A systematic review of food protein–induced enterocolitis syndrome from the last 40 years

Ann Allergy Asthma Immunol 118 (2017) 411e418

Contents lists available at ScienceDirect

Review

A systematic review of food proteineinduced enterocolitis syndrome from the last 40 years Sara Manti, MD *; Salvatore Leonardi, MD y; Annamaria Salpietro, MD *; Giuliana Del Campo, MD *; Carmelo Salpietro, MD *; Caterina Cuppari, MD * * Department y

of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Messina, Italy Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy

A R T I C L E

I N F O

Article history: Received for publication November 15, 2016. Received in revised form January 31, 2017. Accepted for publication February 10, 2017.

A B S T R A C T

Objective: To provide a complete, exhaustive summary of current literature relevant to food proteineinduced enterocolitis syndrome (FPIES). Data Sources: Data have been extracted from PubMed and Science Direct databases. Study Selections: Following the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines, a literature search for peer-reviewed journal articles in English through January 1975 with updates through October 2016 was conducted. Relevant publications were reviewed that included pediatric and adult populations. Information on the study design, sample, intervention, comparators, outcome, timeframe, and risk of bias were abstracted for each article. Results: Of 135 reviewed reports, 52 were included in this systematic review. In accordance with the age at onset, clinical features, and offending foods, it is possible to distiguish different types of FPIES. An immune systemic involvement can occur in patients with FPIES. In addition to the most common causative foods (cow’s milk, soy, and rice), any food can potentially cause FPIES. Although specific diagnostic tests are not available, open food challenge remains the gold standard for FPIES diagnosis. Moreover, because of the lack of randomized clinical trials and of use of different adopted methods, confounding factors might mask critical findings, leading to poor knowledge of this pleiotropic clinical entity. Conclusion: Multicenter studies are needed to better develop an evidence-based approach to pathophysiology, prevalence, diagnosis, and natural history of the disease. Ó 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Introduction Food proteineinduced enterocolitis syndrome (FPIES) is a noneIgE-mediated food hypersensitivity featured by gastrointestinal symptoms, such as profuse vomiting and sometimes also accompanied by diarrhea, and a systemic inflammatory response.1 The timing of food introduction affected the age at onset of FPIES. Usually, the median age at FPIES onset is 5.5 months.2 Not surprisingly, cow’s milk (CM)e and soy-mediated FPIES occurs earlier (3 days to 4 months)3 than solid foodemediated FPIES (4 and 6 months of age), and in approximately 75% of described cases, it occurs after the first or second ingestion of the offensive food.4 Several risk factors for FPIES have been investigated, such as positive family history of atopic diseases (including IgE-mediated food allergy),2 male sex, and cesarean section.2,5,6 The twin birth

Reprints: Sara Manti, MD, Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Via Consolare Valeria, 1 98125, Messina, Sicily, Italy; E-mail: [email protected]. Disclosures: Authors have nothing to disclose.

has not been reported as a risk factor; however, it seems that twins reacted to the same food protein.7 Although FPIES is typically characterized by gastrointestinal involvement, the variable and atypical clinical presentation and the lack of specific diagnostic testing may contribute to a delay in diagnosis.8e10 In light of the above considerations, this systematic review aims to analyze the latest findings and advances in clinical terms, etiology, clinical presentation, causative foods, diagnosis, and natural history in patients affected by FPIES to provide to the scientific community an update on existing current research.

Data Sources and Study Selection Research Strategy and Selection Criteria This systematic review has been conducted according to the Preferred Reporting Items for Systematic Reviews and Metaanalysis guidelines11 using 2 databases: PubMed and Science Direct. On these websites, we searched for articles published from January 1, 1975, to October 2016 using key terms related to FPIES: food proteineinduced enterocolitis syndrome, FPIES, definition,

http://dx.doi.org/10.1016/j.anai.2017.02.005 1081-1206/Ó 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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etiology, diagnosis, and follow-up. The electronic database search strategy applied for PubMed is reported in Table 1. The entire articles were read if the abstract suggested that the article potentially met the inclusion criteria. To identify additional studies that met the inclusion criteria, we also reviewed the references of the selected articles and the ones whose titles suggested that they could have investigated FPIES. Study Selection Articles were included in the review according to the following inclusion criteria: English language, publication in peer-reviewed journals, and year of publication of 1975 or later. Articles were excluded by title, abstract, or full text for irrelevance to the investigated issue. Data Extraction and Quality Assessment Data were extracted by 2 reviewers (A.S., G.D.C,) independently according to the Cochrane guidelines,11 and a third reviewer (S.M.) checked the extracted data for accuracy. Another author (C.C.) was available when there were any disagreements concerning data extraction and/or quality assessment. Abstracts and potential articles were reviewed and identified for retrieval according to the inclusion criteria. The following information was extracted: study author names; study designs (ie, case-control, cross-sectional, and longitudinal), patients characteristics (age, sex), clinical and biological variables, and outcome of interest of the study. Principal outcomes of interest included studies about the clinical terms, etiology, clinical presentation, causative foods, diagnosis, and natural history of FPIES. Given both the considerable heterogeneity in the study design and subjects of the selected studies, characteristics of the investigated populations and the protocols were summarized, and the study outcomes have been reported using descriptive statistics without conducting any meta-analyses. Results In Figure 1, the retrieved articles for the systematic review were reported. Studies evaluating the clinical terms, etiology, clinical presentation, causative foods, diagnosis, and natural history of FPIES are summarized in Tables 2e7. Clinical Terms In accordance with the age of symptom onset, clinical features, duration and severity of symptoms, and offending foods, it is possible to distinguish the following different types of FPIES: according to age of symptom onset: early (mostly within 3 months of age) and late onset (mostly 4e7 months of age); according to clinical features: typical or atypical type (in older patients, positive skin prick test results, and serum specific IgE levels); according to duration and severity of symptoms: acute and chronic symptoms; and according to offending foods: CM or soy FPIES, solid food FPIES, and multiple food FPIES (Table 2).2,12,13 Table 1 List of Search Terms Entered into the PubMed Search Engines for Identification of the Studies for This Systematic Review Search Terms Food proteineinduced enterocolitis syndrome [all fields] FPIES Definition Etiology Diagnosis Follow-up 5 AND English [language] 1975 to date [publication date]

