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Food protein-induced enterocolitis syndrome (FPIES) is a potentially severe presentation of non-IgE-mediated gastrointestinal food allergy (non-IgE-GI-FA) with heterogeneous clinical manifestations. Acute FPIES is typically characterized by profuse vomiting and lethargy, occurring classically 1-4 hours after ingestion of the offending food. When continuously exposed to the incriminated food, a chronic form has been described with persistent vomiting, diarrhea, and/or failure to thrive. Although affecting mainly infants, FPIES has also been described in adults. Although FPIES is actually one of the most actively studied non-IgE-GI-FAs, epidemiologic data are lacking, and estimation of the prevalence is based on a limited number of prospective studies. The exact pathomechanisms of FPIES remain not well defined, but recent data suggest involvement of neutrophils and mast cells, in addition to T cells. There is a wide range of food allergens that can cause FPIES with some geographical variations. The most frequently incriminated foods are cow milk, soy, and grains in Europe and USA. Furthermore, FPIES can be induced by foods usually considered as hypoallergenic, such as chicken, potatoes or rice. The diagnosis relies currently on typical clinical manifestations, resolving after the elimination of the offending food from the infant's/child's diet and/or an oral food challenge (OFC). The prognosis is usually favorable, with the vast majority of the case resolving before 5 years of age. Usually, assessment of tolerance acquisition by OFC is proposed every 12-18 months. Of note, a switch to an IgE-mediated FA is possible and has been suggested to be associated with a more severe phenotype. Avoiding the offending food requires education of the family of the affected child. A multidisciplinary approach including ideally allergists, gastroenterologists, dieticians, specialized nurses, and caregivers is often useful to optimize the management of these patients, that might be difficult.

Purpose of Review Food protein-induced enterocolitis syndrome (FPIES) is considered a rare, non-IgE-mediated food allergy that typically presents in infancy. As there is not a specific biological marker of the disease, diagnosis of FPIES is based on typical symptoms that improve once the offending food is removed from the diet. The most common causative foods are cow’s milk, soy, and rice. For years, we have thought that the typical symptoms and the triggering foods were the same around the world. Recent Findings The epidemiological data are scarce and variable but recent studies suggests that FPIES is not as rare as it is thought but rather misdiagnosed. The clinical symptoms and the offending foods vary depending on the geographic area. Perhaps because different phenotypes might exist due to dietary habits, race, or ethnicity. Summary FPIES symptoms and causative foods are not the same around the world. It is important to know our population in order to reach a correct and early diagnosis of our patients.

Non-immunoglobulin E-mediated gastrointestinal food allergic disorders (non-IgE-GI-FA) include food protein-induced enterocolitis syndrome (FPIES), food protein-induced enteropathy (FPE) and food protein-induced allergic proctocolitis (FPIAP), which present with symptoms of variable severity, affecting the gastrointestinal tract in response to specific dietary antigens. The diagnosis of non-IgE-GI-FA is made clinically, and relies on a constellation of typical symptoms that improve upon removal of the culprit food. When possible, food reintroduction should be attempted, with the documentation of symptoms relapse to establish a conclusive diagnosis. Management includes dietary avoidance, nutritional counselling, and supportive measures in the case of accidental exposure. The prognosis is generally favorable, with the majority of cases resolved before school age. Serial follow-up to establish whether the acquisition of tolerance has occurred is therefore essential in order to avoid unnecessary food restriction and potential consequent nutritional deficiencies. The purpose of this review is to delineate the distinctive clinical features of non-IgE-mediated food allergies presenting with gastrointestinal symptomatology, to summarize our current understanding of the pathogenesis driving these diseases, to discuss recent findings, and to address currents gaps in the knowledge, to guide future management opportunities.

Purpose of Review IgE- and non-IgE-mediated food allergies are increasing in prevalence in children and adults worldwide. A food allergy diagnosis can be associated with a sense of overwhelm and stress and commonly has a negative impact on quality of life. Recent Findings While there is an increased recognition of the psychosocial effects of food allergy, the current research reflects the experience of mostly White, well-educated wealthier populations. Some studies have now explored the psychosocial impact among other populations; however, further study is needed. Summary It is important that physicians and allied health professionals screen for the potentially negative psychosocial effects of food allergy and provide education to promote safety and self-efficacy at each visit; however, time may be a limiting factor. Numerous validated questionnaires are now available to help assess the psychosocial impact of food allergies. Allergy-friendly foods are typically more expensive, and thus, it is imperative that physicians screen for food insecurity as well. Educational resources should be offered regarding living well with food allergies at each visit. For patients and families experiencing anxiety or food allergy burden that is difficult to manage, referral to a mental health provider should be considered. Resources regarding programs to help accessing safe foods should also be available. Further research is needed among diverse populations focusing on interventions to best support patients and families with food allergy.

•Food protein–induced enterocolitis syndrome (FPIES) is a cell-mediated food allergy without involvement of IgE antibodies.•The relevance of the reported cases resides in alerting health care professionals working at pediatric emergency services of the possibility of encountering FPIES-type reactions in celiac children in order to optimize their treatment and avoid unnecessary therapies.•We propose that the appearance of FPIES-type reactions to wheat in celiac patients might be related to a long-term gluten-free diet. Among the possible adverse reactions to gluten, celiac disease, non-celiac gluten sensitivity, and IgE-mediated wheat allergy have been classically described. A non–IgE-mediated reaction similar to food protein–induced enterocolitis syndrome (FPIES) after inadvertent gluten ingestion in a celiac patient was recently reported. We present three children affected by celiac disease with exquisite control, including appropriate adherence to an exclusion diet, who suffered a severe adverse food reaction after unappreciated outdoor ingestion of gluten, meeting the criteria for a definitive diagnosis of FPIES. The strict and prolonged exclusion of gluten from the diet is postulated as the possible trigger for this serious entity after an involuntary transgression. Although the first published cases are recent, we might be witnessing an increase in the frequency of presentation. Therefore, we believe emergency services must be alert to the possibility of diagnosis of FPIES in celiac patients due to involuntary transgressions. The determination of gluten glycoimmunopeptides in urine or stool samples may be useful for certifying the inadvertent consumption of wheat as the cause of FPIES.

