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This common statement of the American Academy of Allergy, Asthma and Immunology (AAAAI) and The European Academy of Allergy and Clinical Immunology (EAACI) provides an update of the 2012 published guidelines on food challenges. The guidelines equally address food challenges in the research and the clinical settings. They first address the diagnostic tests which can guide the decision to conduct a challenge. Safety of food challenges is prime, and the various procedures and safety issues as well as medications potentially involved in challenges are extensively discussed. Challenges are suggested to be conducted with semi-logarithmic incremental doses based on the protein content, typically for IgE-mediated food allergy with intervals of 20-30 min between doses. Specific protocols for other types of reactions such atopic dermatitis or gastrointestinal food allergy are detailed separately. Proper stopping criteria are essential in order to reduce the risk of false-positive diagnoses, but also severe reactions. The guidelines recommend criteria based on "go on," "stop," or "observation." These revised guidelines will clearly provide much needed guidance for food challenges in the research and clinical settings. They will continue to evolve with new diagnostic tests or new needs in the field of food allergy., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Food protein-induced enterocolitis syndrome caused by solid foods (Solid-FPIES) is a non-immunoglobulin E-mediated allergic disease characterized by delayed gastrointestinal symptoms. An oral food challenge (OFC) test, although necessary, can be inconclusive in cases with mild symptoms. Moreover, limited diagnostic marker availability highlights the need for novel surrogate markers. We aimed to examine the efficacy of fecal hemoglobin (FHb), lactoferrin (FLf), and calprotectin (FCp) over time in evaluating gastrointestinal inflammation degree in Solid-FPIES., Methods: This observational study included 40 patients and 42 episodes at Juntendo University Hospital and affiliated hospitals between October 2020 and March 2024 categorized into FPIES (12 patients with 11 egg yolk, 1 fish, and 1 soybean episodes), control (14 patients with 15 episodes), and remission (14 patients). Fecal tests were performed for 7 days following antigen exposure. The ratios of each value were divided by the baseline value and analyzed over time course., Results: The FPIES group had significantly higher peak ratios of all fecal markers than the control group (p < 0.01). The median FHb, FLf, and FCp ratios were 3.25, 9.09, and 9.79 in the FPIES group and 1.08, 1.29, and 1.49 in the control group, respectively. In the remission group, several patients had fluctuating fecal markers despite negative OFC, and one patient was diagnosed with FPIES by OFC with increased load. Receiver operating characteristic curve analyses revealed high diagnostic performance for each fecal marker in FPIES., Conclusions: Sequential fecal marker examination proved valuable in diagnosing Solid-FPIES and evaluating the degree of gastrointestinal inflammation., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Food protein-induced enterocolitis syndrome (FPIES) caused by fish and others is prevalent in the Mediterranean regions but is less frequently reported in Japan. This case report describes a 3-year-old Japanese girl who developed FPIES triggered by multiple seafoods, including swordfish, cod, and squid. The diagnosis was confirmed through oral food challenge tests (OFC), which led to repeated vomiting and an increase in thymus and activation-regulated chemokine (TARC) levels. This case highlights the importance of considering fish-induced FPIES in the differential diagnosis of recurrent vomiting in children and suggests the potential utility of TARC levels in diagnosing and monitoring FPIES.

