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OBJECTIVES: To explore the risk factors associated with cow's milk protein allergy (CMPA) in infants. METHODS: This study was a multicenter prospective nested case-control study conducted in seven medical centers in Beijing, China. Infants aged 0-12 months were included, with 200 cases of CMPA infants and 799 control infants without CMPA. Univariate and multivariate logistic regression analyses were used to investigate the risk factors for the occurrence of CMPA. RESULTS: Univariate logistic regression analysis showed that preterm birth, low birth weight, birth from the first pregnancy, firstborn, spring birth, summer birth, mixed/artificial feeding, and parental history of allergic diseases were associated with an increased risk of CMPA in infants (P<0.05). Multivariate logistic regression analysis revealed that firstborn (OR=1.89, 95%CI: 1.14-3.13), spring birth (OR=3.42, 95%CI: 1.70-6.58), summer birth (OR=2.29, 95%CI: 1.22-4.27), mixed/artificial feeding (OR=1.57, 95%CI: 1.10-2.26), parental history of allergies (OR=2.13, 95%CI: 1.51-3.02), and both parents having allergies (OR=3.15, 95%CI: 1.78-5.56) were risk factors for CMPA in infants (P<0.05). CONCLUSIONS: Firstborn, spring birth, summer birth, mixed/artificial feeding, and a family history of allergies are associated with an increased risk of CMPA in infants.

Timing of Allergenic Food Introduction and Risk of Immunoglobulin E-Mediated Food Allergy: A Systematic Review and Meta-analysis.

Importance: Earlier egg and peanut introduction probably reduces risk of egg and peanut allergy, respectively, but it is uncertain whether food allergy as a whole can be prevented using earlier allergenic food introduction. Objective: To investigate associations between timing of allergenic food introduction to the infant diet and risk of food allergy. Data Sources: In this systematic review and meta-analysis, Medline, Embase, and CENTRAL databases were searched for articles from database inception to December 29, 2022. Search terms included infant, randomized controlled trial, and terms for common allergenic foods and allergic outcomes. Study Selection: Randomized clinical trials evaluating age at allergenic food introduction (milk, egg, fish, shellfish, tree nuts, wheat, peanuts, and soya) during infancy and immunoglobulin E (IgE)-mediated food allergy from 1 to 5 years of age were included. Screening was conducted independently by multiple authors. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was used. Data were extracted in duplicate and synthesized using a random-effects model. The Grading of Recommendations, Assessment, Development, and Evaluation framework was used to assess certainty of evidence. Main Outcomes and Measures: Primary outcomes were risk of IgE-mediated allergy to any food from 1 to 5 years of age and withdrawal from the intervention. Secondary outcomes included allergy to specific foods. Results: Of 9283 titles screened, data were extracted from 23 eligible trials (56 articles, 13 794 randomized participants). There was moderate-certainty evidence from 4 trials (3295 participants) that introduction of multiple allergenic foods from 2 to 12 months of age (median age, 3-4 months) was associated with reduced risk of food allergy (risk ratio [RR], 0.49; 95% CI, 0.33-0.74; I2 = 49%). Absolute risk difference for a population with 5% incidence of food allergy was -26 cases (95% CI, -34 to -13 cases) per 1000 population. There was moderate-certainty evidence from 5 trials (4703 participants) that introduction of multiple allergenic foods from 2 to 12 months of age was associated with increased withdrawal from the intervention (RR, 2.29; 95% CI, 1.45-3.63; I2 = 89%). Absolute risk difference for a population with 20% withdrawal from the intervention was 258 cases (95% CI, 90-526 cases) per 1000 population. There was high-certainty evidence from 9 trials (4811 participants) that introduction of egg from 3 to 6 months of age was associated with reduced risk of egg allergy (RR, 0.60; 95% CI, 0.46-0.77; I2 = 0%) and high-certainty evidence from 4 trials (3796 participants) that introduction of peanut from 3 to 10 months of age was associated with reduced risk of peanut allergy (RR, 0.31; 95% CI, 0.19-0.51; I2 = 21%). Evidence for timing of introduction of cow's milk and risk of cow's milk allergy was very low certainty. Conclusions and Relevance: In this systematic review and meta-analysis, earlier introduction of multiple allergenic foods in the first year of life was associated with lower risk of developing food allergy but a high rate of withdrawal from the intervention. Further work is needed to develop allergenic food interventions that are safe and acceptable for infants and their families.

