Immunology in the clinic review series; focus on type 1 diabetes and viruses: the enterovirus link to type 1 diabetes: critical review of human studies

Abstract

The hypothesis that under some circumstances enteroviral infections can lead to type 1 diabetes (T1D) was proposed several decades ago, based initially on evidence from animal studies and sero-epidemiology. Subsequently, enterovirus RNA has been detected more frequently in serum of patients than in control subjects, but such studies are susceptible to selection bias and reverse causality. Here, we review critically recent evidence from human studies, focusing on longitudinal studies with potential to demonstrate temporal association. Among seven longitudinal birth cohort studies, the evidence that enterovirus infections predict islet autoimmunity is quite inconsistent in our interpretation, due partially, perhaps, to heterogeneity in study design and a limited number of subjects studied. An association between enterovirus and rapid progression from autoimmunity to T1D was reported by one longitudinal study, but although consistent with evidence from animal models, this novel observation awaits replication. It is possible that a potential association with initiation and/or progression of islet autoimmunity can be ascribed to a subgroup of the many enterovirus serotypes, but this has still not been investigated properly. There is a need for larger studies with frequent sample intervals and collection of specimens of sufficient quality and quantity for detailed characterization of enterovirus. More research into the molecular epidemiology of enteroviruses and enterovirus immunity in human populations is also warranted. Ultimately, this knowledge may be used to devise strategies to reduce the risk of T1D in humans.

Fig. 1

Illustration of the two-stage process leading to type 1 diabetes. Enterovirus may influence initiation of autoimmunity, progression from islet autoimmunity to clinical disease, or both. It is also possible that enterovirus influences the risk of developing atypical type 1 diabetes not preceded by islet autoimmunity, such as fulminant type 1 diabetes seen in some cases in Japan .

Fig. 2

Variation of enterovirus prevalence by age, season and method of detection in two longitudinal birth cohort studies [Environmental Triggers of Type 1 Diabetes (MIDIA) and Diabetes and Autoimmunity Study in the Young (DAISY)]. (a) Prevalence of enterovirus RNA by age in nearly 8000 monthly faecal samples from nearly 800 children in MIDIA (unpublished data from ref. [48]). Circles are observed prevalence in age groups, and the line represent smoothed predictions from logistic regression model with a second-degree polynomial. (b) Prevalence of enterovirus RNA in monthly faecal samples from MIDIA children aged 3–36 months, by season [smoothed as in (a), but with restricted cubic splines]. (c) Prevalence of enterovirus infection by age and type of sample in DAISY (data from ref. [12]). Subjects with autoimmunity (n = 140) were tested for enterovirus RNA in rectal swabs (grey line) and serum (red solid line), and enterovirus serology (red dashed line) in samples collected every 3–6 months (serology only in subset of samples, all enterovirus assays conducted in Heikki Hyöty's laboratory). Infections were defined serologically as a doubling or more in optical density in one or more of five immunoglobulin (Ig)M, IgG and IgG enzyme immunoassays (see for details). All curves were smoothed using restricted cubic splines in logistic regression models. Curves must be interpreted with caution because of relatively few positive samples and substantial random variation, cf. (a).

Fig. 3

Studies of enterovirus RNA in serum or plasma from patients with type 1 diabetes diagnosed within 1 month and from healthy controls. (a) Odds ratio for association between enterovirus and type 1 diabetes. Odds ratio estimates had to be calculated using Woolf's formula, as information for matched analysis was not provided in original publications. The I-squared estimate of statistical between study heterogeneity was 0·0%. Odds ratio estimates cannot be calculated from studies with zero observed controls with enterovirus. Overall results (association and heterogeneity) were similar after adding 0·5 to all four cells in the 2 × 2 table for studies with zero observed controls with enterovirus RNA-positive serum (data not shown). (b) Percentage of enterovirus-positive age-matched healthy controls (with exact 95% confidence intervals). (c) Percentage of enterovirus positive type 1 diabetes (T1D) patients. Note that three studies of patients with newly diagnosed T1D did not include matched controls, and are thus not included in panels (a) and (b). References cited (first author and publication year indicated) are ,,–. Data from Oikarinen 2011 include data not presented in original publication, obtained by personal communication from H. Hyöty and S. Oikarinen, Tampere, Finland. Not included are data based on enterovirus detection in peripheral blood mononuclear cells, which were available from Schulte , and also by two other studies ,. Other studies not included were Craig , who did not provide separate data on results based on serum samples (only for positivity in serum and/or faecal samples), and a few studies of type 1 diabetes patients who were not newly diagnosed.