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A large proportion of prescriptions for extensively hydrolyzed cow's milk protein (CMP) in newborns are not based on any scientific data justifying the indication. Many of these prescriptions are old habits or are based on incomplete data. The aim of this article is to analyze these practices and propose recommendations. The following points are covered: (a) indications for extensively hydrolyzed formula based on studies demonstrating their benefits in these situations-newborns with a proven allergy to CMP and occasional prescription of supplements to breastfeeding; (b) possible indications not based on a high level of evidence-re-initiation of feeding due to necrotizing enterocolitis, short bowel syndrome, re-initiation of feeding of newborns following intestinal surgery, and laparoschisis if neither the mother's own milk nor milk from a lactarium is available; (c) unjustified indications-newborns at risk of atopy, prematurity, severe neurological pathologies, newborns who are hemodynamically unstable and/or have congenital cardiopathy, neonatal hypoxic-ischemic encephalopathy treated with hypothermia, and newborns with esophageal atresia or diaphragmatic hernia. By following this classification, the prescriber will be guided to use the milk best suited to the pathology, bearing in mind that each situation must be adapted individually and the tolerance and effectiveness of the food reassessed from a nutritional and functional point of view., Competing Interests: Declaration of competing interest V. Rigourd, A. Heneau, A.L. Virlouvet, A. Basset, E. Herry, B. Jaquemet, A. Lapillonne, M. Bellaiche: no conflicts of interest; P. Tounian: Carrefour, Danone, Lactalis, Materna, Mead Johnson, Nestlé, Novalac, PédiAct, Sodilac., (Copyright © 2024 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

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

The use of lactose and cow milk protein (CMP) as potential allergens in pharmaceuticals and their ability to cause allergic reactions remains a significant concern in medicine. Lactose, a common pharmaceutical excipient due to its inert, inexpensive, and stable properties, is found in many prescription-only and over-the-counter medications. However, despite their widespread use, individuals with lactose intolerance (LI) or cow milk protein allergy (CMPA) may experience adverse reactions to these excipients. This study investigated the prevalence of lactose and other dairy-derived ingredients in pharmaceuticals marketed in Portugal. Using the Summary of Product Characteristics (SmPC) from the INFOMED database, various medications, including analgesics, antipyretics, non-steroidal anti-inflammatory drugs (NSAIDs), and antiasthmatics, were analyzed. Results showed a high prevalence of dairy-derived excipients, particularly in antiasthmatic drugs (62.6%) and NSAIDs (39%). Although CMP are not explicitly mentioned in SmPCs, the presence of lactose as an ingredient poses a risk of cross-contamination. The findings emphasize the need for healthcare professionals to be aware of potential allergens in medications and the importance of developing lactose-free alternatives to ensure the safety of patients with LI and CMPA. Further research is required to assess the safety and implications of lactose in medicines for these populations., (© 2024. The Author(s).)

Neonatal immune regulation transitions from fetal immunity and varies with maturation status, but its role in neonatal cow's milk protein allergy (CMPA) remains unknown. We studied the association between maturation status at birth and neonatal CMPA. Clinical and laboratory data of neonates presenting with CMPA symptoms were retrospectively collected from two tertiary hospitals. Patients were assessed according to gestational age at birth: preterm, late-preterm, and full-term. Fifty-five infants (26 females, 14 preterm, 15 late-preterm, and 26 full-term) were included; 44 were negative for milk-specific immunoglobulin E. Neonatal CMPA was common during moderately premature periods. Preterm infants exhibited longer latency from initial CM exposure to disease onset, lower incidence of bloody stool, and absence of elevated monocyte counts. However, immunoreactivity to CM antigens was retained in all infants. Neonatal CMPA features varied with infant maturation status at birth. Our results improve the understanding of intestinal immunity development, fetal/neonatal immune regulation, and CMPA pathogenesis., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy characterized by gastrointestinal symptom onset within 1-4 hours from trigger food ingestion. In the literature, some authors have previously described the possibility that a patient with FPIES may develop an IgE-mediated allergy to the same trigger food, especially cow's milk (CM). Case Presentation: We reported five cases of CM-FPIES converting to IgE-mediated CM allergy presented at our tertiary pediatric Allergy Unit and performed a review of the literature, aiming to characterize the clinical features of patients who are at risk of developing such conversion. Conclusions: This phenomenon raises the question of whether IgE-mediated and non-IgE-mediated allergies represent a spectrum of the same disease and highlights the need for further investigation to understand the pathophysiological mechanisms of this process.

Cow's milk (CM) is a healthy food consumed worldwide by individuals of all ages. Unfortunately, "lactase-deficient" individuals cannot digest milk's main carbohydrate, lactose, depriving themselves of highly beneficial milk proteins like casein, lactoalbumin, and lactoglobulin due to lactose intolerance (LI), while other individuals develop allergies specifically against these proteins (CMPA). The management of these conditions differs, and an inappropriate diagnosis or treatment may have significant implications for the patients, especially if they are infants or very young children, resulting in unnecessary dietary restrictions or avoidable adverse reactions. Omics technologies play a pivotal role in elucidating the intricate interactions between nutrients and the human body, spanning from genetic factors to the microbiota profile and metabolites. This comprehensive approach enables the precise delineation and identification of distinct cohorts of individuals with specific dietary requirements, so that tailored nutrition strategies can be developed. This is what is called personalized nutrition or precision nutrition (PN), the area of nutrition that focuses on the effects of nutrients on the genome, proteome, and metabolome, promoting well-being and health, preventing diseases, reducing chronic disease incidence, and increasing life expectancy. Here, we report the opinion of the scientific community proposing to replace the "one size fits all" approach with tailor-made nutrition programs, designed by integrating nutrigenomic data together with clinical parameters and microbiota profiles, taking into account the individual lactose tolerance threshold and needs in terms of specific nutrients intake. This customized approach could help LI patients to improve their quality of life, overcoming depression or anxiety often resulting from the individual perception of this condition as different from a normal state.

