Commensal bacteria direct selective cargo sorting to promote symbiosis.

Mucosal immunity protects a host from intestinal inflammation and infection and is profoundly influenced by symbiotic bacteria. Here we report that in mice symbiotic bacteria directed selective cargo sorting in Paneth cells to promote symbiosis through Nod2, a cytosolic bacterial sensor, and the multifunctional protein kinase LRRK2, both encoded by inflammatory bowel disease (IBD)-associated genes. Commensals recruited Nod2 onto lysozyme-containing dense core vesicles (DCVs), which was required for DCV localization of LRRK2 and a small GTPase, Rab2a. Deficiency of Nod2, LRRK2 or Rab2a or depletion of commensals resulted in lysosomal degradation of lysozyme. Thus, commensal bacteria and host factors orchestrate the lysozyme-sorting process to protect the host from enteric infection, implicating Paneth cell dysfunction in IBD pathogenesis.

Severe Immune-Related Enteritis after In Utero Exposure to Pembrolizumab.

Immune checkpoint blockade has become standard treatment for many types of cancer. Such therapy is indicated most often in patients with advanced or metastatic disease but has been increasingly used as adjuvant therapy in those with early-stage disease. Adverse events include immune-related organ inflammation resembling autoimmune diseases. We describe a case of severe immune-related gastroenterocolitis in a 4-month-old infant who presented with intractable diarrhea and failure to thrive after in utero exposure to pembrolizumab. Known causes of the symptoms were ruled out, and the diagnosis of pembrolizumab-induced immune-related gastroenterocolitis was supported by the results of histopathological assays, immunophenotyping, and analysis of the level of antibodies against programmed cell death protein 1 (PD-1). The infant's condition was successfully treated with prednisolone and infliximab.

Phase II study of the safety and efficacy of the anti-PD-1 antibody balstilimab in patients with recurrent and/or metastatic cervical cancer.

OBJECTIVE: This phase II clinical trial evaluated the safety and antitumor activity of balstilimab, an anti-PD-1 antibody, in patients with previously-treated, recurrent/metastatic cervical cancer. METHODS: Eligible patients were 18 years or older with recurrent and/or metastatic cervical cancer and who had relapsed after a prior platinum-based treatment regimen for advanced disease. Balstilimab was administered intravenously at 3 mg/kg once every two weeks, for up to 24 months. The primary endpoint was objective response rate (ORR, RECIST v1.1) as assessed by an independent review committee. RESULTS: At data cutoff, 161 women (median age, 53 years [range 25-81]) were enrolled and treated with balstilimab. Of these, 140 had measurable disease at baseline and one prior line of platinum-based therapy in the metastatic, persistent, or recurrent setting; these patients were included in the efficacy analyses. The ORR was 15% (95% CI, 10.0%-21.8%) and included 5 patients with a complete response and 16 with a partial response. The median duration of response was 15.4 months. In patients with PD-L1-positive tumors the ORR was 20%, however patients with PD-L1-negative tumors also responded to balstilimab (ORR, 7.9%). Responses were not restricted to tumors of squamous cell histology, and an ORR of 12.5% was seen in the subset of patients with cervical adenocarcinoma. The disease control rate was 49.3% (95% CI, 41.1%-57.5%). Immune-mediated enterocolitis (3.1%) and diarrhea (1.9%) were the most common grade 3 or higher treatment-related adverse events. CONCLUSION: Balstilimab demonstrated meaningful and durable clinical activity, with manageable safety, in patients with previously-treated, recurrent/metastatic cervical cancer.

Management of acute food protein-induced enterocolitis syndrome emergencies at home and in a medical facility.