Background: Food protein-induced enterocolitis syndrome (FPIES), a non-IgE-mediated allergy, primarily affects infants and young children. Whether and when tolerance develops seems to vary among populations and trigger foods., Objective: This study aimed to evaluate tolerance development and its assessment in a Swedish cohort., Methods: This was a prospective follow-up study of a Swedish cohort of 113 children, followed at 25 pediatric departments, with acute FPIES. Data on oral food challenges and FPIES resolution were collected through chart reviews and, if incomplete, supplemental caregiver interviews., Results: The median age at last follow-up was 5.6 years (range: 8.7 months to 16.5 years). Eighty-three children (73%) developed tolerance to 96 of 137 (70%) foods: 93% for cow's milk, 92% for oat, and 46% for fish. The median age when tolerance was developed was 36.0 months (interquartile range: 23.7-48.2 months): 24.4 months for cow's milk, 30.1 months for oat, and 49.4 months for fish. Tolerance was determined in hospital in 45% of cases. Five percent demonstrated allergic sensitization to their FPIES trigger food. Age at tolerance development did not differ between sensitized and nonsensitized patients., Conclusions: Most of the children in this Swedish cohort with FPIES achieved tolerance before age 4 years. Cow's milk- and oat-induced FPIES had similar remission patterns, with early resolution. Development of tolerance to fish occurred significantly later compared with all other FPIES-inducing foods., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Food allergies are immune-mediated, complex disorders, which are the source of increasing health concern worldwide. The goal of this review is to present an updated summary of the food allergy (FA) burden among children and adults across different populations, focusing on research from the past 5 years., Recent Findings: FAs impact a growing number of global residents-particularly those residing in higher-income, industrialized regions. Moreover, growing epidemiologic evidence suggests that the population health burden of non-IgE-mediated FAs, such as food protein-induced enterocolitis syndrome, may also be higher than previously reported. FA is a complex trait that impacts infants, children, as well as adults across the globe. The population health burden of both IgE- and non-IgE-mediated FAs is likely to grow in the absence of rapid advances and widespread implementation of effective FA prevention and treatment interventions. Systematic epidemiological research initiatives are needed, both nationally and globally, to better understand and reduce the burden of these allergic diseases., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Peanut introduction guidelines recommend that infants with severe eczema and/or egg allergy consume 6 g of peanut protein weekly to prevent peanut allergy. Rates of new peanut allergy after introduction and adherence remain under study., Objective: To determine compliance with peanut introduction guidelines, rates of new peanut allergy, and reasons for discontinuation of peanut consumption in a cohort of high-risk infants., Methods: A prospective cohort of 4- to 11-month-old high-risk infants (defined as moderate-severe eczema or non-peanut food allergy or a first-degree relative with peanut allergy) with no prior peanut exposure who were determined to not be peanut allergic were recommended to introduce 6 g of peanut protein weekly. Participants were followed to 30 months with 2 in-person visits and monthly questionnaires., Results: Two hundred seventy-seven infants were followed. At last follow-up, 245 (88%) were consuming some peanut protein with median weekly consumption of 3 g (interquartile range: 1-5 g). New peanut allergy developed in 6 (2%), with 2 of those cases consistent with food protein-induced enterocolitis syndrome. Fear of reaction in another household member was the most common reason for peanut discontinuation. Reactions to peanut after introduction in the index infant occurred in <2% of peanut-allergic siblings and in 20% of peanut-allergic parents., Conclusion: We found low rates of new peanut allergy and generally low rates of peanut discontinuation after introduction in our high-risk cohort. However, families of high-risk infants require significant support with introduction, especially those with another peanut-allergic member., (Copyright © 2023. Published by Elsevier Inc.)

