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Cow's milk protein allergy (CMPA) is an immune-mediated reaction to cow's milk proteins, which can involve multiple organ systems including the gastrointestinal tract. Immunoglobulin E (IgE)-mediated response results in rapid onset of allergic symptoms that are easily recognizable. However, delayed (i.e. non-IgE/cell-mediated) or mixed (IgE- and cell-mediated) reactions produce a host of symptoms that overlap with other conditions and vary widely in onset and severity. Determining whether symptoms represent immune-mediated CMPA, non-immunologic reaction to cow's milk, or are unrelated to cow's milk exposure is challenging yet essential for effective management. While the clinical presentation of non-IgE-mediated CMPA can vary, this condition is usually self-limited and resolves by 1 to 6 years of age. Food antigen-specific immunoglobulin G (IgG) panels that are not evidence-based should be avoided because they can lead to overdiagnosis of presumed food intolerances. Overdiagnosis of CMPA can result in overuse of extensively hydrolyzed formulas and have significant cost implications for families. This statement focuses on delayed non-IgE/cell-mediated CMPA and assists health care providers to distinguish between and identify varied reactions to cow's milk, discusses the role of diagnostic testing, and provides management recommendations based on best evidence. [ABSTRACT FROM AUTHOR]

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.

Cow's milk allergy refers to an immunological reaction to milk protein. It is one of the commonest food protein allergies with an estimated prevalence of 0.5% to 3% at 1 y of life. The disease may be IgE or non-IgE mediated or mixed with a wide range of symptoms often involving multiple organ systems. Gastrointestinal manifestations are common in non-IgE disease and may consist of enteropathy, proctocolitis, colic, reflux-like symptoms, constipation, enterocolitis syndrome and eosinophilic esophagitis. The gold standard for diagnosis remains a double-blind placebo-controlled oral challenge. Specific IgE and skin prick tests may predict severe and persistent disease, and aid in deciding on reintroduction or oral immunotherapy; however, they do not contribute to a definitive diagnosis as they indicate only sensitization. In practice, an elimination diet followed by open challenge under medical supervision is often used for diagnosis except when symptoms are severe such as anaphylaxis. Management consists of the elimination of the allergen with resolution of symptoms between 1-4 wk later depending on the type of allergy. Extensively hydrolyzed and Amino acid formulas are used to substitute milk in infants. Soy-based formulas are often utilized in resource-limited settings. Tolerance to the protein develops over time and periodic reintroduction should be attempted every six months after the initial one year of elimination diet. Oral immunotherapy is a newer treatment technique for IgE-mediated disease. There is no firm evidence on prevention apart from recommending breast feeding in early life along with initiating complementary feeding between 4-6 mo age. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Background Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobulin E (IgE) -mediated food allergy predominantly observed in infants and characterized by the delayed onset of vomiting following ingestion of a trigger food. An increase in research and clinical consideration of FPIES has led to the discovery of unique deviations from the standard FPIES triggers and presentations. Case presentation A 34-month-old female patient with a history of consuming okra daily presented to medical attention after developing classic FPIES symptoms to okra beginning at 14-months of age. Conclusions Recently, awareness about the varied nature of FPIES clinical presentation has come to light. This case is the first to describe FPIES to the fruit okra that developed over a 12-month time span after previously tolerating the food. This case serves to emphasize the importance of understanding the range of FPIES symptoms to improve recognition and expedite best practice recommendations.

Food protein-induced enterocolitis syndrome (FPIES) is a rare non-IgE-mediated food allergy that mainly impacts babies and 7toddlers. The exact mechanism of FPIES is not completely understood. By studying the expression of IL-10 and CXCL10 in pediatric FPIES patients, researchers can gain insights into the immune mechanisms underlying this disorder. Peripheral venous blood was collected and subsequently stabilized with RNA pro. Total RNA was extracted and mRNA levels of CXCL10 and IL-10 was determined with real time PCR. Children with FPIES had significantly higher values than the healthy control group (HC) for CXCL10 while FPIES had a significant lower values than the control group for IL-10. Our results show a high production of CXCL10 and a concomitant reduced production of IL-10 in FPIES subjects who have not yet reached tolerance. These data may represent a molecular diagnostic marker for FPIES. [ABSTRACT FROM AUTHOR]