Introduction. The oral food challenge (OFC) for the diagnosis of cow's milk protein allergy (CMPA) poses risks and requires resources. Our objective was to assess conditions and complementary tests used to identify a high probability of CMPA. Population and methods. Secondary analysis of a study of patients seen at a unit of allergy between 2015 and 2018. Pre-testing probabilities associated with symptoms and their combinations and post-testing probabilities after skin prick testing and serum immunoglobulin E (IgE) levels were determined. Results. The data from 239 patients were assessed. A probability greater than 95% was observed for angioedema and a combination of urticaria and vomiting. Based on the cut-off points proposed by Calvani et al., the combination of vomiting with rhinitis, without angioedema, also exceeded 95%. Conclusion. A methodology is provided to identify patients in whom CMPA may be diagnosed without an OFC., (Sociedad Argentina de Pediatría.)

Objective: To investigate the natural history and risk factors for continued allergy in infants with IgE-mediated cow's milk protein allergy (CMPA). Methods: This was a prospective cohort study that included 72 infants under 24 months of age diagnosed with IgE-mediated CMPA in the allergy clinic of the Children's Hospital, Capital Institute of Pediatrics from October 2019 to November 2020. General information, clinical manifestations, serum total IgE, cow's milk specific IgE, and cow's milk protein component specific IgE were collected. Follow-ups were conducted at 24 and 36 months of age, and the patients were divided into the persistent allergy group and the tolerance group based on whether they developed cow's milk tolerance at 36 months of age. Mann-Whitney U test, chi-square test, and binary Logistic regression were used for intergroup comparison and multivariate analysis. Results: Among the 72 CMPA children, there were 42 boys and 30 girls, with an age of 10 (7, 15) months at enrollment. Cow's milk protein tolerance was observed in 32 cases (44%) and 46 cases (64%) at 24 and 36 months of age, respectively. There were 26 cases in the persistent allergy group and 46 cases in the tolerance group. The proportion of respiratory symptoms, history of wheezing, positive specific IgE for α-lactalbumin and the total IgE level in the persistent allergy group were higher than that in the tolerance group (7 cases (27%) vs. 0, 6 cases (23%) vs. 2 cases (4%), 67% (14/21) vs. 26% (10/39), 225 (151, 616) vs. 48 (21, 185) kU/L, χ 2 =10.82, 4.16, 9.57, Z =4.07, all P <0.05). Multivariate Logistic regression analysis showed that anaphylaxis ( OR =21.14, 95% CI 2.55-175.14, P =0.005), a history of allergic rhinitis ( OR =5.94, 95% CI 1.54-22.86, P =0.005), elevated milk specific IgE ( OR =1.04, 95% CI 1.01-1.08, P =0.024), and positive casein specific IgE ( OR =6.64, 95% CI 1.39-31.69, P =0.018) were risk factors for continuous CMPA. Conclusions: Most infants with IgE-mediated CMPA can achieve tolerance within 3 years. Anaphylaxis, a history of allergic rhinitis, elevated milk specific IgE levels, and casein sensitization are risk factors for continuous allergy.

Background: Cow's milk protein allergy (CMPA) is well described in term infants, as opposed to preterm infants. In preterm infants, CMPA shares many gastrointestinal symptoms with necrotizing enterocolitis (NEC). Objectives: To evaluate the presentation of CMPA in preterm infants and to investigate the different diagnostic and therapeutic options. Materials and Methods: We searched for the relevant literature using the medical databases PubMed, Web of Science, and the Cochrane Library. We performed a post hoc analysis on the 25 case reports included in this study. Results: Literature was scarce and heterogeneous. The majority of preterm infants with CMPA were exposed to bovine-based milk proteins before the development of symptoms. The most common clinical manifestations were bloody stools, vomiting, and abdominal distension. Of the 25 cases, only 7 (28%) retained human milk in their diet after diagnosis. In the larger studies, no study has human milk as primary feeding choice after diagnosis. Conclusions: Preterm infants exposed to a type of cow's milk-based formula in their first days of life have a higher risk of developing CMPA. Most of the preterm infants are no longer fed with human milk after the diagnosis of CMPA is made, which is in contrast with current nutrition guidelines in preterm infants. We strongly advocate that human milk with mothers on a cow's milk-free diet is the first choice of feed after the diagnosis of CMPA. Prospective studies are necessary to obtain more information regarding clinical presentation, diagnostic tools, and therapeutic approaches.

Immunoglobulin E (IgE)-mediated cow's milk allergy (CMA) is a common food reaction resulting from the consumption of cow's milk protein (CMP). The clinical manifestations of CMA include mild to severe urticaria, skin-manifested hypersensitivity reactions, and anaphylaxis. Food allergies may affect 8% of children and 10% of adults. The Federal Food, Drug, and Cosmetic Act (FD&C Act) requires that the label of a food must declare the presence of a "major food allergen" (MFA) contained in the food or ingredient. The Food and Drug Administration (FDA) generally regards milk protein concentrate (MPC) as safe for human consumption and use. The increasing use of MPC in formulations raises the need for its revelation in prescription and on labels of over-the-counter drugs. This review investigates oral and topical (including mucosal) preparations containing MPC for dermatologic and other uses and their therapeutic impact. Our findings suggest that for the adult population, the risk of serious cow's milk protein allergy (CMPA) from medications is minimal.

