Du Toit G, Sayre PH, Roberts G, et al. Effect of avoidance on peanut allergy after early peanut consumption. N Engl J Med. 2016;374(15):1435-1443.
This study was a follow-up to the Learning Early About Peanut (LEAP) study in which 640 participants (4-11 months old upon enrollment) with severe eczema, egg allergy, or both were evaluated for peanut allergy with a skin prick test (SPT) at baseline. They were put into 2 groups: those with a positive SPT (wheal 1-4mm; n=98) and those with negative SPT (n=542). Each group was then further divided into 2 more cohorts; 1 was instructed to consume peanuts and the other was advised to avoid peanuts until the children reached 60 months of age.1 Primary outcome measure was the presence of peanut allergy at 60 months. The current study was intended to investigate the rate of peanut allergies in the peanut consumption group compared to the peanut avoidance group after all participants abstained from peanut consumption for 12 months (until 72 months of age).
Randomized, open-label, controlled trial
Participants were recruited from the primary LEAP study group. Data was completely available for 550 participants. Of those, 515 were selected to perform the oral peanut challenge. In the primary trial, these participants had undergone either a peanut avoidance or peanut consumption from baseline (4-11 months) until 60 months of age.
Study Parameters Assessed and Primary Outcome Measures
All participants were to avoid peanuts for 12 months after the conclusion of the original LEAP trial. The primary outcome measure was the percentage of participants who had peanut allergy at the end of this 12-month peanut-avoidance period. Since the primary trial ended when the children were 60 months old, this outcome was measured when the children were 72 months old. Participants (n=515) underwent an oral peanut challenge to determine the presence of peanut allergy at 72 months. Immunological parameters included IgE antibodies to peanut protein Ara h2, as well as peanut-specific immunoglobulin (Ig) G and IgG4 levels. The IgG4:IgE ratio was calculated (higher ratios signify immune modulation).
More research continues to support early introduction of allergenic foods to avoid allergy later in childhood.
Peanut allergy at 72 months was significantly more prevalent in the original peanut-avoidance group (18.6%) than in the peanut-consumption group (4.8%) (P<0.001). The IgE antibodies to peanut protein Ara h2 were less common in the peanut consumption group than in the peanut avoidance group at 72 months (P<0.001). Those in the consumption group continued to have elevated levels of peanut-specific IgG4 and higher peanut-specific IgG4:IgE ratios (P<0.001). More participants in the peanut-avoidance group had adverse events during follow-up, such as eczema, gastroenteritis, and respiratory infections (89.4%), compared to the peanut-consumption group (80.7%). The levels of Ara h2 IgE antibodies remained low at 72 months in the peanut-consumption group, while the levels were significantly higher at 72 months in the peanut-avoidance group (P<0.001). The average wheal size was smaller in the peanut-consumption group at 72 months as well, when compared to the peanut avoidance group (P<0.001).
Interestingly, a new peanut allergy developed in 3 participants of the peanut-consumption group and 3 participants of the peanut-avoidance group between 60 and 72 months of age. The IgG4:IgE peanut ratio declined in these 6 participants during this time.
In this study, peanut allergy incidence was lower in infants introduced to peanuts earlier in life compared to infants who avoided peanuts in infancy, and this effect persisted for 12 months after the introduction period. Those infants who consumed peanuts in their first year of life and until 60 months of age had 74% lower peanut allergy prevalence at 72 months of age after 1 year of peanut avoidance than those who avoided peanuts. This study did not find any significant increase in new peanut allergy incidence in those who avoided peanuts after having consumed them until 60 months of age. The authors conclude that early and prolonged peanut consumption should be recommended to reduce peanut IgE.
