Allergen

Cow's milk is popularly consumed throughout the world. Allergy to cow's milk is prevalent among infants and young children during the first year of life, affecting 0.5-3% at the age of 1 year. Bos d 4 (α-lactalbumin) has been reported as a major allergenic protein found in cow's milk whey fraction. The prevalence of sensitization to Bos d 4 among cow’s milk allergy (CMA) patients varies up to 80%. Milk whey proteins like Bos d 4 are heat-labile and therefore are likely to be destroyed after extensive cooking and baking of milk. Thus, specific immunoglobulin E to Bos d 4 might help assess tolerance to cooked or baked milk. Clinical manifestations of Bos d 4-mediated allergy majorly include anaphylaxis and atopic dermatitis. Cross-reactivity has been observed between antibodies against bovine Bos d 5 (β-lactoglobulin) and Bos d 4 in cow's milk due to the shared amino acid sequence. Bos d 4, present in cow and human milk, was also found to be cross-reactive. Moreover, Bos d 4 from cow's milk has been found to exhibit sequence homology with other mammalian milk proteins (like water buffalo, ewe, goat, pig, donkey, horse, and camel).

Epidemiology

Worldwide distribution

Cow’s milk is popularly consumed worldwide by infants, children, and adults. Allergy to cow’s milk is prevalent among infants and young children, with a high prevalence observed during the first year of life, affecting 0.5-3% at the age of 1 year.

Bos d 4 (α-lactalbumin; ALA), Bos d 5 (β-lactoglobulin, BLG) and Bos d 8 (casein) are considered major allergens present in cow’s milk. According to World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow’s Milk Allergy (DRACMA) Guidelines, the prevalence of allergic reactions towards Bos d 4 among cow’s milk allergy (CMA) patients ranges between 0 and 80%.

A Taiwan-based study reported sensitization towards Bos d 4 among 60% (114/190) of atopic individuals with specific immunoglobulin E (sIgE) towards whole cow’s milk. Among all three milk allergens (Bos d 4, Bos d 5 and Bos d 8) tested, the sensitization towards Bos d 4 and the mean serum level of Bos d 4 sIgEs were found to be the highest. Furthermore, a Poland-based study conducted among 291 children (2-14 years) with a history of CMA also reported sensitization towards Bos d 4 in 18.8% (13/69) of children.

A study in Iran reported allergy against Bos d 4 in 78.3% of patients with CMA (n=86). Furthermore, a study in Italy conducted on 104 children with suspected CMA (n=58) found the prevalence of IgE reactivity towards Bos d 4 to be 27.6% (16/58).Bos d 4 has been reported as a major allergenic protein in cow’s milk, and 51% of patients (n=92) allergic to cow’s milk have reported sensitization toward Bos d 4.

Clinical Relevance

Disease severity

Cow milk allergy is considered one of the most common pediatric food allergies. Milk allergy can be either IgE-mediated or non-IgE-mediated. The clinical manifestations of cow milk protein allergy are reported to be of two types such as immediate (shortly after consumption) and delayed (after hours or days of consumption) responses. The immediate reactions are generally IgE-mediated and can lead to angioedema, urticaria, aggravation of atopic dermatitis (AD), vomiting, in some cases, anaphylaxis, as well as respiratory symptoms (breathing, wheezing, coughing). On the other hand, most delayed reactions are non-IgE mediated and can lead to gastrointestinal symptoms (like enteropathy or proctocolitis) or skin reactions (such as AD).

Milk whey proteins (such as Bos d 4) are heat-labile and therefore destroyed by extensive cooking and baking of milk. Thus, the sIgE level to Bos d 4 may help assess the likelihood of tolerance to cooked or baked milk, and 75% of children with CMA may actually tolerate baked milk products such as muffins, waffles, cakes, and bread.

According to a study, anaphylaxis was reported in 6/15 patients after ingestion of cow’s milk. Furthermore, sIgE against Bos d 4 (18.8 ± 19.6 kU/L (median: 16, range: 0.51–54.9) was observed in these patients.

A study conducted among 950 children with clinically diagnosed AD reported that 60.1% (283/471) of children affected with AD and sensitized to cow’s milk (n=471) exhibited positive sIgE towards Bos d 4.

Diagnostics

Exposure

Cow milk allergy mainly occurs through ingestion.

Cross-Reactivity

Milk of different ruminant species (such as cow, goat, and sheep) is composed of homologous proteins with similar structures and functions, thereby leading to cross-reactivity between the milk proteins.

A prospective cohort study conducted on 38 children (age <14 years) with CMA-associated symptoms detected the rate of cross-sensitization (skin-prick test-based) between goat milk and cow milk to be 63.2% (24/38).

A study reported that IgEs present in the sera of CMA children are able to recognize other mammalian (goat, sheep, and buffalo) milk proteins. However, cross-reactivity was found to be weak with milk proteins of donkeys and mares, and almost none with camel milk protein.

A study conducted among 20 patients with CMA demonstrated cross-reactivity between Bos d 4 present in cow and human milk. The results signified a greater amino acid sequence similarity between these two proteins.

Antibodies against bovine Bos d 5 have been found to exhibit cross-reactivity with the Bos d 4 present in cow’s milk. This cross-reactivity is reported due to the shared amino acid sequence between these two proteins.

Bos d 4 from cow’s milk protein shows sequence homology with water buffalo (99.3%), ewe (97.2%), goat (95.1%), pig (74.6%), donkey (71.5%), horse (72.4%), and camel (69.7%).

Explained Results

Allergen Information

Bos d 4 (α-lactalbumin) is considered a major allergenic protein in cow’s milk.

Clinical relevance

Typical symptoms of CMA include skin reactions (angioedema, urticaria, and atopic dermatitis), gastrointestinal symptoms, respiratory systems, and in some cases, anaphylaxis.

Cross-reactivity

Antibodies against bovine Bos d 4 show cross-reactivity with Bos d 5 present in cow’s milk due to shared amino acid sequence. Bos d 4 from cow’s milk shows sequence homology with other mammalian milk proteins, including water buffalo, ewe, goat, pig, donkey, horse, and camel. Furthermore, cross-reactivity has also been reported between Bos d 4 in cow and human milk.