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The diagnostic challenge of FPIES

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A 3-month-old girl presents to the emergency department (ED). Her mother has been concerned since she was weaned from breast milk onto formula. She seems more “sicky” after feeds. A week ago, she had some formula and, after a few hours, vomited several times, looked pale and then had diarrhoea. She was diagnosed with gastroenteritis, and her mother reverted to breastfeeding again. Today, she was given a bottle of formula. Three hours later, she vomited six times and, again, looked pale and floppy.

In triage, her oxygen sats are 97%, her pulse is 170, her respiratory rate is 50 breaths a minute, her temperature is 36.6°C and her capillary refill time is 3 to 4 seconds. She has a patent airway with no respiratory distress but appears shocked. A venous blood gas shows a metabolic acidosis with respiratory compensation.

She has a raised sodium of 150 and a raised urea of 8.1 but otherwise normal renal function, FBC, CRP and LFTs.

You ask a senior for help. “I’m looking after a 3 month old girl who came in with profuse vomiting shortly after having cows milk protein formula. She now appears to be shocked with a metabolic acidosis. Where do I go next?”

Could this be a cow’s milk protein allergy?

Non-IgE Mediated Cows Milk Protein Allergy – In the case of this infant, the degree of vomiting and dehydration was disproportionate to what is normally expected in a Non-IgE Cows Milk protein (CMP) allergy.

IgE Mediated Cows Milk Protein (CMP) allergy – IgE Mediated CMP allergy can present with vomiting after an ingested allergen. However, other associated signs of hypersensitivity reactions (ie urticaria, angioedema, wheeze or stridor) are usually present.

How about FPIES?

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal food hypersensitivity that can be severe and lead to shock.

FPIES represents the severe end of the spectrum of food protein-induced gastrointestinal disease. Most cases present <12 months of age when foods or formulas are first introduced.

There is a rarer chronic form of FPIES, which occurs with daily ingestion of the food and presents with chronic diarrhoea, intermittent vomiting and failure to thrive. This article refers to acute FPIES.


ANY food protein, especially

  • Cows Milk Protein
  • Hens Egg
  • Fruit and Vegetables
  • Fish

What is the suspected cause of FPIES?

The pathophysiology of FPIES is not well defined and is thought to involve antigen-specific T cells, antibodies, and cytokines as a cause of gastrointestinal inflammation. This inflammation is thought to cause an increased intestinal permeability and fluid shift into the gastrointestinal lumen.

How common is FPIES?

There is limited epidemiologic information, and reports of prevalence vary widely. One study, Katz et al. reported a cumulative incidence of infants with cow’s milk-induced FPIES of 3 per 1000 newborns over a 2-year period at one hospital (0.34%).

What are the associations with FPIES?

Although FPIES is distinct from IgE-mediated disease, many children have comorbid atopy with eczema and food IgE sensitisation.

Most children in Australia have FPIES to one food only. If multiple foods are suspected, then referral to a clinical immunology/allergy specialist is recommended to guide the safe introduction of foods.

Risk factors for FPIES have not been assessed.

Is FPIES inherited?

No. FPIES itself does not appear to be genetic. However, a family history of atpy is present in between 40 and 80% of cases.

What are the clinical findings of FPIES?

FPIES occurs along a spectrum. Presentation can vary from mild to severe.

It usually occurs in infants less than 12 months of age. Commonly, it presents with profuse/projectile protracted vomiting, which has an onset of 1-3 hours after ingestion.

The child can develop diarrhoea (watery or bloody) about 5-10 hours after ingestion. Other symptoms include lethargy, pallor, haemodynamic instability, hypotension (15% cases), and abdominal distension. Severe cases may progress to hypothermia.

The symptoms of FPIES usually resolve within 24 hours after food ingestion, and the child is well in between episodes with normal growth.

What are the investigation findings in FPIES?

Bloods will show

Elevated neutrophil count


Severe cases can progress to methaemoglobinaemia and acidaemia mimicking sepsis

You may also find the following, but these tests are not recommended in routine work-ups:

  • Stool may be positive for frank or occult faecal blood, leucocytes, eosinophils, and increased carbohydrate content.
  • Negative IgE test to the triggering food in most cases
  • Intramural gas and air-fluid levels are sometimes seen on abdominal radiographs.

