Follow-up to Adolescence after Early Peanut Introduction for Allergy Prevention

Abstract

Background: A randomized trial demonstrated consumption of peanut from infancy to age 5 years prevented the development of peanut allergy. An extension of that trial demonstrated the effect persisted after 1 year of peanut avoidance. This follow-up trial examined the durability of peanut tolerance at age 144 months after years of ad libitum peanut consumption.

Methods: Participants from a randomized peanut consumption trial were assessed for peanut allergy following an extended period of eating or avoiding peanuts as desired. The primary end point was the rate of peanut allergy at age 144 months.

Results: We enrolled 508 of the original 640 participants (79.4%); 497 had complete primary end point data. At age 144 months, peanut allergy remained significantly more prevalent in participants in the original peanut avoidance group than in the original peanut consumption group (15.4% [38 of 246 participants] vs. 4.4% [11 of 251 participants]; P<0.001). Participants in both groups reported avoiding peanuts for prolonged periods of time between 72 and 144 months. Participants at 144 months in the peanut consumption group had levels of Ara h2-specific immunoglobulin E (a peanut allergen associated with anaphylaxis) of 0.03 ± 3.42 kU/l and levels of peanut-specific immunoglobulin G4 of 535.5 ± 4.98 μg/l, whereas participants in the peanut avoidance group had levels of Ara h2-specific immunoglobulin E of 0.06 ± 11.21 kU/l and levels of peanut-specific immunoglobulin G4 of 209.3 ± 3.84 μg/l. Adverse events were uncommon, and the majority were related to the food challenge.

Conclusions: Peanut consumption, starting in infancy and continuing to age 5 years, provided lasting tolerance to peanut into adolescence irrespective of subsequent peanut consumption, demonstrating that long-term prevention and tolerance can be achieved in food allergy. (Funded by the National Institute of Allergy and Infectious Diseases and others; ITN070AD, ClinicalTrials.gov number, NCT03546413.).

Figure 1.. Primary Outcome at 60, 72, and 144 Months.

The prevalence of peanut allergy at 60, 72, and 144 months of age is shown in the intention-to-treat analysis for all trial participants (Panel A), among those who had a negative peanut-specific skin prick test result at baseline (Panel B), and among participants who had a positive peanut-specific skin prick test result at baseline (Panel C). The percentage differences and 95% confidence intervals for the differences between the percentage of allergic participants in the LEAP Avoider and LEAP Consumer treatment groups are shown. Confidence intervals were calculated using the unadjusted Wald method. The number of allergic participants and total number of participants within each treatment group are also presented. In the original LEAP trial, participants at high risk for allergy had been randomly assigned to consume peanut beginning in the first 11 months of life (peanut consumption group) or avoid peanut (peanut avoidance group) until 60 months. Between 60 and 72 months, all trial participants were asked to avoid peanut. Between 72 and 144 months, trial participants were eating peanut ad libitum. SPT denotes skin prick test.

Figure 2.. Peanut Consumption and Peanut Protein in Dust.

Panel A shows the average weekly peanut protein in grams consumed in the 4 weeks prior to the 144-month assessment for all tolerant participants in the intention-to-treat population. Panel B shows comparisons of peanut protein concentrations in bed dust of tolerant participants within the peanut avoidance and peanut consumption groups at 144 months. Dust samples from participants’ beds at 144 months were obtained from 40.7% of participants in the peanut avoidance group and 48.6% in the peanut consumption group. Values are presented as micrograms of peanut protein per gram of collected dust. In both panels, gray circles represent peanut avoiders. Green circles represent peanut consumers. Horizontal bars indicate median values. Diamonds, as well as labels, indicate geometric mean values. The geometric mean ratios of LEAP Consumers:LEAP Avoiders, along with the 95% confidence intervals, are shown.

Figure 3.. Immunologic Outcomes for the Peanut Avoidance and Peanut Consumption Groups at Baseline (4 to <11 Months of Age) and at 12, 30, 60, 72, and 144 Months of Age.

