Cow s milk protein allergy in children Nicholas Ware UCL Institute of Child Health CPD verifiable Abstract CMPA (Cow s Milk Protein Allergy) is a relatively common condition in infancy that often presents to primary carers with a diverse range of symptoms. Accurate diagnosis, management and engagement with health professionals is essential to optimising outcomes and saving unnecessary expenditure. Cow s milk allergy is the most common cause of death from food related anaphylaxis in children in the United Kingdom; although rare it makes this a significant topic for review and regular re-evaluation. A number of specific algorithms are available to assist general practitioners and paediatricians with this process. Management is usually based on dietary elimination, dietetic support and symptom management. A referral to Hospital services should be made if a diagnosis is in doubt, or if symptoms are severe or poorly controlled. John Apps UCL Institute of Child Health Keywords Cow s milk protein, allergy (CMPA), IgE, lactose intolerance, hydrolysed formula, elimination diet, enteropathy. Colin Michie Department of Paediatrics, Ealing Hospital NHS Trust, London Correspondence: Nicholas Ware Clinical Lecturer in Adolescent Medicine, UCL Institute of Child Health, London, 30 Guilford Street, London, WC1N 1EH Email: nicholasware@doctors. org.uk Introduction Cow s milk is one of the first foods to be introduced to an infant s diet in large volumes, either as a supplement or instead of breast milk. Cow s milk protein (CMP) antigens are also secreted into the breast milk of lactating mothers who ingest cow s milk. Cow s milk protein allergy (CMPA) is defined as an adverse immunological response to CMP and may involve the skin, the gastrointestinal tract and the respiratory system or produce systemic responses. 1,2 Large birth cohorts have been employed to estimate 2-3% of formula fed and 0.5% of purely breast fed infants develop symptoms from adverse reactions to CMP. 3 Other studies suggest higher incidences of 5-15%, the wide range of these estimates reflecting differing diagnostic criteria. 1 Disparity has been identified between parental perceptions of allergy and accurate diagnosis: as a result it is reported that children may be placed on inappropriate and nutritionally incomplete restriction diets. 4 The majority of CMPA patients will present initially to primary care and so it is important that general practitioners and health visitors are well equipped to diagnose and manage CMPA effectively. Adverse reactions to foods are can be divided into immune-mediated reactions (food allergy) and non-immune-mediated reactions (food intolerance) such as lactose intolerance. Allergic responses may be divided into IgE-mediated reactions (type I hypersensitivity, typically of rapid onset) and non-ige-mediated reactions (type IV hypersensitivity with delayed onset). 1,2 Allergic responses are outlined initially in this review. Immune-mediated reactions to cow s milk (cow s milk protein allergy) IgE-mediated food allergy affects between 3% and 6% of children in the developed world with egg allergy and CMPA is the most prevalent. 1 The exact mechanisms of sensitisation to milk are not fully understood but it is thought that it may occur during fetal life through 70 Copyright 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (2): 70 75
maternal CMP ingestion that transfers across the placenta. 1 CMPA can present early in life before the ingestion of CMP therefore. Once CMPA is established in some patients, allergic reactions can be induced by ingestion or alternative routes of exposure including skin contact (such as by kissing) or inhalation of CMP in cooking vapour. 1 IgE-mediated CMP-induced allergic reactions usually occur rapidly following exposure; they display a range of severity. Mild reactions may present with urticaria and angioedema whilst severe reactions can include anaphylaxis with associated cardiovascular collapse. 1 Cow s milk allergy is the most common cause of death from food related anaphylaxis in children in the United Kingdom. 5 CMP can also cause a range of non-ige mediated reactions. These include a number of CMPA syndromes many of which may overlap and include CMP-induced proctocolitis, allergic dysmotility, CMP-induced enteropathy, food protein-induced enterocolitis syndrome, allergic eosinophilic gastroenteropathies and CMP-sensitive eczema (Box 1). 