In this discussion I will present the arguments that have been used to suggest that schools, daycares, camps, etc must be prepared to deal with anaphylactic reactions to peanut in children. The discussion will begin with the prevalence of food allergy and peanut allergy; the increase in the prevalence of peanut allergy; the severity of reactions to peanut and the likelihood of inadvertent ingestion of peanut by peanut-allergic children. As a result of these data a campaign was started to make schools safe for peanut-allergic children. However, fear of these reactions has driven the schools and other child-care establishments to attempt to provide peanut-free environments. This has been controversial but in the near future may be obviated by a potential treatment for peanut-allergy i.e. monoclonal anti-IgE antibody. This therapy does not cure peanut allergy but makes the peanut-allergic child tolerant of larger quantities of peanut thus reducing the risk associated with inadvertent ingestion of tiny amounts of peanut. If this treatment, which is now in Phase 3 trial, is successful, it will represent the first therapeutic modality to become available for managing peanut allergy.
Food allergy affects about 4 to 6 percent of children Zeiger 2003 or 6 to 8 percent of children younger than three years of age Bock 1987 and about 2 percent of the U.S. population beyond the first decade of life.
According to Sampson's calculations, food allergy is the leading cause of anaphylaxis treated in hospital emergency departments in the United States and many westernized countries. Food allergy accounts for about 30,000 anaphylactic reactions, 2000 hospitalizations, and 150 to 200 deaths each year in the United States Sampson 2003. Allergies to peanuts tree nuts account for the majority of fatal and nearfatal anaphylactic reactions. A national survey indicated that about 1.1 percent of Americans, or 3 million people, are allergic to peanuts, tree nuts, or both.Sampson 2002 Sicherer 1999.
Several studies have estimated the prevalence of peanut allergy from questionnaires in defined populations. Kagan and colleagues surveyed Montreal school children (7768 responders) and categorized the subjects into groups of non-reactors, possible reactors and definite reactors. They measured specific IgE antibody to peanut in the possible and definite reactors. When the IgE antibody was less than 15kU/L, an oral challenge with peanut was performed. (A peanut-specific antibody level of >15 has been reported to be more than 95% likely to be associated with a clinical reaction to peanut, obviating the need for oral challenge). These investigators found that the prevalence of peanut allergy is greater than 1%. Kagan 2003.
Sicherer and colleagues performed a telephone survey in a random sample of subjects in the United States and found that the prevalence of self-reported peanut sensitivity is 0.8%, Sicherer 2003.
The previously cited study on prevalence of self-reported peanut allergy in children as assessed by a randomized telephone survery was compared with a similar study that the authors had performed 5 years previously. They found that the prevalence of self-reported peanut reactions had increased from 0.4% in 1997 to 0.8% in 2002, i.e. doubled Sicherer 2003.
A study performed on the Isle of Wight compared prevalence of peanut sensitization and reactivity in early childhood in 2 sequential cohorts in the same geographic area 6 years apart. In this study the history obtained by questionnaire was corroborated with diagnostic testing. The data indicated that there had been an increase in peanut allergy prevalence from 0.5% to 1.5% between 1994 and 2000 Grundy 2001.
The rate of peanut allergy seems to be increasing even in countries with relatively low ingestion such as Sweden Van Odjik 2001.
Patients reacting to peanut with respiratory symptoms are considered to have had a threatening reaction.
Sicherer studied 122 patients and found that the initial reaction usually occurred at home (median age, 24 months for peanut) and were considered to result from a first exposure in 72% of cases. Eighty-nine percent of the reactions involved the skin (urticaria, angioedema), 52% the respiratory tract (wheezing, throat tightness, repetitive coughing, dyspnea), and 32% the gastrointestinal tract (vomiting, diarrhea) Sicherer 1998.
Vander Leek found that of 83 patients who had reacted to peanut before age 4, 22 out of 83 (27%) had life threatening reactions. As will be discussed below, the percent increased on second reactions Vander Leek 2000.
It seems likely that when children who have been identified as peanut allergic in infancy have a further reaction after accidental ingestion, the reaction is commonly associated with respiratory symptoms and is threatening.
