Food Protein-induced Enterocolitis Syndrome Research Articles

Are pediatricians aware of the mysterious FPIES? Current diagnostic and treatment options. Case report

The prevalence of food allergies continues to grow steadily, and due to certain difficulties in diagnosing allergies not associated with immunoglobulin E, some conditions are little known. Such diagnosis-challenging diseases include food protein-induced enterocolitis syndrome (FPIES), a relatively low-prevalence disease most commonly occurring in early childhood but, in some cases, affecting adults as well. The pathogenesis of FPIES has not been reliably studied. FPIES is associated with elevated serum tryptase and release of pro-inflammatory cytokines, including interleukin-17. A characteristic symptom of FPIES is uncontrollable vomiting, which is probably triggered by the serotonin secreted by enterochromaffin cells, which activates the vagus nerve and the vomiting reflex, determining a good response of vomiting relief with ondansetron, a serotonin receptor antagonist. Changes in gut microbiota composition were also reported in FPIES. FPIES can lead to severe complications such as hypovolemic shock due to the rapid progression of symptoms and rapid dehydration, which often requires hospitalization of patients with acute FPIES. The provoking factors usually include products from the "big nine" allergens: cow's milk, eggs, gluten, soy, nuts, peanuts, fish, seafood, and sesame. FPIES can be acute or chronic; the manifestations slightly differ depending on the disease form. Laboratory diagnosis is difficult due to the lack of reliable biomarkers, and the diagnosis is established clinically and confirmed with an oral provocation test. The key treatment for FPIES is to eliminate the trigger protein from the diet, and depending on the severity of the disease, some patients may be allowed to consume a heat-treated allergen. The prognosis of FPIES is favorable: tolerance to the trigger product in most cases is developed within two years. Further studies are required to clarify the pathogenesis, prevalence, and treatment methods, with prospective follow-up of patients with a history of FPIES and the analysis of concurrent and subsequent diseases, including allergic conditions. The article presents two clinical cases of children diagnosed with FPIES.

Formulation of adult food-protein–induced enterocolitis syndrome diagnostic scoring system differentiating from immediate-type food allergy

BackgroundAdult food-protein–induced enterocolitis syndrome (FPIES) has recently been recognized, and there are no international diagnostic criteria for this disease. Differentiating adult FPIES from immediate-type food allergy reactions and providing specific treatment for each in an emergency are important, but methods have not been developed. ObjectiveTo develop a diagnostic scoring system for adult FPIES by comparing it with an immediate-type food allergy (IgE-mediated food allergy [IgE-FA]). MethodsThis retrospective cohort study of food-avoidant adults based on the diagnostic criteria for adult FPIES reported by Gonzalez et al was conducted through telephone interviews. We compared the clinical profiles of the patients with FPIES and IgE-FA. Adult FPIES-associated factors were extracted using multivariate analysis, and a diagnostic scoring system was developed based on odds ratios. ResultsA total of 48 (16.7%) of 288 adults with food allergies were diagnosed with FPIES; of these, 240 (83.3%) had IgE-FA. Seafood was the most common cause of FPIES in adults (68.8%). Multivariate analysis identified an age of onset older than 26 years, more than 10 episodes, a longer latency period, cold sweat, abdominal distention, and vomiting as adult FPIES-associated factors. An adult FPIES diagnostic scoring system was developed using odds ratios with a high area under the curve (0.978), 100% sensitivity, and 87.0% specificity. ConclusionClinical profiles and an adult FPIES diagnostic scoring system were developed for the first time. This scoring system can be useful in differentiating adult FPIES and IgE-FA when treating food-related acute reactions.

Quality of life in adults with food protein–induced enterocolitis syndrome

Quality of life in adults with food protein–induced enterocolitis syndrome

Whole Exome Sequencing Identifies Epithelial and Immune Dysfunction-Related Biomarkers in Food Protein-Induced Enterocolitis Syndrome.

