Tolerance development in cow's milk-allergic children receiving amino acid-based formula with synbiotics: 36-Months follow-up of a randomized controlled trial (PRESTO Study).

The objective of the present study is to assess the rates of acquired tolerance to cow's milk (CM) after 36 months in subjects who consumed amino acid-based formula with synbiotics (AAF-S) or amino acid-based formula without synbiotics (AAF) during a 1-year intervention period in early life as part of the PRESTO study (Netherlands Trial Register number NTR3725). Differences in CM tolerance development between groups were analysed using a logistic regression model. Results show that the proportion of subjects (mean [±SD] age, 3.8 ± 0.27 years) who developed CM tolerance after 36 months was similar in the group receiving AAF-S (47/60 [78%]) and in the group receiving AAF (49/66 [74%]) (p = 0.253), that is, figures comparable to natural outgrowth of CM allergy. Our data suggest that the consumption of AAF and absence of exposure to CM peptides do not slow down CM tolerance acquisition.

An ESPGHAN Position Paper on the Diagnosis, Management, and Prevention of Cow's Milk Allergy.

A previous guideline on cow's milk allergy (CMA) developed by the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) was published in 2012. This position paper provides an update on the diagnosis, treatment, and prevention of CMA with focus on gastrointestinal manifestations. All systematic reviews and meta-analyses regarding prevalence, pathophysiology, symptoms, and diagnosis of CMA published after the previous ESPGHAN document were considered. Medline was searched from inception until May 2022 for topics that were not covered in the previous document. After reaching consensus on the manuscript, statements were formulated and voted on each of them with a score between 0 and 9. A score of ≥6 was arbitrarily considered as agreement. Available evidence on the role of dietary practice in the prevention, diagnosis, and management of CMA was updated and recommendations formulated. CMA in exclusively breastfed infants exists, but is uncommon and suffers from over-diagnosis. CMA is also over-diagnosed in formula and mixed fed infants. Changes in stool characteristics, feeding aversion, or occasional spots of blood in stool are common and in general should not be considered as diagnostic of CMA, irrespective of preceding consumption of cow's milk. Over-diagnosis of CMA occurs much more frequently than under-diagnosis; both have potentially harmful consequences. Therefore, the necessity of a challenge test after a short diagnostic elimination diet of 2-4 weeks is recommended as the cornerstone of the diagnosis. This position paper contains sections on nutrition, growth, cost, and quality of life.

Effect of lactic acid bacteria fermentation on cow milk allergenicity and antigenicity: A review.

Cow milk is a major allergenic food. The potential prevention and treatment effects of lactic acid bacteria (LAB)-fermented dairy products on allergic symptoms have garnered considerable attention. Cow milk allergy (CMA) is mainly attributed to extracellular and/or cell envelope proteolytic enzymes with hydrolysis specificity. Numerous studies have demonstrated that LAB prevents the risk of allergies by modulating the development and regulation of the host immune system. Specifically, LAB and its effectors can enhance intestinal barrier function and affect immune cells by interfering with humoral and cellular immunity. Fermentation hydrolysis of allergenic epitopes is considered the main mechanism of reducing CMA. This article reviews the linear epitopes of allergens in cow milk and the effect of LAB on these allergens and provides insight into the means of predicting allergenic epitopes by conventional laboratory analysis methods combined with molecular simulation. Although LAB can reduce CMA in several ways, the mechanism of action remains partially clarified. Therefore, this review additionally attempts to summarize the main mechanism of LAB fermentation to provide guidance for establishing an effective preventive and treatment method for CMA and serve as a reference for the screening, research, and application of LAB-based intervention.

[Primary prevention of food allergy in children]. / Prévention primaire de l'allergie alimentaire de l'enfant.

Pediatricians and allergists have noted a recent increase in cases of food allergy and anaphylaxis to peanuts and nuts, affecting very young children with worrying consequences in terms of quality of life. Children suffering from persistent cow's milk protein allergies that do not heal spontaneously are at very high risk of a fatal accident. Based on the findings of these studies, recommendations for primary prevention are made.

Clinical guideline highlights for the hospitalist: Evaluation, management, and prevention of cow's milk allergy.

GUIDELINE TITLE: An ESPGHAN position paper on the diagnosis, management and prevention of cow's milk allergy RELEASE DATE: Journal of Pediatric Gastroenterology and Nutrition, July 26, 2023 PRIOR VERSION: 2012 DEVELOPER: ESPGHAN (European Society of Paediatric Gastroenterology, Hepatology and Nutrition), NASPGHAN (North American Society of Pediatric Gastroenterology, Hepatology and Nutrition) FUNDING SOURCE: ESPGHAN TARGET POPULATION: Infants and young children with suspected cow's milk allergy.