Food protein-induced enterocolitis syndrome (FPIES) is a type of non-immunoglobulin E (IgE)-mediated food allergy. However, in addition to vomiting and diarrhea, IgE-mediated skin or respiratory symptoms may be comorbidities in some patients with FPIES. We described four unusual cases of neonates with FPIES, whose clinical presentations were variable and misleading. All patients experienced vomiting, diarrhea or other gastrointestinal symptoms, and three of them developed IgE-mediated food allergy. Case 1 was admitted to the hospital with convulsions and then developed severe sepsis and necrotizing enterocolitis (NEC)-like appearance. Case 2 was wrongly diagnosed with Stevens–Johnson syndrome due to a severe extravasation rash of the skin and mucous membranes and a systemic inflammatory response. There was unexplained cholestasis in case 3, which might be attributed to food allergy. Asymptomatic elevation of C-reactive protein was the only hint at early-stage FPIES in case 4. Moreover, there were increased serum food-specific IgG values in three of the above cases. After eliminating the offending food, all of the above clinical manifestations rapidly improved in the four cases; thus, we believe that the most correct diagnosis in the described four cases was FPIES. This case report series should further draw clinicians’ attention to FPIES with variable and atypical symptoms. The usefulness of IgG levels in identifying the presence of FPIES is uncertain.

