CMA Management - Neocate

When is early intervention with an AAF recommended?

This section contains a background to CMA. It provides information on managing CMA by appropriate assessment and diagnosis according to relevant guidelines, and advice on when to use an amino acid-based formula for infants and children with CMA.

CMA is a distressing condition for infants and their parents/carers:

CMA is an immune mediated reaction to the proteins within cow’s milk and is one of the most common food allergies affecting 2-5% of infants.¹ Up to 40 000 babies a year in the UK may develop CMA.²

Most cases of CMA present in infancy and the majority of children will grow out of the allergy by the age of 5 years.

CMA can be complex to diagnose as many infants will often present with two or more symptoms frequently seen in infancy.

The most common symptoms are of dermatological, gastrointestinal and respiratory origin

Symptom complexity can delay diagnosis

Data from the UK shows:⁶

It takes an average of 3.6 months from initial GP visit to formal diagnosis

Delayed diagnosis prolongs the distress for infants and their parents and has the potential to impact on infants’ growth and development.

CMA imposes a substantial burden on the NHS

Patients with CMA had a mean of 18.2 clinician visits and cost the NHS an estimated £25.6 million during the first 12 months after initial presentation:⁶

The initial aim of management is prompt and accurate diagnosis, removal of cow’s milk protein from the diet whilst ensuring the nutritional requirements of the infant/child are met using suitable specialist formulas and dietary modification

References

Fiocchi A, Brozek J, Schünemann H, et al. WAO J 2010;3:57-161
2011/12 UK Birth Rate, Office of National Statistics, ONS http://www.ons.gov.uk/ons/taxonomy/index.html?nscl=Population Number of births in UK 2012 = 812,970
Meyer R, Schwarz, C & Shah, N. Current Allergy & Clinical Immunology 2012;25(1):10-17.
Høst A. Ann Allergy Asthma Immunol 2002;89 (6 suppl 1):33-37.
Koletzko S, Niggemann B, Arato A, et al. J Pediatr Gastroenterol Nutr 2012; 55(2):221-229.
Sladkevicius E, Nagy E, Lack G et al. Resource implications and budget impact of managing cow milk allergy in the UK. J Med Econ 2010;13(1):119-28.

Next In This Section CMA Assessment Next Section Case studies

NICE have produced a guideline (CG 116) to aid in the diagnosis and assessment of food allergy in children and young adults. The first steps are initial recognition, an assessment of the symptoms and the allergy focused history. The guideline includes a series of algorithms, which have been reproduced with the permission of NICE for use on this website.

Initial recognition

History and examination

Consider referral to secondary or specialist care

Initial recognition
Consider Food Allergy in a child or young person who:

has one or more signs and symptoms of possible food allergy (pay particular attention to persistent symptoms that involve different organ systems) or
has had treatment for atopic eczema, gastro-oesophageal reflux disease or chronic gastrointestinal symptoms (including chronic constipation) but their symptoms have not responded adequately.

History and Examination
Do not offer allergy tests without first taking an allergy-focused clinical history.

A healthcare professional with the appropriate competencies (a GP or other healthcare professional) should take an allergy-focused clinical history tailored to the presenting symptoms and age of the child or young person using the questions below.

The clinical history should include:

any personal history of atopic disease (asthma, eczema or allergic rhinitis)
any individual and family history of atopic disease (asthma, eczema or allergic rhinitis) or food allergy in parents or siblings
details of any foods that are avoided and why
an assessment of presenting symptoms and other symptoms that may be associated with food allergy, including:
age at first onset
speed of onset
duration, severity and frequency
setting of reaction (for example, at school or home)
reproducibility of symptoms on repeated exposure
what food and how much exposure to it causes a reaction

cultural and religious factors that affect the child’s diet
who has raised the concern and suspects the food allergy
what the suspected allergen is
the child’s feeding history, including age of weaning and whether they were breastfed or formula-fed (if the child is currently being breastfed, consider the mother’s diet)
details of previous treatment, including medication, for the presenting symptoms, and the response to this
any response to the elimination and reintroduction of foods
physical Examination

Based on the clinical history, physically examine the child or young person, paying particular attention to:

growth and physical signs of malnutrition
signs indicating allergy-related comorbidities (atopic eczema, asthma and allergic rhinitis)

Consider referral to secondary or specialist care
Based on the allergy-focused clinical history, consider referral to secondary or specialist care in any of the following circumstances.