Long-term changes in milk component immunoglobulins reflect milk oral immunotherapy outcomes in Finnish children.

BACKGROUND: Milk oral immunotherapy (OIT) may increase the amount of milk protein that can be ingested without triggering an allergic reaction. It is important to understand why some patients benefit from the treatment while others do not. OBJECTIVE: The aim was to define the differences in the milk allergen component-specific (casein, α-lactalbumin, ß-lactoglobulin) immunoglobulin (sIg [sIgE, sIgG4, and sIgA]) levels relative to the long-term outcomes of milk OIT. METHODS: In this long-term, open-label follow-up study, 286 children started milk OIT between 2005 and 2015. Follow-up data were collected at two points: the post-buildup phase and long term (range 1-11 years, median 6 years). Comparisons of sIg levels were made among three outcome groups of self-reported long-term milk consumption (high-milk dose, low-milk dose, and avoidance). RESULTS: A total of 168 (59%) of the 286 patients on OIT participated. Most patients (57%) were in the high-dose group; here, 80% of these patients had a baseline casein sIgE value less than 28 kUA/L, they had the lowest casein sIgE levels at all time (p < .001), their casein sIgG4/IgE levels increased, and long-term casein sIgA was highest compared with the low-dose and avoidance groups (p = .02). Low-milk dose group had the highest casein sIgG4/IgE levels in long term (p = .002). CONCLUSION: The baseline Ig profiles and responses to milk OIT differed depending on long-term milk consumption. Lower casein sIgE levels were associated with better outcome. Milk casein sIgA differed in the long term among high-milk consumers.

Consensus document on the primary prevention of cow's milk protein allergy in infants aged less than 7 days.

INTRODUCTION: Cow's milk protein allergy (CMPA) is the most frequent food allergy in the first year of life. There is no clear consensus regarding its prevention. A recommendation to avoid CMP in the first week of life as a preventive measure in all infants, regardless of their atopic risk, has recently been published. The purpose of this document is to issue a recommendation on the use of extensively hydrolyzed CMP formulas in the first week of life for the primary prevention of CMPA. METHODS: A group of experts was formed with members proposed by the Spanish Association of Pediatrics (AEP), the Spanish Society of Clinical Immunology and Allergology and Pediatric Asthma (SEICAAP), the Spanish Society of Pediatric Gastroenterology, Hepatology and Nutrition (SEGHNP) and the Spanish Society of Neonatology (SENEO). The group conducted a critical review of the evidence on the subject published in the last 10 years. RESULTS: The search yielded 72 studies, of which 66 were rejected for not meeting the inclusion criteria. The final review included 6 documents: 3 clinical trials and 3 systematic reviews, 2 of them with meta-analysis. There was no evidence of a statistically significant reduction in the incidence of CMPA in the infants who received hypoallergenic formulae or exclusive breastfeeding. CONCLUSION: Based on the current evidence, it is not possible to draw clear conclusions about the effect of avoiding CMP in the first week of life for prevention of CMPA. Although there are data that suggest a certain beneficial effect of avoiding CMPA in atopic risk infants, these results are not conclusive enough to extend the recommendation to the general population.

Trends in use of specialized formula for managing cow's milk allergy in young children.