OBJECTIVE: Acute food protein-induced enterocolitis syndrome (FPIES) is characterized by delayed repetitive vomiting after ingestion of a trigger food, and severe reactions may lead to dehydration, hypotension, and shock. We provide recommendations on management of FPIES emergencies in a medical facility and at home. DATA SOURCES: This review summarizes the literature on clinical context, pathophysiology, presentation, and treatment of FPIES emergencies. STUDY SELECTIONS: We referred to the 2017 International Consensus Guidelines for the Diagnosis and Management of FPIES and performed a literature search identifying relevant recent primary articles and review articles on clinical management. RESULTS: Management of FPIES emergencies in a medical facility is based on severity of symptoms and involves rehydration, ondansetron, and corticosteroids. A proactive approach for reactions occurring at home involves prescribing oral ondansetron and providing an individualized treatment plan based on the evolution of symptoms and severity of past reactions. A better understanding of the pathophysiology of FPIES and randomized trials on ondansedron and cocorticosteroid use could lead to more targeted treatments. CONCLUSION: Children with FPIES are at risk for severe symptoms constituting a medical emergency. Management of FPIES emergencies is largely supportive, with treatment tailored to the symptoms, severity of the patient's condition, location of reaction, and reaction history.

The evolution of food protein-induced enterocolitis syndrome: From a diagnosis that did not exist to a condition in need of answers.

OBJECTIVE: Although food protein-induced enterocolitis syndrome (FPIES) was first described approximately 50 years ago and research is increasing, there are still considerable unmet needs in FPIES. This article catalogs the areas of progress and areas for further research. DATA SOURCES: Through our personal experiences in caring for patients with FPIES, our personal research, and a review of the existing FPIES literature as indexed in PubMed, we explored what is known and what is needed in FPIES. STUDY SELECTIONS: The studies that have improved the knowledge of FPIES, defined phenotypes, allowed for better-informed management of FPIES, and laid the groundwork for further research. RESULTS: Further research is needed in the areas of prevalence, natural history, trigger foods, threshold doses, how and when to perform oral food challenges, and immunopathogenesis of this disorder. Development of a biomarker and determination of the best method to treat reactions is also needed. Furthermore, FPIES has a substantial psychosocial and economic impact on families, and more research is needed in developing and implementing ameliorating strategies. CONCLUSION: By partnering together, health care providers, advocacy organizations, and families can continue to advance our understanding and improve the care of patients and families living with FPIES.

Gastrointestinal immunopathology of food protein-induced enterocolitis syndrome and other non-immunoglobulin E-mediated food allergic diseases.

OBJECTIVE: To provide a concise summary of the current literature regarding gastrointestinal immunopathology of food protein-induced enterocolitis syndrome (FPIES) and other non-immunoglobulin E (IgE)-mediated food allergic diseases. DATA SOURCES: Data were extracted from PubMed, MEDLINE, and ScienceDirect databases. STUDY SELECTIONS: Original articles, review articles, and guidelines published in the past 5 years in peer-reviewed journals were first summarized. The original articles cited were then reviewed and relevant results were extracted. RESULTS: Patients with FPIES and non-IgE-mediated food allergic diseases developed vomiting, diarrhea, and food aversion expelled food allergen from their bodies. Aside from T helper type 2 (TH2) immunity, TH1, TH17, innate immunity, and epithelial mucosal barrier defect were also found to be important in the pathogenesis. Eosinophils, widely identified in the biopsy samples, were key players or were late-recruited cells for tissue repairs in those diseases. Intestinal dysbiosis and their metabolites stimulated enterochromaffin cells or enteroendocrine cells to produce serotonin, interfering with intestinal motility and subsequently affecting brain function. FPIES and non-IgE-mediated food allergic diseases were likely part of the atopic march. Allergic inflammation in intestinal mucosa might result in subsequent inflammation in the airway mucosa, suggesting the theory of "one mucosa, one disease." CONCLUSION: The immune responses of FPIES and non-IgE-mediated food allergic diseases were not limited to the gastrointestinal tract, but also trigger wider inflammatory responses beyond it. Further research will be required to determine the systemic effect and intestinal microbiome of those diseases.

Food protein-induced enterocolitis syndrome epidemiology.

