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A 4-week-old boy presented to the hospital with symptoms of diarrhoea and vomiting initially thought to be due to cow’s milk allergy. He was discharged with extensively hydrolysed formula. The patient represented with worsening of symptoms with metabolic acidosis and was screened and treated for sepsis. However, his condition deteriorated further and he developed methaemoglobinaemia. He was transferred to the high dependency unit and was given two doses of methylene blue. Further investigations were carried out, including rapid trio exome sequencing, which identified a homozygous pathogenic Peptidase D (PEPD) variant (c.978G>A, p.(Trp326*)). This was consistent with a diagnosis of prolidase deficiency.

Amino acid-based formulas (AAFs) are similar to most other infant kinds of milk except for one important diffe­rence. Instead of containing whole or broken down cow’s milk protein, they contain amino acids. These individual amino acids are so small that they are not recognised by the immune system as allergens and do not provoke any allergic reaction in children with cow’s milk allergy. In recent studies, AAFs were well tolerated and supported growth in otherwise healthy infants without cow’s milk protein allergy, and in those with cow’s milk protein allergy. Short bowel syndrome, a disorder characterized by diarrhea, malabsorption, fluid and electrolyte disturbances, and eventually malnutrition, is usually caused by massive intestinal resection. Even though the causes of short bowel syndrome are diverse, the management has identical pillars: parenteral nutrition and early enteral nutrition. Enteral nutrition remains an important and controllable factor. The direct trophic effect of nutrients and stimulation of gastrointestinal secretions and hormonal factors enhances intestinal adaptation. AAFs promote rapid weaning of parenteral nutrition after the introduction of an elemental formula. Besides, studies show that they reduce intestinal inflammation (the level of fecal calprotectin).

Although early supplementation with cow's milk formula (CMF) reportedly increases the risk of cow's milk allergy (CMA) in breast-fed infants, little is known about the association between the timing of CMF discontinuation and subsequent CMA development.To elucidate the relationship between the timing of CMF discontinuation and CMA development in infants who received CMF in the early days of life.Using data from a randomized controlled trial of a birth cohort from 4 Japanese hospitals, we performed a subgroup analysis of participants who ingested CMF in the first 3 days of life. We compared the proportions of participants who developed CMA at age 6 months in those who discontinued CMF ingestion before age 1 month ("DISC1-month group"), during age 1 to 2 months ("DISC 1-2-month group"), and during age 3 to 5 months ("DISC 3-5-month group") with those who continued CMF ingestion until age 6 months ("continuous group"). The risk ratios (RRs) and 95% CIs for CMA development were calculated.CMA incidence was significantly higher in the DISC1-month group (n = 7 of 17, 41.2%; RR, 65.7; 95% CI, 14.7-292.5; P.001), DISC 1-2-month group (n = 3 of 26, 11.5%; RR, 18.4; 95% CI, 3.2-105.3; P = .003), and DISC 3-5-month group (n = 7 of 69, 10.1%; RR, 16.2; 95% CI, 3.4-76.2; P.001) than in the continuous group (n = 2 of 319, 0.6%).Early CMF discontinuation, particularly in the first month of life, was associated with CMA development in infants who received CMF in the first 3 days of life.

BACKGROUND Tolerance of baked milk indicates a good prognosis in IgE-mediated cow's milk allergy. OBJECTIVE The present study aims to investigate the predictors of baked milk tolerance, particularly the amount of milk tolerated in the first oral food challenge (OFC) test, in children with IgE-mediated cow's milk allergy. METHODS The study included 35 cases who were diagnosed with IgE-mediated cow's milk allergy upon open OFC testing in the Pediatric Allergy Clinic. Four weeks after the diagnosis, skin prick test (SPT) and OFC were performed with baked milk. Cases who did and did not develop reactions during OFC with baked milk were compared regarding clinical and laboratory parameters. RESULTS Twelve cases (33.3%) did not develop a reaction during OFC with baked milk. Those who had low levels of casein sIgE, β-lactoglobulin sIgE, and β-lactoalbumin sIgE; small SPT wheal diameter for baked milk and β-lactoalbumin; and a large amount of unheated milk tolerated in the first OFC were found to be tolerant to baked milk (p < 0.05). For predicting baked milk tolerance, a cut-off level of the amount of unheated milk tolerated in OFC was calculated as 620 mg [with the area under the curve (AUC) 0.88 (95% confidence interval 0.77-0.99) in ROC curve analysis]. CONCLUSIONS If a child with cow's milk allergy is able to tolerate more than 620 mg of milk protein during challenge with unheated milk, this may show that this child will tolerate baked milk, meaning that the child will be able to tolerate cow's milk in the future.

Cows’ milk allergy (CMA) is one of the earliest manifestations of allergic diseases. Early dietary factors, like maternal diet during pregnancy, may play a role in the development of allergic diseases in the offspring. We aimed to investigate the association between maternal intake of fatty acids during pregnancy and the risk of CMA in the offspring. Our study was conducted in a population-based cohort, the Finnish Type 1 Diabetes Prediction and Prevention study. We collected the maternal dietary data by a validated FFQ. We obtained the information on CMA in the study participants (n 448) from registers and from the parents. Dietary data and information on CMA were available for 4921 children. We used logistic regression in the analyses, and fatty acid intakes were energy adjusted. The maternal intake of SFA, MUFA, PUFA, n-3 PUFA, n-6 PUFA, trans fatty acids, ratio of n-3 PUFA to n-6 PUFA or ratio of linoleic acid to α-linolenic acid was not associated with the risk of CMA in the offspring when adjusted for perinatal factors, background factors, parental history of asthma or allergic rhinitis and infant animal contacts. The intake of α-linolenic acid was associated with a decreased risk (OR 0·72; 95 % CI 0·56, 0·93) of CMA in the offspring of mothers without a history of allergic rhinitis or asthma. In conclusion, the maternal intake of fatty acids during pregnancy is not associated with the risk of CMA in the offspring.

The effects of ultrasound combined with glycation (UCG) on the allergenicity and human microbial community of β-Lg during in vitro digestion were studied by ELISA, cell experiments, and 16S rRNA high-throughput sequencing. UCG modification and subsequent digestion significantly reduced allergenicity. The decrease in the allergenicity of β-Lg depended not only on the low digestibility of glycated β-Lg, which led to the decrease of some peptides with complete immunogenicity, but also the masking effect of glycation on allergen epitopes of β-Lg. Meanwhile, UCG modification and subsequent digestion could alter the structures of intestinal microbiota and the community abundance at phylum, family, and genus levels, such as Bacteroidota, Fusobacteriota, Enterobacteriaceae, Bacteroidaceae, Ruminococcaceae, Bacteroides, and Faecalibacterium. These results show that simulated in vitro digestion of modified β-Lg reduces allergenicity and alters human intestinal microbiota, which could provide a theoretical basis for studying the relationship between intestinal dysbiosis and cow's milk allergy.

Food allergy is a hypersensitive immune reaction to food proteins including cow’s milk protein. Extracellular vesicles (EVs), such as exosomes, are newly discovered intercellular conveyors of functional molecular mechanisms and mediated intercellular interactions involving mast cells and are particularly relevant to allergy. In this study, we investigated whether cow’s milk casein-induced allergy (CIA)-derived EVs can modulate mast cell activation. EVs in CIA mice and control mice were isolated using the ultracentrifugation method and the isolated EVs were quantified using BCA analysis. CIA responses were determined through changes in body temperature and systemic symptom score. The number of EVs was higher in CIA-derived EVs compared to normal EVs. EVs marker proteins such as CD63 and CD9 were elevated in CIA-derived EVs. The levels of EV-associated cytokines such as IL-6, IL-8, and TNF-α were significantly elevated in CIA-derived EVs. In addition, CIA-derived EVs significantly induced degranulation via Lyn kinase activation in mouse bone marrow-derived mast cells and human mast cells. Our results demonstrate that CIA-derived EVs can induce a reaction similar to cow’s milk allergic reaction via mast cell activation. These results provide an insight into the pathology of cow’s milk allergy and a potential therapeutic approach through targeting EV release and/or uptake.

