A systematic literature review and critical appraisal of epidemiological studies on outdoor air pollution and tuberculosis outcomes

Highlights

• PM_2.5 was most frequently associated with active TB.

• Limited evidence of associations exists for PM₁₀, NO₂ and SO₂ and active TB.

• No evidence of association was found for CO and O₃.

Abstract

Ambient air pollution is the leading environmental risk factor for disease globally. Air pollutants can increase the risk of some respiratory infections, but their effects on tuberculosis (TB) are unclear. In this systematic literature review, we aimed to assess epidemiological studies on the association between outdoor air pollutants and TB incidence, hospital admissions and death (collectively referred to here as ‘TB outcomes’). We sought to consolidate available evidence on this topic and propose recommendations for future studies.

Following PRISMA guidelines, we searched PubMed, Web of Science, Google Scholar, and Scopus with no restrictions imposed on year of publication. A total of 11 epidemiological studies, performed in Asia, Europe and North America, met our inclusion criteria (combined sample size: 215,337 people). We extracted key study characteristics from each eligible publication, including design, exposure assessment, analytical approaches and effect estimates. The studies were assessed for overall quality and risk of bias using standard criteria.

The pollutant most frequently associated with statistically significant effects on TB outcomes was fine particulate matter ( < 2.5 µm; PM_2.5); 6/11 studies assessed PM_2.5, of which 4/6 demonstrated a significant association). There was some evidence of significant associations between PM₁₀ ( < 10 µm), nitrogen dioxide (NO₂) and sulfur dioxide (SO₂) and TB outcomes, but these associations were inconsistent.

The existing epidemiological evidence is limited and shows mixed results. However, it is plausible that exposure to air pollutants, particularly PM_2.5, may suppress important immune defence mechanisms, increasing an individual's susceptibility to development of active TB and TB-related mortality.

Considering the small number of studies relative to the demonstrably large global health burdens of air pollution and TB, further research is required to corroborate the findings in the current literature. Based on a critical assessment of existing evidence, we conclude with methodological suggestions for future studies.

Introduction

Despite improvements in recent years, tuberculosis (TB) was the 9^th-leading cause of mortality globally in 2016 (WHO, 2017). About 1.3 million TB-related deaths were recorded in that year (Naghavi et al., 2017, WHO, 2017). The World Health Organization (WHO) estimates that there are around 10 million new cases of TB each year, of which >95% occur in low- and middle-income countries (WHO, 2017). In addition to its overall impact on public health, TB also presents specific economic challenges. Global healthcare spending on TB reached US$ 6.9 billion in 2017, and approximately US$ 12 billion was lost due to TB-related reductions in workforce participation and productivity (WHO, 2017). Despite progress in diagnosis and treatment, TB remains a persistent public health concern and significant contributor to the global burden of disease.

Ambient air pollution is the fifth- and sixth-leading risk factor, respectively, for global deaths and disability-adjusted life-years (DALYs) (Brauer et al., 2016, Cohen et al., 2017). In 2015, 4.2 million deaths and 103.1 million years of healthy life lost were associated with long-term exposure to fine particulate matter ( < 2,5 µm, PM_2.5) (Cohen et al., 2017). Many TB-endemic countries also have high levels of ambient air pollutants. For example, up to 43% of incident TB cases globally are reported in India, Indonesia and China where urban populations are also exposed to some of the highest levels of outdoor air pollution in the world (population-weighted annual mean PM_2.5 from ~60 to ~75 μg/m³) (Chen et al., 2016; Cohen et al., 2017; Kim, 2014; WHO, 2016). While this does not imply any causative role of the latter, it does raise questions about the extent to which ambient air pollution might contribute to initial infection and development of active TB, and the plausibility of such an association. If ambient air pollution is associated with TB, then reducing exposure could potentially yield co-benefits in terms of TB in high burden settings, in addition to other beneficial effects on public health and the environment.

The body of evidence on household air pollution and TB provides some context to the plausibility of a role for ambient air pollution. For example, household air pollution from solid fuel combustion has been significantly associated with active TB in several recent meta-analyses (Jafta et al., 2015, Kurmi et al., 2014). In contrast, however, the role of ambient air pollution as a risk factor for TB remains relatively unexplored. Although ambient air pollution concentrations are considerably lower than those indoors when solid fuels are used, the whole global population is exposed to ambient pollutants over their life course (Brugha and Grigg, 2014, Cohen et al., 2017, Jiang and Bell, 2008, Kim, 2014, Van Vliet et al., 2013).

A small number of in vivo and in vitro studies have reported that air pollutants can significantly increase the risk of Mycobacterium tuberculosis infection and subsequent development of TB by impeding vital defence mechanisms of cellular immunity against mycobacteria (Hiramatsu et al., 2005, Rivas-Santiago et al., 2015, Sarkar et al., 2012). Increased risk of infection and disease progression has been attributed to modified production of inflammatory mediators, primarily cytokines, due to air pollution exposure (IFN-γ, TNF-a, IL-1β, IL-6, IL-10). Cytokines mediate cell signalling to initiate important components of antimycobacterial immunity including macrophage activation and granuloma formation (Hiramatsu et al., 2005, Rivas-Santiago et al., 2015). In addition, iron and other transition metals present in particulate matter generate oxidative stress when inhaled and contribute to an accumulation of iron that favours growth of invading mycobacteria (Ghio, 2014, Zelikoff et al., 2002).

In this study, we aimed to establish the current evidence for whether exposure to ambient air pollutants is associated with TB outcomes (bacteriologically confirmed incident TB, hospital admission, death) by systematically and critically reviewing published epidemiological literature (cohort, case-control, cross-sectional, and ecological studies). We sought to determine if associations are consistent for common air pollutants (PM_2.5, PM₁₀, SO₂, NO₂, CO, O₃). Additionally, we aimed to investigate the exposure assessment and analytical methods used in these studies and propose recommendations for future studies.