Cows Milk Allergy –
An Update on Adverse Reactions
Article written: April 2002
Hippocrates first reported adverse reactions to cows milk around 370 B.C. Since then the prevalence & awareness has increased exponentially. This could be linked to the availability of infant formulas and decreased breast-feeding in some cultures.
Prevalence of adverse reaction to milk
Milk is one of the most common food allergens in children. Studies in several countries around the world show a prevalence of milk allergy in children in the first year of life of around 2%.
Prognosis of cow's milk allergy
In a prospective study of milk hypersensitivity in children through 3 years of age, most children lost the milk allergy by age 3 years of age: 50% by 1 year of age, 70% by 2 years of age, and 85% by 3 years of age.
Cow's milk allergy is defined, as hypersensitivity to cow's milk protein by a mechanism involving the immune system. An adverse reaction to milk that does not involve an immune mechanism is defined as Milk Intolerance.
Isolated milk protein allergens
Cow's milk contains at least 20 protein components that may provoke an antibody response in man. The milk protein fractions traditionally have been subdivided into casein and whey fractions. The caseins are generally found in micellar complexes, which give milk its "milky" appearance & constitute 76-86% of the protein in cow's milk. The casein fraction is precipitated from skim milk by acid at pH 4.6. The noncasein fraction, or whey, accounts for 20% of total milk protein. It consists of β
-lactoglobulin (9% of total milk protein), α
-lactalbumin (4%), bovine immunoglobulin (2%), bovine serum albumin (1%), and minute amounts of various proteins (lactoferrin, transferrin, lipases, etc. that collectively make up 4% of the total milk protein). Extensive heating denatures several of the whey proteins. Many authors have investigated the allergenicity of the milk proteins, but still with little consensus. The problem is that, virtually all commercial sources of whey are contaminated with casein proteins, and vice versa. Utilizing RAST with purified milk proteins, Hoffman concluded that β
-lactoglobulin was the major allergen in cow's milk. Other studies have demonstrated IgE antibodies to α
-lactoglobulin, bovine serum albumin, and bovine gamma globulin in most milk-allergic patients. However, recent studies utilizing sera from children with milk challenge-confirmed hypersensitivity have suggested that caseins are the most allergenic milk proteins. In a recent study by Docena et al casein-specific IgE was found in 80/80 children sera, β
-lactoglobulin-specific IgE in 10/80, and α
-lactalbumin in 5/80. Hugh Sampson's recent study of 69 milk-allergic children confirmed the importance of casein as a major milk allergen and also demonstrated significant reactivity to α
-lactalbumin and β
Cow's milk cross-reactivity
In 1939 Hill reported that 25 of 44 infants with eczema who had positive skin prick tests to cow's milk whey protein also exhibited identical positive skin tests to the whey fraction of goat's milk. In 1983 Juntunen and Ali-Yrkko performed provocation tests in 28 children with cow's milk protein intolerance, and found 22 were also intolerant to goat's milk. The marked antigenic similarity between cow's and goat's milk protein suggests that goat's milk is unlikely to be tolerated in most children with genuine cow's milk protein intolerance.
An even greater antigenic similarity appears to exist between bovine and sheep β
Cow's milk proteins and human milk proteins apparently do not cross-react.
Heat treatment reduces the immunological activity of some milk proteins, but not others. Thus the use of heat-denatured milk (e.g. evaporated milk) is likely to help only cases in which the patient is sensitive to heat-labile protein. Immunoglobulins, bovine serum albumin and α
-lactalbumin are most susceptible to heat denaturation, and casein the least susceptible.
Clinical profile of adverse reactions to cow's milk protein in children
There are 3 patterns of response in children with cow's milk protein intolerance.
Time of onset of symptom after milk challenge
Early (skin) reaction
Intermediate (Gut) reaction
45 mins to 20 hours
Late (Gut & skin) reaction
over 20 hours
Early (Skin) reaction Group
In the early skin reaction group, symptoms begin to develop within 45 minutes of cow's milk challenge. The reaction is either a measles-like rash or hives. The respiratory system can be affected in this group, causing wheezing or rhinoconjunctivitis (sneezing & itchy, red eyes). This reaction usually occurs after small volumes of cow's milk. Hill et al found that almost all (24 out of 26) patients in this group had a positive skin prick test to cow's milk. Cow's milk anaphylaxis is the most important reaction type belonging to this group.
Intermediate (Gut) reaction group
In this group symptoms of vomiting or diarrhoea begin to develop between 45 minutes and 20 hours after cow's milk challenge. Moderate amounts of cow's milk are required to trigger this reaction. About one- third of patients in this group had a positive skin prick test to cow's milk in Hill's study.
Late Reaction Group
Symptoms begin to develop about 20 hours after cow's milk protein challenge. Large volumes of cows milk are required to trigger this reaction. Only about 20% of this group had a positive skin prick test. Almost all patients in this group were older than 6 months. The reaction is usually diarrhoea and or eczema. The Atopy Patch Test (Milk applied to the back for 48 hours) is often positive in this group.
Multiple food protein intolerance (MFPI)
MFPI can be defined as intolerance to more than 5 main foods including EHF and soy formulae (Hill et al 1995).
