Open Access

Addendum guidelines for the prevention of peanut allergy in the United States: Report of the National Institute of Allergy and Infectious Diseases–sponsored expert panel

  • Alkis Togias1,
  • Susan F. Cooper1Email author,
  • Maria L. Acebal2,
  • Amal Assa’ad3,
  • James R. BakerJr4,
  • Lisa A. Beck5,
  • Julie Block6,
  • Carol Byrd-Bredbenner7,
  • Edmond S. Chan8,
  • Lawrence F. Eichenfield9,
  • David M. Fleischer10,
  • George J. FuchsIII11,
  • Glenn T. Furuta12,
  • Matthew J. Greenhawt10,
  • Ruchi S. Gupta13,
  • Michele Habich14,
  • Stacie M. Jones15,
  • Kari Keaton16,
  • Antonella Muraro17,
  • Marshall Plaut1,
  • Lanny J. Rosenwasser18,
  • Daniel Rotrosen1,
  • Hugh A. Sampson19,
  • Lynda C. Schneider21,
  • Scott H. Sicherer20,
  • Robert Sidbury22,
  • Jonathan Spergel23,
  • David R. Stukus24,
  • Carina Venter25 and
  • Joshua A. Boyce26
World Allergy Organization Journal201710:1

https://doi.org/10.1186/s40413-016-0137-9

Received: 13 December 2016

Accepted: 15 December 2016

Published: 6 January 2017

Abstract

Background

Food allergy is an important public health problem because it affects children and adults, can be severe and even life-threatening, and may be increasing in prevalence. Beginning in 2008, the National Institute of Allergy and Infectious Diseases, working with other organizations and advocacy groups, led the development of the first clinical guidelines for the diagnosis and management of food allergy. A recent landmark clinical trial and other emerging data suggest that peanut allergy can be prevented through introduction of peanut-containing foods beginning in infancy.

Objectives

Prompted by these findings, along with 25 professional organizations, federal agencies, and patient advocacy groups, the National Institute of Allergy and Infectious Diseases facilitated development of addendum guidelines to specifically address the prevention of peanut allergy.

Results

The addendum provides 3 separate guidelines for infants at various risk levels for the development of peanut allergy and is intended for use by a wide variety of health care providers. Topics addressed include the definition of risk categories, appropriate use of testing (specific IgE measurement, skin prick tests, and oral food challenges), and the timing and approaches for introduction of peanut-containing foods in the health care provider’s office or at home. The addendum guidelines provide the background, rationale, and strength of evidence for each recommendation.

Conclusions

Guidelines have been developed for early introduction of peanut-containing foods into the diets of infants at various risk levels for peanut allergy.

Keywords

FoodPeanutAllergyPreventionGuidelines

Introduction

Peanut allergy is a growing public health problem. In 1999, peanut allergy was estimated to affect 0.4% of children and 0.7% of adults in the United States [1], and by 2010, peanut allergy prevalence had increased to approximately 2% among children in a national survey [2], with similar results reported in a regional cohort. [3] Peanut allergy is the leading cause of death related to food-induced anaphylaxis in the United States [4, 5], and although overall mortality is low, the fear of life-threatening anaphylactic reactions contributes significantly to the medical and psychosocial burden of disease. In the majority of patients, peanut allergy begins early in life and persists as a lifelong problem. Therefore, cost-effective measures to prevent peanut allergy would have a high effect in terms of improving public health, reducing personal suffering, and decreasing health care use and costs.

The “Guidelines for the diagnosis and management of food allergy in the United States” [6] were published in December 2010 by an Expert Panel and a Coordinating Committee convened by the National Institute of Allergy and Infectious Diseases (NIAID). These guidelines did not offer strategies for the prevention of food allergy and particularly peanut allergy because of a lack of definitive studies at the time. The guidelines indicated that “insufficient evidence exists for delaying introduction of solid foods, including potentially allergenic foods, beyond 4 to 6 months of age, even in infants at risk of developing allergic disease.” This statement differed from previous clinical practice guidelines in the United Kingdom [7] and United States [8], which recommended the exclusion of allergenic foods from the diets of infants at high risk for allergy and is consistent with more recent recommendations regarding primary allergy prevention [912].

