Abstract
Background
Early introduction of dietary peanut in high-risk infants with severe eczema and/or egg allergy prevented peanut allergy at 5 years of age in the LEAP Study; the protective effect persisted after 12 months of avoiding peanuts in the LEAP-On Study. It is unclear whether this benefit is allergen and allergic-disease specific.
Objective
To assess the impact of early introduction of peanut on the development of allergic disease, food sensitization and aeroallergen sensitization.
Methods
Asthma, eczema and rhinoconjunctivitis were diagnosed by clinical assessment. Reported allergic reactions and consumption of tree nuts and sesame were recorded by questionnaire. Sensitization to food and aeroallergens was determined by skin prick testing and specific IgE measurement.
Results
A high and increasing burden of food and aeroallergen sensitization and allergic disease was noted across study time points; 76% of LEAP participants had at least one allergic disease at 60 months of age. There were no differences in allergic disease between LEAP groups. There were small differences in sensitization and reported allergic reactions for select tree nuts; levels were higher in the LEAP consumption group. Significant resolution of eczema and sensitization to egg and milk occurred in LEAP participants; this was not affected by peanut consumption.
Conclusion
Early consumption of peanut in infants at high risk of peanut allergy is allergen-specific and does not prevent the development of other allergic disease, sensitization to other foods and aeroallergens, or reported allergic reactions to tree nuts and sesame. Furthermore, peanut consumption does not hasten the resolution of eczema or egg allergy.
Keywords: Food Allergy, Peanut Allergy, Allergy prevention, Allergen-specific, Asthma. Eczema, Atopic Dermatitis, Rhinoconjunctivitis, Tolerance
INTRODUCTION
Atopic diseases represent a public health concern, particularly in the developed world.(1–3) Atopic conditions rarely occur in isolation and children frequently suffer from multiple allergic diseases. For example, infants with eczema are at higher risk of developing food allergy and asthma, children with egg allergy are at increased risk of developing allergic respiratory diseases, and children with a single food allergy frequently develop additional food allergies.(3)
Early dietary allergen exposure has been shown to be a successful strategy for the prevention of peanut allergy (and possibly egg allergy), however, the specificity of the observed clinical and immunological benefits is not known.(4–10) Peanut, tree nuts and sesame contain seed storage proteins with highly conserved areas of shared identity and homology between their amino acid sequences.(11–13) This raises the important clinical question as to whether cross-sensitization to similar allergens accounts for the frequent co-occurrence of these allergies in allergic populations.
If the consumption of peanut during infancy protects against the development of peanut allergy, it may also protect against the development of related food allergies. Israeli children have a low prevalence of peanut, tree nut and sesame allergy when compared with age-matched UK children.(14) Israeli children consume high quantities of both peanut and sesame from an early age, which is likely to explain the difference in peanut and sesame allergy rates.(14, 15) However, the differences in tree nut allergy cannot be attributed to early tree nut consumption as there were no differences in the age at which tree nuts were introduced between the two countries. Thus the low levels of tree nut allergy may be the result of cross-tolerance induced through earlier, higher and more frequent consumption of peanut and/or sesame in Israel compared with the UK.
Given the possible clinical relevance of cross reactivities between proteins in different foods, and that there is low grade evidence that allergen immunotherapy may prevent new-onset aeroallergen sensitization (16, 17), it is reasonable to investigate whether, similarly, early dietary allergen exposure has an influence on the onset or resolution of co-existent food allergies and/or other atopic diseases.
METHODS
Study design
This is an a priori analysis of the LEAP and LEAP-On Study secondary allergic outcomes.(10, 18) The LEAP Study was a randomized, open-label, controlled trial comparing two strategies to prevent peanut allergy: consumption or avoidance of peanut by high-risk infants until 60 months of age. The LEAP-On Study was a two-sample comparison employing all evaluable study participants from the LEAP Study assessed at 72 months of age after 12 months of peanut avoidance. Both trials were approved by the institutional review board and were overseen by a NIAID Allergy and Asthma Data and Safety Monitoring Board. Informed written consent was obtained for all LEAP and LEAP-On participants from their parent/guardian; full study details have been previously published.
