Discrepancy between Caregivers' Reports and Physicians' Evaluation of Causative Foods in Food Protein-Induced Enterocolitis Syndrome in Japan: The Japan Environment and Children's Study.

INTRODUCTION: Food protein-induced enterocolitis syndrome (FPIES) is a form of non-IgE-mediated gastrointestinal food allergy. FPIES is considered a rare food allergy disorder and is often under-recognized. Therefore, clinicians should have a better understanding of its manifestations and maintain a high index of suspicion for a correct diagnosis. To this end, information about differences in the characteristics of caregiver-reported and physician-diagnosed FPIES is important. METHODS: The present, national, multicentric, prospective birth cohort study, called the Japan Environment and Children's Study (JECS), enrolled a general population of 104,062 fetal records. The characteristics of FPIES in 1.5-year-old children were categorized as cases reported by caregivers or as those diagnosed by a physician using questionnaire data. RESULTS: The prevalence of caregiver-reported and physician-diagnosed FPIES cases was 0.69% and 0.06%, respectively. Among the former, the most common causative food was hen's egg (HE), and the second most common causative food was cow's milk (CM) (51.0% and 17.1% of patients responded to HE and CM, which accounted for 46% and 15% of all the causative foods, respectively). Conversely, among the physician-diagnosed cases, the most common causative food was CM followed by HE (57.7% and 36.5% of patients responded to CM and HE, which accounted for 46% and 29% of all the causative foods, respectively). CM accounted for a significantly higher proportion of causative foods in physician-diagnosed FPIES while HE accounted for a significantly higher proportion of caregiver-reported FPIES (p < 0.05). CONCLUSION: A discrepancy was found in reports of the most common causative food between caregiver-reported and physician-diagnosed cases of FPIES.

Diagnosis and management of food allergy-induced constipation in young children-An EAACI position paper.

The recognition of constipation as a possible non-Immunoglobulin E (IgE)-mediated allergic condition is challenging because functional constipation (unrelated to food allergies) is a common health problem with a reported worldwide prevalence rate of up to 32.2% in children. However, many studies in children report challenge proven cow's milk allergy and constipation as a primary symptom and have found that between 28% and 78% of children improve on a cow's milk elimination diet. Due to the paucity of data and a focus on IgE-mediated allergy, not all food allergy guidelines list constipation as a symptom of food allergy. Yet, it is included in all cow's milk allergy guidelines available in English language. The Exploring Non-IgE-Mediated Allergy (ENIGMA) Task Force (TF) of the European Academy for Allergy and Clinical Immunology (EAACI) considers in this paper constipation in the context of failure of standard treatment and discuss the role of food allergens as culprit in constipation in children. This position paper used the Delphi approach in reaching consensus on both diagnosis and management, as currently published data are insufficient to support a systematic review.

Novel small molecule MRGPRX2 antagonists inhibit a murine model of allergic reaction.

BACKGROUND: Activation of Mas-related G protein-coupled receptor X2 (MRGPRX2) is a crucial non-IgE pathway for mast cell activation associated with allergic reactions and inflammation. Only a few peptides and small compounds targeting MRGPRX2 have been reported, with limited information on their pharmacologic activity. OBJECTIVE: We sought to develop novel small molecule MRGPRX2 antagonists to treat MRGPRX2-mediated allergies and inflammation. METHODS: A computational approach was used to design novel small molecules as MRGPRX2 antagonists. The short-listed molecules were synthesized and characterized by liquid chromatography and mass spectrometry as well as nuclear magnetic resonance. Inhibitory activity on MRGPRX2 signaling was assessed in vitro by using functional bioassays (ß-hexosaminidase, calcium flux, and chemokine synthesis) and receptor activation assays (ß-arrestin recruitment and Western blot analysis) in human LAD-2 mast cells and HTLA cells. In vivo effects of the novel MRGPRX2 antagonists were assessed using a mouse model of acute allergy and systemic anaphylaxis. RESULTS: The novel small molecules demonstrated higher binding affinity with MRGPRX2 in the docking study. The half-maximal inhibitory concentration is in the low micromolar range (5-21 µM). The small molecules inhibited not only the early phase of mast cell activation but also the late phase, associated with chemokine and prostaglandin release. Further, Western blot analysis revealed inhibition of downstream phospholipase C-γ, extracellular signal-regulated protein kinase 1/2, and Akt signaling pathway. Moreover, in the mouse models of allergies, small molecule administration effectively blocks acute, systemic allergic reactions and inflammation and prevents systemic anaphylaxis. CONCLUSION: The small molecules might hold a significant therapeutic promise to treat MRGPRX2-mediated allergies and inflammation.

