Lipid matrix-specific pretreatment method for enhancing the extractability and allergenicity maintenance of bovine milk allergens in ELISA detection.

The presence of various components in the food matrix makes allergen detection difficult and inaccurate, and pretreatment is an innovative breakthrough point. Food matrices were categorised based on their composition. Subsequently, a pretreatment method was established using a combination of ultrasound-assisted n-hexane degreasing and weakly alkaline extraction systems to enhance the detection accuracy of bovine milk allergens. Results showed that more allergens were obtained with less structural destruction, as demonstrated using immunological quantification and spectral analysis. Concurrently, allergenicity preservation was confirmed through liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, a KU812 cell degranulation model, and western blotting. The method exhibited good accuracy (bias, 8.47%), repeatability (RSDr, 1.52%), and stability (RSDR, 5.65%). In foods with high lipid content, such as chocolate, the allergen content was 2.29-fold higher than that of commercial kits. Laser confocal scanning microscopy (LCSM) and scanning electron microscopy (SEM) analyses revealed a significant decrease in fat content after post-pretreatment using our method. In addition, colloidal stability surpassed that achieved using commercial kits, as indicated through the PSA and zeta potential results. The results demonstrated the superiority of the extractability and allergenicity maintenance of lipid matrix-specific pretreatment methods for improving the accuracy of ELISA based allergen detection in real food.

Degree of hydrolysis is a poor predictor of the sensitizing capacity of whey- and casein-based hydrolysates in a Brown Norway rat model of cow's milk allergy.

The use of infant formulas (IFs) based on hydrolyzed cow's milk proteins to prevent cow's milk allergy (CMA) is highly debated. The risk of sensitization to milk proteins induced by IFs may be affected by the degree of hydrolysis (DH) as well as other physicochemical properties of the cow's milk-based protein hydrolysates within the IFs. The immunogenicity (specific IgG1 induction) and sensitizing capacity (specific IgE induction) of 30 whey- or casein-based hydrolysates with different physicochemical characteristics were compared using an intraperitoneal model of CMA in Brown Norway rats. In general, the whey-based hydrolysates demonstrated higher immunogenicity than casein-based hydrolysates, inducing higher levels of hydrolysate-specific and intact-specific IgG1. The immunogenicity of the hydrolysates was influenced by DH, peptide size distribution profile, peptide aggregation, nano-sized particle formation, and surface hydrophobicity. Yet, only the surface hydrophobicity was found to affect the sensitizing capacity of hydrolysates, as high hydrophobicity was associated with higher levels of specific IgE. The whey- and casein-based hydrolysates exhibited distinct immunological properties with highly diverse molecular composition and physicochemical properties which are not accounted for by measuring DH, which was a poor predictor of sensitizing capacity. Thus, future studies should consider and account for physicochemical characteristics when assessing the sensitizing capacity of cow's milk-based protein hydrolysates.

Alteration of Immunoregulatory Patterns and Survival Advantage of Key Cell Types in Food Allergic Children.

All allergic responses to food indicate the failure of immunological tolerance, but it is unclear why cow's milk and egg (CME) allergies resolve more readily than reactivity to peanuts (PN). We sought to identify differences between PN and CME allergies through constitutive immune status and responses to cognate and non-cognate food antigens. Children with confirmed allergy to CME (n = 6) and PN (n = 18) and non-allergic (NA) (n = 8) controls were studied. Constitutive secretion of cytokines was tested in plasma and unstimulated mononuclear cell (PBMNC) cultures. Blood dendritic cell (DC) subsets were analyzed alongside changes in phenotypes and soluble molecules in allergen-stimulated MNC cultures with or without cytokine neutralization. We observed that in allergic children, constitutively high plasma levels IL-1ß, IL-2, IL-4, IL-5 and IL-10 but less IL-12p70 than in non-allergic children was accompanied by the spontaneous secretion of sCD23, IL-1ß, IL-2, IL-4, IL-5, IL-10, IL-12p70, IFN-γ and TNF-α in MNC cultures. Furthermore, blood DC subset counts differed in food allergy. Antigen-presenting cell phenotypic abnormalities were accompanied by higher B and T cell percentages with more Bcl-2 within CD69+ subsets. Cells were generally refractory to antigenic stimulation in vitro, but IL-4 neutralization led to CD152 downregulation by CD4+ T cells from PN allergic children responding to PN allergens. Canonical discriminant analyses segregated non-allergic and allergic children by their cytokine secretion patterns, revealing differences and areas of overlap between PN and CME allergies. Despite an absence of recent allergen exposure, indication of in vivo activation, in vitro responses independent of challenging antigen and the presence of unusual costimulatory molecules suggest dysregulated immunity in food allergy. Most importantly, higher Bcl-2 content within key effector cells implies survival advantage with the potential to mount abnormal responses that may give rise to the manifestations of allergy. Here, we put forward the hypothesis that the lack of apoptosis of key immune cell types might be central to the development of food allergic reactions.