Food protein-induced enterocolitis syndrome (FPIES) is a food allergy that results in repetitive vomiting, lethargy, and pallor within 1 to 4 hours of food ingestion. One of the issues in its management is the introduction of new foods. Over the past 25 years, suggestions have been made mainly based on the likelihood that a given food family could induce an episode of acute FPIES. Thus, foods have been categorized into low, moderate, and high risk. The suggestion was always to postpone the introduction of moderate- or high-risk foods, leaving the decision whether to introduce them at home or in hospital to the doctor. These suggestions were designed for all children with acute FPIES, regardless of their geographical area. However, it is true that these suggestions are the result of expert opinion. In recent years, studies have been published that have shown that the risk category of foods varies according to geographical area and so does the prevalence of single FPIES versus multiple FPIES. For this reason, we believe that the introduction of new foods in the child with acute FPIES can and should be tailored according to the geographical area., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: Food protein-induced enterocolitis syndrome (FPIES) is a form of non-IgE-mediated gastrointestinal food allergy. FPIES is considered a rare food allergy disorder and is often under-recognized. Therefore, clinicians should have a better understanding of its manifestations and maintain a high index of suspicion for a correct diagnosis. To this end, information about differences in the characteristics of caregiver-reported and physician-diagnosed FPIES is important., Methods: The present, national, multicentric, prospective birth cohort study, called the Japan Environment and Children's Study (JECS), enrolled a general population of 104,062 fetal records. The characteristics of FPIES in 1.5-year-old children were categorized as cases reported by caregivers or as those diagnosed by a physician using questionnaire data., Results: The prevalence of caregiver-reported and physician-diagnosed FPIES cases was 0.69% and 0.06%, respectively. Among the former, the most common causative food was hen's egg (HE), and the second most common causative food was cow's milk (CM) (51.0% and 17.1% of patients responded to HE and CM, which accounted for 46% and 15% of all the causative foods, respectively). Conversely, among the physician-diagnosed cases, the most common causative food was CM followed by HE (57.7% and 36.5% of patients responded to CM and HE, which accounted for 46% and 29% of all the causative foods, respectively). CM accounted for a significantly higher proportion of causative foods in physician-diagnosed FPIES while HE accounted for a significantly higher proportion of caregiver-reported FPIES (p &lt; 0.05)., Conclusion: A discrepancy was found in reports of the most common causative food between caregiver-reported and physician-diagnosed cases of FPIES., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy treated by trigger food avoidance and supportive care. Whether the prevalence of different trigger foods is changing with evolving food introduction patterns is unknown. The rate and nature of subsequent reactions after initial diagnosis have not been fully studied., Objective: We sought to characterize how trigger foods have changed over time and investigate the nature of subsequent reactions after initial diagnosis., Methods: We collected data regarding patients' FPIES reactions from 347 patients seen in the University of Michigan Allergy and Immunology clinic for FPIES from 2010 to 2022. Inclusion criteria consisted of pediatric patients diagnosed with FPIES by an allergist based on international consensus guidelines., Results: Most foods including less commonly cited FPIES triggers increased in frequency over time. The most common index trigger was oat. A total of 32.9% (114 of 347) patients experienced a subsequent reaction after education on trigger avoidance and safe home introduction of new foods, with 34.2% (41 of 120) of subsequent reactions to new triggers at home and 45% (54 of 120) to known triggers at home. Of patients reacting subsequently, 28% (32 of 114) experienced a subsequent reaction necessitating an emergency department visit. The most common new subsequent reaction triggers were egg and potato, whereas peanut most commonly triggered reactions on oral food challenge., Conclusions: The risk profile of FPIES triggers may be evolving over time, though high-risk FPIES foods remain common. The subsequent reaction rate after counseling indicates that home food introduction poses risk. This study highlights the need for improved safety of new food introduction and/or prediction methods for FPIES to help prevent potentially dangerous home FPIES reactions., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

For food-allergic patients, hypoallergenic formulas (HFs) are medically indicated, often a primary component of the diet and essential for patient safety, health, nutrition, and overall well-being. Yet, food allergy is not included among the conditions mandated for coverage under federal health programs and private health insurance. The 2022 infant formula crisis has affected many North American families and has particularly influenced patients with food allergies who rely on a limited number of safe HF brands to safely meet their nutritional needs for growth and development. The current formula shortage further highlights the longstanding difficulties faced by families with food allergies in accessing HF. Within this context, this article focuses on chronic barriers faced by patients with food allergies in accessing HF and proposes potential solutions. Legislation is desperately needed to address HF affordability through changes in insurance reimbursement and disparities in access to HF among individuals with food allergy., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

