Growth, Tolerance, and Compliance of Infants Fed an Extensively Hydrolyzed Infant Formula with Added 2'-FL Fucosyllactose (2'-FL) Human Milk Oligosaccharide.

BACKGROUND: The purpose of this study was to evaluate the growth, tolerance and compliance effects of an extensively hydrolyzed formula with added 2'-FL in an intended use population of infants. METHODS: A non-randomized, single-group, multicenter study was conducted. Infants (0-60 days of age) with suspected food protein allergy, persistent feeding intolerance, or presenting conditions where an extensively hydrolyzed formula (eHF) was deemed appropriate were enrolled in a 2-month feeding trial. The primary outcome was maintenance of weight for age z-score during the study. Weight, length, head circumference, formula intake, tolerance measures, clinical symptoms and questionnaires were collected. Forty-eight infants were enrolled and 36 completed the study. RESULTS: Weight for age z-scores of infants showed a statistically significant improvement from study day 1 to study day 60 (0.32 ± 0.11, p = 0.0078). CONCLUSIONS: Overall, the results of the study demonstrate that the study formula was well tolerated, safe and supported growth in the intended population.

'Diagnosing food protein-induced enterocolitis syndrome'.

Food protein-induced enterocolitis syndrome is still a mysterious disease, pathogenically poorly characterized, although the first FPIES case has been described in 1967. Mainly, food protein-induced enterocolitis syndrome diagnosis is based on clinical history. The oral food challenge remains the gold standard to confirm the diagnosis, especially in particular situations. Although there are no diagnostic laboratory or imaging tests which are specific for diagnosis, they could, however, sometimes be helpful to rule out clinical conditions which are similar to food protein-induced enterocolitis syndrome reactions. The purpose of this review is to define the clinical features of FPIES and to summarize the current available tools for the diagnosis of FPIES. This review is intended to be a practical guide for the clinician facing a patient with food protein-induced enterocolitis syndrome avoiding delayed diagnosis with unnecessary laboratory tests and detrimental treatments. Moreover, it highlights the unmet needs in diagnosis that require urgent attention from the scientific community to improve the management of patients with FPIES.

Effect of Avoiding Cow's Milk Formula at Birth on Prevention of Asthma or Recurrent Wheeze Among Young Children: Extended Follow-up From the ABC Randomized Clinical Trial.

Importance: Children with food allergies may develop asthma or recurrent wheeze. Objective: To evaluate whether asthma or recurrent wheeze among children were changed by avoiding supplementing breastfeeding (BF) with cow's milk formula (CMF) in the first 3 days of life. Design, Setting, and Participants: This randomized, unmasked, clinical trial was conducted at 1 university hospital in Japan beginning October 2013 with follow-up examinations occurring until January 2020. A total of 312 newborns at risk for atopy were randomized and assigned to either BF with or without amino acid-based elemental formula (EF) or BF with CMF, with follow-up examinations for participants showing signs of atopy conducted at 24 months. Follow-up examinations ran through January 2020. Interventions: Immediately after birth, newborns were randomly assigned (1:1 ratio) to either breastfeeding with or without amino acid-based elemental formula for at least the first 3 days of life (no CMF group) or breastfeeding supplemented with CMF (≥5 mL/d) from the first day of life to 5 months of age (CMF group). Main Outcomes and Measures: Asthma or recurrent wheeze diagnosed by the pediatric allergy specialists of this trial; subgroups were stratified by serum levels of 25-hydroxyvitamin D and IgE. Results: Of 312 infants (156 [50.0%] randomized to the no CMF group), 302 (96.8%) were followed up at their second birthday: 77 of 151 (51.0%) in the no CMF group and 81 of 151 (53.6%) in the CMF group underwent extended follow-up because of having atopic conditions. Asthma or recurrent wheeze developed in 15 (9.9%) of the children in the no CMF group, significantly less than the children in the CMF group (27 [17.9%]; risk difference, -0.079; 95% CI, -0.157 to -0.002). In participants with vitamin D levels above the median at 5 months of age, asthma or recurrent wheeze developled in 5 (6.4%) children in the no CMF group, significantly less than in the children in the CMF group (17 [24.6%]; risk difference, -0.182; 95% CI, -0.298 to -0.067; P for interaction = .04). In the highest quartile group of total IgE at age 24 months, asthma or recurrent wheeze developed in 2 children (5.3%) in the no CMF group, significantly less than the children in the CMF group (14 [43.8%]; risk difference, -0.385; 95% CI, -0.571 to -0.199; P for interaction = .004). Conclusions and Relevance: The findings of this study suggest that avoiding CMF supplementation in the first 3 days of life has the potential to reduce the risk of asthma or recurrent wheeze in young children, especially among those with high vitamin D or high IgE levels. Trial Registration: umin.ac.jp/ctr Identifier: UMIN000011577.

