Islet Autoimmunity Linked to COVID-19 in Children Susceptible to Type 1 Diabetes

Children younger than 18 months with high genetic susceptibility to type 1 diabetes were at increased risk of developing islet autoimmunity after COVID-19 infection.

Islet autoimmunity is associated with COVID-19 infection in children at increased genetic risk for type 1 diabetes, according to results of a study published in JAMA.

Researchers sought to assess the temporal association between COVID-19 infection and the development islet autoimmunity — a precursor for type 1 diabetes — in early childhood. Between April 2019 and June 2022, 885 infant participants (441 girls; age range, 4.0-7.0 months) with high genetic susceptibility to type 1 diabetes were evaluated, all of whom tested negative for islet autoantibodies at baseline. Participants were included if their estimated risk of developing multiple islet autoantibodies was at least 10% by the age of 6 years. Participants were randomly assigned to receive either oral insulin powder or placebo, administered daily until 3 years of age.

Blood samples were collected from all participants from baseline until 6.5 years of age. Participants also were screened for immunoglobulin G SARS-CoV-2 antibodies, influenza A antibodies, and islet autoantibodies. The presence of autoantibodies against insulin, glutamate acid decarboxylase 65 (GAD65), insulinoma-associated antigen 2 (IA-2), and zinc transporter 8 (ZnT8) served as positive biomarkers for islet autoantibodies.

The primary outcome was either the development of persistent autoantibodies against insulin; GAD65; IA-2; or ZnT8 in 2 consecutive samples and a confirmed second antibody in 1 sample or 1 or more of the antibodies and diabetes. Maternally transferred antibodies were excluded from analysis. The incidence rates (IRs) of antibodies and autoantibodies were compared between groups via chi-squared testing. Cox proportional hazards models were used to assess covariates associated with islet autoantibody development in participants with confirmed SARS-CoV-2 antibodies.

The age of SARS-CoV-2 infection appeared to be critical in the association with islet autoimmunity.

Overall, 170 participants developed SARS-CoV-2 antibodies at a median age of 18 (range, 6-25) months. The IR of positive SARS-CoV-2 antibodies per 100 person-years was 0 from February 2018 to June 2020; 4.4 from July 2020 to December 2020; 21.5 from January 2021 to June 2021; 9.2 from July 2021 to December 2021; and 81.7 from January 2022 to June 2022.

Of note, the incidence rate per 100 person-years of the first development of influenza A antibodies was insignificant throughout the trial period (P =.63).

Further analysis showed islet autoantibodies had developed in 60 participants by 30 months of age, with a cumulative frequency of 6.8% (95% CI, 5.3-7.6). All 60 participants tested positive for islet autoantibodies until the final follow-up visit, and 33.3% developed type 1 diabetes. The rate of islet autoantibody development was significantly higher among participants who tested positive (IR, 7.8 per 100 person-years; 95% CI, 5.3-19.0) vs negative (IR, 3.5 per 100 person-years; 95% CI, 2.2-5.1) for SARS-CoV-2 antibodies (both P =.02).

After adjustments for sex, age, and country in a time-dependent Cox model, SARS-CoV-2-antibody positivity was significantly associated with increased risk for islet autoantibody development (hazard ratio [HR], 3.5; 95% CI, 1.6-7.7; P =.002). For the development of islet autoantibodies within 6 months, the cumulative risk was significantly higher in participants who were positive (7.3%; 95% CI, 4.2-12.7) vs negative (2.9%; 95% CI, 1.8-4.8) for SARS-CoV-2 antibodies (both P =.01).

Factors significantly associated with increased risk for islet autoantibody development included the detection of SARS-CoV-2 antibodies prior to 18 months of age (HR, 5.3; 95% CI, 1.5-18.3; P =.009).

Study limitations were the inclusion of only participants with high genetic susceptibility to type 1 diabetes, the inability to confirm COVID-19 infection via polymerase chain reaction, and the low number of participants who developed islet autoantibodies. The researchers also were unable to exclude possibility of reverse causality, as children who develop islet autoantibodies may be more susceptible to COVID-19 infection.

According to the researchers, “The age of SARS-CoV-2 infection appeared to be critical in the association with islet autoimmunity.”

Disclosure: One study author declared affiliations with industry. Please see the original reference for a full list of disclosures.


Lugar M, Eugster A, Achenbach P, et al; on behalf of the GPPAD Study Group. SARS-CoV-2 infection and development of islet autoimmunity in early childhood. JAMA. Published online September 8, 2023. doi:10.1001/jama.2023.16348