non-IgE Mediated Food Allergy Research Articles

M245 FOOD PROTEIN-INDUCED EOSINOPHILIC GASTROINTESTINAL INFLAMMATION IN AN EXCLUSIVELY BREASTFED INFANT

Non-IgE mediated food allergies generally occur during the first year of life after introduction to formula and/or solid foods. There are limited examples of this in exclusively breastfed infants, although food antigens can potentially be transferred through breast milk.

The Challenge of Home Allergen Re-introductions Using the Ladder Approach in Children With Non-IgE Mediated Gastrointestinal Food Allergy.

Background: Oral food challenges remain the most reliable method for allergy confirmation. Although consensus guidelines have been published to unify Immunoglobulin E (IgE)-mediated challenges, this does not exist for non-IgE mediated gastrointestinal allergies outside of Food Protein Induced Enterocolitis Syndrome. We therefore set out to establish the use of home introduction protocols (HIP) for confirmation of food allergy for milk, soya, egg and wheat using a ladder approach in children with non-IgE mediated allergy.Materials and Methods: Patients with suspected non-IgE mediated gastrointestinal allergies (0–16 years) were recruited following symptom improvement on an elimination diet. All children had skin prick or specific IgE tests to rule out IgE-mediated allergies prior to suggestion the HIP. Number of trials and outcome was documented. HIPs were developed using a published ladder approach for cow's milk as baseline and final dose was calculated based on guidelines for food protein induced enterocolitis syndrome and portions for age from the National Diet and Nutrition Survey. First foods were baked/highly processed and every 4th day patients moved to a more unprocessed/unheated food.Results: From 131 recruited patients, 117 (89.3%) followed the HIP for food allergens. No adverse events were documented. In more than 50% of cases one attempt at the HIP was sufficient to establish allergy status, but many required 2–5 attempts before the outcome was clear. About half of the children were fully tolerant to foods they initially eliminated: 36, 26 and 30% were partially tolerant to milk, soya, and egg and only 15% achieved partial tolerance to wheat. Wheat was the allergen introduced earliest, followed by soya, cow's milk and egg.Conclusions: This study indicates that home HIPs are safe in non-IgE mediated gastrointestinal food allergy and that the ladder approach may be useful in re-introducing allergens in children at home with non-IgE mediated gastrointestinal allergies. From this study we can also conclude that tolerance to processed/baked allergens was observed in many children. Further studies should be performed on the HIP and ideally reintroduction should occur pre-defined time intervals.

Prevalence of IgE-Mediated Food Hypersensitivity to Cereals and Beans Based on Skin Prick Test in Children with Celiac Disease.

BACKGROUND Celiac disease is a non-IgE mediated food allergy, which can cause extensive villus atrophy. Because of increased food allergen absorption, there are elevated IgA and IgG antibodies in these patients, so there is a concern about IgE antibody production against wheat and other cereals. METHODS In this study, we evaluated IgE-mediated hypersensitivity to wheat, rice, and other cereals in children with celiac disease. RESULTS 22 patients (50%) had at least one positive skin prick test to food allergens. The most frequent food allergen was peanut (31.8%), followed by wheat (18.2%), corn (9.1%), and rice (4.5%). The results revealed no significant correlation between age, sex, and the results of the skin prick test (p >0.05). The correlation between diagnosis time of celiac disease and results of skin prick test was also not significant statistically (p >0.05). CONCLUSION Because of the high prevalence of IgE mediated hypersensitivity to cereals and beans in children with celiac disease, a skin prick test might be considered in these patients, especially in refractory cases.

Update on Food protein-induced enterocolitis syndrome (FPIES).

