Observational studies have explored associations between timing of peanut, egg, and milk introduction and food allergy development, noting significant associations with reduced respective rates of milk, egg, and peanut allergy associated with earlier timing of introduction. Interventional studies developed to more definitively explore these outcomes have been published for egg and peanut, and are ongoing for multiple other allergens. This review focuses on the recent publication regarding the LEAP (Learning Early About Peanut Allergy) study, its highly favorable results, the policy implications of its findings, and the horizon for primary prevention as a realistic strategy to prevent food allergy.
Key points
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Prior to 2008, peanut introduction was actively recommended to be delayed in high-risk infants to help prevent peanut allergy development.
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Emerging data in the past 10 years has suggested that early complementary food introduction of high-risk allergens may be protective of food allergy development.
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The LEAP study clearly shows that early, frequent peanut introduction is associated with both primary and secondary peanut allergy prevention in high-risk infants compared to delayed introduction.
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New interim guidance, supported by multiple international organizations, supports early, frequent peanut introduction in high-risk infants, and re-enforces prior guidance that no longer actively recommends delay in any complementary food introduction past 4–6 months in standard-risk infants.
Food allergy is major public health disorder affecting nearly 15 million Americans, including 8% of United States children, at a cost of $24.8 billion annually. Allergic reactions may occur on initial food exposure and range from mild to highly severe (eg, anaphylaxis, and possible fatality), with poor predictability. Several promising treatments are under development, although none presently exist beyond allergen avoidance. Food allergy is associated with anxiety and poor child health-related quality of life (HRQL), poor parent HRQL as a proxy for their child’s experience, and poor parent HRQL as a spillover effect of a perpetual fear of the child reacting from an accidental exposure—something that treatment could prevent. Thus, finding ways to treat food allergy, reduce the risk of a severe reaction occurring, or possibly prevent food allergy from developing are highly desirable. Oral immunotherapy (OIT) and epicutaneous immunotherapy (EPIT) currently offer the most promise as treatment options for those with existing food allergy. Trials of both EPIT and OIT immunotherapy are ongoing, although success rates, treatment duration, and long-term benefits of this experimental therapy are unclear. Moreover, OIT itself carries high risks for inducing allergic reactions and developing secondary illnesses (eosinophilic esophagitis).
Although both OIT and EPIT are highly promising, these strategies could be preempted by efforts to reduce overall rates of food allergy occurrence through primary prevention. Several studies have suggested that nutritional interventions may be associated with reduced odds of developing asthma, eczema, and food allergy. More recently, several studies have been launched focusing on the relationship between early introduction of certain foods and primary prevention of food allergy. Observational studies have explored associations between timing of peanut, egg, and milk introduction and food allergy development, noting significant associations with reduced respective rates of milk, egg, and peanut allergy associated with earlier timing of introduction. Interventional studies developed to more definitively explore these outcomes have been published for egg and peanut, and are ongoing for multiple other allergens. One small trial of egg introduction at 4 months has been published, showing a nonsignificant but lower rate of egg allergy in the early introduction group, balanced by a surprisingly high rate of egg sensitization among previously egg-naïve infants at the start of study. Other studies of egg and other high-risk allergens are ongoing. This review focuses on the recent publication regarding the Learning Early About Peanut Allergy (LEAP) study, its highly favorable results, the policy implications of its findings, and the horizon for primary prevention as a realistic strategy to prevent food allergy.
Peanut allergy: an epidemic out of control?
Peanut allergy affects approximately 1% to 3% of children in westernized nations (United States, United Kingdom, Western Europe, Australia, Canada), and is a growing public health concern. In other parts of the world, peanut allergy is far less of a problem. Reasons for this discrepancy are poorly understood, but there are several hypotheses to explain the differential rates, including timing of introduction of peanut into the diet of infants, genetics, form and preparation of peanut, cultural practices, and the multiple hygiene hypothesis arguments. In the United States, United Kingdom, and Australia, peanut allergy is occurring at nearly 100,000 cases annually. Rates in the United States, measured by parental report in a 3-part phone survey, have tripled during the last decade, although peanut allergy is still not as prevalent as milk or egg allergy. The exact prevalence of peanut allergy is difficult to determine without use of prospective, challenge-based cohorts, a strategy not readily used, although few allergists would argue that peanut allergy has not been increasing.