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., (© 2023 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background: The microbiome associations of food protein-induced enterocolitis syndrome (FPIES) are understudied. We sought to prospectively define the clinical features of FPIES in a birth cohort, and investigate for the evidence of gut dysbiosis., Methods: We identified children diagnosed with FPIES in the Gastrointestinal Microbiome and Allergic Proctocolitis Study, a healthy infant cohort. Children were assessed and stools were collected at each well child visit. The clinical features of the children with FPIES were summarized. Stool microbiome was analyzed using 16S rRNA sequencing comparing children with and without FPIES., Results: Of the 874 children followed up for 3 years, 8 FPIES cases (4 male) were identified, yielding a cumulative incidence of 0.92%. The most common triggers were oat and rice (n = 3, each) followed by milk (n = 2). The children with FPIES were more likely to have family history of food allergy (50% vs. 15.9% among unaffected, p = .03). The average age of disease presentation was 6 months old. During the first 6 months of life, stool from children with FPIES contained significantly less Bifidobacterium adolescentis, but more pathobionts, including Bacteroides spp. (especially Bacteroides fragilis), Holdemania spp., Lachnobacterium spp., and Acinetobacter lwoffii. The short-chain fatty acid (SCFA)-producing Bifidobacterium shunt was expressed significantly less in the stool from FPIES children., Conclusions: In this cohort, the cumulative incidence over the 3-year study period was 0.92%. During the first 6 months of life, children with FPIES had evidence of dysbiosis and SCFA production pathway was expressed less in their stool, which may play an important role in the pathogenesis of FPIES., (© 2023 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Mixed and non-IgE-mediated food allergy is a subset of immune-mediated adverse food reactions that can impose a major burden on the quality of life of affected patients and their families. Clinical trials to study these diseases are reliant upon consistent and valid outcome measures that are relevant to both patients and clinicians, but the degree to which such stringent outcome reporting takes place is poorly studied., Objective: As part of the Core Outcome Measures for Food Allergy (COMFA) project, we identified outcomes reported in randomized clinical trials (RCT) of treatments for mixed or non-IgE-mediated food allergy., Design: In this systematic review, we searched the Ovid, MEDLINE and Embase databases for RCTs in children or adults investigating treatments for food protein-induced enterocolitis syndrome, food protein-induced allergic proctocolitis, food protein-induced enteropathy and eosinophilic gastrointestinal disorders including eosinophilic esophagitis [EoE], eosinophilic gastritis and eosinophilic colitis published until 14 October 2022., Results: Twenty-six eligible studies were identified, with 23 focused on EoE (88%). Most interventions were corticosteroids or monoclonal antibodies. All EoE studies assessed patient-reported dysphagia, usually using a non-validated questionnaire. Twenty-two of 23 EoE studies used peak tissue eosinophil count as the primary outcome, usually using a non-validated assessment method, and other immunological markers were only exploratory. Thirteen (57%) EoE studies reported endoscopic outcomes of which six used a validated scoring tool recently recommended as a core outcome for EoE trials. Funding source was not obviously associated with likelihood of an RCT reporting mechanistic versus patient-reported outcomes. Only 3 (12%) RCTs concerned forms of food allergy other than EoE, and they reported on fecal immunological markers and patient-reported outcomes., Conclusions: Outcomes measured in clinical trials of EoE and non-IgE-mediated food allergy are heterogeneous and largely non-validated. Core outcomes for EoE have been developed and need to be used in future trials. For other forms of mixed or non-IgE-mediated food allergies, core outcome development is needed to support the development of effective treatments., Systematic Review Registration: OSF public registry DOI:10.17605/OSF.IO/AZX8S., (© 2023 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Food protein-induced enterocolitis syndrome (FPIES) is a type of non-IgE-mediated gastrointestinal food allergy. FPIES is characterized by repetitive vomiting without classic IgE-mediated allergic skin or respiratory symptoms 1-4 h after causative food ingestion. The condition may be classified as acute or chronic, typical or atypical, and liquid or solid according to the course of symptoms, presence of IgE antibodies, and causative food, respectively. Since the development of international consensus guidelines in 2017, epidemiological studies have been conducted in many countries. FPIES is a relatively rare disease, with a prevalence of 0.015%-0.7%. However, the number of patients has been increasing in recent years. Most patients develop the disease in infancy. The natural history of FPIES is generally favorable, with most FPIES cases resolving before school age. FPIES is diagnosed using symptoms such as vomiting or diarrhea, or via an oral food challenge (OFC). Currently, no validated biomarker is available for diagnosis, and the mechanisms related to gastrointestinal manifestations and immune system involved in the development of FPIES have not yet been elucidated. Treatment with intravenous fluids and ondansetron is recommended in the acute phase. Long-term management consists of complete causative food elimination and periodic OFC to confirm tolerance. Given that many diagnoses are delayed because of a lack of awareness of the condition, FPIES must be widely recognized by healthcare providers. In the future, it is expected that FPIES pathogenesis will be further clarified, and more objective diagnostic criteria will be developed.

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal food-induced hypersensitivity disorder that occurs mostly in infants. Long considered a rare disease, a recent increase in physician awareness and publication of diagnosis of guidelines has resulted in an increase in recognized FPIES cases. We aimed to conduct a systematic review of FPIES studies in the past 10 years. A search was conducted on PubMed and Embase in March 2022. Our systematic review focused on 2 domains: (1) the most reported FPIES food triggers; and (2) the resolution rate and median age at resolution of patients with FPIES. We found that cow's milk was the most reported trigger globally. Patterns of the most common triggers varied by country, with fish being one of the most common triggers in the Mediterranean region. We also found that the rate and median age of resolution varied by trigger. Patients with FPIES to cow's milk acquired tolerance at a younger age (most by age 3 years), while fish-FPIES was more persistent (mean resolution by age 37 months-7 years). Overall, many studies found a resolution rate of 60% for any food., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