Food protein-induced enterocolitis syndrome (FPIES) is a food allergy primarily affecting infants, often leading to vomiting and shock. Due to its poorly understood pathophysiology and lack of specific biomarkers, diagnosis is frequently delayed. Understanding FPIES genetics can shed light on disease susceptibility and pathophysiology-key to developing diagnostic, prognostic, preventive and therapeutic strategies. Using a well-characterised cohort of patients we explored the potential genome-wide susceptibility factors underlying FPIES. Blood samples from 41 patients with oral food challenge-proven FPIES were collected for a comprehensive whole exome sequencing association study. Notable genetic variants, including rs872786 (RBM8A), rs2241880 (ATG16L1) and rs2289477 (ATG16L1), were identified as significant findings in FPIES. A weighted SKAT model identified six other associated genes including DGKZ and SIRPA. DGKZ induces TGF-β signalling, crucial for epithelial barrier integrity and IgA production; RBM8A is associated with thrombocytopenia absent radius syndrome, frequently associated with cow's milk allergy; SIRPA is associated with increased neutrophils/monocytes in inflamed tissues as often observed in FPIES; ATG16L1 is associated with inflammatory bowel disease. Coexpression correlation analysis revealed a functional correlation between RBM8A and filaggrin gene (FLG) in stomach and intestine tissue, with filaggrin being a known key pathogenic and risk factor for IgE-mediated food allergy. A transcriptome-wide association study suggested genetic variability in patients impacted gene expression of RBM8A (stomach and pancreas) and ATG16L1 (transverse colon). This study represents the first case-control exome association study of FPIES patients and marks a crucial step towards unravelling genetic susceptibility factors underpinning the syndrome. Our findings highlight potential factors and pathways contributing to FPIES, including epithelial barrier dysfunction and immune dysregulation. While these results are novel, they are preliminary and need further validation in a second cohort of patients.

Gut microbiome features in pediatric food allergy: a scoping review.

Increasing evidence suggests that alterations in the gut microbiome (GM) play a pivotal role in the pathogenesis of pediatric food allergy (FA). This scoping review analyzes the current evidence on GM features associated with pediatric FAs and highlights the importance of the GM as a potential target of intervention for preventing and treating this common condition in the pediatric age. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, we searched PubMed and Embase using the keywords (gut microbiome OR dysbiosis OR gut microbiota OR microbiome signatures) AND (food allergy OR IgE-mediated food allergy OR food protein-induced allergic proctocolitis OR food protein-induced enterocolitis OR non-IgE food allergy OR cow milk allergy OR hen egg allergy OR peanut allergy OR fish allergy OR shellfish allergy OR tree nut allergy OR soy allergy OR wheat allergy OR rice allergy OR food sensitization). We included 34 studies reporting alterations in the GM in children affected by FA compared with healthy controls. The GM in pediatric FAs is characterized by a higher abundance of harmful microorganisms (e.g., Enterobacteriaceae, Clostridium sensu stricto, Ruminococcus gnavus, and Blautia spp.) and lower abundance of beneficial bacteria (e.g., Bifidobacteriaceae, Lactobacillaceae, some Bacteroides species). Moreover, we provide an overview of the mechanisms of action elicited by these bacterial species in regulating immune tolerance and of the main environmental factors that can modulate the composition and function of the GM in early life. Altogether, these data improve our knowledge of the pathogenesis of FA and can open the way to innovative diagnostic, preventive, and therapeutic strategies for managing these conditions.

Food protein-induced enteropathy: a revision for the clinician.