Alergia a la leche de vaca: ¿se pueden evitar las pruebas de provocación oral? Un análisis probabilístico basado en datos clínicos / Cow's milk allergy: Can oral food challenges be avoided? A probabilistic analysis based on clinical data

Introducción. La prueba de provocación oral (PPO) para el diagnóstico de alergia a las proteínas de la leche de la vaca (APLV) presenta riesgos y requiere de recursos. Nuestro objetivo fue evaluar condiciones y pruebas complementarias para identificar una alta probabilidad de APLV. Población y métodos. Análisis secundario sobre estudio de pacientes atendidos en una unidad de alergia entre 2015 y 2018. Se determinaron las probabilidades prepruebas asociadas a los síntomas y sus combinaciones, y las probabilidades pospruebas luego de realizadas pruebas cutáneas y determinación de inmunoglobulina E (IgE) sérica. Resultados. Se evaluó la información de 239 pacientes. Se observaron probabilidades mayores al 95 % en pacientes con angioedema y combinación de urticaria y vómitos. Usando puntos de corte propuestos por Calvani et al., la combinación de vómitos con rinitis, sin angioedema, también superó el 95 %. Conclusión. Se ofrece una metodología para identificar pacientes en los que puede diagnosticarse APLV sin realización de PPO.

Introduction. The oral food challenge (OFC) for the diagnosis of cow's milk protein allergy (CMPA) poses risks and requires resources. Our objective was to assess conditions and complementary tests used to identify a high probability of CMPA. Population and methods. Secondary analysis of a study of patients seen at a unit of allergy between 2015 and 2018. Pre-testing probabilities associated with symptoms and their combinations and post-testing probabilities after skin prick testing and serum immunoglobulin E (IgE) levels were determined. Results. The data from 239 patients were assessed. A probability greater than 95% was observed for angioedema and a combination of urticaria and vomiting. Based on the cut-off points proposed by Calvani et al., the combination of vomiting with rhinitis, without angioedema, also exceeded 95%. Conclusion. A methodology is provided to identify patients in whom CMPA may be diagnosed without an OFC.

Escenarios lácteos y microbiota intestinal en los primeros 1000 días / Milk scenarios and gut microbiota in the first 1000 days of life

La leche humana es el estándar de oro para la nutrición del bebé y debe iniciarse en la primera hora de vida. La leche de vaca, de otros mamíferos o las bebidas vegetales no se deben ofrecer antes del año de vida. Sin embargo, algunos niños requieren, al menos en parte, de fórmulas infantiles. Aun con las sucesivas mejoras a lo largo de la historia mediante la incorporación de oliogosacáridos, probióticos, prebióticos, sinbióticos y postbióticos, las fórmulas infantiles siguen siendo perfectibles para reducir la brecha de salud entre los bebés amamantados y aquellos alimentados con fórmula. En este sentido, se espera que la complejidad de las fórmulas siga aumentando a medida que se conozca mejor cómo modular el desarrollo de la microbiota intestinal. El objetivo de este trabajo fue realizar una revisión no sistemática del efecto de los diferentes escenarios lácteos sobre la microbiota intestinal.

Human milk is the gold standard for infant nutrition, and breastfeeding should be started within the first hour of life. Cow's milk, other mammalian milk, or plant-based beverages should not be offered before 1 year of age. However, some infants require, at least in part, infant formulas. Even with subsequent enhancements throughout history, with the addition of oligosaccharides, probiotics, prebiotics, synbiotics, and postbiotics, infant formulas still have room for improvement in reducing the health gap between breastfed and formula-fed infants. In this regard, the complexity of infant formulas is expected to continue to increase as the knowledge of how to modulate the development of the gut microbiota is better understood. The objective of this study was to perform a non-systematic review of the effect of different milk scenarios on the gut microbiota.

