A piece of FPIES – a non-IgE mediated allergy emergency

CASE
A healthy 1-year-old boy was referred to the allergy and immunology clinic by his local health centre for investigation of possible allergy to egg, and advice regarding administration of the yellow fever vaccination. He was atopic with a history of eczema. His parents first gave him a small piece of boiled egg yolk at the age of 10 months. He developed repetitive, protracted vomiting an hour after and became floppy and weak. This was followed by diarrhoea a few hours later. There was no fever, or signs of IgE-mediated allergy such as rash, swelling or dyspnoea. He was taken to a general practitioner who advised oral rehydration and his symptoms resolved within 24 hours. Two months later, he was given a small amount of scrambled egg, and developed severe recurrent vomiting after an hour and became floppy, weak and pale. There were no symptoms of rash, swelling, dyspnoea, fever or diarrhoea. He was taken to the emergency department where oral rehydration was advised and he was observed. Once again all symptoms resolved within 24 hours. Thereafter his parents excluded egg from his diet in all forms, including in baked goods. When seen in the immunology and allergy clinic he had successfully tried a variety of other foods, but had not tried nuts or meat. Skin prick testing with commercial whole egg extract (Stallergenes Greer, NC, USA) was negative, as was prick-to-prick testing with fresh egg white and egg yolk, with positive and negative controls of 8mm and 0mm, respectively. These results strongly suggested that the patient’s symptoms were not due to IgE-mediated allergy. A diagnosis of food protein induced enterocolitis (FPIES) due to egg proteins was made based on the clinical features of protracted vomiting followed by diarrhoea starting one hour after ingestion of egg; the recurrence of symptoms on a subsequent exposure to egg; exclusion of differential diagnoses such as acute gastroenteritis and sepsis and recovery within 24 hours without antibiotics. His parents were advised to exclude egg in all forms from his diet and were given an advice sheet and an emergency action plan to use in case of accidental exposure. They were advised that he is likely to grow out of the condition and that an oral challenge to egg will be required at an older age.

DISCUSSION
Food allergy can be categorised as IgE-mediated, non-IgE mediated or mixed [2]. IgE-mediated food allergy is most common and best understood. It occurs in a sensitised individual upon re-exposure to the allergen. This causes cross-linking of allergen-specific IgE on mast cells and basophils, and results in release of chemicals such as histamine, which mediate the typical symptoms of an allergic reaction such as rapid onset of rash, swelling, dyspnoea and hypotension. Diagnosis is confirmed by detection of specific IgE to the allergen, either by skin prick testing, specific IgE blood tests or supervised oral challenge with the suspected food. Skin prick testing to foods may be performed using either commercial allergen solutions or the fresh food itself, with the latter termed prick-to-prick testing. IgE mediated food allergy is treated by avoidance of the offending food and use of adrenaline and antihistamines in the event of accidental exposure. In contrast, non-IgE-mediated food allergy is less well understood. These are immune-mediated reactions to foods without the involvement of allergen-specific IgE. It presents as delayed or chronic symptoms occurring hours to days after ingestion of the allergen and symptoms predominantly involve the gastrointestinal system. Diagnosis is based on clinical history and symptom resolution on avoidance of the culprit food as there are no diagnostic laboratory tests available. There is no role for adrenaline in treatment. Examples of non-IgE-mediated food allergy include FPIES, food protein-induced allergic proctocolitis (FPIAP), food protein-induced enteropathy (FPIE) and eosinophilic gastrointestinal diseases.

Acute FPIES
FPIES may present as acute or chronic forms, based on the timing and duration of the symptoms. The acute form presents with recurrent, protracted, projectile vomiting within 1-4 hours of ingesting the culprit food, and sometimes diarrhoea within 24 hours. Paediatric patients present unwell, with lethargy, pallor and hypotonia and in severe cases can develop shock. Adult patients present with similar symptoms of severe abdominal pain, nausea and diarrhoea but vomiting may be less prominent, occurring in 60% [3]. Laboratory abnormalities may include elevated white cells, neutrophilia, metabolic acidosis and methemoglobinaemia [4]. The pathophysiology of FPIES appears to involve both the innate and cell mediated immune system, with studies finding activation of neutrophils, eosinophils, natural killer cells, and T cells. This leads to gut inflammation in the colon and ileum causing increased intestinal permeability and fluid shift into the gastrointestinal lumen [4], resulting in characteristic gastrointestinal symptoms. Diagnosis is made on clinical history and oral food challenge, if needed, as there is no reliable biomarker for FPIES at present. Awareness of FPIES is low internationally and the diagnosis is frequently delayed. The first international consensus guidelines for diagnosis of FPIES in children were published in 2017 [5], in which acute, chronic and atypical forms are defined. There are no consensus guidelines regarding adult FPIES to date. These guidelines recommend that diagnosis of acute FPIES in children requires the presence of the major criteria of vomiting 1-4 hours after ingestion of suspected food in the absence of allergic skin or respiratory symptoms accompanied by 3 or more of minor criteria as outlined in Table 1.

