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.

Keywords: Autoimmunity; Islet autoantibodies; Prospective cohort; Respiratory infections; Type 1 diabetes.

Fig. 1

Incidence of islet autoimmunity per 100 person-years (dashed line) peaked between 6 and 9 months of age, and declined thereafter. Incidence of RIE per person-years (solid line) also peaked between 6 and 9 months and declined thereafter. Age-specific RIE rates were strongly correlated with the decline in islet autoimmunity incidence

Fig. 2

(a) RIEs occurring between 0 and 3 months, 3 and 6 months, and 6 and 9 months before the autoantibody seroconversion period were associated with increased risk of islet autoimmunity (p ≤ 0.05 for all), whereas RIE rates in the other 3 month periods were not (p > 0.10). (b) In a multivariate analysis, the presence of a winter but not a spring, summer or autumn RIE, occurring in the 9 month period before seroconversion, was associated with islet autoimmunity. (c) In a multivariate analysis, the specific infections in the winter with significant association with islet autoimmunity were sinusitis, laryngitis and tracheitis, influenza-like illness and common cold