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All patients were not sensitized to -5-gliadin; however, one patient had a slightly elevated wheat-sIgE level of 0.42 kU SB A sb /L. 1 TABLE Characteristics of the seven patients with wheat-induced FPIES. The proportion of patients who became tolerant to wheat increased with age, and at the age of 5 years, six (86%) patients were confirmed to have achieved tolerance and the remaining patient was able to consume 52 mg of wheat protein (Figure 2). Patients who either met the diagnosis criteria based on their history of symptoms or symptoms exhibited during OFC were defined as wheat-FPIES patients. Keywords: food protein-induced enterocolitis syndrome; prognosis; tolerance; wheat EN food protein-induced enterocolitis syndrome prognosis tolerance wheat 1 4 4 03/30/23 20230301 NES 230301 Key message The rate of tolerance acquisition in infants with food protein-induced enterocolitis syndrome caused by wheat increased with age and resolved in most patients by the age of 5 years. [Extracted from the article]

Early diagnosis, food hypersensitivity, egg yolk, food protein-induced enterocolitis syndrome, FPIES, tolerance acquisition Keywords: early diagnosis; egg yolk; food hypersensitivity; food protein-induced enterocolitis syndrome; FPIES; tolerance acquisition EN early diagnosis egg yolk food hypersensitivity food protein-induced enterocolitis syndrome FPIES tolerance acquisition 1 4 4 04/28/22 20220401 NES 220401 ACKNOWLEDGMENTS We thank all patients who participated in this study. Early diagnosis of egg yolk-associated FPIES relates to early tolerance acquisition. [Extracted from the article]

The diagnosis of drug‐induced enterocolitis syndrome (DIES), resembling the typical findings of a well‐known disease, the food protein‐induced enterocolitis syndrome (FPIES), was acknowledged in the first publication on the topic in 2014. Ten cases of DIES have been described so far. Unanswered questions concerning DIES include its pathogenetic mechanism, natural history, the possible presence of predisposing genetic factors, and the potential existence of its atypical forms. DIES is a recently defined and intriguing clinical entity, similar to FPIES but triggered by drugs. It seems well‐defined from the clinical point of view, but its pathogenetic mechanisms are not known. DIES deserves more attention among allergists, especially among the professionals who work with children, and all efforts should be conceived to improve its correct recognition and accurate management. [ABSTRACT FROM AUTHOR]

Keywords: atypical; differential diagnosis; food protein-induced enterocolitis syndrome; low birthweight; necrotizing enterocolitis; preterm newborns; twins EN atypical differential diagnosis food protein-induced enterocolitis syndrome low birthweight necrotizing enterocolitis preterm newborns twins 1 5 5 01/05/22 20220101 NES 220101 CONFLICT OF INTEREST The authors declare that there are no conflicts of interest. In preterm newborns, acute FPIES should be carefully differentiated, in particular, from necrotizing enterocolitis (NEC). In some cases, this finding, which is not typical in FPIES, along with leukocytosis with neutrophilia and thrombocytosis could be an important tool to differentiate between NEC and FPIES in preterm newborns. FPIES was not suspected initially in any of the patients, but other medical and surgical conditions have been hypothesized; in the suspicion of NEC, empiric broad-spectrum parenteral antibiotic therapy was started in three out of six patients (see Table 2 for details). [Extracted from the article]

Keywords: Food protein-induced enterocolitis syndrome; FPIES; Thymus and activation-regulated chemokine EN Food protein-induced enterocolitis syndrome FPIES Thymus and activation-regulated chemokine 1 4 4 01/05/22 20220101 NES 220101 ACKNOWLEDGMENT We thank all patients who participated in this study. A recent report has demonstrated that serum levels of TARC elevate after oral food challenge (OFC) in two patients with FPIES, suggesting that serum TARC levels are potential biomarker of the disease.3 We defined TARC ratio as the ratio of post-OFC to pre-OFC TARC levels. To validate the utility of TARC in the diagnosis of FPIES, we examined TARC ratio in a larger number of patients with FPIES. In contrast to OFC-positive patients, TARC levels showed no changes in any OFC-negative patients who finally achieved tolerances of solid FPIES. [Extracted from the article]

