ts. We excluded 1,340 papers because they were judged not to be related to smoking, IAP, and TB. The remaining 57 articles were obtained for detailed review; 19 of these were excluded because the same studies were published in different journals [11,12], the effect sizes and CIs of interest were not reported or could not be estimated [13–24], there were severe flaws in study design [25–27], or the article was not original [28,29]. Thirty-eight papers were included in the final analysis. Figure 1 delineates the exclusion process and Table 1 summarizes the studies that were included in the final analysis.
Tobacco Smoking and Latent TB Infection
Figure 2 shows the risk of latent TB among smokers compared with nonsmokers in six studies [30–35] on tobacco smoking and latent infection. The studies were conducted in five countries: the US, Spain, South Africa, Pakistan, and Vietnam. Although the timing of smoking (current, former, and ever) in relation to the study varied, we did not differentiate between these reported exposures, because the actual time of TB infection was unknown. There was only one case-control study; for the five cross-sectional studies that were included, we found minimal heterogeneity (I2 = 0%). We also stratified studies that used different cutoffs for the TST; among those analyses that used induration size of 5 mm as the cutoff for a positive test [32,33], the pooled OR for latent TB was 2.08 (95% CI, 1.53–2.83), while among those that used a 10 mm cutoff [30,31,34,35], the pooled OR was 1.83 (95% CI, 1.49–2.23). When we stratified on other quality-associated study characteristics, we found that ORs for TB infection were lower among studies that adjusted for alcohol (Table 2), but that a positive effect of smoking on latent TB remained.
Quality Assessment and Subgroup Analysis: Tobacco Smoking and Latent TB Infection
Tobacco Smoking and Clinical TB Disease
The 23 studies that we identified on the association between tobacco smoking and clinical TB disease were conducted in 12 countries: China/Hong Kong, India, The Gambia, Guinee Conakry, Guinea Bissau, US, UK, Australia, Malawi, Estonia, Spain, and Thailand [2,36–57]. Figures 3–5 shows the risk of clinical TB among current, former, and ever smokers, respectively, compared to nonsmokers for the individual studies. Given the significant heterogeneity among each of these effect estimates, we do not report pooled estimates within each of these three categories; rather, we stratified on important study characteristics within each category for the purpose of sensitivity analysis (Table 3). These analyses show that there was a significantly increased risk of clinical TB among smokers regardless of outcome definition (pulmonary TB versus any TB), adjustment for alcohol intake or socioeconomic status, type of study, or choice of controls. Although stratification by these study-specific variables did not fully explain the variability between studies, heterogeneity was partially accounted for by outcome (pulmonary versus any TB) and by adjustment for alcohol intake. As might be predicted on the basis of biological plausibility, we found a higher risk of clinical TB among smokers when we restricted the analyses to studies that included only cases of pulmonary disease. However, the differences between the effect estimates for pulmonary TB and those for any TB were not statistically significant.
Quality Assessment and Subgroup Analysis: Tobacco Smoking and TB Disease
Tobacco Smoking and TB Mortality
We identified five studies on tobacco smoking and TB mortality in adults [2,58–61], conducted in India, South Africa, and China/Hong Kong. Although all of the studies found a positive association between smoking and TB mortality (Figure 6), there was substantial heterogeneity (I2 = 98.5% among case-control studies) and a five-fold difference between the most extreme effect estimates. We therefore do not report a pooled estimate for this analysis. A dose-response relation was noted in the two [59,60] studies that stratified on dose. When we conducted a sensitivity analysis