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE mediated food allergy (FA) characterized by delayed and severe gastrointestinal symptoms that typically occurs within the first year of life. Many aspects of this pathology are currently unclear. FPIES is classified as a non-IgE immune-mediated FA in which the immune response is thought to act mainly through cell-mediated mechanisms. In patients with FPIES the symptom pattern is determined by the frequency and dose of food allergen in the diet. Diagnosis of FPIES may be difficult, mainly due to the lack of specific biomarkers to confirm or exclude the diagnosis. FPIES is a clinical diagnosis, mainly based on clinical features which, although not specific, are reproducible every time the patient eats the food. Different diagnostic criteria of FPIES were published over time in the literature. The present narrative review aims to analyze the current clinical evidence in epidemiology, pathophysiology, diagnosis, and management of this condition. (www.actabiomedica.it)

Phenotypes and natural history of food protein‐induced enterocolitis syndrome in the east Mediterranean region

Background: Food protein-induced enterocolitis syndrome (FPIES) is a rare non-IgE mediated food allergy. Objective: To delineate the differences in the spectrum of culprit foods, remission patterns, and predictors among varying cultures. Methods: We reviewed demographics, culprit foods, outcomes, and predictors in 81 children with a diagnosis of FPIES who were followed up between 2015 and 2020. Results: Eighty-one patients (55.6% boys) were enrolled, including 72 with acute FPIES and 9 with chronic FPIES. Hen's egg was the most common culprit food (36.6%), followed by fish (26.9%), and cow's milk (21.5%). Interestingly, cow's milk was significantly prevalent in chronic FPIES cases (p = 0.006). The most common clinical symptoms were vomiting (100%), pallor (63.4%), and lethargy (55.9%). Emergency department visits were noted in 39 patients (41.9%), of whom 37 (39.8%) were treated with intravenous (IV) fluid. The subjects were followed up for a median (interquartile range) of 19.4 months (12.3-41.2 months), and 26 subjects (32.1%) achieved tolerance. The median (interquartile range) age at tolerance was 2.5 years (2.1-3.2 years). With regard to the culprit foods, hen's egg was observed more frequently in the subjects with resolved FPIES cases (p = 0.008), whereas fish FPIES cases were high in the persistent group (p = 0.001). IgE sensitization of the culprit food was found to be an independent risk factor for the persistence of FPIES (odds ratio 4.855 [95% confidence interval, 1.131-20.844]; p = 0.034). Conclusion: In our cohort, unlike other published series, hen's egg and fish were the two most common culprit foods. Fish differed from other culprit foods, with significantly delayed onset and persistence, and may create a model that allows for the understanding of the disease.

Eosinophil-Derived Neurotoxin, Tumor Necrosis Factor Alpha, and Calprotectin as Non-Invasive Biomarkers of Food Protein-Induced Allergic Proctocolitis in Infants.

Diagnosis of non-IgE mediated food allergy presents a special challenge due to lack of a single, non-invasive diagnostic method. We selected three fecal biomarkers of allergic inflammation of gastrointestinal origin in order to improve the diagnostic process. Twenty-seven infants with symptoms of hematochezia were prospectively enrolled into this study. All patients underwent a complete differential diagnosis of rectal bleeding. Non-IgE mediated food allergy was confirmed by an open, oral food challenge. The control group included twenty-five infants with functional gastrointestinal disorders. Eosinophil-derived neurotoxin (EDN), tumor necrosis factor alpha (TNFα), and calprotectin concentration were measured in stools of all children by enzyme-linked immunosorbent assays (ELISA) using commercial kits. Median eosinophil-derived neurotoxin and calprotectin fecal levels were significantly higher in the study group than in the control group (p < 0.05). The difference of fecal tumor necrosis factor alpha concentration between both groups was not statistically significant (p > 0.05). The best diagnostic performance was reached in a combination of fecal calprotectin (fCal) and EDN i.e., 88.9% and 84%, respectively. Fecal EDN and fCAl are reliable tools in differentiating between food protein-induced allergic proctocolitis and gastrointestinal functional disorders in infants.

