Non-IgE mediated food allergy
Key Points
- Non-IgE-mediated food allergies are delayed, cell-mediated immune reactions to specific food proteins.
- Diagnosis is clinical, based on a detailed history and symptom resolution after elimination, as allergy testing (e.g. skin prick or serum IgE) is not helpful.
- Management involves strict elimination of the offending food(s); adrenaline and antihistamines are not indicated, as these reactions are non-anaphylactic.
- FPIES (Food Protein-Induced Enterocolitis Syndrome) is a severe variant that can result in vomiting, dehydration, shock, and may require acute medical intervention.
Background
Epidemiology
- Prevalence: ≈ 2 % of Australian/NZ infants (≈ 1 in 50).
- Natural history: ~80 % develop tolerance by 3-5 y; minority remain lifelong.
Food allergies are classified (https://www.rch.org.au/clinicalguide/guideline_index/Non-IgE_mediated_food_allergy/) into:
- IgE-mediated: Rapid onset (typically <60 minutes), involving urticaria, angioedema, bronchospasm, or anaphylaxis.
- Non-IgE-mediated: Delayed onset (hours to days), typically gastrointestinal.
- Mixed IgE and non-IgE: e.g. eosinophilic oesophagitis, atopic dermatitis.
- Non-IgE-mediated food allergies typically present in infancy and often resolve by 3–5 years of age.
- The gastrointestinal tract is the primary site of involvement.
Terminology and Clinical Subtypes
1. Food Protein-Induced Allergic Proctocolitis (FPIAP)
- Pathophysiology: Delayed-type hypersensitivity reaction affecting the rectum and distal colon.
- Typical presentation:
- Onset in the first few months of life.
- Blood-streaked and/or mucousy stools.
- Infant appears well and thriving.
- Management: Maternal dietary elimination if breastfed; switch formula to extensively hydrolysed or amino acid-based if formula-fed.
2. Food Protein-Induced Enteropathy
- Pathophysiology: Chronic inflammatory response affecting the small intestine.
- Typical presentation:
- Persistent loose stools, vomiting, poor weight gain, and irritability.
- May develop secondary lactose intolerance, causing bloating and peri-anal excoriation.
- Diagnosis: Clinical response to elimination and symptom recurrence on re-challenge.
3. Food Protein-Induced Enterocolitis Syndrome (FPIES)
- Pathophysiology: Delayed, profound gastrointestinal hypersensitivity reaction.
- Typical presentation:
- Onset 2–4 hours after ingesting trigger food.
- Repetitive vomiting, lethargy, pallor, and sometimes diarrhoea.
- Risk of hypovolaemia and shock in severe cases.
- Common triggers (Australia): Cow’s milk, soy, rice, oats. Can be triggered by any food.
- Management: Elimination of trigger food; acute episodes may require IV fluids and ondansetron.
Position of Cow’s-Milk Allergy within the Non-IgE Terminology Sphere
| Umbrella term | Precise diagnosis (pathophysiology) | Typical age at presentation | Key clinical features | Immunologic mechanism |
|---|---|---|---|---|
| Cow’s-Milk Protein Allergy (CMPA) | IgE-mediated immune response to casein/whey proteins | Infancy (<12 mo) most common occasionally persists | timing: 15 min – 2 h Urticaria angio-oedema vomiting wheeze anaphylaxis | Food-specific IgE |
| Non-IgE-mediated immune response to casein/whey proteins | see below | timing: ≥ 2 h (often > 4 h) Eczema flares (but not acute hives) protracted vomiting/diarrhoea bloody or loose stools faltering growth (FPE) Skin involvement absent | T-cell mediated | |
| Non-IgE-mediated CMPA subtypes | FPIAP – Food-protein-induced allergic proctocolitis FPE – Food-protein-induced enteropathy FPIES – Food-protein-induced enterocolitis syndrome | FPIAP: first weeks–months of life FPE: early infancy FPIES: median 4–6 mo when solids introduced | See “Key non-IgE entities” below | Delayed (T-cell–dominated) |
| Cow’s-Milk Protein Intolerance (CMPI) † | Catch-all term often used in primary care to label any adverse reaction attributed to cow’s-milk ingestion when the exact mechanism is unconfirmed | Variable | Non-specific GI upset eczema reflux loose stools etc. | May be immune (non-IgE) or non-immune (e.g. lactase deficiency, functional GI disorders) |
- † CMPI–Cow’s-Milk Protein Intolerance is an umbrella term still used by many clinicians, is not a formal diagnostic category in ASCIA or EAACI guidelines.
- Historically used by paediatricians when infants improved on dairy-free formula but without formal testing.
