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Early Allergen Introduction for Preventing Development of Food Allergy.

In 2000, the American Academy of Pediatrics (AAP) recommended that “solid foods should not be introduced into the diet of high-risk infants until 6 months of age, with dairy products delayed until 1 year, eggs until 2 years, and peanuts, nuts, and fish until 3 years of age” in “infants at high risk for developing allergy, identified by a strong (biparental, parent, and sibling) family history of allergy” to help prevent food allergy from developing.1 In 2008, the AAP revised this guidance, stating that new evidence raised “serious questions about the benefit of delaying the introduction of solid foods that are thought to be highly allergic.” A recommendation to not delay solid food introduction beyond 4 to 6 months of life was issued but offered no guidance regarding an optimal timing of introduction.2 However, the estimated prevalence of food allergy in the United States nearly doubled (from 3.4% to 5.1%) between 1999 and 2009, and the estimated prevalence of peanut allergy tripled (from 0.4% to 1.4%) between 1999 and 2011, although it is unclear if guidance regarding delayed introduction of allergenic foods contributed to these increases or how well the 2008 guidance has been followed.3-5 Since the mid-2000s, additional data have demonstrated that early introduction of some dietary allergens may have protective effects against the development of food allergy. This evidence, some of which prompted the 2008 revised recommendations, has evolved from large observational cohorts to more targeted randomized clinical trials.6 In this issue of JAMA, Ierodiakonou and colleagues7 report findings from a systematic review and meta-analysis evaluating this evidence, concluding there is “moderate-certainty” evidence supporting the association between introduction of peanut between ages 4 and 11 months and egg between ages 4 and 6 months and reduction in the risk of developing peanut allergy (risk ratio [RR], 0.29; 95% CI, 0.11-0.74 based on 2 randomized clinical trials with 1550 children) or egg allergy (RR, 0.56; 95% CI, 0.36-0.87 based on 5 trials with 1915 children). The authors also found low-certainty evidence that early fish introduction was associated with reduced allergic sensitization and high-certainty evidence that early gluten introduction was not associated with celiac disease risk. No evidence was found for any effect of the early introduction of other foods or for other allergic or autoimmune outcomes.7 The meta-analysis by Ierodiakonou and colleagues provides statistical support for the concept that early introduction of egg and peanut is associated with reducing the risk of developing these food allergies, but this conclusion should be cautiously interpreted. Even though the analysis found moderate-certainty evidence for a protective association for early dietary introduction of both peanut and egg, the authors were appropriately guarded in support of these findings based on the trial sequential analysis. This analysis was unable to be performed for peanut introduction because of insufficient data. For egg introduction, thousands of additional trial participants would be needed to confirm with reasonable certainty that early egg introduction has an effect size of a 30% risk reduction. Moreover, the individual studies contributing to the pooled estimates have concerns regarding generalizability and unknown effectiveness in clinical populations. Of the 2 peanut trials, only 1 evaluated exclusive peanut introduction. The Learning Early About Peanut Allergy study, which included 641 children, showed strong risk reduction for preventing peanut allergy (RR, 0.19; 95% CI, 0.10-0.36) but was conducted in a very narrowly selected high-risk population (infants 4 to 11 months of age with severe eczema, egg allergy, or both).8 The study used the unconventional approach of stratifying children based on screening for peanut sensitization using skin testing before randomization, an approach that is not recommended in clinical practice given that false-positive test results are common and that identification of sensitization alone does not indicate allergy without a corroborating history of symptomatic ingestion. Furthermore, the necessity and efficacy of the screening approach were never proven or empirically tested in the trial. Lack of replication of the data preclude determination of whether the definition of high risk could be expanded to include other food allergies more likely to be present in the first 4 to 6 months of life than egg allergy (eg, milk, wheat, or soy) or to infants with a family history of atopy.9 In the fall of 2016, the National Institute of Allergy and Infectious Diseases (NIAID)-sponsored policy will be released that formally recommends early peanut introduction for high-risk children as early as 4 to 6 months of age.10 Screening for peanut sensitization is being recommended to counter perceived reluctance of families to introduce peanut at home to high-risk infants despite its limitations and although its use raises challenges of practicality and resource utilization. The forthcoming NIAID-sponsored guideline reflects confidence in the evidence suggesting potential benefit of early peanut introduction with minimal risk, is supported by the findings of the meta-analysis by Ierodiakonou and colRelated article page 1181 Opinion