Enrolment and study procedures
The LEAP Study enrolled infants aged ≥4 to <11 months with severe eczema and/or egg allergy from December 2006 to May 2009.(10) Participants were stratified at baseline into two separate study populations (strata) based on skin prick test (SPT) results for peanut and then randomly assigned to avoid (LEAP avoiders) or consume peanut (LEAP consumers). Analysis in this manuscript combines data from both the SPT positive and SPT negative strata. Participants randomly assigned to consumption were fed at least 6g of peanut protein/week until age 60 months. Clinical assessments were undertaken at baseline (age 4–11 months) and at age 12, 30 and 60 months which included the determination of protocol-defined eczema, asthma, seasonal and perennial rhinoconjunctivitis (further detailed in the Online Repository). The LEAP-On clinical assessment was undertaken at 72 months of age, after 12 months of peanut avoidance in both groups.(18)
SPT and Specific IgE measurement
Immune assessments including skin prick testing (SPT) and specific IgE measurements were conducted; test methodologies and skin prick testing materials have been published.(10) SPT to food allergens: peanut, hen’s egg white (using standardized extract as well as prick-to-prick testing using raw hen’s egg white), cow’s milk, sesame and soya were assessed at baseline, 12, 30, and 60 months (ALK-Abello, Hørshom, Denmark). SPT to all allergens except soya was repeated at 72 months. At 60 and 72 months, Brazil nut, hazelnut, cashew, walnut and almond were also included. Allergen-specific IgE to peanut, hen’s egg white, cow’s milk, sesame, Brazil nut, hazelnut, cashew, walnut and almond was measured at screening, 12, 30, 60 and 72 months using ImmunoCAP (Thermo Fisher, Uppsala, Sweden) Specific IgE to aeroallergens: house dust mite, cat, dog, timothy grass pollen, birch pollen and alternaria mold were measured at 30, 60 and 72 months (Thermo Fisher, Uppsala, Sweden).
Mean SPT and specific IgE values were calculated for the above allergens at all available time points; these means are presented for the Intention-to-Treat (ITT) and Per-Protocol (PP) study populations. We defined sensitization a priori for food allergens as SPT wheal diameter ≥ 3 mm or specific IgE ≥ 0.35 KU/L and aeroallergens as specific IgE ≥ 0.35 KU/L. Based on a previous publication, and on the optimal predictive value for peanut allergic participants in the avoidance arm of LEAP (Online Repository, Page 3.) we make use of high-level cut offs of SPT wheal diameter ≥ 5mm and/or specific IgE ≥ 10 KU/L to define ‘likely food allergy’ in post hoc analyses.(19)
Reported allergic reactions and association with specific IgE sensitization
At 60 months of age, a study questionnaire recorded details of suspected allergic reactions that had occurred over the duration of the trial. Two by two comparisons were made comparing tree nut and sesame reported allergic reactions and specific IgE ≥ 0.35 KU/L to each allergen.
Consumption of tree nuts and sesame
Participant-reported consumption of Brazil nut, hazelnut, cashew, walnut, almond or sesame, on at least one occasion, was assessed from 3-day food diaries completed at 6 study time points.
Statistical analysis
Statistical analyses were performed on all LEAP and LEAP-On Study participants for whom an outcome measurement was obtained on an ITT basis comparing the two randomized treatment groups cross-sectionally. Analyses were also performed on those who met PP criteria for LEAP (details of which have been previously published). Chi-squared, Fisher’s Exact tests, or multivariate logistic regression were used to compare the proportion of participants with each disease outcome of interest at the 0.05 level of significance. These were planned analyses on secondary outcomes, and no adjustments have been made for multiple comparisons. All analyses were performed using SAS software version 9.4 or JMP version 12.
RESULTS
Participants
The characteristics of participants screened and enrolled in the LEAP and LEAP-On Studies have been published.(10, 18)
No difference in development of allergic disease between the LEAP Study intervention groups
No differences were noted between LEAP avoiders and consumers in the rate of asthma, eczema, seasonal rhinoconjunctivitis and perennial rhinoconjunctivitis at 30, 60 and 72 months of age in the ITT population (Figure 1 and Table E1, Figure 2 and Table E3). These findings were replicated in the PP population (Table E2 and Table E4).
Figure 1. Asthma and Rhinoconjunctivitis Burden Over Time.
The rate of protocol-defined asthma, seasonal rhinoconjunctivitis and perennial rhinoconjunctivitis in the consumption (green bars) and avoidance (gray bars) groups in the ITT population at 30, 60 and 72 months are shown. There are no significant differences between the two groups at any time point as assessed by Chi-Squared Tests.
Figure 2. Eczema Severity Bands Over Time (SCORAD).
The percent of individuals with SCORAD assessments for eczema of 0, >0–15, ≥15–40 and >40 are shown at baseline and at 12, 30, 60 and 72 months in the avoidance (left bar of each pair) and consumption groups (right bar of each pair) in the ITT population. There are no significant differences between the two groups at any time point as assessed by Chi-Squared Tests.
i) Eczema
The majority of participants in the ITT population had eczema (defined by SCORAD > 0) at baseline (97% in the avoidance group and 98% in the consumption group); this decreased across study time points to 72 months of age, where 39% of participants in the avoidance group and 37% in the consumption group had eczema (Figure 2). Overall, eczema severity (measured by SCORAD mean (SD)) decreased across study time points from 34.4 (18.9) at baseline to 6.8 (11.2) at 72 months of age (after 12 months of peanut avoidance) (Table E3). There were no significant differences in the presence or severity of SCORAD between LEAP avoiders and consumers at any time point (Figure 2, Table E3). These findings were replicated in the PP population (Table E4).
