Non-IgE-mediated food allergy: Evaluation and management

The most common types of non-IgE-mediated food allergy are food protein-induced enterocolitis syndrome (FPIES) and food protein-induced allergic proctocolitis (FPIAP). FPIES presents with delayed refractory emesis, while FPIAP presents with hematochezia in otherwise healthy infants. Acute management of FPIES includes rehydration or ondansetron, or both. No acute management is required for FPIAP. Long-term management of both disorders includes avoidance of the trigger food. The prognosis for both conditions is a high rate of resolution within a few years’ time.     

Food protein‐induced enterocolitis syndrome: Pitfalls in the diagnosis

Food protein‐induced enterocolitis syndrome (FPIES) represents the severe end of the spectrum of gastrointestinal food hypersensitivity; its acute episodes can culminate in severe dehydration and hypovolemic shock, and its chronic form entails considerable morbidity associated with feeding difficulty and failure to thrive. Nevertheless, awareness for this syndrome remains rather low. Many factors hamper the establishment of FPIES diagnosis. Such factors pertain to the pathophysiological mechanism of the syndrome, causal food proteins, clinical manifestations, diagnostic procedures, differential diagnosis considerations, and prevailing perceptions which may require critical appraisal. Throughout this review, we will present and discuss these issues and put the focus on factors that could lead to under‐diagnosis of FPIES, cause numerous acute episodes, and substantially increase the diseases morbidity and financial burden. We will also address other issues that are clinically relevant to FPIES.     

Rice protein‐induced enterocolitis syndrome with transient specific IgE to boiled rice but not to retort‐processed rice

Described herein is the case of an 8‐month‐old girl with atypical food protein‐induced enterocolitis syndrome due to rice. She presented with vomiting and poor general activity 2 h after ingestion of boiled rice. Oral food challenge test using high‐pressure retort‐processed rice was negative, but re‐exposure to boiled rice elicited gastrointestinal symptoms. On western blot analysis the patient's serum was found to contain IgE bound to crude protein extracts from rice seed or boiled rice, but not from retort‐processed rice. The major protein bands were not detected in the electrophoresed gel of retort‐processed rice extracts, suggesting decomposition by high‐temperature and high‐pressure processing. Oral food challenge for diagnosing rice allergy should be performed with boiled rice to avoid a false negative. Additionally, some patients with rice allergy might be able to ingest retort‐processed rice as a substitute for boiled rice.     

Atopy patch test for the diagnosis of food protein-induced enterocolitis syndrome

Food protein-induced enterocolitis syndrome (FPIES) is thought to be a non-IgE mediated food allergy syndrome. Affected infants typically demonstrate gastrointestinal symptoms after hours after ingestion of the offending food. Traditional allergy testing is not useful for this disorder because tests for food specific IgE are routinely negative. A diagnostic oral food challenge (OFC) is the only method to confirm the diagnosis of FPIES. This prospective study was undertaken to determine whether the atopy patch test (APT) is able to predict the results of the OFC. Nineteen infants with suspected FPIES by clinical history underwent APT to the suspected foods. After APT was performed, subjects underwent OFC to determine whether FPIES was present. The results of APT and OFC were compared and used to calculate sensitivity and specificity of the APT. APT predicted the results of oral food challenges in 28/33 instances. There were 16 cases of FPIES confirmed by oral food challenges. In all 16 cases of FPIES, the APT was positive to the suspected food. However, the APT was positive in five instances where the oral food challenge was negative. All 12 patients with a negative APT had a negative oral food challenge to the suspected food. APT appears to be a promising diagnostic tool for the diagnosis of FPIES.     

食物蛋白诱导的儿童过敏性直肠结肠炎研究进展

回顾总结食物蛋白诱导的儿童过敏性直肠结肠炎的流行病学、致病机制、临床表现、辅助检查、诊断及管理的最新进展.食物蛋白诱导的儿童过敏性直肠结肠炎主要是由非IgE介导的免疫反应,致病机制复杂,与多种因素有关,其症状可表现为哭闹、腹泻、便血、皮疹等,可累及消化、呼吸、皮肤等一个或多个系统.回避饮食有效加上激发试验阳性为诊断的金...     

