NHD CPD eArticle Vol 7.20 by NH Publishing Ltd

NHD CPD eArticle NETWORK HEALTH DIGEST

Volume 7.20 - 30th November 2017

COWS’ MILK PROTEIN ALLERGY IN INFANTS Maeve Hanan Registered Dietitian, City Hospitals Sunderland Maeve works as a Paediatric Dietitian in City Hospitals Sunderland. She also runs a blog called Dietetically Speaking.com which promotes evidencebased nutrition and dispels misleading nutrition claims and fad diets.

Allergy has been called ‘the number one environmental epidemic disease facing children of the developed world’.1,2 Cows’ milk protein allergy (CMPA) is the most common food allergy found in children; with a worldwide prevalence of 1.9-4.9%3 and a UK prevalence of 2-3%.2,4 As milk is a key part of an infant’s diet, the nutritional management of this condition is crucial.

CMPA is a reproducible adverse immune response to one or more of the proteins found in cows’ milk, which usually presents before the age of one and is often outgrown by the age of five.4 The risk of CMPA increases when an infant This article has a history, or family history, of atopy; has been Peer for example, eczema or asthma in the Reviewed by infant, or a family history of eczema, Dr Rosan Meyer, asthma, hay fever or food allergies.5 Paediatric There is evidence that breastfed Research Dietitian, infants have a lower prevalence of Honorary Senior CMPA, with about 7% of formula or Lecturer, Imperial mixed-fed infants developing CMPA College, London compared to about 0.5% of exclusively and Chair of the breastfed infants. Furthermore, breastBDA Food Allergy fed infants are reported to have less and Intolerance severe reactions if they do develop Specialist Group. CMPA.3,6 The primary factor involved in the development of food allergy in infancy is genetic, with a parental atopic

history (asthma, eczema and hayfever) significantly increasing the risk.8 Research has also identified contributing environmental factors, which include smoking during pregnancy, the infant’s gut microbiome which may be affected by route of birth (C-section versus vaginal birth), early antibiotic use and dietary diversity.8,20,21 CMPA is classified as either immunoglobulin E- (IgE) or non-IgEmediated, depending on the type of immune response which occurs. IgEmediated reactions occur when IgE antibodies form in response to cows’ milk protein, which causes the release of histamine from basophils and mast cells;

Just 14 days

can make a difference

Trust Neocate LCP

to provide fast and effective resolution of Cow’s Milk Allergy symptoms

1,2

1. De Boissieu D, Matarazzo P, Dupont C. J Pediatr 1997; 131(5):744-747. 2. Vanderhoof JA, Murray MD, Kaufman S et al. J Pediatr 1997; 131 (5):741-744.

Copyright © 2017 NH Publishing Ltd - All rights reserved. Available for printing and sharing for the use of CPD activities for personal use. Not for reproduction for publishing purposes without written permission from NH Publishing Ltd.

NHD CPD eArticle

Volume 7.20 - 30th November 2017

Table 1: Symptoms of IgE- and non-IgE-mediated CMPA based on the Milk Allergy in Primary Care (MAP) guidelines9 IgE-mediated

Non-IgE-mediated

Respiratory and/or cardiovascular signs of anaphylaxis

No sign of anaphylaxis

Skin: Acute pruritus (itching), erythema (rash), urticaria (hives), angioedema (swelling), flaring of atopic eczema

Skin: pruritus (itching), erythema (rash), significant atopic eczema

Gastrointestinal: Vomiting, diarrhoea, abdominal pain/colic

Gastrointestinal: Vomiting, reflux, food refusal or aversion, abdominal discomfort, loose or frequent stools, perianal redness, constipation, uncomfortable stools, blood and/or mucus in stools in an otherwise well infant, faltering growth

Respiratory: Acute rhinitis (inflammation of the nasal passage nasal itching, sneezing, runny nose, congestion), conjunctivitis

Respiratory: Catarrhal airway symptoms (build-up of mucous in the back of the nose, sinus’ or throat) - usually in combination with one or more of the above symptoms

whereas it is thought that non-IgE-mediated CMPA is caused by T-cells.5 IgE-mediated reactions have a quick onset, usually presenting within minutes to two hours and the symptoms can be severe, such as anaphylaxis, hives and facial swelling.5,9 NonIgE- mediated reactions are more common, often have a more delayed onset (such as two hours to three days) and usually present with less acute symptoms, such as gastrointestinal and skin symptoms. See Table 1 (p28) for a full comparison of symptoms.5,9 Non-IgE-mediated CMPA tends to resolve by the age of three, whereas IgE-mediated CMPA more commonly resolves by the age of five.10 DIAGNOSIS

An allergy focused clinical history and physical examination based on the NICE guidelines for diagnosing food allergy in the under 19s is a crucial part of establishing whether CMPA is present, this usually includes gathering

information on the following:11,7 • the suspected allergen (e.g. cows’ milk); • the history of presenting symptoms (see Table 1) including: age of onset, speed of onset, duration of symptoms, severity of reactions, frequency of reactions, how many organs produced a reaction, locations the reaction has occurred, reproducibility of symptoms, how much of the food causes a reaction; • medication and response to previous treatments; • personal history of atopy (eczema, hay fever, dust allergies, asthma); • family history of atopy; • dietary intake, including cultural factors which affect food choice; • history of infant feeding and weaning if applicable; • history of response to the elimination and reintroduction of foods; • growth and nutritional status.