Background Some studies addressed the issue of omalizumab (OML) effectiveness in children starting their first oral immunotherapy (OIT) attempt but no study investigated the possible role of OML in the setting of patients with persisting milk allergy after a failed OIT attempt. Methods Single‐center, prospective, observational study in a selected group of patients with a persisting and severe cow milk (CM) allergy associated with moderate allergic asthma, in which a previous OIT attempt had already failed. We performed an open oral food challenge (OFC) to identify patients who tolerated less than 173 mg of cow's milk protein. At the end of the recruitment, we have found four patients with a mean age of 16.25 years (8–24) who had suspended a previous OIT attempt and still reacted to an amount of CM equal or below 173 mg. Enrolled patients, after an 8‐week course of OML along with a CM avoiding diet, underwent again an open OFC with CM to re‐evaluate their threshold. Eventually, a new OIT course was started using the same OIT protocol of the previous attempt, maintaining cotreatment with OML for the first 12 months. For each patient, we documented: the threshold of CM at OFC, level of specific immunoglobulin E (IgE) and IgG4 for milk, and quality of life (QoL). Results During OIT the four patients experienced no reactions or extremely mild ones (oral itching, transient mild abdominal pain). All increased their threshold of CM in OML if compared with the baseline and maintained it long after that biologic therapy had discontinued. Specific milk proteins IgG4 levels significantly increased in all. Conclusion In this series, OML was effective in patients with severe CM allergy who had previously failed OIT, allowing milk intake without adverse reactions and improving the QoL.

Background: Cow’s milk allergy is among the most frequent food allergies in young children and one of the risk factors of asthma. Objective: The study aimed to assess the role of Cow’s milk allergy (CMA) to induce asthma and to study the effect cow milk protein on asthmatic and non-allergic children to prevent occurrence of asthma among children. Patients and methods: A case-control study that was carried out in Pulmonology Unit of Pediatric Department, Faculty of Medicine, Zagazig University Hospital. The patients were investigated at Medical Community and Immunology Department. The study included 154 child divided equally into two groups. Group A included patients with bronchial asthma and group B (control) included age- and sex-matched healthy individuals. Iinvestigations: complete blood picture, renal and liver function tests, skin prick test, total immunoglobulin (IgE) was done for all participants. Results: There was high statistically significant difference between the two studied groups as regards skin pick test. There was statistically significant increase in the levels of both total and specific Ig E in allergic group compared to control group. There was high significant increase in the severity recorded in respiratory function test in allergic group compared to control group. There was non-significant difference between the two groups regarding GIT manifestation. There was high statistically significant difference between the two groups regarding skin and respiratory manifestations. Conclusion: CMA can exacerbate the symptoms in children with asthma. Therefore, it is worth considering a possible role of food allergy in asthma in young children, particularly when asthma is not adequately controlled in spite of proper routine management.

Background and objective: Regurgitation symptoms in many GERD infants might affect their nutrition status. This review compares thickeners and hydrolysis formula with cow’s milk in the evolution of regurgitation, weight and stool consistency changes in infants with GERD based on currently available evidence, as the benefits of using AR-F in infants with GERD is still contradictory. There is also evidence that hydrolysed formula plays a crucial role in regulating reflux. Methods: The search terms ‘thickener formula/pre-thickener’ OR ‘cow’s milk allergy/hydrolysis formula’ AND ‘gastro-oesophageal reflux disease (GERD)/regurgitations’ were used to search the electronic databases of NUsearch, Google Scholar, ScienceDirect and PubMed for randomised controlled trials (RCTs) published between 2005 and 2020 for thickened formula and 2010-2020 for hydrolysed formula that involved infants (Results: Seven eligible RCTs met the inclusion criteria. Thickened whey protein formula significantly reduced daily regurgitations by up to 7.7 episodes, while the results were insignificant in thickened or normal extensive hydrolysed casein milk (-4.2 vs -3, respectively). However, rice thickener significantly reduced regurgitation and weight gain by 1.261 kg in two months. An insignificant difference in stool consistency was found in most trials (P >0.05), except for the thickened casein formula as 64% of participants had normal stool density (P= 0.45). Conclusion: This study identified that using either thickening formula or extensively hydrolysed formula significantly reduced the number of regurgitations per day (mean range: -1.2 to -7.1; P

Objectives To identify published economic evaluations of interventions aimed at preventing, diagnosing, or treating food allergies in children. Methods We examined economic evaluations published from 2000 to 2019. Data analyzed included: food allergy type, study population/setting, intervention/comparator, and economic evaluation details. Quality assessment used reporting and economic modeling checklists. Two reviewers simultaneously undertook article screening, data extraction, and quality assessment. Results 17 studies were included: 8 peanut allergy (PA) studies, 8 cow’s milk allergy (CMA) studies, and 1 egg allergy (EA) study. All PA studies reported incremental costs per quality-adjusted life-year gained for diagnostic strategies, management pathways for peanut exposure, and immunotherapies. Immunotherapies rendered inconsistent cost-effectiveness results. CMA studies reported costs per symptom-free day or probability of developing CMA tolerance. Cost-effectiveness of extensively hydrolyzed casein formula for CMA treatment was consistently demonstrated. Early introduction of cooked egg in first year of life dominated all EA prevention strategies. Quality assessment showed average noncompliance for 3.5 items/study (range 0-11) for modeling methods and 3.4 items/study (range 0-8) for reporting quality. Key quality concerns included limited justification for model choice, evidence base for model parameters, source of utility values, and representation of uncertainty. Conclusion Recent cost-effectiveness literature of interventions in PA, CMA, and EA is limited and diverse. Interventions for diagnosis and treatment of CMA and prevention of EA were generally cost-effective; however, results for PA were variable and dependent on effectiveness and utility values used. There is a need to expand economic evaluation of interventions for childhood food allergy and to improve methods and reporting.

Introdução: As alergias alimentares são definidas como uma reação imunológica adversa que se repete mediante a exposição a determinado alimento. Essas reações variam da anafilaxia (mais grave) à manifestações gastrointestinais. O tratamento preconizado das alergias alimentares é a exclusão absoluta do alimento da dieta da criança. Objetivo: Através de uma revisão integrativa de literatura, avaliamos a eficácia da suplementação com probióticos no tratamento de alergias alimentares em crianças, na redução dos sintomas e/ou na aquisição de tolerância, identificando cepa mais eficaz, relação dose-resposta e efeitos adversos de seu uso. Metodologia: Para busca de ensaios clínicos e outras revisões, utilizamos as bases científicas Science Direct, a Scientific Electronic Library Online (SciELO), Biblioteca Virtual em Saúde (BVS), Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), PubMed e MEDLINE, com as palavras-chave “probiotics”, “treatment”, “food allergy”, “children”, e “infant”. Após a aplicação dos critérios de exclusão, foram selecionados quatro ensaios clínicos randomizados, cinco revisões e uma metanálise; a amostra de todos os estudos foi de lactentes com alergia à proteína do leite de vaca (APLV). Resultados: Os estudos apontaram que o uso de fórmula infantil extensamente hidrolisada (FEH) com Lactobacillus rhamnosus GG, em doses de 1x106 a 5x108 cfu/g, é eficaz tanto em acelerar a melhora do eczema atópico, como em induzir tolerância em crianças na faixa de idade de 1 mês a 3 anos que não tenham reações anafiláticas ao leite de vaca. Conclusões: Outros ensaios clínicos com amostras maiores devem ser realizados antes de incluir os probióticos na prática clínica, inclusive para avaliar melhor seu perfil de segurança. Palavras-Chave: Probióticos, Eficácia; Hipersensibilidade Alimentar; Hipersensibilidade a Leite; Criança.

