Parechovirus infection in early childhood and association with subsequent celiac disease

ABSTRACT Importance Celiac disease is an increasingly common immune-mediated disorder. The potential role of infections in celiac disease development is not well characterized. Objective To test whether two frequent enteric viruses, parechovirus and anellovirus, were associated with subsequent celiac disease. Our a priori hypothesis was that children who later developed celiac disease would have a higher frequency of parechovirus infections before transglutaminase 2 antibody development. Anellovirus testing was exploratory, as a potential marker of immune status. Design Matched case-control design nested within a longitudinal birth cohort (the MIDIA study) of children at genetic risk for celiac disease. Setting Children carrying the HLA genotype DR4-DQ8/DR3-DQ2, recruited at birth from the general population throughout Norway during 2001–2007. Participants Of 220 genetically at-risk children tested for celiac disease, 25 fulfilled the case criteria. Each case was matched for follow-up time, birthdate, and county of residence with two randomly selected children free from celiac disease (controls) from the cohort. Exposures Parechoviruses, the primary exposure, are infectious agents capable of replication at high virus loads. Anellovirus, previously proposed to reflect immune status, represent a ubiquitous viral exposure at low loads. Viruses were detected and quantified in monthly stool samples (collected from 3 through 35 months of age) using real-time PCR methods. Main outcome and measures Celiac disease diagnosis according to ESPGHAN 2012 criteria. We retrospectively tested blood samples taken at age 3, 6, 9, and 12 months, and then annually to determine when transglutaminase 2 antibodies developed. Results Parechovirus was detected in 222 of 2005 stool samples (11.1%), and was more frequent in samples from cases before developing transglutaminase 2 antibodies (adjusted odds ratio [aOR] 1.67, 95% CI 1.14–2.45, P=0.01). The odds ratio was higher when both parechovirus and enterovirus were positive in the same sample (aOR 4.73, 95% CI 1.26–17.67, P=0.02). Anellovirus was detected in 1540 of 1829 samples (84.2%). Anellovirus status did not differ significantly between case and control subjects. Conclusions and Relevance Parechovirus infections in early life were associated with development of celiac disease in genetically at-risk children, suggesting a novel preventive target if confirmed in future studies. Key points Question Are parechovirus infections associated with development of celiac disease in childhood? Findings In this case-control study, nested in a cohort of children genetically at risk for celiac disease, a higher frequency of parechovirus gut infections (tested in monthly stool samples) were associated with later celiac disease. Coinfection with both parechovirus and enterovirus was associated with a markedly increased risk for later celiac disease. Meaning The association observed between parechovirus and future celiac disease, suggests that these common enteric infections could play a role in celiac disease development.