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The allergic march can often result in a child with one food allergy phenotype developing other allergic manifestations as they grow older. In this grand round, we describe the case of a child diagnosed with Eosinophilic Esophagitis at an early age, who subsequently developed IgE-mediated allergy to milk and egg. Due to the onset of allergic rhinitis, an additional complication of their teenage years was the development of Pollen Food Syndrome, which further impacted upon the already complex dietary management. These multiple allergies had a consequent effect on nutritional status and provoked considerable psycho-social issues which greatly affected the patient's relationship with food. This case illustrates that for complex patients, a cohesive approach and shared decision making is essential for their diagnosis and management. Working with not only the patient, but their whole family, and considering how best to support them, necessitates a flexible approach. Regular follow-up is important to address changing psycho-social and dietary needs as well as monitoring the resolution of allergies and response to pharmacotherapy. Complex patients need the input of a comprehensive multidisciplinary team, with good access to dietetic and psychological support in order to optimize the quality of life of these individuals and their families.

Aim: To describe clinical presentation and development of tolerance among children with Food protein-induced enterocolitis syndrome (FPIES) in a population in northern Sweden. Methods: A retrospective review of medical records of children presenting with FPIES symptoms from 1 January 2004, to 31 May 2018. Results: Sixty children (65% boys) with FPIES were included. The estimated incidence gradually increased to 0.45% in 2016–2017. The most common food triggers were cow's milk (40%), fish (37%) and oat (23%). Symptoms presented in 31 (60%) children before 6 months and in 57 (95%) before 1 year of age. The median age for FPIES diagnosis was 7 (range 3–134) months and for fish FPIES 13 (range 7–134) months. By 3 years of age, 67% of children with FPIES to milk and oat but none of the children with fish FPIES had developed tolerance. Allergic conditions like eczema and asthma were reported in 52% of the children. Conclusion: The cumulative FPIES incidence was 0.45% in 2016–2017. Most children presented with symptoms before 1 year of age, but the diagnosis was often delayed, especially for FPIES to fish. Tolerance development occurred at an earlier age when FPIES was triggered by milk and oat compared to fish.

Shouling Zhang, Scott Sicherer, M Cecilia Berin, Amanda Agyemang Department of Pediatrics, Division of Allergy and Immunology, Icahn School of Medicine at Mount Sinai, Kravis Children’s Hospital, The Elliot and Roslyn Jaffe Food Allergy Institute, New York, NY, USACorrespondence: Amanda AgyemangDepartment of Pediatrics, Division of Allergy and Immunology, Icahn School of Medicine at Mount Sinai, Kravis Children’s Hospital, The Elliot and Roslyn Jaffe Food Allergy Institute, One Gustave L. Levy Place, Box 1198, New York, NY, 10029, USATel +212 241-5548Email amanda.agyemang@mountsinai.orgAbstract: Non-IgE-mediated food allergies are a group of disorders characterized by subacute or chronic inflammatory processes in the gut. Unlike IgE mediated food allergies that may result in multi-organ system anaphylaxis, the non-IgE mediated food allergies primarily affect the gastrointestinal tract. This review outlines the clinical manifestations, epidemiology, pathophysiology, and management of non-IgE-mediated food allergies. An updated literature search of selected non-IgE-mediated food allergies was conducted for this review using PubMed database to the current year (2021). Reviewed disorders include food protein-induced enterocolitis syndrome (FPIES), food-protein enteropathy (FPE), food protein-induced allergic proctocolitis (FPIAP), and eosinophilic gastrointestinal disorders (EGIDs) such as eosinophilic esophagitis (EoE). While extensive gains have been made in understanding FPIES, FPIAP, FPE, and EoE, more information is needed on the pathophysiology of these food allergies. Similarities among them include involvement of innate immunity, T-lymphocyte processes, alteration of the intestinal lumen at the cellular level with the appearance of inflammatory cells and associated histologic changes, and specific cytokine profiles suggesting food-specific, T-cell, and immune-mediated responses. While FPIES and FPIAP typically resolve in early childhood, EGIDs typically do not. Emerging new therapies for EoE offer promise of additional treatment options. Further studies identifying the immunopathogenesis, associated biomarkers, and mechanisms of tolerance are needed to inform prevention, diagnosis and management.Keywords: food protein-induced enterocolitis syndrome, FPIES, food protein-induced enteropathy, FPE, food protein-induced allergic proctocolitis, FPIAP, eosinophilic gastrointestinal disorders, EGIDs, eosinophilic esophagitis, EoE, pathophysiology

Objective Food protein-induced enterocolitis syndrome (FPIES) is a non–immunoglobulin E-mediated food allergy with potential risk of malnutrition related to the early onset of disease, frequent avoidance of cow's milk, and the possibility of multiple food triggers. This publication is aimed at providing an evidence-based, practical approach to the dietary management of FPIES. Data Sources This is a narrative review summarizing information from national and international guidelines, retrospective studies, population studies, review articles, case reports, and case series to evaluate for nutritional risk and develop guidance for risk reduction in children with FPIES. Study Selections We have included retrospective clinical cohort studies, population-based studies, case reports, and case studies. We did not exclude any studies identified owing to the small number of studies addressing the nutritional management of individuals with FPIES. Results Children with FPIES are at risk of malnutrition owing to suboptimal oral intake, limited food choices, and knowledge deficits related to feeding. In particular, children with 3 or more FPIES triggers seem to be at increased risk for poor weight gain and developing food aversion. Caregivers of children with FPIES also report a high degree of psychosocial burden. Conclusion Appropriate dietary management entails the following 3 essential components: supporting normal growth and development, avoidance of allergens, and advancement of complementary foods. Education to avoid the trigger food and assisting caregivers in creating an individualized, well-designed complementary feeding plan to meet the infant's nutritional needs for optimal growth and development are essential management strategies.