The child or young person has:

faltering growth in combination with one or more of the gastrointestinal symptoms described in signs and symptoms of possible food allergy
not responded to a single-allergen elimination diet
had one or more acute systemic reactions
had one or more severe delayed reactions
confirmed IgE-mediated food allergy and concurrent asthma
significant atopic eczema where multiple or cross-reactive food allergies are suspected by the parent or carer

There is:

persisting parental suspicion of food allergy (especially in children or young people with difficult or perplexing symptoms) despite a lack of supporting history
strong clinical suspicion of IgE-mediated food allergy but allergy test results are negative
clinical suspicion of multiple food allergies

National Institute for Health and Care Excellence (2011) Adapted from CG 116 Food allergy in children and young people. Diagnosis and assessment of food allergy in children and young people in primary care and community setting. London: NICE. Available from www.nice.org.uk/CG116 Reproduced with permission.

Next In This Section Diagnosis Next Section Case studies

CMA can be classified according to whether the allergic reaction is an IgE mediated (within 2 hours) or a non IgE mediated (delayed, chronic) response. The NICE guideline helps determine the type of allergy and outlines the tests that should be used to confirm the diagnosis.

Once an allergy is suspected NICE recommends that an elimination diet should be tried for 2 to 6 weeks. The allergen should then be reintroduced to confirm diagnosis. NICE also recommends that the advice of a dietitian with appropriate competencies should be sought to assist with nutritional adequacies, timings of elimination and reintroduction, and follow-up.

The algorithms found below have been reproduced with the permission of NICE.

Once the diagnosis of the CMA has been confirmed, including the type of allergy (IgE or non IgE), a management plan can be established.

Testing for food allergy

Testing for IgE-mediated food allergy: skin prick test for specific IgE antibodies Testing for non-IgE-mediated food allergy: elimination test

Consider referral to secondary or specialist care

Testing for food allergy
Alternative diagnostic tools not recommended.

Do not use the following alternative diagnostic tests in the diagnosis of food allergy:

vega test
applied kinesiology
hair analysis

Do not use serum-specific IgG testing to diagnose food allergy.

Testing for IgE-mediated food allergy: skin prick test for specific IgE antibodies
Offer a skin prick test and/or blood tests for specific IgE antibodies to the suspected foods and likely co-allergens.

Base choice of test on:

the clinical history and
the suitability, safety for, and acceptability to the child or young person (or their parent or carer) and
the available competencies of the healthcare professional to undertake the test and interpret the results

Tests should only be undertaken by healthcare professionals with the appropriate competencies to select, perform and interpret them.

Only undertake skin prick tests where there are facilities to deal with an anaphylactic reaction.

Interpret test results in the context of clinical history.

Do not use atopy patch testing or oral food challenges to diagnose IgE-mediated allergy in primary care or community settings.

Testing for non-IgE-mediated food allergy: elimination test
Try eliminating the suspected allergen (normally for between 2-6 weeks), then reintroduce. Seek advice from a dietitian with appropriate competencies about nutritional adequacies, timings of elimination and reintroduction, and follow-up.

Taking into account socioeconomic, cultural and religious issues, offer information on:

what foods and drinks to avoid
how to interpret food labels
alternative sources of nutrition to ensure adequate nutritional intake
the duration, safety and limitations of an elimination diet
oral food challenge or reintroduction procedures, if appropriate, and their safety and limitations

If allergy to cow’s milk protein is suspected, offer:

food avoidance advice to breastfeeding mothers
information on appropriate hypoallergenic formula or milk substitute to mothers of formula-fed babies

Seek advice from a dietitian with appropriate competencies.

Consider referral to secondary or specialist care
Based on the allergy-focused clinical history, consider referral to secondary or specialist care in any of the following circumstances.

The child or young person has:

faltering growth in combination with one or more of the gastrointestinal symptoms described in signs and symptoms of possible food allergy
not responded to a single-allergen elimination diet
had one or more acute systemic reactions
had one or more severe delayed reactions
confirmed IgE-mediated food allergy and concurrent asthma
significant atopic eczema where multiple or cross-reactive food allergies are suspected by the parent or carer

There is:

persisting parental suspicion of food allergy (especially in children or young people with difficult or perplexing symptoms) despite a lack of supporting history
strong clinical suspicion of IgE-mediated food allergy but allergy test results are negative
clinical suspicion of multiple food allergies

National Institute for Health and Care Excellence (2011) Adapted from CG 116 Food allergy in children and young people. Diagnosis and assessment of food allergy in children and young people in primary care and community setting. London: NICE. Available from www.nice.org.uk/CG116 Reproduced with permission.

Next In This Section Management Next Section Case studies

CMA is managed by excluding cow’s milk protein from the diet.