Just 14 days

can make a difference

Trust Neocate LCP

to provide fast and effective resolution of Cow’s Milk Allergy symptoms

1,2

1. De Boissieu D, Matarazzo P, Dupont C. J Pediatr 1997; 131(5):744-747. 2. Vanderhoof JA, Murray MD, Kaufman S et al. J Pediatr 1997; 131 (5):741-744.

NHD CPD eArticle

Volume 7.20 - 30th November 2017

Table 2: CMP-free infant formulas* (List of formulas valid at the time of publishing this table)

Extensively hydrolysed formula (EHF) e.g. Althera, Nutramigen 1 & 2, Aptamil Pepti 1 & 2, Cow & Gate Pepti Junior, Similac Alimentum, Pregestimil

EHF is the first-line treatment used for mild to moderate CMPA and is tolerated by >90% of those with CMPA. The CMP is broken down using heat and enzymatic treatment into short peptides and tested to be tolerated by 90% of children with a proven CMPA.22,24 Some EHF also contain probiotics, medium-chain triglyceride (MCT) fat and lactose; the exclusion of lactose in CMP-free formulas is no longer advised routinely as lactose is important to aid calcium absorption, promote healthy gut bacteria and may improve palatability of the formula.4,15 The choice of formula depends on the child’s diagnosis and local CCG preference.

Amino-acid formula (AAF) e.g. Neocate LCP, Nutramigen PURAMINO, Alfamino

AAF is totally cows’ milk free and based on amino acids. Although >90% of infants with CMPA tolerate EHF,9,17,18 there are specific indications for AAF, such as:4,9 • when symptoms persist on an EHF; • anaphylaxis; • severe non-IgE mediated CMPA, e.g.eosinophilic oesophagitis; • severe eczema not improving on standard treatment; • faltering growth ; • multiple food allergies; • severe ongoing symptoms in exclusively breastfed in spite of a maternal elimination diet.

Soya-based formula e.g. Wysoy

Soya-based formulas are only suitable for infants over six months. These are more readily available to buy over the counter and may be more palatable for some infants. It is important to trial soya products with caution as between 2-14% of children with IgEmediated allergy and up to 50% of non-IgE-mediated allergy may react to soya as well when they have CMPA.4,19,25

As well as this allergy-focused history, there are validated tests which can be used to test a suspected IgE-mediated CMPA, such as: skin prick tests to check for IgE antibodies in the skin and specific IgE serum assays to test for circulating IgE antibodies.4,9,11 Oral food challenges are the gold standard to confirm diagnosis, especially if there is any uncertainty about this. For IgEmediated reactions, these take place under medical supervision and can be open or blinded.4 Non-IgE-mediated CMPA can be more difficult to diagnose as there are no validated tests to use, therefore diagnosis is based on a combination of an allergy-focused history and a trial elimination diet and ideally a subsequent reintroduction phase to monitor whether symptoms return.11

It is important to note that there are types of complementary and alternative medicines which offer testing for CMPA, such as kinesiology and hair testing, but as these are not medically approved, they have no place in diagnosis of CMPA.11,22 CMPA can be mistakenly diagnosed as lactose intolerance due to an overlap of symptoms (diarrhoea, abdominal pains, cramps, bloating, flatulence and nausea); however, lactose intolerance is a deficiency of the enzyme lactase rather than an allergy to the protein in cows’ milk, therefore a thorough allergy focused history can avoid misdiagnosis.12,23 Some patients may have secondary lactose intolerance as a result of damage to the gut lining when CMPA is untreated; however, this is usually a transient