ii) Asthma
In the ITT population, the overall rate of asthma increased from 11.2% at 30 months to 16.5% at 60 months and 16.3% at 72 months of age (Table E1). There were no significant differences in rates of asthma diagnosis or the protocol-defined diagnostic criteria between the LEAP avoiders and consumers at 30, 60 or 72 months (Figure 1, Table E1). These findings were replicated in the PP population (Table E2).
iii) Rhinoconjunctivitis
In the ITT population, the overall rate of seasonal allergic rhinoconjunctivitis (SAR) increased from 14.4% at 30 months to 35.2% at 60 months and 46.3% at 72 months of age (Table E1). The rate of perennial allergic rhinoconjunctivitis (PAR) increased from 26.4% at 30 months to 42.4% at 60 months and 51.8% at 72 months of age. Rates of SAR and PAR were similar between LEAP groups at 30, 60 and 72 months of age. (Figure 1, Table E1). These findings were replicated in the PP population (Table E2).
No protective effect on surrogate markers of tree nut and sesame allergy (SPT, specific IgE and reported allergic reactions) in the LEAP Study consumption group
We compared rates of sensitization to tree nut and sesame with peanut. As previously published for peanut, in the consumption group, the mean peanut SPT wheal diameter was significantly lower at all time points after randomization in both the ITT and PP populations (Figure 3). In contrast, the mean peanut specific IgE was only lower in the consumption group at one time point at 72 months of age and only lower in the PP population (Figure 3). Mean Ara h2 IgE was significantly lower in the consumption group at 60 and 72 months in both the ITT and PP populations (Figure 3).
Figure 3. Peanut SPT, Peanut S-IgE, and Ara h2 S-IgE.
Peanut SPT (top panel), Peanut IgE (middle panel), and Ara h2 IgE (bottom panel) in the consumption and avoidance groups in the ITT (left column) and LEAP Per Protocol (right column) populations at 4–11, 12, 30, 60, and 72 months are shown. Boxes represent 25th and 75th centiles and error bars represent 2.5th and 97.5th centiles. Lines connect the means over time for each randomized group. Solid grey lines represent the LEAP avoiders. Dashed green lines represent LEAP consumers. Grey circles represent LEAP avoiders. Green circles represent LEAP consumers. The ‘*’ represent a p-value ≤0.05 resulting from a comparison between the LEAP avoidance and LEAP consumption groups using a two sample t-test. The ‘**’ represent a p-value ≤0.01 resulting from a comparison between the LEAP avoidance and LEAP consumption groups using a two sample t-test.
For tree nuts and sesame, using a priori sensitization levels (SPT wheal diameter ≥ 3 mm or specific IgE ≥ 0.35 kU/L), the only significant difference noted was for walnut in the ITT population; the consumption group had an increased rate of walnut sensitization at 72 months compared with the avoidance group (28.2% vs. 19.9%, p=0.025; Table E5). This difference in walnut sensitization was not seen in the PP population (Table E6).
In post hoc analyses, using higher cut-off levels (SPT wheal diameter ≥ 5mm or specific IgE ≥ 10 kU/L) as a marker of ‘likely food allergy’, there were significant increases in rates to hazelnut, cashew and walnut in the consumption group in the ITT population (Table E7). These differences were largely attenuated in the PP population (Table E8). Considering sensitization by SPT only, mean SPT wheal diameters to tree nuts and sesame were broadly similar between the consumption and avoidance groups in the ITT population. The exceptions were to walnut and cashew at 60 months and to hazelnut at 60 and 72 months, where the mean wheal diameters were larger in the consumption group (Figure 4). In the PP population the only difference between groups was to hazelnut at 72 months (Figure 4). Considering sensitization by IgE only, in the ITT population, mean specific IgE to tree nuts and sesame were generally similar between the consumption and avoidance groups; however, specific IgE was higher in the consumption group for some nuts at more than one time point (Figure 5). Most of these differences were not apparent in the PP population. Only for walnut in the ITT population was specific IgE higher in the consumption group at all time points after baseline. These differences in walnut specific IgE were also apparent in the PP population at 30 and 60 months.
Figure 4. Tree Nut and Sesame SPT (mm).
Sesame, Brazil nut, Walnut, Cashew, Almond, and Hazelnut SPT (mm) results in the consumption and avoidance groups in the ITT (top row) and LEAP Per Protocol (bottom row) populations at 4–11, 12, 30, 60, and 72 months is shown for Sesame and at 60 and 72 months for the other Tree Nut outcomes. Boxes represent 25th and 75th centiles and error bars represent 2.5th and 97.5th centiles. Lines connect the means over time for each randomized group. Solid grey lines represent the LEAP avoiders. Dashed green lines represent LEAP consumers. Grey circles represent LEAP avoiders. Green circles represent LEAP consumers. The ‘*’ represent a p-value ≤0.05 resulting from a comparison between the LEAP avoidance and LEAP consumption groups using a two sample t-test. The ‘**’ represent a p-value ≤0.01 resulting from a comparison between the LEAP avoidance and LEAP consumption groups using a two sample t-test.
