A systematic review and meta-analysis on the association between ambient air pollution and pulmonary tuberculosis

There is inconclusive evidence on the association between ambient air pollution and pulmonary tuberculosis (PTB) incidence, tuberculosis-related hospital admission and mortality. This review aimed to assess the extent to which selected air pollutants are associated to PTB incidence, hospital admissions and mortality. This was a systematic review of studies published in English from January 1st, 1946, through May 31st, 2022, that quantitatively assessed the association between PM2.5, PM10, NO2, SO2, CO, O3 and the incidence of, hospital admission or death from PTB. Medline, Embase, Scopus and The Cochrane Library were searched. Extracted data from eligible studies were analysed using STATA software. Random-effect meta-analysis was used to derive pooled adjusted risk and odds ratios. A total of 24 studies (10 time-series, 5 ecologic, 5 cohort, 2 case–control, 1 case cross-over, 1 cross-sectional) mainly from Asian countries were eligible and involved a total of 437,255 tuberculosis cases. For every 10 μg/m3 increment in air pollutant concentration, there was a significant association between exposure to PM2.5 (pooled aRR = 1.12, 95% CI: 1.06–1.19, p < 0.001, N = 6); PM10 (pooled aRR = 1.06, 95% CI: 1.01–1.12, p = 0.022, N = 8); SO2 (pooled aRR = 1.08, 95% CI: 1.04–1.12, p < 0.001, N = 9); and the incidence of PTB. There was no association between exposure to CO (pooled aRR = 1.04, 95% CI: 0.98–1.11, p = 0.211, N = 4); NO2 (pooled aRR = 1.08, 95% CI: 0.99–1.17, p = 0.057, N = 7); O3 (pooled aRR = 1.00, 95% CI: 0.99–1.02, p = 0.910, N = 6) and the incidence of PTB. There was no association between the investigated air pollutants and mortality or hospital admissions due to PTB. Overall quality of evidence was graded as low (GRADE approach). Exposure to PM2.5, PM10 and SO2 air pollutants was found to be associated with an increased incidence of PTB, while exposure to CO, NO2 and O3 was not. There was no observed association between exposure to these air pollutants and hospital admission or mortality due to PTB. The quality of the evidence generated, however, remains low. Addressing the tuberculosis epidemic by 2030 as per the 4th Sustainable Development Goal may require a more rigorous exploration of this association.

www.nature.com/scientificreports/ Air pollution, currently on several global health agendas, has rapidly become a global problem with the increasing global urbanisation, transportation-related emissions, and increased energy consumption. Air pollution could therefore be an important factor to address on the journey to ending tuberculosis as there are growing concerns of its association to increased tuberculosis-related hospital admissions and deaths 6,7 .
There is a well-known association between different air pollutants and cardio-respiratory diseases [8][9][10][11][12][13][14][15] . However, there is still no conclusive evidence of an association between PTB and outdoor air pollution despite its well-known association to indoor pollution from activities such as smoking and biomass fuel burning [16][17][18] The review by Popovic et al. indicated a possible association between PM 2.5 and PTB outcomes (incidence, hospital admissions and mortality) and reported the contrasting findings from several earlier studies on the association between PM 10 , NO 2 , and SO 2 and PTB 19 , but did not synthesise these findings to determine to what extent these air pollutants are associated to PTB. Also, several studies have been published on this subject after the review by Popovic et al. This review therefore had as objectives to determine if there is an association between the selected air pollutants (PM 2.5 , PM 10 , NO 2 , SO 2 , CO, O 3 ) and PTB incidence, hospital admissions and mortality, and to what extent, by systematically reviewing and quantitatively combining published evidence on this topic.