Background: Oral food challenge (OFC) is the criterion standard for diagnosis of acute food protein-induced enterocolitis syndrome (FPIES). No diagnostic/prognostic biomarkers are available, and OFC assessment criteria are not validated., Objective: To assess clinical-hematological changes and predictors of severity of FPIES reactions at OFC., Methods: This was an observational multicenter prospective study. Children aged 0 to 18 years diagnosed with acute FPIES were recruited at follow-up OFC in 12 tertiary centers in Spain and Italy. OFC outcomes (as positive/negative/inconclusive and mild/moderate/severe) were assessed on the basis of published "2017 FPIES Consensus" criteria. Clinical characteristics were recorded, and full blood cell count was done at baseline, reaction onset, and 4 hours later. Regression analysis was performed to assess predictors of severe reactions at OFC., Results: A total of 81 children had positive OFC (mild in 11% [9 of 81], moderate in 61% [49 of 81], and severe in 28% [23 of 81]). Increase in neutrophils and reduction in eosinophils, basophils, and lymphocytes were observed (P < .05). OFC was inconclusive in 19 cases despite objective signs or neutrophilia. Regression analysis showed that a 2-day OFC protocol where only 25% of an age-appropriate portion is given on day 1 (not sex, age, culprit food, cumulative dose, and previous reaction severity) was associated with reduced odds of severe reaction compared with giving multiple doses in a single day., Conclusions: Distinct hematological changes may help support FPIES diagnosis. Current OFC assessment criteria may not capture the broad spectrum of acute FPIES presentations. This 2-day protocol may be associated with a reduced risk of severe reactions. Future work should aim to develop safer OFC and non-OFC diagnostics for FPIES., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Food protein-induced enterocolitis syndrome (FPIES) is being increasingly recognized as a non-IgE-mediated food allergy; however, it remains unclear if and how the presentation, diagnosis, and management of this disease has changed in recent years., Objective: To reappraise the FPIES cohort at a large US pediatric tertiary referral center., Methods: We performed a retrospective chart review of pediatric patients with FPIES (International Classification of Diseases, Tenth Revision code K52.21) diagnosed in our allergy/immunology clinics between 2018 and 2022., Results: There were 210 children diagnosed with FPIES. Most were White (73.8%), non-Hispanic (71.4%), and male (54.3%) with private insurance (77.6%). Cow's milk was the most common food trigger (35.2%), with the earliest median age of onset of 5 months. The atypical FPIES rate was 13.8%. FPIES was accurately diagnosed in 54.3% at the first medical contact. The oral food challenge pass rate was 73.5%. The rate of trigger resolution at 36 months was 77%., Conclusions: By comparing trends from a previous and current FPIES cohort, we were able to assess the potential impact of various guidelines and practice changes on the diagnosis and management of FPIES at our center. Milk and oat surpassed rice as the most common FPIES triggers; peanut and egg emerged as new FPIES triggers; there was a shorter time to diagnosis and an increased rate of atypical FPIES. Our findings reflect earlier recognition of FPIES and prompt allergy/immunology referral from community physicians, implementation of recent medical society guidelines for infant feeding practices, and growing clinical expertise of allergists at our center., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Some patients with food protein-induced enterocolitis (FPIES)-like allergy do not completely fulfill the diagnostic criteria of the international consensus guideline for FPIES. However, it is unclear whether such FPIES-like patients represent a completely different population from FPIES., Objective: This study aimed to clarify differences in characteristics between patients with FPIES who fully met diagnostic criteria and those who partly met them., Methods: This was a cross-sectional study using data at the time of registration in multicenter, prospective studies of patients with FPIES in Japan. Children who had delayed emesis within 1 to 4 hours and/or diarrhea within 5 to 10 hours after ingestion of food were recruited between March 2020 and February 2022. We examined their compatibility with the diagnostic criteria of the international consensus guideline and their detailed clinical characteristics, including trigger foods, the serving size that elicited symptoms, and antigen-specific IgE antibody titers., Results: Of the 225 patients with FPIES, 140 fully met the diagnostic criteria whereas 79 patients did not fully meet them but demonstrated reproducible symptoms. The frequencies of pallor, lethargy, and diarrhea were significantly higher in those who met the criteria fully, whereas the age at onset, trigger foods, comorbidity, and perinatal information were comparable. Analysis of patients with FPIES to hen's egg revealed significantly higher levels of egg white- and egg yolk-specific IgE in patients who partly met criteria, whereas the serving size eliciting symptoms was comparable., Conclusions: Patients who partly met the diagnostic criteria may have a milder phenotype of FPIES, but this needs to be validated in further studies using biomarkers reflecting the pathophysiology., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Cow's milk allergy (CMA) is one of the most common presentations of food allergy seen in early childhood. It is also one of the most complex food allergies, being implicated in IgE‐mediated food allergy as well as diverse manifestations of non‐IgE‐mediated food allergy. For example, gastrointestinal CMA may present as food protein induced enteropathy, enterocolitis or proctocolitis. Concerns regarding the early and timely diagnosis of CMA have been highlighted over the years. In response to these, guideline papers from the United Kingdom (UK), Australia, Europe, the Americas and the World Allergy Organisation have been published. The UK guideline, 'Diagnosis and management of non‐IgE‐mediated cow's milk allergy in infancy—a UK primary care practical guide' was published in this journal in 2013. This Milk Allergy in Primary Care (MAP) guideline outlines in simple algorithmic form, both the varying presentations of cow's milk allergy and also focuses on the practical management of the most common presentation, namely mild‐to‐moderate non‐IgE‐mediated allergy. Based on the international uptake of the MAP guideline, it became clear that there was a need for practical guidance beyond the UK. Consequently, this paper presents an international interpretation of the MAP guideline to help practitioners in primary care settings around the world. It incorporates further published UK guidance, feedback from UK healthcare professionals and affected families and, importantly, also international guidance and expertise. [ABSTRACT FROM AUTHOR]

Food allergies are classified into three types, “IgE-mediated,” “combined IgE- and cell-mediated” and “cell-mediated/non-IgE-mediated,” depending on the involvement of IgE in their pathogenesis. Patients who develop predominantly cutaneous and/or respiratory symptoms belong to the IgE-mediated food allergy type. On the other hand, patients with gastrointestinal food allergy (GI allergy) usually develop gastrointestinal symptoms several hours after ingestion of offending foods; they belong to the cell-mediated/non-IgE-mediated or combined IgE- and cell-mediated food allergy types. GI allergies are also classified into a number of different clinical entities: food protein-induced enterocolitis syndrome (FPIES), food protein-induced proctocolitis (FPIP), food protein-induced enteropathy (Enteropathy) and eosinophilic gastrointestinal disorders (EGID). In the case of IgE-mediated food allergy, the diagnostic approaches and pathogenic mechanisms are well characterized. In contrast, the diagnostic approaches and pathogenic mechanisms of GI allergy remain mostly unclear. In this review, we summarized each type of GI allergy in regard to its historical background and updated clinical features, offending foods, etiology, diagnosis, examinations, treatment and pathogenesis. There are still many problems, especially in regard to the diagnostic approaches for GI allergy, that are closely associated with the definition of each disease. In addition, there are a number of unresolved issues regarding the pathogenic mechanisms of GI allergy that need further study and elucidation. Therefore, we discussed some of the diagnostic and research issues for GI allergy that need further investigation.

