In the past 20 years, peanut allergy has become a major international health problem, particularly in developed nations, affecting approximately 1% of children under five years of age [1]. The reason for the increased prevalence of food allergies and other atopic diseases is not well understood. If unrecognised, peanut allergy can result in life threatening anaphylaxis, treated as an emergency by injectable epinephrine or oral antihistamines. It is essential that patients who are believed to have the disease receive a thorough workup and appropriate education to avoid peanut containing foods, recognise a reaction and appropriately treat it. Traditionally, primary treatment of the underlying allergy was through avoidance of the food. In recent years, new methods of immune modulation through oral immunotherapy and other modalities have shown promise for possible new treatments in the next several years.
by Dr Michael Land and Dr Wesley Burks

A growing problem

Food allergy in general has been on the rise, and currently affects 6-8% of children less than four years of age, and approximately 4% of the US population over 10 years old [2]. As the leading cause of anaphylaxis treated in emergency rooms in Europe and the US, food allergies in general account for significant morbidity and mortality. Some estimates are as high as 30,000 anaphylactic reactions, 2000 hospital admissions, and 200 deaths per year in the US alone [3].

When specifically looking at peanut allergy, the prevalence rose from 1.3% to 3.2% in the UK in the period from 1989 to 1995. In the US, it is thought that approximately three million people are allergic to peanuts, tree nuts, or both [2]. Studies carried out to explain this rise have not been able to confirm theories that specific exposures such as peanut in the maternal diet or intake of soy formula might increase the risk of developing peanut allergy [4].

Legumes, not nuts!

The peanut is a member of the legume (Fabaceae) family, which sets it apart from other types of "nuts," otherwise known as tree nuts. The allergens implicated in peanut allergy are glycoproteins that are assigned designations

The process by which humans develop food allergies lies within a complex interplay of the immune system with protein processing, antigen presentation, recognition and activation. In genetically predisposed persons who are at risk of developing allergic disease, the peanut proteins are taken up by cells in the gastrointestinal tract and transferred to antigen-presenting cells of the immune system. The proteins are processed into smaller peptide fragments, and presented within special receptors, the major histocompatability complex (MHC) class II molecules, to naïve T helper cells that recognise them [7]. This results in an activation event and may lead to the formation of peanut specific IgE and clinical allergy.

IgE antibodies are immunoglobulin proteins that are specific for certain allergens and, when IgE antibodies bound to a mast cell are crosslinked by recognising an allergen, they induce a downstream cascade of immune activation (release of histamine and other mediators that cause the allergic phenotype). An important concept regarding peanut allergy, or food allergy in general, is that the IgE binding activity is often specific for linear epitopes, or sequences of peptides. In contrast, IgE binding in airborne allergens is more frequently due to conformational epitopes with recognition sites more dependent upon the shape of the protein. For peanut, this binding of specific IgE antibody to the linear epitopes has been demonstrated to correlate with symptom severity [8]. This may explain differences between patients and why some patients have lifelong symptoms.

Arachis hypogaea, or Ara h 1 through Ara h 8 [5, 6]. The two major peanut allergens are Ara h 1 and Ara h 2. The former is a 63.5 kd vicilin family storage protein, while the latter is a 17 kd conglutin family storage protein [5]. Ara h 3 to 7 are able to bind IgE in a minority of peanut allergic patients. Ara h 8 is primarily involved in another condition called pollen-food allergy syndrome [6].

What happens in patients with peanut allergy?

Identifying a clinical peanut allergy relies on a careful clinical history of an immediate allergic reaction. Patients have very typical IgE-mediated allergic symptoms. These typical symptoms may affect four main organ systems: the skin, the respiratory system, the gastrointestinal tract and the circulatory system. Reactions may occur within seconds, but can be delayed up to two hours after ingestion of peanut. Many patients will have some sort of cutaneous symptoms such as hives, swelling, flushing and/or itching. About half of all patients may have some respiratory symptoms such as wheezing, shortness of breath, tightness in the throat, hoarseness or coughing. Approximately one third may have gastrointestinal symptoms such as vomiting, abdominal discomfort or diarrhoea. Anaphylaxis, a systemic form of an allergic reaction, may additionally result in shock involving the cardiovascular system. When this occurs, patients may experience low blood pressure and abnormal heart rhythms [9].