Food allergy has no cure or treatment beyond allergen avoidance and carriage of emergency medications for treatment in the event of an unwanted/unintended exposure. Parents live with a perpetual burden of illness, resulting from a fear that the child will have an unintended allergen ingestion and potentially fatal reaction, and concern for safe accommodation for the child to avoid unintended ingestion. Peanut allergy in particular is problematic, given that it is sometimes associated with severe reactions on initial ingestion in susceptible individuals, occurring with potentially small quantities, and is very unlikely to be outgrown (<20% of cases resolve). Furthermore, peanut allergy has been associated with fatal reactions and reactions occurring from cross-contact/contaminations. Thus, compared with allergens such as milk or egg, which are typically outgrown in childhood, a treatment or cure for peanut allergy would be of particular use because of its protracted nature. Multiple treatments for peanut allergy are under development and can be reviewed elsewhere, including OIT, OIT with preadministration of anti–immunoglobulin E (IgE), EPIT, peanut vaccines, and a hypoallergenic peanut. There is also particularly high interest in developing strategies to prevent peanut allergy from developing, as opposed to treating it once it has occurred.
Prevention of peanut allergy can be thought of in 2 respects. Primary allergy prevention refers to measures or interventions that would prevent a person from developing peanut allergy or any manifestation of an allergic response, such as allergen sensitization (eg, the development of IgE antibodies specific for a particular food, noted on either a positive skin test or serum-specific IgE test). Secondary prevention refers to a cessation or arrest of an allergic process under development, most specifically referring to an already allergen-sensitized individual remaining nonreactive to ingesting that item (eg, the individual has a positive test but does not react when the food is ingested). In the strictest sense, IgE against peanut cannot be formed without prior exposure, but how such exposure occurs in these children is not understood because it seems unintended. A leading hypothesis for how such children become sensitized is that this occurs through environmental exposures (eg, ambient dust that accumulates in the household, nonoral exposures through lotions containing peanut). Such preventative strategies represent potentially cost-effective and widely applicable solutions that may not require a large burden of health service utilization to achieve benefit at a population level, as opposed to treating someone who has already developed allergy.
Peanut allergy: an epidemic out of control?
Peanut allergy affects approximately 1% to 3% of children in westernized nations (United States, United Kingdom, Western Europe, Australia, Canada), and is a growing public health concern. In other parts of the world, peanut allergy is far less of a problem. Reasons for this discrepancy are poorly understood, but there are several hypotheses to explain the differential rates, including timing of introduction of peanut into the diet of infants, genetics, form and preparation of peanut, cultural practices, and the multiple hygiene hypothesis arguments. In the United States, United Kingdom, and Australia, peanut allergy is occurring at nearly 100,000 cases annually. Rates in the United States, measured by parental report in a 3-part phone survey, have tripled during the last decade, although peanut allergy is still not as prevalent as milk or egg allergy. The exact prevalence of peanut allergy is difficult to determine without use of prospective, challenge-based cohorts, a strategy not readily used, although few allergists would argue that peanut allergy has not been increasing.
Food allergy has no cure or treatment beyond allergen avoidance and carriage of emergency medications for treatment in the event of an unwanted/unintended exposure. Parents live with a perpetual burden of illness, resulting from a fear that the child will have an unintended allergen ingestion and potentially fatal reaction, and concern for safe accommodation for the child to avoid unintended ingestion. Peanut allergy in particular is problematic, given that it is sometimes associated with severe reactions on initial ingestion in susceptible individuals, occurring with potentially small quantities, and is very unlikely to be outgrown (<20% of cases resolve). Furthermore, peanut allergy has been associated with fatal reactions and reactions occurring from cross-contact/contaminations. Thus, compared with allergens such as milk or egg, which are typically outgrown in childhood, a treatment or cure for peanut allergy would be of particular use because of its protracted nature. Multiple treatments for peanut allergy are under development and can be reviewed elsewhere, including OIT, OIT with preadministration of anti–immunoglobulin E (IgE), EPIT, peanut vaccines, and a hypoallergenic peanut. There is also particularly high interest in developing strategies to prevent peanut allergy from developing, as opposed to treating it once it has occurred.
