In this issue of Pediatrics, Kutz et al report the incidence of type 1 diabetes (T1D) in youth younger than 20 years in Chile from 2007 to 2023.1 They identified a wave-like pattern in the incidence of T1D following the onset of the pandemic. This began with an increase in 2020 and 2021 that exceeded previous predictions, before declining to predicted rates in 2022 and 2023. This finding is consistent with large registry data from several European countries, including Germany and Scotland, that report a significant but temporary increase in new T1D cases, that was followed by a return to pre-pandemic rates or even a decline below predicted levels, indicating a wave-like pattern.2,3 Data from the Southern hemisphere provided by Kutz et al therefore confirm that this is a global phenomenon. This leads to the crucial question of whether this temporary peak is directly attributable to SARS-CoV-2 infections or whether other factors played a role.Kutz et al suggest that the COVID-19 pandemic may be causal for the altered incidence of T1D, because the increase in T1D manifestations began shortly after the onset of the COVID-19 pandemic. Furthermore, they found that the decrease in T1D incidence emerged after the vaccination against COVID-19 reached 80% coverage in Chile, indicating a potentially protective effect on T1D.1 However, ecological studies found no associations between the risk of T1D onset and the COVID-19 vaccination rates in children.4,5 Contrary to the hypothesis that SARS-CoV-2 could be a viral cause of T1D, population-wide cohort studies consistently did not indicate an increased T1D risk following SARS-CoV-2 infection.6–10Both the Danish study by Zareini et al7 and the Scottish analyses3 point to the possibility of detection bias. Because testing for SARS-CoV-2 was often mandatory for hospitalizations during the pandemic, positivity for SARS-CoV-2 may have been detected more frequently in children admitted due to clinical onset of T1D. This could imply a false association in less controlled trials, which only reflects the coincidence of 2 events, T1D diagnosis and routine COVID testing.Data from Finland showed an increased incidence rate ratio of childhood T1D during the first 18 months of the pandemic compared with a pre-pandemic period. Importantly, among 583 children with newly diagnosed T1D who were tested for SARS-CoV-2 antibodies, only 5 (0.9%) were positive.10 Furthermore, a study using data from 51 970 children and adolescents of 2 large registries in Colorado, USA, and Bavaria, Germany, found no significant association between antibodies against SARS-CoV-2 and the development of multiple T1D-associated autoantibodies or singular high-affinity islet autoantibodies.11 A population-based registry study from Germany analyzed the spatiotemporal associations between the waves of the COVID-19 pandemic and the incidence of T1D in children and adolescents. This study additionally accounted for time lags of up to 12 months between the monthly COVID-19 incidence and the T1D incidence data and found no evidence of a positive association.12A recent Finnish study even showed an inverse correlation—T1D incidence increased during lockdown, when other infections and SARS-CoV-2 circulation were low, and decreased when lockdown ended, while cases with COVID-19 increased sharply.13The COVID-19 pandemic represents an unprecedented global event with profound medical, social, and biological consequences, that provides compelling evidence for the role of environmental factors in triggering the clinical manifestation of T1D. The transient but significant increase in T1D incidence in children during the pandemic period strongly supports the concept that environmental modifiers—beyond genetic susceptibility—play a crucial role in the transition from presymptomatic islet autoimmunity to overt diabetes. Proposed trigger mechanisms include prolonged social isolation with reduced exposure to common microbial antigens, altered viral exposure patterns, psychosocial stress, and changes in lifestyle behaviors, all of which may have influenced immune maturation and regulation during critical developmental windows.The leading hypothesis for the temporary increase is an acceleration of the disease process in individuals with presymptomatic islet autoimmunity, which is supported by the “wave-and-low” patterns.2,3 This theory states that the pandemic conditions did not necessarily cause new T1D cases. Instead, they may have accelerated the transition to clinically manifest disease in children who already had a genetic predisposition and preclinical autoimmunity. This would explain both the temporary increase—the “wave” of cases that would have occurred in the near future anyway—and the subsequent drop in incidence below the predicted level, suggesting that the “pool” of susceptible children has been temporarily “depleted.” This would also fit to the temporary shift of onset of T1D to a younger age during the pandemic.2Indirect factors of the COVID-19 pandemic, such as environmental changes, lifestyle changes, stress, or altered exposure to other common viruses, may be the driving forces behind this acceleration. The German and Finnish studies suggested that the lockdown measures drastically reduced the circulation of many common respiratory viruses.2,10,13,14 According to the hygiene hypothesis, this reduced exposure to microbial triggers in early childhood could deregulate the immune system and increase the autoimmune progression. A rise in IA-2 autoantibody positivity during the pandemic suggests faster progression from isolated isles autoimmunity to clinically overt T1D.15 That the decrease in T1D incidence after the end of the lockdown coincided with a sharp increase in other respiratory infections supports this hypothesis.13,14 Changes in diet and physical activity and an increase in body mass index in children during lockdowns may have additionally contributed to the acceleration of the disease process.15,16One particularly notable finding was the sexual disparities observed during the pandemic-related changes in T1D incidence, with a stronger impact on boys than on girls.10,13 This divergence was not limited to epidemiological data but extended to immunological profiles. For example, the presence of IA-2 and glutamic acid decarboxylase autoantibodies at the onset T1D was positively associated with the COVID-19 pandemic only in boys, whereas ZnT8 autoantibody positivity was negatively associated with the pandemic period only in girls.15 These sex-specific differences suggest that the immunological pathways leading to β-cell autoimmunity may be differentially modulated by environmental stressors, potentially mediated by hormonal, genetic, or epigenetic factors.Placing these findings in the broader context of pediatric autoimmune diseases reveals an interesting contrast. Juvenile idiopathic arthritis, another prototypical autoimmune condition, did not demonstrate a comparable and consistent pandemic-related incidence increase.1 This relative dissociation suggests that the pandemic exerted a more disease-specific effect on T1D rather than acting as a universal amplifier of pediatric autoimmunity. Further insight comes from studies examining the coexistence of autoimmunity. A large registry-based analysis from Germany found no increased proportion of thyroid autoantibodies or transglutaminase antibodies in children diagnosed with T1D during the COVID-19 pandemic compared with pre-pandemic years.15 This finding argues against a generalized activation of autoimmunity. Nevertheless, isolated reports have suggested an increased incidence of Graves’ disease during the pandemic, raising the possibility that certain organ-specific autoimmune disorders may have been differentially affected.17,18 Whether these observations reflect true biological effects, delayed health care utilization, or heightened diagnostic awareness remains an open question.Taken together, the COVID-19 pandemic appears to have exerted a relatively isolated and temporally limited effect on the incidence of pediatric T1D, characterized by marked sexual dimorphism and distinct autoantibody patterns. These findings reinforce the concept of T1D as a disease susceptible to environmental modulation. Beyond its immediate clinical relevance, the pandemic offers a unique opportunity to deepen our understanding of environmental triggers in autoimmunity and may ultimately inform future prevention strategies.
Kamrath et al. (Thu,) studied this question.