[Prevalencia alergia a proteína leche de vaca con escala COMISS, IMPE Chihuahua, marzo a mayo 2022, serie de casos].

Objective: To know the prevalence of CMPA with the scale in patients of the pediatrics external consultation in the Municipal Institute of Pension of Chihuahua in period from march to may 2022, Series of cases. Methods: A search was carried out on CMPA consultations in the period from March to May 2022, permission and informed consent was requested to access the clinical file and retrospectively, an analytical, observational, non- experimental, descriptive study was carried out., the COMISS scale was applied, and formulated a series of cases. Results: The prevalence of CMPA is 0.3%. CMPA positive patients did not have statistically significant differences with the suspects in terms of age, gestational age, birth weight, maternal age, atopy or tobacco. Presenting a series of cases. Conclusions: The prevalence of CMA with the use of COMISS was 0.3%, lower than the prevalence worldwide. The wider use of this scale is suggested to be considered in order to achieve a more accurate diagnosis.

Objetivo: Conocer la prevalencia de la APLV con la escala CoMISS en pacientes de la consulta externa de pediatria en el instituto municipal de pensiones de chi- huahua. en el periodo de marzo a mayo 2022, serie de casos. Métodos: Se realizó una búsqueda sobre las consultas de APLV en el periodo de marzo a mayo 2022, se solicitó el permiso y consentimiento informado para acceder al expediente clínico y de manera retrospectiva, se realizó estudio analítico, observacional, no experimental, descriptivo, se aplicó la escala COMISS, y formulando serie de casos. Resultados: La prevalencia de APLV es de 0.3%, Los pacientes positivos APLV no tuvieron diferencias estadisticamente significativas con los sospechosos en cuanto a edad, edad gestacional, peso al nacer, edad de la madre, atopia o tabaco. Presentando una serie de casos. Conclusiones: la prevalencia de APLV con el uso de COMISS fue del 0.3%, menor a la prevalencia a nivel mundial. Se sugiere el uso más amplio de esta escala para considerar esta patología y lograr un diagnóstico más certero.

Proteomics and Peptidomics As a Tool to Compare the Proteins and Endogenous Peptides in Human, Cow, and Donkey Milk.

Cow's milk is the most widely used ingredient in infant formulas. However, its specific protein composition can cause allergic reactions. Finding alternatives to replace cow's milk and fill the nutritional gap with human milk is essential for the health of infants. Proteomic and peptidomic techniques have supported the elucidation of milk's nutritional ingredients. Recently, omics approaches have attracted increasing interest in the investigation of milk because of their high throughput, precision, sensitivity, and reproducibility. This review offers a significant overview of recent developments in proteomics and peptidomics used to study the differences in human, cow, and donkey milk. All three types of milks were identified to have critical biological functions in human health, particularly in infants. Donkey milk proteins were closer in composition to human milk, were less likely to cause allergic reactions, and may be developed as novel raw materials for formula milk powders.

Very early onset perinatal constipation: Can it be cow's milk protein allergy?

Delayed passage of meconium or constipation during the perinatal period is traditionally regarded as a signal to initiate further work up to evaluate for serious diagnoses such as Hirschsprung's disease (HD), meconium ileus due to Cystic Fibrosis, etc. The diagnosis of HD particularly warrants invasive testing to confirm the diagnosis, such as anorectal manometry or rectal suction biopsy. What if there was another etiology of perinatal constipation, that is far lesser known? Cow's milk protein allergy (CMPA) is often diagnosed in infants within the first few weeks of life, however, there are studies that show that the CMPA allergen can be passed from mother to an infant in-utero, therefore allowing symptoms to show as early as day one of life. The presentation is more atypical, with perinatal constipation rather than with bloody stools, diarrhea, and vomiting. The diagnosis and management would be avoidance of cow's milk protein within the diet, with results and symptom improvement in patients immediately. Therefore, we discuss whether an alternative pathway to address perinatal constipation should be further discussed and implemented to potentially avoid invasive techniques in patients. This entails first ruling out CMPA with safe, noninvasive techniques with diet modification, and if unsuccessful, then moving forward with further diagnostic modalities.

