Enterovirus as trigger of coeliac disease: nested case-control study within prospective birth cohortBMJ 2019; 364 doi: https://doi.org/10.1136/bmj.l231 (Published 13 February 2019) Cite this as: BMJ 2019;364:l231
- Christian R Kahrs, consultant paediatrician123,
- Katerina Chuda, undergraduate student4,
- German Tapia, senior researcher2,
- Lars C Stene, senior researcher2,
- Karl Mårild, senior researcher5,
- Trond Rasmussen, head engineer6,
- Kjersti S Rønningen, senior researcher7,
- Knut E A Lundin, professor89,
- Lenka Kramna, researcher4,
- Ondrej Cinek, professor4,
- Ketil Størdal, senior researcher12
- 1Department of Pediatrics, Østfold Hospital Trust, Grålum, Norway
- 2Norwegian Institute of Public Health, Oslo, Norway
- 3Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- 4Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic
- 5Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at University of Gothenburg and Queen Silvia Children's Hospital, Gothenburg, Sweden
- 6Department of IT and e-health, Division of Institute Resources, Norwegian Institute of Public Health, Oslo, Norway
- 7Department of Pediatric Research, Oslo University Hospital, Oslo, Norway
- 8Department of Gastroenterology, Oslo University Hospital Rikshospitalet, Oslo, Norway
- 9K.G. Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway
- Correspondence to: K Størdal @ketil_st on Twitter) (or
- Accepted 14 January 2019
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.
Contributors: CRK and KS coordinated the coeliac disease sub-study in MIDIA, wrote the analysis plans, and had the primary responsibility for writing the paper. KS and LCS supervised the study, interpreted the data, and reviewed and commented on all drafts. GT did the statistical analysis, contributed with reagents/materials/analysis tools, and reviewed and commented on drafts. OC supervised the laboratory testing of virus PCR, contributed with analysis tools, and reviewed and commented on the data analysis. KC and LK did the laboratory testing of virus PCR and reviewed and commented on drafts. KSR designed the MIDIA study and reviewed and commented on the data analyses. TR, KL, and KM reviewed and contributed to the data processing. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. KS is the guarantor.
Funding: The Research Council of Norway (grant numbers 205086/F20 to GT, 166515/V50 to KSR) and the Project for the Conceptual Development of Research Organization 00064203 (University Hospital Motol, Prague, Czech Republic). CRK received grant support from Østfold Hospital Trust, Kalnes, Norway, and KS received grant support from Oak Foundation, Geneva, Switzerland. The EliA Celikey and EliA Gliadin kits were supported by Thermo Fisher Scientific, Norway. The Norwegian Coeliac Society supported the study financially. The funders had no influence on the contents of this paper.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work other than that described above; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Ethical approval: The study was approved by the Regional Committee for Medical Research Ethics. Written informed consent was obtained from the parents.
Data sharing: The individual raw data are provided in supplementary figure B. The Stata codes for all data handling and analyses are available on request from the corresponding author. Norwegian legislation prevents publication of the full dataset, but data supporting the presented results are available from the authors on reasonable request.
Transparency: The lead author (the manuscript’s guarantor) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
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