In February 2015, the New England Journal of Medicine published the results of the Learning Early about Peanut Allergy (LEAP) trial [13]. This trial was based on a prior observation [14] that the prevalence of peanut allergy was 10-fold higher among Jewish children in the United Kingdom compared with Israeli children of similar ancestry. In Israel, peanut-containing foods are usually introduced in the diet when infants are approximately 7 months of age and consumed in substantial amounts, whereas in the United Kingdom children do not typically consume any peanut-containing foods during their first year of life. The LEAP trial randomized 640 children between 4 and 11 months of age with severe eczema, egg allergy, or both to consume or avoid peanut-containing foods until 60 months of age, at which time a peanut oral food challenge (OFC) was conducted to determine the prevalence of peanut allergy. LEAP trial participants were stratified at study entry into 2 separate study cohorts on the basis of pre-existing sensitization to peanut, as determined by means of skin prick testing: one cohort consisted of infants with no measureable skin test wheal to peanut (negative skin test response) and the other consisted of those with measurable wheal responses (1–4 mm in diameter). Infants with a 5 mm wheal diameter or greater were not randomized because the majority of infants at this level of sensitization were presumed to be allergic to peanut. Among the 530 participants in the intention-to-treat population with negative baseline skin test response to peanut, the prevalence of peanut allergy at 60 months of age was 13.7% in the peanut avoidance group and 1.9% in the peanut consumption group (P < .001; an 86.1% relative reduction in the prevalence of peanut allergy). Among the 98 participants with a measurable peanut skin test response at entry, the prevalence of peanut allergy was 35.3% in the avoidance group and 10.6% in the consumption group (P = .004; a 70% relative reduction in the prevalence of peanut allergy).

The LEAP trial was the first randomized trial to study early allergen introduction as a preventive strategy. Because of the size of the observed effect and the large number of study participants, its outcome received wide publicity in both the medical community and the press. This raised the need to operationalize the LEAP findings by developing clinical recommendations focusing on peanut allergy prevention. To achieve this goal and its wide implementation, the NIAID invited the members of the 2010 Guidelines Coordinating Committee and other stakeholder organizations to develop this addendum on peanut allergy prevention to the 2010 “Guidelines for the diagnosis and management of food allergy in the United States.” Twenty-six stakeholder organizations participated in this 2015–2016 Coordinating Committee. Of note, unrelated to this effort, a consensus statement on behalf of 9 international professional societies regarding the implications and implementation of the LEAP trial findings was published as well [15].

Additional evidence on early introduction of allergenic foods comes from the LEAP-On study [16], which demonstrated the durability of oral tolerance to peanut achieved in the LEAP trial and the Enquiring About Tolerance study [17], which assessed the potential benefits of early introduction of 6 allergenic foods in a non–high-risk cohort.

Development of the 2017 addendum to the 2010 “Guidelines for the diagnosis and management of food allergy”

The process to develop the 2017 addendum closely followed that used in the 2010 guidelines [6].

Coordinating Committee

The NIAID established a Coordinating Committee (CC), the members of which are listed in Appendix A, to oversee the development of the addendum; review drafts of the addendum for accuracy, practicality, clarity, and broad utility of the recommendations in clinical practice; review and approve the final addendum; and disseminate the addendum. The CC members represented 26 professional organizations, advocacy groups, and federal agencies.

Expert Panel

The CC convened an Expert Panel (EP) in June 2015 that was chaired by Joshua Boyce, MD. The 26 panel members, listed in Appendix B, were specialists from a variety of relevant clinical, scientific, and public health areas. Panel members were nominated by the CC organizations, and the composition of the panel received unanimous approval by the CC member organizations.

The charge to the EP was to use the literature review prepared by the NIAID (see the next section) in conjunction with consensus expert opinion and EP-identified supplementary documents to (1) develop evidence-based recommendations for the early introduction of dietary peanut to prevent peanut allergy; (2) agree on principles for grading the evidence; (3) achieve consensus while allowing ample opportunity for consideration of divergent opinions; (4) determine whether the recommendations could extend beyond peanut to other food allergens; and (5) keep patient and societal interests at the forefront. The new recommendations are intended to supplement and modify guidelines 37 to 40 in Section 5.3.4 of the 2010 guidelines: “Prevention of food allergy.”

Literature review

NIAID staff conducted a literature search of PubMed limited to the years 2010 (January) to 2016 (June). Using the following specific search terms ([food allergy or milk allergy or egg allergy or peanut allergy] OR [eczema or atopic dermatitis] AND prevention), PubMed returned more than 1500 articles. NIAID staff reviewed 1506 abstracts and assessed each for relevance to the topic of food allergy prevention with an emphasis on peanut allergy. Sixty-four publications (original research articles, editorials/letters, and systematic reviews) were deemed relevant and placed into 2 tiers: tier 1 contained 18 items considered highly relevant to the early introduction of peanut or other allergenic foods (see Appendix C), and tier 2 contained 46 items on related topics, such as food allergy or eczema prevention.

