COMMENTARY

Peanut Allergy: The Paradigm-Changing Research

An Expert Interview With Matthew J. Greenhawt, MD, MBA, MSc

Laurie Scudder, DNP, NP; Matthew J. Greenhawt, MD, MBA, MSc

Disclosures

August 18, 2015

Editor's Note:
The landmark Learning Early About Peanut Allergy (LEAP) trial,[1] published in February 2015, is revolutionizing the care of children at high risk for peanut allergy. A consensus communication on early peanut introduction and the prevention of peanut allergy in high-risk infants,[2] developed by a host of US and international organizations, was recently released to guide the care of these children until an update to the National Institute of Allergy and Infectious Diseases (NIAID) food allergy guidelines, due to begin this summer, is released. Medscape spoke with Matthew J. Greenhawt, MD, MBA, MSc, a member of the consensus panel and the NIAID-appointed expert panel guideline committee, about this important study and its implications for clinicians and children, as outlined in the consensus communication.

Medscape: The incidence of peanut allergy is increasing—but is it known why?

Dr Greenhawt: Regardless of how it is measured, most studies from the United States and other western countries have shown a rise in peanut allergy over the past 10-15 years. In Australia, where rates of peanut allergy were determined by food challenge (the gold standard in confirming the diagnosis), 3% of the population at 1 year of age was noted to have peanut allergy.[3] In the United States, a prevalence of 1.4% was determined through a randomized digit-dial phone survey, and that rate had tripled over a 10-year period.[4] Peanut allergy is an emerging public health problem.

Peanut allergy can be very severe, and a sizeable proportion of susceptible individuals will react on their first peanut exposure. For most, this is a lifelong allergy. There are no present treatments or a cure for peanut allergy, but several promising approaches are on the horizon, currently being researched in clinical trials.

Medscape: What have recommendations told us until now?

Dr Greenhawt: The American Academy of Pediatrics (AAP) issued guidelines in 2000[5] recommending that children at high risk (defined as a history of allergic disease in a parent or a sibling) should avoid introducing peanuts into the diet until about 3 years of age. It was also recommended that nursing mothers and pregnant women avoid peanuts.

In 2008, these recommendations were updated and revised[6] to state that there was no evidence to delay the introduction of any solid complementary food, including peanuts, past the age of 4-6 months, though it was recommended that children with a family history of allergy seek consultation with a specialist before introduction of high-risk allergens. The 2008 guidance also stated that there was little evidence supporting peanut avoidance while breastfeeding or during pregnancy.

The American Academy of Allergy, Asthma & Immunology (AAAAI) issued similar guidelines in 2013.[7] Thus, both the AAP and the AAAAI have not recommended delay in complementary food introduction for the past few years, but these recommendations stopped short of actively promoting early introduction of high-risk allergens, and they have been cautious regarding the high-risk infant.

Medscape: Let's talk about this important new study. Can you put LEAP into context for us?

Dr Greenhawt: Some early data from the 1990s, from very small studies, suggested that the early introduction of peanut or exposure to peanut in utero or during breastfeeding could be related to later development of peanut allergy. That was in part some of the basis for the recommendation in 2000 to delay the introduction of peanut into a child's diet.

In 2008, Dr George Du Toit and colleagues published a very innovative study[8] exploring differences in the rates of peanut allergy between Jewish children of Ashkenazi (eg, Eastern European) heritage living in London compared with those living in Tel Aviv. It had been previously observed that peanut allergy was not as significant a problem in Israel as it was in the United Kingdom.

To better understand reasons for this discrepancy, investigators examined cohorts of more than 5000 children in each city, querying reported timing of peanut introduction and allergic history. A 10-fold higher rate of peanut allergy was noted in London than in Tel Aviv. After statistical adjustment, the only significant difference between the two groups was that 80%-90% of the Israeli children had peanut introduced into their diets by 9 months of age, whereas almost none of the English children had peanut introduced until much later (age 3 years). It was concluded that timing of introduction was the most likely factor associated with the difference in rates of allergy, but because the study was not a controlled trial, no causal link between timing of introduction and development of peanut allergy could be implied.