Le Syndrome d’entérocolite induite par les protéines alimentaires (SEIPA) : état des lieux des connaissances et pratiques des pédiatres français

BackgroundFood Protein-Induced Enterocolitis Syndrome (FPIES) is an increasingly frequently reported and potentially severe non-IgE mediated food allergy. We sought to determine the level of knowledge about FPIES among French paediatricians. Patients and methodsAn anonymous web-based survey was sent to 1460 French paediatricians. ResultsThere were 375 completed surveys (26% response rate). Among the respondents, 38% declared full knowledge of FPIES, 33% limited knowledge, 22% had simply heard of FPIES, and 6% had never heard of it. When presented with clinical cases, 92% of respondents recognized acute FPIES. Thirty-four percent of paediatricians thought that positive specific IgE ruled out a diagnostic of FPIES, whereas 25% considered that a confirmatory oral challenge was necessary. For management of acute FPIES, 21% recommended adrenaline injection and 91% plasma volume expansion, while 18% prescribed antihistamines and 29% steroids. ConclusionFrench paediatricians have limited knowledge of the manifestations and management of FPIES. There is a need to promote awareness of FPIES to minimise delays in diagnosis and avoid unnecessary or dangerous diagnostic and therapeutic procedures.

Non-IgE Mediated Food Allergy.

Food allergies, defined as an immune response to food proteins, affect as many as 8% of young children and 2% of adults in western countries, and their prevalence appears to be rising like all allergic diseases. In addition to well-recognized urticaria and anaphylaxis triggered by IgE antibody- mediated immune responses, there is an increasing recognition of cell-mediated disorders, such as eosinophilic esophagitis and food protein-induced enterocolitis. Non-IgE-Mediated gastrointestinal food allergies are a heterogeneous group of food allergies in which there is an immune reaction against food but the primary pathogenesis is not a production of IgE and activation of mast cells and basophils. Those diseases tend to affect mainly the gastrointestinal tract and can present as acute (FPIES) or chronic reaction, such as Eosinophilic Esophagitis (EoE), Food Protein-Induced Allergic Proctocolitis (FPIAP). The role of food allergy in Non-EoE gastrointestinal Eosinophilic disorders (Non- EoE EGID) is poorly understood. In some diseases like EoE, T cell seems to play a major role in initiating the immunological reaction against food, however, in FPIES and FPIAP, the mechanism of sensitization is not clear. Diagnosis requires food challenges and/or endoscopies in most of the patients, as there are no validated biomarkers that can be used for monitoring or diagnosis of Non-IgE mediated food allergies. The treatment of Non-IgE food allergy is dependent on diet (FPIES, and EoE) and/or use of drugs (i.e. steroids, PPI) in EoE and Non-EoE EGID. Non-IgE mediated food allergies are being being investigated.

Non-IgE Mediated Food Allergy

Food allergies, defined as an immune response to food proteins, affect as many as 8% of young children and 2% of adults in western countries, and their prevalence appears to be rising like all allergic diseases. In addition to well-recognized urticaria and anaphylaxis triggered by IgE antibody– mediated immune responses, there is an increasing recognition of cell-mediated disorders, such as eosinophilic esophagitis and food protein–induced enterocolitis. Non-IgE-Mediated gastrointestinal food allergies are a heterogeneous group of food allergies in which there is an immune reaction against food but the primary pathogenesis is not a production of IgE and activation of mast cells and basophils.Those diseases tend to affect mainly the gastrointestinal tract and can present as acute (FPIES) or chronic reaction, such as Eosinophilic Esophagitis (EoE), Food Protein-Induced Allergic Proctocolitis (FPIAP). The role of food allergy in Non-EoE gastrointestinal Eosinophilic disorders (Non- EoE EGID) is poorly understood.In some diseases like EoE, T cell seems to play a major role in initiating the immunological reaction against food, however, in FPIES and FPIAP, the mechanism of sensitization is not clear.Diagnosis requires food challenges and/or endoscopies in most of the patients, as there are no validated biomarkers that can be used for monitoring or diagnosis of Non-IgE mediated food allergies.The treatment of Non-IgE food allergy is dependent on diet (FPIES, and EoE) and/or use of drugs (i.e. steroids, PPI) in EoE and Non-EoE EGID.Non-IgE mediated food allergies are being being investigated.

Le syndrome d’entérocolite induite par les protéines alimentaires (SEIPA), quel protocole de soins aux urgences ?

