Meta-Analysis Adds to Evidence for Enterovirus/Type 1 Diabetes Association

Patients with type 1 diabetes are almost 10 times more likely to be infected with enterovirus than are individuals without diabetes, based on the first meta-analysis of studies using molecular diagnosis of the virus. The findings were reported online Feb. 3 in BMJ (2011;342:d35 [doi:10.1136/bmj.d35]).

Although it has been suggested in the literature that enterovirus might play a role in the development of type 1 diabetes, to date there has been no systematic review of molecular studies. Researchers in Australia performed such a review of 25 controlled studies that used molecular methods to investigate such an association. They found a summary odds ratio of 9.8 (P less than .001) for identifying enterovirus in patients with type 1 diabetes, compared with patients without it.

"While the findings from this meta-analysis of observational studies cannot prove that enterovirus infection has a causal role in pathogenesis of diabetes, the results provide additional support to the direct evidence of enterovirus infection in pancreatic tissue of individuals with type 1 diabetes," wrote authors Wing-Chi Yeung, Dr. William D. Rawlinson, and Dr. Maria E. Craig of the University of New South Wales.

For this meta-analysis, two reviewers independently conducted systematic searches for controlled observational studies of enterovirus and type 1 diabetes. They searched the PubMed (from 1965 to May 2010) and Embase (from 1974 to May 2010) databases.

They included only case-control or cohort studies that used molecular methods for viral detection (such as reverse transcription-polymerase chain reaction [RT-PCR], in situ hybridization, or immunostaining for detection of viral capsid protein) to identify current or recent infection in blood, stool, or tissue of patients with prediabetes and diabetes. "Molecular testing is now standard for diagnosis of acute enterovirus infection," they noted.

They classified the studies into two groups – prediabetes and diabetes – depending on whether autoimmunity or type 1 diabetes (newly diagnosed, established type and eventual type 1 diabetes) was the outcome. This systematic review of 33 prevalence studies, involved 1,931 patients and 2,517 nondiabetic individuals.

They identified 34 studies – 9 involving patients with prediabetes (198 cases and 733 controls) and 25 studies of diabetes patients (1,733 cases and 1,784 controls). Thirty studies used RT-PCR or in situ hybridization to detect enterovirus RNA; immunostaining for the enterovirus capsid protein vp1 on autopsy pancreas specimens was used on four studies. Most studies investigated children and adolescents up to age 16 years, though some included adults up to age 53.

The summary odds ratio of identifying enterovirus in patients with prediabetes, compared with patients without diabetes was 3.7 (P less than .001). All but one of the 25 studies of patients with type 1 diabetes had odds ratios greater than one for patients with diabetes testing positive for enterovirus, with a summary odds ratio of 9.8 (P less than .001).

They used sensitivity analyses to test the robustness of the results by country and study quality. In all, 19 studies were conducted in Europe. "There was some evidence for geographical differences; in non-European studies the odds ratio was 13.5, compared with 8.6 in European studies, though there was considerably overlap in the confidence intervals," they wrote.

In addition, "the odds of having an enterovirus infection in people with established diabetes (OR, 11) suggest that persistent enterovirus infection is also common among patients with type 1 diabetes."

The investigators reported that they have no relevant financial relationships.

Patients with type 1 diabetes are almost 10 times more likely to be infected with enterovirus than are individuals without diabetes, based on the first meta-analysis of studies using molecular diagnosis of the virus. The findings were reported online Feb. 3 in BMJ (2011;342:d35 [doi:10.1136/bmj.d35]).

Although it has been suggested in the literature that enterovirus might play a role in the development of type 1 diabetes, to date there has been no systematic review of molecular studies. Researchers in Australia performed such a review of 25 controlled studies that used molecular methods to investigate such an association. They found a summary odds ratio of 9.8 (P less than .001) for identifying enterovirus in patients with type 1 diabetes, compared with patients without it.

"While the findings from this meta-analysis of observational studies cannot prove that enterovirus infection has a causal role in pathogenesis of diabetes, the results provide additional support to the direct evidence of enterovirus infection in pancreatic tissue of individuals with type 1 diabetes," wrote authors Wing-Chi Yeung, Dr. William D. Rawlinson, and Dr. Maria E. Craig of the University of New South Wales.

For this meta-analysis, two reviewers independently conducted systematic searches for controlled observational studies of enterovirus and type 1 diabetes. They searched the PubMed (from 1965 to May 2010) and Embase (from 1974 to May 2010) databases.

They included only case-control or cohort studies that used molecular methods for viral detection (such as reverse transcription-polymerase chain reaction [RT-PCR], in situ hybridization, or immunostaining for detection of viral capsid protein) to identify current or recent infection in blood, stool, or tissue of patients with prediabetes and diabetes. "Molecular testing is now standard for diagnosis of acute enterovirus infection," they noted.

