Food Protein-induced Enterocolitis Syndrome

Masayuki Akashi

doi:10.2302/kjm.2022-0016-IR

Abstract

Food protein-induced enterocolitis syndrome (FPIES) is a type of non-IgE-mediated gastrointestinal food allergy. FPIES is characterized by repetitive vomiting without classic IgE-mediated allergic skin or respiratory symptoms 1–4 h after causative food ingestion. The condition may be classified as acute or chronic, typical or atypical, and liquid or solid according to the course of symptoms, presence of IgE antibodies, and causative food, respectively. Since the development of international consensus guidelines in 2017, epidemiological studies have been conducted in many countries. FPIES is a relatively rare disease, with a prevalence of 0.015%–0.7%. However, the number of patients has been increasing in recent years. Most patients develop the disease in infancy. The natural history of FPIES is generally favorable, with most FPIES cases resolving before school age. FPIES is diagnosed using symptoms such as vomiting or diarrhea, or via an oral food challenge (OFC). Currently, no validated biomarker is available for diagnosis, and the mechanisms related to gastrointestinal manifestations and immune system involved in the development of FPIES have not yet been elucidated. Treatment with intravenous fluids and ondansetron is recommended in the acute phase. Long-term management consists of complete causative food elimination and periodic OFC to confirm tolerance. Given that many diagnoses are delayed because of a lack of awareness of the condition, FPIES must be widely recognized by healthcare providers. In the future, it is expected that FPIES pathogenesis will be further clarified, and more objective diagnostic criteria will be developed.

Introduction

Food protein-induced enterocolitis syndrome (FPIES) is a type of non-IgE-mediated gastrointestinal food allergy along with food protein enteropathy (FPE) and food protein-induced allergic proctocolitis (FPIAP). The main symptom of FPIES is repetitive vomiting 1–4 h after causative food ingestion but without classical IgE-mediated allergic skin or respiratory symptoms. Patients may present with marked pallor or extreme lethargy, diarrhea, and, in severe cases, hypotension or hypothermia.¹ Conditions involving gastrointestinal symptoms, mainly vomiting without allergic skin or respiratory symptoms, caused by food ingestion with suspected allergic involvement have been reported since the 1960s. In the 1970s, such conditions were first described as FPIES, and Powell developed diagnostic criteria in 1986.² In the 2010s, Leonard developed new diagnostic criteria.³ The main diagnostic criteria included disease onset within the first 9 months of life; gastrointestinal symptoms including vomiting without IgE-mediated allergic skin or respiratory symptoms; symptom improvement after causative food discontinuation; and recurrence of symptoms with causative food re-exposure. Subsequently, international consensus guidelines were developed for the first time in 2017.¹ This has led to case-control studies in many countries. The diagnostic criteria for the international consensus guidelines now include vomiting as a requirement and no longer have age-related restrictions.

Table 1 shows FPIES classification according to the course of symptoms (acute or chronic), involvement of specific IgE antibodies (typical or atypical), and causative antigens (liquid or solid). A correct diagnosis of FPIES is sometimes delayed because of gastroenteritis misdiagnosis based on symptoms, age, and other characteristics despite the recently increased number of patients with FPIES. Therefore, many healthcare providers must be aware of this disease. This study reviews the epidemiology, clinical manifestations, pathogenesis, laboratory findings, and management of FPIES.

Table 1. Classification of FPIES

Disease classification	Indicators
Clinical course and symptoms
Acute FPIES	Symptoms with intermittent food exposure Repetitive vomiting 1–4 h after taking causative food Lethargy, pallor, diarrhea Normal development
Chronic FPIES	Onset at repetitive causative food exposure Chronic diarrhea, intermittent vomiting, poor weight, failure to thrive
Specific IgE antibody
Typical FPIES	Negative for specific IgE to causative food
Atypical FPIES^a	Positive for specific IgE to causative food
Causative food
Liquid FPIES	Cow’s milk, soy, breast milk
Solid FPIES	Hen’s egg, rice, fish, wheat

^a Characterized by the development of positive specific IgE antibodies during the course of the disease.

Epidemiology

Prevalence

FPIES is diagnosed from clinical symptoms because there is no definitive biomarker for diagnosis. Before the international consensus guidelines for FPIES were developed in 2017, Powell’s and Leonard’s diagnostic criteria were used in survey form.²^,³ Therefore, the diagnostic criteria for patients diagnosed with FPIES vary depending on the year in which they were studied.

