STOCKHOLM, Sweden — Enterovirus infection appears to be strongly linked to both type 1 diabetes and islet cell autoantibodies, new research suggests.
The strength of the relationship, particularly within the first month of type 1 diabetes diagnosis, “further supports the rationale for development of enterovirus-targeted vaccines and antiviral therapy to prevent and reduce the impact of type 1 diabetes,” according to lead investigator Sonia Isaacs, MD, of the department of pediatrics and child health at the University of New South Wales, Sydney, Australia.
Enteroviruses are a large family of viruses responsible for many infections in children. These live in the intestinal tract but can cause a wide variety of illnesses. There are more than 70 different strains, which include the group A and group B coxsackieviruses, the polioviruses, hepatitis A virus, and several strains that just go by the name enterovirus.
Isaacs presented the data, from a meta-analysis of studies using modern molecular techniques, at the annual meeting of the European Association for the Study of Diabetes (EASD).
The findings raise the question of whether people should be routinely tested for enterovirus at the time of type 1 diabetes diagnosis, she said during her presentation.
Asked by Medscape about the implications for first-degree relatives of people with type 1 diabetes, Isaacs said that they are “definitely a population to watch out for,” with regard to enteroviral infections. “Type 1 diabetes is very diverse and has different endotypes. Different environmental factors may be implicated in these different endotypes, and it may be that the enteroviruses are quite important in the first-degree relative group.”
Asked to comment, session moderator Kamlesh Khunti, MD, PhD, told Medscape that the data were “compelling,” particularly in the short term after type 1 diabetes diagnosis. “It seems that there may be plausibility for enterovirus associated with the development of type 1 diabetes…Are there methods by which we can reduce this risk with either antivirals or vaccinations? I think that needs to be tested.”
And in regard to first-degree relatives, “I think that’s the group to go for because the association is so highly correlated. I think that’s the group worth testing with any interventions,” said Khunti, professor of primary care diabetes and vascular medicine at the University of Leicester, United Kingdom.
Link Stronger a Month After Diagnosis, in Close Relatives, in Europe
The new meta-analysis is an update to a prior review published in 2011 by Isaacs’ group, which found that people with islet cell autoimmunity were more than four times as likely as controls to have an enterovirus infection, and people with type 1 diabetes almost 10 times as likely.
This new analysis focuses on studies using more modern molecular techniques for detecting viruses, including high throughput sequencing and single-cell technologies.
The analysis identified 60 studies with a total of 12,077 participants, of whom 900 had islet autoimmunity, 5081 had type 1 diabetes, and 6096 were controls. Thirty-five of the studies were from Europe, while others were from the United States, Asia, and the Middle East.
Of 16 studies examining enterovirus infection in islet autoimmunity, cases with islet autoimmunity were twice as likely to have an enterovirus infection at any time point compared to controls, a significant difference (odds ratio [OR], 2.07, P = .002.)
Among 48 studies reporting enterovirus infection in type 1 diabetes, those with type 1 diabetes were eight times as likely to have an enterovirus infection compared with controls (OR, 8.0, P < .00001).
In 25 studies including 2977 participants with onset of type 1 diabetes within the prior month, those individuals were more than 16 times more likely to present with an enterovirus infection (OR, 16.2, P < .00001).
“The strength of this is association is greater than previously reported by both us and others,” Isaacs noted.
The association between enterovirus infection and islet autoimmunity was greater in individuals who later progressed to type 1 diabetes, with odds ratio 5.1 vs 2.0 for those who didn’t. The association was most evident at or shortly after seroconversion (5.1), was stronger in Europe (3.2) than in other regions (1.9), and was stronger among those with a first-degree relative with type 1 diabetes (9.8) than those recruited via a high-risk human leukocyte antigen (HLA), in whom the relationship wasn’t significant.
Having multiple or consecutive enteroviral infections was also associated with islet autoimmunity (2.0).
With type 1 diabetes, the relationship with enterovirus was greater in children (9.0) than in adults (4.1), and was greater for type 1 diabetes onset within 1 year (13.8) and within 1 month (16.2) than for those with established type 1 diabetes (7.0). Here, too, the relationship was stronger in Europe (10.2) than outside Europe (7.5).
The link with type 1 diabetes and enterovirus was particularly strong for those with both a first-degree relative and a high-risk HLA (141.4).
The relationship with type 1 diabetes was significant for enterovirus species A (3.7), B (12.7) and C (13.8), including coxsackie virus genotypes, but not D.
“Future studies should focus on characterizing enterovirus genomes in at-risk cohorts rather than just the presence or absence of the virus,” Isaacs said.
However, she added, “type 1 diabetes is such a heterogenous condition, viruses may be implicated more in one type than another. It’s important that we start to look into this.”
Isaacs reports no relevant financial relationships. Khunti has been a consultant, speaker, or received grants for investigator-initiated studies for AstraZeneca, Novartis, Novo Nordisk, sanofi-aventis, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, Bayer, Berlin-Chemie AG / Menarini Group, Janssen, and Napp.
European Association for the Study of Diabetes (EASD) annual meeting: Abstract 236. Presented September 23, 2022.
Miriam E. Tucker is a freelance journalist based in the Washington, DC area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She is on Twitter @MiriamETucker.
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