- The label therefore captured:
- IgE mediated cow’s-milk protein allergy (CMPA)
- Non-IgE CMPA (e.g. FPIAP/FPE) and
- Non-immune disorders such as
- transient lactase deficiency – patients tolerate lactose-free dairy proteins.
- severe gastro-oesophageal reflux
- functional diarrhoea
- When an infant reacts to cow’s-milk formula, first ask “immune or non-immune?”
- Immediate hives / wheeze: think IgE-CMPA.
- Delayed GI-only features: likely non-IgE subtype (FPIAP/FPE/FPIES).
Key Non-IgE Entities Triggered by Cow’s-Milk Protein
- Non-IgE-mediated allergies do not involve mast cell degranulation, hence no role for adrenaline or antihistamines
| Subtype | Latency / Age | Hallmark Features | Management Essentials | Prognosis |
|---|---|---|---|---|
| FPIAP (Food-Protein-Induced Allergic Proctocolitis) | Hours → days First weeks–months | Well, thriving infant; blood-streaked ± mucous stool | Maternal dairy elimination (breast-fed) or EH/AA formula | > 90 % resolve by 12–18 mo |
| FPE (Food-Protein-Induced Enteropathy) | Days → weeks (chronic) Early infancy | Chronic loose stools, vomiting, poor weight gain, peri-anal excoriation; secondary lactose malabsorption common | Dairy elimination; confirm on re-challenge if doubt | Most resolve by 2–3 y |
| FPIES (Food-Protein-Induced Enterocolitis Syndrome) | 2–4 h post-ingestion; onset when solids introduced (median 4–6 mo) | Repetitive profuse vomiting → pallor lethargy possible diarrhoea risk of dehydration/shock | Strict avoidance acute episode → IV fluids ± ondansetron (not adrenaline) | Majority outgrow by 3–5 y |
Differential diagnoses
Non-immune lactose disorders
- Primary adult-type hypolactasia, secondary lactose malabsorption post-gastroenteritis. CMPA tests negative; tolerated lactose-free cow’s milk still contains proteins → will trigger CMPA. allergy.org.au
Other food hypersensitivities
- Soy or egg FPIES/proctocolitis
- Coeliac disease (IgA tTG-positive, villous atrophy)
Functional & reflux disorders
- Infant colic, functional diarrhoea, GORD; symptoms improve with acid suppression or positional therapy, not elimination alone.
Infective or inflammatory GI disease
- Viral/bacterial gastroenteritis, invasive enteritis
- Early-onset IBD or eosinophilic colitis without clear allergen trigger
Surgical/acute abdominal causes
- Pyloric stenosis, malrotation/volvulus, necrotising enterocolitis in preterms.
Systemic / metabolic mimics
- Inborn errors (galactosaemia), immunodeficiencies, bleeding diatheses.
Assessment
- History
- Food exposure and timing of reaction (note food may have been ingested directly by the child or through maternal ingestion via breastmilk in FPIAP and enteropathy)
- Has this food been eaten in past, how often, any prior reactions?
- Details of reaction and duration
- Vomiting
- Diarrhoea
- Stool description, including presence of mucous or blood
- Delayed presentations of lethargy, pallor
- Unsettled behaviour
- Rash (morphology and duration)
- Age at time of initial reaction, timing of other reactions
- Dietary history: breastfeeding (noting any maternal dietary exclusions), formula (including types)
- Growth trajectory, taking note of slow weight gain
- Associated eczema
- Infectious contacts
- Examination
- Assess for dehydration
- Abdominal examination:
- In non-IgE-mediated food allergy presentations, the abdomen should be soft and non-tender
- Consider other causes for presentation if abdomen is distended or tender
- Perianal examination for rash or fissures
- Growth parameters: weight, length, head circumference
- Skin:
- assess for rashes, ie eczema
- petechiae in the setting of bloody stools (consider thrombocytopenia),
- haemangiomas (may also be present in GI tract and present with rectal bleeding)
Summary of conditions
| Proctocolitis | Enteropathy | FPIES | |
| Average age | <6 months | <6 months | <12 months |
| Vomit | Usually not prominent | May be present | Profuse +++ |
| Stools | Blood, mucous usually present | Mucous +/- blood may be present | May have loose stools |
| Lethargy | No | Can be present | Common |
| Pallor | No | Possible | Common |
| Hives | No | No | No |
| Eczema flare | Common (30-50 %) Flares appear 4-24 h after exposure and may be the main clue in otherwise well infants. | Common (30-50 %) Flares appear 4-24 h after exposure and may be the main clue in otherwise well infants. | Uncommon (can co-exist but not provoked by single episode) |