We report the case of a 4-year-old child who presented with vomiting, abdominal pain, and intense pallor 2 h after amoxicillin ingestion. An IgE-mediated reaction was suspected at first, which was finally diagnosed as a drug-induced enterocolitis syndrome. In this rare and poorly described non-IgE-mediated drug allergy, adrenaline is not effective. This diagnostic challenge must be known in order to administer adequate treatment, i.e., antiemetic drugs (ondansetron) and fluid challenge., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Background: The aim of this study was to clarify the clinical characteristics and management of infants with suspected acute food protein-induced enterocolitis syndrome (FPIES) who presented to the pediatric emergency department (ED) before and after the guidelines were published., Methods: This was a retrospective cohort study. We classified the infants as "acute FPIES-like symptoms" who were younger than 12 months of age and visited the pediatric ED of the National Center for Child Health and Development due to vomiting 1-4 h after food ingestion without any causative disease, such as infection. The medical records of those infants in 2015 and 2021 were reviewed. We used the nonparametric Mann-Whitney U test to compare two groups for continuous variables, whereas chi-squared or Fisher's exact tests were used for nominal variables., Results: The number of infants with acute FPIES-like symptoms was 15 (13%) in 2015 and 14 (15%) in 2021. The trigger foods were cow's milk or dairy products in half of the infants, and five as a result of ingestion of hen's eggs in 2021, compared to zero cases in 2015. Five in 2015 and 12 in 2021 required examination at the ED. Three in 2015 and six in 2021 met the diagnostic criteria for acute FPIES in the international consensus guidelines. The emergency physicians did not record at least four minor criteria for acute FPIES in seven in 2015 and five in 2021. No infants (0%) in 2015 and two (14%) in 2021 were referred to the allergy department by an emergency physician., Conclusions: Acute FPIES should be considered one of the differential diagnoses of vomiting, and pediatric medical staff should be aware of FPIES diagnostic criteria and appropriately refer suspected cases to a specialist., (© 2023 Japan Pediatric Society.)