Drug-induced enterocolitis syndrome: Similarities and differences compared with food protein-induced enterocolitis syndrome

In 2014, drug-induced enterocolitis syndrome (DIES) was described for the first time. It is still a poorly known disease with symptoms that typically resemble those of food protein–induced enterocolitis syndrome (FPIES). To date, six more cases of DIES have been described and new clinical diagnostic criteria have been proposed based on those in the international guidelines for FPIES. In this paper, the authors describe three more cases of DIES. In addition, similarities and differences with FPIES have been deeply analyzed. To date, several unanswered questions need to be addressed, but clinicians must be instructed how to identify DIES, in order to make an allergy workup and give definite therapeutic indications to patients, especially in children where DIES seems to be more frequent.     

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??Food protein-induced enterocolitis syndrome??FPIES??is a non-IgE mediated gastrointestinal allergic disorder??and the pathogenesis is still unknown. The clinical manifestations include repetitive severe vomiting and diarrhea. Acute FPIES can result in dehydration??lethargy and even shock. Chronic FPIES is mainly characterized by weight loss and growth retardation. FPIES mainly affects infants and toddlers. Common allergen includes milk??soybean??oats??fish and eggs. The diagnosis is based on typical clinical manifestations and the fact that avoiding possible food source can alleviate the symptoms. If necessary??oral food challenge??OFC?? is required to confirm the diagnosis or to find out the food allergy sources. The key treatment measures are to avoid allergen food and to carry out symptomatic treatment during acute phase.     

Protein‐losing enteropathy and erythema caused by egg allergy in a breast‐fed infant

A 4‐month‐old breast‐fed girl presented with poor weight gain, and had edema and repeated erythema from 5 months of age. The diagnosis of protein‐losing enteropathy (PLE) was confirmed on ^99mTc‐labeled human serum albumin scintigraphy. Specific IgE radioallergosorbent test was class 3 for egg white, class 2 for egg yolk, and negative for other foods. Elimination of egg from the mother's diet and oral epinastine hydrochloride treatment and sodium cromolyn improved hypoalbuminemia, hypogammaglobulinemia, and erythema. PLE and erythema coincident in a breast‐fed infant suggests that IgE‐mediated allergy may play a leading role in some cases of PLE due to food allergy in infants.     

Educational clinical case series for pediatric allergy and immunology: Allergic proctocolitis, food protein-induced enterocolitis syndrome and allergic eosinophilic gastroenteritis with protein-losing gastroenteropathy as manifestations of non-IgE-mediated cow''s milk allergy

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.     

Peanut seed storage proteins are responsible for clinical reactivity in Spanish peanut‐allergic children

Background: Seed storage proteins (SSP; Ara h 1, Ara h 2, Ara h 3) have been shown to be major peanut allergens, although recently, peanut lipid transfer protein has been reported to be an important allergen in the Mediterranean area. We sought to investigate the sensitization pattern to peanut SSP and vegetable pan‐allergens in a group of peanut‐allergic children compared with a peanut‐tolerant group. Methods: One hundred and twenty‐three children who presented with food allergy were included in the study. Tolerance to peanut ingestion was assessed. Specific IgE was determined by ImmunoCAP, and microarray ISAC was performed. Sensitization frequencies and levels of specific IgE were compared between groups. Results: Fifty‐five of 123 children presented symptoms upon contact or ingestion. Frequency of sensitization to Ara h 1, Ara h 2, and Ara h 3 was 60.0%, 72.7%, and 43.6%, respectively, in the group of allergic children vs. 7.4%, 1.5%, and 7.4% in the group of tolerant children. Levels of specific IgE against Ara h 1, Ara h 2, and Ara h 3 were significantly higher in the allergic group (p < 0.001). The frequency of sensitization and the levels of specific IgE against Cor a 8 (36.4% vs. 16.2%) were significantly higher in the allergic children, whereas no significant differences were found for Pru p 3. No differences were seen for other pan‐allergens. Patients sensitized to SSP, regardless of sensitization to nsLTP, were allergic rather than tolerant. Conclusion: In our population, peanut‐allergic children were mainly sensitive to SSP. A few patients were also sensitive to some nsLTPs. No differences were shown in other pan‐allergens.     