Assessing the quality of the body of evidence

For each of the 18 tier 1 references, the EP assessed quality by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [18]. GRADE provides a comprehensive and transparent methodology to develop recommendations for the diagnosis, treatment, and management of patients. In assessing the body of evidence of a group of relevant articles or of a single article, GRADE considers study design and other factors, such as the precision, consistency, and directness of the data. By using this approach, GRADE then provides a categorical assessment of the contribution of individual publications and the overall quality and strength of the body of evidence.

Each publication was assigned a grade according to the following criteria [19, 20]:
  • High: Further research is very unlikely to have an effect on the quality of the body of evidence, and therefore the confidence in the recommendation is high and unlikely to change.

  • Moderate: Further research is likely to have an effect on the quality of the body of evidence and may change the recommendation.

  • Low: Further research is very likely to have an important effect on the body of evidence and is likely to change the recommendation.

A GRADE designation of “low” for the quality of evidence does not imply that an article is not factually correct or lacks scientific merit. For example, a well-designed and executed single-site study of a treatment in a small cohort of highly selected subjects may still yield an overall GRADE rating of “low.” This is because such a study is characterized as providing “sparse” data, and the patient population may not be representative of the at-risk population. Each of these factors reduces the level of evidence from “high,” which is the initial designation for evidence from randomized controlled trials. It is worth emphasizing that these 2 limitations are not of the study per se but of the body of evidence.

Preparation of the draft addendum

The draft version of the addendum, prepared by the NIAID, contained 3 new guidelines and was reviewed, modified, and endorsed by the EP members. The EP-approved document was forwarded to the CC members for review.

Public comment period, addendum revision, and final approval

Concurrent with CC member review, the draft addendum was posted to the NIAID Web site in March 2016 for a period of 45 days to allow for public review and comment. One hundred four comments were received. All comments were reviewed by the EP and the CC, and some contributed to the final revision of the addendum. The final addendum was reviewed and approved by the EP and the CC.

Dissemination of the addendum guidelines

The final addendum is published herein and available through the Internet.

Defining the strength of each clinical guideline

The EP has used the verb “recommends” or “suggests” for each clinical recommendation.

These words convey the strength of the recommendation, defined as follows:
  • Recommend is used when the EP strongly recommended for or against a particular course of action.

  • Suggest is used when the EP weakly recommended for or against a particular course of action.

Addendum guidelines

Table 1 provides a summary of the 3 addendum guidelines to be used as a quick reference.
Table 1

Summary of addendum guidelines 1, 2, and 3

Addendum guideline

Infant criteria

Recommendations

Earliest age of peanut introduction

1

Severe eczema, egg allergy, or both

Strongly consider evaluation by sIgE measurement and/or SPT and, if necessary, an OFC. Based on test results, introduce peanut-containing foods.

4–6 months

2

Mild-to-moderate eczema

Introduce peanut-containing foods

Around 6 months

3

No eczema or any food allergy

Introduce peanut-containing foods

Age appropriate and in accordance with family preferences and cultural practices

The EP came to consensus on the following 3 definitions used throughout the addendum guidelines.
  • Severe eczema is defined as persistent or frequently recurring eczema with typical morphology and distribution assessed as severe by a health care provider and requiring frequent need for prescription-strength topical corticosteroids, calcineurin inhibitors, or other anti-inflammatory agents despite appropriate use of emollients.

  • Egg allergy is defined as a history of an allergic reaction to egg and a skin prick test (SPT) wheal diameter of 3 mm or greater with egg white extract, or a positive oral egg food challenge result.

  • A specialist is defined as a health care provider with the training and experience to (1) perform and interpret SPTs and OFCs and (2) know and manage their risks. Such persons must have appropriate medications and equipment on site.

Addendum guideline 1

The EP recommends that infants with severe eczema, egg allergy, or both have introduction of age-appropriate peanut-containing food as early as 4 to 6 months of age to reduce the risk of peanut allergy. Other solid foods should be introduced before peanut-containing foods to show that the infant is developmentally ready. The EP recommends that evaluation with peanut-specific IgE (peanut sIgE) measurement, SPTs, or both be strongly considered before introduction of peanut to determine if peanut should be introduced and, if so, the preferred method of introduction. To minimize a delay in peanut introduction for children who may test negative, testing for peanut sIgE may be the preferred initial approach in certain health care settings, such as family medicine, pediatrics, or dermatology practices, in which skin prick testing is not routine. Alternatively, referral for assessment by a specialist may be an option if desired by the health care provider and when available in a timely manner.