Once symptoms are treated and improve, a second, late-phase reaction may occur within a few hours. This has been seen in up to a third of patients who had fatal or near fatal reactions [9]. Patients who have other medical problems such as asthma may be at an increased risk of a severe reaction. Other at-risk populations include adolescents and children with a history of additional allergic diseases. Typically, fatal reactions do not occur with the first ingestion of an allergic food. In general, ingestion of peanut (as opposed to skin or air exposure) is necessary for life-threatening symptoms to occur.

Making a diagnosis

A history of a reaction to peanut or peanut-containing food is essential to making a diagnosis. It is important to confirm that an immediate reaction occurred (within minutes up to two hours) as well as the type of symptoms present. Cutaneous, respiratory and gastrointestinal symptoms should be present. The amount of peanut consumed and symptoms following ingestion of similar foods are also important pieces of information to considerl.

Allergy testing should be performed if there is a suspicion raised for peanut allergy. These tests should be used to confirm a suspected history rather than to predict the presence of allergy if there is no history of a reaction. A skin-prick test and/or

in vitro serum level are the two primary tests that help demonstrate the presence of peanut-specific IgE. In order to perform a skin prick test, a small amount of peanut allergen suspended in a diluent is either dropped on the skin and then pricked with a plastic testing device or the skin is pricked after the device has been dipped in the liquid. A positive reaction has occurred if a small bump, called a skin wheal, is raised with surrounding redness (erythaema), called a flare. The result looks like a small mosquito bite. The wheal size may be predictive of the likelihood of having a peanut allergy, but not of the severity of a future allergic reaction [10].

In vitro

Patients who have a clear history of an allergic reaction following peanut ingestion and who are also found to have evidence of peanut-specific IgE do not need further testing. However, if the level of peanut-specific IgE is below 2kU/L, there is a 50% probability of a patient passing a food challenge [12]. Because of this, the positive predictive value of allergen-specific IgE is low when the history is unclear. In these cases, a physician-supervised food challenge is necessary to help confirm the diagnosis [13]. During an oral food challenge, a small amount of peanut butter is first placed on the lip, and the patient is observed for 10-15 minutes. If no symptoms occur, the amount ingested is increased incrementally until about two tablespoons have been given over 1-2 hours. Based on the available literature, about 80% of children will not outgrow their allergy. The 20% that do outgrow it often have low peanut-specific IgE levels to start with and need to be checked once every one to two years to determine if they have outgrown their allergy, particularly around the age of 5-6.

testing for peanut-specific IgE measured using the ImmunoCAP-FEIA system is also predictive of the likelihood of the disease, depending on the level. The test may measure as low as 0.35 kU/L up to 100 kU/L. Levels greater than 14 kU/L have a very high predictive value for the disease, approaching 100% [11]. Patients who have a convincing history but may have antibody levels that are undetected should not be ignored. In contrast, patients who eat peanuts on a regular basis and have never had a reaction to peanuts may present with blood tests demonstrating detectable peanut-specific IgE at low levels. These are likely to have little clinical utility.

Managing peanut allergy

Treating acute reactions begins with educating parents and families to recognise the symptoms of an allergic reaction. Once the diagnosis is made, it is essential to provide a written action plan on the indications for use of medication. Parents should be educated to avoid their children accidentally ingesting peanuts, and to recognise symptoms characteristic of an IgE mediated reaction. In general, children are also advised to avoid tree nuts because of safety concerns from cross-contamination and allergen cross-reactivity.

