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Table 1.  Baseline Characteristics of the Study Population
Baseline Characteristics of the Study Population
Table 2.  Results of Multivariable Logistic Regression for an Association Between Autoantibodies and SARS-CoV-2 Antibody Status, Colorado and Bavaria (N = 51 970)
Results of Multivariable Logistic Regression for an Association Between Autoantibodies and SARS-CoV-2 Antibody Status, Colorado and Bavaria (N = 51 970)
1.
Barrett  CE, Koyama  AK, Alvarez  P,  et al.  Risk for newly diagnosed diabetes >30 days after SARS-CoV-2 infection among persons aged <18 years—United States, March 1, 2020-June 28, 2021.   MMWR Morb Mortal Wkly Rep. 2022;71(2):59-65. doi:10.15585/mmwr.mm7102e2PubMedGoogle ScholarCrossref
2.
Kamrath  C, Rosenbauer  J, Eckert  AJ,  et al.  Incidence of type 1 diabetes in children and adolescents during the COVID-19 pandemic in Germany: results from the DPV Registry.   Diabetes Care. 2022;dc210969. doi:10.2337/dc21-0969PubMedGoogle ScholarCrossref
3.
McQueen  RB, Geno Rasmussen  C, Waugh  K,  et al.  Cost and cost-effectiveness of large-scale screening for type 1 diabetes in Colorado.   Diabetes Care. 2020;43(7):1496-1503. doi:10.2337/dc19-2003PubMedGoogle ScholarCrossref
4.
Ziegler  AG, Kick  K, Bonifacio  E,  et al; Fr1da Study Group.  Yield of a public health screening of children for islet autoantibodies in Bavaria, Germany.   JAMA. 2020;323(4):339-351. doi:10.1001/jama.2019.21565PubMedGoogle ScholarCrossref
5.
Jia  X, Gesualdo  P, Geno Rasmussen  C,  et al.  Prevalence of SARS-CoV-2 antibodies in children and adults with type 1 diabetes.   Diabetes Technol Ther. 2021;23(7):517-521. doi:10.1089/dia.2020.0609PubMedGoogle ScholarCrossref
6.
Hippich  M, Holthaus  L, Assfalg  R,  et al.  A public health antibody screening indicates a 6-fold higher SARS-CoV-2 exposure rate than reported cases in children.   Med (N Y). 2021;2(2):149-163.e4. doi:10.1016/j.medj.2020.10.003PubMedGoogle ScholarCrossref
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    Research Letter
    August 5, 2022

    SARS-CoV-2 Infections and Presymptomatic Type 1 Diabetes Autoimmunity in Children and Adolescents From Colorado, USA, and Bavaria, Germany

    Author Affiliations
    • 1Barbara Davis Center for Diabetes, University of Colorado, Aurora
    • 2Center for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany
    • 3Berufsverband der Kinder-und Jugendärzte eV, Landesverband Bayern, Regensburg, Germany
    • 4Institute of Diabetes Research Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany
    JAMA. 2022;328(12):1252-1255. doi:10.1001/jama.2022.14092

    An increased incidence of clinical diabetes has been reported in children with previous COVID-19.1,2 It is plausible that the virus may trigger autoimmune response to the islets or hasten metabolic decompensation in persons with already established islet autoimmunity. We tested the hypothesis that previous SARS-CoV-2 infection was associated with autoimmunity, which predicts future type 1 diabetes.

    Methods

    In 2020 and 2021, a cross-sectional screening for islet autoantibodies and SARS-CoV-2 antibodies was offered to children and adolescents aged 1 to 18 years participating in the Autoimmunity Screening for Kids (ASK)3 in Colorado, US, and to children aged 1 to 10.9 years enrolled in the Fr1da study4 in Bavaria, Germany. In addition, in Bavaria, autoantibody-negative children were followed up after detection of SARS-CoV-2 antibodies with blood sample collection every 3 months. Screening was approved by the respective institutional review boards. Written informed consent was obtained from parents of each study participant. The race and ethnicity of participants were reported by parents using the US Census categories and included to control for possible confounding.