Background: The Step-Down Approach for Cow's Milk Allergy (SDACMA) trial evaluated the tolerability and the rate of immune tolerance acquisition in CMA children starting dietary treatment with amino acid-based formula (AAF) and then switching to EHCF containing the probiotic Lacticaseibacillus  rhamnosus GG (EHCF + LGG)., Methods: Randomized controlled trial involving IgE-mediated CMA children receiving AAF from at least 4 weeks. EHCF + LGG tolerance was evaluated by the results of double-blind placebo-controlled food challenge (DBPCFC). Subjects tolerating EHCF + LGG were randomly allocated to remain on AAF, or to switch to EHCF + LGG. Immune tolerance acquisition to cow's milk proteins was evaluated with DBPCFC after 12 months of treatment. Allergy screening tests and body growth were also monitored., Results: Sixty IgE-mediated CMA children were enrolled. The proportion of children treated with AAF who resulted tolerant to the first exposure of EHCF + LGG was 0.98 (exact 95% CI 0.91-0.99). The rate of the immune tolerance acquisition to cow milk proteins after 12 months treatment was higher in the EHCF + LGG (0.48, 95% exact CI 0.29-0.67, n/N = 14/29) than in the AAF group (0.03, 95% exact CI 0.001-0.17, n/N = 1/30). There was an absolute benefit increase (ABI) of tolerance rate equal to 0.45 (95% CI 0.23-0.63, Newcombe method 10) for EHCF + LGG versus AAF, corresponding to a NNT of 2 (2-4, Bender's method). A normal body growth pattern was observed in the two study groups., Conclusion: In IgE-mediated CMA children the step-down from AAF to EHCF + LGG is well tolerated and could facilitate the immune tolerance acquisition., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Protein-losing enteropathy (PLE), a rare condition with excessive gastrointestinal protein loss, presents with hypoalbuminemia, edema, or ascites. Several cases of PLE combined with severe iron deficiency anemia (IDA) have been reported in infants and toddlers that were considered to result from excessive cow's milk consumption, although the mechanism has not been clearly established., Methods: We retrospectively reviewed the clinical, laboratory, endoscopic, and radiologic characteristics of patients diagnosed and treated for PLE with IDA between 2015 and 2021. Long-term outcomes were analyzed according to dietary intervention during the follow-up period., Results: A total of 10 patients aged 7.0-26.7 months were enrolled in the study and the median follow-up duration of them was 9.4 months (range, 1.3-18.0). Six of them were fed powdered formula, while two were fed whole cow's milk, and their median daily intake was 700 mL (range, 300-900). The times to normalization of hemoglobin, albumin, and eosinophil count were shorter in patients with dietary elimination of cow's milk protein immediately after diagnosis compared to those with reduced intake or no dietary change., Conclusion: Early complete elimination of cow's milk protein should be considered, especially if the laboratory parameters are not normalized with adequate iron supplementation even though the clinical symptoms show improvement. We would like to draw attention to the possibility of the cow's milk protein in the pathogenesis of the condition through the non-IgE-mediated immune reactions., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Background: Current guidelines emphasize early introduction to potentially allergenic foods, but the optimal timing, amount, and exposure routes for foods other than peanut are not well-established. Cow's milk is often the first allergenic food introduced through infant formulas., Objective: To examine timing of cow's milk protein introduction (CMPI), including interaction with formula supplementation after delivery, in relation to reported cow's milk adverse reactions throughout childhood., Methods: Among children in the Boston, Mass-area Project Viva cohort, we assessed timing of CMPI (<2 weeks, 2 weeks-<6 months, ≥6 months) with questionnaires administered in infancy. Outcomes were (1) parent-reported cow's milk adverse reactions via annual questionnaires from age 2 to 13 years (n = 1298) and (2) milk sensitization (n = 505) and IgE-mediated milk allergy (n = 491) at age approximately 8 years. We used multivariable logistic regression models adjusted for parental atopy history, delivery mode, gestational age at delivery, child race, and census tract median household income, and investigated effect modification by ever/never breast-fed status and formula supplementation in the delivery hospital., Results: A total of 32% were introduced to cow's milk protein at age less than 2 weeks, 38% at age 2 weeks to less than 6 months, and 30% at age 6 months or more. Compared with children with CMPI at age less than 2 weeks, children with CMPI at age 6 months or more had a higher risk of cow's milk adverse reaction at age 2 to 5 years (odds ratio, 2.4 [1.2-4.7]). Children given formula after delivery + CMPI at age less than 2 weeks had the lowest risk overall. Among children not given formula after delivery, CMPI at age 2 weeks to 6 months appeared most protective. Results were similar among ever-breast-fed children. Timing of CMPI was not associated with milk sensitization or IgE-mediated milk allergy in mid-childhood., Conclusions: Early, consistent cow's milk exposure appears protective against adverse reactions to cow's milk., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objectives: Infants with non-IgE-mediated food allergies are often referred to gastroenterologists or immunologists. We hypothesized that there are practice variations between these disciplines in the diagnosis and management of such infants., Methods: A computerized questionnaire was distributed between pediatric gastroenterologists and immunologists. The questions addressed diagnosis, management, and follow-up in 3 scenarios of infants with concern for food protein-induced allergic proctocolitis (FPIAP) due to non-IgE-mediated responses to cow's milk., Results: Three cases of infants with suspected FPIAP were presented: milk-based formula-fed (case 1) or breast-fed (case 2) infants that are well appearing and thriving, and a breast-fed infant who is not growing appropriately along with a personal and family history of atopy (case 3). Fifty-eight pediatric gastroenterologists and 32 immunologists completed the questionnaire. Significant differences between gastroenterologists and immunologists were noted regarding the recommended dietary changes in these scenarios. Moreover, despite available guidelines generated by both societies, most physicians confirm the diagnosis based on resolution of symptoms after the dietary change, without re-exposure to the the suspected trigger. In addition, time for recommended re-exposure in infants with FPIAP was also different; most gastroenterologists recommended waiting until 12 months of age, while immunologists suggested reintroduction earlier, up to 6 months of age., Conclusions: We identified significant practice variations in diagnosis and management of FPIAP between pediatric gastroenterologists and immunologists, with lack of adherence to society guidelines. Joint task forces of primary care pediatricians, gastroenterologists, and immunologists should provide uniform guidelines to standardize care., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Aims: Gastro-oesophageal reflux (GOR) and cow's milk protein intolerance (CMPI) are two frequently occurring conditions found in infancy. The aim of this review is to examine the association between the two., Methods: A literature review was conducted via PubMed, Sciencedirect and Google scholar using search terms "gastro-oesophageal reflux" + "cow's milk protein intolerance". The inclusion criteria were studies from 1985 to present, studies involving infants and studies involving both GOR and CMPI. Exclusion criteria were studies not including infants, or studies involving GOR or CMPI independently., Results: This review revealed varying degrees of co-existence of GOR and CMPI. Iacono et al., Farahmand et al., Kamer et al., and Semeniuk and Kaczmarski, displayed co-occurrence of GOR and CMPI in 41.8%, 33.3%, 46.5%, and 44.9% of infants respectively. In two separate studies by Cavataio et al., concomitance was apparent in 41.6% and 30% of infants. Others suggested a less significant link at 16-20%. Nielsen et al. found 18/42 children to have severe GORD, 10 of whom had CMPI in addition., Conclusion: This review highlights an association between GOR and CMPI. CMPI should be considered, particularly in cases of reflux resistant to pharmacological therapy, as a co-existing or causative entity accounting for symptoms., (© 2021. Royal Academy of Medicine in Ireland.)

