Pathway for the diagnosis and treatment of Cow s Milk Allergy in Children

Pathway for the diagnosis and treatment of Cow s Milk Allergy in Children This pathway is intended for use by both primary and secondary care. Herefordshire NHS promotes breastfeeding as the best form of nutrition for infants and this should be promoted and supported wherever possible. Almost all children with CMA can continue to be successfully breastfed with modification of the mother s diet under the direction of a dietitian. Version 2017-1.4 ID - Digital copy available here: http://nww.herefordshire.nhs.uk/paediatrics/primarycareguidelines/tabid/3241/default.aspx

Table of Contents Page 1. Definition & Background 3 2. Immediate Cow s Milk Allergy (IgE Mediated) 3 3. Delayed Cow s Milk Allergy (non-ige Mediated) 3 4. Lactose Intolerance 4 5. Diagnosis of Cow s Milk Allergy in Primary Care 4 6. Diagnosis of Cow s Milk Allergy in Secondary Care 5 7. Differential diagnoses 5 8. Treatment in Primary Care 6 9. Treatment in Secondary Care 8 10. Specialist Cow s Milk Free Formulas 8 11. Alternatives to Specialist Cow s Milk Free Formulas 10 12. Stopping Specialist Formulas 11 13. Indications for referral to secondary care 12 14. Indications for dietetic involvement 12 15. Secondary care follow-up 13 16. Milk Desensitisation 13 Appendix 1 FPIES 14 Appendix 2 - Home Challenge (MAP) 15 Appendix 3 - The Milk Ladder (MAP) 17 Notes 19 References - 20 Approved Wye Valley Trust Approved Herefordshire CCG Medicines Optimisation Group Date Version Control Version 1.0 December 2016 The definitive version of this pathway & appendices are available on the website: www.wvt.nhs.uk, www.herefordshireccg.nhs.uk Page 2 of 20

1. Definition & Background Cow s Milk Allergy (CMA) may be defined as a reproducible adverse reaction of an immunological nature induced by cow s milk protein. Cow s Milk Allergy can be classified into either immediate-onset, or delayed-onset according to the timing of symptoms and organ involvement. CMA affects 2-4% of infants. It commonly presents in infancy and most affected children present with symptoms by 6 months of age. Onset is rare after 12 months. Most children will outgrow their allergy by school age. Patients who are allergic to Cow s Milk have either: 1. Immediate reactions which are typically IgE mediated (type I reactions), or 2. Delayed reactions which are typically non-ige mediated 2. Immediate Cow s Milk Allergy (IgE Mediated) Immediate allergic reactions to milk usually occur within minutes following the ingestion of small amounts of cow s milk. Presentation varies in severity ranging from mild symptoms in the majority to, rare life-threatening anaphylaxis. Reactions can involve the skin, respiratory tract, gastrointestinal tract, and cardiovascular system (Table 1.). Table 1. Signs of Immediate CMA (IgE mediated) Urticaria (Hives) Angio-oedema Eczema exacerbation Vomiting Diarrhoea - Evidence of Anaphylaxis (rare) Bloody stools Gastro-oesophageal reflux Abdominal pain Rhinitis Wheeze Stridor Difficulty breathing Hypotension/shock Irritability 3. Delayed Cow s Milk Allergy (non-ige Mediated) Delayed reactions are typically non-ige mediated and can present with gastrooesophageal reflux, eczema, diarrhoea, and/or constipation (table 2). These usually present several hours (up to 72 hours) after ingestion of larger volumes of milk. Delayed reactions are not life-threatening except in the case of FPIES**. Table 2. Signs of Delayed CMA (non-ige mediated) Gastro-oesophageal reflux Eczema exacerbation Diarrhoea/constipation Bloody stools Feeding Problems Irritability - Colicky ** Food Protein-Induced Enterocolitis Syndrome (FPIES) Appendix 1 FPIES is a rare, severe non-ige mediated allergy to food (most often milk) affecting the gastrointestinal tract. Classic symptoms of FPIES include profound vomiting, diarrhoea, and dehydration a few hours after allergen ingestion. These symptoms can lead to severe lethargy, change in body temperature and blood pressure, and require hospitalisation and specialist care. Page 3 of 20

