COMMENTARY

Peanut Allergy: New Insights on Treatment and Prevention

Scott H. Sicherer, MD

Disclosures

April 23, 2009

Introduction

Among food allergens, peanut warrants special concern because the allergy is relatively common, typically permanent, and often severe.[1] Studies within the last 15 years have indicated approximately a doubling in the prevalence of peanut allergy among young children,[2,3] and estimates of peanut allergy from studies in North America and the United Kingdom indicate that peanut allergy affects over 1% of children.[2,3,4,5] Among fatalities from food-induced anaphylaxis reported in the United States, peanut is responsible for the majority of deaths.[6,7] Currently, the only proven form of treatment is to avoid ingesting the allergen and to be prepared to treat severe reactions with self-injectable epinephrine. Living with a severe food allergy induces anxiety and reduces quality of life because management requires constant vigilance.[8] These features of peanut allergy have resulted in greater attention to research on prevention and treatment. Novel observations have recently emerged.

New Insights Into an Apparent Epidemic

Between 1998 and 2000, the UK Food Standards Agency[5] and the American Academy of Pediatrics[9] introduced recommendations, aimed at women with infants at risk for allergic disease, to avoid consuming peanut during pregnancy and lactation and to avoid feeding peanut to the child until age 3 years. These recommendations were based on the understanding that exposure to an allergen is required for sensitization.

Studies over the past several years, however, have offered an alternative view on the assumed benefits of peanut avoidance. In a part-retrospective, part-prospective study, Lack and colleagues[10] found no increased risk for peanut allergy when maternal ingestion of peanut occurred during pregnancy or lactation, but they did find an increased risk if the infant was using skin preparations containing peanut oil (odds ratio: 6.8). Recent studies from the same investigators add further support to the notion that lack of oral exposure, and perhaps increased environmental exposure during the time of avoidance of ingestion, may result in increased risk for peanut allergy.[11] Du Toit and associates[12] determined the prevalence of peanut allergy among Jewish schoolchildren in the United Kingdom (5171 children) and Israel (5615 children). The rate of peanut allergy in the United Kingdom was 1.85% compared with 0.17% (P < .001) in Israel, an almost 10-fold higher rate. According to consumption surveys performed independently, peanut is introduced earlier and is eaten more frequently and in larger quantities in Israel than in the United Kingdom. The median monthly consumption in Israeli infants from age 8 to 14 months was 7.1 g compared with 0 g in their UK counterparts. The investigators could not attribute the difference in peanut allergy prevalence to underlying allergic disease, social class, or genetic background, and they believe that the form of peanut eaten by both groups is similar.

In another study from the same research group,[13] questionnaires about peanut consumption were administered to families of children with peanut allergy, families with a child with food allergy to egg but not peanut, and families without allergies. Household peanut consumption among those with peanut allergy was significantly greater (18.8 g) than among those with egg allergy (1.9 g) or without any allergy (6.9 g). After adjusting for variables of household consumption, maternal peanut consumption during pregnancy and lactation were not risk factors. These additional observations further support the theory that not ingesting peanut but being exposed to peanut in the environment could be a cause of increased risk of developing peanut allergy.

Somewhat alarming studies from the United Kingdom showed that peanut was introduced to children at about 13 months in a cohort born in 1989[3] (peanut allergy rate: 0.5%) and near age 3 years in a cohort born in 1999 (peanut allergy rate: 1.8%).[5] However, insights from 2 other UK studies[5,14] raise questions as to whether peanut avoidance advice is related to the increased rate of peanut allergy. For example, Hourihane and colleagues[5] evaluated parents of children in a school cohort born after peanut avoidance recommendations were released and showed that few followed the advice; among those who did, the authors concluded that there was no discernible effect on the prevalence of peanut allergy.

A lack of oral exposure in conjunction with an increased rate of environmental exposure is just one of many theories to explain the increase in peanut allergy. Additional theories include a number of other environmental factors, such as how peanut is prepared (eg, roasted and emulsified), a person's exposure to sunlight and vitamin D (which affects immune responses), other components of maternal and infant diet (eg, fats), and the influence of exposure to infections (the hygiene hypothesis).[1] The hygiene hypothesis suggests that protection from infection (societal "cleanliness," general immunity from vaccinations, widespread use of antibiotics, etc) may result in immune dysregulation, resulting in an increased risk for allergic responses. Additionally, some studies of allergen avoidance in early infancy support long-term reductions in atopy.[15,16] The jury is still out on the relative influence of dietary allergen exposure,[17] but a randomized controlled study is currently under way to determine whether early exposure to peanut in infants at risk for atopy affects outcomes of peanut allergy.[11] Given the lack of evidence for or against peanut avoidance in infants at risk (eg, those with a family history of atopic disease), the American Academy of Pediatrics has rescinded the prior recommendation about maternal and infant avoidance, now indicating that data are insufficient to make firm recommendations.[18]

