Cow's Milk: A Benefit for Human Health? Omics Tools and Precision Nutrition for Lactose Intolerance Management.

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.

Alergia a la leche de vaca: ¿se pueden evitar las pruebas de provocación oral? Un análisis probabilístico basado en datos clínicos / Cow's milk allergy: Can oral food challenges be avoided? A probabilistic analysis based on clinical data

Introducción. La prueba de provocación oral (PPO) para el diagnóstico de alergia a las proteínas de la leche de la vaca (APLV) presenta riesgos y requiere de recursos. Nuestro objetivo fue evaluar condiciones y pruebas complementarias para identificar una alta probabilidad de APLV. Población y métodos. Análisis secundario sobre estudio de pacientes atendidos en una unidad de alergia entre 2015 y 2018. Se determinaron las probabilidades prepruebas asociadas a los síntomas y sus combinaciones, y las probabilidades pospruebas luego de realizadas pruebas cutáneas y determinación de inmunoglobulina E (IgE) sérica. Resultados. Se evaluó la información de 239 pacientes. Se observaron probabilidades mayores al 95 % en pacientes con angioedema y combinación de urticaria y vómitos. Usando puntos de corte propuestos por Calvani et al., la combinación de vómitos con rinitis, sin angioedema, también superó el 95 %. Conclusión. Se ofrece una metodología para identificar pacientes en los que puede diagnosticarse APLV sin realización de PPO.

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.

What is Known About Cow's Milk Protein Allergy in Preterm Infants?

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.

[Natural history and risk factors of IgE-mediated cow's milk protein allergy in infants].

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, χ2=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.

A Review of the Risk of Cow's Milk Protein Allergy in Oral Medication.

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.

Cow's milk allergy: Can oral food challenges be avoided? A probabilistic analysis based on clinical data. / Alergia a la leche de vaca: ¿se pueden evitar las pruebas de provocación oral? Un análisis probabilístico basado en datos clínicos.

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.

Introducción. La prueba de provocación oral (PPO) para el diagnóstico de alergia a las proteínas de la leche de la vaca (APLV) presenta riesgos y requiere de recursos. Nuestro objetivo fue evaluar condiciones y pruebas complementarias para identificar una alta probabilidad de APLV. Población y métodos. Análisis secundario sobre estudio de pacientes atendidos en una unidad de alergia entre 2015 y 2018. Se determinaron las probabilidades prepruebas asociadas a los síntomas y sus combinaciones, y las probabilidades pospruebas luego de realizadas pruebas cutáneas y determinación de inmunoglobulina E (IgE) sérica. Resultados. Se evaluó la información de 239 pacientes. Se observaron probabilidades mayores al 95 % en pacientes con angioedema y combinación de urticaria y vómitos. Usando puntos de corte propuestos por Calvani et al., la combinación de vómitos con rinitis, sin angioedema, también superó el 95 %. Conclusión. Se ofrece una metodología para identificar pacientes en los que puede diagnosticarse APLV sin realización de PPO.

The step-down approach in children with cow's milk allergy: Results of a randomized controlled trial.

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.

The long-term clinical course of protein-losing enteropathy combined with iron deficiency anemia in Korean toddlers: Possible association with cow's milk protein.

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.

Practice Variations in the Management of Infants With Non-IgE-Mediated Cow's Milk Protein Allergy.

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.

Timing of Cow's Milk Protein Introduction and Childhood Adverse Reactions to Cow's Milk.

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.

Síndrome de enterocolitis inducida por proteínas alimentarias que debuta con hiperamoniemia / Hyperammonaemia as onset of food protein-induced enterocolitis syndrome

Dentro de las alergias no mediadas por IgE, la enterocolitis inducida por proteínas alimentarias (FPIES) es el cuadro de mayor gravedad, pudiendo cursar con una clínica muy variada. El FPIES crónico se suele manifestar con letargia, palidez cutánea, desnutrición, vómitos intermitentes y/o diarrea crónica, asociados a múltiples alteraciones analíticas (leucocitosis con desviación a la izquierda, eosinofilia, anemia, trombocitosis, hipoproteinemia, hipoalbuminemia, metahemoglobinemia y acidosis metabólica). La resolución ocurre entre los 3 a 10 días tras la exclusión del alérgeno causante; vuelven a tolerarlo aproximadamente a los 3-5 años de edad. Se presenta el caso clínico de un lactante de 47 días alimentado con fórmula de inicio, que debuta con un cuadro de vómitos y diarreas con deshidratación grave, acidosis metabólica, metahemoglobinemia, hipoproteinemia, hipoalbuminemia e hiperamoniemia, siendo esta última una característica solo referenciada en un caso hasta la actualidad (AU)

Food protein-induced enterocolitis syndrome (FPIES) is the most severe non-IgE-mediated allergies, and has a broad clinical spectrum. Chronic FPIES usually manifests with lethargy, pallor, undernutrition, intermittent vomiting and/or chronic diarrhoea associated with multiple laboratory abnormalities (leucocytosis with left shift, eosinophilia, anaemia, thrombocytosis, hypoproteinaemia, hypoalbuminaemia, methemoglobinemia and metabolic acidosis). It resolves 3 to 10 days after exclusion of the causative allergen, and most patients develop tolerance to the protein again at approximately 3 to 5 years of age. We present the case of a 47-day-old infant who presented with vomiting and diarrhoea with severe dehydration, metabolic acidosis, methaemoglobinaemia, hypoproteinaemia, hypoalbuminaemia and hyperammonaemia, the latter being a feature that has only been described in one other case before. (AU)

Consensus on the diagnosis and treatment of cow's milk protein allergy of the Latin American Society for Pediatric Gastroenterology, Hepatology and Nutrition.

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.

[Loss of tolerance : Anaphylaxis after milk protein shake consumption in an adult sportsman]. / "Loss of tolerance" : Anaphylaxie nach Milcheiweißshake bei einem erwachsenen Sportler.

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.

IgE-mediated cow's milk protein allergy in Singaporean children.

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.