Food protein-induced enteropathy: a revision for the clinician.

Food protein-induced enteropathy (FPE) belongs to non-IgE gastrointestinal mediated food allergies. FPE is a syndrome characterized by diarrhea, weight loss and failure to thrive in young infants. Cow milk is the culprit food that most frequently causes FPE. The prevalence of FPE has not been fully estimated, but it is relatively rare. The diagnosis is based on the clinical manifestations and histological findings through colonoscopy. Laboratory tests are somewhat helpful in the diagnosis, although there are no disease-specific findings. Allergy testing for food specific IgE is not routinely recommended. The cornerstone of the management of FPE is the removal of culprit food from the diet. FPE is usually a transient condition that resolves in most cases by 1-2 years of life. This review addresses the latest findings on FPE, including a practical guide to assist pediatricians treating children with FPE.

Whole Exome Sequencing Identifies Epithelial and Immune Dysfunction-Related Biomarkers in Food Protein-Induced Enterocolitis Syndrome.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a food allergy primarily affecting infants, often leading to vomiting and shock. Due to its poorly understood pathophysiology and lack of specific biomarkers, diagnosis is frequently delayed. Understanding FPIES genetics can shed light on disease susceptibility and pathophysiology-key to developing diagnostic, prognostic, preventive and therapeutic strategies. Using a well-characterised cohort of patients we explored the potential genome-wide susceptibility factors underlying FPIES. METHODS: Blood samples from 41 patients with oral food challenge-proven FPIES were collected for a comprehensive whole exome sequencing association study. RESULTS: Notable genetic variants, including rs872786 (RBM8A), rs2241880 (ATG16L1) and rs2289477 (ATG16L1), were identified as significant findings in FPIES. A weighted SKAT model identified six other associated genes including DGKZ and SIRPA. DGKZ induces TGF-ß signalling, crucial for epithelial barrier integrity and IgA production; RBM8A is associated with thrombocytopenia absent radius syndrome, frequently associated with cow's milk allergy; SIRPA is associated with increased neutrophils/monocytes in inflamed tissues as often observed in FPIES; ATG16L1 is associated with inflammatory bowel disease. Coexpression correlation analysis revealed a functional correlation between RBM8A and filaggrin gene (FLG) in stomach and intestine tissue, with filaggrin being a known key pathogenic and risk factor for IgE-mediated food allergy. A transcriptome-wide association study suggested genetic variability in patients impacted gene expression of RBM8A (stomach and pancreas) and ATG16L1 (transverse colon). CONCLUSIONS: This study represents the first case-control exome association study of FPIES patients and marks a crucial step towards unravelling genetic susceptibility factors underpinning the syndrome. Our findings highlight potential factors and pathways contributing to FPIES, including epithelial barrier dysfunction and immune dysregulation. While these results are novel, they are preliminary and need further validation in a second cohort of patients.

Pediatric idiopathic anaphylaxis: practical management from infants to adolescents.

Idiopathic anaphylaxis (IA) remains a frustrating challenge for both patients and physicians. The aim of this paper is to focus on IA in pediatric ages and suggest possible diagnostic algorithms according to specific age ranges (infants, children, and adolescents). In fact, in a variable percentage of patients, despite extensive diagnostic tests, the cause of anaphylactic episodes cannot be identified. Moreover, the lack of a unanimous IA definition requires a careful and detailed diagnostic workup. Prompt recognition of signs and symptoms, especially in younger children, and an accurate clinical history often allow a choice of the most appropriate diagnostic tests and a correct differential diagnosis.

Elimination Diets in Lactating Mothers of Infants with Food Allergy.

