Acute Food Protein-induced Enterocolitis Syndrome Research Articles

The role of IgE sensitisation in acute FPIES: A systematic review and meta-analysis.

Evidence on the role of IgE sensitisation in acute Food Protein-Induced Enterocolitis Syndrome ('atypical FPIES') is limited. Initial reports claimed association with persistent disease, however recent studies have not replicated this. To systematically review the relationship between sensitisation to the culprit food(s) in acute FPIES and the outcome of follow-up oral food challenges. To assess rates of sensitisation, seroconversion (i.e. switch from negative tests to sensitisation) and phenotype switch to IgE-mediated food allergy over time in individuals with acute FPIES. Systematic review searching 10 databases. Studies of children and adults with acute FPIES diagnosis assessing IgE sensitisation to culprit food at onset or follow-up measured by skin prick or serological test were included. Of 1830 studies identified, 53 were eligible including 3514 participants. Ten studies had an analytical design assessing whether sensitisation was associated with disease persistence, with 4 showing an association and 6 showing no association. In individuals with acute FPIES, the sensitisation rate was 9.8% (95% CI: 7.4-12.1%; 34 studies, 2587 participants, I2 = 82%); the frequency of seroconversion was 1.1% (95% CI: 0.1-2.1%; 9 studies, 673 participants, I2=32%); and phenotype switch occurred in 1.1% (95% CI: 0.4-1.7%; 14 studies, 935 participants, I2 =0%) and 13% (95% CI: 5.5-20.5%, 12 studies, 93 participants; I2=18%) of sensitised participants. We did not find consistent evidence for the relationship between IgE sensitisation and FPIES persistence. We found phenotype switch to IgE-mediated food allergy is uncommon in acute FPIES. IgE-sensitisation in FPIES does not have a clear relationship with clinical outcomes.

The Non-Food-Specific Dynamics for Tolerance Acquisition in Acute Food Protein-Induced Enterocolitis Syndrome.

The Non-Food-Specific Dynamics for Tolerance Acquisition in Acute Food Protein-Induced Enterocolitis Syndrome.

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.

A rare cause of methemoglobinemia; food protein-induced enterocolitis syndrome

Food protein-induced enterocolitis syndrome, an uncommon non-immunoglobuline E mediated food hypersensitivity, is characterized by profuse vomiting, diarrhea and acute dehydration. There are no specific laboratory findings, however leukocytosis, metabolic acidosis and rarely methemoglobinemia may be observed. The primary treatment involves elimination of the food that causes the allergic reaction. Here we report the case of a 45-day-old female infant diagnosed acute food protein-induced enterocolitis syndrome co-existing with methemoglobinemia.

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.

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.

Personalization of Complementary Feeding in Children With Acute Food Protein–Induced Enterocolitis Syndrome

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.

A case report of acute food protein-induced enterocolitis syndrome to walnut

BackgroundFood protein-induced enterocolitis syndrome (FPIES) is a delayed, non-IgE-mediated food allergy. This syndrome was once thought to be rare, but emerging literature suggests an increasing incidence along with more foods being implicated. Also, with the introduction of guidelines on early peanut introduction, peanut-induced FPIES seems to be increasing in Australia and USA. Although most patients are diagnosed with FPIES within the first year of life, most commonly with food triggers to cow’s milk or soy, other phenotypes exist in comparison to this classic presentation. In this case report, we present a patient with late onset of acute FPIES at age 3 to walnut.Case PresentationWe describe a case of FPIES in a 12-year-old boy who had recurrent episodes of repetitive emesis, that began at age 3, each time after consuming walnuts. Mom does not give a history of intentional feeding (or avoidance) of walnut and/ or pecans. She also described possible reactions with pine nuts and macadamia. He was assessed with an oral food challenge to walnut, which triggered an episode of acute FPIES. He developed vomiting with onset 2 h post-ingestion, pallor, lethargy, and required an emergency department visit for anti-emetic medications and oral rehydration therapy. He improved on the therapy and now avoids cashew, pistachio, hazelnuts, walnuts, pecans, pine nuts, and macadamia nuts.ConclusionsThis case report adds to the limited literature that exists on culprit food allergens in FPIES. We present an acute FPIES triggered by the ingestion of walnuts. The diagnosis, common food triggers, and natural history of FPIES are described. There remains a lack of information on the natural history of FPIES, especially towards uncommon food triggers and on FPIES that present beyond infancy.

Food protein-induced enterocolitis syndrome is an important differential diagnosis of vomiting in pediatric emergency.

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. 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. The number of infants with acute FPIES-like symptomswas 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. 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.

Remission of Acute Food Protein-Induced Enterocolitis Syndrome Confirmed by Oral Food Challenges in Japan.

The oral food challenge test (OFC) is the gold standard for evaluating the remission of food protein-induced enterocolitis syndrome (FPIES). Few acute FPIES remissions confirmed by OFC were reported. This study aimed to examine the OFC for Japanese children with acute FPIES to evaluate its remission. A retrospective cohort study was performed on children with acute FPIES with remission evaluation by OFC based on one food challenge dose (1/50, 1/10, 1/2, and full dose per day). Acute FPIES remission was observed in 65.2% of patients (15/23 patients). Vomiting episodes occurred with 1/50 full doses on the first day among 75% of positive patients. The median duration between the onset and OFC was 14 months (IQR, 8–24 months). Soy was the most common causative food, followed by egg yolk, milk, and wheat. All patients could receive OFC safely without intensive care unit care, based on the FPIES OFC protocol. The remission rate of acute FPIES was high. However, vomiting episodes commonly occurred with 1/50 full doses on the first day. This study suggested that our OFC protocol for acute FPIES was safe and feasible, but it might be safer for some patients to start at a minimal loading dose.

