An Algorithm for the Diagnosis and Treatment of Food Protein‐Induced Enterocolitis Syndrome (<scp>FPIES</scp>), 2024 Update

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food hypersensitivity with delayed gastrointestinal symptoms after food ingestion. Initially described as reaction to cow's milk in infants, the understanding of FPIES has grown to include all ages and variable presentations and trigger foods [1]. The following algorithm provides an updated approach to diagnosis and management of FPIES. The incidence of FPIES is estimated between 0.15% and 0.7%, with a slight male predominance in childhood, contrasted with adult female predominance [2]. Diagnosis is often delayed, due to the broad differential diagnosis and lack of diagnostic biomarker [3]. FPIES can manifest as acute, chronic, atypical, and adult-onset phenotypes. Acute FPIES leads to repetitive, projectile emesis generally 1–4 h after ingestion, often accompanied by lethargy and pallor. Diarrhea may follow, usually within 5–10 h. Symptoms typically resolve within 24 h. Growth is normal when the food is eliminated from the diet. In severe cases, hypotension and shock may occur and require resuscitation. In some children, continuous ingestion of the food (most often in infants fed cow's milk or soy based-formulas, rarely breastfeeding), leads to intermittent emesis, chronic watery diarrhea and potentially poor weight gain and failure to thrive. After eliminating the trigger food, symptoms may take several days to resolve. If the food is reintroduced after a period of avoidance, the reaction presents as acute FPIES. This scenario is termed chronic FPIES. Chronic FPIES can be severe and require hospitalization. Adult-onset FPIES to shellfish, fish egg, and cow's milk is being increasingly recognized [4]. Adult-onset FPIES starts after a period of eating foods without symptoms. Risk factors and natural history remain obscure. Patients with atypical FPIES have positive skin testing and/or detectable serum specific IgE to the food causing FPIES symptoms. The relevance of such IgE sensitization is unclear. The possibility of switching to IgE-mediated food allergy or having more persistent disease has been suggested. FPIES is a clinical diagnosis supported by laboratory findings of leukocytosis with neutrophilia, thrombocytosis and stool positive for leukocytes, and eosinophils or increased carbohydrates. Severe FPIES can be associated with metabolic acidosis and, in rare cases, methemoglobinemia. In chronic FPIES, hypoalbuminemia, anemia, eosinophilia, and leukocytosis are more common than in acute FPIES. Oral food challenges are utilized to evaluate resolution of acute FPIES [5]. The common FPIES triggers vary by country/region, possibly reflecting dietary patterns and genetic predisposition. Globally, cow's milk is the most common food, followed by grains (oat and rice), fish, fruits (avocado and banana), and vegetables (sweet potato and squash) [2]. Recently, FPIES to egg and peanut have become more common, potentially associated with an earlier introduction of these foods into the infant diet to prevent IgE-mediated egg and peanut allergy [6]. The differential diagnosis is broad and FPIES requires a high index of suspicion to minimize misdiagnosis, see Figure 1. Management of acute FPIES differs by severity and the patient's age, see Figure 2. Mild cases can be managed at home with oral rehydration and oral ondansetron. Moderate cases usually require emergency room monitoring with intramuscular ondansetron, with or without intravenous (IV) fluid rehydration. In severe cases, IV fluid resuscitation and a single dose of parenteral steroid (e.g., methylprednisolone) may be necessary, although evidence for the use of steroids is lacking. Long-term management relies on avoidance of the culprit food. Registered dietician support may be needed for severe cases and multiple food FPIES to optimize nutrition and dietary expansion. Avoidance of food traces and restricting diet during breastfeeding are rarely recommended. A letter explaining the diagnosis and emergency room management of FPIES is helpful. Oral ondansetron for home use can be prescribed. Food challenges are usually considered 12–18 months after last reaction, considering the severity of previous reactions, natural course of FPIES for the trigger food, as well as nutritional and social value of the food. A.N.W. supervised the project. M.B. drafted the algorithm and manuscript. All authors listed have made substantial contributions to this algorithm, contributed to critical intellectual revisions and edits, and approved of the content of the manuscript and agree to be held accountable for the work. The authors declare no conflicts of interest. The authors have nothing to report.