    Past SARS-CoV-2 infection was defined by the presence of antibodies to both SARS-CoV-2 receptor binding domain and nucleocapsid proteins,5,6 with similar detection thresholds for positivity as assessed by the World Health Organization international standard. Autoantibodies to insulin, glutamic acid decarboxylase, islet antigen 2, and zinc transporter 8 autoantibodies were measured using comparable methods (eMethods in the Supplement). Study outcomes included the presence of multiple or single high-affinity islet autoantibodies that carry, respectively, a 50% and 30% risk of progression to clinical diabetes in 5 years.

    Statistical analyses were performed using R version 4.1.2 (R Core Team). Multivariable logistic regression was used to assess independent associations between previous SARS-CoV-2 infection and islet autoimmunity as well as testing for interactions by study site. Standardized assessments of exposure and outcomes permitted multivariable logistic regression analysis of combined data to maximize statistical power. Covariates included age, sex, family history of type 1 diabetes, and race and ethnicity. Sensitivity analyses were performed excluding siblings and offspring of people with type 1 diabetes and separately excluding youths vaccinated against SARS-CoV-2. Two-tailed P values less than .05 were considered significant.

    Results

    Prior SARS-CoV-2 infections were identified in 1524 (32.3%) of 4717 Colorado youths (median age, 8.6 years; 50.3% female) and in 2862 (6.1%) of 47 253 Bavarian children (median age, 3.9 years; 48.9% female) (Table 1). Multiple islet autoantibodies were detected in 21 Colorado youths (0.45%) and in 141 Bavarian children (0.30%). In addition, 26 (0.55%) and 54 (0.11%) Colorado and Bavarian youths, respectively, were positive for a single high-affinity islet autoantibody. The prevalence of multiple or single high-affinity islet autoantibodies did not significantly differ between youths with vs without previous SARS-CoV-2 infection in Colorado (1.18% vs 0.91%, P = .43) or Bavaria (0.42% vs 0.41%, P = .88). Previous SARS-CoV-2 infection was not significantly associated with the presence of multiple islet autoantibodies (odds ratio, 1.06 [95% CI, 0.59-1.80]; P = .83) or a single high-affinity islet autoantibody (odds ratio, 1.34 [95% CI, 0.70-2.44]; P = .36) controlling for confounders (Table 2).

    There was no significant interaction between the study site and the association with SARS-CoV-2 infection, sex, age, or family history of type 1 diabetes. Sensitivity analyses excluding siblings and offspring of people with type 1 diabetes or vaccinated youths yielded similar results (Table 2). In Bavaria, 465 children were followed up longitudinally after first detection of SARS-CoV-2 antibodies for a median of 8.9 months (IQR, 3.4-10.3) and up to 2 years. None of these children developed islet autoantibodies.

    Discussion

    Screening of more than 50 000 youths in diverse populations of Colorado and Bavaria found no association of SARS-CoV-2 infection with autoimmunity related to development of type 1 diabetes. Study limitations include the low prevalence of autoantibodies, limiting the power to detect an increase in risk associated with SARS-CoV-2 infection. Moreover, the cross-sectional design did not allow determination of whether autoantibodies developed before or after SARS-CoV-2 infection. Long-term follow-up of persons with preexisting autoimmunity is necessary to determine whether SARS-CoV-2 accelerates progression to clinical diabetes.

    Section Editors: Jody W. Zylke, MD, Deputy Editor; Kristin Walter, MD, Senior Editor.
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    Article Information

    Accepted for Publication: July 27, 2022.

    Published Online: August 5, 2022. doi:10.1001/jama.2022.14092

    Corresponding Author: Marian Rewers, MD, PhD, Barbara Davis Center for Diabetes, University of Colorado School of Medicine, 1775 Aurora Ct, B-140, Aurora, CO 80045 (marian.rewers@cuanschutz.edu).

    Author Contributions: Dr Rewers had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Rewers, Bonifacio, Geno Rasmussen, Ziegler.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Rewers, Geno Rasmussen, Ziegler.

    Critical revision of the manuscript for important intellectual content: Bonifacio, Ewald, Geno Rasmussen, Jia, Pyle, Ziegler.

    Statistical analysis: Geno Rasmussen, Pyle, Ziegler.