Prevention of peanut allergy can be thought of in 2 respects. Primary allergy prevention refers to measures or interventions that would prevent a person from developing peanut allergy or any manifestation of an allergic response, such as allergen sensitization (eg, the development of IgE antibodies specific for a particular food, noted on either a positive skin test or serum-specific IgE test). Secondary prevention refers to a cessation or arrest of an allergic process under development, most specifically referring to an already allergen-sensitized individual remaining nonreactive to ingesting that item (eg, the individual has a positive test but does not react when the food is ingested). In the strictest sense, IgE against peanut cannot be formed without prior exposure, but how such exposure occurs in these children is not understood because it seems unintended. A leading hypothesis for how such children become sensitized is that this occurs through environmental exposures (eg, ambient dust that accumulates in the household, nonoral exposures through lotions containing peanut). Such preventative strategies represent potentially cost-effective and widely applicable solutions that may not require a large burden of health service utilization to achieve benefit at a population level, as opposed to treating someone who has already developed allergy.
Preventing peanut allergy through timing of introduction
A Historical Shift of Opinion
In 2000, the American Academy of Pediatrics (AAP) issued guidance on the introduction of complementary foods into the diet of infants to prevent development of allergic disease. In particular, the AAP strongly recommended that peanut introduction be delayed until age 3 years in children at high risk for the development of allergic disease (defined as children with a biparental, parental, or sibling family history of allergy), that nursing mothers should eliminate peanut (and other foods such as milk, egg, and fish) from their diet while nursing, and that pregnant mothers should consider removing peanut from their diet. Clinical guidelines from the United Kingdom in 1998 issued similar recommendations, although the European Society for Pediatric Allergology and Clinical Immunology/European Society for Pediatric Gastroenterology, Hepatology and Nutrition did not recommend these timelines. However, newer recommendations by the AAP in 2008 stated that “the documented benefits of nutritional intervention that may prevent or delay the onset of atopic disease are largely limited to infants at high risk of developing allergy,” nor did evidence support any maternal dietary restriction of foods during pregnancy or breastfeeding or delay of any introduction of complementary foods past 4 to 6 months of life to protect against development of atopic disease in non–high-risk infants. This sentiment was echoed by the American Academy of Allergy, Asthma, and Immunology (AAAAI) in 2013. These AAP and AAAAI guidelines are in line with present recommendations of other international organizations. The Australioasian Society of Allergy and Clinical Immunology, Israeli Association of Allergy and Clinical Immunology, Canadian Society of Allergy and Clinical Immunology, and the European Academy of Allergy and Clinical Immunology make no recommendations advocating delay of introduction of any complementary foods (including high-risk allergens such as peanut), or for pregnant or nursing mothers to avoid any high-risk foods as means of prevention of allergic disease.
Association Study Evidence Supporting Early Peanut Introduction as Protective Against Peanut Allergy
In 2008, Du Toit and colleagues published a provocative and innovative observational study conducted in Tel Aviv, Israel and London, England. This study compared reported societal rates of peanut allergy and timing of peanut introduction. It had been observed that peanut allergy rates were not as extensive in Israel as they were in Western nations. Reasons for this were poorly understood, although culturally it had been noted that in areas where peanut consumption was high during infancy (eg, Middle East, Asia, Africa), peanut allergy was not readily reported. Using validated questionnaire-based responses in 2 cohorts, parents of 5171 United Kingdom and 5625 Israeli Ashkenazi (Eastern European heritage) Jewish children were surveyed about any development of food allergy in the child, other comorbid atopic disease, general demographics, and a food frequency questionnaire asking about maternal prenatal and maternal/child postnatal feeding habits.