OBJECTIVE: Food protein-induced enterocolitis syndrome (FPIES) is a condition with heterogeneous features (ie, age at presentation, severity, food triggers, comorbidities) and is not as rare as initially believed. In the last few years, the first population-based epidemiologic study, few prospective birth cohort evaluating FPIES prevalence, and several larger (>100 patients) studies have been published, making epidemiologic estimation more reliable. In this review, we report on the available data on the epidemiology of FPIES. DATA SOURCES: PubMed review using the following words: FPIES, epidemiology, and prevalence. STUDY SELECTIONS: The review focused on the population-based epidemiologic study, few prospective birth cohort evaluating FPIES prevalence, and several larger (>100 patients) studies. RESULTS: We identified 8 population or cohort studies. CONCLUSION: FPIES is not rare in both children and adults and may affect as many as 900,000 people in the United States alone. Most children and adult with FPIES seem to react to 1 to 2 foods; however, they may need further diet restriction owing to high level of comorbidity with immunoglobulin E-mediated food allergies and eosinophilic esophagitis. Globally, cow's milk, rice/oat, and seafood seem to be the most common triggers.

Advances in understanding immune mechanisms of food protein-induced enterocolitis syndrome.

OBJECTIVE: This review provides an overview of our current understanding of the mechanisms of food protein-induced enterocolitis syndrome (FPIES). DATA SOURCES: To capture recent articles published since our previous comprehensive review on the pathophysiology of FPIES, we performed a literature search through PubMed database, using the search terms FPIES and food protein-induced enterocolitis syndrome from 2016 to the current year. STUDY SELECTIONS: Studies in English containing biomarker or immune data were reviewed and summarized. RESULTS: Studies of peripheral blood fail to exhibit evidence of antigen-specific humoral or cellular immunity underlying clinical reactivity to foods in FPIES. However, growing evidence suggests a robust systemic innate immune activation occurring during FPIES reactions and the activation of neuroendocrine pathways. CONCLUSION: FPIES reactions are associated with marked activation of innate immune and neuroendocrine pathways; however, the mechanism underlying the specific recognition of foods remains elusive.

Food protein-induced enterocolitis syndrome: Dynamic relationship among gastrointestinal symptoms, immune response, and the autonomic nervous system.

OBJECTIVE: To explore the relationship among gastrointestinal (GI) symptoms, immune response, and autonomic nervous system (ANS) in food protein-induced enterocolitis syndrome (FPIES) in relation to the current understanding of disease phenotype and pathogenesis. DATA SOURCES: Relevant studies related to FPIES, GI symptomatology, and ANS were reviewed. Literature search was performed using PubMed, with keyword combinations including but not limited to FPIES, allergic GI disorders, ANS, autonomic dysfunction, dysautonomia, GI, diarrhea, vomiting, neuroimmune, and clinical phenotyping tools. STUDY SELECTIONS: Peer-reviewed case-control studies, observational studies, reviews and guidelines, and systematic reviews related to FPIES and ANS were selected for review. RESULTS: There is limited research directly relating GI symptoms and FPIES to the ANS and immunologic response. To support the proposed mechanisms of action related to patient symptoms, studies relevant to coexisting GI-autonomic processes and FPIES immunologic triggers were examined. These related disease processes were extrapolated to FPIES based on the current knowledge of FPIES phenotype and pathogenesis. CONCLUSION: The etiology of FPIES and the underlying mechanisms triggering symptoms are not well understood. On the basis of the exaggerated GI symptoms and hemodynamic response observed, the ANS likely plays an important role in FPIES, possibly as a compensatory response. The trigger for this cascade of symptoms may be related to the disruption of immunologic homeostasis that typically contributes to immune tolerance. To more accurately evaluate FPIES pathophysiology necessitates understanding the diverse spectrum of presenting symptoms. A consistent and comprehensive symptom assessment tool may improve our understanding of this dynamic relationship.