Breastfeeding is the most important nutrition source for infants. However, managing breastfed infants with signs and symptoms related to food allergy can be difficult. Many studies have shown the presence of different food allergens in breast milk, but the clinical role of these antigens in human milk is still much debated. Milk is the main suspect in exclusively breastfed infants with signs and symptoms attributable to food allergy, even if other foods may be responsible. This narrative review analyzes the recommendations provided by international guidelines to determine the diagnosis and management of IgE-mediated and non-IgE-mediated food allergies in exclusively breastfed infants. Dietary restrictions in lactating mothers of infants with suspected FA are usually not necessary. Only in the very few cases where significant allergy signs and symptoms occur in the infant during exclusive breastfeeding should the lactating mother follow an elimination diet for the suspected food for a short period.

Nutritional and Psychosocial Impact of Food Allergy in Pediatric Age.

Treatment of IgE-mediated food allergy involves avoiding the food causing the allergic reaction. In association, an action plan for allergic reactions is indicated, sometimes including self-injectable adrenaline. In addition to these dietary and medical implications, there are two equally important ones: nutritional and psychosocial. From a nutritional point of view, it is known that children suffering from food allergy have a growth delay in height and weight compared to their non-allergic peers. Specifically, this condition is directly related to the specific food excluded from the diet, the number of foods excluded and the duration of the elimination diet. From a psychosocial point of view, the child often cannot eat the foods other guests eat. Children with food allergy may perceive an aura of parental anxiety around their mealtime and may be afraid that what they eat could have harmful consequences for their health. Furthermore, children's and their parents' quality of life appears to be affected. The need to manage the allergy and the nutritional and psychosocial problems positions the pediatric nutritionist and the child neuropsychiatrist as support figures for the pediatric allergist in managing the child with food allergy.

Shift from Cow's Milk Food Protein-Induced Enterocolitis Syndrome to IgE-Mediated Allergy: Case Series and Literature Review.

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy characterized by gastrointestinal symptom onset within 1-4 hours from trigger food ingestion. In the literature, some authors have previously described the possibility that a patient with FPIES may develop an IgE-mediated allergy to the same trigger food, especially cow's milk (CM). Case Presentation: We reported five cases of CM-FPIES converting to IgE-mediated CM allergy presented at our tertiary pediatric Allergy Unit and performed a review of the literature, aiming to characterize the clinical features of patients who are at risk of developing such conversion. Conclusions: This phenomenon raises the question of whether IgE-mediated and non-IgE-mediated allergies represent a spectrum of the same disease and highlights the need for further investigation to understand the pathophysiological mechanisms of this process.

Exercise-induced bronchoconstriction, allergy and sports in children.

Exercise-induced bronchoconstriction (EIB) is characterized by the narrowing of airways during or after physical activity, leading to symptoms such as wheezing, coughing, and shortness of breath. Distinguishing between EIB and exercise-induced asthma (EIA) is essential, given their divergent therapeutic and prognostic considerations. EIB has been increasingly recognized as a significant concern in pediatric athletes. Moreover, studies indicate a noteworthy prevalence of EIB in children with atopic predispositions, unveiling a potential link between allergic sensitivities and exercise-induced respiratory symptoms, underpinned by an inflammatory reaction caused by mechanical, environmental, and genetic factors. Holistic management of EIB in children necessitates a correct diagnosis and a combination of pharmacological and non-pharmacological interventions. This review delves into the latest evidence concerning EIB in the pediatric population, exploring its associations with atopy and sports, and emphasizing the appropriate diagnostic and therapeutic approaches by highlighting various clinical scenarios.

The importance of clinical history in the diagnosis of drug hypersensitivity in children.

BACKGROUND: In case of suspected hypersensitivity reactions (HRs) to drugs, a challenging area for pediatricians is detecting relevant elements in the parent-reported history, in order to reach a definite diagnosis. We analyzed the concordance between the description of the HR and the medical reports documented at the time of the event. Furthermore, we studied any correlation between clinical history variables and the prediction of true allergy. METHODS: We retrospectively collected 50 charts of children referred to our Allergy Unit, after a previous access to the Emergency Department. We compared the description of the HR at acute phase to the history told by parents. Type and timing of the HR and culprit drug were classified as "known" or "unknown." The diagnosis was confirmed or excluded at the end of the investigations. Logistic regression analysis was performed to find any significant association. RESULTS: The type of the HR was known in 74%, the timing in 28%, and the culprit drug in 98%. We showed that having had a severe HR had an increased odds of remembering the timing; being older >6 years and having had an immediate HR had an increased odds of remembering the type; time to diagnostic was lower in patients whose parents remembered the type of HR. CONCLUSION: Our paper underlines the importance of an accurate anamnesis at the time of the event. Providing the physicians with a standardized Case Report Form could be a useful tool to simplify the diagnostic work-up and minimize mistakes due to lack of memory.