Etiology The mechanisms through which FPIES develops are as yet unclear. FPIES is often considered to be a T-cellemediated disorder; however, recently, humoral response has been also investigated (Table 3).14,15 Cell-Mediated Immune Responses It is hypothesized that the ingestion of food allergens causes T-cell activation and proliferation, leading to release of proinflammatory cytokines, which, in turn, affect permeability barrier and local intestinal inflammation.14 However, to date, the role of T cells in FPIES remains controversial.16,17 In fact, although increased serum peripheral blood mononuclear cell levels were detected in children with FPIES,16 other studies did not confirm these findings.17 Independently by the above-mentioned and conflicting data, authors agree that the inflammation of intestinal mucosa is mediated by increased serum tumor necrosis factor a (TNF-a) levels and decreased expression of transforming growth factor b (TGF-b) receptors.14 In particular, Heyman et al18 reported that TNF-a, released by antigen-specific T cells, acting synergistically with interferon g (IFN-g), known to enhance the effects of TNF-a on intestinal epithelial cells, increases intestinal permeability. These data were supported by the detection of increased fecal TNF-a levels in patients with CM-mediated FPIES.19 The identification of increased TNF-a levels in duodenal biopsy of infants with FPIES and the significant correlation between TNF-a expression and villous atrophy further supported the role of TNF-a in FPIES.20 In contrast, in duodenal biopsy specimens of children with FPIES, decreased serum levels of TGF-b1 levels, a molecule known to counterbalance the destructive effect of T-cell cytokines, have been also found.20 Thus, it has been hypothesized that the impaired function of epithelial barrier function, mediated by increased TNF-a levels and decreased TGF-b receptor 1 values, might contribute to the pathogenesis of FPIES. Successively, a TH2-mediated immune response has been also identified.21 In particular, after ingestion of causative foods, an increase in interleukin (IL) 4 and a decrease in IFN-g expression were detected. Moreover, on acquired immune tolerance, higher serum IL-10 and IFN-g values were recorded.22 The study conducted by Karlsson et al23 identified the immune pathway through which chidren with FPIES achieve immune tolerance. In particular, authors noted that infants outgrowing noneIgE-mediated hypersensitivity to CM reported significantly higher levels of circulating CD4þCD25þ T-regulatory cells, which, in turn, through direct cellcell contact and by production of TGF-b, lead to immune tolerance development. In addition to these T-cellemediated events, the involvement of neutrophils, eosinophils, and lymphocytes has been observed.24 Humoral Immune Response In contrast to healthy children with secretory IgA as the dominant immunoglobulin at the mucosal surface, in children affected by FPIES, jejunal biopsies revealed increased numbers of IgM- and IgA-containing plasma cells.20,25 Elevated serum IgA and IgG antibodies to food proteins have been also described in patients with FPIES.26e28 In particular, higher IgA levels and lower serum milk specific IgG4 antibody levels have been found in children with milk-mediated FPIES when compared with the control group.26 Systemic specific IgE antibody responses are generally absent in FPIES.22,27 However, the increased serum levels of IL-8, secreted by neutrophils and involved in the initiation and amplification of inflammatory processes detected in patients with FPIES, seems to occur through IgE-dependent mechanisms.29 Recently, the critical

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413

Figure 1. Flowchart of the results of the literature search.

role of IL-8 in FPIES has been assessed by a study of Caubet et al.55 Herein, authors reported a significantly higher serum level of IL-8 in patients with FPIES after a positive OFC result compared with those with a negative OFC result. Moreover, patients with resolved CM FPIES (negative OFC result) reported significantly higher serum IL-10 levels, confirming that an increased IL-10 expression is associated with tolerance acquisition in FPIES.55 Moreover, the elevated serum IL-9 levels, also identified in patients with FPIES, could justify the increased intestinal permeability, which, in turn, favors neutrophilic recruitment.20,55 Clinical Presentation It is well documented that the absence of pathognomonic symptoms makes the diagnosis of FPIES difficult, leading frequently to overlap with symptoms of other gastrointestinal conditions. In a review published in 2013, Miceli Sopo et al38 proposed criteria to aid the clinician in FPIES diagnosis that included the following signs

Table 2 Studies Evaluating the Food ProteineInduced Enterocolitis Syndrome Clinical Terms Study

Year

Experimental

Children

Adults

No. of patients

Type of article

Nowak-Wegrzyn et al2 Järvinen et al12 Leonard et al13

2003

e

X

e

14

2013 2013

e e

e e

e e

e e

Original article Review Review

and symptoms: onset of diseases at younger than 2 years (although not mandatory); recurrent vomiting caused by the exposure to trigger food, pallor, and lethargy within 2 to 4 hours and usually lasting less than 6 hours; absence of IgE-mediated symptoms; avoidance of offending protein from the diet results in resolution of symptoms; and recurrence of typical symptoms within 2 to 4 hours of reexposure. The clinical presentation of FPIES can be acute or chronic (Table 4).1 The clinical presentation of acute FPIES is featured by vomiting and pallor, followed by diarrhea, lethargy, and dehydration. Symptoms, occurring on a median of 2 occasions with the suspected food, started 1 to 2 hours after eating the food, whereas the resolution of symptoms occurs within 24 to 48 hours.30 Patients did not report signs and/or symptoms during intercritical periods. Frequent projectile episodes of vomiting is the most common symptom, reported in more than 95% of the cases.31,32 Vomiting occurs 0.5 to 6 hours after ingestion (mean, 2 hours), reaching more than 20 episodes.2 Although lethargy and pallor have been reported in 40% to 100% of cases,5,6,31,33 in a retrospective study32 only 5% of enrolled patients reported lethargy and pallor. Usually approximately 6 hours after ingestion of incriminated food, watery diarrhea occurs in 20% to 50% of patients.1 On the other hand, diarrhea was reported in only 7% of a large US cohort undergoing oral food challenge (OFC).34 Bloody diarrhea has been reported in 4% to 11%5,6,31,33 to 45%.35 Ranging from 5% to 77% of cases of different cohorts,32e34 hypotension has been reported. Ranging from 5% to 24% of cases, other severe symptoms can occur, including dehydration, irritability, loss of consciousness, clamminess, hypotonia,

