Tolerance induction through early feeding to prevent food allergy in infants and children with sensitization against food allergens (TIFFANI): rationale, study design, and methods of a randomized controlled trial.

BACKGROUND: Children with sensitization against foods have to be orally food-challenged before eating these foods for the first time. However, the waiting time for an oral food challenge (OFC) in Germany is about 3-6 months. In contrast, there are hints that an early introduction of allergenic foods might be protective regarding the development of food allergy. The aim of this clinical trial is therefore to investigate, whether an introduction and regular consumption of small amounts of food allergens is safe and will result in an increase of tolerance in children with sensitization against food allergens with unknown clinical relevance. METHODS: In this randomized, placebo-controlled, double-blind, single-center trial, 138 children (8 months to 4 years of age) sensitized to the target allergen(s) hen's egg, cow's milk, peanuts, and/or hazelnuts with unknown clinical relevance will be randomized in a 1:1 ratio to either an active or a placebo group, daily receiving a rusk-like biscuit powder with or without the target allergen(s) for 3-6 months until an OFC will be performed in routine diagnostics. The primary endpoint is an IgE-mediated food allergy to the primary target allergen, after the interventional period. DISCUSSION: Children with sensitization against food allergens with unknown clinical relevance often have to avoid the corresponding foods for several months until an OFC is performed. Therefore, the "window of opportunity" for an early preventive introduction of allergenic foods might be missed. This trial will assess whether an introduction of small allergen amounts will favor tolerance development in these children. TRIAL REGISTRATION: German Clinical Trials Register DRKS00032769. Registered on 02 October 2023.

Dietary management of IgE and non-IgE-mediated food allergies in pediatric patients.

Food allergies (FA) consist of both IgE and non-IgE-mediated entities, with varying phenotypes and overlapping and different considerations for each specific disease presentation. In general, all FAs place children at increased risk for inadequate nutritional intake and negative impacts on their nutritional status, as well as negative impacts on the quality of life for the entire family. To minimize these untoward effects, a multidisciplinary approach should be taken, including consultation and management with a dietitian trained in the varying presentations of FA. Families should be instructed on label reading as a first line of nutritional management. During a nutrition consultation, the age of the child, growth, and nutritional status should be considered. Food refusal should be assessed and addressed. Families should be educated on avoidance and appropriate substitutions. In the case of cow's milk allergy, a suitable specialized formula should be suggested if the infant is not breastfed or if breast milk supply is not sufficient. Other mammalian milk should be avoided and careful consideration should be given before plant-based milk is used in young children. Specific food allergies may differ in terms of advice provided on the level of avoidance required, whether precautionary advisory labels should be avoided, and if a maternal avoidance of the allergen during breastfeeding should be advised. The role of immunonutrition on overall health should be discussed.

Milk and multiple sclerosis: A possible link?

Despite having been formally defined over 150 years ago, the etiology of multiple sclerosis (MS) is still relatively unknown. However, it is now recognized as a multifactorial disease in which genetics, infection, immune function, and environment play a role. We propose an additional piece to the puzzle: milk. In this review, milk is highlighted as a potential risk factor for MS. We examine the overall correlation between bovine milk consumption and the incidence of MS. We then discuss possible mechanisms that may explain the positive association between milk consumption and the development of MS. For instance, butyrophilin (BTN), a milk glycoprotein, can provide molecular mimicry of myelin oligodendrocyte glycoprotein and induce an autoinflammatory response against myelin. Other milk components such as casein, gangliosides, xanthine oxidase, and saturated fats are also analyzed for their potential involvement in the pathophysiology of MS. Finally, we fit milk alongside other well known risk factors of MS: vitamin D levels, Epstein Barr virus infection, and gut dysbiosis. In conclusion, this review summarizes potential mechanisms linking milk as an underappreciated potential risk factor for the development of MS.

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.

Timing of initial symptom onset during milk and wheat challenges: A retrospective study.

BACKGROUND: Allergic reactions to milk appear sooner than those to hen's eggs, irrespective of the total dose of the oral food challenges (OFCs) and type of matrices. The reported median times for the first symptom occurrence are 20-30 min with milk and 50-60 min with eggs. However, allergic reactions due to wheat have not yet been fully investigated. METHODS: This study retrospectively collected data from OFC for milk and wheat conducted at Sagamihara National Hospital and Sendai Medical Center from 2009 to 2023. The time from the start of the OFC to the onset of symptoms was compared between children with cow's milk and wheat allergy. RESULTS: Twenty-five and 13 children reacted to single-dose OFCs with milk products equivalent to 25 mL of raw cow's milk or 15 g of udon noodles, respectively. The median ages of patients with positive challenges were 1.4 and 2.8 years for milk and wheat, respectively, and the median times for the first symptom occurrence were 20 min and 53 min, respectively (p = .006). CONCLUSION: This multicenter study was the first to examine the time of symptom appearance during single-medium-dose milk and wheat challenges. Allergic reactions to wheat appear later than those for milk during OFC. For multiadministration OFC for wheat, the dosing interval should be longer than 60 min. Our findings can help improve the safety of OFCs.