Higher Intake of Nutrients with Antioxidant and Anti-Inflammatory Effects among Children with Cow's Milk Allergy According to the Degree of Elimination.

Children with cow's milk allergy (CMA) have lower bone mineral density and shorter height than children without CMA or non-food allergy (FA), and their final height is also affected. Appropriate nutritional guidance for CMA children is therefore needed. The purpose of this study was to conduct a dietary survey of CMA children and to compare their characteristics according to the degree of elimination. A dietary survey of FA children attending the allergy clinic at Shiga Medical Center for Children, Shiga, Japan, was conducted using the brief-type self-administered diet history questionnaire for Japanese children and adolescents (BDHQ15y). To objectively assess the intake of fruit and vegetables, skin carotenoid levels were measured using the Veggie Meter®. Regarding the degree of CM elimination, of the 147 FA children (89 boys, 58 girls) recruited, 38, 27, and 82 children were allocated to complete-, partial-, and non-elimination groups, respectively. In analyzing the data, boys and girls were combined because there was no difference in sex ratio among the groups. Significantly lower intakes of calcium, animal proteins, and vitamin B2 were observed with increasing degree of CM elimination. Conversely, significantly greater intakes of vegetable proteins, ß carotene, α tocopherol, vitamin C, and polyunsaturated fatty acids, as well as significantly higher levels of skin carotenoids, were observed with increasing degree of CM elimination. Intakes of many nutrients with antioxidant and anti-inflammatory effects were higher with increasing degree of CM elimination, presumably reflecting the efforts of caregivers in identifying alternative foods. However, calcium intake was still inadequate, indicating a need for further encouragement of calcium intake in CMA children.

Food-sensitized pediatric patients show colonic cow's milk protein-specific Th2 cells.

Food allergies have become a health concern worldwide. Around 6% to 10% of children are allergic to cow's milk proteins. We have previously characterized colorectal polyps in patients sensitized to food allergens. These polyps are classified as inflammatory and present a type 2 environment, with elevated interleukin (IL)-13 and IL-4, and are a site of immunoglobulin E synthesis. In this study, we characterized and isolated cow's milk protein-specific T cell lines and T cell clones from the lamina propria of polyps from patients sensitized to these proteins. Isolated T cells responded to cow's milk proteins similarly to peripheral blood T cells, showing antigen-specific cell proliferation and Th2 cytokines release in vitro. T cell clones obtained were all CD4+ T cells and expressed the membrane TCRαß receptor and secreted higher IL-4, IL-5, and IL-13 amounts than unstimulated cells, whereas interferon γ secretion remained unchanged. Remarkably, the gut homing chemokine receptor CCR9 was augmented in cow's milk-specific peripheral and lamina propria T cells, and CCL25 was found to be expressed in the inflammatory polyp tissue and not in the adjacent mucosa. In conclusion, we isolated and characterized cow's milk-specific lamina propria CD4+ Th2 cells from colonic inflammatory polyps. CCR9 expression on these cells, along with increase secretion of CCL25 in the polyp, favors recruitment and cow's milk-specific allergic response within the inflammatory polyp tissue. Our findings may be critical to understand the underlying mechanism that promotes immunoglobulin E synthesis in the colon of cow's milk proteins allergic patients, contributing to the development of novel T cell-targeted immunotherapies.

Evaluation of IgG/IgE-binding capacity and functional properties of enzymatic hydrolysis in skimmed cow milk system.

Cow's milk (CM) allergy is a common food allergy that seriously impacts the growth and development of infants and children. However, CM is an important source of nutrients, and few studies focus on the effects of enzymatic hydrolysis treatment on the whole skimmed CM system. In this study, the IgG/IgE-binding and functional properties of Alcalase-, Protamex-, and Flavourzyme-treated skimmed CM (AT, PT, and FT, respectively) were systematically evaluated. The results showed that the treatment groups were mainly composed of low molecular weight (MW) peptides (<3 kDa), accounting for 94.85%-97.90%. Additionally, the IgG reactivity of these peptides was significantly lower (p < 0.05) than those of higher MW peptides (10-30 kDa and >30 kDa). The IgE reactivity of FT with higher MW peptides was the lowest among these groups, with the OD value reaching 0.089. Moreover, the total amino acid content of hydrolysates of skimmed CM (HM) increased significantly (skimmed CM, 5.94 µg/mL; AT, 123.70 µg/mL; PT: 136.20 µg/mL; FT, 988.72 µg/mL) compared to that in skimmed CM. A total of 10, 10, and 7 flavor compounds were increased in AT, PT, and FT, respectively. Furthermore, the solubility, foamability, and emulsifying ability of HM were significantly improved, being 2.17-fold, 1.52-fold, and 1.96-fold higher in PT than in skimmed CM. These results lay a theoretical foundation for the development of hypoallergenic dairy products.

