s, IAP was assessed by questionnaire on cooking and heating with biomass fuels (wood or dung). Although three of the five studies reported a positive association between biomass use and TB disease, there was significant heterogeneity among the studies (I2 = 74.1% in case-control studies) (Figure 8). We noted that in one study, houses were reportedly well ventilated and therefore the impact of IAP might have been attenuated . The sensitivity analyses are presented in Table 6.
Quality Assessment and Subgroup Analysis: Indoor Air Pollution and TB Disease
When we plotted the natural logarithms of the effect estimates against their standard errors using the methods described by Begg (Figure 9A) , we detected some slight asymmetry of effect estimates among small studies. We also noted that several large studies fell outside the projected lines of the funnel plot, indicating substantial variability among studies with small standard errors. When we repeated this analysis excluding the five mortality studies, we found that the studies with small standard errors clustered within the funnel plot (Figure 9B). We found no evidence for substantial publication bias by either the Begg's test (p = 0.256) or the Egger's test (p = 0.977).
This analysis shows that exposure to tobacco smoke is consistently associated with TB, regardless of the specific types of exposures and specific TB outcomes. Compared with people who do not smoke, smokers have an increased risk of a positive TST, of having active TB, and of dying from TB. Although there were fewer studies for passive smoking and IAP from biomass fuels, those exposed to these sources were found to have higher risks of active TB than those who are not exposed. An important finding of this study is the suggestion that the risk of TB among those exposed to passive smoking is especially high in children who are not normally at high risk for active disease. These findings support the hypothesis that exposure to respirable pollutants from combustion of tobacco and biomass fuels increases the risk of both TB infection and TB disease.
In addition to the positive association demonstrated here, multiples lines of evidence support a causal relationship between combustion smoke and TB. A dose–response relationship has been demonstrated in most of the studies that have stratified on dose; in this meta-analysis, we found that the risk of TB increases with both daily dose of cigarettes and duration of smoking. There is also accumulating evidence for the biological plausibility of this association. Chronic exposure to tobacco as well as to a number of environmental pollutants impairs the normal clearance of secretions on the tracheobronchial mucosal surface and may thus allow the causative organism, Mycobacterium tuberculosis, to escape the first level of host defenses, which prevent bacilli from reaching the alveoli . Smoke also impairs the function of pulmonary alveolar macrophages (AMs), which are not only the cellular target of M. tuberculosis infection but also constitute an important early defense mechanism against the bacteria; AMs isolated from the lungs of smokers have reduced phagocytic ability and a lower level of secreted proinflammatory cytokines than do those from nonsmokers . Recent work has suggested a novel mechanism for this effect; nicotine is hypothesized to act directly on nicotinic acetylcholine receptors on macrophages to decrease intracellular tumor necrosis factor-α production and thus impair intracellular killing of M. tuberculosis . Wood smoke exposure in rabbits has also been shown to negatively affect antibacterial properties of AMs, such adherence to surfaces, ability to phagocytize bacteria, and intracellular bactericidal processes . Boelaert and colleagues  have also proposed an alternative explanation for the impaired ability of macrophages from smokers to contain M. tuberculosis infection. These investigators noted that AMs from smokers have an markedly elevated iron content and that macrophage iron overload impairs defense against intracellular microorganisms through re