Heterogeneity of food protein-induced enterocolitis syndrome (FPIES).

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy with gastrointestinal symptoms such as vomiting and diarrhea. The development of international consensus guidelines for the diagnosis and management of FPIES in 2017 enabled us to compare patients worldwide, regardless of geographic variation in disease features. As a result, it has become clear that there is heterogeneity among patients with FPIES or that there are cases that partly fit the diagnostic criteria for FPIES but have different characteristics. This review highlights the heterogeneity in FPIES characteristics in terms of trigger foods, the age of onset, differences in geographic regions, and symptoms; it further proposes four disease entities, including acute FPIES in children, acute FPIES in adults, chronic FPIES, and early-onset neonatal FPIES, depending on the age of onset and presumed pathophysiology. The major symptoms at onset and trigger foods differ in acute FPIES in children, acute FPIES in adults, and chronic FPIES, whereas the disease entities may share a similar pathophysiology. Early-onset neonatal FPIES may have a different pathophysiology than acute or chronic FPIES, and may not necessarily fulfil the full diagnostic criteria for acute or chronic FPIES described in the international consensus guidelines. Due to the similarity in symptoms, early-onset neonatal FPIES may sometimes be misdiagnosed as necrotizing enterocolitis. We aim to increase awareness of FPIES among medical staff in pediatrics, neonatology, and internal medicine and promote research, to gain a better understanding of the heterogeneity and pathophysiology of FPIES.

A nationwide survey of non-IgE-mediated gastrointestinal food allergies in neonates and infants.

BACKGROUND: Non-IgE-mediated gastrointestinal food allergies (non-IgE-GIFAs) seem to be increasing rapidly worldwide. However, nationwide studies have been limited to food-protein-induced enterocolitis (FPIES) and food-protein-induced allergic proctocolitis (FPIAP), with little attention to other non-IgE-GIFA subgroups. The aim of this study was to elucidate the clinical features of all patients with non-IgE-GIFAs, not just certain subgroups. METHODS: We conducted a nationwide cross-sectional survey of non-IgE-GIFAs in Japan from April 2015 through March 2016. A questionnaire was sent to hospitals and clinics throughout Japan. The questionnaire asked about the number of physician-diagnosed non-IgE-GIFA patients, the status of fulfillment of the diagnostic criteria, tentative classification into 4 clusters based on the initial symptoms, the day of onset after birth, complications, and the suspected offending food(s). RESULTS: The response rate to that questionnaire was 67.6% from hospitals and 47.4% from clinics. Analyses were conducted about "diagnosis-probable" patient cohort (n = 402) and the "diagnosis-confirmed" patients (n = 80). In half of the reported non-IgE-GIFA patients, onset occurred in the neonatal period. The patients were evenly distributed among 4 non-IgE-GIFA clusters. In Cluster 1, with symptoms of vomiting and bloody stool, the onset showed a median of 7 days after birth, which was the earliest among the clusters. Cow's milk was the most common causative food. CONCLUSIONS: In half of the patients, the onset of non-IgE-GIFAs was in the neonatal period. This highlights the importance of studying the pathogenesis in the fetal and neonatal periods.

Outcomes reported in randomized controlled trials for mixed and non-IgE-mediated food allergy: Systematic review.