1,2 Non-IgE-mediated CMPA usually presents 24-48 hours after ingestion and therefore can be more difficult to diagnose. 2,3 Clinical features CMPA presents with a wide variety of clinical manifestations from relatively mild to severe or lifethreatening: no symptoms are pathognomonic. Symptoms usually start in the first month of life or within a week of introducing cow s milk formula. 3 In the majority of cases more than one body system is affected, the most frequent being the skin (50-70%), gastrointestinal tract (50-60%), and respiratory system (20-30%). 3 Cutaneous manifestations include atopic dermatitis (Box 2), angioedema (swelling of the lips or eyelids) and urticaria. 1 3 With urticaria it is important to exclude other causes such as other acute infections or drug reactions. Gastrointestinal manifestations include reflux, vomiting diarrhoea, abdominal pain and colic, constipation (with or without perianal excoriation) and blood in the stools. 1,6,7 Rarely CMPA can present with the symptoms and signs of anaemia without any other gastrointestinal symptoms. If left untreated CMPA can lead to growth faltering and failure to thrive due to poor intestinal absorption of nutrients and food aversion. 1,2,6,7 Respiratory manifestations include rhinoconjunctivitis, chronic cough and wheeze. 1 In severe cases anaphylaxis can occur presenting with acute lip and tongue swelling, stridor and respiratory or cardiovascular collapse. This is obviously a life-threatening emergency requiring immediate treatment. How is it diagnosed? A diagnosis of CMPA commences with a detailed history (Box 2) and thorough physical examination. The gold standard for diagnosis is double blind placebo controlled elimination and challenge testing, however this is often not feasible and open testing is frequently Box 1: Common infant presentations of cow s milk allergy. 1,2,6 11 Atopic eczema NICE recommends that any patient with atopic dermatitis who has suffered a previous reaction to foods or has moderate or severe disease despite optimum treatment may merit a diagnosis of food allergy. Gastro-oesophageal reflux There is a well recognised association between gastrooesophageal reflux and CMPA. A trial of CMP elimination should be considered in infants with other features of atopy who do not respond to optimum reflux treatment. Infant colic Two systematic reviews suggest that hypoallergenic formulas may reduce the symptoms of infant colic. However given the risks associated with cow s milk exclusion the significance of this is uncertain, the cost in terms of feed and input from families is great and evidence for how to wean in this situation is thin. Other gastrointestinal symptoms/syndromes CMPA should be considered in all infants with acute and chronic gastrointestinal problems including proctitis, dietary protein enteropathy and enterocolitis, and eosinophilic gastroenteropathy. The exact relationship between CMPA and constipation is controversial. Full descriptions of syndromes are given in the references. 1,6,7,11 used. 12,13 In infants that are exclusively breast-fed, cow s milk must be completely eliminated from the mother s diet. After elimination the diagnosis may be confirmed with a challenge. Challenge should be performed with adequate supervision. For patients with suspected IgE mediated reactions NICE advises against the use of oral food challenges for suspected IgE mediated allergy within the community. 14 In children who have a history of severe reactions or who have specific IgE positive blood test results, challenge should to be done in hospital with adequate resuscitation support available. 2 In children with a history compatible with type I hypersensitivity, specific CMP IgE testing in the circulation (also known as RAST testing) or referral for skin prick testing should be considered. The higher the result, or the larger the wheal the more likely a patient Box 2: Collecting an optimal History: (adapted from). 1,2,14 What is the suspected allergen? Formula vs Breast milk fed? If necessary details of maternal diet Is the allergen typical for age? Nature of exposure? Oral/Skin/Inhalational? Quantity? Setting? What Symptoms? Severity? Temporal relationship of any reaction to allergen exposure? Speed of onset, duration? Reproducibility on repeated exposure? Response to elimination? Cultural/Religious factors affecting diet? Previous history of allergy/atopy (unusual for CMPA) Is there a family history of atopy or allergy? Are there any indicators of alternative diagnoses e.g. recent rotavirus infection suggesting lactose intolerance? Copyright 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (2): 70 75 71
