In a recent review published in the journal Dr nutrientsResearchers explored the challenges of accurately diagnosing and managing cow’s milk allergy (CMA) in children, addressing gaps between clinical guidelines and real-world practice.
CMA is recognized as the most prevalent and complex childhood food allergy worldwide, with an estimated prevalence varying from 1.8% to 7.5% of immunoglobulin E (IgE)-mediated cases between 1973 and 2008; However, a 2023 European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) report suggests a confirmed trend of under 1%. It often initiates the allergic journey in childhood, but effective prevention strategies remain elusive. Accurate diagnosis and management by healthcare professionals (HCPs) is critical to developing tolerance. Major organizations such as World Allergy Organization (WAO), European Academy of Allergology and Clinical Immunology
(EAACI), the Global Allergy and Asthma European Network (GA2LEN), and ESPGHAN have developed guidelines for conducting CMA. However, these guidelines are often underutilized due to lack of awareness or implementation challenges in daily practice. Further research is essential to develop effective strategies for the prevention and management of CMA, given its complex nature and existing gaps in guideline implementation and real-world clinical application.
Prevalence and incidence of CMA
The prevalence of CMA varies considerably in different studies and regions, and clinical studies and caregiving concepts suggest a prevalence ranging from less than 1% to 10%. A challenge-proven diagnosis rate of 0.54% was found in 12,049 European children in the Europreval Birth Study. Significant regional variation has been noted, particularly in non-IgE-mediated allergies. For example, in the United Kingdom (UK), non-IgE-mediated CMA was more prevalent than IgE-mediated, whereas other European countries reported different or even no data on non-IgE-mediated CMA. Further complicating the picture, recent systematic reviews and meta-analyses report widely varying rates for both self-reported and food-challenge-induced allergy to cow’s milk.
In the United States, certain conditions such as food protein-induced enterocolitis syndrome (FPIES) and allergic proctocolitis (FPIAP) show significant prevalence, although not always confirmed by oral food challenge. Eosinophilic esophagitis (EoE) also shows a significant incidence rate, with CMA being a common allergen in this case.
Signs and symptoms related to cow’s milk allergy. Legend: Patients may also present with mixed IgE and non-IgE CMA symptoms; No symptoms are specific; Symptoms are not related to infection.
Symptoms and diagnostic challenges
CMA presents a wide range of symptoms, including anaphylaxis, which are non-specific and overlap with other diseases, and the recommended duration for diagnostic elimination varies based on the type of allergy. such as IgE or non-IgE-mediated and EoE. Although double-blind placebo-controlled food challenges (DBPCFC) are the gold standard for diagnosis, they are often impractical in daily practice. Open oral food challenges (OFC) are commonly recommended, but their implementation and interpretation can be complex and subjective, especially in non-IgE-mediated cases.
Challenges and parental reluctance in managing OFC
OFCs, especially for IgE-mediated allergies, require careful medical supervision due to the risk of severe reactions. Parental reluctance to administer OFC or reintroduce cow’s milk to their infant’s diet is a significant barrier, potentially leading to underdiagnosis or overdiagnosis of CMA.
Specific challenges in IgE and non-IgE-mediated CMA
Diagnostic tools for IgE-mediated CMA, such as specific IgE measurements and skin prick tests, often give false positive results. They indicate sensitization rather than clinical allergy. The persistence of IgE-mediated CMA and the need for careful management of potential anaphylactic reactions are key concerns.
Non-IgE CMA presents significant challenges in diagnosis, especially in differentiating it from gut-brain interaction (DGBI). The primary diagnostic tool is an elimination diet followed by reintroduction of cow’s milk (CM), but this approach is complicated by the subjective nature of symptom reporting and the lack of specific symptoms unique to non-IgE CMA.
Applications for clinical practice
Breastfeeding should be continued even if CMA or DGBI is suspected, with specialist support as needed. Comfort formulas, while not a definitive solution, offer some benefits and are generally safe. The key question remains: should DGBI and non-IgE CMA be considered part of a spectrum, especially considering the risk of developing other allergies in children with non-IgE mediated CMA? Accurate diagnosis is crucial for effective management and early guidance.
Improving the diagnosis of CMA: Introduction to awareness tools
The cow’s milk-related symptom score (CoMiSS) is a helpful tool in the detection of CMA, particularly useful in clinical trials. It assesses symptoms such as dermatitis, weeping, regurgitation, respiratory problems, and stool irregularity, with scores above 10 suggesting CMA. Despite its usefulness, its potential role in CMA over-diagnosis remains controversial. Experts recommend validating such tools and using them under expert HCP guidance to prevent misdiagnosis. Reliance on subjective reporting, an important aspect of CoMiSS, poses challenges in confirming CMA, requiring advances such as artificial intelligence for more objective symptom assessment to increase the tool’s diagnostic accuracy.
Therapeutic elimination diet in the management of CMA
The goals of managing CMA are symptom resolution, development of tolerance, and normal growth. Primary strategies include avoiding CM protein and for breastfed infants, breast milk is the best source of nutrients. If breast milk is not an option, extensively hydrolyzed formula (eHF) is recommended for mild to moderate symptoms, although a small number of infants may still react due to residual peptides.
Oral immunotherapy (OIT) and formula options
OIT can induce tolerance in some patients, but it is not a universal solution. Although in severe cases, amino acid-based formulas (AAFs) are recommended, soy formulas, once controversial because of phytoestrogens, are now considered safe and nutritionally adequate.
Hydrolyzed rice formula
Hydrolyzed rice formulas (HRFs) have gained popularity because they are completely CM-free and have shown promising results in managing CMA. Recent guidelines recognize HRF as an alternative to EHF, potentially becoming the first choice option in the future. Concerns about arsenic levels in rice require careful monitoring of these sources.
Lactose considerations and management of mild CMA
Lactose, historically excluded from hypoallergenic formulas due to potential CM protein contamination, is now safely included due to technological advances. In mild CMA, dietary elimination may not be necessary, and symptoms can often be managed with medical intervention.
Formulas are increasingly being supplemented with “biotics”. such as Probiotics, prebiotics or synbiotics to mimic the gastrointestinal microbiota of breast-fed infants. These additives show potential to reduce inflammation and infection, but their role in developing tolerance remains unclear. Research into the management of CMA and their effectiveness in promoting oral tolerance continues.
Understanding and managing the natural history of CMA
CMA usually resolves in most children by age 3 years and may precede or occur with other atopic conditions such as asthma and allergic rhinitis. Reintroduction of CM depends on the type of allergy, severity, and age of the child, and proactive management is important to avoid unnecessarily prolonged exclusion of foods.
Reintroduction techniques in infants and young children
Non-IgE-mediated CMA often resolves earlier than the IgE-mediated form, and in cases such as food protein-induced allergic proctocolitis (FPIAP), CM reinitiation may begin after 6 months with periodic reevaluation until tolerance is established. For food protein-induced enterocolitis syndrome (FPIES), a more extended abstinence period is recommended. IgE-mediated CMA reactivation can be monitored by skin prick test (SPT) and serum-specific IgE levels. Baked milk products are often used as an initial reintroduction step, with careful monitoring for severe reactions.
Procedures for older children
Persistence of CMA for more than 3 years indicates a more severe form of allergy. In non-IgE CMA, reintroduction is a collaborative decision with caregivers, with home trials recommended every 6–12 months. For IgE-mediated CMA, children with severe reactions to baked milk or high CM-sIgE levels require careful monitoring and periodic reevaluation. A 50% reduction in CM-sIgE at 24 months is a positive indicator of tolerance development.