Does COVID-19 Cause Type 1 Diabetes in Kids? Time Will Tell

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STOCKHOLM, Sweden — It remains inconclusive whether SARS-CoV-2 infection predisposes children and adolescents to a higher risk of type 1 diabetes. Data from two new studies presented last week, and a research letter just published, add to the growing body of knowledge on the subject, but still can't draw any definitive conclusions.

The latest results from a Norwegian and a Scottish study both examine incidence of type 1 diabetes in young people with a history of SARS-CoV-2 infection and were reported at this year's European Association for the Study of Diabetes (EASD) Annual Meeting.

A 60% increased risk for type 1 diabetes at least 31 days after SARS-CoV-2 infection (adjusted hazard ratio [HR], 1.63) was found in the Norwegian study, while in contrast, the Scottish study only found an increased risk in the first few months of the pandemic, in 2020, but importantly, no association over a much longer time period (March 2020 to November 2021).

In a comment on Twitter on the two studies presented at EASD, session moderator Kamlesh Khunti, MD, professor of primary care diabetes and vascular medicine at the University of Leicester, UK, said: "In summary, two studies showing no or weak association of type 1 diabetes with COVID."

But new data in the research letter published in JAMA Network Open, based on US figures, also found an almost doubling of type 1 diabetes in children in the first few months after COVID-19 infection relative to infection with other respiratory viruses.

Lead author of the Scottish study, Helen Colhoun, PhD, honorary public health consultant at Public Health Scotland, commented: "Data in children are variable year on year, which emphasizes the need to be cautious over taking a tiny snapshot."

Nevertheless, this is "a hugely important question and we must not drop the ball. [We must] keep looking at it and maintain scientific equipoise...[This] reinforces the need to carry on this analysis into the future to obtain an unequivocal picture," she emphasized.

Norwegian Study: If There Is an Association, the Risk Is Small

German Tapia, PhD, from the Norwegian Institute of Public Health, Oslo, presented the results of a study of SARS-CoV-2 infection and subsequent risk of type 1 diabetes in 1.2 million children in Norway.

Of these, 424,354 children had been infected with the COVID-19 virus, and there were 990 incident cases of type 1 diabetes.

"What we do know about COVID-19 in children is that the symptoms are mild and only a small proportion are hospitalized with more serious symptoms. But we do not know the long-term effects of COVID-19 infection because this requires a longer follow-up period," remarked Tapia, adding that other viral infections are thought to be linked to the development of type 1 diabetes, in particular, respiratory infections.

The data were sourced from the Norwegian Emergency Preparedness Register for COVID-19, which gathers daily data updates including infections (positive and negative results for free-of-charge testing), diagnoses (primary and secondary care), vaccinations (also free-of-charge), prescribed medications, and basic demographics.

"We link these data using the personal identification number that every Norwegian citizen has," explained Tapia.

He presented results from two cohorts: firstly, results in children only, including those tested for SARS-CoV-2 infection, and secondly, a full national Norwegian population cohort.

Regarding the first cohort, those under 18 years who tested positive for SARS-CoV-2 infection, from March 2020 to March 2022, had a significantly increased risk of type 1 diabetes at least 31 days after infection, with an adjusted hazard ratio of 1.63 (95% CI, 1.08 - 2.47; P = .02). Adjustments were made for age, sex, non-Nordic country of origin, geographic area, and socioeconomic factors.

For children who developed type 1 diabetes within 30 days of a SARS-CoV-2 infection, the hazard ratio was 1.26 (95% CI, 0.72 - 2.19; P = .42), which did not reach statistical significance.

"The fact that fewer people developed type 1 diabetes within 30 days is not surprising because we know that type 1 diabetes develops over a long period of time," Tapia said.

"For this reason, we would not expect to find new cases of those people who develop type 1 diabetes within 30 days of COVID-19 infection," he explained. In these cases, "it is most likely that they already had [type 1 diabetes], and the infection probably triggered clinical symptoms, so their type 1 diabetes was discovered."

Turning to the full population cohort and diagnoses of type 1 diabetes over 30 days after SARS-CoV-2 infection, the Norwegian researchers found an association, with a hazard ratio of 1.57 (95% CI, 1.06 - 2.33; P = .03), while diagnosis of type 1 diabetes at 30 days or less generated a hazard ratio of 1.22 (95% CI, 0.72 - 2.19; P = .42).

"So very similar results were found, and after adjustment for confounders, results were still similar," reported Tapia.

He also conducted a similar analysis with vaccination as an exposure but found no association between vaccination against SARS-CoV-2 and diagnosis of type 1 diabetes.

"From these results, we conclude that this suggests an increase in diagnosis of type 1 diabetes after SARS-CoV-2 infection, but it must be noted that the absolute risk of developing type 1 diabetes after infection in children is low, with most children not developing the disease," he emphasized.

"There are nearly half a million children who have been infected with SARS-CoV-2 in Norway, but only a very small proportion develop type 1 diabetes."

Scottish Study: No Association Found Over Longer Term

Colhoun and colleagues looked at the relationship between incident type 1 diabetes and SARS-CoV-2 infection in children in Scotland using e-health record linkage.