Milk Allergen Micro-Array (MAMA) for Refined Detection of Cow's-Milk-Specific IgE Sensitization.

BACKGROUND: Immunoglobulin-E(IgE)-mediated hypersensitivity to cow's milk allergens is a frequent cause of severe and life-threatening anaphylactic reactions. Besides case histories and controlled food challenges, the detection of the IgE antibodies specific to cow's milk allergens is important for the diagnosis of cow-milk-specific IgE sensitization. Cow´s milk allergen molecules provide useful information for the refined detection of cow-milk-specific IgE sensitization. METHODS: A micro-array based on ImmunoCAP ISAC technology was developed and designated milk allergen micro-array (MAMA), containing a complete panel of purified natural and recombinant cow's milk allergens (caseins, α-lactalbumin, ß-lactoglobulin, bovine serum albumin-BSA and lactoferrin), recombinant BSA fragments, and α-casein-, α-lactalbumin- and ß-lactoglobulin-derived synthetic peptides. Sera from 80 children with confirmed symptoms related to cow's milk intake (without anaphylaxis: n = 39; anaphylaxis with a Sampson grade of 1-3: n = 21; and anaphylaxis with a Sampson grade of 4-5: n = 20) were studied. The alterations in the specific IgE levels were analyzed in a subgroup of eleven patients, i.e., five who did not and six who did acquire natural tolerance. RESULTS: The use of MAMA allowed a component-resolved diagnosis of IgE sensitization in each of the children suffering from cow's-milk-related anaphylaxis according to Sampson grades 1-5 requiring only 20-30 microliters of serum. IgE sensitization to caseins and casein-derived peptides was found in each of the children with Sampson grades of 4-5. Among the grade 1-3 patients, nine patients showed negative reactivity to caseins but showed IgE reactivity to alpha-lactalbumin (n = 7) or beta-lactoglobulin (n = 2). For certain children, an IgE sensitization to cryptic peptide epitopes without detectable allergen-specific IgE was found. Twenty-four children with cow-milk-specific anaphylaxis showed additional IgE sensitizations to BSA, but they were all sensitized to either caseins, alpha-lactalbumin, or beta-lactoglobulin. A total of 17 of the 39 children without anaphylaxis lacked specific IgE reactivity to any of the tested components. The children developing tolerance showed a reduction in allergen and/or peptide-specific IgE levels, whereas those remaining sensitive did not. CONCLUSIONS: The use of MAMA allows for the detection, using only a few microliters of serum, of IgE sensitization to multiple cow's milk allergens and allergen-derived peptides in cow-milk-allergic children with cow-milk-related anaphylaxis.

Allergenicity reduction of cow milk treated by alkaline protease combined with Lactobacillus Plantarum and Lactobacillus helveticus based on epitopes.

This paper has investigated the residual allergenicity of cow's milk treated by enzymatic hydrolysis combined with Lactobacillus fermentation (Lb. Plantarum and Lb. helveticus). The treated products were comprehensively evaluated by SDS-PAGE, RP-HPLC, ELISA, and Caco-2 models. And the allergenic changes of residual allergenic peptides were explored by DC-T co-culture. The results showed that alkaline protease was the most suitable protease that targeted to destroy epitopes of milk major allergen than trypsin, pepsin, and papain by prediction. And the residual epitopes were reduced to four which was treated by alkaline protease combined with Lb. helveticus. The transport absorption capacity of treated products was almost twice than milk. Meanwhile, the seven residual allergenic peptides were obtained from treated products. Among them, αs1-casein (AA84-90) can be used as an immune tolerance peptide for further study. Lb. helveticus combined with alkaline protease treatment may be considered promising strategy of protect from cow's milk allergy.