Table 1: Diagnostic criteria for acute FPIES

FPIES is more frequently seen in infants and young children, although it can occur in adults. There is limited epidemiological data and the exact incidence is unknown. One study in the United States estimated a prevalence of 0.51% in children and 0.22% in adults, with others reporting a cumulative incidence of 0.7% in infants in Spain, and 0.36% in infants in the United Kingdom [6]. Patients with FPIES often have a personal of family history of atopy, such as asthma, eczema, allergic rhinitis or other food allergy [5,7]. There may be a higher incidence in children with Down’s syndrome [8] Sepsis and gastroenteritis are the major differentials for acute FPIES [5], as they may share similar presenting features of vomiting, diarrhoea, weakness and hypotension and laboratory features of neutrophilia. However, both often present with fever, elevated inflammatory markers and positive identification of microbes in blood cultures and stool samples, which are absent in FPIES. It can be difficult to differentiate FPIES until the patient has presented on multiple occasions after eating the trigger food. Hence, treating the patient for a “worst-case scenario” may be wise until the diagnosis is established. Acute FPIES should be treated as a potential medical emergency. Treatment should be individualised according to the patient’s clinical status, and oral rehydration or intravenous fluids used dependant on the severity of the reaction. Adrenaline and antihistamines are not indicated for FPIES. Oral or intravenous ondansetron is advised in all cases over the age of 6 months to control vomiting. It is thought that the vomiting is due to serotonin release by enterochromaffin cells, so that ondansetron, a serotonin 5HT3 receptor antagonist, helps supress vomiting [9]. There is little published on the use of alternative anti-emetics. Administration of intravenous methylprednisolone, 1mg/kg, can be considered in severe cases although this is not evidence-based [5]. Patients with moderate to severe FPIES should be observed in a medical facility until symptoms resolve. Long term management involves elimination of the trigger food and establishment of an emergency plan for accidental exposure. Dietitian review can be helpful to discuss food avoidance, and in some cases to ensure the child’s diet is nutritionally adequate. There is geographic variation in the causative foods, probably reflecting cultural or genetic differences. Cow’s milk, fish, egg and grains such as rice and oats are the most common triggers of acute FPIES worldwide in children [10], while seafood is the most common trigger in adults. Most patients react to a single food, but a proportion have more than one culprit food, with a combination of cow’s milk and soy being most common in those with multiple triggers. Patients with FPIES should undergo an oral food challenge at an older age to establish whether tolerance has been achieved. Some authors recommend oral food challenge 12 – 18 months after the last reaction to determine acquisition of tolerance [9]. Most children will eventually develop tolerance to the offending food, but the reported timing varies with the food involved and country of study. A recent systematic review found that FPIES resolution occurred in 60% of affected children by age 3 [10]. Tolerance is achieved at a younger age for cow’s milk and rice FPIES as compared to egg and fish FPIES [9]. Studies which assessed the resolution of egg FPIES found the median age at time of resolution ranged from 18 months to 63 months. Tolerance to cooked egg is achieved earlier than tolerance to raw egg, likely because heating egg changes its structure and allergenicity [10].

Other forms of FPIES
Chronic FPIES occurs when the offending food is given on a regular basis; for example, an infant starting cow’s milk or soy milk. Consensus guidelines recommend that the diagnosis of chronic FPIES is defined by intermittent vomiting with diarrhoea during regular ingestion of the food allergen, sometimes with dehydration and metabolic acidosis. These children present with frequent watery diarrhoea and vomiting which are not necessarily temporally related to consumption of the culprit food, and can result in failure to thrive, weight loss, anaemia and hypoalbuminaemia. Cow’s milk or soy, usually in soy milk, are the most common culprits in chronic FPIES. An elimination diet removing the suspect food can be helpful in diagnosis – symptoms should resolve within 3-10 days after elimination of the offending food and return as acute FPIES when the food is reintroduced. It can be a difficult diagnosis due to the wide differential for failure to thrive, which includes coeliac disease and eosinophilic gastroenteropathies. Both conditions present similarly, with vomiting, diarrhoea, failure to thrive and anaemia. Further investigations such as endoscopy may be required to make the diagnosis. Finally, atypical FPIES appears to be a combination of IgE and non-IgE mechanisms; patients present with the symptoms of FPIES but are also skin test positive or specific IgE positive to the offending food. About 25% of these patients develop IgE-mediated allergy to the food in the future [9].

CONCLUSION
Food allergy, both IgE and non-mediated, is increasing in prevalence worldwide. Although the Caribbean region lacks accurate epidemiological figures for allergic conditions, it is expected that allergy related emergencies will increase in a similar manner to other regions. The aim of this paper is to increase awareness and knowledge of FPIES, so that the condition can be considered as a differential in similar paediatric and adult emergency presentations.

Learning points
• The pathophysiology of food allergy may be IgE-mediated, non-IgE-mediated or mixed.
• FPIES is a non-IgE-mediated food allergy that that presents with gastrointestinal symptoms without cutaneous and respiratory symptoms and may be acute or chronic.
• Acute FPIES may present as a medical emergency with protracted vomiting within 1-4 hours of ingesting the culprit food with lethargy, pallor, hypotonia, dehydration and shock. Treatment comprises of anti-emetics such as ondansetron and fluid resuscitation, and avoidance of the culprit food. There is no role for adrenaline.
• Chronic FPIES should be included in the differential for failure to thrive in a patient with frequent intermittent diarrhoea and vomiting.
• Most children will eventually acquire tolerance to the culprit food

Acknowledgements: None
Ethical approval statement: Not applicable
Financial disclosure or funding: No funding was required in creating the manuscript.
Conflict of interest: The authors declared that they have no conflicts of interest.
Informed consent: Informed consent was obtained from the patient’s mother.
Author contributions: Shanti Mahabir had direct patient contact, made the diagnosis and wrote the case report. Vijaya Siew reviewed and edited the manuscript.

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