Objective Scoping review on IgE-mediated cow’s milk allergy prevention. Data Sources Literature search of PubMed database and gray literature. Study Selections Peer-reviewed relevant observational and randomized controlled studies in the pediatric population in the English language were selected and reviewed. Results There is increasing literature supporting the role of early and ongoing cow’s milk ingestion in the prevention of cow’s milk allergy. The studies supporting a preventive role with early cow’s milk ingestion suggest cow’s milk introduction at a very early age (most within the first month of life), suggesting the possibility of a different mechanism of sensitization than other common allergens. It is possible that gut colonization and the diversity and intensity of microbial exposure may play a role in inducing cow’s milk tolerance. It is also possible that vitamin D may have a role in modulating those immune functions. Conclusion Further research regarding the role that early cow’s milk ingestion plays in the prevention of cow’s milk allergy is required, and questions remain. The absolute amount required for tolerance is unclear. Studies in higher risk populations are required. However, there is an intriguing and increasingly more pervasive association between early ongoing cow’s milk ingestion and cow’s milk allergy prevention.

BACKGROUND Two to four percentage of infants are affected by cow's milk allergy (CMA), which persists in 20% of cases. Intervention approaches using early oral exposure to cow's milk protein or hydrolysed cow's milk formula are being studied for CMA prevention. Yet, concerns regarding safety and/or efficacy remain to be tackled in particular for high-risk non-exclusively breastfed infants. Therefore, safe and effective strategies to improve early life oral tolerance induction may be considered. OBJECTIVE We aim to investigate the efficacy of CMA prevention using oral pre-exposure of two selected 18-AA β-lactoglobulin-derived peptides loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) in a whey-protein induced CMA murine model. METHODS The peptides were loaded in PLGA NPs via a double emulsion solvent evaporation technique. In vivo, 3-week-old female C3H/HeOuJ mice received 6 daily gavages with PBS, whey, Peptide-mix, a high- or low-dose Peptide-NPs or empty-NP plus Peptide-mix, prior to 5 weekly oral sensitizations with cholera toxin plus whey or PBS (sham). One week after the last sensitization, the challenge induced acute allergic skin response, anaphylactic shock score, allergen-specific serum immunoglobulins and ex vivo whey-stimulated cytokine release by splenocytes was measured. RESULTS Mice pre-treated with high-dose Peptide-NPs but not low-dose or empty-NP plus Peptide-mix, were protected from anaphylaxis and showed a significantly lower acute allergic skin response upon intradermal whey challenge compared to whey-sensitized mice. Compared with the Peptide-mix or empty-NP plus Peptide-mix pre-treatment, the high-dose Peptide-NPs-pre-treatment inhibited ex vivo whey-stimulated pro-inflammatory cytokine TNF-α release by splenocytes. CONCLUSION & CLINICAL RELEVANCE Oral pre-exposure of mice to two β-lactoglobulin-derived peptides loaded PLGA NPs induced a dose-related partial prevention of CMA symptoms upon challenge to whole whey protein and silenced whey-specific systemic immune response. These findings encourage further development of the concept of peptide-loaded PLGA NPs for CMA prevention towards clinical application.

Background Amino acid-based formula (AAF) is a relevant dietary strategy for paediatric patients affected by cow’s milk allergy (CMA). The present study was designed to evaluate the hypoallergenicity of a new AAF in children with immunoglobulin (Ig)E-mediated CMA. Methods According to the criteria provided by the American Academy of Pediatrics Subcommittee on Nutrition and Allergic Diseases, we designed a prospective trial in CMA children (aged 1–36 months) aimed to demonstrate the hypoallergenicity of the new AAF in 90% of subjects with 95% confidence during the double-blind, placebo-controlled challenge (DBPCFC). A skin prick test (SPT) with the new AAF was also performed. Results Twenty-nine children [all Caucasian, 55.2% male, mean age (±SD) 16.9 ± 5.7 months] were enrolled. The SPT and the DBPCFC with the new AAF were negative in all study subjects. Conclusions The study results support the hypoallergenicity of the new AAF. This formula could be considered an additional dietary option for non-breastfed children affected by CMA. Trial registration The trial was registered in the ClinicalTrials.gov Protocol Registration System (ID number: NCT03909113).

Cow's milk is a highly nutritious biological fluid that provides nourishment and immunity to infants when breastfeeding declines. However, some infants, children, and adults are allergic to cow's milk because milk contains potential allergens in the form of proteins. Casein and whey proteins and their coagulated sub-fractions in the milk such as αS1-casein, αS2-casein, β-casein, κ-casein and α-lactalbumin, β-lactoglobulin, bovine serum albumin, immunoglobulins, lactoferrin, respectively are the major etiological determinant of cow's milk allergy (CMA). Moreover, milk processing techniques such as homogenization and pasteurization alter the milk fat and whey protein's molecular structure and serve them as allergens to the immune system of allergic individuals. Strict exclusion of nutrient-rich milk and other dairy products from diet puts children with CMA at higher nutritional risk. Thus, regular nutritional monitoring, the inclusion of protein and mineral-rich supplements as a substitute for cow's milk, management of animal genetics (sheep, goats, buffaloes, camel, mare, donkey, yak), and milk processing to produce non-allergenic milk by inactivating allergic proteins for designer nutrition is essentially required. This review paper details the prevalence, molecular profiling of milk allergens (proteins), body immune response against CMA, consequences of milk processing, treatment, and novel role of galectins as potentially allergy suppressors.

Background: IgE-mediated reactions constitute 70% of cow's milk-induced allergic reactions (AR). There is no established treatment. Recent evidence suggests that immunomodulation with probiotics represents a safe novel strategy, influencing immunity and inducing tolerance to milk protein antigens by action on human gut microbiota. Current evidence focuses most on the infant population. Objective: We will study the impact of Lactobacillus rhamnosus GG (LGG), compared to placebo, as an effective agent to improve ARs upon exposure to cow's milk in children from 5 to 10 years of age. Methods: This will be a phase II, single-center, randomized, double-blinded, placebo-controlled study, where a total of 200 participants will be treated for 12 months, with either; LGG or placebo, randomly allocated at 1:1. A double-blinded placebo-controlled food challenge (DBPCFC) with cow's milk will be used before and after the intervention. Results will be graded using the PRACTALL scoring system. The primary outcome will be binary – 'passing' by the absence of any AR, or a decrease from the baseline results or 'not passing' the DBPCFC after treatment. Secondary outcomes will include covariate adjustment and subgroup analysis by affected body systems and severity of ARs. Secondary analyses will include a comparison of the proportions of the taxonomic composition of gut microbiota, and quality of life, with baseline measurements. Conclusion: This trial will contribute to filling knowledge gaps about cow's milk allergy management using LGG in this specific population as an affordable and accessible non-pharmacological agent with few recorded side effects. If proven to be efficacious, it has the potential to decrease the worldwide prevalence of CMA and the resulting systemic, familial, and personal burdens.

