The virome in early life and childhood and development of islet autoimmunity and type 1 diabetes: A systematic review and meta-analysis of observational studies

Abstract

Viruses are postulated as primary candidate triggers of islet autoimmunity (IA) and type 1 diabetes (T1D), based on considerable epidemiological and experimental evidence. Recent studies have investigated the association between all viruses (the 'virome') and IA/T1D using metagenomic next-generation sequencing (mNGS). Current associations between the early life virome and the development of IA/T1D were analysed in a systematic review and meta-analysis of human observational studies from Medline and EMBASE (published 2000-June 2020), without language restriction. Inclusion criteria were as follows: cohort and case-control studies examining the virome using mNGS in clinical specimens of children ≤18 years who developed IA/T1D. The National Health and Medical Research Council level of evidence scale and Newcastle-Ottawa scale were used for study appraisal. Meta-analysis for exposure to specific viruses was performed using random-effects models, and the strength of association was measured using odds ratios (ORs) and 95% confidence intervals (CIs). Eligible studies (one case-control, nine nested case-control) included 1,425 participants (695 cases, 730 controls) and examined IA (n = 1,023) or T1D (n = 402). Meta-analysis identified small but significant associations between IA and number of stool samples positive for all enteroviruses (OR 1.14, 95% CI 1.00-1.29, p = 0.05; heterogeneity χ² = 1.51, p = 0.68, I² = 0%), consecutive positivity for enteroviruses (1.55, 1.09-2.20, p = 0.01; χ² = 0.19, p = 0.91, I² = 0%) and number of stool samples positive specifically for enterovirus B (1.20, 1.01-1.42, p = 0.04; χ² = 0.03, p = 0.86, I² = 0%). Virome analyses to date have demonstrated associations between enteroviruses and IA that may be clinically significant. However, larger prospective mNGS studies with more frequent sampling and follow-up from pregnancy are required to further elucidate associations between early virus exposure and IA/T1D.

Keywords: childhood; islet autoimmunity; next-generation sequencing; type 1 diabetes; virome.

FIGURE 1

Flow diagram of study selection

FIGURE 2

Individual and summary odds ratios for positivity for any vertebrate‐infecting virus in children with islet autoimmunity (IA) versus no IA, with stool versus plasma subgroup analysis. All results based on rates of virus positivity as detected by metagenomic next‐generation sequencing. No associations were found between virus positivity in stool or plasma and childhood IA

FIGURE 3

Individual and summary odds ratios for number of samples positive for enterovirus (EV) in children with islet autoimmunity (IA) versus no IA, with stool versus plasma subgroup analysis. All results based on rates of virus positivity as detected by metagenomic next‐generation sequencing. An association was found between childhood IA and number of stool samples positive for EV (odds ratio 1.14; 95% confidence interval 1.00–1.29, p = 0.05; heterogeneity χ ² = 0.50, p = 0.68, I ² = 0%), but not the number of plasma samples positive for EV

FIGURE 4

Individual and summary odds ratios (ORs) for number of stool samples positive for enterovirus B (EV‐B) in children with islet autoimmunity (IA) versus no IA. All results based on rates of virus positivity as detected by metagenomic next‐generation sequencing. An association was found between number of stool samples positive for EV‐B and IA (OR, 1.20; 95% confidence interval 1.01–1.42, p = 0.04; heterogeneity χ ² = 0.03, p = 0.86, I ² = 0%)

FIGURE 5

Individual and summary odds ratios (ORs) for studies examining positivity for enterovirus (EV) in ≥2 consecutive stool samples in children with islet autoimmunity (IA) versus no IA. All results based on rates of virus positivity as detected by metagenomic next‐generation sequencing. An association was found between consecutive EV shedding and childhood IA (OR 1.55, 95% confidence interval 1.09–2.20, p = 0.01; heterogeneity χ ² = 0.10, p = 0.91, I ² = 0%)