Cow's milk protein allergy (CMPA) is the most frequent cause of food allergy in the first months of life. Despite the fact that there are different guidelines and recommendations on the management of children with CMPA, there continues to be great variability in diagnostic and therapeutic criteria in Latin America. The Food Allergy Working Group of the Latin American Society for Pediatric Gastroenterology, Hepatology and Nutrition summoned a group of Latin American experts to reach a consensus and formulate a document to unify diagnostic and therapeutic criteria for CMPA. Three teams were formed, each with a coordinator, and the members of each team developed a series of statements for their corresponding module: a) clinical manifestations and diagnosis; b) diagnostic tools, and c) treatment. A search of the medical literature was carried out to support the information presented in each module and 28 statements were then selected. The statements were discussed, after which they were evaluated by all the experts, utilizing the Delphi method. Their opinions on statement agreement or disagreement were anonymously issued. The final statements selected were those with above 75% agreement and their corresponding recommendations were formulated, resulting in the document presented herein., (Copyright © 2022 Asociación Mexicana de Gastroenterología. Published by Masson Doyma México S.A. All rights reserved.)

Background: Cow's milk protein allergy (CMA) is the second most common food allergy in Singapore. However, there is limited data on local paediatric CMA., Objective: We aimed to describe the demographics, clinical characteristics, natural history and diagnostic performance of skin prick test (SPT) and cow's milk-specific immunoglobulin E (CM-IgE) in Singaporean children diagnosed with IgE-mediated CMA., Methods: A retrospective review of medical records was conducted for children with an SPT performed to cow's milk between 2011 and 2016., Results: There were 355 patients included, 313 cow's milk allergic and 42 cow's milk tolerant. The median age of reaction was 6 months (IQR 4-8). The most common allergic presentation was cutaneous reactions, followed by gastrointestinal reactions. Six patients (1.9%) reported anaphylaxis at initial presentation and 16 children (5.1%) experienced anaphylaxis to cow's milk at least once in their lifetime. Most of the CMA patients (81.8%) acquired natural tolerance by 6 years old. SPT to cow's milk of ≥ 7 mm and CM-IgE of ≥ 13 kU/L showed good discriminative abilities in predicting a failed oral food challenge (OFC) outcome., Conclusions: CMA is a food allergy which commonly presents during infancy, and parents need to be aware of the likelihood of severe allergic reactions, including anaphylaxis. Prognosis for CMA is generally favourable. Future prospective cohort studies are required to better understand the natural history and better define the diagnostic cut-off values for allergy testing in our population.