Methods
This was a systematic literature review and meta-analysis of articles published in English from January 1st, 1946, through May 31st, 2022, that quantitatively assessed the association between ambient air pollution and PTB. The study protocol for this review was registered with the international prospective register of systematic reviews (PROSPERO) with trial registration number CRD42020165888 and has been published 20 . This review was reported according to The RepOrting standards for Systematic Evidence Syntheses (ROSES) for systematic review 21 as presented in Additional file 1.
Deviations from the protocol. There were no deviations from the published study protocol.
Search for articles. A comprehensive search strategy (Additional file 2) combining medical subject headings (MeSH) and free-text searches for the appropriate keywords was developed by the authors and used to search the databases: Medline, Embase, Scopus and The Cochrane Library. The keywords 'air pollution' , 'carbon monoxide' , 'nitrogen dioxide' , 'sulphur dioxide' , 'ozone' , and 'particulate matter' were combined with the keywords 'tuberculosis' , 'incidence' , 'mortality' , 'hospital admission' and their respective synonyms, using the Boolean operator ' AND' in the search strategy. The search was run by the principal investigator (CAD), all searches were limited to the language English and grey literature search was not conducted given the lack of relevant studies from preliminary searches of the grey literature. Search dates of interest were January 1st, 1946, through May 31st, 2022. The search language was in English, and all the database searches were done on the same day, June 5th, 2022. The search was run twice to ensure replicability of results and the same results were obtained with each search run.
Article screening and study eligibility criteria. Screening process. Articles returned by the search were saved on Zotero Version 5.0 reference management software and duplicates of the studies were manually removed by the principal investigator (CAD) with the assistance of the reference management software. More articles were added to the search output by the principal investigator by reviewing the reference list of relevant articles. The titles and abstracts of all the remaining articles were then independently screened for eligibility according to the set eligibility criteria by each of the two independent reviewers (CAD and BMK). The full texts of all the articles retained after the title and abstract screen, were then independently reviewed by the same two independent reviewers (CAD and BMK) for eligibility and inclusion to the analysis. The two independent reviewers compared their findings at the end of both the title and abstract screening and the full text review stages of the article selection process to ensure concordance in their final selection. There were no reviewer disagreements at all stages of the study selection process and no third reviewer to settle discordances as had been planned in the study protocol, was therefore needed due to concordance in the findings of the two independent reviewers. Eligibility criteria. The following criteria were used during the article selection process to determine the eligible studies.
The following studies were included: 1. Population: Studies focused on adults aged 18 and above with PTB 2. Exposure: Studies that reported direct measurements on any of the air pollutants; carbon monoxide (CO), nitrogen dioxide (NO 2 ), sulphur dioxide (SO 2 ), ozone (O 3 ), particulate matter ≤ 2.5 µm (PM 2.5 ) and/or particulate matter ≤ 10 µm (PM 10 ) in any country, region, city or locality; 3. Outcomes: Studies that reported measures of association on the risk of PTB incidence, hospital admission and/or mortality from PTB; 4. Study design/Other: Cross-sectional, case-control, cohorts, case-crossover, ecological and time-series studies that reported on the association between ambient air pollution and PTB.
The following studies were excluded: Potential effect modifiers/reasons for heterogeneity. Between-study heterogeneity was anticipated given the differences in study designs, settings, duration, sample sizes, and population characteristics based on review of existing literature.
Data synthesis and presentation. Meta-analyses were done through random effects models to account for the possibility of between-study heterogeneity. Risk ratios and odds ratios on the incidence of PTB following exposure to the selected air pollutants, and their respective confidence intervals from the various studies, were log-transformed, and the corresponding standard errors derived. Pooled summary estimates for the respective log-transformed measures of association were computed and presented on forest plots. Studies were pooled according to their study designs with ecologic studies and studies that used time-series analysis pooled together, separate from cohort and case-control studies. Heterogeneity between studies was assessed using the Cochrane's Q test, and the I 2 test statistic was reported as a measure of the extent of this heterogeneity. The Begg's and Egger's statistical tests were used for the statistical assessments of publication bias and small study effect 25,26 . All statistical tests and plots were done on STATA version 14.0 statistical software.
Ethics approval and consent to participate. This systematic review does not require ethical approval as it entails a synthesis of data collected from several primary studies. No primary data collection from patients will be done for this systematic review.

Results
Review descriptive statistics. Figure 1 summarises the study selection process.
A total of 12,652 records were returned by the search. Following removal of duplicates, screening of titles and abstracts, addition of studies from the reference list of relevant studies, full-text reviews, 24 eligible studies were retained. Figure 1 summarises the PRISMA flow chart of the study selection process. The studies excluded following full-text review and the reasons for exclusion are presented in Additional file 4.
Narrative synthesis including study validity assessment. Most studies were from Asian countries and a total of 437,255 tuberculosis cases were reported across the 22 studies that reported the number of tuberculosis cases over their study periods (1996-2019) 7,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] . Of the 24 studies included in the review, 10 were time series, 5 were cohort studies (3 retrospective, 2 prospective), 5 were ecologic, 2 were case-control studies (1  Table 2. Twelve studies were of good quality, eleven of fair quality and one of poor quality (Additional file 6). The overall quality of evidence for the association of all 6 air pollutants to the incidence of PTB was graded as low based on the study limitations affecting generalisability of the findings, and some inconsistency across the studies due to the significantly elevated between-study heterogeneity (Additional file 7). Data synthesis. Association between air pollutants and pulmonary tuberculosis Incidence. PM 2.5 . There was a significant association between exposure to PM 2.5 and incidence of pulmonary tuberculosis (PTB), pooled adjusted RR = 1.12 (95% CI: 1.06-1.19), p < 0.001, N = 6, I 2 = 72.4% 7,29,38,39,43,49 . There was no evidence of publication bias (Begg's test, p = 0.133 and Egger's test, p = 0.203). Begg's test, p = 1. Likewise, Xiong et al. 46 reported an association (RR = 3.10, 95% CI: 1.10-8.79) for a 50 µg/m 3 increase in PM 2.5 concentration. The study by Lai et al. 32 (RR = 1.39, 95% CI: 0.95-2.03) which was cohort in design did not find a significant association. Jassal et al. 28 reported an odds ratio of 25.3 (95% CI: 3.38-29.1). PM 10 . There was a significant association between exposure to PM 10    Pulmonary TB Incidence Risk Ratios and CO Figure 3. Forest plot showing the individual and pooled risk ratios and odds ratios for pulmonary tuberculosis incidence for CO and NO 2 . The dashed line on the Forest plot represents the overall pooled estimate. The grey squares and horizontal lines represent the odds ratios of each study and their 95% confidence intervals. The size of the grey square represents the weight contributed by each study in the meta-analysis. The diamond represents the pooled odds ratio and its 95% confidence intervals. www.nature.com/scientificreports/ NO 2 . There was no association between exposure to NO 2 and the incidence of PTB, pooled adjusted RR = 1.08 (95% CI: 0.99-1.17), p = 0.057, N = 7, I 2 = 98% (Begg's test, p = 1 and Egger's test, p = 0.437) (Fig. 3) 46 reported an association (RR = 0.96, 95% CI: 0.93-1.0) for a 5 µg/m 3 increase in O 3 concentration. Table 3 summarises the percentage change in the number of PTB cases for the respective changes in air pollutant concentrations.
Subgroup analysis and meta-regression. Studies were categorised according to their duration (less than 5 years and 5 years or more), location (Asia and others), number of PTB cases (less than 5000 and 5000 or more) and study quality (good and fair/poor). None of these study characteristics could explain the observed heterogeneity across studies, except for study location with regards to exposure to PM 2.5 air pollutant. There was a higher risk of PTB incidence with PM 2.5 exposure in studies conducted out of Asia (Additional file 5).