Food protein-induced enterocolitis syndrome (FPIES) is a potentially severe non-IgE mediated food allergy (FA) that can occur at any age but is most commonly seen in infants. The symptoms, which are almost entirely gastrointestinal, are either chronic, when the offending food is ingested daily, or of the potentially life-threatening acute type (recurrent vomiting, hypotonia, diarrhea, dehydration), and these may be misdiagnosed as they mimic other diseases (e.g. infection, sepsis, anaphylaxis). This disease remains poorly known among clinicians. The “food allergy interest group” of the French Allergy Society associated with the “GroupeFrancophonedeRéanimationetUrgencesPédiatriques” (the French-language Pediatric Emergency and Intensive Care Group) herein sets out and comments upon the diagnosis and emergency care management protocol updated in light of the recent international guidelines. This document may be given by the pediatrician or allergist to the parents, who may then pass it on to the emergency physician in the event of a visit to an emergency department for digestive symptoms potentially related to FPIES.

Non-IgE Mediated Food Allergy

Non-IgE Mediated Food Allergy

Treatment of eosinophilic esophagitis with diets.

Eosinophilic esophagitis (EoE) is a chronic inflammatory esophageal disease triggered and maintained predominantly by food antigens. It represents a unique form of non-IgE mediated food allergy, largely dependent upon delayed, cell-mediated hypersensitivity. First-line therapies for EoE consist on drugs with anti-inflammatory effect (mainly including topic steroids and proton pump inhibitors) and dietary therapy. An elimination diet that avoids the consumption of food triggers currently remains the only therapy targeting the cause of EoE. Currently, available food allergy tests are suboptimal to predict food triggers for EoE, especially in adult patients. Elemental diets consisting in exclusively feeding patients with amino acid-based formulas and empiric 6-food elimination diets (withdrawing milk, wheat, egg, soy, nuts, and fish/seafood for 6 weeks) have consistently shown the best efficacy rates. However, their high level of restriction and the need for multiple endoscopies have hampered their implementation in clinical practice. In contrast, studies on 6-food elimination diets have been instrumental to decipher the most common food triggers in patients with EoE, being milk, wheat/gluten, and egg involved in most of patients from the United States, Spain, and Australia. Hence less restrictive empiric schemes, such as a 4-food elimination diet (dairy, wheat/gluten cereals, egg, and legumes) or a 2-food elimination diet (dairy and milk/gluten) were lately developed with good efficacy rates. A step-up strategy (2-4-6) may enhance patient uptake and promptly identify most responders to empiric diets with few food triggers This review updates the most relevant advances on dietary therapy for pediatric and adult patients with EoE.

An observed serving dose may not be necessary following a standard divided-dose FPIES oral food challenge

Food protein–induced enterocolitis syndrome (FPIES) is a non-IgE–mediated food allergy that typically presents during the first year of life. In most patients, history alone is sufficient to make the diagnosis and identify trigger foods. If the diagnosis is not clear after taking a careful history, an oral food challenge (OFC) is used as the criterion standard to confirm the diagnosis. OFCs are highly useful to determine whether FPIES has been outgrown and are usually attempted within 12 to 18 months after the most recent reaction.

Oral Food Challenge.

Oral food challenge (OFC) is the gold standard for diagnosis of IgE-mediated and non-IgE mediated food allergy. It is usually conducted to make diagnosis, to monitor for resolution of a food allergy, or to identify the threshold of responsiveness. Clinical history and lab tests have poor diagnostic accuracy and they are not sufficient to make a strict diagnosis of food allergy. Higher concentrations of food-specific IgE or larger allergy prick skin test wheal sizes correlate with an increased likelihood of a reaction upon ingestion. Several cut-off values, to make a diagnosis of some food allergies (e.g., milk, egg, peanut, etc.) without performing an OFC, have been suggested, but their use is still debated. The oral food challenge should be carried out by experienced physicians in a proper environment equipped for emergency, in order to carefully assess symptoms and signs and correctly manage any possible allergic reaction. This review does not intend to analyse comprehensively all the issues related to the diagnosis of food allergies, but to summarize some practical information on the OFC procedure, as reported in a recent issue by The Expert Review of Food Allergy Committee of Italian Society of Pediatric Allergy and Immunology (SIAIP).