Food allergies in early childhood. 1. General concepts, etiopathogenesis, and main clinical features

Abnormal immune reactions to food antigens are a rather common event during infancy. Adverse reactions to milk proteins occur in 2.5% of suckling infants. Both IgE and non IgE-mediated allergic mechanisms may be involved in the pathogenesis of food allergy. IgE mediated allergic responses are the most dramatic and the most often diagnosed types. Non IgE mediated food allergy is usually more difficult to diagnose and its clinical course is more chronic. Food induced allergic reactions mediate a variety of symptoms, involving the gastrointestinal and respiratory tract and the skin. A limited number of foods are responsible for the vast majority of allergic reactions: cow milk proteins, egg, fish and peanuts are the main causes. The vast majority of infants with formula-protein intolerance will outgrow their symptoms by the third year of age. Eliminating the food allergens is the only means of dealing with the problem. In part I of this series, immunopathogenic mechanisms and clinical disorders are described.     

Fish allergy in childhood

Fish and its derived products play an important role in human nutrition, but they may also be a potent food allergen. Fish can be an ingested, contact, and inhalant allergen. Gad c I, a Parvalbumin, the major allergen in codfish, is considered as fish and amphibian pan‐allergen. Prevalence of fish allergy appears to depend on the amount of fish eaten in the local diet. In Europe, the highest consumption occurs in Scandinavian countries, Spain and Portugal. In Spain, fish is the third most frequent allergen in children under 2 yr of age after egg and cow’s milk. An adverse reaction to fish may be of non‐allergic origin, due to food contamination or newly formed toxic products, but the most frequent type of adverse reactions to fish are immunologic‐mediated reactions (allergic reactions). Such allergic reactions may be both IgE‐mediated and non‐IgE‐mediated. Most cases are IgE‐mediated, due to ingestion or contact with fish or as a result of inhalation of cooking vapors. Some children develop non‐IgE‐mediated type allergies such as food protein induced enterocolitis syndrome. The clinical symptoms related to IgE‐mediated fish allergy are most frequently acute urticaria and angioedema as well as mild oral symptoms, worsening of atopic dermatitis, respiratory symptoms such as rhinitis or asthma, and gastrointestinal symptoms such as nausea and vomiting. Anaphylaxis may also occur. Among all the species studied, those from the Tunidae and Xiphiidae families appear to be the least allergenic.     

Food protein-induced enterocolitis syndrome – not only due to cow's milk and soy

Over a of 7-year period, six patients (four males, two females aged 3–12 months) were diagnosed with food protein-induced enterocolitis syndrome (FPIES) triggered by foods other than cow's milk and soy: chicken in four, turkey in two, peas in one, and lentils in one (five patients reacted to more than one food type). All reactions developed within 2 h of ingestion of the allergenic food. To exclude other conditions with similar clinical symptoms, three infants underwent work-up for sepsis, one infant underwent work-up to exclude metabolic defects, and one underwent a barium enema to rule out intussusception. All were negative. Pediatricians should be aware that FPIES may be caused by foods other than cow's milk and soy, mainly chicken, turkey and foods from the legume family, and that it may present also in infants older than 6 months.     