Lactose Intolerance versus Cow's Milk Allergy in Infants: A Clinical Dilemma.

Due to its very early introduction, cow's milk is one of the first foods that can cause adverse reactions in human beings. Lactose intolerance (LI) and cow's milk allergy (CMA) are the most common adverse reactions to cow's milk. While LI is due to insufficient small intestinal lactase activity and/or a large quantity of ingested lactose, CMA is an aberrant immune reaction to cow's milk proteins, particularly casein or ß-lactoglobulin. However, the clinical manifestations of LI and CMA, particularly their gastrointestinal signs and symptoms, are very similar, which might lead to misdiagnosis or delayed diagnosis as well as nutritional risks due to inappropriate dietary interventions or unnecessary dietary restriction. Formula-fed infants with LI should be treated with formula with reduced or no lactose, while those with CMA should be treated with formula containing extensive hydrolyzed cow's milk protein or amino acids. This review is therefore written to assist clinicians to better understand the pathophysiologies of LI and CMA as well as to recognize the similarities and differences between clinical manifestations of LI and CMA.

Milk coagulation and gastric emptying in women experiencing gastrointestinal symptoms after ingestion of cow's milk.

BACKGROUND: Gastrointestinal symptoms after drinking milk are often attributed to lactose intolerance or cow's milk allergy. However, some individuals without either condition still report gastrointestinal symptoms after drinking milk. This may be caused by gastric emptying (GE) rate or gastric protein coagulation. This study aimed to compare GE rate and protein coagulation after milk consumption between individuals reporting gastrointestinal symptoms and those without symptoms using a novel gastric MRI approach. METHODS: Thirty women were included in this case-control study, of whom 15 reported gastrointestinal symptoms after drinking milk and 15 were controls. Participants underwent gastric MRI before and up to 90 min after consumption of 250 mL cow's milk. Gastric content volume and image texture of the stomach contents were used to determine GE and changes in the degree of coagulation. KEY RESULTS: GE half-time did not differ between the groups (gastrointestinal symptom group 66 ± 18 min; control group 61 ± 14 min, p = 0.845). The gastrointestinal symptom group reported symptoms from 30 min onwards and rated pain highest at 90 min. The control group reported no symptoms. Image texture analyses showed a significantly higher percentage of coagulum and lower percentage of liquid in the group in the GI symptom group (MD 11%, 95% CI [3.9, 17], p = 0.003). In vitro data suggests that pH and proteolytic enzyme activity influence the coagulum structure. CONCLUSIONS AND INFERENCES: Gastric milk coagulation and emptied fraction of stomach content may differ between individuals experiencing symptoms after milk consumption, possibly due to differences in pH and proteolytic enzyme activity.

Lactose Intolerance - Single Nucleotide Polymorphisms and Treatment.

The majority (about 70%) of the world's population suffers from lactose intolerance. Lactose intolerance leads to long-term discomfort when consuming milk and dairy products, and hence, to their avoidance. Consequently, the intake of important nutrients is reduced, which potentially has a negative impact on the overall health. Knowing the condition - lactose intolerance - will prevent people from unnecessarily restricting dairy products in their diets. In this study, lactose synthesis and catabolism in the human body are presented, also the types of lactose intolerance, as well as the methods of diagnosing this condition, are discussed. Special attention is paid to the genetic causes of this discomfort and to the tests that can be performed. Solutions for the treatment of lactose intolerance have also been proposed, both up-to-date and easily applicable, as well as future developments.

This review highlights the lactose pathway ­ from the mammary gland production to recipient gut hydrolysis.Lactose intolerance associated SNPs known so far are presented and discussed.Advice for people with lactose intolerance is presented in the form of possible treatments and healthy feeding behaviors.

The association of milk products with rheumatoid arthritis: A cross-sectional study from NHANES.

OBJECTIVE: Milk products are a major part of the western diet, but the role of their effect in rheumatoid arthritis (RA) is controversial. The objective of this study was to explore the relationship between milk products and RA in the United States (US) population. METHODS: In the cross-sectional study, a total of 12,813 participants aged 20years or older were selected from the National Health and Nutrition Examination Survey (NHANES). Consumption of milk products was collected by personal interview, and RA status was obtained by self-reported questionnaires. The association between milk products and RA was estimated by using the weighted logistic regression model. RESULTS: We found a negative association of once a day or more milk products intake with self-reported RA prevalence (odds ratio [OR]: 0.68; 95% confidence interval [CI]: 0.53 to 0.86; P<0.001). A linear trend between consumption of milk products and the prevalence of RA (P<0.01) was also observed. In subgroup analysis, protective effects of milk products on RA were more pronounced in several groups (i.e., Mexican Americans, highly educated and drinking individuals, etc.). However, no interaction effect of stratification variables and the frequency of milk products intake with RA was detected. After imputing missing data, the sensitivity analysis showed the same association. CONCLUSION: This study suggested a negative association between consumption of milk products and RA among US population. Further investigations are warranted to validate the causal association and the underlying mechanism.

