Du Toit G, Roberts G, Sayre PH, et al; LEAP Study Team. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015;372(9):803-813.
Randomized, open-label, controlled trial
Six hundred forty infants between the ages of 4 months and 11 months old with severe eczema, egg allergy, or both
Study Parameters and Primary Outcomes
Participants were evaluated for peanut allergy via skin-prick test at baseline and were randomized into 2 groups based on this finding. Each group was then further divided into 2 groups: 1 group was instructed to consume 6 g of peanut snack per week and the other group was advised to avoid peanuts. Peanut intake was maximized at 3.9 g in those who had a positive skin-prick test. The peanut snack was distributed in 3 meals a week until the children reached 60 months of age.
Clinical assessments were taken at baseline (4-11 mo of age) and again when the child reached 12 months, 30 months, and 60 months old. The assessments included skin-prick testing; serum levels of peanut immunoglobulin (Ig)E, IgG, and IgG4; and peanut IgG4:IgE ratio. The primary outcome was the proportion of patients with a peanut allergy at 60 months of age as determined secondary to an oral food challenge.
Of 640 infants, 542 had negative skin-prick tests at baseline. In those with a negative baseline peanut allergy test, 13.7% of the avoidance group and 1.9% of the consumption group were allergic to peanuts at 60 months. This statistically significant difference represents an 86.1% reduction in peanut allergy prevalence.
At baseline, 98 children had positive skin-prick tests. In this group, 35.3% of the avoidance group and 10.6% of the consumption group were allergic to peanuts at 60 months. This statistically significant difference represents a 70.0% reduction in peanut allergy prevalence.
A significant increase in wheal size was found in the peanut-avoidance group only. Patients who were allergic to peanuts at month 60 also had higher peanut IgE levels at that time. Peanut IgE levels increased over time in both the peanut-avoidance and consumption groups, but there were few participants in the consumption group who had very high peanut IgE levels. The levels of peanut IgG and IgG4 were higher in the consumption group than the avoidance group.
Peanut allergies are on the rise and clinicians, parents, and patients want to know why. One theory is the delayed consumption of peanuts in children. A 2008 study found that Jewish children in the United Kingdom have a statistically significant greater prevalence of peanut allergies than Jewish children in Israel. The authors state that the major difference between the children in the 2 regions is the timing of peanut introduction. Peanut exposure is avoided in UK infants. However, infants in Israel have a high amount of peanut exposure.1 Until 2008, the American Academy of Pediatrics encouraged parents to avoid feeding peanuts to babies with any risk of allergy.
The implications of the present study on peanut allergies include the realization that introducing peanuts at an early age appears to be safe and well tolerated even in those who have a positive skin-prick test to peanut and no adverse reaction upon consumption.
Many studies have questioned the validity of food-allergen avoidance in infancy. One study evaluated the relationship between timing of solid food introduction in infancy and the presence of atopy at 6 years old in 2,073 children.2 The authors found that delaying introduction of solid foods past 4 months or 6 months did not reduce the incidence of developing atopic conditions, and those children who with delayed solid food introduction had more frequent food allergies. A 2007 prospective study assessed the association between solid food exposure and eczema.3 Among 4,753 infants, there was an increased risk of eczema for those who avoided egg in the first year of life. The authors of that study rejected the notion of delayed solid food introduction and stated that allergenic foods should not be delayed past 6 months of age in order to prevent atopy. A 2013 publication by Palmer et al concluded that the trend towards lower egg allergy prevalence in infants fed eggs early in life, when studied against a control group, alleviates concerns that early introduction of allergenic foods poses an increased risk for allergy.4 However, in the Palmer study, no protective effect against development of atopy was found by introducing egg early in life either. Additionally, the study found that early egg introduction does significantly elevate egg IgG4 antibody levels.
