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Objective: Acute food protein-induced enterocolitis syndrome (FPIES) is characterized by delayed repetitive vomiting after ingestion of a trigger food, and severe reactions may lead to dehydration, hypotension, and shock. We provide recommendations on management of FPIES emergencies in a medical facility and at home., Data Sources: This review summarizes the literature on clinical context, pathophysiology, presentation, and treatment of FPIES emergencies., Study Selections: We referred to the 2017 International Consensus Guidelines for the Diagnosis and Management of FPIES and performed a literature search identifying relevant recent primary articles and review articles on clinical management., Results: Management of FPIES emergencies in a medical facility is based on severity of symptoms and involves rehydration, ondansetron, and corticosteroids. A proactive approach for reactions occurring at home involves prescribing oral ondansetron and providing an individualized treatment plan based on the evolution of symptoms and severity of past reactions. A better understanding of the pathophysiology of FPIES and randomized trials on ondansedron and cocorticosteroid use could lead to more targeted treatments., Conclusion: Children with FPIES are at risk for severe symptoms constituting a medical emergency. Management of FPIES emergencies is largely supportive, with treatment tailored to the symptoms, severity of the patient's condition, location of reaction, and reaction history., (Copyright © 2021. Published by Elsevier Inc.)

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy., Objective: To better understand provider-level variation in FPIES knowledge and management., Methods: A 23-question online survey was administered to AAAAI members during the spring and summer of 2014., Results: Among 470 respondents, 64% reported "full understanding" of FPIES diagnosis/management; 78.8% reported managing 1 or more patient with FPIES; and 80.4% correctly identified an FPIES case vignette. FPIES was correctly differentiated from infantile colic or food protein-induced allergic proctocolitis by 82.5% and 71.3%, respectively. Among providers currently managing patients with FPIES, 47.5% indicated soy formula, 73.8% breast milk, and 94.5% elemental formula as appropriate substitutes in cow milk (CM)-FPIES. Skin testing is performed by 73.4%; 62.2% obtain serum food-specific IgE testing, 12.7% patch testing, 36.8% oral challenge, and 28% perform no tests. Eighty-four percent provide patients with FPIES with allergy action plans, 72.8% provide a personalized action plan, and 21% prescribe epinephrine autoinjectors. Odds of prescribing epinephrine were lower among those reporting "full understanding" of FPIES (odds ratio [OR], 0.41; 95% CI, 0.21-0.79). Academic providers had higher odds of providing an action plan (OR, 2.4; 95% CI, 1.17-4.98) and performing diagnostic oral food challenge (OR, 1.99; 95% CI, 1.99-3.25), but not of correct vignette differentiation of FPIES from other conditions, correct identification of appropriate CM-FPIES substitutes, or timing for food reintroduction. More years in practice were associated with lower odds of reporting full understanding of FPIES diagnosis/management (OR, 0.96; 95% CI, 0.94-0.99)., Conclusions: Nearly one-third of respondents reported poor familiarity with FPIES. Considerable variation exists in the use of diagnostic tests, management, and choice of "safe" nutrition, indicating a strong need for FPIES practice guidelines., (Copyright © 2017. Published by Elsevier Inc.)

