f2 Cow's milk

Cow’s milk (CM) is a nutrition-rich (proteins, calcium, vitamins, and energy) food typically consumed after processing. Globally, CM is one of the foods popularly consumed by infants, children, and adults. However, allergy to CM is prevalent among infants and young children during the first year of life, affecting 0.5-3% at the age of 1 year. Dairy products based on milk (such as cheese, butter, cream, and yogurt) or baked milk products (such as baked muffins and pizza) are also consumed worldwide. The major allergens found in CM are casein in milk coagulum, α-lactalbumin, and β-lactoglobulin in milk whey. Casein possesses a high degree of allergenicity and antigenicity compared to whey proteins and is a heat-stable protein resistant to processing. On the contrary, whey proteins in milk allergens are reported to be heat labile and affected by processing. Milk sensitization is regarded as a prerequisite for immunoglobulin E (IgE)-mediated milk allergy and is found to be more prevalent than milk allergy. Clinical manifestations of CM allergy (CMA) can be both IgE-mediated [like anaphylaxis, cutaneous reactions, angioedema, urticaria, vomiting, aggravation of atopic dermatitis, gastrointestinal (GI) symptoms, asthma, allergic rhinitis, and rhinoconjunctivitis] and non-IgE mediated (GI symptoms like diarrhea, reflux, abdominal discomfort, mucus, blood in the stool, vomiting, etc.) reactions. Therefore, milk-allergic individuals are recommended to avoid milk and milk-based products in their diet. Additionally, oral immunotherapy might be an effective treatment option for young children with CMA. Most milk-allergic infants are reported to develop clinical tolerance naturally towards CM by 5 years. Moreover, the development of CM tolerance has been reported in children after the early introduction of CM protein as a supplement to breastfeeding during weaning and also by introducing baked-milk products into the diet of children with CMA. An oral food challenge is considered the gold standard for diagnosing CMA. Moreover, milk sIgE testing is also used as an aid in diagnosing milk allergy and monitoring disease development. Persistent sensitization to milk has been regarded as a strong predictor for the later development of aeroallergen sensitization and respiratory diseases in pediatrics. Furthermore, CM has been found to be cross-reactive with buffalo, sheep, camel, goat, mare, and donkey milk; CM-based products has also been reported to be cross-reactive with beef, and cow dander.

Nature

Cow’s milk (CM) is regarded as an essential source of nutritious food that helps in the growth and development of humans due to its rich content of proteins, calcium, vitamins, and energy. On average, domestic cows produce 30 liters (8 gallons) of milk per day, although the amount may vary based on the breed and the cow's age (Huffman 2019). One liter of CM usually contains about 30 to 35 grams of proteins, which can be further divided into two components, including whey [lactoserum; with about 20% of the total CM protein (CMPs)] and coagulum (curd; with about 80% of the CMPs) (Wal 2002).

In many countries, CM is typically consumed after processing, while raw milk consumption is less frequently reported (Verhoeckx, Vissers et al. 2015). Milk-based dairy products (such as cheese, butter, cream, and yogurt) or baked milk products (such as baked muffins and pizza) are also widely consumed worldwide (Visioli and Strata 2014, Agyemang, Saf et al. 2019).

Habitat

The optimal storage condition required for CM is refrigeration (≤ 4^oC). Storage of milk at higher temperatures encourages several microorganisms (present in milk) to secrete degradative enzymes, which could further spoil both raw and processed milk (Zajác, Čapla et al. 2015).

Taxonomy

Cows belong to the order Artiodactyla (that comprises even-toed hoofed mammals), the family Bovidae (comprising of ruminants such as sheep, goats, and antelope), and the subfamily Bovinae (comprising of buffaloes and antelopes). The genus Bos derived its name from the Latin word ‘bos’ used for cows (Huffman 2019).

