IL10 and CXCL10 mRNA expression in food protein-induced enterocolitis syndrome.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a rare non-IgE-mediated food allergy that mainly impacts babies and 7toddlers. The exact mechanism of FPIES is not completely understood. By studying the expression of IL-10 and CXCL10 in pediatric FPIES patients, researchers can gain insights into the immune mechanisms underlying this disorder. METHODS: Peripheral venous blood was collected and subsequently stabilized with RNA pro. Total RNA was extracted and mRNA levels of CXCL10 and IL-10 was determined with real time PCR. RESULTS: Children with FPIES had significantly higher values than the healthy control group (HC) for CXCL10 while FPIES had a significant lower values than the control group for IL-10. CONCLUSIONS: Our results show a high production of CXCL10 and a concomitant reduced production of IL-10 in FPIES subjects who have not yet reached tolerance. These data may represent a molecular diagnostic marker for FPIES.

Contribution of T cell subsets to different food allergic diseases.

Food allergies occur due to a lack of tolerance to the proteins found in foods. While IgE- and non-IgE-mediated food allergies have different clinical manifestations, epidemiology, pathophysiology, and management, they share dysregulated T cell responses. Recent studies have shed light on the contributions of different T cell subsets to the development and persistence of different food allergic diseases. This review discusses the role of T cells in both IgE- and non-IgE-mediated food allergies and considers the potential future investigations in this context.

Severe Food Protein-Induced Enterocolitis Syndrome After Hematopoietic Stem Cell Transplantation: Pediatric Case Report.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy. In the last few years, after the publication of the consensus guidelines, with refined diagnostic criteria and improved awareness, FPIES is diagnosed with increased frequency. However, despite having a background of immune dysregulation, this complication has just been described once in the posttransplant setting, in an adult patient. To the best of our knowledge, there are no reports of pediatric patients developing FPIES after a hematopoietic stem cell transplant (HCT). METHODS: Retrospective review of a pediatric patient who developed severe FPIEs after a HCT. RESULTS: In this case report, the clinical presentation and diagnosis challenges of a pediatric patient who developed severe FPIES after HCT are described. The patient developed severe vomiting, diarrhea, lethargy, and shock and required admission to the pediatric intensive care unit in three occasions before the diagnosis was made. CONCLUSIONS: To the best of our knowledge, this is the first report of severe FPIES post-HCT in a pediatric patient. Physicians who are looking after pediatric patients in the post-HCT setting need to be aware of this possibility and include this entity in the differential diagnosis in order to reduce its associated morbidity.

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

BACKGROUND: Oral food challenge (OFC) is the criterion 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-hematological changes and predictors of severity of FPIES reactions at OFC. METHODS: This was an observational multicenter prospective study. Children aged 0 to 18 years diagnosed with acute FPIES were recruited at follow-up OFC in 12 tertiary centers in Spain and Italy. OFC outcomes (as positive/negative/inconclusive and mild/moderate/severe) were assessed on the basis of published "2017 FPIES Consensus" criteria. Clinical characteristics were recorded, and full blood cell count was done at baseline, reaction onset, and 4 hours later. Regression analysis was performed to assess predictors of severe reactions at OFC. RESULTS: A total of 81 children had positive OFC (mild in 11% [9 of 81], moderate in 61% [49 of 81], and severe in 28% [23 of 81]). Increase in neutrophils and reduction in eosinophils, basophils, and lymphocytes were observed (P < .05). OFC was inconclusive in 19 cases despite objective signs or neutrophilia. Regression analysis showed that a 2-day OFC protocol where only 25% of an age-appropriate portion is given on day 1 (not sex, age, culprit food, cumulative dose, and previous reaction severity) was associated with reduced odds of severe reaction compared with giving multiple doses in a single day. CONCLUSIONS: Distinct hematological 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 be associated with a reduced risk of severe reactions. Future work should aim to develop safer OFC and non-OFC diagnostics for FPIES.

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

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.

A Second Slice of FPIES: A Single-Center Reappraisal of Pediatric FPIES.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is being increasingly recognized as a non-IgE-mediated food allergy; however, it remains unclear if and how the presentation, diagnosis, and management of this disease has changed in recent years. OBJECTIVE: To reappraise the FPIES cohort at a large US pediatric tertiary referral center. METHODS: We performed a retrospective chart review of pediatric patients with FPIES (International Classification of Diseases, Tenth Revision code K52.21) diagnosed in our allergy/immunology clinics between 2018 and 2022. RESULTS: There were 210 children diagnosed with FPIES. Most were White (73.8%), non-Hispanic (71.4%), and male (54.3%) with private insurance (77.6%). Cow's milk was the most common food trigger (35.2%), with the earliest median age of onset of 5 months. The atypical FPIES rate was 13.8%. FPIES was accurately diagnosed in 54.3% at the first medical contact. The oral food challenge pass rate was 73.5%. The rate of trigger resolution at 36 months was 77%. CONCLUSIONS: By comparing trends from a previous and current FPIES cohort, we were able to assess the potential impact of various guidelines and practice changes on the diagnosis and management of FPIES at our center. Milk and oat surpassed rice as the most common FPIES triggers; peanut and egg emerged as new FPIES triggers; there was a shorter time to diagnosis and an increased rate of atypical FPIES. Our findings reflect earlier recognition of FPIES and prompt allergy/immunology referral from community physicians, implementation of recent medical society guidelines for infant feeding practices, and growing clinical expertise of allergists at our center.