BACKGROUND: Excessive use of specialized formula for cow's milk allergy was reported in England, but complete analysis has not been undertaken and trends in other countries are unknown. Some specialized formula products, especially amino-acid formula (AAF), have high free sugars content. We evaluated specialized formula trends in countries with public databases documenting national prescription rates. METHODS: Cross-sectional analysis of national prescription databases in the United Kingdom, Norway and Australia. Outcomes were volume and cost of specialized formula, and proportion of infants prescribed specialized formula. Expected volumes assumed 1% cow's milk allergy incidence and similar formula feeding rates between infants with and without milk allergy. RESULTS: Prescribed volumes of specialized formula for infants rose 2.8-fold in England from 2007 to 2018, with similar trends in other regions of the United Kingdom. Volumes rose 2.2-fold in Norway from 2009 to 2020 and 3.2-fold in Australia from 2001 to 2012. In 2020, total volumes were 9.7- to 12.6-fold greater than expected in England, 8.3- to 15.6-fold greater than expected in Norway and 3.3- to 4.5-fold greater than expected in Australia, where prescribing restrictions were introduced in 2012. In Norway, the proportion of infants prescribed specialized formula increased from 2.2% in 2009 to 6.9% in 2020, or 11.2- to 13.3-fold greater than expected. In 2020, specialized formula for infants cost US$117 (103 euro) per birth in England, US$93 (82 euro) in Norway and US$27 (23 euro) in Australia. Soya formula prescriptions exceeded expected volumes 5.5- to 6.4-fold in England in 1994 and subsequently declined, co-incident with public health concerns regarding soya formula safety. In 2020, 30%-50% of prescribed specialized formula across the three countries was AAF. CONCLUSIONS: In England, Norway and Australia, specialized formula prescriptions increased in the early 21st century and exceeded expected levels. Unnecessary specialized formula use may make a significant contribution to free sugars consumption in young children.

Could Age and Oral Challenge Outcomes Identify High-Risk Patients During Cow's Milk Oral Immunotherapy?

Objective: Severe immunglobuline E (IgE)-mediated reactions during oral immunotherapy (OIT) are major obstacles to treatment. The present study aimed to evaluate and identify clinical and laboratory biomarkers of adverse events during OIT among children with cow's milk (CM) allergy. Study Design: Eighty-six children older than 36 months who had undergone OIT with milk were enrolled. Clinical data, oral food challenge (OFC) test results, and laboratory data were recorded retrospectively. Results: The median duration of the build-up phase of OIT was 19 weeks (min 10-max 40) and the duration of the maintenance phase was 86.5 (min 1-max 132) months. A total of 11,767 CM doses were administered during the build-up phase and adverse reactions were seen in 62 (73.8%) patients with reactions registered for 157 doses among 11,767 (1/75 doses). The number of reactions during the maintenance phase was 41 (47.6%) in 24 (27.9%) patients. There was a significant reduction in the number of reactions (P = 0.000) between the build-up phase and maintenance phase. Adverse reactions and anaphylaxis were higher for patients who had cough during OFC (P = 0.003, P = 0.002, respectively) during the build-up phase and also during the maintenance phase too (P = 0.000). Evaluation for all reactions and anaphylaxis (during build-up and maintenance) with Kaplan-Meier and Cox regression analysis showed class IV-VI of CM-specific immunoglobulin E (sIgE), casein-sIgE and cough during OFC were significantly associated with increased probability of reaction and anaphylaxis. Younger age at onset of OIT was associated with risk reduction (0.017). Conclusion: Laboratory data and reactions during the OFC (especially cough) can help to identify high-risk patients during OIT.

Cow's milk αS1-casein is more sensitizing than goat's milk αS1-casein in a mouse model.

The aim of this study was to compare the sensitization of αS1-CN in cow and goat's milk in a mouse model. Fifty mice were divided into control group, adjuvant control group, cow's milk αS1-CN sensitized group, goat's milk αS1-CN sensitized group and cross sensitized group. Cow's and goat's milk αS1-CN were used to establish a mouse sensitization model. The results showed that cow's milk αS1-CN had higher allergenicity than goat's milk αS1-CN, as can be seen in significantly increased s-IgE and Th2 cell-related inflammatory factors, the proportion of Th2, and the expression of Th2 cell-related transcription factors. Furthermore, the sensitization of cow's milk αS1-CN damaged the intestinal barrier of mice, caused the leakage of LPS, activated the TLR4-NFκB pathway, and thus resulted in the increase of IFN-γ. In addition, mice allergic to cow's milk αS1-CN were less sensitized to goat's milk αS1-CN.

Nutritional Targets in Cow's Milk Protein Allergy: A Comprehensive Review.

