Very early introduction of high-dose gluten was associated with a lower prevalence of celiac disease at 3 years of age in a prespecified secondary analysis from the Enquiring About Tolerance (EAT) infant food allergy prevention trial.
None of the infants in the analysis randomized to the gluten early introduction arm of the study had developed celiac disease by 3 years of age, compared to 1.4% of children for whom exclusive breastfeeding was recommended for at least the first 6 months of life (risk difference 1.4 percentage points, 95% CI 0.6-2.6; P=0.02).
Earlier randomized trials exploring early-life gluten consumption for the prevention of celiac disease showed little or no association between the timing of wheat introduction and disease prevalence, but the findings from the EAT trial analysis “suggest that it may have been premature to discount the effect of age of introduction of gluten on the development of celiac disease,” reported Gideon Lack, MB, BCh, of King’s College London, and colleagues.
Writing in JAMA Pediatrics, the researchers concluded that new randomized clinical trials are warranted “to address the question of whether early introduction of high-dose gluten is an effective strategy for the prevention of celiac disease.”
Pediatric food allergy specialist and researcher Ruchi Gupta, MD, of Northwestern University in Chicago, who was not involved with the analysis, told MedPage Today that the findings suggest high doses of gluten and early introduction could drive protection against celiac disease.
Of four previously reported randomized trials exploring a possible connection, only one — the PreventCD study, published in 2014 — introduced wheat before the age of 6 months, and in that trial the initial daily dose was low (100 mg). It showed no reduction in celiac disease compared to placebo.
The recommended minimum daily dose of gluten in the EAT trial was around 500 mg per day beginning as early as 4 months of age.
“The suggestion that giving a high dose of gluten at a very young age could prevent celiac disease is something that hasn’t really been explored,” Gupta said.
She noted that the EAT study was conducted following the landmark LEAP trial, which showed early introduction of peanuts to significantly reduce peanut allergy at 5 years of age. Based on the LEAP findings, guidelines in the U.S. were changed to recommend early peanut introduction, rather than avoidance, for children at high risk for peanut allergies.
Primary results from EAT were published in 2016, covering early introduction of six allergic foods — peanut, sesame, egg, cow’s milk, cod fish, and wheat — in 1,303 children in the U.K. from the general population randomized to introduction of the foods beginning at 4 months of age (early introduction) or exclusive breastfeeding until at least the age of 6 months (standard introduction). That analysis showed no benefit for early introduction of the foods in the intention to treat analysis, though with the suggestion of a benefit at higher doses in the per-protocol analysis.
The newly published prespecified analysis, which included data from 1,004 study participants, was conducted to further explore the possible role of dosage and timing of wheat introduction in the development of celiac disease.
Mean age at introduction in the early introduction group (EIG) was 4 months (range 4-33 months), versus 7 months in the standard introduction group (SIG; range 5-21 months). At ages 4-5 months, just 2.3% of children in the SIG group had been introduced to gluten, compared to 69.5% of children in the EIG group.
Mean quantity of gluten consumed at ages 4-6 months was 0.49 (SD 1.40) g/wk in the SIG and 2.66 (SD 1.85) g/wk with early introduction (P<0.001).
Mean weekly gluten consumption ranged from 0.08 (SD 1.00) g/wk at age 4 months to 0.9 (SD 2.05) g/wk at age 6 months among controls; with early introduction, it was 1.3 (SD 1.54) g/wk at age 4 months to 4.03 (SD 2.40) g/wk at age 6 months.
“The EAT study differs in comparison with [previous] trials because gluten was introduced from age 4 months and in larger quantities, which is more representative of an age-appropriate portion size,” the researchers wrote. “[I]t may therefore be that both an early introduction and large quantity of gluten are needed to reduce the prevalence of celiac disease in childhood.”
“Our study raises the question as to whether the PreventCD study would have obtained different results if infants had consumed greater quantities of gluten, more similar to those consumed by families in the observational literature from which the early introduction hypothesis originated,” the researchers wrote.
A study limitation cited by the researchers was the diagnosis of celiac disease at different treatment centers.
Gupta noted that the relatively short time frame of follow-up could also be considered a study limitation.
“Food allergies typically present in young children, but celiac disease may not present until the teens or even adulthood,” she said, adding that 3 years of follow-up may not have been long enough.
The EAT study was jointly funded by the UK Food Standards Agency and the Medical Research Council.
Lack reported relationships with the U.K. Food Standards Agency, Medical Research Council, National Institute for Health Research (NIHR), National Peanut Board, Davis Foundation, DBV Technologies, Mighty Mission Me, Novartis, Sanofi Genzyme, Regeneron, and ALK Abello. One co-author also reported a relationship with DBV Technologies.