Food protein-induced enterocolitis syndrome (FPIES) was first described in detail in the late 20th century as a non-IgE-mediated food allergy characterized by delayed gastrointestinal symptoms after ingestion of a trigger food. Although the initial case series reported infants reacting to cow's milk- and soy-based formulas, we now recognize that FPIES affects patients across the age spectrum. This brief review highlights our evolving understanding of FPIES with a discussion of triggers, epidemiology, food challenges, and pathophysiology., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Adult-onset food protein-induced enterocolitis syndrome (FPIES) has been increasingly recognized in recent years. Adult FPIES differs from pediatric FPIES in terms of dietary triggers and symptoms, thus further broadening the clinical phenotypes of the disease. The natural history of FPIES in adulthood is poorly characterized., Objective: To evaluate the natural course of FPIES in adults., Methods: We performed an ambispective study of adults diagnosed with acute FPIES during 2016-2021. Data on age, sex, symptoms, implicated food, and oral food challenge (OFC) outcomes at baseline and during follow-up were analyzed., Results: Forty-two adults were included (83.3% female; median age at diagnosis, 40 years). The predominant symptoms were diarrhea (92.9%) and abdominal cramps (71.4%); vomiting was reported by 59% of patients. The most common triggers were shellfish (n = 19, 45.2%) and fish (n = 19, 45.2%). The mean number of reactions before diagnosis was 6.3 (2-15). Twenty-one OFCs were carried out with the offending food in 15 patients. Six patients achieved tolerance (40%) after a mean of 17.8 months (range, 6-36 months). Twelve of all OFCs performed were positive (57.1%). The absolute leukocyte and neutrophil counts measured before and 1 to 2 hours after the positive challenge showed a mean increase of 3045 and 2736 cells/μL, respectively. Serum tryptase, C-reactive protein, and eosinophil and platelet values did not change significantly after the OFC., Conclusion: Some patients may outgrow adult-onset FPIES., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy characterized by delayed, and potentially severe, gastrointestinal symptoms. Since the advent of a specific diagnostic code and establishment of diagnostic guidelines, our understanding of this condition has grown., Recent Findings: FPIES affects patients from early infancy into adulthood. Any food can be a trigger, and common culprit foods vary geographically and by age. An understanding of the complex underlying immune mechanisms remains elusive, although studies show pan-leukocyte activation, cytokine release, and increased gastrointestinal permeability. Management involves trigger avoidance, and patients may benefit from the support of a dietitian to ensure adequate nutrient intake. Tolerance develops over time for most children, but due to the risk of severe symptoms, re-introduction of a suspected FPIES trigger is recommended only under supervision at an oral food challenge. Studies continue to evaluate the optimal challenge protocol. Caregivers of children with FPIES report high levels of anxiety and stress, which is attributed to the dramatic symptomatology, dietary restrictions, nutritional concerns, lack of confirmatory diagnostic tests, and limited tools for management of reactions. Our understanding of the FPIES diagnosis has improved over the last few decades, but there remain opportunities, particularly regarding discerning the pathophysiology and best management practices., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Patients with food protein-induced enterocolitis syndrome (FPIES) have elevated thymus and activation-regulated chemokine (TARC) levels in the acute phase. However, to the best of our knowledge, no study has evaluated TARC levels in the acute phase of immunoglobulin E-dependent food allergy (IgE-FA). If TARC elevation is a specific response to FPIES among FAs, TARC measurement may help distinguish between FPIES and IgE-FA. Thus, we investigated acute phase TARC levels in patients with FPIES and IgE-FA. Methods: Thirty-one episodes in 16 patients with FPIES and 20 episodes (13 were anaphylaxis) in 20 patients with IgE-FA were included. Patients with eczema were excluded. Serum TARC levels within 6 h of allergic reaction onset and age-adjusted TARC ratios (TARC levels divided by age-specific normal TARC values) were compared between the groups. Results: The median age was 1.1 and 3.6 years in the FPIES and IgE-FA groups, respectively ( P  < 0.001). The median (range) serum TARC (pg/mL) levels were significantly higher in the FPIES group than in the IgE-FA group [1,283 (410-3,821) versus 377 (109-1,539); P  < 0.001]. The median (range) age-adjusted TARC ratios were also significantly higher in the FPIES group [2.56 (0.57-7.86) versus 1.08 (0.15-2.17); P  < 0.001]. The area under the curve (AUC) for TARC to distinguish FPIES from IgE-FA was 0.926, and the AUC for the age-adjusted TARC ratio was 0.850. The odds ratio for FPIES diagnosis per 1,000 pg/mL increase in TARC was 31.6 ( P  = 0.002), and the odds ratio adjusted by age was 17.1 ( P  = 0.016). Conclusion: Acute phase TARC levels were higher in patients with FPIES than in patients with IgE-FA. The increase in acute phase TARC levels was considered to be a specific response to FPIES among FAs. Measurement of TARC levels in the acute phase may help differentiate FPIES from IgE-FA.

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 electronic 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, whereas 43.9% reacted to more than 1 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 = .04) and seafood (P = .023) but not with age of onset. The prevalence of gastrointestinal pathologies such as 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 were correlated with also having a diagnosis of IBS (P = .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., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal food allergy mainly affecting infants and young children. Allergic FPIES reactions differ from IgE-mediated food allergies, for example, regarding elicitors and clinical course., Objective: The aim of our study was to describe causative agents and development of tolerance in German children with FPIES., Methods: We conducted a retrospective survey on children with FPIES from 14 centers in Germany assessing a 6-year period., Results: We analyzed 142 patients with 190 FPIES reactions, 130 of which met acute FPIES criteria and 60 were defined as chronic FPIES. The most frequent eliciting food for acute FPIES was cow's milk, followed by fish, vegetables (eg, potato, pumpkin), meats (eg, beef), and grains. A total of 119 children reacted to 1 food only, 16 children to 2 or 3 foods, and 7 children to ≥4 foods. In chronic FPIES, all but 4 exclusively breastfed infants reacted to cow's milk feeding. IgE sensitization to the triggering food was found in 21 of 152 (14%) cases. Two children developed additional IgE-mediated symptoms upon a food challenge. Time to proof of tolerance was shortest in cow's milk-induced FPIES, and it was shorter in chronic than in acute FPIES., Conclusion: In our national survey, we identified triggers for acute FPIES that partially differ from those reported internationally. Mainly foods introduced early in infant nutrition triggered acute reactions. Time to proven tolerance was shown to be contingent on FPIES symptomatology and on the triggering food. These data should be considered regarding nutritional advice for infants with FPIES., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: Food protein-induced enterocolitis syndrome (FPIES) is a rare non-IgE, cell-mediated food allergy disorder. We aimed to report the demographic characteristics, clinical features, and management of pediatric patients with FPIES., Methods: This retrospective study included all children diagnosed with FPIES at the pediatric allergy departments of the participating twelve study centers from January 2015 to November 2020., Results: A total of 73 patients (39 males, 53.4%) with a male/female ratio of 1.1 were included in the study. The median (interquartile ranges) age at symptom onset was 6 months (0.5-168, 4-9.5). The most frequent offending foods were cow's milk, egg's yolk, fish, and egg's white, identified in 38.4% (n = 28), 32.9% (n = 24), 21.9% (n = 16) and 20.5% (n = 15) of the patients, respectively. The total number of reported FPIES episodes was 290 (3.9 episodes per child). Oral food challenge (OFC) was performed in 54.8% (n = 40) of the patients, and tolerance was detected in 17 OFCs (42.5%) at a median age of 15 months (range 8-132 months)., Conclusion: FPIES is a non-IgE-mediated food hypersensitivity that commonly affects infants and is often misdiagnosed. The pathophysiology of the disease remains unclear and the low awareness of FPIES among physicians and parents highlights the need for more education., (© 2022 S. Karger AG, Basel.)

