What is the best formula for a milk protein allergy

CMPA affects about 7% of formula-fed babies but only about % of exclusively breast-fed babies, who also tend to own milder reactions. Exclusive breast-feeding may also protect babies from developing an allergy to cow’s milk protein after they are weaned[4].

There are a number of diverse proteins in cows milk: there are five protein components in each of the casein and whey fractions of milk. A kid can be allergic to one or more components within either group.

CMPA is more likely in children who own other atopic conditions such as asthma, eczema or hay fever, or if shut family members own those conditions.

The presence of atopic eczema is a predictor for sensitisation to common food allergens. The earlier the eczema starts and the more severe it is, the higher the risk of food allergy[5].

If there are other food allergies, it is more likely that CMPA will persist into later childhood.

Some work has been done looking at the development of food allergies and whether this can be prevented by feeding infants at risk with hydrolysed formula. However, the results own so far not been clear[6, 7].


Differential diagnosis

With such a wide range of symptoms that can be caused by CMPA, the differential diagnosis is extensive, and includes other food allergies, non-food allergies such as pollen, animal dander, other gastrointestinal disorders, pancreatic insufficiency such as in cystic fibrosis, and infections — eg urinary tract infection.


Management [10]

Allergen avoidance

The management of CMPA generally consists of avoidance of the allergen.

If CMPA is the cause of the symptoms then they should resolve within two weeks of stopping cow’s milk.

If the kid is formula-fed, they can be given extensively hydrolysed milk formula such as Nutramigen®, Aptamil Pepti® or Pepti Junior®. These are based on cow’s milk but the proteins are broken below into smaller peptides that are less likely to trigger an allergic reaction.

Babies who own CMPA may own their growth and development impaired by the disorder; however, hydrolysed formula is shown to provide balanced nutrition and to restore normal growth and development[12, 13].

If the symptoms persist on hydrolysed formula but a suspicion of CMPA remains, then attempt an amino acid formula.

These include Nutramigen AA® and Neocate LCP®. Hydrolysed milks are cheaper and are also generally better tolerated, although the flavour and tolerability varies[14].

If the kid is breast-fed and the mom wishes to continue breast-feeding, she must eliminate milk and milk products from her diet. This will include checking ingredients for anything derived from milk, such as casein, whey and lactose. The mom should make certain she is still getting adequate calcium in her diet. It is recommended that she be offered calcium and vitamin D tablets; however, calcium can also come from tinned fish, pulses, almonds, kale, oranges and soya products such as soya milk and tofu[8].

Babies who are being weaned, and older children with persisting CMPA, will need to follow a cow’s milk-free diet as above.

Parents must be advised about how to check the ingredients of processed foods for milk-derived constituents. Children should be referred to a paediatric dietician for advice about maintaining a balanced diet while excluding allergens.

Alternative milks

Soya formulas own been prescribed in the past for CMPA but soya is also a common allergen, so this is no longer routinely advised. About % of children allergic to cow’s milk will also react to soya. Soya milk also contains isoflavones which own a feeble oestrogenic activity.

Other milks, such as pea, oat or coconut, may be used after the age of 2 years, depending on the child’s nutritional status and any other allergies they may own.

A brand fortified with calcium should be used if available. Rice milk is not recommended for children aged under years.

If the symptoms of CMPA persist into older childhood or beyond then patients need to continue to avoid milk and milk products. The proteins in goat’s milk and other mammal milks which may be available are almost identical to those found in cow’s milk, so those are not suitable substitutes. It is significant to maintain an adequate calcium intake. Children who are avoiding cow’s milk for allergy reasons should be referred to a paediatric dietician for specialist advice.

Challenge test

The prognosis of CMPA is excellent with a remission rate of approximately % at 1 year, % at 2 years and % at 3 years[15].Children can own a challenge test every months to see if they are capable to tolerate milk.

It may take several days for the reaction to show, particularly for non-IgE allergy.

The challenge test can be carried out in stages, according to the ‘Milk Ladder’[16]. This is a hierarchy of milk-containing foods, beginning with those least likely to cause a reaction and gradually moving towards being capable to drink a glass of milk. In baked form, such as muffins, cakes or malted milk biscuits, cow’s milk is less allergenic and may be tolerated sooner than unbaked milk.

There is some evidence that including cooked milk in the diet may hasten the resolution of allergy to non-cooked milk[17, 18].

If the kid has had IgE type reactions, particularly if they own been severe, then a challenge test should be carried out under shut supervision.

New treatments

Immunotherapy, in which children are given a gradually increasing dose of milk over a period of several months, is one option which has been tried for children with persisting severe allergy.

The results own been extremely promising, although a Cochrane review concluded that further studies of higher quality were necessary before it can be recommended without reservation[19].


Diagnosis[8]

Allergic reactions can be immunoglobulin E (IgE)-mediated reactions or non-IgE-mediated reactions. Cow’s milk proteins can cause reactions of either type or both together, which can make them hard to diagnose.

IgE-mediated reactions

IgE-mediated reactions trigger histamine release and happen within two hours of milk being consumed. They include skin reactions such as itching, erythema, urticaria and acute angio-oedema, most commonly of the face.

There can be abdominal symptoms such as colicky pain, nausea, vomiting and diarrhoea. Respiratory symptoms can be upper or lower respiratory tract: nasal itching, sneezing, rhinorrhoea, congestion, cough, chest tightness or wheeze.

It is extremely rare for cow’s milk to trigger an anaphylactic reaction. Antihistamines can be used to treat the symptoms. Allergic reactions may be more severe in people with asthma, particularly if the asthma is poorly controlled[9].

This type of allergy can be diagnosed with a skin prick test or a blood test (specific IgE, previously known as RAST). If this type of allergy is suspected, refer the kid to a paediatrician who will arrange for the test to be done in hospital.

Non-IgE-mediated reactions

Non-IgE-mediated reactions happen hours or days after consuming milk.

Skin reactions such as atopic eczema are common, as well as itching and erythema. Abdominal symptoms include colicky pain (including infantile colic), reflux, blood or mucus in stools, constipation or diarrhoea. There may be lower respiratory tract symptoms such as cough, wheeze, breathlessness or chest kid may be pale and tired, and growth may be faltering.

The best way to establish if cow’s milk is causing these symptoms is to exclude it from the diet. There should be an improvement in symptoms within two weeks.


Lactose intolerance[20]

Many people confuse lactose intolerance with CMPA.

Lactose intolerance is an inability to digest lactose, due to an inadequate production of the digestive enzyme lactase.

It is generally a condition of older childhood and adulthood. Worldwide it is extremely common, although it is less prevalent in northern European races. It is unusual for babies and young children to be intolerant of lactose, although they do fairly commonly develop a transient lactose intolerance following an episode of gastroenteritis.

People with a lactose intolerance can often consume products such as yoghurt and cheese in which the lactose has been altered and they may be capable to own little amounts of milk without symptoms. They can generally tolerate lactose-free milk.

Clinical Editor’s comments (October )
Dr Hayley Willacy recommends the recently released international Milk Allergy in primary care guideline[1].

The guideline includes updated recommendations on presentation and recognition of cow’s milk allergy (CMA); diagnosis; management of mild-to-moderate confirmed non-IgE-mediated CMA within primary care; suspected severe non-IgE-mediated CMA and referral. A number of additional resources own been developed alongside the guideline to support parents and carers, including an initial factsheet for parents; a home reintroduction protocol to confirm diagnosis; a milk ladder and milk ladder recipes.

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  • Miraglia Del Giudice M, D'Auria E, Peroni D, et al; Flavor, relative palatability and components of cow's milk hydrolysed formulas and amino acid-based formula.

    Ital J Pediatr. Jun doi: /s

  • Neocate (SHS)

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  • Bloom KA, Huang FR, Bencharitiwong R, et al; Effect of heat treatment on milk and egg proteins allergenicity. Pediatr Allergy Immunol. Dec25(8) doi: /pai Epub Dec

  • Rice milk

  • Liao SL, Lai SH, Yeh KW, et al; Exclusive breastfeeding is associated with reduced cow's milk sensitization in early childhood. Pediatr Allergy Immunol. Aug25(5) doi: /pai

  • Host A, Halken S; Cow's milk allergy: where own we come from and where are we going? Endocr Metab Immune Disord Drug Targets. Mar14(1)

  • Agostoni C, Terracciano L, Varin E, et al; The Nutritional Worth of Protein-hydrolyzed Formulae.

    Crit Rev Food Sci Nutr. (1) doi: /

  • Vandenplas Y, Koletzko S, Isolauri E, et al; Guidelines for the diagnosis and management of cow's milk protein allergy in infants. Arch Dis Kid. Oct92(10)

  • Alfaré (Nestlé)

  • Amino acid formulas

  • Boyano-Martinez T, Garcia-Ara C, Pedrosa M, et al; Accidental allergic reactions in children allergic to cow's milk proteins. J Allergy Clin Immunol. Apr(4) doi: / Epub Feb

  • Vandenplas Y; Lactose intolerance. Asia Pac J Clin Nutr. Suppl 1:S doi: /apjcns

  • Partially hydrolysed cows milk-based (eg, Karicare SensiKare [Nutricia], NAN HA [Nestlé])

  • Venter C, Brown T, Meyer R, et al; Better recognition, diagnosis and management of non-IgE-mediated cow's milk allergy in infancy: iMAP-an international interpretation of the MAP (Milk Allergy in Primary Care) guideline.

    Clin Transl Allergy. Aug doi: /sy. eCollection

  • Extensively hydrolysed formulas

  • Boyle RJ, Ierodiakonou D, Khan T, et al; Hydrolysed formula and risk of allergic or autoimmune disease: systematic review and meta-analysis. BMJ. Mar i doi: /bmj.i

  • Soy formulas

  • Other preparations

  • Yeung JP, Kloda LA, McDevitt J, et al; Oral immunotherapy for milk allergy. Cochrane Database Syst Rev. Nov CD doi: /CDpub2.

  • Lactose-free cows milk-based (eg, Karicare De-Lact, Digestelact [Nutricia], S LF [Wyeth])

  • A2 milk (A2 Australia)

  • Osborn DA, Sinn J; Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants.

    Cochrane Database Syst Rev. Oct 18(4):CD

  • Oat milk

  • Hill DJ, Hosking CS; Food allergy and atopic dermatitis in infancy: an epidemiologic study. Pediatr Allergy Immunol. Oct15(5)

  • Formulas

  • Vandenplas Y, De Greef E, Devreker T; Treatment of Cow's Milk Protein Allergy. Pediatr Gastroenterol Hepatol Nutr. Mar17(1) doi: /pghn Epub Mar

  • Pepti-Junior (Nutricia)

  • Ludman S, Shah N, Fox AT; Managing cows' milk allergy in children.

    BMJ. Sep f doi: /bmj.f

  • Dupont C, Hol J, Nieuwenhuis EE; An extensively hydrolysed casein-based formula for infants with cows' milk protein allergy: tolerance/hypo-allergenicity and growth catch-up. Br J Nutr. Apr (7) doi: /SX. Epub Mar

  • Cows milk-based (including anti-regurgitation)

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  • Amino acid formulas

  • Other preparations

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  • EleCare (Abbott)

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research-article

CPJXXX/Clinical PediatricsMousan and Kamat

Article Clinical Pediatrics , Vol.