In any case, FPIES is relatively rare, with a reported prevalence of 0.015%–0.7%.⁴^,⁵^,⁶^,⁷ In Japan, no large-scale prevalence study of FPIES has been conducted to date. The prevalence of non-IgE-mediated food allergy, which is a disease that includes FPIAP, FPE, and FPIES, is 0.5%.⁸ There are few reports on FPIES changes over time. An Italian study found that FPIES cases more than doubled in the 16 years from 1992 to 2007.⁹ A retrospective study conducted in Japan showed a sharply increased number of patients with FPIES since 2018, especially those caused by hen’s egg.¹⁰

Chronic FPIES is considered uncommon when compared with acute FPIES. Chronic FPIES has been notably more common in Asian countries such as Japan and Korea and less common in Western countries (approximately 7%).¹^,¹¹^,¹² However, a recent survey conducted in Germany revealed that 32% of FPIES cases were classified as chronic FPIES.¹³

Food triggers

Reports from the 1990s revealed milk and soy as the main causative foods for FPIES. However, in the 2000s, cases of FPIES caused by solid foods such as grain and fish were also reported.¹⁴^,¹⁵

The causative food is known to vary between geographic areas. In the United States and Australia, milk and rice are the most frequent causes of FPIES,⁵^,¹⁶^,¹⁷^,¹⁸ whereas fish and crustaceans are more frequent causative foods in addition to milk and rice in Europe, particularly in countries such as Italy, Spain, and Greece where fish consumption is high.¹¹^,¹⁹^,²⁰^,²¹^,²² In Korea, cow’s milk is the most common causative food.²³ In Japan, milk was the causative food of most FPIES until 10 years ago,²⁴^,²⁵ but reports of FPIES caused by hen’s eggs have been increasing since 2016.¹⁰^,¹⁶^,²⁶ Furthermore, the primary antigen for FPIES caused by hen’s egg was egg yolk, not egg white.²⁶ In the United States, the number of cases of FPIES caused by peanuts, which was barely known as a causative antigen in the past, is increasing.²⁷ The recommendation for early peanut consumption has been suspected as a factor in the increasing number of patients with peanut-induced FPIES, and the increased incidence of hen egg-induced FPIES in Japan supports this speculation.¹⁰ The main causative foods for different countries are listed in Table 2.

Table 2. Ranking of foods as causes of FPIES in different countries

Country^a	First	Second	Third	Fourth
USA ⁽³⁵⁾	Rice	Cow’s milk	Oats	Soy
Australia ⁽⁵⁾	Rice	Cow’s milk	Hen’s egg	Oats
Spain ⁽¹²⁾	Cow’s milk	Fish	Hen’s egg	Rice
Italy ⁽¹⁹⁾	Cow’s milk	Fish	Hen’s egg	Rice
UK ⁽¹¹⁾	Cow’s milk	Fish	Hen’s egg	Soy, wheat
Germany ⁽¹³⁾	Cow’s milk	Fish	Beef	Chicken
Japan ⁽¹⁰⁾	Hen’s egg	Cow’s milk	Soy	Wheat
Korea ⁽²³⁾	Soy	Cow’s milk

Unlike the most common causative foods in children, fish and shellfish are the most common causes of FPIES in adults. In addition, women are more likely to develop FPIES than men.²⁸^,²⁹

Causative foods for acute FPIES are diverse and any food can be a causative food, whereas the range of causative foods for chronic FPIES is more limited. Hen’s egg, cow’s milk, and fish have been reported as causative foods for chronic FPIES.³⁰^,³¹^,³²^,³³^,³⁴More than half of patients with FPIES in the United States react to more than one food,¹⁶^,³⁵ whereas the percentage of patients with FPIES who react to multiple foods in other countries ranges from 6% to 32%.⁵^,¹⁰^,¹²^,¹⁹

Many cases of IgE-mediated food allergy are cross-antigenic to fish, with similar allergic reactions to many different species of fish.³⁶ However, more than 50% of patients with FPIES react to only one species of fish.³⁷ Additionally, many patients with IgE-mediated hen’s egg allergy also have allergic symptoms to quail eggs because of cross-reactivity, but there have been some cases of patients with quail egg-induced FPIES who can consume hen’s eggs without any reaction.³⁸^,³⁹ Whether patients with FPIES caused by cow’s milk can consume goat’s milk or sheep’s milk remains unknown. Furthermore, there are no data available on the nut co-allergy rate in patients with FPIES.