The Cow's Milk-Related Symptom Score (CoMiSSTM): Health Care Professional and Parent and Day-to-Day Variability.

The Cow's Milk-related Symptom Score (CoMiSSTM) was created as an awareness tool for cow's milk allergy. The aim of the present study was to analyze the inter-rater variability between a pediatrician, parents, and day to day variability. A Health Care Professional (HCP) and parent filled in the CoMiSS independently and blinded for each other to evaluate inter-rater variability. In order to validate day-to-day variability, a parent filled in the CoMiSS during 3 consecutive days and was compared to the CoMiSS scored by the HCP. The absolute agreement between parent and HCP was 75%, and 92.6% and 100% with a tolerance of 0, 1, and 2 points, respectively, resulting in excellent agreement with an intraclass correlation coefficient (ICC) 0.981 (95% Confidence Interval 0.974-0.986, p < 0.001). Day-to-day variability during 3 consecutive days resulted in an absolute agreement of 30%, increasing to 80% and 88.6% when 2 and 3 points, respectively, were accepted. The ICC was excellent for the parental prospective scores (0.93, 95% CI 0.90-0.96; p < 0.001). Day-to-day variability indicates that CoMiSS has a moderate inter-rater reliability. A very low variability was observed when scored prospectively over three days. Data suggest that the CoMiSS can reliably be scored by parents without additional training.

Food-induced anaphylaxis in infancy compared to preschool age: A retrospective analysis.

OBJECTIVE: Little is known regarding food anaphylaxis in infancy. We aimed to describe specificities of food anaphylaxis in infants (≤12 months) as compared to preschool children (1-6 years). METHODS: We conducted a retrospective study of all food anaphylaxis cases recorded by the Allergy Vigilance Network from 2002 to 2018, in preschool children focusing on infants. RESULTS: Of 1951 food anaphylaxis reactions, 61 (3%) occurred in infants and 386 (20%) in preschool children. Two infants had two anaphylaxis reactions; thus, we analyzed data among 59 infants (male: 51%; mean age: 6 months [SD: 2.9]); 31% had a history of atopic dermatitis, 11% of previous food allergy. The main food allergens were cow's milk (59%), hen's egg (20%), wheat (7%) and peanut (3%) in infants as compared with peanut (27%) and cashew (23%) in preschool children. Anaphylaxis occurred in 28/61 (46%) cases at the first cow's milk intake after breastfeeding discontinuation. Clinical manifestations were mainly mucocutaneous (79%), gastrointestinal (49%), respiratory (48%) and cardiovascular (21%); 25% of infants received adrenaline. Hives, hypotension and neurologic symptoms were more likely to be reported in infants than in preschool children (P = .02; P = .004; P = .002, respectively). Antihistamines and corticosteroids were more often prescribed in preschool children than in infants (P = .005; P = .025, respectively). CONCLUSION: Our study found that in infants presenting with their first food allergy, in a setting with a high rate of infant formula use, the most predominant trigger was cow's milk. As compared to older preschool children, hives, hypotonia and hypotension were more likely to be reported in infants. We believe that this represents a distinct food anaphylaxis phenotype that can further support developing the clinical anaphylaxis criteria in infants.

Testing the Cow's Milk-Related Symptom Score (CoMiSSTM) for the Response to a Cow's Milk-Free Diet in Infants: A Prospective Study.