Egg allergy: An update

Egg allergy is the commonest infant food allergy both in Australia and world‐wide. The clinical presentation of egg allergy is varied – egg is involved in both IgE and non‐IgE‐mediated allergic reactions and has been implicated in conditions such as anaphylaxis, food protein‐induced enterocolitis syndrome, atopic dermatitis and eosinophilic oesophagitis. The clinical presentation, pathophysiology and diagnosis as well as the natural history and management of egg allergy will be discussed. Current theories about primary prevention as well as potential future therapies are presented. Finally, practical information about egg allergy and immunisation is provided.     

Allergies to fruits and vegetables

Allergic reactions to fruits and vegetables are frequently observed in older children and adolescents. They can result from a primary sensitization to food allergens or from a primary sensitization to inhalant allergens such as pollens or latex. In the case of fruit allergies, the stability of the allergens involved is crucial to the sensitization pathway and in the clinical presentation of the food allergy. Two patients allergic to fruits are presented and discussed in the light of the allergens involved. Patient 1 was a 14 yr-old girl with a grass and olive pollen allergy who developed oropharyngeal symptoms typical of the oral allergy syndrome (OAS) with multiple fruits from taxonomically unrelated families, and who was sensitized to profilin. Patient 2 was an 8 yr-old girl, with no pollen allergies, who developed systemic reactions to peach and apple, and who was sensitized to non-specific lipid transfer proteins (LTP). Profilins are labile allergens present in pollens and foods, and sensitization occurs through the respiratory route to pollen profilin. The cross-reactive IgE antibodies generated can elicit local reactions in the oropharyngeal mucosa (OAS) when exposed to fruit profilins. In contrast, LTPs are a family of stable allergens that resist thermal treatment and enzymatic digestion, and can thus behave as true food allergens inducing primary (non-pollen related) sensitizations and triggering systemic reactions. These two cases represent two distinct patterns of sensitization and clinical expression of fruit allergies that are determined by the panallergens involved (LTPs and profilins) and their intrinsic physicochemical properties. Additionally, these two cases also show the improved diagnostic value of Component Resolved Diagnosis, and strengthen its utility in the routine diagnosis and management of patients.     

Prevalence of food allergy among preschool children in northern Thailand

Background: The epidemiology and clinical spectrum of food allergies (FA) confirmed by oral food challenge tests (OFC) in the Southeast Asian countries are limited. The aim of the present study was to examine the prevalence and characteristics of FA among preschool children in northern Thailand. Methods: Five hundred and forty‐six children aged 3–7 years living in Chiang Mai, Thailand participated in this study. A cross‐sectional parent questionnaire survey was conducted. Families with children reporting FA were invited to undergo further investigations with skin prick testing, serum specific IgE, and OFC. Results: A total of 452 out of 546 questionnaires (82.8%) were returned. Forty‐two children (9.3%) were reported to have FA. The five leading allergic foods reported were shrimp, cow's milk, fish, chicken eggs, and ant eggs. The most commonly reported symptom was a skin rash (78.0%), followed by abdominal pain and vomiting (31.1%). Anaphylaxis was found in two children (3.4%), from ant eggs allergy. Eighteen children underwent OFC; five of them were positive to shrimp, fish, and crab. Either skin prick test or serum‐specific IgE was positive in these children. Factors associated with parent‐reported FA included personal and family history of atopic dermatitis. Conclusions: The prevalence of IgE‐mediated FA confirmed on OFC was ≥1.11% (95% confidence interval: 0.41–2.98%). The most common causative food was shrimp. Ant eggs were a unique food allergen causing severe reactions in preschool children in northern Thailand.     