55(11) ­– © The Author(s) Reprints and permissions: DOI: /

Cow’s Milk Protein Allergy Grace Mousan, MD1, and Deepak Kamat, MD, PhD1

Abstract Cow’s milk protein allergy (CMPA) is a common condition encountered in children with incidence estimated as 2% to % in the first year of life. Formula and breast-fed babies can present with symptoms of CMPA. It is significant to accurately diagnose CMPA to avoid the consequences of either under- or overdiagnosis. CMPA is classically categorized into immunoglobulin E (IgE)- or non-IgE-mediated reaction that vary in clinical manifestations, diagnostic evaluation, and prognosis. The most commonly involved systems in patients with CMPA are gastrointestinal, skin, and respiratory.

Evaluation of CMPA starts with excellent data gathering followed by testing if indicated. Treatment is simply by avoidance of cow’s milk protein (CMP) in the child’s or mother’s diet, if exclusively breast-feeding. This article reviews the definition, epidemiology, risk factors, pathogenesis, clinical presentation, evaluation, management, and prognosis of CMPA and provides an overview of diverse options for formulas and their indication in the treatment of CMPA. Keywords cow’s milk, protein, allergy, breast-feeding, formula feeding, Allergic colitis, elimination diet, oral challenge, extensively hydrolyzed formula, amino-acid based formula

Introduction Cow’s milk protein allergy (CMPA) is common in infants.

The symptoms suggestive of CMPA may be found in 5% to 15% of infants.1 However, CMPA is a clinical diagnosis and there is no laboratory test that is diagnostic. Infants who are fed cow’s milk–based formula as well as those who are exclusively breast-fed can develop CMPA.2 CMPA in exclusively breast-fed babies is thought to be due to β-lactoglobulin of cow’s milk that is found in human milk 4 to 6 hours after maternal consumption of cow’s milk.3

Definition Cows’ milk allergy or cow’s milk protein allergy is an immune reaction to proteins found in cow’s milk.4 Milk proteins can either be directly ingested by drinking cow’s milk–based formula or passed through breast milk.

Casein and whey proteins are generally the culprits. CMPA can be immunoglobulin E (IgE) mediated or non–IgE mediated. The World Allergy Organization definition for CMPA is “hypersensitivity reaction brought on by specific immunologic mechanisms to cow’s milk.”4 CMPA should be differentiated from cow’s milk intolerance where the previous is an immune mediated reaction while the latter is generally due to lactase deficiency which is rare in infants except following

gastrointestinal infections.5 Table 1 summarizes diagnostic criteria for CMPA according to Host and Halken1 and for allergic colitis per Fiocchi et al.6

Epidemiology The incidence of CMPA during first year of life is estimated to be 2% tp % while the prevalence of CMPA in breast-fed infants is %,10,11 and it is the most common food allergy in children younger than 3 years,13 Prevalence of CMPA decreases to less than 1% in children 6 years or older According to a Danish cohort study, 54% of CMPA is due to IgE-mediated and 46% is due to non-IgE-mediated immune response A large prospective study from Israel showed that only % of the general population develops isolated rectal bleeding due to CMPA

Misdiagnosis of CMPA It is significant to recognize the importance of diagnosing CMPA correctly in infants because misdiagnosis 1

Children’s Hospital of Michigan, Detroit, MI, USA

Corresponding Author: Grace Mousan, Children’s Hospital of Michigan, Beaubien Boulvard, Detroit, MI , USA.

Email: [email protected]

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Mousan and Kamat

Table 1. Summary of diagnostic criteria for CMPA according to Host and Halken1 and for allergic colitis per Fiocchi et al.6 Diagnostic Criteria for CMPA

Diagnostic Criteria for Allergic Proctocolitis

1. Elimination diet should result in resolution of symptoms 2. Recurrence of the exact same symptoms with the oral challenge 3. Other causes of symptoms love lactose intolerance or gastrointestinal infections are ruled out

1.

Presence of rectal bleeding in an baby with adequate weight and height parameters 2. Exclusion of infectious causes of colitis

leads to unnecessary elimination diet in infants and breast-feeding mothers. Prevalence of a genuine food allergy in general is less than what is perceived by parents,18 In a study from Norway, 35% of children younger than 2 years were labeled by their parents with having a reaction to food (most commonly milk) Majority of infants who get misdiagnosed with CMPA present within the first 3 months of life with nonspecific manifestations typically involving a single system most commonly gastrointestinal or skin.

Factors that were found to be associated with mislabeling as baby having CMPA are atopic dermatitis in the baby and higher maternal academic education

Lymphocytic transformation assays in these infants revealed evidence of circulating memory cells, which suggests involvement of T cells in the pathogenesis of CMPA The mechanism for rectal bleeding in allergic colitis is believed to be due to thinning of mucosa over the enlarged hyperplastic submucosal lymphatic tissue, with subsequent little mucosal ulcerations.

Bleeding is most common when nodules are present in the sigmoid colon and rectum, suggesting friability of the stretched mucosa unmasked by passage of a fecal matter.

Risk Factors

Symptoms of CMPA are best divided into early versus delayed onset. Early onset symptoms happen within minutes to 2 hours after consumption of cow’s milk. Tardy or delayed onset symptoms happen 48 hours and up to 1 week after consumption of cow’s rmilk. As stated earlier, early symptoms are more likely to be IgE mediated and tardy symptoms are more likely to be non-IgEmediated Non-IgE-mediated CMPA is more hard to diagnose because (1) symptoms happen hours to days after milk consumption; (2) symptoms generally involve gastrointestinal system and skin, which are extremely commonly involved in numerous other conditions; and (3) there is no specific laboratory test to confirm or exclude the diagnosis CMPA generally presents within the first month of life and involves 2 or more symptoms in 2 or more systems1 and rarely presents beyond 12 months of age,31 Most common symptoms are skin symptoms followed by gastrointestinal and then respiratory symptoms.1 If symptoms are severe and response to standard treatment is poor, then CMPA needs to be considered to be the cause of gastroesophageal reflux or eczema In exclusively breast-fed infants, CMPA generally presents with atopic dermatitis and/or allergic proctocolitis Allergic colitis generally presents with unused blood mixed with the stool.

Typically, stool is foamy, mucousy, and non–foul smelling, but it can commonly be blood tinged otherwise normal appearing newborn stool. Eczema is

Atopic dermatitis is a risk factor for IgE-mediated common food allergies and the suspicion for CMPA should be stronger in moderate to severe atopic dermatitis that starts in the first 6 months of life,22 Asthma, especially when poorly controlled, is associated with frequent and severe reactions to milk It is controversial if paternal history of atopy is associated with higher incidence of CMPA in infants.

A study published in showed that parental history of atopy alone does not predict which infants are at greatest risk for developing IgE-mediated CMPA While another study25 found that there is increased occurrence of atopy in families of children with eosinophilic proctocolitis (allergic proctocolitis).

Pathogenesis The immunologic mechanism behind the development of CMPA is not yet clear. However, it is clear that CMPA is caused by IgE- as well as non-IgE-mediated immune reactions. IgE-mediated CMPA is better described and it is typically immediate, type 1 hypersensitivity (minutes to 2 hours after consumption of cow’s milk) while nonIgE-mediated CMPA is delayed, type 4 hypersensitivity.

In patients with non-IgE-mediated reactions presence of both CD 8 and CD4 lymphocytes as well as eosinophils in every 3 layers of the colonic mucosa were demonstrated

3. Disappearance of symptoms after elimination of cow’s milk and dairy products from the child’s and/or mother’s diet

Clinical Presentation

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Clinical Pediatrics 55(11)

also a common manifestation of CMPA in exclusively breast-fed babies.1 In IgE-mediated CMPA, about 85% of symptoms are mild while 15% are severe such as stridor and wheezing and about 9% can develop into anaphylaxis within minutes to few hours after ingestion of cow’s milk,31 Symptoms involve oral pruritus, urticaria, rhinorrhea or rhinoconjuctivitis, angioedema of oropharynx, eczema, vomiting, and diarrhea.

In non-IgE-mediated reactions symptoms are not extremely specific and include gastrointestinal symptoms (gastroesophageal reflux disease, vomiting, diarrhea, malabsorption, constipation,33 and bloody stool,28,29) due to gastrointestinal inflammation and dysmotility; skin (atopic dermatitis, urticaria, angioedema); respiratory (wheezing, cough); colic,28,34,35 and food aversion These symptoms are generally chronic and persist despite traditional standard therapies CMPA can sometimes present with failure to thrive (FTT) or isolated iron deficiency anemia, which is the most common nutritional deficiency in patients with CMPA It is reported that 25% of patients with CMPA own iron deficiency anemia Occasionally, irritability and colic may be the only symptom of food allergy Other presentations of non-IgE-mediated CMPA are allergic proctocolitis or food-induced proctocolitis,28 allergic eosinophilic gastroenteritis (esophagitis, enterocolitis, proctocolitis), transient enteropathy (mimics celiac disease), protein-losing enteropathy,1,30,33,39 rectal bleeding,40 and rarely, pulmonary hemosiderosis (Heiners syndrome).1

Evaluation Appropriate diagnosis and avoiding both under- and overdiagnosis is extremely significant.

Missing cases of CMPA can result in continuous blood loss and unnecessary, ineffective treatment of eczema while overdiagnosis can lead to dietary deficiencies and difficulty in reintroducing eliminated food items As always, history remains extremely significant in diagnosing CMPA as well as to differentiate between IgE- and non-IgE-mediated allergy, although it is sometimes not simple to differentiate between these based on history alone. Questions to enquire are the following: What symptoms? How severe? How endless after taking cow’s milk do they occur? How endless do they last?

Which treatments own been tried and how effective were they?29 Enquire if symptoms are related to switching from breast milk to formula. Past medical history should include asking about atopic dermatitis, allergic rhinitis and asthma in older children. Also enquire about any food that was already excluded from the patient’s diet, results, and any food challenges

If IgE-mediated milk protein allergy is suspected based on history, skin prick test, or specific blood IgE level is the next step in diagnosis.

Checking IgE levels are more convenient because the skin prick test should be performed in centers well equipped with managing anaphylaxis and other severe reactions However, history of exposure to the allergen remains the key element in making a diagnosis of cow’s milk allergy because positive skin prick test or high IgE levels only indicate that there is a higher probability of clinical allergy and it is not enough for diagnosis There is actually a controversy whether or not the diameter of the wheal on the skin prick test and the IgE antibody levels specific to cow’s milk protein actually correlate with the probability of developing a reaction to cow’s milk, and persistence or severity of symptoms, When allergy tests do not assist in the diagnosis of suspected CMPA, then elimination diet followed by double blind placebo controlled food challenge is the gold standard for establishing the diagnosis of CMPA Food challenge helps make a diagnosis and differentiate CMPA from other functional gastrointestinal disorders28 and thus decreases the incidence of over-/underdiagnosis However, if ingestion of milk causes immediate symptoms or if the patient had serious reaction and the IgE levels specific for CMP are high then oral challenge is not necessary for diagnosis.

In this case, the patient should follow CMP-restricted diet for at least 1 year6 after which oral challenge can be tried and it should be performed in hospital setting where access to emergency treatment is readily available. Also, if there is clear history of immediate symptoms following CMP ingestion but specific IgE is absent, then hospital based oral challenge is the next step If symptoms are suspected to be non–IgE mediated, allergy testing is not cost-effective28,33,40,48,49 and strict elimination diet is the only dependable diagnostic test.

Diet restriction either for baby or mom should be tried for 2 to 8 weeks and if there is improvement of symptoms with recurrence with reintroduction of cow’s milk, then it strongly supports CMPA. If no improvement of symptoms with diet restriction, then it is unlikely to be CMPA and milk should be reintroduced Exception to this is that some patients require switching to amino acid formulas (AAF) instead of extensively hydrolyzed formulas (eHF) before we can see improvement in symptoms.