Background: Oral food challenges (OFC) in food protein‐induced enterocolitis syndrome (FPIES) are performed to confirm a diagnosis, test for development of tolerance, and find safe alternatives. Objective: We aimed to define OFC outcomes and identify safer test strategies. Methods: OFCs performed in children with FPIES over a 5-year period were reviewed. Results: A total of 160 OFCs were performed in 59 children (median age, 2.3 years). The most commonly tested foods were hen's egg, fish, and cow's milk. Sixty-six OFC results (41.3%) were positive. Twelve (18.2%) reactions were mild, 18 (27.3%) were moderate, and 36 (54.5%) were severe. Intravenous fluid, ondansetron, and corticosteroids were administered in 83.3, 72.7, and 66.7% of the patients, respectively; one patient required hospitalization. A reaction was most likely with fish (odds ratio [OR] 2.878 [95% confidence interval {CI}, 1.279‐6.473]; p = 0.011), and least likely with cow's milk (OR 0.268 [95% CI, 0.082‐0.872]; p = 0.029). Of the 36 OFCs with egg yolk, 23 patients had a failed OFC, and of the 17 OFCs with egg white (all tolerant to egg yolk), only 2 patients had a failed result. Interestingly, two patients tolerated baked whole egg but not egg yolk. In cow's milk FPIES, two patients could consume fermented milk but not fresh milk. Of the 11 patients with anchovy-triggered FPIES, 6 tolerated sea bass, and 5 tolerated trout, whereas 4 patients with sea bass FPIES tolerated trout. Conclusion: The search for alternative food species, processing, or subdivision of a trigger food is common practice in FPIES, which reflects the expectations of children and their families. The experience gained can be put into practice and will contribute to the understanding of the disease mechanism.

Objective To explore the relationship among gastrointestinal (GI) symptoms, immune response, and autonomic nervous system (ANS) in food protein–induced enterocolitis syndrome (FPIES) in relation to the current understanding of disease phenotype and pathogenesis. Data Sources Relevant studies related to FPIES, GI symptomatology, and ANS were reviewed. Literature search was performed using PubMed, with keyword combinations including but not limited to FPIES, allergic GI disorders, ANS, autonomic dysfunction, dysautonomia, GI, diarrhea, vomiting, neuroimmune, and clinical phenotyping tools. Study Selections Peer-reviewed case-control studies, observational studies, reviews and guidelines, and systematic reviews related to FPIES and ANS were selected for review. Results There is limited research directly relating GI symptoms and FPIES to the ANS and immunologic response. To support the proposed mechanisms of action related to patient symptoms, studies relevant to coexisting GI-autonomic processes and FPIES immunologic triggers were examined. These related disease processes were extrapolated to FPIES based on the current knowledge of FPIES phenotype and pathogenesis. Conclusion The etiology of FPIES and the underlying mechanisms triggering symptoms are not well understood. On the basis of the exaggerated GI symptoms and hemodynamic response observed, the ANS likely plays an important role in FPIES, possibly as a compensatory response. The trigger for this cascade of symptoms may be related to the disruption of immunologic homeostasis that typically contributes to immune tolerance. To more accurately evaluate FPIES pathophysiology necessitates understanding the diverse spectrum of presenting symptoms. A consistent and comprehensive symptom assessment tool may improve our understanding of this dynamic relationship.

Introduction and objective: The oral food challenge (OFC) is the gold standard to diagnose food allergy (FA); however, it is not a procedure free from the risk of having significant allergic reactions, even life-threatening.The aims of our study were to evaluate the frequency of positive OFCs performed in chil-dren with a suspected diagnosis of IgE- and non-IgE–mediated (food protein–induced enterocolitis syndrome (FPIES)) FA and how the failed challenges were managed.Materials and methods: A retrospective chart review was done on all children who have had OFCs in a tertiary-care pediatric allergy unit from 2017 to 2019.Results: 682 patients were enrolled and 2206 challenges were performed: 2058 (93%) for IgE-mediated FA and 148 (7%) for FPIES. There were 262 (11.8%) challenge failures. The transfer to the emergency department was required 3 times (1.1%). None of the failed challenges resulted in death or hospitalization and 13.3% challenges did not require any treatment.Conclusions: Our findings confirm that food challenges can be performed safely in a specialized setting by well-trained personnel; all food challenge reactions, even the most serious, were reversible, thanks to a prompt recognition and treatment that generally did not worsen over time.

Background: Food Protein-Induced Enterocolitis Syndrome (FPIES) is a clinically well-characterised, non-Immunoglobulin E (IgE)-mediated food allergy syndrome, yet its rare atypical presen-tation remains poorly understood.Objective: Aim of this study was to present the 10-year experience of a referral centre high-lighting the atypical FPIES cases and their long-term outcome.Methods: FPIES cases were prospectively evaluated longitudinally in respect of food outgrowth and developing other allergic diseases with or without concomitant IgE sensitisation.Results: One hundred subjects out of a total of 14,188 referrals (0.7%) were identified. At pre-sentation, 15 patients were found sensitised to the offending food. Fish was the most frequent eliciting food, followed by cow’s milk and egg. Tolerance acquisition was earlier for cow’s milk, followed by egg and fish, while found not to be protracted in atypical cases. Resolution was not achieved in half of the fish subjects during the 10-year follow-up time. Sensitisation to food was not related to infantile eczema or culprit food, but was related to sensitisation to aeroallergens. In the long-term evaluation, persistence of the FPIES or aeroallergen sensitisation was significantly associated with an increased hazard risk of developing early asthma symptoms. Conclusion: Sensitisation to food was related neither to eczema or culprit food nor to tolerance acquisition but rather to the development of allergic asthma through aeroallergen sen-sitisation. In addition to an IgE profile at an early age, FPIES persistence may also trigger mechanisms switching FPIES cases to a T-helper 2 cells immune response later in life, predis-posing to atopic respiratory symptoms; albeit further research is required.