Sicherer and Sampson calculated a rate of accidental ingestions over 5 years in 122 children studied by questionnaire. Accidental ingestions to peanut occurred in 55% of the patients over a median period of 5.4 years, with an average of two accidents per patient in those experiencing accidents. In contrast to the initial reactions that occurred primarily at home, a larger proportion of the accidental ingestions occurred in school but they also occurred in restaurants especially Asian restaurants. Over 50% of the reactions were associated with respiratory symptoms. Modes of accidental ingestion included sharing food, hidden ingredients, cross-contamination, and school craft projects using peanut butter Sicherer 1998.
Vander Leek et al. followed 83 subjects yearly who had reacted to peanut before age 4. Fifty-eight percent (31/53) of subjects followed up for 5 years experienced adverse reactions from accidental peanut exposure. Regardless of the nature of their initial reaction (when only 27% of reactions were threatening), the majority with subsequent reactions (52%, 31/60) experienced potentially life-threatening symptoms. The group with isolated skin symptoms (11/51, 22%) had lower serum peanut-specific IgE levels than the group with respiratory and/or gastrointestinal symptoms (40/51, 78%) (median: 1.25 kU(A)/L vs 11. 65 kU(A)/L, P =.004, Wilcoxon rank sums test). Despite this, there was no threshold level below which only skin symptoms appeared to occur Vaner Leek 2000.
Zimmerman B, Urch B, Mercado B. Food Allergy: Frequency of Adrenaline Administration. Can J Allergy Clin Immunol 6: 159-61;2001. Ninety-six patients who tested positive to peanut returned for re-assessment and 10 of them had lost the positive skin tests and successfully underwent oral challenge without reacting. Of the 86 patients who retained the positive skin test to peanut, 7 patients had an accidental ingestion of peanut and 6 of the reactions were associated with some form of respiratory symptoms (cough, wheeze or choking) but in only 1 instance was the epipen used.
Hourihane found that Peanut allergy is characterized by more severe symptoms than other food allergies and by high rates of symptoms on minimal contact 1997.
Most parents worry about casual or indirect contact with peanut and the possiblity of a major reaction. Simonte et al explored challenges with skin contact and inhalation of peanut butter in 30 children with mean serum IgE >100 ku/l Simonte 2003. The children underwent double-blind, placebo-controlled, randomized exposures to peanut butter by means of contact with intact skin (0.2 mL pressed flat for 1 minute) and inhalation (surface area of 6.3 square inches 12 inches from the face for 10 minutes). Placebo challenges were performed by using soy butter mixed with histamine (contact), and scent was masked with soy butter, tuna, and mint (inhalation). None experienced a systemic or respiratory reaction. Erythema (3 subjects), pruritus without erythema (5 subjects), and wheal-and-flare reactions (2 subjects) developed only at the site of skin contact with peanut butter. From this number of participants, it can be concluded that casual exposure to peanut butter is unlikely to elicit significant allergic reactions.
Prior to 1990 most allergists only prescribed adrenaline injectors for children who actually had a threatening anaphylaxis and did not prescribe it for patients who only had hives and swelling but no respiratory symptoms. However in 1992, Sampson reported 13 cases of reactions to food in children, 6 fatal and 7 near fatal. Several conclusions were drawn from these case descriptions Sampson 1992.
As a result of this descriptive study consensus statements on the management of peanut sensitivity were prepared and a campaign was started to make schools aware of the danger to peanut allergic children.
Dr. Milton Gold was the principal author of a consensus statement on Anaphylaxis in the Schools and Child Care Settings. Go to OMA Web Site. In these guidelines for schools and childcare settings, an attempt was made to create "peanut-safe" environments since it was felt that "peanut-free" was impossible to guarantee. However, after the school system had finally been convinced to address the problem, many schools attempted to create a "peanut-free" environment. The recommendations issued as a consensus statement are summarized below.
Although for the most part, this consensus statement strives for peanut safe as opposed to peanut-free, many schools have instituted a peanut-free policy. This has led to a lot of controversy.
As mentioned prior to 1990, Allergists would prescribe the adrenaline injectors to specific patients that they felt were at risk for threatening reactions. However the 1992 New England Journal paper by Sampson which described 13 patients suggested that it was not possible to predict the nature of the reactions occurring in peanut-allergic patients based on the nature of their first reaction.
