Impact of the severe acute respiratory syndrome coronavirus 2 pandemic on the incidence of type 1 diabetes mellitus in children in Yamanashi, Japan

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We documented the incidence rates of T1D in Yamanashi Prefecture, Japan, from 1986 to 2018 and expanded our analysis to include cases from 2019 to 2022 to assess the influence of coronavirus disease 2019 (COVID-19) on the incidence of T1D. The annual increase in standardized incidences of T1D among 0- to 14-year-olds was 2.089% per year from 1986 to 2019 (p = .0772) and 2.183% per year from 1986 to 2022 (p = .0331). For the 5-9 year age group, the annual increase in crude incidence from 1986 to 2019 was 6.607% per year (p < .01), and from 1986 to 2022, it was 6.270% per year (p < .001). In Yamanashi Prefecture, Japan, the incidence of pediatric T1D increased during the COVID-19 pandemic from 2020 to 2022. However, this trend was an extension of the increase prior to 2019, suggesting that no direct or indirect effect of COVID-19 on this trend was identified. Health sciences/Diseases Health sciences/Endocrinology Health sciences/Health care Health sciences/Medical research Type 1 diabetes coronavirus COVID-19 SARS-CoV-2 incidence pandemic Figures Figure 1 Figure 2 Background Type 1 diabetes (T1D) is characterized by the autoimmune-mediated destruction of pancreatic islet β-cells, leading to insufficient endogenous insulin production. Although the specific etiology and pathogenesis of T1D are incompletely understood, both genetic predispositions and environmental triggers are believed to play critical roles 1 . Studies involving monozygotic twins have underscored the genetic influence, revealing a concordance rate of 20–65% for T1D, suggesting that 35–80% of the risk may be attributed to environmental factors 2,3 . This significant environmental component is further supported by observations that genetic factors remain relatively constant within populations over time, whereas the incidence of pediatric T1D has increased, potentially implicating changing environmental conditions in its pathogenesis. Evidence supporting the impact of environmental factors on T1D incidence includes increased rates observed among immigrants relocating to areas with higher T1D incidence, such as Sweden 4 , a surge in cases following the Los Angeles earthquake 5 , and a correlation with rising obesity rates 6 . The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic introduced substantial changes to the social and physical environment of children, including lockdowns, curfews, and widespread mask usage, which varied significantly by region. These pandemic-related environmental shifts may have influenced the incidence of T1D. Additionally, among environmental factors, infections with enteroviruses and other gastrointestinal and respiratory viruses are hypothesized to be among the causes of the onset of T1D. This is attributed to virus-induced autoimmunity, which leads to β-cell damage and the production of autoantibodies, resulting in the development of T1D 7–10 . Coronavirus disease 2019 (COVID-19) affects not only the respiratory system but also the intestinal tract 11 , and SARS-CoV-2 has been detected in the β-cells of patients who died from COVID-19 12 . Another report suggested that although there was no increase in islet autoantibodies, direct and indirect damage to β-cells by SARS-CoV-2 infection has been indicated 13 . Based on these reports and hypotheses, COVID-19, a viral gastrointestinal and respiratory infection, may also have some impact on the onset of T1D. In light of these considerations, it is plausible that the multiple stresses induced by the COVID-19 pandemic, including direct viral effects and resulting societal and environmental changes, may have affected the incidence of pediatric T1D. This hypothesis is supported by a growing body of literature documenting variations in pediatric T1D incidence in different regions during the pandemic period. Objectives Our previous research documented the incidence of pediatric T1D in Yamanashi Prefecture from 1986 to 2018, providing a comprehensive baseline before the onset of the COVID-19 pandemic 14 . Building on this foundational work, our current study aimed to elucidate the impact of the COVID-19 pandemic on the incidence of pediatric T1D in the same region. To accomplish this goal, we have expanded our analysis to include newly diagnosed cases of T1D from 2019 to 2022. By integrating these additional data, we aim to: The updated incidence rates of pediatric T1D in Yamanashi Prefecture were calculated, thereby capturing the potential influence of the COVID-19 pandemic on these rates. Prepandemic (1986-2018) and pandemic (2019-2022) incidence rates were compared to identify any significant changes that may indicate an impact of the pandemic on the development of T1D in the pediatric Understanding how global health crises, such as the COVID-19 pandemic, may affect the epidemiology of chronic autoimmune diseases such as T1D is important. Through this investigation, we aimed to provide valuable insights into the interaction between pandemic-induced environmental changes and the incidence of pediatric T1D, with the ultimate goal of informing future healthcare strategies and research directions in the context of global health emergencies. Methods Data collection This study enrolled pediatric patients aged 0–14 years who were diagnosed with their first episode of T1D in Yamanashi Prefecture using a methodology consistent with our previously published work. We used three primary methods to identify new cases of T1D: A detailed examination during routine urinalysis led to a diagnosis of T1D. Collaboration with all medical institutions in Yamanashi Prefecture capable of treating pediatric patients, a total of 10 institutions, to identify first-episode T1D patients presenting for care. Enrollment data were obtained from the Medical Expense Subsidy Project for Specific Pediatric Chronic Diseases, a government support system for patients with diseases such as T1D. This subsidy project provides assistance with medical expenses to encourage enrollment among eligible patients. To ensure comprehensive case ascertainment, we cross-referenced data from these sources to minimize the risk of omitting eligible patients from our study cohort. The Medical Expense Subsidy Project for Specific Pediatric Chronic Diseases facilitates medical cost reductions for enrolled patients, which may influence patient enrollment patterns. To address potential underreporting, our collaborating institutions proactively enrolled eligible patients in the subsidy program to further ensure study inclusivity. In Yamanashi Prefecture, children with new-onset T1D must go to a medical institution where they can be hospitalized, and diabetes education is provided along with diabetes treatment in cooperation with the community and schools. Even if the patient goes to a hospital in a neighboring prefecture for treatment, the possibility of omission in this study is very low because most of them designate a medical institution in their area of residence (our collaborating medical institution) as their emergency site because ambulances cannot cross the prefecture during emergency transport. Therefore, we believe that the possibility of omission in this study is very low. Diagnosis of type 1 diabetes The diagnostic criteria for T1D in this study have changed over time, reflecting advances in the understanding and diagnosis of the disease. For all patients identified prior to 2012, the diagnosis of T1D was made by pediatricians at each participating site. These diagnoses were validated based on evidence of insulin deficiency, indicated by either a fasting serum C-peptide concentration of less than 0.5 ng/mL or a urinary C-peptide excretion of less than 20 µg/day. In addition, the presence of serum autoantibodies associated with T1D, namely, anti-glutamic acid decarboxylase (GAD) antibody, insulin autoantibody (IAA), islet antigen-2 (IA-2) antibody, and islet cell antibody (ICA), was confirmed whenever possible. After 2012, all patients met the Japan Diabetes Society diagnostic criteria for acute-onset T1DM. Patients with acute-onset T1DM were diagnosed as follows: 1) Presentation with classic symptoms of diabetes such as thirst, polydipsia, polyuria, and an expected progression to ketoacidosis within approximately three months of disease onset. 2) Anticipation of the need for continuous insulin therapy shortly after diagnosis, with an expected temporary "honeymoon period”. " 3) The presence of autoantibodies associated with T1D, specifically GAD antibodies, IA-2 antibodies, IAA, ICA, or zinc transporter 8 (ZnT8) antibodies, during the clinical course. In particular, IAA positivity must be confirmed prior to initiation of insulin therapy. 