4 | Discussion

4.1 | Main findings

In this systematic review and meta-analysis of data from large scale participants-based studies, there is ample epidemiologic evidence to show that BCG vaccine might be effective in preventing allergic disease, especially asthma among European and American countries. However, compared with asthma, the risk of developing allergic disease was not reduced for both eczema and rhinitis. In both Asia and Africa, there was no association between BCG vaccine and allergic disease. To the best of our knowledge, this systematic review and meta-analysis is the most comprehensive and latest study between BCG vaccination and allergic disease.
In this study, we found that receiving a BCG vaccine in early childhood reduced the risk of allergic disease, especially asthma. According to other studies on BCG vaccination and asthma, the anti-inflammatory properties of BCG has been tested in murine models of atopic asthma where the mycobacteria were shown to inhibit allergen-induced airway inflammation37. BCG altered the immune balance towards Th1-like activity by decreasing the IL-4 and IL-10 production. The mechanism of IFN-γ-induced inhibition of Th2 responses is not fully understood, but could involve activation of macrophages, direct suppression of developing Th2 lymphocytes, or altered antigen presentation38. The mechanism responsible for the effect of BCG on asthma is more complex than simple changes in the Th1/Th2 balance39 and we hypothesized that early childhood mycobacterial infection promotes the switch from a Th2 to a Th1 profile, therefore inhibiting the expression of atopy.
In European and American countries, the performance of BCG vaccination in preventing asthma is highly significant. This could be attributable to the fact that children born into these regions of the world in which helminth infections and tuberculosis are endemic might derive particular benefits from BCG vaccine40. The protection level of BCG vaccination appear to follow a gradient from poor protection in countries close to the equator towards higher protection with increasing distance from the equator, a gradient that overlaps with exposure to environmental mycobacteria41. Early-life events or diseases, such as perinatal circumstances or early allergen exposure are also reported to increase the prevalence of allergic diseases42. However, heterogeneity might not be present in most stratified analyses among subjects at high risk or of non-Western origin as a result of the small number of studies included. Based on this meta- analysis, the positive protective role of BCG vaccine in allergic disease requires further investigation, especially more cohort studies on children from high risk areas.
As for rhinitis and eczema, there is significant association, even though they may share the same genetic architecture with asthma43. That is likely because some methodologic limitations may have impacted limit our interpretation of the findings. We expected that exploring heterogeneity according to methodologic characteristics of the original studies may have been informative in terms of pinpointing which and in what aspects specific studies have contributed to heterogeneity. As these participants lacked information on the severity of allergic disease especially eczema in the included studies, the applicability of findings to children with varying degrees of severity is therefore uncertain. This may have influenced the resulting protective effective of BCG vaccination in eczema and rhinitis.