They classified the studies into two groups – prediabetes and diabetes – depending on whether autoimmunity or type 1 diabetes (newly diagnosed, established type and eventual type 1 diabetes) was the outcome. This systematic review of 33 prevalence studies, involved 1,931 patients and 2,517 nondiabetic individuals.

They identified 34 studies – 9 involving patients with prediabetes (198 cases and 733 controls) and 25 studies of diabetes patients (1,733 cases and 1,784 controls). Thirty studies used RT-PCR or in situ hybridization to detect enterovirus RNA; immunostaining for the enterovirus capsid protein vp1 on autopsy pancreas specimens was used on four studies. Most studies investigated children and adolescents up to age 16 years, though some included adults up to age 53.

The summary odds ratio of identifying enterovirus in patients with prediabetes, compared with patients without diabetes was 3.7 (P less than .001). All but one of the 25 studies of patients with type 1 diabetes had odds ratios greater than one for patients with diabetes testing positive for enterovirus, with a summary odds ratio of 9.8 (P less than .001).

They used sensitivity analyses to test the robustness of the results by country and study quality. In all, 19 studies were conducted in Europe. "There was some evidence for geographical differences; in non-European studies the odds ratio was 13.5, compared with 8.6 in European studies, though there was considerably overlap in the confidence intervals," they wrote.

In addition, "the odds of having an enterovirus infection in people with established diabetes (OR, 11) suggest that persistent enterovirus infection is also common among patients with type 1 diabetes."

The investigators reported that they have no relevant financial relationships.

Patients with type 1 diabetes are almost 10 times more likely to be infected with enterovirus than are individuals without diabetes, based on the first meta-analysis of studies using molecular diagnosis of the virus. The findings were reported online Feb. 3 in BMJ (2011;342:d35 [doi:10.1136/bmj.d35]).

Although it has been suggested in the literature that enterovirus might play a role in the development of type 1 diabetes, to date there has been no systematic review of molecular studies. Researchers in Australia performed such a review of 25 controlled studies that used molecular methods to investigate such an association. They found a summary odds ratio of 9.8 (P less than .001) for identifying enterovirus in patients with type 1 diabetes, compared with patients without it.

"While the findings from this meta-analysis of observational studies cannot prove that enterovirus infection has a causal role in pathogenesis of diabetes, the results provide additional support to the direct evidence of enterovirus infection in pancreatic tissue of individuals with type 1 diabetes," wrote authors Wing-Chi Yeung, Dr. William D. Rawlinson, and Dr. Maria E. Craig of the University of New South Wales.

For this meta-analysis, two reviewers independently conducted systematic searches for controlled observational studies of enterovirus and type 1 diabetes. They searched the PubMed (from 1965 to May 2010) and Embase (from 1974 to May 2010) databases.

They included only case-control or cohort studies that used molecular methods for viral detection (such as reverse transcription-polymerase chain reaction [RT-PCR], in situ hybridization, or immunostaining for detection of viral capsid protein) to identify current or recent infection in blood, stool, or tissue of patients with prediabetes and diabetes. "Molecular testing is now standard for diagnosis of acute enterovirus infection," they noted.

They classified the studies into two groups – prediabetes and diabetes – depending on whether autoimmunity or type 1 diabetes (newly diagnosed, established type and eventual type 1 diabetes) was the outcome. This systematic review of 33 prevalence studies, involved 1,931 patients and 2,517 nondiabetic individuals.

They identified 34 studies – 9 involving patients with prediabetes (198 cases and 733 controls) and 25 studies of diabetes patients (1,733 cases and 1,784 controls). Thirty studies used RT-PCR or in situ hybridization to detect enterovirus RNA; immunostaining for the enterovirus capsid protein vp1 on autopsy pancreas specimens was used on four studies. Most studies investigated children and adolescents up to age 16 years, though some included adults up to age 53.

The summary odds ratio of identifying enterovirus in patients with prediabetes, compared with patients without diabetes was 3.7 (P less than .001). All but one of the 25 studies of patients with type 1 diabetes had odds ratios greater than one for patients with diabetes testing positive for enterovirus, with a summary odds ratio of 9.8 (P less than .001).

They used sensitivity analyses to test the robustness of the results by country and study quality. In all, 19 studies were conducted in Europe. "There was some evidence for geographical differences; in non-European studies the odds ratio was 13.5, compared with 8.6 in European studies, though there was considerably overlap in the confidence intervals," they wrote.

In addition, "the odds of having an enterovirus infection in people with established diabetes (OR, 11) suggest that persistent enterovirus infection is also common among patients with type 1 diabetes."

The investigators reported that they have no relevant financial relationships.