4) In patients without islet autoantibodies, a fasting serum C-peptide level less than 0.6 ng/mL indicates insufficient endogenous insulin secretion. Based on these criteria, patients meeting criteria 1, 2, and 3 were diagnosed with acute-onset (autoimmune) T1D (type 1A). Those meeting criteria 1, 2, and 4 were classified as having acute-onset T1D (type 1B). Patients meeting the criteria for fulminant onset were diagnosed with fulminant T1D. Incidence calculation We calculated the annual crude and standardized incidences of T1D in the pediatric population (aged 0–14 years) from January 1986 to December 2022. New cases of T1D were prospectively recorded during this period. The annual crude incidence (per 100,000 persons) was determined for each predefined age subgroup (0–4 years, 5–9 years and 10–14 years) by dividing the number of new T1D cases by the corresponding population of the age group, with population data obtained from the Japanese National Census (Statistics Bureau, Japan; Top Page > Browse Statistics > Population Estimates > File; https://www.e-stat.go.jp/en/stat-search/files?page=1&layout=normal&toukei=00200524&tstat=000000090001&metadata=1&data=1 ). The standardized incidence for the 0–14 year age group was calculated using the following formula, where the crude incidence for the subgroups was weighted by the Segi standard world population 15 : Standardized incidence for ages 0–14 = \(\frac{{\sum }_{i=1}^{3}Nipi}{{\sum }_{i=1}^{3}Ni}\) Here, Ni is the standard population number for each age group according to Segi, and pi is the respective crude incidence for the age groups 0–4 years ( p1 ), 5–9 years ( p2 ), and 10–14 years ( p3 ). Diagnosis of Diabetic Ketoacidosis In this study, an effort was made to track the occurrence of diabetic ketoacidosis (DKA) at the initial onset of T1D as thoroughly as possible. The diagnostic criteria for DKA were based on the guidelines of the Japan Diabetes Society. A diagnosis of DKA was considered when patients presented with blood glucose levels ≥ 250 mg/dL, elevated beta-hydroxybutyrate, arterial blood pH ≤ 7.30, and bicarbonate levels ≤ 18 mEq/L. The final diagnosis of DKA was made by the treating physician after confirmation that the criteria were met. Statistical analysis To evaluate temporal changes in T1D incidence both before and during the COVID-19 pandemic (2020–2022), we defined two periods for comparison: 1986–2019 and 1986–2022. Poisson regression analysis was used to assess annual incidence trends, with 95% confidence intervals (CIs) calculated for the annual increase in both crude and standardized incidence. Differences in annual incidence trends between the two periods were tested using z tests, while χ-squared tests were used to compare the incidence of DKA before and during the pandemic. All the statistical analyses were performed with R software, version 4.3.2 ( https://www.R-project.org/ ). A p value of < .05 was considered indicative of statistical significance. Due to the lack of additional ethics committee approval to conduct COVID-19 studies, it was not possible to investigate the presence of COVID-19 infection in the initial patients. Ethical considerations This study was rigorously reviewed and approved by the Institutional Review Board (IRB) of the University of Yamanashi School of Medicine (IRB No: 2020–2215, entitled "Investigation of the Total Number of Pediatric Patients with Type 1 Diabetes Mellitus in Yamanashi Prefecture"). An anonymized dataset was used for patient data collection to protect patient privacy. The opt-out method was used to obtain informed consent, and informational posters were displayed at participating hospitals to allow patients and guardians to decline participation. All study procedures were carefully designed and conducted in accordance with the tenets of the Declaration of Helsinki, ensuring the highest standards of ethical conduct in medical research. Results During the study period from January 1986 to December 2022, a total of 120 pediatric patients who were diagnosed with T1D were enrolled in this study. By 2018, 99 patients were enrolled, and an additional 21 patients (consisting of 9 boys and 12 girls) were enrolled from 2019 to 2022. The sex distribution of the entire cohort consisted of 53 boys and 67 girls (Table 1). In 2019, during the recruitment of new patients under the Medical Expense Subsidy Project for Specific Pediatric Chronic Diseases, a discrepancy was noted in the identification of a male patient who had not previously been seen by our collaborating medical institutions. It was inferred that this patient sought treatment at a hospital in Tokyo, as inferred from the place of registration for subsidized medical expenses. However, due to the noncollaboration status of this hospital with our study and the subsequent inability to conduct a survey, this patient was excluded from our analysis. Therefore, we estimated the case detection rate for our study to be 99.17%, reflecting a comprehensive capture of T1D cases in Yamanashi Prefecture during the study period. Standardized and Crude Incidence The standardized incidences of T1D among individuals aged 0–14 years showed variability during the COVID-19 pandemic period, with incidences of 7.13, 1.84, 2.49, and 5.73 per 100,000 people in 2019, 2020, 2021, and 2022, respectively (Table 1). From 1986 to 2019, the annual increase in the standardized incidence was 2.089% (p = .0772, 95% CI -0.212 to 4.433%/year, standard deviation = .02089). This trend continued into the pandemic period (1986–2022), with an annual increase of 2.183% (p = .0331, 95% CI 0.190 to 4.216%/year, standard deviation = .01025) (Fig. 1). However, a z test comparing the annual rates of increase between the two periods showed no significant difference (p = .952). Analysis by age group showed that the 0–4 year age group maintained a trend similar to that in our previous reports, with a minimal number of cases and no discernible trend from 1986 to 2022. For the 5–9 year age group, the crude incidence increased by 6.607%/year from 1986 to 2019 (p < .01, 95% CI 3.869 to 9.520%/year, standard deviation = .01437) and slightly decreased to 6.270%/year from 1986 to 2022 (p < .001, 95% CI 3.955 to 8.725%/year, standard deviation = .01213), with no significant difference detected between the two periods (p = .858). For the 10–14 year age group, there was an increase from 0.39%/year (p = .651) to 1.09%/year (p = .146) over the same time periods, indicating a nonsignificant increase. Occurrence of Diabetic Ketoacidosis During the 2020–2022 COVID-19 pandemic, 21.4% (3 of 14) of new T1D patients presented with DKA at onset, with the following distribution across age groups: one each in the 0–4, 5–9, and 10–14 age groups. Compared to the prepandemic period (2012–2019), where 25.9% (7 of 27) of patients presented with DKA, the distribution indicated a greater frequency in the 10–14 age group (5 patients). A χ-squared test was used to assess the difference in the proportion of patients who presented with DKA between these two periods (p = 1.0). Discussion Annual increase in incidence in Yamanashi Prefecture According to the analysis of incidence rates from 1986 to 2019 and from 1986 to 2022, significant increases in T1D incidence were observed in the 5–9 year age group for both time periods. However, there was no significant increase in the annual rate of increase in the crude incidence of T1D in the other age groups. The annual rate of increase in standardized incidence in the 0–14 year age group showed an increasing trend from 1986 to 2019, and a significant increase was observed from 1986 to 2022, although the annual rate of increase for these two periods was not significantly different. These results suggest that the COVID-19 pandemic did not significantly alter the incidence of T1D in Yamanashi Prefecture from 2020 to 2022. Furthermore, as previously reported by our group, the trend of young children developing T1D seems to persist throughout the pandemic. A study of pediatric T1D incidence in Oita Prefecture reported an annual increase in T1D incidence of 4.7%. Notably, the Oita study did not find a trend for younger age groups to develop T1D 16 . The difference between the annual increase rates for the 0–14 age group in Oita and Yamanashi prefectures is due to statistical variability, probably caused by the small number of cases in both regions. In fact, the 95% confidence intervals for the annual increase rates in Oita (1.7–7.8%) and Yamanashi (0.2–4.2%) prefectures overlap significantly, indicating no substantial difference between the two. Comparative data from South Korea revealed an incidence of 3.70 per 100,000 people in 2008, with an annual increase of 3–4% from 2008 to 2014 17 . This suggests that the trends observed in these Japanese prefectures are not significantly different from those observed in South Korea, suggesting the possibility of regional similarities in T1D incidence trends in the Asian region. Globally, a younger age of onset of T1D is associated with regions with a lower incidence 18 . It has been hypothesized that the age of onset may be younger in Yamanashi Prefecture, which has a lower incidence rate than Oita Prefecture. However, the limited number of patients in our study makes this speculation inconclusive. Impact during the pandemic in Yamanashi Prefecture Analysis of the standardized incidence of T1D among 0- to 14-year-olds from 2020 to 2022 revealed notable fluctuations, with particularly low rates in 2020 and 2021, followed by a significant increase in 2022 (Fig. 1). This trend is consistent with the sharp decline in viral infections during the early years of the COVID-19 pandemic, which was attributed to the widespread use of masks and outdoor restrictions. Data from the National Institute of Infectious Diseases in Japan support this observation, showing a marked decrease in reported cases of influenzavirus and most enteroviruses during this period. An exception was coxsackievirus A6 (CVA6), which, despite a decrease in reported cases before the pandemic, increased in 2021 and 2022 (Influenzavirus; https://kansen-levelmap.mhlw.go.jp/Byogentai/Pdf/data2j.pdf , Enterovirus; https://kansen-levelmap.mhlw.go.jp/Byogentai/Pdf/data16j.pdf , https://kansen-levelmap.mhlw.go.jp/Byogentai/Pdf/data24j.pdf , https://kansen-levelmap.mhlw.go.jp/Byogentai/Pdf/data26j.pdf , https://kansen-levelmap.mhlw.go.jp/Byogentai/Pdf/data18j.pdf , https://kansen-levelmap.mhlw.go.jp/Byogentai/Pdf/data149j.pdf ). The potential impact of a small outbreak of coxsackievirus type A6 (CVA6) on the increased incidence of T1D in 2022 was considered. However, despite numerous reports linking coxsackievirus type B (CVB) to the onset of T1D 19 , there is little evidence to support the involvement of coxsackievirus type A (CVA) in the development of this disease. Therefore, we postulated that the contribution of this small CVA6 outbreak to the increase in T1D incidence in 2022 is likely to be insignificant. COVID-19 case data from the Yamanashi Prefectural Center for Infectious Diseases ( https://www.pref.yamanashi.jp.e.aao.hp.transer.com/kansensho_portal/index.html ; Home > Announcement from Yamanashi Prefecture CDC > Dissemination of Information > Analysis and