Taxonomic tree of B. domesticus (cow’s milk) (Restani, Ballabio et al. 2009)

Tissue

Cow’s milk is a popular food consumed globally by infants, children, and adults (Muthukumar, Selvasekaran et al. 2020). On average, CM consists of 4.6% carbohydrates (lactose), 3.5% proteins (caseins and whey), 3-4% lipid (triglycerides), 1% mineral salts (sodium, potassium, calcium, magnesium, and phosphorus), vitamins (specifically carotenes, retinol, B1, B2, B6, tocopherol), and 88% water (Verduci, D'Elios et al. 2019).

Milk whey is found to contain the major milk allergens α-lactalbumin and β-lactoglobulin, whereas milk coagulum contains casein as the major allergen (Ito, Futamura et al. 2012). Casein has been reported to possess a higher degree of allergenicity and antigenicity compared to whey proteins (Ito, Futamura et al. 2012). Additionally, bovine serum albumin (BSA), lactoferrins and immunoglobulins are reported as less common antigens found in CM (Verhoeckx, Vissers et al. 2015). Cow milk allergens may lead to both immunoglobulin E (IgE) and non-IgE-mediated reactions (Walsh, Meyer et al. 2016).

The potency and allergenicity of milk allergens may be affected by processing (like heating and homogenization). The processing of milk can either enhance (by unmasking or formation of epitope structure) or reduce (by denaturing or covering the epitopes) milk allergy (Claeys, Cardoen et al. 2013).

Pasteurization of milk allergens at temperatures between 50-90^oC resulted in considerably enhanced IgE-binding by milk proteins (α-lactalbumin and β-lactoglobulin). Fermentation, on the other hand, might strongly suppress the allergenicity of milk allergens (like α-lactalbumin, β-lactoglobulin, and α-and β-caseins) due to the destruction of epitopes, similar to as found in hydrolyzed milk formulas (hypoallergenic) (Bu, Luo et al. 2013, Verhoeckx, Vissers et al. 2015).

Epidemiology     

Worldwide distribution

Allergy to CM is prevalent among infants and young children during the first year of life, affecting 0.5-3% at the age of 1 year (Skripak, Matsui et al. 2007, Flom and Sicherer 2019). However, the estimated prevalence of cow milk allergy (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, Ball et al. 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, Hickstein et al. 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, Sprikkelman et al. 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, Springston et al. 2011, Flom and Sicherer 2019). 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, Kim et al. 2017).

Sensitization of milk refers to the production of IgE antibodies towards milk proteins and is a prerequisite for developing symptoms and an IgE-mediated milk allergy. Therefore, milk sensitization is the first step toward developing milk allergy and is often more prevalent. IgE sensitization has been detected in very young age groups. A Nordic population-based cohort study reported the prevalence of milk sensitization among 3-month-old infants to be 2.5% (27/1100) (Tedner, Cilla et al. 2021). A population-based study (NHANES 2005-2006) conducted in the US on 8203 participants with serological data (aged 1 to >60 years) reported the overall prevalence of milk sensitization to be 5.7%. Furthermore, the highest (22%) sensitization of milk was observed among children aged 1-5 years (Liu, Jaramillo et al. 2010, Flom and Sicherer 2019). In a recent multicenter (China, Russia, and India) epidemiological study, the rate of sensitization to milk among children (6-11 years) was reported to range between 1.2% (Russia) to 6.7% (in China) (Li, Ogorodova et al. 2020).

The natural history of milk allergy

Cow milk allergy has been reported as one of the frequent food allergies affecting children during the first ten years of life (Venkataraman, Erlewyn-Lajeunesse et al. 2018). Typically, CMP allergy has been reported to be initiated during the neonatal stage, then peaks during the first year of life, followed by a resolution of symptoms and a spontaneous development of tolerance and outgrowth of the milk allergy later in childhood or early adolescence (Sackesen, Altintas et al. 2019, Tedner, Cilla et al. 2021). Most (approx. 80%) of milk allergic infants develop clinical tolerance naturally within 5 years (Ito, Futamura et al. 2012, Sackesen, Altintas et al. 2019).

