Compendium of the most significant studies with reference to properties, intake, effects.

D'Auria E, Salvatore S, Pozzi E, Mantegazza C, Sartorio MUA, Pensabene L, Baldassarre ME, Agosti M, Vandenplas Y, Zuccotti G. Cow's Milk Allergy: Immunomodulation by Dietary Intervention. Nutrients. 2019 Jun 21;11(6):1399. doi: 10.3390/nu11061399.

Abstract. Cow's milk proteins cause allergic symptoms in 2% to 3% of all infants. In these individuals, the physiological mechanism of tolerance is broken with subsequent possible sensitization to antigens, which can lead eventually to allergic responses. The present review aims to provide an overview of different aspects of immune modulation by dietary intervention in cow's milk allergy (CMA). It focuses on pathogenetic mechanisms of different CMA related disorders, e.g., gastroesophageal reflux and eosinophilic esophagitis, highlighting the role of dietary management on innate and adaptive immune systems. The traditional dietary management of CMA has greatly changed in the last years, moving from a passive approach, consisting of an elimination diet to relieve symptoms, to a "proactive" one, meaning the possibility to actively modulate the immune system. Thus, new insights into the role of hydrolysates and baked milk in immunomodulation are addressed here. Additionally, nutritional components, such as pre- and probiotics, may target the immune system via microbiota, offering a possible road map for new CMA prevention and treatment strategies.

Inuo C, Tanaka K, Suzuki S, Nakajima Y, Yamawaki K, Tsuge I, Urisu A, Kondo Y. Oral Immunotherapy Using Partially Hydrolyzed Formula for Cow's Milk Protein Allergy: A Randomized, Controlled Trial. Int Arch Allergy Immunol. 2018;177(3):259-268. doi: 10.1159/000490804.

Abstract. Background: Partially hydrolyzed cow's milk protein-based formula (pHF) possesses low allergenicity. Here, we investigate the safety and efficacy of oral immunotherapy using pHF for children with cow's milk protein allergy (CMPA). Objectives: A randomized, double-blind, controlled single-center trial was conducted to evaluate the efficacy and safety of pHF oral immunotherapy in children with CMPA....Conclusions: The results of this trial suggest that, in children with CMPA, tolerance to cow's milk might be safely enhanced by intake of pHF, relative to that of eHF. © 2018 S. Karger AG, Basel.

Qamer S, Deshmukh M, Patole S. Probiotics for cow's milk protein allergy: a systematic review of randomized controlled trials. Eur J Pediatr. 2019 Aug;178(8):1139-1149. doi: 10.1007/s00431-019-03397-6. 

Abstract. Cow's milk protein allergy (CMPA) is the commonest food allergy in infancy and is associated with significant health burden. Given their immune modulatory properties, probiotics have been proposed as a strategy for management of CMPA. We aimed to systematically review efficacy and safety of probiotics in the management of CMPA. Databases PubMed, EMBASE, CINAHL, Cochrane Central Library, and Google scholar were searched in August 2018 for randomized controlled trials (RCT) of probiotic supplementation as an adjunct in the management of infants with suspected/proven CMPA. Primary outcomes were resolution of hematochezia and acquisition of tolerance to CMP at 6, 12, 24, and 36 months. Secondary outcomes included effect on allergic symptoms (SCORAD index), growth, gut microbiota, and adverse effects. A total of 10 RCTs (n = 845; probiotics, 422; control, 423) with low to unclear risk of bias were included. Meta-analysis showed probiotic supplementation was not associated with earlier resolution of hematochezia (n = 87; RR: 1.45 (95% CI: 0.96-2.18), p = 0.08; level of evidence (LOE), very low), in presumed CMPA. In confirmed CMPA, probiotics were associated with higher rate of acquisition of tolerance to CMP at the end of 3 years compared with placebo (N = 493; RR, 1.47; 95% CI, (1.17-1.84); p = 0.0009; LOE, low]. Meta-analysis was not possible for other outcomes. There were no probiotic related adverse effects. Conclusion: Limited low-quality evidence indicates that probiotic supplementation may be associated with earlier acquisition of tolerance to CMP in children with CMPA. Large well-designed trials are essential to confirm these findings. What is Known: • Cow's milk protein allergy (CMPA) is one of the commonest food allergies in children. CMPA is associated with significant socioeconomic burden. • Elimination diet and extensively hydrolyzed formula is the mainstay of the management of CMPA. What is New: • This first systematic review of randomized controlled trials shows that probiotics as an adjuvant can lead to earlier acquisition of tolerance to CMP in children at 36 months of age. However, the evidence is low quality and influenced by data from one large study. • Probiotic supplementation was not associated with earlier resolution of hematochezia.

Çelik MN, Köksal E. Nutritional Targets in Cow's Milk Protein Allergy: A Comprehensive Review. Curr Nutr Rep. 2022 Jun;11(2):329-336. doi: 10.1007/s13668-022-00408-1.