PURPOSE OF REVIEW: Cow's milk protein allergy (CMPA) is known as the most common food allergy in the first year of life. For this purpose, in our review, the regulation of maternal and infant nutrition, and the risks and the issues to be considered in terms of nutrition are discussed from the perspective of a dietitian. RECENT FINDINGS: Therefore, understanding the epidemiology, symptoms, diagnostic criteria, and appropriate treatment of cow's milk protein allergy is crucial for the multidisciplinary team of physicians, dietitians, and nurses working in the clinic. It has been reported that tolerance develops in approximately 50% of infants affected by cow's milk protein in the first year of life. Although CMPA is generally thought to clear up between 1 and 2 years of age, there is insufficient evidence to determine an optimal time to reintroduce cow's milk protein to the diet. Because the elimination diet recommended in the treatment of children with CMPA, adequate protein and calcium intake of the mother and/or baby in the diet should be evaluated. Studies focusing on metabolic bone turnover in children with food allergies are limited. In general, low calcium intake is associated with reduced bone formation in children with CMPA. Therefore, bone health should be focused on and appropriate strategies should be developed in children with CMPA. Unnecessary elimination of milk and its products, which are an important part of nutrition, should be prevented and nutrient deficiencies and growth status should be monitored by dietitians especially working in the field of pediatric nutrition.

Effects of an Extensively Hydrolyzed Formula Supplemented with Two Human Milk Oligosaccharides on Growth, Tolerability, Safety and Infection Risk in Infants with Cow's Milk Protein Allergy: A Randomized, Multi-Center Trial.

This randomized clinical trial (Registration: NCT03085134) assessed if an extensively hydrolyzed formula (EHF) supplemented with two human milk oligosaccharides (HMO) and reduced protein content (2.20 g/100 kcal) supports normal growth in infants with cow's milk protein allergy (CMPA). Secondary outcomes were gastrointestinal tolerability, safety, and effect on infections. Nonbreastfed infants aged 0−6 months with CMPA were enrolled. Body weight, length, and head circumference were measured monthly for 4 months (primary study endpoint), after 6 months, and at the age of 12 months. Of 200 infants screened, 194 (mean age 3.2 months) were randomized. At the 4-month follow-up, daily weight gain for the test formula was noninferior to the control formula; p < 0.005. There were no significant group differences in anthropometric parameters. Both formulas were safe and well tolerated. Infants in the HMO group had a statistically significant reduction in the frequency of upper respiratory tract infections and a lower incidence of ear infections at 12 months (per protocol analysis). The relative risk of lower respiratory tract and gastrointestinal infections was reduced by 30−40%, but this was not statistically significant due to sample size limitations. In summary, the HMO-supplemented formula supports normal growth in infants with CMPA and suggests a protective effect against respiratory and ear infections in the first year of life.

Threshold of Reactivity and Tolerance to Precautionary Allergen-Labelled Biscuits of Baked Milk- and Egg-Allergic Children.

Extremely sensitive food-allergic patients may react to very small amounts of allergenic foods. Precautionary allergen labelling (PAL) warns from possible allergenic contaminations. We evaluated by oral food challenge the reactivity to a brand of PAL-labelled milk- and egg-free biscuits of children with severe milk and egg allergy. We explored the ability of proteomic methods to identify minute amounts of milk/egg allergens in such biscuits. Traces of milk and/or egg allergens in biscuits were measured by two different liquid-chromatography-mass spectrometry methods. The binding of patient's serum with egg/milk proteins was assessed using immunoblotting. None of the patients reacted to biscuits. Egg and milk proteins were undetectable with a limit of detection of 0.6 µg/g for milk and egg (method A), and of 0.1 and 0.3 µg /g for milk and egg, respectively (method B). The immunoblots did not show milk/egg proteins in the studied biscuits. Milk/egg content of the biscuits is far lower than 4 µg of milk or egg protein per gram of product, the minimal doses considered theoretically capable of causing reactions. With high sensitivity, proteomic assessments predict the harmlessness of very small amount of allergens in foods, and can be used to help avoiding unnecessary PAL.

Whole Cow's Milk but Not Lactose Can Induce Symptoms in Patients with Self-Reported Milk Intolerance: Evidence of Cow's Milk Sensitivity in Adults.