This review highlights some of the research advances in anaphylaxis; hypersensitivity reactions to foods, drugs, and insects; and allergic skin diseases that were reported in the Journal in 2013. Studies on food allergy suggest that (1) 7.6% of the US population is affected, (2) a “healthy” early diet might prevent food allergy, (3) the skin might be an important route of sensitization, (4) allergen component testing might aid diagnosis, (5) the prognosis of milk allergy might be predictable through early testing, (6) oral or sublingual immunotherapy show promise but also have caveats, and (7) preclinical studies show promising alternative modes of immunotherapy and desensitization. Studies on eosinophilic esophagitis show a relationship to connective tissue disorders and that dietary management is an effective treatment for adults. Markers of anaphylaxis severity have been determined and might inform potential diagnostics and therapeutic targets. Insights on serum tests for drug and insect sting allergy might result in improved diagnostics. Genetic and immune-mediated defects in skin epithelial differentiation contribute to the severity of atopic dermatitis. Novel management approaches to treatment of chronic urticaria, including use of omalizumab, are being identified. [Copyright &y& Elsevier]

Two case reports of patients with neonatal enterocolitis present the topic of Food Protein-Induced Enterocolitis Syndrome (FPIES). FPIES is a type of food allergy which is not mediated by IgE and which has a severe presentation. Its incidence and prevalence are unknown. Clinical suspicion, diagnosis, and timely management are important in light of likely development of severe complications which can even lead to death. [ABSTRACT FROM AUTHOR]

Non-IgE-mediated gastrointestinal food allergies, including food-protein-induced enterocolitis, enteropathy, proctocolitis and allergic eosinophilic gastroenteritis, seem to be increasing in several regions in the world. However, unlike the case of IgE-mediated food allergy, development of diagnostic laboratory tests and our understanding of the immunological mechanisms involved in non-IgE-mediated gastrointestinal food allergies lag. Although the clinical entities in Western countries have been well established, the clinical phenotypes might differ somewhat among the human races and geographical regions. In Japan, non-IgE-mediated gastrointestinal food allergies have increased sharply since the late 1990s, and clinicians have sometimes experienced confusion because of differences in the clinical phenotypes from those seen in Western countries. Aiming to solve this problem, we performed clinical research and determined a useful method for dividing patients into four clusters with distinctive clinical symptoms. We are confident this method will help in diagnosing and treating these patients. We also tried to clarify the differences between these patients in Japan and Western countries. [ABSTRACT FROM AUTHOR]

In the Mediterranean region, fish is a common cause of food protein-induced enterocolitis syndrome (FPIES) in children. No laboratory tests specific to FPIES are available, and oral food challenge (OFC) is the gold standard for its diagnosis and testing for achievement of tolerance. Children with FPIES to fish are usually advised to avoid all fish, regardless of the species. Fish are typically classified into bony and cartilaginous, which are phylogenetically distant species and therefore contain less cross-reacting allergens. The protein β-parvalbumin, considered a pan-allergenic, is found in bony fish, while the non-allergenic α-parvalbumin is commonly found in cartilaginous fish. Based on this difference, as a first step in the therapeutic process of children with FPIES caused by a certain fish in the bony fish category (i.e., hake, cod, perch, sardine, gilthead sea bream, red mullet, sole, megrim, sea bass, anchovy, tuna, swordfish, trout, etc.), an OFC to an alternative from the category of cartilaginous fish is suggested (i.e., blue shark, tope shark, dogfish, monkfish, skate, and ray) and vice versa. Regarding the increased mercury content in some sharks and other large species, the maximum limit imposed by the European Food Safety Authority (EFSA) for weekly mercury intake must be considered. An algorithm for the management of fish-FPIES, including alternative fish species, is proposed. [ABSTRACT FROM AUTHOR]