Also, if elimination and reintroduction test is positive, allergy testing may be performed to assess the possibility of immediate reaction with future exposure to CMP In general, diet restriction should be kept as short as possible and just endless enough to detect change in symptoms (improvement vs resolution vs no change). In infants with blood in stool because of CMPA, gross blood ceases to happen within 3 weeks of avoidance.

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Mousan and Kamat Table 2.

Summary of indications for amnio-acid based formula in CMPA. Anaphylaxis or severe reactions29 Rectal bleeding leading to hemodynamic instability29 Growth failure with or without hypoproteinemia/severe anemia29 Baby had symptoms with breast milk and later family wants to switch to formula (controversial)29,37 Persistence of symptoms with extensively hydrolyzed formulaa a

Those are estimated <10% of infants with cow’s milk protein allergy but may be higher in case of severe enteropathy or multiple food allergies,55,56 especially severe symptoms in the IgE-mediated type, which is associated with severe atopic dermatitis or failure to thrive,55,59

However, occult blood can be detected till 6 to 12 weeks after avoidance of CMP.

If gross blood is still seen beyond 3 weeks or occult blood is still detected beyond 12 weeks, sigmoidoscopy is the indicated next for diagnosis. The most common cause of persistence of bloody stool in infants with allergic colitis is nodular lymphoid hyperplasia.

Management Breast-feeding should always be the first choice. Second choice is hypoallergenic formula, which can be whey or casein based. IgE mediated: remove cow’s milk protein from the diet. Non–IgE mediated: remove cow’s milk protein as well as soy protein due to cross reactivity with CMP Breast-feeding: In breast-fed infants, the mom should follow CMP-free diet for 3 to 5 days if immediate reaction and for about 2 to 3 weeks if delayed symptoms.

If no improvement in the symptoms, then it is unlikely to be CMPA and mom can resume her regular diet and the kid should be further investigated for other causes of his/her symptoms. If symptoms improve or completely resolve with modifying maternal diet, reintroduction of dairy products into the mother’s diet can be done gradually as endless as the baby is tolerating it If symptoms recur, then the mom should resume CMP-free diet supplemented with calcium mg per day28,50 and IU of vitamin D daily,51 In case symptoms recur despite mother’s strict diet avoiding CMP, the mom has 2 options, either restriction of other allergenic food in her diet or switching to therapeutic (digested cow milk or noncow milk) formula instead of breast milk,53 If severe symptoms, such as severe eczema or enterocolitis with FTT/hypoproteinemia/severe anemia are present in an exclusively breast fed baby, then the baby may be fed therapeutic formula (typically AAF although there is no excellent evidence supporting benefit of AAF over other therapeutic formulas in breast fed babies) while his mom is

following strict CMP-free diet and expressing milk until the child’s condition is stable If symptoms develop when formula is introduced to a previously breast-fed baby, treatment is ideally exclusive breast milk without any maternal elimination diet since the baby was asymptomatic when the baby was drinking only breast milk,37 Formula feeding: Treatment is to replace the formula with extensively hydrolyzed formula (eHF) or amino acid–based formula (AAF).

Common practice is to start with eHF and use AAF only if eHF fails, which is in fact a American Academy of Pediatrics recommendation However, duration after which switching from eHF to AAF should be considered varies from 2 to 8 weeks Some experts recommend that AAF may be considered first-line treatments in infants with CMPA with severe reactions or severe enteropathy (FTT, hypoalbuminemia, etc)58 while others propose that AAF formula and eHF are both accepted first-line options in cases of anaphylaxis, eosinophilic enteropathy, FTT, and severe colitis The European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines recommend using eHF in most of the patients with CMPA because it is more affordable and well tolerated Table 2 summarizes indications for AAF.

A dietitian should be consulted to optimize nutrition of the kid on CMP-restricted diet as both malnutrition and obesity can happen in these patients,60 It is also significant to watch for nutritional deficiencies, especially poor calcium intake. In addition, Epipen is indicated for children with anaphylactic reactions to milk (IgE-mediated allergy) Parents should also be counseled and educated on reading labels and every dairy products as well as any food that has the following components on the label: casein, whey, lactalbumin, albumin, and so on, should be excluded from the child’s diet Table 3 summarizes indications for referral to immunology.

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Clinical Pediatrics 55(11)

Table 3.

Summary of indications for referral to Immunologist in suspected CMPA. When to Refer to a Specialist Severe or systemic reactions Failure to thrive Atopic comorbidities (eg, IgE-mediated cow’s milk allergy with asthma) Multiple food allergies Complicated symptoms Diagnostic uncertainty No response to exclusion diet

In cow’s milk–associated rectal bleeding, it is recommended to continue with elimination diet until symptoms resolve and then reintroduce cow’s milk shortly after resolution of symptoms, which helps decrease unnecessary prolonged elimination diet

Formula Options Extensively Hydrolyzed Formula The European Commission sets the following criteria for the hydrosylate: (1) It should not cause sensitization to the milk protein in animal models when given orally.

(2) It should be tolerated by >90% of children with CMPA in the sample studied The commonly used eHF are Alimentum, Nutramigen LIPIL, Nutramigen with Enflora LGG, and Pregestimil LIPIL. These are lactose free and derived from the milk protein casein. There is no proven benefit of one formula versus other although some studies propose that Nutramigen is tolerated slightly better than other hydrolyzed formulas

Amino Acid–Based Formula The commonly used AAF are Elecare (also with docosahexaenoic acid [DHA]/arachidonic acid [ARA]), Neocate baby (also with DHA/ARA), and Nutramigen AA Lipil.

AAF for 1- to year-old are Elecare, EO28 Splash, Neocate junior, and Vivonex Pediatric.

Other formulas The common soy protein formulas are, Prosobee, Enfagrow soy next step, Excellent start soy plus, Isomil, and Similac go and grow. Soy-based formula for older children ( years) available are Bright Beginnings soy pediatric drink, and ESP-GHAB. Soy-based formulas are not recommended due to cross-reactivity between soy and milk protein In fact, soy is shown to own 60% cross-reactivity with non-IgE-mediated and 14% with

IgE-mediated CMPA Soy formula is also not recommended for infants less than 6 months as it contains isoflavins, which own a feeble estrogen effect,68 In addition, phytate present in soy-based formula decreases the absorption of minerals and trace elements, which makes it less nutritious Rice protein hydrosylates formulas contain proteins not derived from cow’s milk and Novarice is an example and it has the first two of the three recommended added amino acids tryptophan, lysine, and threonine.

However, it is not commercially available in the United States. Rice formula has no clear indication, but still can be an option for vegan families or in infants refusing to take or not tolerating therapeutic cow’s milk based formulas,4,70,71 provided that the baby is older than 6 months. Goat, sheep, donkey, horse, and other mammals’ milks are not indicated for treatment of CMPA and they are not nutritionally appropriate for infants.5,37 In addition, the cross-reactivity with CMP is about 80% Juices made of almond, coconut, chestnut, soy, and rice that are called “milks” are not nutritionally adequate for infants and should not be used to treat CMPA There is no evidence that delaying introducing foods that are known to cause allergy love eggs, fish, and wheat to infants with CMPA is effective in preventing food allergy and therefore these food items should not be avoided unless there is clear allergy to a specific food Currently, there is no evidence that adding probiotics or even Lactobacillus rhamnosus (LGG) to hypoallergenic formula is beneficial,73,74 yet numerous of the commercially available formulas own them.

About 13% to 20% of children with CMPA are allergic to bovine serum albumin and generally to beef and veal meat as well1,75 but overall the majority of children with CMPA tolerate these meat well Therefore, the practice of excluding beef and veal is not recommended in the treatment of CMPA. However, some will argue that in the absence of diagnostic tests (skin tests or radioallergosorbent test), it is logical to avoid these meats during the diagnosis by elimination diet and test their tolerance thereafter. In general, cooked beef is better tolerated because heat destroys some of the allergens.

Inversely, it was observed that 92% of children with beef allergy had allergy to CMP It was suggested in some studies that children with CMPA may develop an allergic reaction to the lactose (depending on the degree of purification) or probiotics (raised on lactose or milk) contaminating cow’s milk proteins However, excluding lactose from the diet due to concern of contamination of cow milk–derived formulas is not recommended due to lack of evidence in literature Regardless, eHF containing purified lactose is available for infants older than 6 months In some

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Mousan and Kamat Table 4.

Natural history of CMPA in diverse populations and settings. Authors/Year of Publication

Country

Number of Subjects

Population/Study Design

Host et al,

Denmark

39 (21 IgE-mediated)

General prospective birth cohort

Vanto et al,

Finland

(95 IgE-mediated)

Garcia-Ara et al, Saarinen et al,

Spain Finland

66 IgE-mediated (75 IgE-mediated)

USA

IgE-mediated

Italy Spain Portugal Germany Israel USA Turkey

IgE-mediated IgE-mediated (66 IgE-mediated) 52 IgE-mediated 54 IgE-mediated IgE-mediated IgE-mediated

Skripak et al, Fiocchi et al, Martorell et al, Santos et al, Ahrens et al, Elizur et al, Wood et al, Yavuz et al,

cases where the kid has CMP enteropathy with diarrhea causing secondary lactose intolerance, lactose-free eHF should be used

Oral Challenge In general, once CMPA is confirmed with restriction/ reintroduction of cow’s milk, diet free in CMP should be continued for at least 6 months or until the patient is 9 to 12 months if non-IgE-mediated CMPA before oral challenge is performed.

For IgE-mediated CMPA with severe, immediate symptoms, diet free of CMP should be continued for 12 to 18 months before oral challenge Generally, for non-IgE-mediated CMPA oral challenge can be done at home unless the anticipated symptoms are severe (like enterocolitis causing diarrhea and vomiting leading to dehydration and need for intravenous fluids)80 while for IgE-mediated CMPA, oral challenge should be performed in the hospital because of the risk of anaphylaxis. First, tolerance to CMP should be assessed by checking IgE levels or performing skin prick test and when tolerance is established, then only a hospital based oral food challenge is performed.

If the oral challenge is positive, elimination diet should be continued for another 6 to 12 months before reevaluation.

Prognosis Overall, CMPA has a extremely excellent prognosis with variations in the rate of CMP tolerance. By age 5 years, 80% to 90% of children develop tolerance to CMP The

Tolerance Rate

56% by 1 y, 77% by 2 y, 87% by 3 y, 92% by 5 y, and 97% by age 15 y Referral prospective 44% by 2 y, 69% by 3 y, and 77% by age 4 y Referral prospective 68% by age 4 y General prospective birth cohort 51% by 2 y, 74% by 5 y, and 85% by age y Referral retrospective 19% by 4 y, 42% by 8 y, 64% by 12 y, and 79% by age 16 y Referral prospective % by age 5 y Referral prospective 82% by age 4 y Referral retrospective 41% by age 2 y Referral retrospective % by age 12 y General prospective birth cohort % by 2 y, 65% by age 4 y Referral prospective 53% by age y Referral retrospective 20% by 2 y, 34% by 4 y, and 39% by age 6 y

tolerance rate is 30% to 50% at 1 year, 55% to 75% at 2 years, and 70% to 90% at 3 years,81 It has been observed that IgE-mediated CMPA resolves in 53% to 57% children by 5 years of age and non-IgE-mediated CMPA generally resolves by years of age Mild proctocolitis due to CMPA, resolves in the majority of infants by the time they turn ,86 Table 4 summarizes multiple studies from diverse countries that looked at the natural history of CMPA (Adapted from Nicolaou et al) A study published in showed that about 70% of patients with IgE-mediated CMPA tolerated baked milk products love cakes and pastries It is thought that proteins in cow’s milk that cause allergic reactions get denatured by heat and are no longer allergic.