Objective Although food protein–induced enterocolitis syndrome (FPIES) was first described approximately 50 years ago and research is increasing, there are still considerable unmet needs in FPIES. This article catalogs the areas of progress and areas for further research. Data Sources Through our personal experiences in caring for patients with FPIES, our personal research, and a review of the existing FPIES literature as indexed in PubMed, we explored what is known and what is needed in FPIES. Study Selections The studies that have improved the knowledge of FPIES, defined phenotypes, allowed for better-informed management of FPIES, and laid the groundwork for further research. Results Further research is needed in the areas of prevalence, natural history, trigger foods, threshold doses, how and when to perform oral food challenges, and immunopathogenesis of this disorder. Development of a biomarker and determination of the best method to treat reactions is also needed. Furthermore, FPIES has a substantial psychosocial and economic impact on families, and more research is needed in developing and implementing ameliorating strategies. Conclusion By partnering together, health care providers, advocacy organizations, and families can continue to advance our understanding and improve the care of patients and families living with FPIES.

Objective Food protein-induced enterocolitis syndrome (FPIES) is typically diagnosed based on a characteristic clinical history; however, an oral food challenge (OFC) may be necessary to confirm the diagnosis or evaluate for the development of tolerance. FPIES OFC methods vary globally, and there is no universally agreed upon protocol. The objective of this review is to summarize reported FPIES OFC approaches and consider unmet needs in diagnosing and managing FPIES. Data Sources PubMed database was searched using the keywords food protein-induced enterocolitis syndrome, oral food challenge, cow milk allergy, food allergy, non-immunoglobulin E–mediated food allergy and FPIES. Study Selections Primary and review articles were selected based on relevance to the diagnosis of FPIES and the FPIES OFC. Results We reviewed the history of FPIES and the evolution and variations in the FPIES OFC. A summary of current literature suggests that most patients with FPIES will react with 25% to 33% of a standard serving of the challenged food, there is little benefit to offering a divided dose challenge unless there is suspicion of specific immunoglobulin E to the food being challenged, reactions typically appear within 1 to 4 hours of ingestion, and reactions during OFC rarely result in emergency department or intensive care unit admission. Conclusion International standardization in the FPIES OFC approach is necessary with particular attention to specific dose administration across challenged foods, timing between the patient’s reaction and offered OFC to verify tolerance, patient safety considerations before the OFC, and identification of characteristics that would indicate home reintroduction is appropriate.

Objective This review provides an overview of our current understanding of the mechanisms of food protein–induced enterocolitis syndrome (FPIES). Data Sources To capture recent articles published since our previous comprehensive review on the pathophysiology of FPIES, we performed a literature search through PubMed database, using the search terms FPIES and food protein–induced enterocolitis syndrome from 2016 to the current year. Study Selections Studies in English containing biomarker or immune data were reviewed and summarized. Results Studies of peripheral blood fail to exhibit evidence of antigen-specific humoral or cellular immunity underlying clinical reactivity to foods in FPIES. However, growing evidence suggests a robust systemic innate immune activation occurring during FPIES reactions and the activation of neuroendocrine pathways. Conclusion FPIES reactions are associated with marked activation of innate immune and neuroendocrine pathways; however, the mechanism underlying the specific recognition of foods remains elusive.

Objective Food protein-induced enterocolitis syndrome (FPIES) is a condition with heterogeneous features (ie, age at presentation, severity, food triggers, comorbidities) and is not as rare as initially believed. In the last few years, the first population-based epidemiologic study, few prospective birth cohort evaluating FPIES prevalence, and several larger (>100 patients) studies have been published, making epidemiologic estimation more reliable. In this review, we report on the available data on the epidemiology of FPIES. Data Sources PubMed review using the following words: FPIES, epidemiology, and prevalence. Study Selections The review focused on the population-based epidemiologic study, few prospective birth cohort evaluating FPIES prevalence, and several larger (>100 patients) studies. Results We identified 8 population or cohort studies. Conclusion FPIES is not rare in both children and adults and may affect as many as 900,000 people in the United States alone. Most children and adult with FPIES seem to react to 1 to 2 foods; however, they may need further diet restriction owing to high level of comorbidity with immunoglobulin E–mediated food allergies and eosinophilic esophagitis. Globally, cow's milk, rice/oat, and seafood seem to be the most common triggers.

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.