In 2014, drug‐induced enterocolitis syndrome (DIES) was described for the first time. It is still a poorly known disease with symptoms that typically resemble those of food protein–induced enterocolitis syndrome (FPIES). To date, six more cases of DIES have been described and new clinical diagnostic criteria have been proposed based on those in the international guidelines for FPIES. In this paper, the authors describe three more cases of DIES. In addition, similarities and differences with FPIES have been deeply analyzed. To date, several unanswered questions need to be addressed, but clinicians must be instructed how to identify DIES, in order to make an allergy workup and give definite therapeutic indications to patients, especially in children where DIES seems to be more frequent. [ABSTRACT FROM AUTHOR]

Background: The method of performing oral food challenge (OFC) in acute food protein–induced enterocolitis syndrome (FPIES) has not been systematically studied. Therefore, there is a certain variability in the choice of the various centers. Methods: Since 2011, we have been performing OFC for acute FPIES with a single dose of culprit food, a full serving size for age. In case of atypical FPIES (skin prick test, SPT, positive), we applied this protocol only if the description of previous adverse reactions was compatible with that of a classic acute FPIES, if other IgE‐mediated food allergies were absent, and if the mean diameter of the wheal evoked by the SPT with the challenged food was ≤5 mm. We have retrospectively analyzed 222 OFCs from 2011 to 2020. The grading of reactions was carried out according to the International Consensus Guidelines on FPIES of 2017. Results: Forty‐eight of 222 OFC (21.6%) failed. The mild reactions were 22 of 48 (45.8%), the moderate ones 22 of 48 (45.8%), and the severe ones 4 of 48 (8.4%) failed OFCs. The tested food processing (in the case of cow milk and chicken egg) did affect neither probability nor severity of the reaction. Patients with positive SPT for the tested food presented four times more severe reactions (2 of 9 failed OFC, 22.2%) than patients with negative SPT (2 of 39 failed OFC, 5.1%) (P =.316). Conclusions: The administration of a single dose in a full serving size for age appears to be a sufficiently safe method for OFC for acute FPIES, with the benefit of saving time. In patients with positive SPT for the tested food, it may be prudent to start with a smaller dose carrying on, in the absence of adverse reactions, with the administration of the full dose after a 4‐hour observation. [ABSTRACT FROM AUTHOR]

Background: Fish is the most common causative food of food protein–induced enterocolitis syndrome (FPIES) in Southern Europe. In children with FPIES, the development of tolerance varies according to the culprit food and specifically fish seems to have a poorer prognosis than other solid foods. We sought to evaluate the fish‐FPIES resolution rate in children. Methods: A descriptive retrospective analysis of children with fish‐FPIES, followed during the last 20 years, was performed. The offending fish, age and symptoms at onset, the coexistence of atopic diseases and FPIES to other foods were registered. All the children included had undergone an oral food challenge (OFC) with the offending fish. We recorded those children that overcame their fish‐FPIES and those that did not outgrow the disease. Results: Seventy children were enrolled in this study (median age: 9 yo; IQR 6.4‐13.8). Forty‐two (60%) achieved tolerance to the offending fish with a median age of 4 years (IQR: 3‐5). Among children ≤5 yo (n = 40), 35 (87.5%) developed tolerance; among 6‐8yo (n = 14), 40% developed tolerance; and only 12.5% among those ≥9 yo (n = 16) developed tolerance. Twenty‐eight children did not outgrow the disease (median age: 8.9 yo; IQR: 9‐13.8). We did not find any statistical differences regarding the offending fish, presence of single vs multiple fish‐FPIES, symptoms at the beginning, coexistence of other atopic diseases or the coexistence of other FPIES, between the children who overcame the disease and those who did not. Conclusion: One in five children with FPIES to fish will not overcome the disease during childhood. [ABSTRACT FROM AUTHOR]