Figure 5. Tree Nut and Sesame Specific IgE (kU/L).
Sesame, Brazil nut, Walnut, Cashew, Almond, and Hazelnut specific IgE (kU/L) in the consumption and avoidance groups in the ITT (top row) and LEAP Per Protocol (bottom row) populations at 4–11, 12, 30, 60, and 72 months are shown. Boxes represent 25th and 75th centiles and error bars represent 2.5th and 97.5th centiles. Lines connect the means over time for each randomized group. Solid grey lines represent the LEAP avoiders. Dashed green lines represent LEAP consumers. Grey circles represent LEAP avoiders. Green circles represent LEAP consumers. The ‘*’ represent a p-value ≤0.05 resulting from a comparison between the LEAP avoidance and LEAP consumption groups using a two sample t-test. The ‘**’ represent a p-value ≤0.01 resulting from a comparison between the LEAP avoidance and LEAP consumption groups using a two sample t-test.
When we compared reported reactions to tree nuts and sesame between the LEAP intervention groups, the only significant difference noted was for Brazil nut in the ITT population where 5 participants in the consumption group reported Brazil nut reactions as compared to 0 in the avoidance group (p=0.031). A similar difference was noted for Brazil nut in the PP population (Table E9). Statistically significant differences were also noted when we compared the number of individuals reporting any or more than one reaction to tree nuts and sesame in both the ITT and PP populations (Table E9). In the ITT population 40 (12.7%) participants in the consumption group reported a reaction to any nut as compared to 23 (7.3%) participants in the avoidance group (p=0.023). Most individuals who reported reactions to a tree nut also had specific IgE ≥ 0.35 kU/L to that nut. However, this was not the case in all subjects. For example, 10 of 26 individuals who reported a reaction to cashew did not have specific IgE of≥ 0.35 kU/L (Table E10).
To assess whether there were differences in consumption of tree nuts or sesame between groups, we compared the number of participants who ever reported eating tree nuts or sesame in the 3-day food diaries (Table E11). The large majority of participants did not report consumption of tree nuts or sesame. Statistically significant differences were noted for hazelnuts and mixed nuts. For hazelnuts, 42 (13.2%) consumers reported eating hazelnut as compared with 21 (6.5%) of participants in the avoidance arm (p=0.005). For mixed nuts, 5 participants in the consumption group reported mixed nut consumption as compared to 0 in the avoidance group (p=0.030).
No difference in rates of and resolution of sensitization to other common foods between the LEAP intervention groups
There were no differences in rates of sensitization to cow’s milk and egg white at any time point in the ITT (Table E12) or PP (Table E13) populations. No differences were noted in ‘likely allergy’ rates using high-level cut offs of ≥ 5mm or ≥ 10 kU/L for SPT and specific IgE respectively (Tables E14 and E15).
The high rate of raw egg white sensitization of 69.7%, in the overall ITT population at baseline decreased with age to 39.1% by 72 months (Table E12). A similar decrease was evident for the rate of SPT wheal ≥ 3 mm to egg white extract (Table E12). Rates of soya sensitization and ‘likely allergy’ in the ITT and PP populations were low, and equivalent between LEAP groups, at all measured time points (Tables E12, E13, E14, and E15).
Increase in aeroallergen sensitization with age in both LEAP Study intervention groups
Sensitization rates increased from 30 to 60 and 72 months for all aeroallergens (house dust mite, cat, dog, timothy grass pollen, birch pollen and Alternaria mold) in both consumption and avoidance groups in the ITT (Figure 6 and Table E16) and PP (Table E17) populations. The most striking increase was for timothy grass pollen sensitization. In the ITT population, the rate in the combined avoiders and consumers group increased from 19.9% at 30 months to 48.7% at 60 months and 57.5% at 72 months (Table E16). There were no significant differences in aeroallergen sensitization between the consumption and avoidance groups at any time point (Figure 6 and Table E16). These findings were replicated in the PP population (Table E17).
Figure 6. Aeroallergen Sensitization.
The prevalence of IgE ≥0.35 for several aeroallergens in the consumption (green bars) and avoidance (gray bars) groups at 30, 60 and 72 months are shown. There are no significant differences between the two groups at any time point as assessed by Chi-Squared Tests.
Similar cumulative allergic disease burden in both LEAP Study intervention groups
At 60 months of age, LEAP participants carried a high cumulative allergic disease burden, considering together eczema, asthma, rhinoconjunctivitis, or any likely food allergy defined as any food allergen SPT ≥ 5mm (Figure 7). The cumulative disease burden was not different between LEAP avoiders and consumers in the ITT population at 60 or 72 months of age (Table E18). When considering the cumulative disease burden in the combined avoiders and consumers group in the ITT population at 60 months, 76% of participants had at least one allergic disease (seasonal and perennial rhinoconjunctivitis, asthma, eczema and likely food allergy) at 60 months of age and 44% had multiple allergic diseases (Figure 7, Table E18).