The diagnosis of cow's milk allergy (CMA) is particularly challenging in infants, especially with non-Immunoglobulin E (IgE)-mediated manifestations, and inaccurate diagnosis may lead to unnecessary dietary restrictions. The aim of this study was to assess the accuracy of the cow's milk-related symptom score (CoMiSSTM) in response to a cow's milk-free diet (CMFD). We prospectively recruited 47 infants (median age three months) who had been placed on a CMFD due to persisting unexplained gastrointestinal symptoms. We compared data with 94 healthy controls (median age three months). The CoMiSSTM score was completed at recruitment and while on the exclusion diet. In 19/47 (40%) cases a response to the diet occurred. At recruitment CoMiSSTM was significantly higher in cases compared to controls (median score 8 vs. 3; p-value: <0.05), 9 cases had a score ≥12 and 8/9 normalized on CMFD. An oral milk challenge was performed in all 19 responders and six of these had a positive reaction to cow's milk (CM). In eight infants IgE allergy tests were positive. The receiver operation characteristic (ROC) curve identified a CoMISSTM score of 9 to be the best cut-off value (84% sensitivity, 85% specificity, 80% positive (PPV) and 88% negative predictive value (NPV)) for the response to CMFD. We found CoMiSSTM to be a useful tool to help identify infants with persisting gastrointestinal symptoms and suspected CMA that would benefit from CMFD.

Influence of Atopic Dermatitis on Cow's Milk Allergy in Children.

Background and Objectives: Cow's milk protein allergy (CMA) is the most common allergy in children. The natural history of CMA is generally favorable and the majority of children reach tolerance during childhood, even if studies show variable results. Atopic dermatitis (AD) is a complex disease from an immunological point of view. It is characterized by an impaired skin barrier function and is often the first clinical manifestation of the so-called "atopic march". The aim of our study is to evaluate, in a cohort of children with CMA, if the presence of AD in the first months of life can influence the atopic status of patients, the tolerance acquisition to cow's milk, the level of specific IgE (sIgE), and the sensitization towards food and/or inhalant allergens. Materials and Methods: We enrolled 100 children with a diagnosis of CMA referred to our Pediatric Allergology Unit, aged 1-24 months at the time of the first visit. Results: 71 children had AD and 29 did not. The mean follow-up was 5.28 years. The CMA manifestations were mainly cutaneous, especially in children with AD (91.6% vs. 51.7%; P < 0.001). Patients with AD showed higher rates of polysensitization to foods and higher levels of both total IgE and sIgE for milk, casein, wheat, peanuts, and cat dander at different ages when compared to patients without AD. We analyzed the presence of IgE sensitization for the main foods and inhalants at various ages in the two groups of patients: a statistically significant difference emerged in the two groups of patients for milk, yolk and egg white, hazelnut, peanuts, soybean, grass pollen and cat dander. Meanwhile, we did not find significant differences in terms of tolerance acquisition toward cow's milk, which was nonetheless reached around 5 years of age in 61% of patients. The level of cow's milk sIgE at the age of 5 years was significantly higher in the group of patients who did not acquire tolerance (38.38 vs. 5.22 kU/L; P < 0.0001). Conclusions: An early barrier deficiency appears to promote the development of allergic sensitization, but does not seem to influence the acquisition of tolerance.

Cow's Milk Substitutes for Children: Nutritional Aspects of Milk from Different Mammalian Species, Special Formula and Plant-Based Beverages.

Cow's milk and dairy are commonly consumed foods in the human diet and contribute to maintaining a healthy nutritional state, providing unique sources of energy, calcium, protein, and vitamins, especially during early childhood. Milk formula is usually made from cow's milk and represents the first food introduced into an infant's diet when breastfeeding is either not possible or insufficient to cover nutritional needs. Very recently, increased awareness of cow's milk protein allergy and intolerance, and higher preference to vegan dietary habits have influenced parents towards frequently choosing cows' milk substitutes for children, comprising other mammalian milk types and plant-based milk beverages. However, many of these milk alternatives do not necessarily address the nutritional requirements of infants and children. There is a strong need to promote awareness about qualitative and quantitative nutritional compositions of different milk formulas, in order to guide parents and medical providers selecting the best option for children. In this article, we sought to review the different compositions in terms of macronutrients and micronutrients of milk from different mammalian species, including special milk formulas indicated for cow's milk allergy, and of plant-based milk alternatives.

Reduced Final Height and Inadequate Nutritional Intake in Cow's Milk-Allergic Young Adults.