has IgE mediated allergy, though does not indicate the severity. 1 Although negative results largely excludes IgE-mediated CMPA (negative predictive value >95%), they do not exclude non-ige-mediated CMPA and so consideration of the type of allergic reaction is important when interpreting the test results. 2,6,7,13,15 Significantly atopic eczema is frequently non-ige mediated. Patch testing is not currently advised. 1,2,12 A child with severe symptoms or uncertain diagnosis should be referred for specialist evaluation (General Paediatric/ Paediatric Allergy/ Paediatric Gastroenterology/ Dermatology as appropriate). Vandenplas et al have proposed European algorithms for the diagnosis and management of CMPA depending on whether infants are exclusively breast-fed or formula-fed and can help in selecting appropriate investigation pathways. 12 In addition NICE guidelines provide more general guidelines and workflows for food allergies in children and young people. 14 Why might this diagnosis be missed? Diagnosing CMPA can be difficult as the symptoms and signs may mimic other common clinical conditions such as gastroenteritis or eczema. Compliance with suggested treatments is also notoriously challenging. In a large prospective birth cohort study involving 2138 families looking at CMPA and egg allergy, more than a third of children with confirmed allergies had not had the causative agent eliminated from their diets. 4 206 children were perceived by their parents to have a food allergy yet only 54% of them had discussed it with their general practitioner. 4 In cases where parents had initiated an elimination diet for their children without the advice of a doctor, a fifth was inappropriate. 4 As highlighted above CMPA can have severe acute and chronic consequences. Accurate diagnosis and treatment is therefore essential to optimise outcome in children with CMPA or parentallyperceived CMPA. Failure to do this can cause families to resort to their own inappropriate treatments or to seek non-validated tests from other paramedical practitioners. 2 Management The key to management of CMPA is the elimination of CMP from the diet. In breast fed infants this includes CMP elimination from mother s diet and must include all dairy products. The requirement for complete CMP avoidance depends on the nature of the individual child s allergy. While the majority of IgE and non-ige-mediated allergic children will require complete elimination, a proportion may tolerate extensively-heated formula milks where the CMP protein is altered by the high temperature used and no longer causes an allergic reaction. Similarly some breast fed infants will not require complete maternal elimination diets as the level of CMP secreted in the breast milk is of no consequence to the infant. If a maternal elimination diet is required it is important to consider the nutritional needs of the infant and the mother, as the mother (particularly with respect to her calcium intake) is often forgotten in this process. In infants feeding on formula milk a hypoallergenic formula should be used. There are a number of different hypoallergenic formula milks available of which Extensively hydrolysed formulas (EHFs) are the predominant used. Over 90% of CMPA infants will tolerate an EHF whilst between 2% and 10% with IgE-mediated disease continue to react to EHF due to the small amount of milk proteins that still remain. 16 These infants will require amino acid formulas (AAFs) that are composed of free amino acids and are considered to be completely non-allergenic. The choice of a suitable hypoallergenic formula will also be dependent on any comorbidities and the palatability of the formula to an individual infant. Other mammalian, soy or rice milk formulas are not recommended due their high antigenic crossover and anaphylactic reactions have been described in CMPA infants using such milks. 