BACKGROUND: Mixed and non-IgE-mediated food allergy is a subset of immune-mediated adverse food reactions that can impose a major burden on the quality of life of affected patients and their families. Clinical trials to study these diseases are reliant upon consistent and valid outcome measures that are relevant to both patients and clinicians, but the degree to which such stringent outcome reporting takes place is poorly studied. OBJECTIVE: As part of the Core Outcome Measures for Food Allergy (COMFA) project, we identified outcomes reported in randomized clinical trials (RCT) of treatments for mixed or non-IgE-mediated food allergy. DESIGN: In this systematic review, we searched the Ovid, MEDLINE and Embase databases for RCTs in children or adults investigating treatments for food protein-induced enterocolitis syndrome, food protein-induced allergic proctocolitis, food protein-induced enteropathy and eosinophilic gastrointestinal disorders including eosinophilic esophagitis [EoE], eosinophilic gastritis and eosinophilic colitis published until 14 October 2022. RESULTS: Twenty-six eligible studies were identified, with 23 focused on EoE (88%). Most interventions were corticosteroids or monoclonal antibodies. All EoE studies assessed patient-reported dysphagia, usually using a non-validated questionnaire. Twenty-two of 23 EoE studies used peak tissue eosinophil count as the primary outcome, usually using a non-validated assessment method, and other immunological markers were only exploratory. Thirteen (57%) EoE studies reported endoscopic outcomes of which six used a validated scoring tool recently recommended as a core outcome for EoE trials. Funding source was not obviously associated with likelihood of an RCT reporting mechanistic versus patient-reported outcomes. Only 3 (12%) RCTs concerned forms of food allergy other than EoE, and they reported on fecal immunological markers and patient-reported outcomes. CONCLUSIONS: Outcomes measured in clinical trials of EoE and non-IgE-mediated food allergy are heterogeneous and largely non-validated. Core outcomes for EoE have been developed and need to be used in future trials. For other forms of mixed or non-IgE-mediated food allergies, core outcome development is needed to support the development of effective treatments. SYSTEMATIC REVIEW REGISTRATION: OSF public registry DOI:10.17605/OSF.IO/AZX8S.

The role of the atopy patch test in the diagnostic work-up of non-IgE gastrointestinal food allergy in children: a systematic review.

The "Atopy Patch Test" (APT) has been proposed as a diagnostic tool for food allergies (FA), especially in children with FA-related gastrointestinal symptoms. However, its diagnostic accuracy is debated, and its usefulness is controversial. The aim of this systematic review was to evaluate the APT diagnostic accuracy compared with the diagnostic gold standard, i.e., the oral food challenge (OFC), in children affected by non-IgE mediated gastrointestinal food allergies, including the evaluation in milk allergic subgroup. Both classical non-IgE mediated clinical pictures and food induced motility disorders (FPIMD) were considered. The search was conducted in PubMed and Scopus from January 2000 to June 2022 by two independent researchers. The patient, intervention, comparators, outcome, and study design approach (PICOS) format was used for developing key questions, to address the APT diagnostic accuracy compared with the oral food challenge (OFC). The quality of the studies was assessed by the QUADAS-2 system. The meta-analysis was performed to calculate the pooled sensitivity, specificity, DOR (diagnostic odds ratio), PLR (positive likelihood ratio), and NLR (negative likelihood ratio) with their 95% confidence intervals (CI). Out of the 457 citations initially identified via the search (196 on PubMed and 261 on Scopus), 37 advanced to full-text screening, and 16 studies were identified to be included in the systematic review. Reference lists from relevant retrievals were searched, and one additional article was added. Finally, 17 studies were included in the systematic review. The analysis showed that APT has a high specificity of 94% (95%CI: 0.88-0.97) in the group of patients affected by FPIMD. Data showed a high pooled specificity of 96% (95% CI: 0.89-0.98) and the highest accuracy of APT in patients affected by cow's milk allergy (AUC = 0.93).      Conclusion: APT is effective in identifying causative food in children with food-induced motility disorders.  What is Known: • Atopy patch test could be a useful diagnostic test for diagnosing food allergy, especially in children with food allergy-related gastrointestinal symptoms. What is New: • Atopy patch test may be a useful tool in diagnosing non IgE food allergy, especially in children with food-induced gastrointestinal motility disorders and cow's milk allergy.

