Milk allergy is, first of all, a food allergy which occurs as a result of an immunological nature response of the human body against one of the milk’s components, most often to a protein or one of its fractions. Basically, a milk allergy is a milk protein allergy (cow’s milk proteins: such as casein, β-lactoglobulin, α-lactalbumin, serum albumin, and immunoglobulins), which affects mainly the infants during their first year of life. Principle cow’s milk allergens are those of casein group, especially α-s1, α-s2 fractions and β-lactoglobulin because its concentration in breast milk is 100,000 lower than in other mammals’ milk of milk formulas. The composition differences of the main proteins in breast milk and cow’s milk are shown in the table below.
Cow’s milk protein allergy is usually a benign condition, which resolves in the first 5 years of life or later in adulthood, unlike allergies to different kinds of nuts and seafood, that can be life long lasting.
Table 1. The composition of the main proteins in breast milk and cow’s milk.
|Protein||Breast (mg/mL)||Cow (mg/mL)|
Cow’s milk protein allergy is the most common food allergies among infants in the USA and the UK. Its prevalence differs depending on the studies and varies between 1,9 and 7,5 % in the formula-fed babies, and between 0,5-1,0% in breastfed infants. The last one can be explained by the cow’s milk protein transfer into the breast milk. In 0.8-0.9% life threatening symptoms like anaphylaxis were noted.
Signs and symptoms
Cow’s milk protein allergy is usually difficult to diagnose, as it is one of the most complex of all the food allergies, and the symptoms can be mistakenly interpreted for other conditions or diseases, frequent during childhood. Any of the followings could be a symptom of a cow’s milk protein allergy:
-skin and mucosa involvement: swelling, urticaria-like rash, eczema, angioedema, erythema, pruritus;
-gastro-intestinal tract signs: nausea, vomiting or reflux, diarrhea or constipation, colicky abdominal pains, food refusal or aversion, perianal redness;
-respiratory signs: nasal itching, sneezing, rhinorrhoea or congestion, conjunctivitis, cough, chest tightness, wheezing or shortness of breath;
-life-threatening symptoms: signs and symptoms of anaphylaxis or other systematic allergic reactions
-other symptoms: restless sleep, excessive crying, failure to thrive, etc.
Skin manifestations occur in 5 to 90 % of cases, whereas gastrointestinal tract symptoms in 32 to 60% of cases.
Types of cows milk allergy
Depending on the time of cow’s milk protein allergy symptoms manifestation, it can be divided into 2 groups:
– Immediate cow’s milk allergy, which is mediated by class E immunoglobulin (Ig E). These are the antibodies that react through an immune response at a second contact with the allergen- in our case cow’s milk proteins. The first contact with the allergens produces the sensitization of the immune cells, which at the following one will be activated and will start the output of the mediators (histamine) into the blood stream and provoke the appearance of the allergic symptoms as swelling, skin rash, edema, wheezing, cough, etc. IgE is responsible for the anaphylactic life-threatening reactions as well, but these ones occur rarely. The immune response is induced within minutes up to 24 hours.
-Delayed cow’s milk allergy, non-IgE mediated immune response. This type of allergy is more complex, has more complicated mechanisms and is harder to diagnose. It is mediated by another class of immunoglobulin and manifests later in time. The symptoms of a delayed cow’s milk allergy a various and not pathognomonic, which makes its diagnosing challenge even for an experienced doctor. It usually manifests with gastrointestinal tract signs, restless sleep, excessive crying and failure to thrive. Similar manifestations can be observed in lactose intolerance, which a non-allergic condition triggered by lactase production deficiency or its complete absence.
An early diagnosis of a cow’s milk protein allergy is very important for the initiation of an adequate management of this condition. The symptoms and the patient’s history together with the laboratory test are the first steps in the evaluation. In the IgE-mediated allergy the specific test, such as IgE level/titer determination and skin prick test are very helpful to confirm de organism sensitization with the cow’s milk protein. While the sensitivity of IgE and the skin prick test id quite high varying between 75% and 94% and respectively 76-94%, it lacks accuracy in the specificity, which consists 36-59% and respectively 56-77%. The negative values do not rule out the diagnosis of a cow’s milk protein allergy.
Dietary elimination test, which consists in excluding any dairy products are also performed in the process of diagnosing of the cow’s milk protein allergy. This one should be as short as possible, but sufficiently long to see the symptoms improvement.
The gold standard in diagnosing the cow’s milk protein allergy remains the standardized oral challenge test (it can be open, single or double blinded, placebo-controlled) with cow’s milk protein. It is very important that these are carried out by a specialist, preferably in a hospital, where an appropriate management of any clinical reactions can be guaranteed. The child should be tested after 2-3 hours after the last meal in order to assure an adequate titration of the cow’s milk protein.
Other tests such as patch, Vega, food-specific IgG lack scientific ground and are not recommended for the diagnosis of the cow’s milk protein allergy.
Management of cow’s milk protein allergy
There are different guidelines that give recommendations concerning the management of the cow’s milk protein allergy: ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology, and Nutrition), (NICE National Institute for Clinical Excellence Guidelines) and MAP ( Milk Allergy in Primary Care). One of the evaluation schemes of cow’s milk allergy is shown below (figure1).