Natural history of cow's milk allergy in children aged 6-12 years.

BACKGROUND: Approximately 50%-90% of children with immediate-type cow's milk allergy (CMA) acquire tolerance by pre-school age. We aimed to investigate the acquisition rate of CMA tolerance in children aged 6-12 years. METHODS: We included children with CMA who persisted until the age of 6. Tolerance was defined as passing an oral food challenge with 200 mL of unheated cow's milk (CM) or consuming 200 mL of CM without symptoms, whereas persistent CMA was defined as fulfilling neither of these criteria by 12 years old. Children receiving oral immunotherapy (OIT) were excluded from the primary analysis. Risk factors associated with persistent CMA were assessed using Cox regression analysis. RESULTS: Of 80 included children, 30 (38%) had previous CM anaphylaxis, and 40 (50%) had eliminated CM completely from their diet. The median CM-specific immunoglobulin E (sIgE) level at 6 years old was 12.0 kUA /L. Tolerance was acquired by 25 (31%) and 46 (58%) children by the age of 9 and 12 years, respectively. At baseline, persistent CMA was associated with higher CM-sIgE levels (hazard ratio 2.29, 95% confidence interval 1.41-3.73, optimal cutoff level 12.7 kUA /L), previous CM anaphylaxis (2.07, 1.06-4.02), and complete CM elimination (3.12, 1.46-6.67). No children with CMA who had all three risk factors (n = 14) acquired tolerance. CONCLUSION: Except for OIT patients, more than half of children with CMA at 6 years old acquired tolerance by 12 years old. Children with CMA who have the risk factors are less likely to acquire tolerance.

The Remaining Challenge to Diagnose and Manage Cow's Milk Allergy: An Opinion Paper to Daily Clinical Practice.

Guidelines and recommendations for the diagnosis and management of cow's milk allergy (CMA) in childhood are based on scientific review of the available evidence. While this approach is the most rigorous, guidelines may not fully address all scenarios encountered by clinicians. Many symptoms of CMA overlap with other common childhood illnesses and are subjectively reported by the caregivers of the infant, as is the interpretation of the dietary interventions. Additionally, many healthcare professionals and caregivers do not follow the recommendations to perform an oral food challenge or reintroduction of cow's milk after a diagnostic elimination diet because (1) the infant is doing well and (2) the carer's fear of symptoms relapsing with this procedure. As a result, CMA in infants may be either under-diagnosed leading to reduced quality of life for families or over-diagnosed, resulting in unnecessary long-term elimination diets and increasing the risk for nutritional deficiencies. This paper discusses some of these controversial topics, focusing on misdiagnosis and mismanagement in clinical practice. The lack of objective diagnostic criteria can hamper the diagnosis and management of CMA in daily practice.

Oral food challenge in children with contact urticaria in reaction to cow's milk.

OBJECTIVE: To evaluate the relationship between the occurrence of contact urticaria in reaction to cow's milk in infants and the diagnosis of cow's milk allergy (CMA) established by supervised oral food challenge. METHODS: In this cross-sectional study, we identified 184 children who had undergone 221 oral food challenge (OFC) at a CMA reference center between July 2015 and August 2019. Of these, 23 (12.5%) had a history of contact urticaria to cow's milk and underwent a total of 30 OFC. Baked cow's milk OFC were excluded, and 21 children were included in the study. All data from clinical history and allergy tests (serum-specific IgE dosages and skin prick test [SPT] with reconstituted cow's milk formula) were recorded on standardized forms. The challenge was conducted with reconstituted cow's milk formula in increasing volumes every 15-20 min. RESULTS: 24 OFC were performed; 13/24 (54.2%) for diagnostic purpose and 11/24 (45.8%) to evaluate cow's milk tolerance. Allergy tests were positive in 14 patients (87.5%). Positive oral challenge outcomes were identified in 7/24. One patient had a late flare of atopic dermatitis and five children presented with immediate urticaria (two generalized urticaria and three perioral urticaria). The median papule diameter was 6.5 mm in patients with a positive OFC and 3.75 mm in the negative group (P = 0.02). CONCLUSION: The occurrence of contact urticaria might be the only manifestation among infants sensitized to cow's milk with tolerance to oral ingestion. Reactions due to oral challenge were related to a larger wheal diameter on the SPT.

