Large, Nationwide Study Links Enterovirus to Type 1 Diabetes

October 20, 2014

Childhood infection with enterovirus increases the risk of developing type 1 diabetes, new research from Taiwan indicates.

"Children that have been infected with enterovirus are 48% more likely to have developed type 1 diabetes," senior author Tsai-Chung Li, MD, of China Medical University, Taichung, Taiwan, told Medscape Medical News.

This is the first nationwide, retrospective cohort study of the association between type 1 diabetes and enterovirus infection, says Dr Li, who with lead author Dr Hsiao-Chuan Lin, also of China Medical University, and colleagues have published their work in Diabetologia.

Although they acknowledge that their study is observational in nature, "the conclusions are solid enough to guide further research on this association," they state.

The findings suggest that a vaccination strategy against enterovirus infection "might slow the rising incidence of type 1 diabetes." However, Dr Li told Medscape Medical News that no antiviral treatment or vaccine is currently available for enterovirus infection.

Although an inactive enterovirus 71 vaccine in development has shown efficacy in preventing hand-foot-and-mouth disease in healthy Chinese children, there was no cross-protection against diseases caused by other enteroviruses.

"A more broadly protective enterovirus vaccine would be more helpful in preventing type 1 diabetes," Dr Li noted.

Type 1 Diabetes: Complex Interplay of Factors

The authors explain that type 1 diabetes is thought to be caused by a complex interaction between genetic susceptibility, the immune system, and environmental factors.

There has been a rapid global increase in the incidence of type 1 diabetes recently, particularly in children under age 5 years and at another peak time, puberty. But incidence still varies greatly between ethnic groups: from about 0.1 per 100,000 person-years in China and Venezuela, to the highest incidence in the world of 64.3 per 100,000 person-years, in Finland.

It's clear that in some countries enterovirus may not play a large role. In Finland, for instance, the prevalence of enterovirus infection is low, so it is thought that genetic background more likely plays a large part in the high incidence rate.

But, in many other places, it is thought that enterovirus and type 1 diabetes may be linked, and this "has been mentioned for more than 4 decades," Dr Li explained. However, prior research examining this issue has consisted of case-control and cohort studies and has been limited by small clinical samples.

Taiwan has generally had a relatively low incidence of type 1 diabetes, but in the past few decades this has escalated and been paralleled by an increase in enterovirus infections, so the team at China Medical University decided to examine the link between the two.

Enteroviral Infections Generally Mild and Self-Limiting

Enterovirus infection encompasses a wide group of viruses, including polioviruses, coxsackieviruses, and echoviruses.

The most commonly diagnosed conditions resulting from infection with these viruses are herpangina (mouth ulcers) — patients may present with fever, pharyngitis, and vesicular and/or ulcerated throat lesions, but the condition is usually benign and self-limiting — and hand-foot-and-mouth disease, the researchers explain.

Hand-foot-and-mouth disease is characterized by a mild fever followed by a rash of flat discolored spots and bumps that may involve the skin of the hands, feet, and oral cavity.

This disease often occurs in small epidemics at nursery schools or kindergartens, usually during the summer and autumn months, Dr Li told Medscape Medical News. With the exception of one outbreak in 1998 —when there was an estimated 1.5 million cases, 405 severe complications, and 78 deaths — most enterovirus infections result in only mild symptoms and sufferers recover from infection without complication.

Enterovirus 71, while causing hand-foot-and-mouth disease, can also result in more severe symptoms, including neurologic or cardiac complications and death, and this is why there is a vaccine in development against the strain, Dr Li added.

To investigate the link between general enterovirus infection and subsequent type 1 diabetes, the researchers used nationwide population-based data from Taiwan's national health insurance system. They looked at type 1 diabetes incidence in children up to aged 18 years with or without diagnosis of enterovirus infection during 2000 to 2008.

The majority of infections (97%) were herpangina (n = 436,372) or hand-foot-and-mouth disease (n = 116,441) and were diagnosed clinically, not by laboratory confirmation of viral infection, because of the generally benign course of these conditions.

Increased Enterovirus Infection Because of Immigration?

The overall incidence of type 1 diabetes was higher in enterovirus-infected children than in the noninfected group (5.73 vs 3.89 per 100,000 person- years), with a hazard ratio of 1.48 for enterovirus-infected vs noninfected children, after adjustment for confounding variables.

"Taiwan has relatively low type 1 diabetes incidence; we believe that the marked escalation of the said incidence in recent decades can be largely attributed to the highly endemic spread of enterovirus infection in Taiwanese children, given that there has been little gene flow and genetic drift in such a short period," the authors say.

Dr Li told Medscape Medical News that one theory of why the incidence of enterovirus infection in Taiwan is increasing is the influx of workers and foreign brides from countries in Southeast Asia, including Thailand, the Philippines, Vietnam, and Indonesia, where enterovirus infection is common.

Enterovirus may thus play a vital role in increasing type 1 diabetes in this region and many others where infection rates are soaring, such as other parts of Asia, Africa, and South America.

Asked about enterovirus D68, which caused an outbreak in the United States this summer, Dr Li said this "has never been found from lab data in Taiwan." Dr Li added: "We also have searched the literature and did not find any paper reporting an association between enterovirus D68 and type 1 diabetes."

Dr Li concluded: "If the association between enterovirus infection and type 1 diabetes is causal, a preventive strategy, such as an effective vaccine against enterovirus infection, may lessen the incidence of type 1 diabetes in Taiwan."

The authors have reported no relevant financial relationships.

Diabetologia. Published online October 17, 2014. Full text

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