Diebrtes

Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies
BMJ 2011; 342 doi: 10.1136/bmj.d35 (Published 3 February 2011)
Cite this as: BMJ 2011;342:d35

Abstract
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 relatedautoimmunity 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 χ2/df=1.3) and clinical type 1 diabetes (9.8, 5.5 to 17.4; χ2/df=3.2).

Conclusions There is a clinically significant association between enterovirus infection, detected with molecularmethods, 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.

Introduction
Type 1 diabetes is believed to result from a complex interplay between genetic predisposition, the immune system, and environmental factors.1 In recent decades there hasbeen a rapid rise in the incidence of childhood type 1 diabetes worldwide, especially in those under the age of 5.2 3 4 5 6 In Europe, from 1989-2003 the average annual increase was 3.9%, too fast to be accounted for by genetics alone.4 Evidence in support of a putative role for viral infections in the development of type 1 diabetes comes from epidemiological studies that have shown a significantgeographical variation in incidence, a seasonal pattern to disease presentation,2 3 7 8 and an increased incidence of diabetes after enterovirus epidemics.9

Enteroviruses are perhaps the most well studied environmental factor in relation to type 1 diabetes. A possible link was first reported by Gamble et al in 1969,10 with many subsequent studies, in humans and animal models of diabetes, showingan association, particularly with coxsackievirus B-4. Higher rates of enterovirus infection, defined by detection of enterovirus IgM or IgG, or both, viral RNA with reverse transcription polymerase chain reaction (RT PCR), and viral capsid protein, have been found in patients with diabetes at diagnosis compared with controls.11 12 13 14 15 16 17 Prospective studies have also shown more enterovirusinfections in children who developed islet autoantibodies or subsequent diabetes, or both; as well as a temporal relation between infection and autoimmunity.13 18 19 20

The relation between enterovirus infection and diabetes is not consistent across all studies,21 22 23 24 however, and the subject remains controversial.25 Furthermore, in animal models viral infections might also protect fromdiabetes.25 A systematic review of coxsackie B virus serological studies did not show an association with type 1 diabetes,26 but to date there has been no systematic review of molecular studies. Based on the hypothesis that enterovirus infection increases the risk of pancreatic islet autoimmunity or type 1 diabetes, or both, we carried out a systematic review of controlled studies that used...