Current Practice in Pediatric Cow's Milk Protein Allergy-Immunological Features and Beyond.

Cow's milk protein allergy is one of the most common pediatric food allergies. It poses a significant socioeconomic burden in industrialized countries and has a profound effect on the quality of life of affected individuals and their families. Diverse immunologic pathways can lead to the clinical symptoms of cow's milk protein allergy; some of the pathomechanisms are known in detail, but others need further elucidation. A comprehensive understanding of the development of food allergies and the features of oral tolerance could have the potential to unlock more precise diagnostic tools and novel therapeutic approaches for patients with cow's milk protein allergy.

Drug-Induced Enterocolitis Syndrome in Children.

Drug-Induced Enterocolitis Syndrome (DIES) is a drug-induced hypersensitivity reaction non-IgE mediated involving the gastrointestinal system that occurs 2 to 4 h after drug administration. Antibiotics, specifically amoxicillin or amoxicillin/clavulanate, represent the most frequent drugs involved. Symptoms include nausea, vomiting, abdominal pain, diarrhea, pallor, lethargy, and dehydration, which can be severe and result in hypovolemic shock. The main laboratory finding is neutrophilic leukocytosis. To the best of our knowledge, 12 cases of DIES (9 children-onset and 3 adult-onset cases) were described in the literature. DIES is a rare clinically well-described allergic disease; however, the pathogenetic mechanism is still unclear. It requires to be recognized early and correctly treated by physicians.

Tolerability and safety of a new elimination diet for pediatric eosinophilic gastritis and duodenitis.

BACKGROUND: Non-esophageal eosinophilic gastrointestinal disorders (non-EoE EGIDs) are chronic inflammatory disorders with massive infiltration of eosinophils into the gastrointestinal tract. Food elimination diets are potentially effective treatments. But the existing dietary therapies have various weak points. We developed a new regimen to compensate for the shortcomings of the elemental diet and 6-food elimination diet. The new regimen consists of an amino-acid-based formula, potatoes, vegetables, fruits and restricted seasonings. We named it the "Rainbow Elimination Diet (ED)." The aims of this study were to evaluate the tolerability and safety of this diet. METHODS: A retrospective medical record examination was conducted at the National Center for Child Health and Development covering the period from January 2010 through December 2018. The medical records of patients (age 2-17 y) with histologically diagnosed non-EoE EGIDs were reviewed. The tolerability, nutritional intake, symptoms, and blood test findings were evaluated. RESULTS: Nineteen patients were offered several kinds of food-elimination diets. Seven patients (eosinophilic gastritis: 5; gastroenteritis: 1; duodenitis: 1) were treated with Rainbow ED. Six patients were compliant with this diet. The median duration of the diet induction phase was 15 days (range 14-30). All 5 patients who had had symptoms just before the induction phase became symptom-free. The body weight decreased in 5 patients (median -0.6 kg), probably because the serum protein increased, resulting in reduced edema. All 5 patients with hypoproteinemia had elevated serum albumin (median 2.9-3.5 g/dL). The ingested nutritional elements were calculated, and most of them were sufficient, except for fat and selenium. CONCLUSIONS: The Rainbow ED was well-tolerated and safe for pediatric non-EoE EGIDs.

[New concept : The milk ladder, the climb to tolerance in non-IgE-mediated cow's milk protein allergy]. / Nouveau concept : l'échelle du lait. La montée vers la tolérance en cas d'allergie aux protéines du lait de vache non IgE-médiée.

Cow's milk protein allergy (CMPA) is the leading cause of food allergy in young children. Despite the spontaneous acquisition of tolerance in the majority of cases at school age, the impact of CMPA on the quality of life of the child and his/her family is clearly more deleterious than in other food allergies. The milk scale, a form of oral immunotherapy, accelerates the acquisition of tolerance such as to curb this negative impact, through a process of gradually reintroducing milk into the diet of the allergic patient. We propose here a French-speaking Belgian version of the milk scale for children with mild to moderate non-IgE-mediated CMPA.