Considering the guidelines, it should take around 4 weeks to diagnose a cow’s milk protein allergy. A recent survey showed that it takes between 8 and 10 weeks a general practitioner in the UK to establish this diagnosis. Some of the practitioners found difficulties in distinguishing between the symptoms of an immediate and a delayed cow’s milk protein allergy, and many of them considered the symptoms to be caused by other common conditions such as colic, lactose intolerance, gastro-esophageal reflux disease, atopic eczema. This fact can be explained by the following: the general practitioners are not very familiar with the cow’s milk protein allergy management guidelines, which creates a barrier in the diagnosing process, making it longer and increases the anxiety and frustration levels among the parents. Parents with depressive symptoms are more likely to have communication issues with the practitioners, being unsatisfied by the medical care.
Fig 1. Evaluation of infants suspected of having cow’s milk protein allergy (CMP) according to the ESPGHAN criteria (Koletzko et al. , permission obtained) eHF extensively hydrolyzed formula AAF amino acid-based formula
Once cow’s milk protein allergy is diagnosed, a strict cow milk protein free diet should be initiated. Mothers who breastfeed must avoid products containing cow milk protein as well, as it transfers into the breast milk and initiates the same reaction as in a child that ingests directly cow milk protein. Any food products that contain cow milk protein should be completely excluded. One should be careful with the following types of products: butter, ordinary margarine, low-fat spread milk, cheese including vegetarian cheese, yogurt, cream, some types of sausages, burgers, tinned meats, and other processed meats, baked beans, mayonnaise, etc. Always check the labels for milk ingredients.
Suitable milk substitutes would be: breast milk for breastfed babies and hypoallergenic formulas for non-breastfed babies. In mild or moderate manifestation of cow’s milk allergy, extensively hydrolyzed formulas are recommended as the first choice, while in severe forms with manifested eczema and generalized anaphylactic reactions, the milk replacement diet should start with amino-acid formulas. Patients with a positive history of anaphylactic reaction should have an adrenaline autoinjector prescribed by the practitioner/pediatrician. Parents should be taught how and when to use it correctly. The dose is calculated by the doctor, individually for each patient depending on the weight.
Soya based fortified drinks can be used for children over 6 month of age.
Other less desirable options are alternative milk “beverages” made of almonds, coconut, hazelnuts, hemp, oats, pea and other pea products, which can be used for older children.
The problem with the last ones is that the nutritive value is insufficient and they lack minerals as calcium which is important for a normal development of the skeletal system and rickets prophylaxis. Adapted milk formulas are usually fortified with calcium supplements and other essential nutrients, while older children and nursing mothers on a milk free diet require calcium and vitamin D supplements. Some studies had shown that the insufficient calcium intake in children with cow’s milk protein allergy, especially when it doesn’t resolve in childhood, can lead to lower bone density and increase the risk of osteoporosis later in life.
Reevaluation and reintroduction of products containing cow’s milk protein
The intervals of evaluation during cow milk protein free diet are questionable, because there are insufficient studies that would indicate a proper assessment time. Depending on child’s age, some of the studies recommend patient reassessment every 3 to 6 months until the age of 12 months, and once in 6 to 12 months after 12 months of age. The goal of the reevaluation is to start reintroducing the cow’s milk protein as soon as possible, as more studies had demonstrated that the delayed introduction of food allergens is associated with an increased rate of developing allergic diseases in future. The earlier statement that delayed the introduction of potentially allergic foods decreases the prevalence of allergic reactions, was replaced by the new opposite recommendations according to the newest guidelines concerning the management of cow’s milk allergy. A reevaluation is a reassessment of the physical symptoms and new laboratory tests: IgE level and skin prick test, as well as an oral challenge test to cow’s milk protein. When physical examination shows no symptoms of allergy and the laboratory tests are inconspicuous, a reintroduction of products containing cow’s milk protein should be considered, although not before the age of 12 months.
The reintroduction of dairy products can be started either at home or in the hospital. In mild cases of cow’s milk protein allergy, with long (6 months) free symptoms period, when the skin prick test is negative or significantly reduced, the intake of dairy products can be started at home. A hospitalized reintroduction of cow’s milk protein is necessary for severe allergic manifestation like severe eczema, excessive vomiting or diarrhea or/with life-threatening reactions (anaphylaxis), complex allergic conditions (when other types of allergies are associated), poorly controlled asthma or with inhaling treatment, decreased parents’ compliance or lack of protocol understanding.
This process is called the “milk ladder”, as it works consequently from less to more. It should be considered only when total tolerance to cow’s milk protein is achieved.
Milk ladder has a few stages, and one should proceed to it very carefully because the classification of milk products depending on the allergic potential is imperfect and can cause an immune response at any of its stages.
A short description of the milk ladder is shown in the figure below.
The first stage starts with smaller amounts, baked dairy products, and matrix. The preparation time is longer comparing with the next stage and the heating temperature is higher. At this level, the products are usually biscuits with a low amount of cow’s milk protein, precisely less than 1 gram of protein per biscuit. The quantity is increased gradually during 5 weeks and then, one can do the transition to the stage 2, which is characterized by larger quantities of baked cookies, cakes, muffins, waffles or products containing margarine or butter. At this stage the products contain less matrix, the baking temperature is lower and the preparation time shorter. The next steps are characterized by less denatured and highly allergenic products. Stage 3 consists of products containing cow’s milk protein like cheese, yogurts, chocolate, puddings, etc, up to heat processed whole cow’s milk. The final stage is consumption of fresh milk products as ice-cream, mousses, uncooked dairy products, etc.
It is very important to proceed carefully to the transition from one stage to another. As soon as any symptoms of cow’s milk allergy may appear, a downgrade to the previous stage should be performed.
Reintroduction of cow’s milk protein products is a very slow and meticulous process. Counseling and training of parents play an important role in achieving the tolerance and leaving the cow’s milk protein allergy behind.