BACKGROUND: Lactose intolerance is the most frequent food intolerance, but many subjects with self-reported milk intolerance (SRMI) are asymptomatic at lactose hydrogen breath test (LHBT). The aim of this study was to evaluate the frequency of lactose intolerance in SRMI patients and their clinical characteristics. METHODS: In a retrospective study, the clinical records of 314 SRMI patients (259 females, mean age: 39.1 ± 13.5 years) were reviewed; 102 patients with irritable bowel syndrome (IBS) served as controls. In a prospective study, 42 SRMI patients, negatives at the LHBT, underwent a double-blind, placebo-controlled (DBPC) whole cow's milk challenge. RESULTS: In the retrospective study, only 178 patients (56%) were lactose maldigesters and intolerant at LHBT; 68% of the subjects with SRMI were suffering from IBS; 74% reported dyspepsia (p = 0.0001 vs. IBS controls); and weight loss was recorded in 62 SRMI patients (20%) (p = 0.01 vs. IBS controls). Duodenal histology showed intra-epithelial lymphocytosis in about 60% of cases. In the prospective study, 36 patients (86%) experienced symptoms during the DBPC cow's milk challenge, and only 4 patients (9%) reacted to placebo (p = 0.0001). CONCLUSIONS: A percentage of SRMI patients were not suffering from lactose intolerance. DBPC revealed that SRMI patients had clinical reactions when exposed to whole cow's milk.

Exploring the Advantages of a Hydrolyzed Rice Formula in the Dietary Management of Infants with Cow's Milk Allergy in the Middle East, North Africa, and Pakistan Region.

Cow's milk allergy (CMA) is the most common food allergy in early childhood, and its prevalence continues to rise. Exclusive breastfeeding is recommended for infants in the first 6 months of life, but this recommendation is poorly adhered to in many parts of the world, including the Middle East, North Africa, and Pakistan (MENAP) region. If the infant is affected by CMA, current guidelines recommend extensively hydrolyzed formulas (eHFs) or amino acid-based formulas (AAFs) in the case of severe symptoms, and hydrolyzed rice formulas (HRFs) where available. In recent years, HRFs have been proposed as a plant-based alternative to cow's milk protein-based eHFs, and updates to current guidelines have been recommended. In 2014, a consensus statement and guidelines were published for the Middle East region on the prevention, diagnosis, and management of CMA. As new advances have been made in the extensively hydrolyzed hypoallergenic infant formula space, along with updated scientific evidence, a workshop of experts from the MENAP region focused on HRF was convened in 2021. This publication summarizes the insights from this meeting. During the consensus part of the meeting, a new approach was discussed and approved by all participants, and agreement was reached that HRF can be recommended as a first-line alternative to cow's milk-based eHF in the dietary management of CMA.

Skin care interventions in infants for preventing eczema and food allergy.