The diagnosis of drug-induced enterocolitis syndrome (DIES), resembling the typical findings of a well-known disease, the food protein-induced enterocolitis syndrome (FPIES), was acknowledged in the first publication on the topic in 2014. Ten cases of DIES have been described so far. Unanswered questions concerning DIES include its pathogenetic mechanism, natural history, the possible presence of predisposing genetic factors, and the potential existence of its atypical forms. DIES is a recently defined and intriguing clinical entity, similar to FPIES but triggered by drugs. It seems well-defined from the clinical point of view, but its pathogenetic mechanisms are not known. DIES deserves more attention among allergists, especially among the professionals who work with children, and all efforts should be conceived to improve its correct recognition and accurate management., (© 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

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., Competing Interests: The authors have no conflicts of interest to declare.

Introduction: Food protein-induced enterocolitis is a non-immunoglobulin E-mediated food allergy with acute manifestations like recurrent vomiting, dehydration, and shock. It is a rare pathology that requires a high index of suspicion. Pseudo-Bartter syndrome (metabolic alkalosis, hypokalemia and hypochloremia in the absence of tubulopathy) is an infrequent complication of cystic fibrosis., Case Report: A 5-month-old boy with recurrent vomiting, dehydration, and shock; who had been breastfed and had consumed baby formula three hours prior to the onset of symptoms. Laboratory tests confirmed hyponatremia, hypochloremic metabolic alkalosis, and hypokalemia in absence of tubulopathy; two iontophoresis showed altered results, stool elastase was decreased, and genetic sequencing confirmed the diagnosis of cystic fibrosis. The provocation test confirmed food protein-induced enterocolitis syndrome., Conclusion: Recurrent vomiting and dehydration after the intake of milk formula must lead to suspicion of food protein-induced enterocolitis syndrome. If pseudo-Bartter syndrome is found, cystic fibrosis must be ruled out.

