Cow’s Milk Protein Allergy: Case Study

Cow’s milk protein allergy

Abstract

Cow’s milk protein allergy (CMPA) is caused by an immune-mediated response to milk proteins and tends to present during the first year of life. This response can vary greatly from an immediate reaction within 2 hours of ingestion to a more delayed reaction which can occur anywhere between 2 to 72 hours later. Overdiagnosis can lead to an unnecessary elimination diet but a delay in diagnosis can cause child and parental distress. It can also be confused with lactose intolerance which is a non-immune mediated response as a result of enzyme deficiency. We review diagnosis and management in this article along with future directions.

History

Drinking animal milks surfaced into the human diet around 10,000 years ago when cattle began to be domesticated. However, the first reactions to dairy were not described until 2,500 years ago by Hippocrates consisting of skin and gastrointestinal symptoms after consumption. Fast forward to today and cow’s milk has become an important part of a child’s diet providing a source of protein and calcium. Cow’s milk protein allergy (CMPA) occurs due to an immune-mediated response to cow’s milk proteins. These can be classified into IgE-mediated reactions which occur within minutes of exposure to non-IgE mediated reactions which occur hours after ingestion. Mixed forms consisting of IgE and non-IgE mechanisms can also exist.

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Epidemiology

CMPA is one of the most common food allergies in the developed world affecting up to 2-7% children in early life. This reduces to 0.5% in exclusively breast-fed infants. The wide variation in prevalence is likely due to different methods of diagnosis and assessment of allergy. Self-reporting results tend to be higher compared to strict food challenge criteria. The Euro-Prevail birth cohort study found incidences of challenge-proven CMPA ranging from 1% in the United Kingdom (UK) and the Netherlands to less than 0.3% in Lithuania, Germany, and Greece in children under 2 years of age. As the natural history of CMPA is one of resolution, analyzing epidemiological data can be difficult. Therefore, the true prevalence probably lies between 2-3% of children.

Pathogenesis and Classification

Classification of CMPA according to mechanism and spectrum is displayed in Figure 1. IgE antibody-mediated or type 1 hypersensitivity reactions occur when an allergen processed by an antigen-presenting cell causes a naïve T cell to become activated to a T helper type 2 (Th2) cell. This Th2 cell produces cytokines which stimulate the B cell to produce IgE antibodies specific to an antigen/allergen. Mast cells and basophils coated by IgE antibodies are now ‘sensitized’ to the allergen. On re-exposure, the allergen binds to the IgE molecules and cross-linking occurs which causes degranulation and release of chemical mediators including histamine, cytokines, leukotrienes, prostaglandins, and tryptase. These cause the wide myriad of clinical features seen and tend to be immediate. They can be limited to one organ like the skin causing urticaria or angioedema to multisystem causing anaphylaxis.

Non-IgE mediated allergy is a delayed cell-mediated type 4 hypersensitivity reaction. This occurs when T helper type 1 cells (Th1) recognize allergens and activate macrophages to produce lytic enzymes and cytotoxic T cells which directly attack host cells causing inflammation. The mechanisms of non-IgE mediated allergy are less well understood and it is thought that other antibody-mediated mechanisms might also be involved.

**talk about FPIES and others here

Figure 1: The spectrum of CMPA

Course

CMPA carries a good prognosis. Studies have shown 2/3rd are tolerant by school age. However, later studies suggest tolerance can also be achieved in adolescence. Non-IgE mediated allergy will resolve earlier than IgE mediated allergy. The predictors of persistence include IgE-mediated allergy, reaction to baked milk on first challenge or exposure, presence of other food allergies especially egg, asthma, and allergic rhinitis.

Diagnosis

History and Examination

IgE-mediated reactions can present with urticaria, angioedema typically of the eyes and lips, and gastrointestinal symptoms like diarrhoea and vomiting. The severe end of the spectrum can include life-threatening anaphylaxis with airway, breathing or circulatory involvement. Non-IgE mediated reactions can also include cutaneous manifestations varying from urticaria to eczema flare-ups. The gastrointestinal system can also be involved including vomiting, diarrhoea or constipation. This can easily be mistaken for other conditions like reflux. Non-IgE mediated reactions can also lead to life-threatening features from gastrointestinal losses secondary to inflammation as seen in food protein-induced enterocolitis syndrome (FPIES). Table 1 summarises the symptoms that can be present in the different types of CMPA according to organ system.