4. Lactose Intolerance Primary lactose intolerance is exceedingly rare in infants of all nationalities. It is most commonly seen in children of non-european decent after their 3 rd year of life. Secondary or Transient lactase deficiency can present at any age and is usually reversible with treatment of the underlying cause (typically gastroenteritis). Lactose free milks should be used in these cases for 6 weeks before ordinary milks and formulas are slowly reintroduced. They are ineffective in CMA. Children with lactose intolerance are not allergic to milk and should not be confused with CMA. 5. Diagnosis of Cow s Milk Allergy in Primary Care Delayed CMA: A detailed allergy-focused history and examination will most often identify children with delayed CMA, and differentiate them from those children who have immediate CMA Resolution of symptoms on a dairy elimination diet over 2-4 weeks, followed by return of symptoms on a home challenge to dairy remains the diagnostic gold standard (Appendix 2). (blood & skin allergy tests are not useful tests in assessing delayed CMA) Immediate CMA: action should ordinarily be to refer to secondary care for further investigations (skin prick and/ or blood testing). Immediate CMA (IgE mediated) Delayed CMA (non-ige mediated) Typical History Typical History Positive Skin Prick tests Positive home challenge test Raised Specific IgE to Milk Negative Skin Prick tests Negative Specific IgE to Milk Table 3. Features of the diagnosis of IgE & non-ige CMA Diagnostic tests of questionable value: Reducing substances can help to confirm a diagnosis of lactose intolerance but has no value in CMA Applied Kinesiology, Vega testing and serum specific IgG testing (York Test) have no value in identifying Cow s Milk Allergy Page 4 of 20

6. Diagnosis of Cow s Milk Allergy in Secondary Care A detailed allergy focused history and examination (NICE) will most often differentiate children with Immediate CMA from those delayed CMA. Delayed CMA: Diagnostic assessment is as for Primary care Immediate CMA: The diagnosis of IgE-mediated food allergy is based on the combination of clinical history, examination, and allergy tests such as Skin Prick Tests (SPT) and/or specific IgE (sige) tests. Very occasionally an oral food challenge (OFC) in hospital is indicated. Fig. 1. Algorithm for the diagnosis of IgE-mediated cow s milk allergy in hospital. 1. A typical history is the immediate onset of symptoms, 2. Skin prick test (SPT). 3. Clinical allergy may be found in young infants with an SPT weal diameter of 2 mm particularly if there is associated flare. 4. Not recommended as a screening test. (BSACI guideline, 2014) 7. Differential diagnoses The differential diagnosis is very wide because symptoms and signs associated with CMA are non-specific (table 4). Table 4. Differential Diagnosis CMA Colic Eczema Constipation Urinary tract infection Gastro-oesopahgeal reflux Other food allergy Faltering Growth Lactose intolerance Page 5 of 20

8. Treatment in Primary Care The MAP Guideline The mainstay of treatment for CMA is the avoidance of cow s milk protein and other mammalian milks (e.g. goat, sheep and buffalo products) whilst maintaining nutritional adequacy by introducing suitable alternatives or supplementing nutrients. Immediate CMA: Action should ordinarily be to refer to secondary care for further investigations and shared management Delayed CMA: These children can usually be managed in primary care. Standard treatment is principally the avoidance of all dairy products, milk substitution, and occasionally dietary supplementation after a home challenge has confirmed the diagnosis (Appendix 2). Breast feeding mothers should almost always be encouraged to continue to breast feed their infants. Breastfeeding mothers may require a milk free diet and calcium supplementation. The approach to treatment is detailed in the MAP guideline included in this pathway on the next page. See figure 2. on page 7. (MAP Guideline) NB: HOME CHALLENGE TO MILK see Appendix 2. Do not normally arrange repeat prescriptions for a specialist Cow s Milk Free formulas unless the diagnosis of delayed CMA is confirmed by challenge. Exceptions to the management of children with delayed CMA in primary care are rare and include children with faltering growth, ongoing symptoms despite dairy exclusion, and in those where there is diagnostic uncertainty (table 5.). Table 5. Indications for referral to secondary care in Delayed CMA Diagnostic uncertainty Faltering growth Does not respond to first line treatment Severe eczema where multiple food allergies are suspected Food Protein-Induced Enterocolitis Syndrome (FPIES) Page 6 of 20

