s 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 reduced production of both tumor necrosis factor-α and nitric oxide.
The available data support a causal link between smoke exposure and either an increased chance of acquiring TB or progression of TB to clinical disease. Our study shows that the risk of latent TB among smokers is quantitatively similar to their risk of active disease, which would suggest that much of the impact of smoking takes place during infection. At the same time, one case-control study selected TST-positive controls, thereby comparing patients who were TST positive and had clinical TB to people who were also TST positive but had not progressed to clinical TB ; that study also found a strong association between smoking and disease, suggesting that smoking may induce progression or reactivation disease in those infected. We included the outcome TB mortality in this study in order to investigate the association between smoke and TB occurrence rather than the association between smoke and TB treatment outcomes. The risk of death from TB among smokers was found to be somewhat higher than the risk of latent infection or disease, possibly because smoking has been identified as a risk factor for poor TB treatment outcomes among those undergoing therapy [57,72,73].
There are several potential limitations to this study. First, our findings are based on the results of observational studies; we cannot, therefore, exclude the possibility of confounding by variables that may be associated with each of the exposures. The issue of confounding is particularly a concern in a meta-analysis of observational studies when effect sizes are relatively small, as was the case in the studies considered in this analysis . We therefore performed a stratified analysis to explore the degree to which potential confounders may have influenced the findings. Among possible confounders, alcohol use is a known risk factor for TB and is closely associated with tobacco use in many populations. Those studies that adjusted for alcohol intake in a multivariable model found that the 