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 T1D16. 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 201417. 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 incidence18. 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 T1D19, 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 cases20.
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 care22. 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.