BACKGROUND: Growth impairment was previously described in milk-allergic children but was not examined in adults on reaching final height. OBJECTIVES: To investigate the dietary intake and final stature of young adults with IgE-mediated cow's milk allergy (IgE-CMA) as compared with nonallergic controls. METHODS: Eighty-seven patients with IgE-CMA, median age 19.5 years (interquartile range [IQR], 17.3-22.7), and 36 control participants without food allergies, median age 22.7 years (IQR, 18.9-26.1), were studied. Anthropometric and nutritional data were collected. Age and gender z-scores were determined according to the Centers for Disease Control and Prevention growth charts. Nutrient intake assessment was based on dietary records. Individuals with conditions or treatments affecting bone metabolism or growth, other than asthma, were excluded. RESULTS: Mean values of height z-scores were significantly reduced in CMA subjects compared with controls (-0.64 ± 0.9 vs -0.04 ± 0.7, P = .001). In contrast, no differences were found between the 2 groups in weight and body mass index z-scores. Patients with CMA had significantly lower intake of protein, and several essential vitamins (A, B12, and riboflavin) and minerals (calcium, potassium, phosphorus, magnesium, and zinc) compared with controls (P < .05), but the intakes of calories, carbohydrate, and fat were not significantly different between the 2 groups. Differences between actual and expected (based on midparental height) height z-scores were comparable in CMA subjects with or without asthma and between those with and without additional food allergies. CONCLUSIONS: Young adults who have CMA from infancy are at risk of not reaching their growth potential. Growth and nutritional monitoring and appropriate dietary intervention are of particular importance in these at-risk individuals.

Ultrasonographic study of intestinal Doppler blood flow in infantile non-IgE-mediated gastrointestinal food allergy.

BACKGROUND: Although non-IgE-mediated gastrointestinal food allergy has increased rapidly in Japan, a small number of reports has evaluated B-mode and Doppler ultrasonographic findings in the acute phase of infantile gastrointestinal milk allergy. The aim of the present study was to compare the diagnostic utility of ultrasonographic findings and laboratory allergic data in non-IgE-mediated infantile gastrointestinal milk allergy. METHODS: Sixteen cases of active non-IgE-mediated infantile gastrointestinal milk allergy, diagnosed by food elimination tests and oral food challenge tests (OFCTs) (group A), 15 cases of acute viral gastroenteritis (AGE) (group B), and 15 controls (group C) were enrolled. 1) B-mode abdominal ultrasound findings, 2) laboratory allergic data including eosinophil counts (Eos), serum IgE, and the antigen-specific lymphocyte proliferation test (ALPT) against milk protein, and 3) vessel density (VD) indirectly quantified by gastrointestinal Doppler flow at jejunum, ileum, and sigmoid colonic mucosae were evaluated and compared among the groups. RESULTS: In the small intestine, wall thickening, dilation, mesenteric thickening, and poor peristalsis were found in 100%, 62.5%, 93.7%, and 100%, respectively, in group A. Eos, IgE, ALPT, and VD were positive in 25.0%, 0%, 87.5%, and 100%, respectively, in group A. Small intestinal VD was significantly greater in group A than in groups B (jejunum p < .001; ileum p < .001) and C (jejunum p < .001; ileum p < .001), with no significant differences between groups B and C (jejunum: p = .74; ileum: p = .73). CONCLUSIONS: Abdominal Doppler ultrasonography and small intestinal VD at symptomatic state can support the diagnosis and evaluation of non-IgE-mediated infantile gastrointestinal milk allergy with symptoms of vomiting, diarrhea, and failure to thrive.

Donkey milk as a supplement in infant formula: Benefits and technological challenges.

The aim of this review paper is to assess the applicability of donkey's milk to infants suffering from Cow Milk Protein Allergy (CMPA) compared to human and other available milk types. The bioactive and immune-supportive character which could be beneficial as a fortifier to the formula-fed infants is described while limitations of this type of milk are also discussed. Studies showed that human and donkey's milk have similar, overall, chemical composition as well as protein homogeneity and antigenic similarities. Several in vitro and in vivo studies showed that donkey's milk has nutraceutical and functional properties that can support immunity, alter metabolism and beneficially modify gut microbiota. Clinical studies illustrated that donkeys' milk is well tolerated (82.6%-88%) by infants. Finally, the effect that processing (i.e. thermal, non-thermal treatments, drying methods) has on donkey milk components is also discussed pointing out the need for minimally processing this type of milk.