Also, it is suggested now that development of tolerance to heat treated CMP actually helps induce tolerance to native cow’s milk protein faster than that with finish avoidance of milk protein containing food items Table 5 summarizes several studies that looked into various prognostic factors for the development of tolerance or persistence of CMPA,82,87, There were some variations in results between studies that were attributed to differences in settings and populations, inclusion and diagnostic criteria, laboratory methods applied and time points of reassessment, and follow-up duration. Other factors not mentioned in the table and found to be associated with persistence of CMPA are allergy to casein compared with other milk proteins, and longer duration of time from ingestion of CMP to symptoms onset

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Clinical Pediatrics 55(11)

Table 5.

Factors related to tolerance and persistence of CMPA. Favor Shorter Duration and Tolerance Clinical  Non-IgE-mediated   Later age at presentation (eg, >1month)   Milder symptoms (eg, gastrointestinal)   Higher eliciting dose (eg, > 10 mL)   Tolerance of heated milk   Absent or mild comorbidities (eg, asthma, rhinitis, eczema, and other food allergies)   No family history of atopy Laboratory   Lower levels of sIgE and/or smaller skin prick test (SPT) wheal size to whole and individual (eg, casein) cow’s milk proteins at diagnosis and follow-up measurements   Significant reduction in sIgE levels and/or SPT wheal size over time   Recognition of specific IgE conformational epitopes, increased binding to IgG4 epitopes  

It is significant to remember that in CMPA recovery does not necessarily mean finish recovery and tolerance, and sometimes the daily dose tolerated by the kid may be limited

On the Horizon Oral immunotherapy is a promising field of research in treatment of CMPA.

It is based on introducing gradually increasing doses of cow’s milk to induce tolerance Further studies are needed to support it as an effective and safe therapy for CMPA. Another promising treatment is omalizumab, monoclonal antibody against IgE either alone or in conjunction with immunotherapy Author Contributions GM did the data gathering and most of the writing of the article and DK was GM’s mentor and helped with editing/correcting/rephrasing.

Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with honor to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

Favor Longer Duration and Persistence IgE-mediated Earlier age at presentation (eg, < 1 month) Severe symptoms (eg, respiratory) Lower eliciting dose (eg, <10 mL) Intolerance of heated milk Present and severe comorbidities (eg, asthma, rhinitis, eczema, and other food allergies) Family history of atopy Higher levels of sIgE and/or larger SPT wheal size to whole and individual (eg, casein) cow’s milk proteins at diagnosis and follow-up measurements Nonsignificant reduction in sIgE levels and/or SPT wheal size over time Recognition of specific IgE linear epitopes, greater sIgE epitope diversity and higher affinity Multiple sensitizations to other foods (eg, egg, soy) and inhalant allergens by sIgE/SPT

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Wal, J. M. Cow’s milk proteins/ Allergy Asthma Immunol.

89(6 Suppl 1) :

Wal, J. M. Immunochemical and molecular characterization of milk y. b. 53(46 Suppl) :

Werfel, S. J., Cooke, S. K., Sampson, H. A. Clinical reactivity to beef in children allergic to cow’s milk.J Allergy Clin Immunol. 99(3) :

Wilson J. Milk intolerance : Lactose intolerance and cow’s milk protein n and Baby Nursing Reviews. 5 :

Woteki, C., Weser, E., Young, E. Lactose malabsorption in Mexican-American children (abstract).The american journal of clinical nutrition. 29 :

Yang, Y. and He, M. The prevalence of lactase deficiency and lactose intolerance in Chinese children of diverse e Medical Journal. (12) :

Young, E., Stoneham, M.

D., Petruckevitch, A., Barton, J., Rona, R. A population study of food intolerance (abstract).Lancet. () :

Zapatero, L., Alonso, E., Fuentes, V., Martinez, M. I. Oral desensitization in children with cow’s milk allergy.J Investig Allergol Clin Immunol. 18(5) :

Zarkadas, M., Scott, F., Salminen, J., Ham Pong, A. Common Allergenic Foods and Their Labelling in Canada — A an Journal of Allergy & Clinical Immunology. 4(3) :

Various baby formulas — such as soy, extensively hydrolysed and amino acid-based formula — that can be used to treat cows milk protein allergy are available in Australia. An analysis of Australian formula-prescribing practices indicated that they did not appear to be in line with authoritative statements and position papers or the guidelines of the Australian Pharmaceutical Benefits Advisory Committee (PBAC).1

In , the Committee on Nutrition of the American Academy of Pediatrics stated that soy formula was a suitable option for treating infants with cows milk protein allergy.2 In April , the Committee on Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) recommended that soy protein formulas should not be used in infants with cows milk protein allergy during the first 6 months of life, because few infants had been studied, and the reported rate of adverse reactions to soy protein was higher in infants under 6 months of age.

This committee also recommended that, when soy formula is used to treat cows milk protein allergy in infants over 6 months of age, tolerance to soy formula be established by clinical challenge.3

The PBAC guidelines once restricted the use of extensively hydrolysed formula to infants with combined intolerance to cows milk protein and soy protein. It also restricted the use of amino acid formula to infants with combined intolerance to cows milk protein, soy protein and extensively hydrolysed formula. In November , the PBAC accepted the advice of its Nutritional Products Working Party to ease the restrictions: the requirement to protest intolerance to soy protein before treating infants with these products was removed.

In , European proposals for treating cows milk protein allergy in formula-fed infants with extensively hydrolysed formula and amino acid formula were outlined in an algorithm.4

Consensus panel

In the light of these considerations, we constituted an Australian panel with representation from every states.

The panel was put together by the two lead authors (A S K and D J H) to represent practising paediatric clinicians. The panel was composed to include clinicians with expertise in paediatric allergy, gastroenterology, neonatology and general paediatrics.

There were two face-to-face meetings, in November  and June , and four telephone conferences. Meetings were co-chaired by A S K and D J H. Panel members (but not the co-chairs) were assigned individual tasks to review practice with regard to treatment as it related to specific clinical syndromes.

After this material had been discussed by the panel, a position was reached. The number of panel members agreeing with the position (in view of the evidence presented) was recorded.

The panel considered the issues and reached a consensus on the indications for use of soy, extensively hydrolysed and amino acid formulas in the treatment of cows milk protein allergy under Australian conditions in general and paediatric practice. As the selection of a formula depends on the syndrome to be treated, the panel has outlined the salient features of the diverse syndromes in breastfed and formula-fed infants.

Selected references to the individual syndromes own been provided.

The spectrum of cows milk protein allergy

Cows milk protein allergy is defined as an immunologically mediated adverse reaction to cows milk protein. It affects about 2% of infants under 2 years of age.5 In this document, we use the term “allergy” in accordance with the World Allergy Organization’s definition (ie, allergy is a hypersensitivity reaction initiated by specific immunological mechanisms).6 Mechanisms may be IgE mediated or non-IgE mediated. Cows milk protein allergy can also happen in exclusively breastfed infants.

Cows milk protein is often the first food protein ingested by formula-fed infants, and allergies present as a range of syndromes.

A correct diagnosis is critical and will often depend on appropriate immunological and morphological investigations. In every cases, the diagnosis is confirmed by observing remission of the symptoms following removal of the protein. If the diagnosis remains uncertain, further confirmation should be obtained by observing relapse following challenge with cows milk protein. As some of the conditions may remit with time, rechallenge with cows milk protein after a period of avoidance is indicated in some cases. A finish discussion of the diagnostic process and ongoing management4 falls exterior the scope of this guideline.

Consensus on the use of formulas

Three diverse types of formula (soy, extensively hydrolysed and amino acid) may be appropriate treatment in specific circumstances (Box 1).

Some preparations are not recommended for treating cows milk protein allergy. The panel considers that there is no put for partially hydrolysed (known as HA) formulas nor other mammalian milks (such as goats milk)7 in treating cows milk protein allergy. The consensus recommendations for using baby formulas to treat allergy syndromes are shown in Box 2. Breastfeeding may be continued, and recommendations are provided for eliminating maternal intake of cows milk protein.

The panel believes the information provided is a guideline for most cases.

However, in severely affected infants or if the diagnosis is uncertain, it may be appropriate to start treatment with an extensively hydrolysed or amino acid-based formula which is not in accordance with this consensus.8 Such a case should be managed by a paediatrician with specific expertise in these disorders.

Cows milk protein allergy syndromes

The syndromes are classified as reactions which develop over minutes, hours or days. The recommendations include advice about the necessity for mothers to eliminate dietary intake of cows milk protein while breastfeeding.

In some situations, failure to thrive affects the choice of formula. Recommendations provide for an alternative formula if treatment with the initial formula is not successful.

Immediate allergic reactions9

Cows milk protein allergy may manifest with erythema, angioedema, urticaria or vomiting. Some infants may own contact urticaria where protein has touched the skin. Typically, there will be evidence of IgE sensitisation (positive skin prick test or an allergen-specific IgE antibody test [RAST] to cows milk).

Symptoms develop within minutes of ingestion of little volumes of milk. Infants with cows milk protein allergy often own other food allergies, in specific to egg and peanut products.

Anaphylaxis is a severe immediate reaction with respiratory tract involvement and/or hypotension. Features of anaphylaxis may be hard to identify in infants. It may be suggested by coughing, wheezing, severe distress, floppiness or collapse.

Food protein-induced enterocolitis syndrome (FPIES)10

FPIES is an unusual disorder which generally presents with acute onset of repeated projectile vomiting, hypotonia, pallor and sometimes diarrhoea 1 to 3 hours after ingestion of cows milk protein.

FPIES may be mistaken for acute gastroenteritis, sepsis or intestinal obstruction, and multiple presentations before the diagnosis is established are not unusual. Typically, FPIES occurs at the first introduction of cows milk protein into the diet. It has not been reported in exclusively breastfed infants. FPIES may also be caused by other food proteins (eg, soy, wheat, rice and chicken). Despite the onset within hours of ingestion, the disorder is not IgE mediated.

Remission has generally occurred by the third year of life.

Atopic eczema11

Atopic eczema is a chronic, relapsing, pruritic inflammatory disease of the skin, generally associated with allergic sensitisation. Food allergy plays a role in some cases of eczema in children. It should particularly be considered in infants with moderate to severe eczema. It is generally associated with high levels of IgE antibodies to common foods (eg, milk, egg and peanut). Egg is the most frequently involved allergen, followed by cows milk protein.

Although IgE antibodies own been implicated in most cases of cows milk protein-induced eczema, about 10% of cases are not IgE associated.

Gastrointestinal syndromes

Infants with cows milk protein allergy may present with vomiting, chronic diarrhoea, malabsorption and failure to thrive. Most of the syndromes are not IgE associated and own other pathogenic immune mechanisms. Cows milk protein allergy is the most commonly identified food allergen sensitivity; however, in some cases, hypersensitivity to multiple food proteins is involved.

Gastrointestinal biopsy may be required to define the disorder.

Gastro-oesophageal reflux disease (GORD)12

About 40% of infants referred for specialist management of GORD own allergy to cows milk protein. These allergic reactions are typically not IgE mediated. In these infants, intestinal biopsy commonly shows partial villous atrophy.

Allergic eosinophilic gastroenteritis13

Common features include weight loss and failure to thrive associated with postprandial vomiting, diarrhoea and, occasionally, blood loss.

In more severe cases, the infants may own iron deficiency anaemia and oedema due to hypoproteinaemia and protein-losing enteropathy.

Food protein-induced enteropathy14

Infants with allergic enteropathy due to cows milk protein may present with diarrhoea, failure to thrive, various degrees of vomiting and, sometimes, hypoproteinaemia and anaemia. Some cases own an associated soy allergy.