Background: Food protein‐induced enterocolitis syndrome (FPIES) is a non-immunoglobulin E mediated food allergy that typically presents with repetitive emesis and may be associated with lethargy, marked pallor, hypotension, hypothermia, and/or diarrhea. Although many foods are known to cause FPIES, peanut-triggered FPIES is emerging due to changes in the feeding practice guidelines, which recommends early peanut introduction in infants. Objective: We aimed to characterize peanut-triggered acute FPIES cases in our pediatric population and to describe their attributes, treatment, and outcomes. We hypothesized that increases in the incidence of peanut-triggered FPIES coincided with implementation of the guidelines for early peanut introduction. Methods: A retrospective chart review was conducted of pediatric patients who presented to Phoenix Children’s Hospital Emergency Department and subspecialty clinics during a 6-year period (January 2013 to September 2019). Results: Thirty-three cases of patients with acute FPIES were identified, five of which were peanut triggered. In those patients with peanut-triggered FPIES, the median age for peanut introduction was 7 months (range, 5‐24 months). Two patients had positive peanut skin-prick test results. All five cases were identified in the past 2 years (2018 to 2019). No peanut-triggered reactions were documented in the preceding 4-year period (2013 to 2017). Conclusion: Peanut may be an emerging trigger of acute FPIES, coinciding with an earlier introduction of peanut in the infant diet after implementation of the new addendum guidelines for the prevention of peanut allergy. Oats and rice were the most common triggers of acute FPIES in our cohort. Further study will help clarify the significance and reproducibility of these findings.

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.

BACKGROUND Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy causing severe acute gastrointestinal symptoms and lethargy, mainly affecting infants and young children. There are geographic variations in its clinical features. This study aimed to describe the clinical characteristics and management of FPIES in Swedish children. METHODS The study included children who presented with acute FPIES during 2008-2017. All Swedish pediatric departments (n = 32) were invited to report their known patients. Data were collected through chart reviews and interviews with parents. RESULTS Eighteen pediatric departments contributed, and 113 patients were included. Most had a family history of atopy (74%), and 51% had an atopic disease. Common trigger foods were cow's milk (26%), fish (25%), oat (22%), and rice (8%). Most patients (85%) reacted to a single food. The median age at first reaction was 3.9 months for cow's milk and 6.0 months for other foods (p

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy characterized by gastrointestinal symptoms, mainly protracted and delayed vomiting. Diagnosis is based on clinical history, and it can be challenging as symptoms are delayed and the causative food is often not very suspicious. Objective: This case report highlights the importance of having a high degree of suspicion to reach a correct diagnosis. Materials and methods: We report an unusual case of FPIES due to zucchini. During the follow-up. Two oral food challenges (OFC) were carried out to evaluate tolerance to the food involved. Results: The first OFC was positive and in the second the child tolerated the food without problems. Conclusions: In this case, the OFC was essential to identify the offending food and to verify that the child had overcome the disease.

Cow’s milk allergy is a common food allergy among infants. Symptoms of cow’s milk allergy are wide-ranging and depend on the mechanism involved. There are immunoglobulin E (IgE)-mediated, non–IgE-mediated, and mixed mechanisms of food allergy. Symptoms of IgE-mediated cow’s milk allergy may be mild or may progress to anaphylaxis, which can be life-threatening. Non–IgE-mediated allergy includes food protein–induced allergic proctocolitis (FPIAP), food protein–induced enterocolitis syndrome, food protein–induced enteropathy, and Heiner syndrome (pulmonary hemosiderosis). These diagnoses comprise about half of all cow’s milk allergies. The most common manifestation of cow’s milk allergy in infants is FPIAP. FPIAP is commonly seen in healthy, full-term infants who present with rectal bleeding and are otherwise well-appearing. This can occur in both formula-fed and exclusively breastfed infants. Food proteins secreted in maternal breast milk can contribute to the development of these symptoms. Maternal cow’s milk elimination diet is often successful in helping resolve symptoms. A period of reintroduction of cow’s milk resulting in re-emergence of symptoms in stable asymptomatic infants is an excellent diagnostic tool to confirm a cow’s milk allergy. Preterm infants are susceptible to food allergy, as demonstrated from several case reports of necrotizing enterocolitis–like illnesses that responded clinically to cow’s milk elimination. Further study is needed about food allergy in the preterm infant population.

Food protein-induced enterocolitis syndrome is still a mysterious disease, pathogenically poorly characterized, although the first FPIES case has been described in 1967. Mainly, food protein-induced enterocolitis syndrome diagnosis is based on clinical history. The oral food challenge remains the gold standard to confirm the diagnosis, especially in particular situations. Although there are no diagnostic laboratory or imaging tests which are specific for diagnosis, they could, however, sometimes be helpful to rule out clinical conditions which are similar to food protein-induced enterocolitis syndrome reactions. The purpose of this review is to define the clinical features of FPIES and to summarize the current available tools for the diagnosis of FPIES. This review is intended to be a practical guide for the clinician facing a patient with food protein-induced enterocolitis syndrome avoiding delayed diagnosis with unnecessary laboratory tests and detrimental treatments. Moreover, it highlights the unmet needs in diagnosis that require urgent attention from the scientific community to improve the management of patients with FPIES.

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.

Background: Post-emetic elevation in thymus and activation-regulated chemokine (TARC) levels has been reported in patients with food protein-induced enterocolitis syndrome (FPIES); however, no studies have investigated differences in TARC levels between FPIES and other diseases. Objectives: We evaluated the clinical usefulness of TARC measurement in differentiating between FPIES and infectious gastroenteritis. Methods: This study included 8 patients with solid-food FPIES (FPIES group; hen’s egg [n = 6], rice [n = 1], and short-neck clam [n = 1]; a total of 11 episodes necessitating emergency department visit or positive result of oral food challenge test) and 17 patients with infectious gastroenteritis (control group), and all patients had no eczema. Post-emetic serum TARC levels and modified TARC levels (serum TARC value – normal mean for each age) were compared between the 2 groups. Results: The median (range) ages for the FPIES and control groups were 0.7 (0.5–6.2) and 1.8 (0.1–4.4) years, respectively (p > 0.05). In the FPIES and control groups, median (range) TARC levels were 2,911 (1,062–7,816) and 600 (277–2,034) pg/mL, and median (range) modified TARC levels were 2,204 (355–7,109) and 129 (0–1,314), respectively. The TARC and modified TARC levels were significantly higher in the FPIES group than in the control group (p < 0.001 for both). Conclusion: In the absence of eczema, post-emetic serum TARC levels might be a potential diagnostic biomarker for distinguishing FPIES from infectious gastroenteritis.