The Natural Course of Adult-Onset Food Protein-Induced Enterocolitis Syndrome

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. To evaluate the natural course of FPIES in adults. 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. 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. Some patients may outgrow adult-onset FPIES.

Adherence to dietary prescriptions in patients with acute food protein-induced enterocolitis syndrome.

ABSTRACTFood protein‐induced enterocolitis syndrome (FPIES) is a non‐Immunoglobulin (non‐IgE)‐mediated food allergy. The elimination diet is the only therapy, the culprit food will be reintroduced if tolerance is acquired. However, it is possible that patients do not follow the recommendations given by the healthcare professional. We investigated if our advice to avoid the trigger food in patients with active FPIES and to reintroduce it in the diet in patients who achieved tolerance had been implemented. We interviewed by telephone the parents of children who were diagnosed with acute FPIES. About 23.2% of our patients disregarded our dietary recommendations: 6/42 (14.3%) of patients who passed a tolerance oral food challenge (OFC) did not eat the trigger food, 4/22 (18.2%) of patients who failed OFC ate the trigger food, and 9/18 (50.0%) of patients who did not perform a tolerance OFC ate the trigger food. We have analyzed some possible influencing factors and no difference was found to be statistically significant. Our results are in line with those reported for IgE‐mediated food allergies. As has already been proposed by others, we suggest reassessing food consumption in all patients after a food challenge.

Proposal of a Questionnaire for Acute Food Protein-induced Enterocolitis Syndrome Diagnosis.

Sopo, Stefano Miceli∗; Mastellone, Francesco†; Sinatti, Dario†; Gelsomino, Mariannita† Author Information

Development of an Action Plan for Acute Food Protein–Induced Enterocolitis Syndrome in Japan

The prevalence of food protein–induced enterocolitis syndrome (FPIES) in Japan has been increasing. However, the disease itself and the treatment options are poorly understood by both patients and medical professionals. Therefore, we developed an action plan for acute FPIES in Japan.

Association of Antibiotic Usage with Food Protein-Induced Enterocolitis Syndrome Development from a Caregiver's Survey.

Food protein-induced enterocolitis syndrome (FPIES) is a frequently misdiagnosed, serious, non-IgE mediated food allergy, and the precise mechanism of disease is unknown. Acute FPIES typically presents with repetitive, profuse vomiting approximately 1-4 hours post ingestion of a food trigger. Chronic FPIES is considered less common and less well characterized. We aimed to better describe FPIES and identify factors that may influence FPIES development through use of a self-reported, caregiver's survey. FPIES and allergy-free infant caregivers completed a survey regarding lifestyle factors that may influence allergy acquisition such as: antibiotic usage and delivery mode. FPIES caregivers reported symptoms, number of food triggers, type of FPIES, and symptoms from breastmilk ingestion. FPIES infants were compared to allergy-free infants to identify factors potentially associated with FPIES. Infant and prenatal maternal antibiotic usage was higher in FPIES infants compared to allergy-free infants (43.8% vs 20.6% and 48.8% vs 23.57%, respectively, p< 0.05). When compared to infants with ACUTE FPIES alone, infants described as BOTH acute and chronic FPIES reported earlier onset of symptoms, more non-specific symptoms and symptoms triggered by breast milk, more antibiotic exposure, and more food triggers (p< 0.05). Antibiotic usage was significantly higher in FPIES infants when compared to allergy-free infants. Work is needed to elucidate the role of antibiotic usage in the etiology of FPIES. Infants reported to have BOTH acute and chronic FPIES were significantly different from infants with ACUTE FPIES alone highlighting the need to more closely examine these different subtypes of FPIES.

Concomitant cow's milk and beef food protein–induced enterocolitis syndrome in a young infant

Acute food protein–induced enterocolitis syndrome (FPIES) is a non–immunoglobulin E (IgE) cell-mediated food hypersensitivity. Common causes include cow's milk (CM), soy, rice, and oat, although any food can be a potential culprit.1

Retrospective analysis of 222 oral food challenges with a single dose in acute food protein-induced enterocolitis syndrome.

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. 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 ≤5mm. 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. 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). 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.

Clinical presentation and management of food protein-induced enterocolitis syndrome in 113 Swedish children.

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. 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. 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 3.9months for cow's milk and 6.0months for other foods (p<0.001, range 1.0month to 9years). 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%). 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.

Criteria for the suspicion and diagnosis of acute food protein-induced enterocolitis syndrome.

Over the past decades, several panels of criteria have been proposed for the diagnosis of acute food protein-induced enterocolitis syndrome (FPIES). However, none of them have been validated by a prospective study. Such a study is not easy to carry out, because even the children who most of us would certainly believe to be suffering from acute FPIES, possibly serious, should be subject to oral food challenge (OFC). Moreover, the presence of different phenotypes of the acute FPIES may mean that some of them do not fit into any of the above criteria panels. Particularly, Vazquez-Ortiz et al. reported that milder cases (1/4 in their Southern European cohort) might not be captured by the 2017 Consensus diagnostic criteria, which are the most shared till date. Those authors, as well as all interested researchers, claim for accurate diagnostic bio-markers which, however, are not available at the moment.

Diagnostic criteria for food protein–induced enterocolitis syndrome: Can we do better?

Acute food protein–induced enterocolitis syndrome (FPIES) is a non–immunoglobulin E (IgE)–mediated food allergy characterized by profuse vomiting usually 1 to 4 hours after ingestion. It is often associated with pallor, lethargy, and diarrhea, and can lead to hypotension and shock. It affects mainly infants when foods are introduced. There are no pathognomonic features or diagnostic biomarkers, partly because the pathophysiology of FPIES is poorly understood. Diagnosis is based on the clinical history and it can be challenging, particularly for nonspecialists.