NHD CPD eArticle

Volume 7.20 - 30th November 2017

Table 3: Food items and ingredients that contain cows’ milk protein4

Butter, butter fat, butter milk, butter oil, casein (curds), caseinates, hydrolysed casein, calcium caseinate, sodium caseinate, cheese, cheese powder, cottage cheese, cows’ milk (fresh, condensed, dried, evaporated, powdered, ordinary infant formulas, UHT, low fat), cream, artificial cream, sour cream, ghee, ice cream, lactalbumin, lactoglobulin, malted milk, some margarines, milk protein, milk powder, skimmed milk powder, milk solids, non-fat dairy solids, non-fat milk solids, milk sugar, whey, hydrolysed whey, whey powder, whey syrup sweetener, yoghurt, fromage frais, lactose

condition as long as a strict cows’ milk protein(CMP) free diet is adhered to.12-13 At the time of writing this article, the updated version of the Milk Allergy in Primary Care (MAP) guideline had not been released; this is called the international Milk Allergy in Primary Care (iMAP) guideline (due to be published on 16th August 2017), as it has been designed to suit an international audience. An updated iMAP six-step milk ladder is also due to be released. ELIMINATING COWS’ MILK PROTEIN

CMP should be completely eliminated from the diet for two to six weeks to see whether the presenting symptoms improve.4,9,11 The NICE guidelines on food allergies in under 19-yearolds highlight that dietetic input is important in order to support with ‘nutritional adequacies, timings of elimination and reintroduction, and follow-up’.11 Breastfeeding mothers are encouraged to continue to breastfeed. but to exclude cows’ milk from their diet, they also need to be assessed as to whether a daily calcium and vitamin D supplement is indicated, bearing in mind that a breastfeeding mother requires 1,250mg of calcium and 10mcg of vitamin D per day.4,9,14 Formula-fed infants need to switch to a hypoallergenic formula24 (see Table 2). It is important to educate breastfeeding mothers, parents and carers of infants of weaning age and older children about interpreting food labels, which foods and ingredients contain cows’ milk protein (see Table 3). It is important to offer alternative food and drinks to ensure a balanced diet, especially in terms of calcium intake, and the duration,

safety and limitations of an elimination diet. It is also crucial to highlight that shop-bought CMPfree milks should be fortified with calcium, vitamin D and B vitamins. Unsweetened CMPfree milks are useful for weaning; however, if there is a concern with faltering growth, then a version with a higher calorie content may be a better choice. Higher calorie dairy-free milks also have an overall nutritional profile which is more similar to full fat cows’ milk and so may be a more suitable choice as a main milk drink from one to two years of age if CMP exclusion is still indicated. Additional high energy high protein dairyfree options in the treatment of faltering growth include: oils, nut butters and dairy free spreads, creams, cheeses, ice creams and puddings. Further nutritional considerations often include general weaning support, minimising reflux, advice on avoiding other allergens where multiple food intolerances occur and aiming to avoid unnecessarily restrictive eating. Information and fact sheets on alternative dairy options can be obtained from the British Dietetic Association (BDA) website: www.bda.uk.com/ As CMPA resolves in the majority of cases, it is important that regular reviews need to take place with a healthcare professional to ensure that the child is developing tolerance to CMPA.4,9 For those with an IgE-mediated CMPA and Food Protein Enterocolitis Syndrome, a wardbased food challenge is needed to test whether tolerance to CMP has developed.4,9 This involves close medical supervision while introducing incremental dosages of cows’ milk.4

NHD CPD eArticle However, for mild to moderate non-IgEmediated CMPA, advice can be given on the gradual reintroduction of cows’ milk using a milk ladder approach; this involves introducing small amounts of products containing wellcooked milk to begin with, as heat treatment alters the protein structure of CMP and reduces allergenicity, and eventually introducing fresh milk if tolerated.9 It is important that parents are advised to continue to include tolerated milk products in their child’s diet and when a step hasn’t been tolerated, to revert to the previous step on the ladder and continue including all foods up to this level, then periodically trying the next step to see if tolerance has been acquired.9 It is best to try reintroductions early in the day to avoid a reaction going unnoticed overnight and the amount of time needed on each step of the milk ladder varies; the MAP milk ladder

Volume 7.20 - 30th November 2017

highlights that this may be one day or one week depending on the individual.9 A milk ladder approach can also be used when a breastfeeding mother is reintroducing CMP into her diet to test for tolerance in her child. From clinical practice, it may be easier to start reintroductions via one route initially rather than introducing CMP to the mother’s diet and the infant’s diet at the same time. CONCLUSION

As CMPA is a nutritionally complex condition, dietitians are central to the management of this, with our involvement spanning from diagnosis through to tolerance development in most cases. Therefore, it is important that we are aware of the full scope of CMPA, so that we can provide the best possible support for the families that we work with.