L'allergie aux protéines de lait de vache (APLV) est la première cause d'allergie alimentaire chez les jeunes enfants. Malgré l'acquisition spontanée d'une tolérance dans la majorité des cas à l'âge scolaire, l'impact négatif de l'APLV sur la qualité de vie de l'enfant et de sa famille est nettement supérieur à celui causé par d'autres allergies alimentaires. L'échelle du lait constitue une forme d'immunothérapie orale qui permet d'accélérer l'acquisition de tolérance pour diminuer cet impact négatif et ce, par un processus de réintroduction progressive du lait dans l'alimentation du patient allergique. Nous proposons ici une version belge francophone de l'échelle du lait pour les enfants atteints d'une forme légère à modérée d'APLV non IgE-médiée.

Food allergy and hypersensitivity reactions in children and adults-A review.

Adverse reactions after food intake are commonly reported and a cause of concern and anxiety that can lead to a very strict diet. The severity of the reaction can vary depending on the type of food and mechanism, and it is not always easy to disentangle different hypersensitivity diagnoses, which sometimes can exist simultaneously. After a carefully taken medical history, hypersensitivity to food can often be ruled out or suspected. The most common type of allergic reaction is immunoglobulin E (IgE)-mediated food allergy (prevalence 5-10%). Symptoms vary from mild itching, stomach pain, and rash to severe anaphylaxis. The definition of IgE-mediated food allergy is allergic symptoms combined with specific IgE-antibodies, and therefore only IgE-antibodies to suspected allergens should be analyzed. Nowadays, methods of molecular allergology can help with the diagnostic process. The most common allergens are milk and egg in infants, peanut and tree nuts in children, and fish and shellfish in adults. In young children, milk/egg allergy has a good chance to remit, making it important to follow up and reintroduce the food when possible. Other diseases triggered by food are non-IgE-mediated food allergy, for example, eosinophilic esophagitis, celiac disease, food protein-induced enterocolitis syndrome, and hypersensitivity to milk and biogenic amines. Some of the food hypersensitivities dominate in childhood, others are more common in adults. Interesting studies are ongoing regarding the possibilities of treating food hypersensitivity, such as through oral immunotherapy. The purpose of this review was to provide an overview of the most common types of food hypersensitivity reactions.

The relationship between dietary elimination and maternal psychopathology in breastfeeding mothers of infants with food allergy.

BACKGROUND: There has been no study evaluating the psychopathology in breastfeeding mothers of infants with food allergy (FA). OBJECTIVE: The aim of the study was to investigate the relationship between dietary elimination and maternal psychopathology, specifically anxiety, depression, and mother-to-infant bonding, in breastfeeding mothers of infants with food allergy. METHODS: Breastfeeding mothers following an elimination diet due to FA in their children aged 1-to-12 months were compared with the healthy controls. The physician-diagnosed FA group was divided into IgE-, non-IgE-mediated, and infants with some minor symptoms which were not enough to make the diagnosis of FA were classified as Indecisive symptoms for FA group. Mothers completed standardized questionnaires including Symptom Checklist 90R, Beck Depression/Anxiety Inventories (BDI/BAI), Postpartum Bonding Questionnaire (Bonding). RESULTS: Of 179 mother and infants, 64 were healthy, 89 were FA, 16 were indecisive symptoms for FA. The mean age of the mothers and infants were 31.1 ± 4.7 years and 6.3 ± 3.6 months, respectively. The physician-diagnosed FA groups had higher scores for anxiety (p = .008), anger (p = .042), depression (p < .001), obsession (p = .002), phobia (p = .008), somatization (p = .002), general symptom index (GSI) (p = .001), BDI (p < .001), BAI (p = .008), and Bonding (attachment [p = .001], anger [p = .019], and total [p = .036]) than the healthy ones. The indecisive symptoms for FA group had a similar score pattern to physician-diagnosed FA, except interpersonal sensitivity, BDI, and attachment. CONCLUSION: Breastfeeding mothers of infants with FA were more anxious, with higher depression scores than controls, and had many psychopathologies which affected bonding. Interventions targeting negativity in caregivers' social relationships are urgently needed.