Case report: Pneumatosis in a neonate with thrombocytopenia absent radius syndrome.

BACKGROUND: Thrombocytopenia absent radius (TAR) syndrome is a rare disease with an estimated prevalence of one in 200,000 live births. TAR is associated with cardiac and renal anomalies as well as gastrointestinal problems such as cow's milk protein allergy (CMPA). Typically neonates with CMPA present with mild intolerance, with few reports in the literature of more severe intolerance resulting in pneumatosis. We present a case of a male infant with TAR syndrome who developed gastric and colonic pneumatosis intestinalis. CASE DESCRIPTION: An eight-day-old male infant born at 36 weeks gestation with a diagnosis of TAR, presented with bright red blood in his stool. At this time he was on full formula feeds. Given continued bright red blood within his stool, an abdominal radiograph was obtained which was consistent with colonic and gastric pneumatosis. A complete blood count (CBC) was notable for worsening thrombocytopenia, anemia and eosinophilia. Once enteral feeds were held there was rapid resolution of the radiographic findings and resolution of his bloody stool. He was ultimately diagnosed with a CMPA. CONCLUSION: Though there are reports of CMPA in patients with TAR, the severity of this patient's presentation with both colonic and gastric pneumatosis is unique. Without the knowledge of the association of CMPA with TAR, this case could have been misdiagnosed and led to reintroduction of cow's milk containing formula, resulting in further complications. This case highlights the importance of a timely diagnosis and severity of CMPA in this population.

Reações de hipersensibilidade a vacinas / Hypersensitivity reactions to vaccines

O desenvolvimento e a ampliação do uso das vacinas durante décadas contribuíram para o controle e erradicação de doenças infecciosas, causando um grande impacto na saúde pública no mundo. A análise de segurança das vacinas percorre criteriosos processos e fases dos estudos clínicos, um dos pilares essenciais para aprovação regulatória e utilização do produto na população. O evento supostamente atribuído à vacinação e imunização (ESAVI), terminologia atual, é definido como qualquer ocorrência médica indesejada após a vacinação que possui, ou não, uma relação causal com o uso de uma vacina ou outro imunobiológico. Cabe ressaltar que eventos adversos mais raros ou inesperados, incluindo os eventos de hipersensibilidade, poderão ocorrer na fase pós-comercialização, quando as vacinas são aplicadas em milhões de pessoas. Neste artigo, serão discutidos os principais aspectos relacionados aos eventos adversos de hipersensibilidade pós-vacinais de interesse do especialista, e os desafios frente ao reconhecimento do agente causal e conduta a ser adotada. Além disso, serão revisados os potenciais alérgenos presentes nas vacinas de uso rotineiro para auxiliar o profissional de saúde na identificação de pacientes com potencial de risco de ESAVI por tais componentes. A atualização do conhecimento acerca da segurança e dos benefícios das vacinas pelos profissionais de saúde, sobretudo em populações especiais, contribui para condutas em imunização mais apropriadas, reduzindo o risco de exposição a um possível alérgeno em pessoas comprovadamente alérgicas às vacinas ou a alguns dos seus componentes, além de evitar contraindicações desnecessárias em eventos coincidentes ou não graves.

The expansion of vaccine use and development in recent decades has contributed to the control and eradication of infectious diseases, causing a major impact on public health worldwide. Vaccine safety analysis, which involves careful processes and clinical study, is one of the essential pillars of regulatory approval and use in the population. In current terminology, events supposedly attributable to vaccination and immunization (ESAVI) are defined as any unwanted medical occurrence after vaccination that may or may not have a causal relationship with vaccines or other immunobiologicals. It is noteworthy that rare or unexpected adverse events, including hypersensitivity, can occur during the post-marketing phase, when vaccines are administered to millions of people. In this article, we will discuss the main aspects of post-vaccine hypersensitivity events of interest to specialists and challenges to recognizing the causal agent and appropriate clinical practice. Potential allergens in routine vaccines will also be reviewed to help health professionals identify patients with a potential risk of ESAVI due to such components. Updating health professionals' knowledge about the safety and benefits of vaccines, particularly in special populations, can contribute to more appropriate clinical practice regarding immunization, reducing the risk of exposure to possible allergens in people with allergies to vaccines or their components, avoiding unnecessary contraindications in coincidental or non-serious events.

