Background: Enteroviruses are routinely detected with molecular methods within large cohorts that are at risk of type 1 diabetes. We aimed to examine the association between enteroviruses and either islet autoimmunity or type 1 diabetes.
Methods: For this systematic review and meta-analysis, we searched PubMed and Embase for controlled observational studies from inception until Jan 1, 2023. Cohort or case-control studies were eligible if enterovirus RNA or protein were detected in individuals with outcomes of islet autoimmunity or type 1 diabetes. Studies in pregnancy or other types of diabetes were excluded. Data extraction and appraisal involved author contact and deduplication, which was done independently by three reviewers. Study quality was assessed with the Newcastle-Ottawa Scale and National Health and Medical Research Council levels of evidence. Pooled and subgroup meta-analyses were done in RevMan version 5.4, with random effects models and Mantel-Haenszel odds ratios (ORs; 95% CIs). The study is registered with PROSPERO, CRD42021278863.
Findings: The search returned 3266 publications, with 897 full texts screened. Following deduplication, 113 eligible records corresponded to 60 studies (40 type 1 diabetes; nine islet autoimmunity; 11 both), comprising 12077 participants (5981 cases; 6096 controls). Study design and quality varied, generating substantial statistical heterogeneity. Meta-analysis of 56 studies showed associations between enteroviruses and islet autoimmunity (OR 2·1, 95% CI 1·3-3·3; p=0·002; n=18; heterogeneity χ 2 /df 2·69; p=0·0004; I 2 =63%), type 1 diabetes (OR 8·0, 95% CI 4·9-13·0; p<0·0001; n=48; χ 2 /df 6·75; p<0·0001; I 2 =85%), or within 1 month of type 1 diabetes (OR 16·2, 95% CI 8·6-30·5; p<0·0001; n=28; χ 2 /df 3·25; p<0·0001; I 2 =69%). Detection of either multiple or consecutive enteroviruses was associated with islet autoimmunity (OR 2·0, 95% CI 1·0-4·0; p=0·050; n=8). Detection of Enterovirus B was associated with type 1 diabetes (OR 12·7, 95% CI 4·1-39·1; p<0·0001; n=15).
Interpretation: These findings highlight the association between enteroviruses and islet autoimmunity or type 1 diabetes. Our data strengthen the rationale for vaccine development targeting diabetogenic enterovirus types, particularly those within Enterovirus B. Prospective studies of early life are needed to elucidate the role of enterovirus timing, type, and infection duration on the initiation of islet autoimmunity and the progression to type 1 diabetes.
Funding: Environmental Determinants of Islet Autoimmunity, European Association for the Study of Diabetes, JDRF, Australian National Health and Medical Research Council, and University of New South Wales.
Competing Interests: Declaration of interests SRI received financial support during completion of the submitted work from the Australian Government (Research Training Program), the University of New South Wales (UNSW; Higher Degree Research Completion Scholarship), the Environmental Determinants of Islet Autoimmunity (ENDIA) study (PhD top-up scholarship), and from the European Association for the Study of Diabetes (EASD; travel grant) for presentation of the submitted work. KWK received financial support during the period in which the work was completed from the Leona M and Harry B Helmsley Charitable Trust (HCT) and the Juvenile Diabetes Research Foundation (JDRF) Australia T1D Clinical Research Network (ENDIA Early-Mid Career Science Accelerator Award 2-SRA-2021-1083-M-B), HCT (ENDIA Science Continuation Grant), and JDRF International (Postdoctoral Fellowship 3-PDF-2020-940-A-N). MEC received financial support during completion of the submitted work from the National Health and Medical Research Council Practitioner Fellowship (APP1136735). All other authors declare no competing interests.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)