This systematic review and meta-analysis of studies on the association between SHS exposure and IBD or pharyngeal carriage of pathogenic bacteria in pediatric populations revealed a consistent and positive association between SHS exposure and invasive meningococcal disease and pharyngeal carriage of N. meningitidis, as well as a positive association with S. pneumoniae carriage. There was also a positive but not statistically significant association with invasive pneumococcal and Hib diseases. The association with Hib carriage was based on only two studies and was null. When subanalyses could be conducted, the pooled effect sizes with and without adjustment for important risk factors were generally similar, becoming slightly smaller for meningococcal and pneumococcal carriage and for invasive Hib disease, and larger for invasive meningococcal and pneumococcal diseases. Studies with laboratory-confirmed diagnosis, the more rigorous outcome, had large and statistically significant effect sizes for meningococcal disease but not for pneumococcal and Hib diseases.
The nonsignificant associations with invasive pneumococcal disease may have been partially due to the relatively small pooled sample sizes (412 cases), whereas that of Hib disease is less likely to be due to sample size (1,228 cases). For Hib disease, studies on the most vulnerable ages (≤6 y old) had larger and significant effect estimates. A factor that may have contributed to the insignificant effects may be the increasing use of Hib vaccine (since 1990) and pneumococcal conjugate vaccines (since 2000). Studies before the vaccine era had larger effect sizes for both Hib and pneumococcal diseases, but these were only statistically significant for Hib. These factors, and the strong association that has been observed between active smoking and invasive pneumococcal disease 
, should motivate additional high-quality studies with large sample sizes to clarify the role of SHS in the etiology of invasive pneumococcal disease.
There are plausible mechanisms for the effects of SHS on bacterial diseases. Both in vivo
and in vitro
experimental studies have found that SHS exposure may induce structural changes in the respiratory tract including peribronchiolar inflammation and fibrosis, increased mucosal permeability, and impairment of the mucociliary clearance 
. It may also decrease immune defenses, e.g., a decreased level and depressed responses of circulating immunoglobulins, decreased CD4+ lymphocyte counts and increased CD8+ lymphocyte counts, depressed phagocyte activity, and decreased release of proinflammatory cytokines 
. All these mechanisms might increase the risk of bacterial invasion and subsequent infection. The significant findings here regarding the association of SHS exposure with bacterial carriage also support a plausible etiological role for SHS in invasive bacterial disease, because asymptomatic carriage is an intermediate step towards invasive disease 
. Asymptomatic carriage itself has a public health implication because it is important in population transmission of infectious bacteria
Strengths and Limitations
This systematic review has strengths and limitations. To the best of our knowledge, this is the first systematic review of the epidemiologic evidence on the association between SHS exposure and pediatric IBD. We were able to include clinical invasive disease as well as the etiologically and epidemiologically important intermediate stage of asymptomatic bacterial carriage. As far as possible, we assessed sensitivity to important methodological design and quality characteristics using meta-regression and subgroup analysis. Our search covered multiple databases without language limitation.
A key limitation of our study was the relatively small number of studies, specifically from developing countries in which the IBD burden is the largest, smoking is increasing, and vaccination coverage may be lower. Notably, two African studies had a nonsignificant effect size for invasive meningococcal disease 
. One of these studies was from northern Ghana, where more than 93% of participants were exposed to fuelwood smoke 
. In addition, negative residual confounding (due to the potential negative association of household smoking with economic status) cannot be ruled out as a source of the nonsignificant negative finding. The second study, from urban South Africa, had included an interaction term between recent upper respiratory tract infection (URTI) and SHS exposure in the multivariate analysis, which had an OR of 3.6 (95% CI 1.4–7.3) 
. If recent URTI itself was caused by SHS and can increase the risk of IBD, then this adjustment would attenuate the true effect of the SHS term. A third African study from The Gambia had an OR of 2.99 (95% CI 1.10–8.14) for pneumococcal disease 
. The limited number of studies from developing countries makes it difficult to assess the role of factors such as background incidence rate, nutritional status, vaccination, and coexposure to wood smoke on the ORs for SHS-IBD association. A second potential limitation is that both the exposure and outcome measurements may have been subject to error, which is likely to have biased our results towards the null and reduced its significance. Third, heterogeneity of effect sizes across studies restricts our ability and confidence to generalize the results of this pooled data analysis to all populations. Fourth, the studies on association with bacterial carriage were distinct from those on IBD and no SHS-IBD studies had assessed carriage at baseline. As a result, we were not able to assess whether SHS exposure only increases the risk for colonization, or increases the risk of subsequent infection, or both. Fifth, because IBD is a complex disease with multiple causes, there is potential for residual confounding in the observational studies included in our analysis. This is especially relevant given that the currently available SHS-IBD studies were case-control or nested case-control studies and those on SHS-bacterial carriage were cross-sectional studies. Our findings on the potential causal associations should motivate new prospective studies. Sixth, our study focused on pediatric SHS exposure and did not assess studies on perinatal SHS exposure as a risk factor for IBD, with some of the effect possibly mediated through low birth weight. 
. Finally, while we assessed the potential for publication bias and report trim-and-fill ORs, the latter estimates are themselves subject to methodologic limitations especially when the number of studies is small 
Despite the limitations of current epidemiologic studies, our meta-analysis provides some evidence of an association between SHS and IBD and pharyngeal carriage, especially in preschool children. Although there are efficacious vaccines against all three pathogens assessed in this study, many children in low-income countries are not covered in routine immunizations and have limited access to case management 
. Vaccine pricing remains an obstacle to uptake, while waning immunity and serotype replacement may undermine long-term vaccine effectiveness 
. Thus scaling up vaccine coverage and case management must be accompanied by nonvaccine interventions, such as environmental interventions, to address the large burden of IBDs. Tobacco smoking and SHS exposure have increased in low-income and middle-income countries, making SHS exposure a global problem 
. While public smoking bans have been effective in reducing adult SHS exposure and adverse health effects 
, children's exposure to SHS may occur at home, where bans may be difficult to enforce 
. An estimated 700 million children worldwide are exposed to SHS at home 
. If the observed effects are causal, our results indicate that in a population where 25% of young children are exposed to SHS (e.g., Brazil or South Africa), 5%–20% of IBD cases may be attributable to this risk factor; the attributable fraction would be 10%–34% in populations where exposure is 50% (e.g., Egypt or Indonesia). Effects of such magnitude should motivate a number of research and intervention steps specifically related to SHS and pediatric IBD: Firstly, there should be well-designed prospective studies with high-quality measurement of exposure, outcome, and potential confounders to overcome the limitations of the current studies. Secondly, interventions that specifically focus on reducing children's exposure at home, schools, and other environments should be pursued. These two directions are particularly important in developing countries where the IBD burden is high and exposure to SHS is high or increasing. Finally, the effects of other combustion pollutant sources that are common in developing countries, especially smoke from wood and animal dung fuels, on IBD should be subject to research.