Kirsi M. Järvinen

Specificity of IgE antibodies to sequential epitopes of hen's egg ovomucoid as a marker for persistence of egg allergy

Background:  Approximately two‐thirds of egg‐allergic infants become tolerant within the first 5 years of life.

Role of conformational and linear epitopes in the achievement of tolerance in cow's milk allergy

Background Cows milk (CM) is one of the leading causes of food allergy in children. However, approximately 85% of milk‐allergic children become clinically tolerant to CM within the first 3 years of life. The mechanisms involved in the achievement of tolerance remain unknown.

Identification of IgE and IgG binding epitopes on β- and κ-casein in cow's milk allergic patients

Background Cows milk allergy (CMA) affects 2.5% of children aged less than 2 years of age. Although β‐ and κ‐casein are considered among the major allergens responsible for CMA, no data are available on their allergenic epitopes in humans.

Use of multiple doses of epinephrine in food-induced anaphylaxis in children

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 cows 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 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.

Clinical features and resolution of food protein–induced enterocolitis syndrome: 10-year experience

BACKGROUND Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy. FPIES diagnosis is frequently delayed because of the absence of classic allergic symptoms and lack of biomarkers. OBJECTIVE We sought to characterize the clinical features and resolution of FPIES in patients evaluated in our practice. METHODS Subjects 6 months to 45 years of age with FPIES were prospectively recruited for oral food challenges (OFCs). Medical records were searched to identify the subjects who did not participate in OFCs. RESULTS Among 160 subjects, 54% were male; median age at diagnosis was 15 months. We performed 180 OFCs to 15 foods in 82 subjects; 30% of the study population had FPIES confirmed based on OFC results. The most common foods were cows milk (44%), soy (41%), rice (22.5%), and oat (16%). The majority (65%) reacted to 1 food, 26% reacted to 2 foods, and 9% reacted to 3 or more foods. The majority were atopic, and 39% had IgE sensitization to another food. Thirty-nine (24%) subjects had positive specific IgE levels to the food inducing FPIES. Among children with specific IgE to cows milk, 41% changed from a milk FPIES to an IgE-mediated phenotype over time. The median age when tolerance was established was 4.7 years for rice, 4 years for oat, and 6.7 years for soy. Median age when milk tolerance was established for subjects with undetectable milk-specific IgE levels was 5.1 years, whereas none of the subjects with detectable milk-specific IgE became tolerant to milk during the study (P = .003). CONCLUSION FPIES typically resolves by age 5 years. Milk FPIES, especially with detectable food-specific IgE, can have a protracted course and eventually transition to acute reactions.

Skin exposure promotes a Th2-dependent sensitization to peanut allergens

Sensitization to foods often occurs in infancy, without a known prior oral exposure, suggesting that alternative exposure routes contribute to food allergy. Here, we tested the hypothesis that peanut proteins activate innate immune pathways in the skin that promote sensitization. We exposed mice to peanut protein extract on undamaged areas of skin and observed that repeated topical exposure to peanut allergens led to sensitization and anaphylaxis upon rechallenge. In mice, this epicutaneous peanut exposure induced sensitization to the peanut components Ara h 1 and Ara h 2, which is also observed in human peanut allergy. Both crude peanut extract and Ara h 2 alone served as adjuvants, as both induced a bystander sensitization that was similar to that induced by the atopic dermatitis-associated staphylococcal enterotoxin B. In cultured human keratinocytes and in murine skin, peanut extract directly induced cytokine expression. Moreover, topical peanut extract application induced an alteration dependent on the IL-33 receptor ST2 in skin-draining DCs, resulting in Th2 cytokine production from T cells. Together, our data support the hypothesis that peanuts are allergenic due to inherent adjuvant activity and suggest that skin exposure to food allergens contributes to sensitization to foods in early life.