Effectiveness of continuous allergenic food intake for acute food protein-induced enterocolitis syndrome.

Continuous intake of allergenic food is a safe and efficient treatment strategy for patients with a prolonged course of acute food protein-induced enterocolitis syndrome. The initial dose, dose escalation rate, and starting age for continuous allergenic food intake need further clarification.

Heterogeneity of food protein-induced enterocolitis syndrome (FPIES).

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy with gastrointestinal symptoms such as vomiting and diarrhea. The development of international consensus guidelines for the diagnosis and management of FPIES in 2017 enabled us to compare patients worldwide, regardless of geographic variation in disease features. As a result, it has become clear that there is heterogeneity among patients with FPIES or that there are cases that partly fit the diagnostic criteria for FPIES but have different characteristics. This review highlights the heterogeneity in FPIES characteristics in terms of trigger foods, the age of onset, differences in geographic regions, and symptoms; it further proposes four disease entities, including acute FPIES in children, acute FPIES in adults, chronic FPIES, and early-onset neonatal FPIES, depending on the age of onset and presumed pathophysiology. The major symptoms at onset and trigger foods differ in acute FPIES in children, acute FPIES in adults, and chronic FPIES, whereas the disease entities may share a similar pathophysiology. Early-onset neonatal FPIES may have a different pathophysiology than acute or chronic FPIES, and may not necessarily fulfil the full diagnostic criteria for acute or chronic FPIES described in the international consensus guidelines. Due to the similarity in symptoms, early-onset neonatal FPIES may sometimes be misdiagnosed as necrotizing enterocolitis. We aim to increase awareness of FPIES among medical staff in pediatrics, neonatology, and internal medicine and promote research, to gain a better understanding of the heterogeneity and pathophysiology of FPIES.

Differences in Characteristics Between Patients Who Met or Partly Met the Diagnostic Criteria for Food Protein-Induced Enterocolitis Syndrome (FPIES).

BACKGROUND: Some patients with food protein-induced enterocolitis (FPIES)-like allergy do not completely fulfill the diagnostic criteria of the international consensus guideline for FPIES. However, it is unclear whether such FPIES-like patients represent a completely different population from FPIES. OBJECTIVE: This study aimed to clarify differences in characteristics between patients with FPIES who fully met diagnostic criteria and those who partly met them. METHODS: This was a cross-sectional study using data at the time of registration in multicenter, prospective studies of patients with FPIES in Japan. Children who had delayed emesis within 1 to 4 hours and/or diarrhea within 5 to 10 hours after ingestion of food were recruited between March 2020 and February 2022. We examined their compatibility with the diagnostic criteria of the international consensus guideline and their detailed clinical characteristics, including trigger foods, the serving size that elicited symptoms, and antigen-specific IgE antibody titers. RESULTS: Of the 225 patients with FPIES, 140 fully met the diagnostic criteria whereas 79 patients did not fully meet them but demonstrated reproducible symptoms. The frequencies of pallor, lethargy, and diarrhea were significantly higher in those who met the criteria fully, whereas the age at onset, trigger foods, comorbidity, and perinatal information were comparable. Analysis of patients with FPIES to hen's egg revealed significantly higher levels of egg white- and egg yolk-specific IgE in patients who partly met criteria, whereas the serving size eliciting symptoms was comparable. CONCLUSIONS: Patients who partly met the diagnostic criteria may have a milder phenotype of FPIES, but this needs to be validated in further studies using biomarkers reflecting the pathophysiology.

Delayed presentation of food protein-induced enterocolitis syndrome (FPIES) to okra in a toddler.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobulin E (IgE) -mediated food allergy predominantly observed in infants and characterized by the delayed onset of vomiting following ingestion of a trigger food. An increase in research and clinical consideration of FPIES has led to the discovery of unique deviations from the standard FPIES triggers and presentations. CASE PRESENTATION: A 34-month-old female patient with a history of consuming okra daily presented to medical attention after developing classic FPIES symptoms to okra beginning at 14-months of age. CONCLUSIONS: Recently, awareness about the varied nature of FPIES clinical presentation has come to light. This case is the first to describe FPIES to the fruit okra that developed over a 12-month time span after previously tolerating the food. This case serves to emphasize the importance of understanding the range of FPIES symptoms to improve recognition and expedite best practice recommendations.