Abstract. 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. © 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Host A, Halken S. Cow's milk allergy: where have we come from and where are we going? Endocr Metab Immune Disord Drug Targets. 2014 Mar;14(1):2-8. doi: 10.2174/1871530314666140121142900. 

Abstract. Since the 1930's the scientific literature on cow's milk protein allergy (CMPA) has accumulated. Over the last decade new diagnostic tools and treatment approaches have been developed. The diagnosis of reproducible adverse reactions to cow's milk proteins (CMP), i.e. CMPA, still has to be confirmed by controlled elimination and challenge procedures. Advanced diagnostic testing using epitope and microarray technology may in the future improve the diagnostic accuracy of CMPA by determination of specific IgE against specific allergen components of cow's milk protein. The incidence of CMPA in early childhood is approximately 2-3% in developed countries. Symptoms suggestive of CMPA may be encountered in 5-15% of infants emphasizing the importance of controlled elimination/milk challenge procedures. Reproducible clinical reactions to CMP in human milk have been reported in 0.5% of breastfed infants. Most infants with CMPA develop symptoms before 1 month of age, often within 1 week after inter introduction of CMP-based formula. The majority has two or more symptoms from two or more organ systems. Approximately 50-70% have cutaneous symptoms, 50-60% gastrointestinal symptoms and 20-30% respiratory symptoms. Symptoms may occur within 1 hour after milk intake (immediate reactions) or after 1 hour (late reactions). The prognosis of CMPA is good with a remission rate of approximately 45 to 50% at 1 year, 60 to 75% at 2 years and 85 to 90% at 3 years. Associated adverse reactions to other foods develop in up to 50% and allergy against inhalants in 50 to 80%. The basic treatment of CMPA is avoidance of CMP. In early childhood a milk substitute is needed. Documented extensively hydrolysed formulas are recommended, whereas partially hydrolysed formulas should not be used because of a high degree of antigenicity and allergenicity associated with adverse reactions. In case of intolerance to extensively hydrolysed formulas and multiple food allergies a formula based on aminoacids is recommended. Alternative milk substitutes such as sheep's and goat's milk should not be used because of a high degree of cross reactivity with CMP. Milk from other mammals such as mare and donkey may be tolerated by some children with CMPA. Soy protein is as allergenic as CMP and soy formula is not recommended for young children with CMPA because of a great risk of development of allergy to soy, whereas soymilk is normally tolerated in older children with CMPA. Recent treatment modalities are oral immunotherapy (OIT) involving the ingestion of increasing amounts of milk allergen on a regular basis to desensitize and potentially permanently tolerize patients to CMP. OIT can increase the reaction thresholds to CMP, but questions about safety and long-term efficacy remain. Anti-IgE therapy with Omalizumab may improve the safety and efficacy of OIT and may provide benefit in monotherapy.

Flom JD, Sicherer SH. Epidemiology of Cow's Milk Allergy. Nutrients. 2019 May 10;11(5):1051. doi: 10.3390/nu11051051.

Abstract. Immunoglobulin E (IgE)-mediated cow's milk allergy (CMA) is one of the most common food allergies in infants and young children. CMA can result in anaphylactic reactions, and has long term implications on growth and nutrition. There are several studies in diverse populations assessing the epidemiology of CMA. However, assessment is complicated by the presence of other immune-mediated reactions to cow's milk. These include non-IgE and mixed (IgE and non-IgE) reactions and common non-immune mediated reactions, such as lactose intolerance. Estimates of prevalence and population-level patterns are further complicated by the natural history of CMA (given its relatively high rate of resolution) and variation in phenotype (with a large proportion of patients able to tolerate baked cow's milk). Prevalence, natural history, demographic patterns, and long-term outcomes of CMA have been explored in several disparate populations over the past 30 to 40 years, with differences seen based on the method of outcome assessment, study population, time period, and geographic region. The primary aim of this review is to describe the epidemiology of CMA. The review also briefly discusses topics related to prevalence studies and specific implications of CMA, including severity, natural course, nutritional impact, and risk factors.

Zepeda-Ortega B, Goh A, Xepapadaki P, Sprikkelman A, Nicolaou N, Hernandez REH, Latiff AHA, Yat MT, Diab M, Hussaini BA, Setiabudiawan B, Kudla U, van Neerven RJJ, Muhardi L, Warner JO. Strategies and Future Opportunities for the Prevention, Diagnosis, and Management of Cow Milk Allergy. Front Immunol. 2021 Jun 10;12:608372. doi: 10.3389/fimmu.2021.608372.