αS1-Casein (encoded by the CSN1S1 gene) is associated with higher rates of allergy than other milk protein components for humans. microRNAs (miRNAs) as small noncoding RNA molecules regulate gene expression and influence diverse biological processes. However, little is known about the regulation of milk protein synthesis by miRNAs in ruminants. In this study, we aim to investigate the regulatory roles of miR-204 family members (miR-204-5p and miR-211) on αS1-casein in goat mammary epithelial cells (GMEC). Here, we observed that the CSN1S1 mRNA level is upregulated, while miR-204-5p and miR-211 (miR-204-5p/-211) abundance is downregulated during peak lactation compared with middle lactation of dairy goats. We found that miR-204-5p/-211 synergistically inhibit αS1-casein expression via directly binding to the 3'-untranslated region (3'UTR) of CSN1S1 in GMEC. miR-204-5p/-211 increase β-casein mRNA (CSN2) and protein abundance, as well as the signal transducer and activator of transcription 5a (STAT5a) activity. Further, miR-204-5p/-211 enhance β-casein expression via the CSN1S1-STAT5a signaling axis and promote β-casein transcription by activating the STAT5 response element located in the CSN2 promoter. In conclusion, miR-204-5p/-211 regulate αS1-casein and β-casein synthesis via targeting CSN1S1 in GMEC, which provide the strategy for manipulating miR-204 family members to reduce milk allergy potential and improve ruminant milk quality for human consumption.

Introduction Early introduction oral immunotherapy (E‐OIT) in the first year of life can be a safe treatment for infants with cow's milk allergy (CMA). Once the protocol is completed, doubts remain whether children achieve tolerance or remain desensitized. According to current guidelines, this is determined by an avoidance period followed by a re‐exposure to the food allergen during an in‐hospital oral food challenge (OFC). In real life, this approach can be complicated, time‐consuming, and anxiety‐provoking for parents. We assessed the long‐term safety of E‐OIT for CMA in a cohort of children who switched to an unrestricted diet without testing the achievement of tolerance at the end of the OIT protocol. Materials and Methods We performed a descriptive analysis of the clinical follow‐up of a cohort of children diagnosed with IgE‐mediated CMA and undergoing E‐OIT protocol in their first year of life. In a previous publication, the same cohort of patients had been studied to assess the feasibility of E‐OIT for CMA. In the present study, we reported the results of a telephone survey, carried out through a questionnaire to their families enquiring about milk consumption and other ongoing atopic conditions of children. Results After an average of 4 years from the start of E‐OIT, 62/73 patients (85% of the historical cohort) participated in the survey. Among them, all 56 patients who had previously successfully completed the protocol reported an unrestricted cow's milk intake. Ninety–three percent of these children did not experience any further allergic reactions, while the remaining 7% described only mild and transitory reactions until the 6‐month period after the end of the protocol. Conclusions This study confirmed the long‐term safety of E‐OIT for CMA and challenged the paradigm of the need for allergen food withdrawal to discern between desensitization and tolerance. It could be a starting point for planning future trials on this issue.

Functional constipation (FC) is one of the most common disorders in childhood and has a neg-ative impact on the quality of life of children. Scientific evidence regarding a causal relation-ship between FC and cow’s milk allergy is controversial, as it is also reported by the latest European Society for Paediatric Gastroenterology, Hepatology and Nutrition-North American Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN–NASPGHAN) rec-ommendations. In the case of FC, routine allergometric tests are not recommended and the cows’ milk-free diet is only proposed in the case of laxative-resistant constipation and only following the advice of an expert. Instead, after a careful review of the literature and in view of the many clinical cases encountered in our clinical practice, we believe that it is useful to propose cows’ milk-free diet as first line for the treatment of FC at least in pre-school children and in children with a personal or family history of atopy or with a previous diagnosis of cow’s milk protein allergy.

Cow’s milk allergy (CMA) is an increasingly common problem among children and adults that requires the use of appropriate diagnostics to eliminate allergic reactions and prevent unnec-essary dietary regimes. The current diagnostics methods are imperfect hence new, more effective methods are still being sought. Component-resolved diagnostics (CRD) is one of them. CRD assesses sensitivity to individual allergen molecules using purified native or recombinant allergens. The present paper reviews the role of CRD in diagnosing CMA, as well as the benefits and limitations of its use, especially in predicting allergy development or acquiring immunotolerance. It examines the possibility of replacing the current gold diagnostic standard with component tests directed against specific milk proteins. In addition, CRD could be helpful in the evaluation of prognosis. However, CRD allows for improvement in clinical management, particularly of polysensitized subjects, there is still no cogent evidence that it offers more efficient CMA diagnostics than existing tests.

Background: Cow’s milk protein allergy (CMPA): The topic of definition still causes confusion among physicians. Words such as “allergy,” “intolerance,” and “hypersensitivity” are used interchangeably. The accepted definition of allergy is “a hypersensitivity reaction triggered by specific immunologic mechanisms”. There is no such thing as “allergy to lactose” but rather lactose intolerance. The authors introduced the acronym “CoMiSS” (cow’s milk-related symptom score). Objective: To evaluate CoMiSS in children with cow's milk allergy at Pediatric Department, Faculty of Medicine, Zagazig University. Patients and Methods: This study was conducted during the period from December 2018 to May 2020. Cow’s milk-related symptom score was assessed. Results: There was statistically significant increase in eosinophilic count among confirmed CMA than no CMA. There was statistically significant higher total score of CoMiSS among confirmed CMA than no CMA, and another one regarding each symptom of CoMiSS score. Accuracy of CoMiSS in diagnosis of CMA was 90.8%. The percentage was for sensitivity (86.4%), specificity (93.4%), positive predictive value (88.3%) when the score is >12 and negative predictive value (92.2%). Conclusion: CoMiSS is a simple, fast, and easy-to-use tool to raise awareness and help in early diagnosis of CMPA, but hard to handle with many of illiterate mothers. CoMiSS is a helpful tool and applicable method to screen for CMPA, though there may be risk of under-diagnosis when CoMiSS≥12 is used as the criterion for early pick-up of CMPA in Egyptian infants.

BACKGROUND Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy causing severe acute gastrointestinal symptoms and lethargy, mainly affecting infants and young children. There are geographic variations in its clinical features. This study aimed to describe the clinical characteristics and management of FPIES in Swedish children. METHODS The study included children who presented with acute FPIES during 2008-2017. All Swedish pediatric departments (n = 32) were invited to report their known patients. Data were collected through chart reviews and interviews with parents. RESULTS Eighteen pediatric departments contributed, and 113 patients were included. Most had a family history of atopy (74%), and 51% had an atopic disease. Common trigger foods were cow's milk (26%), fish (25%), oat (22%), and rice (8%). Most patients (85%) reacted to a single food. The median age at first reaction was 3.9 months for cow's milk and 6.0 months for other foods (p

Background: Cow’s milk is one of the first foods added to infants’ diet and cow’s milk allergy (CMA) is the most common food allergy in the first year of life. The aim of this study was to survey the frequency of infants with cow’s milk allergy using COMISS questionnaire. Methods: In a cross-sectional, descriptive study, 100 infants were selected by a convenient method. Demographic information and clinical manifestations were completed based on COMISS Questionnaire for all infants. Data were analyzed using chi-square and independent t-test. Results: The finding of this study shows that from 100 infants (51 males, 49 females), with a mean age of 3.5 ± 1.4, 61% of them were breastfed, 30% were fed both cow’s milk and breast milk, and 9% were fed only cow’s milk. The probability of cow’s milk allergy using the COMISS Questionnaire was positive in 8% of infants. According to the criteria of this Questionnaire, 65% of infants acquired a score of 0-5, 27% scored 6-11, and 8% scored 12 and above A significant association was found between cow’s milk allergy and infant’s diet (p

