and impair host defence against infection in the lung [31, 32]. It is suggested that NO₂ exposure may play a role in lung injury by inducing the infiltration of alveolar macroscopic (AM) subgroups [33]. The infiltration of AM subgroups produces a large amount of IL-10 to play an anti-inflammatory role and selectively express some matrix metalloproteinases, which may contribute to the pathophysiology of NO₂-induced lung damage [33].

The underlying mechanisms of increased risk of DR-TB owing to air pollution exposure are multi-factorial. Firstly, the immune system consists of a variety of dedicated immune cells. Air pollutants can act on these immune cells, such as epithelial cells [34] and parenchymal cells [35], dendritic cells [36] and lymphocytes [37], and granulocytes [38, 39]. Additionally, air pollutants cause oxidative stress [40] and activate a cascade of immune dysfunction and pro-inflammatory pathways [41]. Pollutants can stimulate cells through polycyclic aromatic hydrocarbons (PAH) sensing pathway [42], Toll like receptors (TLRs) [43] and oxidative and nitrosative stress pathways [44], which in turn stimulate pro-inflammatory intracellular signaling pathways like MAPK and NF-kB pathways.

In the current study, female cases were especially vulnerable to SO2 and O3, while the male cases were especially vulnerable to NO₂. This result shows that the impact of air pollutants on DR-TB may vary by gender. On stratification by age, high PM_2.5 and SO₂ exposure were inversely associated with acute exacerbations of DR-TB for young patients. For old patients, high SO2, NO2 and O3 exposure were positively associated with acute exacerbations of DR-TB. This may be because the elderly may be weaker and have basic diseases, leading to greater vulnerability to air pollutants. The current study revealed that high-risk subgroup was especially vulnerable to PM_2.5, SO₂ and NO₂. This may because these people’s lungs have been damaged, and they are more sensitive to air pollutants than others. In addition, we found that SO₂ has opposite effects on subgroup patients. The positive effects of SO₂ were observed at lag1, lag2 and lag01-lag03 days among old patients, but negative effects were observed at lag6 and lag7 among young patients. Among the patients without a history of treatment, the positive effects of SO₂ were observed at lag0 and lag01, but the negative effects of SO₂ were observed at lag3-5. In the group of high-risk population, the positive effects of SO₂ were observed at lag1, lag2 and lag01-lag04 days, but negative effects were observed at lag6. After careful observation, we found that short-exposure to SO₂ may increase the risk of DR-TB, while long-exposure to SO₂ may reduce acute exacerbations of DR-TB. This may be explained by the reason that, to some extent, SO₂ can inhibit the activity of mycobacterium TB complex [45]. Moreover, in the warm seasons, high O₃ expose increased the risk of acute exacerbations of DR-TB, which may due to higher O₃ concentration in warm seasons. If our findings are confirmed in other regions, it will bring obvious clinical and public health significance, because we can prevent DR-TB by controlling the concentration of air pollutants.

The WHO 2021 global air quality guideline values for SO₂, NO₂ and O₃ are 40 μg/m³, 25 μg/m³ and 100 μg/m³ respectively, while the level 1 limits in China (GB 3095 − 2012) are 50 μg/m³, 80 μg/m³ and 100 μg/m³ respectively. Although the average concentrations of pollutants in this study were lower than WHO and China standards, we still observed a risk to DR-TB from air pollutants. Therefore, we should boost industrial structure optimisation and adjustment, and withdraw the backward production capacity of key industries in accordance with the law; promote the transformation of green and low-carbon energy, strictly control the growth of coal consumption, and vigorously develop new and clean energy; carry out the upgrading of traditional industrial clusters.

This study has some strengths. First, we provided estimations of the impacts of six pollutants on DR-TB and conducted subgroup analyses. Second, high-spatial-resolution air pollution data were used in this investigation to estimate each patient’s exposure. Most early studies used urban average air pollution concentrations for exposure assessment. Third, this study is a provincial level research with a large sample size, including 2,522 newly diagnosed DR-TB cases. Fourth, the data was derived from the DR-TB cohort study in Anhui Province based on TBIMS. Based on China’s national TB control guidelines, any health establishment that discovers TB cases or probable cases must report them via TBIMS. Therefore, through this system, we can accurately grasp the incidence of DR-TB in Anhui Province.

This study also has some limitations. First, the incidence of DR-TB reported in our study may be underestimated. This low detection rate is an essential challenge in the therapy and prevention of DR-TB. The WHO report showed that there were about 450 000 incident patients of multi-drug resistance/rifampin resistance TB in 2021 worldwide, while only 162,000 were diagnosed [1]. Second, the study used outdoor air pollution exposure to assess the impact, but patients may spend most of their time indoors. So, exposure measurement bias cannot be excluded. Third, considering that a decrease in sample size may lead to model instability and unreliable results, we did not conduct subgroup analysis on subgroups with smaller sample sizes after grouping, such as subgroups with worsening respiratory symptoms after treatment, more refined occupational groups, and different types of drug resistance.

NO₂ exposure is associated with an elevated risk of exacerbation of DR-TB. Elderly DR-TB patients, high-risk DR-TB cases and patients with a history of TB treatment need to be made aware of the risk posed by air pollution exposure.