Age of onset

Most patients develop FPIES during infancy, but it can also first occur in adulthood. Until 2012, diagnostic criteria included onset at less than 9 months of age as a mandatory requirement, but this requirement was removed from the international consensus guidelines published in 2017. Generally, FPIES caused by solid foods has a later onset than FPIES induced by milk or soy. The onset of FPIES caused by solid foods such as rice, hen’s egg, or fish is from 5 to 12 months of age. ⁵^,¹² The age of onset of FPIES caused by milk varies by country, ranging from approximately 1 month in Japan and Korea²³^,²⁵ to 3–5 months in the United States, Italy, and Australia.⁵^,⁴⁰^,⁴¹ The reason for the difference in the age of onset of patients with milk-induced FPIES in Asian and Western countries is unknown, but this difference may be a factor in the high prevalence of chronic FPIES in Japan and Korea.

Natural history

The natural history of FPIES varies depending on the causative food and the region. The age of tolerance of FPIES with milk and soy is earlier than that of solid FPIES. Approximately 90%, 75%, and 60% of patients with cow milk-induced FPIES are tolerant by age 2 years in studies conducted in Japan,²⁵ Israel,⁶ and Australia,¹⁷ respectively. However, the tolerance rate at age 3 years in the United States ranges from 20% to 60%.¹⁴^,⁴⁰ Patients with soy-induced FPIES also have different tolerance rates by region, with more than 90% showing tolerance by 10 months in Korea,²³ whereas the tolerance rate at age 5 years in the United States is approximately 30%.⁴⁰ An Australian report showed a 12.5% tolerance rate by age 3 years in patients with hen egg-induced FPIES,¹⁷ whereas a Japanese report showed tolerance of 64% of patients by age 2 years.⁴² The tolerance rate in Europe for patients with fish-induced FPIES aged 2–8 years is 34%.²⁰

Clinical Manifestations and Diagnosis

Acute FPIES

Repetitive vomiting that occurs within 1–4 h after ingesting causative food is an essential symptom of acute FPIES. Pallor and lethargy may occur, and diarrhea may follow these symptoms. In severe cases, symptoms may be accompanied by hypothermia and hypotension. In Japan, approximately 10% of patients with FPIES develop hyperthermia symptoms.¹⁰^,³¹ These symptoms usually resolve within 24 h. The physical growth of patients with FPIES is normal if appropriate causative food elimination is performed. Diagnostic criteria for FPIES according to the international guidelines were published in 2017.¹ According to the criteria, FPIES diagnosis consists of one major criterion and nine minor criteria, and acute FPIES is diagnosed when the major criterion and three of the nine minor criteria are met. The major criterion and nine minor criteria are as follows: major criterion includes vomiting within 1–4 h after ingesting the suspect causative food and the absence of classic IgE-mediated allergic skin or respiratory symptoms; the minor criteria include (1) a second (or more) episode of repetitive vomiting after eating the same suspect causative food, (2) an episode of repetitive vomiting 1–4 h after eating a different food, (3) extreme lethargy with any suspected reaction, (4) marked pallor with any suspected reaction, (5) need for emergency department visit with any suspected reaction, (6) need for intravenous fluid support with any suspected reaction, (7) diarrhea within 24 h (usually 5–10 h), (8) hypotension, and (9) hypothermia. If these diagnostic criteria are not met, an oral food challenge (OFC) test is recommended, wherein acute FPIES is diagnosed if two or more of the aforementioned minor criteria (3, 4, 7, 8, or 9) and an increased neutrophil count of greater than 1500 above the baseline count are present in addition to the major criterion. However, diagnostic criteria based on the international consensus guidelines may lead to overdiagnosis or underdiagnosis because many of these minor criterion items are subjective and there are few cases of hypotension or hypothermia.