A written action plan for an allergic reaction includes appropriate indications for the use of medications as well as the correct dosages of the medicine. Common treatments include antihistamines such as diphenhydramine for hives or cutaneous symptoms, and injectable epinephrine for significant gastrointestinal symptoms, respiratory symptoms and/or shock. Use of an epinephrine autoinjector should be followed by immediate medical attention at an emergency room or urgent care centre for close observation of at least four hours due to the possibility of a late-phase allergic reaction [13].

Why the rise in prevalence?

The rising prevalence of peanut allergy is not well understood, but theories currently being tested include the hygiene hypothesis, which suggests that insufficient exposure to microbes in early life may increase a child’s propensity to develop allergic disorders. This could explain the low incidence of allergic disease in developing countries with poor hygiene practices. Some data suggest that early exposure to peanut, whether

When considering introduction of peanut, no strong data can confirm either recommendations for early or delayed introduction to peanut. Some studies have suggested that early introduction may increase the risk of developing allergy while others suggest that the lack of ingestion early in life may increase the possibility of being sensitised [15]. This remains an area of the field that is under an intense degree of study
and controversy.

in utero, during breastfeeding, or within the first several months of life, may influence the risk of developing peanut allergy, but these studies have not been replicated. Other ongoing research has examined the way peanuts are prepared. Thermal processing of the peanut, causing a reaction between peanut proteins and reducing sugars may lead to the formation of advanced glycation end-products, which may increase their allergenicity, or propensity to bind antibody [14].

What’s next for peanut allergy?

With the rise in prevalence of this problem combined with the severity and life-threatening nature of the disease, different treatments are under development to decrease reactivity in patients. Traditional "allergy shots" or subcutaneous injections have not worked because of the high risk of serious reactions such as anaphylaxis. Newer treatments being developed include different types of immune modulation using cytokine modulation, plasmid DNA, engineered or mutated allergen protein immunotherapy, immunostimulatory sequence-conjugated protein modulated immunotherapy and other types of immune modulation [16]. Non allergen therapies include anti-IgE antibody treatment (Omalizumab) as well as a Chinese herbal therapy FAHF-2 [17]. These treatments are being studied in animal models,

Currently, at our institution, sublingual and oral immunotherapies are being studied in clinical trials. With this type of treatment, small amounts of the peanut are ingested on a regular basis in gradually increasing amounts. Preliminary data indicate that these studies have great potential and offer a promising future for treatment of peanut allergy [18]. We are hopeful that this type of immunotherapy will be an option for our patients in the next decade.

in vitro, and in humans. Studies of different routes of immunotherapy are also underway.

References

1. Lee LA, Burks AW. Ann Rev Nutr 2006; 26: 539–65.

2. Sicherer SH, Munoz-Furlong A, Sampson HA. J Allergy Clin Immunol 2003; 112: 1203–07.

3. Yocum MW

4. Lack G, Fox D, Northstone K, Golding J. N Engl J Med 2003; 348: 977–85.

5. Burks AW

6. Mittag D

7. Strobel S, Mowat AM. Curr Opin Allergy Clin Immunol 2006; 6: 207–13.

8. Shreffler WG

9. Sampson HA, Mendelson L, Rosen JP. N Engl J Med 1992; 327: 380–84.

10. Roberts G, Lack G. J Allergy Clin Immunol 2005; 115: 1291–96.

11. Sampson HA. J Allergy Clin Immunol 2001; 107: 891–96.

12. Perry TT

13. Sampson HA. N Engl J Med 2002; 346: 1294–99.

14. Maleki SJ

15. Lack G

16. Burks W, Lehrer SB, Bannon GA. Clin Rev Allergy Immunol 2004; 27: 191–96.

17. Srivastava KD

18. Varshney P

A full reference list is available from the authors.

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The authors

Michael Land, MD & Wesley Burks, MD

Division of Allergy & Immunology

Department of Pediatrics

Duke University Medical Center

Box 2644 • Durham, NC 27710, USA