Prepublication Release Incidence of COVID-19 and Risk of Diabetic Ketoacidosis in New-Onset Type 1 Diabetes Clemens Kamrath, MD, Joachim Rosenbauer, MD, Alexander J. Eckert, MSc, Angeliki Pappa, MD, Felix Reschke, MD, Tilman R. Rohrer , Prof, Kirsten Mönkemöller, MD, Michael Wurm, MD, Kathrin Hake, MD, Klemens Raile, Prof, and Reinhard W. Holl, Prof DOI: 10.1542/peds.2021-050856 Journal: Pediatrics Article Type: Regular Article Citation: Kamrath C, Rosenbauer J, Eckert AJ, et al. Incidence of COVID-19 and risk of diabetic ketoacidosis in new-onset type 1 diabetes. Pediatrics. 2021; doi: 10.1542/peds.2021- 050856 This is a prepublication version of an article that has undergone peer review and been accepted for publication but is not the final version of record. This paper may be cited using the DOI and date of access. This paper may contain information that has errors in facts, figures, and statements, and will be corrected in the final published version. The journal is providing an early version of this article to expedite access to this information. The American Academy of Pediatrics, the editors, and authors are not responsible for inaccurate information and data described in this version. Downloaded from©202 www.aappublications.org/news1 American Academy by of guest Pediatrics on September 25, 2021 Prepublication Release Incidence of COVID-19 and Risk of Diabetic Ketoacidosis in New-Onset Type 1 Diabetes Clemens Kamrath, MD*1, Joachim Rosenbauer, MD*2,3, Alexander J. Eckert, MSc3,4, Angeliki Pappa, MD5, Felix Reschke, MD6, Tilman R. Rohrer , Prof7, Kirsten Mönkemöller, MD8, Michael Wurm, MD9, Kathrin Hake, MD10, Klemens Raile, Prof11, and Reinhard W. Holl, Prof3,4 * Clemens Kamrath and Joachim Rosenbauer contributed equally to this study. Affiliations: 1 Division of Pediatric Endocrinology and Diabetology, Centre of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany; 2 Institute for Biometrics and Epidemiology, German Diabetes Centre, Leibniz Centre for Diabetes Research at Heinrich Heine University Dusseldorf, Dusseldorf, Germany; 3 German Centre for Diabetes Research (DZD), Munich-Neuherberg, Germany; 4 Institute of Epidemiology and Medical Biometry, ZIBMT, Ulm University, Ulm, Germany; 5 Department of Pediatrics, University Hospital RWTH Aachen, Aachen, Germany; 6 Diabetes Centre for Children and Adolescents, Children's Hospital Auf der Bult, Hannover, Germany; 7 Department of Pediatrics, Saarland University, Homburg/Saar, Germany; 8 Department of Pediatrics, Kinderkrankenhaus Amsterdamer Straße, Cologne, Germany; 9 Department of Pediatrics, Klinik St. Hedwig, University Hospital Regensburg, Krankenhaus Barmherzige Brüder, Regensburg, Germany; 10 Department of Pediatrics, Müritz Klinikum, Waren, Germany; 11 Department of Pediatric Endocrinology and Diabetology, Charité, University Medicine Berlin, Germany Corresponding author: Clemens Kamrath, MD, Division of Pediatric Endocrinology and Diabetology, Centre of Child and Adolescent Medicine, Justus Liebig University, Feulgenstr. 12, 35385 Giessen, Germany, phone: +49 641 985 43411, fax: +49 641 985 43459 email: [email protected] Declaration of interests: Klemens Raile is an advisory board member of Lilly Diabetes Care and Abbott Diabetes Care, and reports paid talks for Sanofi, Dexcom, NovoNordisk and Springer Health Care outside the submitted work. Kirsten Mönkemöller received educational fees from Medtronic outside the submitted work. Funding: The DPV is supported through the German Federal Ministry for Education and Research within the German Centre for Diabetes Research (DZD, grant number: 82DZD14A02). Further financial support was received by the German Robert Koch Institute (RKI) and the German Diabetes Association (DDG). This study was partly funded by the Deutsche Diabetes Stiftung (FP-0433-2020). Role of Funder: The funding organization had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Abbreviations: COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; RR, relative risk; IQR, interquartile range; DPV, Diabetes-Patienten- Verlaufsdokumentation Key words: Corona pandemic; SARS-CoV-2; manifestation; decompensation; pH; fear of infection; hospital admission; diagnostic delay Downloaded from©202 www.aappublications.org/news1 American Academy by of guest Pediatrics on September 25, 2021 Prepublication Release Article Summary: The risk of diabetic ketoacidosis in children with new-onset type 1 diabetes was significantly associated with the regional incidence of COVID-19 cases and deaths during the first wave of the pandemic. What’s