Infants presenting with an acute FPIES reaction can appear septic.

There is no specific biomarker or diagnostic test for FPIES.

Take a careful history establishing a timeline of symptoms in the context of a feeding history.

Management of FPIES in the Emergency Department

  1. Treat underlying shock (bolus 10ml/kg & reassess)
  2. Check blood glucose (BM) and correct if hypoglycaemic (Dextrose 10% 2ml/kg)
  3. If clinical suspicion for sepsis, obtain blood cultures, and inflammatory markers, then cover with appropriate antibiotics (as per local guidance)
  4. Consider maintenance fluid to correct the deficit.
  5. Investigate for surgical causes, serious bacterial infection or IEOM as appropriate
  6. If there is a high suspicion for FPIES:
    • Avoid food triggers
    • Treat vomiting with ondansetron
    • Discuss with local allergy specialists

Cows milk protein was identified as the most likely trigger. She started on hydrolysed formula and the symptoms dissipated.

How is FPIES managed at home?

Acute FPIES is managed with aggressive fluid resuscitation. Approximately 15% of patients can have hypovolaemic shock. Dietary elimination of the offending food is recommended. Some children have cross-reactivity ,e.g. 20-50% of children with cow’s milk FPIES have soy FPIES. FPIES rice and oats may also cross-react (<20%). Children with chicken FPIES should avoid all poultry. Children with fish FPIES should avoid all fish.

If the infant is breastfed, this should continue. There is no need for a maternal exclusion diet. It is very rare to have acute FPIES following a feed. If cow’s milk/soy-induced FPIES, extensively hydrolysed milk formula is usually tolerated. If the FPIES reaction is to extensively hydrolysed milk formula, then use amino acid-based formula.

An emergency management plan should be provided to the family.

Patients should be seen by a dietitian for guidance on complementary food introduction. They can also ensure nutritional adequacy and manage potential oral aversion. Growth parameters should be monitored at regular intervals. Reintroduction of the foods triggering FPIES should occur under medical supervision.

What are the long-term outcomes?

Most cases of FPIES resolve by age 3-4 years, but this varies widely with the population studied and the food triggering FPIES.

Where to from here?

We still do not completely understand the prevalence, risk factors and pathogenesis of FPIES. There are no validated proposed diagnostic criteria, and no protocols guiding the need for oral food challenge and long-term management of FPIES.

There are no known therapeutic approaches to accelerate FPIES resolution and no good longitudinal cohort studies determining natural history and outcomes.

If you don’t think of FPIES, you won’t see it!

Surgical causes of vomiting in infancy

The vomiting infant poses several challenges. The differential is wide, and each has a different management. Take a look at this framework for looking at vomiting.

If the vomiting is so severe as to cause shock then carefully consider surgical causes.

Malrotation and volvulus

In the malrotated gut, the intestine twists around the superior mesenteric artery (SMA) causing an obstruction. This is volvulus. It often presents in the neonatal period with bilious (green) vomits, a distended abdomen and shock. Treat the underlying shock and insert a nasogastric tube and put it on free drainage.

You should have an early conversation with your friendly paediatric surgeons and consider an upper GI contrast study.


In intussusception, the small intestine telescopes into itself causing bowel obstruction and ischaemia. Intussusception presents with acute abdominal pain with pallor, sometimes separated by periods of lethargy. Cherry-red coloured bloody stools are a late sign secondary to bowel ischaemia.

Treat underlying shock, have an early conversation with paediatric surgeons and organise an abdominal ultrasound study, looking for the ‘Doughnut sign’.

Pyloric Stenosis

Pyloric stenosis is a congenital abnormality of the pylorus with a hypertrophied longitudinal layer of muscle. At six to eight weeks of age, as the baby’s volume of feeds increases, this thicker layer of the stomach can lead to an obstructed lumen at the distal end of the stomach. It presents with projectile (no, really projectile) vomits in the second or third month of life.

The classic blood gas shows a hypokalaemic, hypochloraemic metabolic alkalosis, but it can be normal. If you have a high clinical suspicion, then perform an abdominal ultrasound.

But it’s not all surgical. Let’s turn our attention to the medical causes of vomiting in infancy.

Medical causes of vomiting in infancy


Of course, this could be sepsis. Vomiting and shock all point to sepsis. And you’ll need to manage as if it were. But what else could it be?