Epinephrine treatment is infrequent and biphasic reactions are rare in food-induced reactions during oral food challenges in children

BACKGROUND Data about epinephrine use and biphasic reactions in childhood food-induced anaphylaxis during oral food challenges are scarce. OBJECTIVE To determine the prevalence and risk factors of reactions requiring epinephrine and the rate of biphasic reactions during oral food challenges (OFCs) in children. METHODS Reaction details of positive OFCs in children between 1999 and 2007 were collected by using a computerized database. Selection of patients for OFCs was generally predicated on < or =50% likelihood of a positive challenge and a low likelihood of a severe reaction on the basis of the clinical history, specific IgE levels, and skin prick tests. RESULTS A total of 436 of 1273 OFCs resulted in a reaction (34%). Epinephrine was administered in 50 challenges (11% of positive challenges, 3.9% overall) for egg (n = 15, 16% of positive OFCs to egg), milk (n = 14, 12%), peanut (n = 10, 26%), tree nuts (n = 4, 33%), soy (n = 3, 7%), wheat (n = 3, 9%), and fish (n = 1, 9%). Reactions requiring epinephrine occurred in older children (median, 7.9 vs 5.8 years; P < .001) and were more often caused by peanuts (P = .006) compared with reactions not treated with epinephrine. There was no difference in the sex, prevalence of asthma, history of anaphylaxis, specific IgE level, skin prick tests, or amount of food administered. Two doses of epinephrine were required in 3 of 50 patients (6%) reacting to wheat, cows milk, and pistachio. There was 1 (2%) biphasic reaction. No reaction resulted in life-threatening respiratory or cardiovascular compromise. CONCLUSION Older age and reactions to peanuts were risk factors for anaphylaxis during oral food challenges. Reactions requiring multiple doses of epinephrine and biphasic reactions were infrequent.

Milk and soy allergy.

Cows milk allergy (CMA) affects 2% to 3% of young children and presents with a wide range of IgE and non-IgE-mediated clinical syndromes, which have a significant economic and lifestyle effect. It is logical that a review of CMA would be linked to a review of soy allergy because soy formula is often an alternative source of nutrition for infants who do not tolerate cows milk. This review examines the epidemiology, pathogenesis, clinical features, natural history, and diagnosis of cows milk and soy allergy. Cross-reactivity and management of milk allergy are also discussed.

Poor utility of atopy patch test in predicting tolerance development in food protein-induced enterocolitis syndrome