According to a birth cohort study conducted in the Isle of Wight on 1456 patients, a decrease in CMA prevalence has been observed with increased age. The highest (3.5%) prevalence of CMA was found during the first year of life, while the lowest (0.3%) was seen at age 18 years (Venkataraman, Erlewyn-Lajeunesse et al. 2018). Similarly, in another study, the prevalence of CM sensitization was found to be 8.7% in 1-year-old children, whereas <5% among 18-year-old children (Alduraywish, Lodge et al. 2016).

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 and Sicherer 2019).

Furthermore, rare cases of allergic reactions (urticaria, angioedema, etc.) mediated by lactose-containing pharmaceutical products (including dry powder inhalers with fluticasone/salmeterol, methylprednisolone sodium succinate injections) have been reported in individuals with CMA (Kelso 2014, Santoro, Andreozzi et al. 2019).

Pediatric issues

In infants, besides breast milk, breast milk substitute formulas are often the first food introduced to the baby's diet in cases where breastfeeding is insufficient/not possible and later during weaning (Verduci, D'Elios et al. 2019). Exclusively breastfed infants are usually reported to develop only mild-to-moderate reactions toward CMP and rarely life-threatening symptoms (De Greef, Hauser et al. 2012).

Persistent sensitization to milk and egg is a strong predictor for later development of aeroallergen sensitization and respiratory diseases such as allergic rhinitis and allergic asthma (Kulig, Bergmann et al. 1998).

Worldwide distribution

Cow’s milk, CM products, and dairy products are widely consumed globally, and CM contributes to 83% of the total global milk production. Currently, there is also an increase in the usage of other mammalian milk, such as buffalo milk (13%), goat milk (2.3%), sheep milk (1.4%), and camel milk (0.3%) (Verduci, D'Elios et al. 2019).

Ingestion (consumption) of CM or dairy products is considered the main route of exposure (Kaczmarski, Wasilewska et al. 2013).

Cow milk allergy is considered one of the most common pediatric food allergies (Agyemang, Saf et al. 2019). Milk allergy can be either IgE-mediated or non-IgE-mediated (Walsh, Meyer et al. 2016). Generally, the allergic reactions to CMP are IgE-mediated and manifest immediate symptoms (shortly after consumption) (Host 2002), whereas the non-IgE mediated reactions are usually delayed reactions (after hours or days of consumption) (De Greef, Hauser et al. 2012, Walsh, Meyer et al. 2016). The immediate IgE-mediated reactions mainly lead to angioedema, urticaria, aggravation of atopic dermatitis (AD), vomiting, respiratory symptoms, and in some cases, anaphylaxis (De Greef, Hauser et al. 2012, Ito, Futamura et al. 2012). Symptoms of delayed reactions might include AD or gastrointestinal (GI) symptoms like enteropathy or proctocolitis (De Greef, Hauser et al. 2012, Ito, Futamura et al. 2012).

Anaphylaxis

Anaphylaxis due to CMA is considered an immediate (usually within minutes to a few hours) response developed after consuming CM or milk products and is regarded as potentially life-threatening (Fiocchi, Brozek et al. 2010).

An OFC study on CMA children (median age 1.3 years) detected anaphylaxis in 4% (8/215) of children following the consumption of CM (Komata, Soderstrom et al. 2007).

According to the European Anaphylaxis Registry, CM was reported to elicit anaphylaxis in 128 individuals (preschoolers, children, and adolescents) out of 1565 patients (with known elicitors of anaphylaxis) (Grabenhenrich, Dölle et al. 2016, Pouessel, Turner et al. 2018). Furthermore, a Thailand-based study conducted on 73 patients with food-induced anaphylaxis reported CM as one of the triggers of anaphylaxis in 11% of the patients (Nantanee, Suratannon et al. 2022).