For patients with inflammatory bowel disease, cow’s milk allergy, and lactose intolerance, soymilk is a potential alternative to cow’s milk. In this study, we aimed to identify the effects of a soy protein-based low-protein diet on the body and organ weights and the gut microbiome of six-week-old mice fed a diet containing 20% (SP) or 5% (LP) soy protein for 14 days via 16S rRNA (V4) amplicon sequencing. Body weight gain (growth) and liver, spleen, and fat tissue weight were significantly suppressed by the LP diet. Operational taxonomic unit numbers and α-diversity were lower in the LP group than in the SP group. A principal coordinate analysis revealed differences in the gut microbiome compositions of SP and LP mice. The abundances of caecal Roseburia sp., Alistipes sp., and bacteria from the family Muribaculaceae were lower in the LP group than in the SP group. In contrast, the abundance of Desulfovibrionaceae, which is positively correlated with inflammation, was higher in the LP group than in the SP group. These results differed from the effects of a milk casein-based low-protein diet (reported previously). Based on these findings, we conclude that the undesirable effects of a low-protein diet and/or protein deficiency are related to changes in the gut microbiome composition and may differ depending on the kind of proteins used.

Relevance. Dairy-free diet is the basis of cow’s milk allergy (CMA) patient’s management. Duration of the diet is individual, but some children don’t develop tolerance.The aim of the study was to investigate health and growth indices in children with CMA depending on tolerance development by the age of five. Materials and methods. 153 children from 1 to 18 months with diagnosed CMA were included in the prospective study (76.5% with IgE-mediated form). The tolerance was determined after 6–12 months of a milk-free diet and at the age of 5 using an open challenge test. Anthropometry indices (Anthro Plus), levels of specific IgE (Immuno CAP 250) and IgG4 (ELISA) to dietary proteins and the presence of allergic diseases in children also were assessed.Results. 50.3% of children developed tolerance to cow’s milk protein after 6–12 months of a milk-free diet. By the age of 5 63.3% of patients had complete tolerance of dairy products. Partially formed tolerance was observed in 22.9%. 13.8% of patients still had clinical reactions to cow’s milk proteins. Patients with persistent CMA typically had IgE-mediated form, lower growth indices and multiple allergic pathology.Conclusion. The consideration of tolerance development predictors can allow to personalize the management of CMA. Additional researches are needed to clarify the causes of growth indices decline in children with persistent CMA.

Cow’s milk allergy is a common food allergy among infants. Symptoms of cow’s milk allergy are wide-ranging and depend on the mechanism involved. There are immunoglobulin E (IgE)-mediated, non–IgE-mediated, and mixed mechanisms of food allergy. Symptoms of IgE-mediated cow’s milk allergy may be mild or may progress to anaphylaxis, which can be life-threatening. Non–IgE-mediated allergy includes food protein–induced allergic proctocolitis (FPIAP), food protein–induced enterocolitis syndrome, food protein–induced enteropathy, and Heiner syndrome (pulmonary hemosiderosis). These diagnoses comprise about half of all cow’s milk allergies. The most common manifestation of cow’s milk allergy in infants is FPIAP. FPIAP is commonly seen in healthy, full-term infants who present with rectal bleeding and are otherwise well-appearing. This can occur in both formula-fed and exclusively breastfed infants. Food proteins secreted in maternal breast milk can contribute to the development of these symptoms. Maternal cow’s milk elimination diet is often successful in helping resolve symptoms. A period of reintroduction of cow’s milk resulting in re-emergence of symptoms in stable asymptomatic infants is an excellent diagnostic tool to confirm a cow’s milk allergy. Preterm infants are susceptible to food allergy, as demonstrated from several case reports of necrotizing enterocolitis–like illnesses that responded clinically to cow’s milk elimination. Further study is needed about food allergy in the preterm infant population.

Introduction: Cow’s milk allergy (CMA) is one of the most common food allergies especially early in life. A mixture of nondigestible short-chain galacto-oligosaccharides, long-chain fructo-oligosaccharides, and pectin-derived acidic-oligosaccharides (GFA) may reduce allergy development and allergic symptoms in murine CMA. Recently, vitamin D (VitD) has been suggested to have beneficial effects in reducing allergy as well. Objective: In this study, the immune modulatory effect on allergy prevention using the combination of GFA and VitD was investigated. Methods: Female C3H/HeOuJ mice were fed a control or GFA-containing diet with depleted, standard (1,000 IU/kg), or supplemented (5,000 IU/kg) VitD content for 2 weeks before and during whey sensitization (n = 10–15). Mice were sensitized 5 times intragastrically with PBS as a control, whey as cow’s milk allergen, and/or cholera toxin as adjuvant on a weekly interval. One week after the last sensitization, mice were intradermally challenged in both ear pinnae and orally with whey, subsequently the acute allergic skin response and shock symptoms were measured. After 18 h, terminal blood samples, mesenteric lymph nodes, and spleens were collected. Whey-specific immunoglobulin (Ig) E and IgG1 levels were measured by means of ELISA. T cell subsets and dendritic cells (DCs) were studied using flow cytometry. Results: Additional VitD supplementation did not lower the allergic symptoms compared to the standard VitD diet. CMA mice fed the GFA diet supplemented with VitD (GFA VitD+) significantly decreased the acute allergic skin response of whey sensitized mice when compared to the CMA mice fed VitD (VitD+) group (p < 0.05). The effect of GFA was not improved by extra VitD supplementation even though the CMA mice fed the GFA VitD+ diet had a significantly increased percentage of CD103+ DCs compared to the VitD+ group (p < 0.05). The VitD-deprived mice showed a high percentage of severe shock and many reached the humane endpoint; therefore, these groups were not further analyzed. Conclusions: High-dose VitD supplementation in mice does not protect against CMA development in the presence or absence of GFA.

Objective: To assess the notion that milk can cause or aggravate asthma and break this myth. Study Design: A cross sectional study. Place and Duration of Study: Medicine department, Combined Military Hospital Lahore, from Jan 2019 to Dec2020. Methodology: A survey was conducted whereby known asthmatics were questioned about their opinion weather milk aggravates their asthma. Those who confirmed their positive response were exposed to milk and some liquid resembling milk, and their Lung functions were tested after each drink. The 42 patients who considered milk as the primary aggravator were called for the study for spirometry Results: A total of 600 people from the general population were surveyed. Two hundred and six (34.3%) of them were illiterate, 394 (65.6%) were educated from middle to graduates. In the first milk/milk encounter, the combined dyspnea scale showed increase of 50.3% and improvement of 0.008% in FEVI/FVC. In the second substitute/milk encounter, the dyspnea score showed an increase of 61.8% and an increase of 0.90% in FEVI/FVC. In the third milk/substitute encounter the dyspnea score showed a decrease of 22.9% and the FEVI/FVC decreases by 5.5%. In the 4th substitute/substitute encounter, dyspnea scores decreased by 8.4% while the pre and postencounter FEVI/ FVC scores were 2726 and 2711 with 0.55% decrease with insignificant p-value >0.05. Conclusion: Drinking milk or milk substitute has negligible effect on the spirometric parameters.