Figure 2: MAP Guildeline Page 7 of 20

9. Treatment in Secondary Care Immediate CMA: These children may be at risk of developing anaphylaxis and usually require allergy testing, and careful milk reintroduction sometimes in hospital. Management includes strict avoidance of cow s milk protein as for children with delayed CMA. Breast fed infants should continue to be breast fed. Maternal dairy avoidance is only necessary when infants, who are exclusively breast fed, develop symptoms of CMA when dairy is included in the maternal diet. In formula fed infants the 1 st line treatment will be replacement with a suitable extensively hydrolysed formula (EHF), unless there are indications for an Amino Acid Formula (AAF) table 6. Delayed CMA: These children can usually be managed in primary care. Exceptions include children with faltering growth, ongoing symptoms despite dairy exclusion, and in those where there is diagnostic uncertainty (Table 5). 10. Specialist Cow s Milk Free Formulas For CMA infants who are unable to receive breast milk a hypoallergenic formula needs to be selected. The European Society Paediatric Hepatology and Nutrition and the European Society of Paediatric Allergy and Clinical Immunology stipulate that hypoallergenic formulas must be tolerated by 90% of infants with CMA. Two types of formula fit these criteria: 1. Extensively Hydrolysed Formula (EHF) Based on cow s milk, but the milk protein has been extensively hydrolysed to reduce the allergenicity. 90% of children with CMA will respond to a EHF, and it is usually the first line formula in the treatment of both delayed and immediate CMA. 2. Amino Acid Formula (AAF) The protein sources are pure synthetic amino acids and it is completely free of cow s milk protein. AAF is considered less allergenic than EHF and is indicated in infants reacting to EHF and those with specific indicators (table 6.). Table 6: Indications for AAF Previous anaphylaxis to cow s milk Reactions to one or more EHF Faltering Growth Severe symptoms and multiple food allergies Breast fed infants who react when the mother is on a dairy free diet should move to a AAF on cessation of breast feeding. The mother may wish to trial further dietary exclusions prior to stopping breast feeding. Refer for dietetic input. Page 8 of 20

Choosing the correct formula (Table 7.): All specialist formulas have an unpleasant taste and may take several days for an infant to accept them. Please contact a dietitian if further advice is required. Table 7. 1 st Line Formula (EHF) - 90% of children will respond to a EHF NB: ALL FORMULAS ARE LISTED IN ALPHABETICAL ORDER NOT BY PREFERENCE Lactose-free formulas: Nutramigen LGG 1 (<6months) 400g tin Nutramigen LGG 2 (>6months*) 400g tin Similac Alimentum (suitable from birth*) 400g tin Lactose containing formulas*: Althera* 450g tin (suitable from birth*) Aptamil Pepti* 1 (<6 months) 400g and 800g tins Aptamil Pepti 2 (>6 months*) 400g and 800g tins *Children with CMA will not react to Lactose 2 nd Line Formula (AAF) - See: Indications for AAF above NB: ALL FORMULAS ARE LISTED IN ALPHABETICAL ORDER NOT BY PREFERENCE Where a AAF formula is initiated in secondary care then this should be continued in primary care as directed. Formulas Include: Alfamino 400g tin (suitable from birth*) Neocate LCP for 0 12 months 400g tin ( Neocate Active > 12months*) PurAmino 400g tin (suitable from birth*) The constituents will vary between individual Formulas. This may occasionally influence both an infant s clinical tolerance and palatability of that formula. Refer to paediatric dietitian correspondence when available before issuing prescriptions. Ordinarily refer infants that fail to respond to 1 st line formula. * By 2 years of age prescription formulas should normally no longer be required PRESCRIBING THE MILK: 1. For breastfed infants formulas may not be required: Continue breast feeding. Exclude dairy and mammalian milks from the mother s diet for 2-4 weeks if an exclusively breastfed infant is symptomatic. If breastfeeding mothers do not wish to or are unable to follow a milk free diet, an AAF may be needed. If symptoms persist despite maternal dairy avoidance then discuss with, and refer to, a dietitian. Further dietary exclusions may be trialled, or alternatively an AAF formula may be prescribed after discussion with a dietitian. Breastfeeding mothers who require a milk free diet should have a daily calcium supplement (usually 1000mg) and Vitamin D supplement (10mcg/400IU). 2. For Formula fed infants: Initially prescribe 2 tins of 1 st choice EHF formula as an ACUTE prescription in primary care (1 x 400g tin will last ~ 3days) as 1 st choice formula may not be tolerated. If symptoms do not improve after 2-4 weeks, then prescribe 2 tins 1 st choice AAF and review progress. Determining the number of powdered milk tins to prescribe - PTO Page 9 of 20