BACKGROUND: Eczema and food allergy are common health conditions that usually begin in early childhood and often occur together in the same people. They can be associated with an impaired skin barrier in early infancy. It is unclear whether trying to prevent or reverse an impaired skin barrier soon after birth is effective in preventing eczema or food allergy. OBJECTIVES: Primary objective To assess effects of skin care interventions, such as emollients, for primary prevention of eczema and food allergy in infants Secondary objective To identify features of study populations such as age, hereditary risk, and adherence to interventions that are associated with the greatest treatment benefit or harm for both eczema and food allergy. SEARCH METHODS: We searched the following databases up to July 2020: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. We searched two trials registers and checked reference lists of included studies and relevant systematic reviews for further references to relevant randomised controlled trials (RCTs). We contacted field experts to identify planned trials and to seek information about unpublished or incomplete trials. SELECTION CRITERIA: RCTs of skin care interventions that could potentially enhance skin barrier function, reduce dryness, or reduce subclinical inflammation in healthy term (> 37 weeks) infants (0 to 12 months) without pre-existing diagnosis of eczema, food allergy, or other skin condition were included. Comparison was standard care in the locality or no treatment. Types of skin care interventions included moisturisers/emollients; bathing products; advice regarding reducing soap exposure and bathing frequency; and use of water softeners. No minimum follow-up was required. DATA COLLECTION AND ANALYSIS: This is a prospective individual participant data (IPD) meta-analysis. We used standard Cochrane methodological procedures, and primary analyses used the IPD dataset. Primary outcomes were cumulative incidence of eczema and cumulative incidence of immunoglobulin (Ig)E-mediated food allergy by one to three years, both measured by the closest available time point to two years. Secondary outcomes included adverse events during the intervention period; eczema severity (clinician-assessed); parent report of eczema severity; time to onset of eczema; parent report of immediate food allergy; and allergic sensitisation to food or inhalant allergen. MAIN RESULTS: This review identified 33 RCTs, comprising 25,827 participants. A total of 17 studies, randomising 5823 participants, reported information on one or more outcomes specified in this review. Eleven studies randomising 5217 participants, with 10 of these studies providing IPD, were included in one or more meta-analysis (range 2 to 9 studies per individual meta-analysis). Most studies were conducted at children's hospitals. All interventions were compared against no skin care intervention or local standard care. Of the 17 studies that reported our outcomes, 13 assessed emollients. Twenty-five studies, including all those contributing data to meta-analyses, randomised newborns up to age three weeks to receive a skin care intervention or standard infant skin care. Eight of the 11 studies contributing to meta-analyses recruited infants at high risk of developing eczema or food allergy, although definition of high risk varied between studies. Durations of intervention and follow-up ranged from 24 hours to two years. We assessed most of this review's evidence as low certainty or had some concerns of risk of bias. A rating of some concerns was most often due to lack of blinding of outcome assessors or significant missing data, which could have impacted outcome measurement but was judged unlikely to have done so. Evidence for the primary food allergy outcome was rated as high risk of bias due to inclusion of only one trial where findings varied when different assumptions were made about missing data. Skin care interventions during infancy probably do not change risk of eczema by one to two years of age (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.81 to 1.31; moderate-certainty evidence; 3075 participants, 7 trials) nor time to onset of eczema (hazard ratio 0.86, 95% CI 0.65 to 1.14; moderate-certainty evidence; 3349 participants, 9 trials). It is unclear whether skin care interventions during infancy change risk of IgE-mediated food allergy by one to two years of age (RR 2.53, 95% CI 0.99 to 6.47; 996 participants, 1 trial) or allergic sensitisation to a food allergen at age one to two years (RR 0.86, 95% CI 0.28 to 2.69; 1055 participants, 2 trials) due to very low-certainty evidence for these outcomes. Skin care interventions during infancy may slightly increase risk of parent report of immediate reaction to a common food allergen at two years (RR 1.27, 95% CI 1.00 to 1.61; low-certainty evidence; 1171 participants, 1 trial). However, this was only seen for cow's milk, and may be unreliable due to significant over-reporting of cow's milk allergy in infants. Skin care interventions during infancy probably increase risk of skin infection over the intervention period (RR 1.34, 95% CI 1.02 to 1.77; moderate-certainty evidence; 2728 participants, 6 trials) and may increase risk of infant slippage over the intervention period (RR 1.42, 95% CI 0.67 to 2.99; low-certainty evidence; 2538 participants, 4 trials) or stinging/allergic reactions to moisturisers (RR 2.24, 95% 0.67 to 7.43; low-certainty evidence; 343 participants, 4 trials), although confidence intervals for slippages and stinging/allergic reactions are wide and include the possibility of no effect or reduced risk. Preplanned subgroup analyses show that effects of interventions were not influenced by age, duration of intervention, hereditary risk, FLG mutation,  or classification of intervention type for risk of developing eczema. We could not evaluate these effects on risk of food allergy. Evidence was insufficient to show whether adherence to interventions influenced the relationship between skin care interventions and risk of developing eczema or food allergy. AUTHORS' CONCLUSIONS: Skin care interventions such as emollients during the first year of life in healthy infants are probably not effective for preventing eczema, and probably increase risk of skin infection. Effects of skin care interventions on risk of food allergy are uncertain. Further work is needed to understand whether different approaches to infant skin care might promote or prevent eczema and to evaluate effects on food allergy based on robust outcome assessments.

The role of milk feeds and other dietary supplementary interventions in preventing allergic disease in infants: Fact or fiction?