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.

Glycosylation-modified antigens as a tolerance-inducing vaccine platform prevent anaphylaxis in a pre-clinical model of food allergy.

The only FDA-approved oral immunotherapy for a food allergy provides protection against accidental exposure to peanuts. However, this therapy often causes discomfort or side effects and requires long-term commitment. Better preventive and therapeutic solutions are urgently needed. We develop a tolerance-inducing vaccine technology that utilizes glycosylation-modified antigens to induce antigen-specific non-responsiveness. The glycosylation-modified antigens are administered intravenously (i.v.) or subcutaneously (s.c.) and traffic to the liver or lymph nodes, respectively, leading to preferential internalization by antigen-presenting cells, educating the immune system to respond in an innocuous way. In a mouse model of cow's milk allergy, treatment with glycosylation-modified ß-lactoglobulin (BLG) is effective in preventing the onset of allergy. In addition, s.c. administration of glycosylation-modified BLG shows superior safety and potential in treating existing allergies in combination with anti-CD20 co-therapy. This platform provides an antigen-specific immunomodulatory strategy to prevent and treat food allergies.

Goat Milk Allergy and a Potential Role for Goat Milk in Cow's Milk Allergy.

In many parts of the world, goat milk has been part of the human diet for millennia. Allergy to goat's milk, not associated with allergy to cow's milk, is a rare disorder, although some cases have been described. Goat milk proteins have substantial homology with cow's milk proteins and even show cross-reactivity; therefore, they are not advised as an alternative to cow's milk for infants with IgE-mediated cow's milk allergies. However, there are indications that, due to the composition of the goat milk proteins, goat milk proteins show lower allergenicity than cow's milk due to a lower αS1-casein content. For this reason, goat milk might be a better choice over cow's milk as a first source of protein when breastfeeding is not possible or after the breastfeeding period. Additionally, some studies show that goat milk could play a role in specific types of non-IgE-mediated cow milk allergy or even in the prevention of sensitization to cow's milk proteins. This review discusses a possible role of goat milk in non-IgE mediated allergy and the prevention or oral tolerance induction of milk allergy.

Infant Formulas With Partially or Extensively Hydrolyzed Milk Proteins for the Prevention of Allergic Diseases: A Systematic Review and Meta-Analysis of Clinical Trials.

Despite the widely recommended usage of partially hydrolyzed formula (PHF) or extensively hydrolyzed formula (EHF) of milk protein for preventing allergic diseases (ADs), clinical studies have been inconclusive regarding their efficacy compared with that of cow's milk formula (CMF) or breast milk (BM). We aimed to systematically evaluate the effects of PHF or EHF compared with those of CMF or BM on risk of ADs (cow's milk allergy, allergic rhinitis, eczema, asthma, wheeze, food allergy, and sensitization) in children. We searched PubMed, Embase, Cochrane Library, and Web of Science for clinical trials published from inception to 21 October, 2022. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to grade the strength of evidence. Overall, 24 trials (10,950 infants) were included, 17 of which specifically included high-risk infants. GRADE was low for the evidence that, compared with CMF, infants early fed with EHF had lower risk of cow's milk allergy at age 0-2 y [relative risk (RR): 0.62; 95% CI: 0.39, 0.99]. Moderate evidence supported that PHF and EHF reduced risk of eczema in children aged younger or older than 2 y, respectively (RR: 0.71; 95% CI: 0.52, 0.96; and RR: 0.79; 95% CI: 0.67, 0.94, respectively). We also identified moderate systematic evidence indicating that PHF reduced risk of wheeze at age 0-2 y compared with CMF (RR: 0.50; 95% CI: 0.29, 0.85), but PHF and EHF increased the risk compared with BM (RR: 1.61; 95% CI: 1.11, 2.31; and RR: 1.64; 95% CI: 1.26, 2.14). Neither PHF nor EHF had significant effects on other ADs in children of any age. In conclusion, compared with CMF, PHF, or EHF had different preventive effect on cow's milk allergy, eczema, and wheeze. Compared with BM, both PHF and EHF may increase risk of wheeze but not other ADs. Given that most trials included only high-risk infants, more research on non-high-risk infants is warranted before any generalization is attempted. This protocol was registered at PROSPERO as CRD42022320787.