The study involved 1.8 million people under 35 years of age and found very weak, if any, evidence of an association between incident type 1 diabetes and SARS-CoV-2. Medscape Medical News initially reported these data when released as a preprint in February 2022.

Examining data between March 2020 and November 2021, Colhoun and colleagues identified 365,080 individuals up to age 35 with at least one detected SARS-CoV-2 infection during follow-up and 1074 who developed type 1 diabetes.

"In children under 16 years, suspected cases of type 1 diabetes are admitted to hospital, and 97% of diagnosis dates are recorded in the Scottish Care Information – Diabetes Collaboration register [SCI-Diabetes] prior to or within 2 days of the first hospital admission for type 1 diabetes," Colhoun said, stressing the timeliness of the data.

"We found the incidence of type 1 diabetes diagnosis increased 1.2-fold in those aged 0-14 years, but we did not find any association at an individual level of COVID-19 infection over 30 days prior to a type 1 diabetes diagnosis, in this particular dataset," she reported. In young people aged 15-34, there was a linear increase in incident type 1 diabetes from 2015 to 2021 with no pandemic increase, she added.

Referring to the 1.2-fold increase soon after the pandemic started, she explained that, in 0- to 14-year-olds, the increase followed a drop in the preceding months pre-pandemic in 2019. They also found that the seasonal pattern of type 1 diabetes diagnoses remained roughly the same across the pandemic months, with typical peaks in February and September.

In the cohort of under 35s, researchers also found a rate ratio of 2.62 [95% CI, 1.81 - 3.78] within a 30-day window of SARS-CoV-2 infection, but beyond 30 days, no evidence was seen of an association, with a rate ratio of 0.86 [95% CI, 0.62 - 1.21; P = .40], she reported.

She explained her reasons for not considering diagnoses within 30-days of COVID-19 as causative. Echoing Tapia, Colhoun said the median time from symptom onset to diagnosis of type 1 diabetes is 25 days. "This suggests that 50% have had symptoms for over 25 days at diagnosis."

She also stressed that when they compared the timing of SARS-CoV-2 testing to diagnosis, they found a much higher rate of COVID-19 testing around diagnosis. "This was not least because everyone admitted to hospital had to have a COVID-19 test."

Latest US Data Point to a Link

Meanwhile, for the new data reported in JAMA Network Health, medical student Ellen K. Kendall of Case Western Reserve University School of Medicine, Cleveland, Ohio, matched 571,256 pediatric patients: 285,628 with COVID-19 and 285,628 with non-COVID-19 respiratory infections.

By 6 months after COVID-19, 123 patients (0.043%) had received a new diagnosis of type 1 diabetes, but only 72 (0.025%) were diagnosed with type 1 diabetes within 6 months after non-COVID-19 respiratory infection.

At 1, 3, and 6 months after infection, risk of diagnosis of type 1 diabetes was greater among those infected with SARS-CoV-2 compared with those with non-COVID-19 respiratory infection (1 month: HR, 1.96; 3 months: HR, 2.10; and 6 months: HR, 1.83) and in subgroups of patients aged 0-9 years, a group unlikely to develop type 2 diabetes.

"In this study, new type 1 diabetes diagnoses were more likely to occur among pediatric patients with prior COVID-19 than among those with other respiratory infections (or with other encounters with health systems)," note Kendall and coauthors.

"Respiratory infections have previously been associated with onset of type 1 diabetes, but this risk was even higher among those with COVID-19 in our study, raising concern for long-term, post-COVID-19 autoimmune complications among youths."

"The increased risk of new-onset type 1 diabetes after COVID-19 adds an important consideration for risk–benefit discussions for prevention and treatment of SARS-CoV-2 infection in pediatric populations," they conclude.

A study from the US Centers for Disease Control and Prevention (CDC) published earlier this year, as reported by Medscape Medical News, also concluded there was a link between COVID-19 and diabetes in children, but not with other acute respiratory infections. Children were 2.5 times more likely to be diagnosed with diabetes following a SARS-CoV-2 infection, it found.

However, the study has been criticized because it pooled all types of diabetes together and did not account for other health conditions, medications that can increase blood glucose levels, race, obesity, and other social determinants of health that might influence a child's risk of acquiring COVID-19 or diabetes.

"I've no doubt that the CDC data were incorrect because the incidence rate for...diabetes, even in those never exposed to COVID-19 infection, was 10 times the rate ever reported in the US," Colhoun said at EASD. "There's no way these data are correct. I believe there was a confusion between incidence and prevalence of diabetes."

"This paper caused a great deal of panic, especially among those who have a child with type 1diabetes, so we need to be very careful not to cause undue alarm until we have more definitive evidence in this arena," she stressed.

However, she also acknowledged that the new Norwegian study was well-conducted, and she has no methodologic concerns about it, so "I think we just have to wait and see."

Given the inconclusiveness on the issue, there is an ongoing CoviDiab registry collecting data on this very subject.

EASD 2022. Presented September 23, 2022. Abstracts 233 and 234.

Tapia presented on behalf of lead author Gulseth, who has reported no relevant financial relationships. Colhoun has also reported no relevant financial relationships

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