What is the best formula for a milk protein allergy

The clinical signs of secondary lactose intolerance, including perianal excoriation from acidic stools, may be present.

Constipation15

Whether constipation is a clinical manifestation of cows milk protein allergy in infants and young children is controversial. Constipation is a common symptom in early childhood and, in some cases, resolves after removal of cows milk protein from the diet. Cows milk protein-induced constipation is often associated with anal fissures and rectal eosinophilia.

Severe irritability (colic)16

The mechanisms of baby colic are poorly understood.

Colic is not mediated by IgE, and the role of dietary factors is controversial. Persistent crying is a common problem that may affect about a third of young infants and gradually abates by 4 months of age without specific treatment in most cases. In infants with unremitting distress persisting beyond the typical colic period, an underlying organic cause may be more likely. Exclusion of cows milk protein helps in some cases, but these cannot be identified by allergy tests.

Food protein-induced proctocolitis17

Infants with allergic proctocolitis due to cows milk protein allergy generally present with mild diarrhoea and low-grade rectal bleeding.

If the baby is fully breastfed (breast milk colitis), symptoms may be caused by protein transferred via the breast milk. The bleeding is generally observed as stools containing mucus and flecks of blood rather than as candid rectal bleeding. Other systemic features (such as failure to thrive or anaemia) are generally absent, and the infants appear generally well. Rectal biopsies are not usual, but may be required to confirm the diagnosis in more severe or atypical cases.

Eosinophilic oesophagitis18

Eosinophilic oesophagitis is more often identified in older children than in infants, but may happen in both groups.

In infancy, typical symptoms are refusal of food, hard feeding, poor weight acquire and poor response to standard antireflux measures. Older children may present with dysphagia or episodes of impacted food bolus. Endoscopy is necessary to establish the diagnosis, which is based on eosinophilia of the upper and lower oesophagus. Eosinophil numbers are typically lower in infants with peptic reflux oesophagitis. Hypersensitivity to multiple foods may be seen in infants with eosinophilic oesophagitis. In older children and adults, aeroallergens may also be implicated. Therapy may include hypoallergenic diets and swallowed steroid aerosol.

Other conditions associated with eosinophilic infiltration of the little and large bowel require specialist diagnosis and treatment, and may reply to elimination of cows milk protein.

1 Preparations available for treating cows milk protein allergy

Suitable

  • Soy formulas

  • Extensively hydrolysed formulas

    1. Alfaré (Nestlé)

    2. Pepti-Junior (Nutricia)

    3. Amino acid formulas

  • Amino acid formulas

    1. EleCare (Abbott)

    2. Neocate (SHS)

    Contraindicated or not recommended

  • Formulas

    1. Lactose-free cows milk-based (eg, Karicare De-Lact, Digestelact [Nutricia], S LF [Wyeth])

    2. Goats milk-based formula

    3. Cows milk-based (including anti-regurgitation)

    4. Partially hydrolysed cows milk-based (eg, Karicare SensiKare [Nutricia], NAN HA [Nestlé])

    5. Other preparations

  • Other preparations

    1. A2 milk (A2 Australia)

    2. Oat milk

    3. Rice milk

    4. Other mammalian milks (camel, mare, ass, goat and ewe)

    2 Formula feeding in syndromes associated with cows milk protein allergy*

    Syndrome

    Onset of reaction

    Maternal elimination of CMP if breastfeeding?

    Choice of formula


    NHMRC level of evidence‡

    Consensus panel agreement§

    First†

    Second (if first not tolerated)

    Third (if second not tolerated)


    Immediate reaction

    Immediate food allergy

    < 1 h

    Yes

    eHF (< 6 months)

    AAF

    II

    11/11

    Soy (> 6 months)

    eHF

    AAF


    Anaphylaxis

    < 1 h

    Yes

    AAF (followed by urgent consultation with paediatric allergist)

    IV

    11/11


    Food protein-induced enterocolitis syndrome

    1–3 h

    No

    eHF

    AAF

    IV

    10/11


    Delayed reaction


    Atopic eczema

    Hours to days

    Yes¶

    eHF (< 6 months or > 6 months with FTT)

    AAF

    IV

    11/11

    Soy (> 6 months, no FTT)

    eHF

    AAF


    Gastrointestinal syndromes, GORD, allergic eosinophilic gastroenteritis, food protein-induced enteropathy, constipation, severe irritability (colic)

    Hours to days

    Yes¶

    eHF (< 6 months or > 6 months with FTT)

    AAF

    I (severe irritability), III (GORD), IV (others)

    11/11

    Soy (> 6 months, no FTT)

    eHF

    AAF


    Food protein-induced proctocolitis

    11/11

    Formula-fed

    > 24 h

    eHF

    AAF

    IV

    Breastfed

    > 24 h

    Yes¶


    Eosinophilic oesophagitis in infants

    Days to weeks

    Yes

    AAF

    IV

    11/11


    References

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    5 Mullins RJ, Camargo CA. Latitude, sunlight, vitamin D, and childhood food allergy/anaphylaxis. Curr Allergy Asthma Rep. ; [ Links ]

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    Prevalence of eczema and food allergy is associated with latitude in Australia. J Allergy Clin Immunol. ; [ Links ]

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    10 Koletzko S, Niggemann B, Arato A, Dias JA, Heuschkel R, Husby S, et al. Diagnostic approach and management of cow’s-milk protein allergy in infants and children: ESPGHAN GI Committee Practical Guidelines. JPGN. ; [ Links ]

    11 Fiocchi A, Brozek J, Schünemann H, Bahna SL, Berg A, Beyer K, et al.

    World Allergy Organization (WAO) diagnosis and rationale for action against cow’s milk allergy (DRACMA) guidelines. World Allergy Organ J. ; [ Links ]

    12 W.H.O. WHO kid growth standards based on length/height, weight and age. Acta Paediatr. ;S [ Links ]

    13 Holick MF. Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol. ; [ Links ]

    14 Ministério da Saúde (BR), Secretaria de Atenção à Saúde, Departamento de Atenção Básica Saúde da Criança.

    Aleitamento materno e alimentação complementar. Brasília: Ministério da Saúde; [ Links ]

    15 Sociedade Brasileira de Pediatria (BR), Departamento de Nutrologia. Manual de orientação para a alimentação do lactente, do pré-escolar, do escolar, do adolescente e na escola. Rio de Janeiro: SBP; [ Links ]

    16 Suaini NH, Zhang Y, Vuillermin PJ, Allen KJ, Harrison LC. Immune modulation by vitamin D and its relevance to food allergy. Nutrients. ; [ Links ]

    17 Chun RF, Liu PT, Modlin RL, Adams JS, Hewison M. Impact of vitamin D on immune function: lessons learned from genome-wide analysis.

    Front Physiol. ; [ Links ]

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    19 Gashut RA, Talwar D, Kinsella J, Duncan A, McMillan DC. The effect of the systemic inflammatory response on plasma vitamin 25 (OH)D concentrations adjusted for albumin. PLoS One. ; [ Links ]

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    21 Greer FR. Issues in establishing vitamin D recommendations for infants and children.

    Am J Clin Nutr. ;S [ Links ]

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    23 Decsi T, Lohner S. Gaps in meeting nutrient needs in healthy toddlers. Ann Nutr Metab. ; [ Links ]

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    research-article

    CPJXXX/Clinical PediatricsMousan and Kamat

    Article Clinical Pediatrics , Vol. 55(11) ­– © The Author(s) Reprints and permissions: DOI: /

    Cow’s Milk Protein Allergy Grace Mousan, MD1, and Deepak Kamat, MD, PhD1

    Abstract Cow’s milk protein allergy (CMPA) is a common condition encountered in children with incidence estimated as 2% to % in the first year of life. Formula and breast-fed babies can present with symptoms of CMPA. It is significant to accurately diagnose CMPA to avoid the consequences of either under- or overdiagnosis.

    CMPA is classically categorized into immunoglobulin E (IgE)- or non-IgE-mediated reaction that vary in clinical manifestations, diagnostic evaluation, and prognosis. The most commonly involved systems in patients with CMPA are gastrointestinal, skin, and respiratory. Evaluation of CMPA starts with excellent data gathering followed by testing if indicated. Treatment is simply by avoidance of cow’s milk protein (CMP) in the child’s or mother’s diet, if exclusively breast-feeding. This article reviews the definition, epidemiology, risk factors, pathogenesis, clinical presentation, evaluation, management, and prognosis of CMPA and provides an overview of diverse options for formulas and their indication in the treatment of CMPA.

    Keywords cow’s milk, protein, allergy, breast-feeding, formula feeding, Allergic colitis, elimination diet, oral challenge, extensively hydrolyzed formula, amino-acid based formula

    Introduction Cow’s milk protein allergy (CMPA) is common in infants. The symptoms suggestive of CMPA may be found in 5% to 15% of infants.1 However, CMPA is a clinical diagnosis and there is no laboratory test that is diagnostic. Infants who are fed cow’s milk–based formula as well as those who are exclusively breast-fed can develop CMPA.2 CMPA in exclusively breast-fed babies is thought to be due to β-lactoglobulin of cow’s milk that is found in human milk 4 to 6 hours after maternal consumption of cow’s milk.3

    Definition Cows’ milk allergy or cow’s milk protein allergy is an immune reaction to proteins found in cow’s milk.4 Milk proteins can either be directly ingested by drinking cow’s milk–based formula or passed through breast milk.

    Casein and whey proteins are generally the culprits. CMPA can be immunoglobulin E (IgE) mediated or non–IgE mediated. The World Allergy Organization definition for CMPA is “hypersensitivity reaction brought on by specific immunologic mechanisms to cow’s milk.”4 CMPA should be differentiated from cow’s milk intolerance where the previous is an immune mediated reaction while the latter is generally due to lactase deficiency which is rare in infants except following

    gastrointestinal infections.5 Table 1 summarizes diagnostic criteria for CMPA according to Host and Halken1 and for allergic colitis per Fiocchi et al.6

    Epidemiology The incidence of CMPA during first year of life is estimated to be 2% tp % while the prevalence of CMPA in breast-fed infants is %,10,11 and it is the most common food allergy in children younger than 3 years,13 Prevalence of CMPA decreases to less than 1% in children 6 years or older According to a Danish cohort study, 54% of CMPA is due to IgE-mediated and 46% is due to non-IgE-mediated immune response A large prospective study from Israel showed that only % of the general population develops isolated rectal bleeding due to CMPA

    Misdiagnosis of CMPA It is significant to recognize the importance of diagnosing CMPA correctly in infants because misdiagnosis 1

    Children’s Hospital of Michigan, Detroit, MI, USA

    Corresponding Author: Grace Mousan, Children’s Hospital of Michigan, Beaubien Boulvard, Detroit, MI , USA.

    Email: [email protected]

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    Mousan and Kamat

    Table 1. Summary of diagnostic criteria for CMPA according to Host and Halken1 and for allergic colitis per Fiocchi et al.6 Diagnostic Criteria for CMPA

    Diagnostic Criteria for Allergic Proctocolitis

    1. Elimination diet should result in resolution of symptoms 2. Recurrence of the exact same symptoms with the oral challenge 3. Other causes of symptoms love lactose intolerance or gastrointestinal infections are ruled out

    1. Presence of rectal bleeding in an baby with adequate weight and height parameters 2.

    Exclusion of infectious causes of colitis

    leads to unnecessary elimination diet in infants and breast-feeding mothers. Prevalence of a genuine food allergy in general is less than what is perceived by parents,18 In a study from Norway, 35% of children younger than 2 years were labeled by their parents with having a reaction to food (most commonly milk) Majority of infants who get misdiagnosed with CMPA present within the first 3 months of life with nonspecific manifestations typically involving a single system most commonly gastrointestinal or skin.

