Faculty Bibliography

BACKGROUND:About 70% of children with milk allergy tolerate extensively heated milk (HM) products and outgrow their allergy earlier than those who react to HM. OBJECTIVE:To test the hypothesis that HM-tolerant children have a higher precursor frequency of adaptive allergen-specific regulatory T (Treg) cells. METHODS:Allergic, HM-tolerant, outgrown, or control subjects were defined by oral food challenge. PBMCs were cultured with purified caseins and controls for 7 days, and proliferating CD25(+)CD27(+) Treg cells were identified by flow cytometry. Proliferating cells were also characterized for their expression of FoxP3, CTLA 4, CD45RO, and CD127. Allergen-specific Treg cell origin and function were assessed by depletion of CD25(hi) cells before culture. RESULTS:There was a higher percentage (median [25th% to 75th%], 16.85% [7.1-31.7]) of proliferating allergen-specific CD25(+)CD27(+) T cells from cultures of HM-tolerant subjects (n = 18) than subjects with allergy (n = 8; 4.91% [2.6-7.5]; P < .01). Control subjects with no history of milk allergy (n = 7) also had low percentages of these cells (2.9% [2.4-6.0]), whereas outgrown subjects (n = 7) had intermediate percentages (9.0% [2.7-16.4]). There were no significant differences between the patient groups in the frequency of polyclonal Treg cells or allergen-specific effector T cells. Allergen-specific Treg cells were found to be FoxP3(+)CD25(hi)CD27(+), cytotoxic T lymphocyte-associated antigen 4(+), CD45RO(+)CD127(-) and were derived from circulating CD25(hi) T cells. Depletion of the CD25(hi) cells before in vitro culture significantly enhanced allergen-specific effector T-cell expansion. CONCLUSION/CONCLUSIONS:A higher frequency of milk allergen-specific Treg cells correlates with a phenotype of mild clinical disease and favorable prognosis.

BACKGROUND:Prior studies have suggested that heated egg might be tolerated by some children with egg allergy. OBJECTIVE:We sought to confirm tolerance of heated egg in a subset of children with egg allergy, to evaluate clinical and immunologic predictors of heated egg tolerance, to characterize immunologic changes associated with continued ingestion of heated egg, and to determine whether a diet incorporating heated egg is well tolerated. METHODS:Subjects with documented IgE-mediated egg allergy underwent physician-supervised oral food challenges to extensively heated egg (in the form of a muffin and a waffle), with tolerant subjects also undergoing regular egg challenges (in a form of scrambled egg or French toast). Heated egg-tolerant subjects incorporated heated egg into their diets. Skin prick test wheal diameters and egg white, ovalbumin, and ovomucoid IgE levels, as well as ovalbumin and ovomucoid IgG4 levels, were measured at baseline for all subjects and at 3, 6, and 12 months for those tolerant of heated egg. RESULTS:Sixty-four of 117 subjects tolerated heated egg, 23 tolerated regular egg, and 27 reacted to heated egg. Heated egg-reactive subjects had larger skin test wheals and greater egg white-specific, ovalbumin-specific, and ovomucoid-specific IgE levels compared with heated egg- and egg-tolerant subjects. Continued ingestion of heated egg was associated with decreased skin test wheal diameters and ovalbumin-specific IgE levels and increased ovalbumin-specific and ovomucoid-specific IgG4 levels. CONCLUSIONS:The majority of subjects with egg allergy were tolerant of heated egg. Continued ingestion of heated egg was well tolerated and associated with immunologic changes that paralleled the changes observed with the development of clinical tolerance to regular egg.

BACKGROUND:Cow's milk allergy is the most common childhood food allergy. Previously we noted that children who outgrew their milk allergy had milk-specific IgE antibodies primarily directed against conformational epitopes; those with persistent milk allergy also had IgE antibodies directed against specific sequential epitopes. OBJECTIVE:Because high temperature largely destroys conformational epitopes, we hypothesized that some children with milk allergy would tolerate extensively heated (baked) milk products. METHODS:Children with milk allergy were challenged with heated milk products; heated milk-tolerant subjects were subsequently challenged with unheated milk. Heated milk-tolerant, unheated milk-reactive subjects ingested heated milk products for 3 months and were then re-evaluated. Immune responses were assessed in all subjects; growth and intestinal permeability were followed in heated milk-tolerant subjects. RESULTS:One hundred children (mean age, 7.5 years; range, 2.1-17.3 years) underwent heated milk challenges. Sixty-eight subjects tolerated extensively heated milk only, 23 reacted to heated milk, and 9 tolerated both heated and unheated milk. Heated milk-reactive subjects had significantly larger skin prick test wheals and higher milk-specific and casein-specific IgE levels than other groups. At 3 months, subjects ingesting heated milk products had significantly smaller skin prick test wheals and higher casein-IgG(4) compared with baseline; other immunologic parameters, growth, and intestinal permeability were not significantly different. Heated milk-reactive subjects had more severe symptoms during heated milk challenge than heated milk-tolerant subjects experienced during their unheated milk challenge. CONCLUSION/CONCLUSIONS:The majority (75%) of children with milk allergy tolerate heated milk.

