Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies

OBJECTIVE: To review the association between current enterovirus infection diagnosed with molecular testing and development of autoimmunity or type 1 diabetes. DESIGN: Systematic review and meta-analysis of observational studies, analysed with random effects models. DATA SOURCES: PubMed (until May 2010) and Embase (until May 2010), no language restrictions, studies in humans only; reference lists of identified articles; and contact with authors. Study eligibility criteria Cohort or case-control studies measuring enterovirus RNA or viral protein in blood, stool, or tissue of patients with pre-diabetes and diabetes, with adequate data to calculate an odds ratio and 95% confidence intervals. RESULTS: The 24 papers and two abstracts (all case-control studies) that met the eligibility criteria included 4448 participants. Study design varied greatly, with a high level of statistical heterogeneity. The two separate outcomes were diabetes related autoimmunity or type 1 diabetes. Meta-analysis showed a significant association between enterovirus infection and type 1 diabetes related autoimmunity (odds ratio 3.7, 95% confidence interval 2.1 to 6.8; heterogeneity χ(2)/df = 1.3) and clinical type 1 diabetes (9.8, 5.5 to 17.4; χ(2)/df = 3.2). CONCLUSIONS: There is a clinically significant association between enterovirus infection, detected with molecular methods, and autoimmunity/type 1 diabetes. Larger prospective studies would be needed to establish a clear temporal relation between enterovirus infection and the development of autoimmunity and type 1 diabetes.