Exclusive breastfeeding ideally up to 6 months of life is the feed of choice for infants and should be promoted by healthcare professionals. However, when human milk is not sufficient or not available, infant formula, generally cow's milk-based, meeting strictly regulated nutritional and safety requirements, are recommended. Human breastmilk feeding has a positive health impact for both mother and child, but there is limited evidence that it has a long-term protective effect on the development of allergic disease. Some studies have found an association of an increased risk to develop cow's milk allergy with early exposure to cow's milk protein in formula milk. As a result, over the last 30 years, partially hydrolyzed formulas (pHF) have gained popularity and, more recently, become embroiled in a debate about their role in the primary prevention of allergic outcomes. Similar debates exist in regards to the potential preventative effects of pre-, pro- and synbiotics as well as nutritional factors, notably vitamin D and omega-3 fatty acids. This paper aims to critically address these aspects, drawing information from published data interpreted by an international expert group in paediatrics, allergy, gastro-intestinal diseases and nutrition. This group of experts emphasize that human milk is the optimal source of infant nutrition. With regards to pHFs, whilst no harm has been shown with their use and some studies have suggested potential benefit preventing atopic dermatitis in at risk infants, there is insufficient evidence for or against their routine recommendation for primary allergy prevention. The method of hydrolysation differs for every formula. There is insufficient evidence to recommend supplementation with vitamin D, omega-3 LCPUFA, specific prebiotic oligosaccharides or specific probiotic strains during pregnancy, lactation and early life to prevent the development of allergic disease in children. There remains a need for well-designed trials with the currently commercialised pHFs and supplements to allow for better clarity and evidence-based recommendations.

Isotype-Specific Detection of Serum Immunoglobulins Against Allergens.

Type-I hypersensitivity is commonly characterized by increased levels of antigen-specific immunoglobulin (Ig) E. Therefore, it is important for clinical and research investigators to reliably measure serum levels of IgE in allergic patients and animal models. While current ELISA-based methods are simple and commonly performed for the detection of allergen-specific IgE using serum or plasma, they may produce misleading results. This is in part due to decreased sensitivity for IgE in the presence of other Ig isotypes in the same sample, such as IgG, that are typically more abundant than IgE. When assessment of multiple Ig isotypes is necessary, performing optimized assays for individual isotypes requires high sample volumes. Here, we describe an approach to increase the sensitivity for IgE detection while conserving the sample volume needed. This method not only improves the accuracy of serum IgE measurements but also allows simultaneous analysis of other allergen-specific immunoglobulins.

Maternal antioxidant intake during pregnancy and the development of cows' milk allergy in the offspring.

Cows' milk allergy (CMA) is the most common food allergy in young children, and it is often the first manifestation of atopic diseases. Accordingly, very early environmental factors, such as maternal diet during pregnancy, may play a role in the development of CMA, but the evidence is limited. The aim of this study was to investigate the association between maternal intake of antioxidant nutrients during pregnancy and the subsequent development of CMA in the offspring in a prospective, population-based birth cohort within the Finnish Type 1 Diabetes Prediction and Prevention Study. Maternal dietary information during pregnancy was collected with a detailed, validated FFQ. The maternal dietary information and the information on putative confounding factors were available for 4403 children. Information on diagnosed CMA (n 448) was obtained from a medical registry and queried from the parents up to child's age of 3 years. The Finnish food composition database was used to calculate the average daily intake of nutrients. Logistic regression was applied for statistical analyses, and the nutrient intakes were adjusted for energy intake. OR are presented per 1 sd increment of the particular nutrient intake. Maternal total and dietary intake of ß-carotene was associated with an increased risk of CMA in the offspring when adjusted for the putative confounding factors (total OR 1·10, 95 % CI 1·02, 1·20; dietary OR 1·10; 95 % CI 1·01, 1·19). Using dietary supplements containing antioxidants in addition to a balanced diet may not confer any additional benefits.

Hydrolyzed Rice Protein-Based Formulas, a Vegetal Alternative in Cow's Milk Allergy.