Regarding the severity of FPIES, cases that include four or more episodes of vomiting, lethargy, and dehydration that require intravenous fluids are considered severe, whereas milder cases that include vomiting less than three times are considered mild to moderate.¹Unlike patients with IgE-dependent food allergy, who often develop allergic symptoms after the first causative food intake, most patients with acute FPIES do not show symptoms after the first causative food intake and often develop symptoms after multiple or increased intakes of the causative food.⁴²^,⁴³

Chronic FPIES

Chronic diarrhea, poor weight gain or weight loss, failure to thrive, and intermittent vomiting are the main symptoms of chronic FPIES. As symptoms progress, dehydration, hypoalbuminemia, metabolic acidosis, and methemoglobinemia can occur.⁴⁴ Symptoms improve within a few days to a week after discontinuing causative food intake. For an accurate diagnosis, the symptoms must disappear after discontinuing causative food intake, followed by the occurrence of acute vomiting 1–4 h after ingesting the causative food again.

Chronic FPIES is thought to be particularly common in Japan and Korea. The most common causative food of chronic FPIES is milk in Japan and milk or soy in Korea.³⁰^,³¹ Most patients with milk- or soy-induced FPIES in these reports have their age of onset in the neonatal period, unlike in Europe and the United States where the age of onset in patients with milk- or soy-induced FPIES is 3–5 months.⁵^,⁴⁰^,⁴¹ Food intake intervals are short and physiologic vomiting is likely to occur in the neonatal period. These circumstances may cause a delay in diagnosis and may be a factor in subsequent chronicity. In addition, an OFC for diagnosis is often not performed because of concerns about the severity of the disease in chronic FPIES in newborns, and the diagnosis may remain presumptive.

Atypical FPIES

Atypical FPIES is characterized by the development of positive specific IgE antibodies during the course of the disease. In some cases, patients do not present with IgE-mediated symptoms even if they become positive for specific IgE antibodies, whereas others switch to IgE-mediated food allergic reactions such as urticaria or respiratory symptoms. Caubet et al. reported that 7 of 17 cases of cow milk-induced FPIES with positive specific IgE antibodies developed symptoms of IgE-mediated food allergy; the remaining 10 patients continued elimination of causative food and those with atypical milk-induced FPIES were less tolerant than patients with typical milk FPIES.⁴⁰ In another study, Lange et al. reported that IgE-mediated sensitization against the causative food did not influence the probability of tolerance development.¹³

OFC testing

OFC testing is performed in cases that cannot be diagnosed based on clinical symptoms and to confirm spontaneous tolerance. According to the international consensus guidelines, FPIES is diagnosed when two or more of the following are observed: pallor, lethargy, or elevated neutrophil count of greater than 1500 μL⁻¹ with mandatory vomiting 1–4 h after ingestion without cutaneous or respiratory symptoms. Currently, there are no established standards for loading doses or dosing intervals for OFC testing. However, a work group from the American Academy of Allergy, Asthma, and Immunology issued a report on conducting OFC tests that recommended a dosage of 0.06–0.6 g kg⁻¹ per dose in one to three divided doses every 15 min.⁴⁵ Furthermore, the initial dose should not exceed 3 g of protein or 10 g of food in total, and the dose should be lower if there is a history of severe symptoms in the past. However, the 15-min dosing interval may be short because symptoms such as vomiting and pallor in patients with FPIES occur 1–4 h after ingestion. Generally, most patients who have a negative OFC when administering 25% of the full dose can consume the full dose without allergic symptoms.¹⁹^,⁴⁶

Pathophysiology

Antigen specific antibody

FPIES is a non-IgE-mediated food allergy, but some patients become positive for specific IgE antibodies during the course of the disease. Such cases are referred to as atypical FPIES. The percentage of specific IgE antibody positivity varies depending on the country and the causative food. The specific IgE antibody positivity rate for patients with cow milk-induced FPIES is reported as 7%–43%, whereas that for patients with hen egg-induced FPIES is reported as 11%–51%.¹⁰^,⁴⁰ The probability of testing positive for specific IgE antibodies to causative foods other than hen’s eggs and cow’s milk is low. These facts suggest that IgE may be involved in FPIES pathogenesis; however, further investigation is required to determine the role of IgE in FPIES. Studies on the association between FPIES and IgG, IgA, IgM, and IgD have been conducted, but their involvement remains unclear.⁴⁷

Antigen-specific T cells

Several studies have demonstrated that T cells are activated by food antigen stimulation that causes FPIES.²⁴^,⁴⁷ These results suggest that T cells are involved in FPIES pathogenesis. It is reported that stimulation of peripheral blood T cells with the causative antigen in patients with FPIES may elicit response from Th2 cytokines, such as interleukin (IL)-5 and IL-13.²⁴ Th17-related transcription factors and cytokines, including signal transducer and activator of transcription 3, transforming growth factor-beta, and IL-6, are involved in FPIES pathogenesis in addition to Th2 cytokines.⁴⁸ The inflammation caused by these factors is presumed to increase the permeability of the patient’s intestinal tract and causes fluid to shift into the intestinal tract. However, other studies that found allergen-specific T cells in the peripheral blood of FPIES patients also reported that the T cell levels were no different from those in healthy controls.⁴⁹