Medscape: Was this study the basis for the LEAP trial?

Dr Greenhawt: Yes. The same group, led by Dr Du Toit and Dr Gideon Lack, designed a highly innovative interventional trial to determine whether the timing of peanut introduction influences peanut allergy development. The LEAP[1] trial exclusively enrolled high-risk infants, defined as children with severe eczema and/or egg allergy. Egg allergy was included because children with one food allergy are at risk for allergy to other foods, and it was diagnosed either by a large positive skin prick test (SPT) to egg, predictive of egg allergy, or a history of ingesting egg and having a reaction. Eczema severity was determined by reported history of severe rash, frequent use of topical steroids or calcineurin inhibitors, or SCORAD score > 40 (SCORAD is an objective rating system of eczema severity based on body surface area affected). A publication from the LEAP investigators in 2013 had validated these high-risk criteria.[9]

Before study entry, all infants (who were aged 4-11 months) received extensive histories and physical examinations. All underwent baseline peanut SPT to assess for evidence of preexisting peanut sensitization. Those who had a positive SPT with a wheal ≥ 5mm were excluded, because investigators thought this would be highly predictive of having peanut allergy already.

After children with a large SPT were excluded, a final sample of 640 children who had either no SPT reactivity or an SPT wheal < 5 mm were then randomly assigned within these groupings to either start consuming peanut, or to avoid peanuts until the age of 5 years.

For those randomly assigned to eat peanut, the initial introduction was done in the investigator's office, under supervision, as a food challenge. Children assigned to the peanut consumption group ate 2 g of peanut three times a week through age 5 years. The preferred food was Bamba® (Osem; Holon, Israel), a popular Israeli peanut-flavored puffed maize snack similar to Cheez Doodles® (Wise Foods, Inc.; Berwick, Pennsylvania). For some children, peanut butter in mashed banana was used.

The children randomly assigned to avoidance were to strictly avoid peanuts, and there were compliance checks that included household dust sampling to look for levels of ambient peanut protein in the home.

After 5 years, the investigators conducted peanut challenges in the children to determine the rate of tolerance in the two groups. In the peanut avoidance group, 17.2% developed peanut allergy, compared with 3.2% of the children who underwent early peanut introduction—a 14% absolute risk reduction, and a relative risk reduction of 80%. This translated to a number needed to treat (NNT) of 7.1; this is the number of children who would need to be treated with this intervention for one to receive benefit. However, the effects of the intervention were different depending on the SPT.

The NNT in the group with negative baseline peanut SPTs, undergoing primary prevention, was 8.5. However, in the kids with minimally positive SPTs (wheals ≤ 4 mm), undergoing secondary prevention (preventing the evolution of sensitization to becoming a clinical allergy), the NNT was 4, indicating the intervention worked better within that group. This is referred to as "heterogeneity of treatment effect."

Medscape: The amount of peanut protein that the children in this study consumed was 6 g/wk. Why was that amount selected?

Dr Greenhawt: The 2008 study[8] by these investigators included a survey that asked parents the amount of peanut their children ingested, which was estimated to be approximately 7 g/wk. This provided the LEAP study team a relative target amount for peanut ingestion, but was not otherwise a scientifically, rigorously devised endpoint. This dose was also not manipulated in the LEAP trial to test what minimum level of ingestion is necessary for protection. Thus, it is unknown whether 6 g/wk is the right amount, or whether the same effect could be achieved with lesser amounts of peanut protein.

The point I'd like to emphasize is that for children who have peanut introduced early under this protocol, especially those with a positive SPT, parents should be encouraged to feed this food to their child as frequently as possible and incorporate it into the diet like any other food in gradually increasing amounts. Although 6 g/wk is certainly a proven target dose, the specific "right" amount remains an unanswered question.

Medscape: What are some of the key remaining unanswered questions?

Dr Greenhawt: There are several unanswered questions, but I will focus on the three most pressing ones. The first is, what would the outcome have been if there had not been exclusion of patients with SPTs > 5 mm? I think it is fairly unlikely that all of these patients would have failed a food challenge if they had been randomly assigned to early introduction. A certain proportion of them might have failed, but not everybody would have, and there is argument to be made regarding potential lost benefit in this population.