Table 1: Symptoms of CMPA

Investigations

Investigations are dependent on the history and the type of CMPA suspected. The gold standard for diagnosis is a double-blind, placebo-controlled oral food challenge (DBPCFC). In clinical practice, this is not practical, especially in children. Instead, if a non-IgE mediated allergy is suspected then an elimination diet needs to be performed for 2-6 weeks to see if there is a resolution of symptoms followed by reintroduction to see if symptoms reoccur. Again, in clinical practice usually, an elimination diet is commenced to see if symptoms improve, and then this is maintained. Reintroduction is based on reassessment and whether the acquisition of tolerance may have occurred.

Suspected IgE-mediated allergy investigations include the use of serum-specific IgE (sIgE) and skin prick tests (SPT). These tend to be reserved once a referral to secondary care has been made and should only be performed with a history strongly suggestive of CMPA. A positive reaction or sensitization is defined as sIgE ≥ 0.35 kU/L or SPT wheal size ≥3mm.

Moreover, we can start to predict the likely rate of resolution or persistence through the use of component testing (see table 2).

Table 2: Milk components

• Casein (Bosd8)
• Whey

1. 80% of total milk protein
2. 20% of total milk protein

• Heat resistant
• Higher levels associated with being less likely to tolerate baked milk and persistent allergy

1. α-lactalbumin (Bosd4)
2. β-lactoglobulin (Bosd5)

• Bovine serum albumin (Bosd6)
• Extensive heating reduces allergenicity

Differential diagnosis

Management

The majority of infants and children diagnosed with IgE mediated CMPA or non-IgE mediated CMPA will need to undertake full avoidance of all cow's milk and products containing cow's milk. If a breastfed infant is reacting to milk protein via the mother's breast milk, advice on Mum avoiding milk herself will be required. She will also need a supplement of 1000mg Calcium and 10 micrograms of vitamin D daily to prevent nutritional deficiencies. In formula-fed or mixed-fed infants a hypoallergenic formula prescription will be required. In weaned infants and older children, advice on excluding cow's milk protein from the diet is essential. For suspected non-IgE mediated CMPA individuals then a cow's milk avoidance diet should be followed for 2-6 weeks followed by reintroduction. If symptoms recur on reintroduction then cow's milk allergy can be confirmed.

Extensively hydrolyzed formulas (ETFs) are hypoallergenic formulas that are tolerated by the majority (90%) of infants with CMPA. They are either casein or whey dominant formulas based on cow's milk where the proteins have been extensively broken down into smaller peptides that are less well recognized by the immune system. Examples include Apatmil Pepti, Nutramigen with LGG, Similac Alimentum, and SMA Althera. Some contain lactose which can make them slightly more palatable and one contains a probiotic which has some data to support it aiding faster milk tolerance.

Amino acid formulas (AAFs) are also available on prescription. These are made synthetically and do not contain any cow's milk protein, making them suitable for those who require halal diet. There has been some debate as to when AAFs should be used in view of their cost burden and because they may affect development of tolerance. The general consensus is that they should only be used when there has been anaphylaxis to cow's milk protein, in Heiner Syndrome, Eosinophilic Esophagitis, and in severe gastro-intestinal and/or skin presentation, particularly in association with faltering growth. Examples include Neocate LCP/ Neocate Syneo, Nutramigen Puramino, and SMA Alfano.

Soya formula is not advised before the age of 6 months due to the phytate content which may affect nutrient absorption and the isoflavones which may have a weak oestrogenic action. In addition, 25-60% of children with non-IgE mediated CMPA will also react to soya as will a smaller percentage of IgE-mediated CMPA children too.

Calcium-fortified plant drinks can be used as a main cow’s milk alternative over the age of 2 if the child is eating a varied diet with no feeding problems and if growing appropriately. Soya is a good protein source and in the UK there is one suitable brand for children. Fortification is often low in other plant-based drinks and there is no regulation to govern this. There are no growth studies, no data on the absorption of added nutrients (except soya), and no industry regulation on checking the quality of added nutrients. Rice milk has naturally occurring arsenic and is not advised under the age of 4.5 years. Oat drink is low in lysine, an essential amino acid, and nut and seed drinks contain minimal nut/ seed and are very poor nutritionally for young children.