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Table 3 Studies Evaluating the Etiology of Food ProteineInduced Enterocolitis Syndrome Study

Year

Experimental

Children

Adults

No. of patients

Type of article

Caubet et al14 Berin15 Van Sickle et al16 Hoffman et al17 Heyman et al18 Kapel et al19 Chung et al20 Morita et al21 Mori et al22 Karlsson et al23 Wada et al24 Fontaine et al25 McDonald et al26 Shek et al27 Konstantinou et al28 Monteseirin et al29

2011 2015 1985 1997 1994 1999 2002 2013 2009 2004 2016 1975 1984 2005 2014 2004

e e X X X e e e e e e e e e e e

e e e e e X X X X X X X X X X e

e e e e e e e e e e e e e e e X

e e e e e 13 28 89 1 21 5 31 18 140 31 Not specified

Review Review Original article Original article Original article Original article Original article Original article Case report Original article Original article Original article Original article Original article Original article Original article

cyanosis, and IgE-mediated anaphylaxis.9,32,36 Mehr and colleagues5 reported hypothermia (with temperature <36 C) in 24% of enrolled patients. Daily or frequent exposure to offensive foods leads to chronic symptoms, including abdominal distension, intermittent vomiting, and chronic diarrhea, leading to irritability and failure to thrive.37 We believe that the discrepancies in the clinical presentation can be explained by several concomitant factors. In particular, in their studies, the authors enrolled children of different ages. It is known that gut maturation is directly dependent on the age of the infant, and, consequently, food tolerance also increases rapidly with age.56 Thus, it is reasonable that the older cohort reported lower clinical severity. Another confounding factor is the frequency of the food intake. In particular, eating frequency affects the prevalence of symptoms. Therefore, patients avoiding the causative foods reported a minor incidence of symptoms related to food-specific gastrointestinal hypersensitivity. Moreover, the incidence of the symptoms changed according to clinical center. It is reasonable to hypothesize that the patients seen in a tertiary care child health center are different from those hospitalized in a primary center. These discrepancies can produce factitious epidemiologic and clinical data, representing a disease more severe than the reality. Finally, the calculation of an adequate sample size becomes crucial in any clinical study to achieve ethically and scientifically valid results. When few individuals are included in a study, the results cannot be generalized to the population because this sample does not represent the size of the target population. On other hand, when the authors enroll more individuals than required, the study

may not be able to detect the differences between analyzed groups, making the research unethical. Causative Foods Although the most common causative foods of FPIES are CM, soy, and rice, grains (eg, rice, oats, barley, corn), meat (eg, beef, chicken, turkey), vegetables and legumes (eg, potato, squash, string bean, peanut, green pea, lentil), fruit (tomato), eggs, fish (fish and seafood), and probiotic (Saccharomyces boulardii) can also trigger the syndrome (Table 5).10,39,42 According to epidemiologic data coming from a multicenter retrospective study of 66 Italian children,33 it appears that CM was the most common trigger food (65%), followed by fish, egg, rice, soy, corn, poultry, and goat’s milk. Moreover, 56 children (85%) reacted to a single food. These findings were similar to the data from the study by Caubet et al34 in which 35% of their total cohort reacted to multiple triggers but lower than those reported by NowakWegrzyn et al2 in which 80% of patients with FPIES reacted to multiple triggers. Similalry, in other cohort, 70% of the patients reacted to 1 or 2 foods,32 but the enrolled children reported a lower prevalence of rice- and oat-induced FPIES (CM [67%], soy [41%], rice [19%], oat [16%], and egg [11%]).32 Similar prevalence has been reported also in the United Kingdom in which Ludman et al36 recorded that CM, fish, egg, soy, and wheat were the main eliciting foods. To date, few data are available on the onset of breast milkemediated FPIES.43

Table 4 Studies Evaluating the Clinical Presentation of Food ProteineInduced Enterocolitis Syndrome Study

Year

Experimental

Children

Adults

No. of patients

Type of article

Boyce et al1 Nowak-Wegrzyn et al2 Mehr et al5 Katz et al6 Järvinen et al12 Tan and Smith30 Hwang et al31 Ruffner et al32 Miceli Sopo et al33 Caubet et al34 Nomura et al35 Ludman et al36 Hwang et al37 Miceli Sopo et al38

2010 2003 2009 2011 2013 2014 2009 2013 2012 2014 2012 2014 2007 2013

e e e e e e e e e e e e e e

e X X X e e X X X X e X X e

e e e e e X e e e e e e e e

e 14 35 13.019 e 31 23 462 66 160 e 54 142 e

Guidelines Original article Original article Original article Review Original article Original article Original article Original article Original article Review Original article Original article Review

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415

Table 5 Studies Evaluating the Causative Foods of Food ProteineInduced Enterocolitis Syndrome Study

Year

Experimental

Children

Adults

No. of Patients

Type of Article

Nowak-Wegrzyn et al2 Ruffner et al32 Miceli Sopo et al33 Caubet et al34 Ludman et al36 Hojsak et al39 Caubet et al40 González-Delgado et al10 Hwang et al41 Feuille et al42 Nomura et al43

