Convergent data from a variety of sources clearly indicate that food allergy (FA) prevalence has markedly increased over recent decades.1-4 IgE-mediated food allergy is now estimated to directly affect roughly 8% of U.S. children and 11% of U.S. adults, rendering it of major public health importance.5,6 Of U.S. children and adults with FA, nearly half are estimated to have current allergies to multiple foods.7 Both genetic and environmental factors are implicated in the development of food allergies. Research indicates moderate associations between family history of FA (and other allergic diseases like atopic dermatitis and asthma) and increased risk of pediatric FA.8 However, most children with FA do not have a parent with a FA,9 which highlights the importance of early life environmental exposures—the most important of which is arguably the infant diet.
Delay in introducing commonly allergenic solids (e.g. peanut protein, cow’s milk, hen’s egg) has been linked observationally to increased risk of developing allergic conditions, including not only FA, but also asthma and allergic rhinitis.10-12 While the mechanisms for FA development are clearly multi-factorial, a prominent theory — the Dual Allergen Exposure Hypothesis — proposes that when infants are exposed to food proteins through the skin, particularly via an altered, inflamed skin barrier (as can occur in infants with severe eczema), it can promote pro-allergic immune pathways and lead to FA.13 In contrast, according to this Dual Allergen Exposure Hypothesis, oral introduction of commonly allergenic solids—where the infant’s immune system receives its first exposure to these food proteins via their gastrointestinal tract—helps establish an appropriate, (i.e. “tolerogenic”) immune response.
The first rigorous test of this theory was the seminal Learning Early About Peanut (LEAP) study, which showed that introducing developmentally appropriate peanut-containing foods (e.g. Bamba® peanut puffs) between 4-11 months of age in “high-risk” infants (defined as those with eczema and/or egg allergy) resulted in an 81% reduced risk of peanut allergy development by 5 years of age.14 Participants in the intervention group were instructed to feed the baby at least 6g of peanut protein per week, whereas the control group was instructed not to feed any peanut-containing foods. Adherence to the prescribed study protocol was very high among participants, and the very strong preventive effect of early introduction of peanut prompted the National Institute of Allergy and Infectious Diseases (NIAID) to sponsor the 2017 Addendum Guidelines for the Prevention of Peanut Allergy. These guidelines, which remain in effect today, recommend introducing peanut-containing foods at 4-6 months of age to high-risk infants, around 6 months to infants at moderate risk (i.e. those with mild-to-moderate eczema), and in accordance with family preference and cultural practices for the remaining infants deemed at low risk.15
However, while the LEAP study provided valuable data about the primary prevention of peanut allergy, peanut is only one of many commonly allergenic solids and accounts for only a small proportion of the total population-level burden of FA. The single center Enquiring About Tolerance (EAT) randomized controlled trial conducted in the United Kingdom, explored whether the early, deliberate introduction of multiple commonly allergenic solids—cow's milk, peanut, hen's egg, sesame, cod, and wheat—into the infant diet, beginning at 3 months of age, could prevent allergy to these foods.16-18 In this study, 1,303 infants were randomized at 3 months of age to an early introduction group (EIG) with breastfeeding followed by sequential introduction (randomized order of introduction) of 6 allergenic foods or a control group that was exclusively breastfed. The standard introduction group (SIG) followed the UK infant feeding recommendations of exclusive breastfeeding for around 6 months with no introduction of allergenic foods before 6 months of age.
While the intention-to-treat analysis did not identify a statistically significant reduction in FA to ≥1 foods by 1-3 years of age (5.6% in the EIG vs. 7.1% in the exclusively breastfed group, p=0.32), the per protocol analysis found significantly lower prevalence of FA in the EIG group (2.4% vs. 7.3%, p=0.01). The observed difference in FA prevalence was driven by significantly lower prevalence of peanut (0% vs. 2.5%, p=0.003) and egg allergies (1.4% vs. 5.5%, p=0.009) among members of the early peanut introduction group who were adherent to the intervention, compared to the control participants who did not introduce these allergens according to the protocol. While a difference in peanut (1.2% vs. 2.5%, p=0.11) and egg (3.7% vs. 5.4%, p=0.17) allergy prevalence was still present among the EAT study’s intent-to-treat population for both allergens, for neither allergen was this difference statistically significant. However, the failure to detect a significant intervention effect associated with early allergen introduction in the intent-to-treat population must be considered in the context of the low observed rates of adherence to the recommended early introduction protocol. Overall, only 42% of participants assigned to the EIG met the criteria for adherence (3g of allergen protein per week for at least 5 weeks between 3 and 6 months of age). However, it is notable that among infants with visible eczema at enrollment, those in the EIG were significantly less likely to develop any FA (SIG, 46.7%; EIG, 22.6%; P=0.048). Crucially, introduction of multiple allergenic foods during the first year of life in the EAT study did not affect the growth of the participants or the duration of breastfeeding and was safe.