There is no ideal time for testing for development of tolerance. However, it is generally accepted that infants with non-IgE mediated cow’s milk allergy should remain cow’s milk free until the age of 9-12 months or for 6 months post-diagnosis. At this point a milk ladder can be commenced, these start with milk in a baked food as mixing cow’s milk in a flour matrix and heating to high temperature for a long period reduces the milk’s allergenicity. When to start and when and how to progress up the ladder should be ideally supported by a dietitian. Around 75% of children with IgE-mediated cow’s milk allergy will also tolerate cow’s milk in a baked food e.g. cake. Studies have shown that by regularly including such foods in the diets of these children helps to speed up the resolution of their allergy. This may be performed as a hospital oral food challenge or some allergy centers will allow this to be done at home.

Table 3: Brands of formula milks available in the UK for CMPA

• Product name
• Age of suitability
• Type
• Althera
• From birth
• EHF
• Aptamil Pepti 1
• From birth to 6 months
• EHF
• Aptamil Pepti 2
• From 6 months
• EHF
• Nutramigen LGG 1
• From birth to 6 months
• EHF
• Nutramigen LGG 2
• From 6 months
• EHF
• Similac Alimentum
• From birth
• EHF
• Alfamino
• From birth
• AAF
• Neocate LCP
• From birth
• AAF
• Neocate Junior
• From 12 months
• AAF
• Nutramigen Puramino
• From birth
• AAF
• Wysoy
• From 6 months

Soy

UK, United Kingdom; CMPA, Cow’s Milk Protein Allergy; EHF, Extensively Hydrolysed Formula; AAF, Amino Acid Formula

1. Prognosis and explanation to the patient
2. Follow up

• how often?
• by whom?
• how? (e.g. what tests are necessary?)
• complications and disabilities
• rehabilitation

1. Prevention

• Breastfeeding

There is no consistent evidence that breastfeeding is effective for the prevention of allergic diseases. However, breastfeeding is recommended for the many benefits it provides to mother and infant. In the UK exclusive breastfeeding is recommended for the first 6 months of life and to continue breastfeeding during introduction of complementary foods from 6 months. This may help reduce the risk of the infant developing allergies and the acquisition of tolerance, although evidence for this is low. BSACI have produced guidance around preventing food allergy and advocates the early introduction of allergenic foods like egg and peanut (see online resources).

• Probiotics

There is some evidence probiotics can be used as a preventative measure when used antenatally and postnatally to mothers in infants with a high risk of eczema and food allergy. The safety profile of probiotics is good and is one of its main attractions for its use clinically. However, there are a wide variety of commercially available products not subject to the same regulations as medicinal products. There are also many different strains and strengths available and the literature can be quite confusing at times with which one may be more beneficial in a particular condition. Therefore, without further evidence, they should be used cautiously and not routinely.

• Hydrolysed formula

Current consensus is that hydrolyzed formulas should not be used as a means to prevent allergic disease in high-risk infants.

• Online resources

The iMAP Milk Ladder. https://www.allergyuk.org/assets/000/001/297/iMAP_Final_Ladder-May_2017_original.pdf?1502804928

BSACI preventing food allergy in higher risk infants: guidance for healthcare professionals. https://www.bsaci.org/pdf/Early-feeding-guidance-for-HCPs.pdf

References

1. Flom JD, Sicherer SH. Epidemiology of Cow’s Milk Allergy. Nutrients 2019; 11: 1051.
2. Ludman S, Shah N, Fox AT. Managing cow’s milk allergy in children. British Medical Journal 2013; 347: f5424.
3. Luyt D, Ball H, Makwana N, Green MR, Bravin K, Nasser SM, Clark AT. BSACI guideline for the diagnosis and management of cow’s milk allergy. Clinical & Experimental Allergy 2014; 44: 642.
4. Schoemaker AA, Sprikkelman AB, Grimshaw KE, et al. Incidence and natural history of challenge-proven cow’s milk allergy in European children-EuroPrevall birth cohort. Allergy 2015; 70: 963.
5. Zhang GQ, Hu HJ, Liu CY, Zhang Q, Shakya S, Li ZY. Probiotics for prevention of atopy and food hypersensitivity in early childhood. Medicine 2016; 95: 1-10.