Non‐IgE‐mediated gastrointestinal allergies—Do they have a place in a new model of the Allergic March

The rise in food allergy has been described as the “second wave” of the allergy epidemic, with some developed countries reporting a prevalence of 10% of challenge‐proven food allergies. Recognition of the Allergic March has played a crucial role in identifying causality in allergic conditions, linking atopic dermatitis to food allergy and food allergy to other atopic disorders, thereby highlighting opportunities in prevention and the importance of early intervention. This publication will establish the value of weaving the less well‐understood, non‐IgE‐mediated food allergy into the Allergic March and mapping its progression through childhood and its associated co‐morbidities. The proposed non‐IgE‐mediated Allergic March highlights the concomitant presentation of gastrointestinal symptoms and atopic dermatitis as early presenting symptoms in confirmed non‐IgE‐mediated allergies and the later development of atopic co‐morbidities, including asthma and allergic rhinitis, similar to the IgE‐mediated Allergic March. This publication highlights recent observations of a link between non‐IgE‐mediated food allergy in early childhood and functional gastrointestinal disorders in later life and also the reported occurrence of extra‐intestinal manifestations at later ages. Although significant limitations exist in regard to the proposed evolution of the Allergic March model, the authors hope that this publication will influence the management of non‐IgE‐mediated gastrointestinal allergies and inform future research and interventions.     

Practical approach to nutrition and dietary intervention in pediatric food allergy

Although the need for nutritional and dietary intervention is a common thread in food allergy management, the type of food allergic disorder and the identified food allergen will influence the approach to dietary intervention. A comprehensive nutrition assessment with appropriate intervention is warranted in all children with food allergies to meet nutrient needs and optimize growth. However, dietary elimination in food allergy may also have undesirable consequences. Frequently, an elimination diet is absolutely necessary to prevent potentially life‐threatening food allergic reactions. Allergen elimination can also ease chronic symptoms, such as atopic dermatitis, when a food is proven to trigger symptoms. However, removing a food with proven sensitivity to treat chronic symptoms may increase the risk of an acute reaction upon reintroduction or accidental ingestion after long‐term avoidance, so it is not without risk. Additionally, it is not recommended to avoid foods in an attempt to control chronic symptoms such as AD and EoE when allergy to the specific food has not been demonstrated. Ultimately, allergen elimination goals are to prevent acute and chronic food allergic reactions in the least restrictive, but also the safest environment to supply a balanced diet that promotes health and growth and development in children.     

IL‐17E but not IL‐17A is associated with allergic sensitization: results from the LISA study

Herberth G, Daegelmann C, Röder S, Behrendt H, Krämer U, Borte M, Heinrich J, Herbarth O, Lehmann I for the LISAplus study group. IL‐17E but not IL‐17A is associated with allergic sensitization: results from the LISA study.
Pediatr Allergy Immunol 2010: 21: 1086–1090.
© 2010 John Wiley & Sons A/S Functional studies have provided evidence for the importance of IL‐17A and IL‐17E in the regulation of immune responses. IL‐17A is involved in inflammation and IL‐17E is able to induce Th2 cytokine production and eosinophilia. By now it is not clear whether these cytokines correlate with specific IgE levels. The aim of our investigation was to analyse the relationship of these two cytokines to allergic sensitization in context of an epidemiological study. Within the Life style Immune System Allergy study (LISA), we analysed phytohemagglutinin (PHA)‐stimulated blood samples of 6 yr old children for the concentration of IL‐17A and IL‐17E and sera for levels of specific IgE. In total, data from 293 children were available for blood analysis and for the analysis of confounding factors for the allergic sensitization. Among the investigated children, 29% reacted against inhalant and 13.6% against food allergens, whereas 33.1% of children were sensitized to any allergen. IL‐17E was associated with high levels of any specific IgE (adjusted odds ratio (OR) 1.45, 95% confidence interval (CI) 1.11–1.90). Furthermore, children with high IL‐17E responses (>208.8 pg/ml) were sensitized to food and inhalant allergens (OR 1.45, 95% CI 1.02–2.07 and OR 1.35, 95% CI 1.03–1.77, respectively) and to Der p 1 (OR 1.55, 95% CI 1.12–2.15). In contrast, IL‐17A, in trend, was negatively associated to sensitization to timothy (p for trend=0.013) and rye (p for trend=0.026). Concluding IL‐17E production is linked to the amount of specific IgE antibodies in blood samples of 6 yr old children.