Background: We previously reported that the specific IgE levels to αs1-casein (CN) and β-CN in patients with cow’s milk allergy decreased with similar dynamics during oral immunotherapy. Therefore, we hypothesized that αs1- and β-CN have strong cross-reactivity among CN components, despite the low similarity in the full-length amino acid sequences. Methods: The αs1-, β-, and κ-CN were purified from commercial cow’s milk. We recruited 39 patients with cow’s milk allergy and the serum IgE levels for each CN component were measured by enzyme-linked immunosorbent assay (ELISA). Cross-reactivity between CN components was investigated by competitive ELISA against αs1-CN. Sequence homology between CN components at the peptide level was calculated using in silico analysis and quantified by the Property Distance (PD) value. Results: The αs1-CN-specific IgE levels exhibited a strong positive correlation with the β-CN-specific IgE (r = 0.945, P < 0.001). Complete competition was observed by β-CN against αs1-CN, suggesting the presence of common epitopes between them. In silico analysis detected 24 peptide sets with PD values lower than 10 between αs1- and β-CN, and 14 sets between αs1- and κ-CN. The amino acid sequences of αs1- (E61-E70) and β-CN (I12-E21) that showed the lowest PD value (5.30) were present in the characteristic sequence known as casein phosphopeptide (CPP). Conclusion: We detected strong cross-reactivity between CN components. Furthermore, we found highly homologous sequences in the CPP region, which contains a core sequence of “SSSEE” with phosphorylated serine residues.

Background Patients are commonly challenged with foods containing baked milk, for example muffins, yet little is known about the specific allergen content of muffins used in milk challenges or of the effect that baking has on allergenicity. Objective Our objective was to compare the levels of major milk allergens in uncooked and baked muffins using monoclonal immunoassays and IgE antibody binding before and after baking. Methods Uncooked and baked muffins were prepared using recipes from Mount Sinai and Imperial College. Allergen levels were compared by ELISA for Bos d 5 (β-lactoglobulin) and Bos d 11 (β-casein). IgE reactivity was assessed using sera from milk-sensitized donors in direct binding and inhibition ELISA. Results Bos d 5 was reduced from 680 µg/g in uncooked muffin mix to 0.17 µg/g in baked muffins, representing a >99% decrease after baking. Conversely, Bos d 11 levels in baked muffin remained high and only decreased by 30% from a mean of 4249 µg/g in uncooked muffin mix to 2961 µg/g when baked (~181 mg Bos d 11 per muffin). Baked muffins retained ~70% of the IgE binding to uncooked muffin mix. Baked muffin extract inhibited IgE binding to uncooked muffin mix by up to 80%, demonstrating retention of in vitro IgE reactivity. Conclusions and clinical relevance High levels of Bos d 11 in baked muffins pose a risk for adverse reactions, especially in patients who have high anti-casein IgE antibodies.

This research communication relates to the hypothesis that the consumption of raw or unprocessed cow's milk contributes to lowered prevalence of allergies. Thermal pasteurization of bovine milk can result in denaturation of minor whey proteins and loss of their bioactivity. Denaturation of bovine serum albumin (BSA), immunoglobulin G (IgG) and lactoferrin (LF) in skim milk was studied under different temperature (72, 75 or 78°C) and time (0–300 s) combinations. Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) results revealed that denaturation of all 3 proteins occurred at 72°C and progressed with increase in temperature and holding time. About 59% of LF and 12% of IgG denatured under high-temperature short-time (72°C/ 15 s) pasteurization, while BSA was least impacted. To assess modulation of milk immunogenicity, secretion of selected T helper (Th)-type cytokines by human peripheral blood mononuclear cells (PBMCs) was studied in vitro in response to different concentrations of BSA (0.4–1.0 mg/ml) and IgG (0.8–1.6 mg/ml) in unheated skim milk. Addition of IgG at 1.6 mg/ml induced a prominent Th1-skewed cytokine profile that may not trigger a Th2-skewed allergic reaction. BSA did not appear to modulate milk immunogenicity to any significant extent.

Cows' milk allergy (CMA) is a hypersensitivity immune reaction brought on by specific immunologic mechanisms to cow's milk proteins. As one of the most common food allergies in infants, the incidence of CMA during the first year of life is estimated to be nearly 7.5%. Due to the limitation in the knowledge of the pathological mechanism underlying CMA, however, the clinical interventions and therapies remain very unsatisfactory.The transcriptional factor FOXP3 possesses crucial roles in CMA, and increased FOXP3 mRNA expression has a predictive function in faster acquisition of tolerance in infants with CMA. But the exact mechanism remains not fully elucidated.For PAG treatment, PAG (dissolved in saline 30 mg/mL, 0, 5, 10, 20 mg/kg BW) was administered daily intraperitoneally (ip) for one week at the time that 6 weeks after the CMP sensitisation.In the present study, we revealed that the expression of FOXP3 is significantly up-regulated in PBMCs from CMA patients and CMA mice on mRNA and protein level. Furthermore, a dramatic reduction in the FOXP3 TSDR methylation and a significant increase in the expression of TET2 are observed in CMA patients and CMA mice. More importantly, we found that propargylglycine (PAG) significantly alleviates symptoms of CMA in mice by suppressing the expression of FOXP3 through restoring TET2 expression.Our work revealed a novel function of PAG on CMA, which may provide a deeper insight into the pathomechanism of CMA and a novel therapy target for CMA clinical interventions.

BACKGROUND AND OBJECTIVE Treg cells and dietetic factors may play a significant role in the natural acquisition of tolerance in children with cow's milk allergy (CMA). The best marker for Treg lymphocytes is the transcription factor forkhead boxP3 (FOXP3). Objective: We examine the relationship between FOXP3 mRNA expression and serum concentrations of vitamins D and C and the development of different phenotypes of tolerance in children with CMA. MATERIAL AND METHODS The study group comprised 138 infants with CMA and 101 healthy infants. All children underwent oral food challenge, first with an extensively heated milk product and then with unheated products. FOXP3 mRNA expression and serum vitamin C and D concentrations were evaluated. RESULTS At 2 years of life, 54 children (39.1%) still had CMA, 43 (31.2%) were unheated milk-reactive and heated milk-tolerant, while 41 (29.7%) had outgrown their allergy. The mean (SD) level of FOXP3 expression in the study group was 2.07 (1.23), which was lower than the control group value of 2.98 (1.52) (P

Gamma irradiation is a well-known method for sterilizing different foodstuffs, including fresh cow milk. Many studies witness that the low dose irradiation of milk and milk products affects the fractions of the milk protein, thus reducing its allergenic effect and make it potentially appropriate for people with milk allergy. The purpose of this study is to evaluate the relationship between the gamma radiation dose and size of the protein fractions, as potential approach to decrease the allergenic effect of the milk. In this paper, an approach for prediction of the dose in gamma irradiated products by using a Bayesian regularized neural network as a mean to save recourses for expensive electrophoretic experiments, is developed. The efficiency of the proposed neural network model is proved on data for two dairy products – lyophilized cow milk and curd.