Toward Improved Therapies

Environmental allergies, such as pollen allergy, are routinely treated with injection immunotherapy, in which gradually increasing and repeated immunizations with the causal allergen results in a shift in immune responses and improvement in symptoms upon exposure to the allergen. This approach was tried for peanut allergy as well; although somewhat effective, it resulted in too many significant allergic reactions to the injections themselves.[19] Thus, injection immunotherapy with peanut allergen was abandoned and other approaches for treatment have been investigated. Therapies that are currently under investigation and have shown some efficacy in animal models include Chinese herbal medicine and the use of engineered proteins that are similar to peanut but lack some of the allergy-causing protein segments, among other strategies.[1] The use of a humanized monoclonal anti-IGE antibody, an injected therapy which scours the allergy-inducing protein IgE, also showed promise, but the response was not uniform and additional studies are needed.[20]

Most recently, attention has focused on immunotherapy using sublingual (under the tongue) or, more often, oral administration of the allergen-causing food in a controlled clinical setting. This route of treatment is presumed to be safer than injections because there is less direct and immediate exposure of the bloodstream to the allergen. Also, immune effects similar to those of injection immunotherapy (eg, allergen-specific IgG responses increase and IgE responses are modulated) have been observed in preliminary trials.[21] Patients are started on minute amounts of allergen and receive gradually increasing amounts over weeks and months. This approach has been documented in reports over the past 100 years for foods such as egg, milk, fish, fruits and vegetables, and more recently peanut.[22] However, most of the reports were of small groups without controls, so it has been difficult to document the role of patient selection on efficacy, as well as the overall safety and effectiveness of the treatments. Controlled studies are increasingly being reported.[21,23] It should be appreciated that participants in these research studies do not uniformly reach the intended treatment doses so as not to provoke allergic reactions to the treatment doses.

Several reports have emerged regarding oral immunotherapy for peanut. Mansfield[24] described one child with peanut allergy who was treated with a gradually increasing amount of peanut, working up to 2 peanuts twice daily. Clark and colleagues[25] reported 4 subjects treated with peanut oral immunotherapy and compared their threshold to peanut before and after treatment. Each subject tolerated at least 10 whole peanuts in postintervention challenges, an increase in dose threshold of at least 48-, 49-, 55- and 478-fold for the 4 subjects. The lack of a control group hinders the interpretation of these results, however.

In several reports at the American Academy of Allergy, Asthma & Immunology (AAAAI) 2009 Annual Meeting, researchers at Duke University and Arkansas Children's Hospital reported a placebo-controlled study of 10 children. Five were treated with peanut and tolerated about 13 peanuts, compared with 1 peanut for the untreated controls.[26] Peanut allergy skin-prick tests also improved in the treated group. In another pilot study by these researchers, 4 children were able to eat peanut after discontinuing the therapy, but these children possibly had less severe allergy to begin with, and in this uncontrolled pilot study it is not clear whether they would have improved naturally.[27]

Although these studies and reports are extremely promising, there remain a number of concerns that must be addressed in additional studies. For example, does oral immunotherapy provide desensitization or tolerance? Desensitization refers to a state of nonreactivity while an individual continues to take daily treatment doses of the allergen. In contrast, tolerance is permanent, meaning that if the individual discontinues a daily treatment dose for a period of time, he or she would continue to be able to ingest the allergen with no symptoms upon re-exposure. This is an important distinction because there are reports of individuals who have lost their protection after discontinuation of treatment with egg or milk for as little as 2-14 days.[28] In a controlled study of milk and egg immunotherapy, the same percentage of children in the untreated and treatment groups had become fully tolerant of the food at treatment conclusion.[29] Even if oral immunotherapy does not induce tolerance, there are advantages to achieving desensitization: It provides an increased threshold for allergic reactions which could substantially reduce the risk for severe allergic reactions after inadvertent ingestion of the allergen.

It must also be appreciated that the side-effect profile of oral and sublingual food immunotherapy has not been determined. Individuals do experience allergic reactions during the period of increasing doses and even while they are on stable doses.[20,29] The risks and safety of the therapy must also be better defined, and studies are ongoing to determine these parameters.

Summary

Recent studies have increased our awareness of potential ways to prevent and treat peanut allergy. More research, currently under way, will help define the impact of early exposure to peanut on allergy outcomes and will better define the safety and efficacy of therapeutic strategies. In regard to oral immunotherapy, it must be appreciated that this potential treatment carries various serious risks that have not been well defined; therefore, this approach currently remains a research approach and should never be attempted at home.

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