Food protein-induced enteropathy (FPE) belongs to non-IgE gastrointestinal mediated food allergies. FPE is a syndrome characterized by diarrhea, weight loss and failure to thrive in young infants. Cow milk is the culprit food that most frequently causes FPE. The prevalence of FPE has not been fully estimated, but it is relatively rare. The diagnosis is based on the clinical manifestations and histological findings through colonoscopy. Laboratory tests are somewhat helpful in the diagnosis, although there are no disease-specific findings. Allergy testing for food specific IgE is not routinely recommended. The cornerstone of the management of FPE is the removal of culprit food from the diet. FPE is usually a transient condition that resolves in most cases by 1-2 years of life. This review addresses the latest findings on FPE, including a practical guide to assist pediatricians treating children with FPE.

The intestinal microbiome of infants with cow's milk-induced FPIES is enriched in taxa and genes of enterobacteria.

Food protein-induced enterocolitis syndrome (FPIES) is a severe type of non-IgE (immunoglobulin E)-mediated (NIM) food allergy, with cow's milk (CM) being the most common offending food. The relationship between the gut microbiota and its metabolites with the inflammatory process in infants with CM FPIES is unknown, although evidence suggests a microbial dysbiosis in NIM patients. This study was performed to contribute to the knowledge of the interaction between the gut microbiota and its derived metabolites with the local immune system in feces of infants with CM FPIES at diagnosis. Twelve infants with CM FPIES and a matched healthy control group were recruited and the gut microbiota was investigated by 16S amplicon and shotgun sequencing. Fatty acids (FAs) were measured by gas chromatography, while immune factors were determined by enzyme-linked immunosorbent assay and Luminex technology. A specific pattern of microbiota in the gut of CM FPIES patients was found, characterized by a high abundance of enterobacteria. Also, an intense excretion of FAs in the feces of these infants was observed. Furthermore, correlations were found between fecal bifidobacteria and immune factors. These fecal determinations may be useful to gain insight into the pathophysiology of this syndrome and should be taken in consideration for future studies of FPIES patients.

Gut microbiota in infants with food protein enterocolitis.

We explored the effects of two formulas, extensively hydrolyzed formula (EHF) and amino acid-based formula (AAF), on the gut microbiota and short-chain fatty acids (SCFAs) in infants with food protein-induced enterocolitis syndrome (FPIES). Fecal samples of thirty infants with bloody diarrhea receiving EHF or AAF feeding were collected at enrollment, diagnosis of FPIES, and four weeks after diagnosis. The gut microbiota and SCFAs were analyzed using 16 S rRNA gene sequencing and gas chromatography-mass spectrometry, respectively. Microbial diversity of FPIES infants was significantly different from that of the controls. FPIES infants had a significantly lower abundance of Bifidobacterium and a higher level of hexanoic acid compared with controls. In EHF-fed FPIES infants, microbial richness was significantly decreased over time; while the microbial diversity and richness in AAF-fed FPIES infants exhibited no differences at the three time points. By four weeks after diagnosis, EHF-fed FPIES infants contained a decreased abundance of Acinetobacter, whereas AAF-fed FPIES infants contained an increased abundance of Escherichia-Shigella. EHF-fed infants experienced significantly decreased levels of butyric acid and hexanoic acid at four weeks after diagnosis. Infants with FPIES had intestinal dysbiosis and different formulas differentially affected gut microbiota and SCFAs in FPIES infants. We firstly report the impacts of two different nutritional milk formulas on the gut microbial composition and SCFAs levels in infants with FPIES. We show that infants with FPIES have obvious intestinal dysbiosis and different formulas differentially affect gut microbiota and SCFAs in FPIES infants. Understanding the effects of different types of formulas on gut microbial colonization and composition, as well as the related metabolites in infants with FPIES could help provide valuable insights for making choices about feeding practices.

Buckwheat Allergy in Asia.

