By David Stukus, MD
What Do We Know About the Prevention of Peanut Allergy?
For decades, the belief among allergists and pediatricians was that avoidance of allergenic foods would prevent the development of allergy. Previous clinical guidelines published in 2000 by the American Academy of Pediatrics recommended avoidance of all milk products until 1 year of age, egg until 2, and peanut, tree nuts, and seafood until 3. Lo and behold, just 8 years later, the authors realized that there was no evidence to support this approach and the guidelines were not just revised, but also completely reversed, in 2008 to recommend introduction of solid foods, including allergenic foods, into the diet between 4-6 months of age. This stark contrast was met with confusion and reluctance to change the paradigm without solid evidence in support. Pediatricians and parents were left in limbo. Then, in March 2015 The Learning Early About Peanut Allergy (LEAP) study was published in the New England Journal of Medicine. For the first time, the LEAP study very strongly demonstrated that early introduction of peanut to high risk infants does indeed prevent the development of peanut allergy.
The LEAP trial enrolled 640 infants all between 4-11 months of age and randomized them to two groups: one group avoided any peanut until 5 years of age and the other group consumed 2 grams of peanut 3 times a week until 5 years of age. All participants had moderate-to-severe eczema and/or egg allergy and underwent skin prick testing and food challenge at enrollment. The LEAP trial demonstrated a significant reduction in peanut allergy at 5 years of age for infants who consumed compared with those who avoided, including an 86% relative reduction in those with negative skin tests and 70% relative reduction in those with a mild skin test wheal size of 1-4 mm at enrollment. This was the first large-scale study demonstrating the possibility of prevention of food allergy through early introduction.
It is important to understand that the LEAP study findings are not generalizable for several reasons. First, the participants all had moderate-to-severe eczema and/or egg allergy. It remains unknown what effect early introduction of peanut would have for infants without eczema, for those with food allergies other than egg, or for those with a family history of peanut allergy. There is no reason to believe anyone would react differently than this well-chosen cohort of at-risk infants, but we also have no data. Second, the LEAP protocol was very strict with consumption of at least 2 grams of peanut three times per week for 4 years. It remains unknown what the effect would be from eating less amounts less frequently. Third, all infants in LEAP were less than 11 months old, mean age 7.8 months. It remains unknown what would happen if peanut were introduced at 12 months of age or later. However, LEAP data clearly demonstrates an increased risk of larger peanut skin test or failed oral challenge with increasing age. Lastly, LEAP excluded any infants with a wheal size 5 mm. or greater on skin prick testing. 8 mm. is well regarded as the size of wheal on skin testing associated with a 95% likelihood of having a peanut allergy. It is possible that a group of infants with wheal skin test size to peanut between 5-8 mm. would also be able to tolerate and then prevent development of peanut allergy.
Since LEAP was published, not everyone has been a fan of the results. This has no bearing on anyone who already has a peanut allergy, as this is a study looking at prevention. In addition, many parents became upset as they specifically avoided giving their children peanut until later in life only to see their children still develop peanut allergy, and LEAP now shows that this could have potentially (likely) been avoided. All I can say is that recommendations are made based upon the best available current evidence. Hindsight is 20/20, and I share the burden with all of my colleagues that perhaps we gave the wrong advice for a period of time. Physicians make treatment recommendations based upon the best available evidence and current treatment guidelines, both of which are moving targets. One can observe the seemingly constant changes to screening procedures (see: mammograms) or dietary recommendations (see: trans fats, carbohydrates, sugars, etc) to begin to understand how knowledge gaps become filled in by research over a course of years and decades.
Some have screamed that a conflict of interest occurred due to partial funding for the study from the National Peanut Board. However, there were several funding sources for this study, not to mention that trial design, implementation, and interpretation of results was performed by the investigators, not the funders. In a nearly unprecedented manner within the field of allergy/immunology, the study authors made all of their study data available for free to the entire world through TrialShare, which literally allows anyone with interest the capability of pouring through and then re-analyzing all of the data. Lastly, some have taken issue with certain exclusion criteria in LEAP, but careful review of study protocol shows that the authors did a thorough and comprehensive job of studying the possibility of primary prevention of peanut allergy in a cohort of at-risk infants and excluded infants with possible confounding factors such as other co-morbid conditions (extremely common in research studies).
Did LEAP Truly Prevent Peanut Allergy or Just Lead to Desensitization?
