Review Article

The Diagnosis and Management of Food Allergy and Food Intolerances

J. L. Turnbull; H. N. Adams; D. A. Gorard


Aliment Pharmacol Ther. 2015;41(1):3-25. 

In This Article

Non-IgE-mediated Food Allergy

There are three main clinical entities of non-IgE mediated allergy. These are Food Protein-Induced Enterocolitis Syndrome (FPIES), Food Protein-Induced Proctocolitis (FPIP) and the Food Protein-Induced Enteropathies. The immune mechanisms underlying these conditions are not well understood, though TNFα has been heavily implicated. A recent study has also found a possible link with the TH2 response found in IgE-mediated allergy, in that whilst there is no production of IgE, T cells are skewed towards a TH2 response. High levels of IL-13 and TNFα may be key drivers of intestinal epithelial cell damage and eosinophil infiltration, working through activation of the tumour necrosis factor-like weak inducer of apoptosis – fibroblast growth factor-inducible molecule 14 (TEAK-Fn14) axis.[88] Non-IgE-mediated food allergy is almost always confined to childhood, and is less well recognised in adults.[89]

Food Protein-induced Enterocolitis Syndrome

Food protein-induced enterocolitis syndrome is an uncommon food allergy that causes a distinctive and often dramatic reaction to food. It causes solely gastrointestinal symptoms - vomiting with or without diarrhoea. However these symptoms can suddenly worsen, mimicking acute illness such as sepsis or acute abdominal problems.[90] Consequently it is under recognised. The underlying pathophysiology is not well defined, but there is thought to be a key role for stimulation of mucosal T-cells leading to a delayed cell-mediated immune response. TNF-α and a relative lack of expression of TNF-β have been implicated.[91] The resulting inflammation is thought to increase mucosal permeability and lead to rapid fluid shifts that explain the clinical effects.

Food protein-induced enterocolitis syndrome is a disease of babies and young children, as most children become tolerant by 3 years of age. An Israeli birth cohort study found an estimated prevalence of 0.34%.[92] Symptom onset could be as early as a few weeks of age, but may be delayed to around 5 months of age in breast-fed babies.[92] The three most common foods causing FPIES are cow's milk, soy and rice. Rarer triggers include oat and other cereals, a range of orange vegetables (sweet potato, squash, carrot), egg white, legumes (peanut, green pea, string bean), chicken, turkey, fish and banana.[93]

The onset of FPIES symptoms is typically 2 h after exposure, but can range from 0.4 to 4 h.[91] The presentation is with repetitive forceful vomiting, with or without diarrhoea.[91,94] Only the gastrointestinal tract is involved, though fluid depletion can give rise to features of shock with lethargy, pallor and cyanosis.[90] Although symptoms resolve within 6–12 h,[91] these children can present acutely unwell. These patients are frequently treated for sepsis, pyloric stenosis or inherited metabolic disease, due both to their severe compromise and the absence of features that usually evoke consideration of an allergic cause such as very recent ingestion and cutaneous or respiratory phenomena. Furthermore test results in FPIES may show metabolic acidosis, neutrophilia and thrombocytosis.[93] The diagnosis is a clinical one, though the presence of blood, eosinophils, lymphocytes or increased reducing substances in the stools is supportive.[94]

A study of 66 patients found that it takes up to five FPIES episodes to establish a diagnosis, equating to an 8 month delay in diagnosis.[91] Clues to the possibility of FPIES include a more rapid recovery than would be expected in sepsis, infective gastroenteritis or surgical conditions, and being at a stage of dietary transition.

The criteria for diagnosing FPIES (Table 7) are (i) age under 9 months old at diagnosis; (ii) repeated exposure to the incriminated food elicits repetitive vomiting and/or diarrhoea within 24 h; (iii) solely gastrointestinal symptoms; (iv) dietary elimination of the offending food protein resolves symptoms within 24 h. Infants with FPIES are at increased risk of a subsequent IgE-mediated food allergy.[94]

Management of FPIES is allergen avoidance, with associated education and dietetic support. In breast-fed infants, the mother should avoid the offending food only if there has been a documented reaction after maternal consumption.[95] Formula-fed infants will require extensively hydrolysed formulas, with amino acid formulas used only if reactions persist. Accidental allergen exposure will require intravenous or oral rehydration, and in some cases, inotropic support. Steroids may be considered in moderate to severe cases, though there is no evidence that they hasten recovery.[93]

There is wide variation in reported rates of resolution of FPIES. In a study of 44 infants with FPIES to cow's milk, 50% developed tolerance by 1 year and 90% developed tolerance by 3 years.[92] Solid food FPIES appears to persist for longer.[96] After 18–24 months a supervised food challenge should be performed, provided prompt treatment for shock and anaphylaxis is available and intravenous access is already established in those with a history of hypotension.[91,93]

Food Protein-induced Proctocolitis

Food protein-induced proctocolitis is a benign transient condition of otherwise well neonates, who pass blood and mucus in the stool. Cow's milk protein is the most common food culprit. Since it is present in breast milk, exclusively breast-fed infants may get FPIP. In FPIP a cell-mediated reaction to food proteins leads to mixed eosinophilic and lymphocytic inflammation of the colon and rectum. It usually presents in a thriving infant. Diagnosis is based upon the presence of fresh rectal bleeding in the absence of other systemic symptoms. Colonoscopy is not necessary but when performed mucosal biopsies show eosinophilic infiltration. Symptoms should resolve after eliminating cow's milk from the diet or from the mother's diet in breast-fed infants, and should return on re-exposure (Table 7). The importance of re-challenging has been emphasised recently, due to the finding that many infants with rectal bleeding have a transient colitis that resolves spontaneously even without a change in diet. For example Jang studied 16 well neonates with rectal bleeding and abnormal colorectal endoscopic appearances. After initial dietary elimination, almost 90% of these infants had no further bleeding after milk challenge.[97] This concurs with a study that randomised neonates with rectal bleeding to continue their current intake or eliminate cow's milk. Symptoms resolved in the majority of infants in both groups, and only 2 of 19 had symptoms on re-challenge.[98] There is a very low risk of harm from a brief re-challenge and the potential benefits of an unrestricted maternal and infant diet justifies this.

Food Protein-induced Enteropathies

The food-protein enteropathies were first described in the 1960s after the identification of a group of infants with malabsorption associated with cow's milk.[88] Such infants develop chronic diarrhoea, steatorrhoea and poor weight gain within the first months of life. There may be associated anaemia and hypoalbuminaemia. The most common triggers are cow's milk and soy, but similar reactions have also been reported to chicken, rice and fish.[9] Such foods trigger a T-cell mediated immune response within the small intestine, with nonspecific villous atrophy and lymphocytic infiltration. Coeliac disease shares similar pathological mechanisms, but differentiation from coeliac disease is not usually a problem since symptoms of food-protein enteropathy often start before weaning and the introduction of dietary gluten. Diagnosis is based on clinical symptoms and their resolution with allergen avoidance. Endoscopic small bowel biopsy may be helpful. Food protein–induced enteropathies rarely persist beyond 3 years of age, and food challenges may allow earlier reintroduction of milk and other culprit foods.