Diagnosis and management of food allergy-associated gastroesophageal reflux disease in young children-EAACI position paper.

Gastro-oesophageal reflux (GOR) and food allergy (FA) are common conditions, especially during the first 12 months of life. When GOR leads to troublesome symptoms, that affect the daily functioning of the infant and family, it is referred to as GOR disease (GORD). The role of food allergens as a cause of GORD remains controversial. This European Academy of Allergy and Clinical Immunology (EAACI) position paper aims to review the evidence for FA-associated GORD in young children and translate this into clinical practice that guides healthcare professionals through the diagnosis of suspected FA-associated GORD and medical and dietary management. The task force (TF) on non-IgE mediated allergy consists of EAACI experts in paediatric gastroenterology, allergy, dietetics and psychology from Europe, United Kingdom, United States, Turkey and Brazil. Six clinical questions were formulated, amended and approved by the TF to guide this publication. A systematic literature search using PubMed, Cochrane and EMBASE databases (until June 2021) using predefined inclusion criteria based on the 6 questions was used. The TF also gained access to the database from the European Society of Paediatric Gastroenterology and Hepatology working group, who published guidelines on GORD and ensured that all publications used within that position paper were included. For each of the 6 questions, practice points were formulated, followed by a modified Delphi method consisting of anonymous web-based voting that was repeated with modified practice points where required, until at least 80% consensus for each practice point was achieved. This TF position paper shares the process, the discussion and consensus on all practice points on FA-associated GORD.

Clinical presentation and management of food protein-induced enterocolitis syndrome in 113 Swedish children.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy causing severe acute gastrointestinal symptoms and lethargy, mainly affecting infants and young children. There are geographic variations in its clinical features. This study aimed to describe the clinical characteristics and management of FPIES in Swedish children. METHODS: The study included children who presented with acute FPIES during 2008-2017. All Swedish pediatric departments (n = 32) were invited to report their known patients. Data were collected through chart reviews and interviews with parents. RESULTS: Eighteen pediatric departments contributed, and 113 patients were included. Most had a family history of atopy (74%), and 51% had an atopic disease. Common trigger foods were cow's milk (26%), fish (25%), oat (22%), and rice (8%). Most patients (85%) reacted to a single food. The median age at first reaction was 3.9 months for cow's milk and 6.0 months for other foods (p < 0.001, range 1.0 month to 9 years). Repetitive vomiting (100%), lethargy (86%), and pallor (61%) were common symptoms; 40% had diarrhea. Sixty percent visited the emergency department, and 27% of all patients were hospitalized. Most patients were diagnosed clinically (81%). Specific IgE for the trigger food was positive in 4/89 tested patients (4%), and skin prick test for the trigger food was positive in 1/53 tested patients (2%). CONCLUSIONS: In our Swedish study of 113 children, cow's milk, fish, and oat were the commonest trigger foods. Most patients reacted to a single food, and IgE sensitization was rare.

An exploration of factors associated with food protein-induced enterocolitis syndrome: Birth, infant feeding and food triggers.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergic disorder with a well-characterized phenotype, but limited understanding of factors associated with food cross-reactivity, severity and tolerance. METHODS: A retrospective cohort study spanning 20 years on children with acute FPIES from a single paediatric tertiary centre in New South Wales, Australia, focusing on identifying food trigger co-associations and factors associated with reaction severity, multiple trigger FPIES and/or tolerance was performed. RESULTS: A total of 168 individuals with 329 recorded FPIES episodes between 1997 and 2017 were included. 49% were male. The median age at first reaction was 5 months, and median age at diagnosis was 9 months. 73% experienced at least one severe FPIES reaction. Rice (45%), cow's milk (30%) and soya (13%) were the most common triggers. Rice or cow's milk FPIES was strongly associated with increased odds of having multiple trigger FPIES. The odds of having multiple food FPIES and severe reactions were slightly decreased with vaginal delivery. No factors were associated with increased risk of severe reactions. Infants with rice and grains FPIES outgrew their reactions at an earlier age, compared to those with fish FPIES. CONCLUSIONS: Rice remains the most common trigger in Australia with co-associations between rice/oats and cow's milk/soya observed. This suggests that taxonomically related foods may share similar protein structure and trigger similar mechanisms of antigen recognition. Vaginal delivery may have a mild protective effect on the development of multiple FPIES and severe reactions. No other features from birth or infant-feeding history influenced outcomes in FPIES.

