1 | Introduction

Allergy is defined by an inappropriate immune response to one or more foreign antigens. This response can give rise to conditions such as allergic asthma, atopic dermatitis (eczema), allergic rhinitis (hay fever) and anaphylaxis.1Allergic diseases are characterized by a latency period between primary exposure (sensitization) and symptoms (elicitation) that develop upon subsequent exposures, and may involve Ig-E and/or non-Ig-E-mediated responses. An Ig-E-mediated allergic reaction (sometimes called immediate-type hypersensitivity (Type I)) involves the production of Th2 cytokines, which initiate Ig-E production by B cells2. Allergic and autoimmune diseases seem to have increased in prevalence in many countries. In recent decades the prevalence of allergic disorders, including hay fever and bronchial asthma, has increased worldwide. This has mostly occurred in western countries where up to 20% of the population3 and one in three children in economically developed countries4are affected by allergic diseases. Furthermore, allergic diseases, are also leading common chronic diseases; they may have great social and economic impact on both individuals and their families. They are leading causes of chronic illness in young people, having a negative impact on the quality of life and school performance5, for which the reasons are not fully clear. A recent register-based study showed that the lifetime prevalence of asthma and allergic rhinitis at age 10 was 15.6% and 20.4% respectively.6
Vaccination is used worldwide for preventing infectious diseases7. Childhood vaccination plays an important role in the early development of the immune system8. Furthermore, most children with allergic diseases start to have symptoms early in life; these early childhood influences are crucial in the development of allergic diseases.9 The link between vaccination and the risk of allergy was first published in 1994 by Odent et al.10 Since then, numerous publications have investigated this hypothesis11-15. However, most commonly researched is the relationship between Bacille Calmette Guerin (BCG) vaccine and allergic disease, but the consequences remain controversial. The BCG vaccine has been used for almost 100 years to prevent tuberculosis16 and is standard in childhood immunization programs of many countries. Since BCG has been demonstrated to inhibit TH2 immunologic response and antagonize atopy in both human and animal models, it is also a therapeutic model to investigate the effect of early-life stimulation of TH1 cells.17 A recent study showed that BCG may have non-specific beneficial effects on the infant immune system, reducing early atopic diseases.18 The association between BCG and childhood atopic disease has been studied with conflicting results.19 Given the relationship between sample size and statistical power, we conducted a meta-analysis of studies with sample size >100 and assessed as high-quality. We examined the association between BCG vaccine and allergic disease and explored the implications of evidence from existing trials for clinical practice and future research.