    Factors that were found to be associated with mislabeling as baby having CMPA are atopic dermatitis in the baby and higher maternal academic education

    Lymphocytic transformation assays in these infants revealed evidence of circulating memory cells, which suggests involvement of T cells in the pathogenesis of CMPA The mechanism for rectal bleeding in allergic colitis is believed to be due to thinning of mucosa over the enlarged hyperplastic submucosal lymphatic tissue, with subsequent little mucosal ulcerations. Bleeding is most common when nodules are present in the sigmoid colon and rectum, suggesting friability of the stretched mucosa unmasked by passage of a fecal matter.

    Risk Factors

    Symptoms of CMPA are best divided into early versus delayed onset.

    Early onset symptoms happen within minutes to 2 hours after consumption of cow’s milk. Tardy or delayed onset symptoms happen 48 hours and up to 1 week after consumption of cow’s rmilk. As stated earlier, early symptoms are more likely to be IgE mediated and tardy symptoms are more likely to be non-IgEmediated Non-IgE-mediated CMPA is more hard to diagnose because (1) symptoms happen hours to days after milk consumption; (2) symptoms generally involve gastrointestinal system and skin, which are extremely commonly involved in numerous other conditions; and (3) there is no specific laboratory test to confirm or exclude the diagnosis CMPA generally presents within the first month of life and involves 2 or more symptoms in 2 or more systems1 and rarely presents beyond 12 months of age,31 Most common symptoms are skin symptoms followed by gastrointestinal and then respiratory symptoms.1 If symptoms are severe and response to standard treatment is poor, then CMPA needs to be considered to be the cause of gastroesophageal reflux or eczema In exclusively breast-fed infants, CMPA generally presents with atopic dermatitis and/or allergic proctocolitis Allergic colitis generally presents with unused blood mixed with the stool.

    Typically, stool is foamy, mucousy, and non–foul smelling, but it can commonly be blood tinged otherwise normal appearing newborn stool. Eczema is

    Atopic dermatitis is a risk factor for IgE-mediated common food allergies and the suspicion for CMPA should be stronger in moderate to severe atopic dermatitis that starts in the first 6 months of life,22 Asthma, especially when poorly controlled, is associated with frequent and severe reactions to milk It is controversial if paternal history of atopy is associated with higher incidence of CMPA in infants.

    A study published in showed that parental history of atopy alone does not predict which infants are at greatest risk for developing IgE-mediated CMPA While another study25 found that there is increased occurrence of atopy in families of children with eosinophilic proctocolitis (allergic proctocolitis).

    Pathogenesis The immunologic mechanism behind the development of CMPA is not yet clear. However, it is clear that CMPA is caused by IgE- as well as non-IgE-mediated immune reactions.

    IgE-mediated CMPA is better described and it is typically immediate, type 1 hypersensitivity (minutes to 2 hours after consumption of cow’s milk) while nonIgE-mediated CMPA is delayed, type 4 hypersensitivity. In patients with non-IgE-mediated reactions presence of both CD 8 and CD4 lymphocytes as well as eosinophils in every 3 layers of the colonic mucosa were demonstrated

    3. Disappearance of symptoms after elimination of cow’s milk and dairy products from the child’s and/or mother’s diet

    Clinical Presentation

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    Clinical Pediatrics 55(11)

    also a common manifestation of CMPA in exclusively breast-fed babies.1 In IgE-mediated CMPA, about 85% of symptoms are mild while 15% are severe such as stridor and wheezing and about 9% can develop into anaphylaxis within minutes to few hours after ingestion of cow’s milk,31 Symptoms involve oral pruritus, urticaria, rhinorrhea or rhinoconjuctivitis, angioedema of oropharynx, eczema, vomiting, and diarrhea.

    In non-IgE-mediated reactions symptoms are not extremely specific and include gastrointestinal symptoms (gastroesophageal reflux disease, vomiting, diarrhea, malabsorption, constipation,33 and bloody stool,28,29) due to gastrointestinal inflammation and dysmotility; skin (atopic dermatitis, urticaria, angioedema); respiratory (wheezing, cough); colic,28,34,35 and food aversion These symptoms are generally chronic and persist despite traditional standard therapies CMPA can sometimes present with failure to thrive (FTT) or isolated iron deficiency anemia, which is the most common nutritional deficiency in patients with CMPA It is reported that 25% of patients with CMPA own iron deficiency anemia Occasionally, irritability and colic may be the only symptom of food allergy Other presentations of non-IgE-mediated CMPA are allergic proctocolitis or food-induced proctocolitis,28 allergic eosinophilic gastroenteritis (esophagitis, enterocolitis, proctocolitis), transient enteropathy (mimics celiac disease), protein-losing enteropathy,1,30,33,39 rectal bleeding,40 and rarely, pulmonary hemosiderosis (Heiners syndrome).1

    Evaluation Appropriate diagnosis and avoiding both under- and overdiagnosis is extremely significant.

    Missing cases of CMPA can result in continuous blood loss and unnecessary, ineffective treatment of eczema while overdiagnosis can lead to dietary deficiencies and difficulty in reintroducing eliminated food items As always, history remains extremely significant in diagnosing CMPA as well as to differentiate between IgE- and non-IgE-mediated allergy, although it is sometimes not simple to differentiate between these based on history alone.

    Questions to enquire are the following: What symptoms? How severe? How endless after taking cow’s milk do they occur? How endless do they last? Which treatments own been tried and how effective were they?29 Enquire if symptoms are related to switching from breast milk to formula. Past medical history should include asking about atopic dermatitis, allergic rhinitis and asthma in older children. Also enquire about any food that was already excluded from the patient’s diet, results, and any food challenges

    If IgE-mediated milk protein allergy is suspected based on history, skin prick test, or specific blood IgE level is the next step in diagnosis.

    Checking IgE levels are more convenient because the skin prick test should be performed in centers well equipped with managing anaphylaxis and other severe reactions However, history of exposure to the allergen remains the key element in making a diagnosis of cow’s milk allergy because positive skin prick test or high IgE levels only indicate that there is a higher probability of clinical allergy and it is not enough for diagnosis There is actually a controversy whether or not the diameter of the wheal on the skin prick test and the IgE antibody levels specific to cow’s milk protein actually correlate with the probability of developing a reaction to cow’s milk, and persistence or severity of symptoms, When allergy tests do not assist in the diagnosis of suspected CMPA, then elimination diet followed by double blind placebo controlled food challenge is the gold standard for establishing the diagnosis of CMPA Food challenge helps make a diagnosis and differentiate CMPA from other functional gastrointestinal disorders28 and thus decreases the incidence of over-/underdiagnosis However, if ingestion of milk causes immediate symptoms or if the patient had serious reaction and the IgE levels specific for CMP are high then oral challenge is not necessary for diagnosis.

    In this case, the patient should follow CMP-restricted diet for at least 1 year6 after which oral challenge can be tried and it should be performed in hospital setting where access to emergency treatment is readily available. Also, if there is clear history of immediate symptoms following CMP ingestion but specific IgE is absent, then hospital based oral challenge is the next step If symptoms are suspected to be non–IgE mediated, allergy testing is not cost-effective28,33,40,48,49 and strict elimination diet is the only dependable diagnostic test.

    Diet restriction either for baby or mom should be tried for 2 to 8 weeks and if there is improvement of symptoms with recurrence with reintroduction of cow’s milk, then it strongly supports CMPA. If no improvement of symptoms with diet restriction, then it is unlikely to be CMPA and milk should be reintroduced Exception to this is that some patients require switching to amino acid formulas (AAF) instead of extensively hydrolyzed formulas (eHF) before we can see improvement in symptoms. Also, if elimination and reintroduction test is positive, allergy testing may be performed to assess the possibility of immediate reaction with future exposure to CMP In general, diet restriction should be kept as short as possible and just endless enough to detect change in symptoms (improvement vs resolution vs no change).

    In infants with blood in stool because of CMPA, gross blood ceases to happen within 3 weeks of avoidance.

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    Mousan and Kamat Table 2. Summary of indications for amnio-acid based formula in CMPA. Anaphylaxis or severe reactions29 Rectal bleeding leading to hemodynamic instability29 Growth failure with or without hypoproteinemia/severe anemia29 Baby had symptoms with breast milk and later family wants to switch to formula (controversial)29,37 Persistence of symptoms with extensively hydrolyzed formulaa a

    Those are estimated <10% of infants with cow’s milk protein allergy but may be higher in case of severe enteropathy or multiple food allergies,55,56 especially severe symptoms in the IgE-mediated type, which is associated with severe atopic dermatitis or failure to thrive,55,59

    However, occult blood can be detected till 6 to 12 weeks after avoidance of CMP.

    If gross blood is still seen beyond 3 weeks or occult blood is still detected beyond 12 weeks, sigmoidoscopy is the indicated next for diagnosis. The most common cause of persistence of bloody stool in infants with allergic colitis is nodular lymphoid hyperplasia.

    Management Breast-feeding should always be the first choice. Second choice is hypoallergenic formula, which can be whey or casein based. IgE mediated: remove cow’s milk protein from the diet. Non–IgE mediated: remove cow’s milk protein as well as soy protein due to cross reactivity with CMP Breast-feeding: In breast-fed infants, the mom should follow CMP-free diet for 3 to 5 days if immediate reaction and for about 2 to 3 weeks if delayed symptoms.

    If no improvement in the symptoms, then it is unlikely to be CMPA and mom can resume her regular diet and the kid should be further investigated for other causes of his/her symptoms. If symptoms improve or completely resolve with modifying maternal diet, reintroduction of dairy products into the mother’s diet can be done gradually as endless as the baby is tolerating it If symptoms recur, then the mom should resume CMP-free diet supplemented with calcium mg per day28,50 and IU of vitamin D daily,51 In case symptoms recur despite mother’s strict diet avoiding CMP, the mom has 2 options, either restriction of other allergenic food in her diet or switching to therapeutic (digested cow milk or noncow milk) formula instead of breast milk,53 If severe symptoms, such as severe eczema or enterocolitis with FTT/hypoproteinemia/severe anemia are present in an exclusively breast fed baby, then the baby may be fed therapeutic formula (typically AAF although there is no excellent evidence supporting benefit of AAF over other therapeutic formulas in breast fed babies) while his mom is

    following strict CMP-free diet and expressing milk until the child’s condition is stable If symptoms develop when formula is introduced to a previously breast-fed baby, treatment is ideally exclusive breast milk without any maternal elimination diet since the baby was asymptomatic when the baby was drinking only breast milk,37 Formula feeding: Treatment is to replace the formula with extensively hydrolyzed formula (eHF) or amino acid–based formula (AAF).

    Common practice is to start with eHF and use AAF only if eHF fails, which is in fact a American Academy of Pediatrics recommendation However, duration after which switching from eHF to AAF should be considered varies from 2 to 8 weeks Some experts recommend that AAF may be considered first-line treatments in infants with CMPA with severe reactions or severe enteropathy (FTT, hypoalbuminemia, etc)58 while others propose that AAF formula and eHF are both accepted first-line options in cases of anaphylaxis, eosinophilic enteropathy, FTT, and severe colitis The European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines recommend using eHF in most of the patients with CMPA because it is more affordable and well tolerated Table 2 summarizes indications for AAF.