| Weight gain | Not affected | Can be affected | Rarely affected |
| Timing of reaction after ingestion | >few hours-days | >few hours -days | Average 2-4 hours |
| Improvement of symptoms | Over few days to weeks after eliminating trigger food | Over few days to weeks after eliminating trigger food | Once vomiting ceases and fluids tolerated, improvement seen after few hours |
| Unsettled behaviours | Usually not present | May be present | Not a prominent feature |
| Common food triggers | Cow milk, soy | Cow milk, soy | Rice, oats, cow milk, soy, eggs |
| Less common food triggers | Others not common | Others not common | Avocado, chicken, sweet potato, legumes (many others possible) |
| Differential diagnoses | Infectious gastroenteritisEarly onset inflammatory bowel diseaseBleeding disorder | Infectious gastroenteritisEarly onset inflammatory bowel diseaseCoeliac disease (if age > 6 months and child has started solids)Underlying immune-deficiency | Infection (sepsis, meningitis, UTI, gastroenteritis) Pyloric stenosisIntussusceptionBowel obstruction (suspect with bilious vomiting) |
| Prognosis | Excellent; > 90 % resolve by 1–3 y. | Excellent; > 90 % resolve by 1–3 y. | 50–80 % resolve by 3 y (milk/soy earlier, grains later). |
Grading scales of the severity of Non-IgE-mediated gastrointestinal food allergies
Investigations
Routine Investigations
- Not routinely required – diagnosis is clinical based on history and resolution of symptoms with food elimination.
When to Investigate Further
- Persistent blood in stool:
- Order FBE to assess for anaemia or thrombocytopaenia.
- Presence of petechiae:
- Urgent FBE to exclude thrombocytopenia.
- Suspected infectious cause:
- Consider stool MCS and viral PCR.
Allergy Testing
- Skin prick testing and serum-specific IgE testing are not indicated for suspected non-IgE-mediated food allergy.
- These tests do not contribute to diagnosis and may lead to inappropriate dietary restrictions.
Referral Consideration
- If diagnostic uncertainty exists during acute presentation and allergy is suspected:
→ Discuss with Allergy & Immunology team.
Management
1. Proctocolitis / Enterocolitis
- Initial Management
- Eliminate suspected food trigger.
- If cow’s milk is suspected:
→ Advise maternal elimination of dairy if breastfeeding.
→ Clinical improvement may take up to 2 weeks. - If suboptimal or no improvement:
→ Consider eliminating soy, egg, wheat (one at a time).
→ Rarely require >2 eliminations – refer to dietitian if more are needed. - Breastfeeding mothers:
→ Recommend calcium supplementation if dairy/soy are excluded.
- Formula-Fed Infants
- Eliminate cow’s milk and soy protein.
- Trial:
- Extensively hydrolysed formula (EHF)
- Rice-based formula (if available)
- If no response after 2 weeks:
→ Trial amino acid-based formula (AAF) in consultation with a specialist. - Many EHFs are available OTC; AAF requires prescription.
- If no improvement on AAF:
→ Reconsider diagnosis.
- Monitoring
- Ensure regular monitoring of growth and weight gain.
2. Food Reintroduction Strategy
- Consider food reintroduction at ~12 months of age:
- Reintroduce one food at a time every 2–3 weeks.
- Graded cow’s milk challenge:
- Baked milk (e.g. in muffins)
- Hard cheese
- Yoghurt
- Fresh milk
- If delayed symptoms recur:
→ Stop introduction, and retrial after a few months.
- Most children outgrow symptoms by 1–2 years of age.
Food Protein-Induced Enterocolitis Syndrome (FPIES)
Acute Management
- Hydration and antiemetics:
- Ondansetron (oral):
- 8–15 kg: 2 mg
- 15–30 kg: 4 mg
- 30 kg: 6–8 mg
- Ondansetron (oral):
- Consider:
- Fluid resuscitation
- Correction of acid-base and electrolyte imbalances
- Rule out sepsis if child is unwell or not improving.
- Bilious vomiting: requires urgent surgical assessment.
Long-Term Management
- Prior to discharge:
- Provide FPIES Action Plan
- Prescribe ondansetron (oral dispersible)
- Recommend:
- Oral food challenge to confirm trigger
- Avoidance of identified food triggers
- Referral to a paediatric allergist for supervised reintroduction
- Prognosis:
- Most resolve by 2–3 years of age
Referral Triggers
Refer to paediatrician, paediatric allergist or gastroenterologist if:
- Poor or absent response to standard food eliminations.
- Failure to thrive, persistent loose stools, or eczema unresponsive to elimination diet.
- Suspect underlying immunodeficiency (e.g. SCID).