Figure 7. Cumulative Burden Venn Diagram at 60 Months of Age.
The number of participants in the ITT population with protocol defined eczema, rhinoconjunctivitis, asthma or any likely food allergy are shown for the avoidance group (top left), consumption group (top right) and total study group (bottom). This illustrates the very high rate of single and multiple allergic diseases in the study population. Figures are numbers (percentage) of participants.
Strong association between peanut allergy and allergic disease
We constructed six multivariate logistic regression models including peanut allergy outcome, baseline egg allergy, and baseline SCORAD to assess their impact on the development of asthma, seasonal rhinoconjunctivitis, and perennial rhinoconjunctivitis separately at 60 and 72 months of age. Peanut allergy at 60 and 72 months was strongly associated with asthma, seasonal rhinoconjunctivitis, and perennial rhinoconjunctivitis in the ITT population at the same time point (Figure 8 and Table E19, p <0.001 for the association of peanut allergy with all three allergic diseases at both time points). Similarly, baseline egg allergy was associated with seasonal rhinoconjunctivitis (p=0.019) and perennial rhinoconjunctivitis (p=0.042) but not with asthma (p=0.848) at 60 months. Similar findings were apparent at 72 months (Figure 8 and Table E19). The association of asthma with peanut allergy, as opposed to its lack of association with egg allergy, is not explained by baseline SCORAD since the latter does not influence the development of asthma (Table E19).
Figure 8. Peanut and Egg Allergy Associations with Development of Allergic Diseases.
The rate of protocol-defined asthma (left), seasonal rhinoconjunctivitis (middle) and perennial rhinoconjunctivitis (right) at 60 (top) and 72 (bottom) months are shown in those with neither egg nor peanut allergy, egg allergy only, peanut allergy only or both egg and peanut allergy. The number of subjects contributing to each group is presented in the denominator while the number of subjects with each allergic disease within each group is presented in the numerator of the values annotated within each bar. Presence of egg allergy was defined per inclusion criteria at baseline, whereas peanut allergy was defined at 60 and 72 months. P-values resulting from a multivariate logistic regression model (outcome of interest being each allergic disease) adjusted for peanut allergy, baseline egg allergy and baseline SCORAD are annotated within each panel.
DISCUSSION
This study found that oral tolerance induction to peanut in the LEAP Study is specific for both allergen and allergic disease, i.e. early consumption of peanut had no preventative effect on development of asthma, allergic rhinoconjunctivitis or surrogate markers of co-existent food allergies (SPT, specific IgE and reported tree nut and sesame reactions), and did not hasten the resolution of the eczema or egg allergy that were key inclusion criteria for LEAP participation. The noted similarities in allergic disease burden between LEAP intervention groups is in contrast with the marked reduction in peanut allergy observed in the consumption group (Figure E1).
The allergen-specificity of the LEAP intervention is confirmed by the finding that manifestations of allergic disease in the LEAP population followed the typical trajectory in young children with no differences noted between groups (excepting peanut allergy in LEAP consumers). Sensitization to hen’s egg white and cow’s milk (Tables E12 – E15) and rates and severity of eczema decreased across all time points (Table E3 and Table E4). In contrast, we observed a significant rise in aeroallergen sensitization and both seasonal and perennial rhinoconjunctivitis across all measured time points (Figure 1 and Figure 6). The burden of asthma was high and equal between LEAP groups rising from 11.2% at 30 months of age to 16.3% at 72 months of age (Table E1).
When considering the association between peanut allergy, baseline egg allergy and other allergic diseases, strong associations were noted with eczema, seasonal and perennial rhinoconjunctivitis at 60 and 72 months of age (Figure 8, Table E19). Peanut allergy was also strongly associated with asthma; this relationship was independent of baseline eczema and/or egg allergy (Figure 8). The LEAP study demonstrated that peanut consumption was strongly associated with the prevention of peanut allergy but did not prevent asthma. (Figure E1) The environmental and genetic risk factors for asthma and peanut allergy are therefore likely distinct.
There was no evidence that peanut consumption protected against tree nut and sesame sensitization. Surprisingly there was a small signal that peanut consumption was associated with an increase in sensitization to tree nuts and sesame. We found higher SPT and specific IgE levels to tree nuts and sesame in the LEAP consumption group compared with the avoidance group at most time points, and at times these differences met statistical significance. In addition, a significantly higher proportion of individuals (p=0.023) in the consumption group reported an allergic reaction to one or more tree nuts. These findings contrast with the LEAP study findings at 60 months of age where challenge-proven peanut allergy, peanut SPT diameter and Ara h 2 levels (Figure 3) were all markedly reduced within the LEAP consumption group compared with the avoidance group.
It is possible that early peanut consumption did result in the slightly increased rate of sensitization to tree nuts and could potentially result from exposure to small quantities of epitopes cross-reactive with those of tree nuts. There is literature to suggest that low-level allergen exposure (to aeroallergens) results in allergic responses whereas high-level allergen exposure drives tolerance.(20, 21) In addition, individuals in the consumption group may have had levels exposure to tree nuts potentially sufficient to drive sensitisation but insufficient to induce tolerance.