Current and future perspectives on the consensus guideline for food protein-induced enterocolitis syndrome (FPIES).

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE mediated food allergy presenting with delayed onset of projectile vomiting in the absence of cutaneous and respiratory symptoms. The pathophysiology of FPIES remains poorly characterized. The first international consensus guidelines for FPIES were published in 2017 and provided clinicians with parameters on the diagnosis and treatment of FPIES. The guidelines have served as a resource in the recognition and management of FPIES, contributing to an increased awareness of FPIES. Since then, new evidence has emerged, shedding light on adult-onset FPIES, the different phenotypes of FPIES, the recognition of new food triggers, center-specific food challenge protocols and management of acute FPIES. Emerging evidence indicates that FPIES impacts both pediatric and adult population. As a result, there is growing need to tailor the consensus guidelines to capture diagnoses in both patient groups. Furthermore, it is crucial to provide food challenge protocols that meet the needs of both pediatric and adult FPIES patients, as well as the subset of patients with atypical FPIES. This review highlights the evolving clinical evidence relating to FPIES diagnosis and management published since the 2017 International FPIES Guidelines. We will focus on areas where recent published evidence may support evolution or revision of the guidelines.

Fish Allergy and Related Conditions in Children: A Review.

Fish allergy is the important food allergies in childhood, often persisting into adulthood. It can cause severe hypersensitivity reactions, including fatal anaphylaxis; furthermore, avoiding-fish diet has negative nutritional and psychological effects. Recent research studies focus on epitope structures and aim to develop sensitive and specific diagnostic tools, which have a better correlation with clinical reactions. Protocols with hypoallergenic parvalbumin or other recombinant antigens are also under study and will likely lead to new immunotherapy protocols. IgE-mediated fish allergy differs substantially from other forms of immunological adverse reactions to fish, such as Food Protein-Induced Enterocolitis Syndrome and eosinophilic esophagitis. In addition, fish ingestion can cause non-immunological adverse reactions, such as in the case of scombroid poisoning, anisakiasis and toxic poisoning. This review aims to summarize the characteristics of the main immunological and non-immunological fish reactions, analyzing the epidemiology, clinical manifestations, diagnosis and therapy, with a particular focus on clinical management.

Psychosocial Impact of Food Allergy on Children and Adults and Practical Interventions.

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. 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.

A nationwide survey of non-IgE-mediated gastrointestinal food allergies in neonates and infants.

BACKGROUND: Non-IgE-mediated gastrointestinal food allergies (non-IgE-GIFAs) seem to be increasing rapidly worldwide. However, nationwide studies have been limited to food-protein-induced enterocolitis (FPIES) and food-protein-induced allergic proctocolitis (FPIAP), with little attention to other non-IgE-GIFA subgroups. The aim of this study was to elucidate the clinical features of all patients with non-IgE-GIFAs, not just certain subgroups. METHODS: We conducted a nationwide cross-sectional survey of non-IgE-GIFAs in Japan from April 2015 through March 2016. A questionnaire was sent to hospitals and clinics throughout Japan. The questionnaire asked about the number of physician-diagnosed non-IgE-GIFA patients, the status of fulfillment of the diagnostic criteria, tentative classification into 4 clusters based on the initial symptoms, the day of onset after birth, complications, and the suspected offending food(s). RESULTS: The response rate to that questionnaire was 67.6% from hospitals and 47.4% from clinics. Analyses were conducted about "diagnosis-probable" patient cohort (n = 402) and the "diagnosis-confirmed" patients (n = 80). In half of the reported non-IgE-GIFA patients, onset occurred in the neonatal period. The patients were evenly distributed among 4 non-IgE-GIFA clusters. In Cluster 1, with symptoms of vomiting and bloody stool, the onset showed a median of 7 days after birth, which was the earliest among the clusters. Cow's milk was the most common causative food. CONCLUSIONS: In half of the patients, the onset of non-IgE-GIFAs was in the neonatal period. This highlights the importance of studying the pathogenesis in the fetal and neonatal periods.

Cow's Milk Protein Allergy.