Discussion
Exposure to PM 2.5 , PM 10 and SO 2 air pollutants was found to be associated with an increased incidence of PTB, while exposure to CO, NO 2 and O 3 was not. There was no observed association between exposure to these air pollutants and hospital admission or mortality due to PTB. The findings of this review are particularly relevant given the increasing global concentrations and exposure to some air pollutants such as SO 2 and PM 2.5 over the past decades 50,51 . Public health strategies aimed at ending the tuberculosis epidemic would therefore have to work alongside interventions aimed at improving overall air quality and addressing air pollution 51 .
Air pollutants including O 3 and NO 2 mainly originate from volatile organic compounds, combustion processes including heating, power generation, the engines of vehicles and ships and also from industry emissions 52 . SO 2 originates from the burning of fossil fuels for power generation and the smelting of sulfur-containing mineral ores 52 . PM 2.5 and PM 10 which consist of particles of organic and inorganic substances are typically suspended in the air 52 . Air pollutants have been previously associated with the development of cardio-respiratory diseases in both children and adults 8,9,11 . Traffic-related pollution and several air pollutants such as O 3 , NO 2 , PM 2.5 and PM 10 , have not only been associated with exacerbations of asthma and chronic obstructive pulmonary disease, but have also been implicated in the development of these conditions especially in childhood 11,53,54 . Air pollutants are known to increase the risk of infection when inhaled as they dampen the natural defence barriers of the respiratory tract, inhibit muco-ciliary clearance, inhibit macrophages and initiate a chronic inflammatory response with the release of pro-inflammatory mediators 55,56 . In a similar way, exposure to particulate matter for example has immunomodulatory effects on antimycobacterial activity through impaired expression of important cytokines and chemokines which are important in controlling mycobacterial infections 57,58 . This reduced antimycobacterial host immune response predisposes to tuberculosis infection.
Measures and policies in various sectors such as the transport, housing and industry sectors are known to reduce air pollutions, including; prioritising walking and cycling in cities, using low-emission vehicles; using clean technologies that reduce industrial emissions; improving access to clean household energy for heating, lighting and cooking; making cities more green; using low-emission fuels and combustion-free power sources, among others 52 . In 2015, the WHO member states adopted a resolution for enhanced global response to the adverse health effects of air pollution, and the WHO has been overseeing this response through; the production of air quality guidelines and exposure limits to these air pollutants 52 .
Even though the studies by Ge et al. 59 and Xu et al. 60 reported a possible association between short-term exposure to SO 2 , our review did not assess outpatient PTB visits as an outcome. This is therefore a subject amenable to further exploration.
The studies in this review were conducted over a 24-year period and we did not observe a particular change or variation in the trend of the reported associations between exposure to the air pollutants and PTB incidence www.nature.com/scientificreports/ www.nature.com/scientificreports/ over time across the older and newer studies. Close to four fifth of the studies in our review were conducted in Asia and up to half of the studies were in China, which could affect the generalisability of the findings of this review, however, China is still a high-burden country for tuberculosis 61,62 . The observed between-study heterogeneity highlights the need for more uniform study designs and methods in future studies aiming to assess this association.
Interpretation of the findings from this review should take into consideration some limitations. This review did not assess the contribution of indoor air pollution and other comorbidities to the increased risk of PTB incidence, hospital admission and mortality. The different study designs and methodologies affected the types of confounders that could be adjusted for in the different studies and therefore introducing inconsistency in the adjustment of confounders across studies. This review, therefore, focused on the strongest reported associations between air pollutant exposure and PTB incidence rather than on the duration of exposure to the air pollutants.

Conclusion
Exposure to PM 2.5 , PM 10 , NO 2 and SO 2 air pollutants was found to be associated with an increased incidence of PTB, while exposure to CO and O 3 was not. These findings of this study and the overall quality of the evidence highlight the need for more rigorous exploration of this association.

Data availability
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.