However, there are a number of other explanations for these unexpected findings. First, the increase in tree nut sensitization observed in the consumption group was not statistically consistent over time in that the effect sizes were smaller and more variable compared to peanut. Second, to minimize false negatives, no adjustments were made for multiple comparisons which increases the likelihood of false positive findings. Third, if eating peanut causes an increase in tree nut sensitization and reported allergic reactions, we would expect to see a greater effect in the PP analyses where infants ate more peanut compared to the ITT analyses; however, this was not evident for either the a priori sensitization thresholds (compare Tables E5 and E6) nor the high-level sensitization thresholds which are more indicative of clinical allergy. This suggests that these small statistically significant differences in sensitisation do not represent important clinical differences (compare Tables E7 and E8). Fourth, the differences in reported allergic reactions may arise through an ascertainment bias as a consequence of increased exposure to tree nuts and sesame in participants randomised to peanut consumption (Table E9). In support of this, consumption data recorded in 3-day food diaries does suggest more frequent consumption in the LEAP consumption group (Table E11). In addition this method may underestimate differences in consumption patterns, as compared to a food frequency questionnaire (as was used to record both frequency and quantity of peanut consumption in LEAP participants). Finally, although there was overall a significant increase in reported reactions to tree nuts and sesame in the consumers compared to avoiders, between 20 to 50% of individuals with a reported reaction had specific IgE ≤ 0.35 kU/L to the reported nut which suggests that some reported reactions do not represent true allergic reactions (Table E10).
In contrast with allergy and dietary data in Israel (where higher and more frequent peanut consumption patterns are associated with low rates of reported tree nut and sesame allergy, we demonstrate that peanut consumption in the LEAP Study does not protect against tree nut and sesame allergy and, furthermore our data raise the possibility that peanut consumption may cause sensitization to tree nuts (14, 15). However, in the absence of oral food challenges to tree nuts and sesame, the clinical significance of these small and inconsistent differences in surrogate markers of food allergy remains unclear. The LEAP Trio Study will make a more detailed assessment of these differences at age 10 years.
A strength of this study is that we describe secondary allergy outcomes for eczema, asthma, seasonal and perennial rhinoconjunctivitis using rigorous a priori criteria in a population of infants with a high allergic disease burden and for which peanut consumption successfully reduced the rate of peanut allergy. The major limitation of this study is the absence of OFCs to tree nuts and sesame. An additional limitation is that severe eczema and/or egg allergy served as enrolment criteria thereby minimising the opportunity to assess peanut consumption as an intervention to prevent the onset of these allergic conditions.
Despite the dramatic decrease in peanut allergy in participants randomized to peanut consumption, the overall allergic disease burden in LEAP Study participants is high, but equivalent, between LEAP groups at 60 months and 72 months of age (after 12 months of peanut avoidance). This demonstrates that oral tolerance induction to peanut in the LEAP Study is specific for both allergen and allergic disease. The underlying immune mechanisms associated with tolerance to peanut do not alter the natural history of allergic disease.
Different prevention strategies, or strategies that include multiple dietary interventions, need to be tested to assess whether the reduction in peanut allergy observed in the LEAP consumption group can be extended to other common food allergens and allergic diseases.
Supplementary Material
Clinical Implications.
Prevention of peanut allergy through early peanut consumption is allergen-specific and allergic-disease specific.
The immune mechanisms underlying tolerance to peanut do not hasten the resolution of other allergic disease.
Capsule Summary.
The early consumption of peanut in high-risk infants is allergen-specific and protects against peanut allergy but does not prevent the development of sensitization to other allergens or allergic diseases.
Acknowledgments
Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers NO1-AI-15416, UM1AI109565, HHSN272200800029C and UM2AI117870. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support came from Food Allergy Research & Education (FARE), McLean, VA; the Medical Research Council & Asthma UK Centre; the UK Department of Health through the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St. Thomas’ NHS Foundation Trust, in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. The clinical trials unit is supported by the National Peanut Board, Atlanta, Ga. The UK Food Standards Agency provided additional support for the costs of phlebotomy. Prof Gideon Lack acknowledges the Davis Foundation for academic support.
We thank the many nurses, dietitians, doctors and administrative staff of the Guy’s and St Thomas’ NHS Foundation Trust Children’s Allergy Service for clinical and logistical assistance over the period of the study; Poling Lau for administrative support in the preparation of this manuscript. Above all, we are indebted to all of the children and their families who generously took part in this study.