There is certainly some logic that there may be a "predictive" level for a SPT beyond which the patient is highly probable to react, but such levels have been very difficult to assess in someone who has never consumed peanut previously, as opposed to in persons with a known reaction history. However, it is fair to wonder whether at least some children with an SPT ≥ 5 mm would receive similar or even greater benefit than those with an SPT between 1 and 4 mm, and I think this is an important question to pursue when trying to extrapolate potential benefit to the general population.

The second question pertains to what would happen if a child starts early peanut introduction, then stops eating peanut after a particular period. The study explored 5 years of consumption. The question remains as to how long peanut consumption would have to continue to confer benefit.

A second phase of this study will be looking at this specific question. This study, called LEAP-ON will evaluate the persistence of tolerance to peanut, and whether continued consumption of peanuts is required to be able to safely eat peanuts, or if one can intermittently eat or outright discontinue early introduction and remain tolerant. This is an important outcome to establish.

The third unanswered question relates to how well the "high-risk" children were specified and how applicable these findings may be to children with lesser or no risk factors. For example, should children with allergy to foods other than egg (eg, cow's milk) be considered high risk and thus candidates for early introduction of peanut? Should there be a uniform classification for eczema severity? Should other previously used criteria for risk, such as family history, be included? Would children with minimal or no risk also benefit? In addition, it may be fair to ask if the same degree of benefit would be seen in other (non-UK) populations. All these issues are very important to determine.

Although some degree of replication of clinical trial findings is customary in medicine, there are obviously some practical issues to consider regarding whether or how any of these lingering questions could be answered. Foremost, some have advocated that it may not be ethical to repeat the study and intentionally withhold an intervention (e.g. early intervention, shown to be beneficial) even to answer these burning questions. In addition, the trial was expensive and time-consuming, and may not be feasible to repeat. This trial was labor-intensive and involved multiple highly skilled individuals. Thus, some of these questions may remain unanswered.

Medscape: Can you tell us about the development of the consensus communication[2]?

Dr Greenhawt: The consensus communication is a truly international document. Organizations signing on to the document include AAP; AAAAI; the American College of Allergy, Asthma & Immunology; the Canadian Allergy, Asthma and Immunology Foundation; the European Academy of Allergy and Clinical Immunology; the Australasian Society of Clinical Immunology and Allergy; the Japanese Society of Allergology; the Israel Association of Allergy and Clinical Immunology; the Asia Pacific Association of Allergy, Asthma and Clinical Immunology; the Society for Pediatric Dermatology, and the World Allergy Organization.

Each organization nominated members to contribute to the creation of interim recommendations, and broad opinion was deliberately sought. The document represents a majority consensus from among these groups regarding the optimal translation of the LEAP study findings into a working policy document that is applicable for multiple countries. One issue that has been raised is that peanut allergy isn't as looming a problem in all countries, and thus these recommendations may be less applicable in those parts of the world.

Societies that previously recommended delayed peanut introduction now have very clear evidence from a randomized controlled trial that there may be a better approach. Previously, this issue could only be addressed with expert opinion. Although the document has some ambiguity, it is the consensus recommendation of a worldwide group of experts that recommends that peanut can be safely introduced into the diet of high-risk infants (eg, those similar to participants in the LEAP study) between 4 and 11 months of life. It also reinforces that most international societies do not advocate delay in introduction of complementary weaning foods, including peanut, in the standard-risk infant.

For clinicians in the United States and Canada, I think this communication makes a lot of sense. Considering how many children have eczema and would be considered at risk, there could be an enormous number of cases prevented each year. Hopefully in 5-10 years, this translates to a low prevalence of peanut allergy, and fewer children seeking evaluation for this issue. Creating new policy, with guidelines based on high-quality data, is a big step toward that goal, but the most important aspect going forward will be provider and patient buy-in of the recommendations.

Part 2 of this interview explores the clinical implications of this important new study, and the role of the primary care pediatric provider in identification and management of at-risk children.

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