Food protein-induced enterocolitis syndrome oral food challenge: Time for a change?

OBJECTIVE: Food protein-induced enterocolitis syndrome (FPIES) is typically diagnosed based on a characteristic clinical history; however, an oral food challenge (OFC) may be necessary to confirm the diagnosis or evaluate for the development of tolerance. FPIES OFC methods vary globally, and there is no universally agreed upon protocol. The objective of this review is to summarize reported FPIES OFC approaches and consider unmet needs in diagnosing and managing FPIES. DATA SOURCES: PubMed database was searched using the keywords food protein-induced enterocolitis syndrome, oral food challenge, cow milk allergy, food allergy, non-immunoglobulin E-mediated food allergy and FPIES. STUDY SELECTIONS: Primary and review articles were selected based on relevance to the diagnosis of FPIES and the FPIES OFC. RESULTS: We reviewed the history of FPIES and the evolution and variations in the FPIES OFC. A summary of current literature suggests that most patients with FPIES will react with 25% to 33% of a standard serving of the challenged food, there is little benefit to offering a divided dose challenge unless there is suspicion of specific immunoglobulin E to the food being challenged, reactions typically appear within 1 to 4 hours of ingestion, and reactions during OFC rarely result in emergency department or intensive care unit admission. CONCLUSION: International standardization in the FPIES OFC approach is necessary with particular attention to specific dose administration across challenged foods, timing between the patient's reaction and offered OFC to verify tolerance, patient safety considerations before the OFC, and identification of characteristics that would indicate home reintroduction is appropriate.

Frequency of positive oral food challenges and their outcomes in the allergy unit of a tertiary-care pediatric hospital.

INTRODUCTION AND OBJECTIVE: The oral food challenge (OFC) is the gold standard to diagnose food allergy (FA); however, it is not a procedure free from the risk of having significant allergic reactions, even life-threatening.The aims of our study were to evaluate the frequency of positive OFCs performed in children with a suspected diagnosis of IgE- and non-IgE-mediated (food protein-induced enterocolitis syndrome (FPIES)) FA and how the failed challenges were managed. MATERIALS AND METHODS: A retrospective chart review was done on all children who have had OFCs in a tertiary-care pediatric allergy unit from 2017 to 2019. RESULTS: 682 patients were enrolled and 2206 challenges were performed: 2058 (93%) for IgE-mediated FA and 148 (7%) for FPIES. There were 262 (11.8%) challenge failures. The transfer to the emergency department was required 3 times (1.1%). None of the failed challenges resulted in death or hospitalization and 13.3% challenges did not require any treatment. CONCLUSIONS: Our findings confirm that food challenges can be performed safely in a specialized setting by well-trained personnel; all food challenge reactions, even the most serious, were reversible, thanks to a prompt recognition and treatment that generally did not worsen over time.

Atypical food protein-induced enterocolitis syndrome in children: Is IgE sensitisation an issue longitudinally?

BACKGROUND: Food Protein-Induced Enterocolitis Syndrome (FPIES) is a clinically well-characterised, non-Immunoglobulin E (IgE)-mediated food allergy syndrome, yet its rare atypical presentation remains poorly understood. OBJECTIVE: Aim of this study was to present the 10-year experience of a referral centre highlighting the atypical FPIES cases and their long-term outcome. METHODS: FPIES cases were prospectively evaluated longitudinally in respect of food outgrowth and developing other allergic diseases with or without concomitant IgE sensitisation. RESULTS: One hundred subjects out of a total of 14,188 referrals (0.7%) were identified. At presentation, 15 patients were found sensitised to the offending food. Fish was the most frequent eliciting food, followed by cow's milk and egg. Tolerance acquisition was earlier for cow's milk, followed by egg and fish, while found not to be protracted in atypical cases. Resolution was not achieved in half of the fish subjects during the 10-year follow-up time. Sensitisation to food was not related to infantile eczema or culprit food, but was related to sensitisation to aeroallergens. In the long-term evaluation, persistence of the FPIES or aeroallergen sensitisation was significantly associated with an increased hazard risk of developing early asthma symptoms. CONCLUSION: Sensitisation to food was related neither to eczema or culprit food nor to tolerance acquisition but rather to the development of allergic asthma through aeroallergen sensitisation. In addition to an IgE profile at an early age, FPIES persistence may also trigger mechanisms switching FPIES cases to a T-helper 2 cells immune response later in life, predisposing to atopic respiratory symptoms; albeit further research is required.