Innate immunity

Given that the diagnostic criteria for FPIES include criteria for elevated neutrophils, neutrophils may be involved in FPIES pathogenesis. A report of elevated fecal eosinophil-derived neurotoxin in an OFC for patients with FPIES suggests that eosinophils are also involved in FPIES pathogenesis. Moreover, monocytes, lymphocytes, and natural killer cells are thought to be involved in FPIES pathogenesis.⁵⁰

Pathogenesis of gastrointestinal symptoms in FPIES

Serotonin plays an important role in vomiting and diarrhea, which are the main symptoms of FPIES. Serotonin is stored in enterochromaffin and sensory enteroendocrine cells in the digestive tract. These cells are activated by ingesting causative food in patients with FPIES, and serotonin is secreted. Serotonin stimulates the central nervous system, thereby inducing nausea and vomiting, and stimulates the enteric nervous system, thereby inducing diarrhea and vomiting.⁵⁰

Laboratory Testing

Several studies have been conducted on tests to assist FPIES diagnosis, but no definitive test method has been established to date.

Food-specific IgE test

Given that FPIES is a non-IgE-mediated food allergy, testing for specific IgE antibodies to the causative food is not always necessary. However, some patients become positive for specific IgE antibodies at diagnosis or during the course of the disease, especially in relation to hen’s eggs and cow’s milk. In addition, the symptoms for some of these patients change to IgE-mediated food allergy. Therefore, measuring the specific IgE antibodies to these foods over time may be useful to support diagnosis and conduct OFC.

Allergen lymphocyte stimulation test (ALST)

T cells are thought to play a major role in FPIES pathogenesis, which means that the ALST is a suitable test for FPIES. Some reports suggest its effectiveness, especially in Japan.²⁴^,⁵¹ The positive rate of the ALST for FPIES is 70%–80%, but it can also show a positive result in healthy individuals. In contrast, other studies have concluded that ALST is not useful for FPIES diagnosis.⁵²

Other blood tests

Kimura et al. reported that serum C-reactive protein levels 24 h after food intake were increased from those before intake in 11 of 18 patients with FPIES who had a positive OFC.⁵³Makita et al. reported that blood thymus and activation-regulated chemokine (TARC) levels were higher in FPIES patients visiting the emergency department or conducting OFC than in gastroenteritis or sepsis patients, and that high TARC levels persisted for 6–24 h after the onset of symptoms.⁵⁴ They also reported that blood TARC levels at the onset of symptoms in FPIES patients were higher than those in patients with IgE-mediated food allergy at the onset of symptoms, and measuring blood TARC levels in patients presenting to the emergency department with vomiting symptoms may be useful in distinguishing emesis caused by FPIES from vomiting caused by gastroenteritis and IgE-mediated food allergy.⁵⁵ However, evaluation of blood TARC level should be conducted with care in patients with eczema because they already have elevated blood TARC levels.

Atopy patch test (APT)

Like the ALST, the APT may be an appropriate test for FPIES diagnosis because it examines the response of T cells to antigen stimulation. One study reported that the APT predicted FPIES diagnosis in 28 of 33 patients.⁵⁶ However, another study reported the APT sensitivity rate as 11.8%.⁵⁷ Hence, the APT is not recommended as a test method for FPIES diagnosis.

Stool testing

Neutrophils and eosinophils may be present in the stool of patients with FPIES.⁵⁸ However, the undetected presence of these cells does not rule out FPIES diagnosis. Bloody stools are reported to be present in approximately 4%–11% of patients with FPIES.⁵⁹Fecal calprotectin is a marker of neutrophil inflammation marker that has been reported to be elevated in patients with FPIES.⁶⁰

Endoscopy and biopsy

Given that FPIES diagnosis is determined by clinical symptoms such as vomiting or diarrhea and an OFC, endoscopy and biopsy are generally not performed.