We describe the case of a man who developed an acute allergic reaction for the first time in his life directly after drinking a protein shake after a workout session. Allergy diagnostics, including skin prick testing and the determination of specific IgE antibodies revealed sensitizations to cow's milk and hen's egg. Due to the association between the onset of symptoms after ingestion of a milk protein shake, a type-1-allergic reaction to milk protein was suggested. The patient denied a provocation test, although this could have been an opportunity to elucidate the role of physical exercise in this case. We suspect in the present case a loss of tolerance of early childhood sensitization due to repetitive high protein exposure in the context of physical activity. The patient was provided information regarding dietary and emergency management., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

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., (Copyright © 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Infants affected by Heiner syndrome (HS) display chronic upper or lower respiratory tract infections, including otitis media or pneumonia. Clinically, gastrointestinal signs and symptoms, anemia, recurrent fever and failure to thrive can be also present. Chest X-rays can show patchy infiltrates miming pneumonia. Clinical manifestations usually disappear after a milk-free diet. The pathogenetic mechanism underlying HS remains unexplained, but the formation of immune complexes and the cell-mediated reaction have been proposed. Patients usually outgrow this hypersensitivity within a few years. The aim of this review is to provide an updated overview on the current evidence on HS in children, with a critical approach on the still undefined points of this interesting disease. Finally, we propose the first structured diagnostic approach for HS.

Functional constipation (FC) is one of the most common disorders in childhood and has a negative impact on the quality of life of children. Scientific evidence regarding a causal relationship 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) recommendations. 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., Competing Interests: The authors declare no conflicts of interest.

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.

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.

This investigation has been performed to show the efficacy of Lactobacillus rhamnosus GG (LGG) together with milk-free diet in patients with cow's milk protein allergy (CMPA). This multicentre prospective investigation has been performed in 0-12 months of age children diagnosed as CMPA clinically and biochemically. Patients have been randomly divided in to two groups. İnfants in probiotic group were received with cow's milk protein free diet and per oral (p.o.) daily 1X10 9 CFU LGG and in placebo group with milk-free diet and placebo. Mothers of all breast-fed patients have been put on milk-free diet and all patients fed with formula, offered to extensively hydrolysed formula. Symptoms like diarrhoea, vomiting, mucousy or bloody stool, abdominal pain or distension, constipation, dermatitis and restiveness were recorded at the beginning and weekly during the receiving dietary by the investigator. One-hundred infants diagnosed CMPA were included in this double-blind placebo controlled study. Forty-eight infants placed in probiotic group and 52 in placebo group. After 4 weeks of receiving dietary, infants in probiotic group have showed statistically significant improvement in symptoms of bloody stool, diarrhoea, restiveness and abdominal distension (p ≤ 0.001). Whilst statistically significant improvement was also observed in symptoms of mucousy stool (p = 0.038) and vomiting (p = 0.034), no significant improvement were observed in abdominal pain (p = 0.325), constipation (p = 0.917) and dermatitis (p = 0.071). In this study we observed significant improvement in symptoms of infants diagnosed CMPA receiving dietary LGG with cow's milk-free diet.

Aim: Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobulin E (IgE)-mediated food allergy, which is confined to the gastrointestinal tract and occurs most frequently in the first year of life. Our aim was to examine the clinical features, causative agents and outcomes of Greek children with FPIES., Methods: This was a five-year (2013-2017) retrospective study, based on chart reviews of 78 children with FPIES from six Greek paediatric allergy centres., Results: Only five children needed an oral food challenge (OFC) for diagnosis, but 54 children (69%) had OFCs to monitor tolerance development. The most common problems were fish and milk, which affected affecting 42 (54%) and 25 (35%) of children, respectively. The median age of tolerance based on the results of the negative OFCs occurred by 34.0 (26.6-58.4) months. Fish and milk were tolerated by 24 (57%) and 13 (52%) of children by 43.8 and 24.3 months, respectively. Coexisting IgE sensitisation to the offending food was related to delayed tolerance., Conclusion: Fish and milk were the most common food allergies in our series of Greek children with FPIES. Cases with IgE sensitisation to the food trigger took longer to resolve their allergies., (©2019 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Introduction and aim: The aim of our research is to evaluate and compare commonly performed diagnostic tests, and to examine the psychological disorders induced by this food allergy. Children with symptoms suggesting cow's milk protein allergy were included in this study (n = 47). Blood and saliva samples were collected from the participants. Parents were asked to fill in a questionnaire constructed by the research team (containing the DSM-5 symptoms checklist about attention deficit hyperactivity disorder). Method: One of the most widely used diagnostic tool is the skin allergy test, which was performed in 47 subjects (n = 47, mean age: 7.36 years); only 2 children showed positive test result for cow's milk. Lymphocyte transformation test was observed to be positive in 8 children (17%), 4 subjects demonstrated questionable results. In our sub-study about psychological symptoms (n = 43, mean age: 7.88 years), the score was according to the attention deficit hyperactivity disorder symptom checklist before the diet (6.88, SD: 4.43) and showed significant decrease after 3 months of the elimination diet (4.48, SD: 3.69, p = 0.001). Scores of children with sleep disorder (10.62, SD: 4.23) also represented a significant reduction after 3 months of the diet (6.69, SD: 4.59, p = 0.009). Salivary cortisol levels did not show significant changes before and after elimination diet. Results: According to our data, skin allergy testing and lymphocyte transformation test are not reliable diagnostic tools for establishing the diagnosis. Conclusion: We conclude that a significant improvement in clinical symptoms can only be achieved with a strict elimination diet. Orv Hetil. 2019; 160(33): 1311-1318.