Figure 1 provides recommended approaches for evaluation of children with severe eczema, egg allergy, or both before peanut introduction.
Fig. 1

Recommended approaches for evaluation of children with severe eczema and/or egg allergy before peanut introduction. *To minimize a delay in peanut introduction for children who may test negative, testing for peanut-specific Ige may be the preferred initial approach in certain health care settings. Food allergen panel testing or the addition of sIgE testing for foods other than peanut is not recommended due to poor positive predictive value

A peanut sIgE level of less than 0.35 kUA/L has strong negative predictive value for the diagnosis of peanut allergy [21]. Therefore, peanut sIgE testing may help in certain health care settings (eg, family medicine, pediatric, or dermatology practices, where skin prick testing is not routine) to reduce unnecessary referrals of children with severe eczema, egg allergy, or both and to minimize a delay in peanut introduction for children who may have negative test results. However, the EP emphasizes that a peanut sIgE level of 0.35 kUA/L or greater lacks adequate positive predictive value for the diagnosis of peanut allergy, and an infant with a value of 0.35 kUA/L or greater should be referred to a specialist.

Thus, peanut sIgE testing can place an infant into one of 2 categories (Fig. 1):
  • sIgE Category A: If the peanut sIgE level is less than 0.35 kUA/L (ImmunoCAP), the EP recommends that peanut should be introduced in the diet soon thereafter, with a cumulative first dose of approximately 2 g of peanut protein given in this feeding. This can be given as a feeding at home (Appendix D), considering the low likelihood of a severe allergic reaction. If the caregiver or health care provider has concerns, a supervised feeding can be offered at the health care provider’s office (Appendix E).

  • sIgE Category B: If the peanut sIgE level is 0.35 kUA/L or greater (ImmunoCAP), the EP recommends that the child be referred to a specialist for further consultation and possible skin prick testing.

The EP does not recommend food allergen panel testing or the addition of sIgE testing for foods other than peanut because of their poor positive predictive value, which could lead to misinterpretation, overdiagnosis of food allergy, and unnecessary dietary restrictions [6].

SPTs with peanut extract can place an infant in one of 3 categories (Fig. 1):
  • SPT Category A: If an SPT to peanut extract produces a wheal diameter of 2 mm or less above saline control, the EP recommends that peanut be introduced in the diet soon after testing, with a cumulative first dose of approximately 2 g of peanut protein given in this feeding. This can be given at home (Appendix D), considering the low likelihood of a severe allergic reaction. If the caregiver or health care provider has concerns, a supervised feeding can be offered at the health care provider’s office (Appendix E).

  • SPT Category B: If an SPT to peanut extract produces a wheal diameter of 3 to 7 mm greater than that elicited by the saline control, the EP suggests that a supervised peanut feeding or a graded OFC be undertaken at a specialist’s office or a specialized facility (see Appendices E and G, respectively). Infants in this category can be sensitized without being allergic to peanut and might benefit from early peanut consumption. If the supervised peanut feeding or graded OFC yields no reaction, the EP recommends that peanut should be added to the child’s diet. If the supervised peanut feeding or the graded OFC results in an allergic reaction, the EP recommends that the child should strictly avoid dietary peanut and the family should be counseled regarding food allergy management.

  • SPT Category C: If an SPT produces a wheal diameter 8 mm or greater than that elicited by the saline control, the likelihood of peanut allergy is high. Children in this category should continue to be evaluated and managed by a specialist. [2123]

How much dietary peanut protein to introduce

If the decision is made to introduce dietary peanut based on the recommendations of addendum guideline 1, the total amount of peanut protein to be regularly consumed per week should be approximately 6 to 7 g over 3 or more feedings (see Appendix F). In the LEAP trial, at evaluations conducted at 12 and 30 months of age, 75% of children in the peanut consumption group reported eating at least this amount of peanut, based on analysis of a 3-day food diary recorded just before the evaluation.

Rationale

Infants with severe eczema, egg allergy, or both are at high risk for the development of peanut allergy. Significant evidence on this group is available from the infants who participated in the LEAP trial or were screened for the LEAP trial but were not enrolled because of a large SPT response (>4 mm). At 60 months of age, approximately 23% of peanut avoiders and those infants not enrolled had food allergy [24].

Balance of benefits and harms

In the LEAP trial, among the 530 participants in the intention-to-treat population with negative baseline SPT responses to peanut, 13.7% of the avoidance group and 1.9% of the consumption group had peanut allergy at 60 months of age (P < .001; a 12.6% absolute risk reduction and an 86.1% relative risk reduction in the prevalence of peanut allergy, resulting in a number needed to treat of 8.5 [number of infants needed to have early introduction of peanut to prevent peanut allergy in one child]). Among the 98 participants with positive peanut SPT responses at entry, 35.3% of the avoidance group and 10.6% of the consumption group had peanut allergy at 60 months of age (P = .004; a 24.7% absolute risk reduction and a 70% relative risk reduction in the prevalence of peanut allergy, resulting in a number needed to treat of 4).