1 Goats milk is also thought to be nutritionally deficient so in the UK it is advised that this should not be used in any child under one year of age. There have been recent concerns on the possible effects of the phyoestrogen content in soya milk, so current recommendations are that soy should only be used for infants over six months of age. 1 Symptoms from CMPA should be also managed accordingly with either topical or systemic treatments (such as emollients and antihistamines) as appropriate. Patients at risk of anaphylaxis need to be given adrenaline pens and extensive education on when and how to use them. 17 In the case of allergic eosiniphilic gastroenteropathies, dietary elimination may be insufficient and other pharmacological treatments required, including antihistamines, steroids, sodium chromoglycate and leukotriene receptor antagonists. Adequate dietetic support is important in the management of CMPA. All hypoallergenic formulas are fortified with vitamins and minerals but many infants will not consume adequate amounts to meet their nutritional requirements and there are often issues with taste. Breastfed infants over six months of age and CMPA infants having less than 500mls of formula per day need to be prescribed a vitamin supplement that contains vitamin D. Whilst most hypoallergenic formulas contain calcium, infants taking low levels of formula without any dairy products may also require calcium supplementation. Elimination diets that are initiated without the advice of an appropriate healthcare professional can cause significant morbidity to the child and the mother through inadequate intake of important nutrients, in extreme cases inappropriate elimination diets has been reported to lead to rickets. 18 Prognosis Both IgE and non-ige-mediated CMPA often resolve during childhood as tolerance develops. Large birth cohort 72 Copyright 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (2): 70 75
studies have shown on follow-up that CMPA usually resolves within the first few years of life, with 60-75% of patients becoming tolerant by two years of age and 84-87% by three years of age. 3 Allergy is more likely to persist in those with IgE-mediated allergy, as are the development of further atopic diseases such as asthma. 3 Regular challenge to determine the development of tolerance is an important aspect of safe management. This is usually delayed until after the first year. 2 Serial skin prick testing and specific serum IgE levels may be used to help guide timing of re-challenge, and in patients who have had severe reactions and continue to have positive tests remove the need for challenge. Following a negative challenge, a normal diet can be gradually re-introduced. Prevention There has been considerable interest and controversy in studies investigating prevention of the development of CMPA. 19 22 A Cochrane review has found limited evidence supporting the use of EHF in preference to cow s milk formula but did not find any benefit compared to breast milk. 21 Updated guidelines from the European Academy of Allergology and Clinical Immunology (SP-EAAC) also supports exclusive breast feeding or the use of extensively hydrolysed formula milks, as well as complete avoidance of solids that contain CMP for the first four to six months of life to reduce the incidence of CMPA developing in high risk infants, (such as those who have a first degree relative with formally diagnosed atopy). 22 This reinforces the current general advice of exclusive breast feeding for the first six months of live. Lactose intolerance: Non-immunemediated sensitivity to cow s milk Lactose intolerance may be mistaken for non-igemediated CMPA by patients, parents and doctors - it is important to distinguish between the two. Lactose is a disaccharide sugar in cow s milk which is broken down by an enzyme lactase in the small intestine. Almost all infants have some lactase activity. Primary lactose intolerance is a genetically inherited inability to process lactose effectively and is more evident in those over six months of life and is more common in those of Afro-Caribbean ethnicity. Far more common is secondary lactose intolerance where lactase expression is lost due to inflammation or structural damage to the intestinal villi (enteropathy). This commonly follows gastroenteritis (particularly rotavirus) and other enteropathies such as coeliac disease. It is usually reversible and effective treatment of the causative condition usually results in a full recovery. There is also a form of congenital lactose intolerance where intestinal lactase is completely absent. This is extremely rare, presenting with faltering growth and persistent diarrhoea, and treatment requires lifelong lactose elimination. Lactose intolerance usually presents with excess flatus, abdominal distension, abdominal pain, explosive diarrhoea, nausea and perianal excoriation. Symptoms are limited to the gastrointestinal tract (in contrast to CMPA which usually affects >1 system). 