    Obtained funding: Rewers, Ziegler.

    Administrative, technical, or material support: Rewers, Ewald, Geno Rasmussen, Jia, Ziegler.

    Supervision: Rewers, Bonifacio.

    Other - Measurement of antibodies: Bonifacio.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: The ASK Study (3-SRA-2018-564-M-N) is funded by JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, and Janssen Research and Development LLC. Additional support came from the Courtenay C. and Lucy Patten Davis Foundation and the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (University of Colorado Diabetes Research Center grant DK116073). The Fr1da Study was supported by grants from LifeScience-Stiftung (HMGU 2014.01 and HMGU 2016.01), Juvenile Diabetes Research Foundation International (1-SRA-2014-310-M-R, 3-SRA-2015-72-M-R, 3-SRA-2019-718-Q-R), the Bavarian State Ministry of Health and Care (Gesund.Leben.Bayern, LP00228), The Leona M. and Harry B. Helmsley Charitable Trust (G-1911-03274), and the German Center for Diabetes Research (DZD e.V.). This work was supported by a grant from the German Federal Ministry of Education and Research (FKZ01KX1818).

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Group Information: The members of the ASK Study Group can be found at https://www.askhealth.org/about-us and the Fr1da Study Group at https://www.typ1diabetes-frueherkennung.de/informationen-fuer-aerzte/the-fr1da-study-group.html.

    Additional Contributions: We thank Brigitte I. Frohnert, MD, PhD, Hanan Shorrosh, BS, Kimber Simmons, MD, Marisa Stahl, MD, Andrea K. Steck, MD, and Liping Yu, MD (Barbara Davis Center University of Colorado, Aurora), Peter Achenbach, MD, Marlon Scholz, CTA, and Franziska Voss, MS (Institute of Diabetes Research Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany), and Esra Karapinar, MD (Technical University Munich, School of Medicine, Forschergruppe Diabetes at Klinikum rechts der Isar, Munich, Germany), for their contributions and critical review of the manuscript as well as other members of the ASK Study Group and Fr1da Study Group. They were supported by the ASK and Fr1da studies.

    References
    1.
    Barrett  CE, Koyama  AK, Alvarez  P,  et al.  Risk for newly diagnosed diabetes >30 days after SARS-CoV-2 infection among persons aged <18 years—United States, March 1, 2020-June 28, 2021.   MMWR Morb Mortal Wkly Rep. 2022;71(2):59-65. doi:10.15585/mmwr.mm7102e2PubMedGoogle ScholarCrossref
    2.
    Kamrath  C, Rosenbauer  J, Eckert  AJ,  et al.  Incidence of type 1 diabetes in children and adolescents during the COVID-19 pandemic in Germany: results from the DPV Registry.   Diabetes Care. 2022;dc210969. doi:10.2337/dc21-0969PubMedGoogle ScholarCrossref
    3.
    McQueen  RB, Geno Rasmussen  C, Waugh  K,  et al.  Cost and cost-effectiveness of large-scale screening for type 1 diabetes in Colorado.   Diabetes Care. 2020;43(7):1496-1503. doi:10.2337/dc19-2003PubMedGoogle ScholarCrossref
    4.
    Ziegler  AG, Kick  K, Bonifacio  E,  et al; Fr1da Study Group.  Yield of a public health screening of children for islet autoantibodies in Bavaria, Germany.   JAMA. 2020;323(4):339-351. doi:10.1001/jama.2019.21565PubMedGoogle ScholarCrossref
    5.
    Jia  X, Gesualdo  P, Geno Rasmussen  C,  et al.  Prevalence of SARS-CoV-2 antibodies in children and adults with type 1 diabetes.   Diabetes Technol Ther. 2021;23(7):517-521. doi:10.1089/dia.2020.0609PubMedGoogle ScholarCrossref
    6.
    Hippich  M, Holthaus  L, Assfalg  R,  et al.  A public health antibody screening indicates a 6-fold higher SARS-CoV-2 exposure rate than reported cases in children.   Med (N Y). 2021;2(2):149-163.e4. doi:10.1016/j.medj.2020.10.003PubMedGoogle ScholarCrossref
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