Comparatively, peanut allergy prevalence was 1.85% in the United Kingdom versus 0.17% in Israel, with an adjusted relative risk for peanut allergy in the United Kingdom of 5.8 (9.8 among elementary school children). The prevalence of peanut allergy remained significantly higher in the United Kingdom cohort even among just the high-risk groups, such as children with eczema (6.46% vs 0.79%). Similar differences in prevalence were seen for tree nut allergy and sesame allergy, but not milk or egg allergy (although these trended toward significance). After statistical adjustment, the only significant factor associated with the difference in peanut allergy prevalence was timing of peanut introduction, for which 69% of Israeli children had reported peanut introduction by 9 months compared with just 10% of the children in the United Kingdom. The Israeli children consumed up to a median of 7.1 g of peanut protein in the first year of life approximately 8 times per month, versus a median of 0 g of peanut in the United Kingdom. Moreover, significantly fewer mothers in the United Kingdom reported consuming peanut while breastfeeding. The investigators concluded that the reduced rate of peanut allergy in Israel was most likely associated with the timing of introduction (and not explained by differences in baseline atopy, sociodemographics, genetics, or allergenicity of commonly consumed peanut-containing products). However, despite this strong association, these data were observational and could not imply any causality. Other observational data regarding early peanut introduction has been restricted to sensitization rates only. In an inner-city observational birth cohort, Joseph and colleagues noted that early reported peanut introduction (by 4 months) was protective against developing peanut sensitization in children with a family history of allergic disease, whereas delay until 1 year of age was associated with a 4.3-fold increased odds of sensitization.
A New Hope in Preventing the Onset of Peanut Allergy
Given the fairly strong association noted in their study between Tel Aviv and London, the same United Kingdom team conducted an innovative study, the LEAP trial. LEAP was a single-center, open-label, randomized, controlled interventional study conducted in infants at high risk for developing allergic disease, to definitively test the effect of timing of peanut introduction on the rate of peanut allergy development. Over a 3-year period, 834 United Kingdom children between the ages of 4 and 11 months with severe eczema egg allergy, or both ( Box 1 ) were screened for enrollment, with 118 excluded because of lack of severe eczema. All remaining children underwent further screening with peanut skin-prick testing (SPT), and were then stratified into 2 groups based on the test size. Those with negative (0 mm) tests comprised one group, and those with minimally positive tests (1–4 mm) comprised the second. A total of 76 children with SPT of 5 mm or larger were excluded from randomization on the suspicion that they were highly likely to be peanut allergic. The remaining 640 children were then randomized, within the SPT-positive and SPT-negative groups, respectively, to either begin immediate peanut introduction and consumption of up to 6 g of peanut protein thrice weekly, continued through age 5 years, or to not have any peanut exposure until age 5. All children randomized to early introduction had their initial feeding performed in the office under observation. A total of 7 children reacted to this initial feeding and were instructed to avoid peanut. All children in the study were then followed over the next 4 years at set intervals. Their families filled out detailed dietary frequency questionnaires and symptom questionnaires, and selected families agreed to household dust surveillance to determine ambient environmental peanut levels.
- 1.
Age 4 to 11 months at screening, having either or both
- a.
Severe eczema—self-defined by questionnaire
- i.
Frequent need for topical steroids or calcineurin inhibitors
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Parental description of “a very bad rash in joints and creases” or “a very bad itchy, dry, oozing, or crusted rash”
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SCORAD grade (≥40)
- i.
- b.
Egg allergy: skin-prick test 6 mm or larger in a person without a history of known egg ingestion, or skin-prick test 3 mm or larger in an infant with a history of egg ingestion and subsequent development of allergic symptoms
- a.
- 2.
Screening peanut allergy skin test: wheal smaller than 5 mm
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