BACKGROUND:Food allergy is the most common cause of anaphylaxis outside the hospital setting. OBJECTIVE:We sought to determine the rate, circumstances, and risk factors for repeated doses of epinephrine in the treatment of food-induced anaphylaxis in children. METHODS:Anonymous questionnaires were distributed to families of children with food allergies during allergy outpatient visits to a food allergy referral center. Demographic information, allergy and reaction history, and details regarding the last 2 anaphylactic reactions requiring epinephrine were collected. RESULTS:A total of 413 questionnaires were analyzed. Seventy-eight children (median, 4.5 years of age; range, 0.5-17.5 years) reported 95 reactions for which epinephrine was administered. Two doses were administered in 12 (13%) and 3 doses in an additional 6 (6%) reactions treated with epinephrine. Peanut, tree nuts, and cow's milk were responsible for >75% of reactions requiring epinephrine. Patients receiving multiple doses of epinephrine more often had asthma (P = .027) than children receiving a single dose. The amount of food ingested or a delay in the initial administration of epinephrine were not risk factors for receiving multiple doses. The second dose of epinephrine was administered by a health care professional in 94% of reactions. CONCLUSION/CONCLUSIONS:In this referral population of children and adolescents with multiple food allergies, 19% of food-induced anaphylactic reactions were treated with more than 1 dose of epinephrine. Prospective studies are necessary to identify risk factors for severe anaphylaxis and to establish rational guidelines for prescribing multiple epinephrine autoinjectors for children with food allergy.

Food-induced anaphylaxis is a steadily increasing problem in westernized countries and now represents the leading cause of anaphylaxis in the outpatient setting, particularly in children. Much of our knowledge of the pathophysiology of food-induced anaphylaxis comes from animal studies. Food anaphylaxis in humans is thought to be entirely IgE mediated. Several features appear to be unique to these reactions; factors such as exercise can lower the "threshold" for anaphylaxis in certain susceptible individuals. Different methods of thermal processing can modify the allergenicity of food proteins. Alteration of stomach pH can allow for incomplete digestion of food proteins, leading to increased absorption of intact food allergens. Low serum platelet-activating factor acetylhydrolase may predispose to fatal food-induced anaphylaxis. With a greater understanding of the pathophysiology of food-induced anaphylaxis, novel approaches not only to identify those at risk, but to treat and ultimately prevent food-induced anaphylaxis, are on the horizon.

Cow's milk protein allergy is the most common food allergy in infants and young children. It is estimated that up to 50% of pediatric cow's milk allergy is non-IgE-mediated. Allergic proctocolitis is a benign disorder manifesting with blood-streaked stools in otherwise healthy-appearing infants who are breast- or formula-fed. Symptoms resolve within 48-72 h following elimination of dietary cow's milk protein. Most infants tolerate cow's milk by their first birthday. Food protein-induced enterocolitis syndrome presents in young formula-fed infants with chronic emesis, diarrhea, and failure to thrive. Reintroduction of cow's milk protein following a period of avoidance results in profuse, repetitive emesis within 2-3 h following ingestion; 20% of acute exposures may be associated with hypovolemic shock. Treatment of acute reactions is with vigorous hydration. Most children become tolerant with age; attempts of re-introduction of milk must be done under physician supervision and with secure i.v. access. Allergic eosinophilic gastroenteritis affects infants as well as older children and adolescents. Abdominal pain, emesis, diarrhea, failure to thrive, or weight loss are the most common symptoms. A subset of patients may develop protein-losing enteropathy. Fifty percent of affected children are atopic and have evidence of food-specific IgE antibody but skin prick tests and serum food-IgE levels correlate with response to elimination diet poorly. Elemental diet based on the amino-acid formula leads to resolutions of gastrointestinal eosinophilic inflammation typically within 6 wk.

Food allergy has emerged as an important target for research on curative treatment and prevention, with most efforts focusing on peanut, cow's milk, and egg allergy. This article reviews the recent developments in the potential treatments for IgE-mediated food allergy using native and engineered recombinant food proteins.

Food allergy is defined as an immune system-mediated adverse reaction to food proteins. Class 1 food allergens are represented by peanut, egg white, and cow's milk; they are heat- and acid-stable glycoproteins that induce allergic sensitization via gastrointestinal tract and cause systemic reactions. Class 2 food allergens are homologous to proteins in birch tree pollen and class 2 food allergy develops as a consequence of respiratory sensitization to the cross-reactive pollen. Class 2 food allergens are very heat-labile and tend to induce reactions limited to oral allergy symptoms. In contrast, plant nonspecific lipid transfer proteins are resistant to heating and tend to induce systemic reactions. Analysis of IgE-binding epitopes with SPOT membranes revealed that cow's milk-, egg- and peanut-allergic subjects without IgE antibodies against certain sequential epitopes of the major allergens were more likely to achieve tolerance than subjects whose IgE antibodies were directed against those epitopes. Subsequently, peptide microarray showed a correlation between reaction severity and the intensity of IgE binding and the number of epitopes recognized of patients' immune responses against peanut allergens. Taken together, these data suggest that the epitope recognition pattern and intensity of IgE binding are important determinants of severity and duration of food allergy.