The objective of this study was to assess the quality and consistency of recommendations in clinical practice guidelines (CPGs) and expert consensus on paediatric cow\'s milk protein allergy (CMPA) to serve as a foundation for future revisions and enhancements of clinical guidelines and consensus documents. We conducted a comprehensive literature search across several databases, including the Chinese Biomedical Literature Database (CBM), PubMed, Embase, Web of Science, UpToDate, ClinicalKey, DynaMed Plus and BMJ Best Practice. We spanned the search period from the inception of each database through October 1, 2023. We integrated subject headings (MeSH/Emtree) and keywords into the search strategy, used the search methodologies of existing literature and developed it in collaboration with a librarian. Two trained researchers independently conducted the literature screening and data extraction. We evaluated methodological quality and recommendations by using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) and AGREE-Recommendations for Excellence (AGREE-REX) tools. Moreover, we compared and summarized key recommendations from high-quality CPGs. Our study included 27 CPGs and expert consensus documents on CMPA. Only four CPGs (14.8%) achieved a high-quality AGREE II rating. The four high-quality CPGs consistently provided recommendations for CMPA. The highest scoring domains for AGREE II were \'scope and purpose\' (77 ± 12%) and \'clarity of presentation\' (75 ± 22%). The lowest scoring domains were \'stakeholder involvement\' (49 ± 21%), \'rigor of development\' (34 ± 20%) and \'applicability\' (12 ± 20%). Evaluation with AGREE-REX generally demonstrated low scores across its domains.   Conclusion: Recommendations within high-quality CPGs for the paediatric CMPA showed fundamental consistency. Nevertheless, the methodology and recommendation content of CPGs and the expert consensus exhibited low quality, thus indicating a substantial scope for enhancement. Guideline developers should rigorously follow the AGREE II and AGREE-REX standards in creating CPGs or expert consensuses to guarantee their clinical efficacy in managing paediatric CMPA. What is Known: • The quality of clinical practice guidelines and expert consensus on paediatric cow\'s milk protein allergy (CMPA) remains uncertain. • There is a lack of clarity regarding the consistency of crucial recommendations for CMPA management. What is New: • Improving the methodological quality of guidelines and consensus on CMPA requires greater emphasis on stakeholder engagement, rigorous development processes, and practical applicability. • The recommendations from four high-quality guidelines align. However, addressing clinical applicability, integrating values and preferences, and ensuring actionable implementation are critical to improving the quality of all guidelines.

There is still an unmet need for a reliable and straightforward biomarker to diagnose and monitor cow\'s milk protein allergy (CMPA). Fecal calprotectin (FC) has been reported as a biomarker for CMPA. Therefore, the meta-analysis aimed to evaluate the value of FC in the diagnosis and monitoring of CMPA.
PubMed, EMBASE, and the Cochrane Library up to April 2022 were searched for relevant studies. Pooled standardized mean difference (SMD) and 95% confidence intervals (CIs) were determined using the forest plot. Heterogeneity was used to determine the fixed or random-effect model.
Twelve studies including 310 patients and 217 controls were available for the meta-analysis. The FC levels in children with CMPA were significantly higher than in healthy control (SMD = 1.15; 95% CI: 0.38-1.91). After elimination diet treatment, FC levels were reduced considerably with the pooled SMD of 0.87 (95% CI: 0.48-1.26).
The results indicated that FC could be a simple and reliable biomarker for diagnosing CMPA, especially in non-IgE-mediated CMPA infants. Besides, calprotectin was also potential for predicting therapy response of CMPA.