Dissemination Materials (YCDC Report) > COVID-19 infection/infection status by age > All periods (PDF:337KB); https://www.pref.yamanashi.jp.e.aao.hp.transer.com/documents/101638/nendaibetu.pdf ) revealed a clear pattern in the emergence of COVID-19 cases over the course of the pandemic. While the number of COVID-19 cases in the prefecture was minimal in 2020 and 2021, a marked increase was observed in 2022 (Japanese era name; Reiwa 4), especially among children and adolescents under 10 years of age, with 4847 and 4586 cases reported in August and 2022, respectively. This increase in COVID-19 cases continued after August, a critical time for public health in our prefecture. When these results are contrasted with the T1D incidences, the distribution of T1D cases in 2022 did not coincide with the timing of the surge in COVID-19 cases. Specifically, there was one patient in January, two each in April, May, and June, one in September, and one in November. This distribution suggested that the increase in the number of pediatric T1D patients in Yamanashi Prefecture preceded the most rapid increase in the number of COVID-19 patients (after July 2022) (Fig. 2). This pattern is similar to observations in Scotland, where no direct correlation was found between the COVID-19 epidemic and the increase in T1D cases 20 . Year-to-year fluctuations in T1D cases in Yamanashi Prefecture have been observed since before the pandemic, suggesting that the fluctuations in T1D incidence from 2020 to 2022 are likely part of a continuing trend rather than a pandemic-induced deviation. This assertion is supported by the timing and nature of the emergence of COVID-19 cases in Yamanashi Prefecture, suggesting that the direct impact of the pandemic on T1D incidence may be limited. In addition, the analysis of SARS-CoV-2 variants during the pandemic, as reported by the Genome Analysis Center at our institution (Yamanashi Prefectural Central Hospital) 21 , did not reveal any discernible pattern suggesting a correlation between specific SARS-CoV-2 variants and T1D incidence (Fig. 2). This further supports the notion that the observed increase in T1D cases, especially in 2022, may not be directly attributable to the COVID-19 pandemic or specific viral variants. Yamanashi Prefecture's response to the COVID-19 pandemic included a state of emergency from April 16, 2020, to May 14, 2020, followed by priority measures to prevent the spread of disease from August 20, 2021, to September 12, 2021. Analysis of the number of T1D cases during these periods did not show any significant fluctuations corresponding to these public health measures. This suggests that while measures were critical for controlling the spread of COVID-19, they did not directly affect the incidence of T1D within the prefecture. DKA during the pandemic During the COVID-19 pandemic, an increase in the incidence of DKA at the time of initial illness was reported worldwide, possibly because of a decline in hospital functionality and patient reluctance to seek medical care 22 . However, our analysis in Yamanashi Prefecture reveals a contrasting scenario. In the three-year period from 2020 to 2022, coinciding with the pandemic, there was no significant difference in the number of pediatric patients who presented with DKA at the onset of illness compared with that in the prepandemic period from 2012 to 2019. This observation is noteworthy in the context of public health responses in larger metropolitan areas, such as Tokyo and Osaka, where states of emergency were declared 4 times and priority preventive measures were implemented 3 or 4 times against COVID-19 from 2020 to 2022. In contrast, Yamanashi Prefecture, with a comparatively smaller population, implemented each measure only once. This suggests that the smaller population size and perhaps more manageable COVID-19 case load in Yamanashi Prefecture facilitated more effective epidemic control, thereby minimizing disruptions to the functioning of the healthcare system and mitigating patients' reluctance to seek medical care. As a result, the expected increase in DKA cases at the onset of the outbreak, which is commonly observed in regions with a greater burden on the healthcare system, was not observed in Yamanashi Prefecture. This finding indirectly supports the hypothesis that the observed increase in DKA incidence in other regions may be due to the combined effects of decreased hospital accessibility and patients' reluctance to seek timely medical intervention. Limitations The main limitation of this study is the small number of T1D patients. This reflects the low incidence of T1D in Japan and the small population of Yamanashi Prefecture. This limitation is important because it may inherently affect the fact that the COVID-19 epidemic had no statistically significant effect on T1D incidence; the inability to measure islet autoantibodies prior to T1D onset or to track SARS-CoV-2 infection history in newly diagnosed patients further limits our understanding. In particular, our insight into the proportion of individuals who develop T1D after SARS-CoV-2 infection is limited, which may obscure the subtle relationship between the pandemic and the incidence of T1D. Conclusion In Yamanashi Prefecture, the association between T1D incidence and the COVID-19 pandemic from 2020 to 2022 during the pandemic was considered to be small. In addition, as mentioned above, there was little change in the rate of increase in standardized incidence among 0- to 14-year-olds from 1986 to 2019, before the pandemic, and from 1986 to 2022, including the pandemic. In other words, although incidences increased during the pandemic, this increase followed the prepandemic trend. This pattern is consistent with observations from Scotland 20 , Denmark 23 , Germany 24 , and Oita Prefecture, Japan 16 . Despite the unprecedented global impact of the COVID-19 pandemic, it is likely that the pandemic did not have a significant direct or indirect effect on the incidence of pediatric T1D in these regions. In Yamanashi Prefecture, as well as in the aforementioned locations, the data suggest that factors contributing to the increasing incidence of T1D predate the pandemic and may involve a complex interplay of genetic, environmental and possibly other viral influences not directly related to SARS-CoV-2. This finding is important because it highlights the need to continue investigating the multifactorial causes of T1D beyond the scope of the COVID-19 pandemic. In light of these findings, it is imperative that future research delve deeper into understanding the drivers behind the increasing incidence of pediatric T1D, examining not only the impact of infectious diseases but also broader environmental and genetic factors. Such studies will be critical in developing targeted interventions and preventive measures to curb the rising trend of T1D worldwide. In addition, the experience of managing chronic diseases such as T1D during the pandemic provides valuable lessons for health systems worldwide and underscores the importance of maintaining accessible and effective care even during public health crises. In conclusion, while the COVID-19 pandemic has affected many aspects of health care and disease dynamics, its impact on the incidence of pediatric T1D in Yamanashi Prefecture appears to have been negligible. This underscores the importance of having a comprehensive perspective to understand and address the challenges associated with T1D. Declarations Funding statement The authors have no funding to declare. Conflict of interest disclosure The authors declare no conflicts of interest associated with this manuscript. Ethics approval statement The study was approved by the Institutional Review Board of the School of Medicine of Yamanashi University (IRB number: 2020-2215, titled "Investigation of the Total Number of Pediatric Patients with Type 1 Diabetes Mellitus in Yamanashi Prefecture"). Patient consent statement All study participants provided informed consent that was obtained in the form of opt-out. Author contributions Tomohi.S., Ko.K., and S.A. designed the study. Hiro.Y. did the statistical analysis. Tomohi.S. wrote the manuscript. Ko.K., Ki.K., M.M., and S.A. provided clinical advice. All the authors have read and approved the final manuscript. References Ilonen, J., Lempainen, J. & Veijola, R. The heterogeneous pathogenesis of type 1 diabetes mellitus. Nat. Rev. Endocrinol. 15 , 635-650 (2019). Redondo, M.J. et al. Genetic determination of islet cell autoimmunity in monozygotic twins. BMJ 318 , 698-702 (1999). Redondo, M.J. et al. 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Infections in early life and development of type 1 diabetes. JAMA 315, 1899-1901 (2016). Lönnrot, M. et al. Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: the TEDDY study. Diabetologia 60 , 1931-1940 (2017). Lamers, M.M. et al. SARS-CoV-2 productively infects human gut enterocytes. Science 369 , 50-54 (2020). Steenblock, C. et al. Viral infiltration of pancreatic islets in patients with COVID-19. Nat. Commun. 12 , 3534 (2021). Ben Nasr, M. et al. Indirect and direct effects of SARS-CoV-2 on human pancreatic islets. Diabetes 71 , 1579-1590 (2022). Saito, T. et al. Incidence of childhood type 1 diabetes mellitus in Yamanashi Prefecture, Japan, 1986-2018. Endocrinol. Diabetes Metab. 