The LEAP-On study [24] demonstrated that the benefits achieved in the LEAP trial persisted when LEAP trial peanut consumers subsequently avoided peanut for 1 year from 60 to 72 months of age. This indicates that the oral tolerance achieved in the LEAP trial was durable.

The LEAP trial did not include infants with SPT wheals greater than 4 mm, and therefore no data are available on the potential effectiveness of peanut consumption in preventing peanut allergy in this group. However, EP members believe it is possible that some of these infants may benefit from early introduction of peanut provided that they tolerate oral peanut.

As shown in Fig. 1, the EP recommends that infants with severe eczema, egg allergy, or both, with peanut sIgE levels of less than 0.35 kUA/L or with a peanut SPT wheal of 2 mm or less have dietary peanut introduced as early as 4 to 6 months of age without a need for further evaluation. This recommendation is supported by expert opinion and analysis of the LEAP population findings. In the LEAP trial, infants consuming peanut in this post hoc defined category had a relative risk reduction of 79% of having peanut allergy at 60 months of age compared with infants who avoided peanut.

In the LEAP trial, at study entry, all infants randomly assigned to the consuming group had a baseline peanut OFC. Of the 272 infants with no wheal induced by peanut SPT and who received a baseline oral peanut challenge, only 1 had a reaction presenting as an erythematous urticarial rash that was graded as a “moderate” adverse event and was treated successfully with chlorpheniramine. Among the 29 infants with a wheal diameter of 1 to 2 mm who received a baseline oral peanut challenge, 2 had reactions, which also presented with mild symptoms not requiring treatment with epinephrine. Therefore, for the SPT Category A children, the risk of a severe reaction to peanut at first introduction is low, and introduction of peanut at home is an option. However, it is understandable that some caregivers of infants with severe eczema, egg allergy, or both may be uncomfortable introducing dietary peanut at home. In such cases the health care provider should offer the option of a supervised feeding of a peanut-containing food in the office.

The rate of positive peanut OFC results at baseline for infants with a 3 to 4 mm wheal diameter (4/17 infants) was higher than in infants with 0 to 2 mm wheal diameters (3/301 infants), but the elicited symptoms were mild. Infants with larger wheal diameters (>4 mm) were not included in the LEAP trial, and therefore no safety data are available from this group. However, based on the Australian HealthNuts study, which conducted peanut OFCs in a large number of older (12–18 months old) children from the general Australian population, the rate of reactions to peanut is expected to be substantially higher with increasing SPT wheal diameter [21, 23]. In the HealthNuts study [23] an SPT wheal diameter of 8 mm or greater had a 95% positive predictive value for peanut allergy (positive oral peanut challenge result). Therefore, the EP recommends that for SPT Category B infants (3 to 7 mm SPT wheal diameter), a supervised feeding or a graded peanut OFC should be conducted in a specialist’s office or a specialized facility (Appendix G). SPT Category C infants are considered high risk for established allergy to peanut and should not receive peanut-containing foods in their diet, unless such foods are recommended by a specialist after further evaluation.

Quality of evidence: Moderate

The designation of the quality of evidence as “moderate” (as opposed to “high”) is based on the fact that this recommendation derives primarily from a single randomized, open-label study: the LEAP trial. However, it should be noted that the assessment of the LEAP trial’s primary outcome was based on a double-blind, placebo-controlled OFC. Furthermore, confidence in this recommendation is bolstered by the large effect size demonstrated in the LEAP trial and prior epidemiologic data that peanut allergy is relatively infrequent in Israel, where early childhood consumption of peanut is common.

Contribution of expert opinion

Significant.

Additional comments

  1. 1.

    Breast-feeding recommendations: The EP recognizes that early introduction of peanut may seem to depart from recommendations for exclusive breast-feeding through 6 months of age [25, 26]. However, it should be noted that data from the nutrition analysis of the LEAP cohort [27] indicate that introduction of peanut did not affect the duration or frequency of breast-feeding and did not influence growth or nutrition.

     
  2. 2.

    Age of peanut introduction: For children with severe eczema, egg allergy, or both, the EP recommends that introduction of solid foods begins at 4 to 6 months of age, starting with solid food other than peanut, so that the child can demonstrate the ability to consume solid food without evidence of nonspecific signs and symptoms that could be confused with IgE-mediated food allergy. However, it is important to note that infants in the LEAP trial were enrolled between 4 and 11 months of age and benefitted from peanut consumption regardless of age at entry. Therefore, if the 4- to 6-month time window is missed for any reason, including developmental delay, infants may still benefit from early peanut introduction. On the other hand, older age at screening is associated with larger wheal diameters induced by peanut SPT and hence a higher likelihood of established peanut allergy [28].