Food allergy to previously tolerated foods: Course and patient characteristics.

BACKGROUND: The acquisition of food allergy (FA) to previously safely consumed basic food proteins is an unusual presentation of immunoglobulin E (IgE)-mediated allergic disease. OBJECTIVE: We sought to characterize patients who developed FA to previously tolerated foods (FA-PTF), including underlying reasons for and length of elimination diet of previously tolerated foods. METHODS: Patients (n = 30) with complaints consistent with FA to foods previously consumed safely were evaluated. Clinical history was obtained, and skin prick testing and graded oral food challenges (OFC) were performed. One fatal case of FA-PTF was reported by a physician. RESULTS: Twenty-two of 30 patients (ages 1.2-50 years) were diagnosed with FA-PTF by OFC to milk (n = 17), egg (n = 2), and peanuts (n = 3). One additional patient with FA-PTF had a fatal reaction to milk. Anaphylactic reactions were reported in 12 of these 23 FA-PT patients (52%); 8 experienced multiple episodes. Atopic dermatitis was diagnosed in 52% (12/23) of patients, 8 of 12 as severe; overall, 18 of 23 (78%) of patients had marked personal atopic background. Sixteen patients (70%) initiated an elimination diet, 12 of whom did so on advice from a health care provider, before the appearance of allergic symptoms. However, in 4 patients with FA-PTF, reactivity to the food protein emerged during uninterrupted consumption. CONCLUSION: Food allergy to previously tolerated foods primarily appears after an elimination diet in atopic patients. Anaphylactic reactions are common. Health care providers should consider these risks before recommending elimination diet of tolerated foods.

Cow's Milk Protein Allergy.

Cow's milk protein allergy (CMPA) is a common condition encountered in children with incidence estimated as 2% to 7.5% in the first year of life. Formula and breast-fed babies can present with symptoms of CMPA. It is important to accurately diagnose CMPA to avoid the consequences of either under- or overdiagnosis. CMPA is classically categorized into immunoglobulin E (IgE)- or non-IgE-mediated reaction that vary in clinical manifestations, diagnostic evaluation, and prognosis. The most commonly involved systems in patients with CMPA are gastrointestinal, skin, and respiratory. Evaluation of CMPA starts with good data gathering followed by testing if indicated. Treatment is simply by avoidance of cow's milk protein (CMP) in the child's or mother's diet, if exclusively breast-feeding. This article reviews the definition, epidemiology, risk factors, pathogenesis, clinical presentation, evaluation, management, and prognosis of CMPA and provides an overview of different options for formulas and their indication in the treatment of CMPA.

Milk hypersensitivities: where is the grey line regarding their dietary management?

The proportion of people suffering or reporting to have a hypersensitivity caused by cow's milk consumption is increasing, and even health professionals often face difficulties into elaborating properly with a milk reaction due to misdiagnosis. The scope of this review is to present literature data that lead into putting the border line between cow's milk allergy and cow's milk intolerance, mainly focusing on how the different pathophysiology leads to their different dietary diagnosis and management.

Cow's Milk Allergy and Bone Mineral Density in Prepubertal Children.

BACKGROUND AND OBJECTIVES: Recent data suggest that cow's milk allergy (CMA) has become more persistent, prolonging treatment via strict elimination of cow's milk products into a period of skeletal growth. The objectives of this study were to compare bone mineral density (BMD), vitamin D status, and dietary intakes of calcium and vitamin D between prepubertal children with persistent CMA and those with non-cow's milk food allergies (NCMA) as control subjects and to assess the use of and compliance to calcium and vitamin D supplementation among children with persistent CMA. METHODS: Fifty-two children with persistent CMA and 29 with NCMA were recruited. BMD was measured by using dual energy radiograph absorptiometry, and vitamin D status was assessed by using plasma 25-hydroxyvitamin D concentrations. Calcium and vitamin D intakes, as well as compliance to calcium and vitamin D supplementation, were recorded. RESULTS: Lumbar spine BMD z scores were significantly lower in children with CMA. Low bone mass was detected in 6% of the CMA group compared with none in the NCMA group. Children with CMA displayed significantly lower calcium intakes than control subjects. Vitamin D status was not reduced in children with CMA compared with control subjects. Fewer than one-half of children with CMA reported the use of calcium and vitamin D supplements. However, adherence was high among supplement users, with a mean compliance rate of 5.5 days per week. CONCLUSIONS: These prepubertal children with persistent CMA had lower lumbar spine BMD z scores than children with NCMA, which likely resulted from lower calcium intake.