4 (2), e00214 (2020). Segi, M. Cancer mortality for selected sites in 24 countries (1950-57). Department of Public Health, Tohoku University of Medicine, Sendai. Matsuda, F., Itonaga, T., Maeda, M. & Ihara, K. Long-term trends of pediatric type 1 diabetes incidence in Japan before and after the COVID-19 pandemic. Sci. Rep. 13, 5803 (2023). Kim, J.H. et al. Increasing incidence of type 1 diabetes among Korean children and adolescents: analysis of data from a nationwide registry in Korea. Pediatr. Diabetes 17 , 519-524 (2016). Patterson, C.C. et al. Incidence trends for childhood type 1 diabetes in Europe during 1989-2003. Lancet 373 , 2027-2033 (2009). Carré, A. et al. Coxsackievirus and type 1 diabetes: Diabetogenic mechanisms and implications for research. Endocr. Rev. 44 , 737-751 (2023). McKeigue, P.M. et al. Relationship of incident type 1 diabetes to recent COVID-19 infection: Cohort study using e-health record linkage in Scotland. Diabetes Care 46 , 921-928 (2023). Hirotsu, Y. et al. Lung tropism in hospitalized patients following infection with SARS-CoV-2 variants from D614G to Omicron BA.2. Nat. Med. 3 , 32 (2023). Elgenidy, A. et al. Incidence of diabetic ketoacidosis during COVID-19 pandemic: a meta-analysis of 124,597 children with diabetes. Pediatr. Res. 93 , 1149-1160 (2023). Noorzae, R. et al. Risk of type 1 diabetes in children is not increased after SARS-CoV-2 infection: A nationwide prospective study in Denmark. Diabetes Care 46 , 1261-1264 (2023). Tittel, S.R. et al. Did the COVID-19 lockdown affect the incidence of pediatric type 1 diabetes in Germany? Diabetes Care 43 , e172-e173 (2020). Table Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.xlsx Table 1. Number of cases of type 1 diabetes and incidence (per 100,000 person-years) among children in each age group from 1986 to 2022. Cite Share Download PDF Status: Published Journal Publication published 02 Jan, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 18 Jul, 2024 Reviews received at journal 17 Jul, 2024 Reviewers agreed at journal 10 Jul, 2024 Reviews received at journal 27 Jun, 2024 Reviewers agreed at journal 13 Jun, 2024 Reviews received at journal 15 May, 2024 Reviewers agreed at journal 15 May, 2024 Reviewers invited by journal 02 Apr, 2024 Editor assigned by journal 02 Apr, 2024 Editor invited by journal 02 Apr, 2024 Submission checks completed at journal 01 Apr, 2024 First submitted to journal 16 Mar, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4114246","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":280366422,"identity":"1a282daa-238a-4734-8aac-dc35872bd539","order_by":0,"name":"Tomohiro Saito","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/UlEQVRIiWNgGAWjYLCCBAYGOTibDUzx4FYNlkpIYDAmUQvQmsQGhI0EgD17+8MPD3/YpG84fjrxc0FNXR4fA/PDDwwyd3DbwnPGWCIhIS13w5nczdIzjh0uZmNgM5Zg4HmGW4tEDgNQy+HcDQdyN0jzsB1IbGNgMAOKH8ajJf3xD6CWdIPzbzf/5vlXB9TC/o2AlgQzkC0JBjdyt0nztjEDtfAQsOXMGTOLhLQ0w5k33m6z5u07nNjGzFMskYDHL+zt7Y9v/rCxkec7n7v5Ns+3usT57e0bP3zswR1icKBwAMZiBuLEngM4VcKBfAMK9wcRWkbBKBgFo2CkAAChn1UJP3tVggAAAABJRU5ErkJggg==","orcid":"","institution":"University of Yamanashi","correspondingAuthor":true,"prefix":"","firstName":"Tomohiro","middleName":"","lastName":"Saito","suffix":""},{"id":280366423,"identity":"3ff4fed1-0ff7-44c2-a960-0ad634da9b20","order_by":1,"name":"Mie Mochizuki","email":"","orcid":"","institution":"University of Yamanashi","correspondingAuthor":false,"prefix":"","firstName":"Mie","middleName":"","lastName":"Mochizuki","suffix":""},{"id":280366424,"identity":"bac9c1d0-c26a-42a8-9141-608aa35ff270","order_by":2,"name":"Kisho Kobayashi","email":"","orcid":"","institution":"University of Yamanashi","correspondingAuthor":false,"prefix":"","firstName":"Kisho","middleName":"","lastName":"Kobayashi","suffix":""},{"id":280366425,"identity":"647c9372-9d2b-4566-9aba-821e59c034e4","order_by":3,"name":"Hiromune Narusawa","email":"","orcid":"","institution":"University of Yamanashi","correspondingAuthor":false,"prefix":"","firstName":"Hiromune","middleName":"","lastName":"Narusawa","suffix":""},{"id":280366426,"identity":"88061af2-e825-4e38-baf5-635b9ef81249","order_by":4,"name":"Daisuke Watanabe","email":"","orcid":"","institution":"University of Yamanashi","correspondingAuthor":false,"prefix":"","firstName":"Daisuke","middleName":"","lastName":"Watanabe","suffix":""},{"id":280366427,"identity":"668e3964-7639-457e-9108-6c002b336816","order_by":5,"name":"Koichi Makino","email":"","orcid":"","institution":"University of Yamanashi","correspondingAuthor":false,"prefix":"","firstName":"Koichi","middleName":"","lastName":"Makino","suffix":""},{"id":280366428,"identity":"3b2c91b2-ff01-4a99-b613-f1405d7dc05a","order_by":6,"name":"Hideaki Yagasaki","email":"","orcid":"","institution":"University of Yamanashi","correspondingAuthor":false,"prefix":"","firstName":"Hideaki","middleName":"","lastName":"Yagasaki","suffix":""},{"id":280366429,"identity":"98e24cdc-acc2-462d-9352-e25bf66da66a","order_by":7,"name":"Kazumasa Sato","email":"","orcid":"","institution":"University of Yamanashi","correspondingAuthor":false,"prefix":"","firstName":"Kazumasa","middleName":"","lastName":"Sato","suffix":""},{"id":280366430,"identity":"6f3647b4-62bb-4565-ac90-7af2f733be05","order_by":8,"name":"Tomoaki Sano","email":"","orcid":"","institution":"University of Yamanashi","correspondingAuthor":false,"prefix":"","firstName":"Tomoaki","middleName":"","lastName":"Sano","suffix":""},{"id":280366431,"identity":"dfa33e0b-f149-4704-af34-58677c5a9f01","order_by":9,"name":"Masanori Ohta","email":"","orcid":"","institution":"University of Yamanashi","correspondingAuthor":false,"prefix":"","firstName":"Masanori","middleName":"","lastName":"Ohta","suffix":""},{"id":280366432,"identity":"3a8e4c94-c4de-40dc-a58e-8a618f6cf04b","order_by":10,"name":"Hiroshi Yokomichi","email":"","orcid":"","institution":"University of Yamanashi","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Yokomichi","suffix":""},{"id":280366433,"identity":"a9acd80f-9d92-4301-b3a1-a6f756642fe3","order_by":11,"name":"Shin Amemiya","email":"","orcid":"","institution":"Saitama Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shin","middleName":"","lastName":"Amemiya","suffix":""},{"id":280366434,"identity":"29ea5576-28e1-4455-af7e-914282c93d74","order_by":12,"name":"Koji Kobayashi","email":"","orcid":"","institution":"University of Yamanashi","correspondingAuthor":false,"prefix":"","firstName":"Koji","middleName":"","lastName":"Kobayashi","suffix":""}],"badges":[],"createdAt":"2024-03-16 17:46:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4114246/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4114246/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-84654-z","type":"published","date":"2025-01-02T15:57:50+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":53507949,"identity":"0d7d0583-53fb-4e84-8359-e41c45b6b30a","added_by":"auto","created_at":"2024-03-26 20:49:47","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":570953,"visible":true,"origin":"","legend":"\u003cp\u003eThe standardized incidence of type 1 diabetes among 0- to 14-year-old children in Yamanashi Prefecture between 1986 and 2022 was 2.18% (p = .033, n = 120, Poisson regression test).\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4114246/v1/e161f97f0b5f71a6d715d304.jpg"},{"id":53508509,"identity":"0c80542d-d5b9-49cb-bfa2-b30ea82d7705","added_by":"auto","created_at":"2024-03-26 20:57:47","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":375904,"visible":true,"origin":"","legend":"\u003cp\u003eThe dotted bars represent the number of COVID-19 patients aged 0-9 years, and the solid bars represent the number of COVID-19 patients aged 10-19 years. One asterisk represents a patient with T1D.\u003c/p\u003e\n\u003cp\u003eD614G, alpha, delta, BA.1.1, and BA.2 represent SARS-CoV-2 variants.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4114246/v1/b05f0edcd12cdd33209aea0e.jpg"},{"id":73093421,"identity":"95e6536d-142a-46f9-82d3-2c2b27e41097","added_by":"auto","created_at":"2025-01-06 16:17:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1437712,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4114246/v1/f70699c4-6cc8-416b-ae5a-631cd06a4c67.pdf"},{"id":53507951,"identity":"e3b1720b-0854-48f9-992b-6b1ed0160e46","added_by":"auto","created_at":"2024-03-26 20:49:47","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":12371,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1.\u003c/p\u003e\n\u003cp\u003eNumber of cases of type 1 diabetes and incidence (per 100,000 person-years) among children in each age group from 1986 to 2022.\u003c/p\u003e","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4114246/v1/9bbc5279ba24831de7d6b82a.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of the severe acute respiratory syndrome coronavirus 2 pandemic on the incidence of type 1 diabetes mellitus in children in Yamanashi, Japan","fulltext":[{"header":"Background","content":"\u003cp\u003eType 1 diabetes (T1D) is characterized by the autoimmune-mediated destruction of pancreatic islet \u0026beta;-cells, leading to insufficient endogenous insulin production. Although the specific etiology and pathogenesis of T1D are incompletely understood, both genetic predispositions and environmental triggers are believed to play critical roles\u003csup\u003e1\u003c/sup\u003e. Studies involving monozygotic twins have underscored the genetic influence, revealing a concordance rate of 20\u0026ndash;65% for T1D, suggesting that 35\u0026ndash;80% of the risk may be attributed to environmental factors\u003csup\u003e2,3\u003c/sup\u003e. This significant environmental component is further supported by observations that genetic factors remain relatively constant within populations over time, whereas the incidence of pediatric T1D has increased, potentially implicating changing environmental conditions in its pathogenesis.\u003c/p\u003e\n\u003cp\u003eEvidence supporting the impact of environmental factors on T1D incidence includes increased rates observed among immigrants relocating to areas with higher T1D incidence, such as Sweden\u003csup\u003e4\u003c/sup\u003e, a surge in cases following the Los Angeles earthquake\u003csup\u003e5\u003c/sup\u003e, and a correlation with rising obesity rates\u003csup\u003e6\u003c/sup\u003e. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic introduced substantial changes to the social and physical environment of children, including lockdowns, curfews, and widespread mask usage, which varied significantly by region. These pandemic-related environmental shifts may have influenced the incidence of T1D.