Food protein‐induced enterocolitis syndrome: Pitfalls in the diagnosis

Food protein‐induced enterocolitis syndrome (FPIES) represents the severe end of the spectrum of gastrointestinal food hypersensitivity; its acute episodes can culminate in severe dehydration and hypovolemic shock, and its chronic form entails considerable morbidity associated with feeding difficulty and failure to thrive. Nevertheless, awareness for this syndrome remains rather low. Many factors hamper the establishment of FPIES diagnosis. Such factors pertain to the pathophysiological mechanism of the syndrome, causal food proteins, clinical manifestations, diagnostic procedures, differential diagnosis considerations, and prevailing perceptions which may require critical appraisal. Throughout this review, we will present and discuss these issues and put the focus on factors that could lead to under‐diagnosis of FPIES, cause numerous acute episodes, and substantially increase the diseases morbidity and financial burden. We will also address other issues that are clinically relevant to FPIES.     

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??Oral allergy syndrome??OAS?? is an IgE-mediated acute oropharyngeal hypersensitivity to food??which is caused by cross-reactivity between proteins in fresh fruits or vegetables and pollens??with a prevalence of 5% to 24 % in children. A variety of food protein antigens have been implicated in OAS. The most classic of these cross-reactive antigens include birch antigen Betv1??profilin and lipid transfer proteins??LTPs??. Symptoms are usually manifested as numbness??itching or swelling of the lips or mouth??itching or oedema of the lips?? throat??palate or gingiva??erythema of the face and tightness of the throat. OAS can be diagnosed based on clinical history??antigen-specific immunoglobulin E testing??skin prick testing and oral food challenge. If the diagnosis is established??patients should be instructed to avoid the fresh fruits and vegetables that cause symptoms??and emergency administration of epinephrine should be given for severe??generalized reactions.     

Rice protein‐induced enterocolitis syndrome with transient specific IgE to boiled rice but not to retort‐processed rice

Described herein is the case of an 8‐month‐old girl with atypical food protein‐induced enterocolitis syndrome due to rice. She presented with vomiting and poor general activity 2 h after ingestion of boiled rice. Oral food challenge test using high‐pressure retort‐processed rice was negative, but re‐exposure to boiled rice elicited gastrointestinal symptoms. On western blot analysis the patient's serum was found to contain IgE bound to crude protein extracts from rice seed or boiled rice, but not from retort‐processed rice. The major protein bands were not detected in the electrophoresed gel of retort‐processed rice extracts, suggesting decomposition by high‐temperature and high‐pressure processing. Oral food challenge for diagnosing rice allergy should be performed with boiled rice to avoid a false negative. Additionally, some patients with rice allergy might be able to ingest retort‐processed rice as a substitute for boiled rice.     

Non‐IgE‐mediated gastrointestinal food allergies in children

Non‐IgE‐mediated gastrointestinal food allergic disorders (non‐IgE‐GI‐FA) including food protein‐induced enterocolitis syndrome (FPIES), food protein‐induced enteropathy (FPE), and food protein‐induced allergic proctocolitis (FPIAP) are relatively uncommon in infants and young children, but are likely under‐diagnosed. Non‐IgE‐GI‐FA have a favorable prognosis, with majority resolving by age 3–5 years. Diagnosis relies on the recognition of symptoms pattern in FPIAP and FPIES and biopsy in FPE. Further studies are needed for a better understanding of the pathomechanism, which will lead eventually to the development of diagnostic tests and treatments. Limited evidence supports the role of food allergens in subsets of constipation, gastroesophageal reflux disease, irritable bowel syndrome, and colic. The immunologic pathomechanism is not fully understood and empiric prolonged avoidance of food allergens should be limited to minimize nutrient deficiency and feeding disorders/food aversions in infants.     

Anaphylaxis after prick‐to‐prick test with fish

Skin prick testing is the diagnostic procedure for allergies and is considered to be safe. It is usually performed using the prick and the prick‐to‐prick method. Herein is described a pediatric case of anaphylaxis during prick‐to‐prick testing with raw fish in a patient who had consumed fish without any systemic allergic reactions beforehand, to illustrate that skin prick testing should be carefully planned and performed with caution in order to avoid potentially serious risks for the patient.     

New validated recipes for double‐blind placebo‐controlled low‐dose food challenges

Double‐blind placebo‐controlled food challenges are considered the most reliable method to diagnose or rule out food allergy. Despite this, there are few validated challenge recipes available. The present study aimed to validate new recipes for low‐dose double‐blind placebo‐controlled food challenges in school children, by investigating whether there were any sensory differences between the active materials containing cow's milk, hen's egg, soy, wheat or cod, and the placebo materials. The challenge materials contained the same hypoallergenic amino acid–based product, with or without added food allergens . The test panels consisted of 275 school children, aged 8–10 and 14–15 yr, respectively, from five Swedish schools. Each participant tested at least one recipe. Standardized blinded triangle tests were performed to investigate whether any sensory differences could be detected between the active and placebo materials. In our final recipes, no significant differences could be detected between the active and placebo materials for any challenge food (p > 0.05). These results remained after stratification for age and gender. The taste of challenge materials was acceptable, and no unfavourable side effects related to test materials were observed. In summary, these new validated recipes for low‐dose double‐blinded food challenges contain common allergenic foods in childhood; cow's milk, hen's egg, soy, wheat and cod. All test materials contain the same liquid vehicle, which facilitates preparation and dosing. Our validated recipes increase the range of available recipes, and as they are easily prepared and dosed, they may facilitate the use of double‐blind placebo‐controlled food challenges in daily clinical practice.     

Milk-induced pulmonary disease in infants (Heiner syndrome)

Heiner syndrome (HS) is a food hypersensitivity pulmonary disease that affects primarily infants, and is mostly caused by cow's milk (CM). Only a few reports have been published, which may be due to its misdiagnosis. We review here a series of eight cases. When first diagnosed they were 4-29 months of age. They were fed CM from birth and their chronic respiratory symptoms began at age 1-9 months. The symptoms were in the form of cough in seven, wheezing in three, hemoptysis in two, nasal congestion in three, dyspnea in one, recurrent otitis media (OM) in three, recurrent fever in four, anorexia, vomiting, colic or diarrhea in five, hematochezia in one, and failure to thrive (FTT) in two. All had radiologic evidence of pulmonary infiltrates. High titers of precipitating antibodies to CM proteins were demonstrated in six of six and milk-specific immunoglobulin E (IgE) was positive in one of two. Pulmonary hemosiderosis (PH) was confirmed in one patient who showed iron-laden macrophages (ILM) in the bronchoalveolar lavage (BAL), gastric washing, and open lung biopsy. Additional findings, in a descending frequency, were eosinophilia, anemia, and elevated level of total IgM, IgE or IgA. Milk elimination resulted in remarkable improvement in symptoms within days and clearing of the pulmonary infiltrate within weeks. Parents consented to milk challenge in only three cases, all of whom developed recurrence of symptoms. After 2 yr of milk avoidance in one patient, milk challenge was tolerated for 2 months, and then the patient developed symptoms, serum milk precipitins, pulmonary infiltrate, and ILM. The HS should be suspected in young children with chronic pulmonary disease of obscure cause. The diagnosis is supported with a positive milk precipitin test and improvement on a trial of milk elimination. Severe cases may be complicated with PH, which should be suspected in the presence of anemia or hemoptysis and be confirmed with the demonstration of ILM.