MFPA can also be defined as allergy to more than 1 basic food e.g. milk, wheat, egg, and soy. When the most common foods like milk, wheat and egg are eliminated from the infant's diet the patient may be at risk of inadequate nutrition and consequently abnormal growth, in the absence of adequate dietary advice.
Infant Formulas in cow’s milk intolerant infants
Soy formulas offer equivalent nutritional benefits as extensively hydrolyzed formulas, but are often cheaper and more palatable.
In New Zealand, like most other developed countries physicians were reluctant to recommend soy formulas to cow's milk-allergic infants since previous studies showed that up to 47% of milk allergic infants can have adverse reactions to soy.
A recent study published in the Journal of Paediatrics, February 2002; Volume140: 219-224, looked at 170 infants with documented cow's milk allergy, and they were randomly assigned to receive either soy formula or an extensively hydrolysed formula. The study concluded: "Soy formula was tolerated by most infants with IgE-associated and non-IgE-associated cow's milk allergy. Development of IgE-associated allergy to soy was rare. Soy formula can be recommended as a first-choice alternative for infants more than 6 months of age with cow's milk allergy."
This study does not alter my practise for infants with cow's milk allergy under the age of 6 months.
In some countries, goat milk has traditionally been recommended for patients with cows milk allergy. Goat milk is not nutritionally complete. It is a poor source of certain vitamins, especially folic acid and vitamins B6, B12, C, and D, but is rich in minerals. Goat and cows milk share identical epitopes (allergens). As a result, goat milk is usually not tolerated by children with cows milk allergy.
Extensively Hydrolysed formula (EHF)
An alternative cow's milk substitute is a milk formula in which the protein content is hydrolysed cow's milk protein. These formulae often have a poor flavour and tend to be expensive. Whey proteins are easily denatured by heat but casein is highly resistant. Denaturation of whey by heat treatment explains why some heat-treated milks, such as evaporated milk, are occasionally tolerated by a child with cow's milk protein intolerance.
Work done by Aas in 1987 suggests that the minimum size of an allergenic peptide is one with 14 amino acid residues.
The most effective means of reducing the allergenicity of food proteins is by decreasing the molecular size by proteolysis. In theory, the smaller the molecular weight the better, but advantages of reducing allergenicity may be offset by poor palatability. In other words, turning milk protein into amino acids would abolish allergenicity, but the resulting solution would be unpalatable and have no resemblance to milk.
Enzymatic hydrolysis of casein and whey has been used to develop a number of casein or whey hydrolysate milk formulae.
The European Society of Paediatric Allergy and Clinical Immunology (ESPACI) define extensively hydrolysed formulae as follows:
A formula based on hydrolysed proteins with fragments small enough not to induce allergic reactions in sensitised children.
Extensively hydrolysed formulae shall fulfil the criteria of 90% clinical tolerance in infants with proven IgE-mediated CMA (95% confidence interval) as specified by the American Academy of Paediatrics Nutritional Committee. Therefore, about 10% of cow's milk allergic children could react to EHF.
The exact frequency of allergy to EHF is not known. However, it is speculated to be up to 19%.
Casein hydrolysates have been used for almost 50 years. Several studies have shown them effective in cows milk allergy. Whey hydrolysates are a more recent alternative, they appear to have a similar clinical tolerance.
Types of cow's milk protein hydrolysate formulae
Casein hydrosylate formulae
Whey hydrosylate formulae
In New Zealand up until last year, Nutramigen was the extensively hydrolysed formula available. This has been replaced by the whey hydrosylate, Pepti-Junior. To my knowledge, there has been 1 report of "Anaphylaxis requiring Adrenaline", in an 11-month-old infant in Queenstown. This allegation should serve to remind us that extensively hydrolysed formulae are not non-allergenic and they can cause allergy in cow's milk allergic infants.
Partially Hydrolysed formulae contain peptides large enough to cause allergic reactions to cow's milk protein and are not recommended for the treatment of cow's milk allergy.
In New Zealand there is a Nestle Infant formula available, called NAN HA 1, which is a 100% partially hydrolysed whey protein. It offers better formula tolerance and is recommended for high-risk infants before they show any sign of cow's milk allergy. It is not suitable for the treatment of cow's milk allergy.
Clinical trials show NAN HA 1 helps to reduce the onset of some allergic symptoms.
Synthetic Amino acid-based formulae
Neocate is the synthetic 100% amino acid based hypoallergenic formulae available in New Zealand. It has very good taste, and usually very well tolerated, but is very expensive.
Neocate is used to treat symptoms of persistent and severe food allergy, such as:
Multiple Food Protein Intolerance
Allergy to extensively hydrolysed formulae
Early onset food allergy with poor weight gain
GER unresponsive to standard therapy
It is also used as the placebo in DBPCFC for diagnosis of milk allergy.
The fat component is safflower oil, coconut oil and soy oil. The multiplicity of fat sources raises some theoretical possibility of intolerance.
Breast Milk and Cows milk Allergy
Breast milk is the ideal food for infants and is even tolerated by some infants with cows milk allergy. Transfer of cows milk protein in breast milk causes symptoms in most cows milk allergic infants. It is therefore important that the nursing mother eliminates milk from her diet.