Milk proteins have been hypothesized to protect against type 2 diabetes (T2DM) by beneficially modulating glycemic response, predominantly in the postprandial status. This potential is, amongst others, attributed to the high content of whey proteins, which are commonly a product of cheese production. However, native whey has received substantial attention due to its higher leucine content, and its postprandial glycemic effect has not been assessed thus far in prediabetes. In the present study, the impact of a milk protein hydrolysate of native whey origin with alpha-glucosidase inhibiting properties was determined in prediabetics in a randomized, cross-over trial. Subjects received a single dose of placebo or low- or high-dosed milk protein hydrolysate prior to a challenge meal high in carbohydrates. Concentration-time curves of glucose and insulin were assessed. Incremental areas under the curve (iAUC) of glucose as the primary outcome were significantly reduced by low-dosed milk peptides compared to placebo ( p = 0.0472), and a minor insulinotropic effect was seen. A longer intervention period with the low-dosed product did not strengthen glucose response but significantly reduced HbA 1c values ( p = 0.0244). In conclusion, the current milk protein hydrolysate of native whey origin has the potential to modulate postprandial hyperglycemia and hence may contribute in reducing the future risk of developing T2DM., Competing Interests: C.S., A.W., T.D., T.S.: employees of contracted research organization. M.W. is an independent statistician supporting with data analysis. The study was financially supported by Ingredia S.A., France. The sponsors contributed to the discussion about the study design and selection of outcome measures prior to the study start. Planning and organization of the study and its realization, data analysis and report generating were independently undertaken solely by BioTeSys GmbH and M.W. The authors from BioTeSys GmbH and M.W. declare no conflict of interest regarding the publication of this paper.

Cow´s milk is one of the most important and basic nutrients introduced early in life in our diet but can induce IgE-associated allergy. IgE-associated allergy to cow´s milk can cause severe allergic manifestations in the gut, skin and even in the respiratory tract and may lead to life-threatening anaphylactic shock due to the stability of certain cow´s milk allergens. Here, we provide an overview about the allergen molecules in cow´s milk and the advantages of the molecular diagnosis of IgE sensitization to cow´s milk by serology. In addition, we review current strategies for prevention and treatment of cow´s milk allergy and discuss how they could be improved in the future by innovative molecular approaches that are based on defined recombinant allergens, recombinant hypoallergenic allergen derivatives and synthetic peptides.

Allergy risk has become a significant public health issue with increasing prevalence. Exclusive breastfeeding is recommended for the first six months of life, but this recommendation is poorly adhered to in many parts of the world, including the Middle-East region, putting infants at risk of developing allergic sensitization and disorders. When breastfeeding is not possible or not adequate, a partially hydrolyzed whey formula (pHF-W) has shown proven benefits of preventing allergy, mainly atopic eczema, in children with a genetic risk. Therefore, besides stimulating breastfeeding, early identification of infants at risk for developing atopic disease and replacing commonly used formula based on intact cow milk protein (CMP) with a clinically proven pHF-W formula is of paramount importance for allergy prevention. If the child is affected by cow's milk protein allergy (CMPA), expert guidelines recommend extensively hydrolyzed formula (eHF), or an amino acid formula (AAF) in case of severe symptoms. The Middle-East region has a unique practice of utilizing pHF-W as a step-down between eHF or AAF and intact CMP, which could be of benefit. The region is very heterogeneous with different levels of clinical practice, and as allergic disorders may be seen by healthcare professionals of different specialties with different levels of expertise, there is a great variability in preventive and treatment approaches within the region itself. During a consensus meeting, a new approach was discussed and unanimously approved by all participants, introducing the use of pHF-W in the therapeutic management of CMPA. This novel approach could be of worldwide benefit., Competing Interests: Yvan Vandenplas has participated as a clinical investigator, and/or advisory board member, and/or consultant, and/or speaker for Abbott Nutrition, Astel Medica, Danone, Nestle Health Science, Nestle Nutrition Institute, Nutricia, Mead Johnson Nutrition, United Pharmaceuticals, and Wyeth. None of the other authors have a conflict of interest.

The diurnal rhythm of bone remodeling suggests nocturnal dietary intervention to be most effective. This study investigated the effect of bedtime ingestion of a calcium-fortified, milk-derived protein matrix (MBPM) or maltodextrin (CON) on acute (0-4 h) blood and 24-h urinary change in biomarkers of bone remodeling in postmenopausal women with osteopenia. In CON, participants received 804 ± 52 mg calcium, 8.2 ± 3.2 µg vitamin D and 1.3 ± 0.2 g/kg BM protein per day. MBPM increased calcium intake to 1679 ± 196 mg, vitamin D to 9.2 ± 3.1 µg and protein to 1.6 ± 0.2 g/kg BM. Serum C-terminal cross-linked telopeptide of type I collagen (CTX) and procollagen type 1 amino-terminal propeptide (P1NP), and urinary N-telopeptide cross-links of type I collagen (NTX), pyridinoline (PYD) and deoxypyridinoline (DPD) was measured. Analyzed by AUC and compared to CON, a -32% lower CTX ( p = 0.011, d = 0.83) and 24% ( p = 0.52, d = 0.2) increase in P1NP was observed for MBPM. Mean total 24 h NTX excreted in MBPM was -10% ( p = 0.035) lower than CON. Urinary PYD and DPD were unaffected by treatment. This study demonstrates the acute effects of bedtime ingestion of a calcium-fortified, milk-based protein matrix on bone remodeling.