2003 2013 2012 2014 2014 2006 2011 2016 2009 2014 2011

e e e e e e e e e e e

X X X X X X X X X e X

e e e e e e e e e e e

14 462 66 160 54 5 1 16 1 e 176

Original article Original article Original article Original article Original article Original article Case report Original article Case report Review Original article

significantly associated with FPIES in 14 Japanese infants.44 In particular, serum CRP levels recorded during OFC significantly correlated with CRP values detected at disease onset. Moreover, serum CRP levels were significantly higher in children with fever, suggesting an incremental stepwise in the FPIES protocol.44 Data coming from other studies conducted by the same research group suggest that serum CRP level could be considered as useful biomarker to make a correct diagnosis.45 Among patients with FPIES, eosinophilia has been associated with disease severity. In particular, Kimura et al46 reported, in 113 infants with CM-induced FPIES, that the percentage of peripheral blood eosinophils was highest in patients with vomiting, bloody stool, and diarrhea simultaneously (12.9%) and lowest in patients with exclusively diarrhea (3.2%). A significant difference has been also found in the percentage of peripheral blood eosinophilia between early- (10 days) and late-onset (>10 days) FPIES, identifying the existence of 2 types of eosinophilia in infants with FPIES: conspicuous and mild eosinophilia in early- and late-onset FPIES, respectively. Metabolic acidosis and stool examination, usually revealing occult blood, leukocytes, Charcot-Leyden crystals, and reducing substances, may also support the presence of FPIES.37 Typically, laboratory findings normalize, and clinical improvement is seen within 48 hours of avoiding the causative food.1

Because of the great variation in feeding practices in each country and the extreme phenotypic spectrum featuring FPIES, it is reasonable to hypothesize that the epidemiologic discrepancies might be attributable to the difficulty to recognize the disease. Diagnosis Laboratory findings Although there are no pathognomomic laboratory findings specific to FPIES, elevated white blood cell count with left shift is consistent with FPIES (Table 6).5 Acute symptoms are usually characterized by an increase in neutrophils by 5.500 to 16.800 cells/ mm3 (mean increase, 9.900 cells/mm3), peaking 6 hours after ingestion of the offensive foods.2,5 In the clinical study performed by Mehr et al,5 thrombocytosis and leukocytosis were the most common laboratory findings detected after FPIES reactions. Moreover, no statistically significant corelation between thrombocytosis and leukocytosis and clinical presentation (frequency of episodes), as well as with other laboratory parameters (eg, hemoglobin level, mean corpuscular volume, white blood cell count, neutrophil count, and hematocrit level), was reported.5 Serum hypoalbuminemia (albumin <3.5 g/dL) and a rapid decrease in serum albumin levels are important laboratory factors in 142 infants (aged 15 to 45 days) affected by milk-induced FPIES.32 In the same cohort, methemoglobinemia was also observed in 18.8%, acquiring an important diagnostic value to assess massive gastrointestinal inflammation.37 Increased serum C-reactive protein (CRP) levels, detected 24 hours after the last ingestion of the causative food, were

Serum specific IgE levels and skin prick test In accordance with the FPIES definiton, a noneIgE-mediated food-induced allergic disorder, the results of allergy tests, such as serum food specific IgE levels and skin prick tests, are often

Table 6 Studies Evaluating the Diagnosis of Food ProteineInduced Enterocolitis Syndrome Authors Nowak-Wegrzyn et al Mehr et al5 Katz et al6 Järvinen et al12 Morita et al21 Hwang et al31 Ruffner et al32 Miceli Sopo et al33 Caubet et al34 Hwang et al37 Nomura et al43 Kimura et al44 Kimura et al45 Kimura et al46 Kessel and Dalal47 Fogg et al48 Järvinen et al49 Hwang et al50 Jayasooriya et al51

2

Year

Experimental

Children

Adults

N. patients

Type of article

2003 2009 2011 2013 2013 2009 2013 2012 2014 2007 2011 2016 2014 2016 2011 2006 2012 2008 2007

e e e e e e e e e e e e e e e e e e e

X X X e X X X X X X X X X X X X X X X

e e e e e e e e e e e e e e e e e e e

14 35 13.019 e 89 23 462 66 160 142 176 14 116 113 1 19 38 16 1

Original article Original article Original article Review Original article Original article Original article Original article Original article Original article Original article Original article Original article Original article Case report Original article Original article Original article Case report

416

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Table 7 Studies Evaluating the Natural History of Food ProteineInduced Enterocolitis Syndrome Study

Year

Experimental

Children

Adults

No. of patients

Type of article

Boyce et al1 Mehr et al5 Katz et al6 Tan and Smith30 Hwang et al31 Ruffner et al32 Miceli Sopo et al33 Caubet et al34 Frith et al52 Caubet et al53 Ruiz-García et al54

2010 2009 2011 2014 2009 2013 2012 2014 2013 2013 2014

e e e e e e e e e e e

e X X e X X X X X X X

e e e X e e e e e e e

e 35 13.019 31 23 462 66 160 Not specified 1 16

Guidelines Original article Original article Original article Original article Original article Original article Original article Original article Case report Original article