Imported allergens in Italy: an emerging issue.

Imported allergens are involved in many allergic reactions, with unexpected and unusual implications. They can be involved in developing asthma, allergic rhinoconjunctivitis, Hymenoptera venom allergies and food allergies. Imported allergens can be implied in respiratory allergies attributable to commercial practices and accidental diffusion through air currents that have introduced non-native species in new geographical contexts. Ambrosia artemisiifolia L., a plant native to North America and currently in the western part of Lombardy, represents an example. Moreover, a variation in the pollen concentration in the Northwest Tuscany area and Trentino Alto-Adige was observed. Cannabis sativa is another imported allergen used frequently by adolescents. Regarding potential imported food allergens, there is no validated list. Imported food allergens derive from ethnic foods, referring to Mexican/Latin American, Chinese/Japanese, Southeast Asian, Arab/Middle Eastern and African cuisine. Four insect flours were recently introduced to the European and Italian markets (Acheta domesticus, Alphitobius diaperinus, Tenebrio molitor and Locusta migratoria). The association between the accidental introduction through commercial traffic, climate change, and the absence of natural enemies in the destination ecosystem is related to the introduction of a specific Hymenoptera, Vespa velutina, in Italy and Europe. External events attributable to human activities, such as climate change and the introduction of non-native plants, foods and Hymenoptera through trade, have contributed to the issue of imported allergens. Making the correct diagnosis and guiding the diagnostic and therapeutic path in this particular context represent the concerns of the pediatric allergist.

Fatal food anaphylaxis in adults and children.

Anaphylaxis is a life-threatening reaction characterized by the acute onset of symptoms involving different organ systems and requiring immediate medical intervention. The incidence of fatal food anaphylaxis is 0.03 to 0.3 million/people/year. Most fatal food-induced anaphylaxis occurs in the second and third decades of life. The identified risk factors include the delayed use of epinephrine, the presence of asthma, the use of recreational drugs (alcohol, nicotine, cannabis, etc.), and an upright position. In the United Kingdom (UK) and Canada, the reported leading causal foods are peanuts and tree nuts. In Italy, milk seems to be the most common cause of fatal anaphylaxis in children < 18 years. Fatal food anaphylaxis in Italian children and adolescents almost always occurs outside and is characterized by cardiorespiratory arrest; auto-injectable adrenaline intramuscular was available in few cases. Mortality from food anaphylaxis, especially in children, is a very rare event with stable incidence, but its risk deeply impacts the quality of life of patients with food allergy and their families. Prevention of fatal food anaphylaxis must involve patients and their families, as well as the general public, public authorities, and patients' associations.

How to manage drug-virus interplay underlying skin eruptions in children.

The majority of viral rashes occurring during an antibiotic therapy are considered as a drug hypersensitivity reaction (DHR). Differentiating a viral rash versus a DHR is difficult or even impossible. In delayed DHRs the interplay between viruses and drugs is summarized according to the recent literature. The question is if the same reaction will again occur in case of drug re-exposure in absence of the concomitant viral infection because of persistent immune reactivity. Epstein Barr Virus (EBV) and Human Herpes virus 6 (HHV-6) models are analyzed in case of maculopapular exanthemas (MPEs) and drug reaction with eosinophilia and systemic symptoms (DRESS) over a course of drug therapy. MPEs are the most common skin manifestation during a viral infection and a concomitant drug therapy. In type IVb reactions to drugs a hapten/pro-hapten mechanism and a pharmacological interaction (p-i mechanism) are described as the 2 major ways to make T cells response functional. Rarely the altered repertoire model is involved. The Human Leukocyte Antigen (HLA) predisposition is an additional essential factor that can facilitate DHR. In MPEs rarely a DHR is confirmed by allergy testing. Severity and duration of MPEs, the presence of eosinophilia and systemic symptoms make more reliable the persistent nature of the reaction. Research on this topic is needed in order to provide the clinicians with instruments to decide when to suspect future reactions upon drug re-exposure even in the absence of a viral infection, because those patients should be investigated by a complete drug allergy work up.