More research continues to support early introduction of allergenic foods to avoid allergy later in childhood. A February 2016 study of 300 children found that children with peanut allergies had a significantly greater age of first exposure to peanuts than children without peanut allergies.2 Another recent study of breastfed infants evaluated the effect of early allergenic food exposure. The infants were randomized to receive either early introduction of peanut, cooked egg, cow's milk, sesame, whitefish, and wheat or to follow standard recommendations of sole breastfeeding until 6 months of age.3 The prevalence of any food allergy was significantly lower in the group of infants who underwent early introduction compared to the control group. The prevalence of peanut and egg allergy was significantly lower in the early introduction group. However, these findings were found in per-protocol analysis only and not in the intention-to-treat analysis. While it appears to be practically difficult to introduce this many allergenic foods to infants, according to one recent study the early introduction is possible and does not appear to affect infant breastfeeding.4 Lastly, an April 2016 review of current literature supports these findings and concludes that early introduction of allergenic foods reduces the risk of food allergy.5
This current study is not the only study to demonstrate that when children consume common allergens sooner in life, their allergen-specific IgE seems to go down while allergen-specific IgG goes up. A 2013 study found this same result with early egg exposure.6 However, other studies have demonstrated opposite findings. A prospective study of 239 children followed from birth to age 5 found that those with positive peanut IgE antibodies who avoided consuming peanuts had high levels of peanut-specific IgG and IgG4 antibodies compared to non-sensitized children.7 This seems to contradict the findings of the current study (that those with lower peanut IgE have higher peanut IgG antibodies). However, reviews have concluded that peanut oral immunotherapy, that is, the introduction of peanut in low doses over time, does suppress the IgE response and elevate IgG4 antibodies as the immune system shifts away from a type 2 T helper (Th2)- dominant model.8 It appears that IgG4 antibodies may be used as an indicator of tolerance or as a marker of IgE suppression.9
Early consumption of peanuts appears to lead to higher levels of peanut-specific IgG4 antibodies, conferring some immune modulation of the IgE-based overt, allergic response. Small amounts of antigenic exposure slowly over time will induce B cells to produce IgG4 over IgE, therefore signaling a shift from Th2 dominance to Th1 dominance.10 However, 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 (T1DM). It is unclear if, perhaps, excessive cow’s milk-specific IgG antibodies from early cow’s milk exposure may play a role in the etiology of T1DM in a genetically predisposed population. A study of children with genetic predisposition for T1DM found that the children who later developed T1DM had elevated levels of IgG to beta-lactoglobulin, a major protein of cow’s milk, compared to controls.11 Further research needs to be done regarding the effect of early solid food introduction on IgG4-related Th1 dominance and the incidence of Th1-dominant autoimmune disorders. A recent animal study found correlations between elevated milk- and egg-specific IgG antibodies in rats of a rheumatoid arthritis model.12 This study suggests food-specific IgG antibodies may contribute to the development of certain autoimmune disorders. Of course, the cause of autoimmunity is not fully understood and more research into the contribution of foods and their effects on immune function is needed.
Based on this current study and other recent research, clinicians may want to consider altering current recommendations by suggesting that children without current peanut allergy status begin introduction of peanuts earlier in infancy in order to prevent peanut allergies later in life. Infants should be first tested for a peanut allergy, and if positive, great caution should be taken with a protocol-driven, slow introduction of peanuts under professional guidance.
- 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. 2015;372(9):803-813.
- Bedolla Barajas M, Alcala-Padilla G, Morales Romero J, Camacho Fregoso J, Rivera Mejía V. Peanut allergy in Mexican children: what is the effect of age at first consumption? Iran J Allergy Asthma Immunol. 2016;15(1):53-61.
- Perkin MR, Logan K, Tseng A, et al. Randomized trial of introduction of allergenic foods in breast-fed infants. N Engl J Med. 2016;374(18):1733-1743.
- 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. 2016;137(5):1477-1486.e8.
- Elizur A, Katz Y. Timing of allergen exposure and the development of food allergy: treating before the horse is out of the barn. Curr Opin Allergy Clin Immunol. 2016;16(2):157-164.
- 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.e1.
- Sverremark-Ekström E, Hultgren EH, Borres MP, Nilsson C. Peanut sensitization during the first 5 yr of life is associated with elevated levels of peanut-specific IgG. Pediatr Allergy Immunol. 2012;23(3):224-229.
- Deol S, Bird JA. Current opinion and review on peanut oral immunotherapy. Hum Vaccin Immunother. 2014;10(10):3017-3021.
- Ponce M, Diesner SC, Szépfalusi Z, Eiwegger T. Markers of tolerance development to food allergens. Allergy. 2016;71(10):1393-1404.
- Matsuoka T, Shamji MH, Durham SR. Allergen immunotherapy and tolerance. Allergol Int. 2013;62(4):403-413.
- Luopajärvi K, Savilahti E, Virtanen SM, et al. Enhanced levels of cow's milk antibodies in infancy in children who develop type 1 diabetes later in childhood. Pediatr Diabetes. 2008;9(5):434-441.
- Li J, Yan H, Chen H, et al. The pathogenesis of rheumatoid arthritis is associated with milk or egg allergy. N Am J Med Sci. 2016;8(1):40-46.