\u003c/p\u003e\n\u003cp\u003eAdditionally, among environmental factors, infections with enteroviruses and other gastrointestinal and respiratory viruses are hypothesized to be among the causes of the onset of T1D. This is attributed to virus-induced autoimmunity, which leads to \u0026beta;-cell damage and the production of autoantibodies, resulting in the development of T1D\u003csup\u003e7\u0026ndash;10\u003c/sup\u003e. Coronavirus disease 2019 (COVID-19) affects not only the respiratory system but also the intestinal tract\u003csup\u003e11\u003c/sup\u003e, and SARS-CoV-2 has been detected in the \u0026beta;-cells of patients who died from COVID-19\u003csup\u003e12\u003c/sup\u003e. Another report suggested that although there was no increase in islet autoantibodies, direct and indirect damage to \u0026beta;-cells by SARS-CoV-2 infection has been indicated\u003csup\u003e13\u003c/sup\u003e. Based on these reports and hypotheses, COVID-19, a viral gastrointestinal and respiratory infection, may also have some impact on the onset of T1D.\u003c/p\u003e\n\u003cp\u003eIn light of these considerations, it is plausible that the multiple stresses induced by the COVID-19 pandemic, including direct viral effects and resulting societal and environmental changes, may have affected the incidence of pediatric T1D. This hypothesis is supported by a growing body of literature documenting variations in pediatric T1D incidence in different regions during the pandemic period.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur previous research documented the incidence of pediatric T1D in Yamanashi Prefecture from 1986 to 2018, providing a comprehensive baseline before the onset of the COVID-19 pandemic\u003csup\u003e14\u003c/sup\u003e. Building on this foundational work, our current study aimed to elucidate the impact of the COVID-19 pandemic on the incidence of pediatric T1D in the same region. To accomplish this goal, we have expanded our analysis to include newly diagnosed cases of T1D from 2019 to 2022. By integrating these additional data, we aim to:\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003eThe updated incidence rates of pediatric T1D in Yamanashi Prefecture were calculated, thereby capturing the potential influence of the COVID-19 pandemic on these rates.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePrepandemic (1986-2018) and pandemic (2019-2022) incidence rates were compared to identify any significant changes that may indicate an impact of the pandemic on the development of T1D in the pediatric\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eUnderstanding how global health crises, such as the COVID-19 pandemic, may affect the epidemiology of chronic autoimmune diseases such as T1D is important.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eThrough this investigation, we aimed to provide valuable insights into the interaction between pandemic-induced environmental changes and the incidence of pediatric T1D, with the ultimate goal of informing future healthcare strategies and research directions in the context of global health emergencies.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eData collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study enrolled pediatric patients aged 0\u0026ndash;14 years who were diagnosed with their first episode of T1D in Yamanashi Prefecture using a methodology consistent with our previously published work. We used three primary methods to identify new cases of T1D:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003e\n \u003cp\u003eA detailed examination during routine urinalysis led to a diagnosis of T1D.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eCollaboration with all medical institutions in Yamanashi Prefecture capable of treating pediatric patients, a total of 10 institutions, to identify first-episode T1D patients presenting for care.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eEnrollment data were obtained from the Medical Expense Subsidy Project for Specific Pediatric Chronic Diseases, a government support system for patients with diseases such as T1D. This subsidy project provides assistance with medical expenses to encourage enrollment among eligible patients.\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eTo ensure comprehensive case ascertainment, we cross-referenced data from these sources to minimize the risk of omitting eligible patients from our study cohort. The Medical Expense Subsidy Project for Specific Pediatric Chronic Diseases facilitates medical cost reductions for enrolled patients, which may influence patient enrollment patterns. To address potential underreporting, our collaborating institutions proactively enrolled eligible patients in the subsidy program to further ensure study inclusivity.\u003c/p\u003e\n\u003cp\u003eIn Yamanashi Prefecture, children with new-onset T1D must go to a medical institution where they can be hospitalized, and diabetes education is provided along with diabetes treatment in cooperation with the community and schools. Even if the patient goes to a hospital in a neighboring prefecture for treatment, the possibility of omission in this study is very low because most of them designate a medical institution in their area of residence (our collaborating medical institution) as their emergency site because ambulances cannot cross the prefecture during emergency transport. Therefore, we believe that the possibility of omission in this study is very low.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiagnosis of type 1 diabetes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe diagnostic criteria for T1D in this study have changed over time, reflecting advances in the understanding and diagnosis of the disease. For all patients identified prior to 2012, the diagnosis of T1D was made by pediatricians at each participating site. These diagnoses were validated based on evidence of insulin deficiency, indicated by either a fasting serum C-peptide concentration of less than 0.5 ng/mL or a urinary C-peptide excretion of less than 20 \u0026micro;g/day. In addition, the presence of serum autoantibodies associated with T1D, namely, anti-glutamic acid decarboxylase (GAD) antibody, insulin autoantibody (IAA), islet antigen-2 (IA-2) antibody, and islet cell antibody (ICA), was confirmed whenever possible.\u003c/p\u003e\n\u003cp\u003eAfter 2012, all patients met the Japan Diabetes Society diagnostic criteria for acute-onset T1DM. Patients with acute-onset T1DM were diagnosed as follows:\u003c/p\u003e\n\u003cp\u003e1) Presentation with classic symptoms of diabetes such as thirst, polydipsia, polyuria, and an expected progression to ketoacidosis within approximately three months of disease onset. 2) Anticipation of the need for continuous insulin therapy shortly after diagnosis, with an expected temporary \u0026quot;honeymoon period\u0026rdquo;. \u0026quot; 3) The presence of autoantibodies associated with T1D, specifically GAD antibodies, IA-2 antibodies, IAA, ICA, or zinc transporter 8 (ZnT8) antibodies, during the clinical course. In particular, IAA positivity must be confirmed prior to initiation of insulin therapy. 4) In patients without islet autoantibodies, a fasting serum C-peptide level less than 0.6 ng/mL indicates insufficient endogenous insulin secretion.\u003c/p\u003e\n\u003cp\u003eBased on these criteria, patients meeting criteria 1, 2, and 3 were diagnosed with acute-onset (autoimmune) T1D (type 1A). Those meeting criteria 1, 2, and 4 were classified as having acute-onset T1D (type 1B). Patients meeting the criteria for fulminant onset were diagnosed with fulminant T1D.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIncidence calculation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe calculated the annual crude and standardized incidences of T1D in the pediatric population (aged 0\u0026ndash;14 years) from January 1986 to December 2022. New cases of T1D were prospectively recorded during this period. The annual crude incidence (per 100,000 persons) was determined for each predefined age subgroup (0\u0026ndash;4 years, 5\u0026ndash;9 years and 10\u0026ndash;14 years) by dividing the number of new T1D cases by the corresponding population of the age group, with population data obtained from the Japanese National Census (Statistics Bureau, Japan; Top Page\u0026thinsp;\u0026gt;\u0026thinsp;Browse Statistics\u0026thinsp;\u0026gt;\u0026thinsp;Population Estimates\u0026thinsp;\u0026gt;\u0026thinsp;File; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.e-stat.go.jp/en/stat-search/files?page=1\u0026amp;layout=normal\u0026amp;toukei=00200524\u0026amp;tstat=000000090001\u0026amp;metadata=1\u0026amp;data=1\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe standardized incidence for the 0\u0026ndash;14 year age group was calculated using the following formula, where the crude incidence for the subgroups was weighted by the Segi standard world population\u003csup\u003e15\u003c/sup\u003e:\u003c/p\u003e\n\u003cp\u003eStandardized incidence for ages 0\u0026ndash;14 =\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\frac{{\\sum }_{i=1}^{3}Nipi}{{\\sum }_{i=1}^{3}Ni}\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003cp\u003eHere, \u003cem\u003eNi\u003c/em\u003e is the standard population number for each age group according to Segi, and \u003cem\u003epi\u003c/em\u003e is the respective crude incidence for the age groups 0\u0026ndash;4 years (\u003cem\u003ep1\u003c/em\u003e), 5\u0026ndash;9 years (\u003cem\u003ep2\u003c/em\u003e), and 10\u0026ndash;14 years (\u003cem\u003ep3\u003c/em\u003e).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eDiagnosis of Diabetic Ketoacidosis\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eIn this study, an effort was made to track the occurrence of diabetic ketoacidosis (DKA) at the initial onset of T1D as thoroughly as possible. The diagnostic criteria for DKA were based on the guidelines of the Japan Diabetes Society. A diagnosis of DKA was considered when patients presented with blood glucose levels\u0026thinsp;\u0026ge;\u0026thinsp;250 mg/dL, elevated beta-hydroxybutyrate, arterial blood pH\u0026thinsp;\u0026le;\u0026thinsp;7.30, and bicarbonate levels\u0026thinsp;\u0026le;\u0026thinsp;18 mEq/L. The final diagnosis of DKA was made by the treating physician after confirmation that the criteria were met.