LEAP-On Study Team
Clinical support: Susan Chan, Adam Fox. Nursing Staff: Mable Abraham, Muhsinah Adam, Louise Coverdale, Claire Duncan, Amy Nixon, Una O’Dwyer-Leeson, Victoria Offord, Aine Sheridan, Fiona Watson, Natalie Witham. Dietitians: Kathryn Cockerell, Gail Harland, Tiffany Miller, Charlotte Stedman. Study management and administration: Catherine Clarke, Richard Cleaver, Gemma Deutsch, Alicia Parr. Laboratory projects: Natalia Becares, Matthew Crossley, Natalia do Couto Francisco, Kerry Richards, Ewa Pietraszewicz, Alick Stephens, Asha Sudra, Rianne Wester, Alastair Wilson, Celine Wu. Play Specialists: Jenna Heath, Kathryn Hersee. Phlebotomist: Devi Patkunam. ITN Staff: Adam Asare, Eduard Chani, Judith Evind, Noha Lim, Audrey Plough, Judith Evind, Don Whitehouse. NIAID Staff: Margarita Gomez Lorenzo, Joy Laurienzo Panza. Rho Federal Systems Staff: Jackie Johnson, Jack Hu, Travis Mason.
Abbreviations
- CI
Confidence interval
- ITT
Intention-to-treat
- PAR
Perennial Allergic Rhinoconjunctivitis
- PP
Per Protocol
- SAR
Seasonal Allergic Rhinoconjunctivitis
- SCORAD
SCORing Atopic Dermatitis
- SPT
Skin Prick Test
- LEAP Study
Learning Early About Peanut Allergy Study
- LEAP-On Study
12 month extension of LEAP Study: Persistence of Oral Tolerance to Peanut
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Contributor Information
George du Toit, Department of Paediatric Allergy, Division of Asthma, Allergy and Lung Biology, King’s College London and Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom
Peter H. Sayre, Division of Hematology-Oncology, Department of Medicine, University of California, San Francisco
Graham Roberts, University of Southampton and Southampton NIHR Biomedical Research Centre, Southampton and David Hide Centre, Isle of Wight, United Kingdom
Kaitie Lawson, Rho Federal Systems Division, Chapel Hill, NC
Michelle L. Sever, Rho Federal Systems Division, Chapel Hill, NC
Henry T. Bahnson, Immune Tolerance Network, University of California, San Francisco
Helen R. Fisher, Department of Paediatric Allergy, Division of Asthma, Allergy and Lung Biology, King’s College London and Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom
Mary Feeney, Department of Paediatric Allergy, Division of Asthma, Allergy and Lung Biology, King’s College London and Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom.
Suzana Radulovic, Department of Paediatric Allergy, Division of Asthma, Allergy and Lung Biology, King’s College London and Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom
Monica Basting, Department of Paediatric Allergy, Division of Asthma, Allergy and Lung Biology, King’s College London and Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom
Marshall Plaut, National Institute of Allergy and Infectious Diseases, Bethesda, MD
Gideon Lack, Department of Paediatric Allergy, Division of Asthma, Allergy and Lung Biology, King’s College London and Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom
References
- 1.Muraro A, Halken S, Arshad SH, Beyer K, Dubois AE, Du Toit G, et al. EAACI food allergy and anaphylaxis guidelines. Primary prevention of food allergy. Allergy. 2014;69(5):590–601. doi: 10.1111/all.12398. [DOI] [PubMed] [Google Scholar]
- 2.Nwaru BI, Hickstein L, Panesar SS, Muraro A, Werfel T, Cardona V, et al. The epidemiology of food allergy in Europe: a systematic review and meta-analysis. Allergy. 2014;69(1):62–75. doi: 10.1111/all.12305. [DOI] [PubMed] [Google Scholar]
- 3.Venter C, Maslin K, Patil V, Kurukulaaratchy R, Grundy J, Glasbey G, et al. The prevalence, natural history and time trends of peanut allergy over the first 10 years of life in two cohorts born in the same geographical location 12 years apart. Pediatr Allergy Immunol. 2016;27(8):804–11. doi: 10.1111/pai.12616. [DOI] [PubMed] [Google Scholar]
- 4.Bellach J, Schwarz V, Ahrens B, Trendelenburg V, Aksunger O, Kalb B, et al. Randomized placebo-controlled trial of hen’s egg consumption for primary prevention in infants. The Journal of allergy and clinical immunology. 2016 doi: 10.1016/j.jaci.2016.06.045. [DOI] [PubMed] [Google Scholar]
- 5.Natsume O, Kabashima S, Nakazato J, Yamamoto-Hanada K, Narita M, Kondo M, et al. Two-step egg introduction for prevention of egg allergy in high-risk infants with eczema (PETIT): a randomised, double-blind, placebo-controlled trial. Lancet. 2017;389(10066):276–86. doi: 10.1016/S0140-6736(16)31418-0. [DOI] [PubMed] [Google Scholar]