The Nutritional Value of Protein-hydrolyzed Formulae.

Allergy to cow's milk proteins is a challenging condition in early infancy. Allergic infants may be predisposed to impairments of growth from either the disease itself or the nutritional constraints of the exclusion diet they should follow. Formulae based on extensively hydrolyzed cow's milk proteins are widely used, representing therapy, and constituting 100% nutrient source in the first four to six months of life and half the daily nutrient intake in the second semester of life. In some cases, these products are used also for preventive purposes. Some impairments in growth have been reported for infants using these products, even if mostly limited to the first year of life, with no apparent consequences in either the medium or long term. The macronutrient content of infant formulae based on protein hydrolysates, whichever the source, should carefully be tested not only as far as the optimal utilization of nitrogenous sources but also on the nature and metabolic fate of non-nitrogen caloric sources, represented by carbohydrates and fats, and micronutrients, particularly iron. It is recommended that studies aimed at the allergologic effects of these products also include an appropriate nutritional evaluation to determine their efficiency.

The effect of elimination diet on the growth of a child with milk allergy - a systematic review.

BACKGROUND: Cow's milk is the most common food allergen in children under 3 years of age. Milk allergy is treated by eliminating milk from the diet. METHODS: The present study was conducted according to international guidelines for systematic reviews. RESULTS: In all three articles included in the current study, children with milk allergy were of lower weight than the controls. Furthermore, in one of the studies included, growth of the children with mild allergy was stunted. DISCUSSION: The current review shows that milk allergy is associated with stunted growth in childhood. The reasons for this growth retardation are unclear.

[Evaluation of Efficacy and Safety of Longterm Feeding with Amino Acid-Based Formula in Infants with Cow's Milk Protein Allergy: Results of the Open-Label Prospective Controlled Post-Registration Trial].

Background: The cow's milk allergy (CMA) prevalence is 2−3% in children under one year. Approximately in 5% of cases transferring to extensively hydrolysed formula (eHF) doesn't lead to disappearance of CMA symptoms. Aims: Evaluation of efficacy and safety of amino-acid formula (AAF) longterm feeding in children under one year and development of predictors of successful transfer from AAF to eHF. Materials and Methods: In open-label prospective post-registration trial duration of 365 days were included 43 children aged from 3 to 12 months with CMA. CMA was based on Russian and international guidelines. When a patient was included in the trial, child received eHF for 4 weeks with the evaluation of the effect of elimination diet (ED): in case of absence of effect, for diagnostic purposes child feed with AAF for 2 weeks and upon receiving the effect, child continued to receive it for at least 6 months. Diet was considered effective if there were observed disappearance of clinical manifestations of CMA during of formula using. Results: Children fed with AAF gain weight and increased height statistically higher during the first 6 months, compared with children receiving eHF, but without subsequent difference in a year. After 4 weeks' of AAF feeding, there was a significant decrease in SCORAD index from 46.84 (SD 4.164) to 2.52 (SD 2.204) (p=0.005); disappearance of gastrointestinal manifestations of CMA from 3 to 14 day. After 4 weeks, the 100% normalization of previously elevated faecal calprotectin (p<0.05) was observed; and after 6months. ED, in 60% of children normalization of the index of activation of basophils with milk was observed. 38.7% of children were transferred to eHF in 6 months, 12.9% and 25.8% in 9 and 12 months respectively. Conclusions: Use of AAF for children with CMA is an effective and safe treatment without lengthening the period of elimination, which is necessary for the formation of tolerance to cow's milk protein and has a positive impact on weight and height. Normalization of specific activation of basophils with milk could be considered as a predictor of successful transfer from AAF to eHF in children with CMA.