Epigenome alterations in food allergy: A systematic review of candidate gene and epigenome-wide association studies.

OBJECTIVE: The aim of this study was to systematically review the evidence across studies that assessed DNA methylome variations in association with food allergy (FA). DESIGN: A systematic review of the literature and meta-analysis were carried out within several databases. However, the risk of bias in the included articles was not evaluated. DATA SOURCES: PubMed, Cochrane Database of Systematic Reviews, and Web of Science were used to search up to July 2022. ELIGIBILITY CRITERIA: We included targeted and epigenome-wide association studies (EWASs) that assessed DNA methylome alterations in association with FA in adult or paediatric populations. RESULTS: Among 366 publications, only 16 were retained, which were mainly focused on FA in children. Seven candidate gene-targeted studies found associations in Th1/Th2 imbalance (IL4, IL5, IL10, INFG, IL2 and IL12B genes), regulatory T cell function (FOXP3 gene), Toll-like receptors pathway (TLR2, CD14 genes) and digestive barrier integrity (FLG gene). Nine EWAS assessed the association with peanut allergy (n = 3), cow's milk allergy (n = 2) or various food allergens (n = 4). They highlighted 11 differentially methylated loci in at least two studies (RPS6KA2, CAMTA1, CTBP2, RYR2, TRAPPC9, DOCK1, GALNTL4, HDAC4, UMODL1, ZAK and TNS3 genes). Among them, CAMTA1 and RPS6KA2, and CTBP2 are involved in regulatory T cell function and Th2 cell differentiation, respectively. Gene-functional analysis revealed two enriched gene clusters involved in immune responses and protein phosphorylation. ChIP-X Enrichment Analysis 3 showed eight significant transcription factors (RXRA, ZBTB7A, ESR1, TCF3, MYOD1, CTCF, GATA3 and CBX2). Ingenuity Pathway Analysis identified canonical pathways involved, among other, in B cell development, pathogen-induced cytokine storm signalling pathway and dendritic cell maturation. CONCLUSION: This review highlights the involvement of epigenomic alterations of loci in Th1/Th2 and regulatory T cell differentiation in both candidate gene studies and EWAS. These alterations provide a better insight into the mechanistic aspects in FA pathogenesis and may guide the development of epigenome-based biomarkers for FA.

Dietary Factors May Delay Tolerance Acquisition in Food Protein-Induced Allergic Proctocolitis.

BACKGROUND: Dietary and environmental factors may influence tolerance acquisition in food protein-induced allergic proctocolitis (FPIAP). This retrospective observational study explored the role of maternal diet during pregnancy and breastfeeding in tolerance acquisition in infantile FPIAP. METHODS: Breastfed infants with FPIAP from six diverse regions in Greece were divided into two groups, based on development of tolerance to the trigger food: Group A (n = 43), before, and Group B (n = 53), after, the 6th month of age. Maternal diet during pregnancy and breastfeeding was elicited using the Mediterranean Diet Score Questionnaire and the Mediterranean Oriented Culture Specific Semi-Quantitative Food Frequency Questionnaire. RESULTS: Mean age at diagnosis of FPIAP (1.5 months) and weaning (5.5 months) were the same in both groups. The main trigger was cow's milk. Group A received infant milk formula earlier than Group B. Group B had a higher incidence of asthma/wheeze, siblings with milk allergy, maternal smoking and rural residence. On multivariate analysis, earlier resolution of FPIAP was associated with higher maternal education and with salt intake and consumption of goat/sheep cheese during pregnancy and olive oil during breastfeeding. Consumption of multivitamins during pregnancy and meat, winter fruits, green vegetables, butter, salt, "ready-to-eat" meals and pastries during breastfeeding were correlated with longer duration of symptoms. CONCLUSIONS: Mothers of children with FPIAP to cow's milk protein can be advised to eat more yogurt, cheese and olive oil during subsequent pregnancies, and avoid multivitamins, grilled food, "ready-to-eat" meals, pastries, meat and alcohol during breastfeeding, to reduce the duration of FPIAP presenting in future infants.

The long-term clinical course of protein-losing enteropathy combined with iron deficiency anemia in Korean toddlers: Possible association with cow's milk protein.