Abstract. The prevalence of food allergy has increased over the last 20-30 years, including cow milk allergy (CMA) which is one of the most common causes of infant food allergy. International allergy experts met in 2019 to discuss broad topics in allergy prevention and management of CMA including current challenges and future opportunities. The highlights of the meeting combined with recently published developments are presented here. Primary prevention of CMA should start from pre-pregnancy with a focus on a healthy lifestyle and food diversity to ensure adequate transfer of inhibitory IgG- allergen immune complexes across the placenta especially in mothers with a history of allergic diseases and planned c-section delivery. For non-breastfed infants, there is controversy about the preventive role of partially hydrolyzed formulae (pHF) despite some evidence of health economic benefits among those with a family history of allergy. Clinical management of CMA consists of secondary prevention with a focus on the development of early oral tolerance. The use of extensive Hydrolysate Formulae (eHF) is the nutrition of choice for the majority of non-breastfed infants with CMA; potentially with pre-, probiotics and LCPUFA to support early oral tolerance induction. Future opportunities are, among others, pre- and probiotics supplementation for mothers and high-risk infants for the primary prevention of CMA. A controlled prospective study implementing a step-down milk formulae ladder with various degrees of hydrolysate is proposed for food challenges and early development of oral tolerance. This provides a more precise gradation of milk protein exposure than those currently recommended. Copyright © 2021 Zepeda-Ortega, Goh, Xepapadaki, Sprikkelman, Nicolaou, Hernandez, Latiff, Yat, Diab, Hussaini, Setiabudiawan, Kudla, van Neerven, Muhardi and Warner.

Santoro A, Andreozzi L, Ricci G, Mastrorilli C, Caffarelli C. Allergic reactions to cow's milk proteins in medications in childhood. Acta Biomed. 2019 Jan 29;90(3-S):91-93. doi: 10.23750/abm.v90i3-S.8169. 

Abstract. 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.

Abbring S, Xiong L, Diks MAP, Baars T, Garssen J, Hettinga K, van Esch BCAM. Loss of allergy-protective capacity of raw cow's milk after heat treatment coincides with loss of immunologically active whey proteins. Food Funct. 2020 Jun 24;11(6):4982-4993. doi: 10.1039/d0fo01175d.

Abstract. The allergy-protective capacity of raw cow's milk was demonstrated to be abolished after heat treatment. The heat-sensitive whey protein fraction of raw milk is often implied to be the source of this allergy-protective effect, but a direct link between these proteins and the protection against allergic diseases is missing. This study therefore aimed at investigating the mechanistic relation between heat damage to whey proteins and allergy development. Raw cow's milk was heated for 30 min at 50, 60, 65, 70, 75, or 80 °C and the native whey protein profile of these differentially heated milk samples was determined using LC-MS/MS-based proteomics. Changes in the native protein profile were subsequently related to the capacity of these milk samples to prevent the development of ovalbumin-induced food allergy in a murine animal model. A substantial loss of native whey proteins, as well as extensive protein aggregation, was observed from 75 °C. However, whey proteins with immune-related functionalities already started to denature from 65 °C, which coincided with the temperature at which a loss of allergy protection was observed in the murine model. Complement C7, monocyte differentiation antigen CD14, and polymeric immunoglobulin receptor concentrations decreased significantly at this temperature, although several other immunologically active whey proteins also showed a decrease around 65 °C. The current study demonstrates that immunologically active whey proteins that denature around 65 °C are of importance for the allergy-protective capacity of raw cow's milk and thereby provides key knowledge for the development of microbiologically safe alternatives to raw cow's milk.

ensabene L, Salvatore S, D'Auria E, Parisi F, Concolino D, Borrelli O, Thapar N, Staiano A, Vandenplas Y, Saps M. Cow's Milk Protein Allergy in Infancy: A Risk Factor for Functional Gastrointestinal Disorders in Children? Nutrients. 2018 Nov 9;10(11):1716. doi: 10.3390/nu10111716. 

Abstract. The role and prevalence of cow's milk protein allergy (CMA) in functional gastrointestinal disorders remains unclear. The aim of this review is to update knowledge on the relationship between CMA and functional abdominal pain disorders (FAPDs) in children. Cochrane Database and Pubmed were searched from inception using general and specific terms for CMA and functional gastrointestinal disorders. CMA is reported as a predisposing or coexisting factor in a wide range of functional gastrointestinal disorders in infants and children. Pathogenesis of both conditions is complex and multiple mechanisms including dysmotility and hypersensitivity might contribute to the clinical manifestations. Data supporting the possible role of food allergies in the pathogenesis of FAPDs are limited. CMA may predispose to early life inflammation and visceral hypersensitivity, which in turn might manifest as FAPDs. The diagnosis of either CMA or FAPDs and distinction between them is challenging because of nonspecific and overlapping symptoms. Lack of accurate allergy tests in non-IgE (immunoglobulin E) mediated cases is also problematic. Oral food challenge, following an elimination diet, should be performed to diagnose a suspected non-IgE CMA allergy in children with FAPDs. In the management of FAPDs, an elimination diet should be considered for a limited period to verify if the symptoms improve or resolve.