f231 Cow's milk, boiled

Cow's milk (CM) is a major food source, highly valued for its nutritional content and high digestibility. Caseins, e.g. Bos d 8, are the main thermostable CM proteins. Caseins exhibit significant cross-reactivity with homologues from other species, such as goats and sheep. Cow's milk allergy (CMA), including boiled milk allergy, affects about 3% of children in their first three years but is less common in adults. The global prevalence of CMA varies, with environmental and genetic factors playing significant roles in its development. Immediate, delayed and mixed type allergic reactions can occur, which manifest skin, respiratory, gastrointestinal, and severe systemic responses like anaphylaxis. The management of CMA includes avoiding CM and its products, substituting with low allergenic and nutritionally adequate milk alternatives, and oral immunotherapy in selected cases. The diagnosis of IgE-mediated CMA relies on clinical history supported by specific IgE testing, skin prick tests, avoidance regimens, and in some cases oral food challenges. 

Nature

Cow's milk (CM) is a staple food in the diets of billions worldwide and is considered a complete nutritional source. Proteins represent 4-5% of CM composition, equivalent to 40-50 g/L (Antunes 2023). Based on their thermostability and water solubility, CM proteins are categorized as casein proteins (80%, thermostable) and whey proteins (20%, thermolabile) (Linhart 2019). Casein proteins, collectively termed Bos d 8, form heteromultimers of four isoforms α-S1- casein (Bos d 9), α-S2-casein (Bos d 10), β-casein (Bos d 11), and κ-casein (Bos d 12) (IUIS/WHO, Jensen 2022). CM is extensively processed before it is consumed and is rarely ingested in its raw state in Westernized diets (Verhoeckx 2015).

Taxonomy

Cows belong to the order Artiodactyla, which includes even-toed hoofed mammals and are part of the Bovidae family (NCBI 2020).

Taxonomic tree of Bos taurus (NCBI 2020)

Tissue

The primary allergens in boiled CM are caseins. 

Worldwide distribution

CM allergy (CMA) is prevalent among infants and young children during the first year of life, affecting 0.5-3% at the age of 1 year (Skripak 2007, Flom 2019). However, the estimated prevalence of CMA may differ based on variations in study populations, geographical location, clinical history of the patient, IgE testing, oral food challenge (OFC), or self-reporting of allergy (Luyt 2014).

A systematic review involving 42 studies on CMA in Europe reported the prevalence of CMA to be 1.6% across all age groups (based on OFC or history of CMA) (Nwaru 2014). Another review study reported the overall prevalence of CMA to be 0.9% and a country-wise prevalence of 1.8% in the United States (US) (1-5 years), 2.9% (3 years) in the United Kingdom, and 0.5% (3-5 years) in Israel (Sicherer 2011). The average prevalence of confirmed CMA among children (during the first two years) in Europe was found to be 0.54% in a Europe-based multicenter study conducted on 12,049 children (≤ 2 years) (Schoemaker 2015). Furthermore, the self-reported prevalence of milk allergy in food-allergic children (of all ages) was found to be 21.1% (702/3339) in a US-based cross-sectional survey (Gupta 2011). A Korean study involving 1353 children and adolescents (0-18 years) reported CM to be one of the most frequent (28.1%) causes of immediate food-allergic reactions (Jeong 2017).

Risk factors

According to a review study, high-risk populations such as individuals with atopic diseases and multiple food allergies might be prone to CMA. Other CMA-associated risk factors are family history and ethnicity/race. CMA has also been observed to be more prevalent among male children compared to females, whereas this situation reverses during adulthood (Flom 2019).

Boiling and processing of milk can destroy bioactive components and beneficial microbes that may play a role in protecting against allergic diseases as suggested in (Pfefferle 2010) and reviewed in (Deckers 2021).

Worldwide distribution

CM is the predominant variety of milk consumed globally, comprising 83% of the total milk production worldwide (Verduci 2019). CM is extensively processed before it is consumed and is rarely ingested in its raw state in Westernized diets (Verhoeckx 2015).

Route of exposure    

Main

IgE-dependent CMA is categorized as a class 1 food allergy, due to sensitization to an ingested allergen (Kaczmarski 2013).

Secondary

Research has shown that in some children with severe CMA, contact and inhalation might also trigger some allergic reactions (Santoro 2019).