Poor prognosis of food protein-induced enterocolitis syndrome to fish.

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.

Non-IgE-Mediated Drug Hypersensitivity Reactions.

PURPOSE OF REVIEW: Non-IgE-mediated drug reactions have traditionally been poorly defined and studied, though they are the most common form of hypersensitivity. Their presentations are highly variable and can range in severity from mild, cutaneous-only reactions to severe systemic disease. RECENT FINDINGS: The most notable advance in non-IgE-mediated hypersensitivity reactions is in diagnostics. HLA alleles have traditionally been used for identifying certain patients at risk for abacavir hypersensitivity syndrome, but more recent studies have shown several other HLA alleles associated with severe cutaneous adverse reactions with various medications. This article also highlights the use of delayed intradermal testing for radiocontrast media and patch testing for delayed antibiotic reactions. Drug reactions remain a major cause of morbidity and reason for treatment changes. Non-IgE-mediated reactions have had an increase in research interest over the past decade with an increased emphasis on better understanding the clinical presentation and underlying pathophysiology.

Differential Cytokine Expression in the Duodenum and Rectum of Children with Non-Immunoglobulin E-Mediated Cow's Milk Protein Allergy.

BACKGROUND: Cow's milk protein allergy (CMPA) is the most prevalent food allergy in children, and its pathogenesis remains poorly understood. It has been shown that the combination of genetic predisposition, perinatal factors, and intestinal imbalance of the immune response mediated by cytokines may play an essential role in CMPA pathogenesis. AIM: To characterize the gene expression of Th1, Th2, and Th17 cytokines in the duodenum and rectum in patients with CMPA. METHODS: This is an observational, descriptive, cross-sectional, prospective study. We used specific IgE (ImmunoCAP®) in serum and biopsies from the rectum and duodenum for the detection of cytokine messenger RNA levels by real-time PCR in patients with a positive oral food challenge for CMPA. We analyzed the relative quantification of the gene expression of cytokines by real-time PCR, and we used the housekeeping gene GAPDH for normalization purposes. RESULTS: Thirty children (13 male and 17 female) were evaluated. All patients had an open challenge for CMPA. IgE specific to casein, alfa-lactalbumin, and beta-lactoglobulin was negative in all patients. In terms of cytokine levels, the levels of TNFα, IL-6, IL-12 (Th1), IL-4, IL-10, IL-13 (Th2), and IL-17 were found to be higher in the rectum than in the duodenum (p < 0.05). IL-15 was found to be higher in the duodenum than in the rectum (p < 0.05). CONCLUSIONS: In the present study we observed that the immune response in CMPA seems to be mediated by a Th1, Th2, and Th17 cytokine profile, with the rectum being the main affected site.

An unusual case of food protein-induced enterocolitis syndrome due to zucchini.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy characterized by gastrointestinal symptoms, mainly protracted and delayed vomiting. Diagnosis is based on clinical history, and it can be challenging as symptoms are delayed and the causative food is often not very suspicious. OBJECTIVE: This case report highlights the importance of having a high degree of suspicion to reach a correct diagnosis. MATERIALS AND METHODS: We report an unusual case of FPIES due to zucchini. During the follow-up. Two oral food challenges (OFC) were carried out to evaluate tolerance to the food involved. RESULTS: The first OFC was positive and in the second the child tolerated the food without problems. CONCLUSIONS: In this case, the OFC was essential to identify the offending food and to verify that the child had overcome the disease.