Breast feeding is always the preferred way to feed an infant. If an infant is being breast fed, the mother needs to follow an exclusion diet with the support of the dietitian to ensure that the maternal diet is adequate. Calcium and Vitamin D supplements are recommended.

Should the mother need to provide top ups to breast milk, the use of an amino acid based formula is recommended in CMA. The ranges of B-lactoglobulin (BLG) levels and peptide sizes of cow’s milk protein in breast milk are similar to those in an eHF, therefore reaction to these in breast milk are likely to then also occur with an eHF.¹

Formula fed infants will need to be provided with a replacement hypoallergenic formula, either an extensively hydrolysed or amino acid formula.

It is important to understand:

Up to 10% of infants with uncomplicated CMA and up to 40% of infants with more complex allergy may be intolerant to an eHF.²

AAF formulas were found to be effective where symptoms persist (even if their intensity has decreased) with an eHF.

There are specific times where the use of an amino acid formula is indicated.

1

Infants still reacting to an eHF^1,2,3,4

2

Anaphylaxis^3,4,6

3

Faltering Growth^2,3,4

4

Severe Eczema^1,2,3

5

Multiple Food Allergies^1,8

6

Symptoms whilst on breast milk^1,2,8

7

Severe Gastrointestinal Symptoms^1,2,3,6

Infants still reacting to an eHF^1,2,3,4

Symptoms not fully resolved on an eHF

Up to 10% of infants with uncomplicated CMA
Up to 40% of infants with more complex CMA
Infants who don't settle and continue to have some symptoms after 2 to 4 weeks on one eHF, even if the intensity of symptoms has decreased
Infants whose symptoms do not fully resolve should be changed to an AAF:
2-4 weeks iMAP⁵
2-8 weeks BMJ

Anaphylaxis^3,4,6

Anaphylactic reactions are the most severe form of allergic reactions
Common symptoms are throat-swelling, itchy rash and low blood pressure
Life-threatening anaphylactic reactions to cow's milk are rare. but can occur
AAFs are most suitable for anaphylaxis to cow's milk as the risk of a reaction is removed^4,5

Faltering Growth^2,3,4

Optimal management of a food allergy is important because the velocity of growth in infancy is substantially higher than at any other age
Faltering growth and weight loss does not always occur as a result of CMA, therefore a child with normal growth should not be disregarded when considering a diagnosis of CMA⁷
UK data shows that children with food allergies are more underweight than the general population, and this is linked to the number of foods excluded in their diets⁷
There does seem to be a trend toward higher failure of an eHF in patients with non-IgE-mediated gastrointestinal CMA⁸ along with ongoing growth faltering possibly related to persistent unnoticed inflammation of the gastrointestinal tract and/or the skin increasing nutrient requirements⁴
Evidence shows that even if an infant is clinically symptom free, catch up growth is more optimal on an AAF and therefore should be used in the presence of faltering growth^9,10
Guidelines recommend the use of an AAF for all infants with CMA that also present with faltering growth^2,4

Severe Eczema^1,2,3

Eczema is the skin manifestation of a multi-system disease and can present as an immediate reaction or a delayed reaction
There is a strong association between infant eczema and food allergy and this is positively associated with the severity of the eczema
NICE guidelines recommend to consider a food allergy in infants with moderate to severe eczema, not controlled by optimum management, particularly if this is associated with gut dysmotility
NICE recommends offering a 6-8 week trial of a hypoallergenic formula in place of cow's milk for bottle fed infants < 6 months with moderate to severe eczema not controlled by optimal management
Greater vigilance when selecting a hypoallergenic formula may be required in infants with both severe skin and gastrointestinal symptoms²
Guidelines recommend that an AAF is most suitable for infants with severe eczema who are breastfed (BSACI)^2,11
An AAF should be used for infants who have severe eczema if symptoms persist on an eHF or the infant has faltering growth⁴

Multiple Food Allergies^1,8

Infants with proven reactions to other food proteins (in addition to cow's milk) may have the condition multiple food protein allergy (MFPA)
There is strong evidence to support the use of an AAF in infants with MFPA - 12 papers have specifically looked at the efficacy of Neocate in MFPA
When a number of foods are eliminated from the diet of the multiple food allergic child, it becomes more challenging to meet full nutritional requirements. An AAF should be used if the infant has faltering growth⁴
Infants with MFPA may take longer to tolerate an eHF¹² and if symptoms persist on an eHF an AAF should be used⁴