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eTo evaluate temporal changes in T1D incidence both before and during the COVID-19 pandemic (2020\u0026ndash;2022), we defined two periods for comparison: 1986\u0026ndash;2019 and 1986\u0026ndash;2022. Poisson regression analysis was used to assess annual incidence trends, with 95% confidence intervals (CIs) calculated for the annual increase in both crude and standardized incidence. Differences in annual incidence trends between the two periods were tested using z tests, while \u0026chi;-squared tests were used to compare the incidence of DKA before and during the pandemic. All the statistical analyses were performed with R software, version 4.3.2 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.R-project.org/\u003c/span\u003e\u003c/span\u003e). A p value of \u0026lt;\u0026thinsp;.05 was considered indicative of statistical significance.\u003c/p\u003e\u003cp\u003eDue to the lack of additional ethics committee approval to conduct COVID-19 studies, it was not possible to investigate the presence of COVID-19 infection in the initial patients.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEthical considerations\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThis study was rigorously reviewed and approved by the Institutional Review Board (IRB) of the University of Yamanashi School of Medicine (IRB No: 2020\u0026ndash;2215, entitled \u0026quot;Investigation of the Total Number of Pediatric Patients with Type 1 Diabetes Mellitus in Yamanashi Prefecture\u0026quot;). An anonymized dataset was used for patient data collection to protect patient privacy. The opt-out method was used to obtain informed consent, and informational posters were displayed at participating hospitals to allow patients and guardians to decline participation. All study procedures were carefully designed and conducted in accordance with the tenets of the Declaration of Helsinki, ensuring the highest standards of ethical conduct in medical research.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eDuring the study period from January 1986 to December 2022, a total of 120 pediatric patients who were diagnosed with T1D were enrolled in this study. By 2018, 99 patients were enrolled, and an additional 21 patients (consisting of 9 boys and 12 girls) were enrolled from 2019 to 2022. The sex distribution of the entire cohort consisted of 53 boys and 67 girls (Table\u0026nbsp;1).\u003c/p\u003e\n\u003cp\u003eIn 2019, during the recruitment of new patients under the Medical Expense Subsidy Project for Specific Pediatric Chronic Diseases, a discrepancy was noted in the identification of a male patient who had not previously been seen by our collaborating medical institutions. It was inferred that this patient sought treatment at a hospital in Tokyo, as inferred from the place of registration for subsidized medical expenses. However, due to the noncollaboration status of this hospital with our study and the subsequent inability to conduct a survey, this patient was excluded from our analysis.\u003c/p\u003e\n\u003cp\u003eTherefore, we estimated the case detection rate for our study to be 99.17%, reflecting a comprehensive capture of T1D cases in Yamanashi Prefecture during the study period.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStandardized and Crude Incidence\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe standardized incidences of T1D among individuals aged 0\u0026ndash;14 years showed variability during the COVID-19 pandemic period, with incidences of 7.13, 1.84, 2.49, and 5.73 per 100,000 people in 2019, 2020, 2021, and 2022, respectively (Table\u0026nbsp;1). From 1986 to 2019, the annual increase in the standardized incidence was 2.089% (p\u0026thinsp;=\u0026thinsp;.0772, 95% CI -0.212 to 4.433%/year, standard deviation\u0026thinsp;=\u0026thinsp;.02089). This trend continued into the pandemic period (1986\u0026ndash;2022), with an annual increase of 2.183% (p\u0026thinsp;=\u0026thinsp;.0331, 95% CI 0.190 to 4.216%/year, standard deviation\u0026thinsp;=\u0026thinsp;.01025) (Fig.\u0026nbsp;1). However, a z test comparing the annual rates of increase between the two periods showed no significant difference (p\u0026thinsp;=\u0026thinsp;.952).\u003c/p\u003e\n\u003cp\u003eAnalysis by age group showed that the 0\u0026ndash;4 year age group maintained a trend similar to that in our previous reports, with a minimal number of cases and no discernible trend from 1986 to 2022. For the 5\u0026ndash;9 year age group, the crude incidence increased by 6.607%/year from 1986 to 2019 (p\u0026thinsp;\u0026lt;\u0026thinsp;.01, 95% CI 3.869 to 9.520%/year, standard deviation\u0026thinsp;=\u0026thinsp;.01437) and slightly decreased to 6.270%/year from 1986 to 2022 (p\u0026thinsp;\u0026lt;\u0026thinsp;.001, 95% CI 3.955 to 8.725%/year, standard deviation\u0026thinsp;=\u0026thinsp;.01213), with no significant difference detected between the two periods (p\u0026thinsp;=\u0026thinsp;.858). For the 10\u0026ndash;14 year age group, there was an increase from 0.39%/year (p\u0026thinsp;=\u0026thinsp;.651) to 1.09%/year (p\u0026thinsp;=\u0026thinsp;.146) over the same time periods, indicating a nonsignificant increase.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOccurrence of Diabetic Ketoacidosis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the 2020\u0026ndash;2022 COVID-19 pandemic, 21.4% (3 of 14) of new T1D patients presented with DKA at onset, with the following distribution across age groups: one each in the 0\u0026ndash;4, 5\u0026ndash;9, and 10\u0026ndash;14 age groups. Compared to the prepandemic period (2012\u0026ndash;2019), where 25.9% (7 of 27) of patients presented with DKA, the distribution indicated a greater frequency in the 10\u0026ndash;14 age group (5 patients). A \u0026chi;-squared test was used to assess the difference in the proportion of patients who presented with DKA between these two periods (p\u0026thinsp;=\u0026thinsp;1.0).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cstrong\u003eAnnual increase in incidence in Yamanashi Prefecture\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to the analysis of incidence rates from 1986 to 2019 and from 1986 to 2022, significant increases in T1D incidence were observed in the 5\u0026ndash;9 year age group for both time periods. However, there was no significant increase in the annual rate of increase in the crude incidence of T1D in the other age groups. The annual rate of increase in standardized incidence in the 0\u0026ndash;14 year age group showed an increasing trend from 1986 to 2019, and a significant increase was observed from 1986 to 2022, although the annual rate of increase for these two periods was not significantly different. These results suggest that the COVID-19 pandemic did not significantly alter the incidence of T1D in Yamanashi Prefecture from 2020 to 2022. Furthermore, as previously reported by our group, the trend of young children developing T1D seems to persist throughout the pandemic.\u003c/p\u003e\n\u003cp\u003eA study of pediatric T1D incidence in Oita Prefecture reported an annual increase in T1D incidence of 4.7%. Notably, the Oita study did not find a trend for younger age groups to develop T1D\u003csup\u003e16\u003c/sup\u003e. The difference between the annual increase rates for the 0\u0026ndash;14 age group in Oita and Yamanashi prefectures is due to statistical variability, probably caused by the small number of cases in both regions. In fact, the 95% confidence intervals for the annual increase rates in Oita (1.7\u0026ndash;7.8%) and Yamanashi (0.2\u0026ndash;4.2%) prefectures overlap significantly, indicating no substantial difference between the two.\u003c/p\u003e\n\u003cp\u003eComparative data from South Korea revealed an incidence of 3.70 per 100,000 people in 2008, with an annual increase of 3\u0026ndash;4% from 2008 to 2014\u003csup\u003e17\u003c/sup\u003e. This suggests that the trends observed in these Japanese prefectures are not significantly different from those observed in South Korea, suggesting the possibility of regional similarities in T1D incidence trends in the Asian region.\u003c/p\u003e\n\u003cp\u003eGlobally, a younger age of onset of T1D is associated with regions with a lower incidence\u003csup\u003e18\u003c/sup\u003e. It has been hypothesized that the age of onset may be younger in Yamanashi Prefecture, which has a lower incidence rate than Oita Prefecture. However, the limited number of patients in our study makes this speculation inconclusive.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImpact during the pandemic in Yamanashi Prefecture\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalysis of the standardized incidence of T1D among 0- to 14-year-olds from 2020 to 2022 revealed notable fluctuations, with particularly low rates in 2020 and 2021, followed by a significant increase in 2022 (Fig.\u0026nbsp;1). This trend is consistent with the sharp decline in viral infections during the early years of the COVID-19 pandemic, which was attributed to the widespread use of masks and outdoor restrictions. Data from the National Institute of Infectious Diseases in Japan support this observation, showing a marked decrease in reported cases of influenzavirus and most enteroviruses during this period. An exception was coxsackievirus A6 (CVA6), which, despite a decrease in reported cases before the pandemic, increased in 2021 and 2022 (Influenzavirus; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://kansen-levelmap.mhlw.go.jp/Byogentai/Pdf/data2j.pdf\u003c/span\u003e\u003c/span\u003e, Enterovirus; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://kansen-levelmap.mhlw.go.jp/Byogentai/Pdf/data16j.pdf\u003c/span\u003e\u003c/span\u003e, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://kansen-levelmap.mhlw.go.jp/Byogentai/Pdf/data24j.pdf\u003c/span\u003e\u003c/span\u003e, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://kansen-levelmap.mhlw.go.jp/Byogentai/Pdf/data26j.pdf\u003c/span\u003e\u003c/span\u003e, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://kansen-levelmap.mhlw.go.jp/Byogentai/Pdf/data18j.pdf\u003c/span\u003e\u003c/span\u003e, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://kansen-levelmap.mhlw.go.jp/Byogentai/Pdf/data149j.pdf\u003c/span\u003e\u003c/span\u003e). The potential impact of a small outbreak of coxsackievirus type A6 (CVA6) on the increased incidence of T1D in 2022 was considered. However, despite numerous reports linking coxsackievirus type B (CVB) to the onset of T1D\u003csup\u003e19\u003c/sup\u003e, there is little evidence to support the involvement of coxsackievirus type A (CVA) in the development of this disease. Therefore, we postulated that the contribution of this small CVA6 outbreak to the increase in T1D incidence in 2022 is likely to be insignificant.