OBJECTIVE: A2 adenosine receptor (A2AR) is a novel promising target for the treatment of inflammatory and allergic diseases. However, its role in the development of cow\'s milk protein allergy (CMPA) has not been elucidated. The present study was designed to investigate the function of A2AR in CMPA development.
METHODS: BALB/c mice were sensitized and challenged with ovalbumin (OVA) to induce allergic responses. The model was assessed by detecting allergic responses and plasma-specific IgE levels. The levels of A2AR were measured by PCR and flow cytometry. The subpopulation of Treg cells was analysed.
RESULTS: The mice sensitized and challenged with OVA showed classic allergic symptoms, such as acute allergic skin responses, increased anaphylactic shock symptom scores, and higher levels of total IgE, OVA-specific IgE, IgG1 and IgG2a. OVA-sensitized mice and CMPA patients showed decreased levels of A2AR and Treg cells. Interestingly, we observed a positive correlation between A2AR expression and Treg levels in CMPA patients. Further study showed that the A2AR agonist CGS21680 blocked OVA-induced allergic reactions, and the A2AR antagonist KW-6002 amplified allergic responses. Interestingly, CGS21680 not only activated the A2AR-mediated signalling pathway but also caused an increase in the population of Treg cells. In contrast, KW-6002 therapy decreased the levels of Tregs in allergic mice.
CONCLUSIONS: A2AR expression is downregulated in CMPA. The A2AR-mediated pathway negatively regulates the development of CMPA, at least in part, by amplifying the differentiation of Tregs.

OBJECTIVE: Research is limited regarding biochemical markers of bone metabolism among children with cow\'s milk protein allergy (CMPA). We aimed to determine differences in vitamin D and bone metabolism markers between infants with CMPA and healthy infants and explore relationships between these in a cross-sectional study.
METHODS: In total, we included 41 children diagnosed with CMPA and under systematic medical and nutritional care at our center, and 50 healthy children as a control group. We reviewed demographic and clinical characteristics and measured serum biomarkers.
RESULTS: We found that serum 25-hydroxyvitamin D (25(OH)D) levels among infants in the CMPA group were significantly lower than those in the control group, and levels of bone-specific alkaline phosphatase (BALP), serum phosphorus, and serum calcitonin were reduced. Pearson correlation analysis showed that serum 25(OH)D concentrations in the CMPA group were negatively correlated with parathyroid hormone but not significantly correlated with calcitonin and BALP. Logistic regression showed that CMPA was a risk factor for vitamin D deficiency.
CONCLUSIONS: Our study indicated that CMPA was associated with disturbances in bone metabolism. Levels of vitamin D in children with CMPA were lower than those in healthy children. CMPA was a risk factor for vitamin D deficiency.

BACKGROUND: There are few approved biomarkers for diagnosis and monitoring of cow\'s milk protein allergy (CMPA), thus the oral food challenge remains to be the golden diagnostic standard. A potential biomarker is fecal calprotectin, a cytosolic protein, elevating in the presence of intestinal mucosal inflammation. We aimed to undertake a scoping review of the evidence pertaining to the current status of fecal calprotectin used for diagnosis and monitoring CMPA in children, and tried to indicate the aspects needed to be concerned in the future investigations and researches.
METHODS: A scoping review was performed using the literature searched from PUBMED, EMBASE, and Web of Science Databases until July 2019 on the studies about the application of fecal calprotectin as a biomarker of CMPA in children. Studies were examined according to the inclusion and exclusion criteria. Data were extracted, and a narrative synthesis was conducted to summarize and analyze.
RESULTS: Thirteen studies with different study design embracing 1238 children were included. The age range was from infants to adolescents. Most children with CMPA presented gastrointestinal symptoms, among which hematochezia was most common. Amount of data suggested that infants with CMPA represented elevated levels of fecal calprotectin, particularly with distinct significance in non-IgE-mediated CMPA groups. Decreases of fecal calprotectin after elimination diet were demonstrated in enrolled studies. However, no matter in the CMPA positive or negative groups, the changes of fecal calprotectin before or after challenge showed no significance. Contradictory results were generated from studies on the role of fecal calprotectin in predicting allergic disease.
CONCLUSIONS: Available evidence is not sufficient to confirm the utilization of fecal calprotectin both in diagnosis and monitoring of CMPA and predicting for allergic disease. More clinical and bench researches with elaborate design should be conducted and the exact cut-off values of fecal calprotectin in different groups remain to be determined.