Background: The diagnosis of cow's milk protein allergy(CMPA) may be easily misdiagnosed due to its lack of specific symptoms. Thus, experts have proposed the use of Cow's milk-related symptom scores (CoMiSS) to predict CMPA. There has been no relevant report on the clinical application value of CoMiSS in Chinese children. This study aimed to evaluate the effect of CoMiSS in early identification of CMPA in Chinese infants., Methods: We calculated CoMiSS for 38 infants with suspected CMPA diagnosed in the pediatric gastroenterologic clinic in our hospital. After 4 weeks of dietary elimination and symptomatic improvement, these infants returned to our hospital to undergo oral food challenge (OFC). The ROC curve was used to determine the sensitivity and specificity of CoMiSS and evaluate the effect of CoMiSS in early identification of CMPA in Chinese infants. We didn't determine the CoMiSS of presumed healthy infants as control group., Results: Of 38 infants who underwent OFC testing, the average CoMiSS of infants with positive OFC testing was 7.4 ± 2.3, while the average CoMiSS of infants with negative OFC testing was 4.1 ± 1.6, and there was a significant difference between two groups(F = 2.13, P<0.05). The area under the ROC curve (AUC) of CoMiSS was 0.89, and the best diagnostic cut-off point was 5.5. The sensitivity of CoMiSS was 87.5%, while the specificity of CoMiSS was 78.6%., Conclusion: CoMiSS is a simple and operable method to screen for CMPA, though there may be a risk of under-diagnosis when CoMiSS≥12 is used as the criterion for early identification of CMPA in Chinese infants. More multi-center studies are needed to evaluate whether the factors such as bloody stool should be included in CoMiSS or CoMiSS≥6 can be used as the criterion for early identification of CMPA in Chinese infants.

Objectives: This French multicenter, cross-sectional, observational study aimed to describe the family history of atopy in infants with cow's milk protein allergy (CMPA), and the related diagnostic approaches used by specialists in a real-life ambulatory setting., Patients and Methods: In total, 1674 infants with suspected CMPA [median age 4.5 months (range: 0.1-18.0), males 54%] were enrolled in the study by 466 private physicians (pediatricians: 97%). Family history of atopy was defined as a known history of atopy in at least one first- (father, mother, and/or sibling) and/or second-degree relative (grandparents, uncles, and aunts), as reported by parents to physicians., Results: Atopy in a first-degree relative was more common among infants with documented or high probability of CMPA (in 84% and 80% of cases, respectively, vs. the other subgroups, P=0.005). Most infants experienced digestive (92%) and skin (61%) symptoms suggestive of CMPA. Delayed reactions were reported in 64% of infants. According to a post-classification based on the results of previous diagnostic tests and procedures, 1133 infants (68%) had highly probable (52%) or documented CMPA (16%). In these infants, a history of atopy was reported in first- and/or second-degree relative(s) in 86% of cases (81% in first-degree relatives). Whatever the family history of atopy, the characteristics of the infants were similar, except for fewer pets in the case of negative family atopy (14% vs. 25%, P<0.001). Atopy in a parent was more frequent in infants who presented with the first signs suggestive of CMPA within the first 6 months of life vs. those with later first symptoms (75% vs. 65%, P=0.063)., Conclusion: This French study confirms the high rate of family history of atopy in first-degree relatives of infants with probable or documented CMPA., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Foods for special medical purposes (FSMPs) with a protein fraction made of hydrolyzed rice protein (HRPs) have been on the market in Europe since the 2000s for the treatment of cow's milk protein allergy (CMPA). HRP formulas (HRPFs) are proposed as a plant-based alternative to cow's milk protein-based extensively hydrolyzed formulas (CMP-eHF) beside the soy protein formulas whose use in CMPA is controversial. HRPFs do not contain phytoestrogens and are derived from non-genetically modified rice. HRPFs are strictly plant-based apart from the addition of vitamin D 3 (cholecalciferol). As the amino acid content of rice proteins differs from that of human milk proteins, the protein quality of these formulas is improved by supplementation with free lysine, threonine, and tryptophan. The consumption of HRPFs has risen: for example, in France HRPFs account for 4.9% in volume of all formulas for children aged 0-3 years. Several studies have shown the adequacy of HRPFs in treating CMPA. They ensure satisfactory growth from the 1st weeks of life for infants and toddlers, both in healthy children and in those with CMPA. HRPFs can be used to treat children with CMPA either straightaway or in second intention in cases of poor tolerance to CMP-eHF for organoleptic reasons or for lack of efficacy. In France, the cost of HRPFs is close to that of regular infant or follow-on formulas., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: Overall early exposure to allergenic foods in the infant's diet is a new strategy for preventing food allergy to that allergen, but the optimal timing of exposure for different allergens is not known., Objectives: We aimed to examine the relationship between exposure to cow's milk protein in the first 3 months of life and risk of cow's milk allergy at age 12 months., Methods: HealthNuts is a longitudinal population-based food allergy study that recruited 5,276 twelve-month-old infants. Skin prick testing to cow's milk was conducted on the second half of the cohort (n = 2,715) and sensitization defined as a wheal ≥2 mm. Cow's milk allergy was defined as a parent-reported reaction to cow's milk consistent with IgE-mediated allergy together with evidence of sensitization. Early exposure to cow's milk protein was captured through parental questionnaire administered at 1 year of age and defined as consumption of cow's milk-based infant formula during the first 3 months of life., Results: Forty-two percent of infants were exposed to cow's milk in the first 3 months of life (n= 1,977/4,712) and 87% of these infants were also breastfed. Early exposure to cow's milk protein was associated with a reduced risk of cow's milk sensitization (adjusted odds ratio [aOR] 0.44, 95% confidence interval [CI] 0.23-0.83), parent-reported reactions to cow's milk (aOR 0.44, 95% CI 0.29-0.67), and cow's milk allergy (aOR 0.31, 95% CI 0.10-0.91) at age 12 months. Age at exposure to cow's milk protein was not associated with the risk of other food allergies., Conclusions: Exposure to cow's milk protein in the first 3 months of life was associated with a reduced risk of cow's milk allergy. These findings are from an observational study and clinical trials are warranted to further assess this association before any recommendations to infant feeding guidelines can be made., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: Cow's milk is a frequent trigger of allergic reactions in childhood. Cow's milk proteins can be present in pharmaceutical excipients., Methods: We have analyzed paediatric literature on allergic reactions to cow's milk proteins in medication, focusing on the different routes of administration (inhaled, parental and oral)., Results: Dry-powder inhalers may contain lactose as excipient. Lactose can be rarely contaminated with milk proteins and it may induce allergic reactions in patients with cow's milk allergy. Case reports have described immediate hypersensitivity reactions to methylprednisolone sodium succinate 40 mg injection, a formulation that contains lactose as excipient. Some cases of anaphylaxis after receiving diphteria-tetanus-pertussis vaccine injection in children allergic to milk have been reported. Cow's milk proteins can be detected also in oral polio vaccine, certain probiotics and lactulose syrup., Conclusions: We suggest caution in administration of pharmaceuticals containing milk allergens in children allergic to milk.