3 The diagnosis is made by initiating an elimination diet and observing for resolution of symptoms. Assessing stools for reducing sugars and a hydrogen breath test are particularly useful diagnostic tools in older children. However these tests but are frequently positive in those with the condition as infants. 1 Further Reading 1. du Toit G, Meyer R, Shah N, et al. Identifying and managing cow s milk protein allergy. Arch Dis Child Educ Pract Ed. 2010; 95(5): 134 44. 2. Suggested European guidelines for diagnosis and management of CMPA: Vandenplas Y, Brueton M, Dupont C, et al. Guidelines for the diagnosis and management of cow s milk protein allergy in infants. Archives of Disease in Childhood 2007; 92(10): 902 8. 3. In depth review of gastrointestinal manifestations of CMPA: Sampson HA, Sicherer SH, Birnbaum AH. A technical review on the evaluation of food allergy in gastrointestinal disorders. American Gastroenterological Association. Gastroenterology 2001; 120(4): 1026 40. Useful Websites 1. http://guidance.nice.org.uk/cg116/ 2. www.cks.nhs.uk 3. www.nhs.uk/conditions/food-allergy/pages/diagnosis.aspx. 4. www.milk.co.uk - from the dairy council- provides lots of info on milk and related nutrition in general 5. www.allergyuk.org - a charity - includes information sheets etc. References 1. du Toit G, Meyer R, Shah N, et al. Identifying and managing cow s milk protein allergy. Arch Dis Child Educ Pract Ed. 2010; 95(5): 134 44. 2. Apps JR, Beattie RM. Cow s milk allergy in children. BMJ 2009; 339: b2275 b2275. 3. Høst A. Frequency of cow s milk allergy in childhood. Ann. Allergy Asthma Immunol. 2002; 89(6): 33 7. 4. Eggesbø M, Botten G, Stigum H. Restricted diets in children with reactions to milk and egg perceived by their parents. J. Pediatr 2001; 139(4): 583 7. 5. Macdougall CF, Cant AJ, Colver AF. How dangerous is food allergy in childhood? The incidence of severe and fatal allergic reactions across the UK and Ireland. Archives of Disease in Childhood 2002; 86(4): 236 9. 6. Sampson HA, Sicherer SH, Birnbaum AH. AGA technical review on the evaluation of food allergy in gastrointestinal disorders. American Gastroenterological Association. Gastroenterology 2001; 120(4): 1026 40. 7. Sicherer SH. Clinical aspects of gastrointestinal food allergy in childhood. Pediatrics. 2003; 111(6): 1609 16. 8. NICE. Atopic eczema in children [Internet]. [cited 2011 Oct 27];Available from: http://www.nice.org.uk/guidance/index.jsp?action =byid&o=11636. 9. Lucassen PLBJ, Assendelft WJJ, Gubbels JW, et al. Effectiveness of treatments for infantile colic: systematic review. BMJ 1998; 316(7144): 1563 8. 10. Garrison MM, Christakis DA. A systematic review of treatments for infant colic. Pediatrics 2000; 106(1 Pt 2): 184 90. 11. Allen KJ, Davidson GP, Day AS, et al. Management of cow s milk protein allergy in infants and young children: An expert panel perspective. Journal of Paediatrics and Child Health 2009; 45(9): 481 6. 12. Vandenplas Y, Brueton M, Dupont C, et al. Guidelines for the diagnosis and management of cow s milk protein allergy in infants. Archives of Disease in Childhood 2007; 92(10): 902 8. 13. Heine RG, Elsayed S, Hosking CS, et al. Cow s milk allergy in infancy. Curr Opin Allergy Clin Immunol 2002; 2(3): 217 25. 14. NICE. CG116 Food allergy in children and young people: quick reference guide [Internet]. [cited 2011 Oct 28];Available from: http://guidance.nice. org.uk/cg116/quickrefguide/ pdf/english. Copyright 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (2): 70 75 73