    A practical consideration for applying this guideline at 4 to 6 months of age is that infants visit their health care provider for well-child evaluations and infant immunizations at this time. This provides a fortuitous opportunity for eczema evaluation, caregiver reporting of egg allergy, and, if needed, referral to a specialist for peanut allergy evaluation before dietary introduction of peanut.

     
  3. 3.

    Considerations for family members with established peanut allergy: The EP recognizes that many infants eligible for early peanut introduction under this guideline will have older siblings or caregivers with established peanut allergy. The EP recommends that in this situation caregivers discuss with their health care providers the overall benefit (reduced risk of peanut allergy in the infant) versus risk (potential for further sensitization and accidental exposure of the family member to peanut) of adding peanut to the infant’s diet.

     
  4. 4.

    Children identified as allergic to peanut: For children who have been identified as allergic to peanut, the EP recommends strict peanut avoidance. This may include those children in SPT Category B who fail the supervised peanut feeding or the OFC, or those children in SPT Category C who, on further evaluation by a specialist, are confirmed as being allergic to peanut. These children should be under long-term management by a specialist.

     

Addendum guideline 2

The EP suggests that infants with mild-to-moderate eczema should have introduction of age-appropriate peanut-containing food around 6 months of age, in accordance with family preferences and cultural practices, to reduce the risk of peanut allergy. Other solid foods should be introduced before peanut-containing foods to show that the infant is developmentally ready. The EP recommends that infants in this category may have dietary peanut introduced at home without an in-office evaluation. However, the EP recognizes that some caregivers and health care providers may desire an in-office supervised feeding, evaluation, or both.

Rationale

The LEAP trial did not target infants with mild or moderate eczema. The EP considered the potential risk/benefit ratio of early dietary peanut introduction in infants with mild-to-moderate eczema and concluded that the individual and societal benefits of introducing peanut in this population would be significant. The EP has no reason to believe that the mechanisms of protection of early dietary peanut differ in infants with mild-to-moderate eczema from those that lead to protection in infants at higher risk of peanut allergy.

Balance of benefits and harms

The LEAP trial included only infants with severe eczema or egg allergy based on careful medical history. Therefore, some infants who participated in the LEAP trial based on the presence of egg allergy had atopic dermatitis severity scores (SCORAD scores [29]) at screening that would have placed them in the moderate or mild eczema category. The EP considered the outcomes of these children and concluded that infants with mild-to-moderate eczema would likely benefit from early peanut introduction.

Quality of evidence

Low.

The quality of evidence is low because this recommendation is based on extrapolation of data from a single study.

Contribution of expert opinion

Significant.

Additional comment

Additional support for early introduction of peanut in infants who do not have severe eczema comes from the Enquiring About Tolerance study [17], which enrolled infants from the general population at 3 months of age and sequentially introduced 6 allergenic foods beginning at the time of enrollment. These children were not intentionally selected based on increased risk of food allergy or atopy. Although the intention-to-treat group did not show benefit, most likely because of relatively poor compliance with feeding recommendations, the children in the per-protocol group who had peanut introduced early in infancy showed a significant reduction in peanut sensitization and peanut allergy at age 3 years. This study also provides support for guideline 3 below.

Addendum guideline 3

The EP suggests that infants without eczema or any food allergy have age-appropriate peanut-containing foods freely introduced in the diet together with other solid foods and in accordance with family preferences and cultural practices.

Rationale

No evidence exists for restricting allergenic foods in infants without known risks for food allergy. The probability for development of peanut allergy in such children is very low. However, approximately 14% of all children with peanut allergy at age 12 to 18 months in the HealthNuts Study lacked known risk factors for food allergy [16]. Consequently, because such children constitute a significant majority of any birth cohort, they contribute substantially to the overall societal burden of peanut allergy. The EP finds no evidence to suggest that mechanisms of oral tolerance induction would differ in these infants from the immunologic mechanisms that are protective in infants at higher risk of peanut allergy. Thus, the early introduction of dietary peanut in children without risk factors for peanut allergy is generally anticipated to be safe and to contribute modestly to an overall reduction in the prevalence of peanut allergy. Furthermore, in countries such as Israel, where peanut products are a popular component of the diet and where they are introduced early in life, the prevalence of peanut allergy is low [14].

Balance of benefits and harms

The EP acknowledges that any analysis of benefit and harm in this population relies primarily on expert opinion and is subject to current differences in regional/societal rates of peanut consumption and peanut sensitization. In countries where peanut products are not widely consumed by adults, early dietary introduction of peanut could lead to an increase in sensitization and allergic manifestations. Hence the EP cautions that this guideline be implemented in the context of societal routines/norms.

