What is the appropriate evaluation and management for a child under 2 years old presenting with repetitive vomiting, lethargy, and possible diarrhea after ingestion of specific foods, suspecting Food Protein‑Induced Enterocolitis Syndrome (FPIES)?

FPIES Evaluation in Children Under 2 Years

Diagnose FPIES clinically using the international consensus criteria: vomiting 1-4 hours after food ingestion (major criterion) plus at least 3 minor criteria including lethargy, pallor, need for IV fluids, diarrhea within 24 hours, or hypotension. 1

Immediate Clinical Assessment

Distinguish Acute vs. Chronic FPIES

Acute FPIES presents with:

• Repetitive vomiting starting 1-4 hours (range 30 minutes to 6 hours) after intermittent food exposure 1
• Lethargy and marked pallor accompanying the vomiting 1
• Diarrhea developing 5-10 hours post-ingestion in many cases, potentially bloody 1
• Complete symptom resolution within 24 hours after food elimination 1
• Normal growth and asymptomatic periods between exposures 1

Chronic FPIES occurs only in infants <4 months with daily formula ingestion:

• Intermittent vomiting, chronic diarrhea, and failure to thrive 1
• Hypoalbuminemia and poor weight gain 1
• Resolution within 3-10 days after switching to hypoallergenic formula 1
• Acute symptoms develop when food is reintroduced after avoidance 1

Severity Stratification

Mild-to-moderate FPIES: 1

• 1-3 episodes of vomiting (may be bilious)
• Decreased activity level and pallor
• Self-resolving with oral rehydration at home
• Mild watery diarrhea (occasionally bloody)

Severe FPIES: 1

• ≥4 episodes of projectile, repetitive vomiting with dry heaving
• Profound lethargy
• Dehydration requiring IV fluids
• Hypotension, hypothermia, abdominal distention
• Metabolic acidosis or methemoglobinemia 1
• Requires hospitalization

Diagnostic Criteria Application

For Acute FPIES Diagnosis

Major criterion (required): 1

• Vomiting 1-4 hours after suspect food ingestion
• Absence of classic IgE-mediated skin or respiratory symptoms

Minor criteria (need ≥3): 1

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

Critical caveat: If only a single episode has occurred, strongly consider diagnostic oral food challenge to confirm diagnosis, as viral gastroenteritis is common in this age group and can mimic FPIES 1

For Chronic FPIES Diagnosis

Essential criterion: 1

• Resolution of symptoms within days after food elimination
• Acute recurrence (vomiting 1-4 hours, diarrhea within 24 hours) when food is reintroduced

Without confirmatory challenge, chronic FPIES diagnosis remains presumptive 1

Laboratory Evaluation

Optional but Supportive Laboratory Tests

Complete blood count with differential: 1, 2

• Leukocytosis with neutrophilia (>1500 neutrophils above baseline)
• Thrombocytosis in 65% of acute FPIES cases
• Baseline CBC before oral food challenge can serve as comparator

Metabolic panel when severe presentation: 1, 2

• Metabolic acidosis
• Electrolyte abnormalities
• Hypoalbuminemia (particularly in chronic FPIES)

Methemoglobinemia assessment if cyanosis present despite normal oxygen saturation 1, 2

Stool examination (when diarrhea present): 1

• Frank or occult blood
• Leukocytes, eosinophils, Charcot-Leyden crystals
• Increased carbohydrate/reducing substances

IgE Testing Considerations

Food-specific IgE testing helps phenotype but does not exclude FPIES: 1

• Classic FPIES: IgE-negative
• Atypical FPIES: IgE-positive (associated with more protracted course and delayed resolution) 3
• Approximately 25% develop food-specific IgE antibodies and may transition to immediate food allergy 3

Identify Common Food Triggers

Most Common Triggers by Age

Infants <9 months (early-onset): 1

• Cow's milk and soy formulas (most common in US: 25-50% of cases)
• Can occur in exclusively breastfed infants but rare 3