Prominent Indomethacin-Induced Enteropathy in Fcgriib Defi-cient lupus Mice: An Impact of Macrophage Responses and Immune Deposition in Gut.

A high dose of NSAIDs, a common analgesic, might induce lupus activity through several NSAIDs adverse effects including gastrointestinal permeability defect (gut leakage) and endotoxemia. Indomethacin (25 mg/day) was orally administered for 7 days in 24-wk-old Fc gamma receptor IIb deficient (FcgRIIb-/-) mice, an asymptomatic lupus model (increased anti-dsDNA without lupus nephritis), and age-matched wild-type (WT) mice. Severity of indomethacin-induced enteropathy in FcgRIIb-/- mice was higher than WT mice as demonstrated by survival analysis, intestinal injury (histology, immune-deposition, and intestinal cytokines), gut leakage (FITC-dextran assay and endotoxemia), serum cytokines, and lupus characteristics (anti-dsDNA, renal injury, and proteinuria). Prominent responses of FcgRIIb-/- macrophages toward lipopolysaccharide (LPS) compared to WT cells due to the expression of only activating-FcgRs without inhibitory-FcgRIIb were demonstrated. Extracellular flux analysis indicated the greater mitochondria activity (increased respiratory capacity and respiratory reserve) in FcgRIIb-/- macrophages with a concordant decrease in glycolysis activity when compared to WT cells. In conclusion, gut leakage-induced endotoxemia is more severe in indomethacin-administered FcgRIIb-/- mice than WT, possibly due to the enhanced indomethacin toxicity from lupus-induced intestinal immune-deposition. Due to a lack of inhibitory-FcgRIIb expression, mitochondrial function, and cytokine production of FcgRIIb-/- macrophages were more prominent than WT cells. Hence, lupus disease-activation from NSAIDs-enteropathy-induced gut leakage is possible.

Secretion of c-di-AMP by Listeria monocytogenes Leads to a STING-Dependent Antibacterial Response during Enterocolitis.

Stimulator of interferon genes (STING) acts as a cytoplasmic signaling hub of innate immunity that is activated by host-derived or bacterially derived cyclic dinucleotides. Listeria monocytogenes is a foodborne, facultative intracellular pathogen that secretes c-di-AMP and activates STING, yet the in vivo role of the STING pathway during bacterial pathogenesis remains unclear. In this study, we found that STING-deficient mice had increased weight loss and roughly 10-fold-increased systemic bacterial burden during L. monocytogenes-induced enterocolitis. Infection with a L. monocytogenes mutant impaired in c-di-AMP secretion failed to elicit a protective response, whereas a mutant with increased c-di-AMP secretion triggered enhanced protection. Type I interferon (IFN) is a major output of STING signaling; however, disrupting IFN signaling during L. monocytogenes-induced enterocolitis did not recapitulate STING deficiency. In the absence of STING, the intestinal immune response was associated with a reduced influx of inflammatory monocytes. These studies suggest that in barrier sites such as the intestinal tract, where pathogen-associated molecular patterns are abundant, cytosolic surveillance systems such as STING are well positioned to detect pathogenic bacteria.

Gut Microbiome and Immune Checkpoint Inhibitor-Induced Enterocolitis.