Objective To summarize evidence on the efficacy and safety of the use of extensively hydrolyzed formulas (EHFs) for the treatment of children with cow's milk allergy (CMA). Design Systematic review of randomized controlled trials (RCTs) per PRISMA guidelines. The risk of bias of included RCTs was assessed using the Cochrane Collaboration's risk of bias tool. In general, a narrative synthesis of the findings was performed. When sufficient data were available, a meta-analysis using the random-effect model was performed. Data sources The Cochrane Library, MEDLINE, and EMBASE databases were searched up to February 2020. Eligibility criteria RCTs, including cross-over trials, assessing children of any age with any type of CMA that compared use of a formula containing extensively hydrolyzed bovine proteins (whey and/or casein) with use of any other formula for CMA management, were eligible for inclusion. Each type of EHF was evaluated separately. Outcome measures included allergic reactions (ie gastrointestinal, dermatological, and respiratory symptoms), growth, tolerance acquisition to cow's milk proteins, health-related quality of life, and safety. Results Fifteen trials reported in 18 publications (1285 children) fulfilled the inclusion criteria. The study findings were limited by numerous methodological issues, including differences in outcome measures and their definitions, lack of pre-specified protocols and/or trial registration, and poor reporting of adverse events, methods of sequence generation and allocation concealment. The EHF products evaluated to date appear to be well-tolerated by most children with CMA. However, published studies do not allow for any conclusion to be reached regarding the benefit of one formula over another formula intended for CMA management. Conclusions This systematic review highlights the need for standardized treatment protocols, including an agreed-upon standardized set of outcomes that should be measured and reported in all clinical trials of specialized milk formula for the management of CMA.

Milk allergy is among the most common food allergies present in early childhood, which in some cases may persist into adulthood as well. Proteins belonging to both casein and whey fractions of milk can trigger an allergic response in susceptible individuals. Milk is present as an ingredient in many foods, and it can also be present as casein- or whey-enriched milk-derived ingredients. As whey proteins are more susceptible to thermal processing than caseins, conventional methods often posed a challenge in accurate detection of whey allergens, particularly from a processed complex food matrix. In this study, a targeted mass spectrometry method has been developed to detect the presence of both casein and whey allergens from thermally processed foods. A pool of 19 candidate peptides representing four casein proteins and two whey proteins was identified using a discovery-driven target selection approach from various milk-derived ingredients. These target peptides were evaluated by parallel reaction monitoring of baked cookie samples containing known amounts of nonfat dry milk (NFDM). The presence of milk could be detected from baked cookies incurred with NFDM at levels as low as 1 ppm using seven peptides representing α-, β-, and κ-casein proteins and three peptides representing a whey protein, β-lactoglobulin, by this consensus PRM method.

Objectives Infants with cow's milk allergy (CMA) are in need of a substitute formula up to 2 years. The are three requisites for a substitute of milk in CMA: tolerability, nutritional adequacy, and cost‐effectiveness. We evaluate here the tolerability of a new amino acid–based infant formula for the management of CMA. Methods In a phase III/IV prospective, multicentre, open‐label, international study, infants and children with immunoglobulin E‐mediated CMA were exposed to a diagnostic double‐blinded, placebo‐controlled food challenge with a new amino acid formula by Blemil Plus Elemental using Neocate as the placebo. If tolerant to it, the study formula was integrated into the patients’ usual daily diet for 7 days. Efficacy on day 7 was assessed in terms of symptoms associated with CMA, amount of formula consumed, nutritional and energy intake, and anthropometric data. Results Thirty children (17 M and 13 F; median age, 1.58; range, 0.08‐12.83 years) completed the open challenge and were able to consume the study formula for at least 7 days. No signs or symptoms of allergic reactions were recorded among children assuming either the test or the control formula, with a lower 95% one‐sided confidence interval for the proportion of subjects who did not experience allergic reactions above 90%. Sixteen patient under the age of two continued with the optional extension phase. Conclusions The study formula meets the American Academy of Pediatric criteria for hypoallergenicity and is well tolerated in short‐term use. During optional phase, growth of the patients was not hindered by the study formula., This study provides data on a new amino acid formula, documenting the hypoallergenicity of such a preparation in a cohort of children with milk allergy. These children are in need of a substitute formula especially up to 2 years. We designed a study in compliance with the rules and procedures indicated by the American Academy of Pediatric regarding studies on new special formulas to be included in the therapeutic options.

Purpose of review The aim of this review is to describe the role of precision medicine in the diagnosis, treatment, and monitoring of cow's milk allergy. Recent findings The development of 'omics' sciences in the field of food allergy has led to a better understanding of the allergenicity of cow's milk proteins and significant advances in the knowledge of the pathogenesis and mechanisms of cow's milk allergy. Omics-based technologies allow the practitioner to better differentiate cow's milk allergy subtypes and to predict cow's milk allergy (CMA) persistence over time. Precision medicine extends the role of the oral food challenge, to determine the individual's threshold doses, and to establish tolerance to baked milk products. Other than symptom relief, dietary strategies are currently being investigated for the potential to induce tolerance. Oral immunotherapy offers a treatment option for patients with severe and persistent IgE-mediated CMA. Individual baseline-immune profiles may be predictive of cow's milk oral immunotherapy safety and efficacy.Patient data derived from current technology, in combination with the patient's history, can be translated into treatments targeted at patient-tailored interventions. Summary The identification of novel biomarkers may improve diagnostic accuracy and also predict patient responsiveness to treatments. Integration of patient data will become increasingly important as omics technologies become more widely used in the clinical setting.

Several factors are fundamental to support child growth and development, including nutrition. Beside Energy, protein is the key of balanced dietary macronutrients intake as the building block of child growth. While several micronutrients, i.e. calcium, iron, zinc and vitamins are needed for both optimal growth and development. Among protein-rich foods for young children, cow’s milk formula has several limitations, i.e. cow’s milk allergy and low fiber content. Although has a low bioavailability for iron absorption, plant-rich protein can be an alternative for young children to be used, i.e. as a soy isolate protein formula. However, to the fact of low fiber content in soy isolate protein formula, it is then need further consideration to have a fiber enrichment. We highlight the fiber content in child formula to the extent of its benefit for gastrointestinal health in relation to gut movement in preventing constipation, or its role as a functional food with its prebiotics capacity. This article aims to review a suitable type of fiber used for the enrichment for a soy isolate protein formula.

BackgroundFood processing, including heat‐treatment, can affect protein structure and stability, and consequently affect protein immunogenicity and allergenicity. A few studies have shown that structural changes induced by heat‐treatment impact the intestinal protein uptake and suggest this as a contributing factor for altered allergenicity.ObjectiveTo investigate the impact of heat‐treatment of a whey‐based protein product on allergenicity and tolerogenicity as well as on intestinal uptake in various animal models.MethodsImmunogenicity and sensitising capacity of the heat‐treated whey product was compared to that of the unmodified product by intraperitoneal and oral exposure studies, while tolerogenic properties were assessed by oral primary prevention and desensitisation studies in high‐IgE responder Brown Norway rats.ResultsHeat‐treatment of whey induced partial protein denaturation and aggregation, which reduced the intraperitoneal sensitising capacity but not immunogenicity. In contrast, heat‐treatment did not influence the oral sensitising capacity, but the heat‐treated whey showed a significantly reduced eliciting capacity compared to unmodified whey upon oral challenge. Heat‐treatment did not reduce the tolerogenic properties of whey, as both products were equally good at preventing sensitisation in naïve rats as well as desensitising already sensitised rats. Results from inhibitory ELISA and immunoblots with sera from sensitised rats demonstrated that heat‐treatment caused an altered protein and epitope reactivity. Protein uptake studies showed that heat‐treatment changed the route of uptake with less whey being absorbed through the epithelium but more into the payer's patches.Conclusion & Clinical RelevanceThese results support the notion that the physicochemical features of proteins affect their route of uptake and that the route of uptake may affect the protein allergenicity. Furthermore, the study highlights the potential for heat‐treatment in the production of efficient and safe cow's milk protein‐based products for prevention and treatment of cow's milk allergy.