Impact of processing on the sensitising capacity and cross-reactivity of cow's and camel milk proteins in a Brown Norway rat study.

Infant formulas based on hydrolysed cow's milk proteins are used when breastfeeding is not feasible in cow's milk allergic infants. Camel milk has been shown to be well-tolerated by the majority of children with cow's milk allergy (CMA) and may be a substitute in management of CMA. Here we aimed to evaluate the impact of processing on immunogenicity, sensitising, antibody-binding and cross-reactive capacity of cow's and camel milk. Cow's and camel milk were processed by means of enzyme hydrolysis or heat treatment. Brown Norway rats were immunised with PBS, non-processed, enzyme hydrolysed or heat-treated cow's or camel milk. In vivo tests were performed for evaluation of clinical signs. Blood and faecal samples were analysed for levels and specificity of antibody responses. Cow's and camel milk showed similar sensitising capacity. Processing decreased the sensitising capacity of cow's milk, yet only enzyme hydrolysis but not heat treatment decreased the sensitising capacity of camel milk. Processing affected the specificity of antibodies raised in the rats, though the effect differed between cow's and camel milk. The study showed a low cross-reactivity between cow's and camel milk, which was decreased with processing, suggesting that processing of camel milk may improve its usefulness in CMA management.

Reducing the Allergenicity of ß-Lactoglobulin by Covalent Modification with Different Contents of Epigallocatechin Gallate (EGCG): In Vitro and In Vivo Studies.

ß-Lactoglobulin (ßLG) is a major allergen in bovine milk protein. This study was designed to investigate changes in ßLG structure, digestibility, and allergenicity induced by covalent binding modification with different contents of (-)-epigallocatechin 3-gallate (EGCG). The reaction of EGCG conjugation with ßLG reached saturation at a molar ratio of 1:60 ßLG:EGCG. Conjugation with EGCG altered the ßLG structure, decreased IgE-binding capacity, and increased digestibility in a dose-dependent manner. In vivo studies showed that covalent conjugation with EGCG can reduce ßLG-induced allergic symptoms with reducing levels of IgE, histamine, and mast cell protease-1 (mMCP-1) and the percentage of sensitized mast cells. Allergenicity was reduced more effectively in saturated ßLG-EGCG conjugates compared to semisaturated conjugates. Observed changes in IFN-γ, IL-4, IL-5, IL-10, and TGF-ß levels suggested that ßLG-EGCG conjugates were able to promote Th1/Th2 immune balance. These findings further our understanding of the relationship between the degree of polyphenol conjugation and the allergenicity of food allergens.

Epidemiología de la alergia alimentaria en la edad pediátria / Epidemiology of food allergy in children

La incidencia de alergia alimentaria (AA) en niños es del 2-8%. Más del 90% de las AA en los lactantes son causados por leche de vaca (LV), huevo de gallina, soya, maní, nueces, trigo, pescado y mariscos. Existen algunos factores de riesgo para el desarrollo de AA. El impacto de la LM sobre el desarrollo de las alergias es controversial. Hay un 0.21% de APLV neonatal. La introducción antes del 4 mes de vida de más de 4 alimentos está asociada con un mayor riesgo de dermatitis atópica. La prueba de provocación oral a los alimentos es una herramienta valiosa en el diagnóstico inicial y el manejo de las reacciones adversas a los alimentos. Los síntomas sugestivos de APLV pueden ser encontrados en cerca del 5-15% de los niños. La hipersensibilidad mediada por IgE a la proteína de la LV, es predominantemente una enfermedad del período del lactante.

The incidence of food allergy (FA) in children of 2-8%. Over 90% of FA in infants are caused by cow's milk (CM), chicken egg, soy, peanuts, tree nuts, wheat, fish and seafood. There are some risk factors for the development of FA. The impact of breastfeeding on the development of allergies is controversial. There is a 0.21% of neonatal CMPA. The introduction before 4 months of life of more than 4 foods is associated with an increased risk of atopic dermatitis. The oral challenge test to food is a valuable tool in the initial diagnosis and management of adverse reactions to food. Symptoms suggestive of CMPA can be found in about 5-15% of children. The IgE-mediated hypersensitivity to the protein in the CM, is predominantly a disease of the infant period.