Urinary Tract Infection

vomiting without diarrhoea in an unwell infant should always prompt clinicians to consider a urinary tract infection, particularly in a febrile infant. In the sick infant with vomiting and diarrhoea without a corroborating family history of sick contacts with similar symptoms, don’t be reassured by the presence of diarrhoea – an unhappy gut due to a UTI can lead to diarrhoea, too.

Inborn errors of metabolism (IEOM)

IEOM can often present with profuse vomiting, dehydration and acidosis. Maintain a high clinical suspicion in early newborn presentations, failure to thrive in infancy or a family history of stillbirth, sudden infant death or consanguinity.

Always check a blood gas and ammonia in a sick infant to rule-out time-critical metabolic emergencies. DFTB has a wealth of metabolic resources in our module and posts.


Jlidi S, Ben Youssef D, Ghorbel S, Mattoussi N, Khemakhem R, Nouira F, Chaouachi B. La sténose hypertrophique du pylore du nourrisson: a propos de 142 cas [Infantile hypertrophic pyloric stenosis. Report of 142 cases]. Tunis Med. 2008 Jan;86(1):63-7

Justice FA, Auldist AW, Bines JE. Intussusception: trends in clinical presentation and management. J Gastroenterol Hepatol. 2006 May;21(5):842-6

Liacouras CA. Evaluation and management of a child with vomiting. Pediatr Case Rev. 2002 Jan;2(1):3-13

McCollough M, Sharieff GQ. Abdominal surgical emergencies in infants and young children. Emerg Med Clin North Am. 2003 Nov;21(4):909-35

Nowak-Wegrzyn A, Berin MC, Mehr S. Food protein-induced enterocolitis syndrome. J Allergy Clin Immunol Pract 2020;8:24–35.

Nowak-Węgrzyn A, Chehade M, Groetch ME, et al. International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: Executive summary-Workgroup Report of the Adverse Reactions to Foods Committee, American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol 2017;139:1111–26.

Raghuveer TS, Garg U, Graf WD. Inborn errors of metabolism in infancy and early childhood: an update. Am Fam Physician. 2006 Jun 1;73(11):1981-90

Stiefel G, Alviani C, Afzal NA, Byrne A, du Toit G, DunnGalvin A, Hourihane J, Jay N, Michaelis LJ, Erlewyn-Lajeunesse M. Food protein-induced enterocolitis syndrome in the British Isles. Arch Dis Child. 2021 Aug 26:archdischild-2020-320924

Venter C, Brown T, Shah N, et al. Diagnosis and management of non-IgE-mediated cow’s milk allergy in infancy – a UK primary care practical guide. Clin Transl Allergy 2013;3:23.


  • Shane is a PEM Education Fellow at the Leicester Royal Infirmary in the UK. PEM MSc at University of Edinburgh. Excellent procrastinator, average footballer, terrible at latte art. He/him.

  • Adele is a Registrar in Emergency Medicine at Leicester Royal Infirmary in the UK. Mother & photographer. SEND advocate. Preferred pronouns: She/her. She/her.

  • Since 2012, Gary has been a Consultant in Paediatric Allergy at the University Hospitals of Leicester NHS Trust, having been trained at St Mary Hospital, London and University Hospital Southampton Foundation Trust. He completed an Allergy MSc at Imperial College London and now regularly lectures on the food allergy module for the Allergy MSc at University of Southampton. Gary has previously served as one of the RCPCH specialist advisory committee members for Allergy, Immunology and Infectious Diseases. Gary is the lead author for the BSACI nut allergy guidelines and has recently co-lead a national BPSU study on FPIES. He is on the board of trustees for Allergy UK. Preferred pronouns: He/him.

  • Clementine David is a trainee in Clinical Immunology and Allergy with an unrivalled affiliation for gelato. While an Aussie at heart, she is currently residing as an expat in Hong Kong’s Happy Valley, balancing her time between antigens and Octonauts.



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2 thoughts on “The diagnostic challenge of FPIES”

  1. Great post. One thing, in the cmpa section it says:
    no other associated signs of hypersensitivity reactions (ie urticaria, angioedema, wheeze or stridor) are usually present.
    Is the ‘no’ an error?