\u003c/p\u003e\n\u003cp\u003eCOVID-19 case data from the Yamanashi Prefectural Center for Infectious Diseases (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.pref.yamanashi.jp.e.aao.hp.transer.com/kansensho_portal/index.html\u003c/span\u003e\u003c/span\u003e; Home\u0026thinsp;\u0026gt;\u0026thinsp;Announcement from Yamanashi Prefecture CDC\u0026thinsp;\u0026gt;\u0026thinsp;Dissemination of Information\u0026thinsp;\u0026gt;\u0026thinsp;Analysis and Dissemination Materials (YCDC Report)\u0026thinsp;\u0026gt;\u0026thinsp;COVID-19 infection/infection status by age\u0026thinsp;\u0026gt;\u0026thinsp;All periods (PDF:337KB); \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.pref.yamanashi.jp.e.aao.hp.transer.com/documents/101638/nendaibetu.pdf\u003c/span\u003e\u003c/span\u003e) revealed a clear pattern in the emergence of COVID-19 cases over the course of the pandemic. While the number of COVID-19 cases in the prefecture was minimal in 2020 and 2021, a marked increase was observed in 2022 (Japanese era name; Reiwa 4), especially among children and adolescents under 10 years of age, with 4847 and 4586 cases reported in August and 2022, respectively. This increase in COVID-19 cases continued after August, a critical time for public health in our prefecture. When these results are contrasted with the T1D incidences, the distribution of T1D cases in 2022 did not coincide with the timing of the surge in COVID-19 cases. Specifically, there was one patient in January, two each in April, May, and June, one in September, and one in November. This distribution suggested that the increase in the number of pediatric T1D patients in Yamanashi Prefecture preceded the most rapid increase in the number of COVID-19 patients (after July 2022) (Fig.\u0026nbsp;2). This pattern is similar to observations in Scotland, where no direct correlation was found between the COVID-19 epidemic and the increase in T1D cases\u003csup\u003e20\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eYear-to-year fluctuations in T1D cases in Yamanashi Prefecture have been observed since before the pandemic, suggesting that the fluctuations in T1D incidence from 2020 to 2022 are likely part of a continuing trend rather than a pandemic-induced deviation. This assertion is supported by the timing and nature of the emergence of COVID-19 cases in Yamanashi Prefecture, suggesting that the direct impact of the pandemic on T1D incidence may be limited.\u003c/p\u003e\n\u003cp\u003eIn addition, the analysis of SARS-CoV-2 variants during the pandemic, as reported by the Genome Analysis Center at our institution (Yamanashi Prefectural Central Hospital)\u003csup\u003e21\u003c/sup\u003e, did not reveal any discernible pattern suggesting a correlation between specific SARS-CoV-2 variants and T1D incidence (Fig.\u0026nbsp;2). This further supports the notion that the observed increase in T1D cases, especially in 2022, may not be directly attributable to the COVID-19 pandemic or specific viral variants.\u003c/p\u003e\n\u003cp\u003eYamanashi Prefecture's response to the COVID-19 pandemic included a state of emergency from April 16, 2020, to May 14, 2020, followed by priority measures to prevent the spread of disease from August 20, 2021, to September 12, 2021. Analysis of the number of T1D cases during these periods did not show any significant fluctuations corresponding to these public health measures. This suggests that while measures were critical for controlling the spread of COVID-19, they did not directly affect the incidence of T1D within the prefecture.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDKA during the pandemic\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the COVID-19 pandemic, an increase in the incidence of DKA at the time of initial illness was reported worldwide, possibly because of a decline in hospital functionality and patient reluctance to seek medical care\u003csup\u003e22\u003c/sup\u003e. However, our analysis in Yamanashi Prefecture reveals a contrasting scenario. In the three-year period from 2020 to 2022, coinciding with the pandemic, there was no significant difference in the number of pediatric patients who presented with DKA at the onset of illness compared with that in the prepandemic period from 2012 to 2019.\u003c/p\u003e\n\u003cp\u003eThis observation is noteworthy in the context of public health responses in larger metropolitan areas, such as Tokyo and Osaka, where states of emergency were declared 4 times and priority preventive measures were implemented 3 or 4 times against COVID-19 from 2020 to 2022. In contrast, Yamanashi Prefecture, with a comparatively smaller population, implemented each measure only once. This suggests that the smaller population size and perhaps more manageable COVID-19 case load in Yamanashi Prefecture facilitated more effective epidemic control, thereby minimizing disruptions to the functioning of the healthcare system and mitigating patients' reluctance to seek medical care.\u003c/p\u003e\n\u003cp\u003eAs a result, the expected increase in DKA cases at the onset of the outbreak, which is commonly observed in regions with a greater burden on the healthcare system, was not observed in Yamanashi Prefecture. This finding indirectly supports the hypothesis that the observed increase in DKA incidence in other regions may be due to the combined effects of decreased hospital accessibility and patients' reluctance to seek timely medical intervention.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe main limitation of this study is the small number of T1D patients. This reflects the low incidence of T1D in Japan and the small population of Yamanashi Prefecture. This limitation is important because it may inherently affect the fact that the COVID-19 epidemic had no statistically significant effect on T1D incidence; the inability to measure islet autoantibodies prior to T1D onset or to track SARS-CoV-2 infection history in newly diagnosed patients further limits our understanding. In particular, our insight into the proportion of individuals who develop T1D after SARS-CoV-2 infection is limited, which may obscure the subtle relationship between the pandemic and the incidence of T1D.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn Yamanashi Prefecture, the association between T1D incidence and the COVID-19 pandemic from 2020 to 2022 during the pandemic was considered to be small.\u003c/p\u003e\n\u003cp\u003eIn addition, as mentioned above, there was little change in the rate of increase in standardized incidence among 0- to 14-year-olds from 1986 to 2019, before the pandemic, and from 1986 to 2022, including the pandemic. In other words, although incidences increased during the pandemic, this increase followed the prepandemic trend. This pattern is consistent with observations from Scotland\u003csup\u003e20\u003c/sup\u003e, Denmark\u003csup\u003e23\u003c/sup\u003e, Germany\u003csup\u003e24\u003c/sup\u003e, and Oita Prefecture, Japan\u003csup\u003e16\u003c/sup\u003e. Despite the unprecedented global impact of the COVID-19 pandemic, it is likely that the pandemic did not have a significant direct or indirect effect on the incidence of pediatric T1D in these regions. In Yamanashi Prefecture, as well as in the aforementioned locations, the data suggest that factors contributing to the increasing incidence of T1D predate the pandemic and may involve a complex interplay of genetic, environmental and possibly other viral influences not directly related to SARS-CoV-2. This finding is important because it highlights the need to continue investigating the multifactorial causes of T1D beyond the scope of the COVID-19 pandemic.\u003c/p\u003e\n\u003cp\u003eIn light of these findings, it is imperative that future research delve deeper into understanding the drivers behind the increasing incidence of pediatric T1D, examining not only the impact of infectious diseases but also broader environmental and genetic factors. Such studies will be critical in developing targeted interventions and preventive measures to curb the rising trend of T1D worldwide.\u003c/p\u003e\n\u003cp\u003eIn addition, the experience of managing chronic diseases such as T1D during the pandemic provides valuable lessons for health systems worldwide and underscores the importance of maintaining accessible and effective care even during public health crises.\u003c/p\u003e\n\u003cp\u003eIn conclusion, while the COVID-19 pandemic has affected many aspects of health care and disease dynamics, its impact on the incidence of pediatric T1D in Yamanashi Prefecture appears to have been negligible. This underscores the importance of having a comprehensive perspective to understand and address the challenges associated with T1D.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no funding to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest disclosure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest associated with this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Institutional Review Board of the School of Medicine of Yamanashi University (IRB number: 2020-2215, titled \u0026quot;Investigation of the Total Number of Pediatric Patients with Type 1 Diabetes Mellitus in Yamanashi Prefecture\u0026quot;).