    A dietitian should be consulted to optimize nutrition of the kid on CMP-restricted diet as both malnutrition and obesity can happen in these patients,60 It is also significant to watch for nutritional deficiencies, especially poor calcium intake. In addition, Epipen is indicated for children with anaphylactic reactions to milk (IgE-mediated allergy) Parents should also be counseled and educated on reading labels and every dairy products as well as any food that has the following components on the label: casein, whey, lactalbumin, albumin, and so on, should be excluded from the child’s diet Table 3 summarizes indications for referral to immunology.

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    Clinical Pediatrics 55(11)

    Table 3.

    Summary of indications for referral to Immunologist in suspected CMPA. When to Refer to a Specialist Severe or systemic reactions Failure to thrive Atopic comorbidities (eg, IgE-mediated cow’s milk allergy with asthma) Multiple food allergies Complicated symptoms Diagnostic uncertainty No response to exclusion diet

    In cow’s milk–associated rectal bleeding, it is recommended to continue with elimination diet until symptoms resolve and then reintroduce cow’s milk shortly after resolution of symptoms, which helps decrease unnecessary prolonged elimination diet

    Formula Options Extensively Hydrolyzed Formula The European Commission sets the following criteria for the hydrosylate: (1) It should not cause sensitization to the milk protein in animal models when given orally.

    (2) It should be tolerated by >90% of children with CMPA in the sample studied The commonly used eHF are Alimentum, Nutramigen LIPIL, Nutramigen with Enflora LGG, and Pregestimil LIPIL. These are lactose free and derived from the milk protein casein. There is no proven benefit of one formula versus other although some studies propose that Nutramigen is tolerated slightly better than other hydrolyzed formulas

    Amino Acid–Based Formula The commonly used AAF are Elecare (also with docosahexaenoic acid [DHA]/arachidonic acid [ARA]), Neocate baby (also with DHA/ARA), and Nutramigen AA Lipil.

    AAF for 1- to year-old are Elecare, EO28 Splash, Neocate junior, and Vivonex Pediatric.

    Other formulas The common soy protein formulas are, Prosobee, Enfagrow soy next step, Excellent start soy plus, Isomil, and Similac go and grow. Soy-based formula for older children ( years) available are Bright Beginnings soy pediatric drink, and ESP-GHAB. Soy-based formulas are not recommended due to cross-reactivity between soy and milk protein In fact, soy is shown to own 60% cross-reactivity with non-IgE-mediated and 14% with

    IgE-mediated CMPA Soy formula is also not recommended for infants less than 6 months as it contains isoflavins, which own a feeble estrogen effect,68 In addition, phytate present in soy-based formula decreases the absorption of minerals and trace elements, which makes it less nutritious Rice protein hydrosylates formulas contain proteins not derived from cow’s milk and Novarice is an example and it has the first two of the three recommended added amino acids tryptophan, lysine, and threonine.

    However, it is not commercially available in the United States. Rice formula has no clear indication, but still can be an option for vegan families or in infants refusing to take or not tolerating therapeutic cow’s milk based formulas,4,70,71 provided that the baby is older than 6 months. Goat, sheep, donkey, horse, and other mammals’ milks are not indicated for treatment of CMPA and they are not nutritionally appropriate for infants.5,37 In addition, the cross-reactivity with CMP is about 80% Juices made of almond, coconut, chestnut, soy, and rice that are called “milks” are not nutritionally adequate for infants and should not be used to treat CMPA There is no evidence that delaying introducing foods that are known to cause allergy love eggs, fish, and wheat to infants with CMPA is effective in preventing food allergy and therefore these food items should not be avoided unless there is clear allergy to a specific food Currently, there is no evidence that adding probiotics or even Lactobacillus rhamnosus (LGG) to hypoallergenic formula is beneficial,73,74 yet numerous of the commercially available formulas own them.

    About 13% to 20% of children with CMPA are allergic to bovine serum albumin and generally to beef and veal meat as well1,75 but overall the majority of children with CMPA tolerate these meat well Therefore, the practice of excluding beef and veal is not recommended in the treatment of CMPA. However, some will argue that in the absence of diagnostic tests (skin tests or radioallergosorbent test), it is logical to avoid these meats during the diagnosis by elimination diet and test their tolerance thereafter. In general, cooked beef is better tolerated because heat destroys some of the allergens. Inversely, it was observed that 92% of children with beef allergy had allergy to CMP It was suggested in some studies that children with CMPA may develop an allergic reaction to the lactose (depending on the degree of purification) or probiotics (raised on lactose or milk) contaminating cow’s milk proteins However, excluding lactose from the diet due to concern of contamination of cow milk–derived formulas is not recommended due to lack of evidence in literature Regardless, eHF containing purified lactose is available for infants older than 6 months In some

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    Mousan and Kamat Table 4.

    Natural history of CMPA in diverse populations and settings. Authors/Year of Publication

    Country

    Number of Subjects

    Population/Study Design

    Host et al,

    Denmark

    39 (21 IgE-mediated)

    General prospective birth cohort

    Vanto et al,

    Finland

    (95 IgE-mediated)

    Garcia-Ara et al, Saarinen et al,

    Spain Finland

    66 IgE-mediated (75 IgE-mediated)

    USA

    IgE-mediated

    Italy Spain Portugal Germany Israel USA Turkey

    IgE-mediated IgE-mediated (66 IgE-mediated) 52 IgE-mediated 54 IgE-mediated IgE-mediated IgE-mediated

    Skripak et al, Fiocchi et al, Martorell et al, Santos et al, Ahrens et al, Elizur et al, Wood et al, Yavuz et al,

    cases where the kid has CMP enteropathy with diarrhea causing secondary lactose intolerance, lactose-free eHF should be used

    Oral Challenge In general, once CMPA is confirmed with restriction/ reintroduction of cow’s milk, diet free in CMP should be continued for at least 6 months or until the patient is 9 to 12 months if non-IgE-mediated CMPA before oral challenge is performed.

    For IgE-mediated CMPA with severe, immediate symptoms, diet free of CMP should be continued for 12 to 18 months before oral challenge Generally, for non-IgE-mediated CMPA oral challenge can be done at home unless the anticipated symptoms are severe (like enterocolitis causing diarrhea and vomiting leading to dehydration and need for intravenous fluids)80 while for IgE-mediated CMPA, oral challenge should be performed in the hospital because of the risk of anaphylaxis. First, tolerance to CMP should be assessed by checking IgE levels or performing skin prick test and when tolerance is established, then only a hospital based oral food challenge is performed.

    If the oral challenge is positive, elimination diet should be continued for another 6 to 12 months before reevaluation.

    Prognosis Overall, CMPA has a extremely excellent prognosis with variations in the rate of CMP tolerance. By age 5 years, 80% to 90% of children develop tolerance to CMP The

    Tolerance Rate

    56% by 1 y, 77% by 2 y, 87% by 3 y, 92% by 5 y, and 97% by age 15 y Referral prospective 44% by 2 y, 69% by 3 y, and 77% by age 4 y Referral prospective 68% by age 4 y General prospective birth cohort 51% by 2 y, 74% by 5 y, and 85% by age y Referral retrospective 19% by 4 y, 42% by 8 y, 64% by 12 y, and 79% by age 16 y Referral prospective % by age 5 y Referral prospective 82% by age 4 y Referral retrospective 41% by age 2 y Referral retrospective % by age 12 y General prospective birth cohort % by 2 y, 65% by age 4 y Referral prospective 53% by age y Referral retrospective 20% by 2 y, 34% by 4 y, and 39% by age 6 y

    tolerance rate is 30% to 50% at 1 year, 55% to 75% at 2 years, and 70% to 90% at 3 years,81 It has been observed that IgE-mediated CMPA resolves in 53% to 57% children by 5 years of age and non-IgE-mediated CMPA generally resolves by years of age Mild proctocolitis due to CMPA, resolves in the majority of infants by the time they turn ,86 Table 4 summarizes multiple studies from diverse countries that looked at the natural history of CMPA (Adapted from Nicolaou et al) A study published in showed that about 70% of patients with IgE-mediated CMPA tolerated baked milk products love cakes and pastries It is thought that proteins in cow’s milk that cause allergic reactions get denatured by heat and are no longer allergic.

    Also, it is suggested now that development of tolerance to heat treated CMP actually helps induce tolerance to native cow’s milk protein faster than that with finish avoidance of milk protein containing food items Table 5 summarizes several studies that looked into various prognostic factors for the development of tolerance or persistence of CMPA,82,87, There were some variations in results between studies that were attributed to differences in settings and populations, inclusion and diagnostic criteria, laboratory methods applied and time points of reassessment, and follow-up duration. Other factors not mentioned in the table and found to be associated with persistence of CMPA are allergy to casein compared with other milk proteins, and longer duration of time from ingestion of CMP to symptoms onset

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    Clinical Pediatrics 55(11)

    Table 5.

    Factors related to tolerance and persistence of CMPA. Favor Shorter Duration and Tolerance Clinical  Non-IgE-mediated   Later age at presentation (eg, >1month)   Milder symptoms (eg, gastrointestinal)   Higher eliciting dose (eg, > 10 mL)   Tolerance of heated milk   Absent or mild comorbidities (eg, asthma, rhinitis, eczema, and other food allergies)   No family history of atopy Laboratory   Lower levels of sIgE and/or smaller skin prick test (SPT) wheal size to whole and individual (eg, casein) cow’s milk proteins at diagnosis and follow-up measurements   Significant reduction in sIgE levels and/or SPT wheal size over time   Recognition of specific IgE conformational epitopes, increased binding to IgG4 epitopes  

    It is significant to remember that in CMPA recovery does not necessarily mean finish recovery and tolerance, and sometimes the daily dose tolerated by the kid may be limited

    On the Horizon Oral immunotherapy is a promising field of research in treatment of CMPA.

    It is based on introducing gradually increasing doses of cow’s milk to induce tolerance Further studies are needed to support it as an effective and safe therapy for CMPA. Another promising treatment is omalizumab, monoclonal antibody against IgE either alone or in conjunction with immunotherapy Author Contributions GM did the data gathering and most of the writing of the article and DK was GM’s mentor and helped with editing/correcting/rephrasing.

    Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with honor to the research, authorship, and/or publication of this article.

    Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

    Favor Longer Duration and Persistence IgE-mediated Earlier age at presentation (eg, < 1 month) Severe symptoms (eg, respiratory) Lower eliciting dose (eg, <10 mL) Intolerance of heated milk Present and severe comorbidities (eg, asthma, rhinitis, eczema, and other food allergies) Family history of atopy Higher levels of sIgE and/or larger SPT wheal size to whole and individual (eg, casein) cow’s milk proteins at diagnosis and follow-up measurements Nonsignificant reduction in sIgE levels and/or SPT wheal size over time Recognition of specific IgE linear epitopes, greater sIgE epitope diversity and higher affinity Multiple sensitizations to other foods (eg, egg, soy) and inhalant allergens by sIgE/SPT

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    Various baby formulas — such as soy, extensively hydrolysed and amino acid-based formula — that can be used to treat cows milk protein allergy are available in Australia. An analysis of Australian formula-prescribing practices indicated that they did not appear to be in line with authoritative statements and position papers or the guidelines of the Australian Pharmaceutical Benefits Advisory Committee (PBAC).1

    In , the Committee on Nutrition of the American Academy of Pediatrics stated that soy formula was a suitable option for treating infants with cows milk protein allergy.2 In April , the Committee on Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) recommended that soy protein formulas should not be used in infants with cows milk protein allergy during the first 6 months of life, because few infants had been studied, and the reported rate of adverse reactions to soy protein was higher in infants under 6 months of age.