Clinical relevance

CMA is regarded as one of the most frequent food allergies among children (Arasi 2022). CMA presents a spectrum of clinical symptoms of varying severity. Clinical features can manifest as either "immediate" or "delayed" reactions. Approximately 60% of CMA cases are IgE-mediated, though this proportion may vary based on the study population and age (Giannetti 2021). These allergies result in the onset of symptoms within minutes to an hour after allergen exposure. They can affect multiple organs, including the skin (manifesting as urticaria and angioedema) (Giannetti 2019), the respiratory system (leading to rhinitis, rhinorrhea, asthma, wheezing, and laryngeal edema/stridor), the gastrointestinal tract (oral allergy syndrome, pain, nausea, flatulence, vomiting, and diarrhea), and the cardiovascular system (resulting in anaphylaxis) (Fiocchi 2022).

The other 40% of cases are divided between non-IgE-mediated and mixed types. Typical non-IgE-mediated forms of CMA include enteropathy, Heiner syndrome, food protein-induced proctitis, and food protein-induced enterocolitis syndrome (Giannetti 2021, Haddad 2024).

Non-IgE-mediated reactions typically exhibit a delayed onset, with symptoms appearing within one hour to several days after CM ingestion. Similar to IgE-mediated reactions, these can manifest as various symptoms, most commonly affecting the gastrointestinal system or skin. Gastrointestinal symptoms, such as nausea, bloating, intestinal discomfort, and diarrhea, resemble those of lactose intolerance and may result in misdiagnosis. On the other hand, anaphylaxis is not associated with non-IgE-mediated mechanisms (Fiocchi 2022). Additionally, mixed forms of CMA, involving both IgE- and non-IgE-mediated pathways, can exhibit cell-mediated or humoral mechanisms, presenting with both acute and chronic symptoms (Giannetti 2021)

Diagnostic relevance

Boiled milk or casein IgE testing can be used to indicate whether a patient with CM sensitization is likely to tolerate cooked or baked milk products (Agyemang 2019, Cogurlu 2025).

A correlation exists between allergen-specific IgE levels for milk and the outcomes of OFCs, which are affected by age. Younger children tend to react to lower concentrations of specific IgE antibodies in milk compared to older children (Komata 2007).

Prevention and Therapy

Prevention strategies

Allergen Immunotherapy

Cow's milk oral immunotherapy (OIT) can enhance milk tolerance, but its benefits should be weighed against the risk of adverse effects (Brozec 2022). In a retrospective study of 64 children with cow's milk allergy and high specific IgE levels to casein, 27 children (42.2%) achieved desensitization to fresh milk through an oral food challenge after receiving OIT with heated cow’s milk (Gruzelle 2020).

Avoidance

The management of CMA involves avoiding CM and its products and substituting them with an allergenically and nutritionally appropriate milk alternative. The selection of a CM substitute should be based on the age of a child, allergy severity, and the nutritional profile of the substitute (Luyt 2014).

Molecular Aspects    

Allergenic molecules

The primary allergens in boiled CM are caseins.

As of July 8^th, 2024, a total of 5 casein allergens (4 isoforms and a global denomination) in cow’s milk have been identified and included in the World Health Organization/International Union of Immunological Societies (IUIS/WHO Bos taurus).

Biomarkers of severity

In a study from Japan with 83 children clinically diagnosed with CMA (61/83) or sensitized but with no allergic reactions to milk at the time of examination (22/83), it was found that high levels of casein specific IgE antibodies was strongly associated with milk allergy and might be associated with prolonged allergy (Ito 2012). In a study involving a small number of subjects (n=6), it was reported that sensitization to heat-stable casein allergens is associated with more severe CMA (Schocker 2019).

Cross-reactivity

IgE-mediated cross-reactivity between caseins from cow and related species can be expected due to casein conserved structural homology. Milk caseins from cow exhibit high amino acid sequence homologies, averaging 96% with buffalo, 91% with sheep, and 88% with goat milk (Restani 2009).

Explained results

Allergen Information

The primary allergens in boiled CM are caseins that retain their allergenicity after heat treatment.

Clinical information

Sensitization to CM heat-stable casein allergens is associated with more severe CMA. Boiled milk or casein IgE testing can be used to indicate whether a patient with CM sensitization is likely to tolerate cooked or baked milk products.

Cross-reactivity

IgE-mediated cross-reactivity between caseins from cow and related species can be expected due to casein conserved structural homology.

Compiled by Turacoz.

Reviewed by Dr. Joana Vitte, June 2025