Background An increasing number of infants are diagnosed with food protein-induced enterocolitis syndrome ( FPIES), a non-IgE-mediated food allergy. Until now, T-cell, food-specific mechanisms have been hypothesized. Methods Sixteen children (11M, 5F), affected by FPIES from cow's milk, wheat, fruit, rice, and others, experienced 25 acute episodes managed at our emergency department ( ED) and eight FPIES reactions during oral food challenges ( OFC). We compared the laboratory data in resting conditions, in the absence of infectious diseases, with data collected during the 25 acute ED episodes (blood samples drawn at 2-12 hours) and the eight positive OFCs (three samples at 2, 6, and 12 hours). The onset of symptoms was used as a reference time point. Results In basal conditions, total IgE, WBC, neutrophil and eosinophil count, CRP, and SGPT were found normal. LDH and SGOT values were high (627.81±97.88 and 45.75±10.26 UI/L, respectively). During ED reactions, LDH and SGOT increased to 794.21±247.28 ( P=.028) and 51.08±16.99 UI/L ( P=.14) and neutrophils count and CRP to 8.44±3.82×103/μL ( P=.0009) and 3.27±5.73 mg/dL ( P=.0014), respectively. During positive OFC, LDH and SGOT did not vary significantly; CRP increased from 0.14±0.18 to 2.49±3.65 mg/dL ( P=.00189) and neutrophil count from 2.79±1.42 to 7.10±3.98×103/μL ( P=.00096). Conclusions FPIES reactions are characterized by neutrophilia and by a time-dependent, significant increase in CRP, indicating that inflammatory mechanisms are in place. This suggests new directions for research on FPIES pathogenesis. [ABSTRACT FROM AUTHOR]

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

The article presents several case studies related to Food protein–induced enterocolitis syndrome (FPIES), a non–IgE‐mediated food allergy in infants. Topics discussed include symptoms of FPIES like repetitive vomiting and diarrhea of ingesting the offending food; mentions the increasing level of thymus and activation‐regulated chemokine (TARC); and information on the TARC elevation for the diagnosis of FPIES.

Background Food protein-induced enterocolitis ( FPIES) is an uncommon, non-IgE-mediated food allergy that usually debuts in infancy with profuse vomiting, lethargy, and pallor 2-4 h following ingestion of the offending food. Its immune mechanism is not known. We aimed to describe the clinical features and outcome of children with fish- FPIES as well as to investigate on cellular immune response implicated. Methods Prospective and follow-up clinical study of children with FPIES by fish over a period between 2004 and 2013 was conducted. Measurement in vitro of both cytokine production in peripheral blood mononuclear cells ( PBMCs) and expression of HLA- DR in monocyte-derived dendritic cells stimulated with fish extracts. Results Sixteen children (seven male and nine female) were included, with a mean age of onset at 10 months. Diagnosis was established after a median of 4 reactions. Twelve patients were treated in emergency room, and two were admitted in intensive care. Patch tests were positive in six patients. Skin prick tests ( SPTs) and specific IgE to all fish tested were negative. Only three children reached tolerance at a mean age of 4.5 years. Eight children avoided fish because of positive oral food challenge ( OFC) after 6 years of age. Other patients have not been challenged because of parent refusal to OFC or a recent diagnosis. TNF-α was increased in patients, and a significant elevation of the HLA- DR marker was also observed in these patients vs. control donors. Conclusions FPIES caused by fish in many cases presents with severe clinical manifestations. Patch test has poor diagnostic value, and OFC is the gold standard to test tolerance. The cytokine TNF-α may be implicated in the clinical symptoms. Higher expression of HLA- DR in dendritic cells has also been detected in our patients. [ABSTRACT FROM AUTHOR]