Formulas adapted to infant feeding, although most of the time made from cow's milk proteins, can be made from hydrolyzed rice protein but they must be classified as "formulas for specific medical needs", according to European regulations. The nutritional quality of rice proteins is thus suitable to be used in infant formulas giving that it is supplemented by certain amino acids which can be lacking. Besides, hydrolysis is required to facilitate their water solubility and digestibility. Owing to a low allergenicity of rice and to the absence of the cross-allergy between milk proteins and rice proteins, these formulas are adapted to the diet of children with cow's milk protein allergy (CMPA), which explains their growing use in some countries. However, CMPA, an expanding disorder, has consequences for growth, bone mineralization, and often has an association with allergy to other foods, including cow's milk extensive hydrolysate, so that a surveillance of the adaption of hydrolyzed rice protein formulas (HRPF) to CMPA, the absence of unexpected side effects, and the appropriate response to its various health hazards seems mandatory. This paper analyses the health problem deriving from CMPA, the industrial development of hydrolyzed rice protein formulas, and the limited number of clinical studies, which confirms, at the moment, a good allergic tolerance and safety. The goal is to better advise heath care professionals on their use of HRPFs during CMPA.

New insights into food protein-induced enterocolitis in children.

Food protein-induced enterocolitis syndrome (FPIES) represents a non-IgE-mediated food allergic disorder with delayed gastrointestinal symptoms that may evolve in a medical emergency. Clinically, FPIES can be distinguished into acute and chronic phenotypes. FPIES is mainly diagnosed in infancy however the onset at older ages is being progressively described. The pathogenetic mechanism underlying FPIES remains mainly unexplained, but an alteration of food-specific T-cell response has been proposed. The diagnosis of FPIES is primarily clinical, since there are not available specific biomarkers. Oral food challenge (OFC) is the gold standard for diagnosing FPIES or excluding the onset of tolerance to the triggering food. Management of FPIES includes an acute phase treatment and a maintenance therapy with the strict food avoidance until challenge, in order to prevent new attacks and avoid nutritional alterations. Acute management requires hydration that can be performed orally or intravenously according to clinical status. Long-term management of FPIES is based on the avoidance of the culprit food(s) and supervised introduction of other high-risk foods if never taken before among infants before 12 months of age. There is a compelling need of future achievements in FPIES research for the definition of underlying disease pathogenesis and potential therapeutic point of care.

Novel approach to visualize the inter-dependencies between maternal sensitization, breast milk immune components and human milk oligosaccharides in the LIFE Child cohort.

BACKGROUND: Numerous studies have shown that specific components of breast milk, considered separately, are associated with disease status in the mother or the child using univariate analyses. However, very few studies have considered multivariate analysis approaches to evaluate the relationship between multiple breast milk components simultaneously. AIM: Here we aimed at visualizing breast milk component complex interactions in the context of the allergy status of the mother or the child. METHODS: Milk samples were collected from lactating mothers participating in the Leipziger Forschungszentrum für Zivilisationskrankheiten (LIFE) Child cohort in Leipzig, Germany. A total of 156 breast milk samples, collected at 3 months after birth from mother/infant pairs, were analyzed for 51 breast milk components. Correlation, principal component analysis (PCA) and graphical discovery analysis were used. RESULT: Correlations ranging from 0.40 to 0.96 were observed between breast milk fatty acid and breast milk phospholipids levels and correlations ranging from 0 to 0.76 between specific human milk oligosaccharides (HMO) were observed. No separation of the data based on the risk of allergy in the infants was identified using PCA. When graphical discovery analysis was used, dependencies between maternal plasma immunoglobulin E (IgE) level and the breast milk immune marker transforming growth factor-beta 2 (TGF-ß2), between TGF-ß2, breast milk immunoglobulin A (IgA) and TGF-ß1 as well as between breast milk total protein and birth weight were observed. Graphical discovery analysis also exemplifies a possible competition for the fucosyl group between 2'FL, LNFP-I and 3'FL in the HMO group. Additionally, dependencies between immune component IgA and specific HMO (6'SL and blood group A antigen tetraose type 5 or PI-HMO) were identified. CONCLUSION: Graphical discovery analysis applied to complex matrices such as breast milk composition can aid in understanding the complexity of interactions between breast milk components and possible relations to health parameters in the mother or the infant. This approach can lead to novel discoveries in the context of health and diseases such as allergy. Our study thus represents the first attempt to visualize the complexity and the inter-dependency of breast milk components.