One of the unanswered questions from LEAP is in regards to mechanism of action. While there was a dramatic reduction in peanut allergy at 5 years of age for infants who consumed regularly versus those who avoided, the study was not designed to investigate why this occurred. Oral immunotherapy for food allergy is not a cure, but offers a way to desensitize and potentially develop tolerance or prevent severe reactions from occurring with accidental ingestion. Oral immunotherapy requires daily ingestion of the food allergen in very small amounts in order to maintain desensitization. Missed doses or prolonged periods of time in between doses can cause a loss of the desensitized state and lead to allergic reaction with the next exposure. This is an extremely important concept not well understood by many seeking the ‘food allergy cure’ that does not yet exist. Is it possible that LEAP merely led to prolonged desensitization? The authors were determined to find out.
The Persistence of Oral Tolerance to Peanut (LEAP-On) study was published in the New England Journal of Medicine in March 2016 and used the same participants from LEAP. LEAP-On asked all children in both the avoidance and consumption groups to strictly avoid peanut for 12 months, after their oral challenge at 60 months of age. This was to try and determine whether peanut allergy was truly prevented through early introduction, or whether these infants were being desensitized, similar to oral immunotherapy.
LEAP-On enrolled 88.5% of participants from the original trial (556 children). Study authors monitored adherence to peanut avoidance during the 12 months of subsequent avoidance and noted high rates in both groups, with 90.4% in the original peanut avoidance group continuing avoidance compared with 69.3% in the peanut consumption group. (Kudos to the 70% of parents who agreed to remove peanut from their children’s diet not knowing whether they may develop peanut allergy after 4 years of tolerance.)
After 12 months of peanut avoidance, there was no significant increase in children developing peanut allergy from the group that previously consumed; 3.6% at 5 years of age, compared with 4.8% at 6 years. There were a total of 3 new cases of peanut allergy in both groups. In addition, the original peanut consumption group continued to have much lower rates of peanut allergy after completion of LEAP-On, 4.8% vs 18.6%.
Does LEAP-ON Change Anything?
So what does this all mean? According to the new data from LEAP-On, early introduction of peanut to infants at high risk for development of peanut allergy not only dramatically reduces rates of peanut allergy at 5 years of age, but also shows this effect to be sustained after one year of avoidance. This is likely due to true prevention, as opposed to a prolonged desensitization.
We still do not know the exact duration or amount of consumption necessary to induce sustained tolerance. LEAP participants consumed 2 grams of peanut 3 times per week for 4 years. Is it possible that eating peanut ad lib or for shorter duration will have the same effect? This remains unknown. However, we have clear and strong evidence that early and sustained consumption of peanut in high risk infants is effective in preventing the development of food allergy, and now in sustaining unresponsiveness.
Currently, when I meet a parent (or expectant mother) with a 4-11 month old infant who has moderate-to-severe eczema and/or egg allergy, I am thrilled to have the opportunity to discuss the LEAP study findings and implications. I offer skin prick testing to peanut and have had tremendous success introducing peanut butter to infants in my office setting. Every single one has a look of wide-eyed wonderment at the new experience for their taste buds. Significant breakthroughs such as this do not come along frequently in medicine. Being able to offer families a likely preventative strategy brings great joy to these parents (many of whom have older children with existing peanut allergy) and myself as well.
Information from the original LEAP and new LEAP-On studies will be used to formulate new guidelines to help pediatricians and allergists encourage the introduction of peanut to all infants, with recommendations to test and/or challenge first for those at high risk. The National Institute of Allergy and Infectious Disease is coordinating these guidelines, with input from food allergy experts from across North America and Europe. Goal for publication is sometime in 2016.
In the meantime, we must continue to help parents and pediatricians understand exactly what the data from these research studies has taught us. Parents of newborns should discuss these implications with their child’s pediatrician or allergist prior to introducing peanut. Pediatricians should start discussing this with parents at the 4-month well child visit. Allergists need to continue educating everyone as to what this all means.
It has been suggested that it takes approximately 10-15 years before new guidelines are adopted into clinical practice. Let’s all hope it doesn’t take that long to prevent a new generation of infants from developing peanut allergy.
David Stukus, MD, is board certified in Allergy/Immunology and is an Assistant Professor of Pediatrics at Nationwide Children’s Hospital and The Ohio State University in Columbus, Ohio. His clinical and research interests focus on asthma and food allergies, especially improving education and adherence for patients and families. As part of his research, Dr. Stukus has created novel technology and educational tools using mobile health apps to improve the care of patients, for which he was recognized with the Nationwide Children’s Hospital Department of Pediatrics Junior Faculty Award in November 2013. Dr. Stukus has been an active member of the medical advisory team for Kids with Food Allergies since 2009 and was elected to the Board of Directors for the Asthma and Allergy Foundation of America in 2014. Lastly, Dr. Stukus actively engages with food allergy support groups and participates in social media on twitter through @AllergyKidsDoc.