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy of infancy whose pathophysiology is poorly understood., Objectives: We set out to identify and phenotype allergen-responsive cells in peripheral blood of a cohort of subjects undergoing supervised food challenge for FPIES., Methods: We profiled antigen-responsive cells in PBMCs by flow cytometry, and examined cells in whole blood obtained before and after challenge by CyTOF mass cytometry and RNAseq., Results: Using a CD154-based detection approach, we observed that milk, soy, or rice-responsive T cells, and TNF-α-producing CD154 + T cells, were significantly lower in those with outgrown FPIES compared with those with active FPIES. However, levels were within the normal range and were inconsistent with a role in the pathophysiology of FPIES. Profiling of whole blood by CyTOF demonstrated profound activation of cells of the innate immune system after food challenge, including monocytes, neutrophils, natural killer cells, and eosinophils. Activation was not observed in children with outgrown FPIES. We confirmed this pattern of innate immune activation in a larger cohort by RNAseq. Furthermore, we observed pan-T-cell activation and redistribution from the circulation after a positive food challenge but not in those who had outgrown their FPIES., Conclusions: Our data demonstrate a compelling role of systemic innate immune activation in adverse reactions elicited by foods in FPIES. Further investigation is needed to identify the mechanism of antigen specificity of adverse reactions to foods in FPIES., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Food protein-induced enterocolitis (FPIES) is a non-IgE cell- mediated food allergy that can be severe and lead to shock. Despite the potential seriousness of reactions, awareness of FPIES is low; high-quality studies providing insight into the pathophysiology, diagnosis, and management are lacking; and clinical outcomes are poorly established. This consensus document is the result of work done by an international workgroup convened through the Adverse Reactions to Foods Committee of the American Academy of Allergy, Asthma & Immunology and the International FPIES Association advocacy group. These are the first international evidence-based guidelines to improve the diagnosis and management of patients with FPIES. Research on prevalence, pathophysiology, diagnostic markers, and future treatments is necessary to improve the care of patients with FPIES. These guidelines will be updated periodically as more evidence becomes available., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Non-IgE-mediated gastrointestinal food allergic disorders (non-IgE-GI-FA) including food protein-induced enterocolitis syndrome (FPIES), food protein-induced enteropathy (FPE), and food protein-induced allergic proctocolitis (FPIAP) are relatively uncommon in infants and young children, but are likely under-diagnosed. Non-IgE-GI-FA have a favorable prognosis, with majority resolving by age 3-5 years. Diagnosis relies on the recognition of symptoms pattern in FPIAP and FPIES and biopsy in FPE. Further studies are needed for a better understanding of the pathomechanism, which will lead eventually to the development of diagnostic tests and treatments. Limited evidence supports the role of food allergens in subsets of constipation, gastroesophageal reflux disease, irritable bowel syndrome, and colic. The immunologic pathomechanism is not fully understood and empiric prolonged avoidance of food allergens should be limited to minimize nutrient deficiency and feeding disorders/food aversions in infants., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy manifesting within 1 to 4 hours of food ingestion with repetitive emesis and lethargy., Objective: We sought to characterize immune responses to casein in children with FPIES caused by cow's milk (CM)., Methods: Total IgE and IgM, CM-specific IgG, and casein-specific IgE, IgG, IgG 4 , and IgM levels, as well as immunoglobulin free light chains, were measured in both patients with active and those with resolved CM-FPIES. Proliferating casein/T-effector cell counts were measured in children with CM-FPIES, children with IgE-mediated CM allergy, and those tolerating CM. Cytokine concentrations in the supernatants were quantified. Serum cytokine and tryptase levels were measured before and after a positive oral food challenge (OFC) result and compared with levels in those with a negative OFC result., Results: We found low levels of CM and casein-specific IgG and casein-specific IgG 4 in patients with CM-FPIES versus those tolerating CM (P < .05). Although we found both a high CD4 + T cell-proliferative response and T H 2 cytokines production after casein stimulation in children with CM-FPIES, results were similar to those in control subjects. Significantly lower secretion of IL-10 and higher secretion of IL-9 by casein-stimulated T cells were found in patients with CM-FPIES versus those with IgE-mediated CM allergy. Lower baseline serum levels of IL-10 and higher tryptase levels were found in active CM-FPIES versus resolved CM-FPIES. We found a significant increase in serum IL-10 and IL-8 levels after a positive OFC result., Conclusions: We confirm the paucity of humoral response in patients with CM-FPIES. IL-10 might play a key role in acquisition of tolerance in patients with CM-FPIES. Increased serum IL-8 levels in patients with active FPIES suggest neutrophil involvement. Elevated baseline serum tryptase levels in patients with active FPIES suggest low-grade intestinal mast cell activation or increased mast cell load., (Copyright © 2016. Published by Elsevier Inc.)

Food protein-induced enterocolitis syndrome (FPIES) is a rare, non-immunoglobulin E-mediated gastrointestinal food allergy primarily diagnosed in infancy, but has also been reported in older children and adults. Acute FPIES reactions typically present with delayed, repetitive vomiting, lethargy, and pallor within 1 to 4 hours of food ingestion. Chronic FPIES typically presents with protracted vomiting and/or diarrhea, and weight loss or poor growth. Common foods triggering FPIES include cow's milk, soy, rice, oats, fish, and egg. More detailed diagnostic criteria may help in increasing awareness of FPIES and reducing delayed diagnoses or misdiagnoses., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Food protein-induced enterocolitis (FPIES), allergic proctocolitis (FPIAP), and enteropathy (FPE) are among a number of immune-mediated reactions to food that are thought to occur primarily via non-IgE-mediated pathways. All three are typically present in infancy and are triggered most commonly by cow's milk protein. The usual presenting features are vomiting with lethargy and dehydration in FPIES; bloody and mucous stools in FPIAP; and diarrhea with malabsorption and failure to thrive in FPE. Diagnosis is based on convincing history and resolution of symptoms with food avoidance; confirmatory diagnostic testing other than food challenge is lacking. The mainstay of management is avoidance of the suspected inciting food, with interval challenge to assess for resolution, which usually occurs in the first years of life. Studies published in the past few years clarify common presenting features, report additional culprit foods, address potential biomarkers, and suggest new management strategies.

