Chronic Food Protein-induced Enterocolitis Syndrome Research Articles

Food protein-induced enterocolitis syndrome (FPIES): Beyond the guidelines

Background: Food protein‐induced enterocolitis syndrome (FPIES) is a non‐immunoglobulin E (IgE) cell mediated food allergy that can cause severe symptoms and is considered an allergic emergency. Objective: To describe FPIES epidemiology and appraise the approach to diagnosis and management. Methods: A review of the relevant articles published in the peer-reviewed journals since the publication of the First International FPIES Consensus Guidelines in 2017. Results: FPIES is estimated to affect 0.51‐0.9% of children and 0.22% of adults in the United States. It typically presents with protracted, projectile vomiting, which occurs within 1‐4 hours of ingesting culprit foods, sometimes followed by diarrhea within 24 hours of ingestion. In ∼15‐20% of severe cases, patients go into hypovolemic or distributive shock. In chronic FPIES, infants may have failure to thrive and weight loss. The most common triggers include cow’s milk, oat, rice, and avocado, with egg and peanut being more frequently reported. Examples of other common fruit and vegetable triggers include banana, apple, and sweet potato. FPIES can be classified into acute, chronic, adult-onset, or atypical subtypes. FPIES is associated with comorbid atopic conditions of IgE-mediated food allergy, atopic dermatitis, asthma, allergic rhinitis, and eosinophilic esophagitis. The natural history of infantile FPIES is generally favorable, with the exception of fish FPIES. Seafood FPIES in adults has low rates of resolution over 3‐5 years. Correctly identifying FPIES can be challenging because there are no specific biomarkers for diagnosis and the constellation of symptoms may mimic those of infectious enteritis or sepsis. Management relies on dietary food avoidance, periodic re-evaluations for tolerance with oral food challenges, and management of acute reactions with rehydration and antiemetic ondansetron. Although the pathophysiology of FPIES remains poorly understood, underlying mechanisms such as cytokine release, leukocyte activation, and impaired gastrointestinal mucosal barrier function may act as cornerstones for further research. Conclusion: Prevention, laboratory diagnostic testing, and strategies to accelerate tolerance development are urgent unmet needs in FPIES.

Recent topics on gastrointestinal allergic disorders.

Gastrointestinal (GI) allergies are broadly associated with food allergies and divided into groups based on the degree of allergen-specific immunoglobulin E (IgE) involvement: IgE-mediated, non-IgE-mediated, and mixed. Non-IgE-mediated GI food allergies are mostly observed in neonates and infants and include food protein-induced enterocolitis syndrome (FPIES), food protein-induced allergic proctocolitis (FPIAP), and food protein-induced enteropathy (FPE). In addition to the classical phenotype, unique phenotypes such as vomiting and bloody stool, suspected sepsis, and overlapping eosinophilic GI disorders (EGIDs) have increased in Japan over the past 2 decades. Some of these cases were defined as having chronic FPIES. More recently, cases of hen's-egg FPIES in Japan have increased dramatically since 2018, albeit for unknown reasons. Typical mixed-type food allergies are EGIDs, characterized by prominent eosinophil infiltration in the GI tract leading to GI symptoms. EGIDs are broadly classified into eosinophilic esophagitis (EoE) and non-EoE EGIDs that involve the GI tract with the exception of the esophagus. Of the EGIDs, EoE is the best known, as the number of cases has increased dramatically in Western countries, whereas pediatric EoE remains rare in Asia and non-EoE EGIDs may be more prevalent in Japan. A recent Japanese national survey showed that pediatric non-EoE EGIDs were persistent and severe compared to those in adults, possibly requiring further effective therapeutic options. Among the EGIDs, FPIAP is pathologically diagnosed as an infantile form of eosinophilic colitis. In addition, recent FPIES and FPE cases also involved eosinophilic inflammation. Recent cases of GI allergies may be associated with type 2 inflammation. A better understanding of the interactions between GI allergies and type 2 inflammation may clarify the pathogenesis of the recent increase in GI allergies.

Different Patterns of Foods Triggering FPIES in Germany

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. The aim of our study was to describe causative agents and development of tolerance in German children with FPIES. We conducted a retrospective survey on children with FPIES from 14 centers in Germany assessing a 6-year period. 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. 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.

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.

Unique features of non-IgE-mediated gastrointestinal food allergy during infancy in Japan.

An increase in incidence of unique phenotypic non-IgE-mediated gastrointestinal food allergies (non-IgE GIFAs) has occurred in Japan ahead of Western countries. There are differences in clinical features of non-IgE GIFAs in Western and Japanese patients. As this phenotype has now come to be recognized internationally, we describe it in this review. A large number of Japanese patients with non-IgE GIFAs present with vomiting accompanied by bloody stool, putting them between food protein-induced enterocolitis syndrome (FPIES) and food protein-induced allergic proctocolitis. Some neonates and early infants with non-IgE GIFAs who present with fever and elevated C-reactive protein have symptoms consistent with severe systemic bacterial infections (e.g., sepsis). Some of these cases have now been defined in international guidelines as chronic FPIES. Eosinophils might be involved in the inflammatory process observed. The incidence of FPIES and food protein-induced allergic proctocolitis is increasing in Western countries and likely worldwide, after it has increased in Japan. The phenotype observed in Japan shows distinct clinical features compared with the classical phenotype, that is, increased levels of eosinophils, suggestive of 'eosinophilic shift' alongside symptomatic differences, making it difficult to categorize.