Since publication of the EAT study, numerous randomized trials have explored the effectiveness of early introduction of commonly allergenic solids, namely milk and egg, for primary prevention of allergy to those foods. For example, the Japanese PETIT trial was terminated early due to the strong preventive effect of egg protein introduction (29.4% risk difference) between 4-6 months of age among a high-allergy risk population.19 More recent data from the Japanese SPADE study also indicate that even earlier introduction of cow’s milk between 1-2 months can prevent cow’s milk allergy in a general population sample while not competing with breastfeeding.20 Finally, the Scandinavian PreventADALL study recently concluded that FA (measured at 3 years of age) can be prevented by the introduction of peanut, cow’s milk, egg, and wheat in small quantities starting at 3 months of age.21 Like the EAT study, this study found that early introduction of commonly allergenic solids is safe in a general population sample and that it did not interfere with breastfeeding.
Overall, the LEAP and EAT studies along with the more recent studies summarized above support the safety of deliberate introduction of peanut and other highly allergenic food proteins along with other complementary foods during infancy and demonstrate the potential of such approaches to reduce FA incidence early in life among all risk strata.22 This emerging evidence was recently considered by an international work group comprised of experts from all major North American Allergy Societies, who issued a new “Consensus Approach to the Primary Prevention of Food Allergy through Nutrition.” This work group concluded that there “is strong evidence supporting that peanut-containing foods should be introduced into the infant’s diet starting around 6 months of life, but not before 4 months of life, and that cooked egg/egg-containing products (e.g. boiled, scrambled, or baked egg) should be introduced in a similar time frame.”
With respect to other common food allergens, the work group recommended to “not deliberately delay the introduction of other potentially allergenic complementary foods (cow’s milk, soy, wheat, tree nuts, sesame, fish, shellfish), once introduction of complementary foods has commenced at around 6 months of life but not before 4 months.” 23
Taken together, these data provide strong support for the safety and effectiveness of early introduction of allergenic solids for the primary prevention of FA. Many questions remain regarding the optimal dose, timing, frequency, and format of how these foods should be introduced for maximum preventive benefit; however, given the population’s growing burden of FA it is imperative that we find answers. One such effort is the CAN DO study, which is currently underway at Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University, and Rush University medical centers. This study is testing the effectiveness of early, frequent introduction of small amounts of commonly allergenic solids (including soy yogurt) starting around 4 months of age for prevention of allergic disease. The results of this study aim to inform the next generation of infant feeding guidelines and help pave the way to a healthier, less food-allergic future.
- Ma L, Danoff TM, Borish L. Case fatality and population mortality associated with anaphylaxis in the United States. J Allergy Clin Immunol. Apr 2014;133(4):1075-83. doi:10.1016/j.jaci.2013.10.029
- Rudders SA, Banerji A, Vassallo MF, Clark S, Camargo CA, Jr. Trends in pediatric emergency department visits for food-induced anaphylaxis. J Allergy Clin Immunol. Aug 2010;126(2):385-8. doi:10.1016/j.jaci.2010.05.018
- Branum AM, Lukacs SL. Food allergy among U.S. children: trends in prevalence and hospitalizations. NCHS Data Brief. Oct 2008;(10):1-8.
- Keet CA, Savage JH, Seopaul S, Peng RD, Wood RA, Matsui EC. Temporal trends and racial/ethnic disparity in self-reported pediatric food allergy in the United States. Ann Allergy Asthma Immunol. Mar 2014;112(3):222-229 e3. doi:10.1016/j.anai.2013.12.007
- Gupta RS, Warren CM, Smith BM, et al. The Public Health Impact of Parent-Reported Childhood Food Allergies in the United States. Pediatrics. Dec 2018;142(6)doi:10.1542/peds.2018-1235
- Gupta RS, Springston EE, Warrier MR, et al. The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics. Jul 2011;128(1):e9-17. doi:10.1542/peds.2011-0204
- Warren CM, Aktas O, Manolo L,Bartell T, Gupta RS The Epidemiology of Multi-food Allergy in the United States-A population-based study Annals of Allergy, Asthma & Immunology. 2022 Dec 31;S1081-1206(22)02012-9.