Buckwheat (BW) allergy is a significant issue in Asia. This review delves into three types of BW allergy: immediate food allergy; food-dependent, exercise-induced anaphylaxis (FDEIA) as a subset of immediate food allergy; and food protein-induced enterocolitis syndrome (FPIES); by comparing data from Asian and non-Asian countries. Most studies on BW have been published in Japan and Korea, and only a few studies on the topic have been done outside Asia. To date, seven components of common BW (Fagopyrum esculentum) and four components of Tartary BW (Fagopyrum tartaricum) have been implicated in BW allergy. Although BW-sIgE has limited utility for evaluating immediate BW allergy, Fag e 3-specific IgE, one of the components of common BW, and the skin prick test are diagnostically useful. The present review aims to shed light on the current state of knowledge, highlight research gaps, and suggest future directions in the management and understanding of BW allergy.

IgE and non-IgE food allergy: A review of immunological mechanisms.

Food allergic (FA) conditions have been classified as immunoglobulin E (IgE) and non-IgE-mediated reactions that affect as many as 8% of young children and 2% of adults in Western countries, and their prevalence seems to be rising. Although the immunologic basis of IgE-mediated FA is well established, the mechanisms that govern non-IgE-mediated FA are not well understood and are marked by a paucity of comprehensive insights. The purpose of the present report is to examine the current classification and epidemiology of non-IgE-mediated FA, the latest immunologic mechanisms that underlie the three most commonly cited non-IgE FA conditions, viz., eosinophilic esophagitis, food protein-induced enterocolitis, and food protein-induced allergic proctocolitis, and explore what allergist/immunologists in practice should be aware of with regard to the condition. An extensive research was conducted in medical literature data bases by applying terms such as FA, non-IgE allergy, tolerance, unresponsiveness, cytokines, CD4+ T helper cell pathways, and key cytokine pathways involved in FA. Current evidence now supports the view that immune dysregulation and cytokine-induced inflammation are the fundamental bases for both IgE- and non-IgE-mediated FA. The existing non-IgE-related FA literature is mostly characterized by a relative dearth of mechanistic information in contrast to IgE-mediated FA, in which the immunologic underpinnings as a T helper type 2 directed entity are well established. Although the need for future methodologic research and adherence to rigorous scientific protocols is essential, it is also necessary to acknowledge past contributions that have given much to our understanding of the condition. In the present report, a novel signature cytokine-based classification of IgE-mediated and non-IgE-mediated allergy is proposed that may offer a novel template for future research in the field of non-IgE-mediated FA. The present report provides an overview of the current classification and frequency of IgE- and non-IgE-mediated FAs, and offers insights and potential solutions to address lingering questions, particularly when concerning the latest immunologic mechanisms that underlie the pathogenesis of non-IgE-mediated FA. Although some progress has been made in recent years toward making diagnostic and treatment options available for these conditions, there still remain many lingering questions and concerns to be addressed, which can be fully understood by future research.

Syndrome d’entérocolite induit par les protéines alimentaires au poisson et aux fruits de mer dans une population pédiatrique belge

Study objectiveThe study aims to analyse 36 children presenting with acute fish and shellfish food protein-induced enterocolitis syndrome. Patients and methodsThis is a retrospective, single-centre study conducted between 2016 and 2024. Diagnosis was established based on the international diagnostic criteria published in 2017. ResultsThe most frequently implicated foods were cod and prawns. The median age at first reaction was 12 months for fish and 61 months for shellfish. Only one out of 35 patients showed positive allergological tests, but 21 out of 36 patients had a personal history of atopy. Twenty-eight patients reacted exclusively to fish, 6 exclusively to shellfish, and 2 to both. Eight patients reacted to multiple types of fish, while 13 tolerated types of fish other than the one responsible for the initial reaction. Four children also reacted to other types of food. ConclusionThis study confirms that fish is one of the most important triggers of food protein-induced enterocolitis in children in Europe and that reactions to shellfish are more frequent at a later age. These patients generally tolerate other types of fish and shellfish than those responsible for the initial reaction. Therefore, it is important to encourage patients to incorporate other varieties of these foods in their diet, if necessary with an introduction through an oral food challenge.

Shift from Cow's Milk Food Protein-Induced Enterocolitis Syndrome to IgE-Mediated Allergy: Case Series and Literature Review.