Food aversion and poor weight gain in food protein-induced enterocolitis syndrome: a retrospective study

Food protein-induced enterocolitis syndrome (FPIES) is a form of non-IgE mediated gastrointestinal food allergy. Insufficient data exist in regards to gastrointestinal history and outcome, particularly comorbidity, family history, food aversion, and poor body weight gain. This aim of the study is to identify the gastrointestinal outcomes and related risk factors in FPIES. We analyzed the clinical features and gastrointestinal outcomes of FPIES patients retrospectively at four hospitals in Boston. 203 FPIES patients were identified, including 180 only with acute FPIES, 8 with chronic FPIES, and 15 with both. Oat (34.5%), rice (29.6%), and cow’s milk (19.2%) were the most common food triggers. The prevalence of personal history with allergic proctocolitis (23.2%) and family history with inflammatory bowel diseases (9.4%) and celiac disease (7.3%) were higher than the general population. Compared to the FPIES patients triggered by 1 or 2 foods, the risk of developing food aversion increased in cases triggered by 3 or more foods (adjusted odds ratio (OR) = 3.07 [95% confidence interval (CI), 1.38 – 6.82], P = .006). The risk of poor body weight gain increased in FPIES triggered by cow’s milk (adjusted OR = 3.41 [95% CI, 1.21 – 9.63], P = .02) and banana (adjusted OR = 7.63, [95% CI, 2.10 – 27.80], P = .002). Gastrointestinal comorbidities and family history were common in FPIES patients. FPIES patients with 3 or more triggers were at risk of food aversion. Patients with cow’s milk and banana triggered FPIES were at risk of poor body weight gain.

Chronic food protein–induced enterocolitis syndrome due to solid food

Chronic food protein–induced enterocolitis syndrome due to solid food

Food aversion and poor weight gain in food protein–induced enterocolitis syndrome: A retrospective study

Food protein-induced enterocolitis syndrome (FPIES) is a form of non-IgE-mediated gastrointestinal food allergy. Insufficient data exist in regard to gastrointestinal history and outcome, particularly comorbidity, family history, food aversion, and poor body weight gain. We sought to identify the gastrointestinal outcomes and related risk factors in FPIES. We analyzed the clinical features and gastrointestinal outcomes of patients with FPIES retrospectively at 4 hospitals in Boston. Two hundred three patients with FPIES were identified, including 180 only with acute FPIES, 8 with chronic FPIES, and 15 with both. Oat (34.5%), rice (29.6%), and cow's milk (19.2%) were the most common food triggers. The prevalence rates of personal history with allergic proctocolitis (23.2%) and family history with inflammatory bowel diseases (9.4%) and celiac disease (7.3%) were higher than those in the general population. Compared with patients with FPIES with 1 or 2 food triggers, the risk of developing food aversion increased in cases triggered by 3 or more foods (adjusted odds ratio, 3.07; 95% CI, 1.38-6.82; P= .006). The risk of poor body weight gain increased in FPIES triggered by cow's milk (adjusted odds ratio, 3.41; 95% CI, 1.21-9.63; P= .02) and banana (adjusted odds ratio, 7.63; 95% CI, 2.10-27.80; P= .002). Gastrointestinal comorbidities and family history were common in patients with FPIES. Patients with FPIES with 3 or more triggers were at risk of food aversion. Patients with FPIES with cow's milk and banana as triggers were at risk of poor body weight gain.

Food Protein-Induced Enterocolitis Syndrome: a Comprehensive Review.

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

A FORMULA-FED INFANT WITH PROFOUND DEHYDRATION, SINUS VENOUS THROMBOSIS, AND INTRACRANIAL HEMORRHAGE

Introduction Chronic food protein-induced enterocolitis syndrome (FPIES) is a non-IgE gastrointestinal food allergy, typically manifesting in infancy with intermittent emesis and diarrhea, which may progress to dehydration and hypovolemic shock. Here we describe a case of chronic FPIES with previously unreported complications, including sinus venous thrombosis and intracranial hemorrhage. Case Description This female infant, the product a full term, healthy pregnancy, was initially thriving on soy formula until the 3 rd week of life when she developed progressively worsening diarrhea, emesis, and lethargy. By day of life 20, she was noted to have severe dehydration with 22% weight loss from birth. Laboratory abnormalities included anion gap metabolic acidosis, elevated lactate, hyperammonemia, hypoalbuminemia, neutrophilia with bandemia, hypereosinophilia, and thrombocytosis. Full sepsis work-up was negative as was testing for inborn errors of metabolism. Clinical course was complicated by seizures, respiratory failure, intracranial hemorrhage, and sinus venous thrombosis. Upon withdrawal of soy-based formula, laboratory abnormalities gradually improved. Resumption of feeds with extensively hydrolyzed cow's milk formula resulted in intermittent emesis. Concerned for chronic FPIES, the patient transitioned to amino acid-based formula with improvement in gastrointestinal symptoms. Discussion Here we present the first reported case of chronic FPIES complicated by sinus venous thrombosis and intracranial hemorrhage. Her diagnosis of chronic FPIES is presumptive without confirmatory food challenge; this has yet to be performed due to severity of initial presentation and patient's current young age of 2 months. This case highlights the potential severity of presentation, which may represent a barrier to timely diagnosis.