Résumé Les auteurs rapportent l’observation d’un enfant présentant un syndrome d’entérocolite induite par les protéines alimentaires de viandes de volaille, bœuf, porc, lapin, agneau suivi jusqu’à l’âge de 12 ans. La maladie avait débuté à l’âge de 7 mois chez un nourrisson qui tolérait par ailleurs le lait et l’œuf de poule. Le diagnostic a été confirmé par un test de provocation oral. La tolérance à la viande de bœuf et de porc a été acquise à 4 ans et au lapin à 6 ans. À 12 ans, l’enfant ne tolère toujours pas les volailles et l’agneau. We present three new cases of enterocolitis induced by fish proteins in children. Their presenting symptoms were abdominal pain (2/3), vomiting (2/3), and pallor (3/3). The diagnosis was confirmed by negative skin prick-tests, specific IgE assay and by a positive oral provocation test with increased polynuclear cells in two of the three cases. One of the three cases had a history of atopy and all three had a family history of atopy. We discuss the management of this syndrome (rehydration, corticotherapy) and the interest of individualized contact at school. [ABSTRACT FROM AUTHOR]

In the Mediterranean region, fish is a common cause of food protein-induced enterocolitis syndrome (FPIES) in children. No laboratory tests specific to FPIES are available, and oral food challenge (OFC) is the gold standard for its diagnosis and testing for achievement of tolerance. Children with FPIES to fish are usually advised to avoid all fish, regardless of the species. Fish are typically classified into bony and cartilaginous, which are phylogenetically distant species and therefore contain less cross-reacting allergens. The protein β-parvalbumin, considered a pan-allergenic, is found in bony fish, while the non-allergenic α-parvalbumin is commonly found in cartilaginous fish. Based on this difference, as a first step in the therapeutic process of children with FPIES caused by a certain fish in the bony fish category (i.e., hake, cod, perch, sardine, gilthead sea bream, red mullet, sole, megrim, sea bass, anchovy, tuna, swordfish, trout, etc.), an OFC to an alternative from the category of cartilaginous fish is suggested (i.e., blue shark, tope shark, dogfish, monkfish, skate, and ray) and vice versa. Regarding the increased mercury content in some sharks and other large species, the maximum limit imposed by the European Food Safety Authority (EFSA) for weekly mercury intake must be considered. An algorithm for the management of fish-FPIES, including alternative fish species, is proposed.

Background: We reported that post-emetic serum thymus and activation-regulated chemokine (TARC) levels may be a potential biomarker to diagnose solid food protein-induced enterocolitis syndrome (FPIES). However, there are no reports on the relationship between FPIES severity and serum TARC levels., Methods: The subjects were 13 cases of FPIES (hen's egg=10, Wheat=1, rice=1, short-neck clam=1) for a total of 22 events (7 emergency outpatient visits, 9 positive and 6 negative results of oral food challenge test). Serum TARC levels at 6 and 24 h after antigen ingestion were compared between the symptomatic and asymptomatic events and the mild-moderate and severe events. We also evaluated the correlation between vomiting duration and serum TARC levels., Results: The median serum TARC (pg/ml) in the asymptomatic, mild-moderate, and severe events were 546, 1093, and 3127 at 6 h after ingestion, and 910, 2053, and 6496 at 24 h after ingestion, respectively. The serum TARC level was significantly higher in the symptomatic events than the asymptomatic events, and it was significantly higher in the severe events than the mild-moderate events (p < 0.01). There was a moderate correlation between serum TARC levels and vomiting duration., Conclusion: Post-emetic serum TARC correlates with the severity of FPIES. It is expected that this information will lead to an objective evaluation of the severity of FPIES.

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy that usually presents in infancy. Cow's milk, soy, and grains are the most common food triggers. FPIES can present as a medical emergency with symptoms including delayed persistent emesis or diarrhea that can lead to severe dehydration and hemodynamic instability with abnormal laboratory markers. Diagnosis can often be made based on clinical history and noted improvement in symptoms once the suspected triggers have been removed from the diet, with oral food challenge as the gold standard for confirmation of diagnosis in unclear cases., (Copyright © 2017 Elsevier Inc. All rights reserved.)