Background: The study describes the demographic features, culprit foods, clinical features and outcomes for children presenting with acute fish and/or shellfish food protein-induced enterocolitis syndrome (FPIES) infour Italian paediatric allergy centres. Methods: A retrospective/prospective study was undertaken. All children diagnosed with fish or shellfish FPIES were enrolled. The diagnosis of FPIES was based on Sicherer's or Miceli Sopo clinical criteria. Skin prick tests (SPT) were performed in all patients, at the time of diagnosis and prior to OFC. Results: Seventy children were enrolled. Mean age at first episode was 14 months (range 6-46 months); mean age at diagnosis was 34 months (range 6-164 months). Sole and cod were the fish most commonly implicated. Fifty-seven of 70 (81%) children had FPIES exclusively to fish, 37 of 57 (65%) children had single-fish FPIES, 20 of 57 (35%) multiple-fish FPIES, nine of 70 (13%) presented adverse reactions exclusively to shellfish, and four of 70 (6%) presented adverse reactions to both fish and shellfish. Only four (5.7%) children presented episodes of acute FPIES with different foods (2 to cow's milk, 1 to egg, 1 to beef); in all cases, onset was prior to that of fish or shellfish FPIES. Fifteen of 70 (21%) children tolerated fish other than the offending fish. Twenty-four of 70 (34%) children achieved tolerance (age range 24- 102 months). Conclusions: The chief peculiarities of acute fish and shellfish FPIES, compared to more frequent cow's milk or soy FPIES, are (i) later age of onset, (ii) longer persistence and (iii) possibility of tolerating fish other than the offending fish. Adverse reactions with shellfish are possible. [ABSTRACT FROM AUTHOR]

Keywords: food protein-induced enterocolitis syndrome; international consensus guidelines; ondansetron; oral food challenge; pediatrics EN food protein-induced enterocolitis syndrome international consensus guidelines ondansetron oral food challenge pediatrics 1588 1589 2 10/04/21 20211001 NES 211001 To the Editor, We read with great interest the paper Miceli Sopo et al,1 published. The authors described their experience with performing an oral food challenge (OFC) for acute food protein-induced enterocolitis syndrome (FPIES), with a single dose in a full serving size for the age of the culprit food, followed by a 4-h observation period. In terms of severity of reaction, the ondansetron was administered in 1/2 (50%) versus 12/22 (54%) of mild reactions, 4/6 (66.7%) versus 8/22 (36%) of moderate reactions, and 9/9 (100%) versus 3/4 (75%) of severe reactions in our and Miceli Sopo et al, studies, respectively. [Extracted from the article]

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

Cow's milk protein allergy is the most common food allergy in infants and young children. It is estimated that up to 50% of pediatric cow's milk allergy is non-IgE-mediated. Allergic proctocolitis is a benign disorder manifesting with blood-streaked stools in otherwise healthy-appearing infants who are breast-or formula-fed. Symptoms resolve within 48–72 h following elimination of dietary cow's milk protein. Most infants tolerate cow's milk by their first birthday. Food protein-induced enterocolitis syndrome presents in young formula-fed infants with chronic emesis, diarrhea, and failure to thrive. Reintroduction of cow's milk protein following a period of avoidance results in profuse, repetitive emesis within 2–3 h following ingestion; 20% of acute exposures may be associated with hypovolemic shock. Treatment of acute reactions is with vigorous hydration. Most children become tolerant with age; attempts of re-introduction of milk must be done under physician supervision and with secure i.v. access. Allergic eosinophilic gastroenteritis affects infants as well as older children and adolescents. Abdominal pain, emesis, diarrhea, failure to thrive, or weight loss are the most common symptoms. A subset of patients may develop protein-losing enteropathy. Fifty percent of affected children are atopic and have evidence of food-specific IgE antibody but skin prick tests and serum food-IgE levels correlate with response to elimination diet poorly. Elemental diet based on the amino-acid formula leads to resolutions of gastrointestinal eosinophilic inflammation typically within 6 wk. [ABSTRACT FROM AUTHOR]