The gut microbiome is increasingly being described as one of the underlying mechanisms for development of immune checkpoint inhibitor (ICI)-induced colitis. Similarities in gut microbiome profiles have been found among various diseases associated with intestinal inflammation, including inflammatory bowel disease. Certain bacterial species have been reported to be preventive for colitis, as well as beneficial for cancer outcome, in patients receiving ICI therapy. Alternatively, other bacterial classes have been shown to be associated with immunologic alterations causing intestinal inflammation with subsequent increase in the risk of ICI-related colitis. Gut microbiome manipulation by fecal transplantation has been proposed as one of the modalities to ameliorate inflammation in patients with ICI-related colitis refractory to immunosuppressive therapy. Additional investigations are needed to clarify the role of gut microbiome in the pathogenesis of ICI-related colitis.

Comparison of methemoglobin levels in food protein-induced enterocolitis syndrome and other gastrointestinal diseases in neonates.

INTRODUCTION AND OBJECTIVES: Methemoglobinemia has been reported to be associated with severe food protein-induced enterocolitis syndrome (FPIES). However, no reports have evaluated methemoglobin (MHb) levels in FPIES without symptomatic methemoglobinemia or the usefulness of MHb measurement for the diagnostic prediction of FPIES. To evaluate the MHb levels of patients with neonatal-onset FPIES and determine whether MHb levels are higher in FPIES than in other gastrointestinal diseases. PATIENTS AND METHODS: Eleven neonates with severe acute FPIES (FPIES group) and 139 neonates with other gastrointestinal diseases (non-FPIES group) were included in this study. Patient characteristics, symptoms, and venous blood test values (MHb, pH, HCO3-, and C-reactive protein) were evaluated. RESULTS: The median age at onset was 16 days vs. 1 day; males comprised 64% vs. 46%, the median gestational age was 38 weeks vs. 38 weeks, the median birth weight was 2710g vs. 2880g, and the median hospitalization duration was 31 days vs. 6 days for the FPIES vs. non-FPIES groups, respectively. MHb (%) was higher in the FPIES group than in the non-FPIES group [median (range), 1.1 (0.6-10.9) and 0.6 (0.3-1.2), respectively, p<0.001]. There were no differences in terms of pH, HCO3-, and C-reactive protein (p>0.05). In the receiver operating characteristic analysis for FPIES diagnosis based on MHb (%), the area under the curve was 0.885, specificity was 97.1%, and sensitivity was 72.7% at a MHb cutoff of 1.0. CONCLUSION: High MHb levels may help diagnose severe acute FPIES in neonates, but careful evaluation is needed.

Cytokine Expression by Human Macrophage-Like Cells Derived from the Monocytic Cell Line THP-1 Differs Between Treatment With Milk from Preterm- and Term-Delivering Mothers and Pasteurized Donor Milk.

Immunomodulatory proteins from human milk may enhance the protection and development of the infant's gut. This study compared the immunomodulatory effects of treatment with milk from preterm-(PM) and term-delivering (TM) mothers and pasteurized donor milk (DM) on cytokine gene expression in human macrophage-like cells derived from the monocytic cell line THP-1. The gene expression of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-12 (p40), IL-10 and GAPDH in macrophages treated with PM, TM and DM at steady and activated (inflammatory) states were measured using real-time reverse transcription-polymerase chain reaction. TNF-α and IL-6 in macrophages (both states) with DM were higher than PM or TM. IL-10 in steady state macrophages with DM was higher than PM whereas DM increased IL-10 in activated macrophages compared with TM. TM increased IL-6 and IL-12 (p40) in steady state macrophages compared with PM. IL-12 (p40) in activated macrophages with TM was higher than PM. IL-10 in steady state macrophages with TM was higher than PM. These results suggest that DM induces higher gene expression of pro-inflammatory and anti-inflammatory cytokines in macrophages compared with PM or TM. PM reduced gene expression of pro-inflammatory cytokines compared with TM, which may decrease the development of necrotizing enterocolitis and systematic inflammation.

Remission Patterns of Food Protein-Induced Enterocolitis Syndrome in a Greek Pediatric Population.