In search of a tolerance-induction strategy for cow's milk allergies: significant reduction of beta-lactoglobulin allergenicity via transglutaminase/cysteine polymerization

OBJECTIVE: To explore the use of β-lactoglobulin polymerized using microbial transglutaminase and heating to identify whether protein polymerization could reduce in vivo allergenicity and maintain in vitro and ex vivo immunoreactivity for use in tolerance-induction protocols. METHODS: Based on previous protocols applied in mice and children, we performed in vivo challenges (using a skin prick test) with native and polymerized β-lactoglobulin in adult patients with an IgE-mediated allergy to plactoglobulin. In vitro humoral immunoreactivity was analyzed using immunoblotting. Cell-mediated immunoreactivity was analyzed using ex vivo challenges with native and polymerized β-lactoglobulin and monitored by leukocyte adherence inhibition tests. RESULTS: The skin tests demonstrated that there was a significant reduction in immediate cutaneous reactivity after polymerization. Polymerization did not decrease the immunoblotting detection of s-IgE specific to β-lactoglobulin. Cell-mediated immunoreactivity, as assessed by ex vivo challenges and leukocyte adherence inhibition tests, did not exhibit significant differences between leukocytes challenged with native versus polymerized β-lactoglobulin. CONCLUSIONS: The polymerization of β-lactoglobulin decreased in vivo allergenicity and did not decrease in vitro humoral or ex vivo cell-mediated immunoreactivity. Therefore, we conclude that inducing polymerization using transglutaminase represents a promising technique to produce suitable molecules for the purpose of designing oral/ sublingual tolerance induction protocols for the treatment of allergies.

Alergia a la proteína de la leche de vaca: propuesta de Guía para el manejo de los niños con alergia a la proteína de la leche de vaca / Cow’s milk protein allergy: proposed guidelines for the management of children with cow’s milk protein allergy

El diagnóstico y manejo de la alergia a la proteína de leche de vaca es un verdadero desafío en la práctica pediátrica. Como se trata de una patología que pareciera estar aumentando en nuestro medio, de un modo similar a lo comunicado en otras latitudes, hemos considerado conveniente proponer una normalización de la nomenclatura y de la metodología diagnóstica. Un grupo de pediatras especialistas se ha reunido para realizar una Propuesta de Guía para el manejo de los niños con alergia a la proteína de la leche de vaca. El objetivo ha sido difundir el conocimiento actual de la fisiopatología, factores ambientales y sus manifestaciones clínicas, para colaborar con el pediatra mediante algoritmos que faciliten su manejo integral.

Cow’s milk allergy is a growing concern in the practice of pediatrics. The impression of an increasing incidence, similar to what has been reported in other latitudes, has determined the need for guidelines to help in the diagnosis and treatment of this disease. A group of pediatric specialists met to discuss the “state of the art” and propose local guidelines to deal with cow’s milk allergy. The aim has been to contribute in the understanding of the pathophysiology, environmental factors, and clinical expressions of this problem, and help pediatricians in the overall management.

Desempenho de pais de crianças em dieta de exclusão do leite de vaca na identificação de alimentos industrializados com e sem leite vaca / The performance of parents of children receiving cow's milk free diets at indentification of commercial food products with and without cows's milk

OBJETIVO: Investigar o desempenho de pais de crianças em dieta isenta da proteína do leite de vaca no reconhecimento de expressões e alimentos que contenham ou não proteínas do leite de vaca. MÉTODOS: Foram entrevistados 24 pais de crianças em dieta de exclusão do leite de vaca e derivados e 23 sem necessidade de nenhum tipo de dieta de exclusão. Foi questionado se reconheciam 12 expressões relacionadas ao leite de vaca. A seguir, foi solicitado que classificassem 10 produtos industrializados quanto ao conteúdo ou não de proteínas do leite de vaca. RESULTADOS:Termos iniciados com a palavra leite foram os mais reconhecidos pelos dois grupos. Os responsáveis por crianças em dieta de exclusão reconheceram mais freqüentemente as palavras proteína do leite de vaca, traços do leite e formulação ou preparação láctea (p < 0,05). Caseína, caseinato, lactoalbumina e lactoglobulina foram reconhecidas por menos de 25,0 por cento dos entrevistados. O número de identificação correta dos 10 produtos industrializados foi maior para os produtos com leite de vaca nos dois grupos. A mediana de acertos dos produtos com leite de vaca (n = 5) pelos pais em dieta de exclusão (4,0) foi maior que a do grupo controle (3,0; p = 0,005). Leitura de pelo menos um rótulo associou-se com maior chance de identificação correta de mais de cinco dos 10 produtos (razão de chance = 8,0). CONCLUSÃO:Apesar de orientados, os pais de crianças em dieta de exclusão não estão plenamente preparados para sua correta realização, indicando a necessidade de aprimoramento das orientações para essa dieta de exclusão.