Cow's milk allergy refers to an immunological reaction to milk protein. It is one of the commonest food protein allergies with an estimated prevalence of 0.5% to 3% at 1 y of life. The disease may be IgE or non-IgE mediated or mixed with a wide range of symptoms often involving multiple organ systems. Gastrointestinal manifestations are common in non-IgE disease and may consist of enteropathy, proctocolitis, colic, reflux-like symptoms, constipation, enterocolitis syndrome and eosinophilic esophagitis. The gold standard for diagnosis remains a double-blind placebo-controlled oral challenge. Specific IgE and skin prick tests may predict severe and persistent disease, and aid in deciding on reintroduction or oral immunotherapy; however, they do not contribute to a definitive diagnosis as they indicate only sensitization. In practice, an elimination diet followed by open challenge under medical supervision is often used for diagnosis except when symptoms are severe such as anaphylaxis. Management consists of the elimination of the allergen with resolution of symptoms between 1-4 wk later depending on the type of allergy. Extensively hydrolyzed and Amino acid formulas are used to substitute milk in infants. Soy-based formulas are often utilized in resource-limited settings. Tolerance to the protein develops over time and periodic reintroduction should be attempted every six months after the initial one year of elimination diet. Oral immunotherapy is a newer treatment technique for IgE-mediated disease. There is no firm evidence on prevention apart from recommending breast feeding in early life along with initiating complementary feeding between 4-6 mo age.

A possible unexpected link: Could wheat elimination trigger food protein-induced enterocolitis syndrome in a celiac disease patient?

Cases of association between celiac disease and wheat allergy have been described in the literature. However, to date, no reported cases have linked celiac disease with wheat food protein-induced enterocolitis syndrome (FPIES). We report a case of this association. A child diagnosed with celiac disease at the age of 2 years, following a gluten-free diet, experienced uncontrollable vomiting, and subsequent hypotension within 2 h of accidental ingestion of wheat flour. As a result, the child required hospitalization for fluid therapy. A similar episode occurred when the child turned 5 y, again resulting from accidental gluten ingestion. This time, the symptoms included vomiting, hypotension, and a loss of consciousness, leading to hospitalization for rehydration treatment. After this second episode, on suspicion of FPIES, the patient was referred to the pediatric allergists, who confirmed the diagnosis. To our knowledge, this is the first case of an association between celiac disease and FPIES. It has been hypothesized that exclusion diets in food-allergic children may lead to an increase in specific immunoglobulin E levels for those foods and, consequently, the risk of anaphylaxis. However, FPIES is not an immunoglobulin E-mediated condition. Hence, further investigations are warranted to elucidate the underlying mechanisms linking these 2 disorders.

A detailed intake-status profiling of seafoods in adult food-protein-induced enterocolitis syndrome patients.

BACKGROUND: Adults with food-protein-induced enterocolitis syndrome (FPIES) often develop severe abdominal symptoms after eating seafood. However, no investigation of a food elimination strategy for adult FPIES patients has been performed to date. METHODS: We conducted a retrospective cohort study of seafood-avoidant adults by telephone interview, based on the diagnostic criteria for adult FPIES reported by González et al. We compared the clinical profiles, abdominal symptoms, and causative seafoods between FPIES and immediate-type food allergy (IgE-mediated FA) patients. We also profiled the detailed intake-status of seafoods in adult FPIES patients. RESULTS: Twenty-two (18.8 %) of 117 adults with seafood-allergy were diagnosed with FPIES. Compared with the IgE-mediated FA patients, FPIES patients had an older age of onset, more pre-existing gastrointestinal and atopic diseases, more episodes, longer latency and duration of symptoms, more nausea, abdominal distention, and severe abdominal pain, and more frequent vomiting and diarrhea. In particular, abdominal distention-reflecting intestinal edema and luminal fluid retention-may be the most distinctive characteristic symptom in adult FPIES (p < 0.001). Bivalves, especially oysters, were the most common cause of FPIES. Strikingly, intake-status profiling revealed that many FPIES patients can safely ingest an average of 92.6 % of seafood species other than the causative species. CONCLUSIONS: There are many differentiators between FPIES and IgE-mediated FA, which may reflect differences in the underlying immunological mechanisms. Although seafood FPIES is unlikely to induce tolerance, many patients can ingest a wide variety of seafood species after a long period from onset.

Diagnostic and Management Strategies of Food Protein-Induced Enterocolitis Syndrome: Current Perspectives.

Food protein-induced enterocolitis syndrome (FPIES) is a form of non-IgE mediated food allergy that presents with delayed gastrointestinal symptoms after ingestion of the trigger food. The data regarding FPIES are sparse, despite being recognized as a distinct clinical entity. This narrative review presents the characteristics of this disorder in the pediatric population, as well-standard diagnostic and management protocols. FPIES can be classified into acute and chronic subtypes, and some cases may develop into an IgE-mediated allergy. Given that skin prick tests and specific IgE levels are negative in the majority of cases, diagnosis relies on clinical history and oral food challenges. Management involves elimination diets, assessment of tolerance through oral food challenges, and rehydration in the event of a reaction. Future research should focus on improving diagnostic methods, illustrating underlying pathogenesis and biomarkers, and assessing long-term natural history. Increased knowledge and awareness for FPIES are required.