What is Food Protein-Induced Enterocolitis Syndrome (fPIES)?

What is FPIES (Food Protein-Induced Enterocolitis Syndrome)?

FPIES is a non-IgE-mediated food allergy that causes severe, delayed gastrointestinal reactions characterized by profuse, repetitive vomiting starting 1-4 hours after eating a trigger food, often accompanied by lethargy, pallor, and potentially life-threatening dehydration or shock. 1

Core Clinical Features

Acute FPIES presents with a distinctive pattern that distinguishes it from typical food allergies and viral gastroenteritis 1:

• Vomiting onset: Begins 1-4 hours after ingestion (can range 30 minutes to 6 hours), not the immediate reaction seen in IgE-mediated allergies 1
• Vomiting character: Profuse, projectile, repetitive (≥4 episodes in severe cases), often bilious with dry heaving 1
• Associated symptoms: Marked pallor, lethargy progressing to extreme lethargy, decreased activity level 1
• Diarrhea: Develops in many cases within 5-10 hours, can persist up to 24 hours, occasionally bloody 1
• Absence of typical allergic symptoms: No hives, wheezing, or immediate anaphylactic features 1

Severe presentations can include 1:

• Dehydration requiring IV fluids
• Hypotension and hypovolemic shock
• Hypothermia
• Metabolic acidosis
• Methemoglobinemia
• Abdominal distention

Chronic FPIES Phenotype

Chronic FPIES occurs only in infants <4 months old receiving regular formula or food exposure 1:

• Intermittent, progressive vomiting and watery diarrhea (occasionally bloody) 1
• Poor weight gain or failure to thrive 1
• Hypoalbuminemia in severe cases 1
• Critical distinguishing feature: Complete symptom resolution and normal growth when trigger food is eliminated, but reintroduction causes acute FPIES reaction 1

Pathophysiology

FPIES is classified as a non-IgE-mediated food allergy, though the exact mechanism remains incompletely understood 1:

• Involves antigen-specific T cells, cytokines, and intestinal inflammation affecting the colon and ileum 1
• Causes increased intestinal permeability and fluid shift into the gastrointestinal lumen 1
• Activates innate immune system with pan-leukocyte activation 2, 3
• Atypical cases: Some patients have IgE positivity to the trigger food, associated with more protracted course 1
• Successful use of ondansetron suggests neuroimmune mechanism involvement 1

Common Trigger Foods

Geographic and age-related patterns exist 1:

• Most common overall: Cow's milk, soy, rice, and oat 1
• Infants <6 months: Cow's milk and soy formula (presenting earlier due to earlier introduction) 1
• Infants 6-12 months: Solid foods, particularly rice and oat 1
• United States pattern: Soy-induced FPIES common (25-50% of cases), combined rice/oat reactions in one-third of rice FPIES 1
• Geographic variations: Fish common in Italy/Spain; rice most common grain except in Italy 1
• Newer recognition: Egg, peanut, avocado, banana, apple, sweet potato increasingly reported 3
• Adults: Fish/shellfish and egg with delayed-onset vomiting and history of previous tolerance 1

Epidemiology

FPIES is not rare 1, 2:

• Cumulative incidence in infants: 0.34% (3 per 1000 newborns) 1
• Population prevalence in US infants: 0.51% 2, 3
• Adult prevalence: 0.22% 3
• Typical onset: 2-7 months of age when formula or solid foods introduced 1

Diagnostic Approach

Diagnosis is primarily clinical based on characteristic history 1:

Major criterion (required):

• Vomiting 1-4 hours after suspect food ingestion without classic IgE-mediated allergic skin or respiratory symptoms 1

Minor criteria (need ≥3): 1

1. Second or more episode of repetitive vomiting with same food
2. Repetitive vomiting episode with different food
3. Extreme lethargy with reaction
4. Marked pallor with reaction
5. Emergency department visit required
6. IV fluid support required
7. Diarrhea within 24 hours (usually 5-10 hours)
8. Hypotension
9. Hypothermia

Critical diagnostic consideration: If only single episode occurred, oral food challenge strongly recommended to confirm diagnosis, as viral gastroenteritis is common in this age group 1

Laboratory Findings (Supportive, Not Diagnostic)

No specific biomarkers exist for FPIES 1, 2:

• Increased white blood cell count with neutrophilia 1
• Thrombocytosis 1
• Stool positive for leukocytes, eosinophils, or increased carbohydrate content 1
• Metabolic acidosis in severe cases 1
• Methemoglobinemia in severe cases 1
• IgE testing typically negative (though atypical cases exist) 1

Key Distinguishing Features from Other Conditions

FPIES vs. Viral Gastroenteritis: 1, 4

• Rapid symptom resolution within hours (not days)
• Absence of fever
• No significant C-reactive protein elevation
• Reproducible with food re-exposure

FPIES vs. IgE-mediated Food Allergy: 1

• Delayed onset (1-4 hours vs. minutes)
• No urticaria, angioedema, or respiratory symptoms
• Negative skin prick tests and specific IgE in classic cases

FPIES vs. Sepsis: 4, 5

• Rapid resolution without antibiotics
• Afebrile presentation
• Normal or only mildly elevated inflammatory markers
• History of food trigger

Common Pitfalls

FPIES is frequently misdiagnosed 4, 5:

• Often mistaken for viral gastroenteritis, sepsis, or surgical emergency 4, 5
• Diagnosis delayed for many months due to lack of physician awareness 5
• Single episodes may be dismissed without proper follow-up 1
• Foods perceived as "hypoallergenic" (rice, oat) can be triggers 2

Natural History and Prognosis

Most infantile FPIES resolves over time 3, 6:

• Generally favorable prognosis for cow's milk, soy, and grain triggers 3
• Exception: Fish FPIES has lower resolution rates 3
• Adult-onset seafood FPIES shows low resolution rates over 3-5 years 3
• Tolerance development monitored through supervised oral food challenges 3, 6

Associated Conditions

FPIES patients have increased rates of atopic comorbidities 3:

• IgE-mediated food allergies 3
• Atopic dermatitis 3
• Asthma 3
• Allergic rhinitis 3
• Eosinophilic esophagitis 3