Determining the number of powdered milk tins to prescribe: N.B. Prescribe 2 tins initially to confirm acceptability as an ACUTE prescription Table 8. Number of Tins to prescribe in 1 month < 6 months 6-12 months > 12 months 13 x 400g/450g tins 7-13 x 400g/450g tins 7 x 400g/450g tins OR OR OR 6 x 900g tins 3-6 x 900g tins 3 x 900g tins Notes: These are approximate requirements but if an infant is requiring substantially fewer tins then refer to dietitian to review the nutritional adequacy of the diet. Ensure the amount of formula prescribed is appropriate for age of the infant. The highest requirement is usually just before weaning. Breastfeeding mothers may require a milk free diet and supplemental calcium and Vitamin D EHF and AAF prescription milks should only be used under medical supervision First prescriptions should be for only 2 tins on ACUTE prescription initially until compliance / tolerance is established (wastage is frequently reported locally). However more tins may need to be prescribed if the trial is over a holiday period e.g. Christmas Refer to the recent correspondence with the clinician & dieticians when available Advise parents to allow 24-48 hours for pharmacies to obtain stock. A longer time may be required over bank holidays. Repeat dispensing arrangements with a community pharmacy may be helpful for some patients. Parents should be made aware that the formulas contain sweeteners that increase the risk of dental decay. Advice is to clean baby s teeth twice per day i.e. in the morning and after last feed at night. Remind patients to follow the advice given by the manufacturer regarding making the feed and the safe storage of the feed once opened. The manufacturer s advice on making up bottles of Nutramigen LGG does not comply with current government advice. Care must be taken as they recommend using water at less than 70 degrees Celsius. 11. Alternatives to Specialist Formulas Soya products should not be prescribed to infants (< 1 year) unless advised by a paediatric consultant or dietitian due to: 1. the high incidence of soya allergy in infants allergic to cows milk protein (10-35%), and the 2. presence of phytoestrogens in soya formulas. Soya should never be prescribed in infants under 6 months of age unless on specialist advice e.g. for galactosaemia. Soya formula is not suitable for vegans since the Vit D is derived from an animal source. Alpro-Soya 1+ is suitable for vegan infants >12 months and available in supermarkets to purchase. Soya drink, with added calcium, is suitable for children over 1 year of age. Rice Milk is not suitable for children under four and half years due to its arsenic content. Goat and other animal milks have similar proteins to cow s milk and therefore are not recommended for infants with CMA. Almond, oat, & coconut milks are not recommended due to their relatively poor nutritional value, but can be used in complementary feeding. Page 10 of 20

12. Stopping Specialist Formulas It is appropriate to try reintroduction of dairy from 12 months of age in children with delayed CMA. This can be performed at home when there have been only mild symptoms on exposure to milk, and there has been no reaction in the past 3 to 6 months. Use a milk ladder for home reintroduction. Cow s Milk Allergy usually resolves by school age, often in a child s second or third year of life. Consequently dairy elimination is followed by careful reintroduction of milk in the second year of life or later in most children with delayed CMA (non-ige mediated). Many children will initially tolerate well-cooked (baked) milk products, then lightly cooked milk products, and finally uncooked fresh milk. Reintroduction is done in a step wise fashion using a milk ladder (Appendix 3). Figure 3. The Milk Ladder (Appendix 3) By 2 years of age prescription formulas should normally no longer be required. Please refer to dietitian to assess diet if still on prescription formula. Review and consider stopping cow s milk free formula prescription where the infant is able to eat or drink dairy e.g. cow s milk, cheese, yoghurt, ice cream, custard, chocolate, cream, butter, ghee. Children who have had severe symptoms may need reintroduction performed under hospital supervision and should be referred to secondary care (Table 9). Table 9: When to consider Hospital Reintroduction of Dairy Any previous moderate to severe reaction (incl. FPIES) Immediate (IgE-mediated) Milk allergy Reactions to trace exposure Regular asthma preventative treatment Multiple or complex allergies Parents unable to understand protocol Page 11 of 20

13. Indications for referral to secondary care (Table 9.) Most children with delayed CMA can be safely managed in primary care and can be expected to outgrow their CMA by the time they go to school. They are not at risk of anaphylaxis on accidental exposure to cow s milk or on attempts at re-introduction to milk via the milk ladder except in those children with FPIES. Table 9. Indications for referral to secondary Care Diagnostic uncertainty Immediate CMA (IgE-mediated) Faltering growth Does not respond to first line treatment Severe eczema where multiple food allergies are suspected Food Protein-Induced Enterocolitis Syndrome (FPIES) 14. Indications for Dietetic Involvement Dietary advice should only be given by health professionals with appropriate competencies. Training sessions will be organised to give health visitors the necessary competencies Table 10: Children should be referred when: Faltering growth it is important to monitor length as well as weight More than one food allergy includes breast feeding mothers Infants with IgE mediated allergy Infants on AAF Infants who are not taking adequate amounts of infant formula, or Where there are concerns about the nutritional content of a child s diet Page 12 of 20