The recommendations remain consensus guidelines and there is some controversy over the ease with which the EpiPens are prescribed. Hourihane defended the prescription of Epinephrine autoinjectors to most individuals who are allergic to peanut 2001.
It has also been reported that in about 10% of anaphylactic episodes where adrenaline has been administered promptly, there has been a poor response with resulting fatalities Bock 2001.
In fact, several studies including our own, have shown that despite being taught the use of the EpiPen, less than 30% of patients actually use it when it is appropriate and the reaction involves some sort of respiratory symptoms. In our study Go to Study 96 patients with a positive skin test to peanut were reassessed a mean of 3 years after the first visit. Overall, 26 of the patients had a total of 41 reactions to various foods. Of the 41 reactions, 7 were to peanut and 6 involved respiratory symptoms of cough or wheeze or gasping. All patients were taken to an emergency setting but only one received adrenaline prior to be taken to the emergency department. Of the 34 non-peanut reactions (which occurred with diverse foods including nuts, fish, shellfish, milk, egg, kiwi, spice, rice, mushroom, cantaloupe, turkey, sesame, celery, candy), 15 reactions were associated with respiratory symptoms but the epipen was administered in only 5 instances. One mother, in the panic surrounding the reaction, held the auto-injector up side down and injected her own thumb.
Clearly at every visit to the doctor's office for whatever reason it is appropriate to ask about epipen use and provide refresher teaching. After having done that, if there is still failure to use the epipen when appropriate, some other strategy must be devised to improve compliance. None of the patients in the study cited failed to survive. That might be attributable to the fact that they went to emergency departments but at the same time that this study was underway, we saw two patients who were not part of the study and who had asthma that was under poor control at the time of their reactions. They also failed to use an epipen, which was not prescribed in one case and was used very late in the second case. They survived but barely and both had to be intubated and admitted to an intensive care unit.
With the increase in numbers of peanut-allergic patients and the data suggesting that threatening reactions to peanut are frequent, patients and their worried families have been waiting for some form of treatment to come available. There is now a treatment on the horizon which, while not a cure, reduces the risk of reaction to a small amount of peanut and therefore should reduce the fear of inadvertent contact creating threatening reactions. That should eliminate the need for "peanut-free" environments.
This is the Phase 2 study of a treatment for peanut allergy. A Phase 2 study is a small study to establish the safety of the drug and the effective dose. Because the Phase 2 study gave positive results with no significant adverse effects, there is now a large multi-center phase 3 study underway. Successful completion of the Phase 3 study will lead to the treatment becoming available.
In order to understand this abstract it is necessary to understand some basic allergy and immunology. First, IgE is the type of immunoglobulin that governs allergy. When an allergic individual becomes allergic to peanut, they make IgE antibody to the peanut allergen(s). This antibody sits on the surface of certain cells called Mast cells and Basophils. When the peanut allergic individual accidentally eats peanut, the peanut allergens are grabbed by the IgE antibody to peanut sitting on the cells. That causes the cells to release "mediators" like histamine that cause all the symptoms of anaphylaxis.
If something could prevent or block the IgE from sitting on the cells then the cells would not have anything on their surface that would be able to react with peanut allergens and therefore they would not release any mediators.
In this research a very special antibody to human IgE was created in the mouse. When this antibody is injected into humans, it binds to IgE in the humans including IgE that reacts with peanut. This mouse antibody prevents the human IgE from sitting on the Mast cells and Basophils. However when mouse protein (the mouse antibody to human IgE) is injected into a human, the human recognizes it as foreign and rejects it. So the mouse antibody has been modified so that when it is injected into humans it is not recognized as foreign and therefore is not cleared more rapidly from the human body. The monoclonal antibody binds to human IgE on the part of the IgE molecule that binds to the surface of Mast cells and Basophils and in that way prevents the IgE from binding to the cells.
In the present study, this modified mouse antibody to human IgE was tested at different doses for the ability to prevent reactions to peanut protein given to the peanut allergic subjects. The study involved 84 patients with a history of immediate reactions to peanut and the history was confirmed by oral challenge. The dose of peanut flour that would start a reaction to peanut was established by a double-blind, placebo-controlled oral food challenge. Three doses of the special modified mouse antibody to human IgE (150, 300, or 450 mg) or placebo were injected subcutaneously every four weeks for four doses. The patients underwent a final oral food challenge with peanut flour within two to four weeks after the fourth dose.