Food protein‐induced enterocolitis syndrome (FPIES) is a non‐IgE-mediated food allergy that primarily affects the gastrointestinal tract. The underlying pathophysiology of FPIES has yet to be fully elucidated; however, FPIES is believed to be secondary to intestinal inflammation after exposure to a food antigen, which thereby leads to increased permeability and fluid shifting into the intestinal lumen. FPIES is categorized into acute and chronic forms. Acute FPIES is characterized by repetitive vomiting that occurs 1‐4 hours after food ingestion. Severe vomiting may progress to dehydration, lethargy, and pallor, which potentially leads to hypovolemic shock. In some patients, diarrhea may present within 24-hours of food ingestion. Patients are clinically well between acute episodes. Chronic FPIES presents with intermittent vomiting and/or diarrhea, followed by failure to thrive. FPIES characteristically presents in infancy, with resolution of the disease typically occurring by school age. However, analysis of recent data indicates that FPIES may persist into adulthood. In addition, late- or adult-onset FPIES has also been reported. The diagnosis of FPIES is based on clinical history; however, oral food challenge currently remains the criterion standard for diagnosis. Management of FPIES requires strict avoidance of food triggers, and treatment requires rapid fluid rehydration. Currently, there are no reliable biomarkers to diagnose FPIES; however, investigations to better understand the role of the innate immune system have been promising. Future studies are needed to better understand the true prevalence and pathophysiology of FPIES.

Introduction: Food protein-induced enterocolitis syndrome (FPIES) is a gastrointestinal syndrome due to a non-IgE mediated food hypersensitivity. The most common triggers are cow's milk and soy. Fish is one of the most frequently reported causes in Spain.The objective of this study is to describe the clinical characteristics of patients diagnosed with (FPIES) in a paediatric allergy clinic. Material and methods: A retrospective descriptive study was carried out by reviewing medical records of patients diagnosed with FPIES in the Paediatric Allergy Unit of the Miguel Servet Children's Hospital from the years 2007 to 2017. Results: A total of 135 patients were diagnosed during the study period, of whom 45% were male and 55% were female. The mean age at diagnosis was 11 ± 1.5 months and the mean age of improvement was 2 years and 6 months ± 2.5 years (n = 83). A personal history of atopy was observed in 31.9%. The main trigger foods were: white fish (41.4%), cow's milk (25.1%), and egg (15.5%). A conversion to IgE-mediated allergy was seen in 4.4% of patients.There was vomiting in 81.5% of the cases, with a mean of 1.75 ± 1.1 h of latency, as well as diarrhoea in 41.5%, with a mean of 7.86 ± 15.16 h of latency, and decline in 30.4% with a mean latency of 3.81 ± 11.57 h. Discussion: In our series, the most frequent trigger of the FPIES was fish. It was manifested mainly by late vomiting and a tolerance was reached mostly at 2 years 6 months. Resumen: Introducción: La enterocolitis inducida por proteínas de la dieta, o también conocida como food protein-induced enterocolitis syndrome (FPIES), es un síndrome gastrointestinal de hipersensibilidad alimentaria no mediada por IgE. Los desencadenantes más comunes son la leche de vaca y de soja. El pescado es una de las causas reportadas con más frecuencia en España.El objetivo de esta investigación es describir las características clínicas de los pacientes diagnosticados de FPIES en nuestra consulta de alergología pediátrica. Material y métodos: Estudio descriptivo retrospectivo, realizado mediante revisión de historias clínicas de los pacientes diagnosticados con FPIES en la Unidad de Alergología Pediátrica del Hospital Infantil Miguel Servet desde 2007 a 2017. Resultados: Desde enero de 2007 hasta diciembre de 2017 fueron diagnosticados 135 pacientes: 45% hombres y 55% mujeres. La edad media al diagnóstico fue de 11 ± 1,5 meses y la edad media de superación 2 años y 6 meses ± 2,5 años (n = 83). Un 31,9% presentó antecedentes personales de atopia. Los principales alimentos desencadenantes fueron: pescado blanco (41,4%), leche de vaca (25,1%) y huevo (15,5%). Un 4,4% presentó conversión a alergia IgE mediada.El 81,5% de los casos presentó vómitos, con una media de 1,75 ± 1,1 horas de latencia; diarreas en un 41,5%, con una media de 7,86 ± 15,16 horas de latencia; decaimiento en el 30,4% con una media de 3,81 ± 11,57 horas de latencia. Discusión: En nuestra serie el desencadenante más frecuente fue el pescado. Se manifestó principalmente por vómitos tardíos, y alcanzó una tolerancia en su mayoría hacia los 2 años 6 meses.