negative.1,32 However, Caubert et al34 detected, among 160 patients, that most of the enrolled population was atopic, and, moreover, 24% of the patients had positive specific IgE levels to the food that induced FPIES. In addition, although any statistically significant differences were reported among the included clusters, positive serum specific IgE levels were detected in 37% of the patients.43 Some patients reported also positive skin prick test results to offending foods.6,33,47 Although these findings could apparently be in contrast with the FPIES definition, a noneIgE-mediated food hypersensitivity, acute FPIES reactions are associated with TH2 skewing of the T-cell cytokine profile and with gastrointestinal inflammation, further enhancing the mucosal permeability to food proteins and their presentation to the immune system57; thus, both pathogenic conditions might predispose individuals to developing specific IgE to food, which can eventually lead to a classic IgE-mediated reactions.34,43,57 In particular, IgE antibodies to the causal food have been detected either at presentation or during follow-up,58 especially in children with a prolonged course of allergy and a high rate of concomitant atopic diseases,2,59 identifying a new and more sever clinical phenotype of FPIES, which is known as atypical FPIES.57 Moreover, because these observations have been highlighted in late-stage disease, we believe that to include screening for total and food specific IgE would be prudent for purposes of follow-up and to adapt the OFC protocol, especially in patients in which an anaphylactic reaction can occur. Atopic patch testing Fogg et al48 evaluated the ability of the atopic patch test (APT) to accurately predict the presence or absence of FPIES compared with the OFC. Nineteen children of 4 to 29 months of age with suspected FPIES underwent an APT for the suspected foods. To confirm whether FPIES was present, the same patients also underwent OFC. After that, the results of diagnostic tests were compared. Although the APT result was false positive in 5 instances, 16 cases of FPIES confirmed by an OFC were also assessed by an APT, appearing as a promising diagnostic tool for the diagnosis of FPIES characterized by a sensitivity of 100%, a specificity of 71%, a positive predictive value of 75%, and a negative predictive value of 100%.48 To date, similar findings have not been reported by other research. In 25 children with a mean age of 3.3 years, Järvinen et al49 performed APTs before OFCs, reporting a poor utility of APTs in predicting tolerance development in FPIES (sensitivity of 11.8%, specificity of 85.7%, positive predictive value of 40%, and negative predictive value of 54.5%). Thus, it appears clear that the role of APTs in the diagnosis of FPIES requires further investigation. Oral food challenge Although OFC is the gold standard for FPIES diagnosis, it has been associated with a risk of systemic reactions.1 Therefore, OFC for diagnostic confirmation can be omitted when the clinical course

is typical. In infants with a strongly suspected history of FPIES, confirmatory OFCs for initial diagnosis are not mandatory. However, when the OFCs can be avoided to establish a diagnosis of FPIES, follow-up OFCs are needed,1 and different approaches have been recommended.12,31 Järvinen et al12 suggested a conservative approach, such as follow-up OFCs every 18 to 24 months in patients without recent reactions. On the contrary, follow-up OFCs are recommended after 12 months of age for CM and between 6 and 8 months of age for soy.31 The OFC for FPIES is a hazardous and long procedure, requiring tight control and surpervision during and after the OFC period.1 Recently, Miceli Sopo et al60 proposed to perform an OFC with a mixture of foods that are considered at risk (eg, legumes, cereals, poultry) but not yet introduced into the diet of children younger than 1 year. Making an OFC with a mixture saves a considerable number of hospital admissions than performing an OFC for each food. However, if an OFC with mixture is not clarified, the child will be subjected to an OFC for each food. Thus, the authors concluded that in countries where the prevalence of multiple food FPIES is low, OFC with a mixture of causative foods can avoid an unnecessary elimination diet. OFC is performed by administering food, 0.15 to 0.6 g/kg, in 3 equal doses every 15 minutes. A lower dose, 0.06 g/kg, is used in patients with a history of severe reactions.2 The total amount of food protein should not exceed 3 to 6 g or 10 to 20 g of total food weight or 100 mL of total liquid. Independently by the adopted procedures, the OFC result is considered positive when 3 or more criteria, such as emesis and/or diarrhea, fecal blood, fecal leukocytes, fecal eosinophils, and an increase in peripheral polymorphonuclear leukocytes count of greater than 3,500 cells/mm3, are recorded. More recent studies supported changes in the abovementioned criteria.5,6 Authors suggested that the OFC result would be considered positive if repetitive emesis occurred within 30 to 240 minutes after food ingestion in the absence of skin or respiratory allergic symptoms. Diarrhea, abdominal pain, hypotension, lethargy, and laboratory findings are considered as minor clinical criteria.5,6 Gastric juice analysis As an additional confirmatory test, Hwang et al50 proposed gastric juice analysis after equivocal oral challenges. Gastric juice leukocytes higher than 10 cells per high-power field were observed in 15 of 16 positive CM challenges after 3 hours, whereas none of the 8 age-matched control infants had gastric juice leukocyte counts higher than 10 cells per high-power field. Antigen-specific lymphocyte stimulation test Although the antigen-specific lymphocyte stimulation test is a well-known method investigating antigen-specific T-cell response, its usefulness for diagnosis of FPIES is considered controversial.21 Recently, Morita et al21 found that the lipopolysaccharide

