Early infections are associated with increased risk for celiac disease: an incident case-referent study

Abstract

Background: Celiac disease is defined as a 'chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals'. Sweden has experienced an "epidemic" of celiac disease in children below two years of age. Celiac disease etiology is considered multifactorial; however, little is known regarding potential risk- or protecting factors. We present data on the possible association between early infectious episodes and celiac disease, including their possible contribution to the Swedish celiac disease epidemic.

Methods: A population-based incident case-referent study (475 cases, 950 referents) with exposure information obtained via a questionnaire (including family characteristics, infant feeding, and the child's general health) was performed. Celiac disease cases were diagnosed before two years of age, fulfilling the diagnostic criteria of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition. Referents were randomly selected from the national population register after fulfilling matching criteria. The final analyses included 954 children, 373 (79%) cases and 581 (61%) referents, with complete information on main variables of interest in a matched set of one case with one or two referents.

Results: Having three or more parental-reported infectious episodes, regardless of type of infection, during the first six months of life was associated with a significantly increased risk for later celiac disease, and this remained after adjusting for infant feeding and socioeconomic status (odds ratio [OR] 1.5; 95% confidence interval [CI], 1.1-2.0; P=0.014). The celiac disease risk increased synergistically if, in addition to having several infectious episodes, infants were introduced to dietary gluten in large amounts, compared to small or medium amounts, after breastfeeding was discontinued (OR 5.6; 95% CI, 3.1-10; P<0.001).

Conclusion: This study suggests that having repeated infectious episodes early in life increases the risk for later celiac disease. In addition, we found a synergistic effect between early infections and daily amount of gluten intake, more pronounced among infants for whom breastfeeding had been discontinued prior to gluten introduction. Regarding contribution to the Swedish celiac disease epidemic, which partly was attributed to concurrent changes in infant feeding, early infections probably made a minor contribution via the synergistic effect with gluten amount.

Figure 1

Flow chart depicting participation in the study. Numbers of children and percentages are given in the boxes. In total, 714 children with suspected celiac disease (abbreviated as CD in the figure) were reported to the register. Consent to participate was obtained for 475 cases below two years of age with a celiac disease diagnosis based on three consecutive small intestinal biopsies. Boxes with dotted lines indicate excluded children. Two referents to each case were randomly selected after matching criteria were fulfilled. Grey shaded areas indicate invited infants and those included in the final analysis.

Figure 2

Interaction between early infectious episodes and gluten amount. Large amount of gluten-containing foods is represented by solid lines, and dotted line represents small-medium amounts. An interaction i.e. a synergistic effect, between infectious episodes and gluten is depicted by the non-parallelism between the two lower and two upper lines. The interaction was more pronounced in infants when breastfeeding was discontinued prior to gluten introduction. Odds ratios with 95% confidence intervals, with reference 0–2 early infections, gluten introduced in small-medium amounts during on-going breastfeeding, listed from lowest to highest risk estimate were; 1.2 (0.8-2.1), 1.8 (1.1-2.9), 2.6 (1.4-5.0), 2.7 (1.7-4.3), 2.9 (1.8-4.5), 3.2 (1.8-5.9) and 5.6 (3.1-10).