Quality of evidence

Low.

Contribution of expert opinion

Significant.

Clinical implications: These guidelines will help health care providers with early introduction of peanut-containing foods in infants at various risk levels for peanut allergy. Early introduction of peanut will result in the prevention of peanut allergy in a large number of infants.

Abbreviations

CC: 

Coordinating Committee

EP: 

Expert Panel

GRADE: 

Grading of Recommendations Assessment, Development and Evaluation

LEAP: 

Learning Early about Peanut Allergy

NIAID: 

National Institute of Allergy and Infectious Diseases

OFC: 

Oral food challenge

sIgE: 

Specific IgE

SPT: 

Skin prick test

Declarations

Acknowledgements

There are none.

Funding

Not applicable

Availability of data and materials

Not applicable.

Authors’ contributions

AT, DR and SC wrote the document based on the EP deliberations, and the EP authors reviewed, edited, and approved the submitted version. All authors read and approved the final manuscript.

Competing interests

A. Assa’ad received travel support from the American College of Allergy, Asthma & Immunology (ACAAI); was an elected member of the Board of Directors for the American Academy of Allergy, Asthma, & Immunology (AAAAI) from March 2012 to March 2016; has consultant arrangements with Aimmune; is employed by Cincinnati Children’s Hospital Medical Center; has received grants from DBV Technologies, Aimmune, Stanford Foundation, TEVA Pharmaceuticals, GlaxoSmithKline, the National Institutes of Health (NIH), Astellas, and Food Allergy Research & Education (FARE); and has received payment for lectures from the ACAAI. C. Byrd-Bredbenner and G. J. Fuchs III have received travel support from the NIH/National Institute of Allergy and Infectious Disease (NIAID). E. S. Chan has received travel support from the NIAID, has received grants from DBV Technologies, and has received payment for lectures from Pfizer, Sanofi, Mead Johnson, and Nestle. D. M. Fleischer has received travel support from the NIAID; is a board member for the National Peanut Board, the FAACT Medical Advisory Board, and the FARE Medical Advisory Board; has consultant arrangements with Adamis Pharmaceuticals Corporation, INSYS Therapeutics, DBV Technologies, Aimmune Therapeutics, Intrommune Therapeutics, and Kaleo Pharma; is employed by University Physicians; has received grants from Monsanto Company, Nestle Nutrition Institute, DBV Technologies, and Aimmune Therapeutics; has received payment for lectures from Nestle Nutrition Institute; and has received royalties from UpToDate. M. J. Greenhawt has received a grant from the Agency for Healthcare Research and Quality (1K08HS024599-01, Career Development Award); has received travel support from the NIAID and the Joint Taskforce on Allergy Practice Parameters; has a board membership with the National Peanut Board; has consultant arrangements with Adamis Pharmaceuticals, the Canadian Transportation Agency, Nutricia, Nestle/Gerber, Aimmune, Kaleo Pharmaceutical, and Monsanto; is an Associate Editor for the Annals of Allergy, Asthma, and Immunology; has received payment for lectures from the ACAAI, Reach MD, Thermo Fisher Scientific, the California Society for Allergy and Immunology, the Allergy and Asthma Network, the New England Society for Allergy, UCLA/Harbor Heiner Lectureship, Medscape, the Western Michigan School of Medicine, the Canadian Society of Allergy and Clinical Immunology, and the Pennsylvania Society for Allergy and Immunology. R. S. Gupta has consultant arrangements with BEFORE Brands and DBV Technologies; has received grants from the NIH, FARE, and Mylan LLC; has received payment for lectures from Grand Rounds; and has received royalties from Createspace Independent Publishing Platform. S. M. Jones is on the Research Advisory Board for FARE; is on the Scientific Advisory Board for Aimmune; has consultant arrangements with Stallergenes; has received grants from the NIH/NIAID (Consortium of Food Allergy Research and Immune Tolerance Network–IMPACT Trial), FARE, Aimmune Technologies, DBV Technologies, and the National Peanut Board; has received payment for lectures from the Kansas City Allergy Society, Mercy Children’s Hospital, Riley Children’s Hospital, Southwester Medical School–Children’s Medical Center, the European Academy of Allergy & Clinical Immunology, the New York Allergy & Asthma Society, the University of Iowa Paul M. Seebohm Lectureship in Allergy, and the Iowa Society of Allergy, Asthma, and Immunology. A. Muraro has consultant arrangements with Meda, Novartis, and Menarini; is employed by Padua University Hospital; and has received payment for lectures from Meda and Menarini. L. J. Rosenwasser is a board member for the World Allergy Organization. H. A. Sampson has consultant arrangements with Allertein Therapeutics, Genentech/Roche, Sanofi, Stallergenes, Danone, and Merck; is employed part time as Chief Scientific Officer for DBV Technologies; has received grants from the NIAID and the Immune Tolerance Network; has received royalties from UpToDate and Elsevier; has been offered stock options in DBV Technologies; and is chairman of PhARF Award Selection Committee for Thermo Fisher. L. C. Schneider is on the Medical Advisory Board for FARE, has received a grant from DBV Technologies, and has received stock/stock options in Antera Therapeutics. S. H. Sicherer has received grants from the NIAID, FARE, and HAL Allergy; has received royalties from UpToDate; and is serving as Associate Editor for the Journal of Allergy and Clinical Immunology: In Practice. R. Sidbury has received travel support from the NIH and the Hawaii Dermatology Seminar, has consultant arrangements with Anacor, has provided expert witness testimony on behalf of Roche in Accutane–inflammatory bowel disease cases, has received a grant from Epidermolysis Bullosa Research Partnership, has received payment for lectures from the Taiwanese Dermatological Society, and has received royalties from UpToDate. J. Spergel has consultant arrangements with DBV Technologies and Danone; has received grants from DBV Technologies, Aimmune Therapeutics, and the NIH; has received payment for lectures for Dartmouth College, the ACAAI, and the Florida Allergy Society; and has received stock/stock options in DBV Technologies. D. R. Stukus has received payment for lectures from the ACAAI. C. Venter has consultant arrangements with Danone and Nestle, has received payment for lectures from Mead Johnson, and has received travel support from Thermo Fisher. The rest of the authors declare that they have no relevant conflicts of interest.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Declarations