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contained in some commercially available CM proteins are able to induce an antigen nonspecific response, impairing the tests result.21 Endoscopy Endoscopy, not usually performed in classic FPIES, revealed friable mucosa with rectal ulceration and bleeding.2 Biopsies revealed variable villous atrophy, tissue edema, crypt abscesses, and increased lymphocytes, eosinophils, and mast cells.2 Immunohistochemical analysis revealed IgM- and IgA-containing plasma cells, increased TNF-a, and decreased TGF-b type 1 receptors.2 Radiology Radiologic findings were air-fluid levels, nonspecific narrowing, and thumbprinting of the rectum and sigmoid and thickening of the plicae circulares in the duodenum and jejunum with excess luminal fluid.51 Resolution of radiologic abnormalities after dietary restriction has been assessed.2 Natural History As a consequence of differencences in the atopic disease prevalence, lack of specific diastostic testing, and adopted methods, the reported rates of FPIES resolution are variable across countries (Table 7).34 Nevertheless, all experts agree that there is a higher and rapid rate of recovery for FPIES.1 In an Israeli cohort of CM-mediated FPIES,6 50% resolved by 1 year of age, 89% by 2 years of age, and 94% by 30 months of age, and only a single patient had a challenged-proven reaction after the age of 3 years. Similar results were obtained in Korea,31 Australia,5 and Italy.33 Particularly, the Korean study reported 64% tolerance of CM at the age of 10 months31; Mehr et al5 reported resolution of 83% of soy FPIES and 80% of rice FPIES by 3 years of age; and in the Italian cohort, the age of resolution of FPIES to solid foods was later than that of CM or soy.33 On the contrary, in a retrospective study of 310 patients, Ruffner et al32 revealed less favorable results: 35% of patients outgrew their FPIES disease by the age of 2 years, and only 70% outgrew their sensitivity by 3 years. However, by school age (5 years old) more than 85% lost their reactivity to milk, although in 2 patients, FPIES persisted until adolescence. Unlike infants with FPIES, in the adult cohort of Tan and Smith,30 the clinical course of disease appeared different. Specifically, abdominal pain occurred in 77.4% of patients; 71% had vomiting, and 58.1% had diarrhea. Moreover, more than half of the patients had concomitant allergic diseases: 38.7% reported allergic rhinitis, 19.4% asthma, and 3.2% eczema. Furthermore, because patients continued to avoid the causative foods, authors did not observe resolution of food-specific gastrointestinal hypersensitivity. However, some patients, through unintentional self-challenge, had long histories, with reactions that occurred at up to 30-year intervals.30 Notably, these differences between children and adults in natural FPIES history suggest a different underlying pathogenic mechanism.61 In fact, indirect evidence from previous studies on the histopathology of gut biopsy specimens in adults with gastrointestinal food allergy indicates that T-cellemediated release of proinflammatory cytokines and an attenuated anti-inflammatory response resulted in an increased intestinal permeability, malabsorption, and dysmotility, causing FPIES.14,20 The age of recovery for FPIES to soy and CM has been also investigated, with controversial results. In several studies,5,32,33 the age of recovery of FPIES to soy appears to be similar to milk, whereas other research reported that soy-mediated FPIES persists to an older age.2,52,53 In particular, in the study by Nowak-Wegrzyn et al,2 by 3 years of age, 15 (60%) of 25 cases of CM FPIES had resolved, 6 (27%) of 27 cases of soy FPIES had resolved, 4 (40%) of 10 cases of rice FPIES had resolved, and 2 (67%) of 3 cases of vegetable FPIES had resolved. Other studies reported higher rates of

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resolution by 3 years of age. Reflecting the later age of introduction of solid foods to the diet, FPIES to solid foods tends to appear and recovery occurs at a later age.34,52 Miceli Sopo et al33 reported CM tolerance at a mean age of 24 months compared with solid food tolerance at a mean age of 53 months. Caubet et al53 assessed food tolerance at a median age of 4.7 years for rice, 4 years for oats, 6.7 years for soy, and 5.1 years for CM. The median age of resolution for FPIES to fish and egg was the highest at approximately 60 months.33 However, any differences in resolution between solid and liquid foods in other cohorts have been also reported.32,54 Conclusion FPIES is a noneIgE-mediated food hypersensitivity featured principally in acute or chronic gastrointestinal symptoms. Generally, FPIES is a condition with a favorable course. However, as a consequence of its pleiotropic clinical presentation and the lack of specific diagnostic testing, FPIES is often misdiagnosed.8e10 First, FPIES is perceived as a rare syndrome; therefore, it is not included in the initial diagnostic approach of the clinician. Second, the clinical picture of FPIES changes according to the frequency of the intake of the inciting food; thus, marked differences in the severity of symptoms can occur. Moreover, especially in an acute episode, the patient often presents with clinical manifestations resembling other diseases, such as infection, metabolic disorders, or surgical emergencies, confounding the diagnosis. Moreover, because of the lack of specific laboratory and radiographic findings to FPIES, the diagnosis is based on the history and constellation of clinical symptoms with clinical improvement after withdrawal of the suspected causal protein. Furthermore, nonspecific symptoms can contribute to wrong or delayed diagnosis; thus, FPIES can easily evolve in severe illness, also causing a major risk of repeated reactions and additional and often unnecessary procedures. Future descriptions of the prevalence, pathophysiology, diagnosis, and natural course of FPIES are needed. Most studies investigating FPIES are in fact limited by their retrospective nature, which leads to potential recall bias when recording disease onset, number and frequency of episodes, symptom latency, severity, and duration. Importantly, it is critical to perform the most appropriate methods when conducting clinical studies to avoid pitfalls and mistakes. References [1] Boyce JA, Assa’ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergy in the united states: summary of the NIAID- sponsored expert panel report. J Allergy Clin Immunol. 2010;126:1105e1118. [2] Nowak-Wegrzyn A, Sampson HA, Wood RA, Sicherer SH. Food proteininduced enterocolitis syndrome caused by solid food proteins. Pediatrics. 2003;111:829e835. [3] Gryboski JD. Gastrointestinal milk allergy in infants. Pediatrics. 1967;40: 354e362. [4] Australian Institute of Health and Welfare Canberra 2010. Australian National Infant Feeding Survey. Indicator Results. 2011. http://www.aihw.gov.au/ WorkArea/DownloadAsset.aspx?id¼10737420925. Accessed October 2016. [5] Mehr S, Kakakios A, Frith K, Kemp AS. Food protein-induced enterocolitis syndrome: 16-year experience. Pediatrics. 2009;123:e459ee464. [6] Katz Y, Goldberg MR, Rajuan N, Cohen A, Leshno M. The prevalence and natural course of food protein-induced enterocolitis syndrome to cow’s milk: a large-scale, prospective population-based study. J Allergy Clin Immunol. 2011;127:647e653.e1-e3. [7] Shoda T, Isozaki A, Kawano Y. Food protein-induced gastrointestinal syndromes in identical and fraternal twins. Allergol Int. 2011;60:103e108. [8] Guibas GV, Tsabouri S, Makris M, Priftis KN. Food protein-induced enterocolitis syndrome: pitfalls in the diagnosis. Pediatr Allergy Immunol. 2014;25:622e629. [9] Caubet JC, Szajewska H, Shamir R, Nowak-We˛ grzyn A. Non-IgE-mediated gastrointestinal food allergies in children. Pediatr Allergy Immunol. 2017;28: 6e17. [10] González-Delgado P, Caparrós E, Moreno MV, et al. Clinical and immunological characteristics of a pediatric population with food protein-induced enterocolitis syndrome (FPIES) to fish. Pediatr Allergy Immunol. 2016;27: 269e275.