Non-IgE-mediated food allergic disorders account for up to 40% of milk protein allergy in infants and young children. We aim to review the recent literature and to provide an update on diagnosis and management of food protein-induced enterocolitis syndrome (FPIES) and food protein-induced allergic proctocolitis (FPIAP). The peer-reviewed articles indexed in PubMed have been reviewed. FPIES manifests in infants as profuse, repetitive vomiting and lethargy, often with diarrhea, leading to acute dehydration, or weight loss and failure to thrive, in chronic form. FPIES is caused most commonly by cow's milk (CM) and soy proteins; rice, oat, and other solid foods may also trigger FPIES. FPIES rarely occurs in the exclusively breastfed infants. FPIES is underrecognized; children are often mismanaged as having acute viral gastrointestinal illness, sepsis, or surgical disease, delaying diagnosis of FPIES for many months. Approximately 25% of children with FPIES develop food-specific IgE antibodies and some transition to immediate food allergy; IgE positivity is associated with a more protracted course. FPIES is a self-limiting condition, with most cases resolving by age three to five years. Ondansetron may be helpful in managing acute FPIES. FPIAP is a benign condition of bloody stools in a well-appearing infant, with usual onset between one and four weeks of age. Up to 60% of cases occur in exclusively breastfed infants and resolve with maternal elimination of CM and soy proteins. The majority of cases resolve by age 12 months. FPIES may transition to IgE-mediated food allergy in some patients; IgE positivity to the FPIES food is a marker of a more persistent disease. FPIAP is benign and resolves by age 12 months in most patients.

Background: Food protein-induced enterocolitis syndrome (FPIES) is a gastrointestinal hypersensitivity disorder with a poorly understood pathophysiology and no biomarkers to aid in diagnosis., Objective: To investigate humoral and cellular responses to casein in children with milk-FPIES, including the role of casein-specific (cs) IgA and T-cell mediated TGF-β responses., Patients and Methods: Thirty-one children previously diagnosed with milk-FPIES were challenged with milk. Twelve age-matched children with FPIES to other foods and 6 milk-tolerant children without a history of FPIES were used as controls. Casein-specific IgE, IgG, IgG4, and IgA were measured in serum and TGF-β levels in supernatants of casein-stimulated PBMCs., Result: Twenty-six children with milk-FPIES reacted (active milk-FPIES) and five tolerated milk (milk-FPIES resolved) during food challenge. All of them had significantly lower levels of csIgG, csIgG4, and csIgA than control children (p-value<0.001). There were no TGF-β responses in supernatants of active milk-FPIES children., Conclusion: Children with milk-FPIES have low levels of csIgG, csIgG4, and csIgA. In particular, children with active FPIES to cow's milk have deficient T-cell mediated TGF-β responses to casein, rendering TGF-β a promising biomarker in identifying children who are likely to experience FPIES reactions to this allergen. Prospective studies are needed to validate these findings, elucidate their role in FPIES pathophysiology, and establish the diagnostic utility of TGF-β in milk-induced FPIES., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy. FPIES diagnosis is frequently delayed because of the absence of classic allergic symptoms and lack of biomarkers., Objective: We sought to characterize the clinical features and resolution of FPIES in patients evaluated in our practice., Methods: Subjects 6 months to 45 years of age with FPIES were prospectively recruited for oral food challenges (OFCs). Medical records were searched to identify the subjects who did not participate in OFCs., Results: Among 160 subjects, 54% were male; median age at diagnosis was 15 months. We performed 180 OFCs to 15 foods in 82 subjects; 30% of the study population had FPIES confirmed based on OFC results. The most common foods were cow's milk (44%), soy (41%), rice (22.5%), and oat (16%). The majority (65%) reacted to 1 food, 26% reacted to 2 foods, and 9% reacted to 3 or more foods. The majority were atopic, and 39% had IgE sensitization to another food. Thirty-nine (24%) subjects had positive specific IgE levels to the food inducing FPIES. Among children with specific IgE to cow's milk, 41% changed from a milk FPIES to an IgE-mediated phenotype over time. The median age when tolerance was established was 4.7 years for rice, 4 years for oat, and 6.7 years for soy. Median age when milk tolerance was established for subjects with undetectable milk-specific IgE levels was 5.1 years, whereas none of the subjects with detectable milk-specific IgE became tolerant to milk during the study (P = .003)., Conclusion: FPIES typically resolves by age 5 years. Milk FPIES, especially with detectable food-specific IgE, can have a protracted course and eventually transition to acute reactions., (Copyright © 2014. Published by Mosby, Inc.)