Drug-induced enterocolitis syndrome (DIES), little known due to its recent description, is analogous to food protein–induced enterocolitis syndrome (FPIES). Both processes are more frequent in pediatric age and share diagnostic criteria, the main one being the appearance of persistent vomiting 1–4 hours after ingestion of the drug or food, in the absence of IgE-mediated allergy symptoms.

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy that has been well-characterized clinically, yet it is still poorly understood. Acute FPIES is characterized by vomiting 1–4 h and/or diarrhea within 24 h after ingestion of a culprit food. Chronic FPIES is the result of chronic exposure to an offending food that can result in chronic watery diarrhea, intermittent vomiting, and failure to thrive. FPIES typically presents in infancy and self-resolves by school age in most patients. Adult-onset FPIES is rare, but it has been reported. Cow’s milk and soy are the most common triggering foods in infants in the US, and as solids are introduced in the diet, FPIES reactions to grains (rice, oat) increase in prevalence. Variability in common trigger foods exists depending on the geographical origin—for example, fish is a frequent trigger in Spanish and Italian patients. Heavy reliance on a detailed history is required for the diagnosis as physical exam findings, laboratory tests, and/or imaging studies are suggestive and not specific for FPIES. Oral food challenges remain the gold standard for confirming diagnosis, and the challenge protocol may be for an individual depending on risk of reaction, prior reaction severity, and positive-specific IgE status. The recent development of diagnostic criteria in 2017 will serve to increase recognition of the disorder and allow for early implementation of management strategies. Acute management during reactions includes IV hydration, anti-emetics, and IV corticosteroids. Reaction prevention strategies include strict food avoidance until the physician deems a food reintroduction challenge clinically appropriate. Future efforts in FPIES research should be aimed at elucidating the underlying disease mechanisms and possible treatment targets.

Cow’s milk allergy (CMA) is one of the most common presentations of food allergy seen in early childhood. It is also one of the most complex food allergies, being implicated in IgE-mediated food allergy as well as diverse manifestations of non-IgE-mediated food allergy. For example, gastrointestinal CMA may present as food protein induced enteropathy, enterocolitis or proctocolitis. Concerns regarding the early and timely diagnosis of CMA have been highlighted over the years. In response to these, guideline papers from the United Kingdom (UK), Australia, Europe, the Americas and the World Allergy Organisation have been published. The UK guideline, ‘Diagnosis and management of non-IgE-mediated cow’s milk allergy in infancy—a UK primary care practical guide’ was published in this journal in 2013. This Milk Allergy in Primary Care (MAP) guideline outlines in simple algorithmic form, both the varying presentations of cow’s milk allergy and also focuses on the practical management of the most common presentation, namely mild-to-moderate non-IgE-mediated allergy. Based on the international uptake of the MAP guideline, it became clear that there was a need for practical guidance beyond the UK. Consequently, this paper presents an international interpretation of the MAP guideline to help practitioners in primary care settings around the world. It incorporates further published UK guidance, feedback from UK healthcare professionals and affected families and, importantly, also international guidance and expertise.

Drug-Induced Enterocolitis Syndrome (DIES) is a drug-induced hypersensitivity reaction non-IgE mediated involving the gastrointestinal system that occurs 2 to 4 h after drug administration. Antibiotics, specifically amoxicillin or amoxicillin/clavulanate, represent the most frequent drugs involved. Symptoms include nausea, vomiting, abdominal pain, diarrhea, pallor, lethargy, and dehydration, which can be severe and result in hypovolemic shock. The main laboratory finding is neutrophilic leukocytosis. To the best of our knowledge, 12 cases of DIES (9 children-onset and 3 adult-onset cases) were described in the literature. DIES is a rare clinically well-described allergic disease; however, the pathogenetic mechanism is still unclear. It requires to be recognized early and correctly treated by physicians.

Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobulin E (IgE)-mediated food allergy characterized by gastrointestinal symptoms such as vomiting and diarrhea. Since 2018, hen’s egg yolk has been the most common trigger for FPIES in Japan, whereas typical egg white (TEW) FPIES remains rare. Herein, we present two cases of acute TEW FPIES in young children. A 17-month-old girl experienced recurrent vomiting and lethargy following egg white ingestion, despite previously tolerating half an egg yolk and 5 g of egg white. Initial tests showed no sensitization markers (egg white-specific IgE < 0.1 kUA/L; ovomucoid [OVM]-specific IgE < 0.1 kUA/L; skin prick test [SPT] negative). Three oral food challenges (OFCs) at 6-month intervals at our hospital all triggered vomiting and lethargy. Procalcitonin and thymus- and activation-regulated chemokine levels remained elevated for 24 hours, and even after 31 months, the patient had not achieved egg white tolerance. A 14-month-old girl presented with vomiting and lethargy after egg white ingestion while on a strict egg yolk- and egg white-free diet. Blood tests again showed no sensitization markers (egg white-specific IgE < 0.1 kUA/L; OVM-specific IgE < 0.1 kUA/L; SPT negative). Two OFCs at 6-month intervals confirmed FPIES, and even after 2 years, the patient had not achieved egg white tolerance. These cases highlight that egg white can trigger FPIES. Thorough medical history taking and diagnostic evaluation, including OFCs, are essential to distinguish FPIES from immediate-type food allergies.