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy characterized by gastrointestinal symptom onset within 1-4 hours from trigger food ingestion. In the literature, some authors have previously described the possibility that a patient with FPIES may develop an IgE-mediated allergy to the same trigger food, especially cow's milk (CM). Case Presentation: We reported five cases of CM-FPIES converting to IgE-mediated CM allergy presented at our tertiary pediatric Allergy Unit and performed a review of the literature, aiming to characterize the clinical features of patients who are at risk of developing such conversion. Conclusions: This phenomenon raises the question of whether IgE-mediated and non-IgE-mediated allergies represent a spectrum of the same disease and highlights the need for further investigation to understand the pathophysiological mechanisms of this process.

Vivre avec le syndrome d’entérocolite induite par les protéines alimentaires (SEIPA) : impact sur la qualité de vie des patients et de leurs familles

The food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy, often underdiagnosed despite an increasing prevalence. This study aims to assess the impact of FPIES on the quality of life and identify risk factors for psychosocial distress. We collected data from a cohort of 48 pediatric patients with FPIES, recruited by private and hospital allergists through telephone interviews with families. Quality of life, assessed through QUALIN and Peds QL questionnaires, is generally preserved, but psychopathological aspects and sociability are affected. Parental concerns are significant, with 61% experiencing anxiety during the food diversification period. Regarding emotional well-being, 85% of parents express concerns, while FPIES induces stress in 75% of them. Family activity limitations affect 62% of families. FPIES impacts the social life of children (54%) and has a significant financial impact on 57% of families. Negative influences on quality of life include a history of hospitalization, the number of emergency room visits for FPIES, cow's milk as a triggering food, and FPIES to multiple foods. These results emphasize the importance of considering psychosocial dimensions in the overall management of FPIES.

Le syndrome d’entérocolite induite par les protéines alimentaires (SEIPA) en Alsace : description d’une cohorte de 48 patients et analyse des spécificités régionales des aliments déclencheurs

The Food Protein-Induced Enterocolitis Syndrome (FPIES) is a non-IgE-mediated food allergy, primarily manifesting in young children through vomiting. There are numerous differences regarding the implicated foods depending on the country and population studied. The study focused on a regional cohort of 48 children with FPIES in France, aiming to identify the most common triggers and provide appropriate dietary advice to families. Data were collected through telephone interviews with the families of FPIES patients. The results revealed that cow's milk was the most frequent trigger (67%), followed by egg (21%), beef, and fish (10% each). A correlation between reactions to beef and cow's milk was observed. The most commonly reported symptoms were vomiting, followed by abdominal pain, pallor, and diarrhea. IgE sensitization was present in 19% of tested children, with no statistically significant influence on FPIES recovery. In conclusion, this study emphasizes the significance of regional peculiarities in FPIES trigger foods and suggests that dietary recommendations should be adjusted accordingly.

Clinical-Hematological Changes and Predictors of Severity in Acute Food Protein–Induced Enterocolitis Syndrome Reactions at Oral Food Challenge: A Multicenter Observational Study

BackgroundOral food challenge (OFC) is the gold standard for diagnosis of acute Food Protein-Induced Enterocolitis Syndrome (FPIES). No diagnostic/prognostic biomarkers are available, and OFC assessment criteria are not validated. Objective. To assess clinical-haematological changes and predictors of severity of FPIES reactions at OFC. MethodsObservational multicentre prospective study. Children aged 0-18 years diagnosed with acute FPIES were recruited at follow-up OFC in 12 tertiary centres in Spain and Italy. OFC Outcomes (as positive/negative/inconclusive and mild/moderate/severe) were assessed based on published ‘2017 FPIES Consensus’ criteria. Clinical characteristics were recorded, and full blood count was done at baseline, reaction onset and 4 hours later. Regression analysis was performed to assess predictors of severe reactions at OFC. Results81 children had positive OFC (mild in 11% (9/81), moderate in 61% (49/81), severe in 28% (23/81)). Increase in neutrophils and reduction in eosinophils, basophils and lymphocytes was observed (P-value<0.05). OFC was inconclusive in 19 cases despite objective signs or neutrophilia. Regression analysis showed a 2-day OFC protocol where only 25% of an age-appropriate portion is given on day 1 (not gender, age, culprit food, cumulative dose and previous reaction severity) was associated with reduced odds of severe reaction compared to giving multiple doses in a single day. ConclusionDistinct haematological changes may help support FPIES diagnosis. Current OFC assessment criteria may not capture the broad spectrum of acute FPIES presentations. This 2-day protocol may associate a reduced risk of severe reactions. Future work should aim to develop safer OFC and non-OFC diagnostics for FPIES.