Cutaneous reactions

Cutaneous reactions are reported as one of the most common immediate reactions to milk in children, observed in more than half of the CMA children (Host 2002) and might result in conditions like angioedema, urticaria, acute pruritis, etc. (De Greef, Hauser et al. 2012).

An OFC test conducted on CMA children (median age 1.3 years) observed that 99% (213/215) of children and 4% (9/215) of children exhibited cutaneous and mucous membrane reactions, respectively, with CM (Komata, Soderstrom et al. 2007).

Gastrointestinal symptoms

GI symptoms have been found to be one of the most frequent CMA-associated reactions. According to a review study, about 50-60% of children with CMA are found to exhibit GI symptoms. CMA-related GI symptoms can be either IgE-mediated, non-IgE mediated, or a combination of both (Host 2002).

Patients with CMA might experience vomiting immediately after consumption of CM. Diarrhea is reported as a delayed response; however, in some instances, it can also be an immediate response (Fiocchi, Brozek et al. 2010). Additionally, abdominal or colic pain has also been reported (Venter, Brown et al. 2017).

An OFC study on CMA children (median age 1.3 years) reported that 7% (14/215) of children developed GI symptoms towards CM (Komata, Soderstrom et al. 2007).

Atopic Dermatitis

Atopic dermatitis is a chronic, inflammatory skin disease typically related to allergic sensitization. A study reported that around one-third of the pediatric population with AD (moderate to severe) is allergic to food, which further affects AD progression. In addition, studies from different countries revealed that CM could be considered one of the major allergenic foods in children with AD (Fiocchi, Brozek et al. 2010).

In a prospective Danish birth cohort study on 553 newborns, 11% (61/553) were diagnosed with AD [IgE and skin prick test (SPT)-based], and 26% (16/61) among them were sensitized to CM (Johnke, Norberg et al. 2006).

Moreover, the severity of AD (eczema) in infants may depend on the age of onset (early-onset results in severe condition) and the level of specific IgE (sIgE) towards CM (higher level leads to severity) (Fiocchi, Brozek et al. 2010).

A prospective analysis of 100 infants with CMA (average age 8.74 months) detected AD in 71 of them. These AD patients showed elevated sIgE levels for CM at different ages compared to non-AD patients; particularly at 6 months, the sIgE was highest (Giannetti, Cipriani et al. 2019).

Allergic rhinitis and rhino-conjunctivitis

Milk protein-associated respiratory allergy (such as acute rhinitis and/or conjunctivitis) is rarely prevalent among adults and, in some cases, related to occupational allergy (Bonadonna, Senna et al. 2003, Venter, Brown et al. 2017). Moreover, a review study on children with CMA reported around 20-30% prevalence of respiratory symptoms among the patients (Host 2002).

A study has reported CMA-mediated clinical manifestations of respiratory symptoms like sneezing, acute rhino-conjunctivitis along with watery nasal secretion, and tearing (Martorell-Aragonés, Echeverría-Zudaire et al. 2015).

Asthma

A study in Spain reported higher sIgE levels against CM among 83% (5 out 6) of children with asthma experiencing severe accidental allergic reactions (Boyano-Martínez, García-Ara et al. 2009). Moreover, a Portugal-based study also reported asthma as a predictive factor for the persistence of CMA in 51.2% of 82 children (> 2 years and tolerated CM beyond that age or persisted with CMA until the study’s end) (Santos, Dias et al. 2010).

Other diseases

Non-IgE mediated reactions

Individuals with suspected CMA symptoms have been found to possess mild-moderate-severe non-IgE mediated clinical reactions toward CM (Venter, Brown et al. 2017). The manifestations of GI symptoms (such as colic pain or irritability, vomiting, diarrhea, reflux, abdominal discomfort, mucus, or blood in the stool) usually occur within 2-72 hours post-consumption of CMP. Moreover, skin reactions, including erythema, pruritis, moderately persistent AD, and non-specific rashes, have also been reported as non-IgE-mediated allergic reactions toward CMP (Venter, Brown et al. 2017).