OBJECTIVE: To investigate how well the parents of children on cow's milk free diets perform at recognizing whether or not expressions describe and foods contain cow's milk proteins. METHODS: Interviews were conducted with 24 parents of children on cow's milk and by-products exclusion diets and 23 parents of children with no need for any type of exclusion diet. They were asked if they recognized 12 expressions relating to cow's milk. They were then asked to classify 10 commercial food products in terms of whether or not they contained cow's milk proteins. RESULTS: Terms that included the word milk were more often recognized by both groups of parents. The parents of children on exclusion diets recognized the terms cow's milk protein, traces of milk and milk formulation or preparation most frequently (p < 0.05). Less than 25.0 percent of those interviewed recognized casein, caseinate, lactalbumin and lactoglobulin. Both groups correctly identified more of the commercial products containing cow's milk than those free from milk. The median number of products containing cow's milk (total = 5) correctly identified by the parents of children on exclusion diets (4.0) was greater than for the control group (3.0; p = 0.005). Reading at least one label was associated with a greater chance of correctly identifying more than five of the 10 products (odds ratio = 8.0). CONCLUSIONS: Despite having received guidance, the parents of children on exclusion diets were not fully prepared to manage these diets, indicating a need for improvements to the instruction provided when indicating exclusion diets.

Food allergy: a practical update from the gastroenterological viewpoint / Food allergy: a practical update from the gastroenterological viewpoint

OBJETIVOS: Apresentar uma revisão atualizada e crítica sobre alergias alimentares, focando principalmente em tratamento e prevenção. FONTES DOS DADOS: Revisão da literatura publicada obtida através do banco de dados MEDLINE, sendo selecionados os mais atuais e representativos do tema (2000-2006). A pesquisa incluiu os sites da European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) e American Academy of Pediatrics (AAP). SíNTESE DOS DADOS: A prevalência de doenças alérgicas tem aumentado nas últimas décadas e alergia alimentar parece fazer parte desse aumento. Alergia alimentar é muito mais comum em pediatria e apresenta impacto médico, financeiro e social significativos em crianças menores e suas famílias. Tratamento e prevenção da alergia alimentar são desafios maiores do ponto de vista da saúde pública e para as comunidades médica e científica. Há muita informação incorreta e condutas médicas discutíveis nessa área. Apresentamos e discutimos as recomendações publicadas pelos Comitês de Nutrição da ESPGHAN juntamente com a Sociedade Européia Pediátrica de Alergologia e Imunologia Clínica (ESPACI) e AAP. CONCLUSÃO: Excesso de diagnósticos de alergia alimentar é bastante prevalente. Há necessidade de uniformização de definições e procedimentos diagnósticos. O objetivo primário do manejo deve ser o de instituir medidas efetivas de prevenção das alergias alimentares. Há necessidade de métodos precisos para confirmar ou excluir o diagnóstico. Os pacientes necessitam tratamento apropriado através da eliminação de alimentos que causam sintomas, ao mesmo tempo evitando os efeitos adversos nutricionais e o custo de dietas inadequadas.

OBJECTIVE: To present an up-to-date and critical review regarding food allergies, focusing mainly on treatment and prevention. SOURCES: Review of published literature searched on MEDLINE database; those data which were the most up-to-date and representative were selected (2000-2006). The search included the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the American Academy of Pediatrics (AAP). SUMMARY OF THE FINDINGS: The prevalence of allergic diseases has increased over the last decades, and food allergy seems to be part of this increase. Food allergy is much more common in pediatrics and has a significant medical, financial and social impact on young children and their families. Treatment and prevention of food allergy is a major challenge for public health, scientific and medical communities. There is a lot of misinformation and the medical management of this condition is still discussable. We present and discuss the guidelines regarding criteria for the prevention of food allergy and atopic diseases published by the Nutrition Committees of ESPGHAN jointly with the European Society for Pediatric Allergy and Clinical Immunology (ESPACI) and AAP. CONCLUSION: The overdiagnosis of food allergy is quite prevalent. There is a need for standardization of definitions and diagnostic procedures. The primary goal of therapy should be to first establish effective means of preventing food allergies. There is a need for accurate diagnostic methods to confirm or rule out the diagnosis. Patients need appropriate treatment by eliminating foods that cause symptoms, while avoiding the nutritional side effects and the cost of inappropriate diets.