Non-immediate (non-IgE mediated) food allergy in infancy

Food allergy (FA) is an immunologic adverse reaction to food exposure. The immunologic mechanism could be either IgE or non-IgE mediated or a mixed one. IgE-mediated symptoms typically develop within 20 minutes to two hours after ingestion of culprit food, while non-IgE mediated symptoms occur later, up to several days after ingestion. Non-IgE mediated food allergy encompasses a wide range of diseases affecting the gastrointestinal tract, proctocolitis and food protein induced enterocolitis syndrome (FPIES) being the most frequent in infancy. The most common food allergen in infants responsible for non-IgE mediated FA is cow’s milk, followed by soy, cereals and hen’s egg. About 5% to 10% infants with FA are reactive to more than three foods and very few to six or more. The diagnosis of non-IgE mediated disease depends on detailed history, physical examination, response to elimination diets and oral provocation challenges (OFCs), as there are no specific biomarkers. The management of FA requires avoidance of ingestion and periodic evaluation through supervised OFCs in order to determine whether the patients can tolerate other forms of offending food and/or when they are able to reintroduce it in their diet.

International survey on growth indices and impacting factors in children with food allergies.

Elimination diets required for the management of food allergies increase the risk for poor growth in children. Currently, no worldwide data exist on this topic and limited published data exist on the impact of atopic comorbidity, type of allergy and foods eliminated on growth. We therefore set out to perform a worldwide survey on growth and impacting factors in food allergic children. A prospective growth survey was performed of children (aged 0-16years) on an elimination diet with confirmed immunoglobulin (Ig)E and non-IgE mediated food allergies. Data collected included: weight-for-age, weight-for-height, height-for-age, head circumference, body mass index, type of food allergy and eliminated foods, allergic comorbidities and replacement milk/breast milk. Multivariable regression analysis was used to establish factors that affected growth. Data from 430 patients from twelve allergy centres were analysed: median age at diagnosis and data collection was 8months and 23months, respectively. Pooled data indicated that 6% were underweight, 9% were stunted, 5% were undernourished and 8% were overweight. Cow's milk elimination lead to a lower weight-for-height Z-scores than other food eliminations and mixed IgE and non-IgE mediated allergy had lower height-for-age Z-scores than IgE mediated allergy. Children with only non-IgE mediated allergies had lower weight-for-height and body mass index. Atopic comorbidities did not impact on growth. Stunting is more common in children with food allergies than low weight. Children particularly at risk of poor growth are those with non-IgE and mixed IgE and non-IgE mediated allergies, as well as those with cow's milk allergy.

Deep analysis of immune response and metabolic signature in children with food protein induced enterocolitis to cow\u2019s milk

BackgroundFood Protein-Induced Enterocolitis Syndrome (FPIES) is considered to be a non-IgE mediated food allergy. However, its pathogenesis remains poorly understood and biomarkers are lacking. We aimed to perform in-depth characterization of humoral and cellular immune responses in children with cow’s milk (CM)-FPIES and investigated whether there is a FPIES metabolomic signature.MethodsChildren with CM-FPIES and control subjects with an IgE-mediated CM allergy (IgE-CMA), both avoiding CM, were recruited on the day of an oral food challenge. Blood samples were collected before the challenge. Total and specific levels of IgE, IgG1-4, IgA, IgM and IgD to various whey and casein allergens and to their gastroduodenal digestion products were measured in plasma, using plasma from CM-tolerant peanut allergic patients (IgE-PA, not avoiding CM) as additional controls. Cytokine secretion and cellular proliferation were analyzed after stimulation of PBMC with different CM allergens. Metabolomic profiles were obtained for plasma samples using liquid chromatography coupled to high-resolution mass spectrometry.ResultsNine children with CM-FPIES and 12 control subjects (6 IgE-CMA and 6 IgE-PA) were included. In children with CM-FPIES, total Ig concentrations were lower than in control subjects, specific Ig against CM components were weak to undetectable, and no specific IgE against CM digestion products were detected. Moreover, in CM-FPIES patients, we did not find any Th cell proliferation or associated cytokine secretion after allergen reactivation, whereas such responses were clearly found in children with IgE-CMA. Plasma metabolic profiles were different between CM allergic patients, with significantly lower concentrations of various fatty acids and higher concentrations of primary metabolites such as amino acids in CM-FPIES compared to IgE-CMA patients.ConclusionsIn CM-FPIES, both humoral and cellular specific immune responses are weak or absent, and this is not related to CM avoidance. A metabolomic signature was identified in patients with CM-FPIES that may be useful for the diagnosis and management of this disease.