Lactose intolerance is a non-immunogenic condition with a diminished ability to digest lactose due to a deficiency of lactase (enzyme). The common symptoms of lactose intolerance include abdominal discomfort, flatulence, diarrhea, bloating, etc. Non-IgE mediated CMA is often confused with lactose intolerance and may lead to a needlessly restricted diet (Luyt, Ball et al. 2014, Walsh, Meyer et al. 2016).

Challenge tests

An OFC is regarded as the gold standard for diagnosing CMA (Komata, Soderstrom et al. 2007, Flom and Sicherer 2019). However, OFC is often considered time-consuming, resource-intensive, and potentially risky (Petrosino, Scaparrotta et al. 2018).          

In-vitro diagnostics

Milk sIgE testing is used as an aid in diagnosing milk allergy and monitoring disease development. Using sIgE diagnostic values has been reported to be beneficial for physicians in deciding when and how it is necessary to perform an OFC to estimate the potential risk of CMA to the patient´s health. In addition, monitoring of reduction in sIgE levels can also be beneficial in predicting the development of tolerance towards CM among children with CMA, further confirmed by OFC tests (Panel, Boyce et al. 2010).

In patients with persistent milk allergy, milk sIgE levels are found to be higher in the first two years of life compared to those developing tolerance (Panel, Boyce et al. 2010). This was further evident from a study conducted on 115 children (< 24 months; with AD and CMA), which reported a progressive reduction of CM sIgE in serum of patients developing milk tolerance (about 50% of children of age > 24 months became tolerant to CM by 67 months of age) compared to the patients with persistent milk allergy (Suh, Lee et al. 2011).

Allergen immunotherapy

Various studies have reported oral immunotherapy (OIT) as an effective treatment option for young children with CMA (Taniuchi, Takahashi et al. 2017). The European Academy of Allergy and Clinical Immunology (EAACI) guideline on OIT in food allergy suggests starting CM OIT in children around 4-5 years old because, at this age, 50-90% of the children have already outgrown their allergy (Pajno, Fernandez-Rivas et al. 2018). Also, the EAACI Molecular Allergology User´s Guide proposes that molecular diagnosis may be utilized to identify subjects at higher risk of experiencing side effects from milk OIT and to monitor the development of desensitization and tolerance (Anna Nowak-Wegrzyn 2016).

For example, a milk-based OIT study conducted on 76 patients (with persistent CMA) reported that 72% (55/76) of patients developed tolerance and attained the target maintenance dose (200 ml) for CM during OIT. Moreover, the study revealed high levels of the milk allergen components like α-lactalbumin, β-lactalbumin and casein before OIT starts could predict a less successful OIT outcome with a lower maintenance dose reached (Kuitunen, Englund et al. 2015).

Prevention strategies

Complete elimination (avoidance) of milk and milk-based products from the diet is considered the main treatment for CMA. However, complete avoidance of proteins present in cow´s milk might adversely impact the growth and development of infants or children (Bu, Luo et al. 2013). Hence, for infants with CMA, breastfeeding (if possible) and/or alternative formula (like hydrolyzed or amino acid-based formula or soy formula) should be considered as a source of nutrition (de Silva D, Geromi M et al. 2014, Manuyakorn and Tanpowpong 2019).

Furthermore, CMA patients are usually recommended to avoid other mammalian milk, like goat’s milk and sheep’s milk, owing to the presence of highly cross-reactive allergenic molecules (Sampson, Aceves et al. 2014).

Early introduction of CMP as a supplement to breastfeeding and during weaning might be beneficial in developing tolerance towards CM (Katz, Rajuan et al. 2010). Additionally, the introduction of baked-milk products (muffins, bread, and cakes) in the diet of children with CMA has been reported to enhance milk tolerance and is even considered a positive treatment alternative for patients with CMA (Sackesen, Altintas et al. 2019).