Symptoms whilst on breast milk^1,2,8

Breast feeding is always the preferred way to feed an infant, however exclusively breast fed babies can also develop CMA due to cow's milk protein in the maternal diet transferring through breast milk⁶
For exclusively breastfed babies, the mother should be put on an exclusion diet under dietetic supervision⁵
The ranges of B-lactoglobulin (BLG) levels and peptide sizes of cow's milk protein in breastmilk are similar to those in an eHF. If the infant reacts to these peptides in breastmilk it is more likely they will react to an eHF²
An AAF is indicated in infants:
requiring a nutritional supplement/ “top up” formula in addition to a maternal exclusion diet
where the mother cannot follow an exclusion diet
where an eHF has not achieved symptom resolution or the infant has faltering growth

Severe Gastrointestinal Symptoms^1,2,3,6

Eosinophilic Oesophagitis (EoE):

Criteria required for diagnosis¹⁴
Symptoms of oesophageal dysfunction
Eosinophilic inflammation localised to the oesophagus, with at least 15 eosinophils/high-power field (hpf) in oesophageal mucosal biopsy specimens
Exclusion of other recognised causes of oesophageal eosinophilia, including proton pump inhibitor-responsive oesophageal eosinophilia (PPI-REE)
Management approaches for EoE involves a combination of medication, elimination diets and dilation
Guidelines strongly support the use of an AAF first line for EoE^1,2,6,11,4
The use of an AAF has been reported to induce remission in 88%-96% of children with EoE
Rapid symptom improvement and lack of side effects with nutritional management make an AAF a beneficial option for the management of
EoE

Severe Gastrointestinal Symptoms:

Severe delayed gastrointestinal symptoms (e.g enteropathies, unresponsive rectal bleeding and FPIES)
GORD, unresponsive to treatment
An AAF should be used in the above conditions if symptoms persist on an eHF or the infant has faltering growth⁴
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 AT. BMJ 2013;347-355
4. Meyer R, Groetch M, Venter C. J Allergy Clin Immunol Pract 2017.09.003
5. Venter C, Brown T, Meyer R et al.Clinical and Translational Allergy 2017,7: 26. August 2017.
6. Fiocchi A, Brozek J, Schünemann H, et al. WAO J 2010;3:57-161
7. Meyer R, De Koker C, Dziubak R et al. J Hum Nutr Diet 2013 (Aug): 1-9
8. Hill DJ, Murch SH, Rafferty K et al. Clin Exp Allergy 2007;37(6):808-822
9. Niggemann B, Binder C, Dupont C et al. Pediatr Allergy Immunol 2001;12(2):78-82
10. Isolauri E, Sütas Y, Makinen-Kiljunen S et al. J. Pediatr 1995;127(4):550-557
11. Luyt D et al. Clinical and Experimental Allergy 2014;44:642-672
12. de Boissieu D, Dupont C. J Pediatr 2002;141(2):271-273
13. Fiocchi A, Brozek J, Schünemann H, et al. WAO J 2010;3:57-161
14. Liacouras C et al. American Journal of Gastroenterology 2014;109:515-520

Breast feeding provides the best nutrition for babies. Neocate is intended for bottle-fed infants and is a Food for Special Medical Purposes (FSMPs) and must be used under medical supervision. eHF=Extensively Hydrolysed Formula; CMA= Cow's Milk Allergy; AAF=Amino Acid-Based Formula; GI= Gastro Intestinal

Next In This Section CMA Overview Next Section Case studies

Next In This Section CMA Overview Next Section

Next In This Section Next Section

Symptom complexity can delay diagnosis

CMA imposes a substantial burden on the NHS

References

Initial recognition

History and Examination

Consider referral to secondary or specialist care

Testing for food allergy

Testing for IgE-mediated food allergy: skin prick test for specific IgE antibodies

Testing for non-IgE-mediated food allergy: elimination test

Consider referral to secondary or specialist care

Infants still reacting to an eHF1,2,3,4

Symptoms not fully resolved on an eHF

Anaphylaxis3,4,6

Faltering Growth2,3,4

Severe Eczema1,2,3

Multiple Food Allergies1,8

Symptoms whilst on breast milk1,2,8

Severe Gastrointestinal Symptoms1,2,3,6

Eosinophilic Oesophagitis (EoE):

Severe Gastrointestinal Symptoms:

References

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Infants still reacting to an eHF^1,2,3,4

Anaphylaxis^3,4,6

Faltering Growth^2,3,4

Severe Eczema^1,2,3

Multiple Food Allergies^1,8

Symptoms whilst on breast milk^1,2,8

Severe Gastrointestinal Symptoms^1,2,3,6