Purpose of Review: Food protein-induced enterocolitis syndrome (FPIES) is a poorly understood non-IgE-mediated food hypersensitivity, primarily affecting infants and toddlers. There are few data regarding pathophysiology of FPIES that suggest local intestinal imbalance between TNF-α and TGF-β. Patients frequently present with multiple reactions, which are characterized by projectile, repetitive emesis, dehydration, lethargy, and failure to thrive. Despite the severity of presentation, the diagnosis is frequently delayed, and patients often undergo extensive and invasive evaluation prior to reaching the diagnosis., Recent Findings: Reviews published in the last year provide a general approach to diagnosis and management of FPIES and aim to increase awareness and understanding of FPIES among general pediatricians., Summary: Multicenter studies are necessary to reevaluate and modify the oral food challenge criteria. Research on the pathophysiology of FPIES reactions is necessary to provide insight into the evidence-based approach to diagnosis and management of FPIES. Registries are needed to understand the phenotype, triggers, and prevalence of FPIES.

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal food hypersensitivity that manifests as profuse, repetitive vomiting, often with diarrhea, leading to acute dehydration and lethargy or weight loss and failure to thrive if chronic. FPIES is elicited most commonly by milk and soy proteins; however, rice, oat, and other solid foods may also elicit FPIES. Certain FPIES features overlap with food protein-induced enteropathy and proctocolitis, whereas others overlap with anaphylaxis. FPIES is not well recognized among pediatricians and emergency department physicians; the affected children are often mismanaged as having acute viral gastrointestinal illness, sepsis, or surgical disease, delaying diagnosis of FPIES for many months. The aim of this review is to provide case-driven presentation of the features of FPIES. Although randomized clinical trials on management options are missing, the relevant current literature and authors' experience are reviewed in detail., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: To provide an overview of clinical manifestations, diagnosis and pathophysiology of food protein-induced enterocolitis syndrome (FPIES), an under-recognized and often misdiagnosed nonimmunoglobulin E-mediated food hypersensitivity. This review will highlight updates on natural history and clinical management., Recent Findings: The main developments in FPIES involve epidemiology, common presentation and variants thereof, and natural history. Improved understanding and recognition of FPIES have influenced changes in clinical management., Summary: A large prospective population-based study reported cow's milk-FPIES cumulative incidence to be 0.34% by 1 year of age; immunoglobulin E-mediated cow's milk allergy was 0.5%. A case report has suggested that FPIES pathophysiology involves Th2 activation, and a shift away from Th2 signalling may be associated with resolution. Appreciation of the frequent incidence of multiple food-FPIES has influenced anticipatory guidance. Two case reports have described FPIES to food proteins in maternal breast milk. The threshold dose for FPIES reactivity may decrease with successive episodes. Reports from different populations indicate that children may outgrow FPIES sooner than previously thought.

Food protein-induced enterocolitis syndrome (FPIES) is an under-recognized and frequently misdiagnosed non-IgE-mediated food hypersensitivity disorder, characterized by severe vomiting and/or diarrhea. Despite the potential severity of acute reactions, FPIES can be considered self-limiting as avoidance of the incriminating allergen(s) leads to resolution of symptoms. Symptoms typically begin in the first month of life in association with failure to thrive and may progress to acidemia and shock. Although FPIES is well established as a distinct clinical entity, its pathophysiology has not yet been clearly defined and requires further characterization. Several immunologic alterations have been reported in FPIES, suggesting the involvement of antigen-specific T cells and their production of proinflammatory cytokines that regulate the permeability of the intestinal barrier. Humoral immune responses may also be involved in the pathomechanism of FPIES. The aim of this article is to delineate the immunological characteristics of this disorder based on the existing reports and to review the possible pathophysiologic basis of this disease.