Enterovirus infection during early childhood triggers coeliac disease
A higher frequency of enterovirus, but not adenovirus, infection during early childhood may increase the risk of later coeliac disease, suggests a recent study, adding new data on the role of viral infections in the aetiology of coeliac disease.
After a mean of 9.9 years, 25 of 220 children were diagnosed with coeliac disease after screening and were matched to two controls each. Of the 2,135 blood samples taken, 370 (17 percent) tested positive for enterovirus, which was significantly more frequent in those collected before development of coeliac disease antibodies in patients than in controls (adjusted odds ratio [aOR], 1.49; 95 percent CI, 1.07–2.06; p=0.02). [BMJ 2019;364:l231]
Such association was limited to infections after gluten introduction. Risk estimates were higher in high quality samples (>100,000 copies/μL; aOR, 2.11; 1.24–3.60; p=0.01) and long-lasting infections (>2 months; aOR, 2.16; 1.16–4.04; p=0.02).
Coeliac disease was significantly associated with both commonly detected species of enterovirus (ie, Enterovirus A and Enterovirus B). This association did not appear for infections during or after development of coeliac disease antibodies. Moreover, no association was found between adenovirus infection and coeliac disease.
“Although the effect sizes are relatively small, this study suggests that infections with enterovirus in early life could be one among several key risk factors for development of a disease with lifelong consequences,” researchers said.
“Our observations suggest that, rather than a specific enterovirus species or type driving the association, several enterovirus types, high titre and long duration infections in the period after introduction of gluten were involved,” they added.
The collective results are compatible with a mechanism by which infections may disrupt the mucosal barrier with increased translocation of gluten peptides into the mucosa as the initial event in tolerance loss, according to researchers. [Cell Mol Gastroenterol Hepatol 2017;3:150-162]
Furthermore, they speculate that enteroviruses may provide a danger signal that can “activate dendritic cells acting as antigen presenting cells for CD4-positive gluten reactive T cells in the presence of transglutaminase-modified gluten peptides.” [Nat Rev Immunol 2013;13:294-230; Science 2002;296:301-305; Science 2017;356:44-50]
Enteric barrier disruption prior to autoantibodies development in patients with coeliac disease may explain the susceptibility to enterovirus. However, researchers surmise that enterovirus is the cause of impaired barrier functions, which then heightens the risk of coeliac disease.
The present case-control study is nested within the Norwegian birth cohort recruited between 2001 and 2007 and followed to September 2016. Participants included children carrying the HLA genotype DR4-DQ8/DR3-DQ2 conferring increased risk of coeliac disease.
Main outcomes measure was coeliac disease diagnosed according to standard criteria. Researchers tested coeliac disease antibodies in blood samples taken at age 3, 6, 9 and 12 months and then annually. The association between viral infections before development of antibodies and coeliac disease was assessed using aORs from mixed effects logistic regression model.
“Given the limited number of cases, we call for corroboration in similar studies and preferably interventional studies to reach conclusions about causality,” researchers said.