Enterovirus as trigger of coeliac disease: nested case-control study within prospective birth cohort

Abstract

Objective: To determine whether infection with human enterovirus or adenovirus, both common intestinal viruses, predicts development of coeliac disease.

Design: Case-control study nested within Norwegian birth cohort recruited between 2001 and 2007 and followed to September 2016.

Setting: Norwegian population.

Participants: Children carrying the HLA genotype DR4-DQ8/DR3-DQ2 conferring increased risk of coeliac disease.

Exposures: Enterovirus and adenovirus detected using real time polymerase chain reaction in monthly stool samples from age 3 to 36 months.

Main outcome measure: Coeliac disease diagnosed according to standard criteria. Coeliac disease antibodies were tested in blood samples taken at age 3, 6, 9, and 12 months and then annually. Adjusted odds ratios from mixed effects logistic regression model were used to assess the relation between viral infections before development of coeliac disease antibodies and coeliac disease.

Results: Among 220 children, and after a mean of 9.9 (SD 1.6) years, 25 children were diagnosed as having coeliac disease after screening and were matched to two controls each. Enterovirus was found in 370 (17%) of 2135 samples and was significantly more frequent in samples collected before development of coeliac disease antibodies in cases than in controls (adjusted odds ratio 1.49, 95% confidence interval 1.07 to 2.06; P=0.02). The association was restricted to infections after introduction of gluten. High quantity samples (>100 000 copies/μL) (adjusted odds ratio 2.11, 1.24 to 3.60; P=0.01) and long lasting infections (>2 months) (2.16, 1.16 to 4.04; P=0.02) gave higher risk estimates. Both the commonly detected enterovirus species Enterovirus A and Enterovirus B were significantly associated with coeliac disease. The association was not found for infections during or after development of coeliac disease antibodies. Adenovirus was not associated with coeliac disease.

Conclusions: In this longitudinal study, a higher frequency of enterovirus, but not adenovirus, during early childhood was associated with later coeliac disease. The finding adds new information on the role of viral infections in the aetiology of coeliac disease.

Fig 1

Enrolment of study sample. “Invited” children are those who were still actively participating (delivering samples, questionnaires) at start of coeliac disease sub-study and were invited to participate; “participated” are those who consented to participate and were screened for coeliac disease antibodies. *Two cases were excluded from analyses, one owing to missing stool samples and one owing to incorrect use of diagnostic criteria. †Children with positive coeliac disease antibodies at first screening test but for whom follow-up did not confirm coeliac disease diagnosis (n=10) were excluded from further analyses; control children with high antibody titres (>10 times cut-off) (n=2) in old samples but with normal values at screening were excluded and replaced by new controls selected using same matching criteria. ‡One matched control was excluded from analysis owing to missing stool samples

Fig 2

Timeline of study

Fig 3

Development of coeliac disease antibodies. Figure illustrating definition of before, during, and after development of coeliac disease antibodies. Dots represent faecal samples. Primary analysis included only stool samples collected up to age at last antibody negative blood sample for cases and corresponding age for matched controls. Pre-planned sub-analyses explored same association for stool samples collected during development of coeliac disease antibodies (between last negative and first antibody positive blood sample) and samples collected after first antibody positive blood sample