Infants >9 months (late-onset): 1, 4

• Rice (most commonly reported grain trigger)
• Oat (combined rice/oat FPIES in ~30% of rice cases)
• Other grains (barley)
• Vegetables (sweet potato, squash, string beans, peas)
• Poultry (chicken, turkey)

Geographic variations: 1

• Fish common in Italy and Spain
• Soy less common in Australia, Italy, Israel compared to US

Multiple Food Triggers

High risk for multiple food hypersensitivities: 4

• 78% of solid food-FPIES patients react to >1 food
• 50% react to >1 grain
• 64% with solid food-FPIES also have cow's milk/soy-FPIES
• Overall 48% of all FPIES patients reactive to multiple foods

Differential Diagnosis Exclusion

Key Distinguishing Features from Other Conditions

Viral gastroenteritis: 1

• FPIES resolves within hours vs. several-day course for viral illness
• No temporal relationship to specific food intake in gastroenteritis
• Fever more common in viral illness

Bacterial food poisoning (Staph aureus, Bacillus cereus): 5

• Similar 1-4 hour onset but no recurrent pattern with specific foods
• Common-source outbreak pattern
• Resolves within 24-48 hours without dietary modification

Sepsis: 4, 6

• FPIES commonly misdiagnosed as sepsis (57% undergo sepsis evaluations)
• Temporal relationship to food ingestion distinguishes FPIES
• Resolution with food avoidance confirms FPIES

Surgical abdomen: 6

• 22% of FPIES patients receive surgical consultation
• Absence of obstruction on imaging
• Food-related temporal pattern excludes surgical causes

Oral Food Challenge Protocol (When Indicated)

Indications for OFC

Diagnostic OFC indicated when: 1

• Only single episode occurred (to distinguish from viral gastroenteritis)
• Confirming chronic FPIES diagnosis
• Assessing for resolution of known FPIES

OFC Administration Protocol

Pre-challenge preparation: 1

• Perform in supervised setting with immediate IV access
• Some experts strongly recommend securing peripheral IV before challenge
• Baseline CBC with differential optional (valuable for research, optional clinically)

Dosing protocol: 1

• Total dose: 0.06-0.6 g protein/kg (typically 0.3 g/kg)
• Maximum: 3 g protein or 10 g total food (100 mL liquid)
• Administer in 3 equal doses over 30 minutes
• Observe 4-6 hours after final dose

Modified protocols for high-risk patients: 1

• Lower starting doses for history of severe reactions
• Longer observation between doses
• More gradual administration if detectable sIgE present

OFC Interpretation Criteria

Positive OFC (diagnostic of FPIES): 1

• Major criterion: Vomiting 1-4 hours after ingestion without IgE-mediated symptoms
• Plus ≥2 minor criteria: lethargy, pallor, diarrhea 5-10 hours post-ingestion, hypotension, hypothermia, neutrophil increase ≥1500 above baseline

Important caveats: 1

• Rapid ondansetron use may avert minor criteria (pallor, lethargy)
• Not all facilities can perform timely neutrophil counts
• Treating physician may consider challenge positive with major criterion alone in some clinical contexts

Common Diagnostic Pitfalls

Delayed diagnosis is extremely common: 6

• Median of 2-5 reactions before correct diagnosis
• Only 2 of 19 children (11%) discharged with correct diagnosis from initial ED visit 6

Unnecessary investigations to avoid: 6

• 34% undergo abdominal imaging unnecessarily
• 28% undergo septic evaluation
• 22% receive surgical consultation

Do not assume low allergenic potential excludes FPIES: 4

• Cereals, vegetables, and poultry (typically regarded as low allergenic) are common triggers
• Consider FPIES even in exclusively breastfed infants when solid foods introduced

Do not dismiss based on single food exposure: 4

• Maternal ingestion during breastfeeding does NOT cause FPIES unless food fed directly to infant