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy diagnosed via history and/or an oral food challenge (OFC)., Objective: To determine allergists' approach to FPIES OFCs., Methods: A web-based survey was e-mailed to 1100 randomly selected American Academy of Allergy, Asthma and Immunology members., Results: A total of 132 individuals responded (12% response rate). A total of 95.5% (n = 105) of respondents perform OFCs in their practice, but only 58.7% (n = 71) perform FPIES OFCs. The median number of FPIES OFCs in children was reported as 3 per year (range, 0-76); all but 1 respondent (2.5%) had not performed any FPIES OFCs in adults. The most common FPIES OFC foods were cow's milk, rice, lightly cooked egg, oat, soy, baked milk, and baked egg. The decision to offer FPIES OFCs was based on the severity of past reactions, the patient and family's desire, and the patient's age. FPIES OFCs were most commonly performed in an outpatient setting, with placement of peripheral intravenous access depending on the severity of past reactions and with a serving appropriate for age divided into 3 equal portions administered over 30 minutes. There was significant variability in the approach to conducting FPIES OFCs. Most respondents (87.4%, n = 127) indicated that specific guidelines for performing FPIES OFCs would be helpful., Conclusions: Our study highlights the discordance in allergists' practices performing OFCs for IgE-mediated food allergy compared with FPIES. The lack of universal agreement on the optimal way to perform OFCs in FPIES demonstrates the need for future studies to develop a standardized protocol for FPIES OFCs., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy characterized by profuse vomiting within hours of ingestion of the causative food. We have previously reported that FPIES is associated with systemic innate immune activation in the absence of a detectable antigen-specific antibody or T-cell response. The mechanism of specific food recognition by the immune system remains unclear., Objective: Our aim was to identify immune mechanisms underlying FPIES reactions by proteomic and flow cytometric analysis of peripheral blood., Methods: Children with a history of FPIES underwent supervised oral food challenge. Blood samples were taken at baseline, at symptom onset, and 4 hours after symptom onset. We analyzed samples from 23 children (11 reactors and 12 outgrown). A total of 184 protein markers were analyzed by proximity ligation assay and verified by multiplex immunoassay. Analysis of cell subset activation was performed by mass cytometry and spectral cytometry., Results: Symptomatic FPIES challenge results were associated with significant elevation of levels of cytokines and chemokines, including IL-17 family markers (IL-17A, IL-22, IL-17C, and CCL20) and T-cell activation (IL-2), and innate inflammatory markers (IL-8, oncostatin M, leukemia inhibitory factor, TNF-α, IL-10, and IL-6). The level of the mucosal damage marker regenerating family member 1 alpha (REG1A) was also significantly increased. These biomarkers were not increased in asymptomatic challenges or IgE-mediated allergy. The level of phospho-STAT3 was significantly elevated in myeloid and T cells after challenge in individuals with symptoms. Mass cytometry indicated preferential activation of nonconventional T-cell populations, including γδ T cells and CD3 + CD4 - CD8 - CD161 + cells; however, the potential sources of IL-17 in PBMCs were primarily CD4 + T H 17 cells., Conclusions: These results demonstrate a unique IL-17 signature and activation of innate lymphocytes in FPIES., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

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., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

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 < 0.001, range 1.0 month to 9 years). Repetitive vomiting (100%), lethargy (86%), and pallor (61%) were common symptoms; 40% had diarrhea. Sixty percent visited the emergency department, and 27% of all patients were hospitalized. Most patients were diagnosed clinically (81%). Specific IgE for the trigger food was positive in 4/89 tested patients (4%), and skin prick test for the trigger food was positive in 1/53 tested patients (2%)., Conclusions: In our Swedish study of 113 children, cow's milk, fish, and oat were the commonest trigger foods. Most patients reacted to a single food, and IgE sensitization was rare., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: The method of performing oral food challenge (OFC) in acute food protein-induced enterocolitis syndrome (FPIES) has not been systematically studied. Therefore, there is a certain variability in the choice of the various centers., Methods: Since 2011, we have been performing OFC for acute FPIES with a single dose of culprit food, a full serving size for age. In case of atypical FPIES (skin prick test, SPT, positive), we applied this protocol only if the description of previous adverse reactions was compatible with that of a classic acute FPIES, if other IgE-mediated food allergies were absent, and if the mean diameter of the wheal evoked by the SPT with the challenged food was ≤5 mm. We have retrospectively analyzed 222 OFCs from 2011 to 2020. The grading of reactions was carried out according to the International Consensus Guidelines on FPIES of 2017., Results: Forty-eight of 222 OFC (21.6%) failed. The mild reactions were 22 of 48 (45.8%), the moderate ones 22 of 48 (45.8%), and the severe ones 4 of 48 (8.4%) failed OFCs. The tested food processing (in the case of cow milk and chicken egg) did affect neither probability nor severity of the reaction. Patients with positive SPT for the tested food presented four times more severe reactions (2 of 9 failed OFC, 22.2%) than patients with negative SPT (2 of 39 failed OFC, 5.1%) (P = .316)., Conclusions: The administration of a single dose in a full serving size for age appears to be a sufficiently safe method for OFC for acute FPIES, with the benefit of saving time. In patients with positive SPT for the tested food, it may be prudent to start with a smaller dose carrying on, in the absence of adverse reactions, with the administration of the full dose after a 4-hour observation., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

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 children 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., Competing Interests: The authors declare not to have conflict of interest.