Diagnostic tests are lacking in food protein-induced enterocolitis (FPIES), a non–immunoglobulin E, presumably T cell–mediated food allergy disorder. FPIES typically presents in infancy with profuse vomiting and diarrhea 2 to 4 hours after ingestion of the allergen, combined with a left-shift in peripheral blood leukocytes, occasionally causing profound dehydration, hypotension, and lethargy.1 Chronic exposure results in failure to thrive and hypoalbuminemia.1 FPIES is elicited commonly by milk and soy protein,1 oat, rice, and other foods.2 Oral food challenge (OFC) is performed to follow tolerance development in FPIES, but protracted emesis and dehydration necessitate fluid resuscitation in up to 50% of reactive challenges. Therefore, OFC to confirm the diagnosis of FPIES can be associated with high risk. The atopy patch test (APT) has been suggested as a promising diagnostic test for FPIES3 based on the potential involvement of allergen-specific T lymphocytes, which have been cloned from APT biopsy specimens,4 in FPIES pathophysiology.5 Furthermore, it was recently shown that cutaneous exposure to food antigens can reprogram gut-homing effector T cells in lymph nodes to express skin-homing receptors, eliciting skin lesions on cutaneous food allergen contact.6 We performed APT in children with FPIES before OFC performed to monitor tolerance development. All these children had a history of reaction suggestive of “typical” FPIES as proposed by Sicherer et al1 (acute onset of severe, repetitive emesis within 1–4 hours of ingestion) to at least 1 of the following foods: milk, soy, oat, or rice. The study was approved by the Institutional Review Board. Informed consent was obtained from parents and assent from children when appropriate. A standard APT panel of cow milk, soybean, rice, and oat was performed on each patient within a week before OFC as described previously.3 Briefly, a thick paste of nonfat dried milk powder or soy, rice, or oat flour in normal saline was applied into Finn Chambers placed on the back with Scanpore tape (Allerderm Laboratories, Inc., Petaluma, California). Vanicream (Pharmaceutical Specialities Inc, Rochester, Minnesota) was used as a negative control. Patches were removed after 48 hours; reactions were blindly scored by a study physician at 72 hours. Erythema alone was considered “irritation” (negative); positive reactions included erythema with infiltration (+), or with few papules (++), several papules (+++), and vesicles (++++).7 Inpatient OFCs were performed by administering food in 3 equal doses over a 45-min interval with a peripheral intravenous line in place. The total amount of challenge food was calculated as (0.15–) 0.6 g food protein (or 17.6 mL liquid milk, 20.3 mL liquid soy milk, 9 g infant rice cereal, or 4.5 g infant oat cereal) per kilogram body weight. Positive challenges comprised symptoms and laboratory findings as described previously.8 We performed 38 nonblinded challenges in 25 subjects (15 males, 10 females) at median age of 3.3 years (range, 1.5–16.8 years) (Table 1). Their most recent FPIES reaction had occurred a median of 24.5 months (range, 14.5–79 months) before the OFC. Of the 38 OFCs, 16 (42%) were positive and included vomiting and sometimes other symptoms (Table 1), within a median of 2.5 hours (range, 2–6.2 hours) from the start of the challenge to a total dose in all the patients; only 2 subjects had a positive APT. Among the 23 negative OFCs, 2 subjects had a positive APT. The median age was comparable between those with a positive and negative OFC. The APT had sensitivity of 11.8%, specificity 85.7%, positive predictive value 40%, and negative predictive value 54.5%. A total of 102 tests were done as part of the APT panel to foods other than the offending food; 5 were positive. In 3, food was tolerated; in 2, food had not yet been introduced. Table 1 Characteristics of the study population and test results according to the trigger fooda The discrepancy compared with the report by Fogg et al (sensitivity of 100%, specificity 71%, positive predictive value 75%, negative predictive value 100%)3 may be attributable to the fact that we considered only palpable infiltration as a positive reaction, as recommended by the European Academy of Allergy and Clinical Immunology/Global Allergy and Asthma European Network.7 The median age in the study by Fogg et al3 was younger, and the median time since the most recent reaction was shorter (12 months, range 4–29 months), which could represent a group of children with more “active” disease. However, their reaction rate was not significantly higher than ours (48.5% vs 42%). It is possible that the activation capacity of responsible T cells diminishes over time resulting in a negative APT. However, this was not the case in the gut mucosa during a positive OFC. In conclusion, APTs to common food allergens have poor utility in the follow-up prediction of outgrowing FPIES in children.

Mammalian milk allergy: clinical suspicion, cross-reactivities and diagnosis

Purpose of reviewCows milk allergy affects 2–3% of young children, the economic impact of which necessitates search for simple diagnostic tools and affordable milk substitutes. This review examines recent studies on the diagnosis of cows milk allergy as well as on the allergenicity of milk from other mammalian species. Recent findingsResolution of symptoms during strict milk avoidance and their re-appearance during the double-blind, placebo-controlled milk challenge remains the gold standard for the diagnosis of cows milk allergy. Allergic eosinophilic esophagitis/gastroenteritis requires confirmatory endoscopic biopsy. There are increasing data in various populations on cut-off points based on positive predictive values for skin prick test and milk-specific IgE measurements to aid in the diagnosis of cows milk allergy and to decrease the number of unnecessary food challenges. For non-IgE-mediated manifestations, noninvasive diagnostic tests are still largely lacking. The significant homology between milk from cow, sheep and goat results in clinical cross-reactivity. However, mares or donkeys milk may be tolerated by some individuals. SummaryData have been accumulating on the utility of diagnostic tools for mostly IgE-mediated milk allergy and allergenicity of milk from other mammalian species, although further studies are sought.