In a recent study published in the journal JAMA, researchers examined whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 infections were linked to the development of islet autoimmunity that precedes the onset of type 1 diabetes during childhood.
Study: SARS-CoV-2 Infection and Development of Islet Autoimmunity in Early Childhood. Image Credit: Dragoljub Bankovic / Shutterstock
The onset of type 1 diabetes among the pediatric population is preceded by the production of autoantibodies against the proteins in the islet β-cells in the pancreas. The susceptibility for autoantibody development is the highest at the age of one and is determined by the genes involved in immune function, the functioning of islet β-cells, and viral infection response. Viral infections of the respiratory system in the first year of life are believed to contribute to islet autoimmunity.
The coronavirus disease 2019 (COVID-19) pandemic substantially increased childhood exposure to a respiratory virus, and various studies have reported an increase in the incidence of type 1 diabetes after the onset of the pandemic. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to cause infections in the pancreas and could potentially trigger islet autoimmunity. However, the development of islet autoantibodies has not been conclusively linked to SARS-CoV-2 infections, and it is essential to understand how exposure to SARS-CoV-2 during childhood contributes to the etiology of type 1 diabetes in the pediatric population.
About the study
In the present study, the researchers reported the results of the Primary Oral Insulin Trial (POINT) conducted between 2018 and 2021, which enrolled infants between the ages of four to seven months with at least a 10% genetically defined risk of developing islet autoimmunity.
The study collected blood samples longitudinally to detect islet autoantibodies, with baseline sample collection at the onset of the study when the infants were between four and seven months of age and the next five visits corresponding to infant ages six to 10 months, eight to 12 months, 12 to 16 months, 17 to 20 months, and 21 to 25 months, respectively. After the sixth visit, samples were collected every six months till the age of 6.5 years.
Luciferase immunoprecipitation assays were used to measure the immunoglobulin G (IgG) antibodies against the SARS-CoV-2 receptor binding domain, spike protein S2 subunit, and nucleocapsid protein. The antibodies against the HA1 antigen of the hemagglutinin 5 neuraminidase 1 (H5N1) influenza A virus were also measured. For the baseline samples that tested positive, the immunoglobulin A (IgA) antibodies were also tested to determine whether the antibody positivity was due to the transfer of maternal antibodies.
Radio-binding assays were employed to test the samples for islet autoantibodies against insulinoma-associated antigen 2 (IA-2), glutamate acid decarboxylase 65 (GAD65), zinc transporter 8 (ZnT8), and insulin. Samples that tested positive for GAD65 were retested using enzyme-linked immunosorbent assay (ELISA). All samples were considered positive only if they tested positive at two independent laboratories.
The primary outcomes that were measured were the persistent and confirmed development of multiple islet β-cell autoantibodies, comprising autoantibodies against GAD65, IA-2, insulin, and ZnT8. Infants that tested positive for maternal antibodies with longitudinally declining antibody levels were excluded from the study, and the viral antibody incidence rates and islet autoantibodies were determined from the remaining samples.
The findings suggested that SARS-CoV-2 infections showed a temporal association with the development of islet β-cell autoantibodies in infants with a genetic predisposition to type 1 diabetes. Of the 884 infants included in the study, 170 developed antibodies against SARS-CoV-2 between six and 25 months, and of these 170, 60 developed islet autoantibodies.
Furthermore, the development of islet autoantibodies in six of the children coincided with the development of antibodies against SARS-CoV-2 in six of the infants, while another six infants tested positive for islet autoantibodies after the visit where they tested positive for antibodies against SARS-CoV-2.
The hazard ratio for islet autoantibody production in children who tested positive for antibodies against SARS-CoV-2 was 3.5 after adjusting for age, sex, and country. Furthermore, the incident rate per 100 person-years for the development of islet autoantibodies was 3.5 in infants without antibodies against SARS-CoV-2 and 7.8 in infants who had SARS-CoV-2 antibodies. Infants with antibodies against SARS-CoV-2 at a younger age (below 18 months) were also more likely to develop islet autoantibodies.
Overall, the findings reported that SARS-CoV-2 infections in infants who were genetically susceptible to type 1 diabetes showed a temporal association with the development of islet β-cell autoantibodies. The study showed that COVID-19 was a risk factor for the development of islet autoimmunity in infants with a higher genetic risk of type 1 diabetes.
- Lugar, M., Eugster, A., Achenbach, P., von, Berner, R., Rachel, Casteels, K., Larsson, E., Gemulla, G., Kordonouri, O., Lindner, A., Lundgren, M., Müller, D., Oltarzewski, M., Rochtus, A., Scholz, M., Szypowska, A., Todd, J. A., Ziegler, A., & Bonifacio, E. (2023). SARS-CoV-2 Infection and Development of Islet Autoimmunity in Early Childhood. JAMA. https://doi.org/10.1001/jama.2023.16348, https://jamanetwork.com/journals/jama/fullarticle/2809621