EAACI guidelines on the diagnosis of IgE-mediated food allergy.

This European Academy of Allergy and Clinical Immunology guideline provides recommendations for diagnosing IgE-mediated food allergy and was developed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Food allergy diagnosis starts with an allergy-focused clinical history followed by tests to determine IgE sensitization, such as serum allergen-specific IgE (sIgE) and skin prick test (SPT), and the basophil activation test (BAT), if available. Evidence for IgE sensitization should be sought for any suspected foods. The diagnosis of allergy to some foods, such as peanut and cashew nut, is well supported by SPT and serum sIgE, whereas there are less data and the performance of these tests is poorer for other foods, such as wheat and soya. The measurement of sIgE to allergen components such as Ara h 2 from peanut, Cor a 14 from hazelnut and Ana o 3 from cashew can be useful to further support the diagnosis, especially in pollen-sensitized individuals. BAT to peanut and sesame can be used additionally. The reference standard for food allergy diagnosis is the oral food challenge (OFC). OFC should be performed in equivocal cases. For practical reasons, open challenges are suitable in most cases. Reassessment of food allergic children with allergy tests and/or OFCs periodically over time will enable reintroduction of food into the diet in the case of spontaneous acquisition of oral tolerance.

Cold Anaphylaxis in Children: Italian Case Series and Review of the Literature.

Chronic urticaria (CU) is one of the most common skin disorders worldwide. Among the inducible subgroup of CU, cold urticaria (ColdU) can affect both children and adults and is the only type associated with the risk of anaphylaxis without cofactors. In the scientific literature, data about cold anaphylaxis (ColdA) are poor, especially at pediatric age, and little is known about risk factors associated with the onset of systemic reactions and about the criteria for prescribing adrenaline auto-injectors (AAIs) in these patients. We describe the clinical characteristics and management of a case series of 21 patients with a history of ColdA, and we compare them with the pediatric case reports and case series published so far. On the basis of the scientific literature and of our case series of patients, we suggest that AAI should be prescribed to all high-risk patients: those with urticaria caused by cold-water immersion, oropharyngeal reactions, and with a previous history of systemic symptoms or anaphylaxis.

Allergic Proctocolitis: Literature Review and Proposal of a Diagnostic-Therapeutic Algorithm.

Allergic proctocolitis (AP) is a benign condition, frequent in childhood, that is classified as a non-IgE-mediated food allergy. The prevalence is unknown; however, its frequency appears to be increasing, especially in exclusively breastfed infants. Clinical manifestations typically begin in the first few months of life with the appearance of bright red blood (hematochezia), with or without mucus, in the stool of apparently healthy, thriving infants. Most cases of AP are caused by cow's milk proteins; however, other allergens, such as soy, egg, corn, and wheat, may be potential triggers. Diagnosis is based on the patient's clinical history and on the resolution of signs and symptoms with the elimination of the suspected food antigen from the diet and their reappearance when the food is reintroduced into the diet. The treatment of AP is based on an elimination diet of the trigger food, with resolution of the symptoms within 72-96 h from the beginning of the diet. The prognosis of AP is good; it is a self-limiting condition, because most children can tolerate the trigger food within one year of life, with an excellent long-term prognosis. The purpose of this review is to provide an update on the current knowledge and recommendations in epidemiological, diagnostic, and therapeutic terms to the pediatricians, allergists, and gastroenterologists who may find themselves managing a patient with AP.