From a mean starting level of sensitivity of 178 to 436 mg of peanut flour in the various groups, the mean increases in the oral-food-challenge threshold were 710 mg in the placebo group, 913 mg in the group given 150 mg of the modified mouse antibody to human IgE, 1650 mg in the group given 300 mg of modified mouse antibody to human IgE, and 2627 mg in the group given 450 mg of modified mouse antibody to human IgE (P<0.001 for the comparison of the 450-mg dose with placebo, and P for trend with increasing dose <0.001). The modified mouse antibody was well tolerated and did not create any more side effects than the placebo injection.
A 450-mg dose of modified mouse anti-human IgE significantly and substantially increased the amount of peanut flour that could be tolerated on oral food challenge from a level equal to approximately half a peanut (178 mg) to one equal to almost nine peanuts (2805 mg). This is an effect that should translate into protection against most accidental ingestions of peanuts.
The clinical data confirmed the direct role of IgE in peanut-induced allergic reactions and demonstrate that the special modified mouse anti-human IgE, at a dose of 450 mg subcutaneously every four weeks, significantly increased the threshold of sensitivity to peanut antigen, as assessed by oral food challenge, to a level that should translate into at least partial protection against most unintended ingestions of peanut. Although these results are highly encouraging, the mouse antibody is still an experimental drug, and approval for general use will require confirmation of these results in additional studies i.e. a larger Phase 3 study.
The following is a case history of a patient seen in my office who has sensitivity to several foods and would clearly benefit from the therapy described above.
14 year old male
As a toddler, ate a peanut butter cookie and vomited and ate a carrot cake with walnut and vomited. These episodes were not recognized as allergic and at age 2.5 years, ate a cookie with nuts and developed swollen tongue, swollen lip, hives and wheezing. He was taken to an emergency and after that avoided peanut and nuts. However at age 10 he ate a candy that he was given at school that contained hazelnut. He ate the candy on the way home from school and began having symptoms. When he got home, he tried to administer the EpiPen but could not operate it . He developed respiratory symptoms and had trouble talking. He was taken to an emergency department where he was treated with intravenous Benadryl and adrenaline.
About 1 month before the office visit, he ate pretzels with sesame seeds and developed a swollen tongue with some respiratory difficulty. He took ventolin but got no relief and fell to the ground gasping. His mother injected him with the EpiPen and he got relief. He was taken to an emergency department.
He has developed swollen lips after pea soup. When he eats raw carrots, celery and cucumber, green and yellow beans, banana, kiwi and peach, he develops itching of the mouth and throat. He tolerates banana in banana bread. He has had no known problem with latex.
He has always tolerated fish but had a fish burger recently and had itching, throbbing mouth symptoms similar to when he eats peanut. The fish was a white fish in batter and a bun that may have had sesame seeds. He used the EpiPen and went to an emergency department.
He has had asthma symptoms with colds and at that time uses inhaled steroid and ventolin. Between viral infections, he is off the inhaled steroid and uses ventolin a few times per week before exercise. He had eczema when he was very young and has constant rhinorrhea and stuffy nose.
SKIN TESTS: Postive to peanut, a series of nuts, fish, sesame, sunflower, peas, cat, dog, tree including birch pollen, ragweed and indoor mould. Negative to a pet hamster and latex.
LABORATORY TESTS: A serum IgE was 624 (normal 0-432) while a peripheral eosinophil count was 0.9 x 109/L. The total IgE is not that high while the peripheral eosinophils are elevated.
INTERPRETATION: This lad should benefit greatly from treatment with monoclonal anti-IgE antibody. His asthma does not seem to be under full control and the addition of the monoclonal antibody could help with asthma control. His total IgE will fall during the treatment and since it is not specific, that should help with all his food allergies. He will still avoid peanut, nuts, fish and seeds but the treatment should reduce the fear of a small inadvertent reaction setting off an anaphylaxis, thus making it less likely that he needs a peanut-free environment.
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