SARS-CoV-2 Infection and Development of Islet Autoimmunity in Early Childhood

Abstract

Importance: The incidence of diabetes in childhood has increased during the COVID-19 pandemic. Elucidating whether SARS-CoV-2 infection is associated with islet autoimmunity, which precedes type 1 diabetes onset, is relevant to disease etiology and future childhood diabetes trends.

Objective: To determine whether there is a temporal relationship between SARS-CoV-2 infection and the development of islet autoimmunity in early childhood.

Design, setting, and participants: Between February 2018 and March 2021, the Primary Oral Insulin Trial, a European multicenter study, enrolled 1050 infants (517 girls) aged 4 to 7 months with a more than 10% genetically defined risk of type 1 diabetes. Children were followed up through September 2022.

Exposure: SARS-CoV-2 infection identified by SARS-CoV-2 antibody development in follow-up visits conducted at 2- to 6-month intervals until age 2 years from April 2018 through June 2022.

Main outcomes and measures: The development of multiple (≥2) islet autoantibodies in follow-up in consecutive samples or single islet antibodies and type 1 diabetes. Antibody incidence rates and risk of developing islet autoantibodies were analyzed.

Results: Consent was obtained for 885 (441 girls) children who were included in follow-up antibody measurements from age 6 months. SARS-CoV-2 antibodies developed in 170 children at a median age of 18 months (range, 6-25 months). Islet autoantibodies developed in 60 children. Six of these children tested positive for islet autoantibodies at the same time as they tested positive for SARS-CoV-2 antibodies and 6 at the visit after having tested positive for SARS-CoV-2 antibodies. The sex-, age-, and country-adjusted hazard ratio for developing islet autoantibodies when the children tested positive for SARS-CoV-2 antibodies was 3.5 (95% CI, 1.6-7.7; P = .002). The incidence rate of islet autoantibodies was 3.5 (95% CI, 2.2-5.1) per 100 person-years in children without SARS-CoV-2 antibodies and 7.8 (95% CI, 5.3-19.0) per 100 person-years in children with SARS-CoV-2 antibodies (P = .02). Islet autoantibody risk in children with SARS-CoV-2 antibodies was associated with younger age (<18 months) of SARS-CoV-2 antibody development (HR, 5.3; 95% CI, 1.5-18.3; P = .009).

Conclusion and relevance: In young children with high genetic risk of type 1 diabetes, SARS-CoV-2 infection was temporally associated with the development of islet autoantibodies.

Figure 1.. SARS-CoV-2 Antibodies, Influenza A(H1N1) Antibodies, and Islet Autoantibodies

A, The age of the children and date of follow-up study visits of 885 children included in the study. The boxed areas represent the interquartile range (q1-q3) of dates for each study visit and the center line, the median. B, The cumulative number of new cases for SARS-CoV-2 antibodies was 170 and for influenza A(H1N1) antibodies was 101 over time to age 2 years. The numbers of new cases of islet autoantibodies (multiple or single and diabetes) was 60 until 2.5 years of age. Each dot indicates a new case; the larger dots indicate multiple cases on the same day. The numbers underneath the x-axis indicate the number of children tested for all antibodies in each 3-month period and corresponding to the end of the indicated month. C, Kaplan-Meier curves of the cumulative frequency of islet autoantibodies over 12 months from study entry of children recruited and followed up between February 2018 and June 2020 (n = 560) and children who had their first follow-up visit from July 2020 (n = 325).

Figure 2.. Islet Autoantibodies and Their Temporal Relationship to SARS-CoV-2 Antibodies

A, Frequency of children who tested positive for islet autoantibodies at the end of each month of the study is shown for 712 children who tested negative for SARS-CoV-2 antibodies and 165 children who tested positive for SARS-CoV-2 antibodies before age 18 months (visits 2, 3, or 4) or at age 18 or 24 months (visits 5 or 6). Five children who tested positive for SARS-CoV-2 antibodies developed islet autoantibodies prior to testing positive for SARS-CoV-2 antibodies and are included in the SARS-CoV-2 antibody–negative group. Dots indicate months when there were new cases of children who tested positive for islet autoantibodies. The size of the dot indicates the number of new cases (1, 2, or 3). The cumulative number of children in each group are presented at the end of each 3-month period and corresponding to the end of the indicated month. B, From February 2018 through September 2022, the incidence rate of islet autoantibodies in 877 children is stratified by when they tested negative for SARS-CoV-2 (48 islet autoantibody–positive cases) and when they tested positive for SARS-CoV-2 antibodies (12 islet autoantibody-\–positive cases). For the children who tested positive for SARS-CoV-2, the incidence rate is calculated for islet autoantibodies that developed either in the same visit or after the first visit after testing positive for SARS-CoV-2. The incidence rate of islet autoantibodies is also shown from July 2020 to September 2022 for 735 children through the last time they tested negative for SARS-CoV-2 (27 islet autoantibody–positive cases) and for the 170 children who tested positive for SARS-CoV-2 from the last visit they tested negative for SARS-CoV-2 antibodies to the first visit they tested positive for SARS-CoV-2 antibodies (6 islet autoantibody–positive cases) and from the first visit they tested positive for SARS-CoV-2 antibodies and the next visit (6 islet autoantibody cases). The data markers represent the incidence rate and the whiskers, 95% CIs. ^aThe number of children who developed islet autoantibodies. C, Kaplan-Meier curves of the cumulative frequency of islet autoantibody seroconversion among 731 children who were islet autoantibody negative in June 2020 from the time of first SARS-CoV-2 antibodies (n = 165) and for children who did not develop SARS-CoV-2 antibodies from the first sample after June 2020 (n = 566). Five children who developed islet autoantibodies prior to the development of SARS-CoV-2 antibodies are not included in the SARS-CoV-2 antibody–positive group.

Figure 3.. Stratified Analyses of the Association Between SARS-CoV-2 Infection and Islet Autoantibody Development

A, Univariable Cox proportional hazards model performed on 165 SARS-CoV-2 antibody–positive children who were negative for islet autoantibodies at the time of SARS-CoV-2 antibody seroconversion. Each covariate was binary with the risk category and the number of islet autoantibody–positive events and total number in each category indicated. B, Incidence rate of islet autoantibodies from July 2020 in children younger than age 12 months (study visits 2 and 3), age 12 to 16 months (study visit 4), age 17 to 20 months (study visit 5), and age 21 to 25 months (study visit 6) stratified for their SARS-CoV-2 antibody status as positive or negative at each age category. The SARS-CoV-2 antibody–positive category at each age group includes cases that were positive up to and including the indicated age group. The incidence rate at each age category is calculated for the number of new islet autoantibody events observed in the interval from the preceding age category. For the children positive for SARS-CoV-2, new islet autoantibody events observed together with or after a previous SARS-CoV-2 antibody seroconversion are included.