Management

Emergency management

Acute FPIES is characterized by repeated vomiting, which in severe cases can lead to hypovolemic shock. Therefore, prompt treatment of these symptoms is needed. Mild or moderate symptoms, such as vomiting three times or less or mild lethargy, can be treated at home with oral rehydration, but severe symptoms should be treated in an emergency room.

Aggressive isotonic fluid infusion should be administered if hypovolemic shock, preshock, or repeated vomiting of three or more episodes is observed. A bolus dose of 10–20 mL kg⁻¹ of an isotonic solution should be given and repeated as needed.¹

Ondansetron is a serotonin 5-HT3 receptor antagonist and is reported to improve emesis that may occur in the FPIES OFC.⁶¹^,⁶²^,⁶³ However, in some countries, including Japan, ondansetron is not covered by insurance as a treatment for vomiting caused by FPIES. The efficacy of domperidone, frequently used to treat vomiting in children with gastroenteritis, is unknown. The use of corticosteroids is not recommended at this time because of a lack of evidence. Similarly, adrenaline is not recommended as a treatment for FPIES because of a lack of evidence. However, adrenaline should be used without delay when IgE-mediated food allergy symptoms are suspected.¹For cases in which metabolic acidosis and methemoglobinemia are observed, bicarbonate or methylene blue should be administered.⁶⁴^,⁶⁵

In cases of acute FPIES, symptoms resolve quickly (within 4–12 h) after discontinuing causative food intake. However, patients with chronic FPIES may require temporary bowel rest or continuous fluid infusion because diarrhea and other symptoms may persist for several days.

Long-term management

Daily life management for patients with FPIES consists of complete causative food elimination, diet alteration, and treatment of symptoms at presentation. Re-exposure with an OFC should be performed at the appropriate time. Nutritional support is essential, especially for patients with FPIES caused by cow’s milk in early infancy and for patients with FPIES caused by multiple foods.

Dietary avoidance

Unlike patients with IgE-mediated food allergy, patients with FPIES are treated with complete causative food elimination. However, it has also been reported that some patients can consume processed hen’s eggs or cow’s milk products without vomiting.⁶⁶ Currently, there is no evidence that continued intake of processed products improves spontaneous resolution of FPIES. Most patients with soy-induced FPIES can consume seasonings such as soy sauce and miso; therefore, these foods should not be eliminated if doing so adds to the burden of daily living.

Management of patients with cow’s milk FPIES

In cases of FPIES caused by cow’s milk, it is recommended that patients use breast milk or an extensively hydrolyzed formula. However, some patients with cow’s milk FPIES may consume amino acid milk with no improvement in symptoms even with an extensively hydrolyzed formula.⁴⁰^,⁶⁷^,⁶⁸ Some patients also react to breast milk.⁶⁹^,⁷⁰

Introduction of new foods

Most patients with FPIES in countries other than the United States have only one causative food, so there is no need to eliminate other foods. Guidelines recommend supervised introduction of solid foods for patients with severe milk-induced or soy-induced FPIES because of the high frequency of solid FPIES.¹However, approximately half of FPIES patients will develop the condition after multiple causative food intakes.⁵

Timing of reintroduction

Periodic re-exposures should be performed because most FPIES cases resolve spontaneously. Re-exposure should be supervised by a physician because it may lead to serious symptoms such as hypovolemic shock. Although the timing of an OFC has no definitive standard, OFC testing in the United States is generally performed within 12–18 months after the last symptom.¹^,⁷¹ The OFC should be performed at a time when spontaneous tolerance is expected for each causative food. The OFC may be performed at intervals of less than 1 year because most patients with FPIES caused by cow’s milk or soy show remission by 2 years of age. It is also reported that patients with hen egg-induced FPIES should undergo the OFC at 6- to 12-month intervals because nearly 70% of these patients show remission by 2 years of age.⁴² Furthermore, given that patients with fish-induced FPIES are less likely to show remission, an OFC should be conducted after the age of 5 years.⁷²

Conclusions

Since the development of the international consensus guidelines for FPIES in 2017, epidemiological studies on the prevalence, causative foods, and prognosis of FPIES have been conducted in many countries. However, the pathogenesis of FPIES remains unclear. It is expected that more objective diagnostic criteria for FPIES will be developed in the future and pathogenesis of the disease will be clarified.

Acknowledgments

The author thanks Maruzen-Yushodo (https://kw.maruzen.co.jp/kousei-honyaku/) for English language editing.

Conflicts of Interest

The author declares no conflict of interest.

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