Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: the TEDDY study

Abstract

Aims/hypothesis Respiratory infections and onset of islet autoimmunity are reported to correlate positively in two small prospective studies. The Environmental Determinants of Diabetes in the Young (TEDDY) study is the largest prospective international cohort study on the environmental determinants of type 1 diabetes that regularly monitors both clinical infections and islet autoantibodies. The aim was to confirm the influence of reported respiratory infections and to further characterise the temporal relationship with autoantibody seroconversion. Methods During the years 2004–2009, 8676 newborn babies with HLA genotypes conferring an increased risk of type 1 diabetes were enrolled at 3 months of age to participate in a 15 year follow-up. In the present study, the association between parent-reported respiratory infections and islet autoantibodies at 3 month intervals up to 4 years of age was evaluated in 7869 children. Time-dependent proportional hazard models were used to assess how the timing of respiratory infections related to persistent confirmed islet autoimmunity, defined as autoantibody positivity against insulin, GAD and/or insulinoma antigen-2, concordant at two reference laboratories on two or more consecutive visits. Results In total, 87,327 parent-reported respiratory infectious episodes were recorded while the children were under study surveillance for islet autoimmunity, and 454 children seroconverted. The number of respiratory infections occurring in a 9 month period was associated with the subsequent risk of autoimmunity (p < 0.001). For each 1/year rate increase in infections, the hazard of islet autoimmunity increased by 5.6% (95% CI 2.5%, 8.8%). The risk association was linked primarily to infections occurring in the winter (HR 1.42 [95% CI 1.16, 1.74]; p < 0.001). The types of respiratory infection independently associated with autoimmunity were common cold, influenza-like illness, sinusitis, and laryngitis/tracheitis, with HRs (95% CI) of 1.38 (1.11, 1.71), 2.37 (1.35, 4.15), 2.63 (1.22, 5.67) and 1.76 (1.04, 2.98), respectively. Conclusions/interpretation Recent respiratory infections in young children correlate with an increased risk of islet autoimmunity in the TEDDY study. Further studies to identify the potential causative viruses with pathogen-specific assays should focus especially on the 9 month time window leading to autoantibody seroconversion.

Association Between Early-Life Antibiotic Use and the Risk of Islet or Celiac Disease Autoimmunity

“…Meanwhile, evidence is mounting for a role of viral infections in the etiology of T1D and CD in the TEDDY study, with gastrointestinal and respiratory infections associated with an increased risk of CDA and IA, respectively. 30,31 …”

Incidence and trend of type 1 diabetes and the underlying environmental determinants

“…Not only are more cases of T1D diagnosed in winter, but in The Environmental Determinants of Diabetes in the Young (TEDDY) study, a significant increase in the risk for islet autoimmunity was seen only when respiratory infection episodes appeared at a high frequency, namely in winter . Serum enterovirus RNA was also more frequently detected in autumn and winter in participants of The Diabetes Prediction and Prevention (DIPP) study .…”

The association between stressful life events and respiratory infections during the first 4 years of life: The Environmental Determinants of Diabetes in the Young study

“…The fact that this association was found not only when NLEs and RIEs were recorded in the same time frame (current NLE) but more so when NLEs were measured in time periods prior to the report of RIEs adds further weight to the finding. Documenting this association in the TEDDY population supports the hypothesis that cumulative stress may influence the development of IA and T1D by increasing the child's risk for respiratory infection, which in turn increases the child's risk of IA and T1D (Lönnrot et al, ).…”

“…The molecular mimicry theory suggests that epitope mimicry between a virus and human proteins can activate autoimmune diseases like T1D (de Oliveira Andrade et al, ). Respiratory infections were reported to increase the risk for T1D autoimmunity in the BABYDIET (Beyerlein et al, ; de Beeck & Eizirik, ), MIDIA (Rasmussen, Witso, Tapia, Stene, & Ronningen, ), ABIS (Wahlberg, Vaarala, Ludvigsson, & for the ABIS Study Group, ), and The Environmental Determinants of Diabetes in the Young (TEDDY; Lönnrot et al, ) studies.…”

“…The goal of this paper was to conduct a prospective analysis of the association between stressful NLEs and the development of respiratory infections during the same interval—the first 4 years of a TEDDY child's life. Any link between NLEs and respiratory infections confirmed in a prospective analysis would provide one mechanism by which life stress could increase a child's risk of IA and T1D (Lönnrot et al, ).…”