Purpose of review First described in the mid 20th century, it was just in the last decade that diagnostic and treatment guidelines for food protein-induced enterocolitis syndrome (FPIES) were established. Awareness of the diagnosis is improving, and epidemiologic data are emerging. Recent findings Recent studies suggest that FPIES may affect as many as 0.5% of children worldwide. FPIES in adults is usually triggered by seafood and may be more common than previously thought. Many patients with FPIES have other allergic disorders. Summary With refined diagnostic criteria and improved awareness, FPIES is now diagnosed with increasing frequency, and epidemiologic data are emerging. FPIES appears to be increasing in prevalence, and the frequent association with other allergic disorders suggests a shared predisposition or immune mechanism that remains to be elucidated.

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy that manifests with projectile, repetitive emesis that can be followed by diarrhea and may be accompanied by lethargy, hypotonia, hypothermia, hypotension, and metabolic derangements. FPIES usually starts in infancy although onset at older ages is being increasingly recognized. FPIES is not rare, with the cumulative incidence of FPIES in infants estimated to be 0.015% to 0.7%, whereas the population prevalence in the US infants was 0.51%. FPIES diagnosis is challenging and might be missed because of later (1-4 hours) onset of symptoms after food ingestion, lack of typical allergic skin and respiratory symptoms, and food triggers that are perceived to be hypoallergenic. Diagnosis is based on the recognition of symptoms because there are no biomarkers of FPIES. The pathophysiology remains obscure although activation of the innate immune compartment has been detected. Management relies of avoidance of food triggers, treatment of accidental exposures, and periodic re-evaluations with supervised oral food challenges to monitor for resolution. There are no strategies to accelerate development of tolerance in FPIES. Here we review the most important current concepts in epidemiology, pathophysiology, diagnosis, and management of FPIES.

Food protein induced enterocolitis syndrome (FPIES) can present with diarrhea, hypovolemia and electrolyte imbalance in infancy. We present a case of life-threatening methemoglobinemia in a 1-month-old infant, a rare complication of FPIES triggered by cow ’s milk protein intake. A previously healthy 1-month-old boy presented with lethargy, increased work of breathing and 2-day history of vomiting. Review of systems revealed a 3-week history of diarrhea. He was lethargic, shocky and dusky, and was intubated for persistent hypoxia. His blood work revealed severe acidemia with pH of 6.95 and methemoglobin level of 66% (normal range < 3%). His methemoglobin level and clinical status normalized following volume resuscitation, packed red blood cell transfusion and prompt intravenous methylene blue administration. Further investigations revealed a diagnosis of FPIES which was managed with a hypoallergenic formula. Methemoglobinemia should be considered in young infants presenting with severe vomiting and diarrhea, secondary to dietary protein intolerance syndromes. Prompt management with methylene blue and fluid resuscitation can result in excellent prognosis, along with specific ongoing management for FPIES. Int J Clin Pediatr. 2020;9(2):35-40 doi: https://doi.org/10.14740/ijcp366

As the incidence of cow ’s milk protein allergy (CMPA) has increased in the last decades in both breastfed and formula fed infants, possible pitfalls in its diagnosis and management are also increasing. This is especially evident in non-IgE milk allergy due to the considerable delay between the appearance of clinical symptoms after ingestion of the allergen, and the non-specific gastrointestinal symptoms that characterize it. The misdiagnosis could often be combined with inappropriate use of either partially hydrolyzed or amino acid-based infant formula for the management of symptoms. The aim of the paper is to present two cases to illustrate common pitfalls in diagnosis and management of CMPA with divergent gastrointestinal syndrome manifestations: food protein-induced allergic proctocolitis and food protein-induced enterocolitis syndrome, in an effort to increase awareness of these conditions and to guide clinicians in day-to-day practice when facing suspected cases of CMPA. Int J Clin Pediatr. 2020;9(3):98-102 doi: https://doi.org/10.14740/ijcp375

Breastfeeding is currently recommended as the optimal source of nutrition to infants. However, there are several studies that have shown clinical IgE- and non-IgE-mediated reactions to foods in exclusively breastfeeding infants, specifically to cow's milk, egg, peanut, and fish. Literature suggests that antigenic food proteins present in human milk can be found in substantial enough amounts to elicit clinical reactions in some, already-sensitized infants, including anaphylaxis, eczema exacerbation, and non-IgE-mediated gastrointestinal food-allergic syndromes. Diagnosis of food allergy in a breastfed infant and identification of the trigger foods in the mother's diet can be especially challenging in infants with delayed symptoms, such as eczema and gastrointestinal symptoms. Management is further complicated in infants with atopic dermatitis, who have increased caloric needs and therefore in whom nutrition is an extremely important factor for growth and development. One needs to balance possible benefits with risks of further food sensitization through the skin when foods are eliminated from their diets. We review here the literature on clinical presentation and evidence for food allergy in exclusively breastfed infants, including the presence of food antigens in human milk. Incorporating clinical experience and the available data, which largely come from case reports and small, nonrandomized studies performed in referral centers with several limitations, we propose a novel algorithm to diagnosis and management, with emphasis on nutritional considerations.