Published on behalf of the American Academy of Allergy, Asthma & Immunology; American College of Allergy, Asthma & Immunology; Canadian Society of Allergy and Clinical Immunology; Society for Pediatric Dermatology; World Allergy Organization; and Society of Pediatric Nurses.

Copublished in the Journal of Allergy and Clinical Immunology; Annals of Allergy, Asthma & Immunology; Allergy, Asthma & Clinical Immunology; World Allergy Organization Journal; Pediatric Dermatology; and the Journal of Pediatric Nursing.

The article is a work of the United States Government; Title 17 U.S.C 105 provides that copyright protection is not available for any work of the United States government in the United States. Additionally, this is an open access article distributed under the terms of the Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0), which permits worldwide unrestricted use, distribution, and reproduction in any medium for any lawful purpose.

Authors’ Affiliations

(1)
National Institute of Allergy and Infectious Diseases
(2)
Food Allergy Research & Education
(3)
Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati
(4)
Food Allergy Research & Education, McLean, and the Division of Allergy and Clinical Immunology, University of Michigan Health System
(5)
Department of Dermatology, University of Rochester Medical Center
(6)
National Eczema Association
(7)
Department of Nutritional Sciences, Rutgers University
(8)
Division of Allergy and Immunology, Department of Pediatrics, BC Children’s Hospital, University of British Columbia
(9)
Departments of Dermatology and Pediatrics, University of California, San Diego School of Medicine, Rady Children’s Hospital
(10)
Section of Allergy and Immunology, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado Denver School of Medicine
(11)
Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Kentucky College of Medicine, Kentucky Children’s Hospital
(12)
Digestive Health Institute, Children’s Hospital Colorado, Aurora, and the Section of Pediatric Gastroenterology, University of Colorado Denver School of Medicine
(13)
Division of Academic General Pediatrics and Primary Care, Department of Pediatrics, and the Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine
(14)
Northwestern Medicine, Central DuPage Hospital
(15)
Division of Allergy and Immunology, Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children’s Hospital
(16)
Metro DC Food Allergy Support Group
(17)
the Food Allergy Referral Centre, Department of Women and Child Health, Padua University Hospital
(18)
University of Missouri-Kansas City School of Medicine
(19)
Division of Allergy and Immunology, Department of Pediatrics, Harvard Medical School
(20)
Division of Pediatric Allergy and Immunology, Icahn School of Medicine at Mount Sinai
(21)
Division of Allergy and Immunology, Boston Children’s Hospital
(22)
Department of Pediatrics, Division of Dermatology, Seattle Children’s Hospital, University of Washington School of Medicine
(23)
Division of Allergy and Immunology, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania
(24)
Department of Pediatrics, Section of Allergy and Immunology, Nationwide Children’s Hospital, Ohio State University College of Medicine
(25)
Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center
(26)
Departments of Medicine and Pediatrics, Harvard Medical School

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