Issue 127 cows milk protein allergy in infants

PAEDIATRIC

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 has a history, or family history, of atopy; for example, eczema or asthma in the infant, or a family history of eczema, For full article asthma, hay fever or food allergies.5 references please email There is evidence that breastfed info@ infants have a lower prevalence of CMPA, networkhealth with about 7% of formula or mixed-fed group.co.uk infants developing CMPA compared to about 0.5% of exclusively breastfed This article infants. Furthermore, breastfed infants has been Peer are reported to have less severe reactions Reviewed by if they do develop CMPA.3,6 The primary factor involved in the development Dr Rosan Meyer, of food allergy in infancy is genetic, Paediatric Research Dietitian, with a parental atopic history (asthma, Honorary Senior eczema and hayfever) significantly Lecturer, Imperial increasing the risk.8 Research has also identified contributing environmental College, London factors, which include smoking during and Chair of the BDA Food Allergy pregnancy, the infant’s gut microbiome and Intolerance which may be affected by route of birth Specialist Group.

(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; whereas it is thought that non-IgEmediated 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 Non-IgEmediated 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

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REFERENCES: 1. Sampson HA et al. J Pediatr 1991;118(4):520-525. 2. Data on file.

Abbott Laboratories Ltd., 2013 (Similac Alimentum case studies). 3. Borschel MW and Baggs GE. T O Nutr J 2015;9:1-4. 4. Koo WWK et al. J Am Coll Nutr 2006;25(2):117-122.

IMPORTANT NOTICE: Breastfeeding is best for babies, and is recommended for as long as possible during infancy. Similac Alimentum is a Food for Special Medical Purposes and should be used under the supervision of a healthcare professional.

Date of preparation: July 2015 RXANI150117

THIS IS HUGE After months of coping with the sleepless worry and heartbreaking cries of her cow’s milk allergy, suddenly, a little moment like this doesn’t seem so little after all.

• Proven efficacy – hypoallergenic and has been shown to relieve symptoms1,2 • Proven to be well tolerated – 96% of infants tolerated Similac Alimentum3 • Palm oil and palm olein oil free – supports calcium absorption and bone mineralisation4 SIMILAC ALIMENTUM. FOR BIG LITTLE MOMENTS.

PAEDIATRIC 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

• 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.

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 28

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about this. For IgE-mediated 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 condition as long as a strict cows’ milk protein(CMP) free diet is adhered to.12-13

7 Red Flag Indicators for when to use an AAF 1. INFANTS SYMPTOMATIC ON AN eHF1-3 2. SEVERE GI SYMPTOMS1-4 3. FALTERING GROWTH2,3,5 4. MULTIPLE FOOD ALLERGIES1,5 5. SEVERE ECZEMA1-3,5 6. INFANTS SYMPTOMATIC ON BREAST MILK1-3,5 7. ANAPHYLAXIS3,4

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Neocate: The UK’s No. 1 Amino Acid-Based Formula References: 1. Koletzko S, Niggemann B, Arato A, et al. J Pediatr Gastroenterol Nutr 2012; 55(2):221-229. 2. Venter C, Brown T, Shah N, et al. Clinical and Translational Allergy 2013; 3(1):23. 3. Ludman S, Shah N, Fox A. BMJ 2013; 347-355. 4. Fiocchi A, Brozek J, Schünemann H, et al. WAO J 2010; 3:57-161. 5. Hill DJ, Murch SH, Rafferty K et al. Clin Exp Allergy 2007; 37(6):808-822. 6. De Boissieu D, Matarazzo P, Dupont C. J Pediatr 1997; 131(5):744-747. 7. Vanderhoof JA, Murray MD, Kaufman S et al. J Pediatr 1997; 131 (5):741-744.

Neocate is a Food for Special Medical Purposes for use under medical supervision, after consideration of all feeding options including breastfeeding. eHF=Extensively Hydrolysed Formula; AAF=Amino Acid-Based Formula; GI= Gastro Intestinal

For more information visit www.neocate.co.uk

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

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-year-olds 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, www.NHDmag.com August/September 2017 - Issue 127

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PAEDIATRIC 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

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 ward-based 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 30

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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 well-cooked 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 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.

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For further information contact our Healthcare Professional Helpline on 0800 996 1234 or visit www.eln.nutricia.co.uk/cma References: 1. Verwimp JJ et al. Eur J Clin Nutr. 1995;49 (Suppl1):S39-S48. 2. Giampietro PG et al. Pediatr Allergy Immunol. 2001;12:83-86. 3. Arslanoglu S et al. J Biol Regul Homeost Agents.

2012;26:49-59. 4. Campden BRI conducted a blind taste test using a home usage design with a sample of 100 Dieticians and General Practitioners from 16.11.2016 to 09.12.16. Participants rank ordered the extensively hydrolysed formula (EHF) milk samples (Danone Aptamil Pepti, Abbott Similac Alimentum, Nestle SMA Althera and Mead Johnson Nutramigen LGG) in term of overall liking and answered a series of attitudinal questions in relation to the impact of EHF’s palatability on infants with CMA and their families. The results from the ranking showed that the Danone Aptamil Pepti sample was liked signifi cantly more than all the other three samples tested. * A home usage test assessment was carried out between 16/11/16 and 9/12/16 on the 4 products indicated for cows’ milk allergy from birth and included 100 UK healthcare professionals.

IMPORTANT NOTICE: Aptamil Pepti 1 & 2 are foods for special medical purposes for the dietary management of cows’ milk allergy. They should only be used under medical supervision, after full consideration of the feeding options available including breastfeeding. Aptamil Pepti 1 is suitable for use as the sole source of nutrition for infants from birth, and/or as part of a balanced diet from 6-12 months. Aptamil Pepti 2 is suitable for babies over 6 months as part of a mixed diet.

17-026 / June 2017