BACKGROUND: Protein-losing enteropathy (PLE), a rare condition with excessive gastrointestinal protein loss, presents with hypoalbuminemia, edema, or ascites. Several cases of PLE combined with severe iron deficiency anemia (IDA) have been reported in infants and toddlers that were considered to result from excessive cow's milk consumption, although the mechanism has not been clearly established. METHODS: We retrospectively reviewed the clinical, laboratory, endoscopic, and radiologic characteristics of patients diagnosed and treated for PLE with IDA between 2015 and 2021. Long-term outcomes were analyzed according to dietary intervention during the follow-up period. RESULTS: A total of 10 patients aged 7.0-26.7 months were enrolled in the study and the median follow-up duration of them was 9.4 months (range, 1.3-18.0). Six of them were fed powdered formula, while two were fed whole cow's milk, and their median daily intake was 700 mL (range, 300-900). The times to normalization of hemoglobin, albumin, and eosinophil count were shorter in patients with dietary elimination of cow's milk protein immediately after diagnosis compared to those with reduced intake or no dietary change. CONCLUSION: Early complete elimination of cow's milk protein should be considered, especially if the laboratory parameters are not normalized with adequate iron supplementation even though the clinical symptoms show improvement. We would like to draw attention to the possibility of the cow's milk protein in the pathogenesis of the condition through the non-IgE-mediated immune reactions.

[Infant gastroesophageal reflux disease: physiological or pathological ?] / Reflux gastrooesophagien du nourrisson : physiologique ou pathologique ?

INFANT GASTRO-ESOPHAGEAL REFLUX DISEASE: PHYSIOLOGICAL OR PATHOLOGICAL ? Gastroesophageal reflux (GER) is defined by the rise of gastric contents into the esophagus, with or without externalization. GER is very common in young infants, with a peak around 4 months, and most often physiological due to high milk intakes and inappropriate relaxation of the lower esophageal sphincter. Evoking a GER disease (GERD) is not always obvious due to signs of poor specificity (crying, irritability, regurgitation). On the other hand, one should not miss warning signs evocative of GERD complicated by esophagitis or of recurrent upper respiratory or ENT infections, or even differential diagnoses (cow milk protein allergy, eosinophilic esophagitis, congenital malformations or brain tumours, etc.). The diagnosis of GERD is clinical but investigations can sometimes be discussed like esophagogastroduodenal endoscopy, 24- hour pH-metry, esophagogastroduodenal follow through. The mechanisms of GERD should be clearly explained to parents and physiological GER should be treated with non-drug measures (adaptation of milk intakes/volumes, thickeners). In the absence of improvement, avoidance of cow's milk proteins for 2 to 4 weeks can be proposed, or even treatment with proton pump inhibitors.

REFLUX GASTRO-OESOPHAGIEN DU NOURRISSON: PHYSIOLOGIQUE OU PATHOLOGIQUE ? Le reflux gastro-oesophagien (RGO) est défini par la remontée du contenu gastrique dans l'oesophage, avec ou sans extériorisation. Le RGO est très fréquent chez le nourrisson, avec un pic vers 4 mois. Il est le plus souvent physiologique, en raison d'une alimentation lactée importante et d'une relaxation inappropriée du sphincter inférieur de l'oesophage. Évoquer un RGO pathologique n'est pas toujours évident, car ses symptômes ont une mauvaise spécificité (pleurs, irritabilité, régurgitations). En revanche, il ne faut pas passer à côté de signes d'alarme évocateurs d'un RGO compliqué par une oesophagite ou par des infections respiratoires hautes ou ORL récidivantes, ni négliger les diagnostics différentiels (allergie aux protéines du lait de vache, oesophagite à éosinophiles, malformations congénitales ou tumeurs cérébrales...). Le diagnostic de RGO est clinique, mais certains examens complémentaires peuvent parfois être discutés : endoscopie oesogastroduodénale, pH-métrie des 24 heures, transit oesogastroduodénal. Il convient de bien expliquer aux parents les mécanismes du RGO et de prendre en charge sa forme physiologique par des mesures non médicamenteuses (adaptation des prises/volumes de lait, épaississants). En l'absence d'amélioration, une éviction des protéines du lait de vache peut être proposée pendant deux à quatre semaines, voire un traitement par inhibiteurs de la pompe à protons.