Cow\'s milk protein allergy, which occurs in approximately 5-10% of the population of infants and children, has become an important public food safety problem. As a major allergen in cow\'s milk, the most abundant protein casein (CN) is considered to be potent in inducing food allergy. In recent years, ultrasound treatment has played a significant role in the field of colloidal particulate system. In this study, we found that ultrasound treatment dramatically decreased the diameter of a CN particle to less than 100 nm in the presence of Tween 80, producing colloidal casein (c-CN) with high transparency. The electrophoretic and transmission electron microscopy analysis showed that the advanced protein structure of CN changed significantly. In addition, the enzyme-linked immunosorbent assay with allergic sera showed that the immunoglobulin-E-binding capacity of c-CN was significantly decreased. In the meantime, the LAD2 mast cell line degranulation assay demonstrated that ultrasound treatment made CN hypoallergenic. The colloidal and hypoallergenic properties of c-CN were stably maintained for more than 30 days. Likewise, the allergenicity of fresh whole milk also decreased after ultrasound treatment. This work provided an effective way to reduce the allergenicity of milk allergen, which could be beneficial to the production of hypoallergenic cow\'s milk.

The symptoms of cow\'s milk protein allergy (CMPA) in infancy can be non-specific which may delay a correct diagnosis and cause adverse clinical outcomes. The diagnosis of non-IgE-mediated CMPA is particularly complex as it involves a 2 to 4 week elimination diet followed by oral food challenge (OFC). The Cow\'s Milk-related Symptom Score (CoMiSS) is a clinical resource for primary healthcare providers which aims to increase awareness of CMPA symptoms to facilitate an earlier diagnosis. The aim of the present study is to assess if the CoMiSS can be used as a potential diagnostic tool in infants with suspected CMPA.
Exclusively formula-fed infants aged 0-6 months presenting with symptoms suggestive of CMPA will be included in this prospective, multicentre trial which will be conducted in 10 centres in China. All infants will commence a 2-week trial of an amino acid-based formula (AAF) while eliminating all cow milk protein from their diets. After the AAF treatment period, infants will undergo an open OFC in hospital with standard cow\'s milk formula, followed by an open home challenge for another 2 weeks. Clinical symptoms will be documented on standardised symptom scorecards. The CoMiSS will be determined at study entry (CoMiSS 1, before the start of the AAF), after 2 weeks (CoMiSS 2, before the OFC) and after a further period of 2 weeks or when symptoms suggestive of CMPA reappear (CoMiSS 3). Weight and length will be measured at each visit. The difference between CoMiSS 1 and 2 as a predictor of the OFC outcome will also be assessed. The diagnostic accuracy of the baseline CoMiSS will be calculated.
The study was approved by the Hunan Children\'s Hospital Medical Ethics Committee, Hunan, China. The findings of this trial will be submitted for publication in a peer-reviewed journal in paediatric nutrition or gastroenterology. Abstracts will be submitted to the relevant national and international conferences.
NCT03004729; Pre-results.

Cow\'s milk is the most common cause of food-protein-induced enterocolitis syndrome (FPIES). The aim of this study was to examine the clinical features and treatment outcomes of infants with severe FPIES to cow\'s milk. We reviewed all infants ≤ 12 months of age who were hospitalized and diagnosed with severe FPIES to cow\'s milk between 1 January 2011 and 31 August 2014 in a tertiary Children\'s Medical Center in China. Patients\' clinical features, feeding patterns, laboratory tests, and treatment outcomes were reviewed. A total of 12 infants met the inclusion criteria. All infants presented with diarrhea, edema, and hypoalbuminemia. Other main clinical manifestations included regurgitation/vomiting, skin rashes, low-grade fever, bloody and/or mucous stools, abdominal distention, and failure to thrive. They had clinical remission with resolution of diarrhea and significant increase of serum albumin after elimination of cow\'s milk protein (CMP) from the diet. The majority of infants developed tolerance to the CMP challenge test after 12 months of avoidance. In conclusion, we reported the clinical experience of 12 infants with severe FPIES to cow\'s milk, which resulted in malnutrition, hypoproteinemia, and failure to thrive. Prompt treatment with CMP-free formula is effective and leads to clinical remission of FPIES in infants.