ng 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 excluding the study conducted in India where TB may have been differentially overdetected among smokers [2,61], heterogeneity was markedly reduced (I2 = 38.6%). Other sensitivity analyses are demonstrated in Table 4.
Quality Assessment and Subgroup Analysis: Tobacco Smoking and TB Mortality
Passive Smoking and TB
We identified five studies on passive smoking and TB, of which four were case-control studies assessing the risk of clinical TB [50,53–55,62,63] and one a cross-sectional study on the risk of latent infection . Two studies did not exclude active smokers while assessing passive smoking and were, therefore, not included in the analysis of passive smoking and TB [50,53]. Figure 7 shows the individual effect measures for the studies on active disease; each found a positive association between passive smoking and TB. The heterogeneity among the studies was largely explained by the age of the participants; the risk of TB among children exposed to passive smoking was significantly higher than it was among adults (p = 0.002), and there was no remaining heterogeneity within the subgroups stratified by age. The single study examining the risk of latent TB infection among those exposed to passive smoking reported an OR of 2.68 (95% CI, 1.52–4.71) . Sensitivity analyses for these estimates are given in Table 5.
Quality Assessment and Subgroup Analysis: Passive Smoking and TB Disease
A dose response was found in both of the two studies that stratified on exposure intensity; one found that TB risk increased with the number of cigarettes smoked by the family per day , and the other found that close and very close contact with smoking household members was strongly associated with TB (adjusted OR 9.31 [95% CI, 3.14–27.58]), while distant contact was not (adjusted OR 0.54 [95% CI, 0.25–1.16]) .
IAP and Clinical TB Disease
Only five studies of IAP and TB were identified (Figure 8) [36,42,48,65,66]. Of these, only two studies adjusted for tobacco smoking [42,66] while three others did not [36,48,65]. In each of the studie