Enteroviruses and risk of islet autoimmunity or type 1 diabetes: systematic review and meta-analysis of controlled observational studies detecting viral nucleic acids and proteins

Sonia R Isaacs; Anju Roy; Brieana Dance; Emily J Ward; Dylan B Foskett; Anna J Maxwell; William D Rawlinson; Ki Wook Kim; Maria E Craig

doi:10.1016/S2213-8587(23)00122-5

Enteroviruses and risk of islet autoimmunity or type 1 diabetes: systematic review and meta-analysis of controlled observational studies detecting viral nucleic acids and proteins

Lancet Diabetes Endocrinol. 2023 Aug;11(8):578-592. doi: 10.1016/S2213-8587(23)00122-5. Epub 2023 Jun 27.

Authors

Sonia R Isaacs¹, Anju Roy¹, Brieana Dance¹, Emily J Ward¹, Dylan B Foskett¹, Anna J Maxwell¹, William D Rawlinson², Ki Wook Kim¹, Maria E Craig³

Affiliations

¹ Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; Serology and Virology Division (SAViD), NSW Health Pathology, Virology Research Laboratory, Prince of Wales Hospital, Sydney, NSW, Australia.
² Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW, Australia; Serology and Virology Division (SAViD), NSW Health Pathology, Virology Research Laboratory, Prince of Wales Hospital, Sydney, NSW, Australia.
³ Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; Serology and Virology Division (SAViD), NSW Health Pathology, Virology Research Laboratory, Prince of Wales Hospital, Sydney, NSW, Australia; Institute of Endocrinology and Diabetes, Children's Hospital at Westmead, Westmead, Sydney, NSW, Australia; Specialty of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. Electronic address: m.craig@unsw.edu.au.

PMID: 37390839
DOI: 10.1016/S2213-8587(23)00122-5

Abstract

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 χ²/df 2·69; p=0·0004; I²=63%), type 1 diabetes (OR 8·0, 95% CI 4·9-13·0; p<0·0001; n=48; χ²/df 6·75; p<0·0001; I²=85%), or within 1 month of type 1 diabetes (OR 16·2, 95% CI 8·6-30·5; p<0·0001; n=28; χ²/df 3·25; p<0·0001; I²=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.

Publication types

Meta-Analysis
Systematic Review
Research Support, Non-U.S. Gov't

MeSH terms

Australia
Autoimmunity
Diabetes Mellitus, Type 1*
Enterovirus*
Female
Humans
Nucleic Acids*
Observational Studies as Topic
Pregnancy
Prospective Studies

Substances

Nucleic Acids