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[11] Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62: e1ee34. [12] Järvinen KM, Nowak-We˛ grzyn A. Food protein-induced enterocolitis syndrome (FPIES): current man- agement strategies and review of the literature. J Allergy Clin Immunol Pract. 2013;1:317e322. [13] Leonard SA, Nowak-Wegrzyn A. Manifestations, diag- nosis, and management of food protein-induced enter- ocolitis syndrome. Pediatr Ann. 2013;42: 135e140. [14] Caubet JC, Nowak-Wegrzyn A. Current understanding of the immune mechanisms of food protein-induced enterocolitis syndrome. Expert Rev Clin Immunol. 2011;7:317e327. [15] Berin MC. Immunopathophysiology of food protein-induced enterocolitis syndrome. J Allergy Clin Immunol. 2015;135:1108e1113. [16] Van Sickle GJ, Powell GK, McDonald PJ, Goldblum RM. Milk- and soy proteininduced enterocolitis: evidence for lymphocyte sensitization to specic food proteins. Gastroenterology. 1985;88:1915e1921. [17] Hoffman KM, Ho DG, Sampson HA. Evaluation of the usefulness of lymphocyte proliferation assays in the diagnosis of allergy to cow’s milk. J Allergy Clin Immunol. 1997;99:360e366. [18] Heyman M, Darmon N, Dupont C, et al. Mononuclear cells from infants allergic to cow’s milk secrete tumor necrosis factor a, altering intestinal function. Gastroenterology. 1994;106:1514e1523. [19] Kapel N, Matarazzo P, Haouchine D, et al. Fecal tumor necrosis factor alpha, eosinophil cationic protein and IgE levels in infants with cow’s milk allergy and gastrointestinal manifestations. Clin Chem Lab Med. 1999; 37:29e32. [20] Chung HL, Hwang JB, Park JJ, Kim SG. Expression of transforming growth factor b1, transforming growth factor type I and II receptors, and TNF-a in the mucosa of the small intestine in infants with food protein-induced enterocolitis syndrome. J Allergy Clin Immunol. 2002;109:150e154. [21] Morita H, Nomura I, Orihara K, et al. Antigen-specific T- cell responses in patients with non-IgE-mediated gastrointestinal food allergy are predominantly skewed to T(h)2. J Allergy Clin Immunol. 2013;131:590e592. [22] Mori F, Barni S, Cianferoni A, Pucci N, de Martino M, Novembre E. Cytokine expression in CD3þ cells in an infant with food protein-induced enterocolitis syndrome (FPIES): case report. Clin Dev Immunol. 2009;2009:679381. [23] Karlsson MR, Rugtveit J, Brandtzaeg P. Allergen-responsive CD4þCD25þ regulatory T cells in children who have outgrown cow’s milk allergy. J Exp Med. 2004;199:1679e1688. [24] Wada T, Matsuda Y, Toma T, Koizumi E, Okamoto H, Yachie A. Increased CD69 expression on peripheral eosinophils from patients with food protein-induced enterocolitis syndrome. Int Arch Allergy Immunol. 2016;170:201e205. [25] Fontaine JL, Navarro J. Small intestinal biopsy in cows milk protein allergy in infancy. Arch Dis Child. 1975;50:357e362. [26] McDonald PJ, Goldblum RM, Van Sickle GJ, Powell GK. Food protein- induced enterocolitis: altered antibody response to ingested antigen. Pediatr Res. 1984;18:751e755. [27] Shek LP, Bardina L, Castro R, Sampson HA, Beyer K. Humoral and cellular responses to cow milk proteins in patients with milk-induced IgE-mediated and non-IgE-mediated disorders. Allergy. 2005;60:912e919. [28] Konstantinou GN, Bencharitiwong R, Grishin A, et al. The role of caseinspecific IgA and TGF-b in children with food protein-induced enterocolitis syndrome to milk. Pediatr Allergy Immunol. 2014;25:651e656. [29] Monteseirin J, Chacon P, Vega A, et al. Human neutrophils synthesize IL-8 in an IgE-mediated activation. J Leukoc Biol. 2004;76:692e700. [30] Tan JA, Smith WB. Non-IgE-mediated gastrointestinal food hypersensitivity syndrome in adults. J Allergy Clin Immunol Pract. 2014;2:355e357. [31] Hwang JB, Sohn SM, Kim AS. Prospective follow-up oral food challenge in food protein-induced enterocolitis syndrome. Arch Dis Child. 2009;94: 425e428. [32] Ruffner MA, Ruymann K, Barni S, Cianferoni A, Brown-Whitehorn T, Spergel JM. Food protein-induced enterocolitis syndrome: insights from review of a large referral population. J Allergy Clin Immunol. 2013;1:343e349. [33] Miceli Sopo S, Giorgio V, Dello Iacono I, Novembre E, Mori F, Onesimo R. A multicentre retrospective study of 66 Italian children with food proteininduced enterocolitis syndrome: different management for different phenotypes. Clin Exp Allergy. 2012;42:1257e1265. [34] Caubet JC, Ford LS, Sickles L, et al. Clinical features and resolution of food protein-induced enterocolitis syndrome: 10-year experience. J Allergy Clin Immunol. 2014;134:382e389. [35] Nomura I, Morita H, Ohya Y, Saito H, Matsumoto K. Non-IgE-mediated gastrointestinal food allergies: distinct differences in clinical phenotype between Western countries and Japan. Curr Allergy Asthma Rep. 2012;12: 297e303.

