Progression from single to multiple islet autoantibodies often occurs soon after seroconversion: implications for early screening
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KeywordsIncidence Multiple islet autoantibodies Type 1 diabetes
To the Editor: Multiple islet autoantibodies mark a pre-clinical stage of type 1 diabetes, with 70% progression to clinical diabetes within 10 years of seroconversion . Broad application of screening for multiple islet autoantibodies may, therefore, become an attractive instrument to identify asymptomatic type 1 diabetes and prevent severe metabolic disarrangements and ketoacidosis. In contrast to multiple islet autoantibodies, only a minority of children who are, and remain, single islet autoantibody-positive develop type 1 diabetes within 10 years of follow-up. Nevertheless, many multiple islet autoantibody-positive children are likely to have transitioned from single to multiple islet autoantibodies. We [2, 3], and others  have reported that multiple islet autoantibody-positive children frequently seroconvert in the first 2 years of life, but little is known of the timing of transition from single to multiple islet autoantibody positivity. This knowledge is important for the design of screening and re-screening strategies. Here we analysed the prospectively followed German BABYDIAB/BABYDIET birth cohort [2, 5] to address this.
Children in the BABYDIAB/BABYDIET studies were routinely tested for islet autoantibodies at the ages of 9 months and 2 years, and every 3 years thereafter; children who were positive for one or more islet autoantibodies were tested every 6 months. In a subgroup of children with high genetic risk participating in the BABYDIET intervention study, routine testing for islet autoantibodies was carried out at 3 month intervals from the age of 3 months to 3 years and annually thereafter. Persistent islet autoantibody positivity was defined as a positive result for the same islet autoantibody in at least two consecutive samples.
The findings indicate that multiple islet autoantibodies largely appear close to initial seroconversion in children with a family history of type 1 diabetes. Initial seroconversion is often within the first 2 years of life in children who develop multiple islet autoantibodies and progression to diabetes appears to be linear early in these children . On the basis of these findings we suggest the following guidelines: (1) a screen at around 2–4 years of age to identify a large proportion of the children who become multiple islet autoantibody positive during childhood and (2) follow-up screening around 2 years later in children who are single islet autoantibody positive or restriction of follow-up testing to those at high risk as defined by HLA genotype. These guidelines could change as more information about autoantibody seroconversion is obtained. The data also indicates that intervention in single islet autoantibody-positive young children to prevent multiple islet autoantibodies will be logistically difficult because of the rapid progression in most cases who become multiple islet autoantibody positive. These findings, which are supported by those of the DIPP study , will eventually enable the implementation of a cost-effective early islet autoantibody screening programme in the population at large.
We thank A. Knopff, M. Scholz, C. Matzke, A. Wosch, L. Schneider, S. Riethausen, J. Stock and K. Warncke (Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Neuherberg, Germany) for data collection and expert technical assistance and also R. Puff (Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Neuherberg, Germany) for laboratory management.
The work was supported by grants from the Kompetenznetz Diabetes mellitus (Competence Network for Diabetes mellitus), funded by the Federal Ministry of Education and Research (FKZ 01GI0805-07, FKZ 01GI0805), and the JDRF (No 17-2012-16), and funding from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.). This work was supported by iMed – the Helmholtz Initiative on Pesonalized Medicine. EB is supported by the DFG Research Center and Cluster of Excellence – Center for Regenerative Therapies Dresden (FZ 111).
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
RC acquired and reviewed the data, undertook statistical analysis and interpretation of the results and drafted the manuscript. EG contributed to acquisition, analysis and interpretation of data and contributed to the writing of the manuscript. CW undertook statistical analysis and interpretation of the results and contributed to the writing of the manuscript. PA provided input to the statistical analysis and contributed to the writing of the article. EB provided major input to analysis and interpretation of data and contributed to the writing of the manuscript. AGZ designed the study, is Principal Investigator of the BABYDIAB study, provided input to the analysis and contributed to the writing of the manuscript. All listed authors approved the final version of the manuscript. AGZ takes responsibility for the integrity of the work as a whole.