Food Sources of Animal Protein in Relation to Overall and Cause-Specific Mortality-Causal Associations or Confounding? An Analysis of the EPIC-Heidelberg Cohort.

While prior prospective iso-caloric substitution studies show a robust association between higher intake of animal protein and risk of mortality, associations observed for mortality risk in relation to major food sources of animal protein have been generally more diverse. We used the EPIC-Heidelberg cohort to examine if confounding, notably, by smoking, adiposity, or alcohol intake, could cause inconsistencies in estimated mortality hazard ratios (HR) related to intake levels of different types of meat and dairy products. Higher intakes of red or processed meats, and lower intakes of milk or cheese, were observed among current heavy smokers, participants with obesity, or heavy alcohol drinkers. Adjusting for age, sex, and total energy intake, risk models showed increased all-cause, cardiovascular, and cancer-related mortality with higher red or processed meat intakes (HR ranging from 1.25 [95% confidence interval = 1.15-1.36] to 1.76 [1.46-2.12] comparing highest to lowest tertiles), but reduced risks for poultry, milk, or cheese (HR ranging from 0.55 [0.43-0.72] to 0.88 [0.81-0.95]). Adjusting further for smoking history, adiposity indices, alcohol consumption, and physical activity levels, the statistical significance of all these observed was erased, except for the association of processed meat intake with cardiovascular mortality (HR = 1.36 [CI = 1.13-1.64]) and cheese intake with cancer mortality (HR = 0.86 [0.76-0.98]), which, however, were substantially attenuated. These findings suggest heavy confounding and provide little support for the hypothesis that animal protein, as a nutrient, is a major determinant of mortality risk.

Evaluation of Children with Cow's Milk Allergy Who Received Measles or Measles, Mumps, and Rubella Vaccines Containing Alpha-Lactalbumin.

Objective: Cases of cow's milk allergy (CMA) who reacted to measles or measles, mumps, and rubella (MMR) vaccines containing alpha-lactalbumin have been reported. The purpose of this study was to assess patients with CMA who received measles or MMR vaccines containing alpha-lactalbumin, as well as the characteristics of those who developed reactions to these vaccines. Study Design: Patients followed up in the allergy clinic for CMA and who received measles or MMR vaccines containing alpha-lactalbumin at 9 or 12 months of age were included in the study, and their characteristics were analyzed retrospectively from the hospital registry system. Results: Forty-nine patients were included in the study. Six patients received the measles vaccine, whereas 43 patients received the MMR vaccine containing alpha-lactalbumin. Vaccine skin tests were performed on these 6 patients. One patient had a positive intradermal test, so an alternative vaccine not containing alpha-lactalbumin was administered. The other 5 patients were vaccinated, and no reaction was observed. Anaphylaxis was observed in 3 of 43 patients who received the MMR vaccine containing alpha-lactalbumin. In all of these patients, the first reaction to dairy products was anaphylaxis. In 2 of those patients, cow's milk-specific IgE (spIgE) levels were >100 kU/L, and alpha-lactalbumin-spIgE levels were also high at 97 and 90 kU/L. The third patient's cow's milk-spIgE level was 15.9 kU/L, whereas the alpha-lactalbumin-spIgE level was 0.04 kU/L. Conclusion: Especially in patients with an initial reaction of anaphylaxis to dairy products and high cow's milk-spIgE levels, the risk of reaction is high with the MMR vaccine.

"Frequency of fatal and recurrent anaphylaxis due to COW'S milk: A systematic review and meta-analysis of observational studies".

Cow's milk allergy can result in anaphylactic reactions. The estimated prevalence of cow's milk allergy in developed countries ranges from 0.5% to 3% at age 1 year. Our objective was to perform a systematic review and, if possible, a meta-analysis to assess the frequency of fatal and recurrent anaphylaxis induced by cow's milk. We searched PubMed/MEDLINE, EMBASE, and the Web of Science for studies that had assessed fatal and recurrent anaphylaxis induced by cow's milk for the population of a country or at least an administrative region. Our review included cohort, cross-sectional, and registry studies that had assessed the incidence or prevalence of recurrent anaphylaxis or the incidence of fatal anaphylaxis due to cow's milk. The pooled prevalence of recurrence (PR) for at least an episode of anaphylaxis was 26.98% (3.85-189.1). Teymourpour et al (Iran) reported the highest PR (53.10%); the two studies with the lowest PR were from France (5.2 and 0.42, respectively) (p < .01). Nine studies on fatal anaphylaxis were selected (41 deaths) and found to be highly heterogeneous (I2 = 75.9%). Levy et al and Bassagio et al reported the highest incidence rate (IR 0.15 and 0.6 deaths per million persons-year). The PR of anaphylaxis was approximately one quarter of patients with anaphylaxis due to cow's milk, while deaths from anaphylaxis caused by cow's milk were very rare, although some studies report rates as high as 15 times the lowest IR.