The association between environmental exposures during childhood and the subsequent development of crohn's disease in the Western Cape
Background: A subtype of inflammatory bowel disease, Crohn’s disease is thought to represent a complex interaction between environmental factors, a defective immune system, the gastrointestinal microbiome and genetic susceptibility. Aim: The focus of this study was to investigate the association between environmental exposures during childhood and the subsequent development of Crohn’s disease, thus the two primary aims were to: 1) conduct a systematic review of the literature evaluating environmental risk factors during childhood, defined by studies either as, age intervals (e.g., 0-5, 6-10 and 11-18 years), or more 'broadly' as 0-18 years; and 2) investigate the association between childhood environmental exposures during three age intervals (0-5, 6-10 and 11-18 years), as well as frequency of childhood infections and the future development of Crohn's disease based on a score analysis, using a subset of previously collected data from a completed doctoral thesis involving a case control study design in study population, in the Western Cape, South Africa. The aim included a primary analysis of the latter dataset for childhood infections. Design: For the first aim of the study, a systematic search was conducted during March 2015 in electronic databases, such as EMBASE, EBSCOhost (Medline), Ovid, Scopus and World Cat, PubMed and Biomed Central, to identify epidemiological studies that examined the association between childhood environmental exposures and the subsequent development of Crohn's disease. Studies evaluating childhood exposure either by age intervals, or more broadly, from birth until 18 years were included. The environmental exposures evaluated in the review were; farm animal contact, place of upbringing, sibship size, household pets, primary water source and hot water availability. Of the 181 identified articles, 16 were included in the final systematic review. The second aim of the study involved a post hoc analysis of a subset of findings from the completed doctoral research by Abigail Basson with regard to the multiple logistic regression analysis evaluating environmental risk factor exposure during three age intervals; 0-5 years, 6-10 years and 11-18 years. In the present research, two different methodological approaches were undertaken. Briefly, exposure variables, of similar nature, were combined into subgroups and assigned weighting scores. The two 'subgroup models' were designated as: Group A and Group B. Based on these premises, a score analysis was performed, and the difference in scores, between case and control groups, was compared. In addition, multiple logistic regression models were conducted on a subset of original data from the aforementioned completed doctoral study to assess the association between the frequency of childhood infections between 0-20 years and risk of Crohn’s disease development. Following this, a score analysis was again performed. Results: Sixteen studies were included in the systematic review. Of the five studies that investigated the association between place of upbringing during the age interval 0-5 years and the subsequent development of Crohn's disease, three found no significant association; however of the three studies evaluating place of upbringing during the age intervals 6-10 and 11-18 years, only one study identified a significant association. Three studies investigated exposure to farm animals during the age interval 0-5 years, of which, two identified a significant association. Of the latter three studies, two investigated farm animal contact during the age intervals 6-10 and 11-18 years, but only one reported a significant association during these age intervals. Notably, this was the study which had failed to identify an association during the 0-5 year age interval. Both studies which broadly evaluated farm animal exposure during 'childhood' reported that not having contact with animals significantly increased the risk of developing Crohn's disease. Of the five studies that investigated exposure to pets during the age interval 0-5 years, only one identified a significant risk association, namely with exposure to cats. Of the three which investigated pet exposure during the age intervals 6-10 years and 11-18 years, one identified a significant association, for both age intervals. Five studies investigated pet exposure during 'childhood'; one found that having a pet significantly increased the risk of developing Crohn's disease, two reported that not having a pet significantly increased risk in developing Crohn's disease, whereas the remaining studies found no significant association. Only one study evaluated primary water source during the three age intervals; during the age interval 0-5 years and 11-18 years, having piped tap or bottled water was significantly associated with CD development. Of the four studies investigating primary water source during ‘childhood’, only one reported a significant association between primary water source and the development of Crohn's disease. The availability of hot water during the age interval 0-5 years was significantly associated with Crohn's disease development in one of the three relevant studies. Two studies investigated hot water availability during 6-10 and 11-18 years, however both failed to identify a significant association. When broadly evaluated, hot water availability during 'childhood' was significantly associated with Crohn's disease risk, in two of the three relevant studies. None of the studies which investigated sibship size and the risk of future Crohn's disease development during defined age intervals reported a significant association. Only two of the seven studies that evaluated sibship size during childhood reported a significant association. Results of the score analysis revealed a significant difference during all three age intervals between the case and control groups with Group A and Group B, with cases having significantly lower exposure scores (approximately 30% and 40% lower, respectively), when compared with that of controls. On multiple logistic regression analysis, subjects who never had tooth decay/cavity (OR = 1.78; 95% CI, 1.05-3.04), periodontitis (OR = 1.95; 95% CI, 1.10, 3.48), diarrhoea (OR = 2.71; 95% CI, 1.62-4.62), gastritis (OR = 2.13; 95% CI, 1.30-3.35), or mouth ulcers (OR = 2.02; 95% CI, 1.12-3.70), at least once per year or more, were at an increased risk for later development of Crohn's disease, when compared to those who were exposed to these infections at least once per year or more. There was a significant difference in exposure scores between the case and control groups (OR = 0.88; 95% CI, 0.82-0.94), thus indicating that cases had 12% less exposure to childhood infections from birth until the age of 20 years, when compared to the controls. Conclusion: The systematic review of the literature provides evidence in support of the hygiene hypothesis, in that delayed exposure to immunostimulatory microbes through the environmental exposures increases the risk for future CD development, in genetically susceptible individuals. In addition, the literature supports that the childhood environment plays an important role in the aetiology of Crohn's disease. However, the lack of consistent findings between studies, particularly those which have broadly defined ‘childhood’ implies that timing of exposure plays a crucial role in this ever evolving paradigm. Results from the score analysis provide insight into the 'compound' effects from multiple environmental exposures in the aetiology of Crohn's disease. While the present research was unable to provide any explanation for the underlying mechanism of disease pathogenesis, overall, the findings have important implications for future IBD-related studies as they demonstrate the importance of accounting for environment as a 'whole' when conducting epidemiological studies, as opposed to focusing on individual environmental factors, as well as that it is imperative to investigate environmental exposures within the context of defined age intervals.