BACKGROUND: Data on the prevalence and clinical course of food protein-induced enterocolitis syndrome (FPIES) vary between populations and according to the culprit food. OBJECTIVE: To evaluate the incidence, clinical characteristics, and remission patterns of FPIES among children in a Greek pediatric allergy referral center. METHODS: We retrospectively studied children with acute FPIES. Data on age, sex, type of reaction, the implicated food, and oral food challenge (OFC) outcomes at baseline and upon reevaluation were analyzed. RESULTS: Between October 2010 and March 2017, 72 (38 males) out of 15,114 subjects who had been referred to our department due to any reported allergic symptoms were diagnosed with acute FPIES. The most commonly implicated foods were cow's milk (CM) (45.8%), fish (34.7%), rice (9.7%), egg (6.9%), and chicken (2.8%). The mean age at diagnosis was 7.1/19.3/9.1/18.7/8.7 months for those with CM/fish/rice/egg/chicken FPIES, respectively. Sixty-nine OFCs were performed, of which 8 were diagnostic and 61 for tolerance evaluation. The type of culprit food was significantly associated with the outcome of the tolerance OFCs. OFCs to fish resulted positive at a significantly higher rate (12/22; 54.5%) than OFCs to CM (4/29; 13.7%), rice (1/5; 20%), egg (0/3; 0%), and chicken (0/2; 0%) (p = 0.01). The time period between diagnosis and tolerance acquisition was prolonged in the fish FPIES cases (74.8 months; 95% CI: 57.9-91.6) compared to that with other foods such as CM (20.7 months; 95% CI: 17.3-24.1), rice (31.8 months; 95% CI: 21.9-41.7), and egg (24.3 months; 95% CI: 10.7-37.9), as shown in a Kaplan-Meier analysis (log-rank, p < 0.001). When the fish FPIES children were assessed for tolerance, OFCs were significantly more often positive than in CM FPIES children (52 vs. 18.1%; p = 0.03), despite the fact that the children were challenged at an older age (fish: 70.4 months, 95% CI: 58.3-82.5, vs. CM: 26.57 months, 95% CI: 21.1-32, p < 0.001). CONCLUSIONS: Acute FPIES had a low incidence in our population. CM and fish were the two most frequent elicitors. Significantly delayed presentation and prolonged remission was noted for FPIES caused by fish.

Oral Food Challenge in Food Protein-Induced Enterocolitis Syndrome by Fish: Is There Any Room for Improvement?

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal food hypersensitivity usually due to cow's milk or soy. Among the solid foods, rice is one of the most causative foods worldwide, but it varies depending on the geographic area. In the Mediterranean countries, fish is one of the most important triggers of FPIES. There is not a specific biological marker for the disease that allows us to confirm the diagnosis or to predict when tolerance to the offending food has been achieved, so all patients with a FPIES diagnosis undergo an oral food challenge (OFC) at least once. The OFC is a risky procedure and many patients develop severe symptoms. OBJECTIVE: We sought to evaluate the safety of a new OFC protocol in children with fish-FPIES. METHODS: A retrospective study was performed over a 22-year period (1996-2018). We compared two methodologies used in the OFC: Method 1 that consisted in giving several doses during the same day versus Method 2 that consisted in giving a unique dose per day on 2 or three non-consecutive days. RESULTS: A total of 75 positive OFC with fish done in 40 children were included. Forty-three (57.3%) OFC were performed following Method 1 and 32 (42.7%) with Method 2.The severity of the symptoms of the OFC done with Method 1 was mostly moderate (41.9%) followed by severe (39.5%) and mild (18.6%). The adverse reactions with Method 2 were mostly mild (68.8%) and only 18.8 and 12.5% presented moderate or severe symptoms, respectively. CONCLUSIONS: OFC performed in children with fish-FPIES are risky and many patients develop moderate or severe symptoms after this procedure. We propose a new protocol that has demonstrated to improve safety.