Data are shown for participants who met the per-protocol criteria for the primary trial. Panel A shows the log₁₀-transformed levels of peanut-specific immunoglobulin (Ig) E in participants in the avoidance and consumption groups. Panel B shows the log₁₀-transformed levels of Ara h2-specific IgE. Panel C shows the log₁₀-transformed levels of peanut-specific IgG4. Panel D shows the log₁₀-transformed peanut-specific IgG4:IgE ratio. Panel E shows wheal sizes after the peanut-specific skin-prick test. The solid black lines show the group mean at each assessment. Dots represent individual participants (blue indicates that the participant did not have peanut allergy, and red indicates allergy at 144 months). The red lines represent participants who were allergic at 144 months of age. The gray shading represents the density of the distribution of the participants. The log₁₀ of the ratio of peanut-specific IgG4:IgE was calculated after peanut-specific IgG4 levels were converted from milligrams per liter to nanograms per milliliter and the peanut-specific IgE levels were converted from kilo unit per liter to nanograms per milliliter with the use of the formula (IgG4/[IgE × 2.4]).

Figure 3.. Immunologic Outcomes for the Peanut Avoidance and Peanut Consumption Groups at Baseline (4 to <11 Months of Age) and at 12, 30, 60, 72, and 144 Months of Age.

Data are shown for participants who met the per-protocol criteria for the primary trial. Panel A shows the log₁₀-transformed levels of peanut-specific immunoglobulin (Ig) E in participants in the avoidance and consumption groups. Panel B shows the log₁₀-transformed levels of Ara h2-specific IgE. Panel C shows the log₁₀-transformed levels of peanut-specific IgG4. Panel D shows the log₁₀-transformed peanut-specific IgG4:IgE ratio. Panel E shows wheal sizes after the peanut-specific skin-prick test. The solid black lines show the group mean at each assessment. Dots represent individual participants (blue indicates that the participant did not have peanut allergy, and red indicates allergy at 144 months). The red lines represent participants who were allergic at 144 months of age. The gray shading represents the density of the distribution of the participants. The log₁₀ of the ratio of peanut-specific IgG4:IgE was calculated after peanut-specific IgG4 levels were converted from milligrams per liter to nanograms per milliliter and the peanut-specific IgE levels were converted from kilo unit per liter to nanograms per milliliter with the use of the formula (IgG4/[IgE × 2.4]).

Figure 4.. Proportion Density Plot for Peanut-Specific IgE and Ara h2-Specific IgE.

Shown are the relative distributions of peanut-specific immunoglobulin (Ig) E and Ara h2-specific IgE between the peanut consumption (shown in green) and avoidance (shown in gray) groups for participants who met the per-protocol criteria for the primary trial. The vertical reference lines indicate where the higher end of the distribution begins to differ at the 95% confidence level between the randomized groups using bootstrap sampling of 1000 replicates of the upper percentiles. Peanut-specific IgE and Ara h2-specific IgE values are log₁₀-transformed.

Figure 5.. Immunologic Outcomes According to Allergy Status.

Participants were categorized as “stayed allergic,” “stayed tolerant,” “tolerant to allergic,” or “allergic to tolerant.” Shown are the log₁₀-transformed Ara h2-specific immunoglobulin (Ig) E levels, log₁₀-transformed peanut-specific IgE levels, wheal size on skin-prick testing for peanut, log₁₀-transformed peanut-specific IgG4 level, and log₁₀-transformed IgG4:IgE ratios at each assessment for the avoidance group (Panel A) and the consumption group (Panel B). Data are shown only for participants who met the per-protocol criteria in the primary trial and differ from the data reported at the end of LEAP-On, in which immunological outcomes are shown for participants who met the per-protocol criteria in both the primary trial and the follow-up trial. Lines represent population means. The log₁₀ of the ratio of peanut-specific IgG4:IgE was calculated after peanut-specific IgE levels were converted from kilo unit per liter to nanograms per milliliter with the use of the formula (IgG4/[IgE × 2.4]).