15. Indications for Secondary Care Follow-up 1. Most children with immediate CMA (IgE mediated) who require ongoing skin prick testing (SPT) or serum specific IgE testing. Decreasing cow s milk sensitivity reflected in smaller weal size on SPT suggests the development of tolerance, and is typically a prerequisite to a home/hospital oral milk challenge in children with immediate CMA. 2. Children with delayed CMA who require onward referral to secondary care (table 5), and in whom milk tolerance has not yet developed. 3. Children with additional health concerns that merit hospital follow up. 16. Milk Desensitisation Whilst most children will spontaneously grow out of their cow s milk allergy by 5 years of age, a significant proportion will remain allergic. Traditionally management of these individuals has been limited to dairy exclusion with replacement by dietary alternatives. Oral tolerance induction (OTI) as a treatment for cow s milk allergy offers a promising management option in individuals where it persists beyond an age at which it is expected to resolve. It involves the administration of increasing doses of cow s milk during an induction phase, starting with a dose small enough not to cause a reaction and continuing to a target dose or until the treated individual s symptoms preclude further dose increments. This is followed by a maintenance phase with regular intake of the maximum tolerated amount of cow s milk. There are risks of adverse reactions associated with OTI with symptoms occurring as frequently as in one in six doses. There are still a number of unanswered questions requiring further research. OTI is not currently recommended for routine clinical practice. Patients that may benefit from OTI in Herefordshire are referred to tertiary centres that offer OTI. 17. References Luyt, D., Ball, H., Makwana, N., Green, M.R., Bravin, K., Nasser, S.M. and Clark, A.T. (2014) BSACI guideline for the diagnosis and management of cow s milk allergy, Clinical & Experimental Allergy, 44(5), pp. 642 672. doi: 10.1111/cea.12302. NICE (2011) Food allergy in under 19s: Assessment and diagnosis. Available at: https://www.nice.org.uk/guidance/cg116 (Accessed: 3 March 2017). Venter, C., Brown, T., Shah, N., Walsh, J. and Fox, A.T. (2013) Diagnosis and management of non-ige-mediated cow s milk allergy in infancy - a UK primary care practical guide, Clinical and Translational Allergy, 3(1), p. 23. doi: 10.1186/2045-7022-3-23. Page 13 of 20

APPENIDX 1. FPIES (Food Protein Induced Enterocolitis Syndrome) Food protein induced enterocolitis syndrome (FPIES) is an unusual type of food allergy. It is much less common than IgE mediated food allergy, and usually only occurs in babies and very young children. FPIES is caused by an allergic reaction to a food which causes inflammation of the small and large intestine. It differs from normal food allergy as: It is usually a delayed reaction Symptoms are normally limited to the gut (there is no skin rash or swelling) It is not caused by IgE antibodies It is not associated with anaphylaxis, so adrenaline is NOT used to treat the reaction What are the symptoms? In general, the reaction begins around 2 4 hours after eating the trigger food. The child develops profuse vomiting, frequently followed by diarrhoea or loose stools which can last for several days. Occasionally a shorter time frame may be seen. In the most severe FPIES reactions, vomiting and diarrhoea can cause serious dehydration. These children may become pale, floppy, have reduced body temperature and/or blood pressure during a reaction. These children may be mistaken as having an infection, as their blood tests may show an increased white cell count which is often seen in infection. FPIES is not caused by IgE antibodies, so children experiencing reactions do not develop itchy swollen skin, rashes or facial swelling. However, it is possible for a child with FPIES to also have other allergies including food allergies which do involve IgE antibodies. Sometimes, children with FPIES have more mild reactions, and if they continue to eat the trigger foods, the allergy can result in poor growth. Which Foods can Trigger FPIES? The most common triggers are cows milk (dairy) and soy. However, almost any food can cause an FPIES reaction, including rice, cereals such as oats, certain vegetables (frequently from the legume family) and meats such as chicken and turkey. Some children have FPIES to more than one food protein. Diagnosis There is no allergy test which can confirm a diagnosis of FPIES. This can make FPIES difficult to diagnose. Your doctor may recommend an oral food challenge when the history is not clear, or if foods from a similar food group are tolerated into the diet. Treatment The only treatment for FPIES is to avoid the trigger food. Your doctor will advise as to how to alter the diet to achieve this, and you may receive advice from a dietitian if the foods to be removed include a major food group. There is no specific treatment for a child during an FPIES reaction. However, they often respond to intravenous (IV) fluids, due to the dehydration. There is no role for the use of adrenaline devices in the management of FPIES. Does FPIES Resolve? Most children outgrow FPIES by the time they are about three to four years of age. The best way to determine whether a child has outgrown their FPIES is for them to be challenged to the food in hospital under close supervision. Page 14 of 20

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