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient consent statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll study participants provided informed consent that was obtained in the form of opt-out.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTomohi.S., Ko.K., and S.A. designed the study. Hiro.Y. did the statistical analysis. Tomohi.S. wrote the manuscript. Ko.K., Ki.K., M.M., and S.A. provided clinical advice. All the authors have read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eIlonen, J., Lempainen, J. \u0026amp; Veijola, R. The heterogeneous pathogenesis of type 1 diabetes mellitus. \u003cem\u003eNat. Rev. Endocrinol.\u003c/em\u003e \u003cstrong\u003e15\u003c/strong\u003e, 635-650 (2019).\u003c/li\u003e\n \u003cli\u003eRedondo, M.J. et al. Genetic determination of islet cell autoimmunity in monozygotic twins. \u003cem\u003eBMJ\u003c/em\u003e \u003cstrong\u003e318\u003c/strong\u003e, 698-702 (1999).\u003c/li\u003e\n \u003cli\u003eRedondo, M.J. et al. Concordance for islet autoimmunity among monozygotic twins. \u003cem\u003eN. Engl. J. Med.\u003c/em\u003e \u003cstrong\u003e359\u003c/strong\u003e, 2849-2850 (2008).\u003c/li\u003e\n \u003cli\u003eHussen, H.I., Moradi, T. \u0026amp; Persson, M. The risk of type 1 diabetes among offspring of immigrant mothers in relation to the duration of residency in Sweden. \u003cem\u003eDiabetes Care\u003c/em\u003e \u003cstrong\u003e38\u003c/strong\u003e, 934-936 (2015).\u003c/li\u003e\n \u003cli\u003eKaufman, F.R. \u0026amp; Devgan, S. An increase in newly onset IDDM admissions following the Los Angeles earthquake. \u003cem\u003eDiabetes Care\u003c/em\u003e \u003cstrong\u003e18\u003c/strong\u003e, 422 (1995).\u003c/li\u003e\n \u003cli\u003eFerrara, C.T. et al. Excess BMI in childhood: A modifiable risk factor for type 1 diabetes development? \u003cem\u003eDiabetes Care\u003c/em\u003e \u003cstrong\u003e40\u003c/strong\u003e, 698-701 (2017).\u003c/li\u003e\n \u003cli\u003eWang, K. et al. Association between enterovirus infection and type 1 diabetes risk: A meta-analysis of 38 case-control studies. \u003cem\u003eFront. Endocrinol. (Lausanne)\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 706964 (2021).\u003c/li\u003e\n \u003cli\u003eLloyd, R.E., Tamhankar, M. \u0026amp; Lernmark, \u0026Aring;. Enteroviruses and type 1 diabetes: Multiple mechanisms and factors? \u003cem\u003eAnnu. Rev. Med.\u003c/em\u003e \u003cstrong\u003e73\u003c/strong\u003e, 483-499 (2022).\u003c/li\u003e\n \u003cli\u003eBeyerlein, A., Donnachie, E., Jergens, S. \u0026amp; Ziegler, A.G. Infections in early life and development of type 1 diabetes. JAMA 315, 1899-1901 (2016).\u003c/li\u003e\n \u003cli\u003eL\u0026ouml;nnrot, M. et al. Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: the TEDDY study. \u003cem\u003eDiabetologia\u003c/em\u003e \u003cstrong\u003e60\u003c/strong\u003e, 1931-1940 (2017).\u003c/li\u003e\n \u003cli\u003eLamers, M.M. et al. SARS-CoV-2 productively infects human gut enterocytes. \u003cem\u003eScience\u003c/em\u003e \u003cstrong\u003e369\u003c/strong\u003e, 50-54 (2020).\u003c/li\u003e\n \u003cli\u003eSteenblock, C. et al. Viral infiltration of pancreatic islets in patients with COVID-19. \u003cem\u003eNat. Commun.\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 3534 (2021).\u003c/li\u003e\n \u003cli\u003eBen Nasr, M. et al. Indirect and direct effects of SARS-CoV-2 on human pancreatic islets. \u003cem\u003eDiabetes\u003c/em\u003e \u003cstrong\u003e71\u003c/strong\u003e, 1579-1590 (2022).\u003c/li\u003e\n \u003cli\u003eSaito, T. et al. Incidence of childhood type 1 diabetes mellitus in Yamanashi Prefecture, Japan, 1986-2018. \u003cem\u003eEndocrinol. Diabetes Metab.\u003c/em\u003e \u003cstrong\u003e4\u003c/strong\u003e(2), e00214 (2020).\u003c/li\u003e\n \u003cli\u003eSegi, M. Cancer mortality for selected sites in 24 countries (1950-57). Department of Public Health, Tohoku University of Medicine, Sendai.\u003c/li\u003e\n \u003cli\u003eMatsuda, F., Itonaga, T., Maeda, M. \u0026amp; Ihara, K. Long-term trends of pediatric type 1 diabetes incidence in Japan before and after the COVID-19 pandemic. Sci. Rep. 13, 5803 (2023).\u003c/li\u003e\n \u003cli\u003eKim, J.H. et al. Increasing incidence of type 1 diabetes among Korean children and adolescents: analysis of data from a nationwide registry in Korea. \u003cem\u003ePediatr. Diabetes\u003c/em\u003e \u003cstrong\u003e17\u003c/strong\u003e, 519-524 (2016).\u003c/li\u003e\n \u003cli\u003ePatterson, C.C. et al. Incidence trends for childhood type 1 diabetes in Europe during 1989-2003. \u003cem\u003eLancet\u003c/em\u003e \u003cstrong\u003e373\u003c/strong\u003e, 2027-2033 (2009).\u003c/li\u003e\n \u003cli\u003eCarr\u0026eacute;, A. et al. Coxsackievirus and type 1 diabetes: Diabetogenic mechanisms and implications for research. \u003cem\u003eEndocr. Rev.\u003c/em\u003e \u003cstrong\u003e44\u003c/strong\u003e, 737-751 (2023).\u003c/li\u003e\n \u003cli\u003eMcKeigue, P.M. et al. Relationship of incident type 1 diabetes to recent COVID-19 infection: Cohort study using e-health record linkage in Scotland. \u003cem\u003eDiabetes Care\u003c/em\u003e \u003cstrong\u003e46\u003c/strong\u003e, 921-928 (2023).\u003c/li\u003e\n \u003cli\u003eHirotsu, Y. et al. Lung tropism in hospitalized patients following infection with SARS-CoV-2 variants from D614G to Omicron BA.2. \u003cem\u003eNat. Med.\u003c/em\u003e \u003cstrong\u003e3\u003c/strong\u003e, 32 (2023).\u003c/li\u003e\n \u003cli\u003eElgenidy, A. et al. Incidence of diabetic ketoacidosis during COVID-19 pandemic: a meta-analysis of 124,597 children with diabetes. \u003cem\u003ePediatr. Res.\u003c/em\u003e \u003cstrong\u003e93\u003c/strong\u003e, 1149-1160 (2023).\u003c/li\u003e\n \u003cli\u003eNoorzae, R. et al. Risk of type 1 diabetes in children is not increased after SARS-CoV-2 infection: A nationwide prospective study in Denmark. \u003cem\u003eDiabetes Care\u003c/em\u003e \u003cstrong\u003e46\u003c/strong\u003e, 1261-1264 (2023).\u003c/li\u003e\n \u003cli\u003eTittel, S.R. et al. Did the COVID-19 lockdown affect the incidence of pediatric type 1 diabetes in Germany? \u003cem\u003eDiabetes Care\u003c/em\u003e \u003cstrong\u003e43\u003c/strong\u003e, e172-e173 (2020).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e "}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Type 1 diabetes, coronavirus, COVID-19, SARS-CoV-2, incidence, pandemic","lastPublishedDoi":"10.21203/rs.3.rs-4114246/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4114246/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"It is hypothesized that the biopsychosocial stress associated with the severe acute respiratory syndrome coronavirus 2 pandemic (SARS-CoV-2), in combination with the immunologic effects of SARS-CoV-2 and pancreatic β-cell dysfunction, may have contributed to the onset of type 1 diabetes (T1D) in children. We documented the incidence rates of T1D in Yamanashi Prefecture, Japan, from 1986 to 2018 and expanded our analysis to include cases from 2019 to 2022 to assess the influence of coronavirus disease 2019 (COVID-19) on the incidence of T1D. The annual increase in standardized incidences of T1D among 0- to 14-year-olds was 2.089% per year from 1986 to 2019 (p = .0772) and 2.183% per year from 1986 to 2022 (p = .0331). For the 5-9 year age group, the annual increase in crude incidence from 1986 to 2019 was 6.607% per year (p \u003c .01), and from 1986 to 2022, it was 6.270% per year (p \u003c .001). In Yamanashi Prefecture, Japan, the incidence of pediatric T1D increased during the COVID-19 pandemic from 2020 to 2022. However, this trend was an extension of the increase prior to 2019, suggesting that no direct or indirect effect of COVID-19 on this trend was identified.","manuscriptTitle":"Impact of the severe acute respiratory syndrome coronavirus 2 pandemic on the incidence of type 1 diabetes mellitus in children in Yamanashi, Japan","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-26 20:49:42","doi":"10.21203/rs.3.rs-4114246/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-18T05:37:32+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-17T14:59:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"180138033602560739183527195395787891993","date":"2024-07-10T09:33:00+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-27T23:08:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"207742298622776179630764736088492961857","date":"2024-06-13T16:35:12+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-15T11:58:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"278697437524906516229128893168961344842","date":"2024-05-15T11:26:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-02T14:05:27+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-02T14:03:17+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-04-02T08:53:17+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-02T03:49:16+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-03-16T17:45:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5b51e7b1-7d4a-4aab-9234-dbe92f63861e","owner":[],"postedDate":"March 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":29526681,"name":"Health sciences/Diseases"},{"id":29526682,"name":"Health sciences/Endocrinology"},{"id":29526683,"name":"Health sciences/Health care"},{"id":29526684,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2025-01-06T16:04:04+00:00","versionOfRecord":{"articleIdentity":"rs-4114246","link":"https://doi.org/10.1038/s41598-024-84654-z","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-01-02 15:57:50","publishedOnDateReadable":"January 2nd, 2025"},"versionCreatedAt":"2024-03-26 20:49:42","video":"","vorDoi":"10.1038/s41598-024-84654-z","vorDoiUrl":"https://doi.org/10.1038/s41598-024-84654-z","workflowStages":[]},"version":"v1","identity":"rs-4114246","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4114246","identity":"rs-4114246","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}