Objectives: Guidance and evidence supporting routine use of partially hydrolyzed formula (pHF) versus intact cows' milk protein (CMP) formula are limited in non-exclusively breastfed infants. The aim of this review was to better clarify issues of routine use of pHF in non-exclusively breastfed infants who are not at risk for allergic disease by using a systematic review and Delphi Panel consensus., Methods: A systematic review and Delphi consensus panel (consisting of eight8 international pediatric allergists and gastroenterologists) was conducted to evaluate evidence supporting growth, tolerability, and effectiveness of pHF in non-exclusively breastfed infants., Results: None of the studies reviewed identified potential harm of pHF use compared with CMP in non-exclusively breastfed infants. There was an expert consensus that pHF use is likely as safe as intact CMP formula, given studies suggesting these have comparable nutritional parameters. No high-quality studies were identified evaluating the use of pHF to prevent allergic disease in non-exclusively breastfed infants who are not at risk for allergic disease (e.g., lacking a parental history of allergy). Limited data suggest that pHF use in non-exclusively breastfed infants may be associated with improved gastric emptying, decreased colic incidence, and other common functional gastrointestinal symptoms compared with CMP. However, because the data are of insufficient quality, the findings from these studies have to be taken with caution. No studies were identified that directly compared the different types of pHF, but there was an expert consensus that growth, allergenicity, tolerability, effectiveness, and clinical role among such pHF products may differ., Conclusions: Limited data exist evaluating routine use of pHFs in non-exclusively breastfed infants, with no contraindications identified in the systematic review. An expert consensus considers pHFs for which data were available to be as safe as CMP formula as growth is normal. The preventive effect on allergy of pHF in infants who are not at risk for allergic disease has been poorly studied. Cost of pHF versus starter formula with intact protein differs from country to country. However, further studies in larger populations are needed to clinically confirm the benefits of routine use of pHF in non-exclusively breastfed infants. These studies should also address potential consumer preference bias., (Copyright © 2019. Published by Elsevier Inc.)

Background: Allergy to cow's milk protein is a common problem in children. The clinical manifestations of the reactions that are mediated by IgE are varied and the anaphylactic reactions can be life-threatening., Clinical Case: A girl at an age of four months and a half that, five minutes after consuming cereal with cow's milk, had rashes in the perioral area and extensive pruritic micropapular lesions associated with vomit and inspiratory stridor. She received adrenaline by intramuscular injection and antihistamines by intravenous injection. She was first evaluated in a service of allergy treatment when she was six months and twenty days old. The results of the allergen-specific immunoglobulin E test were positive. The treatment was initiated with a hydrolyzed rice formula and supplementary feeding., Conclusions: Anaphylaxis can be the first and last manifestation of a food allergy. The right education for parents about strictly avoiding the food that triggered the allergic reaction and the right training in the use of intramuscular adrenalin may result in a better prognosis for patients.

Objective: Cow's milk allergy is the most common food allergy in childhood. Changes occur in the protein structure of milk during yogurt fermentation. This study aimed to determine whether children who are diagnosed with a cow's milk allergy can tolerate yogurt., Methods: We performed a yogurt challenge test on 34 children who were diagnosed with a cow's milk allergy in our Pediatric Allergy Outpatient Clinic. The mean age of 24 male and 10 female children was 24 ± 13 months., Results: A reaction was observed in 17 (50%) patients, whereas no reaction was observed in the other 17 (50%) during an oral yogurt challenge test that was performed in all of the 34 patients with a cow's milk allergy. Cow's milk-specific immunoglobulin E levels were significantly lower in the group of children who could tolerate yogurt than in the group of children who could not tolerate yogurt., Conclusion: Yogurt is tolerated by half of children with a cow's milk allergy when subjected to a challenge test performed with yogurt, which is consumed as much as milk in Turkey.