Plant food allergy: Influence of chemicals on plant allergens

Plant-derived foods are the most common allergenic sources in adulthood. Owing to the rapidly increasing prevalence of plant food allergies in industrialized countries, the environmental factors are suspected to play a key role in development of allergic sensitization. The present article provides an overview of ways by which chemicals may influence the development and severity of allergic reactions to plant foods, with especial focus on plant allergens up-regulated under chemical stress. In plants, a substantial part of allergens have defense-related function and their expression is highly influenced by environmental stress and diseases. Pathogenesis-related proteins (PR) account for about 25% of plant food allergens and some are responsible for extensive cross-reactions between plant-derived foods, pollen and latex allergens. Chemicals released by anthropogenic sources such as agriculture, industrial activities and traffic-related air pollutants are potential drivers of the increasing sensitization to allergenic PRs by elevating their expression and by altering their immunogenicity through post-translational modifications. In addition, some orally-taken chemicals may act as immune adjuvants or directly trigger non-IgE mediated food allergy. Taken together, the current literature provides an overwhelming body of evidence supporting the fact that plant chemical exposure and chemicals in diet may enhance the allergenic properties of certain plant-derived foods.

Food protein-induced enterocolitis syndrome in children: what's known? What's new?

Food protein-induced enterocolitis syndrome (FPIES) is an under-recognized and frequently misdiagnosed non-IgE mediated food allergy syndrome. Affected infants show gastrointestinal symptoms few hours after ingestion of the incriminating food. Pathophysiology of FPIES has not yet been clearly defined and needs further characterization. The common allergy tests are not helpful for this disorder and tests for food specific IgE are usually negative. A diagnostic oral food challenge (OFC) is the method to confirm the diagnosis of FPIES. This review summarizes what is known about epidemiology, pathophysiology, clinical characteristics and diagnosis and what's new about therapeutic options of FPIES.

Estudio de validez diagnóstica de la prueba de hemorragia oculta fecal en lactantes con proctocolitis alérgica inducida por proteína alimentaria

Food protein-induced allergic proctocolitis (FPIAP) is the most frequent presenta tion of non-IgE mediated food allergy (FA). The diagnosis is made by oral food challenge, however, non-invasive diagnostic tests are not available. In Chile, the fecal occult blood test (FOBT) is fre quently used to confirm FPIAP, however, there are no studies that support this practice. To establish the diagnostic validity of FOBT in the evaluation of infants with FPIAP. Case-control study with prospective recruitment of infants with rectal bleeding and suspicion of FPIAP, and controls were healthy infants, in whom the FOBT was conducted. All cases underwent an elimination diet, after which the diagnosis of FPIAP was confirmed by oral food cha llenge. 25 cases and 29 controls were included without significant differences in age, gen der, type of delivery, feeding, and maternal age. The cases had higher rates of allergic comorbidities, medication use, and family history of allergy. The FOBT was positive in 84% of cases and in 34% of controls (p < 0.001). The sensitivity of the FOBT for the diagnosis of FPIAP was 84%, specificity was 66%, positive predictive value 68%, and the negative predictive value 83%. The area under the ROC curve was 0.75 (CI 95% 0.61-0.88). Although the FOBT has an adequate sensitivity to diagnose FPIAP in infants with rectal bleeding, this test had abnormal results in more than a third of healthy infants. Therefore, the routine use of FOBT is not recommended for the diagnosis of FPIAP.