known on this Subject: Significant delays in diagnosis and treatment were reported during the COVID-19 pandemic, leading to increased rates of diabetic ketoacidosis in children. Temporal associations between delayed hospital presentations or treatment initiations and pandemic containment measures have been reported. What this Study adds: This study found that the regional 7-days incidence of COVID-19 cases and deaths, rather than nationwide pandemic containment measures such as social distancing, were associated with risk of ketoacidosis and in children with new-onset type 1 diabetes. Contributors’ Statement Page Dr. Kamrath had the idea of this study, conceptualized the study, interpreted the analyses, drafted the initial manuscript, and reviewed and revised the manuscript. Dr. Rosenbauer conceptualized the study, analyzed the data, supervised the statistical analysis, and critically reviewed and revised the manuscript. Mr. Eckert carried out the initial analyses, and reviewed and revised the manuscript. Prof. Holl conceptualized the study, coordinated and supervised data collection, acquired funding for the study, and critically reviewed the manuscript for important intellectual content. Dr. Pappa, Dr. Reschke, Prof. Rohrer, Dr. Mönkemöller, Dr. Wurm, Dr. Hake, and Prof. Raile collected data, and critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work. Dr. Kamrath and Dr. Rosenbauer contribute equally to this study. Downloaded from©202 www.aappublications.org/news1 American Academy by of guest Pediatrics on September 25, 2021 Prepublication Release Abstract Objectives: The aim of this study was to quantify the relative risk of diabetic ketoacidosis at diagnosis of type 1 diabetes during the year 2020, and to assess whether it was associated with the regional incidence of COVID-19 cases and deaths. Methods: Multicenter cohort study based on data from the German Diabetes Prospective Follow- up Registry DPV. The monthly relative risk (RR) for ketoacidosis in 2020 was estimated from observed and expected rates in 3,238 children with new-onset type 1 diabetes. Expected rates were derived from data of 2000-2019 using a multivariable logistic trend regression model. The association between the regional incidence of COVID-19 and the rate of ketoacidosis was investigated by applying a log-binomial mixed effects model to weekly data with Germany divided into five regions. Results: The observed versus expected frequency of diabetic ketoacidosis was significantly higher from April to September and in December (mean adjusted RRs, 1.48–1.96). During the first half of 2020, each increase in the regional weekly incidence of COVID-19 by 50 cases or one death per 100,000 population was associated with an increase in the RR of diabetic ketoacidosis of 1.40 [95% CI, 1.10–1.77; p=0.006] and 1.23 [1.14–1.32; p<0.001], respectively. This association was no longer evident during the 2nd half of 2020. Conclusions: These findings suggest that the local severity of the pandemic rather than health policy measures appear to be the main reason for the increase in diabetic ketoacidosis, and therefore for the delayed use of health care during the pandemic. Introduction The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread quickly across Europe and America during March and April, 2020 (1). Within Germany, however, there were large regional differences in the number of COVID-19 cases and deaths – the South, namely the federal states of Bavaria and Baden-Württemberg, and the West, namely North Rhine-Westphalia, of Germany were particularly affected at the beginning of the pandemic (2). In response to the pandemic, nationwide health policy measures to contain the spread of SARS-CoV-2 were swiftly implemented in Germany in order to achieve social distancing, such as restrictions on social contacts, school closures, and the general recommendation to stay at home. While the rates of new cases of COVID-19 increased remarkably during March and peaked in early April, and Downloaded from©202 www.aappublications.org/news1 American Academy by of guest Pediatrics on September 25, 2021 Prepublication Release deaths related to COVID-19 peaked in mid-April in Germany, the rates declined thereafter and stabilized at lower levels in May and June (1,2). In early October, however, COVID-19 cases showed another sharp increase in a second COVID-19 wave, with a peak in late December (1,2). The pandemic has also resulted in harm to patients who were not affected by COVID-19. Admissions for health care during the pandemic have markedly