[36] Ludman S, Harmon M, Whiting D, du Toit G. Clinical presentation and referral characteristics of food protein-induced enterocolitis syndrome in the United Kingdom. Ann Allergy Asthma Immunol. 2014;113:290e294. [37] Hwang JB, Lee SH, Kang YN, Kim SP, Suh SI, Kam S. Indexes of suspicion of typical cow milk protein-induced enterocolitis. J Korean Med Sci. 2007;22: 993e997. [38] Miceli Sopo S, Greco M, Monaco S, Tripodi S, Calvani M. Food protein-induced enterocolitis syndrome, from practice to theory. Expert Rev Clin Immunol. 2013;9:707e715. [39] Hojsak I, Kljai c-Turkalj M, Misak Z, Kolacek S. Rice protein-induced enterocolitis syndrome. Clin Nutr. 2006;25:533e536. [40] Caubet JC, Nowak-We˛ grzyn A. Food protein-induced enterocolitis to hen’s egg. J Allergy Clin Immunol. 2011;128:1386e1388. [41] Hwang JB, Kang KJ, Kang YN, Kim AS. Probiotic gastrointestinal allergic reaction caused by Saccharomyces boulardii. Ann Allergy Asthma Immunol. 2009;103:87e88. [42] Feuille E, Nowak-Wegrzyn A. Definition, etiology, and diagnosis of food protein-induced enteocolitis syndrome. Curr Opin Allergy Clin Immunol. 2014; 14:222e228. [43] Nomura I, Morita H, Hosokawa S, et al. Four distinct subtypes of non-IgEmediated gastrointestinal food allergies in neonates and infants, distinguished by their initial symptoms. J Allergy Clin Immunol. 2011;127:685e688. [44] Kimura M, Ito Y, Tokunaga F, et al. Increased C-reactive protein and fever in Japanese infants with food protein-induced enterocolitis syndrome. Pediatr Int. 2016;58:826e830. [45] Kimura M, Shimomura M, Morishita H, Meguro T, Seto S. Serum C-reactive protein in food protein-induced enterocolitis syndrome versus food proteininduced proctocolitis in Japan. Pediatr Int. 2016;58:836e841. [46] Kimura M, Shimomura M, Morishita H, Meguro T, Seto S. Eosinophilia in infants with food protein-induced enterocolitis syndrome in Japan [published online September 10, 2016]. Allergol Int. http://dx.doi.org/10.1016/j.alit.2016. 08.003. [47] Kessel A, Dalal I. The pendulum between food protein- induced enterocolitis syndrome and IgE-mediated milk allergy. Acta Paediatr. 2011;100: e183ee185. [48] Fogg MI, Brown-Whitehorn TA, Pawlowski NA, Spergel JM. Atopy patch test for the diagnosis of food protein-induced enterocolitis syndrome. Pediatr Allergy Immunol. 2006;17:351e355. [49] Järvinen KM, Caubet JC, Sickles L, Ford LS, Sampson HA, Nowak-We˛ grzyn A. Poor utility of atopy patch test in predicting tolerance development in food protein-induced enterocolitis syndrome. Ann Allergy Asthma Immunol. 2012; 109:221e222. [50] Hwang JB, Song JY, Kang YN, et al. The significance of gastric juice analysis for a positive challenge by a standard oral challenge test in typical cow’s milk protein-induced enterocolitis. J Korean Med Sci. 2008;23:251e255. [51] Jayasooriya S, Fox AT, Murch SH. Do not laparotomize food- protein-induced enterocolitis syndrome. Pediatr Emerg Care. 2007;23:173e175. [52] Frith K, Campbell D, Joshi P, et al. The first 12 months of FPIES surveillance in Australia. Intern Med J. 2013;43:1. [53] Caubet JC, Bencharitiwong R, Masilamani M, Sampson HA. T cell responses to food proteins in acute food protein-induced enterocolitis (FPIES). J Allergy Clin Immunol. 2013;131:AB183. [54] Ruiz-García M, Díez CE, García SS, del Río PR, Ibáñez MD. Diagnosis and natural history of food protein-induced enterocolitis syndrome in children from a tertiary hospital in central Spain. J Investig Allergol Clin Immunol. 2014; 24:354e356. [55] Caubet JC, Bencharitiwong R, Ross A, Sampson HA, Berin MC, NowakWe˛ grzyn A. Humoral and cellular responses to casein in patients with food protein-induced enterocolitis to cow’s milk. J Allergy Clin Immunol. 2017;139: 572e583. [56] Rodríguez JM, Murphy K, Stanton C, et al. The composition of the gut microbiota throughout life, with an emphasis on early life. Microb Ecol Health Dis. 2015;26:26050. [57] Leonard SA, Nowak-We˛ grzyn A. Food protein-induced enterocolitis syndrome: an update on natural history and review of management. Ann Allergy Asthma Immunol. 2011;107:95e101. quiz 101, 162. [58] Sicherer SH, Eigenmann PA, Sampson HA. Clinical features of food proteininduced enterocolitis syndrome. J Pediatr. 1998;133:214e219. [59] Levy Y, Danon YL. Food protein-induced enterocolitis syndromednot only due to cow’s milk and soy. Pediatr Allergy Immunol. 2003;14:325e329. [60] Miceli Sopo S, Bersani G, Cerchiara G, Monaco S. Oral food challenge with a mixture of ‘at risk’ foods in children with FPIES. Pediatr Allergy Immunol. 2016;27:874e876. [61] Lin XP, Magnusson J, Ahlstedt S, et al. Local allergic reaction in foodhypersensitive adults despite a lack of systemic food-specific IgE. J Allergy Clin Immunol. 2002;109:879e887.