The implications of the present study on peanut allergies include the realization that introducing peanuts at an early age appears to be safe and well tolerated even in those who have a positive skin-prick test to peanut and no adverse reaction upon consumption. In these patients, limiting peanut intake to 3.9 g per week is advised. Unlike the previously mentioned egg study, there was a drastic protective effect noted in those eating peanuts, regardless of whether there was a baseline reaction via skin prick test or not.
Another interesting finding of this study is the significantly higher elevation of peanut-specific IgG4 in the consumption group compared to the avoidance group. This confirms Palmer’s findings, which also showed a significant elevation in egg-specific IgG4 with early egg exposure. The mechanism may be similar to that of peanut oral immunotherapy (POIT). POIT results in suppression of mast cells, basophils, and IgE-positive B cells through exposure to allergens in small doses over long periods of time.5 With exposure to small doses of allergens over a long period of time, B cells start to favor the production of IgG4 over IgE, indicating a shift of the immune response from Th2 dominance to Th1 dominance.6 While this immune shift may explain the reduction in atopy and food allergies, excessive antigen-specific IgG4 antibodies may pose other unknown health risks. For example, there is an established correlation between early cow’s milk ingestion and Th1 dominant type 1 diabetes mellitus (TIDM). A 2013 article explains that TIDM has an earlier age of onset, around 4 years old, for those infants exposed to cow’s milk under 3 months of age, and the overall risk for TIDM is highest when milk is given before a child is 4 months old.7 Further research should be done regarding the effect of early solid food introduction on Th1 dominance and the incidence of Th1-dominant autoimmune disorders.
In addition to promoting IgG4 antibody production, oral immunotherapy may also achieve clinical effect by induction of regulatory T cells (Tregs), which dampen allergic responses. One study evaluated peanut-allergic participants undergoing oral immunotherapy to peanut protein for 24 months, followed by a 3-month withdrawal period and an oral food challenge at 27 months. The study found that those undergoing oral immunotherapy had a higher number of peanut-specific Tregs 12 months after initiating therapy. In addition to the number of Tregs, epigenetic changes were observed in those who gained and then maintained a tolerance to peanuts. This implies that it is not just number of the Tregs but also their function that confers immune tolerance or its absence.8 This implication also may allay some of our concerns that there may be increased autoimmune risk from increased antigen-specific IgG4 antibody production.
[Editors' note: For additional information on the health benefits of peanuts, read "Heart-health Benefits of Peanuts" in this issue of Natural Medicine Journal.]
- Du Toit G, Katz Y, Sasieni P, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol. 2008;122(5):984-991.
- Zutavern A, Brockow I, Schaaf B, et al. Timing of solid food introduction in relation to eczema, asthma, allergic rhinitis, and food and inhalant sensitization at the age of 6 years: results from the prospective cohort birth study LISA. Pediatrics. 2008;121(1):44-52.
- Filipiak B, Zutavern A, Koletzko S, et al. Solid food introduction in relation to eczema: results from a four-year prospective birth cohort study. J Pediatr. 2007;151(4):352-358.
- Palmer DJ, Metcalfe J, Makrides M, et al. Early regular egg exposure in infants with eczema: A randomized controlled trial. J Allergy Clin Immunol. 2013;132(2):387-392.
- Santos AF, James LK, Bahnson HT, et al. IgG4 inhibits peanut-induced basophil and mast cell activation in peanut-tolerant children sensitized to peanut major allergens. J Allergy Clin Immunol. 2015 Feb 7. [Epub ahead of print]
- Matsuoka T, Shamji MH, Durham SR. Allergen immunotherapy and tolerance. Allergol Int. 2013;62(4):403-13.
- Kamal Alanani NM, Alsulaimani AA. Epidemiological pattern of newly diagnosed children with type 1 diabetes mellitus, Taif, Saudi Arabia. Sci World J. 2013 Oct 9;2013:421569.
- Syed A, Garcia MA, Lyu SC, et al. Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3). J Allergy Clin Immunol. 2014;133(2):500-510.