References 1 World Health Organisation (2007). Global surveillance, prevention and control of chronic respiratory diseases; www.who.int/gard/publications/ GARD%20Book%202007.pdf 2 Venter et al (2013). Diagnosis and management of non-IgE-mediated cows’ milk allergy in infancy - a UK primary care practical guide; www. ncbi.nlm.nih.gov/pmc/articles/PMC3716921/#B1 3 Fiocchi et al (2010). World Allergy organisation diagnosis and rationale for action against cows’ milk allergy (DRACMA) guidelines 4 Luyt et al (2014). BSACI guideline for the diagnosis and management of cows’ milk allergy; www.bsaci.org/guidelines/milk-allergy 5 NICE (2015). Cows’ milk protein allergy in children; https://cks.nice.org.uk/cows-milk-protein-allergy-in-children 6 Caffarelli et al (2010). Cows’ milk protein allergy in children: a practical guide; https://ijponline.biomedcentral.com/ articles/10.1186/1824-7288-36-5 7 Skypala IJ, Venter C, Meyer R, et al. The development of a standardised diet history tool to support the diagnosis of food allergy. Clin.Transl. Allergy 2015;5:7 8 Saarinen (2000). Risk factors and characteristics of cows’ milk protein allergy; http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/saarinen/riskfact.pdf 9 The MAP Guideline available at: http://cowsmilkallergyguidelines.co.uk/.The new iMAP Guidelines will be published on 16th August 2017 10 Saarinen et al (2005). Clinical course and prognosis of cows’ milk allergy are dependent on milk-specific IgE status 11 NICE (2011). Food allergy in under 19s: assessment and diagnosis; www.nice.org.uk/guidance/CG116 12 NHS Choices (2016). Lactose intolerance; www.nhs.uk/Conditions/lactose-intolerance/Pages/Introduction.aspx 13 Shaw and Lawson (2014). Clinical Paediatric Dietetics 4th edition 14 Department of Health (1991). Dietary reference values for food and energy and nutrients for the United Kingdom 15 ESPGHAN (2012). Diagnostic approach and management of cows’ milk protein allergy in infants and children: ESPGHAN GI Committee Practical Guidelines; www.espghan.org/fileadmin/user_upload/guidelines_pdf/Diagnostic_Approach_and_Management_of_Cow_s_Milk.28.pdf 16 Canani (2013). Formula selection for management of children with cows’ milk allergy influences the rate of acquisition of tolerance; www.ncbi. nlm.nih.gov/pubmed/23582142 17 Cafferelli et al (2002). Determination of allergenicity to three cows’ milk hydrolysates and an amino acid-derived formula in children with cows’ milk allergy www.ncbi.nlm.nih.gov/pubmed/12002741 18 European Society of Paediatric Allergy and Clinical Immunology (1993). Hydrolysed cows’ milk formulae: allergenicity and use in treatment and prevention 19 Klemola et al (2002). Allergy to soy formula and to extensively hydrolyzed whey formula in infants with cows’ milk allergy www.ncbi.nlm.nih.gov/ pubmed/11865274 20 Muraro A, Halken S, Arshad SH, et al. EAACI food allergy and anaphylaxis guidelines. Primary prevention of food allergy. Allergy 2014;69:590-601. 21 Grimshaw K, Logan K, O’Donovan S, et al. Modifying the infant’s diet to prevent food allergy. Arch.Dis.Child 2016. 22 Muraro A, Werfel T, Hoffmann-Sommergruber K, et al. EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy. Allergy 2014;69:1008-1025. 23 De Koker CE, Shah N, Meyer R. The differences between lactose intolerance and cow’s milk protein allergy. J Fam.Health Care 2014;24:14-8, 20. 24 Host A, Koletzko B, Dreborg S, et al. Dietary products used in infants for treatment and prevention of food allergy. Joint Statement of the European Society for Paediatric Allergology and Clinical Immunology (ESPACI) Committee on Hypoallergenic Formulas and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition. Arch Dis Child 1999;81:80-84. 25 Agostoni C, Axelsson I, Goulet O, et al. Soy protein infant formulae and follow-on formulae: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 2006;42:352-361. Copyright © 2017 NH Publishing Ltd - All rights reserved. Available for printing and sharing for the use of CPD activities for personal use. Not for reproduction for publishing purposes without written permission from NH Publishing Ltd.

NHD CPD eArticle NETWORK HEALTH DIGEST

Volume 7.20 - 30th November 2017

Questions relating to: Cows’ milk protein allergy in infants. Type your answers below, download and save or print for your records, or print and complete by hand. Q.1

What are the factors involved in the development of cows’ milk protein allergy (CMPA in infants)?

Q.2

Describe the two classifications of CMPA.

Q.3

What information is required in order to diagnosis the presence of CMPA?

Q.4

Explain the validated tests that can be used in the diagnosis of IgE-mediated CMPA.

Q.5

What is the difference between CMPA and lactose intolerance?

Q.6

Explain the first line treatment used for mild to moderate CMPA.

Q.7

What is the advice given to breastfeeding mothers for eliminating CMP?

Q.8

Explain the specific indications for the use of amino-acid formula (AAF).

Q.9

Describe the milk ladder approach for the reintroduction of cows’ milk in the management of CMPA.

Please type additional notes here . . .