- Zaslavsky JM. Family History of Atopy in Food Allergy Development. J Allergy Clin Immunol. 2019;143, AB83
- Koplin JJ, Allen KJ, Gurrin LC, Peters RL, Lowe AJ, Tang ML, Dharmage SC, HeaKoplin JJ, Allen KJ, Gurrin LC, Peters RL, Lowe AJ, Tang ML, Dharmage SC, HealthNuts Study Team. The impact of family history of allergy on risk of food allergy: a population-based study of infants. International journal of environmental research and public health. 2013 Nov;10(11):5364-77.lthNuts Study Team. The impact of family history of allergy on risk of food allergy: a population-based study of infants. International journal of environmental research and public health. 2013 Nov;10(11):5364-77.
- Roduit C, Frei R, Depner M, et al. Increased food diversity in the first year of life is inversely associated with allergic diseases. J Allergy Clin Immunol. Apr 2014;133(4):1056-64. doi:10.1016/j.jaci.2013.12.1044
- Venter C, Maslin K, Holloway JW, et al. Different Measures of Diet Diversity During Infancy and the Association with Childhood Food Allergy in a UK Birth Cohort Study. J Allergy Clin Immunol Pract. Jun
- 2020;8(6):2017-2026. doi:10.1016/j.jaip.2020.01.029
- Nwaru BI, Takkinen HM, Kaila M, et al. Food diversity in infancy and the risk of childhood asthma and allergies. J Allergy Clin Immunol. Apr 2014;133(4):1084-91. doi:10.1016/j.jaci.2013.12.1069
- Lack G. Early exposure hypothesis: where are we now? ClinTransl Allergy. 2011;1, S71
- Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. Feb 26 2015;372(9):803-13. doi:10.1056/NEJMoa1414850
- Togias A, Cooper SF, Acebal ML, et al. Addendum guidelines for the prevention of peanut allergy in the United States: Report of the National Institute of Allergy and Infectious Diseases-sponsored expert panel. J Allergy Clin Immunol. Jan 2017;139(1):29-44. doi:10.1016/j.jaci.2016.10.010
- Perkin MR, Logan K, Bahnson HT, et al. Efficacy of the Enquiring About Tolerance (EAT) study among infants at high risk of developing food allergy. J Allergy Clin Immunol. Dec 2019;144(6):1606-1614 e2. doi:10.1016/j.jaci.2019.06.045
- Perkin MR, Logan K, Marrs T, et al. Enquiring About Tolerance (EAT) study: Feasibility of an early allergenic food introduction regimen. J Allergy Clin Immunol. May 2016;137(5):1477-1486. 8. doi:10.1016/j.jaci.2015.12.1322
- Perkin MR, Logan K, Tseng A, et al. Randomized Trial of Introduction of Allergenic Foods in Breast-Fed Infants. N Engl J Med. May 5 2016;374(18):1733-43. doi:10.1056/NEJMoa1514210
- Natsume O, Kabashima S, Nakazato J, Yamamoto-Hanada K, Narita M, Kondo M, Saito M, Kishino A, Takimoto T, Inoue E, Tang J. Two-step egg introduction for prevention of egg allergy in high-risk infants with eczema (PETIT): a randomised, double-blind, placebo-controlled trial. The Lancet. 2017 Jan 21;389(10066):276-86.
- Sakihara T, Otsuji K, Arakaki Y, Hamada K, Sugiura S, Ito K. Randomized trial of early infant formula introduction to prevent cow’s milk allergy. Journal of Allergy and Clinical Immunology. 2021 Jan 1;147(1):224-32.
- Skjerven HO, Lie A, Vettukattil R, Rehbinder EM, LeBlanc M, Asarnoj A, Carlsen KH, Despriee ÅW, Färdig M, Gerdin SW, Granum B. Early food intervention and skin emollients to prevent food allergy in young children (PreventADALL): a factorial, multicentre, cluster-randomised trial. The Lancet. 2022 Jun 25;399(10344):2398-411.
- Logan K, Bahnson HT, Ylescupidez A, Beyer K, Bellach J, Campbell DE, Craven J, Du Toit G, Clare Mills EN, Perkin MR, Roberts G. Early introduction of peanut reduces peanut allergy across risk groups in pooled and causal inference analyses. Allergy. 2022 Dec 11.
- Fleischer DM, Chan ES, Venter C, Spergel JM, Abrams EM, Stukus D, Groetch M, Shaker M, Greenhawt M. A consensus approach to the primary prevention of food allergy through nutrition: guidance from the American Academy of Allergy, Asthma, and Immunology; American College of Allergy, Asthma, and Immunology; and the Canadian Society for Allergy and Clinical Immunology. The Journal of Allergy and Clinical Immunology: In Practice. 2021 Jan 1;9(1):22-43.