What causes food protein-induced enterocolitis syndrome (FPIES)?

Causes of Food Protein-Induced Enterocolitis Syndrome (FPIES)

Food protein-induced enterocolitis syndrome (FPIES) is primarily caused by an abnormal non-IgE-mediated immune response to specific food proteins, with cow's milk, soy, rice, and oats being the most common triggers in infants. 1

Common Food Triggers

The food proteins that most commonly trigger FPIES vary by geographic region:

• Most common triggers globally:

  • Cow's milk
  • Soy
  • Rice
  • Oats 1

• Geographic variations:

  • United States: Cow's milk and soy (25-50% of cases)
  • Italy and Spain: Fish is a common trigger
  • Australia: Rice is frequently reported 1

• Other reported triggers:

  • Grains (especially rice)
  • Legumes
  • Poultry
  • Fruits and vegetables (banana, apple, sweet potato, avocado) 2
  • Rice beverage (as a novel trigger) 3

Timing of Onset

FPIES typically develops when trigger foods are first introduced into an infant's diet:

• Cow's milk and soy-induced FPIES: Usually presents at younger age (<6 months)
• Solid food-induced FPIES: Typically presents between 6-12 months
• Median age of solid food-induced FPIES onset: 5-7 months 1

Pathophysiological Mechanisms

While the exact pathophysiology remains poorly understood, several mechanisms appear to be involved:

• Non-IgE-mediated immune reaction: Unlike typical food allergies, FPIES does not involve IgE antibodies 4
• Innate immune system activation: Evidence suggests activation of the innate immune compartment 4
• Mucosal barrier dysfunction: Impaired gastrointestinal mucosal barrier function 2
• Inflammatory response: Characterized by:
  • Increased white blood cell count with neutrophilia
  • Thrombocytosis
  • Presence of fecal leukocytes and eosinophils 1

Risk Factors and Associated Conditions

Several factors may influence FPIES development:

• Comorbid atopic conditions: FPIES is associated with:

  • IgE-mediated food allergies (2-12% of patients)
  • Atopic dermatitis
  • Asthma
  • Allergic rhinitis
  • Eosinophilic esophagitis 2

• Geographic and dietary factors: Differences in populations, atopic disease prevalence, breastfeeding practices, and dietary habits may contribute to regional variations in FPIES triggers 1

• Potential genetic factors: Although specific genetic markers have not been definitively identified, genetic factors likely play a role in susceptibility 1

Clinical Presentation Types

FPIES can manifest in different clinical patterns:

• Acute FPIES: Characterized by repetitive vomiting 1-4 hours after food ingestion, sometimes followed by diarrhea within 24 hours

• Chronic FPIES: Results from daily ingestion of the trigger food, causing intermittent vomiting, chronic diarrhea, poor weight gain, or failure to thrive

• Atypical FPIES: Food-specific IgE positive (compared to classic FPIES which is IgE negative)

• Adult-onset FPIES: Rare but reported, particularly with seafood triggers 2, 5

Important Clinical Considerations

• No specific biomarkers exist for FPIES diagnosis; it remains a clinical diagnosis based on history and symptom pattern 2

• Children with cow's milk-induced FPIES and IgE sensitization to cow's milk (atypical FPIES) may have more persistent disease beyond 3 years of age 1

• The natural history of infantile FPIES is generally favorable with most cases resolving by school age, with the exception of fish FPIES which tends to persist longer 2

• Multiple food triggers can occur in the same patient, with cross-reactivity between related food groups (e.g., 80% cross-reactivity between legumes and soy) 1