- 6.Palmer DJ, Metcalfe J, Makrides M, Gold MS, Quinn P, West CE, et al. Early regular egg exposure in infants with eczema: A randomized controlled trial. The Journal of allergy and clinical immunology. 2013;132(2):387–92.e1. doi: 10.1016/j.jaci.2013.05.002. [DOI] [PubMed] [Google Scholar]
- 7.Palmer DJ, Sullivan TR, Gold MS, Prescott SL, Makrides M. Randomized controlled trial of early regular egg intake to prevent egg allergy. The Journal of allergy and clinical immunology. 2017;139(5):1600–7.e2. doi: 10.1016/j.jaci.2016.06.052. [DOI] [PubMed] [Google Scholar]
- 8.Perkin MR, Logan K, Tseng A, Raji B, Ayis S, Peacock J, et al. Randomized Trial of Introduction of Allergenic Foods in Breast-Fed Infants. The New England journal of medicine. 2016 doi: 10.1056/NEJMoa1514210. [DOI] [PubMed] [Google Scholar]
- 9.Wei-Liang Tan J, Valerio C, Barnes EH, Turner PJ, Van Asperen PA, Kakakios AM, et al. A randomized trial of egg introduction from 4 months of age in infants at risk for egg allergy. The Journal of allergy and clinical immunology. 2016 doi: 10.1016/j.jaci.2016.08.035. [DOI] [PubMed] [Google Scholar]
- 10.Du Toit G, Roberts G, Sayre PH, Bahnson HT, Radulovic S, Santos AF, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. The New England journal of medicine. 2015;372(9):803–13. doi: 10.1056/NEJMoa1414850. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Barre A, Sordet C, Culerrier R, Rance F, Didier A, Rouge P. Vicilin allergens of peanut and tree nuts (walnut, hazelnut and cashew nut) share structurally related IgE-binding epitopes. Molecular immunology. 2008;45(5):1231–40. doi: 10.1016/j.molimm.2007.09.014. [DOI] [PubMed] [Google Scholar]
- 12.Beyer K, Grishina G, Bardina L, Grishin A, Sampson HA. Identification of an 11S globulin as a major hazelnut food allergen in hazelnut-induced systemic reactions. The Journal of allergy and clinical immunology. 2002;110(3):517–23. doi: 10.1067/mai.2002.127434. [DOI] [PubMed] [Google Scholar]
- 13.Masthoff LJ, van Hoffen E, Mattsson L, Lidholm J, Andersson K, Zuidmeer-Jongejan L, et al. Peanut allergy is common among hazelnut-sensitized subjects but is not primarily the result of IgE cross-reactivity. Allergy. 2015;70(3):265–74. doi: 10.1111/all.12554. [DOI] [PubMed] [Google Scholar]
- 14.Du Toit G, Katz Y, Sasieni P, Mesher D, Maleki SJ, Fisher HR, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. The Journal of allergy and clinical immunology. 2008;122(5):984–91. doi: 10.1016/j.jaci.2008.08.039. [DOI] [PubMed] [Google Scholar]
- 15.Dalal I, Binson I, Reifen R, Amitai Z, Shohat T, Rahmani S, et al. Food allergy is a matter of geography after all: Sesame as a major cause of severe IgE-mediated food allergic reactions among infants and young children in Israel. Allergy: European Journal of Allergy and Clinical Immunology. 2002;57(4):362–5. doi: 10.1034/j.1398-9995.2002.1s3412.x. [DOI] [PubMed] [Google Scholar]
- 16.Di Bona D, Plaia A, Leto-Barone MS, La Piana S, Macchia L, Di Lorenzo G. Efficacy of allergen immunotherapy in reducing the likelihood of developing new allergen sensitizations: a systematic review. Allergy. 2017;72(5):691–704. doi: 10.1111/all.13104. [DOI] [PubMed] [Google Scholar]
- 17.Kristiansen M, Dhami S, Netuveli G, Halken S, Muraro A, Roberts G, et al. Allergen immunotherapy for the prevention of allergy: A systematic review and meta-analysis. Pediatr Allergy Immunol. 2017;28(1):18–29. doi: 10.1111/pai.12661. [DOI] [PubMed] [Google Scholar]
- 18.Du Toit G, Sayre PH, Roberts G, Sever ML, Lawson K, Bahnson HT, et al. Effect of Avoidance on Peanut Allergy after Early Peanut Consumption. The New England journal of medicine. 2016;374(15):1435–43. doi: 10.1056/NEJMoa1514209. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Santos AF, Douiri A, Becares N, Wu SY, Stephens A, Radulovic S, et al. Basophil activation test discriminates between allergy and tolerance in peanut-sensitized children. The Journal of allergy and clinical immunology. 2014;134(3):645–52. doi: 10.1016/j.jaci.2014.04.039. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Platts-Mills T, Vaughan J, Squillace S, Woodfolk J, Sporik R. Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study. Lancet. 2001;357(9258):752–6. doi: 10.1016/S0140-6736(00)04168-4. [DOI] [PubMed] [Google Scholar]
- 21.Woodcock A, Lowe LA, Murray CS, Simpson BM, Pipis SD, Kissen P, et al. Early life environmental control: effect on symptoms, sensitization, and lung function at age 3 years. American journal of respiratory and critical care medicine. 2004;170(4):433–9. doi: 10.1164/rccm.200401-083OC. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.