duced 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 effect of smoking was reduced, but not eliminated. Those studies that controlled for the effect of alcohol were also less heterogeneous as a group than those that did not, a finding which suggests that some of the variability may have resulted from differences in alcohol consumption. Other risk factors that may confound the association between smoking, passive smoking, and IAP and TB include socioeconomic status, gender, and age. Although it is impossible to fully exclude bias introduced by residual confounding, we found that the effects the exposures on TB remained after adjustment for these factors.
More than half of the studies in our review are case-control studies. These used different approaches to the selection of controls, including sampling from hospitals and clinics, from household members, and from the community. Since smoking is associated with a wide range of diseases, the choice of hospital- or clinic-based sampling may lead to over-representation of smokers among the controls, thereby biasing the results toward the null. Similarly, since people dwelling in the same household may share behavioral risk factors, controls chosen from households of smoking TB patients may have been more likely to smoke than would the general population . When we compared the effect estimates for studies stratified on the basis of the control selection strategy, we found that studies that had not used population-based controls tended to report lower effect estimates, consistent with our expectation of a bias toward the null among studies that used hospital- and household-based controls.
Other potential sources of bias include possible misclassification of both exposure and outcome status. The assessment of tobacco smoking relied on self-reported behavior, which may not have been accurate especially among those who consider smoking to be stigmatizing, such as women in some cultural settings. The exposure “current smoking” may also have been subject to reverse causation. Patients are often diagnosed with TB months or more 