Background Food Protein-Induced Enterocolitis Syndrome (FPIES) is a non-IgE mediated food allergy most commonly presenting in infants. The most common food triggers include soy, cow’s milk and grains. Symptoms may include intractable vomiting, diarrhea, lethargy, pallor, abdominal distention, hypotension and/or shock. Oral food challenges (OFCs) given at food protein dose of 0.06–0.6 g/kg in 3 equivalent doses administered over a few hours are recommended in guidelines to confirm a diagnosis. Case presentation The patient is a 6-month-old girl with a history of severe FPIES symptoms to egg. In our clinic, we perform OFC with 1/100 serving dose on visit 1 and then increase the dose monthly. The patient takes the tolerated dose daily at home between visits. An OFC to baked egg at 1/100 of a serving was performed and was well-tolerated on her initial visit. The patient remained on the same dose upon returning home. Within 1-week, she developed FPIES symptoms including watery diarrhea and severe emesis requiring ondansetron. She required an Emergency Department visit for one of the reactions. Conclusions Our patient had severe FPIES symptoms with a small amount of egg. We believe that administration of three large food challenge doses on one clinic visit, as guidelines currently suggest, does not allow adequate time for symptoms to appear. Our patient likely would have suffered a severe reaction. Also, this guidelines protocol does not allow for monitoring of more delayed or chronic FPIES. We propose a modified protocol to OFCs with cautious up-dosing to allow for safer OFCs and monitoring of chronic FPIES. We have implemented an OFC approach where only one food challenge dose (starting with 1/100 of final dose) is given at each visit. The up-titration of the dose is completed every 4-weeks with one dose only. When the serving sized dose is reached and tolerated, the food can be maintained in the diet.

The prevalence of allergy is increasing across the world, and asthma is the most common chronic disease in children. Exclusive breastfeeding does decrease the occurrence of eczema in the first 2 years of life, and a longer duration of breastfeeding decreases wheezing in the first 2 years of life. A longer duration of breastfeeding protects against asthma even up to 5 years of age. Food allergies in breastfeeding infants do occur, although the exact timing and mechanism(s) of sensitization are poorly understood. Maternal elimination diets in pregnancy and/or lactation do not prevent atopic disease, but infant avoidance of foods and maternal elimination diet may be useful in infants with diagnosed food allergies and specifically food protein induced enterocolitis syndrome. An expert panel of the American Academy of Pediatrics now recommends early introduction (4 to 6 months of age) of infant-safe forms of peanuts to decrease the risk for peanut allergy in at-risk infants.

Down syndrome (DS) is one of the most common chromosomal anomalies. Gastrointestinal disorders in DS are predominantly related to anatomical anomalies and celiac disease. In 2015, the first two cases of non-IgE-mediated food allergy in patients with DS were described. However, gastrointestinal symptoms experienced by subjects with DS have never been related to a possible non-IgE-mediated food allergy and a Food Protein-induced Enterocolitis syndrome (FPIES). A retrospective descriptive single-center study was conducted. Subjects included were children with acute FPIES who entered our institutional follow-up protocol between January 2013 and January 2020. Among the 85 patients (forty-nine boys—57.6%), ten (11.76%) were children with DS. In our population, the FPIES triggers included different foods (such as milk, egg, fruit, fish, wheat, soy, beef, etc.). Nine patients with DS showed FPIES reactions after ingesting cow’s milk (one even with beef and three with soy), while the last one was affected by FPIES to fish. Considering the subgroup of patients affected by cow’s milk FPIES (40 subjects overall), 22.5% had a diagnosis of DS. Patients with DS experienced acute FPIES reactions with a severity degree slightly higher than that reported in other patients, ranging from mild-moderate to severe or very severe. During the acute reactions, the patients with DS showed increased white blood cell production, absolute neutrophil count and C-reactive protein levels. This series provides a starting point for novel hypothesis-testing clinical research and possible specific immunological alterations in FPIES children with or without DS.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) in adults is being increasingly recognized; however, little is known about its characteristics. OBJECTIVE: To describe the clinical characteristics, prognosis, and associated factors in adult FPIES. METHODS: A 10-year prospective study was conducted in the Allergy Section of Alicante General Hospital in adults diagnosed with FPIES. Detailed interviews with patients and oral food challenges (OFCs) were performed to confirm diagnosis or evaluate for tolerance. Comorbidities and possible risk factors were analyzed retrospectively through electronical medical records to assess their association with the disease. RESULTS: One hundred and seven adults with FPIES (93.5% female) were followed for a median of 6.2 years. Abdominal pain was the most common manifestation (96.3%), followed by diarrhea (72%) and vomiting (60.7%). Seafood (59.8%), egg (14%), and milk (10.3%) were the most common triggers, while 43.9% reacted to more than one food group. We performed 49 OFCs: 9 to confirm diagnosis and 40 to evaluate for tolerance. After a median 3.5 years, 16.8% achieved tolerance. Resolution was correlated inversely with duration of the disease (p=0.04) and seafood (p=0.023) but not with age of onset. The prevalence of gastrointestinal pathologies like irritable bowel syndrome (IBS), eosinophilic esophagitis, inflammatory bowel disease and celiac disease was higher than in the general population. A higher number of FPIES triggers was correlated with also having a diagnosis of IBS (p=0.02). CONCLUSIONS: Although adult FPIES normally persists, some patients achieve tolerance. Adults with FPIES have a relatively high prevalence of gastrointestinal pathologies. The predominance of women may be related to hormonal factors. The clinical differences with pediatric FPIES warrant a revision of diagnostic criteria in adults.