Cow's milk–associated chronic food protein–induced enterocolitis syndrome exacerbated by extensively hydrolyzed formula

Cow's milk–associated chronic food protein–induced enterocolitis syndrome exacerbated by extensively hydrolyzed formula

Non–IgE-mediated gastrointestinal food allergy

Non-IgE-mediated gastrointestinal food-induced allergic disorders (non-IgE-GI-FAs) account for an unknown proportion of food allergies and include food protein-induced enterocolitis syndrome (FPIES), food protein-induced allergic proctocolitis (FPIAP), and food protein-induced enteropathy (FPE). Non-IgE-GI-FAs are separate clinical entities but have many overlapping clinical and histologic features among themselves and with eosinophilic gastroenteropathies. Over the past decade, FPIES has emerged as the most actively studied non-IgE-GI-FA, potentially because of acute and distinct clinical features. FPIAP remains among the common causes of rectal bleeding in infants, while classic infantile FPE is rarely diagnosed. The overall most common allergens are cow's milk and soy; in patients with FPIES, rice and oat are also common. The most prominent clinical features of FPIES are repetitive emesis, pallor, and lethargy; chronic FPIES can lead to failure to thrive. FPIAP manifests with bloody stools in well-appearing young breast-fed or formula-fed infants. Features of FPE are nonbloody diarrhea, malabsorption, protein-losing enteropathy, hypoalbuminemia, and failure to thrive. Non-IgE-GI-FAs have a favorable prognosis; the majority resolve by 1 year in patients with FPIAP, 1 to 3 years in patients with FPE, and 1 to 5 years in patients with FPIES, with significant differences regarding specific foods. There is an urgent need to better define the natural history of FPIES and the pathophysiology of non-IgE-GI-FAs to develop biomarkers and novel therapies.

Clinical manifestations of food protein-induced enterocolitis syndrome

Purpose of reviewTo raise awareness among healthcare providers about the clinical and laboratory findings in acute and chronic food protein-induced enterocolitis syndrome (FPIES).Recent findingsFPIES can be caused by trivial exposure or rare foods.SummaryFPIES is a non-IgE-mediated reaction that usually presents with acute severe repetitive vomiting and diarrhea associated with lethargy, pallor, dehydration, and even hypovolemic shock. Manifestations resolve usually within 24–48 h of elimination of the causative food. In chronic cases, symptoms may include persistent diarrhea, poor weight gain, failure to thrive, and improvement may take several days after the food elimination. In the acute cases, laboratory evaluation may reveal thrombocytosis and neutrophilia, peaking about 6 h postingestion. Depending on the severity, metabolic acidosis and methemoglobinemia may occur. In chronic cases, anemia, hypoalbuminemia and eosinophilia may be seen. Radiologic evaluation or other procedures, such as endoscopy and gastric juice analysis may show nonspecific abnormal findings. The diagnosis is based on clinical manifestations. Further studies looking at the phenotypes of FPIES are needed to identify clinical subtypes, and to understand the predisposing factors for developing FPIES compared with immediate-type, IgE-mediated gastroenteropathies.

Manifestations, Diagnosis, and Management of Food Protein-Induced Enterocolitis Syndrome

CME EDUCATIONAL OBJECTIVES 1. Recognize manifestations, diagnosis, and management of food protein-induced enterocolitis syndrome (FPIES) in an outpatient setting. 2. Assess nutritional needs and provide anticipatory guidance for dietary management. 3. Recognize the indications of when to refer for assessment of resolution of FPIES using physician-supervised food challenges. Food protein-induced enterocolitis syndrome (FPIES) is an under-recognized non-immunoglobulin E (IgE)-mediated gastrointestinal food allergy affecting primarily infants and toddlers. An abnormal response to food antigen resulting in local inflammation is thought to lead to increased intestinal permeability and fluid shift. The primary features of acute FPIES are repetitive, projectile vomiting, lethargy, pallor, diarrhea, and dehydration. Chronic FPIES is typically seen in young infants with continued exposure to cow's milk or soy-based formula. Biomarkers are lacking and patients may undergo extensive workups for their symptoms, which often leads to a delay in diagnosis and puts infants at risk for feeding difficulties, nutritional deficiencies, and failure to thrive. This review will provide a guide in how to recognize the clinical features of and manage FPIES.