15. Caffarelli C, Baldi F, Bendandi B, et al. Cow s milk protein allergy in children: a practical guide. Italian Journal of Pediatrics 2010; 36:5. 16. Høst 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(1): 80 4. 17. McLean-Tooke APC, Bethune CA, Fay AC, et al. Adrenaline in the treatment of anaphylaxis: what is the evidence? BMJ 2003; 327(7427): 1332 5. 18. Medeiros LCS, Speridião PGL, Sdepanian VL, et al. [Nutrient intake and nutritional status of children following a diet free from cow s milk and cow s milk by-products]. J Pediatr (Rio J) 2004; 80(5): 363 70. 19. Muraro A, Dreborg S, Halken S, Høst A, et al. Dietary prevention of allergic diseases in infants and small children. Part III: Critical review of published peer-reviewed observational and interventional studies and final recommendations. Pediatr Allergy Immunol 2004; 15(4): 291 307. 20. Greer FR, Sicherer SH, Burks AW. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics 2008; 121(1): 183 91. 21. Osborn D, Sinn J. Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants [Internet]. In: The Cochrane Collaboration, Sinn J, editors. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2006 [cited 2011 Oct 27]. Available from: http://www2.cochrane.org/reviews/ en/ab003664.html. 22. Høst A, Halken S, Muraro A, et al. Dietary prevention of allergic diseases in infants and small children. Pediatric Allergy and Immunology 2008; 19(1): 1 4. The Diabetic Eye Course in association with master class - cpd course The Diabetic Eye Course Format: The course consists of a full day workshop involving lectures and practical demonstrations of techniques Fees: 99.00 + Vat A one-day course for GPs & Optometrists Tuesday 4th September 2012 74 Institute of Health Sciences www.ipcauk.org 73 Newman Street, London, W1T 3EJ Tel: +44 (0) 207 6373544 Fax: +44 (0) 207 580 7166 Email: info@ipcauk.org Copyright 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (2): 70 75
Online Verifiable Learning for CPD Clinical Focus Primary Care 2012; Vol 6: No 2 Accredited Learning for CPD go to www.ipcauk.org & follow the links to Clinical Focus on the Home page If you participate in this activity you may place your verifiable performance in your appraisal folder. You are advised to follow the instructions carefully: 1. CPD activity is only available online. 2. Please complete the CPD activity for the articles PRIOR to reading them 3. Redo the CPD activity for the articles after reading the issue and assess the gain in your knowledge 4. The CPD activity related to the articles is classified as verifiable educational activity 5. On completion of the activity a downloadable certificate can be printed and included in an appraisal folder. Cow s milk protein allergy in children 1. In Cow s Milk Protein Allergy body system is most commonly affected? Select only ONE option. a. Gastrointestinal b. Respiratory c. Cardiovascular d. Skin e. Musculoskeletal 2. Which ONE of these Cow s Milk Protein Allergy syndromes is most likely to require pharmacological treatment? a. CMP-induced proctocolitis b. Allergic dysmotility c. CMP-induced enteropathy d. Food protein-induced enterocolitis syndrome e. Allergic eosiniphilic gastroenteropathy 3. In an exclusively breast fed infant with atopic eczema how long should a maternal Cow s Milk Protein elimination diet be carried out for? a. 1 week b. 2 weeks c. 4 weeks d. 6 weeks e. Should not be carried out at all 4. What is the dose of I.M. adrenaline for a 2 month old infant having an anaphylactic reaction? a. 50mcg b. 100mcg c. 150mcg d. 300mcg e. 500mcg 5. Which ONE of these foods provides the best alternative source of vitamin D for a mother on an elimination diet? a. One large egg b. One tablespoon of fortified margarine c. One ready-to-eat cereal box d. One cup of whole fat milk e. One tablespoon of cod liver oil f. One cup of orange juice fortified with vitamin D g. 3.5 ounces of cooked liver 6. Which ONE of these formulas is an amino acid formula and therefore suitable for those infants who react to extensively hydrolysed formulas? a. Nutramigen b. Alimentum c. Pregestimil d. Neocate e. SMA gold 7. When do vitamin supplements need to be prescribed in infants with Cow s Milk Protein Allergy? Select only ONE option. a. When having <300mls formula per day b. When having <500mls formula per day c. When having <700mls formula per day d. When exclusively breast fed at 6 months age e. When exclusively breast fed at 9 months age 8. What dose of abidec is appropriate for a 6 month old infant? a. 0.2mls daily b. 0.3 mls daily c. 0.5 mls daily d. 0.6 mls daily e. 1ml daily Copyright 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (2): 70 75 75