    This committee also recommended that, when soy formula is used to treat cows milk protein allergy in infants over 6 months of age, tolerance to soy formula be established by clinical challenge.3

    The PBAC guidelines once restricted the use of extensively hydrolysed formula to infants with combined intolerance to cows milk protein and soy protein. It also restricted the use of amino acid formula to infants with combined intolerance to cows milk protein, soy protein and extensively hydrolysed formula. In November , the PBAC accepted the advice of its Nutritional Products Working Party to ease the restrictions: the requirement to protest intolerance to soy protein before treating infants with these products was removed.

    In , European proposals for treating cows milk protein allergy in formula-fed infants with extensively hydrolysed formula and amino acid formula were outlined in an algorithm.4

    Consensus panel

    In the light of these considerations, we constituted an Australian panel with representation from every states.

    The panel was put together by the two lead authors (A S K and D J H) to represent practising paediatric clinicians. The panel was composed to include clinicians with expertise in paediatric allergy, gastroenterology, neonatology and general paediatrics.

    There were two face-to-face meetings, in November  and June , and four telephone conferences. Meetings were co-chaired by A S K and D J H. Panel members (but not the co-chairs) were assigned individual tasks to review practice with regard to treatment as it related to specific clinical syndromes.

    After this material had been discussed by the panel, a position was reached. The number of panel members agreeing with the position (in view of the evidence presented) was recorded.

    The panel considered the issues and reached a consensus on the indications for use of soy, extensively hydrolysed and amino acid formulas in the treatment of cows milk protein allergy under Australian conditions in general and paediatric practice.

    As the selection of a formula depends on the syndrome to be treated, the panel has outlined the salient features of the diverse syndromes in breastfed and formula-fed infants. Selected references to the individual syndromes own been provided.

    The spectrum of cows milk protein allergy

    Cows milk protein allergy is defined as an immunologically mediated adverse reaction to cows milk protein. It affects about 2% of infants under 2 years of age.5 In this document, we use the term “allergy” in accordance with the World Allergy Organization’s definition (ie, allergy is a hypersensitivity reaction initiated by specific immunological mechanisms).6 Mechanisms may be IgE mediated or non-IgE mediated.

    Cows milk protein allergy can also happen in exclusively breastfed infants.

    Cows milk protein is often the first food protein ingested by formula-fed infants, and allergies present as a range of syndromes. A correct diagnosis is critical and will often depend on appropriate immunological and morphological investigations. In every cases, the diagnosis is confirmed by observing remission of the symptoms following removal of the protein.

    If the diagnosis remains uncertain, further confirmation should be obtained by observing relapse following challenge with cows milk protein. As some of the conditions may remit with time, rechallenge with cows milk protein after a period of avoidance is indicated in some cases. A finish discussion of the diagnostic process and ongoing management4 falls exterior the scope of this guideline.

    Consensus on the use of formulas

    Three diverse types of formula (soy, extensively hydrolysed and amino acid) may be appropriate treatment in specific circumstances (Box 1).

    Some preparations are not recommended for treating cows milk protein allergy. The panel considers that there is no put for partially hydrolysed (known as HA) formulas nor other mammalian milks (such as goats milk)7 in treating cows milk protein allergy. The consensus recommendations for using baby formulas to treat allergy syndromes are shown in Box 2. Breastfeeding may be continued, and recommendations are provided for eliminating maternal intake of cows milk protein.

    The panel believes the information provided is a guideline for most cases.

    However, in severely affected infants or if the diagnosis is uncertain, it may be appropriate to start treatment with an extensively hydrolysed or amino acid-based formula which is not in accordance with this consensus.8 Such a case should be managed by a paediatrician with specific expertise in these disorders.

    Cows milk protein allergy syndromes

    The syndromes are classified as reactions which develop over minutes, hours or days. The recommendations include advice about the necessity for mothers to eliminate dietary intake of cows milk protein while breastfeeding.

    In some situations, failure to thrive affects the choice of formula. Recommendations provide for an alternative formula if treatment with the initial formula is not successful.

    Immediate allergic reactions9

    Cows milk protein allergy may manifest with erythema, angioedema, urticaria or vomiting. Some infants may own contact urticaria where protein has touched the skin. Typically, there will be evidence of IgE sensitisation (positive skin prick test or an allergen-specific IgE antibody test [RAST] to cows milk).

    Symptoms develop within minutes of ingestion of little volumes of milk. Infants with cows milk protein allergy often own other food allergies, in specific to egg and peanut products.

    Anaphylaxis is a severe immediate reaction with respiratory tract involvement and/or hypotension. Features of anaphylaxis may be hard to identify in infants. It may be suggested by coughing, wheezing, severe distress, floppiness or collapse.

    Food protein-induced enterocolitis syndrome (FPIES)10

    FPIES is an unusual disorder which generally presents with acute onset of repeated projectile vomiting, hypotonia, pallor and sometimes diarrhoea 1 to 3 hours after ingestion of cows milk protein.

    FPIES may be mistaken for acute gastroenteritis, sepsis or intestinal obstruction, and multiple presentations before the diagnosis is established are not unusual. Typically, FPIES occurs at the first introduction of cows milk protein into the diet. It has not been reported in exclusively breastfed infants. FPIES may also be caused by other food proteins (eg, soy, wheat, rice and chicken). Despite the onset within hours of ingestion, the disorder is not IgE mediated. Remission has generally occurred by the third year of life.

    Atopic eczema11

    Atopic eczema is a chronic, relapsing, pruritic inflammatory disease of the skin, generally associated with allergic sensitisation.

    Food allergy plays a role in some cases of eczema in children. It should particularly be considered in infants with moderate to severe eczema. It is generally associated with high levels of IgE antibodies to common foods (eg, milk, egg and peanut). Egg is the most frequently involved allergen, followed by cows milk protein. Although IgE antibodies own been implicated in most cases of cows milk protein-induced eczema, about 10% of cases are not IgE associated.

    Gastrointestinal syndromes

    Infants with cows milk protein allergy may present with vomiting, chronic diarrhoea, malabsorption and failure to thrive.

    Most of the syndromes are not IgE associated and own other pathogenic immune mechanisms. Cows milk protein allergy is the most commonly identified food allergen sensitivity; however, in some cases, hypersensitivity to multiple food proteins is involved. Gastrointestinal biopsy may be required to define the disorder.

    Gastro-oesophageal reflux disease (GORD)12

    About 40% of infants referred for specialist management of GORD own allergy to cows milk protein. These allergic reactions are typically not IgE mediated. In these infants, intestinal biopsy commonly shows partial villous atrophy.

    Allergic eosinophilic gastroenteritis13

    Common features include weight loss and failure to thrive associated with postprandial vomiting, diarrhoea and, occasionally, blood loss.

    In more severe cases, the infants may own iron deficiency anaemia and oedema due to hypoproteinaemia and protein-losing enteropathy.

    Food protein-induced enteropathy14

    Infants with allergic enteropathy due to cows milk protein may present with diarrhoea, failure to thrive, various degrees of vomiting and, sometimes, hypoproteinaemia and anaemia. Some cases own an associated soy allergy. The clinical signs of secondary lactose intolerance, including perianal excoriation from acidic stools, may be present.

    Constipation15

    Whether constipation is a clinical manifestation of cows milk protein allergy in infants and young children is controversial.

    Constipation is a common symptom in early childhood and, in some cases, resolves after removal of cows milk protein from the diet. Cows milk protein-induced constipation is often associated with anal fissures and rectal eosinophilia.

    Severe irritability (colic)16

    The mechanisms of baby colic are poorly understood. Colic is not mediated by IgE, and the role of dietary factors is controversial. Persistent crying is a common problem that may affect about a third of young infants and gradually abates by 4 months of age without specific treatment in most cases.

    In infants with unremitting distress persisting beyond the typical colic period, an underlying organic cause may be more likely. Exclusion of cows milk protein helps in some cases, but these cannot be identified by allergy tests.

    Food protein-induced proctocolitis17

    Infants with allergic proctocolitis due to cows milk protein allergy generally present with mild diarrhoea and low-grade rectal bleeding. If the baby is fully breastfed (breast milk colitis), symptoms may be caused by protein transferred via the breast milk. The bleeding is generally observed as stools containing mucus and flecks of blood rather than as candid rectal bleeding.

    Other systemic features (such as failure to thrive or anaemia) are generally absent, and the infants appear generally well. Rectal biopsies are not usual, but may be required to confirm the diagnosis in more severe or atypical cases.

    Eosinophilic oesophagitis18

    Eosinophilic oesophagitis is more often identified in older children than in infants, but may happen in both groups. In infancy, typical symptoms are refusal of food, hard feeding, poor weight acquire and poor response to standard antireflux measures. Older children may present with dysphagia or episodes of impacted food bolus. Endoscopy is necessary to establish the diagnosis, which is based on eosinophilia of the upper and lower oesophagus.

    Eosinophil numbers are typically lower in infants with peptic reflux oesophagitis. Hypersensitivity to multiple foods may be seen in infants with eosinophilic oesophagitis. In older children and adults, aeroallergens may also be implicated. Therapy may include hypoallergenic diets and swallowed steroid aerosol.

    Other conditions associated with eosinophilic infiltration of the little and large bowel require specialist diagnosis and treatment, and may reply to elimination of cows milk protein.

    1 Preparations available for treating cows milk protein allergy

    Suitable

  • Soy formulas

  • Extensively hydrolysed formulas

    1. Alfaré (Nestlé)

    2. Pepti-Junior (Nutricia)

    3. Amino acid formulas

  • Amino acid formulas

    1. EleCare (Abbott)

    2. Neocate (SHS)

    Contraindicated or not recommended

  • Formulas

    1. Lactose-free cows milk-based (eg, Karicare De-Lact, Digestelact [Nutricia], S LF [Wyeth])

    2. Goats milk-based formula

    3. Cows milk-based (including anti-regurgitation)

    4. Partially hydrolysed cows milk-based (eg, Karicare SensiKare [Nutricia], NAN HA [Nestlé])

    5. Other preparations

  • Other preparations

    1. A2 milk (A2 Australia)

    2. Oat milk

    3. Rice milk

    4. Other mammalian milks (camel, mare, ass, goat and ewe)

    2 Formula feeding in syndromes associated with cows milk protein allergy*

    Syndrome

    Onset of reaction

    Maternal elimination of CMP if breastfeeding?

    Choice of formula


    NHMRC level of evidence‡

    Consensus panel agreement§

    First†

    Second (if first not tolerated)

    Third (if second not tolerated)


    Immediate reaction

    Immediate food allergy

    < 1 h

    Yes

    eHF (< 6 months)

    AAF

    II

    11/11

    Soy (> 6 months)

    eHF

    AAF


    Anaphylaxis

    < 1 h

    Yes

    AAF (followed by urgent consultation with paediatric allergist)

    IV

    11/11


    Food protein-induced enterocolitis syndrome

    1–3 h

    No

    eHF

    AAF

    IV

    10/11


    Delayed reaction


    Atopic eczema

    Hours to days

    Yes¶

    eHF (< 6 months or > 6 months with FTT)

    AAF

    IV

    11/11

    Soy (> 6 months, no FTT)

    eHF

    AAF


    Gastrointestinal syndromes, GORD, allergic eosinophilic gastroenteritis, food protein-induced enteropathy, constipation, severe irritability (colic)

    Hours to days

    Yes¶

    eHF (< 6 months or > 6 months with FTT)

    AAF

    I (severe irritability), III (GORD), IV (others)

    11/11

    Soy (> 6 months, no FTT)

    eHF

    AAF


    Food protein-induced proctocolitis

    11/11

    Formula-fed

    > 24 h

    eHF

    AAF

    IV

    Breastfed

    > 24 h

    Yes¶


    Eosinophilic oesophagitis in infants

    Days to weeks

    Yes

    AAF

    IV

    11/11


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