Non-IgE-mediated food allergies are a group of disorders characterized by subacute or chronic inflammatory processes in the gut. Unlike IgE mediated food allergies that may result in multi-organ system anaphylaxis, the non-IgE mediated food allergies primarily affect the gastrointestinal tract. This review outlines the clinical manifestations, epidemiology, pathophysiology, and management of non-IgE-mediated food allergies. An updated literature search of selected non-IgE-mediated food allergies was conducted for this review using PubMed database to the current year (2021). Reviewed disorders include food protein-induced enterocolitis syndrome (FPIES), food-protein enteropathy (FPE), food protein-induced allergic proctocolitis (FPIAP), and eosinophilic gastrointestinal disorders (EGIDs) such as eosinophilic esophagitis (EoE). While extensive gains have been made in understanding FPIES, FPIAP, FPE, and EoE, more information is needed on the pathophysiology of these food allergies. Similarities among them include involvement of innate immunity, T-lymphocyte processes, alteration of the intestinal lumen at the cellular level with the appearance of inflammatory cells and associated histologic changes, and specific cytokine profiles suggesting food-specific, T-cell, and immune-mediated responses. While FPIES and FPIAP typically resolve in early childhood, EGIDs typically do not. Emerging new therapies for EoE offer promise of additional treatment options. Further studies identifying the immunopathogenesis, associated biomarkers, and mechanisms of tolerance are needed to inform prevention, diagnosis and management.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a frequently misdiagnosed, serious, non-IgE mediated food allergy, and the precise mechanism of disease is unknown. Acute FPIES typically presents with repetitive, profuse vomiting approximately 1-4 hours post ingestion of a food trigger. Chronic FPIES is considered less common and less well characterized. OBJECTIVE: We aimed to better describe FPIES and identify factors that may influence FPIES development through use of a self-reported, caregiver’s survey. METHODS: FPIES and allergy-free infant caregivers completed a survey regarding lifestyle factors that may influence allergy acquisition such as: antibiotic usage and delivery mode. FPIES caregivers reported symptoms, number of food triggers, type of FPIES, and symptoms from breastmilk ingestion. FPIES infants were compared to allergy-free infants to identify factors potentially associated with FPIES. RESULTS: Infant and prenatal maternal antibiotic usage was higher in FPIES infants compared to allergy-free infants (43.8% vs 20.6% and 48.8% vs 23.57%, respectively, p< 0.05). When compared to infants with ACUTE FPIES alone, infants described as BOTH acute and chronic FPIES reported earlier onset of symptoms, more non-specific symptoms and symptoms triggered by breast milk, more antibiotic exposure, and more food triggers (p< 0.05). CONCLUSION. Antibiotic usage was significantly higher in FPIES infants when compared to allergy-free infants. Work is needed to elucidate the role of antibiotic usage in the etiology of FPIES. Infants reported to have BOTH acute and chronic FPIES were significantly different from infants with ACUTE FPIES alone highlighting the need to more closely examine these different subtypes of FPIES.

Characteristics of chronic milk-dependent food protein-induced enterocolitis syndrome (FPIES) in children from the region of Western Pomerania were studied. Prospectively, 55 children were diagnosed at a median of 2.2 months. The open food challenges (OFC), morphologies, milk-specific IgE (sIgE) (FEIA method, CAP system), and skin prick tests (SPTs) were examined. Vomiting and diarrhea escalated gradually but quickly led to growth retardation. Of the infants, 49% had BMI &lt, 10 c, 20% BMI &lt, 3 c, 25% had anemia, and 15% had hypoalbuminemia. During the OFCs we observed acute symptoms that appeared after 2–3 h: vomiting diarrhea and pallor. A total of 42% children required intravenous hydration. Casein hydrolysates or amino acids formulae (20%) were used in treatment. In 25% of children, SPT and milk sIgE were found, in 18%—other food SPTs, and in 14% allergy to other foods. A transition to IgE-dependent milk allergy was seen in 3 children. In the twelfth month of life, 62% of children had tolerance to milk, and in the twenty-fifth month—87%. Conclusions. Chronic milk-dependent FPIES resolves in most children. By the age of 2 children are at risk of multiple food sensitization, and those who have milk sIgE are at risk to transition to IgE-mediated milk allergy. Every OFC needs to be supervised due to possible severe reactions.

Non-IgE-mediated gastrointestinal food allergy (non-IgE-GI-FA) is the name given to a series of pathologies whose main entities are food protein-induced allergic proctocolitis (FPIAP), food protein-induced enteropathy (FPE), and food protein-induced enterocolitis syndrome (FPIES). These are more uncommon than IgE-mediated food allergies, their mechanisms remain largely unknown, and their diagnosis is mainly done by clinical history, due to the lack of specific biomarkers. In this review, we present the latest advances found in the literature about clinical aspects, the current diagnosis, and treatment options of non-IgE-GI-FAs. We discuss the use of animal models, the analysis of gut microbiota, omics techniques, and fecal proteins with a focus on understanding the pathophysiological mechanisms of these pathologies and obtaining possible diagnostic and/or prognostic biomarkers. Finally, we discuss the unmet needs that researchers should tackle to advance in the knowledge of these barely explored pathologies.

Food-protein-induced enterocolitis syndrome (FPIES)was notrecognized as a specific disorder until the 1970s(1). While the European Academy of Allergy and Clinical Immunology (EAACI) Guidelines addressed FPIES in 2014(2),it was only in 2017 that the first international consensus guidelines foritsdiagnosis and treatment werepublished (3). Acute FPIES usually presents with repetitive vomiting, diarrhea associated with pallor, lethargy, dehydration, hypotension and even shock in most severe cases.

This study aimed to investigate the clinical characteristics of severe food protein-induced enterocolitis syndrome (FPIES) in patients with Down syndrome. We report the cases of three infants with Down syndrome who were diagnosed with FPIES. All patients presented with hypovolemic shock, metabolic acidosis, and acute kidney injury after introducing a milk-based formula. They required aggressive fluid resuscitation and alternative nutrition. All three patients survived without any complications after the treatment. FPIES may cause hypovolemic shock in infants with Down syndrome and these patients need prompt fluid resuscitation.