Background Amino acid‐based formulas (AAFs) are used for the dietary management of cow's milk allergy (CMA). Whether AAFs have the potential to prevent the development and/or symptoms of CMA is not known. Objective The present study evaluated the preventive effects of an amino acid (AA)‐based diet on allergic sensitization and symptoms of CMA in mice and aimed to provide insight into the underlying mechanism. Methods C3H/HeOuJ mice were sensitized with whey protein or with phosphate‐buffered saline as sham‐sensitized control. Starting 2 weeks before sensitization, mice were fed with either a protein‐based diet or an AA‐based diet with an AA composition based on that of the AAF Neocate, a commercially available AAF prescribed for the dietary management of CMA. Upon challenge, allergic symptoms, mast cell degranulation, whey‐specific immunoglobulin levels, and FoxP3+ cell counts in jejunum sections were assessed. Results Compared to mice fed with the protein‐based diet, AA‐fed mice had significantly lower acute allergic skin responses. Moreover, the AA‐based diet prevented the whey‐induced symptoms of anaphylaxis and drop in body temperature. Whereas the AA‐based diet had no effect on the levels of serum IgE and mucosal mast cell protease‐1 (mMCP‐1), AA‐fed mice had significantly lower serum IgG2a levels and tended to have lower IgG1 levels (P = .076). In addition, the AA‐based diet prevented the whey‐induced decrease in FoxP3+ cells. In sham‐sensitized mice, no differences between the two diets were observed in any of the tested parameters. Conclusion This study demonstrates that an AA‐based diet can at least partially prevent allergic symptoms of CMA in mice. Differences in FoxP3+ cell counts and serum levels of IgG2a and IgG1 may suggest enhanced anti‐inflammatory and tolerizing capacities in AA‐fed mice. This, combined with the absence of effects in sham‐sensitized mice indicates that AAFs for the prevention of food allergies may be an interesting concept that warrants further research., This study demonstrates that an amino acid‐based diet can at least partially prevent clinical symptoms of cow's milk allergy (CMA) in mice. Differences in FoxP3+ cell counts and serum levels of IgG2a and IgG1 suggest enhanced anti‐inflammatory and tolerizing capacities in mice fed the amino acid‐based diet.

Background Tolerance development is an important clinical outcome for infants with cow's milk allergy. Objective This multicenter, prospective, randomized, double-blind, controlled clinical study (NTR3725) evaluated tolerance development to cow's milk (CM) and safety of an amino acid–based formula (AAF) including synbiotics (AAF-S) comprising prebiotic oligosaccharides (oligofructose, inulin) and probiotic Bifidobacterium breve M-16V in infants with confirmed IgE-mediated CM allergy. Methods Subjects aged ≤13 months with IgE-mediated CM allergy were randomized to receive AAF-S (n = 80) or AAF (n = 89) for 12 months. Stratification was based on CM skin prick test wheal size and study site. After 12 and 24 months, CM tolerance was evaluated by double-blind, placebo-controlled food challenge. A logistic regression model used the all-subjects randomized data set. Results At baseline, mean ± SD age was 9.36 ± 2.53 months. At 12 and 24 months, respectively, 49% and 62% of subjects were CM tolerant (AAF-S 45% and 64%; AAF 52% and 59%), and not differ significantly between groups. During the 12-month intervention, the number of subjects reporting at least 1 adverse event did not significantly differ between groups; however, fewer subjects required hospitalization due to serious adverse events categorized as infections in the AAF-S versus AAF group (9% vs 20%; P = .036). Conclusions After 12 and 24 months, CM tolerance was not different between groups and was in line with natural outgrowth. Results suggest that during the intervention, fewer subjects receiving AAF-S required hospitalization due to infections.

Necrotizing enterocolitis is one of the most common and worrying diseases in neonates, commonly shown in premature neonates, and is associated with significant mortality and morbidity. Necrotizing enterocolitis is characterized by intestinal mucosal injury that can progress to transmural bowel necrosis, and radiologically it can present with either pneumatosis intestinalis or portal venous gas. It is postulated to develop in an immunocompromised host in the setting of bacterial colonization, usually after administration of non-breast milk feed. Cow's milk allergy association with necrotizing enterocolitis has not been well determined, and the pathophysiology is still not clear. Necrotizing enterocolitis is very rare following living donor liver transplant. In our case, a 6-year-old boy who was doing well in the postoperative period had sudden worsening of general condition after he was started on milk feed. On evaluation and reexploration, he was diagnosed with necrotizing enterocolitis and later succumbed to death.

Immunoglobulin G; Anaphylaxis; Casein Inmunoglobulina G; Anafilaxis; Caseína Immunoglobulina G; Anafilaxi; Caseïna

Characteristics of chronic milk-dependent food protein-induced enterocolitis syndrome (FPIES) in children from the region of Western Pomerania were studied. Prospectively, 55 children were diagnosed at a median of 2.2 months. The open food challenges (OFC), morphologies, milk-specific IgE (sIgE) (FEIA method, CAP system), and skin prick tests (SPTs) were examined. Vomiting and diarrhea escalated gradually but quickly led to growth retardation. Of the infants, 49% had BMI &lt, 10 c, 20% BMI &lt, 3 c, 25% had anemia, and 15% had hypoalbuminemia. During the OFCs we observed acute symptoms that appeared after 2–3 h: vomiting diarrhea and pallor. A total of 42% children required intravenous hydration. Casein hydrolysates or amino acids formulae (20%) were used in treatment. In 25% of children, SPT and milk sIgE were found, in 18%—other food SPTs, and in 14% allergy to other foods. A transition to IgE-dependent milk allergy was seen in 3 children. In the twelfth month of life, 62% of children had tolerance to milk, and in the twenty-fifth month—87%. Conclusions. Chronic milk-dependent FPIES resolves in most children. By the age of 2 children are at risk of multiple food sensitization, and those who have milk sIgE are at risk to transition to IgE-mediated milk allergy. Every OFC needs to be supervised due to possible severe reactions.

Food allergy is an immune system reaction to a particular food, milk being the most common one. β-Lactoglobulin (β-Lg) is the main ingredient of milk protein and the main cause of infant milk allergy. On such an occasion, the determination of β-Lg is very important and the electrochemical sensors are a good alternative for this purpose since they are sensitive, selective and inexpensive. In this work, an electrochemical aptasensor was fabricated for the quantitative detection of β-Lg in hypoallergenic formula (HF) milk. A tri-functional hairpin (HP) was designed, which was composed of an aptamer sequence, a nicking site and a DNA sequence (T1). In the absence of β-Lg, the aptamer part hybridized with T1 to form a stable stem-loop structure. However, in the presence of β-Lg, the capture of the aptamer sequence towards β-Lg caused the reconstruction of HP and thus the nicking sites were exposed. Then, the nicking enzyme was activated and T1 could be released, which bound with the end of the hairpin 1-methylene blue (HP1-MB)/HP2-MB conjugation on the Au nanoparticle (AuNP) modified electrode surface. Thus, the insulating property of the electrode was enhanced and the current response of MB decreased, which built the quantitative basis for β-Lg detection. In this way, the proposed aptasensor exhibited a wide linear range of 0.01–100 ng mL−1 and a low detection limit of 5.7 pg mL−1. This aptasensor also displayed high selectivity, reproducibility and stability, and became a promising platform for β-Lg detection in real food samples.