Food Protein-Induced Enterocolitis Syndrome

From Practice to Theory

Stefano Miceli Sopo; Monica Greco; Serena Monaco; Salvatore Tripodi; Mauro Calvani

Expert Rev Clin Immunol. 2013;9(8):707-715.

FPIES Differential Diagnosis

Victor's Story: Why Is Everything Over Me?

Victor ate for the first time a homogenized fruit baby food containing 3% ground rice when he was five months old. He was fed with the same baby food, increasing its dose, for a week, until one day, 2 h after the food ingestion, he started to vomit repetitively (4−6 vomits), became pale and hyporeactive and also started to suffer from diarrhea. Due to his serious clinical condition, Victor was hospitalized for a few days with a diagnosis of acute gastroenteritis. Fifteen days later the baby ate two teaspoons of rice cream and 2 h after the ingestion, presented with the same symptoms of the previous episode. He was re-hospitalized and once more doctors believed the cause was gastroenteritis. During the time spent in the hospital, when Victor recovered completely, he was fed with rice cream and Victor had a third episode presenting with vomit, pallor, hyporeactivity and diarrhea. On that day he was examined by a pediatrician with expertise in allergies and so was finally issued the diagnosis of FPIES caused by rice. Rice-specific IgEs were negative.

Victor's story teaches us that FPIES is frequently confused with an acute gastroenteritis; actually, it can even be wrongly diagnosed as sepsis, acute abdomen, metabolic disesases and necrotizing enterocolitis. None of the abovementioned conditions resolves in a few hours from their onset, as FPIES does, and this is a very typical aspect of this syndrome. FPIES is also confused with anaphylaxis and both these diseases actually have the same duration but, as FPIES diagnostic criteria point out, there are no IgE-mediated signs and symptoms, such as urticaria and angioedema, in this syndrome.

FPIES Pathogenesis and Diagnostic Tests

Katie's story teaches us something more: when we visited Katie we suggested to perform an atopy patch test (APT) with sole, even if at that time (2004) we did not know anything about FPIES. It was only in 2006 that Fogg published his study,^[6] which reported a 100% negative predicting value of APT in FPIES. This seemed very useful information, as we were able to exclude FPIES in all the children who had a single episode with a negative APT. Unfortunately a short time later Zapatero et al.^[7] and Jarvinen et al.^[8] proved the inefficiency of this test, so that APT could not be considered a relevant tool for FPIES diagnosis. Moreover, specific IgE research turned out not to be useful for the diagnosis because it is usually negative, with the exception of 5% of cases, which are defined as 'atypical', as they have positive specific IgE. Bridget, Ernst, Katie and Victor all had negative SPTs. This evidence supports the hypothesis that FPIES pathogenesis is cell-mediated and this is without doubt the most accepted immunepathogenetic theory; furthermore, some variations in blood cytochine levels, which are increasing for TNF-α and decreasing for TGF-β, were observed.^[9] For these reasons, the idea to evaluate the diagnostic performance of APT, a skin test that aims to unveil a cell-mediated immune reaction, is correct; unfortunately, this test is not yet sufficiently standardized and reproducible. Anyway, someone is beginning to think that specific IgEs could play a role in FPIES and they suppose that they might be expressed only along the GI tract. In Box 1 we show the reasons that lead us to imagine that FPIES could have a combined pathogenesis, at least sometimes.

The last point of Box 1 could have a significant impact on young patients' quality of life. In fact, nowadays the chance of tolerating the culprit food if baked or well-matured (as parmesan 36 months) in the case of CM, has been demonstrated only for IgE-mediated FAs.^[13–15] Cell-mediated FAs could not have this privilege due to their immunological mechanisms. However, we found that four out of seven children suffering from CM FPIES tolerated the culprit food if baked (e.g., cake or biscuits).^[12] If pathogenesis of FPIES is erected on an exclusive cell-mediated mechanism, tolerance versus the offending food well-cooked could not be possible in an active FPIES. In fact, denaturation of conformational epitopes, caused by high and prolonged temperatures, should not obstruct the antigen–receptor link, as happens in the majority of the cases of IgE-mediated allergies. In fact, T-cell receptors (TCRs) recognize antigenic peptides derived from proteins degraded and exposed on cellular surface of dendritic cells through link with MCH1 receptors present on own surface and not specific for that allergen, but independent from its structural conformation.^[16] In conclusion, as Caubet et al.^[9] wrote, it is not possible to exclude a possible IgE role in FPIES pathogenesis. We think that FPIES is a FA halfway between the IgE-mediated and cell-mediated forms and, moreover, that there are different phenotypes of FPIES. In some of them, IgE and related cytokines may play a significant role. However, we are aware that it may be a controversial theory and that authors' opinions on this may vary.

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Table 1. Acute and chronic FPIES clinical manifestations.
Acute FPIES	Chronic FPIES
Important and repetitive vomiting (constant)	Regurgitation, small amounts of vomit
Lethargy (frequent)	Lethargy
Hyporeactivity (frequent)	Failure to thrive
Pallor (frequent)	Dehydration
Diarrhea (inconstant and tardive)	Diarrhea, sometimes bloody
Dehydration (rare)	Abdominal distention
Hypothermia (rare)	Hypotension (rare)

Table 2. Diagnostic criteria of FPIES.
Powell, 1986²	Leonard et al., 2012¹	Miceli Sopo et al., 2013
Less than 9 months of age at initial presentation (reaction)	Less than 9 months of age at initial diagnosis	Less than 2 years of age at first presentation (frequent feature but not mandatory)
Exposure to the incriminated food elicits repetitive vomiting and/or diarrhea within 4 h without any other cause for the symptoms	Repeated exposure to causative food elicits gastrointestinal symptoms without alternative cause	Exposure to the incriminated food elicits repetitive and important vomiting, pallor, hyporeactivity and lethargy within 2–4 h. Diarrhea may be present, much less frequently and later. The symptoms last a few hours, usually less than 6 h
Symptoms limited to the GI tract	Absence of symptoms that may suggest an IgE-mediated reaction	Absence of symptoms that may suggest an IgE-mediated reaction
Avoidance of the offending protein from the diet results in resolution of symptoms	Removal of causative food results in resolution of symptoms	Avoidance of the offending protein from the diet results in resolution of symptoms
A standardized food challenge or isolated re-exposure elicits the typical symptoms	Re-exposure or oral food challenge elicits typical symptoms within 4 h	Re-exposure or oral food challenge elicits typical symptoms within 2−4 h. Two typical episodes are needed to deliver the definitive diagnosis

Box 1. Clues in favor of a specific IgE role in food protein-induced enterocolitis syndrome pathogenesis.
There are some cases with positive specific IgEs against the culprit food, even if their levels are low. In one child,, during an episode of acute FPIES caused by rice, a plasmatic cytokinic trend similar to those of IgE-mediated allergic reactions was observed, with an increase of IL-4 and a decrease of IFN-γ [10]. The fact that symptoms arise 2 h after the ingestion of the culprit food is not a typical feature either of classical IgE-mediated forms (the reaction usually appears long before 2 h) or of classical non-IgE-mediated forms (which usually manifest long after 2 h). Few patients (with positive specific IgE research) present a shift in symptoms from those of FPIES to those of gastrointestinal anaphylaxis [11]. Regarding CM FPIES, there is a report about the capability of tolerating the culprit food if well-cooked (baked) [12].