Prevalence and clinical presentation of food protein-induced enterocolitis syndrome in an adult allergy/immunology clinic

Prevalence and clinical presentation of food protein-induced enterocolitis syndrome in an adult allergy/immunology clinic

Medical algorithm: Diagnosis and management of adult food protein-induced enterocolitis syndrome.

Medical algorithm: Diagnosis and management of adult food protein-induced enterocolitis syndrome.

Resolution of Food Protein-Induced Enterocolitis Syndrome—A Long-Term Follow-Up Study of 113 Swedish Children

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. This study aimed to evaluate tolerance development and its assessment in a Swedish cohort. 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. 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. 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.

Food protein-induced enterocolitis syndrome in adults: review and practice recommendations

Food protein-induced enterocolitis syndrome (FPIES) is an allergic disorder that manifests as reproducible gastrointestinal symptoms within hours of ingestion of the causative food, which can progress to dehydration and hypotension. Historically, FPIES has been recognized as a disease affecting the pediatric population but it can also develop de novo in adults. The pathophysiology is not well understood; however, the local adaptive immune system and gene expression linked to innate immune activation are implicated. Adult-onset FPIES has some differences with pediatric FPIES. Vomiting may be absent, while abdominal pain is the most common manifestation. A clear predominance in women occurs, being seafood the most common trigger, although many other foods have also been implicated. Diagnosis of adult-onset FPIES is based on a thorough clinical history but in many cases, it should be followed by an oral food challenge (OFC), due to the absence of vomiting in some patients and the lack of confirmatory diagnostic test. The first-line treatment for acute FPIES reactions is fluid replacement, by the oral route in mild to moderate reactions or via the intravenous route in severe reactions. Ondansetron may be effective in shortening the duration of emesis. Management of patients after diagnosis includes dietary advice and follow-up with supervised OFC at regular intervals to monitor for resolution. Tolerance to the trigger food in children is commonly achieved, a finding not so common in adult-onset FPIES. The aim of this article is to review the most important current concepts in epidemiology, pathophysiology, diagnosis, and management of FPIES.

Navigating Food Allergies: Advances in Diagnosis and Treatment Strategies.

Food allergy is a major health concern worldwide, encompassing both immunologic and non-immunologic reactions. This review thoroughly examines the pathophysiology, clinical manifestations, and treatment options for various types of food allergies. Immunologic food allergies, including IgE-mediated reactions such as oral allergy syndrome and systemic anaphylaxis, pose various diagnostic and management challenges. Non-IgE-mediated reactions such as food protein-induced enterocolitis syndrome, dermatitis herpetiformis, and proctocolitis necessitate individualized patient care.In addition, mixed reactions such as eosinophilic esophagitis and atopic dermatitis complicate the clinical picture. Skin prick tests, serum-specific IgE tests, and oral food challenges are all necessary for accurate food allergy diagnosis. The primary therapeutic options are allergen avoidance, epinephrine-based emergency management, and emerging treatments like immunotherapy. Our review emphasizes the importance of multidisciplinary collaboration and ongoing research in improving our understanding and managing food allergies, promising a brighter future for those affected.